Genes are an essential part of who we are as individuals, and impact heavily on our susceptibility to various health conditions.
In recent years, it’s been popular to talk about how certain gene variations (SNPs) can impact on your propensity to have certan health issues (e.g. MTHFR gene variants and methylation problems, etc.) But beyond SNPs, there may be even deeper genetic issues at play for many people with complex chronic illnesses.
A few weeks ago, Michael McEvoy asked me if he could come on the podcast to talk about some new research he’s looking into (and a theory he’s developing around it) on something called the RCCX gene cluster. He believes that this may be a key to understanding many complex illnesses such as CFS, Fibromyalgia, EDS, POTS, and various autoimmune diseases.
Interestingly, it predominately affects women, and it seems to affect women who are uniquely intelligent (even geniuses in many cases), and who have special and unique talents. So there seems to be some kind of evolutionary tradeoff at play here, where genes that lead to benefits in some areas lead to higher potential for issues in other areas.
This week, Michael McEvoy is back to share his expertise on these specific genes and how they affect health. (For those of you who did not listen to our previous podcast with Michael. Michael McEvoy is the Founder of Metabolic Healing and Cofounder of TrueReport. He is recognized as a thought leader, systems creator, educator and integrator of diverse clinical modalities and he has created the Metabolic Healing Institute.)
WARNING: I must issue a warning with this podcast. This will be an extremely challenging interview to listen to for many of you — it is very detailed and complex in certain aspects of the science, and is rich in scientific jargon. At the end of the podcast, I even said to Michael that I’m going to have to get a trophy or t-shirt made for him because he’s won the prize for geekiest science podcast I’ve ever done. It’s great, exciting material, but again, I do feel compelled to warn you that this may just be too complex and too jargony for those of you without a strong background in science. If you don’t have a background in science, and you don’t have chronic complex illness, honestly, you may want to skip this one to avoid frustration of not being able to understand much of what’s being said. Or if you love a challenge, feel free to listen in.)
But if you have a chronic complex illness or your have hypermobility issues, this is a must-listen podcast.
It is the second time in a few weeks that I have Michael McEvoy as a guest on the podcast. Last time, we talked about the extracellular matrix and how this is a secret key to health and energy. If you haven’t had a chance to listen to it, I would strongly recommend that you listen to that here prior to this one.
In this podcast, you’ll learn
- The autoimmune conditions that can be affected by the RCCX gene cluster
- The pros and cons of RCCX
- The link between complex chronic illness and hypermobility
- The evolutionary tradeoff of genius and illness
- The unorthodox way to identify if you have RCCX gene cluster issues
- Michael’s theory about the RCCX gene cluster and the stress response system (HPA axis)
- How the RCCX gene region is affected by retroviruses
- How the lymphatic system is connected to RCCX
- How each gene mutation has its own benefits and drawback
- The connection between the Cell Danger Response (CDR) and the RCCX gene cluster
Download or listen on iTunes
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The Fascinating Genes (RCCX) That May Be Behind Many Complex Chronic Illnesses (CFS, Fibromyalgia, EDS, POTS, autoimmune diseases) with Michael McEvoy – Transcript
Ari Whitten: Guys, this is Ari Whitten and welcome back to The Energy Blueprint podcast. I am here for the second time with Michael McEvoy who is the Founder of Metabolic Healing and Cofounder of TrueReport. He is recognized as a thought leader, systems creator, educator and integrator of diverse clinical modalities. He has created the Metabolic Healing Institute out of the need for deeper clinical applications and clarity of vision in the field of functional medicine and integrative healthcare.
I’ve already had him on the podcast once and it was a blast so I’m excited to have this new, what I promise is going to be an extremely geeky conversation around some sets of genes that are very, very interesting and potentially very insightful. Michael reached out to me a few days ago and said he’s got this theory around this really cool stuff and wants to come on and talk about it and would I want to talk about it and I said yes.
Today, when I went to go do some background reading, I regretted saying yes because the stuff is so complex that I’m like, geez, I’ve never had a harder time prepping for an interview than this one. Welcome Michael with all of that said. Everybody, get ready for some geeky science talk.
Michael McEvoy: Thanks Ari for having me and for letting me go on about this stuff. This is great. This is going to be interesting.
What RCCX is
Ari Whitten: Yeah. What is this stuff all about? This theory is on something called RCCX which is a set of different genes. It’s described differently by different people. They use different terms like RCCX module and genotype and there’s a lot of different words that kind of get thrown around here. What the heck is RCCX and why should anybody care about this?
Michael McEvoy: I’ll trail you that question by talking about the advent of genomic testing as of the last several years, even decades for that matter. As we know, there’s been an extraordinary explosion of data in research aggregation pertaining to various aspects of human genetics. From this process, since the human genome was fully sequenced 20 some years ago now, there’s been just a huge push forward.
In the alternative health world, there has been many attempts over the last several years especially since the advent of direct to consumer genetic testing such as from companies like 23andMe and AncestryDNA and some of these other companies where there’s a lot of people out there who are looking at creating health programs and supplement programs that are based upon their genetic data.
The majority of that type of data and the majority of this kind of fever about genetics and what’s called nutrigenomics, the interaction between genes and nutrients and now they give you supplements, diet and all this stuff is largely convoluted.
Ari Whitten: Yeah.
Michael McEvoy: I would argue that the application of that information has largely been a failure in terms of being able to significantly impact a person’s health by using genetic information. The majority of that is, of all this stuff that I’m referring to, nutrigenomics is based around what are called singular nucleotide polymorphisms or SNPS. Basically, singular nucleotide polymorphisms are like little parts of a gene that make up the whole gene.
The majority of the research about genetics is about SNPS, singular nucleotide polymorphisms and the unbelievable amount of studies and data that’s been done on the different disease, associations with singular nucleotide polymorphisms and then the alternative world, we can take methyl folate if you have an MTHFR mutation or “mutation”, it’s not really a mutation, it’s technically a variation, if you will or take some other supplement because you have this SNP or take that supplement if you have that SNP.
That approach generally doesn’t work.
Ari Whitten: Yeah.
Michael McEvoy: It really doesn’t work … There’s a lot of reasons why it doesn’t work but there’s a lot of misinformation, there’s a lot of misinterpretation, there’s a lot that we just don’t know about singular nucleotide polymorphisms and the incidence of disease. We know that there’s associations, associations [inaudible] or any causation, there’s a lot of factors that regulate how our genes express so just because you see your 23andMe report and you say, “My God. I’ve got a 43.5% chance of getting Parkinson’s disease by the time I’m 62 and a quarter.”
We have to take that stuff very, very … with a grain of salt because there’s a lot of different variables and the status of the SNP is only one little tiny thing. With all of that said, when we talk about this RCCX gene cluster, we are not talking about singular nucleotide polymorphisms, we’re talking about a different area of our genetics which is basically called … a part of our genetics, it’s sort an anomalous part of our human genetics that we still are learning about called copy number variations, CNVs, copy number variations.
Copy number variations are a very, very interesting part of human genetics because there are pretty rare occurrence. They only come … copy number variation gene sequence is only comprised something like 4.5% to 9% of human genetics which is not a huge percent but we know that copy number variations are strongly associated to a lot of different disease processes especially chronic disease processes, complex diseases.
As we start to learn more about copy number variations, we start to realize that they greatly influence gene expression and that’s significant because singular nucleotide polymorphisms don’t necessarily directly influence gene expression, there are other things that do and when it kind of the rubber meets the road in terms of genetics and health is what’s the gene expression that’s going on because we know that there’s the role of genetics and disease, that’s true but it’s very complicated.
I just wanted to start up by saying that RCCX, when I tell people about what RCCX is, we are not talking about the majority of scientific research that’s been done on SNPS, singular nucleotide polymorphisms, we’re talking about a very rare part of human genetics, that’s copy number variations and all of the different problems that copy number variations are known to cause when we have different genotypes, different forms of those copy number variations.
Does that help to put the perspective into this a little bit?
The interaction between RCCX copy number variations and gene expression
Ari Whitten: Yeah, absolutely. That was actually … One of my first questions was going to be to clarify the difference between SNPS and this RCCX copy number variations stuff. What’s the interaction between these copy number variations and gene expression? What’s the connection there?
Michael McEvoy: Copy number variations are prone to causing genomic instability for a number of reasons. I’ll start also by saying that it’s very difficult to discuss the role of genetics in disease without also simultaneously discussing the role of genetics in evolution that’s because with all genetic variations that we possess, whether you’re talking about SNPS or copy number variations or anything related to genetics, there’s always two sides of the coin.
Ari Whitten: I’m so glad that you’re broaching this topic because it’s so neglected in my opinion by so many people talking about genes.
Michael McEvoy: Yeah. There’s a reason why we’ve inherited … I like to think that there’s a reason why we’ve inherited certain gene sets, certain gene types, certain SNP variations and those largely are about diversity in the human population and the strengths and weaknesses that are associated with those different genetic variations. There are always two sides to a coin so for example, the gene that leads to sickle cell anemia protects you from malaria so it’s two sides of the coin. Yes, you have sickle cell anemia but you’re also protected from this very bad pathogen.
There’s a lot of other examples of that as you start to mine the research about genetics so I think that that’s a central thing that needs to be discussed when talking about what RCCX actually represents because as we learn about the genes that actually comprise RCCX, we actually find how critical they are, how essential they are to the entire physiology. Some individuals that have this RCCX genotype or different RCCX genotype have a genius level of intelligence, intellect. Oftentimes, they have a very high emotional intelligence, not only IQ but emotional intelligence.
Michael McEvoy: Again, this is a specific phenotype within the genotype. This phenotype also may possess-
Ari Whitten: Michael, it might be good to just define those terms, genotype and phenotype for people not familiar with that.
Michael McEvoy: A good way to think of that is genotype is like the gene combination that you have and the phenotype is what gets expressed, if you will, if that definition suffices in layman’s terms. Sometimes, I use those interchangeably because I’m not thinking clearly. What we were saying. We were saying-
The Pros and Cons of RCCX
Ari Whitten: Pro and cons of RCCX.
Michael McEvoy: Right. The certain people that have certain RCCX genotypes, they are often brilliant. They often have a genius intellect and emotional intelligence and are highly in tune with different emotional parts of themselves. I would even argue that there are spiritually advanced individuals in some cases but they have … often, they have a preponderance of chronic disease and an intolerance to stress and they may border on mental illness or have full-blown schizophrenia or bipolar disorder so it’s two sides of the coin.
It’s a tradeoff, right? It’s an evolutionary tradeoff to have genius intelligence but borderline psychosis at the same time or chronic disease or autoimmune disease running through the family, right? That’s an important thing to discuss and to understand about human genetics, the flip sides of it and really, as we get into the composition of this gene cluster and we learn about the disease associations that are so strongly profoundly linked to the genes on this cluster and all of the things that can go wrong and do go wrong with individuals that have been proven to go wrong with individuals, to me, the RCCX gene cluster doesn’t only represent one of the most significant parts of the human genome but also is a central part to how our bodies are designed, how we are programmed to defend ourselves against the threat of danger.
Danger in the context of pathogenic influence, danger in the context of stress, danger in the context of fear. In the pre-evolutionary times, the RCCX genotype probably would not have survived in the wild because generally, they’re intolerant to stress and they probably would have been killed so evolutionarily, they would have had to have adapted in some other way and they adapted through their intelligence and their intellect.
That is how I envision the evolutionary development of the RCCX genotype through the ages is I believe as we look, we’ll probably eventually discover that many of the most brilliant minds throughout human history were probably RCCX monomodular forms or different variations and died from various complex diseases largely because of their genetic susceptibility.
Ari Whitten: I just had this weird visual pop into my head as you were describing this, like a bee colony with a queen bee where the queen bee is just sitting in this very insulated environment protected from all the stressors as all the worker bees are doing all the work and bringing back resources to the queen bee but the queen bee is the dominant ruling force. Maybe this is exaggerating too much but envisioning as this highly intelligent being that’s controlling the colony while all the other worker bees are exposed to all the stresses and doing all the work and all that stuff.
I just wanted to mention that because that was a visual that popped into my head.
Michael McEvoy: I love it. I love it. I was actually just using an analogy that RCCX is like a wasp’s nest. As you start to really look at it, it’s a wasp’s nest when you start to really see what’s happening here. Yeah. We have here a copy number variation that’s prone to genomic instability that’s highly susceptible to genetic instability and by genomic instability, I mean that because … What is a copy number variation? Let’s define that.
A copy number variation is a gene sequence that the genes that make up that sequence, first of all, they tend to behave as one gene as opposed to four separate genes so when one gene is affected, they all tend to be affected. That’s significant. The other thing that we can say about copy number variations is that what they really are is they are … basically the cluster of these genes will create duplications of themselves and then these miniature duplications will then be laid out on the chromosome itself. That’s a phenomenon that actually is what’s defining copy number variation.
The problem with that is that the copy number variations, these little pseudogenes and these copies that get made of these genes can create a lot of genetic instability. When the DNA gets converted to RNA and the RNA gets converted to a protein or enzyme that the body uses, this copy number variation can create havoc in that process.
Symptoms and visions associated with the RCCX gene cluster
Ari Whitten: Fascinating stuff and thank you for skillfully navigating very complex stuff. In order to avoid losing people with too much complex science, let’s go a little practical right now and talk about what exactly are some of the symptoms and visions that are associated with this gene cluster?
Michael McEvoy: Yeah, what I’d like to do, Ari, is to give you a summary of the common classical phenotype of RCCX. The best way that I found to evaluate who these people are in the population is by taking an inventory of the family history and that often helps to really tip the scale in terms of understanding who we’re dealing with because the families … the people that have an unfavorable RCCX genotype, you’ll see a lot of common themes in the family. The first thing I look at is the symptoms that are associated with joint hypermobility and skin hyperelasticity.
In our last podcast, we were talking about the extracellular matrix and the associations between extracellular matrix dysfunction and the prevalence of joint hypermobility, double-jointedness, hyperelasticity of the skin and all of the different problems that that can cause. When you see somebody that has joint hypermobility, there is oftentimes a high preponderance of other conditions and/or symptoms of diseases, a term that’s called comorbidities. There are multiple conditions and/or diseases occurring within somebody’s body.
To me, when I’m looking to evaluate an RCCX phenotype, the first thing I’m looking for is, is the person, do they joint hyperextensibility? Can their thumbs do this or can their fingers … can they pull their fingers all the way back to touch their forearm? Do their elbows hyperextend? Do their knees hyperextend? In some severe cases, dislocation of the joints and severe forms of Ehlers-Danlos syndrome, Morvan syndrome. That’s the first tipoff.
Now, that’s not the only thing but if those hypermobility symptoms also involve autoimmune diseases, again, these autoimmune diseases could be in the individual question or in the family members even. The primary autoimmune diseases that are associated with the RCCX cluster are all those that are basically associated with complement C4 deficiency, just one of the genes and they are lupus with a preponderance of 75% of individuals with lupus are believed to be C4 deficient. Boom.
Lupus, rheumatoid arthritis, celiac disease, Graves’ disease, type 1 diabetes and ankylosing spondylitis. Those are probably the top six types of autoimmune diseases that if an individual is hypermobile plus has hypermobility plus one of those autoimmune diseases, there’s a pretty good chance that there’s something going on with their RCCX cluster that needs to be sussed out.
Now, we’re not stopping there because that’s only a little bit of it so the other part of it is that are there people in the family with mental illness or neuropsychiatric conditions? Schizophrenia and bipolar disorder are strongly linked to a complement C4 deficiency. Oftentimes, these people say, “Yeah. My mother is schizophrenic and my sister has lupus and I’m hypermobile and I can do all this. I can do all these hypermobile things with my shoulders and my arms and I have always been able to do that.”
Sometimes, you’ll see cardiac valve deformity or abnormalities where you have bicuspid or tricuspid valve abnormalities that arise and that’s again, because of the tenascin X extracellular matrix, the TNXB gene which is part of the RCCX region. If there are a collagen and connected tissue deficiency, it can co-segregate with valve-related problems. Bowel diseases, I should also mention celiac disease and Crohn’s disease could run parallel with RCCX because the tenascin gene which is part of the RCCX cluster is critical as part of the basement membrane in the intestinal mucosal barrier in the submucosal layer so that’s strongly linked here as well.
You could start by looking at the family history of mental illness, of autoimmune disease. Autism is strongly linked to a complement C4B deficiency where two studies found consistently and each of these studies was looking at two different populations of 80 patients with an autism diagnosis, 40% exhibited a complement C4B deficiency which is right there on the RCCX cluster.
Ari Whitten: Michael, can you quickly define the complement C4, what that is for people?
Michael McEvoy: Complement C4 is one of the most important immune proteins that is involved in a part of the immune system known as the innate immune system. The innate immune system is older. It predates the antibody system so antibodies help to form memory but they also … immunological memory of infections so you can remember to fight a pathogen once you had it but antibodies play an important role in binding the different pathogens to help recruit inflammation and all that.
C4 as well as some of the other complements, they’re called complement proteins are a critical part of the innate immune system and that innate immune system is like the first … it’s really involved in the first danger signal that takes place. If a virus is passing through my tissue and has now made its way through my extracellular matrix and my cells are detecting viral infiltration, this will cause the recruitment of complement C4 and complement C2 and some of these other complements to come and basically innate, to infiltrate and to create immunological responses that will result in inflammation and then the recruitment of antibodies.
C4 is critical for that process. Complement C4 is also critical for a process known as dendritic and synaptic pruning. In fact, the literature has found that of all of the different genes that are in the central nervous system that are involved in dendritic and synaptic pruning which is … I should define what that means. Think of, you’ve got a fruit tree that’s overgrowing. In order for that tree to bear fruit and to be healthy, you’ve got to trim back the branches.
When our brains are developing from the time we come out of the womb to adolescence basically, we have these processes, the trim and maintain our neural tissue and synapses so that we can kind of not have a lot of clutter and junk. Of all the genes that are involved in that pruning process, complement C4 has been shown to be the most significant so that’s one of the reasons why it’s strongly linked … deficiency of C4 is strongly linked to schizophrenia, it’s linked to bipolar disorder and it’s also strongly linked to autism.
Ari Whitten: Basically, you have brain connections that … a preponderance of brain connections that in a person with higher C4 and maybe without the RCCX cluster, they would prune those synaptic connections and in this case, you have all sorts of brain connections that are there that really maybe shouldn’t be there or wouldn’t be there in a person with a different gene variation?
Michael McEvoy: Totally. The pruning process is a really complicated thing and I really only understand a small amount of it. I’m sure the neuroscientists probably understand more but we know that there’s got to be balanced and there’s got to be the right kind of pruning going on and we know that in autism for example which is now arguably an epidemic, maybe [inaudible] at this point that in autism, synaptic pruning is … deficiency of synaptic pruning is a known major contributing problem.
I recently wrote this article and talked about it and showed some of the papers that are published about this. Complement C4 is right there and you basically got a C4B deficiency which creates problems in the expression of the neighboring C4A gene and the RNA and all that. The process isn’t working right and there’s something really significant going on there but it links right back to RCCX.
Testing for RCCX
Ari Whitten: Are there any test that one can get to determine if they have RCCX or is it more like symptom-based like what you’re describing, somebody is going to have the experience like, “My mom has lupus and my brother has schizophrenia and I can do all these weird hypermobile things”, and maybe also positive side to that like, “My mom is a super genius.”
Michael McEvoy: Right. Totally.
Ari Whitten: Can somebody go to 23andMe and find out if they have this gene cluster or is it more based on those symptoms and family history?
Michael McEvoy: No. Currently as it is at this time, there’s only a very small handful of labs in the world that are capable of sequencing the RCCX gene region. You can’t go to 23andMe and get this cluster sequenced. You can’t walk into LabCorp or Quest Diagnostics to get it sequenced either. It’s found, and I’ll just say this really quickly since we’re on the genetics part. The region that … The gene region on chromosome 6 that RCCX is found in is known as the MHC region or the HLA MHC set of genes. It’s said to have what’s called a very long linkage disequilibrium which basically means that this is a really, really, really complicated part of our human genetics that is involved in immune response and immune signaling and inflammation and it’s just a whole parade of complex genes that have so much different variability and RCCX is literally right smack in the middle of this complex thing. We’re dealing with a very complex gene cluster in the middle of arguably the most complex part of the human genome.
Scientists really don’t have a great way of … Unless you’re involved in scientific research, study, there’s not something … this isn’t something you can necessarily get clinically done yet. Even if you did, even if you went to those small, maybe five labs in the world that can do it, even if you did that, there’s still a lot of things that they can’t assess because they just haven’t done that depth of research to know what’s really going on here.
In terms of the copy number variation, like as I was saying before, the cluster can create all of these different pseudo miniature genes that create the instability and the problems. All of the little anomalous events that are taking place there which are really significant really haven’t been totally sussed out. We know that they’re happening but there hasn’t been a research team that’s really put the big picture together and said, “This thing is … This is the thing that you really be looking at. Look at the whole thing here. It’s unbelievable.”
Ari Whitten: Putting the pieces together to figure out whether this is relevant to you still … it sounds like it revolves a lot around that family history.
Michael McEvoy: Yeah. To answer your question, right now, the best way to figure out who has some unfavorable RCCX genotype that’s probably associated with their conditions is by looking at those associations of their own medical health history and those of their family and looking at the whole thing and saying, yeah that all make sense because all of these diseases are very strongly linked to the genes on the RCCX cluster.
How cortisol levels are affected by your genes
Ari Whitten: It sounds like you could say with some degree of confidence, a good degree of confidence that if somebody has that, if they report those kinds of things like, my mom has bipolar and my sister has lupus and I’m hypermobile, it sounds like you could probably say with a high degree of confidence that RCCX is prevalent there. Is that accurate?
Michael McEvoy: Yeah. I would say that that’s such a … because there are so many very strong associations between diseases and this cluster of genes especially the prevalence of certain diseases like lupus, like a 75% probability that you’re C4 deficient. Then there was actually a study that looked at the association between lupus and hypermobility. Who decided to do that? They found 48% or something. That’s significant. 40% of autistic kids with a C4B deficiency. That’s significant. A huge percentage of schizophrenia with C4 deficiency, that’s significant.
The frequency and the type of illnesses and the disease and the frequency of those diseases are all pointing to this cluster as being highly significant. The other thing I wanted to mention before we forget is the fact that in the middle of this RCCX gene cluster is the gene that makes cortisol, the body’s main stress response hormone and the other one being aldosterone which is the gene that … it’s the same gene that makes them … the gene that retains our sodium levels and regulates our salt balance.
That’s very significant for a number of reasons. Obviously, adrenal problems have been studied and debated continuously and endlessly for a very long time to where you have a lot of the conventional medical system denying that there’s such a thing as adrenal fatigue to other practitioners using that as a diagnostic to somewhere in the middle saying, “It’s not really adrenal fatigue, it’s HPA access dysregulation.” What I’m saying is that, okay, adrenal fatigue is a nonsensical diagnosis. Okay. I’ll go with as far as … sure, of course because there’s always something deeper going on, right?
What all of these viewpoints haven’t really taken into account is that the gene that’s actually making the adrenal hormone cortisol is involved in this highly complex gene cluster that’s strongly linked to different diseases and genetic instability and problems so it leads to a further investigation into what really is going on then with cortisol and its relationship because these four genes tend to co-segregate, they tend to behave like one gene rather than four separate genes because that’s been established.
That means that if we have problems with cortisol, we might have problems with our innate immune system and we might have problems with our cell danger response and we might have problems with autoimmune disease and we might have problems with hypermobility in some cases or we might have problems with our ability to prune our synapses properly. As you look at the research on this, it’s like there are so many things that start to unfold and from a researcher and clinician, I start to look at this and I have been doing this for 12 years or so and I say, “Wow. Now I’m starting to see the associations between why so many people that get sick say it’s all my adrenals.”
It’s not all your adrenals but the fact that the major gene that is producing your cortisol for your adrenal cortex is highly involved in a lot of different immunological processes.
Ari Whitten: On that point specifically, what would you actually expect to see if you did cortisol measurements on a person with this RCCX?
Michael McEvoy: There has been some initial investigation into that. We know that there are different genotypes of RCCX. There’s actually something like 16 different possible genotypes for an RCCX person, somebody with RCCX. Even one in 16 but even within that, there’s more because the degree of different mutation of each of the genes could also … that also has to be taken into consideration and that’s not necessarily diagnosed or defined by the modular forms themselves.
The most extreme form of … The gene that makes cortisol is known as CYP21A2 and it codes for an enzyme known as 21-hydroxylase. It basically takes your progesterone and it makes cortisol and aldosterone from that. In the most extreme case of CYP21A2 deficiency where there’s enough gene … not enough gene product gets produced, that causes a condition known as congenital adrenal hyperplasia or CAH which is another … that’s another RCCX association.
Congenital adrenal hyperplasia is basically when that gene that makes cortisol is so deformed or mutated or damaged or problematic that you’re not making enough cortisol. What winds up happening is you have a bottleneck where you get too many androgenic hormones because the progesterone goes over to the other pathway so a lot of the people with congenital adrenal hyperplasia also known as CAH develop a syndrome known as polycystic ovarian syndrome, an ovarian cyst and that’s the link and the connection between the prevalence of CAH, congenital adrenal hyperplasia and hypergonadism and high androgens and ovarian cysts.
That’s an extreme case of full-blown CYP21A2 deficiency. Now, it’s been known for 30 years that milder forms of 21-hydroxylase deficiency exist and Sharon Meglathery who’s a psychiatrist that originated the synthesis, the synthesis of the RCCX theory believes that as much as 20% of the population has some … at least a mild form of 21-hydroxylase deficiency. The literature says isn’t that high if that’s 30 some years ago but it’s still high enough to be significant in different racial populations, different races.
Ari Whitten: You would expect to find that people with RCCX would have a much higher prevalence of 21-hydroxylase deficiency and low cortisol levels basically?
Michael McEvoy: That definitely occurs and I’ve seen the suspected phenotype that matches the profile that has lower cortisol levels but the other thing that we have to address is that, and this is where it even gets more complicated is that the adrenal glands are not the only cell in the body that makes cortisol. CYP21A2 is actually found in different tissues throughout the body. That’s significant because it shows us that the standardized testing that we use whether it is blood, saliva or urine are still very limited in what they can show us in terms of what-
Ari Whitten: You’re alluding to measuring cortisol inside of cells.
Michael McEvoy: Yeah. That’s a really difficult thing. You can’t really do that clinically so we can’t really get the most accurate picture. There have been attempts to actually do what’s called ACTH stimulation which is basically, they administer the parent hormone of cortisol which is the pituitary hormone ACTH to the suspected RCCX types to see what the response would be and many of them did get sick as expected because they would just not be able to convert to cortisol rapidly or readily.
Is there a trend for low circulating cortisol or low urinary cortisol or low serum cortisol in people with mild 21-hydroxylase deficiency? I don’t know and I don’t know if anyone has really done an in-depth study of that yet.
Ari Whitten: I’ve only looked at the research on chronic fatigue syndrome specifically and there’s definitely a portion of people, roughly 30% of people with chronic fatigue syndrome who will show up as having low cortisol, like 15% will have high and the majority will have normal. In Robert Naviaux’s metabolomics study with chronic fatigue syndrome, cortisol was normal but it’s still very possible that there is a specific segment of those people that has 21-hydroxylase deficiency and low cortisol.
Michael McEvoy: Yeah. I think that that’s probably true and we can’t measure … the metabolomics is a good test because it’s a blood profile of 500 different metabolites and there’s a lot of data there. Chronic fatigue syndrome, myalgic encephalomyelitis may very well be linked to RCCX in some cases. There was about 10 years ago, a lot of research coming out about the role of different types of retroviruses in chronic fatigue syndrome and this led to a lot of different controversy.
Ari Whitten: Yeah.
How endegenous retroviruses are affected by the RCCX gene region
Michael McEvoy: There were a lot of different papers that were published about this, not only Judy Mikovits’ paper but there were papers coming out of Europe that was showing different retroviruses that were being expressed in chronic fatigue syndrome and they were trying to link this to being the sole thing or one of the major ideologies with it. What we know is that the RCCX gene region has in it two retroviral elements. I’m going to go into this just a little bit because it’s really important and it’s also an area of research that needs more intention.
We know retroviruses are a type of a virus known as RNA virus and they differ from viruses because they produce … they basically can be reversed … what’s called reverse transcription but about 13 … somewhere between 8% and 13% of our human genetics, our DNA is actually contained in them retroviruses and it’s actually retroviruses that played a part of our evolution and probably a very important role actually in our evolutionary process.
The RCCX gene cluster contains in it two retroviral elements. One of the retroviruses is known as HERV-K and HERV-K is actually situated within the complement C4 gene in the cluster. The presence of retroviruses in genes is known to cause deletions and duplications to nearby genes. The presence of retroviruses in the DNA is known to become reactivated in certain states of cell danger signaling. The presence of retroviruses is known to activate certain parts of the innate immune system such as complement C4 which is where the HERV-K is found in … one of the genes that it’s found in and we know that certain chronic illnesses involve the activation of endogenous retroviruses like HERV-K, HERV-H and HERV-W.
Autism has been shown to have … studies showing that HERV-K is present in autism so retroviral activation as Naviaux has pointed out is the, as he calls them, the sixth step of the cell danger response process, the mobilization of endogenous retroviruses from within the nuclear genome and retroviral-like elements. The RP1 gene on the RCCX cluster contains in it a retroviral-like element known as a long interspersed nuclear element or a line also known as a retrotransposon and we know that these things can cause DNA mutation as well as problems to gene expression like the retrovirus can.
We got a bag of tricks here with RCCX and we’ve got … Now, where I’m at with this whole thing is I look at what these genes actually do physiologically, what they encode for and I look at the whole picture and say, what is this cluster all about? What is this? Yes, we have these disease associations all over the place and that’s enough research to keep you busy for a year just looking at the different associations but the big picture to me is what does it represent?
What it represents to me is it represents the epicenter of the cell danger response process, not only the epicenter of the cell danger response process but I would say the epicenter of the entire physiological danger response orchestra that coordinates the response from the endocrine system, your cortisol, from the nervous system, your complement C4, from your innate immune system and from the reverse transcription of retroviral elements from within the nuclear genome to activate innate immune activities.
Ari Whitten: Yeah. This is fascinating. One of the things that I was reading up on to prep for this interview was Dr. Meglathery, how do you say her name? Meglathery.
Michael McEvoy: Meglathery.
Ari Whitten: About pushing through this concept of, that people with this particular RCCX module or gene cluster tend … There were various phrases that she used like the hormonal MLU wires the brain towards hyperresponsiveness, toward stress or to being not very resilient as well as to pushing through to simultaneously having this tendency to not listen to the body when you’re in stress and to push through these cues from the body telling you to rest and to just keep going, keep going which also has interesting parallels to there’s research talking about self-critical perfectionist types, being more prone to various chronic diseases.
[inaudible] does work … There’s a guy in the UK who does a lot of stuff with his amygdala, a retraining program for people with chronic fatigue.
Michael McEvoy: Right. Totally.
How people with the RCCX phenotype are prone to emotional processing disorders
Ari Whitten: Talks a lot about these very driven, perfectionist types of people who tend to push through stress so there’s a lot of interesting parallels going on here.
Michael McEvoy: The research that’s been done that I found on patients with congenital adrenal hyperplasia which is the most extreme form of 21-hydroxylase deficiency finds that these patients tend to have abnormally sized hippocampus and/or amygdala. They’re limbic brain abnormalities. It’s likely because in the incidence of a 21-hydroxylase deficiency, in utero, the embryological development and the stem cell abnormalities that may ensue because of the embryological development leads to abnormal … different brain development.
A lot of the people with RCCX phenotype typically have a very high intelligence but they also have … they’re also prone to emotional processing disorders, PTSD probably because, and Sharon believes this and I’ve discussed at length with her that it’s probably due to the abnormal limbic brain development and because of the abnormalities with 21-hydroxylase but I also think that actually because … The genetic research, and I’ll just make … ramble for a second that the genetics research on CYP21A2 has been shown to actually mediate the copy number variation.
That means that if you’ve got certain abnormalities within different regions of the CYP21A2 gene, that will lead to either a monomodular RCCX genotype or a bimodular RCCX genotype or a trimodular RCCX or a quadramodular RCCX genotype that the CYP21A2 gene and its activities and behaviors is regulating how many copies get made of the other genes. Now, the modular forms, monomodular, bimodular, trimodular, quadramodular are actually defined, genetically defined by the number of complement C4 repeats there are.
If you have a monomodular form, you have one C4 repeat. If you have a bimodular form, you have two C4 repeats, three, you’ve got trimodular. That tells me that the cortisol gene is controlling the expression of complement C4 and the number of different C4s you have will tell you how many different retroviruses you have, how many HERV-K retroviruses you have and the studies that link type 1 diabetes and lupus find that those individuals tend to have the low copy number, the monomodular forms. That’s why the research has concluded that HERV-K retrovirus confers a protective effect against autoimmune disease.
While the retroviral researchers are looking at the role of HERV-K in inciting diseases like cancer and autoimmune disease and CFS/ME and autism. I love Judy Mikovits, I’ve sat with her on many occasions, I know her on one personal basis but what all of these people need to see and what we all need to see is that retroviruses play important protective roles in how the immune system is supposed to behave. What the research suggests is that if we don’t have enough of these HERV-K retroviruses in the C4 genes, we don’t have adequate protection. We can’t complete the part of our cell danger response that need to be completed.
Ari Whitten: Yeah.
Michael McEvoy: That’s when I think problems begin to rise.
The Cell Danger Response
Ari Whitten: Yeah. Fascinating stuff. I want to dig into the cell danger response a little bit and maybe if you could briefly define it and then I have a couple of questions for you from there. For people unfamiliar with the term cell danger response, a lot of people on my audience have heard me use it before but maybe you can describe that a bit.
Michael McEvoy: Dr. Robert Naviaux uses the term cell danger response and has been doing the majority of the research … and his team has been doing the majority of research on the cell danger response as an ancient coordinated intracellular protective series of events that is basically a code for how we’re supposed to defend ourselves from the threat of danger, how our cells are supposed to defend themselves from the threat of danger.
We normally think of defense as the immune system itself. While that’s true, there are actually things that come before the immune system is involved in responding to the threat of danger and those processes are inside of our host cells and those processes involve a complex series of events that leads to different changes in how the metabolism of that cell is going to function and it’s going to shift its metabolism from a race car or a mitochondria, we think if we’re going up to fourth gear, high performance mitochondria, high performance ATP production. We’re on that mitochondrial speedway, we’re doing 240 miles an hour and our 911 Porsche souped-up engine.
Then when we have the threat of danger come, our cells go from fourth gear to second gear to even sometimes first gear. The machinery inside of the cell shuts down as a protection against the threat of danger. The DNA stops synthesizing as much, the mitochondria stop operating, the same way, oxygen doesn’t get consumed in the cell, free radicals get made inside of the cell to basically fight the infection or toxins that are happening and then ultimately, what will take place is that the mitochondria will start taking the ATP molecules that are made in the cell and start throwing them out into the extracellular space outside of the cell.
That extracellular ATP becomes a sickling molecule that causes the recruitment of other immune cells and the breakdown of mast cells which are in the extracellular matrix and connective tissue and will basically perpetuate the cell danger response alerting and alarming neighboring cells that the threat of danger is here and this is a warning sign. Normally, these processes are ongoing until they’re no longer needed and then they all recede in the turbulence and the water, if using the analogy of the storm, cell danger response storm recedes and everything, there’s a calm after the storm, everything goes back to normal and metabolism works again.
In chronic disease process, it’s now being shown that the cell danger resignaling is not resolving as it should and it’s leading to developmental problems and autism, it’s leading to neurodegenerative diseases and Parkinson’s and Alzheimer’s, it’s involved in mast cell activation disorder, it’s involved in a lot of different diseases.
How the Cell Danger Response and RCCX are tied together
Ari Whitten: This ties into the whole RCCX concept. In a number of ways, it ties into this concept of low resilience and fragility in the face of stressors and maybe also, the threshold at which point the cell danger response gets activated. Would you say that’s accurate?
Michael McEvoy: Yeah. I would say that’s accurate and I would add to that that we now know and according to Naviaux’s research that cortisol … We normally think of the adrenal hormone cortisol, how do we make cortisol? It’s the HPA axis, hypothalamic pituitary adrenal axis and then the brain signals, you have … what is it, CRH to ACTH and then ACTH to the adrenals downstream to make cortisol and they’re just [inaudible].
We now know that that does not need to happen in a cell danger response process. We can access cortisol faster and from other cell types through purinergic signaling. Extracellular ATP can cause us to make cortisol without the brain and that’s because there’s an immediate need for it as a way to change the inflammatory state, to change the tissue pH to set the stage for the rest of the physiology to come in and respond to this threat of danger.
In terms of the involvement here of purinergic signaling in the cell danger response, we know that purinergic signaling plays a critical role in the central nervous system and is involved in synaptic function, is involved in normal synaptic pruning. We know that purinergic signaling is involved in the innate immune system which is right there with complement C4 so we know that there are these associations that exist.
There’s a fifth gene on the backside of the RCCX cluster that is technically not a part of it but is definitely influencing behaviors and it’s known as SKIV2L. The SKIV2L gene regulates the RNA exosome which plays a critical role in the splicing of RNA and a lot of these processes that are antiretroviral and antiviral. When we have the mobilization of a retrovirus, this is going to create the grounds for cell danger response activation. When the retrovirus from the DNA gets mobilized with our nuclear genome, this will eventually lead to the release of ATP into the paracellular or extracellular environment leading to the purinergic signal.
There’s a number of ways in which the cell danger response process can become activated and is associated with and is involved with RCCX.
The practical take away
Ari Whitten: It’s fascinating stuff. I think my final question to you is what practical knowledge can one take from all of this discussion? Let’s say somebody is listening to this, they’re resonating strongly with all of this information, they go, it’s like that person we described earlier, “Yeah, I have hypermobility. I’ve got schizophrenia in the family. I’ve got bipolar, I’ve got lupus and other autoimmune diseases. I really think that I have RCCX in the family and maybe that’s playing a part in these symptoms that I’m experiencing. Is there any practical aspect of this that … of this knowledge that I can use to benefit my life?”
Michael McEvoy: I’m a clinician. The reason why I’ve been so adamantly pursuing this area of research is because I want to help people and I want to help people that are chronically ill. I work with clients that are suffering from complex illness. I’ve sought for many years to try to explain and to develop theories and rational explanations for why they’re suffering and what can be done about it and what it is that can explain this.
Of all the research that I’ve ever done on any subject, this area of research pertaining to RCCX is the most significant that I’ve ever come across and it explains the complexity and comorbidities of diseases in different people in a way that no other theory has ever been close or capable of explaining. That led me to understand what could be done therapeutically and clinically to help these people? Since that time where I’ve really embraced this theory and have continued to do research on it, I’ve developed a number of … I’ve been working with these types of clients, finding them, or they’re finding me rather.
Ari Whitten: I’m sure that you’re going to have a number of them reaching out to you-
Michael McEvoy: I would imagine so. They often come to me in tears because they just said that I’ve explained all of these problems that them and their family have been going through. They’re empathic, oftentimes, so sensitive to emotions and other people’s energy. The other thing is they’re often highly empathic individuals. Where I am with it currently is I think that probably one of the most important therapeutic targets for working with this type of a client is, and I’ll summarize it by saying one phrase, modulate the extracellular matrix, control the physiology.
I believe that one of the big keys to the puzzle of RCCX involves being able to control the extracellular matrix in different ways. By doing that, we are able to modulate the entire physiology. The reason I can say that is that the primary food stuff that the extracellular matrix is comprised of is known as polysaccharides which are sugar complexes.
Polysaccharides make up the collagen, make up the proteoglycans, make up the integrins that cells have to adhere to in order for the matrix to operate and to communicate.
The polysaccharides also are a critical part of the innate immune system’s response to the threat of infection. Complement C4 as a protein uses ficolin and polysaccharides as a way to combat mold, and lyme, and viruses, and pathogens. The activation of those innate immune processes utilize polysaccharides. That is what the lectin pathway of the complement immune system is for, is to create adhesive, sticky bonds to pathogens.
Polysaccharides, as we start to study their effect physiologically, they regulate so many different things that we never even think about. They’re controlling the matrix. We can use different polysaccharides like 1,3-beta-glucans, like polysaccharides from lion’s mane mushroom, and from [inaudible 01:01:47] aloe vera and polysaccharides from different supplemental foods, medicinal sources as one way, one way of providing a framework for the extracellular matrix but also providing these polysaccharides needed for the innate immune system.
That’s one thing, but there’s a lot of different therapies that I’ve started to develop in order to work with this complex phenotype, a lot of the emotional processing therapies, some people talk about the use of low-dose naltrexone. I’ve had tremendous success with cannabidiols, CBD oil, because there have actually been some studies that have shown that the fibroblast extracellular matrix-producing cells actually have endocannabinoid receptors on them, that we can produce more extracellular matrix constituents as well as regulate certain parts of our immune system through the use of CBD oil.
We can use other types of therapies to control the stress response, emotional processing [inaudible 01:02:49] therapeutic referring to as a great adjunct. I’ve seen that worked tremendously.
I think that there’s a lot of different ways that we can modulate an RCCX phenotype. I had some great successes with some clients that have been very complex, that have had complex illness for a very long time that I suspected were RCCX and I started to really put together my understanding and application to that from a clinical standpoint.
It really takes the ability to see the whole picture of each individual and to construct therapies that are designed to support all of these pathways that are affected adversely by this phenotype.
As I said before there’s always a flipside, there’s always another side of the coin. If we are able to emphasize the strengths instead of the weaknesses, we’re able to improve health. To me, that’s what health is all about, is we’re not … by improving health, we make disease less. By removing all of the offending things that are preventing us from having health and by doing all the right things and all the good things that will help our body to be healthy, we will be healthier.
How the lymphatic function, RCCX, and the Extracellular Matrix are connected
Ari Whitten: Absolutely. So, there’s another question that I thought of as you were describing this that I meant to ask you which is, are you familiar with Raymond Perrin’s research at all? He’s a chronic fatigue researcher in the UK who’s got a very specific theory of the genesis of chronic fatigue syndrome and has developed a specific technique to affect it.
He thinks it has a lot to do with the lymph system specifically and poor lymph drainage of toxins, and specifically poor lymph drainage of the lymphatic system in the brain-
Michael McEvoy: Sure.
Ari Whitten: at night.
Michael McEvoy: Right.
Ari Whitten: I’m wondering to what extent there might be overlap between RCCX, the extracellular matrix issues and lymphatic function. Are you aware of any-
Michael McEvoy: Yeah.
Ari Whitten: connection there?
Michael McEvoy: The glymphatic or the glial lymphatic system is the brain’s way to detoxify. Some of the research that has been done over the last few years had shown that when we sleep … Because in order for lymph to pump, you have to have muscular contraction. Well, you don’t have muscular contraction of the brain, but in sleep what’s believed to happen is the brain shrinks as the brain cell shrink in size and there are other ways that seem to promote the lymphatic drainage in the lymph vessels in the head.
What’s important to understand is that the lymphatic vessels are the tributaries of our immune fluids, lymphatic fluid, extravascular fluid that is bathing ourselves, that are providing the nourishment to our cells as well as removing wastes and harmful toxins from our cells. It is, the lymph is the battleground of our immune system. It is the battleground and the highway of our immune system as well as our nutritive source of how we obtain nutrients, our cells receive their nourishment.
The lymphatic system runs through the extracellular matrix, and so when we talk about modulating the extracellular matrix, we are directly talking about modulating our lymphatic system. It’s, in partial, part of that entire process.
Ari Whitten: That’s right. Thought you might be interested in the connection between all these ideas you’ve been talking about and this guy’s clinical experience like, hey he’s saying it’s all about lymph flow and he has developed a specific lymph drainage technique that allowed people beneficial effects from so-
Michael McEvoy: Great.
Ari Whitten: I thought the parallels are interesting there.
Michael McEvoy: The lymphatic system plays a critical role in the physiology of the body and it’s something that you’re not going to actually find in most physiology textbooks. You’re not going to find an adequate discussion of the importance of the lymph.
Yes, we know that the lymph is involved in … when cancer spreads, the metastasis, but it does so much to basically … to provide the battleground and the maturation processes for our immunological reactions.
The gene region HLA which is the cell surface antigen processing genes which is where RCCX is found on chromosome 6, those antigen presenting cells that are presenting antigens to different immune cells are … that’s happening in the lymphatic system and lymphatic organs so there are direct links to how these things play out.
We know that in RCCX that … Well, what we don’t know is, we don’t know what other genes RCCX is affecting outside of the RCCX region but we know that that copy number variations in the presence of retroviruses and gene sections can influence other genes. There’s been talk about C2 and C4 being directly related, there’s talk about how the DRB1 genes and the HLA2 region are associated with RCCX. More research is needed to find out the relationships here; but suffice to say, it definitely ties to the lymph for a number of reasons.
Ari Whitten: Yeah. It’s fascinating stuff.
I have one more request of you, a very challenging request and that is I would like to ask you to do a two-minute big picture overview of all of these concepts, which admittedly is very challenging. If it goes to three or four minutes, I totally understand.
I know is that a lot of listeners are going to be listening to this and just be overwhelmed by a lot of the different mechanisms and maybe get lost in some of that. I just want to make sure that those people don’t end on a frustrated note where they’re like, I don’t understand 90% of what this guy just talked about.
Can we break this down into a two-minute big picture overview of here’s the gene cluster, they lead to these mechanisms, synaptic pruning, hormonal milieu stuff, [Saldinger ] stuff, and that leads to these symptoms and conditions and then here’s what you want to focus on if it sounds like it might be an issue for you. Is that doable?
Michael McEvoy: Yup.
Ari Whitten: Okay.
Michael McEvoy: If any of the following seems to fit you or your family, you have a very high probability that there is something significant and adverse going on with the RCCX gene region in your body and/or in your family’s body.
If you or anyone in your family has joint hypermobility or joint hyperextensibility or skin hyperelasticity plus an array of other conditions and/or symptoms or diseases associated with those, you likely have RCCX. If that’s occurring, you would also probably have an autoimmune disease like lupus, like type 1 diabetes, like celiac disease or Crohn’s disease or rheumatoid arthritis, or ankylosing spondylitis.
You might have people in the family that had schizophrenia, bipolar disorder diagnosed with autism; you might have people in the family that have posttraumatic stress disorder, emotional processing difficulties, that may be you.
You might be highly emphatic. You might be a highly fragile person that is very sensitive but is also very high intelligence. You may have the inability to process stress and have an intolerance to stress. You might have bruising on your skin. You might have problems with blood clotting, the tips of your fingers might become blue and discolored. You might have circulatory problems. You might have chronic fatigue syndrome or myalgic encephalomyelitis. You might have chronic viral infections that for years and years don’t resolve. You might have an array of conditions associated with fatigue and chronic intolerance to stress. You might have visual and auditory disturbances.
If any of these symptoms or syndromes sounds like it could be you or if this makes a lot of sense to you, there’s a very high probability that your RCCX gene region is highly involved and is creating a lot of problems in your gene expression and is one of the major contributing factors to your health issues and that it is my invested life’s work at this point to find solutions for that.
Ari Whitten: Beautiful. Awesome, man. Well, this has been absolutely fascinating stuff. I have to say that you absolutely have won the price for the geekiest podcast I had ever done, so congratulations. I need to have a trophy or a T-shirt made or something.
It’s fascinating stuff. It’s brilliant stuff. Thank you for so skillfully navigating all of these extremely complex concepts and putting a lot of these pieces together. Really, amazing.
For anybody listening who’s resonating with a lot of these symptoms, and I’m sure that a number of people are like, “Yeah, this sounds exactly like me,” I highly encourage you to reach out to Michael.
Michael, where can people reach you?
Michael McEvoy: You can please go to our site, metabolichealing.com. That’s metabolichealing.com. We have clinical consulting for chronic illness. I’m particularly focused on finding these people and helping them in my consulting practice.
If you’re a healthcare practitioner, you can learn about our Metabolic Healing Institute in the courses and our curriculum and all that. That’s what we can do, metabolichealing.com.
Ari Whitten: Awesome, man. Well, thank you again so much. Really such a pleasure to have this discussion with you. It’s been enlightening for me and I’m sure to many of our listeners.
Enjoy the rest of your night, and thank you again.
Michael McEvoy: Thanks Ari.
The Fascinating Genes (RCCX) That May Be Behind Many Complex Chronic Illnesses (CFS, Fibromyalgia, EDS, POTS, autoimmune diseases) with Michael McEvoy – Show Notes
What RCCX is (1:37)
The interaction between RCCX copy number variations and gene expression (7:51)
The Pros and Cons of RCCX (11:25)
Symptoms and visions associated with the RCCX gene cluser (16:58)
Complement C4 (22:28)
Testing for RCCX (26:30)
How cortisol levels are affected by your genes (30:15)
How endegenous retroviruses are affected by the RCCX gene region (41:05)
How people with the RCCX phenotype are prone to emotional processing disorders (46:30)
The Cell Danger Response (50:26)
How the Cell Danger Response and RCCX are tied together (54:19)
The practical take away (57:18)
How the lymphatic function, RCCX, and the Extracellular Matrix are connected (1:04:08)