In Episode #44, Dr. Jill Interviews Dr. Ritchie Shoemaker on the latest in GENIE testing, molecular hypometabolism and inflammation-driven by Actinomyces, endotoxins and mold or other toxic exposures.
More Reading: What is Metabolic Endotoxemia?
Dr. Jill
Dr. Jill Carnahan is Your Functional Medicine Expert® dually board certified in Family Medicine for ten years and in Integrative Holistic Medicine since 2015. She is the Medical Director of Flatiron Functional Medicine, a widely sought-after practice with a broad range of clinical services including functional medical protocols, nutritional consultations, chiropractic therapy, naturopathic medicine, acupuncture, and massage therapy. As a survivor of breast cancer, Crohn’s disease, and toxic mold illness she brings a unique perspective to treating patients in the midst of complex and chronic illness. Her clinic specializes in searching for the underlying triggers that contribute to illness through cutting-edge lab testing and tailoring the intervention to specific needs.
Featured in Shape Magazine, Parade, Forbes, MindBodyGreen, First for Women, Townsend Newsletter, and The Huffington Post as well as seen on NBC News and Health segments with Joan Lunden, Dr. Jill is a media must-have. Her YouTube channel and podcast features live interviews with the healthcare world’s most respected names.
A popular inspirational speaker and prolific writer, she shares her knowledge of hope, health, and healing live on stage and through newsletters, articles, books, and social media posts! People relate to Dr. Jill’s science-backed opinions delivered with authenticity, love and humor. She is known for inspiring her audience to thrive even in the midst of difficulties.
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#44: Dr. Jill interviews Dr. Ritchie Shoemaker about GENIE testing & more…
Dr. Jill 00:12
Hello, everyone. We're live on Facebook with Dr. Ritchie Shoemaker, who's here in audio today. I am really excited to introduce a longtime colleague and someone I respect just because of all the pioneering work he has done in the field of mold-related illness, CIRS, and anything related to biotoxins. What we're going to go deeper into today is the GENIE test that he's developed along with colleagues. We're going to dive into what that actually looks like and why this is groundbreaking research, including the recently published review article that I have here on my desk from Trends in Diabetes in Metabolism about hypometabolism. So we're going to dive into that, and I will let Dr. Shoemaker explain.
Dr. Jill 00:58
Before I dive into that, just a few housekeeping [points]: You can find us here. This will be recorded. You can watch it later if you missed it the first time. And be sure to check out my YouTube channel—all free videos—and interviews with other physicians who have great content for you.
Dr. Jill 01:16
Dr. Ritchie Shoemaker is a recognized leader in patient care research and education and a pioneer in the field of biotoxin-related illness. He has dedicated his life and career to uncovering the link between the toxic slew found in many of our buildings and homes and the vast amount of misdiagnosed… As any of you who have been in this world as patients or have family members who have been sick—you know how this goes—you get shuffled around from doctor to doctor to doctor. And then no one really understands what's happening or finds solutions for you.
Dr. Jill 01:47
So, this has been really groundbreaking because he has been an absolute leader and one of the first to pioneer what's actually happening with patients who are exposed to biotoxins. We often assigned this ‘fibromyalgia', ‘chronic fatigue', and again, ‘hypometabolism', ‘weight gain', etc. We put them in these categories, but we're not really looking for the root cause. So again, Dr. Shoemaker has been absolutely instrumental by uncovering the real sciences behind these illnesses and attacking the problem with clinical studies and sound research.
Dr. Jill 02:17
The other thing he does is publish; he's actively researching and publishing peer-reviewed [articles] in the literature for the things that we're talking about today, which is exciting because that's what really brings the science forward. He led the way, not only identifying the true cause of these afflictions but also curing many in his community that were deemed “incurable”. He truly feels it's imperative that patients educate themselves, and now he's committed his time and resources to providing the tools.
Dr. Jill 02:44
His website is survivingmold.com. If you've been around for any sort of time, I'm sure you've seen his website. [There are] tons of resources there, lots of research, and you can do a visual contrast test there. You can just download all kinds of great information. And I know you're continuing to keep that up-to-date. So, Dr. Shoemaker, thanks for that long introduction. Welcome, and thank you for joining me today.
Dr. Ritchie Shoemaker 03:05
Well, thank you for having me. This is quite a pleasure. I appreciate the invitation.
Dr. Jill 03:10
Yes, it truly is. It really, really is. Like I was telling you before, and just to be public, I have the utmost respect. You really, truly were one of the pioneers who started to name what was happening and describe for the rest of us physicians some of the underlying mechanisms that, before that, were not understood and were not put together as far as how they could relate to an environmental exposure. And again, what we're finding now, and what I want to learn from you today, is that it's not just mold; it's this water damage slew that includes all kinds of things that activate the cytokine response. Before we jump into that, I know your story, [as] many people do, but tell us a little bit about way back when you first got into biotoxin illness and how that happened in your life.
Dr. Ritchie Shoemaker 03:55
Well, it's [been] 25 years now, my silver anniversary, since the days when I was a very happy, rural primary care physician and [running a] solo practice, [in a] beautiful neck of the woods here in the bottom of the eastern shore on the east side of the Chesapeake Bay. We can see Washington some days. Oh no, that's Sarah Palin [who] can see Russia. I got that wrong. We can't quite see Washington, but we can certainly see beautiful scenery, and it's an idyllic place to live and raise a family.
Dr. Ritchie Shoemaker 04:26
I was pleased to be a primary care physician doing what I wanted to do as an outpatient practice. And along comes some looming disaster in the waterways. The Pocomoke River drains into the Chesapeake Bay. There are 22 other estuaries that we were worried about, as it turns out. But something happened. Our habitat changed. Fish that normally would swim away rapidly, when here comes a boat or somebody else, started acting erratically and swimming in circles.
Dr. Ritchie Shoemaker 04:56
There were a few fish kills in 1996. People who worked around the fish kills harvesting live fish—we call them watermen [but] you might want to call fishermen—they get crabs and “orsters”… And that's how you say oyster; it's “orsters”. I've got to be proper here. Specifically, these folks had direct contact with droplets of water and fish with skin problems called lesions. And, you know, fish are always getting lesions, and the scales and slime don't really fix them all the time. So this was not a true surprise, but the illness was new. The illness was not just “I'm tired.” It was “I'm tired and my brain doesn't work.” “I'm tired, my brain doesn't work, and my joints hurt.” Add to that diarrhea. Secretory diarrhea was a real facet of this problem. Skin problems—there was a diversity of lesions that we saw. A biopsy just showed some lymphocytic infiltrate—not a real clue along the way.
Dr. Ritchie Shoemaker 05:59
But these people were acutely affected. And guess how much of the world's literature there was on people like this one? Zero. So were they just “a gomer”. And you remember what a gomer is, right? “Get out of my emergency room.” You know, these folks are people I knew. I would see them at Walmart. I'd see them on the street. We built a nature trail with them. So these are good, honest, hardworking people. They're not making things up. They're not trying to get out of work. And the story is heard over and over again.
Dr. Ritchie Shoemaker 06:31
But interestingly, in 1997, a TV announcer from Channel 7 out of Washington named Brad Bell sent a water sample from the Pocomoke down to a lab in North Carolina at NC State, where JoAnn Burkholder had been looking at an organism called Pfiesteria. It sounds like hysteria, but Pfiesteria had been active in the Tamaco Sound and Neuse River and what have you. And there are lots of problems with fish kills, and anybody who said they were sick was almost hounded into silence.
Dr. Ritchie Shoemaker 07:07
So [there were] no cases, no studies, and no human illness. And lo and behold, we had Pfiesteria in the Pocomoke River. Well, what this little organism does is normally have a very slow-moving phase of its life where it kind of crawls along the bottom of the river. But if another Pfiesteria comes along and releases a toxin, that toxin is actually a pheromone. It's a signal for feeding and breeding. So you would suddenly get a bloom of Pfiesteria organisms. They would make a cyst drop back into the river, and away they went.
Dr. Ritchie Shoemaker 07:42
What happened that this new monster with multiple life forms could grow in our river? Nutrients had no change. They ended up being blamed, of course; government officials like to do that. But what was new were additives to the water column. A blue mold was now wiping out tomatoes and wiping out tobacco in areas where water would be run off during rain events into the North Carolina sounds, what have you, into the Neuse River. And the Pocomoke River would be where we would see a sudden bloom that would come and go—feeding and breeding and next.
Dr. Ritchie Shoemaker 08:19
It turned out that what was toxic in the water was copper, in that it would kill things that the slow-moving phase of Pfiesteria would like to eat. Then there were also dithiocarbamates—special old-fashioned fungicides that killed off the things that ate Pfiesteria. So you had a double whammy. That says this organism is going to be fast-moving in the water column, and it's going to not have any predators. So it made toxins more and more and more.
Dr. Ritchie Shoemaker 08:49
More people got sick, and I got inundated with people. “Ritchie, you've got to do something.” Secretory diarrhea—well, you and I are old-time family doctors. We know full well that colostyramine, a non-absorbable anion-binding resin with an anion radius of 1.4 angstroms, will bind very nicely to negative charge anions and make life easy. Because the match of what we saw in toxins later on was a negatively charged ring of about 1.43 angstroms that matched to 1.4 angstroms—the positive side chains of colestyramine. We have a mechanism now to stop what's called enterohepatic or GI gastrointestinal liver recirculation because the toxins we make come out, secreted against the gradient in the bile, down into the duodenum, reabsorbed in the jejunum, and on you go. People did not self-heal unless very strange things happened.
Dr. Ritchie Shoemaker 09:51
But, you know, this diarrhea I couldn't fix. I tried everything: Motrin and steroids—anything that anyone in practice would think about. But I said, “Why not use something to stop the secretory diarrhea? [Let me] give people some sleep for God's sake so they're not going 10 times in the middle of the night.” And lo and behold, the very first patient in 1997 called me back two days later and said: “Boy, that stuff is great. It stopped my diarrhea.” “Well, of course. I gave it to you for that reason. I'm glad to hear that.” And she goes, “But you know, my memory is back. My cough is gone. I can breathe through my nose, and I'm not short of breath.” I'm going: “Wait a minute. Wait a minute.”
Dr. Ritchie Shoemaker 10:35
Well, I had a bunch of people in charts sitting on my desk saying, “I haven't been able to help this person,” because the labs were all the same. Nothing abnormal at all. Just like we know today, normal sedimentation rates. We didn't know then why high viscosity gave normal sedimentation rates, but that's for another day. But specifically, what happened is that I was faced with a decision: “Am I going to be firing shotguns from a family practice gun that says, ‘I'm going to give people medicine, even if I don't know the physiology, even if I don't know the pathophysiology.'?” But if I can make them better, will I do something like that?” Kind of like with COVID, people [inaudible], “What are they going to do?” And maybe we'll have time to talk about VIP and COVID—it's a great story—and secretory physiology. I'll tell you what…
Dr. Ritchie Shoemaker 11:24
But with that in mind, over 200 patients later, I had a winner because I still didn't have the physiology, but I had a mechanism that I could [use to] help people who were adversely affected. Well, guess what? There was some criticism. Amazing! It's a free country, so you can criticize Ritchie, you know? But that was done, and needless to say, when I said ‘copper' and I thought dithiocarbamates, nobody ever heard of such a thing. Yet when you chemically disrupt… I mean, you're a big into Roundup and all that stuff, and I can argue with you, and you can argue with me. So there we go. But specifically, if we are looking at an environmental source, an environmental disturbance, would that be different if it was a different organism besides a dinoflagellate? Well, here came a phone call from the St. Lucie River: “We've got a problem with cryptoperidineopsis. Twenty-five years [later], I can still remember that name. How about that?
Dr. Jill 12:20
That's good.
Dr. Ritchie Shoemaker 12:22
Person, man, woman, camera, TV, right? Okay. Oh, no, it's somebody else. You know that joke?
Dr. Jill 12:29
Uh-huh. Maybe you and me only, but…
Dr. Ritchie Shoemaker 12:32
All right, anyway. But anyway, sure enough, what happened in the St. Lucie River, which is on the east coast of Florida, is that when Lake Okeechobee fills up, the water that's breaching the top of 18 feet down of Lake Okeechobee has got to be vented. And you can't put it in the Everglades and the Cape Sable sparrows, just as you can't put it down in the Clusa Hatchey. So they sent it through all the channels and canals into the St. Lucie [river]. And as soon as they opened the C-73 lock, you knew that three days later there was going to be a bloom of dinoflagellates.
Dr. Ritchie Shoemaker 13:08
And guess what was in that pore water that Florida proved?—Maryland never did. It was copper and dithiocarbamates. So here we had the same thing. So it blooms next in Lake Okeechobee. “Well, my goodness, look at what's going on there!” Of course, in the Okeechobee [River] in Florida, that part is full of phosphate in the water. And you're going to be giving nurturing and nutrients to cyanobacteria. Every single state has cyanobacteria. We think about the pond scum. But sure enough, they had the same symptoms [that] Pfiesteria patients did. They had the same lab abnormalities. They were all zero. And by this time, we finally had a diagnostic test—visual contrast sensitivity—thanks to Ken Hudnell.
Dr. Jill 13:55
That's brilliant. Even though it's not specific, it's such a great tool. How did that come about? Was that research that you had found for biotoxins? Or how did you find that visual contrast?
Dr. Ritchie Shoemaker 14:08
Ken was a neurotoxicologist for the US EPA. He was based in Research Triangle Park, and he had studied some organic compounds affecting the visual pathways. He could show a defect in dry-clean workers as opposed to tetrachloroethylene and all these other things. And there's lots of stuff that I don't know about that they used. Hydrocarbons could also cause a problem with the ability to see an edge—illusibility—where gray meets gray. Where black equals white, then you can see an edge. But if you turn down the black and make it grayer, and you darken up the white to make it grayer, you'll find a point of extinction where you can't see a line that has a certain shade. That point of extinction became the point that we could put on a graph, and we could do the same test in multiple places and show the same abnormality.
Dr. Ritchie Shoemaker 15:02
Then, when we found that in Pfiesteria, I called up Ken because he was the first person in the world to publish on VCS and Pfiesteria. I said, “Ken, I can fix this illness.” He said, “Well, look, let's do before and after VCS and bingo! Within four days, we had an answer. We now have the first biomarker. But how come some people were swimming at Williams Point? There are 10 people; three people got sick and seven people didn't. Well, it couldn't be [because of] drinking beer. Everybody in Somerset County drinks beer—you know that. Cigarettes, age, or disease? No, no, no. It wasn't till 2000. I started reading up on HLA, and look at this: Here were the immune response genes. “Oh, my God!” There was no teaching back then in medical school. And we knew about HLA-B27 but not HLA-DR.
Dr. Ritchie Shoemaker 15:50
But anyway, sure enough, that was the answer. And we needed to collect enough data to prove that there was a genetic susceptibility, as shown by increased incidence and cases compared to incidence and controls. And when that ratio exceeded 2.0 to 1, we had relative risk. So we now had symptoms. We had normal laboratories. We had HLA. We had VCS. What else was there? Well, it turns out—here comes along 1998—people with Lyme disease. Well, they had the same visual contrast deficit and the same symptoms. “I'll give them colestyramine the same way I always do.” And hopefully, they didn't get constipated, and “I hope all the good things happen.” Well, they didn't. They weren't able to take it long enough to figure it out. They got slammed. They could barely lift their heads off the pillow.
Dr. Ritchie Shoemaker 16:43
Sure enough, this was the first clue that cytokines were involved. When cytokines were involved, I started reading about VEGF. And now low VEGF was involved. And now MMP-9 told us about endotoxins. And one after another. I think I was the original publisher of 25 different biotoxin biomarkers for CIRS illness—chronic inflammatory response disease—and we have two more that are coming out next week. But specifically, what we now were seeing is the commonality among exposure to biotoxins—which are small compounds [that are] less than a thousand daltons; teeny, tiny little things—that had the ability to move from cell to cell. But more importantly, they had the ability to be secreted against the gradient out of bile to dump into the duodenum.
Dr. Ritchie Shoemaker 17:30
And if we had colestyramine… Thanks to Ray Stricker. Ray was the first from Lyme to say, “Try Welchol.” And he was right. That worked. We could now come after these folks. But not everybody got better. And Tim Roberts from Australia was working with me on a different case. “And tell me about this—MARCoNS.” Well, Tim told me about MARCoNS, and sure enough, we had it too. As time has gone on, MARCoNS have been a real flash point.
Dr. Ritchie Shoemaker 17:55
It separates me and you here, Jill, just to tell you the truth, because the use of particular medications and antifungals, especially, will induce horizontal gene transfer and create massive antibiotic resistance in MARCoNS. And MARCoNS—boy, are they ubiquitous! They love to breed with anybody else and share little bits of DNA and antibiotic resistance factors. We knew from burn units that as soon as you use antifungals and antibiotics together in a bad burn, guess what? You had resistant fungi and resistant staphs—the same antibiotic resistance factors. Wow! Amazing! And that's true to this day. So I'm going to argue about antifungals. They are really going to get you when we come to GENIE, but that's all right.
Dr. Jill 18:45
So first of all, I'm glad to hear your opinion on this and the science, because really, I want to be the best scientist that I can be. What I've seen that makes a difference is that we have immune-compromised [individuals]. Those people are the subclass that really has a different treatment group, and those people are full of opportunistic infections, like fungal infections. And I find the antifungals in the immune-compromised to be life-saving.
Dr. Ritchie Shoemaker 19:14
So tell me what the definition of immunocompromised is.
Dr. Jill 19:19
Yes. So, deficiency of total IgG. And now the literature is supporting even deficiencies in IgM or IgE. That's a brand new definition. But classically, the combined gammoglobulinopathies—those are pretty severely ill people that cannot—
Dr. Ritchie Shoemaker 19:34
Oh, boy. Good luck finding a lot of those cases. I used to track my immunoglobulin panels, and finding gamma globulin deficiency or any of the four types of IgG was rare.
Dr. Jill 19:47
Well, my population is very different, though. See, that's why I think there is a difference in this. And I really have nothing but respect. So I love talking about this in a respectful way because I do believe that they're overused. But on the other hand, I actually do have a large percentage of immune-compromised patients. I don't know if that's just because of the people I treat. So it is a different ballgame for them. They require antifungals in order to overcome because they cannot mount a response innately.
Dr. Ritchie Shoemaker 20:14
Well, it's time you publish that and [inaudible].
Dr. Jill 20:17
You're right. You're right.
Dr. Ritchie Shoemaker 20:19
Don't just tell me because I want to see: What does the data show? This is something new. And if it's legit, it'll stand up to peer review. And certainly, that's the way to go. But to go back to where we were talking, it became clear that in 1998, the first persons I saw who had a Pfiesteria-like illness and who didn't have Pfiesteria exposure were nowhere near the Pokemoke River. All they had was a closet that was full of this black stuff that was growing when the roof leaked.
Dr. Jill 20:52
So how many years was that between the first river exposure and this mold? How many years passed?
Dr. Ritchie Shoemaker 20:58
[It was] 1997 to 1998. By that time, we had our first mold patients before we had Lyme patients. But we had dinoflagellates and cyanobacteria, [which] is the first. But then there were some people who didn't get better. MARCoNS had to be eradicated. And back then, we could use bact spray with great results. Not anymore. But then it became clear that we fixed the colestyramine deficiency, or Welchol deficiency. Fixed that, and MARCoNS was gone. People still were not getting better. “Well, what else?” Well, here—MMP-9 elevation. “Oh, my God, I can fix that too. It's a marker for TH1 cytokines.” And then we had the insight: “Well, how about low VEGF?” And then along came C4a. Oh, my goodness was C4a the big player!
Dr. Ritchie Shoemaker 21:47
Finally, in 2008, I begged—finally, begged, begged, begged—because all the time, for example, with MMP-9, there was a lab called Esoteric's outside Denver that agreed to do MMP-9s for me. I was the only person in the country who had that data. I was the only person who had HLA. I was the only person treating this with colestyramine. Now, a few others came along later, and they said they were the first. But I published first. Anyway, having said all that, the same approach to classical science of looking at data of cases versus controls—prospective reexposure trials to prove risk. That's the only way you can prove risk—[through] prospective studies. So we had the sequential activation of innate immune elements and multiple papers along that way in litigation. And I hope you're doing litigation, but specifically, we needed a voice to not only convince physicians but also convince the attorneys because you don't change the law if you don't change the attorneys. And the laws are dastardly…
Dr. Ritchie Shoemaker 22:49
But anyway, the whole issue is that along with the legal testimony work came multiple publications, and suddenly we had a robust literature. So the robust literature has continued to grow. And in 2003 and 2004, the Human Genome Project was going on. You remember. A billion dollars. And “What in the world are they doing all this [for]? I don't understand all this stuff.” But having said all that, transcriptomics started evolving in 2005, and differential gene activation sort of first got attention in cancer, a little bit in vascular disease. But still, it's a Rosetta stone that's unscratched. And along comes Jimmy Ryan, who's a transcriptomist—a brilliant man. He started working with me. Jimmy said, “Well, we need to raise a million dollars.” “Sure!”
Dr. Jill 23:43
How did you first connect? How did you connect with Jimmy?
Dr. Ritchie Shoemaker 23:46
With ciguatera, a dinoflagellate illness. Jimmy was working at the National Marine Biotoxin Lab in Charleston. I went down to give some talks on Pfiesteria and ciguatera. He was doing stuff with John Ramsdell that I didn't know about. They didn't know about the human health [aspect], so I said, “Why don't we work together?” So that got started with the mold pieces. But in 2010, we published a paper on ciguatera, which is a marine dinoflagellate that makes people ill. Be sure to ask if people have had fish from the Garona Reef [as] part of your differential diagnosis. But having said that, nobody does.
Dr. Ritchie Shoemaker 24:21
At any rate, when Jimmy was able to convince me to raise the money to buy a Lumina Sequencer—next-generation sequencing, an RNA-seq—we could see that of the 50,000 genes that we could sequence in CIRS patients, there were 2,000 that were always abnormal. We went to those 2,000 genes, looked at the greatest signal-to-noise ratios, and looked at diversity. We wanted cytokine pathways. We wanted coagulation pathways. And we wanted to look at what was going on with the lack of ribosomal RNA. Ribosomes weren't working right. We couldn't get mRNA to attach to start making a protein. We couldn't make amino acids added to a daisy chain, so we didn't have elongation. We didn't have a termination. This RNA was not there. What was suppressing it? That led to the discovery of the sarcin-ricin loop.
Dr. Ritchie Shoemaker 25:21
Remember, ribosomes have two big structures: The large subunit and the small subunit. They're sandwiched around a little tiny piece, which is where all this protein and amino acid stuff works. Sarcin—most people haven't heard of sarcoma inhibitors, but they have heard of ricin, a plant toxin. And ricin works by splitting off the adenosine moiety at position 15 on this loop that's necessary for this whole structure to work. And every single living creature—you name it—has a sarcin-ricin loop.
Dr. Ritchie Shoemaker 25:58
And four billion years ago, look at the biowarfare we had—fungi dealing with spirochetes. My gosh, spirochetes are dealing with dinoflagellates. All this stuff is going on [with] cyanobacteria making the first oxygen in the environment. These organisms made ribotoxins that would take the adenosine moiety out. They also made ribosome-inhibitory proteins, and those compounds are with us today. They are creating the hypometabolism that starts with ribosomes in the cytoplasm but extends the ribosomes in mitochondria: Mitoribosomes. So if you've got a ribosome in the mitochondria, there's got to be a gene to program for RNA, right? Well, there were a thousand genes from mitochondria. Now there's 37 at last count. Thirty-seven. Where did the other thousand go? Well, you know, they migrated to the nucleus. They are nuclear-encoded mitochondrial genes, and they're subject to transcription factors. So the same transcription factors.
Dr. Ritchie Shoemaker 27:08
Oh, boy, when I tell you about TGFβ-1, oh, my goodness! The same transcription factors that are differentially associated with gene replication, activation, or suppression. Remember, there are four layers, and the disease we're talking about is that disease is lack of regulation, of lack of regulation, of lack of regulation, of lack of regulation of DNA transcription. And if you understand that, you'll see why nuclear transcription factors, microRNA, some of the long non-coding RNAs, and then housekeeping genes are regulatory for gene transcription. Now, you'll hear a lot of people talking about methylation and all this stuff. And I just kind of yawn because you're missing the boat if you think about methylation because there are more demethylators than there are methylators. There are more acetylators than deacetylators, but both of those are constant. So epigenetic stuff is four different structural layers of gene transcription. Don't start me on methylation. It'll ruin a good day.
Dr. Ritchie Shoemaker 28:14
Having said all that, to go a little further, what Jimmy found is that a collection of mitochondrial-encoded nuclear genes control ATP synthases. And look at what we want. We want pyruvate to be broken down from glycogen and from glucose. We want glucose to be taken up by glucose transport proteins 1 and 4. They are solute carriers. In comes glucose into the cell. There are other mechanisms as well. But there is the vital role of insulin and insulin receptors. Then insulin receptor substrate 2 regulates metabolic pathways like crazy.
Dr. Ritchie Shoemaker 29:01
And don't you know? Jimmy found abnormalities in metabolism as well. So we had ATP synthases. If you don't make ATP, the poor mitochondria are being victimized. People are saying this is a mitochondrial disease, for God's sake! No, it's not. It's just a lack of ATP synthases. And look at actinomyces. Oh, my goodness. Look what they do. Pyrsine A knocks out complex I. Oligomycin knocks out complex III. We can affect the electron transport chain with actinos found in water-damaged buildings. Oh my! Who has never heard of such a thing? Well, just wait until you see valinomycin, monensin, and nigerisin, because those block the voltage-dependent anion channel.
Dr. Ritchie Shoemaker 29:48
Now, you know, [inaudible] now is that this little pore sits on the outside wall, the outer membrane of the mitochondria. And if it's open, you will have [the following] migrating inside the cell: Ions—okay, that's a good idea. Solutes—okay. ADP—ah, that's where you make ATP from ADP. And pyruvate—ah, that's how pyruvate gets into the inner mitochondrial space. And then the transport protein will take it from the inner membrane and put it into the electron transport chain in the Krebs cycle. That's where you use all your ATP. But if your pyruvate doesn't get in, what happens to it? It stays in the cytoplasm, and pyruvate cannot be sitting around because it's going to cause trouble. And pyruvate gets converted into what? Lactic acid. Oh no! Lactic acid is secreted against the gradient, but glucose is still being pumped in, making new compounds, and there will be a diversion of those new compounds into the building blocks that the cell needs to reproduce. Oh!
Dr. Jill 30:53
So let me talk really quick, Dr. Shoemaker; this is brilliant! I'm following you every bit of the way, but for the average listener, there are two things I want to talk about. Basically, if you're listening and wondering about this biochemistry that I find fascinating that Dr. Shoemaker is explaining brilliantly, what he's talking about is the cellular energy makers. The energy producers in each cell are broken. What we get from that is this exercise intolerance. He's talking about lactic [acid] being in the cytoplasm. And when that accumulates, you'll have that muscle soreness, the fibromyalgia, or the chronic fatigue. So what he's describing is, on a biochemical level, what happens after you get exposed to mold or some of these other biotoxin pathways: The chronic fatigue, the fibromyalgia, the muscle pain, and the exercise intolerance where you're sore two to three days later. These are the biochemical pathways, if I'm right, Dr. Shoemaker, of what we see in clinical practice. It's so relevant.
Dr. Ritchie Shoemaker 31:53
There's way more. There's way more. I'm on a roll, so let me get back on it. You're right to clarify. Thank you. So the question then comes: If we've got pyruvate being made in lactic acid and secreted against the gradient, is there a medical condition for which we see extra lactic acid? Yes, it's called metabolic acidosis. And if the cell is getting ready to divide, making all these extra building blocks, that kind of physiology is called proliferative physiology. Proliferative physiology means you only get two molecules of ATP from each bit of pyruvate and four total for that whole situation. But you make building blocks, and along comes this whole mechanism of lack of energy storage. So you've now got metabolic acidosis and proliferative physiology.
Dr. Ritchie Shoemaker 32:45
What else goes with that? Now, I know that you've had some health issues in the past and used to talk about them in public, so I'm not breaking any secrets. I was disabled by pulmonary hypertension in 2012. It's the reason I stopped doing medicine because the cardiologist said, “Put your things in order.” Well, those are kind of nice words to hear. So where did my pulmonary hypertension come from? So, I started looking at people. We could identify proliferative physiology. I'm going to get to that in just a second. And we said, “If they've got metabolic acidosis, what else do they have?” Well, lo and behold, 80% of them have pulmonary hypertension; 80% of them have T-regulatory cell deficiency. They all do. They all do.
Dr. Jill 33:27
Yes, I agree. They all do.
Dr. Ritchie Shoemaker 33:31
And that's where they also get injury to gray matter nuclei, injury to cortical gray, and enlargement of the superior lateral ventricle. We can show the mechanism objectively without any guessing or any ridiculous psychological exams. We can show in black and white the definable objective pattern of injury. And we published a paper in 2017 showing we can fix that. And we still can. We're on a roll with that. So now we've gone from the physiology of hysteria—what in the hell is that?—to the molecular biology of proliferative physiology, as opposed to energy storage, associated with metabolic acidosis, associated pulmonary hypertension, and associated T-reg cells. Where does all the autoimmunity come from? Where's all the tissue-based inflammation? Lack of Tregs. Oh my gosh. T effector cells are [inaudible].
Dr. Jill 34:23
I want to pause really quick to clarify that, just for the layperson. So we have Th17 and Treg cells. And then we have Th1 and Th2. But T-reg cells are like the bodyguards that are like: Hey, calm down. Don't overreact. We don't need to react to too much out there. Everything's okay. And they help us not to be either overreactive to pathogens or overreactive to ourselves and create autoimmunity. They're really important. If you don't have Treg cells, you're going to be on fire for autoimmunity and on fire for inflammation and cytokine production. And most people with this illness have elevated TgF-beta, which drives Th17, and a reduction in Treg cells, which is what Dr. Shoemaker is [inaudible].
Dr. Ritchie Shoemaker 35:01
There's more. You haven't listened to me recently. There's way more.
Dr. Jill 35:04
Oh yes. There's more. I'm trying to keep it really simple. [laughs] Go ahead.
Dr. Ritchie Shoemaker 35:09
Let's go back to: What else did Jimmy Ryan show us? I talked about VDAC, this pore. It turns out that translocases… And if you don't know what a translocase is, join the club; I didn't know. But it sounds like it moves from one location to another—a translocase. This protein is necessary to move mitochondrial proteins through the pore and through this complex into the inner membrane of the mitochondria. And if your translocases are depressed or deficient, if you don't have that mRNA, will you get mitochondrial proteins coming into the inner matrix of the mitochondria? Well, the answer is no.
Dr. Ritchie Shoemaker 35:49
So we talked about actinos. I mentioned, probably too quickly, that actinos disrupt VDAC. They do. Translocases affect VDAC as well. And it turns out that the more genes that Jimmy started looking at… We started looking at beta-tubulin and α-tubulin 4A. When we looked at the associated findings of people with abnormalities of these two cytoskeleton structures, these microtubule structures, we found that they had a mean of 6.15 gray matter nuclear atrophy and area atrophy out of 8 total compared to controls that would have 0.9. So they were hugely abnormal. What do those tubulins do? Jill, can you answer my question? What do they do to the VDAC?
Dr. Jill 36:36
No, tell me.
Dr. Ritchie Shoemaker 36:38
They block it. So in proliferative physiology now, when we fix VDAC, we can also fix gray matter nuclei. We were using VIP in my protocol to fix gray matter atrophy. I didn't know we were fixing VDAC. But specifically, we now had the poker hand that 90% of people with chronic fatigue illnesses—whether they're CIRS patients, heart failure patients, cancer patients, renal failure patients, or psychiatric fatigue patients—if they have proliferative physiology, they have hypometabolism. Now, the hypometabolism is made worse if IRS2 is elevated. Why?
Dr. Jill 37:23
Let's pause here, Dr. Shoemaker. You and I know what that is. Let's just describe it for the average person. What does that actually mean? What is hypometabolism?
Dr. Ritchie Shoemaker 37:32
Molecular hypometabolism, or MHM, is not the same as hypometabolism. I try to save time. But this is suppression of RNA genes, suppression of mitochondrial genes, and suppression of mitoribosomal nuclear genes. So all these gene suppressions due to impairment of the sarcin-ricen loop are where this illness comes from. It's really simple. It's really simple. And all this gobbledygook… It's really simple. If you've got hypometabolism, you're going to have proliferative physiology. If you've got proliferative physiology, you will do worse. If you start having problems with the insulin receptor substrate, that opens the door to letting more glucose in, therefore more pyruvate, and therefore more lactic acid. And if you say, “I'm going to use a keto diet,” my cringe buzzword, you either get glycolysis… If you've got IRS2, glycolysis is going nuts. You either get glycolysis or you've got fatty acid oxidation. And if you've got fatty acid oxidation, glycolysis will be depressed. But if you get glycolysis upregulation, which we do if you're proliferative, the keto diet is not going to work. You'll get a lot of placebo effects. But in terms of glycolysis and physiology, you won't get what you want.
Dr. Jill 38:55
Well, I just want to comment, because in clinical practice, what I have seen is exactly what you're describing. I completely understand there's a percentage of people who do not do well on a keto diet, nor should they be doing it because they don't have the ability to utilize the alternatives for fuel.
Dr. Ritchie Shoemaker 39:09
Don't use keto if you've got molecular hypometabolism. Later on, if IRS2 is suppressed, your keto works fine. But if IRS2 is up, it doesn't work fine. There's a reason for that.
Dr. Jill 39:19
And this is also why we're basically seeing the induction of pre-diabetes, diabetes, and metabolic syndrome.
Dr. Ritchie Shoemaker 39:25
Well, there are multiple mechanisms, including, remember, these assimilation pathways I was telling you that glucose can use to make cell division. You will also have the hexosaminidase synthetic pathway that results in the creation of insulin resistance. Now, that's by action on fat cells, not by glucose. We need to change our thoughts. There is also intracellular insulin resistance from monensin and nigerisin, which is something for another day. But that's what actinomycetes do. There are multiple ways to impair glucose metabolism. But here we go now. What else do we see in GENIE? Apoptosis, or programmed cell death, is a mechanism to take care of cells that are programmed to die. And [inaudible] will label a cell, saying: It's your time to go. And here come natural killer cells, provided they've got a T-cell synapse. And they don't in CIRS. Uh-huh!
Dr. Jill 40:24
Again, just to clarify for those of you listening, apoptosis is how we don't get cancer. It's how we take the dead cells and tell them: Hey, get out of here. Don't be a nuisance. Don't cause trouble—when their cell life is over, for a simplistic form.
Dr. Ritchie Shoemaker 40:39
Remember, apoptosis starts with mitochondrial changes. Mitochondria rules the classical pathway for apoptosis.
Dr. Jill 40:48
But they're targeted when there's mitochondrial dysfunction for cell death.
Dr. Ritchie Shoemaker 40:51
Well, I'm going to disagree with that one. That's all right. I've got a nice lecture showing the mechanisms that will go along with that. A little separate. The activation of caspase signals is not the same. Specifically, what we're looking at is programming a cell to die and packaging cell components like DNA and RNA and mitochondria and the endolaplasmic reticulum and ribosomes; packaging them inside of a membrane so that when they're released into circulation, that membrane protects the contents from being recognized as a foreign invader.
Dr. Jill 41:28
Like [inaudible], like, damage associated pathways.
Dr. Ritchie Shoemaker 41:32
Sure, but what we're looking at [is that] 15% of CIRS patients and 15% of chronic illness patients have defective apoptosis. And they only have RIPK1, a gene that interacts with RIPK3 and will kill the cell. Now, COVID uses this pathway. HIV uses this pathway. Pay attention. This cell will be killed if it's harboring a virus, most commonly. The virus can block apoptosis, but the cell says: Okay, you've blocked apoptosis, Mr. Virus; I'm going to kill you. I'm going to commit suicide with necropoptosis. There's 12 of these apoptosis, and specifically, what will happen here is that there will be a release of the cell contents without membrane packaging, so you have an endogenous inflammatory cascade like crazy!
Dr. Jill 42:22
Yes. This is the cell danger response that Dr. Naviaux wrote about.
Dr. Ritchie Shoemaker 42:27
Well, we're going to talk about that because what comes first [is] the gene activation or gene suppression or mitochondrial response. And by the way, when Dr. Naviaux was writing about that, he was saying that that is part of the dauer physiology of this nematode called C. elegans, [which] has been well studied. That goes in dauer as a stage of hibernation. That is not what we call oxidative glycosylation. It's deoxidative, so it's anaerobic. So, aerobic glycolysis versus anaerobic glycolysis. So what Bob was talking about was anaerobic glycolysis, in fact. This is aerobic glycolysis. It's very important to make that distinction.
Dr. Ritchie Shoemaker 43:11
So now we're looking at other elements of GENIE. How about coagulation? Jimmy has published, and I've been co-authoring papers since 2015 that [show] in biotoxin illnesses, coag genes are upregulated. And lo and behold, here is this ton of work out of Rochester, Rockefeller University in New York City, looking at the vascular hypothesis for neuronal injury. And I'm sure you're familiar with that because here we have coagulation elements that will be bound to one of the precursors in Alzheimer's to bind and make a clot in the vascular bed. That clot will create distal hypoxia so that more bad guys, more tau will be made so that we've got ApoE/Aβ. It's just amazing.
Dr. Ritchie Shoemaker 44:12
But what if you've got coagulation genes upregulated? Will you make more coag products to be bound in the brain? Yes. And you can look at the difference between the 10 genes we look at for coag. If you've got two upregulated, you'll have two or three genes that are too small. But if you've got four genes upregulated for coag, the mean number of gray matter nuclear atrophy is 4.5 just from the coag genes.
Dr. Ritchie Shoemaker 44:41
I told you a couple of times that I wanted you to go back to be thinking about TGF-β1. As it turns out, because we're running out of time, if we are looking at the fundamental difference between you and me: I see exposure; you see exposure. I see immune reactivity; I'm not sure you do. And the difference is exposure—so what? Who cares if you're exposed? It turns out that if you have a proteomic response, that person should care. But if you have the immune response, that illness is very, very different and much worse.
Dr. Ritchie Shoemaker 45:20
For years, I have said that I cringe when I see certain HLA types, 4353 and 11352B, [and people] saying, “These are the dreaded… ” Well, as it turns out, the link from exposure… And we can measure. Hopefully, you're using a lab that will measure species abundance, not just one species, not just streptomyces griseus that you get from Mycometrics. There's nothing wrong with that, but we're looking for species abundance. We use EnviroBiomics. I have no plug for them; there's no conflict of interest. But if we look at the actinos in this whole situation, what we are looking at are mechanisms to show exposure. Then we can look at particular immune markers. And that's proprietary. That will show us that there has been a reaction to the actino compounds. These are intracellular compounds.
Dr. Ritchie Shoemaker 46:14
Actinos make more compounds than anything else. It's the biggest genus of all in microbiology. But if actinos are exposed and there is an immune response, there will be activation of the TGF-β1 receptor—1, 2, or 3. And that receptor links to SMAD—all the different SMADs, nuclear transcription factors. So now we've got the mechanism. It's more common in 4353 by far—22 times what the normal population is in people with exposure and reactivity. But if you get activation of this receptor, the downstream pathways—not just SMAD, not just nuclear transcription—are also the same basic building blocks that insulin receptors do. It is the link of metabolism to inflammation in a brand-new way. And this is stuff we publish for the first time next week. So it is uncanny.
Dr. Ritchie Shoemaker 47:17
So now we're looking at the link and saying, “All right, do you have a link for actinos?” “Yes.” “Do you have a link for mycotoxins?” “Yes.” “Do you have a link for endotoxins?” “Oh, yes, we do!—CD14 and TOA4. Well, which is more common in 1,000 mold patients now? What's more common? It's those links that turn on if you're exposed to mycotoxins? No, they're not first. Actinos are first. How about mycotoxins being number two? No, endotoxins are number two. Mycotoxins are 7% of the problem—7% of the immune responses.
Dr. Ritchie Shoemaker 47:57
So the activity of this whole metabolic structure and the basic difference between proliferative physiology versus energy conservation should make sense. Biology has limited mechanisms to act upon. We don't have a million different genes. We got 50,000. That's plenty. But specifically… Go ahead. I've got one more point to make.
Dr. Jill 48:22
No, I was just going to say that I want to link to it because LPS endotoxemia has always been a big plug for me. Even with COVID, we see that the underlying cytokine activation of LPS [which] is underlying 90% of the illness in the United States. And even in a water-damaged building, what you're saying is that mold is not the primary trigger; it's endotoxins.
Dr. Ritchie Shoemaker 48:41
No, it's not.
Dr. Jill 48:45
I actually agree with you on that.
Dr. Ritchie Shoemaker 48:45
I want you to read a little bit more about red blood cells' ability to bind endotoxins to the endothelium. So this whole idea [is that] every time you've got a bowel movement, you pee, or you have some intermittent activity, there will be endotoxins in the blood. But red cells take care of it pretty fast. So be careful on that one. I want to go back to a couple of other—
Dr. Jill 49:07
Well, all I want to say there, though, is the data on endotoxemia. There is so much literature to support [it]. You want to talk about the most research out there. Endotoxemia has a lot of data to support it as the—
Dr. Ritchie Shoemaker 49:21
And the mechanism by which you get sustained endotoxemia has a very crummy literature. It's a very small literature [inaudible].
Dr. Jill 49:26
I would agree. I totally agree. I just wanted to clarify because I think we agree on more than you think we do. So I know you have to go, but why don't you, for the last maybe five minutes or so, kind of summarize? Then, just for those of you listening, Dr. Schoemaker is talking about the GENIE test. I will include links to his recently published article, and [I'll do the same] when the next one comes out. So I'll be sure to get those links from you, Dr. Shoemaker, and include those. And then I will also include information on the test that you're talking about because a lot of people are asking: “What's GENIE?” They want to know more. You'd have to work with your doctor to get it ordered. Is that correct, Dr. Shoemaker?
Dr. Ritchie Shoemaker 49:58
Yes. The CLIA license will be coming around before long. [There were] a couple of things I wanted to touch on. There are a lot of folks in the chronic fatigue world who think that viral activation is a big deal. And they say it is, say it is, say it is. Fortunately, compounds made by neutrophils called defensins will be activated if there are viral infections. So we give you two defensins.
Dr. Jill 50:19
I saw that. And you can actually, with the GENIE, help identify which persons are more affected by viral activation or not.
Dr. Ritchie Shoemaker 50:26
Viral or not viral. It's actually less than 10% of the total. But similarly, bacterial infection. Here's the easiest way to detect Bartonella, by the way: Lyme—the mechanisms that we use were published in transcriptomics of Lyme in 2016. Boquet's paper was with John Aucott and Charles Chiu from UCSF. We can tell you if you don't have Lyme disease in the last six months; we can tell you if you've been treated in the last six months. It's kind of neat.
Dr. Ritchie Shoemaker 51:01
The other thing that's bothered me for so long has been chemical sensitivity. And I'm going to take just one minute. I've seen plenty of people with chemical sensitivity. I can recognize them when I talk to them. But finding an accepted case definition for chemical sensitivity—good luck. You've seen people with food sensitivities. You've seen people with drug sensitivities. It all turns out that if we look at Icarus, the anti-inflammatory pathway, and add up Icarus, if Icarus is positive and VIPR1, this VIP receptor is negative, those people are chemically sensitive. And the low-dose VIP protocol we've got will fix that—Icarus VIP—and fix the chemical sensitivity. We're going to publish that very soon. But it's just fascinating.
Dr. Ritchie Shoemaker 51:50
The other piece for GENIE that people need to know is that the marker for CIRS, the marker for persistent illness, is a lack of normal antigen presentation. In defective antigen presentation, we know about HLA. We've talked about HLA. But look at the antigen presentation of the dendritic cell, a professional antigen-presenting cell, to a naive T cell. Aha! CD3D—boom! We can look at that with one test! We can look at CD48. What we're really looking at now has to do with histamine for folks who think they've got mast cell activation syndrome. If the genes for histamine are upregulated, you don't have mast cell activation; you've got genes that are the basis of histamine release. That's why so many people with mast cell activation will have normal tryptases and normal [inaudible] because they don't have the disease. They've got, instead, histamine release.
Dr. Ritchie Shoemaker 52:52
The last thing to say is that relapse… We stratify people by five stages. Stage one is treatment-naive. Stage two is after my protocol. Stage three is after VIP. Stage four is off VIP, cured. But the fifth stage is relapse. Within two days, 100% of patients with re-exposure and reactivation of the immune reactivity will have a return of proliferative physiology—we treat that effectively with the protocols; it's so nice that we have that—and the return of IRS2 upregulation. Within two days! So the next prospective study is going to take volunteers, usually those in litigation or willing to do anything and do the [inaudible] protocol. That wins the legal cases very nicely. But break down the re-exposure on day one into four-hour increments so we can see how fast the proliferative physiology occurs. I think it'll be less than eight hours. Eight hours—that's all it takes!
Dr. Jill 53:59
Unbelievable! And yet, I completely believe it. I mean, truly, that's fascinating. So you've got the paper coming out soon. You'll have to be sure to send that to me, and I'll share it with everybody who's listening. And then, as these come out, we'll have to get on here again and talk about your next data set with exposure and hypometabolism and how quickly that occurs.
Dr. Ritchie Shoemaker 54:19
And immunoreactivity. The link between inflammatory illness and metabolic illness goes hand in hand. You cannot deal with this illness without both elements.
Dr. Jill 54:32
Absolutely. Well, Dr. Shoemaker, thank you so much for your generous time with us today. I know everybody's just really enjoying this. There are lots of comments. I'll have to go back and post. I'll be sure to share with you the link here and then when it's on YouTube, in case you want to share or use it in any way. And I really do appreciate your time and your expertise. And thank you, as always, for being such a leader in this field. We greatly appreciate it!
Dr. Ritchie Shoemaker 54:55
Well, thank you for those kind words. It's good words to go home on. See you.
Dr. Jill 54:58
Yes. Okay, bye-bye.
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