EPISODE 239

[INTRODUCTION]

[0:00:01] ANNOUNCER: Welcome to the BetterHealthGuy podcast, where we take a deep dive into complex chronic conditions and explore ways to build resilience, improve vitality, and achieve better health. To stay updated on Scott's work, you can sign up for his newsletter in the show notes, where you'll also find ways to support the show and help make more episodes like this one possible. If you find the podcast valuable, please subscribe, rate, or leave a review, as it helps the show reach additional listeners exploring similar questions.

The content of this show is for informational purposes only and is not intended to diagnose, treat, or cure any illness or medical condition. Nothing discussed on this podcast should be considered medical advice. As always, please discuss any health-related decisions with your own personal medical authority. And now, here's Scott, your BetterHealthGuy.

[0:00:58] SCOTT: Welcome to episode 239 of the BetterHealthGuy podcast. If you are searching for answers on your path to better health, I might just be your guy. Today we discuss Beyond Mold: Exploring the Continent of the Cell Danger Response with my guest, Dr. Andrew Heyman. He is an internationally recognized expert in integrative and metabolic medicine. He is currently the Fellowship Director of Integrative Medicine at the George Washington University and is responsible for overseeing graduate education and multiple degree programs.

He created the first master's degree in integrative medicine in the United States within a major academic center and developed additional graduate curricula in nutrition, metabolic medicine and performance, men's health, biotoxin exposure and neurodegeneration, and administrative health services in wellness settings.

Dr. Heyman has held board certifications in family medicine, integrative medicine and anti-aging and regenerative medicine. He also served as the Director of Academic Affairs for the American Academy of Anti-Aging Medicine for a decade, overseeing all educational programs globally.

Since 2014, Dr. Heyman has maintained a clinical and research focus on biotoxin illnesses and exposure to water damaged buildings. He has published almost two dozen papers in peer-reviewed academic journals on the subject and edited the first medical textbook on the topic. He is considered one of the world's leading experts in this area, having presented his work to Congress, testified in dozens of mold-related legal cases, and provided professional education to countless practitioners globally.

He is the founder of Beyond Mold, a complete medical and health resource for individuals and families suffering from mold illness. Dr. Heyman has been featured on the Discovery Channel, Martha Stewart Living, Ladies' Home Journal, and Natural Health Magazine. He's appeared in many other television and print venues and is a widely sought-after and celebrated speaker around the world on many integrative medicine topics.

Today in part one of our discussion here in episode 239, we talk about approaching recovery from complex chronic illness through the lens of the Cell Danger Response. We explore the Cell Danger Response and testing options. We begin our discussion on CDR1. And in part two in episode 240, we continue our discussion on CDR1 and then explore CDR2, CDR3, and Dr. Heyman's five-phase treatment model. I hope you enjoy this conversation as much as I did. And now part one of my interview with Dr. Andrew Heyman.

[INTERVIEW]

[0:03:51] SCOTT: It is my honor today to have Dr. Andrew Heyman on the show to talk with us about the latest research and treatment strategies for those people dealing with mold, biotoxin illness, CIRS, and related conditions. I'm super excited today to gain some insights from the lens through which Dr. Heyman views these conditions. Thanks so much for being here.

[0:04:10] DR. HEYMAN: Thanks for having me. I'm really excited to spend some time with you on this.

[0:04:14] SCOTT: So let's start with your personal health journey. What was it that led you to the work you're doing today to improve the lives of so many with these complex chronic conditions? Were you personally impacted by things like mold or maybe even Lyme disease?

[0:04:29] DR. HEYMAN: I was. And I think like a lot of people, you just don't see it coming. And I was someone who very early on in my life had sort of found my way into that notion that health is a value and it's something that matters to your quality of life and it should be pursued in its own right. How we all do that is different depending on sort of who we are and the context in which we live.

So as a preamble to that question, I was originally trained at 17 years old in traditional Chinese medicine and Japanese Zen Shiatsu. I was a freshman in college, and I had been almost sort of accidentally introduced to Shiatsu in particular when I was taking a Tai Chi course being taught by another student. And I immediately fell in love with it. But it was a language and an approach and really a worldview that I had not encountered before.

I mean, I was your typical Jew from the suburbs of Washington, D.C. and lived a very middle-class life. But there was that moment where the instructor was actually showing me some Shiatsu techniques, and it was like a revelation. There was something about it that contacted something inside of me that I had never reached before. And it felt magical. It felt authentic. It penetrated through sort of the connective tissue of mind and down into spirit. And it opened something up inside that I didn't know was there and was probably just sort of laying dormant that the healing arts and what that means for someone's life and sort of how they live their life was ignited.

And I started formally training in this discipline. I found a training program just outside of my college campus. My parents thought I was nuts. And my dad, famous line is, "What the hell is a Jew from the suburbs doing learning about this weirdo Chinese medicine stuff? Don't you have enough on your plate from college?" And I said, "I have to pursue this. And I knew that it was going to set the course for me professionally for probably many years.

And so, I got certified, graduated college. And it was an amazing journey. I was trained by Zen and Tibetan Buddhist monks, also experts from Thailand and Vietnam, and of course Japan and China, and it changed how I saw myself and how I saw the world. One of the things of course that inspired was both mindfulness but also just a sense of wanting to be healthy in general. I'd always grown up being athletic. But when I graduated college, I became pretty serious about training for triathlons. And it was just part of my identity. I love riding my bike. I love running. And that was just part of who I was. It was not just a pursuit but part of my identity.

And I say all this because at a very young age I really cared about my health. For a while, I was vegan, and then I was macrobiotic, and then I was playing around with other diets and wanting to sort of optimize my physiology and functioning and health in general. And I felt indestructible. I mean, I really did. And I had gone to one of the best colleges in the country. I was then accepted to one of the best master's programs in health management in the country. And then I was accepted in one of the best medical schools in the country. So, there was some kind of ego around this in terms of I'm firing on all cylinders, mind, body and spirit.

In my fourth year of medical school, I had a chance to do an elective. And while I was at University of Michigan, I wanted to be back home near where I grew up. And I had a chance to spend about a month at a little integrative clinic in the countryside of Virginia. And it was just a wonderful opportunity to take a little time off and kind of decelerate from the rigors of medical school.

So, I went to Virginia. I stayed at the clinic. It was in the rolling hills of the Virginia countryside. And at the time, I was training for an Ironman. I had hired a coach and was really serious about all this stuff. And I remember after a training run, just sort of a six mile, almost kind of a recovery run, I felt an itch on the back of my left knee. And I didn't think much of it but kind of reached down and realized that there was something there, and it was an embedded tick.

Well, what did I do? I picked it off and didn't think much of it. And let me tell you, Scott, you don't learn anything about Lyme in medical school. And I certainly didn't learn about it in residency or kind of post-residency. Nobody writes about it in the conventional circles. As a primary care physician, a family doc, you're trained that just a little bit of doxy and you're fine. So, I didn't think much of it. I had no experience with anyone who had been really sick from it.

And a few months later, I noticed I was becoming a bit more short of breath. I was sweating more than usual. I was more anxious. In fact, there was a point at which I started sweating through my clothing. And I had no idea why. I was usually kind of a cool customer, but it was super embarrassing. I used to take towels or tissue paper and put it under my arms. I even was able to finagle some Botox and was starting to shoot Botox under my arms. I had no idea what was going on. But i had a frame of reference for my health. And because I was performing all the time, running and cycling and swimming, I could tell I nosedived. I never got a chance to do that Ironman because my fitness declined pretty quickly and I had no idea why.

I thought maybe it was related to residency and being on call and all that sort of stuff. Looking back, I realized it was Lyme. But it wasn't until 10 years later that I had left University of Michigan and I had a parade of self-described Lyme patients because everybody there knew about it. I didn't. And I had actually, ironically enough, joined that very integrative clinic that I had gone to during medical school and realized that these people had all the same symptoms that I was experiencing.

The only moment during that journey where I should have really paid attention, I remember rotating with a neurologist, and this was sort of several years after the tick bite, and he looked at me, he said, "You know, Andy, you've got Bell's palsy." And I said, "I've noticed this, but we keep going in life." And sure enough, looking back, I should have paid attention. My decline in health, my fatigue, my shortness of breath, my anxiety, my sweating, my Bell's palsy. I mean, how many more signs do you need that I was dealing with this? And there it was. And so, I had Lyme disease. And it changed me fundamentally in a lot of ways.

I would imagine a lot of your listeners probably have had the same journey in a sense where it just kind of landed on them and it ruined their life. I don't know if you've kind of heard a similar story before, but certainly that was my journey and it mattered. You don't see it coming. A lot of us don't see it coming. And many of us, I think we've had it for a long time and never really knew that feeling grumpy and tired and out of shape was not just a feature of aging, that something happened to us that was meaningful. It certainly happened to me.

[0:11:56] SCOTT: So much of our discussion today will focus on your treatment approach within the context of the Cell Danger Response. Many of us have followed the work of Dr. Bob Naviaux for probably a decade now where the mitochondria can, as you say, shift from being energy plants to battleships. A threat essentially shifts the mitochondria and the cells into a survival mode, a protective response.

My mentor in this realm has been Dr. Neil Nathan. We did a great podcast on that a couple of years ago. The problem that I always had with the Cell Danger Response was that it seemed to be more theory than something that had clinical practical application. And so when I started learning about your work, kind of the light bulb went on and I said, "Ah, now this is how we apply it." So we didn't have back then really any metabolomic tests. The therapeutics were unclear. People talked about Suramin. Nobody could get Suramin. So, this is the first conversation where I'm seeing that clinical application.

So, let's maybe start. You kind of coming, people maybe know you from the CIRS model. So, talk to us a little bit about how CIRS is a treatment model not based on a biological foundation and how the Cell Danger Response is a more fully realized theory of cellular defense and resolution without an operational clinical approach. Talk to us about how you move from CIRS being more the country to Cell Danger Response being the continent, which CIRS is within. And how looking at that Cell Danger Response expanded the work that you can do clinically with your patients today.

[0:13:29] DR. HEYMAN: Yeah. It's certainly been a journey. And I think I have the luxury of having my patients be my best teachers. And I think if you're humble enough; and this goes way back to my original training in Chinese medicine and shiatsu. And I remember there was this moment where they said you're not allowed to touch another person until you can show mindfulness and healing presence. And that means diminishing your own ego to be fully available to the current state of your patient so that you can absorb as much information from them as possible. All the nuances, all the patterns, all the things that make up where they are at in this moment.

And I think I'd like to think as a physician I've brought that humility forward into my standard medical practice that presence, listening, observation of patterns, not being defined by kind of one intellectual framework or structure that you learn more from your failures than you do from your wins. And in this very muddy world of exposure-based medicine or whatever you want to call it, I've seen sort of the full spectrum of both incredible successes as well as outright failures. And I realized over time that I had basically kind of what I felt like was in some sense reached an intellectual limit, the outer boundary of CIRS in particular.

And I can say that with some level of confidence because I was there from the beginning when we first started doing research in NeuroQuant. I was there in the beginning when we first developed GENIE. I was there writing the papers on Actinomycetes and endotoxins and beta-glucans. I was there when more recently Ritchie became very interested in Parkinson's and the triple-positive idea. And this notion that in some ways of CIRS was progressing in its kind of understanding of what it was looking at.

But in parallel to this; and let me say it's been a privilege to be his sort of main research partner and dear friend, and sort of not have any reservations about the model, that I applied it as it was and sort of saw the good, the bad, and the ugly. And I can say that with real authenticity. With that being said, I felt like I had sort of reached a limit.

If you look at two pieces of information, one, let's start with the treatment. The treatment itself, this sort of 12-stage process ending with VIP, is both brilliant in and of itself, but also, quite frankly, outdated. It's 20 years old in its sort of understanding of the illness. But it's brilliant because if you think about when Ritchie had made those early decisions on using binder therapy to reduce inflammation, paired with the great insight, I think, of using VIP, vasoactive intestinal peptide, at the end, which reframed, and now we know better, is, among other things, a safety signal to the body. It's one of the major ones. It's not the only one, but it's one of the major ones.

And so how he got to those ideas at that time 20-plus years ago, I have no idea. I mean, that's the sign of a genius. And Ritchie is a genius in his own right. But it hasn't changed as a model, even though there have been new insights inside the CIRS world. And as I was writing papers with Ritchie on these "new insights", what I realized in this kind of second category of the science that underlies the illness is that it was a terrain that we felt we were planting flags in along the way saying, "This is CIRS". So, in GENIE, it was the hypometabolism, or was the down-regulated T-cell receptors, or was the proliferative physiology, or the MAP kinases that we were beginning to kind of map out what was underneath of this. Beyond that model that he had defined the biotoxin pathway, which was more the physiologic level, we were looking at the genomic level. And we were seeing things in the genomics that we couldn't see in the measurements of TGF-β1 and VEGF and the rest.

But what did we find? We found at core that this was essentially a mitochondrial disorder, that the genes that appear to be relevant that pointed in the direction of pattern abnormality were all mitochondrial in origin. And it got me thinking about, "Well, what's the other published research on mitochondrial acquired illnesses?" Not inborn, not genetic, but just what happens to the mitochondria and chronic illness over time.

And there's a whole body of research on this. And I realized that we were mapping territory that, quite frankly, had already been mapped by very senior research groups around the world. But the one person who really started to put the pieces together that landed the mitochondria into almost this behavioral model of how does the body react to threats, and he found that biological organizing principle. So, Dr. Naviaux at his research lab at UC San Diego, he was doing some very sophisticated mitochondrial metabolomics. And he showed that there was this predictable, coordinated response of the mitochondria to cellular threats.

And what was fascinating to me at sort of the descriptive level was that in many ways, the organizing principle, the very center of the cell that was designed to keep you alive and to protect your health and protect your vitality was not the nucleus. It was the mitochondria. And so to that end, this notion that what we were looking at was the most incredibly important component of how we should be thinking about the ways in which people had chronic fatiguing illnesses. And that was a huge revelation for me because now I was seeing where that innate immune response gets triggered by the mitochondria, how that transitions into hypometabolism and proliferative physiology. And then where do we find our way home? That's part of that healing response.

And you mentioned Suramin, which is one of those final healing signals that basically it says, "It's okay. You're out of danger." And so, he built this, not just conceptual model, he built a biological model of the ways in which the mitochondria behave towards cellular threats. And it was fascinating.

But for many years, there were primary components of it that we just couldn't measure. How do we know that you're in Cell Danger Response? How do we know what stage you're in? And some of that still we don't know. But we're starting to be able to put some of the pieces in place and infer with other kinds of adjacent labs. That's the model that I've expanded to. And what that says is it fully describes CIRS and then says there's a whole other landscape that we need to also understand. The way I describe it is that CIRS is the country, Cell Danger Response is the continent that surrounds that country.

What that does, two things. Number one, it validates the CIRS model. Yes, innate in immune inflammation to a trigger. Yes, transition to hypometabolism and aerobic glycolysis. Yes, the need to have a safe pathway home with things like VIP. He got all of that right. But there's a whole bunch of other stuff that we need to understand that sets in and around those more limited ideas, and that's what sort of the Cell Danger Response basically defined for us.

[0:22:19] SCOTT: So, you mentioned chronic fatiguing illnesses. So, when we look at this model that you've created beyond mold and CIRS, which we're going to talk much more about, are conditions like ME/CFS, or Long COVID, or fibromyalgia, multiple sclerosis, Parkinson's, maybe ALS or cancer, or maybe we have kids with autism or PANS/PANDAS, does this same model apply to many conditions beyond what we might have thought about in the country of CIRS?

[0:22:49] DR. HEYMAN: You know, it's interesting. I just did a podcast with Dr. Gordon. And he's also kind of very involved in the space. And if you listen to the other "experts", and there were a variety of them, and the topic for the weekend was this weird mixture of mold, Lyme, MCAS, Long COVID, ME, Chronic Fatigue Syndrome. And what's interesting is that in many ways, every speaker, to some degree, talked about this complex model that if you're going to undo or unravel Long COVID, you got to get MCAS right, and you got to get the gut right, and you got to get rid of other pathogens, and you got to deal with mold and other stuff. That Long COVID is probably not just instigated by the presence of spike protein in a chronic infection, but that it's a signal if you got sick from long; or developed Long COVID because you were exposed to COVID, you have other fish to fry.

And I think Naviaux would be smiling and nodding his head saying, "That's the point. That as you load the mitochondria with threat after threat after threat, eventually they shift into battleship mode." And whatever label you want to call it because of, let's say, that primary instigating sort of trigger, whether you got through the door because of Lyme, or stress, or mold, or whatever it is, we all end up in the same spot. And some of us have multiple triggers, like I did. I had Lyme disease, but then I got sick from mold. I didn't develop some of the other stuff like MCAS and POTS and those sorts of things, but these triggers build on themselves.

And the CDR accommodates for that, that you enter CDR1 because of either a single meaningful exposure or more likely loading exposures, loading triggers. And then eventually the mitochondria make that ultimate shift. We turn on that integrated stress response of the mitochondria that then signals the cell membrane to turn on CDR1.

I think everybody's probably different. And that's where I believe the model should be not just single exposure, but total load over the person's resiliency and reserves. That some people can absorb a tremendous amount of exposures and stress and toxins and be totally fine, that their resiliency systems are intact. And other people, at some point, they hit their limit where the load overwhelms resiliency, and that's when the mitochondria shift.

My guess is that that's different for everyone. But that's sort of the model that I think. If you're an ME guy, or COVID guy, or mold guy, or Lyme guy, I think we all end up in the same spot. Because if you listen to about 20 different "experts" on all those different subjects, we're all basically saying the same thing. We all end up in the same place.

[0:25:56] SCOTT: So, if we kind of extend then on that total load concept, a lot of people use this bucket analogy where symptoms are the overflowing of the bucket. Jill Carnahan likes to talk about creating margin in the bucket so we have some reserves, and thus reduce or eliminate symptoms. So, we can either open more drains in the bucket through detoxification, drainage support. We can turn off or turn down the faucet or the hose that's filling the bucket by removing or reducing triggers. Some of us maybe have smaller buckets because of our genetic predispositions, because of how our nervous system is wired, because of our state of sympathetic dominance, those kinds of things. I'm wondering when you look at this kind of total load this bucket analogy, what aspects of that overlap with your work and which of the approaches of opening the drains, turning off the faucet, or increasing the size of the bucket is where the magic happens?

[0:26:59] DR. HEYMAN: I think it's all of it. And I don't think it's one thing. I think that in my sort of model of kind of following the CDR, you're trying to do two things. One, reduce the load but at the same time build resiliency and send safety signals. If you really look at what Naviaux says, the mitochondria are waiting for the right signals at the right time to transition from CDR1 to CDR2 to CDR3.

And the way I describe it is CDR1 is your house is on fire, meaning active exposure. Something has happened to turn on that innate inflammation. In CIRS world, it would be a "biotoxin". And in that language, then we're talking about organisms or fragments of organisms, mold, Actinos, endotoxins, beta-glucans, and then a whole variety of other biological actors that trigger that mechanism.

What Naviaux talks about is there's all sorts of other things that can do that as well, whether it's heavy metals, chemicals, emotional stress, physical trauma, traumatic brain injury, EMFs, you name it, that the mitochondria are tuned to all sorts of potential threats. And so, to that end, at least in the model that I look at, I focus first on CDR1 to say, "Well, what's in that bucket and what can we drain?" And that includes both turning off the inflammation, but draining any sort of toxins that might be resident in the tissues and the cell membranes. I focus on reducing inflammation first, then I move into detox, and then I move into microbial recovery, especially with the gut. I'm tuning up CDR1, and we want proof that that's happening.

So, yes, it's an exposure-based model, but then you also mentioned kind of resiliency, which I think lives mostly in CDR3, which is the safety signals of when to come home. And VIP is just one of them, and we can certainly talk more about that. But what lives in the middle? It's one of the biggest blind spots, I think, of the CIRS model, and that is to say, "Okay, we've reduced exposure. We've turned off inflammation. You're passing your visual test. We've drained chemicals and metals. We've beat up some bugs. We've sealed linings and barriers and boundaries. Microbiome is better." Now we're transitioning to CDR2 because the alarm is off. We need to rebuild the house. And that's to me two things. One, metabolism writ large, which could include nutrients, and hormones, and diet, and that sort of stuff. But the biggest gap has been how do we measure the mitochondria directly.

Our closest test in this world in general is GENIE, but even that's an adjacent test. It's not a direct test of the mitochondria per se. It's not telling you what they're doing today. What it's measuring is the signals that are being sent from the DNA to say, "Hey, go do this." Right? It's mitochondrial signaling. And there's all sorts of issues, I think, around that. But that's the biggest gap, I think, in what we do.

And if you can't measure the mitochondria directly, you don't really know where the patient is at. And we tend to skip over that and say, "Well, they're passing their VCS test, their blood labs look normalized, they're out of exposure, let's start VIP." That's the criteria. I now have the ability to measure mitochondria. And what we're finding is that in all these patients that I check the boxes of getting them to VIP properly, and I'm a purist in that regard, if I measure their mitochondria now, I'm finding most of them have problems still that have been overlooked. It's the difference between getting them part of the way and hopefully all of the way.

[0:30:58] SCOTT: You call these conditions trauma-based illnesses, where we're both hyperreactive, but we're also exhausted, where we need that safety and sanctuary or safety signals. Talk to us about what you mean by trauma-based illnesses. I think so many of us were gaslit by the medical profession, by our friends, by our families, essentially told that these conditions were really all in our head, in our mind. So sometimes hearing that, I think people have kind of a recoiling type response at the beginning. So, what is the scope of trauma when referring to these conditions as trauma-based illnesses?

[0:31:37] DR. HEYMAN: I love the question. And I think there's a couple pieces to it. One is trauma with a capital T with respect to all the ways in which we send danger signals to the mind and the body. And the world of psychology has mapped that emotional landscape of where do emotional traumatic events live in the psyche? And what Naviaux did is said that those signals also live in the soma. They live in the mitochondria. That those same signals of danger and threat arrive at the cell membrane and they get transitioned down to the mitochondria, and that there's a coordinated cellular response that mirrors and maps an emotional response.

And one of the parallels that I think is profound is that in the same way when a person can have what we call an Adverse Childhood Event, meaning an emotionally traumatic event that carries forward into adulthood, that in some ways we remain emotionally stuck and we keep reliving and replaying that trauma in our mind. And it's very hard to break. It turns out the same thing is true with the cells, that you can have an exposure that's meaningful in terms of turning on Cell Danger Response. You can even remove that exposure. We can live well beyond that exposure. A temporary virus, a traumatic brain injury, some sort of exposure that kind of came and went. You lived in mold for a little while and then you moved out. But once we turn on that CDR mechanism, what happens is we start to replay that idea cellularly and we also can remain stuck.

So, in this model, then, we need to appreciate the fact that some people have had exposures that are still active and others might be somewhat historical. But the model remains symmetrical, that whether it's an emotional event, a physical event, or something in between, what happens is we keep replaying that. This has a couple terms to it. Molecular scarring is one, and it's the notion that we remain stuck in this pattern.

And so, to me, that idea that trauma as a model means we are being exposed to the vagaries of life that then transition us into these models of illness that have been very hard to measure and equally hard to deal with therapeutically. And yet, this is where a lot of us land, sort of a broken nervous system, a broken immune system, mitochondria that won't transition, a psyche that's been so injured that all of our best therapy seems to not be able to reach the emotional balance that that everybody's sort of seeking. And yet, I think in many ways, that's what represents this model.

[0:34:54] SCOTT: The term that came to mind for me as you were kind of going through that is cellular rumination.

[0:34:59] DR. HEYMAN: Yeah.

[0:35:00] SCOTT: And we just keep playing it over and over again, because I certainly have been guilty of that.

[0:35:06] DR. HEYMAN: Yeah. And when it's happening subconsciously, when it's happening on the cell level, what are the ways we contact that, right? To sort of reset that mitochondrial behavior, that mitochondrial rumination. Because what happens is just like when we have emotional trauma in childhood, these are defense mechanisms that are designed to preserve your life. And it's meant to say, "I'm now on high alert. And I'm not going to let any new threat push me over the edge." But what does that mean mechanistically? We become hyper-reactive to the world around us. Smells, sounds, emotional stress, food, things that would be kind of normal in life begin to have an abnormal impact. This is the mast cell community. This is the hypersensitive community within CIRS. This is those people who just feel like they have to live in a bubble or otherwise their body and mind go haywire.

The mitochondria are doing this on purpose, but what's happened is you've lost your reserve. And the mitochondria have said, "Enough is enough. I'm going to react to everything. Whatever it is." And I know I have lots of patients who feel this way to one degree or another. They get that sense that they can't go anywhere without feeling like some part of them is reacting.

[0:36:30] SCOTT: So, let's talk a little bit about testing. You've said that a standard workup was never built to detect a body stuck in a chronic alarm state from an environmental exposure. Asking them to find mold illness is like searching a dark room with a flashlight pointed at the wrong wall.

So, we're going to dig deeper into some of the newer tests like GDF15, FGF21 as we get into the stages of the Cell Danger Response. But what tests from the CIRS toolbox have remained important in this expansion model? If we think about VCS, we're going to talk more about HLA, TGF-β1, C4a, MMP9, MSH. You mentioned NeuroQuant and GENIE. So, which of those still rise to the occasion? And then what are your thoughts on things like urine mycotoxin testing or mycotoxin antibody testing?

[0:37:22] DR. HEYMAN: Let's unpack this a little bit. So, let's rebuild the CDR framework. CDR1, the house is on fire. So, you had an exposure of some sort and we're in that innate inflammatory response. Very classic CIRS-y in a sense. And so, let's just take CDR1 for a second. What are our markers within the CIRS world that are classically and uniquely suited to measuring inflammation? Well, there's only a couple, but they're helpful.

My most helpful is the visual test. And in some ways, it's a direct measure of central neurologic inflammation. I really feel like I couldn't practice therapeutically without it. And this notion that we need to gate progress based on transitioning from a fail to a pass, in thousands of patients, I've learned that it's actually really meaningful.

And I also often talk about how if the visual test represents brain inflammation. If the brain's on fire, typically the rest of the body's just not very happy. And patients always ask me, "Well, why aren't you detoxing me? Why aren't you changing my diet? Why aren't you balancing my hormones? Or what about this new fancy peptide?" I say, "Look, if you've got a brain on fire, You and I can change your diet until the cows come home." We can try and drain heavy metals and chemicals. We can do things with your microbiome. We can sort of deal with pathogens and other stuff. But what we've learned is that none of those approaches and none of those treatments tend to work very well if you have this sort of central buried inflammation.

And so, I've learned to have the discipline of moving people through improving their visual test first, making the transition and then we kind of move on to other things. I've learned that the logic of Shoemaker, putting the visual test first, waiting until transition, was insightful and meaningful. My research team has developed kind of a new and modern visual test. It needed a lot of updating. We've done a lot of work calibrating it and making it true to grayscale and pixel size. And I think it's become a very reliable digital tool. And I use it with every single patient.

In addition to that, in the CIRS world, the next most direct inflammatory marker is MMP-9. It's a direct measure of tissue level inflammation. In addition to that, the C4a and C3a. The only practical challenge, of course, is getting a proper C4a and C3a. Right now, Colorado is really the only place that still runs it correctly. You can get it through LabCorp. They add a preservative, so it's not really reliable.

In addition to that, you can run standard inflammatory markers like an IL-6 or CRP, or look at the neutrophil-to-lymphocyte ratio. There are a variety of inflammatory tools that we sort of have at our disposal to say, "Yes, this person's inflamed." But one of my anchors is still the visual test.

In addition to that, once the person passes the visual test, I then sort of flip into a; let's call it a Neil Nathan model, where once we've dealt with the home, they're improving their inflammatory load, they're doing a bit better. That's when I might do some urine mycotoxin testing. Why? Because once they're passing their visual test, and we assume that they're out of exposure, there can still be some residual internal exposure. That we know some mycotoxins are not only lipid soluble but can kind of live in the body for a while. And I think that's when we start looking at more kind of detox agents like N-acetylcysteine, glutathione, charcoal, chlorella, clay.

And you can get pretty fancy and targeted with respect to what mycotoxins are still residual and then how do we fully extract them from the system. This is, of course, one of the big dividing points between the CIRS world and the Neil Nathan world. That in the CIRS world, we say urine mycotoxin testing is too blunt of an instrument. We don't know if it's coming from the diet. We don't know if it's really impacting people clinically. We don't really pay a lot of attention to it. We don't do it.

In the Neil Nathan world, he'll tell you it was one of the big missing pieces. That in fact, if you have someone passing the visual test and still symptomatic, when you do urine mycotoxin testing, you really should strip them out. And he's seen a lot of patients have another level of improvement when he does that. So, I blend the two. I say, "Look, we're going to do a full clean out with you. I want to get you as healthy as possible. Let's use both." So, I'm not a purist in this regard. I'm a lumper, not a splitter. So, once we transition the visual test.

From there, we can, if we want, do chemical testing, heavy metal testing, depending on the person's history. I have a big background in chelation and heavy metal work, so it's natural for me to ask questions around that and to deal with it. So, we go from looking at inflammation and using the gate of the visual test and some of these other markers, and then I get into sort of pathogens and detox, and then from there into the gut. So that's kind of CDR1. Hopefully that was helpful just as kind of a beginning overview, and then I'll kind of get into other pieces.

I have the privilege of running a new IRB-approved research study on NeuroQuant with Dr. Ross, who did all the original work. In fact, he was the inspiration to Dr. Shoemaker in teaching him about the value of NeuroQuant. At the time, and this was back in 2013 and 2014, when we published that original research, we were really only looking at 11 brain centers with the kind of core NeuroQuant software. We knew that was limited.

And since then, Dr. Ross has developed a newer platform, essentially, that we can now look at critically 240 brain centers. And the literature has grown on the patterns of injury that we see with other related conditions. So, we know a bit better about what a TBI might look like within a NeuroQuant model or a structural MRI model. We know what anxiety and depression and neurodegenerative diseases might look like. And we also understand that these exposures live somewhere in their own lane.

What's really interesting about that idea; he and I have had a lot of discussion. Dr. Ross, for those of you who don't know, he's triple board-certified in neurology, psychology, and traumatic brain injuries, published at least 20 papers on structural MRI with these related exposures. So, he's a real expert in this regard. And what we found interestingly is that the one category that closely maps to the idea of mold exposure is traumatic brain injury. And where they overlap in particular is the degree of interstitial edema or essentially inflammation and swelling.

And it turns out that there's a mixture in the TBI pattern where we see areas that swell in other areas that shrink or atrophy. That's really unique. Because under most other circumstances and most other brain diagnoses, it's usually just atrophy or shrinking. So TBI was special in the sense of the degree of both swelling and shrinking. It turns out in mold exposure, there's on average more swelling and less shrinking.

The patterns overlap, but they're not the same. But they are related in this kind of other special category. But now in our new study, we're looking at more brain centers. We want to refine the pattern. We want to come to better conclusions about how to map the NeuroQuant.

The algorithms that are being used right now are very old. They're a very blunt instrument. People kind of come to conclusions of, "Oh, this is a mold pattern, this is a Lyme pattern." I don't even send my patients to do that interpretation anymore because it's outdated. We need a new model. And so we're building that right now.

In terms of GENIE, that's a whole interesting subject. When it comes to GENIE; what is GENIE? So, bear with me on this one because I feel like it's something that people don't really fully understand. It's a powerful tool, but it needs to be applied in a certain kind of context.

And so, to that end, we're now in the world of omics. And the way I liken it is, everybody's heard the term genetics, and we've also heard the term genomics. It turns out that these are not the same idea. Genetics is really very simply the ability to measure the structure of genes, meaning what did I inherit? This is the world of MTHFR, meaning am I heterozygous? Am I homozygous? Meaning do I have some change to the MTHFR gene that I inherited? Do I have a big change that I inherited to the gene? And what are other genes that I've inherited that might be meaningful to my health? The idea is that if you have a physical alteration to your gene, somehow that predicts some aspect of your health or just functioning in general.

It was actually one of my mentors many years ago who was appointed by Congress to run the Human Genome Project out of University of Michigan, Francis Collins. And so, he basically figured out what the human genome was and published that in 2002. We thought at the time, now that we can map the human genome and we know the structure of everybody's genes, all illness will fall at the feet of medicine. But we realized over time how wrong we were, that just knowing the structure of a gene did not really tell us much about the functioning of the body overall. That meant the production of omics, and that is to say the life of a gene, how genes turn on and off, and what were the signals that come off the DNA to tell the cell what to do. And so, the world of omics was born.

And so, there are layers to the world of omics. There's the gene level, the DNA level, which we call the genome. There is the first expression that's read off the genome called the transcriptome, and that's RNA. So we go from DNA to RNA. So, RNA is sort of a mirror image. Then the RNA goes to what are called ribosomes, and they're strung together through the ribosome. They're kind of zipped together. And RNA that's connected becomes a protein.

So, we can measure the RNA that's being produced, but then we can also measure the protein level. That's called the proteome. And then finally, proteins are folded and glommed together, and we make small molecules, and that's called the metabolome.

Dr. Naviaux's work measures the metabolome. He measures the end expression of what the mitochondria are doing. And so, to that end, where GENIE lives is the transcriptome, which is to say it measures RNA.

And so, if you think about it, what it's really doing is measuring the signal off the DNA of the mitochondria and basically is saying, "Okay, here's the instruction set that it's sending the cell to create a metabolic response." But here's the thing we don't often talk about. Point number one, up to really 40% of the RNA signal appears in the metabolome. That there's a huge amount of variability between what comes off the DNA and what ends up in the metabolome. Why is that? Because every layer of the omics model is regulated.

Some signals are fully extinguished. Some signals are partially extinguished. So just when you when you read a GENIE and you're looking at what that reaction is, we don't really know exactly what actually; is going to be in fact be appearing at the cell level. It gives us a sense of what's going on.

And in addition to that, we're now using GENIE in sort of two ways. One way I'm comfortable with and a different way I'm not as comfortable with. One is diagnostically, meaning can I look at a GENIE and say whether or not I think this person has had a meaningful exposure? And even further, to what?

There are different genes that kind of turn on and off. And when I read a GENIE, I can tell whether or not there's a pattern present that says kind of CIRS, not CIRS, CDR, not CDR in general. More recently, we're trying to go a step further, which I think is a bit of an overreach to say, "If we look at a GENIE and we see certain genes turning on, it can be predictive of a current or future illness."

The problem with that is not only are signals extinguished, but also they're quite transient. And if you're going to do predictive modeling using transcriptomics, you need to know the genome of the patient. You need to know broader clinical context. You need to have a huge sample size to be able to say for certain that with this particular set of findings, it is somewhat predictive of a future event. None of that exists in the CIRS literature.

And so, sort of the triple positive idea of predicting Parkinson's, for example, you need an enormous sample size to be able to do something like that over a long period of time. We don't have that kind of data. So, it's very inferential at best. But do I think GENIE is helpful to say if I see a pattern, can I use it to make a diagnosis? Yeah. I can see the idea of exposure. I can see inflammation. I can see hypermetabolism. I can see proliferative physiology. I can see elements of the CDR kind of beginning to appear within GENIE. So that's where I think it's helpful, kind of upfront. But I don't really like talking about using it as a predictive tool. I think that's a little too far if you really look at the literature.

[0:52:09] SCOTT: So maybe one more piece there that I'm not completely clear on its utility, how helpful is GENIE in providing specific causation of why the person has CIRS?

[0:52:23] DR. HEYMAN: So the great debate. I would say if you look in section three of GENIE, caspases-3, 8, 10, they're relatively pathognomonic or relatively specific for fungal exposure. So, in that what's called an apoptosis category, if you see caspases turning on, then I think we can begin to get to a conclusion on are beta-glucans present or fungal elements present.

With that being said, when you look at Section 9 and 10, Section 9 are MAP kinases, and Section 10 are basically essentially toll-like receptors. Where I think the great debate is, is Section 9. And this notion that MAP kinases in particular are somehow directly predictive of either an Actinomycetes exposure and/or mold exposure. And we use cutoffs. So, Dr. Shoemaker talks about if it's sort of two or less genes that are active in terms of MAP kinases, it's probably Actinos. And if it's three or more, it's probably mold. And these criteria have changed a little bit over time, but essentially that's the thinking.

Now, if you look at what are MAP kinases, they're just the stress signaling pathways inside the cell. They're part of the intracellular transduction system, where there's a signal that's coming from the outer cell membrane going to the nucleus or going to the mitochondria, and MAP kinases are enzymes that get turned on as that signal is transduced.

Are MAP kinases specific to mold exposure or Actinomycetes? No, they're not. Do we think that one pattern versus another relates to a type of exposure? Well, that's where Dr. Shoemaker went. I'm not so convinced. I think it's a signal the cell is stressed. I think there could be all sorts of exposures that might be present that's triggering Section 9. I'm much less confident on making that interpretation, but that's kind of where we went.

Now, with that being said, that thinking did open up the notion of Actinomycetes and looking at other biological triggers. So, there was some value in it. But again, I don't think it's as specific as we've made it out to be. Section 10, on the other hand, toll-like receptors, they are induced by lipopolysaccharides and endotoxins. And that's clear in the literature. So, when you see section 10 turning on, then I think we can be relatively certain that there is some kind of endotoxin.

Now in the CIRS world, we've been fixated on external endotoxins. But our guts also have gram-negative bacteria that can produce endotoxins and we can even run panels to show lipopolysaccharide production. And so there can be some endogenous endotoxin. This is where I also think the CIRS model fails because it doesn't really take into account the biggest internal inflammatory engine, which is the gut, and whether or not it's producing endotoxins too that are getting picked up on GENIE. And I know there have been people that say, "Oh no, GENIE is only picking up external." Well, there's no way you know that. It's probably picking up internal endotoxins too.

[0:55:34] SCOTT: That's a light bulb moment right there, that the endotoxins that are produced within our own microbiome could potentially have a negative impact on our health. You mentioned the MTHFR conversation. I think one of the challenges with that and with these SNPs is many people then take on the persona of brokenness or not fixable. And you said recently you've not found MTHFR playing a big role in this illness and/or its recovery. There was a moment in time where MTHFR was kind of the “it” problem.

And so, I like that perspective because I think if we believe we're broken and can't get better, that we epigenetically are influencing our overall genetic expression in a much more broadly impacting way than whatever MTHFR is doing to us. And it sounds like you're of the opinion that rather than looking at SNPs, which are potential, that we want to actually be looking at function over potential.

[0:56:32] DR. HEYMAN: Yeah.

[0:56:33] SCOTT: So let's talk then another genetic conversation, HLA-DR. So, I happen to be a 4-3-53, with a 4-3-53 that we generally think of as being more difficult. I'm not going to use the terminology that we often hear because I think, again, that sends a message that's not a safety signal. Was the journey easy for me getting better? No. Was that HLA 4-3-53 deterministic of my potential for getting better? Doesn't appear to have been. So how important is knowing someone's HLA in your model today? What does it tell you about their propensity to develop one of these conditions when they're exposed to a trigger? What does it tell you about their potential to recover? Is HLA something we should hang our hat on? And could someone's HLA act essentially as the opposite of a safety signal, depending on the messaging around it, how that's communicated? And then if we are one of those HLAs that are believed to be more challenging, what can you say to give someone hope that they can still regain their life? What matters more, HLA or total load?

[0:57:44] DR. HEYMAN: So, I'm kind of a total load guy. And HLA sort of fits into a similar narrative that maybe the MTHFR does. And that is to say, are genetics predictive of your health status and vulnerability? And it turns out – I mean, if you go to sort of the big university center genetic counseling groups, there's very little about our genes that are deterministic for our health. And even the world's experts will tell you that. Only under very specific circumstances are certain genes that we're born with so critical to a pathway or a mechanism that it fundamentally alters and shapes who we are and the trajectory of our health.

So, the idea of these kind of inborn errors or inborn issues of genetic mutations or SNPs, as we call them, I think have been greatly overstated in our field in particular. The big boys don't talk about this, but we do. And a lot of it; I mean, you and I both lived through a lot of fads in this field. And at one point, MTHFR was the it thing. It was the answer to ME, and CFS, and chronic infections, and poor detox, and my body's filling up with chemicals and heavy metals. And so, this narrative started to build and there were a few voices in particular that were driving that narrative.

Supplement companies in particular really picked up on this and a few of them actually built genetic interpreters. So you could run a 23andMe or some other genetic screening and then submit it to the company. And they would tell you what genes were present, what SNPs in particular, and what those SNPs were associated with in terms of chronic illnesses.

Our field got very fixated, of course, on detox in particular. This is very much almost a naturopathic idea. And the notion was if you have an MTHFR defect, or an MTRR defect, or COMT, or any of the other related ones, oh my gosh, you're a poor detoxifier and that's why you're so sick.

If you talk to the companies; and I certainly did. I know how the sausage is made in our field. And I know where the skeletons are buried. And I've had the privilege of sort of teaching at the highest levels with the largest organizations in the world on these topics and subjects. And I have direct relationships with a lot of these companies. And they will tell you that as they ran these genetic profiles through their sort of whiz-bang calculator and then made recommendations on personalized detox programs for people, specialized amounts of methylfolate, or hydroxy B12, or amino acids like lysine and taurine, or whatever it was, that as they track people, they really, quite frankly, didn't see very many individuals improving. That the clinical model failed.

And there was this big rush to push these detox programs. But a lot of patients will say they spent quite a bit of money on these big regimens and never, quite frankly, felt a lot better. And so to that end, it kind of fell out of favor. It was replaced at some point by other fads and other trends and other new it things. And we went from MTHFR to MCAS.

And Dr. Afrin started producing his work and publishing in 2014. And all of a sudden, everything was about MCAS. And then soon after that, it was once again Epstein-Barr. And after that, it was sort of connective tissue issues and so on and so forth. So, you and I have kind of lived through the trends in a sense. But from a literature standpoint, HLA and MTHFR sort of fit into the same category.

So, HLA then I sort of treat the same way. And that is on chromosome six, there are certain gene sequences that are meant to tune the immune system in particular. And all of that might be fine. But whether or not it plays such a central role in someone's vulnerability and/or ability to recover, I've sort of begun to question for a number of reasons.

Number one, if you look at the origin story of HLA, it was something that Dr. Shoemaker put together as a poster in 2002. And he had looked at a handful of subjects and said, "Well, I think these HLA are pretty important in terms of vulnerability to exposure." But that was essentially it. There was really no more scientific deep dive into whether or not HLA really mattered.

So, we have sort of an old comment that took life on its own. And people were looking for a reason why they were sick. And HLA was very compelling in that regard. In the same way that people said, "Oh, I'm an MTHFR person, poor detoxifier." We saw the same thing in the CIRS world, "Oh, I'm a 4-3-53. I have the dreaded gene. I'm screwed."

In addition to that though, if you look at the literature on HLA, it says something different, that there are three disease categories that locate to HLA problems. And they actually all say together the opposite of Shoemaker's assertion. So, the Shoemaker assertion is simply that if you have any of these HLA patterns, you have the propensity to turn on your innate immune system and not transition easily to the adaptive side of the immune system, which would therefore reduce the ability to turn on t cells and b cells. But also, that in fact diseases like autoimmune processes live in the adaptive side. So, we kind of askew the notion of autoimmune conditions in his model and say, "We're stuck with the fire and we can't turn it off."

What the three different disease patterns show with HLA is exactly the opposite. So post-Lyme, Borreliosis, meaning exposed to Borrelia, and a bronchitic disorder. Basically, ABPA, it's called. All of these say the exact opposite, that if certain HLAs are present, you are more likely to develop an autoimmune process with HLA defects post-Lyme, Borreliosis, and ABPA. Not innate immune inflammation.

Even more important, I think, is this notion that we hear this term 24% of the population has these HLA defects, and therefore it's a huge potential number of people that are really sick from their homes. And so there have been some studies looking at the prevalence of HLA in the population. Dr. Rappaport did a little bit of work and found that in certain populations, up to 90% of them carry these genes, certain HLA sequences. And other sequences are very underrepresented in the population. But certainly the average doesn't come out to 24%.

In addition to that, if that 24% number held, we would see a lot of large randomized controlled trials that would be affected by the presence of HLA. And I'll give you just one example. I heard the other day that Dr. Shoemaker made the comment that GLP-1s don't work in CIRS. Well, let's parse that for a moment. If that were true, it would mean that in an obese population where GLP-1s were studied, in a large randomized selected group of subjects, potentially up to 24% of that study group would not respond to GLP-1s. That that's what it means essentially. And of course, they didn't find that.

And again, mechanistically, I think GLP-1s have an interesting role to play in CIRS. But we would see the presence of HLA in all sorts of large-scale research studies. And we don't so there's lots of sort of lines of evidence, let's say, that I think sort of potentially discounts the HLA as being the final arbiter of are you vulnerable or can you get better.

I also think sort of more modern-day science has uncovered these terms, these ideas of what are called molecular echoing, molecular scarring, that the cells remember, and that this notion of toxic load is what creates the vulnerability. The molecular echoing and scarring keep us kind of stuck in that process. And so too does the upper layer, which we haven't really talked about, which is the integrated stress response of the mitochondria that that can get stuck turned on. And that there's a certain gene sequence that does that. And so for all these reasons, I think, yes, people are vulnerable, yes, people can get stuck, but not for the HLA reason. I think HLA, the idea of it was right, but the specifics of it I don't think hold up to scrutiny.

[1:06:40] SCOTT: So, we're going to get deeper into some of these tests in the CDR2 conversation, but I kind of want to get people a little bit of an understanding of some of these newer things that you're exploring, which do help you determine in which phase of the CDR the person may be. Though we're going to talk more about that, that a person is not in a specific CDR stage, that any cell can be in its own CDR1, 2, or 3, and even nearby cells can be in a different stage. But let's talk a little bit about the idea that the Cell Danger Response is the mitochondria sending out extracellular ATP as a danger signal. Do we have a way today to measure extracellular ATP levels in the blood? And then building on this danger signal assessment, one of the exciting things emerging from your work is this growth differentiation factor 15 and fibroblast growth factor 21. So GDF 15, FGF 21 as indicators of stress or danger.

Again, we're going to talk more about them, but can you talk to us a little bit about those tests, how they inform your clinical care of the patient? What do they tell you? Are they elevated in CDR1 and 2, potentially even CDR3? How often would you run these tests as you're moving someone through the phases, the five phases of your treatment model that we're going to talk about? And how readily available are these tests? Can any doctor order them today, or are they still more research-based?

[1:08:10] DR. HEYMAN: All the questions. You're now attempting to take the deep dive. And so, let's put on our pointy-headed academic hats. And let me summarize first. So, we talked a bit about CDR1, which is the house is on fire. And this is a notion of sort of exposures, whether that's biotoxins, chemical or physical toxins like heavy metals. It can be pathogens such as Lyme or Candida. It could be dysbiosis and sort of abnormalities in gut function. Any or all and more can keep this in CDR1.

But what happens when we put the fire out? What happens when we extinguish that innate inflammation and MMP9 resolves, and C4a resolves, and we're passing the visual test, and we've corrected the diet, and fixed the microbiome, and beat up some bugs, and drain some compounds? What's next? Well, we're now in CDR2, which is, okay, part of your house burned down from the fire. Now we need to rebuild it. And that's an interesting idea. And it's where I think I had pointed out with Dr. Shoemaker my own opinion in terms of what we're seeing in GENIE and why.

So, in section one and two of GENIE, we can see gene-related changes at the transcriptome level that would indicate hypometabolism and proliferative physiology, which essentially said differently is called aerobic glycolysis and/or the Warburg effect.

Otto Warburg in the 1940s had identified that cells have alternate energy burning pathways. One of the most prolific and common was aerobic glycolysis, that there was a preferential dependence on burning sugar as opposed to oxygen, even when oxygen was present. Why would that be? It turns out if you look at some developmental biology literature, the brain, for example, up until adulthood is about 30% dependent on aerobic glycolysis. Why? Because as the cells shift to burning sugar, they are much better at rebuilding tissues, that in fact it's preferential in that regard. And we call that part proliferative physiology. So, we turn down the body's ability to burn oxygen, we become more glucose dependent, and therefore we start building up tissues and beginning the repair process.

And so, in the CIRS world, we pointed out sort of "it's negative" in the sense that, yeah, we're burning sugar instead of oxygen, which is a main source of fatigue, and shortness of breath, and post-exertional malaise, and weight gain, and hormonal disruption, and all sorts of side effects in a sense of aerobic glycolysis. But the body's doing this on purpose because you burn part of your house down. What is one of the major organs that we found changes due to these exposures? Well, the brain. So, the body has to do something to turn up its ability to repair.

In sort of CIRS language, it was termed, for example, "Oh, aerobic glycolysis is bad, and therefore our findings on NeuroQuant related to a brain on ice, and that aerobic glycolysis is a signal and/or potentially the pathological process of injury." My opinion was just the opposite, that the body underneath the inflammatory process is attempting to repair, and it's doing it through predictable mechanisms. The two organ systems that are most dependent on aerobic glycolysis for that process of repair, interestingly, are in some ways maybe the two most vital organs. It's the brain and the heart.

And so, the notion that we've shifted into the Warburg effect quite frankly is very predictable. If you've been inflamed for a long period of time and we see tissue and cellular level changes, no wonder there's this defensive shift in CDR2. Now, usually it's probably happening near the beginning anyway, but it's happening underneath the fire in a sense. What are the CIRS markers that relate to CDR2 in this regard of this body's attempt to repair? Interestingly, TGF-β1 and VEGF. They're, in fact, growth factors, Transforming Growth Factor Beta 1. Vascular Endothelial Growth Factor.

So just because they're high doesn't mean that that's abnormal and/or, in the treatment model within CIRS, should it actually, in fact, be extinguished? Maybe that's the body's potential for repair. And so if you place the classic CIRS markers into their proper context, it might very well be that we're measuring the right thing, but our interpretation is exactly the opposite of really what it should be. And I've become more and more a strong believer that if you follow the molecular biology of the Cell Danger Response, that the path opens up that notion of sort of a positive framing of aerobic glycolysis, elevated TGF-β1 and VEGF, for example. We're going to talk in terms of CIRS and or GENIE findings in section one and two in particular. So, I can map the CIRS language to CDR in a way that I think makes more meaning.

Now, as we move into CDR2, what are we left with? And this is one of, I think, the big gaps in CIRS, and that is to say, you can remove the exposure, you can turn off the inflammation. But that doesn't mean you're out of the woods yet. You're now in CDR2, which is repair.

Now, what does the body need for repair? It needs a healthy metabolism full of substrates and nutrients to rebuild the tissues and organs, and you need properly functioning mitochondria to do that. So how do we know do we have a normal metabolism, but also how do we know do we have a normal mitochondria? Well, it's much easier to measure metabolism, right? So, you can measure cortisol and insulin and thyroid and nutrients and reproductive hormones and all the rest. And we do that with real ease, especially within sort of the anti-aging model. But how do we measure the mitochondria. This is maybe the biggest blind spot in sort of what we've been doing up until now.

And there are really two layers that we need to consider. One is, are there regulatory mechanisms that modify or turn on the Cell Danger Response, number one? And then number two, how do we measure the mitochondria directly? Let's take that first layer of is there sort of a layer that represents kind of the first signaling path that turns on the Cell Danger Response? And there is one. And it's called the integrated stress response of the mitochondria. And it's signaled by a very specific pathway. And it's a series of proteins and enzymes that get turned on in a order. And it starts with OMA1. And it ends with a very important compound called ATF.

So, when ATF is upregulated, then we know that the integrated stress response is turned on, that the mitochondria are now getting the signal, "Hey, there's a threat," and we need to go into CDR. Now, what are the molecules that get turned on as a result of this first layer of the integrated stress response? Well, there are two primary ones that we can now measure. There's GDF15 and FGF21.

It turns out, though, that mitochondrial researchers have been looking at these two compounds for a number of years, and they're very complementary, but they really don't do the same thing. But the ATF4 is the convergence point, meaning if we have any kind of cellular threat, we're going to turn on that integrated stress response first. We'll see elevations of these stress markers of the GDF15 and the FGF21. And that says that we're sending the signal to the mitochondria to enter CDR2 or CDR.

But there's a difference in terms of why GDF15 or FGF21 goes up, and also their clinical impact. And this is where they sort of diverge. GDF15 primarily affects the brain in particular. It does not have effects on the rest of the body. And when it's elevated, it can induce nausea, it induces lower appetite, and it says go into a sort of a protected state because you're under threat. It has no direct peripheral metabolic activity. But when it goes up, it's very important as a stress signal.

Now, there are a number of reasons why GDF15 might go up. We also know that it's elevated in kidney disease and other processes too. So, you need to be careful about looking at GDF15 alone. In addition to that, FGF21 also goes up when ATF4 is triggered. But FGF21 has broader effects in the body. And in fact, it might be limited to what's called β-Klotho. And β-Klotho is now one of these interesting molecules that we can also potentially measure. And some people claim to intervene on, but you have to be outside the country to do that in terms of these anti-aging and longevity clinics, that FGF21 is very important for protecting the body, protecting vital organs and tissues like the liver, the pancreas, distinct brain regions.

And so, they're very complementary in this regard. But FGF21 is often triggered by nutrient deficiencies in addition to offering what we call substrate priority. And that is to say it has direct peripheral metabolic action. So GDF15 works centrally. FGF21 works potentially peripherally.

And because they can be triggered under different states, if you only have elevation of one or the other, it's not as helpful to know whether or not it's mitochondrial in origin. But if they're both elevated, the sensitivity and the specificity really means we've triggered that integrated stress response of the mitochondria.

Now why is that important? It means that the mitochondria are getting the signal to turn on CDR. Could there be a circumstance where that first pathway, that stress pathway, where we're producing GDF15 and FGF21 together, could it be permanently upregulated even if the trigger's gone? And the answer is yes, that there is a risk that our body will stay in this primed stress state. And the CDR will continue to get the signal that we're under threat even if we don't turn off an integrated stress response.

[1:19:17] SCOTT: Can we then test for ATF4 separate from GDF15 and FGF21 or no?

[1:19:24] DR. HEYMAN: No, we can't. So, we can test for GDF15 and FGF21. I think the best place to do that is Children's Hospital of Colorado. You can send samples there. It's a bit of a rigmarole to kind of get the whole thing going, but it is available to practitioners. And Mayo Clinic, but they're a bit more restrictive. So you can send it to Colorado. And they'll tell you whether or not these markers are elevated. If they're both elevated, we know that we're still in that mitochondrial stress state.

And by virtue of that, so think about this then, guess what might be falsely abnormal? A GENIE. So, if we're in CDR and we're producing signals that are saying, "Hey, I'm being exposed," but all of that is just because this particular pathway is activated and turning on CDR, we could be seeing false positives and everything from C4a and TGF-β1, to markers inside GENIE. And think about what that means practically. There are people who are continually pursuing cleaning their home because their GENIE says, "Oh, your MAP kinases and toll-like receptors are activated," when in fact it's merely because we haven't turned off the CDR.

There's a risk of molecular echoing. There's a risk of false positives because of turning on the integrated stress response and that also has to do with GADD34. GADD is what turns off ATF4 essentially. There are ways to sort of support GADD34. But yes, we can measure GDF15 and FGF21. And then we can start to get into measuring mitochondria directly.

[1:21:04] SCOTT: And are GDF15 and FGF21 generally something we see more elevation of during CDR2, even though they are danger or stress signals than we might in CDR1?

[1:21:17] DR. HEYMAN: So, we'll see them in CDR1 and CDR2 because basically it's the signal to turn the whole game on. But again, if you've convinced yourself that you've gated CDR1, you're passing your visual test, you've cleared your mycotoxins, you're out of exposure, you've drained chemicals and metals, you've dealt with your pathogens, you've fixed your microbiome, and now you're transitioning to CDR2. And if GDF15 and FGF21 are still elevated, if you think you've done your due diligence, it's probably more likely a false positive, as opposed to they're still elevated because the mitochondria are still under threat.

So that's where the art of medicine comes in. But at least we can begin to map because you and I can't measure extracellular ATP. We can't measure sphingolipids or other things that Naviaux measured in his lab, but we can descriptively map the CDR. And that then gets into being able to directly measure the mitochondria. And there are two tests that do that. One is the Seahorse assay, and the other is the citrate synthase pathway.

So, if you map GDF15 and FGF21, and then also directly measure mitochondrial function, you get a very clear picture of what you're left with after you've dealt with what turned the fire on in the first place.

[1:22:34] SCOTT: So, one of the really important things that I think you said there that I just really want to underscore is that the lack of safety signals can impact test results. And an ongoing abnormal test result could be an ongoing alarm rather than an ongoing presence of a trigger or a tiger.

[1:22:54] DR. HEYMAN: That's right.

[1:22:55] SCOTT: Yeah, that's kind of important.

[1:22:58] DR. HEYMAN: You think? I mean, because what you end up happening is these patients are using a limited set of labs and pursuing treatment, pursuing small particle cleaning and pursuing repeat testing and looking for new exposures when, in fact, they might have already done their due diligence. They might have already be out of that exposure, and/or they've missed something.

And I think quite frankly, one half of the equation is kind of biological exposures, but then the other half; and this gets into the nuance of do you use a Neil Nathan model or kind of a CDR3 model of what about emotional trauma and the way in which it's sort of buried in the nervous system? And is that what is impairing the person from progressing? I'm sort of more and more convinced it's a really big deal for people, that if you're sick with this long enough, you become traumatized, or you're traumatized and then you become sick with this thing.

And so, I don't think we're paying enough attention to dealing with these issues, certainly not within the CIRS model. I think other groups have done a bit better job of saying, "Well, wait a minute, the vagal nerve, the autonomic nervous system, parasympathetic tone, a history of emotional trauma." We got to look at this stuff. We got to deal with it. We can't just ignore it. It's what keeps us in CDR, but it also is what for many people will release us out of CDR as well. That there's no special peptide, there's no special nutrient or hormone. It's just that you haven't fully dealt with your psychological landscape. Do not underestimate an injured nervous system, an injured emotional psyche in this illness.

So, Neil Nathan would say you do it up front. I'm not so sure. I think there are some people where you've got to just be a bricklayer. Let's just get the person out of exposure, passing the visual test, reduce their inflammation, get them doing better and feeling better a little bit. And then we can deal with sort of emotional issues, whether I plop that into CDR2 or even wait until CDR3. It depends how big of a problem we think the emotional landscape is. And that's kind of patient specific. But Neil is very, hey, upfront, deal with this. I'm a little more nuanced.

[1:25:02] SCOTT: He changed my perspective on that years ago as well. I used to think of it as much later. Let's address the tiger when the tiger is now a kitten, but your limbic system, nervous system is still seeing the tiger rather than the kitten and you need to recalibrate. And I think part of why he focuses on the limbic and vagal piece first is particularly in more sensitive patients where they can't even tolerate treatment, right? You give them one capsule of charcoal and they're blown out for two weeks. It seems to kind of smooth things out and maybe increase the size of the toolbox. But yeah, very, very interesting perspective there.

I want to just briefly touch on the innate and adaptive immune conversation where we, again, think of CIRS as being more ongoing activation of innate immunity without a proper adaptive immune response. How many levers do we have to calm the overactivation of the innate immune system, but to also support a proper response of the adaptive immune system? Can things like vitamin D be helpful for mitigating that potential dysregulation or lack of response on the adaptive side? Or maybe better said, how do we optimize the communication between the innate and adaptive immune system?

[1:26:18] DR. HEYMAN: It's a great question. And I think there's different ways of getting at this, of kind of measuring T cells, and B cells, and all of that. But if you think about what's the first bridge essentially between an antigen presentation and the adaptive immune response? It's T cells, T cell receptors.

And in fact, we saw this to some degree in GENIE, that in section 12, there's typically down regulation in T cell receptor function. But whether or not that actually appears in the biology of the individual, we need to do more testing. We can get very fancy in this regard. But what do I do? I look at a specific T helper cell panel, and I want to know CD3 count, CD4 counts and natural killer counts. I think that's the core of the idea of whether or not the adaptive immune system has been impaired and/or remains suppressed.

Now, do I do that up front? No. Because I think a lot of patients, if you get CDR1 right and you get CDR2 right, the adaptive immune response tends just to come back online. So where do I measure it? Well, I use it as a gating for CDR3. So, I say, "Where am I at? And did I do everything I need to do?" I kind of do a panel.

So, I get through CDR1, I get through CDR2. We do metabolic optimization. We do mitochondrial optimization, which is a world in and of itself and a really interesting one. I've spent the better part of two years actually building pretty sophisticated algorithms to look at mitochondrial testing and figure out exactly what people need to kind of stoke their mitochondria.

Then we move to CDR3, and I kind of do a check. And I do labs that sort of map to all three categories. So I'll relook at inflammatory markers like MMP-9, IL-6, the neutrophil to lymphocyte ratio, CRP, visual test. I want to get a sense of is this person still inflamed? And do I think they're still under exposure?

CDR2 will be GDF15, FGF21, my T helper panel. But then that's where I'll also look at reactivated viruses, because a lot of these viruses kind of appear as a result of the illness. But if you get other treatments right, they kind of disappear. Many of them are what are called DNA viruses. So Epstein-Barr, CMV, HHV-6. That if you get the other stuff right, the immune system tends to come back online, we'll never get rid of the presence of those viruses that are essentially what we call intercalated into our DNA. But if we strengthen our immune system, which I think is the best way to deal with these viruses, they tend to get better, whether it's Epstein-Barr early antigen or what have you.

So, what I'll do in CDR2 is I'll measure the T helper panel. I'll measure some viral load. I'll try and look at mitochondrial markers if I can get those available to me. I'm trying to map CDR2. I'll also go back if I need to and relook at metabolic markers, or I might have to redo a mitochondrial assessment to really make sure that I've cemented CDR2, which means I put all the building blocks in place. And that includes metabolism and the immune system.

CDR2 for me is what I would call clinical immunometabolism. And I'm not the first person to use that term, but I like the term. CDR3, that's safety signals. Yeah, I look at VIP and MSH, but I'll look at heart rate variability and sort of other markers of stress like cortisol. And I'll look at hormones through the lens of am I getting diurnal patterns or biological variation where we need it? Because one of the reasons why people don't heal is because the body is in that stuck state and under threat. So, one thing that the body does is it sedates a lot of these normal mechanisms or responses that are subject to what we call chronobiology.

You and I would know this in terms of what we call adrenal fatigue. But what that really means is the brain has said, "I can't take any more stress. I'm turning down the HPA axis. I'm not going to let you make cortisol anymore." So, when we see flattening of our chronobiology, we know that there's work to do to give safety signals. So, if VIP is low, MSH is low, HRV is low, flattening of signals, then I know I'm; if everything else is normal, I know I'm in CDR3. So, we need to kind of give people the support they need to move out of that.

I have most of my patients follow their heart rate variability. So, I know that from the beginning, and we watch that improve over time. But we're still left with it, then we really focus on that. Plus, we give those sorts of biological regulators like peptides such as VIP, and KPV, and whatever I can get my hands on to improve that sort of final phase and get them over the finish line.

So I’ll remap them to figure out, "Am I still stuck? Did I do all this stuff and somehow there's still CDR1 residual? Did I do my work in CDR2? Have these markers normalized? Does the immune system come back online? Is metabolism balanced?" Ideally, I can get, if I can, GDF15 and FGF21. Are those normalized? Then I know I'm in CDR3. And we do sort of that final healing and repair, and we get people kind of fully healed.

And if you think about what we've done as a process, we've got them out of exposure, balanced their metabolism, re-regulated their immune system, fixed their nutrient pools, balanced their hormones. We've done all sorts of things to re-regulate the system. Whether or not they got in there because of COVID, or emotional stress, or Lyme, or mold, if you follow the CDR model and you do it correctly, you're going to fix a lot of things along the way. And that's where I see sort of the power of this.

[1:31:42] SCOTT: I mentioned that a person as an entire organism is not in a given phase of the Cell Danger Response. That each cell, neighboring cells, they can be in different stages. So when we're looking at these tests, what does that reality mean? Is it that we're getting kind of the average of the preponderance of cells in a certain CDR stage? You mentioned certain markers where they kind of give you a little more clue for CDR1, 2, or 3. But is all of this kind of a average or dominant CDR stage for the overall patient? And then how does GENIE align with that model? Can you look at someone's GENIE and also get another lens into whether they're in CDR1, 2, or 3?

[1:32:23] DR. HEYMAN: It's a good question. And I think once you sort of map the person and we kind of take them through the process, we're gating them from one section to the next. And so there are kind of two pieces to this. One is, is gating occurring in a way where it's becoming relatively predictable? That we assess and treat, and assess and treat, and assess and treat?

And if that's happening and what I do is because I put on, again, my pointy headed academic hat. What we've done is we've tied the visual test to validated symptom scale and validated quality of life markers. So, in the research literature, these are the best ways to track whether or not a patient has improved outcomes.

If we're moving them through the CDR and they're getting better and better and better, their gates are falling, they're improving based on both self-report and objective markers, I have a good sense that we are absolutely on the right track. With that being said, when we do these measurement tools; so when we do these measurements, there is that notion from Naviaux of what's called mosaicism, and that is to say different cells in the same tissue can be in different states of CDR.

And so, is there a way to sort of acknowledge that or measure that? No. Is there a way to treat each cell differently? Of course not. No. Are the measurements that we're taking some totals? Yes, they're sort of the average of where a person is at.

And if you follow his thinking down to the cellular level, unfortunately, sometimes you can treat one cell properly because let's say it's in CDR2, but that's like the very wrong thing to do if its neighbor is in CDR1. There's no way to avoid that. So, we're still in the world of averages. We're still in the world of treating the whole person. And as long as they're progressing in the right direction overall, we say, "Okay, even against the notion of mosaicism, we're okay." And thank goodness, I think in general, in the real world, practically speaking, that's what we see. We see people progressing.

[1:34:37] SCOTT: You talk about the five danger signals as part of the new science. So, I'm wondering if you can talk a little bit about the survival threat categories and how those recruit or trigger sensors. And are these what represent the danger signals that initiate the Cell Danger Response? What are some of the triggers that impact those five danger signals? Do things like Actinobacteria, endotoxins, and beta-glucans trigger the same five sensors that mold or Lyme might? And do certain triggers potentially impact multiple sensors?

[1:35:14] DR. HEYMAN: So, there are five main sensors that we can look at. These are kind of the trigger pathways. And interestingly, they're all sort of major in terms of what they detect and how they converge basically down to the integrated stress response. If you think about it, we have these sensor systems, these special receptors. There are five pathways, essentially. And then they converge down to the integrated stress response of the mitochondria that then ATF4 sends the signal through the cell membrane to the mitochondria itself to turn on CDR. And that's where you get the extrusion of extracellular ATP. And the cell is now letting its neighbors know that it's now in CDR and it's been under stress.

Now, there are these five kinds of sensor pathways that are resident to the way in which we're always looking at or sensing for threats. TRP, prostaglandins, PTX3, CGRP, and then the PACAP VIP pathway. And so, each particular pathway tends to be attuned to different kinds of signals. But oftentimes, signals are sort of pleiotropic in and of themselves. So, they'll turn on two or three or four of these pathways simultaneously. And interestingly, they can in fact suppress at the same time.

So, if you take water damaged buildings as a model, for example, mycotoxins, lipopolysaccharides, beta-glucans, MVOCs, Actinobacteria, they'll trigger all five pathways. And they'll turn on the first four. And in fact, it's been shown to suppress PACAP and VIP at the same time. So, you get this imbalance in a sense of the five, but they're all triggered simultaneously.

It turns out that that's not unique. So chemical exposures, heavy metals, chronic stress, EMFs and radiation, chronic infections, they've all been mapped to these sensor pathways. But again, they all converge down to the integrated stress response, turning on essentially ATF4. So, it doesn't matter kind of how you get there. And even if you only turn on one of the pathways, you can still turn on CDR. You don't need all of them turned on or most of them turned on.

Interestingly, one of them is really; it's receptors that concentrate in the respiratory system, in particular TRP. And I find that fascinating because TRP is obviously part of what we're probably exposed to with breathing and mycotoxins. And what I've learned is that it's where I think inhaled VIP shines. Because if TRP is – and we can't sort of measure this, but we can sort of kind of work it out intuitively. If we think that it's a respiratory exposure activating TRP1, it's probably worth doing a nasal VIP. We now have access to a chewable VIP, which sort of bypasses TRP, but potentially gets to trigger pathways, maybe even better.

And so, I found that some patients do really well on inhaled VIP and others do really well on chewable VIP as sort of part of that safety signaling at the end. And oftentimes I'll combine it where I might do sort of the first few months of inhaled, a nasal spray, and then I'll switch to the chewable to try and hit all of the receptors, all five pathways as best as I can to kind of turn on the VIP PACAP pathway as sort of effectively as possible. To me, this is all sort of fascinating. And it matters in terms of sort of a clinical outcome.

[1:39:02] SCOTT: So let me see if I kind of have the idea here. So, we have this integrated stress response that triggers ATF4. We then have GDF15, FGF21 as indicators of a non-terminating integrated stress response, that that integrated stress response is ongoing. So then tie in for us the GADD34 to turn off those danger signals. How is GADD34 the brake? And how does that break potentially fail leading to that chronic activation of the integrated stress response and thus negatively impacting our health longer term?

[1:39:40] DR. HEYMAN: Great question. So GADD34 is part of the mechanism by which the non-resetting – I haven't mentioned this, but there's sort of the whole pathway starts with what's called eIF2α and ends with ATF4. And what's the brake on of the integrated stress response or how do we remove the danger signal? It's an enzyme called GADD34.

And so, what are some ways in which we can deal with GADD34? Well, it turns out that there is, as I've been looking into it, a variety of natural compounds that we can reach for. Interestingly, and I find this fascinating, potentially GLP-1s don't work directly, but they have sort of a global mechanism, which we think kind of reaches that GADD34.

And so, what are people doing with GLP-1s? Well, there's a small body of literature, admittedly so, but interestingly, and I think I mentioned before, I think GLP-1s play a really important role potentially in some people, microdosing GLP-1s for mast cell activation. And that by microdosing GLP-1s, we help sedate mast cell activity.

Well, it turns out that GLP-1s seem to also support GADD34. And what we want is to dephosphorylate or to take off a phosphate group from eIF2α so we kind of turn off the integrated stress response. Well, it turns out VIP does that as well as bioflavonoids. And these are the pigments in plants. So quercetin, bromelain, any sort of antioxidant. And there's also some kind of "anti-aging compounds" that are also strong antioxidants like genistein and others that I've identified in the literature that support GADD34.

And what we're trying to do is send the signal that is saying, "Hey, you're safe again. You don't need to be in this sort of upregulated state." And so, if you're convinced clinically that you've done your due diligence in CDR1, you've extinguished the fire, you've removed the triggers, you're out of that exposure idea, the fire's not burning down the house anymore, but we see perpetuation of sort of that stress mitochondrial state, I think it's worth trying microdosing GLPs or doing some of these other things.

In fact, think about it, in the classic; and this might blow your mind. But in the classic sort of CIRS model, what do we do up front for patients that are so hypersensitive that they can't start binder therapy? Low-dose VIP. And where do we think that's working? Well, it turns out potentially it's sedating mast cells, but it's also likely working at that level of GADD34. And so, it's offloading that stress response so the person's not so reactive, so they can absorb those initial treatments that we want to get them going on, like binders, for example. And so, I think these ideas are starting to converge in ways which are finally beginning to make sense.

[1:42:54] SCOTT: So, at a high level then, your approach to treatment is to remove the triggers, quiet the alarms, and send safety signals, a term I first heard about from Dr. Izabella Wentz. You discussed putting out the fire in CDR1, rebuilding in CDR2, and then moving back in as part of CDR3. So, let's talk about each of those stages.

First, can you give us an idea of the approximate duration or amount of time that a patient going through your three stages, five phases, CDR1, 2, and 3 treatment process, how long might that take for someone to more fully recover with the model that you're currently using clinically?

[1:43:34] DR. HEYMAN: So, I would say that the average inside CDR1, because it depends on dealing with your environment to some degree. And the home is sort of, I think, the longest issue because there's a lot to coordinate if the home is the cause. Getting the right assessment, getting a person in to do any sort of remediation and then effective small particle cleaning.

In terms of kind of the other things where it has to do with removing other triggers, whether it's chemicals, or minerals, or even pathogens, or microbiome stuff, that goes faster. Unless there's true Lyme. So Lyme is its own separate category. But in general, elements of CDR1 go fast as long as you've dealt with the home. The home is, I think, what kind of prolongs it the most in terms of getting out of exposure and turning off the main elements of the fire.

So, let's call it average of six months at least of sort of doing all of that, which is dealing with the home, taking a binder, passing the visual test, detoxifying, dealing with pathogens, gut related issues, food testing, gut testing, microbiome testing, all of the rest. Six months plus.

CDR2 is interesting because if you think about what those layers are, it's assessing for metabolism and also mitochondrial function. We haven't talked too much about the mitochondrial function piece. I mentioned seahorse and citrate synthase, but all of that can be done relatively expeditiously and a plan in place with respect to targeted nutrient repletion, hormonal therapy, peptides, or other targeted compounds to restore normal mitochondrial function. That can go pretty quickly, two or three months, just to kind of get them going. It doesn't mean you're done with all that, but at least it gets them going in terms of balancing their sort of metabolic and mitochondrial state.

If you do all of that right and now, you're in CDR3, then that's another kind of prolonged state. If you just take VIP; and I know we've talked about other things in CDR3. But if you just take VIP, my recommendation to patients is you're going to be on VIP for minimum six months and on average somewhere between 6 and 12 if we get it right. But that doesn't necessarily include maybe some other supportive treatments, whether those are nutrients, or peptides, or other factors that the person might need to fully resolve paralleled with dealing with some of the residual emotional issues. So that's when we really go after heart rate variability training, measuring vagal tone, using vagal nerve stimulators, or getting into kind of issues, emotional trauma, whatever it is. That's another 6 to 12 months.

So we're talking full recovery a couple of years at least. But the good news is most people are feeling pretty good relatively early in the process if we get everything right. Doesn't mean you're done. But it means you're on the journey. And by that time, people are really bought into the process. And they feel that this is a way of being very complete with an approach to a person's health.

And I think that's the secret to this, that if you go back to our original comments on load and resiliency, you have to go through all these things to rebuild the person up and to gain their health back, that it's not as easy as just taking a few nutrients or a few medications, and now all of a sudden everything's fixed. If you were sick and in this category, it means that you've had too much load, not enough resiliency, and that usually means your health has been pretty compromised to one degree or another.

So, if you're in CDR, it's trauma-based. We take it seriously. We take it a step at a time and we rebuild you. But it's going to take some time. Anybody who promises a quick fix, they're selling snake oil. It just doesn't happen that way. Our bodies are not built that way. We know that if you look at the molecular biology of Naviaux, each step is gated in a very specific way. It takes time.

So, I tell people this is a marathon. It's not a sprint. And you better have some grit. Because there are going to be moments where you kind of question, "Why am I doing this? What am I doing?" It's a long-term process. But if you ask patients who fully recovered, when they come out the other side, what was the thing that really got you through? What was the thing that you needed to really embrace? And it's that spirit of persistence, that spirit of I'm not giving up. Those are the ones that come out the other side. And they sort of fight and claw their way forward and figure out ways to sort of change their environment, change their mental health, change their biology. And we reset the system so they have more resiliency.

[1:48:12] SCOTT: I think for many of us, the message of these illnesses is about prioritizing ourselves and taking better care of ourselves and regaining health and retaining health, at least from my lens, is a lifelong process. It's not like, "Oh, I'm done and now I'm going to go back to all the things I did before and expect to get a different result." Right? This is going to be a lifelong process.

So, let's talk more about CDR1, which is putting out the fire. You have three phases of treatment that are part of this CDR1 stage. So, when someone's in CDR1 or the midst of the fire, you see VCS test failures, high MMP9, high hsCRP, or IL-6. You have that activation or inflammatory state of the macrophages, that innate immune system activation. That chronic innate immune activation can lead to injuries of the brain, the heart, the gut, and other tissues.

And as part of your approach to treatment in CDR1, the three phases that you've documented in your recent publication, which I'll put in the show notes. Fantastic read. I suggest people take a look at that. Phase one is brain health and trigger removal. Phase two is pathogen reduction. And phase three is gastrointestinal health and antigenic load reduction. You also refer to these as silencing the alarm, clearing hidden infections and healing the gut and rebuilding nutrition.

In that CDR model, we have to have some type of threat, or inciting, or initiating event, or events, or trigger, or triggers that push us into that Cell Danger Response. So, I'm wondering if we can differentiate at all, maybe the more common threats that trigger Cell Danger Response versus other things that maybe we have to address. They're not the original triggers. I'm going to call them persistence factors. So, if I think about things like mold and COVID or spike proteins, Lyme, co-infections, I think endotoxins in some scenarios, depending on the exposure, I think of those more as inciting or initiating events or triggers. Certainly, you mentioned a TBI could be one as well. Are there other common triggers of those five sensors?

And then are there some things that are more persistence factors, like maybe Actinobacteria, maybe a toxic terrain, maybe heavy metals or chemicals, maybe EMFs, maybe viruses. How do you separate those initiating events or inciting events from those that continue to weigh down the system and drive persistence of the Cell Danger Response?

[1:50:51] DR. HEYMAN: It's a great question. And sort of any of the ones that you mentioned as persisters could also potentially be inciters, if we want to kind of use that language. What I would say is that this just gets into listening to the patient's story. And there's usually sort of two narratives. One is the slow and steady trickle of decline where they're not really sure kind of when it started or where it started. And those are the ones that are kind of harder to unpack because now all bets are off in terms of what this could be. On the other hand, sometimes people kind of point to a year or a month or a move where they say, "This is when it began."

What's interesting to me though, is that if we if we talk about what are the most common things at least from what I've seen, one of the more common narratives is – and it's not the only one, but I'm fascinated by this, is if you really listen carefully to patients, they'll often say that there was a stressful time in their lives that predated when they started getting sick from their home, for example. And usually that's by one or two years. That it was a divorce, or a loss of a loved one, or some kind of event that really destabilized the person emotionally.

And at some point, after that, we see activation of the innate immune system and that kind of ongoing decline where they realize that their health is fundamentally changed and they start looking for a more molecular biological cause, not realizing that maybe that stressful time was a primer.

And again, I think about primers, kind of what was the thing that got that person in trouble. Now, sometimes like me, for example, I got a tick bite and it sort of initiated all of that. But remember, I mean, I was in medical school. I was under a lot of stress. I was a bit older. I didn't go to medical school right away. I felt like that was a bit of a disadvantage energy wise to some degree. I also couldn't totally relate to my classmates because I had already been out in the world and had my own life and lived experience and had been a practitioner for 10 years in my own right. So, there were some stressors that were happening kind of around the Lyme bite. But remember, it took almost 10 years for me to feel really sick.

So, the common things for me are stress, environmental exposure, to some degree tick bites. But honestly, I think as a community, we tend to overread tick bites and we over-read Lyme. I think there's too much kind of false positives out there with testing. And people kind of chase those bugs and chase and chase and chase. And sometimes I'm not convinced that they're really there, really present.

A lot of the testing is not great. And maybe it's becoming more reliable. But having a clinic in Virginia, which was literally ground zero for Lyme disease, and I certainly immersed myself in that world completely and totally, it's a murky world in particular to see if those are present. But they can be, and I think they're real. But sometimes they're hard to find.

In addition to other exposures, I don't think metals or chemicals often trigger it per se unless it's a major exposure. I mean, I do have a patient, for example, who, by virtue of her work, she was in and out of chemically contaminated environments. I think at some point it does reach a level. But for the average everyday person, unless you're like a pesticide applicator, I think that's background noise. I think that's part of the persistence, metals and chemicals. They don't kind of tip the edge.

In addition to that, I don't think food on its own does it, but that's a persister because it creates that internal damage. And then not just as a primer, but kind of stress in general is a big trigger for people. And I think, again, we don't sort of fully embrace that.

The other model that I think there is some validity to this, and maybe it's kind of just this narrow view into what can be chronic, which is essentially overtraining syndrome. That if you're a high-level athlete and you've pushed yourself too far, what happens? People flip into inflammatory chemistry. And we see the same kind of hormonal abnormalities, the same kind of a sickness syndrome with a pro-inflammatory state. But oftentimes with a bit of rest and recovery and repair, people can get out of that.

But it's interesting that the molecular profile is pretty similar, but not necessarily permanent, unless you're an endurance athlete. And we know that people can have sort of prolonged impairment with that post-exertional malaise, for example, and actually aerobic glycolysis when you do cardiopulmonary testing and elite athletes that have just trained too much for too long. But we see it more in endurance athletes. But it is interesting to me that when we push ourselves too much too long even if you're not an endurance athlete, that alone, sort of just the challenges of life, and getting through, and making a living, and trying to be the best person you can. There is something about the effort itself that I think can kind of predispose people, that in today's world we all feel like we have to work really hard to maintain a status quo, that life is not easy. And there's something about that background noise that I think also sets people up for flipping over. I think those are kind of the big ones.

And then metals, chemicals, reactivated viruses, that's all noise in the background that can be dealt with over time. And I do that. I mean, I like to give phospholipids and other things that are kind of drainage. And we start pulling out some of those compounds in the background. But the big ones are I think our environment, stress, certain kinds of infections, those sorts of things.

[1:56:43] SCOTT: So phase one, which is trigger removal or silencing the alarm, is about removing those ongoing environmental chemical triggers, clearing biotoxins, supporting liver and bile, the whole drainage piece, and reducing neuroinflammation. So here you're removing the external exposure from the patient or removing the patient from the exposure. What do you see being done right versus being done wrong when it comes to environmental testing and mitigation or remediation? How helpful is air sampling? I still am shocked when I talk to people that that's all they did and what we're relying on. How helpful is ERMI, HERTSMI-2? How important is small particulate cleaning as part of every proper remediation? Can fogging without source removal resolve these environmental triggers that are driving CDR1? And can most people in your experience fix or improve their current environment? Or are there a subset of your patients that need to find a new one?

[1:57:45] DR. HEYMAN: All good questions. And so the asterisk, of course, is that I'm not an IEP. So, I don't want to talk out of turn in terms of the what to do. But here's my perspective in general. If we are reacting to our environment, our lived space, there are two issues that are going on simultaneously. Number one, I think the big mistake is that we believe that our environment, a healthy environment, is a sterile environment. It never is.

And there is a natural microbiome that exists in our living space as much as inside of us or outside in the soil, for example. And I think a better model a better language instead of thinking kind of sterile not sterile is loss of immune tolerance, that we have become compromised in terms of our interaction with the microbial world. And that means externally and internally.

And I'll paint a picture for you that I think really highlights that. There's a series of very interesting research studies that came out of Italy, and their challenge was how do we prevent communicable diseases in hospital settings? They realized that what they call CC or chemical cleaning, the kind of standard approach that you would see in any hospital around the world, wasn't working. And even when it was "done right' with the normal solutions, they still saw patients that were getting sick.

So, what did they do instead? They said, "Well, if sterility is not necessarily the goal, and we assume that there's a natural healthy microbiome that we can live in and be surrounded by, what do we do about that?" And so they developed a model where they actually aerosolized healthy bacteria that they knew would necessarily compete with the presence of pathogens, viruses, other bacteria that were accumulating on surfaces or being inhaled or breathed as part of the local air environment. And what do they find? They found just that, that the bacteria that they aerosolized started to compete with resources and outcompete, so that they saw a natural decline in viruses and bacteria that were making people further sick in the hospital.

And in fact, they were seeing reduced rates of communicable diseases in the hospital or what they call hospital acquired infections or HAIs. And so they went from kind of single hospital studies to multi-hospital studies. And now you find on the market companies that you can buy or purchase for your home these aerosolizers for different kinds of bacteria.

And I think the jury's still out about sort of what's the optimal mix of those sorts of things, but it really to me kind of highlighted this notion that whether or not you do perfect remediation or "small particle cleaning", your home is never sterile. And therefore, it's the wrong model of clean not clean, HERTSMI level, ERMI level, that there is something about both the microbes that are present that can protect your health, but also your resiliency and/or your loss of tolerance. That two things have to happen simultaneously. One, yes, you measure the home and you try and get it clean. But also, you need to be building your resiliency along the way. And so you're less reactive, that you're building your microbiome tolerance in a sense.

And through these mechanisms of kind of offloading other triggers, improving immune response, helping to detoxify, balancing the mitochondria and getting you out of that stress mode, those are all the mechanisms by which you build that resiliency. But I do think we have it wrong on the building side. And this notion of buying filters and small particle cleaning and that in our heads, we go from a high HERTSMI to a low HERTSMI. And therefore, we're going from less sterile to more sterile. That's wrong as a model.

And I would love to see the industry shift and ask a different set of questions about what microbes should be present? In what amounts? How do they crowd out bad actors? And how do we replace those in a healthy way? What should we measure both in terms of positive and negative microbial exposure in our environment? One day we're going to get there. But I don't think we're there yet. I think we're still stuck in that sterile, not sterile model. And that's where I see the greatest deficiencies.

Now, you can get into the technicalities about, yes, air sampling is less accurate in a sense than surface sampling and dust sampling. But I think it all matters. I think we should measure air. I think we should measure surfaces. I think we should measure VOCs. And we just see what's present.

The other piece that I think we've kind of gotten wrong, and this gets into sort of my relationship with my very dear friend, Marilee, who founded Branch Basics, and the notion that the other side of the exposure coin in our home are chemicals. I don't think we talk enough about the presence of noxious chemicals in the home that are usually cleaning agents and other things that are under the kitchen sink or in the bathroom or wherever. And how do we remove those chemicals effectively and live in a healthier environment that's more chemical-free and microbial balance that supports people's health? That's the direction that I think we need to be going.

So, one of the things I do with my patients is I recommend Branch Basics, a free course called Toss the Toxins. And it teaches people how to remove chemicals from their home. I think that's the other flame that we're missing that we just can't say it's all biotoxin. We can't say it's just all microbes. That we also need to pay equal attention to our chemical exposure in the home. If you do both of those, I think you'll go further faster.

The third big category which I wish I knew more about but I think nobody knows a lot are EMFs, and the notion that we're now living in an electro smog. And I think that's probably contributing to all of this too, but that's the murkiest of the three in terms of what should we do about it. But I do think those are the big three. We tend to focus on one. I think the model is wrong in terms of sterility, but we should also at least be focusing on the chemical side of the equation too.

[2:03:49] SCOTT: So, let's talk then a little bit about binders. You use Cholestyramine and Colesevelam, or Welchol. You talk about okra beets. But interestingly, you also talk about activated charcoal and bentonite. And you have a formula, I believe, called EnviroBind as well. Some practitioners suggest that natural binders have limited or no value. Others use them heavily or even exclusively. So, I'm wondering if you can talk a little bit about your thoughts on binders and maybe the potential that natural binders have properties that are beneficial beyond just the focus on charge-based binding alone.

[2:04:28] DR. HEYMAN: Yeah, great question. So again, I'm a bit of a lumper. I'm not a splitter. And also remember, you scratch my surface. And yes, sort of maybe to the outside world, MD, appointment at George Washington University, academic research. I'd like to be as thoughtful as possible as I approach these things. But underneath of that, remember, I'm integrative, I'm anti-aging, I like the natural stuff. That's sort of a home base for me. And it has been for many, many, many years, actually long before I got into the mold and Lyme area.

And so, I was using clay and charcoal and zeolite for all sorts of reasons, quite frankly, long before I started prescribing Colesevelam or Cholestyramine. And what I learned, I think, were a couple of things. Number one, those bile acid sequestrants, the prescription agents like Welchol and cholestyramine, Colesevelam, they absolutely are effective in binding inflammatory compounds, probably binding some mycotoxins and reducing that inflammatory load and getting people to pass the visual test. There is no doubt in my mind that in the right selected patient they can be incredibly effective. And I've seen in many ways sort of more effective than just doing the natural binder route.

With that being said, as I mentioned before, once the person's passing the visual test, I think it's okay at that point if they've cleaned up their diet, they're let's say on a low mold diet, they clean up their home. So, the urine hopefully is just showing you what's resident in the tissues.

And then adding in some of those compounds such as charcoal and clay and chlorella, that might be good at pulling out other mycotoxins. And as you know, I like phospholipids. I like to do glutathione support, all of which is part of that idea of kind of stripping out that residual mycotoxin load. So, I go from sort of a Shoemaker model, if you will, to a Neil Nathan model.

And I'm open to all of it because I think that there is some benefit to the notion of are you still carrying a toxic load even after you pass your visual test? So in the background, I'm kind of doing this long, slow detox using lipids and bile support and other agents to pull out chemicals and metals and mycotoxins even though that first layer feels very CIRS-y in terms of Colesevelam or Cholestyramine, which is, I think, perfectly reasonable.

I also think if practitioners aren't using them or don't know how to use them, they should. But conversely, I do think there's a role for kind of that longer, deeper detox that embraces not just Neil Nathan, but the CDR model, to say, as you would say, there's sort of these modifiers or persister compounds that just sort of make things worse because we all carry a burden of chemicals. We all carry a burden of heavy metals. You need to know what you're doing with those. It's easier to get rid of chemicals than heavy metals. If you want to do a true heavy metal detox, you really basically need a prescription chelating agent. My preferred one is DMSA. And I'll usually pulse it every Saturday and Sunday because it's a broad-spectrum chelator to get out mercury, and lead, and cadmium, and arsenic, and the rest of the bad actors. But people can benefit from that. That's sort of where I am with binders.

Charcoal is a nice broad detoxifier for the gut. I don't think it's nearly as strong or specific as a Colesevelam or Cholestyramine when it comes to mycotoxins. But I think it's pretty good in general. And as long as a person's progressed past the visual test, I think that's the right place for a product like ours like EnviroBind to continue to pull out some of these residual compounds.

[2:08:07] SCOTT: That's part one of my interview with Dr. Andrew Heyman. Don't miss part two of our discussion in episode 240, where we continue our discussion on CDR1 and then get into CDR2, and CDR3, and more on Dr. Heyman's five-phase treatment model. You won't want to miss it.

[2:08:28] ANNOUNCER: Thank you for listening to today's episode of the BetterHealthGuy podcast. You can learn more about today's guest, including relevant links and resources in the show notes. This podcast may provide community discounts and occasionally share links from affiliate partners. You can find this and other episodes on YouTube, Spotify, Apple Podcasts, Amazon Music, iHeart, and more. To learn more about Scott's personal journey to better health, visit BetterHealthGuy.com. Join us next time on the BetterHealthGuy podcast.

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