Cell Danger Response – The Cause Your Doctor Doesn’t Know About

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Content By: Ari Whitten, Eric Gordon, MD, Robert Naviaux, MD, and Dr. Eric Balcavage

In this episode of The Energy Blueprint, we’re revisiting episodes featuring three experts in the world of mitochondrial research and the cell danger response, i.e., your body’s intelligent but double-edged response to stress or injury—Dr. Eric Balcavage, Dr. Robert Naviaux, the originator of the cell danger response hypothesis, and Dr. Eric Gordon.

The Cell Danger response is a fascinating model that helps us better understand why chronic illness persists in some people and how we can best address the underlying causes. 

If you’ve been living with persistent symptoms that nothing will touch, please listen to this episode for new ideas on what might be happening and how to return to everyday life, disease and symptom-free.

Table of Contents

In this podcast, you’ll learn:

  • Why your innate intelligence activates the cell danger response and actually decreases energy-producing mitochondria when your body senses a threat
  • 3 key factors you should be aware of before you get mitochondrial tests or take mitochondrial supplements
  • Dr. Balcavage’s powerful message about health: poor health isn’t necessarily your fault, but it is your responsibility 
  • The exact steps you can take (starting today, no matter your fitness level) to get your body unstuck and out of danger mode 
  • The fascinating two-sided physiology that keeps you fit and healthy but can also make you incredibly ill
  • Why Dr. Naviaux believes it’s time to adopt a new medical paradigm to address illnesses like chronic fatigue, Lyme, long COVID, and other chronic diseases
  • The 3 stages of the cell danger response and why getting stuck in any stage can be detrimental to your health

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Dr. Eric Gordon - Transcript

The Cell Danger Response

Dr. Gordon: I really want to get to the CDR for a reason [crosstalk]-

Ari: Let’s get there right now.

Dr. Gordon: -is because it ties in what we’re talking about. Just let me just a little– My main point is the cell danger response is something that Dr. Naviaux who gave it its name. I don’t think he loves it anymore but he’s stuck with it. The first thing people have to understand about it is it’s just a story. It’s a framework for understanding how our body works. The reason I emphasize that I’ve spoken about this in medical symposium here and there at meetings. People come up to me and ask me and ask afterwards, “Is this the CDR?”

When they’re having a patient and it’s like I guess I’m not very good at explaining it. The point is the cell danger response is the immune response that’s choreographed by your mitochondria. That’s how you defend yourself against all threat. It doesn’t matter if it’s an angry neighbor or if it’s a bullet or a bug. This is just your body orchestrates a response and Dr. Naviaux has called back to cell danger response and he has stuck the mitochondria in the middle of it.

I always want to remind my people is that I’m sure that other smart people will find other organelles that they can say this one is in the middle of it. I happen to find his way of looking at very helpful because it’s the old story who’s the most essential organ, the brain or the rectum? If the rectum stops working, the brain does too, so it’s a circle. We need it all. Still, the mitochondria produces energy but it also senses the electron flow and the raw material flow in the cell. By sensing it decides when things are safe and when things are not safe it signals the whole body.

It’s just that when you start looking at the body as a system as a network of information and flow. When somebody tells you you have long COVID or when somebody tells you you’ve got chronic Lyme or you have mast cell disease or you’ve got whatever the flavor or parasite, whatever the flavor of the month of the year is, because these things wax and wane. When I started everything was Candida and then it was all parasites and then it was all Lyme and then it was all Bartonella and then Babesia or Babesia and Bartonella, I forget where it’s in.

Then it was all hypercoagulability and mast cells and mold, I mean it’s everything. It just depends on your sensitivity and your exposure. So don’t get hung up and don’t look at lists of symptoms on the internet and decide you’ve got Bartonella, because as I say, one man’s Bartonella list is another man’s Babesia list.

Dr. Gordon: Anyway. Beginning to understand that when you’re chronically ill, okay and I guess people should include in chronically ill things that we consider– Well, they are chronic illness, but people sometimes forget that when you’re chronically ill, you’re chronically inflamed, I guess that’s my point. Chronic illness is chronic inflammation. What people don’t get is that it also includes, like insulin resistance is chronic inflammation, hypertension is chronic inflammation, renal disease is chronic inflammation. It’s just what happens when your body tries to protect itself and then can’t stop.

I always compare this to psychology, because again, psychology is just a more alive model. Chinese medicine is actually a much more alive model than our current medical model, because it’s alive, it understands balance. Medicine tends to do black and white. So when your mitochondria sense something is off, they go through a pattern. Now, they go through a similar pattern every night or every day in something we’ve called a health cycle where you break down some tissue, you build up.

Your mitochondria aren’t signaling that this cell is sick or that the mitochondria will break apart and will then decide if they’re going to survive. If they decide to die, the cell decides to die. It’s good you repair it, but the repair mechanism is minor. What we call the healing cycle is when you need the contractor. The health cycle is what you do every day. You can fix the hole in the wall with a nail hole or something, maybe you can. [laughs] I used to be able to. The constant daily repair that we go through is the health cycle, but when we get injured, we go into the healing cycle, and that where people get stuck.

I guess I’m landing a good point is that that leads to chronic inflammation because your mitochondria gets stuck either in the first step where they’re not really producing energy at all, they’re just producing ATP as a signaling molecule. Your cells are burning glucose at that point. That’s why a lot of people who are really sick feel better when they eat sugar or simple carbs because that’s what they’re burning. In order to really burn fat your mitochondria have to be working.

If your mitochondria are ground out, they’re busy making a little bit of ATP, but they’re using that as a signaling molecule rather than as an energy production molecule, you’re going to be tired because that’s the first– That’s what Dr. Naviaux used to call, I still like it, the CDR1, the first step. That’s the first step in injury. You get cut, you get local infection, you call in your innate immune systems, but the cells are busy killing a bug that’s in the inside or binding up a toxin. When they’re doing that, they’re not busy making more of themselves.

The mitochondria stop making energy, which creates high oxygen tension inside the cell. That’s another little detail, I don’t [unintelligible 00:49:44] is that the mitochondria are the part of your cell that uses oxygen because not much else in the body really uses the oxygen in any significant level, okay? The mitochondria use oxygen and make water out of it. They add hydrogen and they make water when they finish making ATP or just before they finished the last step. When they stop doing that, the oxygen concentration inside the cell rises, which creates oxidative stress Which is what your body’s using.

Dr. Naviaux likes to call that oxidative shielding because that’s the first step in killing those viruses. This is a self-protective mechanism, but if you don’t shut that down within a day or two or three, then you’ve got chronic oxidative stress going on in your body. You have other mechanisms to create plenty of oxidative stress. It’s not the only one, but this turns it on. When it should happen, is that then the nucleus seeing the higher oxidative stress starts pouring out chemicals that are antioxidants. That’s probably one of the reasons a lot of the herbs, which many of them are pro-oxidants.

Many things like artemisinin, many of them are prooxidants, but they work because they stimulate the antioxidant response of the body. You have this. That’s CDR1, which usually should be short-lived. This is chronic and this is also where you’re innate immune system, the neutrophils, and the macrophages are coming in. That’s that first, like, thinking of COVID again. That should be happening in the first week of COVID. Unfortunately, COVID is smart enough to screw up that system in the beginning and get it to be out of balance.

Oops, let me not go there. I’m sorry. I interviewed Dr. Bredesen and I was so impressed with a man who can keep everything in a very orderly fashion. [laughs] My brain doesn’t work that way, so I apologize to the audience. Anyway, just to be clear, CDR1 is this inflammatory time. During this time, you’re going to have what we call sickness behavior. Sickness behavior is you’re tired, you’re irritable, you don’t want to eat, you want to be left alone. You often have a low-grade fever, because it’s self-protective.

If you live with a bunch of people and you’re getting sick and you’re going to be hanging out and spewing all around them, it’s not healthy. It’s not about masks, but we do spread respiratory pathogens by breathing and talking. Anyway, that’s the CDR1. The CDR2 is when you’re starting to heal. Okay. Now you have to rebuild some of that damaged tissue. At this point, the mitochondria, what’s interesting, they’re still not making a lot of ATP, but they’re making a bunch more. They’re using a lot of their energy to produce building blocks for the cell.

Things that will make RNA and DNA, the building blocks. Your cells are still burning sugar. Again, this is a level that we often see in people with hypertension or stuck here people with insulin resistance, they often have places in their body. That’s the other thing that I want to emphasize is the CDR is a local phenomenon. It’s rarely happening throughout your whole body at the same time. Usually, it’s wherever there is the insult, if it’s the whole body, people usually die. It’s called sepsis, all the organs are screwed up.

Ari: Maybe there’s some in-between territory. Because let’s say you have a local injury to a specific part of your body, then you have a local CDR reaction, but you don’t necessarily get systemic symptoms from that. Part of the CDR as I understand is the systemic level signaling of pure energic molecules. Some of these energy molecules that are circulating, that are causing systemic symptoms, whether those symptoms might be present in the case of autism or in the case of chronic fatigue syndrome.

Dr. Gordon: Absolutely. Yes. It’s the signaling that becomes systemic.

Ari: Yes.

Dr. Gordon: You can have 5 or 10% of your liver is inflamed, that’s what we often see. People with cirrhosis, they have little patches to start with because there’s only some cells that are stuck in that CDR2 place where they’re building tissue and they’re not really communicating well with these tissues around them. They release chemicals. That’s the whole thing about senescence. Maybe is the senescent signaling molecules that these cells that are stuck in various places in your body in CDR1, CDR2, or even CDR3, and let me just run through those real quick.

Ari: Please.

Dr. Gordon: The details of CDR, it’s just the idea that there are stages. One is this acute inflammatory stage, two is this rebuilding stage. The reason I’m emphasizing the glucose metabolism is because this is like cancer cells. When cells become cancerous, they’re using what we call Warburg metabolism, which people thought was causing cancer. No. It’s what the mitochondria do when you’re having cells that are rapidly reproducing. [chuckles] They’re busy making the building blocks, and the cells using glucose to make energy.

The mitochondria are not using up as much oxygen. They always thought that the mitochondria was disordered. I guess that’s one of the important pieces of this long story is that in, except for maybe I think there’s 400 known mitochondrial diseases, which are all extremely rare, [chuckles] and most people who have them die when they’re young. The vast majority of people have normal mitochondria. Again, we are now going to the molecular level, so people are doing mitochondrial genomics on people who are mild.

Yes. You can find that there’s this SNP for the first cytochrome. That’s a big one. People are finding the first complex one in the electron transport chain. You can have some SNP so you don’t bind NAD that well. That alone does not make you sick. When you’re sick, that can make it worse. It’s cool to find out that, it’s because sometimes those people do respond to a little more NAD, which is cool. The point is, is that you’re not sick because of that SNP, [chuckles] we just happen to find it because we were looking for it.

Anyway, so that’s CDR 2 is this building, and that’s where stem cells are being called in, and all kinds of good things are happening. CDR 3 is when these newly built cells are learning to communicate with their neighbors. That’s when there’s cell receptors because remember in CDR 1, one of the first things that happens is the cell membrane hardens. You’ve got all those nice lipids with proteins in between them and those proteins change shape, and the lipids change of configuration. The cell membrane itself becomes less permeable, and it also stops taking in the signals.

This goes into, my basic thing about how to help people get well is you have to restore communication throughout the system. CDR 3 is about that in a big way because that’s when the cell is learning that, “Hey, I’m a liver cell and I have to communicate with these guys around me, and I have to send out the right signals to the rest of the body. I’m now going to start listening to the thyroid hormones, and the adrenal hormones and all that soup of information the cell is going to start listening to.

What you have when you have senescent cells, and they’re not listening to the information as clearly, and they’re sending out old signals. Or they’re sending out signals that would be appropriate if you’re trying to still fight something. Unfortunately, when we keep doing that, as we get older, we get creakier. [crosstalk]

Ari: In that way of speaking there, you’re likening senescent cells to being stuck in CDR in the CDR.

Dr. Gordon: Exactly. One, two, or three. Doesn’t matter which one, they’re senescent cells because they’re releasing proteins and exosomes. Exosomes, not just the mRNA vaccine, but exosomes are one of the major ways that we’re just discovering that your body communicates. They’re little lipids with proteins stuck in the middle. When your cell gets sick, it starts spewing out these exosomes as communication molecules, and it keeps doing it. It’s just one of the way we communicate that they’re just beginning to get.

20 years ago, people thought exosomes were cellular debris or were just nothing. They didn’t know what they were. Welcome to junk DNA. Oops. There’s very little junk in the system. [laughs] We just don’t understand it. Anyway, so when a cell is not operating back to the mature interactive cell in the community, when it’s stuck in any phase of this self-protective response, it is sending out dangerous signals to the body. Now again, a bit more– Luckily, we are in an incredibly redundant system because every time you read about what’s wrong with the body, and you start going deep because you think, “Oh, my god, I’m going to die because I got this or I got that, and somehow we managed to keep going. [chuckles] Your C-reactive protein is six, “Oh, my god, you’re going to have a heart attack tomorrow.” No, no. I know plenty of people in their 80s with CRPs that are high and they survive.

We get too hung up on these numbers like they’re the only signals we know how to read so far but they’re signals out of billions of signals. We have to remember that. People get really scared when they get an abnormal blood test. Sometimes you should, sometimes it is bad but lots of times, it’s just, “Yes, we should do something, but you’re not going to die from it.” The system is incredibly redundant and resilient.

That’s CDR1, 2, 3. I know you’re wanting to make another point so I’ll shut up.

The benefits of the Cell Danger Response

Ari: Let me ask you this. The CDR, it’s worth saying, is performing a positive role as well in facilitating our survival in response to stress, in response to cellular damage, cellular threats, danger. It is an intelligent, adaptive response to respond to things that threaten us. Now–

Dr. Gordon: I think what I want to make is that it’s just how your body communicates. See, that’s what’s so funny is because he’s identified the CDR is, like I said, when something’s really broken but you’re using that same system and at gentler level every day. Everytime you go to sleep, your body is going through these healing cycles. That was my clumsy analogy about fixing something simple at home. That’s what you’re doing every day.

Ari: During hormetic stress as well, and during exercise, during cold exposure, during heat exposure, during breath holding practices, we are engaging it. We are essentially training it and, I would say, resetting the system. I think, Dr. Naviaux, I’ve spoken to him in person, I had the privilege a few years back of going to his lab for mitochondrial medicine at the University of California, San Diego, having a little private session with him and I spoke to him about hormetic stress. He hasn’t said much about it publicly, but he lit up when I started speaking to him about that because he knew it’s like pressing the reset button on the system.

Dr. Gordon: It’s training. It’s training your system. I’m sorry. It’s just that– Yes, Bob lights up. That’s what makes him funny. You give him an idea and [onomatopoeia].

Ari: [chuckles]

Dr. Gordon: That’s it. It’s because we need to keep in training and that’s why when you’re a couch potato, and you get hurt, it’s so– It hurts because the system is creaky. It hasn’t been practiced. You need to keep it going. It’s a system. That’s why, I think, I’m so glad that you emphasize that, that this is nothing wrong, nothing broken. It’s how your body works. The problem is when the signal isn’t modulated correctly and that’s because some other thing is- you’re either lacking in nutrients, maybe an immune cell has gotten out of whack.

Ari: That’s the question I wanted to segue into is the system can get stuck. We’re supposed to be able to oscillate between going into the CDR when we need it, and then coming out of it and restoring, as Dr. Naviaux calls it, peacetime metabolism. Mitochondria are now shifting into, I call it, energy mode. They’re pumping out lots of energy and we’re no longer in wartime metabolism trying to defend against threats. The problem is sometimes the CDR can get stuck in wartime metabolism. Explain why that is. You would do a lot of work on chronic Lyme disease, long COVID is a big focus of yours now and you just did a summit on that. I don’t know when it’s coming out. When is your stuff coming out?

Dr. Gordon: Oh, next week, February 7th.

The link between mitochondrial dysfunction and chronic illness

Ari: Okay, awesome. We’ll get this podcast out right away then. Obviously, I think this aspect that we’re talking about here as far as the CDR getting stuck, the body getting stuck, the mitochondria getting stuck in wartime metabolism is a big part of these chronic illnesses. What is happening there in terms of your paradigm?

Dr. Gordon: Is that since this is a communication system, and I’m sure there are multiple levels of it, but simplistically in my head, I usually focus on the immune system. Immune cells, by the way, also, their mitochondria change just the same way as an aside but I won’t say more about that. I look at the immune system because it’s like you look at– Well, long Covid is a great example, is that who got really sick, who died, and who got long Covid.

Many people thought they were healthy before they got sick but usually when we dig down, we find that there was underlying insulin resistance, old infection that their body- like an Epstein-Barr. All of us have Epstein-Barr almost but some of us, we have excessive amounts of B cells that have the EBV, the Epstein-Barr virus, living in there. Senesce, quiet, not reproducing, but every time that B cell reproduces it can reproduce, and when it does- or you can reproduce a piece of it and that can spark your immune system. People live with that and they don’t notice it.

They’re just people not maybe like if they work too hard and they exercise too hard, and they party too much, and the next day they might really feel like crap and take two days to recover. They just thought, “That was nothing,” but their immune system is always a little bit more amped up than normal. When they get sick, their immune system is already on high alert and it doesn’t know how to go through the process of quieting itself down because you see–

Another circle, the people talk about the innate immune system and the macrophages and neutrophils and the T cells and the B cells, and the NK cells like everybody’s got separate jobs. They do on a gross level, but on the communication levels if the neutrophils don’t work right, don’t send out the right signals, the macrophages don’t work right, they don’t give the T cells the right signals and so the T regulatory and T helper signals don’t work right.

They all work because the system is so redundant but the thing is that it has to work really well to get well. To let everybody know that the war is over, you have to have a good communication system. If you’ve got soldiers who are like the Japanese soldier who they found, the old story, the guy who was still fighting in the jungle 40 years after the war ended because nobody told him. Okay. [laughs] That happens in your body. The communication drops a little bit.

What I find is that usually there’s a toxin exposure that your body couldn’t deal with. Just another quick aside for people, it’s usually not the level of the toxic exposure, it’s just your sensitivity to it because Dr. Naviaux, he hasn’t published it yet, but he looked at 1,200 toxins in about 1,000 people, and the difference between the sick people and the healthy people–

Ari: There really wasn’t [crosstalk]

Dr. Gordon: [crosstalk] in the quantity. Again, there’s always the exception. If you get enough of something that you’re going to eventually get sick but we’re talking about the levels that the government would like us to think is safe because it’s too complicated to realize how they’re not.

Ari: If it’s not objectively, differences in the degree of exposure, let’s say the amount of virus that’s present, the amount of Epstein-Barr virus that’s in a person’s system, the amount of mold toxins, the amount of other chemicals or heavy metals or something, then it has to be the individual’s susceptibility to that or ability to be resistant to that stressor. Is that correct or what [crosstalk]

Dr. Gordon: It’s biochemical individuality. We are different. There are people who used to be able to work in battery factories that had incredible lead exposures in the ’50s. The lead levels that was acceptable, at least, I remember by the ’70s, they were down to 80. Now we know they should be down to nothing or one microgram or liter. It’s just we didn’t know. The point is- but there were lots of people who worked in those factories who felt fine and there were other people who walked in and worked for a day, went home, and felt sick and had headaches. The difference in what we can– I mean, I can eat anything. People I live with if they eat the food’s out for a day, you’ll give them a bellyache. I can eat stuff that’s been sitting out for a week. We’re all different.

APOE4 is probably good for something. We don’t get infections. That’s what people have to understand. I always say is that we all respond pretty much the same way to a bullet, but to a feeling we all respond very differently, and to a [unintelligible 01:10:45]. They said something like, in the beginning, 50% of people with COVID were asymptomatic, so it’s clear that it’s us. The reason that people get stuck in CDR1, 2, and 3 can be very variable.

One of the things that we were going to tie in, [chuckles] I’m going to reach for it, is structure. Nobody talks about structure. One of the things that I see as a regular doctor is that people come in and nobody paid attention to how tight, how stuck, how things– You might have chronic fatigue, but if your body isn’t communicating with your left arm because you had an old injury that never healed, that’s going to get in the way of your healing because the blood flow is not going to be good there.

Dr. Robert Naviaux - Transcript

The Cell Danger Response

Dr. Naviaux:  The cell danger responses an evolutionarily conserved universal biologic response to  environmental stress, threat, infection or injury. And, you know, it’s a normal and reflexive part of  life. We need it to learn and adapt. We need it, you know, to give gains after exercise. We also  need it to fight infections and heal from injuries and to heal from psychological traumas. So the  KDR starts by sensing stress or injury in mitochondria in the cell. And if the threat is slight, like a  papercut or scrape or a common cold, the seed is confined to those, in fact those affected  tissues. And if the injury or threat to life is large or infection as severe as with a heart attack or  stroke, Lyme disease or a SARS-CoV-2 infection, for example, mitochondria and cells trigger a multi-system and multilayered response that ultimately involves both the brain and body. So,  you know, our research has given us a glimpse of a connection between many chronic illnesses.  And when we performed Metabolomic analysis of over a dozen different complex disorders  ranging from primary mitochondrial diseases through autism spectrum disorder.

Myalgic Encephalomyelitis and and chronic fatigue syndrome, Gulf War Illness, Depression,  Suicidal Ideation, ALS. We found that the pathways that were dysregulated by the so called age  response are common to a common denominator in each. And since we know that genes and  environmental risk factors that cause these disorders are actually different in different patients  with the same disease, it got us thinking that it’s not the specific pathogenic trigger that creates  a specific disease. Instead, it is. Each chronic disorder is caused by a single shared biological  response to over hundreds of different pathogenic triggers. And this common biologic response  we call the CCR.

 Ari: What can I ask you? What are some of those triggers?

Dr. Naviaux: Well, some of those triggers are, you know, a brilliant infection in Lyme and EBV infection,  SARS-CoV-2 infection. It can be hazardous ball. The volatile organic compounds in you know, in  you know, in the workplace you. It can be a head trauma. It can be. Well, just anything that  causes a a stress outside of the normal range of homeostasis ends up triggering, you know, the  cell danger response to greater and lesser degrees. Mm hmm. So, you know, when we started  thinking about this, we needed to find a way of integrating, you know, all the strong work that  has already occurred that uses what we call the pathogenesis paradigm. And we began to think  of causes of disease in two classes, and many different genes. And environmental factors can  lead to a disease like autism spectrum disorder or, you know, amyotrophic lateral sclerosis illness  that each disease or disorder can be diagnosed by, you know, specific symptoms.

So the causes are different in each patient, but the core symptoms are the same. This led us to  think about this concept of penultimate and ultimate causes. And so the study of penultimate  causes of illness is well known. That is the study of pathogenesis. Pathogenesis is the study of  different genes and environmental factors that initiate the injury, trigger the KDR and start the  entry into the healing cycle. In contrast, the study of ultimate causes is the study of the shared  biologic response that used to exit from the dynamic process that maintains chronic illness. Now  that’s the study of solid Genesis. Pathogenesis creates the injury, solid Genesis effects the repair.  These are distinct pathways. And it’s important to remember that the path to healing cannot be  traveled by retracing the path that led to the illness.

The path to healing is not just the simple reversal of the path to illness

Ari: Can you elaborate on that, what you mean about that last part, that the path to healing is not just the simple reversal of the path to illness.

Dr. Naviaux: Yeah. So for example, if we develop a pneumococcal pneumonia, we have a bacterial infection of  the lung that can be treated with antibiotics, that can eradicate the bacterium. But then there’s  a lot of damage that’s done to the, you know, to the lung tissue that has to be repaired and, you  know, actually, you know, the removal of the bacterium is just the first step. But energy and  resources from the body have to be, you know, redirected toward, you know, rebuilding all the  broken alveoli and the blood vessels and to reestablish the architecture of the lung. So. So, yeah.  Just knowing. Yeah. Yeah. So that’s one example. And, you know, we could talk about, you know,  head traumas and traumatic head, you know, traumatic brain injuries. You know, frequently  when an injury has occurred, it has a, you know, this long lasting effect that, you know, just  knowing what the original cause was, you know, doesn’t actually help you to resolve the final the  chronic symptoms.

Ari:  So you said the ultimate causes of disease. You described it as things that I’m sort of  paraphrasing here, but things that prevent cellugenesis, things that block the healing cycle.

Dr. Naviaux: Yes.

Ari: What’s going on there? How would you describe that? Or what kinds of things prevent the body from entering the healing cycle or completing it?

Dr. Naviaux: Well, sometimes it can be a secondary infection, sometimes. So sometimes it’s helpful to, you  know, think of these in the simplest terms. So if you have a cut and it’s partially healed, but then,  you know, stretch it over overhand and break it open again, the healing process has to go back to  the beginning. It has to start again. It can’t just, you know, pick up where you left off. Same thing.  If you remove a scab from a scraped knee goes back to the beginning, the same thing happens.  And it’s actually been measured in the crashes and chronic fatigue syndrome is that you can, you know, go from one state of metabolism to a state that’s more dependent on glycolysis and more inflammatory. That’s, you know, after a crash that then requires you to make your way back to  your baseline after that after the crash. So I guess the you know, the important thing to  remember is that reentry can, you know, keep you in the healing cycle. But sometimes what  happens is the you, you know, the cells that initiated the signals of danger and threat that  triggered the initial cell danger response. And the brain that is responding to sensory  information sent from the cells haven’t yet been convinced that the world is safe enough to heal  yet. And so, you know, it keeps the signals going that maintain defense even when the, you  know, the actual triggers are, in fact, gone.

Ari: I know. I sent you a list of questions I wanted to ask you for this this interview prior to it. I want to  jump a little bit ahead, because I feel it’s a natural segway with where we are, where where we’re  at in this conversation. So just going further on, cellugenesis, do you feel that this concept that  you’re describing as far as the healing cycle has been incorporated or properly incorporated into  the the conventional medical paradigm, the Western medical paradigm?

Dr. Naviaux: Not at all. In fact, you know, our training in the scientific method and in Western medicine has really focused on the things that have been successful up to now, which is, you know, in Western  thinking, typically isolate a single variable in doing your experiments. And, you know, listen with your experiments, ask a question of nature and then listen to the results and design a new experiment that’s very effective when a disease or process is regulated by single things. But what we find in the vast majority of chronic illness is that they’re plural causal. That means, you know, that’s a term that was used by hun cilia. That basically means that, you know, for example, you can take, you know, a disorder like LSD and you can have an ascending mutation that can lead to it. You can have a TDP 43 mutation that could lead to it. Now they almost never happen in the same patient. They’re just different things, different ways to get to the same, you know, the same problem. And so ultimately, you know, so we’ve been taught to think about diseases in a way that has been effective in the past but is not very effective. It at understanding dynamical processes.

Okay. So then and you know, a lot of our inspiration comes from the fields of ecology and  evolutionary biology. And so that led to us thinking about solid Genesis as a dynamic process that has regulate, you know, regulators that can, you know, drive outcomes in one direction or another, but or or not on and off switches. Okay. And so you know what? I think a solid genesis as a multilayered process that starts with mitochondria and cellular changes that ultimately can  grow to change whole body behavior and metabolism and the autonomic and endocrine  systems and the microbiome are always engaged, you know, when the KDR is activated. But  because solid Genesis, you know, healing is energy and resource consuming, you have to actually  take materials to heal a broken bone or to recover from a heart attack, for example, that, you  know, you can’t restore, you know, full and vibrant health without being able to redirect those  energy and resources away from self-defense and back to normal cellular functions. Mm hmm.  So I guess, yeah.

So that kind of leads to this natural idea that, you know, we talk about pathogenesis based  approaches to medicine that’s filling the, you know, this book that has been you know, we’ve  been writing for the past 5000 years of written history that I call the first book of medicine that  really is based on the pathogenesis paradigm and has been very, very effective or, you know,  many acute disorders. But I believe that to discover effective treatments for chronic illness, we need a new paradigm and a new way to do medical research for discovery. And I think that, you know, study of social justice based treatments and the process of the molecular process of healing, we hope. Right. The pages of the second book of Medicine.

Dr. Eric Balcavage - Transcript

The role of mitochondria and cell danger response

Ari Whitten, MS So with that in mind, what is defense mode and what role do the mitochondria have in that? Because as most people are taught in their high school and college and graduate school and medical school biology classes, basically mitochondria, what people know is they’re the powerhouse of the cell and most people’s knowledge stops there. And, you know, in graduate school, in medical school, it’s like it goes a little bit further and basically they’ll teach you a story that, you know, mitochondria are one of many different organelles in the cell, but they’re basically framed as these sort of mindless energy generators that just take in carbs and fats and pump out ATP. And what you’re alluding to here, very much like my work, heavily influenced by Dr. Robert Naviaux’s and the cell danger response is that mitochondria are way more important than we ever learned in biology and physiology courses in our formal educations.

Eric Balcavage, DC Yeah. I think what we’ve learned from Naviaux’s work and others is that the mitochondria have the ability to sense the energy flow through a cell and there’s a certain amount of energy that we need for the cell to run smoothly. And when there’s a drop in energy, it’s like somebody flicked the smoke detector or it’s smoke, a fire alarm in the factory. Right. And so, whoa, there’s a problem here. And now, all of a sudden, instead of making widgets, we’re going to shift to getting anybody who’s not important out of here. And everybody else is going to be focused on trying to find a threat and put out the if it’s a fire. Right.

And I think that might account what we’re learning about the mitochondria. And, you know, for anybody listening to this, we know probably this much of what we know, we think we know this much and we really probably know this much. So we all this stuff, we say we’re simplifying it, dumbing it down, but we mitochondria seem to have ability to sense energy flow. And when they sense that there’s a drop in energy flow that can initiate the change in physiology from manufacturing, making peptides and proteins and hormones and all of these other things too, saying, hey, there’s some type of energy, something stealing energy here, it’s a potential threat. And let’s shift to defense mode. Slow down the manufacturing and start into defense mode. And then Navy oh in his paper talks about a whole bunch of different steps to that cell danger physiology and that and that process. And reducing mitochondrial numbers and function is a large part of a protective cell danger response and people might consider why would that be a protective response? If you’re taking the thing that’s actually generating energy, how could it possibly be that having fewer of those, it’s better.

And the reason for that, at least in what we believe right now, is that when we have cells that are in this state of low stress, what we call homeostasis or manufacturing mode, those cells are bringing glucose and fats and other resources into the cell. They’re jamming them into the mitochondria to be converted in through the credits cycle and something called the electron transport transfer or chain to turn food energy into cellular energy. And the process of that is awesome, especially when we have oxygen to drive the process because we could take one glucose molecule and make 36 ATP, which is its energy cellular energy units. So we get great return on in our investment and any excess we can drive off as heat and create a little some other side effects that are beneficial to the cell, just cell. That process of going through that Krebs cycle, electron transport chain making that cellular energy results in a little bit of exhaust. Just like driving your car, you’re still driving a gas car is going to create a little bit of exhaust. And so that sounds bad, like it’s making some waste that comes out. Yeah, you’re making some exhaust. We call those free radicals. Well, that doesn’t sound good. Well, the good news is the cell also makes, as with many things, in cellular physiology for the free radicals we make, we also have a system inside the cell that makes anti oxidants things to kind of balance out those free radicals that are being generated so that we don’t damage the cell as part of the process of making cellular energy.

So that’s how it should work in a low stress state. But one of the defense mechanisms to find a threat, it’s a bacteria virus, an organism is to ramp up some of those free radicals and ramp up inflammatory chemicals, which could damage the cell if they were excessive. But they’re also part of the tools that we use to deal with the threat. So the cellular intelligence is pretty smart. If I have all the exhaust and I’m making this regular mitochondrial function blocks, I have more free radicals that are being generated as part of my defense response, way, way more free radicals being generated. And I have the ability to make antioxidants. And so if I don’t do something, I either have to make more antioxidants or I need to decrease the free radicals. Otherwise, we have excessive, free, radical formation.

We call that oxidative stress. And that’s what creates damage and destruction to the cell cellular intelligence. Is this smarter than that? So what it does is it says, hey, what’s the more important thing here, making cellular energy or defending myself, defending myself? So what am I going to do? I’m going to downregulate the mitochondria. I have a mate that’s cellular energy, but I’ll also make less exhaust. Then I can use those antioxidants to deal with the fallout from this defense mechanism without causing damage and destruction to the cell. My opinion, based on some of the sites.

Ari Whitten, MS So you said earlier, I loved when you were describing sort of the overview of the paradigms of how conventional medicine looks at thyroid conditions and how a lot of alternative and functional medicine practitioners look at it and how you look at it. Similarly, there’s this other layer to what you’re describing at the mitochondrial level where there’s another parallel of of what’s going on, where where, you know, when when I started talking about mitochondria ten years ago, it was it was a strange thing to be doing. And I would get a lot of funny looks. And I was saying, you know, mitochondria are really important to this energy and fatigue story. And everybody else was focused on adrenal fatigue and thought I was crazy.

Now mitochondria are in vogue and everybody’s talking about mitochondria. But there is a what I would say and I think you’d agree that there’s a very simplistic frame and understanding about mitochondria and most functional medicine practitioners basically approach it by saying, you know, they run some tests and we don’t even really have very good tests for mitochondrial function. But they run some tests, maybe organic acids tests or maybe a few other things that indirectly might indicate mitochondrial function or deficiencies of certain nutrients and cofactors needed for mitochondrial energy production. And based on that, they’ll say, Oh, you have mitochondrial dysfunction here, take this acetyl l-carnitine and de ribose and alpha lipoic acid and coke ten and PCU and boom. Now we’re solving your mitochondrial dysfunction. And what you are talking about is something considerably more sophisticated than that. So describe the difference between what your approaches to understanding and fixing mitochondrial function versus the one I just presented.

Eric Balcavage, DC Well, I think the big argument that is made when we look at tests like organic acid test and other tests or somebody says you have mitochondrial dysfunction, but anybody who’s got chronic illness, I think they I’ll make the argument or the agreement that, yes, there’s changes in your mitochondrial function that don’t make you feel awesome. But after that, I have a real issue because what somebody would say is, okay, what you have is if you have your mitochondrial not working, therefore it’s broken. And therefore the primary reason it’s broken is because it doesn’t have enough micronutrients. So I’m going to give you B12 CoQ10 up above in my argument would be first of all, if you have that many micronutrient deficiencies, then the issue is probably not that you need a mitochondrial supplement. What you need is better diet, better digestion, better gut functioning physiology, better assimilation of those things, not just more stuff, right? So that’s problem. If you have that many micronutrient deficiencies, then you’ve got to start with why? Why am I so deficient in nutrients? So that’s part one.

And then but that also goes to why I might have mitochondrial downregulation in the first place, right? Because maybe I have this chronic dysbiosis, maybe I have a leaky gut, maybe I have a dysregulated immune system. All of these dangerous things are going on. The second part of that is we make the assumption that the cell has no control. And then if I just give enough stuff with the Will of the Jedi, it is going to go into the cell and it’s going to work the way I want it to. And that’s what’s it would love if that happened. But how many you know, how many times I told my kid to go clean the room and they didn’t do it? I mean, and you expect me to get then supplement. I’m giving you to work the way I wanted to write.

I have almost no control of my kids at times, and yet I have more control of them than I have. What I give you as a supplement. Right. The other problem that goes on is we make assumptions like that sometimes based on labs that aren’t well validated in what they’re really measuring or showing. And when you really do look at mitochondrial, when somebody’s got reduced mitochondrial function like Culture ten comes up all the time. But if you look at the literature and research, Q10 is often not deficient when somebody has downregulated mitochondria. Why? Because they’re not using it. Because the mitochondria is not using the same load of CoQ10, so they don’t have sufficient deficient levels. You’ll hear that with people where they have hypothyroidism, so they’re going to have low coax. You know, when you have downregulation of T3 in the cell, you actually have more coax. You tend because they can’t use it efficiently, so they don’t need more. They need to the better thing. We need to step back and say, hmm, why is the cell working like this? You know, ultimately, could there be some mitochondrial dysfunction?

Yeah, we can make that argument and talk about things that may cause the mitochondria to truly be dysfunctional. But I don’t think it’s just as simple as just give B6 B12. I think we do that too often with stuff, and I think it’s one of the problems, the same thing we do with thyroid physiology. Well, I don’t like that number, so let me give you more of that and that’ll make it work. Well, no. It also assumes that the cell has no control. I like the cell does not get to be able to control what’s going on inside it. And I think we do have enough literature that suggests that the cells actually get to control what happens inside. There’s a level of intelligence that we don’t fully understand that cells get to determine what crosses the membrane, what gets into the mitochondria, what doesn’t go into mitochondria. So I think it’s a very naive approach when we consider that it’s as simple as that. My argument is if we think that the mitochondria is damaged or dysfunctional, then we should ask the question why? And honestly, when I look at mitochondrial tests, I when I you can look at organic acid, but one of the tests I really like to run as it’s a test if I’m looking at mitochondria is the might a swab plus from Watts I can’t think of Teresa lab name not a mess yeah but.

Ari Whitten, MS The test is called Midas swab.

Eric Balcavage, DC Yeah, it’s called a minus swab. Or might a swab plus. And essentially it’s a swab. You look at mitochondria so we can see mitochondrial density and we can see how well complex one, two, three and four work. And some of the strategies that you know, when people are on a strategy and I’m like, okay, well let’s see how it works. And we look at their mitochondria is not working any better because it’s the wrong strategy. And even when it comes to thyroid physiology, what I’ll see is people on higher levels of mitochondria are on thyroid support that are given by their physicians. They don’t have better mitochondrial capacity and function, but what they often have is higher mitochondrial density and more oxidative stress, because you’re pushing the thyroid hormone will increase mitochondrial density, but now you’re creating more mitochondria. The cell, as part of the defense missing, was trying to reduce the mitochondrial density. The fewer mitochondria now with potentially less resources coming into the cell, it’s a recipe for more oxidative stress and damage, which I’ve seen over the years.

Ari Whitten, MS I want to stress to everybody listening the importance of understanding, paradigm understanding one one’s frame, one’s lens, or the way that they understand what the problem is. As an example of this, one might understand depression and say one might look at depression and say, Oh, this is a chemical imbalance in the brain. You’ve got a deficiency of this neurotransmitter, too much of that neurotransmitter. And this has arisen just for random reasons or due to one’s personal genetics and because of this random imbalance of neurotransmitters in the brain. Here’s this chemical that will interrupt the way that these nerves function so that you produce more of this chemical or so that we prevent the re uptake of this chemical. So in other words, the paradigm is depression is the result of a randomly or genetically developed chemical imbalance in the brain that requires a drug intervention to fix it. Or alternatively, I would argue much more sophisticated and science based understanding of depression would see depression as a very natural and normal result of a person being out of harmony in some way, being not aligned with either eating healthy, living healthy.

And we know, of course, that nutrition impacts brain function and mood and depression. We know, of course, that exercise impacts that. We know sleep and circadian rhythm impacts it. We know light impacts it. We know toxins and inflammations and gut health impacts it. Right. So we start to see all these layers emerge. We know that social connection impacts it. We know that we have all of these these lay out, like also how aligned you are with, you know, if you’re working a soul sucking job that you’re not passionate about and that’s how you’re spending your days, like it’s pretty reasonable to be depressed.

Whereas if you’re spending your days doing something you love and you’re passionate about, you probably are going to be in a different mood. And we know that all of these dimensions, we have lots and lots of literature showing all of these dimensions impacting on brain function, mood and neurotransmitter balance. And ultimately, this, this whether you are depressed or a happier person. And in light of all of that knowledge, it’s actually ridiculous, absurd and totally unscientific to reduce myopically reduce depression down into just a random chemical imbalance in the brain. And this is just our unintelligent body doing this for random reasons. Here’s this drug to fix your chemical imbalance. And so what you’re talking about is essentially the same thing at the level of the body. You have a lot of people who are in a rush to do chemical interventions and treat the body as unintelligent and what you are arguing in favor of is seeing the body through a lens that says, why is the body why is the intelligent body doing this and responding in this way? And that totally changes the types of interventions that you will do, the types of approaches you’ll use to try to fix that.

Eric Balcavage, DC Yeah, well and I think based on what you said, we’d say, hey, that if you have better gut physiology, you have probably better neurotransmitter function. Okay, so I have a potentially compromised neurotransmitter function. Okay, well, then what are the things that can influence it? Well, your gut. Well, maybe we should take a look at that. I forget about that. Let’s just give you this drug. Let’s just bypass the thing. And it’s. But we do that with everything we know. Exercise increases, mood increases, dopamine levels. Right. Makes us feel good. Increased serotonin makes us feel well. But I’m depressed. Do you exercise? No. Well, maybe the issue isn’t that you need a drug. Maybe the issue is you need to do the things that are going to create that positive environment. You may be doing a lot of things or have a lot of things going on in your environment that are creating not. It’s still, in my opinion, it’s still an appropriate response, at least at the onset, right? If you have a bad gut, the appropriate response might be, well, I’ve got an infection. I need to move serotonin away from or move tryptophan away from me making serotonin and drive it down. The Clinton lytic acid pathway and makes them maybe things that can be used as more toxin to deal with this organism or that threat. Right. Feeling stressed? Oh, I’m. I’m. I have insomnia.

Well, maybe the reason you have insomnia is because you have this stress response going on. Your body’s like, whoa, we’re in danger. We don’t need to take a deep sleep. I don’t really need that level of melatonin. I really need my body to be more alert. So I’m going to drive that tryptophan away from serotonin and make more stimulatory chemicals. So, you know, I think it’s sometimes we just assume that the body intelligence isn’t working. I think it is work if it’s responding or adapting to whatever is going on in that environment. So that’s where we have to ask what’s going on in your environment that’s creating this to manifest. So we have to, but that’s hard, right? That takes more than five or ten or 15 minute visit every four months or a couple times a year. And it doesn’t leave us too much room to not take care of ourselves.

Okay. I mean, we know other model allows it to be like it’s an external, it’s a disease or disorder. I’m not in control. It just happened to me in the model that we’re talking about is more where somebody has to say, not my fault, it’s not fully my fault. There’s a lot of things that could have happened, but it’s my responsibility to make the change. And I think that’s the really important part. I think sometimes people hear the message like, Oh, you telling me I did. It’s my diet, did this or whatever. It’s not necessarily your fault, but it is your responsibility. Once you’re educated that you have to take care of yourself. You just can’t do the catch on the dashboard and say, Take me wherever and expect that you’re going to get to where you want your path to plan the strategy. If you want to be healthy and be functional and most people aren’t, they’re not worried about their health and, well, their well-being until they’re in a state of chronic illness and disease. Unfortunately.

How to get out of the mitochondrial cell danger response

Ari Whitten, MS So let’s get practical. How do let’s say the people, let’s say a person listening to this and probably most people are who are listening to this or in this category are in defense mode to some extent have symptoms. Whether those symptoms are hypothyroid ism or brain fog or depression or chronic fatigue or whatever else, we can see them through this paradigm as a reflection, as part of the intelligent body’s adaptive response to being chronically overwhelmed by these stressors. Danger signals.

Eric Balcavage, DC Right?

Ari Whitten, MS How do we get the body unstuck? How do we get it out of danger mode and put it back in energy mode where the mitochondria are switched back online and are functioning optimally?

Eric Balcavage, DC I wish it was sexy. All right. Would I mean, I wish it was.

Ari Whitten, MS Make it sexy. Make it sexy.

Eric Balcavage, DC But it comes back to, I think, number one and, you know, shameless plug. You know, how they all know Halderman and I wrote a book called The Thyroid Box. And that is what, you know, the third part of our book, we don’t have any supplement recommendations, the lifestyle and diet and all the things that aren’t sexy. But if you really want to start to recover your health, you’ve got to take a look at what I talk about called the fitness factors. And those are the things that are really influence how your body is in a manufacturing mode or is in cell defense mode. So you look at your emotional fitness like what’s going on in my life, what’s going on between the six inches of my ears, like, what am I thinking about? What am I focusing on and what am I were? If I’m in worry mode all the time about something in the past or something in the future, you’re not living in the present and that takes a lot. Create trust. So what is your emotional fitness? And then once you and for my clients, I give them a scale 0 to 10, I ask them like each of these fitness factors, give yourself a scale 0 to 10 and rate yourself, and we’ll look at emotional fitness, physical fitness, metabolic fitness.

That’s how the chemistry of the body’s working. We’ll look at dietary fitness, sleep fitness, respiratory fitness. We’ll look at your habitual fitness. What are the things you do day in, day out, things you may realize and things you don’t realize you do every day. And when we put all those pieces together for what most of my clients, we just start with, okay, well, this is the week. It’s one. Your sleep is terrible. Let’s take a let’s now you scored that the worst let’s look at your habits and behaviors that center around sleep and let’s start there and we start there now while they’re working on those things, I’m also looking at their chemistry and what can I use dietary nutritionally to kind of tweak some of those systems. That’s the crux of how I get my clients well. And people say, well, you’re a thyroid specialist. Which thyroid hormone? Listen, I typically I’m taking people I’m get people off of thyroid medication. Their stuff they’re taking is not converting. Well, they’ve got mixed in this belief that they can just Whac-A-Mole it with three, three, four, two, one, whatever, and it’s going to work. And they and they after years, months or years, they realize it doesn’t work and they actually feel worse. And so it’s not sexy, but it’s you. You have to look with an objective lens. In most times we need a third party to actually help us look objectively at what’s going on.

And we have to say this is an area that you feel is a problem. It looks like it’s a problem. Now, what can we do incrementally to start making changes and to bring your level of fitness up in this category? If we think about it from an in from a physical fitness perspective, I can’t I don’t I don’t lift. I don’t run. I can’t do it. I can’t do that. Can you walk 5 minutes? No. Great. Let’s walk for. Okay, I can do that. Great. Now we started and now we have a building block that we don’t need strength training. No, I can’t do it. What can’t you do? I can’t do anything. And you get out of a chair. Well, yeah, I can get out of a chair. Can you do three times in a row. Yes. Right now we’re doing some physical fitness, but we’ll give them a physical fitness test in the beginning. From an environmental standpoint, what’s your toxic load around in your environment? Like where do your personal products, what are your what’s your sleep? What’s your cleaning products? Right. What are your electronic stress that’s going on?

Right. Then look at the things that we can do to reduce things that are stressful on the physiology and do things that can raise them up. That fitness scale, none of it sexy. But if you want to be healthy and stay well, the solution rarely comes in a bottle you know and that’s it’s not attractive because in people who make supplements and recommend them, I recommend them too. But they’re not a long term strategy. They are a short term strategy to help us get to the next level. But ultimately, if we want to get somebody out of cell stress response and get them back into feeling physiology, we have to identify the stressors, reduce or eliminate them. Who has greater degree is possible and then then support the recovery of those tissues back to normal function physiology. And when you do that, it miraculously people start to feel and function better. I mean, crazy without a lot of drugs, without lifetime of supplementation. It’s these fundamental things. But a lot of people don’t want to do those things or they’re not aware that the things that they’re doing potentially cause them to be unhealthy.

Show Notes

00:00 – Coming Up!
01:22 – Intro
08:17 – Dr. Eric Gordon: The Cell Danger Response
26:17 – The benefits of the Cell Danger Response
29:42 – The link between mitochondrial dysfunction and chronic illness
36:53 –  Dr. Robert Naviaux: The Cell Danger Response
41:45 – The path to healing is not just the simple reversal of the path to illness
50:42 – Dr. Eric Balcavage: The role of mitochondria and cell danger response
1:11:45 – How to get out of the mitochondrial cell danger response

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