The Extracellular Matrix — A Secret Key to Health and Energy with Michael McEvoy

Content By: Ari Whitten

The extracellular matrix – a secret key to health and energy. You might be wondering ”what the heck is the extracellular matrix and why should I care about it?” The Extracellular matrix is a supportive network comprised of connective tissue, collagen fibers, the lymphatic vessels, and all of the tributaries in the lymphatic system that creates the environment between and around your cells. It is not just for the physical support of the cells, but also is integral to the function and behavior of the cells in many different important ways. It controls the lifecycle of the cell, and modulates the behavior of the cell, and modulates and influences how growth factors are utilized. Ultimately, it turns out that focusing on the environment surrounding your cells (your extracellular matrix) may be just as important  — and sometimes even more important — than what’s going on inside the cell. It is the physical and biochemical support network of your cells.

So, what does that mean to your health and wellbeing?

This week, I am interviewing Michael McEvoy, a clinician, writer, educator, who has created diverse health-related and functional medicine courses and is the founder of Metabolic Healing. In this interview, he’s talking all about the extracellular matrix, why it is a potential contributor to disease and fatigue, and how you can strengthen and heal it.


In this podcast, you’ll learn

  • What the extracellular matrix (ECM) is and how it works
  • The common pesticide that can trigger dysfunction in the extracellular matrix
  • How the extracellular matrix is linked to certain autoimmune conditions
  • How hypermobility can be a symptom of extracellular matrix dysfunction (and the steps to take to lessen hypermobility symptoms)
  • The most beneficial therapies to heal and strengthen our extracellular matrix
  • The link between the extracellular matrix and Cell Danger Response (and how poor ECM health can lead to getting locked in Cell Danger Mode)
  • The problem with reductionism in modern medicine, and why true medical breakthroughs often don’t go mainstream

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Ari Whitten: Hey everyone, welcome back to The Energy Blueprint podcast. I’m your host, Ari Whitten, and today I have with me a special guest Michael McEvoy, who is someone whose work I followed for a long time and who’s work I really admire and I’ve wanted to have to have on this podcast for a very long time. So welcome Michael, and actually before I officially welcome you let me read your bio.

Michael McEvoy is the founder of Metabolic Healing. He’s been involved in clinical practice since 2007. In addition to functioning as a clinician and writer, he’s a teacher, educator, and systems creator of diverse health-related and functional medicine curriculum and modalities. And I have to say on a personal note, I know a number of our colleagues have gone through his courses and have just said that they’re kind of top-notch, they’re the best things out there. So it’s on my agenda to go through your courses as well.

So welcome, Michael, it’s a pleasure to have you on.

Michael McEvoy: Thanks Ari, it’s good to be here.

Ari Whitten: Yeah. So I saw you in the recent documentary also that we were both featured in, The Human Longevity Project, and I have to say that you and Dr. Ted Achacoso were my two favorites. Those were the people where I was like, “Yes! These guys are awesome, these guys get it.” So it’s great to connect with you. And I know we have a number of common interest but I know that we also have a number of areas where we have also very different interests and that you’ve gone very deep on some very cool topics that I haven’t. And so I’m really excited to hear about that and talk to you about some of these areas that you’ve been exploring.

So one of the ideas that was presented by our mutual friend Jason Prall when I threw out the idea to have you on the podcast was for us to talk about the extracellular environment. And this is something that’s really not a common thing for people to talk about in the health realm. I mean almost nobody is talking about this. And there was a quote that I read in one of your articles on this subject where you quoted – I forget the person’s name but I have the quote here-

Michael McEvoy: I think it’s Alfred Pissinger.

Ari Whitten: Yes, I think that’s the one. And the quote says, “Western physiology has the habit of reducing the function of the cell to an incomprehensible maze of cellular biology. This has led to the discovery of elaborate biochemistry pathways as well as the extraordinary study of the human genome. With these intricate studies the extracellular environment has largely been neglected. Yet, the extracellular environment plays a vital governing and inseparable role in the function of the cell.”

So with that in mind, I would love for you to give kind of an overview what the extracellular environment is because a lot of people listening probably have never even heard that term and have no idea what the hell that even means. I know there’s a lot of angles to this and a lot of different aspects to this extracellular environment so we can kind of approach it from different aspects, but can you give kind of a broad overview of what that even means, this term extracellular environment?

Michael McEvoy: I’ll start up by saying that I’m still learning what the extracellular matrix is. And the deeper that I go into researching the extracellular matrix the more I realize that so much has been lost and so much is yet to be discovered. I’m now kind of at a point where I’m looking at the influence of physics and cell membrane electrophysiology and even water research and how all of these things are affecting the environment that cells live in. So we know that we’re comprised largely of cells and … That quote you read, I think that was actually something that I had just blurbed out.

Ari Whitten: Oh, maybe that’s why-

Michael McEvoy: There was a Pissinger quote in there and the Pissinger quote, I’ll just paraphrase that. So Pissinger was a German doctor and researcher who really kind of has been seen as one of the pioneers of extracellular matrix therapeutics, extracellular matrix research. And Pissinger, the opening statement of his book is related to how the concept of a cell when it is isolated from its environment is a morphological abstraction. And that is the opening statement of this really profound book called Matrix and Matrix Regulation by Alfred Pissinger.

And so as you get into this you start to realize that we have spent a tremendous amount of time looking at all of the intricate pathways inside of the cell, the genomics, even the mitochondria, cell membrane dynamics, go on and on and on forever about all that stuff. But we have to appreciate that the cell does not exist in an isolated state. Our cells literally are existing in a truly holistic environment with its extracellular space.

And that extracellular matrix is comprised of a lot of different things. It’s comprised of what is referred to as the matrisome or basically the network of connective tissue and collagen fibers, but it’s also comprised of the lymphatic vessels which run through the connective tissue, and all of the tributaries in the lymphatic system.

The extracellular matrix also will include in it immunological factors. For example, mast cells and macrophages are highly concentrated in the extracellular matrix, coordinating different immunological responses. The extracellular matrix is integral to the function and behavior of the cells in many different important ways. The extracellular matrix controls the lifecycle of the cell, modulates and influences the behavior of the cell, modulates and influences how growth factors are utilized. And that may be one of the most interesting and important parts of the matrix function, is its ability to regulate growth factors. And we know that there’s about 15 to 20 growth factors of the body that are modulated by the extracellular matrix glycoproteins.

And so when somebody has … I’m interested in the pathophysiology, what goes wrong when disease ensues, and particularly interested in certain diseases and conditions that involve abnormalities to the extracellular matrix, degradation to the extracellular matrix. And so a lot of the research that I’ve been doing as of late has been looking at many of the mechanisms that will eventually cause a degradation to the matrix, a breaking down of the matrix, and a subsequent set of different processes that ensue that cause a number of different symptoms.

And so the more that we can start to understand the significance of the extracellular environment as it relates to the health of the body the better we’ll be able to understand what we need to be doing proactively as well as therapeutically to treat such individuals.

Why medical professionals in the US only focus on what is going on inside the cells rather than the extracellular matrix

Ari Whitten: Yeah, it’s interesting because I think here in the US we’ve really focused on what’s going on inside of the cell and it’s very much about different cellular parts and genes and so on and the biochemistry of that. But I’m under the impression that there are certain kind of paradigms and schools of thought in Europe that have become quite popular that are really focused on the extracellular environment, the extracellular matrix. Why do you think that that has happened? Why do you think that the US has kind of gone down this pathway of focusing on just kind of these isolated cells and what’s going on inside of them versus this environment that surrounds all of our cells?

Michael McEvoy: Well, I think that it’s a common thing for western physiology and biology in general to isolate things and to study things in isolated, fragmented forms. And we have many examples of that going back a very, very long time. And in this day and age the research is so focused on very small, fragmented parts of the human body that we often very easily lose sight of the bigger picture.

There’s many schools of thinking in Europe, particularly in Germany, that have for many decades now been focused on creating more holistic models of medicine that’s based on regulation physiology, that’s based around concepts of bioenergetics and the effects that these things are having on the extracellular terrain of the body. For example, Helmut Schimmel was the first person to actually use the term functional medicine somewhere in the late ’90s, and he was influenced by a lot of these homotoxicologists that were influenced by people that were studying the extracellular environment and looking for ways to change and influence and impact the health and the physiology of the body by manipulating, by modulating, by attenuating the matrix as a whole.

So I think that, to answer the question, it’s a habit of western sciences, western biology especially, to become fragmented in such a way where it’s easy to overlook the forest that you’re in and to just focus on the most smallest and, I would argue, abstract concepts. But really in that process we lose the greater vision.

What diseases are caused by a dysfunctional extracellular environment

Ari Whitten: Very interesting. So on a practical level, what kinds of things result from a dysfunctional extracellular environment? Or maybe another way of phrasing this would be what indications are there? What symptoms or conditions might a person have that indicate that there’s something wrong with the extracellular environment?

Michael McEvoy: I’ll start up by saying that the extracellular matrix, I see it as a meeting place for the entire physiology of the body. A meeting place, a battleground, as well as a protective barrier, as a communicative epicenter where the immune system, the nervous system, and the endocrine systems all converge and meet to basically create a homeostatic balanced environment.

And we have a lot of evidence of this based upon the actual constituents that are present in the matrix. When the matrix becomes dysfunctional we lose our ability to regulate our neuroendocrine system. So we normally think of the nervous system, the central and autonomic systems, and the immune system and the endocrine systems as separate systems.

But it’s becoming more increasingly obvious that these systems are not in any way separate, they are intricately related to one another and they intimately talk to one another in order to accomplish many of the same goals. The matrix is this place where these three systems can converge, where these three systems can express their functionality and to basically influence everything from the way we think, our behavior, to the way that our cells function, to the way that oxygen is delivered to the tissues, to the way that our tissues remain hydrated, to the ways in which we’re able to remove harmful toxins from our cells and our tissues. These are some of the many different functions of an operating matrix.

When the matrix becomes compromised … Well, let’s look at some basic conditions and disease processes that definitely involve degradation to the extracellular matrix. So for example, autoimmune diseases are a good example of this, and this is especially true of rheumatoid arthritis as well as in lupus erythematosus. These are connective tissue diseases that have resulted in a variety of different abnormalities. We can think of other types of autoimmune diseases which might involve matrix dysregulation. We can think of conditions such as hypermobility, Lyme disease, chronic illness, chronic fatigue syndrome, mold toxicity, or chronic inflammatory response syndrome. All of these things involve on some level a dysfunction or a degradation or a compromise to the extracellular matrix.

In the example of chronic inflammatory response syndrome or CIRS as it’s now become known, we know that one of the initial processes that is involved is basically the infiltration of metalloproteinases, MMP9 specifically, which essentially bores a hole into the extracellular matrix to begin the degradation of collagen and connective tissue so that the infiltration of immune cells and innate immune responders can then penetrate through to the affected area. This incites inflammatory activity, and in the case of CIRS this inflammatory activity is run amok.

So we see this is happening a lot in many different conditions. This can be happening in environmental toxic exposure such as living in a water-damaged building. It can occur in borreliosis or Lyme disease where we have similar mechanisms that our innate immune system is responding and generating inflammation that does not resolve as it needs to.

The consequence of this is that when the matrix becomes compromised we start to see many of the characteristic symptoms of this. So in CIRS, for example, we’ll often see symptoms of peripheral neuropathy, we could see symptoms of pseudohypoxia or tissue hypoxia where there is a lower oxygen concentration, discoloration of the tips of the fingers and the tips of the toes. One of the mechanisms of this is that one of the endothelial growth factors called VEGF has its binding sites, activation sites, and maturation sites within different extracellular matrix glycoproteins. And so if those glycoproteins are not being synthesized, are being degraded, then many of these growth factors, including VEGF, TGF beta 1, insulin growth factor 1, can’t bind and can’t mature properly. Consequently we have symptoms that arise: tissue hypoxia as I mentioned, peripheral neuropathy is another possible symptom, loss of cognitive function. Remember that the matrix, it’s everywhere, it’s pervasive, it’s ubiquitously found in every organ and tissue of the body.

So there’s many different consequences of this and as we’re starting to learn and really as we start to get deeper and deeper into this science and in this research we find out that certain individuals have a much higher predisposition to having problems in extracellular matrix function because of genetic predispositions, for example. Individuals that have joint hyperlaxity or joint hypermobility, which is very common, had at least some degree of extracellular matrix dysfunction.

I was told incidentally by a doctor who is the head of two integrative medicine clinics in California that 70 to 80% of his patients are hypermobile, and he only deals with the sickest of the sick. I’ve had patients told me that after their illness had ensued that they became hypermobile, that suddenly their skin became hyperelastic or their elbows and shoulders and wrists and fingers became more hyperextensible as a result of their chronic illness. The reason for this is because in these types of chronic illnesses the extracellular matrix has been degraded to an extent where the collagen and the ability to synthesize collagen has been impaired.

Ari Whitten: Fascinating. You mentioned there are certain genetic conditions where a person might have a proneness to extracellular matrix dysfunction. In that kind of vein, I’m wondering what the level of evidences or what the kind of layers of evidence are that allow us to discern whether extracellular matrix dysfunction is a cause or a consequence of or just a co-occurring phenomenon in a lot of these diseases. Is there evidence of any kind that we can look to that says, “This dysfunction at the level of the extracellular matrix is clearly a cause or a contributing factor to this condition or to this symptom”?

Michael McEvoy: Well, so for example, there’s a number of different so-called genetic diseases which involve collagen deficiency of various kinds. So Ehlers-Danlos syndrome, for example, or EDS is probably the most common. Then you have Marfan syndrome which is very similar. And then you’ve got some even very rare genetic conditions that are very similar in that certain types of collagen aren’t being made.

A genetic disease is different from these genetic singular nucleotide polymorphisms that you hear all about: MTHFR and APOE4, all of these things. Not to minimize those, but a true genetic mutation as we really call it is essentially when you have a knockout of a gene to where the end gene product, the protein or the enzyme that gets made, basically it’s not there. This is referred to often as haploinsufficiency when a gene product is so mutated from genetic defect that the functional enzyme doesn’t get made sufficiently.

So these are happening in true clinically diagnosed Ehlers-Danlos syndrome and Marfan syndrome. But we now know based upon some of the more recent research that the classification of Ehlers-Danlos syndrome – which by itself is often changing, there used to be 13 different types and now I think there’s only 11, and so they argue which is which – but we now know that some of the newer science that’s come out like the research from Chen and Morrissette, 2016, showed that individuals could have coexisting congenital adrenal hyperplasia with Ehlers-Danlos syndrome. And previously that wasn’t possible, there’s no way that that could be possible from a genetic standpoint. But we now know that that is possible. And so it calls into question whether or not haploinsufficiency, the gene is even necessary … It may not even matter. I don’t think that it does because I witnessed many different individuals with sever joint hypermobility that were not diagnosed with Ehlers-Danlos syndrome yet they have the same symptom profile and illness profile to somebody that does.

Ari Whitten: What does that symptom profile look like? Just out of curiosity.

Michael McEvoy: Well, the symptom profile of Ehlers-Danlos syndrome usually involves far more than hyperlaxity of the joints. It involves usually a complex dysregulation, a multi-system atrophy, a comorbidity, its comorbidity meaning multi-symptom, multi-disease, multi-everything going on. Very common symptoms in EDS and in individuals that think they have or might have EDS include some of the stuff that I’ve already mentioned such as the tissue hypoxia, extremely weak extremities or extremely weak muscle tone, muscle function, motor function has been reduced. The oxygen saturation of the tissues may be lower. Individuals may suffer from postural orthostatic tachycardia. They may suffer from mass cell activation disorder. They may suffer from chronic fatigue or they’ve been diagnosed with CFS/ME. They may have autoimmune disease. They may have lupus or RA or even history of that in the family. They may have CAH, congenital adrenal hyperplasia. They might have problems with blood clotting, which is rapid in the EDS community. They may have endometriosis or PCOS, very common among individuals with hypermobility. These are very common things that you start to see coexisting with this disease phenotype.

And what I’ve been doing over the past 14, 16 months is really looking at why and what are the best theories that could possibly explain these coexisting morbidities. We can have more detailed discussions about what some of those theories are, but in actuality they all share one common theme: it’s extracellular matrix dysfunction. And as you begin to look at the function of what the extracellular matrix is doing, the growth factors that it regulates, the ability for … So for example, one of the largest concentrations of mast cells, which are basically a type of immune cell that release histamine as well as other chemical mediators, these mast cells are found in extraordinarily high concentrations in the connective tissue of the extracellular matrix. And they have a dual function.

So a lot of us hear about mast cell activation disorder, mast cell activation syndrome, of which there is just chronic histamine intolerance, and then histamine intolerance eventually became MCAS – in a very short period of time now people are calling it MCAS, it’s no longer histamine intolerance. But the point is is that these mast cells have dual functions. They don’t only degrade and release histamine and serotonin and other mediators, they are also part of the regenerating and rebuilding phase of the matrix. But the mast cells are in a communicative kind of crosstalk with the cells that produce the extracellular matrix constituents called fibroblasts. You can think of the fibroblast cells as spiders, I like to think of them as spiders, and the matrix is the web that gets spun out from these fibroblasts.

And so when you have matrix dysregulation, when you have mast cell activation disorder you have some type of matrix involvement that’s going on. You have something that’s taking place that’s causing these mast cells to shift from a balanced state or a state of repair and regeneration to granulation and degradation. So we have to look at more causal factors. We know that environmental toxins can play a tremendous role in matrix dysregulation because of the fact that the glycosaminoglycans – and forgive me for keeping just brambling on – but the glycosaminoglycans which are one of the major constituents of the extracellular matrix, they’re often referred to as GAGs. The GAGs are negatively charged, they’re sulfated, and so a negatively-charged anion is going to attract positively-charged cations. And it’s been speculated for decades that positively-charged trivalent cationic metals like aluminum and mercury and cadmium, aluminum having a triple valent plus charge, are going to bond to the sulfate tails of the extracellular matrix glycosaminoglycans, causing potential autoimmune and/or immunological and/or inflammatory innate immune responding kinds of effects.

So Stephanie Seneff, the MIT scientist who’s done a tremendous amount of research publishing with [inaudible 00:26:09], was speculating based upon the overwhelming amount of evidence that the Monsanto chemical glyphosate from the ground up chemical … The glycine of the connective tissue is being replaced by glyphosate, they’re very, very similar in structure. And then all of her research kind of goes deeper into investigating these possible autoimmune effects because the metalloproteinases and the matrix can’t break down the glyphosate protein link bonds and so you’ve got all kinds of different problems going on.

How glyphosate affect the connective tissues

Ari Whitten: This interview is going like … There were three moments during that time that you were talking where I was about ask you a question and then I didn’t ask you the question and you actually started talking about the very thing I was going to ask you about.

Let’s go a little deeper into this because there’s a couple of things that tie into what you’re talking about. One is Robert Naviaux’s work, and I know that you’ve written a bit about the cell danger response, purinergic signaling and how that relates to the mast cells that you were just referring to. And then Stephanie Seneff’s work around the glycosaminoglycans and glyphosate and that sort of stuff. You kind of already started talking about Stephanie Seneff’s so maybe go a little deeper in that and then we can talk about Naviaux’s work a little bit.

Michael McEvoy: So glycine is probably the simplest most used amino acid in the human body and it’s integral in our DNA synthesis processes. It’s integral in so many different mechanisms that it’s really different to talk about what glycine is not being involved in. Glycine is one of the amino acids that’s used in the synthesis of glutathione, which is our most ubiquitous intracellular antioxidant system. But I should say that the highest concentration of glycine in the human body is in connective tissue, which is the extracellular matrix.

And so Stephanie Seneff postulated in the paper a couple of years ago that the chemical glyphosate is likely being substituted for glycine in the connective tissue. And so obviously the problem here is that glyphosate is very toxic. There’s been dozens of studies published around the world that have speculated that glyphosate is a probable carcinogen, it’s a probable neurotoxin, it probably causes gastrointestinal dysregulation, it might be strongly ideological with celiac disease because the celiac disease seems to have the same or very similar ideology to the effects that glyphosate toxicity has on the gut. So that research is profoundly significant because glyphosate is ubiquitously found in the environment now, it’s very difficult to avoid it even if you eat all organic foods. It’s everywhere and it’s a major problem. And some researchers even speculate that it’s one of the core problems in neurodegenerative diseases especially in some like autism, but that’s other doctors inside of this talking about that kind of stuff.

So clearly the environment that we live in, which has become increasingly more challenged with toxins of various kinds, is going to challenge our ability to have a proper functioning extracellular matrix. And consequently if the matrix is being compromised our immune system is going to become overreactive and the function of our cells is going to be impaired in many different ways.

How the extracellular matrix is connected with the Cell Danger Response

Ari Whitten: Beautiful. So let’s talk about how Robert Naviaux’s work ties into all of this now. And I think most of my listeners are probably familiar with hearing me talk about the cell danger response to some degree, but probably a little refresher would be great for a lot of people.

Michael McEvoy: So the cell danger response is a very fascinating and important concept, and I would argue one of the most important evolving bits of scientific research that’s been happening over the last several years. And it actually came out of the earlier research that had been going on since the mid ’90s and the late ’90s when they began to identify what are now being known as damage-associated molecular patterns and pathogen-associated molecular patterns. And then you’ve got other things going on like long interspersed nuclear elements and heat shock proteins and different proteins that modulate the opening and closing of the mitochondrial membrane.

And so all of this research is basically pointing to a highly conserved, ancient evolutionary process that is built into the symbiotic cells – which I’m referring [inaudible] cells and [inaudible] – these highly conserved evolutionary processes that are integral in the protection against perceived threat. Before the adaptive and even before the innate immune system is responding to threat, the cells and particularly the signals that are occurring within the mitochondria are sensing that there has been a threat to the particular cell in question.

And so consequently as a result of this highly complex, conserved danger system that’s in-built into the cells we have a series of events that takes place that alters the metabolism of the cell, changes, downregulates from fourth gear to second gear, shuts the methylation down, shuts down the consumption of energy of ATP, and now we have a coordinated defense program that’s now being initiated by the mitochondria. And this becomes a coordination. So the ATP gets ejected out of the cell into the extracellular or pericellular extracellular environment, leading to a number of additional processes including the recruitment of the innate immune system.

So basically what Dr. Naviaux has done is he’s synthesized a lot of these important concepts and he’s expounded on them by conducting further research using his blood metabolomics profile first in mice and then in a small set of humans to basically try to plot out 500 blood metabolites to find out and understand how cells tend to behave and what pathways are involved and what basically is going on. And what Naviaux and his team postulated and discovered is that the purinergic receptors and the purinergic signaling, which is all this extracellular nucleotides: ATP, but also ADP, UDP, these other purines get thrown out of the cell into the pericellular extracellular environment and begin coordinating different inflammatory events. But these extracellular nucleotides, they can then bind to different purinergic receptors and essentially perpetuate the cell danger response.

So it turns out that the activation and the binding of these purinergic receptors, this is the most common receptor type in the human physiology. Purinergic receptors are abundant in every tissue type and I believe virtually every cell type, maybe every cell type, including the central nervous system. They’re essential for development and for neural development and for growth and maturation. Their activation in certain cell types activates the mTOR system which is the anabolic growth process. So we clearly must have purinergic signaling in order to coordinate growth processes. However, it’s become clean that this danger signaling is highly relying on purinergic signaling and certain purine receptors like the P2X and the P2Y receptors to perpetuate this cell danger signaling. Now, that’s a good thing because this means that our cells have evolved to protect themselves and have a highly evolved, complex set of coordinated events to basically make sure that that happens. The problem is that for some people this process of cell danger signaling does not recede and it perpetuates and results in or contributes greatly to a disease process.

Ari Whitten: Right. And to phrase a little differently, it’s meant to turn on transiently in the context of some kind of clear threat, whether toxic exposure or an infection or a trauma or something like that, and then it’s meant to recede and go away. But in some people it seems to stay switched on basically.

Michael McEvoy: Absolutely. You just nailed it. So we have to have it, we need to have it, and for most of us it recedes. In chronic illness it doesn’t recede, it stays on all the time. Now, it could stay on all the time, you could have many discussions about why that is and we don’t exactly know yet the more intricate mechanisms of what is causing that continual perpetuation. We know that from Naviaux’s research that the purinergic receptor activity is perpetuating to an extent but we suspect that it all comes back to mitochondria because the mitochondria are highly involved in coordinating these series of the events. Well we think of the mitochondria as only producing ATP, but we now know that that’s only a partial truth. We know that the mitochondria are highly sensitive to light and to electrochemical energy and to photons. We know that the ATP are integral in this damage-associated molecular pattern signaling and cell danger response.

So the more we learn about what the mitochondria really are doing, then I believe that has to go back to evolutionary biology to look at the origins of how that symbiosis event originally occurred. I think that a lot of it is going to come back to understanding how a Proteobacteria invaded our cells and became the main workers and coordinators of the interesting things that happen. So I think it’s going to come down to a better understanding of microbes, bacteria, and the origins of how the mitochondria [inaudible] invaded our cells.

Ari Whitten: Fascinating. So this whole cell danger response, how does that tie into the extracellular matrix and also to mast cells specifically?

Michael McEvoy: So the extracellular matrix, part of the damage-associated molecular pattern process involves the breakdown of hyaluronic acid. Hyaluronic acid is one of the four major glycosaminoglycans that provide a number of important functions. For example, hyaluronic acid in its normal state is integral for the hydration of the tissue, it helps to draw water or biological electrolyte solution to the connective tissue. Hyaluronic acid also provides a certain degree of stability and stabilization to the connective tensile strength just like the other glycosaminoglycans do. It probably is involved in electrochemical communication through created ion and water balance mechanisms. But we know that when there’s a cell danger or damage-associated molecular pattern process going on this leads to the breakdown of hyaluronic acid. And those hyaluronic acid fragments are then basically DAMPs, they’re damage-associated molecular protein fragments that are now being recognized by the metalloproteinases to come and take down the rest of the ship, come and break down the matrix further, bore further holes in the process so that the immune cells can penetrate.

So that’s one way in which the extracellular matrix is affected by the cell danger response, but there’s many, many others.

For example, one of the processes of the cell danger response involves the transitioning of vitamin D calcitriol into an inactive metabolite. This is going to have a direct effect on collagen synthesis in the fibroblasts as well as the change in hormonal synthesis.

In terms of how mast cells are affected, remember that mast cells are right there in the extracellular matrix, in the connective tissue, and that when these purines and these extracellular ATP binds to the receptor of the mast cell it causes these mast cells to basically burst, degranulate, and release histamine and so you become highly symptomatic.

Again, I want to kind of bring it back because I don’t want to just talk about these things in kind of a localized context even though these little things are happening. The matrix itself, and this is something that Pissinger identified within a series of electrodermal tests and basically looking at how reflex arcs work with the brain and the connective tissue. We know that the matrix is a communication center, it is of itself a highly intelligent network of tissue and cells that when one part of the matrix is affected the entire matrix is aware of the threat. And that is something that Pissinger demonstrated repeatedly in the 1960s, ’70s, and probably up [inaudible] ’80s and ’90s, is that the matrix is in itself an entire organism or an entire organ system that is in a communication with itself and with the associated organs.

So when you have matrix dysregulation it has a systemic effect, not necessarily just a localized effect. When your mast cells are degranulating in your forearm and you’re itching like mad, that is having a direct effect on receptors in the brain, that is having a direct effect on the hypothalamus and the HPT access and the ability for certain hormones to be released. We know that the release of cortisol is going to have an effect on the matrix. We know that the release of estrogen and progesterone are also going to have an effect on the matrix. Different concentration gradients are going to have an effect on the matrix. The status of a person’s hydration is going to affect the matrix. The exposure of different light is known to affect the matrix. We know that near infrared light increases collagen synthesis. We know that near infrared light attracts water to the connective tissue. We know that the extracellular matrix is very similar in its effects that if you look at the matrisome, if you look at the tunnel-like structures that the extracellular substance is comprised of, it’s remarkably similar to Dr. Gerald Pollack’s description of exclusion zone water in which you have these lipophilic tubules that are ejecting protons and are creating a highly negative charge to maintain this water fluid concentration gradient and hydration gradient. That’s happening in the extracellular matrix and all the work in ’80s and ’90s show that, even before Pollack.

So what we’re after here is a truly more holistic way of understanding pathology, of understanding physiology and how really the matrix is an organ. I don’t know if anyone realizes this, but the interstitium was just recognized as an organ system just weeks ago. Well, the interstitium is basically a bunch of spaces filled inside of the extracellular matrix, part of the extracellular matrix. I would argue that the organ system is everything that’s around the interstitium. But the interstitium has these polysaccharides and jellylike polysaccharides and proteins. Well, polysaccharides are the basic substrate or the source of all these glycosaminoglycans that make up the collagen and the connective tissue.

The interstitium

Ari Whitten: Yeah, fascinating stuff. And again, I was just about to ask you about the interstitium and this kind of new discovery that we’re seeing headlines in the media about and you brought that up again.

Michael McEvoy: Well, I mean it’s kind of absurd in a sense, and I’ll just comment on that. Because in the oldest systems of medicine on this planet, including Chinese medicine, if you read the Neijing, which one of the oldest Chinese medicine texts, they talk about the triple burner, the triple heater san jiao channel as being the organ that includes everything but has no form. And so a lot of the really innovative acupuncture thinkers like Dr. Daniel Keown, for example, somebody that I really follow, who’s basically flipping physiology upside down and he’s a trained medical doctor looking at what the Chinese were aware of thousands of years ago. He’s saying, and I agree with him, that the interstitium is the triple burner.

So there’s this remarkable relationship between these ancient systems. And in fact, one of Pissinger’s main research projects was the use of acupuncture and the effect that that’s having on matrix function. And he was able to demonstrate clearly how the insertion of a single acupuncture needle into connective tissue caused what he calls leukocytolysis or the breakdown of billions of white blood cells. Instantaneously they begin to degrade, releasing all kinds of chemicals and essentially creating a broadband communication from the site of injection to the distant parts of the matrix.

How to strengthen the extracellular matrix

Ari Whitten: I’m glad you brought this up, there’s a couple of things here. And I want to kind of take this practical now and talk about some of the big factors that disrupt matrix functioning, you’ve already alluded to some of them, and then also talk about some of the strategies to build the health of the matrix, and acupuncture is potentially one of those.

A couple of things here. One is there seems to be some positive research on acupuncture and there also seems to be some research saying, “Hey, it’s no better than placebo effect.” So that’s kind of one thing that I was hoping to get your take on, is why there seems to be so much research that doesn’t really show profound effects.

But the other thing is in western scientific terms most people can’t really explain what acupuncture is doing. The Chinese medical explanation of it is it’s affecting certain meridian pathways. But in western medical science those meridian pathways aren’t recognized. So it’s kind of this weird thing where they’re like, “Well, we can’t really explain what’s going on in western medical science terms.”

Michael McEvoy: I disagree. If you look at embryology you can clearly explain how acupuncture is working, and that’s something that Dr. Daniel Keown has done better than anybody else that I know. So if you look at how organ systems are formed from a base template of the embryo, for example, we begin to see that the channels in the Chinese medical context or the acupuncture context are basically a representation of fascia and connective tissue that have formed as a result of embryology. And so the work of Keown and his teachers have identified this, and in my opinion – and I’m not a Chinese medical practitioner but I have kind of dabbled in some of the research – when you look at the acupuncture system from an embryological standpoint and from the standpoint of fascia and how fascia and embryology are intimately connected from the earliest stage of embryological development when we were just a template on a blank slate and that template began to grow slowly, the liver, for example, would grow and become the liver channel, the kidney meridian would grow out of the similar context. The other example, the channels in the arms would grow out of where the large intestine was. And so you have this outward growth in embryology which, if you look at the channels, in my opinion it clearly elucidates how the system actually works.

So I think that a lot of the research that has been done in acupuncture, first of all it’s looking at using certain acupuncture points from the traditional Chinese system which we’re actually more or less … That’s like the post-Maoist acupuncture that came post 1972 when the Nixon administration went to China and they witnessed the open heart surgery using needles and a local anesthetic with the chest cavity wide open and how the hell is that possible. But as a result of that Chinese medicine evolved to the United States and it was basically post-Maoist.

But aside from that, you had all these other existing acupuncture systems like the Tung [inaudible] systems, for example, that were based not on single points but on channel theory. And so there’s kind of these other schools that never really got press that had been used in China for thousands of years. So a lot of the research-

Ari Whitten: There also seems to be some other schools. There’s Japanese texts on acupuncture that seem to operate based on different points. I’ve seen practitioners who are Chinese acupuncturists and Japanese acupuncturists and they both kind of will tell you that what they’re doing is superior to what the other person was doing.

Michael McEvoy: Right. So any system eventually becomes dogmatic in a certain sense. To me, the basic research on where acupuncture should be going in the future – I’m talking about understanding it from more a physiology perspective – I think has to turn to embryology. And when you start looking at it from that perspective you start to understand how the Chinese were able to make sense of it. So I’d recommend checking out Dr. Daniel Keown for that [crosstalk].

Ari Whitten: Is he in Florida, by the way?

Michael McEvoy: No, he’s in the UK, he’s in London.

Ari Whitten: Oh, okay. I’m thinking of another acupuncturist Dr. Daniel something.

Okay, so acupuncture being something that can potentially benefit matrix functioning. What are some of the other big factors that damage matrix functioning and what are some of the big factors that people can maybe think about implementing to benefit the health of their extracellular matrix? I know that’s a very broad question.

Michael McEvoy: So as a clinician, I’m very interested in trying to figure out how things work. And when things don’t work I get even more interested in why things don’t work. And I’m interested in what causes complex illness. I’m interested in understanding the mechanisms of the health issues of my clients and really trying to understand those on a much deeper level. And that’s basically how I am.

So a lot of the research that I’ve done has kind of been around understanding how certain individuals are more predisposed to illness and certain illnesses especially. So it came to my realization that people that have even mild joint hypermobility often have many different complex health issues. Not always because there’s always outliers, but are often very prone and susceptible to different types of illness. There’s a phenotype that arises as a result of that. And again, it comes back to the collagen synthesis component, but it also involves understanding the complex interactions of how the connective tissue is involved with the nervous system, the immune system, and the endocrine system through different feedback loops and things like this.

So individuals that … And this is one phenotype that I’ve been looking at, is people that have hypermobility, even mild hypermobility, and trying to source out who in my client population has that going on and can I find any links to that hypermobility and any of the symptoms and conditions that they may be dealing with. And I found a lot of correlation to that. And since having really delved into this I’ve developed various therapeutic approaches which, fortunately, has seem to work for some percentage of these clients – not everyone, but a pretty substantial percent.

And so I’m continuously evolving my understanding of how to develop more integrated therapies for these people that have suspected matrix dysfunction. It doesn’t necessarily only involve people with hypermobility however because … And just to that point, I’ll say that because hypermobility involves defects in collagen synthesis or decorin synthesis or different things that should be integral to the function of the matrix, because that’s happening at least to some extent it’s something that I’m looking at. But clearly anybody can suffer from matrix dysregulation. In chronic illness especially you see this phenotype a lot, you see a lot of these same kinds of conditions: mast cell disorder, you see POTS. And when you start to see these things in clusters you start to see correlation.

So part of the research I started doing last year was on this gene cluster on chromosome six. This is a whole other discussion. But trying to suss out that phenotype through just identifying patterns and recognizing symptoms that they might have has led me to a deeper understanding and appreciation of what types of therapies could be useful for these people.

And so I think I’ve hit on some important key points. A lot of this is not my research, I have to credit people like Deborah Cusack for developing the Cusack Protocol for Ehlers-Danlos syndrome which is definitely a very good starting point for people that have hypermobility..

So,   harides have a role to play for sure in regulating matrix function. It really depends on the situation. I’ve seen other things going on with some of these people that have kind of this hypoxia issue. I suspect that there’s problems with the cytochrome systems in some cases. There might be poor porphyria, or Porphyria, that’s going on in some cases, which is basically a condition, the secondary Porphyria, which is problem in synthesizing heme. So, there could be cytochrome dysregulation, suspected postural orthostatic tachycardia. There could be salt wasting. I think that RCCX, which is this cluster of genes and chromosome 6s, probably strongly ideological in some of these people.

I have theories about why that is, but we can use different therapeutic modalities. We can use stuff just as simple as non-psychoactive cannabis CBD oil, for example, to help regulate stress response as well as promoting GABAergic signaling to turn off the fight or flight response. CBD has been very useful to me, especially with these people that have this phenotype of matrix dysregulation. It seems to act in similar ways to, like, [Nodel’s] Naltrexone, which other people in these different circles seem to be using with some degree of effect. So, it can modulate the pain response and pain receptors and things like this.

We can use other things too. We can use a sodium ascorbate, which is a form of vitamin C, but I know that there’s not a lot of research showing the difference between using sodium ascorbate versus, you know, ascorbic acid or calcium ascorbic. But, I think there probably is a difference in their effect. But anyhow, vitamin C is integral in the function of the matrix. In the extra cellular matrix, ascorbic plays an important role as an antioxidant in the endothelium especially. And so when you have scurvy for example, that is basically as a result of collagen break-down.

So, we need copper. Copper and vitamin C are integral to the processes of collagen synthesis. There’s a form of EDS, Ehlers-Danlos, that’s basically lysyl oxidase deficiency, which is a transport protein for copper in the connective tissue. I have observed, in other people with hyper-mobility, that there’s indications to me of low copper, either low serum or plasma copper, or low VEGF, or I’ve seen how taking supplemental copper in higher amounts can actually have a benefit to the regulation of some of these functions, that are often outward.

So, you know, there’s different ways of modulating. You know, there’s other things that seem to show up too, like the orthostatic tachycardia’s difficult. Mass cell stuff is really difficult to treat effectively, but it can correct by, you know, by using certain therapies. Like, I do use infrared sauna. I do find that that has benefit, that light therapy can correct matrix dysregulation.

The thing that we need to really address, I think, is the toxicity factor, because a lot of people that are having matrix dysregulation are probably very prone and susceptible to different environmental. Those positively charged metals are probably binding to, you know, the negatively charged groups just as we suspect, you know. I mean, again, this stuff needs to be really looked at more intensively in research. But, a lot of the early Germans tried to use different systems of medicine to create a more holistic way of supporting the function of the matrix. We know that we can support the lymphatic with it. You know, consider that the lymphatic system is a neglected part of human physiology. You know, try and look for the lymphatic system in a basic physiology textbook: you’re not going to find much.

Ari Whitten: Yeah.

Michael McEvoy: But, no, you know, no nutrition gets to the cell without the lymphatic system. It’s the transport system as well as a battleground for the immune system. And the maturation of our dendritic cells and our T-cells is largely dependent upon what’s going on in the, you know, the lymphatic fluids. And the lymphatic fluids run through the connective tissue. And so, there’s cross-talk that’s happening between all of these systems. We can use things like lymphatic drainage massage. We could sue different ways to stimulate the lymphatic system: jumping on a trampoline, doing exercise, sauna therapy, to mobilize the lymphatic system; muscular contraction to do that.

So, we need to really approach matrix dysregulation from a holistic viewpoint, while taking into account the problems that each individual is presenting with.

The most beneficial therapies for optimizing the extracellular matrix

Ari Whitten: So, you mentioned toxins being a big factor. Some of the most beneficial things: sauna, light exposure, near-Infrared light; big fan of that. And I know you’re presenting a holistic view, and I’m kind of doing this very myopic reductionist take on it. Just try to summarize this. But, to just kind of list off some of the most beneficial therapies that you’ve found, are there any other things worth mentioning here?

Michael McEvoy: Well, again I think that we have to recognize the factors that are causing matrix dysregulation. So, if it’s mold, we have to address that; if somebody’s living in a water-damaged building and they’re highly susceptible to that, their matrix is being bored. Their metalloprotein is not … and they can test the MMP-9 level, and if it’s elevated, it’s suggesting that the matrix is being degraded, because metalloprotein is breaking it down.

So, we have to first understand what is the cause of the matrix dysregulation. If a person is taking a Cipro, for example, or any of the floral quinolone antibiotics, they act by degrading matrix proteins. So, you know, there’s a lot of different variables. So, instead of throwing a boatload of supplements at somebody, we need to first address what’s going on on an individual basis that’s causing this problem to begin with.

Ari Whitten: Yeah.

Michael McEvoy: At least develop some educated clinical hypothesis about it. I mean, you know, the thing with clinical hypotheses is that you’re not going to be right 100%. You’ll be right maybe 20 to 30% of the time. But maybe something that you’ve recommended has made an impact, and if you’re close then hopefully, you know, you’re getting closer.

Ari Whitten: Yeah.

Michael McEvoy: So, supporting basic matrix function. So, marine red algae has been shown in some research to inhibit metalloproteinase-9, to increase collagen synthesis; I have witnessed that, in an individual’s Crohn’s disease for example. Had joint hyper-mobility in his [distill 00:07:43] fingers; he’s almost able to touch his forearms with the tips of his fingers. And, you know, high levels of C-reactive protein. He began taking a regimen of sulfated polysaccharides from marine red algae and increased the dosage of vitamin C, and within about 10 to 14 days he became 30% less hyper-mobile in his finger joints. And all of these inflammatory markers: the C-reactive protein at one point was over 200, and it completely normalized.

Ari Whitten: Wow.

Michael McEvoy: So, there’s something to it. And there’s evidence that these therapies are having an effect. And, you know, it’s obviously going to take a long time before the research catches up to it if it’s ever done. There is some research that’s been done, but … anyway. I don’t anticipate anybody doing widespread clinical trials on this.

The reason why this stuff is very difficult is that there’s not a lot of clinical testing to use to evaluate the function of the extra-cellular matrix. There’s a few, but, you know, MMP-9, maybe TGF beta, but that’s non-specific. You know, there’s not a lot. The matrix is a dynamic, moving living thing that is constantly breaking down and being regenerated. And that bio-rhythm is going to change.

You know, so being able to look a these things from … We need new systems for being able to look at this stuff. We can’t use these antiquated old systems. One of the problems I have with scientific research is that they study one disease, or one condition, and one variable. But the reality is that chronic illness is not … There’s no such thing as a single cause to a single disease. And furthermore, these people that we see with complex illness, they have multiple symptoms across multiple system atropy going on. How are you going to study that?

You know, like Dale Bredesen study with Alzheimer’s was rejected because it was too complicated!

Ari Whitten: Right.

Michael McEvoy: He’s trying to study 140 different factors in Alzheimer’s disease, but meanwhile, “Here’s your drug to treat acetylcholinesterase.” Forget it! It’s not working! We need to develop more complex models for addressing complex illness, otherwise it’s failure. Medicine will never evolve.

Ari Whitten: 100%. So, I know that we had in mind to cover some of Heinrich Kramer’s work as well, and there was a few other topics we wanted to cover, but we’ve already gone over like an hour and a half, and I want to be sensitive to your time here. But maybe we’ll have to do a part two of this podcast, and I’d love to have you on again.

And, Michael, thank you so much for doing this. This has been a pleasure, and I think that listeners are really going to enjoy hearing this very novel, non-typical conversation about some of the factors that are affecting their health; they’re going on outside of their cells. So, this has been fascinating for my own edification as well.

So, thank you so much. It’s really been a pleasure to have you on, and I look forward to part two.

Michael McEvoy: Thanks, Ari, for having me.

Ari Whitten: Yeah.

The Extracellular Matrix — A Secret Key to Health and Energy with Michael McEvoy – Show Notes

Why medical professionals in the US only focus on what is going on inside the cells rather than the extracellular matrix (8:07)
What diseases are caused by a dysfunctional extracellular environment (10:46)
How glyphosate affect the connective tissues (26:53)
How the extracellular matrix is connected with the Cell Danger Response (29:55)
The interstitium (43:25)
How to strengthen the extracellular matrix (45:07)
The most beneficial therapies for optimizing the extracellular matrix (59:50)


extracellular matrix
A highly functioning extracellular matrix is supported by a strong immune system.
Check out the podcast with Dr. Guillermo Ruiz on how you can boost your immune system to increase energy

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