Immunometabolism: The Next Frontier in Systems Biology

Welcome to the Evolution of Medicine podcast! In our latest episode, we sit down with Andrew Heyman, MD, an internationally recognized expert integrative and functional medicine who currently serves as program director of integrative and metabolic medicine at The George Washington University and as the director of academic affairs at the American Academy of Anti-Aging Medicine (A4M). In this episode, Dr. Heyman discusses mitochondrial medicine, the latest in genetic research and our understanding of the cell healing cycle, and the functional aspects of cell metabolism and related genomics.

While this may sound like an educationally hefty half-hour, Dr. Heyman’s teaching approach, deeply rooted in scientific evidence and expert patient care, is easily accessible to both new learners and seasoned practitioners alike. If you enjoy this episode and want to learn more, we’re also sharing an opportunity to continue learning with Dr. Heyman and a panel of speakers he’s curating for an upcoming conference event. Highlights of this episode include:

• What mitochondrial medicine is and why it is important in integrative and functional medicine
• New research on genes and how they turn on and off
• Dr. Heyman’s experience treating Lyme disease and mold-related conditions, and what he’s learned about their impact on the brain
• The possibility of completing reformulating how we understand cell function and what controls those processes
• And so much more!

Resources mentioned in this podcast:
Advances in Mitochondrial Medicine Conference

James Maskell: Hello and welcome to the podcast. This week, we feature Dr Andrew Heyman. He is the medical director of the Integrative Medicine Group at George Washington University and he’s also the director of academic affairs for the American Academy of Anti-Aging Medicine, or A4M. Today, we spoke about mitochondrial medicine, and this is a half an hour you do not want to miss. We looked at new understanding of the genes and how genes turn on and off, the cell healing cycle, we talked about what he learned from dealing with things like mold and Lyme and the impact that it has on the brain. It was a super-fascinating half an hour, and there’s an opportunity to continue learning with Dr. Heyman and some of the speakers that he’s curating. So, listen in to the episode for that, but it was a really fascinating half an hour. Enjoy.

James Maskell: So, a warm welcome to the podcast, Dr. Andrew Heyman. Welcome, doc.

Andrew Heyman: Thanks, James. Great to be here.

James Maskell: It’s been a while since we’ve had you here on the platform and been super excited to reconnect and just hear a little bit about what you’d been up to. We’ve known each other for a long time, and I know that you’re always on the cutting edge of what’s happening in integrative and functional medicine. So, maybe I’d just love to start off. A topic came up the other day that I saw that you were getting in…you were putting on a conference for, and it was called mitochondrial medicine. Obviously, mitochondria’s been a hot topic in different circles, biohacking, functional medicine, and different areas. So, could you…maybe we could start off with an understanding of what is mitochondrial medicine and why is it important?

Andrew Heyman: I think that, for me and our research group, there has been a revelation around the role the mitochondria play in a variety of chronic illnesses. If you think back to what we all originally learned about the mitochondria, as being, essentially, the power pack of each cell producing ATP, and that’s where our knowledge ends. Functional medicine picked up on that idea and attempted to answer the question, well, at least in chronic fatigue states, “What can we do to help charge the mitochondria?” So, supplements like coenzyme Q-10 and carnitine and alpha lipoic acid would come up over and over for years, and that’s where I think our clinical attention for the mitochondria was held for a long time, and bind included.

Andrew Heyman: More recently, because of the research that I’ve done in chronic-fatiguing illnesses and, in particular, bio talks and exposure, what we’ve learned is that the mitochondria play an incredibly central role in controlling a number of different cell processes. It makes sense because it has to make decisions around “Where do the energetics of the cell get devoted?” not just understates of health and vitality, but in particular, under self-threat. Those threats come in the form of self-stressors, toxins, exposures, nutrient deficiency states. Basically, a wide variety of inputs.

Andrew Heyman: It turns out that the mitochondria actually shape the cell response. We didn’t know this. It turns out, in particular, that as the mitochondria sense the stressors that are occurring, it turns on certain genetic sequences and turns off other sequences in favor. So, for example, it will shift how ATP is produced, where energy is placed, usually in favor of cell defense. In particular, what we’ve learned around turning down cell activity to weather the storm. It is an incredible insight in the way that mitochondria work as almost an internal brain for the cell itself.

Andrew Heyman: In addition to that, there are phases through which the mitochondria function, and we’ve learned the ways in which when the mitochondria and the cell more broadly gets stuck in a phase, certain diseases arise. So, this is a huge insight for us that we’re now just not looking at the mitochondria as an engine to produce ATP, but really an organizing principle for not just cell health, but almost this systems’ biology health as a result. So, I’m very excited about the insights that are emerging in a variety of different research groups, including ours.

James Maskell: Yeah, that’s really, really exciting. I see so much of that in the way that people are talking about clinical practice. I guess, one of the things that comes up with getting so detailed, like, inside the cell, is, “What does it take to unwind this type of thing?” and I think most practitioners who are listening to this, either they are a functional medicine doctor or they work with a functional medicine team, but maybe they don’t have the whole bag of tricks available to themselves. So, what is the care structure in your mind that allows practitioners to undo some of that damage in the most consistent and organized way?

Andrew Heyman: So, let me start by answering that, first, from the perspective of “How did my research group get to the level of the mitochondria?” It was through the framework of biotoxin exposure. You can enter the mitochondrial door through innumerable chronic illnesses, but ours was biotoxin exposure, and this really had to do with water-damaged environments and also, related to that, tick-borne illnesses, like Lyme disease. We knew that the broad result is fatigue, and that was the primary complaint in this particular patient population. For a number of years, we had worked out a model of the ways in which the body would respond to these exposures and, in particular, a very specific kind of inflammatory response that occurs throughout the person in all tissues, in all organs, including brain, and that was interesting for us.

Andrew Heyman: It began to explain some of the symptoms, but not all of them. One of the insights that we generated is that this type of inflammation, which is relatively unique, not only causes symptomatic consequences but also damages the brain itself. This was an important insight for us because it turned out that the fingerprint of injury on the brain was unique to the exposure, that there were certain physical changes that occur because of a water damage environment, different than Lyme disease, different than stress or concussion or MS or a variety of neurodegenerative diseases.

Andrew Heyman: So, as we started looking at brain scans, we had to ask the question, “Well, if the symptoms between a mold exposure and Lyme disease are the same and the inflammatory markers that we can measure in the blood are basically the same, why is it that the brain scans are different?” So, that’s when we started to do genomics research, and in particular, an area called transcriptomics, and this is basically the measurement of RNA production. It tells us which genes are on and which are off.

Andrew Heyman: We first scanned the full 30,000 gene compliment in our subject population. We then narrowed to about 2,000 genes and then further narrowed to 900, and now we’re down to about 188 genes. What’s interesting to us is this unique inflammation was being generated through genetic switches in the mitochondria. This, to me, was a revelation in and of itself, that, in fact, the mitochondria were responsible for a variety of inflammatory pathways, that they weren’t just coordinating energy production, but also helping to influence the immune system.

Andrew Heyman: As we measured these 188 genes that existed uniquely in the mitochondria, what we found is that certain genes turn on or off in a mold exposure, different ones turn on or off in Lyme disease, others turn on or off in post-Lyme syndrome, meaning a Lyme patient treated with antibiotics. We could also see the cell shifting from a pro-energy, anti-inflammatory phenotype, meaning, what we call, M2, into a pro-inflammatory, low energy, cell danger response of an M1 phenotype, that, in fact, the whole mitochondria shifts as a result of these exposures. This, to us, was an enormous insight.

Andrew Heyman: We also saw that, as a result of this abnormal gene expression, then ribosomes, which are the mechanism where cells make proteins out of RNA, didn’t know which proteins to make very well. We also saw abnormal lipid expression, so the cell membranes around the mitochondria become damaged, the cell membrane around the cell itself also becomes injured, and so you’d begin to see this cascade of molecular events from the genomics and transcriptomics through ribosomal protein production and then all the way up through the metabolomics and, more generally, whole system expression.

Andrew Heyman: So, then the question becomes, “Well, what do you do about this?” The first piece is making sure that whatever threat or stressor that initially turned all this on is eliminated. For us, of course, it’s dealing with the biotoxins. In this model, it could be other types of stressors and threats, whether it’s other infections or exposures or toxins or emotionally traumatic events. My guess is they’re these final, common pathways that influence this mitochondrial activity.

Andrew Heyman: So, number one is you have to deal with the exposure itself. Number two, which functional practitioners are very adept at, is lifestyle interventions, stress management, healthy diet, moderate exercise, and lots of rest, because what you’re trying to do is reset the immune system and mitochondrial function overall. Interestingly, if you want to find an overlap with something that’s in vogue, but I actually think has real molecular import, it’s the role of fasting and resetting these molecular gene switches so that you get restoration of normal genomic response. So, fasting, in particular, especially through what are called the mTOR pathways, are probably going to prove themselves to be an important therapeutic intervention. That’s part and parcel of the lifestyle.

Andrew Heyman: Beyond that, what we do is a lot of very aggressive lipid replacements, and I don’t mean fish oil. So, we know Omega-3s and 6s play an important role in cell membrane health, but even more importantly are the other phospholipids, phosphatidylcholine, phosphoethanolamine, and phosphatidylinositol. The outer cell membrane is mostly made of phosphatidylcholine. The inner cell membranes and leaflets, especially around the mitochondria, are made of the phosphoethanolamine, the phosphatidylinositol and cardiolipin products as well. So, what we essentially do is give our patients lots of lipids, which amounts to, basically, an oil change, but what that does is it begins to restore normal cell chemistry from the outside in. Then, one of the other unique features that we found is that we can actually turn on more normal gene expression through peptide therapy.

Andrew Heyman: So, one, in particular, is called vasoactive intestinal peptide. We have actually studied it widely now and we’ve shown that as we move patients down the road to health and we’re beginning to restore normal mitochondrial function and greater ATP production and where we’re healing cell membranes and they’re doing all the lifestyle interventions, the final piece to restore normal genomics, meaning get those genes to go back to their normal behavior, is we give this spatial active intestinal peptide, and it’s offered as a nasal spray. Unfortunately, it’s a prescription, so it’s really only reserved for prescribers at this point, but it does something magical and it influences the ways in which the genetic sequences of the mitochondria behave, and they basically go back to normal. There’s reregulation of gene response.

Andrew Heyman: My sense is fasting might be doing something similar, maybe not fully, but we’re going to keep finding new therapies that basically touch how genes behave, and that, for us, is pure, that, essentially, we restore normal molecular activity by influencing how genes are functioning. So, we’re not even answering the question, “What genes do you have?” That’s kind of old school genetics of “Do I have an MTHFR gene or a COMT?” That’s five, 10 years ago. Now, we’re able to answer the question, “Well, with the genes you have, what are the genes doing? Are they on? Are they off? Are they responding to inputs appropriately? Are they working against you?” It turns out that the gene sequences in the mitochondria in particular are really the crossroads of all of this activity, and so the therapeutic interventions for us have become very specific, very targeted and incredibly powerful for getting these patients better.

Andrew Heyman: It’s a whole new model of care, and one that basically rejects the disease model and really focuses on cell activity and self-healing and cell metabolism. It basically just tears down the conventional medical model of disease-based illness and really gets into the more process and functional and genomic aspects of how our bodies basically behave and respond to threats and stressors. It’s an enormous insight, and it’s certainly not ours only. There are other research groups that are beginning to target the same ideas, but it’s a whole new day, essentially, for clinical medicine from that perspective.

James Maskell: Yeah, super exciting. Thanks for sharing that. So, what are the types of diseases or diagnoses that you feel are most likely to be touched on with this mechanism?

Andrew Heyman: So, certainly, any of the chronic fatiguing illnesses, pain-related syndromes, autoimmune diseases, mood disorders, neurodegenerative diseases. I’ll give you some insight. We have some early data already that is part of the genomic expression of these patients that have abnormal mitochondrial responses. Part of the pathways that get turned on are coagulation pathways, and there are very minute amounts of fibrinogen and other inflammatory proteins that are created in the vascular system, and what we’re finding is that if you pair the idea of a biological exposure, let’s say mold, to the abnormal cell energetics and genomic expression of low-ATP output and fatigue plus activation of coagulation pathways and the brain-related changes that we’ve already identified, we’ve actually built a model for vascular dementia. When we give those patients VIP therapy, we have shown, within three months, we can reverse their vascular dementia.

Andrew Heyman: So, as we uncover these molecular aspects of illness, as we tie together these events into one framework, we now can relook at more standard disease topics and say, “Now, we understand why a certain subsegment of patients within dementia, especially vascular dementia, present the way they do, and it opens up new therapeutic categories. The other one that we’ve seen targeted within the mitochondria, and this is one of those new in vogue topics, is this whole notion of mass cell activation. Everybody’s really hot on “Are your mast cells leaking?”

Andrew Heyman: Well, guess what? It turns out some of the histamine pathways are also triggered because of cell stress and mitochondrial abnormal activation, that some of the genes that are responsible for histamine production are in the mitochondria. So, it’s not so much that when you have patients that are presenting as very histaminic are suffering from mast cell disease. Many of them probably have had an exposure that are turning on these histamine pathways. So, the model holds though in terms of dealing with a stressor event, restoring normal cell energetics, turning off the gene sequences, and lo and behold, they’re histaminic response improves, too.

Andrew Heyman: So, we’re seeing the overlap between what maybe in the past were terms, adrenal fatigue, fibromyalgia, mood disorders, neurodegenerative diseases, but now have a better explanatory model for why these patients are so sick, why don’t they typically respond very well to conventional or functional therapies and how we’re making breakthroughs to get these patients actually back to a normal, vital state of health.

James Maskell: Yeah, that’s awesome. So, if…I mean, obviously, you’re a lot further ahead in this, but if a doctor’s listening to this and they’re practicing functional medicine and they’re thinking, “Okay. How do I fit this in?” if you were to take a patient with some of those issues and decide on a care plan, how would you organize, I guess, fasting, behavior change, functional medicine interventions and these new concepts in an order that would deliver the most health for most people at the least cost?

Andrew Heyman: So, I’m going to make a plug. I don’t normally do this, but I do think it’s worthwhile because there’s no simple answer to your question. It’s a very good question, but there’s no simple answer. With the George Washington University event that’s coming up in Dallas in [October], I will be going over all of the steps that you would need to go through to restore normal cell energetics and mitochondrial health. The reason why there is not a single answer is because there’s really a total approach and a protocol that we go through.

Andrew Heyman: The first piece is we deal with the exposure. The second is we start to target that inflammatory response that’s typically occurring in the brain and in other organs. So, we use some specialized therapies to reduce neuro-inflammation, special ginseng extracts, certain forms of turmeric that cross the blood-brain barrier, specialized forms of magnesium that are new to the market, beyond magnesium-3 and 8, for example.

Andrew Heyman: So, we start to deal with the neurologic inflammation and excitation in particular. We then add in another set of specialized therapies to start doing that oil Change that I mentioned. High-dose phosphatidylcholine as well as some other types of lipids that are derived from flax and staph flour oil to increase membrane fluidity and mitochondrial functioning. That’s all the opening move. We then start working on the diet. We have patients do some intermittent fasting, light activity only, because, typically, these patients are really compromised, they have a lowered VO2 max and, often, impaired exercise tolerance, so we like them to walk, but not high-intensity exercise until they start really repairing and recovering.

Andrew Heyman: We then begin adding in some other specialized immunomodulators and we take advantage of the fact that these patients usually have very small lipid-soluble inflammatory compounds that are dissolved in the bile. So, we use a set of special binders that suck the inflammation out of the digestive tract in particular. Turns out okra and beets are really good as natural binders. Sometimes, patients or practitioners think of charcoal and clay and chlorella. Those are not as well-suited for the type of inflammation that we see in these fatigued patient populations. Okra, beets work much better. Usually, they need to have lots of fiber, so we add in some fiber as well as colostrum to modulate the immune function along the gut lining, and we start to see clinical improvement in these patients where they’re less inflamed, their brains are working better, their energy is starting to climb.

Andrew Heyman: Then, we start doing deeper detox with these patients for heavy metals and chemicals, we balance their hormones, we do food testing and make sure that they’re on a targeted diet. Then, finally, we end with the specialized therapy, such as VIP, which is one of the neuropeptides that we use. I also use BPC 157 as well as some other peptides as well, but those are the two main ones. BPC 157 turns off neuroinflammation and the VIP resets the genomics of the mitochondria. So, unfortunately, it’s not one thing. It’s really a process, but it’s how we take our sickest of patients and we get them back to health.

James Maskell: Absolutely. Yeah. Look, ultimately, that’s who showing up. I think I saw something the other day that the average functional medicine patient has 40 symptoms and six diagnoses. So, if you’re dealing with those kinds of patients, great to have such a wide variety of tools to be able to use and really understand those phases because, ultimately, that’s really what’s required if you’re going to rewind and reverse something that’s being that chronic for that long. You mentioned a conference, October 4th and 5th, in Dallas. That’s with George Washington. I know you brought together the speakers on this one. Is there any one speaker that you feel stands out as someone who’s on the cutting edge that people shouldn’t miss?

Andrew Heyman: I do. His name is Dr. Bob Naviaux, and he’s got a mitochondrial research center at UC-San Diego. His work mostly focuses on the metabolomics mitochondrial expression, which compliments nicely our research in the genomics of mitochondrial expression. So, between the two, we begin to have a full picture of not only genes that are on or off, but what are the downstream molecular consequences of that, and that’s the whole emerging world of metabolomics in particular. It’s that space that fits between genes and blood expression of the proteome. His research lab, in particular, specializes in the metabolomics of the mitochondria.

Andrew Heyman: His work, especially, both on the healing cycle of the mitochondria as well as what he calls the cell danger response, meaning the pathway through which the cells and the mitochondria become injured and begin to shift their metabolism, is extraordinary. We’ve basically arrived at a similar place through two different modes of inquiry, whether it’s metabolomics or genomics, but both of our roads have led to the mitochondria, and he fills in a lot of gaps that I think are really important to understand for attendees as well as the broader framework of “What is the cell danger response, what are the steps that occur as a cell basically devolves into this low energy state, and then how do we go about thinking about repairing it?” He has his perspective, we have ours, and I think together, we form a full framework that, to me, represents a new model of medicine.

Andrew Heyman: Interestingly, I was speaking with him yesterday on the phone. He was presenting at an internal medicine conference and one of the head administrators from the NIH was there and he came up to Bob after his lecture on the cell danger response and the healing cycle, and he said, “Bob, your work is extraordinary, but we have a problem,” and he said, “What’s the problem?” He said, “Well, if you’re right, and that’s a big if, if you’re right, we’ve wasted literally billions of dollars of funding over decades of therapy chasing disease states when we really should’ve looked at the functional aspects of cell metabolism and its related genomics.” We’re at that precipice right now. We’re basically…We might be completely reformulating how we understand how cells function and what controls those processes.

Andrew Heyman: So, to me, the conference represents the first time a learner can really dip their toe in that water and have a deeper understanding of why our patients are so sick…as you say, usually our patients have seen multiple providers without good answers…and why even what I would call traditional functional medicine fails. That model of adrenal fatigue and nutrient depletion and hormone balancing and the rest only takes patients so far, and I think it’s time for, again, a revisioning of how we look at our patients, and this conference in October, it will be, I think, the first reveal of an entirely new model of how we treat our patients. That, to me, is really exciting to bring in thought leaders like Dr. Naviaux, who can act as a guide for us as we look to bring our practices to the next level.

James Maskell: Yeah, it’s super interesting. You know, one thing I just want to ask you before we leave, the first time we met, and this is probably, like, eight or nine years ago, we were having a conversation about homotoxicology, which is something that I was interested in then and is something that is still kind of a long way away. It seems like just with the ordering that you’re ordering things, like getting the basic functions of the body down, then opening up different pathways before you go deeper into dealing with the body at a cellular level, it rings true in my head a little bit. What are your thoughts on that? I know it’s not something that’s talked about that much in functional medicine circles, but are we moving towards a world where that kind of thesis of how the body heals and works is reasonable?

Andrew Heyman: I think your insight is really timely. What I would also say is in my own training, not so much in Reckeweg’s work of homotoxicology, which is a certain strain of homeopathy, and a very powerful one, but I can speak a bit more authentically from the model of traditional Chinese medicine, which is where my original training was, that in all of these older healing approaches, what they attempted to do was, through the power of observation, understand the stages that a person goes through in very acute detail from the observer perspective, from health to illness.

Andrew Heyman: What all of these approaches have in common, including homotoxicology, is the way in which they stage the unwinding or the dissolution of the energetics of the individual. Homotoxicology, in particular, has a very structured model for that. It uses its own language and approach and, of course, the interventions mostly relate to homeopathy, although they do invoke other therapies, too, but it really was a brilliant, descriptive framework.

Andrew Heyman: What’s happening now is that what’s old is being made new, that the observational component to managing the disease process, which was more empirical in nature in the past, is now being given a biological reality, an objective explanatory model. My sense is that we’re now finally uncovering the subtle features that were observed over thousands of years, but now we’re getting closer to a more modern interpretation of what we’ve seen in the human experience of illness over the course of millennia. The convergence of the old and the new, that what was thought to be unscientific from a certain perspective, is now being revitalized.

Andrew Heyman: In my estimation, it should, in some cases, be revered as people like Reckeweg and others who were doing homotoxicology as extraordinary visionaries and they just didn’t have the tools that we now have in terms of measuring genomics and proteomics and metabolomics that we have a biological reality to better explain what they were observing in their patient populations decades ago. So, I get very excited about this stuff as you can tell. I think your insight of seeing the potential connection between those models is correct.

James Maskell: You know, it’s amazing you say that. Thank you for sharing that. Having been involved in that world for eight years, my partner and I, very specifically, went to functional medicine because we see that that’s probably the future, but I’m just not sure how far in the future it is. Is that five years out? Is that 10 years out? Is that 50 years out? But obviously, this is right on the cutting edge, and if you want to get onto the cutting edge, no better time than in Dallas. I’ll be there, I know you’ll be there, Dr Heyman.

James Maskell: Really validating to hear that, that this is coming quicker and quicker and that… yeah…with modern tools, you can really understand just some of the thinking process that was going on for some of these people. To hear you say visionary is very rewarding because I felt the same way, but I was kind of in an extremely small minority and I had no real medical training, so what the hell did I know? But that’s super interesting to hear you say that. So, thank you, and we’ll look forward to the conference.

Andrew Heyman: Yeah, I really appreciate it. To have this opportunity to talk about these topics and invite people to learn with us as we move forward is really a wonderful opportunity. So, thanks for your time.

James Maskell: Absolutely. So, yeah, you can find out more. We’ll have details about the conference in the show notes, but we’re very excited to have Dr. Andy Heyman here. He is the medical director at the Institute of Integrative Medicine, a segment of George Washington, and also the director for academic affairs for A4M. Please check out the show notes for all the things that we spoke about today. Thanks so much for listening. I think this was an incredible episode, and hopefully gets your mind racing over the summer about what’s going to be possible in the next decade in our field. The future of chronic disease is right here. Thanks so much for listening. I’m your host, James Maskell, and we’ll see you next time.