MCAS, COVID & Cancer: Advanced Genetics Part 1

Bob Miller, CTN

Well, was a pleasure to be with you. You and I go way back, I do believe, and I wanted to thank you for all the other times you participated to our seminars, and you were always a very well received speaker. You always did a great job. And congratulations to you on putting together this summit. I mean, what a major task this must be. And I wish you all the success that this helps a lot of people and I’m sure it will.

Beth O’Hara, FN

Thank you so much, Bob. Now I know everybody’s always curious how people get into their field. How did you get into the area of genetics?

Bob Miller, CTN

Well, interesting. I was, well firstly in Traditional Naturopathy. I was an executive in the cable television industry and came down with a severe, severe case of ulcerative colitis. Was in the hospital for 21 days, lost half my blood, got near death, and they wanted me to cut out the colon. And being the stubborn Dutchman I am, I thought, “There has gotta be something else I can do here.” And that’s why I got interested in, you know, herbalism at the time and then natural health. And of course, everything’s just fine. So that’s been 30 some years ago, and I just became totally fascinated by the whole subject. Then it was maybe 10 or 12 years ago, learned about genetics and it was that proverbial love at first sight. Being the geek that I am, I thought, “This is really cool,” that we can just buy a simple saliva test, you know, get hundreds of thousands of pieces of information and connect the dots. And of course, that’s what we’re doing, we’re connecting the dots. So that’s why I created the software that’s only available to health professionals, but what we do is we connect the dots. I think we’ve gotta move away from, “Oh, I have this snip or this mutation, therefore this problem,” I believe it’s much more complex. And it is interconnection of symptoms, and labs, and many, many other things. So we need to look at this in a very in depth fashion. And that’s what we’re trying to do.

Beth O’Hara, FN

And I love your metaphor, I use this a lot with my own clients that it’s definitely not an, “If you have MTHFR it’s this, if you have this variant, you have CBS, you have to cut out all the sulfur,” and you say a lot of times it’s like playing 3D chess underwater. And so that’s what we’re looking at. We’ve gotta look at these genetics in the context of people’s symptoms, in the context of their lab testing, and then how do we best support them? And handling that, and that’s what I love about your approach. So we’re gonna dive into some significant biochemistry and I’ll do my best to try to translate that for people who may not be as familiar with it. But I know you’re gonna share some slides because what we’re gonna talk about and look at, there’s a lot of visual components that will help people. And if you’re driving and you can’t watch it, go ahead and listen to the talk, but then you might wanna come back and look at it again, and look at these slides so you have the visuals.

Bob Miller, CTN

Absolutely. Okay, well, let’s dig in. I’m gonna start with a slide share here. And is that working okay?

Beth O’Hara, FN

Yeah, we’re good to go.

Bob Miller, CTN

All righty. As Beth said, I’m Bob Miller, and this information is educational and informational. We’re not giving any medical advice here. And couple years ago I had a professional artist draw this; the 3D just game played underwater as we just mentioned. And it really is multiple factors, and there isn’t simple easy things. Now, don’t be overwhelmed by this chart. But what I’m going to do is this is what we’re gonna be talking about for the entire webinar. So what I’d like to do is give you the high view, you know, the view from 10,000 feet. Then for the rest of the webinar here, we’re going to dig into the details.

Beth O’Hara, FN

And Rob, I just wanna tell people, because this is downloadable, we’re gonna have this link available for you at mastcell360.com/summit, where you can get all your summit resources, you’ll find your coupon codes and you can download this map.

Bob Miller, CTN

Absolutely. So for those people who like to geek out on this, they feel free to download it. And there’s a good chance that what we’ll be downloading in October, ’cause this was recorded, might be even improved upon from what we’re looking at here. Now, what I’d like to point out where you see these little purple circles or ovals, these are enzymes. And enzymes take one substance combined with something else and make something new. And as you learned earlier, you can have what are called SNPs, where the enzyme can be upregulated or downregulated. Then I’ll explain some of these other things as we move along. So I’m going to get a little bit bigger picture here, and I’m gonna start up here. Here’s where we’re going to start. There is an enzyme called tumor necrosis factor alpha. And we’ll talk about that in detail. And it’s our friend because when we are exposed to mycotoxins, Clostridia, Bartonella, lipopolysaccharides, this guy kicks in and says, “Hey, we have a problem here. We need to take care of this.” So it stimulates inflammation and stimulates another inflammatory enzyme. And these names don’t really much matter, just know that they’re inflammatory. But it’s called NF kappa B. Then that stimulates another enzyme called NADPH oxidase. Then we have some friends, the sirtuins, maybe some people have heard of those already, they’re related to longevity. SIRT1 actually calms these guys down a little bit. The NOX enzyme stimulates a cytokine called interleukin six, I’m sure with COVID, people have heard of the cytokine storm. This whole summit is based upon mast cells. Many ways we get mast cells, but the NOX enzyme stimulates it. 

And of course, you all know that mast cells stimulates histamine. I’m sure you all know that. Now here’s something that you may not know. There’s an enzyme called iNOS, inducible nitric oxide synthase. And eNOS, endothelial nitric oxide synthase. Endothelial nitric oxide synthase makes the nitric oxide that dilates our blood vessels and does good things for us. The iNOS kicks in when we have a pathogen of some sort, and creates a lot of oxidative stress. And if this iNOS is running too fast, we suppress our eNOS. So I’m sure Beth, you see this many times, that people have cold hands and feet. Because their iNOS is overrun and eNOS is inhibited. Now again, I’m going through things quickly, I’m gonna go through all of this in detail for the rest of our talk. Then that iNOS will do something called, it’ll activate our platelets. And you know, when I first started out I thought platelets were cool little things that floated around, and if we had a cut or an injury, it would clot so it didn’t bleed to death. End of story. Much more complex. And we’ll talk about that. The main thrust of our talk here today, is gonna be about something called RANTES. And I would suspect that very few people have heard about this. So hold on, I’ll explain that in a little bit. The activated platelet stimulates something called sCD40L, and we’ll get into that a bit later. Now the next thing that happens is-

Beth O’Hara, FN

I just wanna call out this VEGF as well, because some of these markers, people are used to looking at with Lyme and multi toxicity as inflammatory markers, they may have actually had that blood work run. And what we’re looking at are, we know mast cell activation syndrome is an inflammatory condition, and we’re looking at the actual mechanisms that are happening that are stimulating these mast cells across the various 200 different types of receptors.

Bob Miller, CTN

Absolutely, yeah. We’ll get into detail on VEGF and MDSC. Then tumor necrosis factor also stimulates an enzyme called the COX enzyme that actually pulls something called arachidonic acid out of the cell membrane. And we’ll get into phospholipase A2. That then comes down, creates something called thromboxane A2, again activates the platelets. And then finally, there’s a third pathway that we’re gonna dig into. There’s an enzyme called Interleukin 6, that again is our friend, unless it’s overactive. And we’ll talk about all the things that stimulate that, but look what it does. It creates a free radical called superoxide, mast cells, histamine. Histamine stimulates the RANTES. The RANTES stimulates the mast cells that stimulates the histamine. So we have a feedback loop here. And I’m sure many people who are dealing with mast cells and histamine are frustrated because they try to do so many things. Nothing seems to work. And then-

Beth O’Hara, FN

Cascades we’re just, we keep flaring and it gets worse and more outta control.

Bob Miller, CTN

Absolutely. Then we all know the benefits of the omega-3s. Well there are enzymes called fatty acid desaturases. And ELOVL2, we’ll show more charts on these, talk about them. They make something called protectins and resolvins, and they calm down these platelets. So what we’ve been finding is that people who are exposed to mycotoxins, mycotoxins, Clostridia, Bartonella, any other form of lipopolysaccharide, and this even appears to be what’s happening with the the COVID long-haulers, that this whole thing gets revved up, the person is over there, their COVID, it’s gone, but they’re still sick. And one of the hypothesis that’s out there, it kicks off this pathway and then it just keeps feeding upon itself. So that’s the big view. And if you’re a little overwhelmed at this point, don’t worry about it. But for those who like the big picture, we thought we’d give the big picture first, then we’re gonna dig into the details.

Beth O’Hara, FN

This is a perfect example, Bob, of why we can’t just look at a single snaps, because you can see just this one section is so interrelated with so many other areas. And I remember when we were creating the first big NutriGenetic map, and the biochemistry map, and finding all these pathways that fed into each other, this is why we really have to move beyond, if we have MTHFR, throw some methyl folate at somebody. And then there’s a timing in the introduction of these things as well.

Bob Miller, CTN

Absolutely. And that’s why so many people, you know, I’m sure both of us talk to folks all the time who say, “Oh, I can’t take anything.” And the reason being is they may be… And one of my responses to that, “Well the reason you’re maybe having a negative response, is because it’s working.” And they look at me like, “What do you mean?” Well, it’s trying to turn something on, and the body’s so inflamed it can’t handle it.

Beth O’Hara, FN

Yeah, it’s too early, too soon.

Bob Miller, CTN

Yes, it’s too early. Yeah. I should have had another slide here, but I had another slide that shows a house burning down, and people are washing the windows and mowing the lawn. So one of my favorite sayings is, “When the house is burning down, don’t wash the windows and mow the lawn, put out the fire.” And too many people try to do other things first. “Oh, I’m tired. Let me take some things for energy.” “Oh, I’ve got heavy metals, let me do a big detox.” Many times we have to just calm everything down first. One of my favorite sayings is, “I’d rather be a little too late than too soon.” Now let’s move on to RANTES. It’s a funny, funny name. Regulated upon Activation Normal T-cells Expressed and Secreted. Seriously? How did they come up with that name? But it’s also called CCL5. It’s a pro-inflammatory mediator of the cytokine chemokine family. This is the key word right here, regulates the mobilization and survival of immune inflammatory cells from the bloodstream into tissues and other areas of injury infection. Is that a good thing? Sure. Unless it’s over active. So this is the study that says, “Sustained production is associated with several detrimental effects. And treatments that interfere with RANTES are associated with improved outcomes.” So that’s what RANTES is. And everything we’re gonna talk about today, is how multiple things will cause the RANTES to be upregulated.

Beth O’Hara, FN

And for Bob, for people who this is all brand new for, I just wanna explain to them that cytokines and chemokines are cell signalers in the immune system. Mast cells make lots of cytokines, then these other cells make cytokines and chemokines. So this RANTES is helping to regulate those. And some of these cytokines, chemokines are pro-inflammatory, some are anti-inflammatory. So it’s modulating the inflammation response, which should be a good thing until you have a big issue where it’s out of control. And a lot of people now know the name cytokine storm. So there are some roles in all of what you’re talking about with that as well.

Bob Miller, CTN

Absolutely. Now, RANTES is produced by all of these things, but we’re just gonna focus on the platelets, ’cause that’s our discussion here today. But key point here, RANTES stimulates histamine secretion by mast cells. It recruits T-cells, macrophages, eosinophils, and basophils to sites of inflammation. Again, a good thing unless it’s overactive. And that’s the key point of being overactive. Now, I’m gonna burn through these pretty quickly, but here’s a couple conditions. RANTES plays a fundamental role in histamine and serotonin generation. We’ll talk about serotonin later and cell function in mast cells. And here is a study of eczema and they were shown to play an important role in the orchestration of the eosinophil infiltration and making eczema worse, was shown to reflect the severity of the disease. Now this has been pre-print as of this time, maybe it’ll be peer-reviewed by the time this plays, but they’re talking about, our study shows that COVID-19 is very much a RANTES disease. Demonstrating- So this doctor and his team started measuring RANTES in the long-haulers and in COVID, demonstrating 100 times normal levels of RANTES in critically ill, five times normal levels even in mild moderate cases. And this came from Bruce Patterson, MD. 

So what they found is that when they lowered the RANTES, these people had reduced viral load in the COVID-19. So again, this isn’t a cure for the COVID, we’re not saying this is cures it, but clearly once it starts running and you’re in that long haul, this seems to be what’s happening. The RANTES is much higher. Here is, and again I’m not gonna read all of this, but they’re just talking about that the RANTES increases the liver damage and liver disease. I’m gonna burn through these quickly. Autism spectrum disorder. RANTES and other chemokines were shown to be higher when compared with typically-developing children. Supports the hypothesis that altered chemokine levels are involved in autism spectrum disorders. Studies saying that this could be a potential biomarker for autism spectrum disorder.

Beth O’Hara, FN

That makes sense. All these are inflammatory conditions in different areas of the body.

Bob Miller, CTN

Neuroinflammation. Chemokines like RANTES control the recruitment of leukocytes. And something called Met-RANTES that knocked it down, was shown to reduce progression of heart disease. And they’re saying this is a potentially new therapeutic strategy for cardiovascular disease. Inflammatory bowel disease. So they looked at the colonic tissue from patients with various IBDs, and it was greatest in the severely inflamed tissue, the chemokine-expressing cells. RANTES was expressed infrequently by T-lymphocytes in normal colon. So the bottom line of this study is, significant redundancy in the generation of these chemokine signals in chronic inflammation in inflammatory bowel disease. That’s your Crohn’s and ulcerative colitis. Lung disease. Found profound elevation of plasma IL-6 in the SARS-COVID-2 V in the COVID-19. And also for respiratory virus, infection of respiratory epithelial cells and an upregulation of the CCL5, which is the RANTES. And the level of the RANTES in the upper airway secretions correlate positively with this disease severity. Here’s a study showing that it’s higher in prostate cancer. And I’m sure as we do research, we’re going to find more and more where this is upregulated. Because if you think of the RANTES as being part of the VEGF, lowering the immune system, increasing the histamine, and increasing the mast cells, the list is probably gonna get longer and longer. So I’m sure this is just a snippet of all the things involved with the elevated RANTES and.

Beth O’Hara, FN

We know there’s a huge mast cell connection with cancer.

Bob Miller, CTN

Absolutely.

Beth O’Hara, FN

And so this is just filling is more of these links that we- and we’ve got mast cell connections with the different disorders you just went through.

Bob Miller, CTN

Now, this is just a beginning of what stimulates RANTES. So platelets will stimulate the RANTES, and as I said, we looked at different ways that the platelets can get activated. Lyme disease. So here they’re showing that the- That we were exposed to the Borrelia, the bacteria responsible for Lyme, it’s strong inducer of the chemokines. So, and I’m sure you see many people who have mycotoxins and Lyme together, and these are the ones that are really struggling. Now we showed you earlier that, that the tumor necrosis factor stimulates NF-kappa-B, but they’re saying that the strength and kinetics of RANTES has been shown to be highly dependent on the preexistence of NF-kappa-B. And I’ll show you another chart of that in just a moment. And iron, you know, we… What’s interesting, back in 2016, we won the research award in Helsinki for our Lyme disease, because we showed that the people with chronic Lyme had more than five times- Five times more absorption of iron through a gene called the HFE genes. We just observed it. Now what we’re finding is that, aha, this iron stimulates NF-kappa-B, and tumor necrosis factor activity. So we knew that excess iron was always a problem, but it’s just based upon this new research that we find that this iron that’s not regulated or in excess, stimulates.

Beth O’Hara, FN

Well and many people, I just wanna- That’s a great pearl and many people are so worried about low iron. But these inflammatory conditions, especially men and women who aren’t menstruating, we’ll see that iron start to accumulate and we’ve gotta look at a whole iron picture. But what you’re saying is that has a role in stimulating these inflammatory pathways as well.

Bob Miller, CTN

Yeah, that was a new one for me. I mean, we talked about the Fenton reaction for a long time, and as we’ll show later iron even stimulates the iNOS sensor. Here’s a peer-reviewed study. The histamine from the mast cells has been shown to enhance the production of RANTES. All right, so here’s back to this chart here. So now we’ll look at one more time. Mycotoxins; Clostridia, Bartonella, lipopolysaccharides, stimulates TNF-A, and NF-kappa-B, and I didn’t mention that in the quick review, but you can have genetic mutations in the HFE genes, which causes you to over absorb iron, which you can see also stimulates these guys right here. And then interestingly, mercury induces NF-kappa-B. The COX enzyme that we’ll show you later in the iNOS. glyphosate increases NF-kappa-B. So why do we see, you know, mast cell activation getting worse? Yes, there’s a genetic component, but nothing has changed genetically. There’s nobody running around today different than they were before. I believe what’s changing is the environment. The mercury, the mold getting stronger, more Lyme disease, glyphosate. So people who had genetic predispositions, 75 years ago, it didn’t matter. But now those who have genetic weakness and were exposed to this ever increasing amount of environmental toxins, are being impacted. That’s the only reason why I can think mast cell activation is so much higher today, because our genetics aren’t different today than they were before, but the environmental factors are.

Beth O’Hara, FN

Absolutely. I say that often where the canaries in the coal mine, most of us with mast activation syndrome are the ones waving the flags saying, “Hey guys, this world is too toxic. We’re the ones getting hit first, but is toxic for everybody.”

Bob Miller, CTN

Yes, my grandfather was a coal miner, and he told me stories of how they would take the cage with the canary. And if the canary ever fell over dead, because they had smaller lungs, they knew that if they didn’t get out they’d be next.

Beth O’Hara, FN

‘Cause there were toxic gasses in the mine shack, yeah.

Bob Miller, CTN

And the canary had the effect of it before the workers did. So that’s where that term comes from, “Canary in the coal mine.” Now, these are just some of the environmental factors, Clostridia, Bartonella, lipopolysaccharides, mercury, glyphosate. And then I listed the SNPs that are involved here. As you had mentioned, we’ve formulated some products, these are just the names of them. And there’s one under development. We’ll probably have this by the time this summit plays, something called hydroxyl blocks to slow down the iron Cystocalm 6, to calm down the Interleukin 6. NADPH protect to calm this down. So with precisions we have to go in there and decide where we need to do support. In other words, it’s not the, “Do this for the mast cells.” We have to find out where the overactivity is, and jump in and give precision care.

Beth O’Hara, FN

And, Bob, for people who aren’t familiar, could you just tell them about lipopolysaccharides and also what gain of function means?

Bob Miller, CTN

Oh, sure, yeah. Lipopolysaccharide is just gram negative bacteria. And yeah, I should have explained that. So when there are mutations in the SNPs or in the genes, many times you’ve probably heard that it slows down. In other words, if there’s one SNP that’s estimated at 70% it’s efficient, two SNPs, maybe 30 or 40, but there are a couple of genetic mutations that when it’s mutated, it actually runs faster. So you can see here this TNF-A, we’ll talk about this in a little bit, the mutation there actually makes it respond more. Mutations in HFE cause it to absorb more iron, not less.

Beth O’Hara, FN

So sometimes also called a upregulation.

Bob Miller, CTN

Upregulation, Yes, there’s upregulation and downregulation. So here’s tumor necrosis factor. This is the specific RS number, in in genetics there’s an RS number that goes with everything. And this is what we measure in functional genomic analysis. And when this one’s mutated, it’s a gain of function. So TNF is an inflammatory cytokine produced during acute inflammation, and it signals to leading to either necrosis or apoptosis. Clearly our friend, unless it’s excessive. So it’s important for resistance to infection and cancers. But what it does, it stimulates something called PLA-2, and I showed you that earlier but I’ll go back to it later. That results in increased arachidonic acid, Thromboxane A2, thus leading to platelet activation and increased RANTES. So the key here is when it’s excessive, we didn’t have this, life wouldn’t exist, it’s not bad, but if it’s too much, that’s when it harms us.

Beth O’Hara, FN

You sometimes talk about this like Goldilocks. Can you explain that?

Bob Miller, CTN

Oh, sure. We all know Goldilocks and the three bears. You know, one was too hot, one was too cold. One was too hard, one was too soft. But baby bear’s was just right. So I often say, “Let’s refer back to Goldilocks and the three bears.” Too little or too much is a problem. There’s like a bell curve for many things. So TNF-A is our friend, unless it’s excessive. And if kappa-B is our friend, unless it’s excessive. And it’s a problem if we didn’t have it. If this was too low, we’d be overrun by bacterias or pathogenic diseases. Too high, it attacks us. That’s the key, finding that sweet spot, so to speak. So NF-kappa-B, and by the way, I probably ought get an artist to draw something like that. That’d be cute to have a drawing like that. NF-kappa-B is a family of transcription factors that concerns roles in the immune system. They regulate inflammation, cell survival, primarily through the activation of the NF-kappa-B pathway. 

So again, a good thing unless it’s excessive. So we have been finding, just observing, that many times people who have a heterozygous, but particularly when people have homozygous here, which is not very common, these people have inflammation, they just can’t seem to get under control. And no wonder, okay? So here’s a study that says, “In response to endotoxins, the lipopolysaccharide, LPSs, due to gram-negative sepsis, human monocytes are triggered to produce large quantities of the tumor necrosis factor. So when we get exposed to these things, that’s when we get the TNF-A moving into action. And then it also includes activation of the NF-kappa-B, and the concentration of RANTES has been shown to increase due to the addition of the tumor necrosis factor alpha and lipopolysaccharides. So again, it all comes down to when it’s excessive. Now, mold. This is a a great plain mold test. Here’s ochratoxin, gliotoxin. Ochratoxin- I’m sorry, say again?

Beth O’Hara, FN

That’s a lot of gliotoxin.

Bob Miller, CTN

It sure is, yeah, this person wasn’t doing too well. Ochratoxin is a natural fungal secondary metabolite, and it significantly modulates IL-2, and tumor necrosis factor alpha. So there’s the reference to the peer-reviewed study that the ochratoxin will stimulate TNF-A and begin that cascade. Now we’re gonna be adding to this list, but these are some of the TNF-A inhibitors, black cumin, curcumin, quercetin, and milk vessel. And of course, some people can’t take quercetin, because of COMT issues or others, but that’s all part of the stuff we’re putting into the software to give people warnings when something may not be appropriate. But I’m personally a big fan of black cumin seed oil. The ancients used to say that it cures everything but death. I think that’s a little bit of an exaggeration, but it is pretty powerful.

Beth O’Hara, FN

That’s a great antiviral as well as the mast cell stabilizer. All of these are, curcumin, quercetin, very good mast cell stabilizers as well.

Bob Miller, CTN

Now, SIRT1. I’m really gaining a lot of respect for SIRT1. Some people, of course, say it’s sirtuins, other people say sirtuins. It does more, but we’re emphasizing how it inhibits NF-kappa-B and NOX. So you’ll see here that SIRT1, when this line goes this way and here, means it inhibits NF-kappa-B and NOX. And if you, you know, start researching sirtuins, you’ll find that anybody who’s looking at longevity, is looking at the sirtuins and how to boost them. It’s one of the most well-studied sirtuins, significant role in development. It decreases during our aging. By the way, it is NAD-dependent, we may talk about that a little bit. Decreased levels are found in the aging liver, and it regulates a lot of enzymes. I mean, your AMPK, which is autophagy, your FOXOs which are anti-inflammatory, your superoxide dismutase, your NOS3, which is your circulation, and inhibits these inflammatory ones including IGF-1 and mTOR. 

By the way, when our 2017 or 2018 study on Lyme disease, we showed that those with chronic Lyme had many factors that would cause mTOR to be upregulate. For those who don’t know, mTOR stands for a million target of rapamycin, the growth of new cells. Is that important? Sure. If we didn’t have that, the sperm and the egg would never become the baby. The baby would never become the adult. We wouldn’t have new cells. But there’s also something called autophagy, the cleaning of the cells. So if we have mTOR running all the time, we don’t clean the cells. And then mTOR is inflammatory. Now, this one really surprised me. I mean, we all know that high-fructose corn syrup’s probably not good for us, but this blew me away. High fructose corn syrup inhibits SIRT1. Wow, that’s a big deal. So as you can imagine, there are mutations that weaken SIRT1. So if somebody’s got a weak SIRT1, and they’re eating a lot of high fructose corn syrup, they’re really more prone to inflammation. So have you ever, Beth, have you ever heard the analogy, “Where does high fructose corn syrup exist?” And the answer is, “Everywhere.” It’s just in so many foods.

Beth O’Hara, FN

So many packaged foods have have it. Even things that you wouldn’t think of as being sweet and sodas. And so this is a great look at how this can have an inflammatory mechanism beyond just raising blood sugar and having insulin issues. And then gosh, you combine that with having too much iron, you’re really gonna be in trouble there.

Bob Miller, CTN

What we’ve been observing, I mean, this is just a clinical observation. When somebody has an upregulation of TNF-A, upregulation of iron, down regulation of SIRT1, these are the folks that are just going to one clinic after another, “What’s wrong with me?” Particularly when they’re exposed to mold and/or Lyme disease, or of some other pathogen that’s stimulating this. Resveratrol, quercitin, and intermittent fasting, may activate SIRT1 activity. What also should have been put on here, is NAD feeds SIRT1. That’s your nicotinamide mononucleotide that makes the NAD plus. I’m not gonna read this. I mean, are people gonna have access to the slides, Beth, though?

Beth O’Hara, FN

If you will send them to me, we can make them available on our summit page.

Bob Miller, CTN

Yeah, so we’ll make these slides available. And again, I’m not gonna read this, this will be just too boring to read all this. But for people who wanna understand what the SIRT1 does, I would highly encourage you to look at this slide and look at how many factors this SIRT1 is related to. So we are finding SIRT1 mutations to be incredibly significant. Now this slide, we will dig into a little bit. SIRT1 supports eNOS, that’s the endothelial nitric oxide synthase, the blood flow. It supports the production of an antioxidant called SOD. And as we discussed, inhibits NOX and NF-kappa-B, but it’s probably worth repeating that a couple of times. It also inhibits mTOR, mTOR inhibits autophagy, and SIRT1 also helps an enzyme that clears histamine. So you can see why this is so important. High-fructose corn syrup inhibits resveratrol supports, and nitrates like from your beat root. But you know, some people can’t do that for the oxalates.

Beth O’Hara, FN

Arugula is good source.

Bob Miller, CTN

Oh, that’s right, yes. Arugula, yes. SIRT1, here’s the RS number. And nobody seems to know why, but when this is homozygous, there’s a lot of anxiety, not quite sure what causes it. But again, the people who are really struggling, often have the SIRT1 mutation.

Beth O’Hara, FN

Maybe neural inflammation.

Bob Miller, CTN

Likely, yeah. And I don’t know if it’s just histamine or glutamate, but it really wreaks havoc on individuals. Now, here is a little bit more on the mast cells. There is a gene called the KIT genes, that when they are mutated- And sorry, I don’t have ’em on here, but they’d be right here. Mutations in the KIT genes, again, are gain of function, and the mast cells over-respond when there’s KIT genes. And then there’s a product called MC stabilizer that Beth was the formulator for. And we use a lot of that to calm down the mast cells. So you can just see how this pattern just keeps going down through here. Now we’re gonna switch over to histamine. As you make this histamine, the mast cells make the histamine, there’s a lot of enzymes involved with clearing histamine. One of the ways we do it is by cortisol, which comes from progesterone. You can have genetic mutations that will slightly inhibit the progesterone to cortisol. You can also have progesterone deficiency. There’s an enzyme called diamine oxidase, made by the a ABP1 enzyme that degrades histamine. There’s the histamine raising foods, of course, that will raise this. There’s an enzyme called histamine and methyl transferase that degrades histamine. And what’s interesting, you can have perfect HNMT, but if you don’t have something called SAMe, the co-factor for methylation, it’s like having a brand spanking new car without any gas. It just sits there and does nothing. Then here’s your MAO-A. And again, there’s something called FAD from riboflavin. So if you don’t have enough riboflavin, doesn’t matter whether you have mutations here or not, it’s not gonna work.

Beth O’Hara, FN

It’d just be two.

Bob Miller, CTN

Yes. And then SIRT1 also inhibits this. So if you’ve got a SIRT1 mutation, don’t have enough FAD, and you have perfect genetics on MAO, it’s not gonna do anything. I mean it’ll do something, but it’ll be way underperforming.

Beth O’Hara, FN

It’s just that the other one is signaling to turn the MAO on, it’s a regulator.

Bob Miller, CTN

Yes. So that’s why we have to look at more than just the SNP. You know, people can say, “Oh, I don’t have any HNMT, I’m okay.” Well maybe not. If you have difficulty with methylation, and don’t have enough SAMe, it’s not gonna work. Okay?

Beth O’Hara, FN

And this also great chart, Bob, because so many people only think about DAO or HNMT with breaking down histamine, but we know that it’s much more complex than that.

Bob Miller, CTN

And I wanna cover two more here. There’s a process called glucuronidation. Have you ever heard of that, Beth?

Beth O’Hara, FN

Little bit.

Bob Miller, CTN

Can we tell that story?

Beth O’Hara, FN

Sure, go ahead.

Bob Miller, CTN

Okay, so we had a conference, what? Three years ago maybe? And we wanted to look at the phase two detox pathways. And I talked to Beth and I said, “There’s a couple subjects here, how about if you speak on glucuronidation?” And I think your response was, “Gluco what?”

Beth O’Hara, FN

And I remember saying, “Oh, it won’t be that hard.”

Bob Miller, CTN

Yes.

Beth O’Hara, FN

“There’s only about two pages in my big biochemistry, you know, detoxification textbook.” And then six months later, I had the slide deck done because of the mounds of research on it.

Bob Miller, CTN

And lemme just say, I was so impressed and so proud of you, the job that you did. I mean, you really dug deep. And clearly, I think that goes down as probably one of the best presentations ever on glucuronidation, so…

Beth O’Hara, FN

Thank you.

Bob Miller, CTN

And then I think you- Yeah, they had the privilege to work with Neil Nathan, Dr. Neil Nathan, to look at the literature, and you found that glucuronidation is probably one of the biggest clearers of mycotoxins, so…

Beth O’Hara, FN

That’s right, it’s been a game changer.

Bob Miller, CTN

Yeah. So anyway, congratulations to you on doing that. So you went from “gluco what?” to probably one of being one of the top experts on glucuronidation, so… Now, this is so if you have problems specifically with the UGT1A4, you’re not gonna clear histamine through glucuronidation. People probably don’t even know that. Clinical observation only. But when we see people have a lot of SNPs on UGT1A4, these are people that usually have a lot of histamine and can’t seem to clear it. Now, another one that most people don’t know anything about is HDC, histidine decarboxylase. And this is what actually makes histamine, it takes the amino acid histamine, along with B6, and makes histamine. Now, I didn’t list it here, but there’s actually genetic mutations that can slow your degradation of B6. So what do you think happens if some well-meaning person says, “Oh, you need a B complex with 50 to 100 milligrams of B6,” and this HDC is upregulated, and there are genetic mutations that upregulate HDC? That B complex can just drive that histamine through the roof. And I’m sure you’ve seen that. People taking a B complex or a B vitamin having a horrible result. Am I correct on that?

Beth O’Hara, FN

Sometimes, absolutely. Especially sensitive people. And, you know, this really drives home as well, Bob, people developing histamine intolerance after exposure to all these different things that are cleared by glucuronidation, is mold toxins, chemicals, a vast majority of chemicals, medications, our hormones, so much goes through this pathway, it’s our most important phase two pathway.

Bob Miller, CTN

Absolutely. Now, Bob Miller hypothesis, you know, everything I talk about, I make sure there’s peer-reviewed studies on, and if I ever just give you a hypothesis, I always wanna tell you that. So this in three bucks will get you a cup of coffee. But I think when mast cells are firing, they send a signal to HDC that says, “Give me more histamine.”

Beth O’Hara, FN

Yes, it’s part of that cell danger response. And that’s documented in that literature. So there is studies on that, Bob.

Bob Miller, CTN

Oh, there is? Okay.

Beth O’Hara, FN

And part of cell danger response is upregulation in HDC. And that cell danger response, which we’ve got a whole talk on as well for the summit, but part of that cell danger response being triggered by things like mold toxins, chemical toxicity, pathogens like Lyme, will increase that production or that conversion of that histidine amino acid to histamine. So there’s another avenue where you’re increasing the histamine for that inflammatory protective response, but then it’s getting overdone, and then the glucuronidation pathway to clear this is broken down, the gut’s impacted by all these things, so you lose your DAO, and your ability to produce the DAO. And this is where we get these huge increases in histamine intolerance.

Bob Miller, CTN

Absolutely. I should point out, you know, again, many people that are tired, they think, “Well I need some amino acids. Gosh, that’s good.” Well, if you would take too much histamine, you could in theory feed this pathway as well. So there’s so many ways that we can think we’re doing good things, and we’re actually shooting ourselves in the foot. I know in my consulting sometimes I’ve often said I think I help people just as much by taking them off things. So they can, you know, if you’re taking a lot of things that B6 and you don’t degrade the B6, it’s like, I think you’re shooting yourself in the foot here. Now I’m not anti-B6. I mean, B6 is needed for so many processes, but if you don’t degrade it and it’s hanging around and you have excess, back to Goldilocks and the three bears, not too much or not too little.

Beth O’Hara, FN

And we’ve gotta clear out these pathways and just clear this load so things aren’t clogged up. And then you can get back to doing things like amino acids or B6. But it goes back to that order of operations and doing things in the right- The right process, and the right order at the right time for each person.

Bob Miller, CTN

Absolutely. Now, you’ll find this interesting. Iodine, testosterone, and ECGC, calm down HDC. That’s why we formulated a product that doctors use called DAO support. And not only has diamine oxidase, but a little bit of iodine, ECGC, and black cumin seed oil to calm this guy down. That can be very important. Now, what’s happening to young boys? Testosterone levels is dropping. If you talk to college professors, they say, you know, “Tell me about the young boys.” The term that always comes up is “fragile”. They don’t have the resilience and the strength they did. And that possibly could be because of testosterone levels going down. I mean, testosterone does a lot, this isn’t the only thing, but interestingly, we need testosterone to keep HDC under control. All right, histamine stimulates iNOS expression and NF-kappa-B signaling pathway. So look at all the damage this histamine is doing. And I just rea- I mean it’s probably in the last three, four months that we found these studies. I mean you’ve really gotta dig through the medical literature to find this stuff, but it’s astonishing. And when I saw this, that histamine stimulates iNOS, it’s like, “Seriously?” And then we saw this one before, but it’s worth putting again, enhances RANTES. So if somebody really wants to dig into histamine, I think most people know Dr. Jill Carnahan. We’ve done a couple of videos with her, and if you go to YouTube, Dr. Jill Carnahan histamine intolerance, this will pop up. 

And we do a 45-minute talk just on histamine. Now, I wanna talk about nitric oxide. It’s one of the simplest molecules, two atoms, nitrogen and oxygen. That’s it. But it’s considered one of the most significant molecules in the body, crucial to your wellbeing. I mean there it is, just two molecules. It’s a vasodilator, causes the blood vessels to expand. Obviously needed for the circulatory system, blood pressure, nutrients to the muscles and organs, stimulates the brain, helps men with erectile function, that’s why they take Viagra and Cialis. Increases energy, supports wound healing, supports the immune system. A signaling molecule in the cardiovascular and nervous systems influencing every body organ including the lungs, liver, kidneys, stomach, genitals, and of course, the heart. And that’s why sometimes people carry nitroglycerin with them. You know, they get chest pain, they put the nitroglycerin in their mouth and it boosts their nitric oxide. Again, I’m not gonna read this, this is way too much to read. If you download the slides, you can see all the benefits of nitric oxide. Now you’re probably gonna say, “I’ve heard that before, Bob.” We can have too much or too little. Now, the eNOS enzyme is what makes the nitric oxide that dilates our blood vessels. The iNOS enzyme is your body’s defense. So you-

Beth O’Hara, FN

The different types of nitric oxide here.

Bob Miller, CTN

Yes, but it’s a lot more of it. The eNOS makes small amounts to dilate the blood vessels. The iNOS makes massive amounts of it to kill pathogens. So once again, our immune system has to protect us. iNOS generates very high amounts to fight bacteria, virus, and fungus. Total elimination is shown to increase susceptibility to various infections. So without, iNOS, we’d probably die of infection. But once again, when we overshoot and we create too much, we have a problem. So excessive nitric oxide from iNOS up-regulation has been associated with many health concerns. Tissue damage and organ dysfunction. Again, what’s there to help us, in excess hurts us. Now again, you can download the map here, or we’re gonna have it in the link, if somebody really wants to dig in. And I’m not gonna go through this entire map, but I’m just gonna show a little bit of it here. So here’s your eNOS,