#13 The role of Mast Cells in complex illness: what they are and how to calm them with Dr. Theoharis Theoharides

[Music] Welcome to Make Visible, the podcast shining a light on complex chronic illness. I am your host Emily Kate Stevens and I've been living with an energy limiting condition since 2020. Here I will speak to the world's leading experts to bring you the latest science research and insights into invisible illnesses, including MCFS, EDS, fibromyalgia, pots, long COVID and more. Welcome, I hope that you're all having a reasonable day. This week I have the pleasure of bringing you an interview that I recorded in person with Dr. Theo Harris, Theo Herrides, in Florida, where he is now a professor at the Institute of Neuroimmune Medicine at Nova South Eastern University in Clearwater. He has over 40 years experience researching mast cells, calling himself the mast cell master. I went to him for an overview of what these cells are responsible for in our body, how they might be contributing to these invisible illnesses, looking at the crossovers discussing better diagnostics, and considering how we might inhibit their activation, preventing these allergic-like symptoms from taking place, rather than treating it after the fact. I hope that you enjoy it. Dr. Theo Harris, Theo Herrides, thank you. Perfect. So much for joining. You are probably the only person that just pronounced my name perfectly. I go for Dr. Theo for sure. Dr. Theo, it is such a pleasure to actually be here meeting you in person. Thank you. Likewise. What a joy. Really what I would like to focus on today is one of the things that I ask our audience for every week is for feedback and to tell us what they need more information about. And I have had a lot of people asking me about mast cells, mast cell activation syndrome, but for an explanation of what this is. And so of course, I came to the mast cell master. I think this is one of those symptoms. Possibly people are feeling it as a symptom, this mast cell activation in long-cavid that's, therefore, got more prevalence than it had previously. But I think that it's possibly something that is fairly underrepresented or misunderstood, amongst the general population. And I'm not just talking about patients, I'm talking about physicians as well because I know that you have talked historically about how people approach their physician with a certain condition. And you have the understanding that perhaps that is mast cell activation. Well, it could be a better time to have this conversation because I was actually invited to write a review on mast cell activation, comorbidities and lookalikes. And I'm 90% through, in fact, I'm finishing it up downstairs. I'm raising a lot of the issues that I'm sure you have in mind, many of those in your audience have in mind. So let me start by the fact, there are many misnomers. So we talk about allergies, ketopic diseases, mast cell activation, mast cell activation and specified mast cell activation syndrome, conditions with mast cell activation, a topic inflammation, and the list goes on and on. So the scientific, the medical community has just not gotten together as of yet to really define what we're talking about. And of course, patients are left scratching their heads as to what do I really have. In a month or so, I'm giving a lecture about mast cell activation in multiple chemical sensitivities syndrome that seems to be just like mast cell activation. And in fact, I think it is. And I'm not suggesting we change the mentholature necessarily. We don't really have to rediscover the will about what is the basis for many of these conditions. But we need to again, that understanding that they might possibly all have the same basis. So about 15 years ago, I actually taped an episode out of the blue. I was actually giving a lecture in Copenhagen. And two patients approached me and they had complex problems along the lines where we're discussing. So we created an episode with this YouTube and it's called "My mystery symptoms and mast cells." So there was no question then and there's given more no question now that the mast cells are everywhere. So let's start with the fact that they're everywhere. They're in every tissue in the body, especially tissues exposed to the outside, like eyes, nose, mouth, lungs, skin, gut. They're also inside the brain. And in fact, that critical part of the brain that connects the hypothalamus that regulates everything in our body with a pituitary that releases all the hormones in the body. It's called the median eminence. It's a little stock connecting the two has more mast cells per unit volume than our skin. Yet our brain doesn't get a large of reactions. We used to think that the mast cell, which has 1,000 secretory granules, can store and release about 100 molecules. As of about a year ago, now we're two 350 molecules that can release. And yet, we're still dealing only with histamine and maybe look at trines that constrict the bronchi. We had a loss about how others other molecules are released when they are released and to make things even worse, if we were to assume that a mast cell will be triggered by epitectylatrigal, whatever the trigger might be. The first hormone released under stress called corticodropin releasing factor in Europe or corticodropin releasing hormone, C-R-F or C-R-AIDS in the States resets the reactivity of the mast cells. That means that individuals, my have had some history of allergic-like problems. Let's call them that for now. They undergo a major surgery event or car accident. It got from me at someone dies in the family and now they're allergic to everything. Code on code allergic. So we know that the mast cells are not static and they will respond to pretty much anything. And there's no question from work other colleagues have done that they respond to pathogens. There can be bacteria, there can be fungi, there can be viruses. And not only they stimulate the mast cells, but they themselves reset the reactivity of the mast cells. Hence, people that might have been done with COVID for instance, now they have all kinds of symptoms that are reminiscent of activation of the mast cells. And I think what's interesting there is in the things that you mentioned is you're not only talking about something that infiltrates the body in a pathogenic way. You also mentioned you said God forbid someone dies in the family. So you're talking about psychological impacts, the trauma in that sense and not differentiating that against a physical problem. Not at all. Both physical and emotional stress will release those hormones, especially CRF. The difference is that while for instance, someone had let's say, eczema, which is more allergic type, might undergo a mental stress well event and now they're kind of will be covered with eczema. We've seen hundreds of patients like that. But what we're entering now, an era where the triggers are hidden. So if someone let's say we're sick with COVID or they had immunocluosis at some point and now we have viral reactivation, then we'll trigger the mast cells and now that might either respond to triggers, they had been quiet for a very long time or new triggers that are showing up now. Does it always tend to be one big trigger like a COVID like a virus or that's kind of analogy of a glass of water and you add a bit more and you add a bit more. So can the mast cells operate in that way? So you have a virus and then you have emotional trauma and then you have something that you were already triggered by maybe it's a chemical, maybe it's a cleaning chemical. No, I agree with you. Eventually the glass overflows. Is there that if there is a distinct event, it's easier for a patient to understand it and convey it to a physician or my remember that everything started after that. And as you said, that can be an incident after an incident, incident is eventually leading up. So it can be these small increments? In medicine, we always look for triggers because it's easier to say, well, there's a trigger, but we don't really look for inhibitors. I mean, my mast cells don't fire. Yours may. So why? It may be that you're exposed to triggers, but their individuals would never be exposed to any trigger that I can put my finger to, and yet they respond. So if we were to look for possible inhibitors in our body, in general, in medicine, we don't have that many inhibitors. We have a couple of molecules that inhibit enzymes that break down protein, so alpha-2 microglobalin, alpha-1 antitripsin. Well, that's about it. And I don't believe nature, you know, God over 300 million years didn't actually end hours with some inhibitors. So one of our major efforts is to identify why we are not looking for possible inhibitors. Give you an example. We had done a small experiment a long time ago, but it was n equals 1, 1 particular experiments of Google could really publish it. We took blood from an individual about 26 years of age, female working in my lab with your permission, of course. And blood from an individual had severe muscle problems, okay? And we culture muscle cells in the laboratory. So what we did is we removed half of the medium we put in the tube that we culture the muscle cells. And in one instance, we were playing with the medium from the normal individual, quote, unquote normal. And the other was the pressure on muscle problems. And then we stimulated the cells with a neuropeptide, co-substant speed. Well, the cells in the medium of the other was normal individual, fired less. And the ones in the muscle sort of person fired much more. But there was nothing else, same trigger. So something in the blood of the otherwise normal individual was preventing the stimulation. And in the other instance was actually making the stimulation worse. So is that suggesting that people that gets this muscle activation, this flood of muscle, however we want to call it, this kind of reaction? Are lacking that inhibitor in their body? That's what I'm implying that we have to deal with the balance of the triggers and then the possible lack of innate inhibitors. And I think they're both true. Except that until now, no one is actually uncovered an innate, internally inhibitor of the muscle cells. And I've spent my last 40 years looking for one and I'm still looking. Because I have some clues as to what might be possible. Right. In nature, there are ways for us to potentially look for such. For instance, lizards have lots of muscle cells. They don't get allergic reactions. Same goes for fish, sharks, where they're gonna live. Don't get allergic reactions. They have lots of muscle cells. So obviously, number one, they're doing something there other than sacramid allergies, which they don't get, or they're prevented from doing that. So I think the science, we might get back to this, is someone misguided in the way we approach solving problems. So number one, we still don't understand the function of the muscle, other than in this type of reaction we're talking about. Number two, we're not looking for possible inhibitors. And there's no way that signs will come up with drugs that block everyone of the 350 molecules that are at least for the muscles. That's why we only have anti-histamine and maybe a couple of anti-lucatriides. And it's actually those molecules that are released from the mast cells that are the problem rather than the mast cells themselves. Can you talk to me about that process of the way in which the mast cells impact the body, the root that they take? Depending on the trigger, different things will come out. If you're unlucky and you get into an afflactic shock, the muscle will explode like a hand-grain aid and release pretty much everything. And unless we act quickly, you're doomed. If you're allergic to something specific like a food or pollen or something, we know where the trigger is. So either you avoid the trigger or we do what we call immunotherapy. We kind of get your body used to that trigger and eventually the body says, "I'm in to bother anymore." Is that the sublingual? I need a drop of tiny drops, yes. But you can do it a hundred different things you do. One, two, three, however, I'm very important. Then we're left no knowing what triggers. So if I scratch someone's under our or the back and all of a sudden in one minute or a red line where I scratch, then these are the muscles in the skin reacted just to the pressure. And in fact, most of the patients I deal with that have complex issues that relate to the muscles. Do get that red line, we call that dermatographia. That's the quickest way to find out that the muscles in that person's body are ready to fire and who might not know the triggers. Now once they release, some molecules are released and destroyed very quickly. Some molecules will linger on for a very long time. Some cross into the brain, some don't cross into the brain. And that's why we have such different symptoms in all individuals because the molecules released from the muscle will affect every cell in the body. Back in 2015 or whatever it was, I and colleagues wrote a review in the New England Journal of Medicine and I was grateful to the Journal still am because they allowed us to use a title, "Must sells must-to-siteosis in related conditions." It was the first time they would start talking about related conditions. Now, going back to the misnomerase, but what we call what? For some reason, my colleagues decided that if you have a telltale history of allergic like problems and we give you the only thing we have anti-histamine, so you do a little better. And if only one of the molecules released from the muscles, called triptase, it's metendorized, it's a part of the leading enzyme. It's high within 48 hours of an episode. Then we call it muscle activation disorder, syndrome, MCAS. It's almost impossible to get a triptase measure within 48 hours of an episode, unless you have an individual encounter. Most hospitals have no clue what triptase is and they send it out anyhow. So there's no way to address the patient with the shop at the emergency room if they're going to get a triptase results a week later from whichever company they send you to. And therefore, I don't understand why everybody's stuck with either wanting to be identified with MCAS, my selectivity in syndrome, or have a diagnosis that they're going to have to be identified with. 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I'm just trying to limit myself to the extent that whether there is repeated evidence that muscles or muscle activation is involved, then I'll make the leap of faith and say, "Yes, they are the problem." There are other instances where muscle activation might be just something happening at the same time, but not necessarily the beginning and the end of that condition until, for the otherwise. The reason why I'm being a little more cautious in medicine in general and even within the specialty of allergy, we don't talk about all these other problems. We focus, unfortunately, on just allergies. So there aren't any manifestations where things are outside the box and say exactly what he said. There's evidence that there's muscle activation in migraines, in this and that and the other thing. And therefore, should make physicians aware of the fact so that when patients show up, we know what we're talking about. I just got a desperate email from a lady from Brazil who showed up at a major hospital in Maryland last week and she had issues like we were discussing and they basically told her it's only her mind. And she went out and said, "I have a lactic crisis and almost died." So, physicians are just not aware of these issues. Now, I understand that in emergency, we're not likely to deal with a complex disease. But there should be us somewhere out there working collectively to address this problem. To give you an example. In irritable bowel syndrome, we have lots of symptoms that otherwise are found in muscle activation disorders. So you've got diarrhea, sometimes you might have constipation, mostly diarrhea. You can have hypertension, you can have headaches. All of these are similar to symptoms that one experiences in muscle activation disorders in general. So colleagues look for more muscle cells in the gut. But it's difficult to biopsy because you don't know where the muscles will be high in the gut. And most of the times, the results are negative because you don't know where to biopsy. A colleague of ours, Dr. Minor, many years ago, said that maybe the illusical junction is the best place in a biopsy. And I wrote actually an editorial, years back, it's not the numbers of muscles, it's the activation of the muscles. Because you might have 100 muscles that are quiet. And then you have 10 muscles that are going crazy releasing everything. In which case you might never see them, but the mediators will be there. So for instance, if I suspect that someone has muscle activation problems, we thought without potentially IBS, I will ask them to do actually total histamine in the stool. Why? Because if history is released outside the body, it will be destroyed with one minute and it will end up in the urine as methyl histamine, the breakdown product. If however it's released in the gut, it's going to be histamine. It's not going to be broken down. So if I actually measure total histamine in the stool, in size, something is happening in the gut, whether I can measure the number of muscles or not, just give you an example. How one can approach and potentially help solve some of those problems, because then you would want some interventions that mostly address those in the gut. Back when we were talking about muscles in my grains, other than when I mentioned earlier where the muscles are in the brain, the meninges, the three membranes that cover the brain are loaded with muscles. That's why we thought they were actually involved in my grains. Well, back then, 20 years ago, I was saying it might be actually a model called CGRP that is involved. Well, no paid attention to the five years ago, and now we have 10 drugs that are CGRP blockers. Well, why didn't take us 20 years to do that? In mind you, I had three US and international patterns on this, but university, I've been Boston, I thought they were irrelevant and never did anything about it. And that's that. So, it's not even just the science you get actually to the bridge where you say, well, here it is, let's test it, and then they tell you you're crazy. Nothing's going to happen. Then you wish 20 years and all of a sudden, yes, it works. When you talk about that, you talk about specifically the mast cell in the brain for migraine, and you were talking about doing biopsies of the gut for mast cells, for irritable bowel syndrome. Do we know that mast cells are active in that area that is affected? So, if it is headache-related, is that normally mast cells within some area of the head? Or is it the case that these are always activated in the brain, neurologically, and then the symptoms that prevail are actually driven by the neuroimplamation of the mast cells? Well, it's a difficult question to answer. You're right, in the sense. I mean, we have mast cells in the meninges, we have mast cells in the brain, and we don't have any symptoms. What are they doing? Well, either they're just quiet there, because 300 million years ago, the head-or-old plane, how they don't, or the potential triggers for the mast cells in the brain are not there. The mast cells, as I said earlier, basically protect the blood-brain barrier. They kind of literally embrace the blood-brain barrier. So, if the mast cells fire, they open up the blood-brain barrier. Now, blood-borne substances are going to get into the brain, and the defenders of the brain and the microgear are going to go crazy trying to fight them, and you're going to get an out-new inflammation. So, what is the mitriger of the mast cells in that part of the brain? Well, high temperature will do it. I mean, people, they get, for instance, a sunstroke, or very high temperature, and the mast cells will fire, and then all of a sudden, we'll start having all kinds of issues, neuropsychological and other issues. And that's absolutely true. Heat, for instance, and stress, as we said earlier, are the biggest triggers, and most common triggers, or mast cell activates and disorder individuals? Emotional, mental stress, or physical stress? Whatever stress, it could be mental stress, physical stress. So, if you have a sunstroke, you're going to have both emotional and physical stress. The physical is that the heat-basic, the temperature opens up the blood-brain barrier, and all kinds of things will get in. And then, all of a sudden, you have headache, the headache will be a stress, and that excessive pain-basic, is the problem. I guess I'm getting back to the fact that there are three issues in my mind. One is, let's recognize that in a number of conditions, complex or otherwise, mast cells are activated, whatever we call it, they are activated. And therefore, the first thing we should do is try to limit the potential triggers and see if we can block the mast cells. That would be the initial address to any such problem until we know otherwise. And we can do that. You can either avoid certain conditions, whether it's polling, whether it's food, whether it's stressful circumstances. Of course, you might not be able to avoid everything, but at least you can limit it. And in some circumstances, we don't even know where the trigger is. I was lecturing in Australia about eight years ago, and I was stunned by the fact that many people that ate red meat were having actually allergic-like problems. I was never aware of that. And as it turns out, colleagues in Australia and us later uncovered that one, let's call it antigen, a substance called alpha-gal, which is found only in pork and beef, can make people allergic. And to make things worse, if you're actually living close to hoods, whether it might be deer and squirrels, then tick can bite the squirrels in the deer. And if they bite you, you might not get other diseases such as lying disease, but they'll carry the alpha-gal. Now you become allergic to alpha-gal. We didn't know that. Now it's become a major problem. It's called alpha-gal syndrome. And to the worse, because most of the dietary supplements, drugs, cosmetics, have actually gelatine. And other products that come from mammalian sources, and you wouldn't know it. I've got persons who kind of turn red on their face, who used to call that actually mouth allergy. And then we just allergic to alpha-gal, which is found in chopstick or lipstick. Oh, I'm allergic to. I can't eat things with gelatine, but I think it's because I'm allergic to self-adulxite. -Elegic? -You might not. -No, you might not get that. -I'm reactive and post-COVID. I'm reactive to so many things. There were just so many things. But the problem is identifying, like you just said. So even in just in the shells of the capsules that all of us who have these symptoms, start taking all of these multiple supplements. And that she then you often don't have any idea of all of the various types of chemicals and components that you're taking. -True. -True. So that is an issue. And trying to therefore break down what is the trigger is one of the biggest problems. Because yes, eliminate that trigger when you have that trigger. When you know what that trigger is, but a lot of the time we don't know. Could you just for our audience give me a run through of the list of symptoms that you see as a result of some kind of mass cell situation? Gustry-Denstel problems are quite frequent. It might not be frangiria, but it might be like a bloating kind of pain type of thing that comes especially associated with food. That's one. Eating is not really the most common symptom that we see even though you might show up. But brain fog is. You know, you cannot concentrate anymore. You start forgetting words. And of course that all facade and it's not in the domain of the allergies. So they don't even believe that that's possibly true. I see a lot of flashing of the neck and torso, especially people are upset, which means that just that circumstance, the trigger of the mass cells, without any particular allergy, etc. So it is the otherwise not directly my cell related symptoms that trigger me to think that there might be a problem because if it's chronic eating, you know, we call it. chronic spontaneous lubrication, for instance. So we have a name for that. If it's an exima, we have a name for that. If we're still doing it, where an exima is, because there are many processes being involved. And probably one of the most typical trigger points for me is if we give some an anti-histamines, and they don't respond. That is telling me that the other molecules and histamines that have been released from the vast cells, which means that the muscles are activated. Because I really believe that these are all the other molecules that are causing the problems, and are not necessarily the histamine. I agree. Okay. Let's say you've got franco-eat-or-eat-or-issues, and you get, usually we can give as many times as four times recommended goes of an anti-histamine. But that time you start getting sedated, of course. Beat is made. So if I push the constraints of four times that, then you're not doing well, muscles are activated and something else is going on. And which makes it really hard to also eliminate to try and mark out what it is, because someone takes an anti-histamine and thinks, "Oh, well, the anti-histamines had no effect, so it's not that. It's not that kind of reaction." Well, unfortunately, what the allergist would say, "Well, it's not an allergy." And they forget that the muscles could be doing all those other things without necessarily releasing histamine. That's what everybody's stuck to histamine and treetace being released. And unfortunately, we don't even try to block the mass cells. As I said earlier, we've got drugs that kind of kill the mass cells. We call them, we put them into apoptosis. And those are the drugs that block the enzyme, which is basically called tyrosine kinase, or C-Kit, which is on the surface of the mass cells. And the stem cell factor, among other factors, trigger the muscle to multiply. So yes, if you have a thousand cells and I bring them down to ten, the symptoms are going to be fewer. But it doesn't inhibit the mass cells. While in muscle activation disorders, you have a normal number of muscles that just fire like crazy. And in fact, I have some sustaining muscle cytosis patients that don't have very many symptoms, which is kind of crazy, because you would imagine they'll have lots of symptoms. So that's in any sense where you can see that they have the problem, but then they're not symptomatic. Correct. Correct. They're to minority, but they're there. So, and the only drugs we have to really block the mass cells at every other cell is actually what we call glucocorticoids, like steroids, like cortisone. But you can't give this forever. If someone has a lot of elastic shock, I'll cover them. That's when we started using some natural molecules that actually can block the mass cells, at least in the laboratory, 100%, just a matter of getting enough concentration in the body to help actually the mass cells quite down over time. So, if we think about something like, and you've also written a paper on this, the role of mass cell activation in asthma, and in that sort of breathing difficulty, which has been quite prevalent in the post-COVID condition. Correct. That's a lot of the time addressed using corticosteroids. Correct. And, and I know so many people who have had corticosteroids for various different things in the past five years, they just seem to be a lot of people are developing sorry, acarthritis, or these kind of things. You believe that there are natural things that we can use. Absolutely. Absolutely. Instead of suppressing the immune system, because that's the other thing that we haven't actually mentioned is that that mass cell, it's all part of the immune and the endocrine system. And so suppressing things is putting everything back. What are the things I hate about supplements is that they give crazy names that mean nothing. So you see so many supplements that say immune support. Yeah. Well, if I have inflammation, I don't want to support the immune system. I don't want to make it worse. I want to regulate the immune system. So all of those supplements, about 80% of the supplements say new support, new disease, new death. And they might be doing the wrong thing altogether. For instance, there is an immune support system in support supplement that has human. Your human has histamine and human triggers the mass cells. So whoever was the idiot that would actually come in on a histamine, it's beyond me. So people come up with all kinds of stuff without any reasoning to. Well, they don't know the science, they don't talk to anybody to tell them about the science. I started working on a class of monocle flavonoids 30 years ago. And there is a review of mine that was published in the Journal of Pharmacological Reviews, along with Dr. Middleton, who's one past and one of his colleagues. This has become a classic in pharmacologists. It's received about 30,000 citations just they pay per loan. There are 3,000 flavonoids in nature. Do we know all of them? Of course we don't. So you will see things like bio flavonoids, soy flavonoids or whatever flavonoids. Recently, I was talking to an unfortunate cancer patient that is actually estrogen positive. Well, I said, "Don't even. That's soy." Because soy and soy flavonoids are estrogenic. They're going to make your cancer worse. How would you know unless someone tells you that the flavonoid you're getting is from soy because they don't tell you the source. Another tip source is actually peanut shells. They don't tell you that. So if you're allergic to peanuts and you get those flavonoids, you're going to have a reaction. And no one is regulating these things. So over the years, we came down to a couple of flavonoids that seem to be pretty good. One is quercetin, which I guess you know, and the other is luteoli. In 98% similar, structure wise, or similar. The problem is that they're not absorbed more than 10% from the gut. So my colleagues will say, "Well, I give you two grams a day. Eventually something will be absorbed." What happens is you absorb 10% to 100 milligrams. You're left with 1800 milligrams in the gut. You shut down. You got by a flora and now you get seabulls, swollen, tested and overgrowth. And now you start chasing your tail because you don't absorb your vitamins. You can absorb your whole bunch of other things. So too much of something you don't necessarily good. So that's why we mix it up with olive oil because anytime you have oil and powder and you give it energy, you shake it up so to speak. You create little spheres called hyposomes and you trap the solid inside. That way you absorb about five times more from the gut than you would take powder alone. And that just enables the gut to hold this in a little bit, that's it. Correct. And so we created a number of those. One is called pure lute, which is only luteoli. One is called neuroprotect that allows you to get into the brain, for instance, for people that have all kinds of problems. And to the extent that the trigger might have been a pathogen, like a virus or fungi, mold, et cetera, we created brain gain that had actually burbring in it. That is also anti-bacterial. So we're trying, since we don't have drugs to make combinations that are 98% pure from a solid grade. They're actually back with a lot of science. And they try to address different types of mastselectivation disorders within reason until we come up with a better way to do that. So explain to me, please, what the effect, the impact the luteoline has. Have you found an inhibitor? Is it just boosting your system in a different way? Luteoline inhibits the mastseller, it's no question about it. In the laboratory, 100%. It's just that we need to translate that to our body, and our body is not a test tube. We kind of extrapolate if you wish. Luteoline is out of flavonoids. Are lipid solubol. So if someone is very obese, a lot will go into the fat, and it will never reach the areas where he's supposed to go. If someone has, let's say, irritable bowel syndrome, you might not be absorbing it, so you might not be absorbed. It's not available in any way to inject it, for instance, because it's not a drug. So we'll be struggling to make, actually, a nasal spray, so we might get in the brain through the or factory nerve that communicates our brain with the outside world. If we could get into our blood, would that be more effective? Absolutely yes. So this is a legal standpoint that you're not allowed to inject, things that are not classified as drugs. Or what flips it over to being something like that? Well, companies are not interested because they're not patent-covering this. They're natural molecules. So unless you create something that is similar to let's say Luteoline, it has a chemical version. But that will take another 10 years before we can actually get in the market because that's the going rate. So what we're trying to do is combine molecules, not only Luteoline has to be absorbed, but it's broken down in the liver as it should be, that's what the liver does. Cursed in is broken down a little faster because of its structure. So we combine Luteoline and Cursed in to use Cursed in for its own actions as a little as a decoy to allow the Luteoline to stay longer because of its structure, it gets into the brain as well. And does the question inhibit the montho? It will inhibit it as well. Just about a month ago, we published a paper where we compared, basically, four different flavonoids trying to get to even better flavonoids. In fact, we came up with even better, which is called tetramethoxylventyline. But when you try to order this spouter from anyone out there, it's $10,000 per kilogram. That will make it excruciating the expense for anybody to buy in the market. So unless someone is interested in making that available in large quantities to drop the price down, it's almost meaningless to talk about it. However, if we were to make a skin lotion for people that have, let's say, eczema or chronic eating, etc., you'd only need that much of this flavonoid because now you're putting it directly on the skin. It has it that's there to be absorbed. The problem is with all the flavonoids are yellow. So you basically paint someone over it. So, but tetramethoxyletyoline does not have color. And therefore, we created a cream that's called gentle derm that has 1% tetramethoxyletyoline, it works very well with good publications and one can use it on the skin. - Does that only work? - Topically. - On the skin, or does it absorb into the body? - We've been using it for anybody because it's very hydrating. It's totally high-pollargenic, except you don't put it in your eyes. You can put it on your skin anywhere, whether you have any lesions or not. - But could that help? - Yes. - With IBS, potentially. - Cool. So what we're trying to say basically is if you combine, let's say, pure lute luteoline or neuroprotect, that's, of course, end luteoline. With a gentle term, now you get it from two sources. You're gonna get as much as you can and then your skin hair here is amazing. It's the biggest source of space on your body, basically. Eventually, you will absorb some of the methoxylide. And we also published a paper within the year where we compared head to head, the only drug that is known to be a mast cell blocker, although it's a miserably low inhibitor called Chromelin. So Chromelin is available. A lot of people use it as a mast cell blocker, but both we and others have shown it's a very, very weak blocker of human mast cells. It worked very well in rats and that's telling you we cannot use the animals necessarily as a surrogate for humans. So we pre-incubated human culture mast cells with either luteoline or Chromelin, 10 minutes, same concentration stimulated by two different triggers. Luteoline was by far better than Chromelin. But Chromelin is a drug and people use it. Luteoline is not a drug. They don't feel like using it. - So yeah, 10 years is basically what you're saying. It needs to turn luteoline or something. - Into a drug. And it wouldn't be luteoline. You'll have to be a new molecule that might be much better. So in fact, we're doing a lot of science here, a lot of work. Using both cultured microglia and cultured mast cells in a different setting now, rather than isolated mast cells. - When you say cultured, what does that mean? Does that mean that I take it from humans originally? - Correct. So what we do is we obtain blood either from normal individuals or individuals might be chronic fatigue. It might be Parkinson's, it might be whatever. And then out of the blood cells, we grow out what are called pre-portant stem cells. And then if you read the right growth factors, you can trigger the cells to go in different directions. So we can grow mast cells, we can grow microglia, we'll grow neurons. And one of the first ones to do that. But until now, pretty much everybody was using isolated cultured cells. It's of the mast cell and we give it a trigger. And then we can measure what comes out and then we can try to block it. However, the mast cells don't leave in isolation. In the skin, they have fibroblase, they have endothelial cells. In the gut, you've got the gut in your corsa, in the brain, you've got the microglia, the neurons. So what we're now creating is what they're called human organoids on a chip. So we basically have a self-containing combator. And then in the plate, we have a central well where we put neurons, let's say in the case of autism or chronic fatigue or long COVID. And then we have satellite wells. And we put the mast cells or the microglia or endothelial cells. And we can either trigger them separately, we can do them altogether with different triggers. To find out what is the worst scenario possible that would do the most damage to the neurons. So now we might have a surrogate for what might be, let's say, autism, my departions and so on, et cetera. And now we can use that surrogate to start screening natural molecules or repurposing drugs to find out what can either prevent it or reverse it after the fact. That will get us within a couple of years enough, I think, no molecules to start doing clinical trials. And it's still natural molecules, unless we repurpose drugs. But so far, there are no repurposed drugs that can do that. The unfortunate thing, as I'm sure you can gather, is no one's supporting this kind of research. I've been doing studies funded by the National Institute of Health. And no one ever had a request for applications just to study the biology of the mast cell. I always got funded either through examiner, through psoriasis, or some other source trying to convince them. And this brings us to what we started the conversation with. I put an application in a couple of times, both to the Department of Defense and the NIH, or the role of mast cells in COVID. Lots of evidence, and we've been discussing that they might be involved. The answer from those critiquing the application was, what the hell do the mast cells have to do with long COVID? Well, if I knew, I wouldn't be applying, right? And I'll out. You know? It's like the chicken and the egg all the time. So that's why some God bless them, entrepreneurs, have actually been using money from.com companies, and Silicon Valley, to say, here's the money. Just show me what you can do, kind of thing. But usually these are new companies that have been developed rather than give it to people like us. Because it takes at least two cycles, will grant agents before something gets funded. So two cycles means two years. So it takes you half a year to write it, two years to wait. But that time, we've lost thousands of patients who are suffering out there. That's not how science should be working. We should be able to say, look, we don't understand what MCSF is. We don't understand what long call it is. Here's a billion dollars, collect the 10 past people in the world, just like they did with not that we should have done it with a Manhattan project. Put them together and figure it out. But isn't that the thing? Looking at something like the masks cells in this way, actually enables us to start looking at multiple of these conditions together, still keeping them as separate conditions. And therefore, in terms of the funding, or in terms of the potential pharmacological interventions that could be developed by Big Pharma, which is, when it comes down to it, what people are interested in, making money from these things that they can develop. If you're grouping in, not just a million MCFS patients, but you're grouping in 8 million of these people, 4 million of these people, and you're pulling everyone together and saying, but if we research this, if you're actually right, and I wish that that would be the way to go, but the more complicated things get, the less likely it is that anybody will fund them. Because they want a clear condition with a silver bullet, type of thing, which doesn't work. In all honesty, there is some truth to the difficulty as well. I don't mean to bed mouth here, my colleagues. Because it's very difficult to do a clinical study when you have so many different symptoms. We tend to say, I'd like, as Virgin, I'm going to show you the expression population as possible, because you've got to decide what your primary objective is. And every time you have a secondary objective, there's something called the Bumferoni principle in statistics. You've got to double the number of patients and keeps on going. So if someone shows up with 10 different code-on-code comorbidities, it's impossible to do a clinical study. And then you end up basically doing a study of N equals 1. I can actually make one patient do better. Maybe there will be enough to trigger an ex-patient. Except for perhaps they're not comorbidities, perhaps they are from the research. It might not be done. You're perhaps they are all from the same root. And it's a matter of getting back to understanding that. That's why I have some of my lectures in the paper that I'm pointing out now. I've got a daisy in the center of the daisy of the mast cell. And the first set of petals, although we absolutely know mast cell are involved in. Tell me. So we know asthma, allergy, eczema, et cetera. Then I've got another set of petals where we suspect very strongly the mast cell are involved. It might be irritable bowel disease. It might be multiple chemicals in sedivity. It might be sick homes syndrome, which is mold, et cetera. And then you've got another set of petals where we're talking about one COVID chronic fatigue fibromyalgia, where the evidence is there. It's telling us, yes, go that direction. But no one is really going that direction. And I think one of the problems with many of those conditions that you've mentioned is that you've possibly started with something that is triggered by a mast cell activation. Or something like that. But because it has then been impacting the body for that length of time, particularly if you're looking at ME/CFS patients who have been sick for a long, long time. You then look at the degradation on organs or on certain parts of the body of having that symptom for X number of years. So if you've got palpitations for that length of time, what does that actually do to your body? What I usually tell patients, and we saw patients just before I came here with my colleagues, is why not necessarily put all the eggs in one basket. So I'm saying, look, let's assume that this is mast cell activation disorder in general. What can we do to help you for more do we know? Regardless of any laboratories, because the laboratories will end up basically a square root one anyhow. So I'll give someone let's say a month with what I think is the best approach to call them the mast cells. Let them come back in a month or two, and see how many of those got better, and what is coming from left. That's one approach. With this concept of open exploration in medicine, and not necessarily keeping it within that very medical. or what people tend to be medical box, because you're also talking about natural products, you're talking about more holistic approach as well. Who out there is doing what you consider to be really exciting research currently, or coming up with ideas that really might move things. - For the things we're talking about, I dare say no. - Really? - Yeah, because there are some good companies that have developed very important drag for severe mastocytosis, I say, that aggressive mastocytosis, et cetera. We thank them enormously for that. But no one is addressing everything else. And the people that used to do, or were very interested in mast cell related work, are retiring already, have retired. We're talking about, you know, battlefield, we're talking about met COVID-19, we're talking Swarge in Virginia, Mariana Castell said Harvard just moved out. And there's a fact that there's no, no, because it continues to be not only a shifting field, but a field that is not really helpful. I remember talking to a colleague in Michigan who was seeing a lot of patients. And he said, my practice was about to collapse, because this patient's for good reason, require about two hours at least per visit. And I don't get to reimburse for more than half an hour. So how can I actually keep on going? So I'll insert an institution that can support such clinicians and the research, we're not gonna go anywhere. And now we're facing, as you know, with the fact that research and establishments are shut down and IA stopped giving money. The indirect cost that kept institutions going from 60% is down to 15%. Colombia will just told the shut down $300 million because they were using DEI, we don't know where to go. They're firing 75,000 of VA research employees. So we're gonna lose it a whole generation of science. And for better or worse, other people are gonna go ahead of us, but there's nobody else. It was a wonderful colleague, Marcus Mauer, the charity hospital in Berlin. And he died while he was hiking in Italy about a year ago and we lost one of the best people we ever had. So I'm just worried that not gonna be, you know, a lot of people if any, researching. - So we got to take the initiative across in Europe for now and see if we can start. - Whoever can, there are good groups in Europe. And one was started by actually Marcus Mauer. But there are very little researches being done on this field that I know from what I read at least. And the genetics are not gonna help us because this is not a really genetic problem. I mean, there might be a familiar problem like with a hyper-trip to see me, for instance, which is a genetic kind of problem. And the other issue is that if we get stuck with trip days, if people were published a year ago and then Mariana Castell's wrote in a tutorial about it, the looks of about 110 patients that had high trip days, no diagnosis, just high trip days. And then they looked at the diagnosis. 20 to 30% of them had hyper-trip to see me. So not muscle disorder, not muscle activation, anything else. 30% of them had chronic kidney disease for crying aloud. When no idea, I have no idea what trip days does in chronic kidney disease. In the remaining, we're severe aggressive muscle cytosis or muscle leukemia. So from those 150 patients that had trip days, very few had actually muscle activation, if any problems, which just kind of takes us back to the fair. We need better markers of muscle activation. - Which, that filters out to so many of the conditions that we have mentioned today, is that understanding in terms of having that marker or having these one things that identify them as a specific condition. - Well, in major reason why I moved from Boston year was a professor of medicine at TOS for 35 years. And it was at Yale University for 50 years before that, is because this institute, you know, run by non-saclimus, thinks outside the box. So not only were doing integrated of approach and the science that is not integrated is solid. So we're not cutting cordons if someone needs a driver to get a drug. But at the same time, we're looking what else we can give. But it allows basically the research. So they're supporting this type of research we're talking about. And we're applying for this. And they have a very good track record of doing bi-lucinical trials. So my hope is, as he has been, I mean, right now, we're just starting a new clinical trial for Long COVID. With the product that I hope develop, the company's called Algonaut, they made the other products as well. It's called Viral Protect. It's got four natural ingredients, each ingredient independently blocking a different target of the coronavirus. So one blocks the binding to the ACE receptor, one blocks the serenester ACE that actually cleaves that to allow that to go in. The third molecule blocks the polymer ACEs that allow the virus to proliferate. And the other blocks, told like receptor four, that allows the production of the cytokines. Whereas you know in medicine, the more targets we get, the more likely that we will get actually a response. So we're doing this study now in Long COVID patients. It's going to start in a month or so. And that's the beauty we can actually do the study, because they've access to the patients. - So who stands out in terms of the research? It's the team here that you work with at NSU essentially. - Yeah, it's the team we can brainstorm together. We can think clinically and basic science. And we feel that we can actually turn the basic science into clinical trial quickly. Because otherwise, it's almost meaningless. It will take forever. And maybe to finish with an example of where things can go wrong. Ettaftsa used to teach a course, advances and failures in drug discovery. So I'll pick up 10 topics over the last 50 years who are both a scientific community and the Wall Street were drooling over something and he failed miserably. Give you an example. Until now, we've been saying that Alzheimer's due to beta amyloid plaques. Well, millions of dollars have been spent, clinical trials, and they alternate out zero. And what is absolutely incredible to me is that the only drug that came out of Boston, by agent with the company, on a clinical scale of one to 15, the benefit was 0.45. So with the benefit, where the best would have been 15, if we had the benefit, half a point on this scale was only the benefit and he had was approved by the FDA and it costed about $100,000 a year. And his children's work. And 10 to 15% of those get a D-Mine the Brain. So that's how desperate we are. And now, my colleagues that were behind beta amyloid plaques forever at MIT in Harvard, now are saying it's inflammation against the amyloid plaques. And for some reason, some people develop more inflammation than others. Because 30% of the people that die of all days have beta amyloid plaques and they've never gotten the measurements. But we use the word inflammation, you need to scream angly. Eximism inflammation is your skin. Asmism inflammation your lungs. Multiple sclerosis inflammation in your brain. But they're not the same. So we should be more careful about what we are identifying, which takes us back to their search we're doing. What we have actually the central well with the neurons and the satellite cells, once we stimulate them, we can pluck out basically the cells and do RNA sequencing and find out which specific molecule was actually activated, even though I had no idea where and how to measure it. Then we can say, okay, let's measure it and then we'll go back to the patients and see if we can pick those up, in which case we'll have an objective diagnosis materially or on, which are also missing in many of these conditions. So I know, I give you a near full here, but, (laughing) and I'm passionate about this and I'm passionate for exactly the reason we started the conversation. We just ignore these patients with multiple problems because we don't know how to deal with them and they're in difficult patients in quotation because they're well studied, they ask questions or we don't know the answers and it's easier to say, "Tell me your mind." (upbeat music) - So fabulous to meet the man in person. I have linked a lot of information about him and about mast cells in the show notes. So please do go and look there and please feedback. Let me know what you thought of the conversation. Let me know what you'd like to explore further. Let me know if there are other things that you would like me to try and include in those show notes in future. And as ever, please, please do like, rate, subscribe and send me all your feedback. I wish you a great week. (upbeat music) Thank you for listening to Make Visible. Please do like, follow or subscribe to listen to our next episode where we'll be uncovering more insights into complex chronic illness. This was brought to you by the team at Visible, a group of scientists and engineers whose lives have been affected by energy limiting health conditions. We're building wearable technology that's helping 100,000 people measure and manage their complex chronic illness. 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