The Science Of Longevity: Treating Aging As Disease With Dr. Thomas Ichim
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Hello, this is Richard Jacobs with the Finding Genius Podcast. My guest today is Thomas Ichim. He's the CSO of Amorta Bio. So we're going to talk about senolytic immunotherapy, immunotherapy for cells that are old and called senolytic. So we're going to go into that. Dr. Ichim is a seasoned biotech entrepreneur. He's been in it over 20 years. He's launched and grown and realized the value of multiple biotech companies.

He's renowned for his advances in regenerative medicine and immunotherapy. He's been a manager, a vice president, as well as president and CEO of emerging biotech startups and billion-dollar public enterprises. He holds a PhD in immunology and has published 130 more peer-reviewed articles than I have and authored three textbooks. So welcome, Thomas. Thanks for coming. Thank you. Thank you very much, Richard. It's an honor to be on your podcast. Like I was saying, I've heard a lot about you, and I'm really glad to be here.

Oh, well, thank you. Well, tell me, I hear about your background. You've been in biotech for a long time. I guess just going, you know, just to start, what got you interested in biotech and in

in working in all these companies, what has become your goal, like your mission? Well, I think my mission pretty much is to help people that are suffering. I mean, if you really think about it, life is pretty empty. You know, money doesn't really mean anything. You know, the materialistic things, you know, they come and they go. But at the end of the day, where you really leave is your ideas and your ability to make a difference in the state of human suffering and the state of human existence. And specifically how I got into...

into this whole thing was when I was nine years old, they did an IQ test on me and I scored very highly. And several years later, two years later, my mom was diagnosed with leukemia. So I was, you know, I mean, it was terrible, but in a way it was the best thing that happened to me because I focused all my life on cancer research, on leukemia. And as you know, Richard, the leukemia is a stem cell disease. So by studying leukemia, you study stem cells.

So I was very active. My first peer-reviewed abstract I published when I was like 17. I got my first patent issued when I was 19. And, you know, I've been in the field very aggressively from the point of view originally about saving my mom. And my mom passed away in 2010 when I was, I guess, like 30 or something.

And then after my mom passed away, I just became really obsessed with stem cells and with longevity and how we can apply concepts that we learn in longevity to actual diseases instead of just focusing on making people live longer. You know, a clinical trial for a longevity product is going to take 20, 30 years, and the investors don't like that kind of timeframe. So one of the things I became obsessed with after my work in the area of oncology was

was stem cells regeneration and longevity and how we can apply stem cells to very acute situations. For example, like COVID-19, we did some work and we published a paper on using mesenchymal stem cells to shut down the acute inflammation. You know, we have some work that we're doing now that's very exciting that we'll get into. But again, to answer your question directly, I got into biomedical sciences because my mom got leukemia and I wanted to help my mom and other mothers like that who

were dying of this terrible condition. Were you able to help her or was it just too early in your life, in your career? No, it was, you know, this is something and my mom actually wrote a book about this. Unfortunately, it's in Romanian so it's difficult to read but no, what happened was back then they didn't have the internet so me and my mom would go to the library. God bless my mom. I mean, usually I don't

Don't talk about this on interviews, but me and my mom, my mom and I would go to the Kitchener Public Library. This was up in Canada, Kitchener, Ontario. And we found out that there was a new treatment called Interferon. And there's a new treatment for leukemia called Interferon that they were administering in Toronto. Toronto is about 100 miles away. So we went to our doctor and we said, look, is there a way we could get on this clinical trial? And the doctor said, oh, you know, it's far away. You know, you shouldn't.

You shouldn't trouble yourself. There's not too much opus, highly experimental. But my mom insisted. And because she got on that treatment, she ended up living another life. She ended up being a stable disease on that treatment for about 10 years. So she got leukemia when I was 11 until about I was 21. She was stable. Then she stopped responding to interferon. We started doing something called placental vaccinations.

and this may be of some interest to you. So placental vaccination is under the idea that the placenta is similar to cancer, and if you immunize against placenta, you can get antibody responses that cross-react from the placenta to the cancer. That caused my mom to go on remission for about two or three years, and after that, the kinase inhibitors came. Kinase inhibitor is a new class of drug. First kinase inhibitor,

My complete coincidence was designed exactly for my mom's type of leukemia. I didn't have anything to do with it. It was just God, I guess. But it was funny because, you know, out of all the types of hematological malignancies, out of all the types of cancers, the first kinase inhibitor, which is a small molecule that specifically blocks the mutated protein, the first one was in my mom's leukemia, which was CML. And that gave my mom another like 15 years. So at the end of the day, my mom ended up passing away when I was about, I was

And she got leukemia when I was 11. And, you know, when I was 11, they said she was going to die in three to four years. So it just shows you how important science is and medical research and how we have to be advocates for the importance of funding medical research and funding the biotech industry. Because if it wasn't for medical research, she would have died in three or four years. When she got leukemia, my youngest sibling, Matthew, Matthew was six years old.

six months old and she was breastfeeding him. You know, now Matthew is an accountant at KPMG and she got to see Matthew grow up. She got to see Matthew get a CPA and, you know, it was just something. So that's the power of science and that's something that motivates us and, you know, being in the biotech industry

So sometimes we forget why we're here, but every time I hear stories like this or every time I think about the reason why we did get into this field to begin with, it's something that sets apart this field from, I think, any other type of human activity. Yeah, no, that's great. Hey, your mom had about 20 more years than she otherwise would. That's fantastic. Exactly, yeah. So what is your current work about? Let's fast forward to that and talk about some of the nuances of it.

So the current work is very interesting. It's a very interesting concept. It's basically how to fight aging. Fighting diseases of aging and fighting aging has disease. So what exactly that means is we found we

we have two platforms to fight aging and to fight diseases of aging. First platform is to kill all cells. This is called senolysis, killing senescent cells. So this is very exciting. This all came to news as news to me. So about seven years ago, eight years ago, a guy at

at the Cleveland Mayo Clinic called James Kirkland. He found out that if you kill senescent cells, you start to rejuvenate the body. So very peculiar. So senescent cells, just to give a little bit of a background, when a cell multiplies at about the 50th cell division, it undergoes what's called senescence, which is like it becomes a zombie.

It doesn't die, but it doesn't really live either. What I mean is, it sits there, and we just saw these cells accumulate and do nothing. This Dr. Kirkland and people after him found that the senescent cell starts to produce different senescent-associated secretory phenotypotes. What that means is, once the cell reaches this critical 50 doubling, it produces all these poisons.

They're poisoning the cells around them. So aging is an infectious process, infectious synthesis. How do we know this? Because he published papers where he would take cells from mice that are a human equivalent of like 80 years old and put those cells into the fat pad of mice that are a human equivalent of 20. Those mice would start accelerated aging. So is that because they're very active in like cell signaling?

And so maybe they drown out or obfuscate normal cell-to-cell signaling and cause things to act in the wrong way? That's a really good idea. And again, this field is moving so quickly that it might be what you just said. What we do know so far is this. They secrete inflammatory cytokines. Specifically, they secrete a lot of interleukin-6s.

interleukin-11, interleukin-23 receptor. These inflammatory cytokines induce accelerated aging by stimulating inflammation. Inflammation causes oxidative stress, causes activation of neutrophils, myocytes. Those things produce free radicals, which then tell the cells around, around the senescent cells, the young cells, they accelerate their aging.

So it's a production of information. And we know this because if you take senescent cells and you block these senescent-associated secretory phenotype proteins, then they do not accelerate senescence. But here's the crazy thing. In the major publication, I'm sure there's a lot, but in the major one that a lot of people cite, what they did was they measured grip strength.

Grip strength of the mouse and ability to dangle from a structure. The older mice, they lose grip strength, just like humans lose muscle mass. When you would kill the senescent cells with what they call senolated compounds, you would regain the grip strength. How do people kill senescent cells? They kill them with something called, the original one is a combination. You're going to love this. My life has been with all sorts of weird coincidences. The drug they used to kill senescent cells was a drug that my mom used.

It's a leukemic drug called Dasatinib. And they found, as Dr. Kirkland found, that Dasatinib, you know, we still have some Dasatinib at home, by the way. But what they do is Dasatinib combined with a natural drug called quercetin. This combination of Dasatinib and quercetin induces selective killing of most of the senescent cells.

And how it does this, by the way, is because the senescent cells rely on a protein called BCL-2. See, BCL-2 stops cells from dying. So when a cell decides it's going to be senescent, it upregulates its BCL-2 so it doesn't die, but it doesn't live. And what I mean by doesn't live is it stops performing its usual function. So, for example, a liver cell's function is to have cytochrome P450 and detoxify stuff.

A senescent liver cell still hangs around, stops detoxifying stuff. It just sits there and gathers space. But then what Dr. Kirkland found on people after him is that it spits out this toxic stuff. So here's the bottom line. If you kill senescent cells, there are so many publications that are coming out at a geometrical rate. If you kill senescent cells, you improve health.

a lot of the human chronic conditions. Big peer-reviewed papers published, for example, disc degeneration, like lower back pain, where the nucleus propolis cells that maintain the cushion in your disc, they start atrophying. A lot of that is senescence.

If you give senolytic inhibitors, you prevent the onset and progression of disc degeneration. If you give senolytics to a mosa, you give a lot of alcohol, you prevent the cirrhosis. If you give senolytics to a mosa after a stroke, you reduce the infarct volume and you accelerate the neurological, what is it called, the brain function coming back after a stroke is accelerated recovery.

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How do you administer this? What if you did an infusion of quercetin and desatinib through the blood? You just take it orally. Why not do something like if you don't know, I would think not just one cell type becomes senescent and at different rates, I'm sure they do in different people. So if you administer it through blood, would it not preferentially reduce

reduce the senolytic cells in various body systems and organs as they transit? It does. Absolutely. You're absolutely right. That's exactly what it does. But here's the catch. The catch is it doesn't work that well. I mean, it works well, but first of all, the satinib, you've got to remember still, it's a cancer drug. It's got its own toxicities.

BCL2, the gene that they're targeting, BCL2 is an anti-apoptotic gene, which means it stops cells from dying, but it's also found in healthy cells too. So the desatinib-quercetin combination, which is good, it has helped, it helps, but it's not a complete magic bullet. So this is where we come in. And

By the way, so they are doing clinical trials with the satin and perquercetin. They had some beautiful data in idiopathic pulmonary fibrosis in humans. It's a terrible disease where you get scarring of the lungs. As the name implies, no one knows why it's idiopathic, but people found out it is the pathology associated with accelerated senescence.

And the satin, of course, is going to have some good effects. There's also another drug, another senolytic that everybody uses called ABT-263. It's an anti-lymphoma drug. And yeah, it's got its own set of issues. But so what we do, here's what we do. We always say it's better to let the body heal itself or to leverage what the body does. So if it's okay with it, we'll take a quick step back.

If you think about stem cell therapy, what is the only stem cell therapy that really works? There's only one stem cell therapy, which is hematopoietic transplantation, bone marrow transplant. Bone marrow transplantation, what you do is you're not asking the bone marrow to become a cardiomyocyte or you're not asking the bone marrow to replace your liver. All you're asking the bone marrow to do is do what it normally does, which is

make blood, except you're telling it to make blood not in the same person, but in a different person. So for example, if I have leukemia, what they would do, because you and I are brothers, Richard, what they would do is they would give me a lethal dose of radiation and chemotherapy to kill all of my blood-making cells, because what that does is it kills my leukemic cells, but also kills the blood-making stem cells.

And then what they do is they rescue me by giving me your bone marrow. And your bone marrow knows to make blood. So it gets a little confused. Sometimes it might attack me. It's a little thing called grab versus host. But for the main part, bone marrow transplantation has cured tens of thousands of people with leukemia. Now, the first company that I made and sold, I used that same principle. And I said, look,

The blood vessels get made, blood vessels get made in the woman's endometrium every month. Why don't I just take that same cell that makes blood vessels in the woman's endometrium and put in the muscle of ischemic diabetics to increase blood supply? And we did that. We made a company called Medistem, got FDA clearance to begin clinical trials, and then we sold the company to Intrexon. So now we're doing the same thing. Now we're saying to ourselves, what is the body's normal way to get rid of senescent cells?

Well, it is. It's the immune system. The immune system has different mechanisms that it uses to recognize and kill cells once they become senescent. The problem is this. If that's the case, why do we get old? The problem is that, well, two reasons. One, the immune system gets old. Once the immune system starts to get old, then it cannot kill the senescent cells itself. So these are little books. Oh, so that's why to do this is...

close to naturally as possible, you want to remove the senescent cells from the immune system to DH it, and then it will take care of everything else. Exactly. Well, yes, that's the idea. How we do this is basically we revive the immune system by using an approach that we've used before and other people have used before, which is called dendritic cells.

So with dendritic cells, these are the most potent immune activating cells. So dendritic cells, they usually live in the skin, but you can find them anywhere. But what they do is they sit around and they gobble up different pieces of protein. If they gobble up a protein that is dangerous to the body, then they get activated and

and then they in turn instruct T cells to kill it. So the dendritic cell, it has been used and has been FDA approved for treatment of prostate cancer. So people with prostate cancer, what they do is they take their blood, they make dendritic cells, and they make dendritic cells that have a special protein found only on prostate cancer cells.

a PSMA, prostate-specific membrane antigen. So they take this PSMA, I believe it's PSMA, it's PAP, PSMA, I think, and they put it on the dendritic cell, and then the dendritic cell activates the T cell to go and kill prostate cancer. We are doing the same thing, except instead of using

prostate cancer, we're killing senescent cells. And instead of using that protein, what we do is we make senescent cells from the person, from the patient. That way we have a personalized anti-senoletic immunotherapy. How do we do this? We take a little skin biopsy and from the skin biopsy we grow specific cells. Those cells are the same cells that surround the tumor. See, when tumors start growing, they produce this scar tissue around them that's primarily senescent cells.

So we mimic that process in the lab by taking a skin biopsy and growing these cells. Then we take the blood from the patient and we grow dendritic cells. Then we take it at a two-to-one ratio. We take the senescent cells, we kill them, we feed them to the dendritic cells, then we put this in the body. Once you put this in the body, then the immune system goes crazy. And so how far are we?

So we have 20 patents filed, pending, and we have demonstrated in animal models. We have one publication, one peer-reviewed publication, showing that if you administer this senescent cells that have been fed to dendritic cells, if you administer this combination, we call this Senovax. If you administer this to mice with lung cancer, the lung cancer goes into remission. So we've demonstrated that.

We have announced by press release, but we have not published it. We're in the process of publishing some mechanistic data on specifically how this works, how the dendritic cells that we fed senescent cells programmed the T cells to go kill the cancer. Very exciting thing is that we've observed that this works not only in lung cancer, but it also works in pancreatic and glioma and breast cancer.

So we're very excited about the data. We're in the process of going through the FDA. And the exciting thing is there's still something exciting that we've announced we haven't published. We will be publishing this soon. As you pointed out with quercetin and desatinib, if you're going to give an acetylalytic, something like quercetin, if you're going to be giving that to the body,

There were all sorts of senescent cells getting removed, not just the ones surrounding the cancer. So this is something that has us very excited. When you say administered, do you administer by injection or pill or?

We administer it by injection, by intradermal injection. And so what it does, you do not need this to go through the whole body. You just need it like, it's just like a vaccine. When you inject the vaccine, you put it here, but the effects are systemic because the antigen-presenting cell, the dendritic cell, goes into the lymph node, and that's what stimulates the T cells, and the T cells go and circulate everywhere, and the B cells go and make antibodies that circulate everywhere. But the exciting thing is this, that this antisensitized immune system not only seems to inhibit the cancer, but...

It stimulates multiplication of bone marrow cells. So what we believe is happening, so if you take bone marrow, by the experiments we did, what we did was we would take mice, we'd immunize them, and then we would give them chemotherapy to kill off the bone marrow. When the bone marrow comes back after being killed off, when it recovers, it recovers a lot quicker than the mice that received Sinovac. And we believe that this is because there are senescent cells that are preventing bone marrow from coming back after

And it was not just that we believe this, but people have published that if you give small molecule, if you give quercetin and desatinib after radiation, the bone marrow accelerates quicker. So we're seeing this as a central vaccine. We're seeing it not only as it's potentially as a cancer therapy, but also to be able to reduce some of the senescence that has come into the body as a result of other cancer therapies.

You know, if you look at somebody who's gone through chemotherapy, you can tell they look 10 years older. And that's because it's published. Chemotherapy not only induces dying of healthy multiplying cells, but cells that are not actively multiplying chemotherapy can induce innocence. Question here. When you're harvesting the blood from somebody, do you induce any kind of fever or sickness in them to kind of ramp up the immune system? And then when you're harvesting the blood...

it may have a lot more immunological components in it. And when you make it, you know, when you refashion it to be re-injected, maybe it'll be more efficacious. I don't know. Very, very good point. And, you know, they do this, for example, they do this in certain protocols, do this. What we do is once we have the blood outside of the body, that's where we activate it. So we take the blood from purified, we take out the white cells. So we spin it down. I don't know if Jake, Richard, if you've ever seen this, but you put the blood,

and they put a little density gradient on the bottom of the tube. And then what happens is you have a layer of only white blood cells. We collect that layer only of white blood cells, and we put it in a special media containing several cytokines. That media activates the dendritic cell stem cells, the dendritic cell precursors to multiply. So we get a lot of these dendritic cells.

Then we feed the dendritic cells, we feed them the senescent antigens, then we make them go crazy by stimulating them in vitro. That way, we don't need to get the whole person sick. But to your point, the protocols you're talking about, you may remember at the turn of the century, turn of the last century, there was a

physician called William Corley. And what he did is he would purposely get people sick to ramp up their immune response. And that causes almost the same amount of remissions as checkpoint inhibitors do today. So there definitely is something for hyperthermia and for inducing the whole body sickness. The problem with William Corley's approach

was that he could not control it and some people died. But, you know, you see this whole sickness too, like even with, you know, the modern day name for now is cytokine syndrome. And, you know, now we're a lot better at controlling it than we were back then. But yes, the sickness is definitely something. It's one of those strange cases where the sickness could actually be a good thing.

Have you used this in animal models? And what about organoids, too? That's a very good question. No, that's short answers. No, we have not. It's difficult with organoids because you would have to have an immune system in the organoid and have that interaction going. Oh, so, yeah, that's true. You need to at least have chained organoids, like...

You know, heart chained to liver, chained to other organs to see. Do they have that? Some people I've spoken to, yes, they're starting to do that because you may not see toxicity, let's say, in the heart, but then, you know, the liver gets it, and now it changes it to a compound that then becomes toxic downstream to the kidneys, let's say. So that's why they're doing...

than what I've seen chained organoid systems now. I've never heard it. See, that's the beautiful thing. That's why I always wanted to have a podcast, like I was saying before, because the amount of cool stuff that you learn, Richard, must be just amazing. Yeah, I've never heard of this word, chained organoid. I will look at it. But yes, look, I've got an approval.

Going back to the story about my mom, how she was taking the placental vaccine, what happened was after I sold my company Medistem, after I sold the company that made stem cells from the endometrium for the diabetic feet, I had some money on my hands and I said, what do I want to do with my life? I made a company where we actually got FDA approval to do clinical trials on

placental vaccines, very similar to the one my mom got. The one my mom got was considered an alternative medicine. It was available only in Bahamas and it was completely uncharacterized. So what we did is we did a deep dive into the cellular mechanisms of action. The reason why I'm saying this is we have gotten FDA approval

Me and my partner, Boris Resnik, we had a CRO who would do clinical trials for other companies, but we also had our own clinical trials. So we've gotten many FDA approvals, and we're very confident that all we're going to need right now to go into humans, we're just going to need a little bit more animal safety data that the FDA will allow you.

The FDA is moving more and more towards organoids, but these kind of things are more for small molecules. So with small molecules, like you said, there's all sorts of different toxicity issues. But when you're doing immune modulation, one of the things with immune modulation is to date from what we have seen, and we have had regulatory consultations

So there really are no organoid-type models that represent the functioning immune system that you can connect to the multiple different organs and have something in vivo. There's humanized mice, and we do have some data on the humanized mice where you put human tumors and human immune cells and the human vaccine. But yeah, right now we are not using organoids. Okay.

So how long does this immune boosting effect last? Like, what is the profile of it? Does it cause, again, a cytokine storm that needs to be controlled? Like, is there a

big bump up in activity and then it slowly goes down? Or like, what does this look like at people? And do you need to control the administration so it works better instead of maybe just one big pulse? What happens is that this is antigen specific. So for checkpoint inhibitors where you see this cytokines 12, what you're doing is you're taking the brakes off the whole immune system.

So checkpoint inhibitors are molecules like CTLA-4 and PD-L1, and these are inhibitory molecules that block any kind of immune response. Once you block the blockers, when you give antibodies to these, you have the whole immune system going crazy. With what we're doing, we are only stimulating immunity against senescent cells.

the senescent cells that we lice, that we took from the person's skin, we expand the cells, we make them senescent. So because the immune response, because the senescent burden of the body is a lot smaller, we have not seen any kind of cytokines to them at all. We have done extensive tests

extensive studies on cytokines. What we see when we inject mice with the Sinovac is we do see a reduction in some of these cytosine-associated proteins. So, for example, which indicates that they're reducing the number of cytosine cells. But in terms of cytotoxic reactions and cytokine storms, we have done multiple immunizations. One of the things, because we've gone through the FDA, one of the things the FDA always asks you to do when we've done these studies

is to inject that twice, two times, four times, and even 10 times, the dose that you plan to be going into humans on a per kilogram basis. And we've done this, so we have seen no excessive immune activation. Again, the reason is, if you look at dendritic cell therapies as a whole, so the dendritic cell therapy, you feed the dendritic cell whatever you want to get the T cells to get mad and kill.

So for example, if you want to immunize against herpes virus, you take herpes virus proteins, you feed them to the dendritic cell, and you inject those dendritic cells. Because you're inducing immunity only to one type of antigen, you never get systemic cytokine syndrome or the cytokine storm. You get the cytokine storm when you use checkpoint inhibitors, and sometimes you get it in a curative way.

With cur-T, it's a little different. With cur-T, you're taking all of the cells, a lot of the cells, transfecting a very strange construct that the body's never seen before. The human body in all of history has never seen a T cell with a B cell receptor on it. That's why they call it cur, chimeric antigen receptor.

So the body's never seen something like this. And when you introduce something that the body's never seen as completely genetically modified, and you're modifying the whole population you see, the whole population of T cells, you see some strange things happening, especially in carotid because the carotids initially, the ones that were really good are against CD19 on B cells. Basically what happens is this kills all the B cells. So you have a person walking around without...

The second, you know, we classical immunologists, we think of the immune system as being T cells and B cells. People with lymphoma, after you give them CAR-T, they don't have B cells anymore for the rest of their lives. And, you know, people at the beginning were horrified, but the hematologists were saying, hey, if you have this type of B cell lymphoma, you're going to die in several months. You know, better to live without B cells but be alive. It's just like the plus or minuses of organ transplantation. You know, if you need to go into a kidney,

If you don't take immune suppression, that donor kid is going to die in several weeks. But you're going to be alive if you take immune suppression. You just have to be careful and make sure you don't get infections and with antibiotics and supportive care. So it's always a dance. I have a way out thought that just came to my mind. I know it's not really in your purview, but...

Is there any senescence in microbiome that people have? Has that been observed, and how does that interact with our somatic cells? This is why I draw you a line of questioning, because microbiome can induce acceleration of senescence. And from the other point of view, if senescence is affecting the microbiome, I don't know if anybody's even looked at that. I'm going to check. We might have to name you as a co-inventor on one of the passes. Yes.

This is a very strange, very strange, but very logical idea. So with what we do about the microbiome, I'm sure you're very familiar with these studies. If you take the microbiome from somebody who's lean and in great shape and you transfer it to somebody who's obese or metabolic syndrome, you see an active protection and a reduction.

And then when you look at the senescent cells, so if you look at the senescent cell burden of somebody who's obese, after they've taken microbiome from somebody who's lean, you see a decrease in the senescent cell burden. So the microbiome we know can definitely affect systemic levels of inflammation, and those levels of inflammation, they can definitely change the microbiome. But can, so the microbiome stimulates inflammation, and the inflammation can stimulate senescence. That's well known. But

But can the senescent cells promote outgrowth of specific pathological microbiomes? That's a question that, to my knowledge, nobody's addressed. But I'm going to look because that's a very, very interesting question. Because let me give you an example. I saw you have a Twitter, and I followed you on Twitter. My Twitter is at exosome. And I was just tweeting several days ago. I was just tweeting that, oh, shit, it didn't let me follow, but I'm going to try following it again.

Because I've reached the maximum number of people I can follow. I'm going to try following it again, your podcast. But the point is that I was tweeting about microbiome. If you have dysbiosis and you administer stem cells, the stem cells don't work. That there's specific butyric acid and certain metabolites made by the microbiome that when you're dysbiotic, the stem cells will not work.

So that correlation is a very interesting correlation. And as you know, the more stem cells you have, the less senescence you have. So microbiome-stimulating senescence, definitely there's rationale for that. But the senescence that's messing up the microbiome, that's something where we have to look like... Here's why...

I'll just give you a couple of quick threads that are coming together. So a long time ago, I interviewed Florencia McAllister. I forget where she is, but they observed differing microbiomes locally around the tumors of, you know, in a pancreas. Normal pancreatic tissue had a certain microbiome. The tumor-laden pancreatic tissue was different. And you talked about the...

You know, the cell membrane, you know, different proteins are expressed senolytic cells. So therefore, they would attract a different microbium to them. And then you also said like tumor cells will have a senolytic or senescent cells around them as a border, as an outside border. Yeah. That's probably why it changes their interaction with the microbiome in a different one forms because there's different molecules now being exchanged.

So I think there is a big interplay in all this. No, I think definitely. And I think the tumor microbiome question is just fascinating. And, you know, for example, there was, I believe his name was William Reif back in San Diego. And William Reif was talking about these microbial-type particles that he called, I believe he called them somatids. And you could see these in the blood, but you could only see them with a special microscope.

And, you know, everybody said it was crazy. But now we understand, you know, with the microbiome, the microbiome revolution is all because we can only grow in culture 0.001 of everything in the microbiome. So once we had the ability to see this whole zoo, the way I think about it as a zoo, because there's all these different species, we're only able to see them through a 16S liposomal sequencing. You cannot culture those things. So the microscope, a lot of them are too small or you just can't see them. So now...

that we understand the microbiome. And this is a whole revolution because, as you may have seen in the studies, I believe it was the New England Journal of Medicine or Lancet, there was a study where they looked at checkpoint inhibitors. People who are non-responsive, people who were on antibiotics and had gut dysbiosis, they lived something like four months on checkpoint inhibitors.

People that did not have antibiotics and were not dysbiotic lived like 17 months. These are huge number of differences, huge differences. And the microbiome, this microbiome revolution, I still believe to some extent is more or less scratching the surface. And from what we know back away, it's not being implemented. You go to the oncologist, you ask about dysbiosis, they laugh at you. They say it has nothing to do with anything. Well, that's wrong. It has a lot to do, it even has to do with chemotherapy resistance.

the microbiome. So, I mean, you have to think about this, 100 microbial cells, at least 100 to 1,000 microbial cells in your gut for every mammalian cell that you have. That's why they call it the second genome, right? Very interesting, very interesting stuff. Okay. So what do you expect that you're going to be able to make a breakthrough on in maybe the next...

A couple of years. The breakthrough is this. So we, there's two things. So we, we talked about the analytics analytics. We hope to get the FDA clearance this year. I have a clinical trial completed, clinical trial completed probably 2026. And that's going to allow us to IPO at 2026, 2027. You know, we, we IPO at two other companies, creative medical technology,

I took that on NASDAQ and fibrobiologics. I was the chief scientific officer. We went to NASDAQ. So all of these technologies, cell-based technologies, this one that we're doing, I was very excited. Breakthrough number one is going to be a completely new first-in-class way of treating cancer as a monotherapy and as an adjuvant therapy to current immunotherapies. One of the most exciting things we're looking at is current T-cells still have not penetrated

solid tumors. That's because, in our opinion, the senescent cells are the center of acts more excited about the possibility of potentially allowing, unlocking the potential of CAR T into solid tumors. The second thing that we did not talk about is the cellular rejuvenation program. The cellular rejuvenation program might be even more interesting. I figured there's going to be a big group of people that hear this and they say, oh, I want this treatment every six months to stay young and healthy and all that.

Yeah, we're not going to be able to do that because it's highly regulated with FDA. Oh, no, I know, but I'm just saying, believe me, people are going to be interested. Oh, yeah. There'll be offshore outfits popping up that will offer this and all that probably. Yeah. No, it's definitely possible. Now, the other thing is the cellular rejuvenation program. Cellular rejuvenation program, what we do is we take our blood, and we've done this from a 76-year-old person. We've done it from multiple people. We take our adult blood.

And from that blood, we generate an immortal cell, a cell that never dies. That cell is similar to an iPSC cell. We call them personalized regenerative cells. So what this is, is we take from the blood what we call a mutable stem cell. We have a special population that we have IPR. We...

expand that cell, and from that we take it and we make it into like an iPSC cell, a very early pro-reported cell. From that very early pro-reported cell, then we bank it, and we can make an unlimited supply. The beautiful thing, so people have published this, but the biotech field more or less hasn't even come out to this. A pro-reported cell can be multiplied forever and does not develop mutations. So with that,

We are making several things. Our lead program is liver failure. We're making hepatocytes. Liver is a multi-billion dollar disease, liver failure. Right now, the only two options are liver transplant or hepatocyte transplantation. Hepatocyte transplantation is basically...

the single hepatocytic cells. This has been demonstrated to cure liver failure, it's just we don't have enough hepatocytes. We've already demonstrated, we've already manufactured a scalable number of hepatocytes so that they work in two models of liver failure, permatensic chloride and acetaminophen-induced liver failure, and now we're pushing this towards the clinic.

The other thing that's even more exciting is the mesenchymal cells. Mesenchymal cells are autologous repair cells. They're repair cells. They can repair a variety of tissues. Right now, the big problem is mesenchymal stem cells got approved by the FDA in January of this year for treatment of Gravers' host from the company Mesoblast. Mesenchymal stem cells, you've heard, they're used outside of the U.S. with some pretty spectacular results. Here's the problem. If you use autologous, if you use your own, you don't have enough of them.

There's only so much bone marrow you can suck out of a bone. If you use adipose, again, you don't have enough. There's only so much fat tissue. If you use allergenic, you can use younger ones, but the problem is they end up getting rejected. So sure, the allergenic one is immature because the mature is not seen by the immune system. But when you differentiate it to cardiomyocyte, that's going to be a mature cell. If it's going to be beating fast, that's going to be rejected by the immune system.

So what we do is we take the blood, generate this pluripotent young stem cell. From that one, we can make young mesenchymal stem cells. And they're autologous. So with these young mesenchymal stem cells, we are doing different. We're using them in liver failure as well. So we have two liver failure programs. But these young mesenchymal stem cells can be used for a variety of things, including for complete anti-aging. You may have seen the publications with a heterochromatic transfer where you take the

plasma from you take the circulation of a young mouse and you surgically tie a young mouse to an old mouse and then you can see rejuvenation of the old mouse. As you've seen there's different people that are collecting young blood and using young blood. Well basically you can have your own source of young blood, your own source of the young growth factors such as cloth or GDF 11, FGF and so on

You can have your own eternal supply of this through these. So right now, the main focus of our company is two things. Kill out the old cells and then replace them with new cells. And we're taking a very cautious approach, diving into an indication that has no current value.

treatment available for it. We're looking at stage four lung cancer patients that have not had, that have not responded or failed response to immunotherapy and standard therapies. So we're diving into that to obtain proof of concept that we can kill all cells. At the same time, we're diving into liver failure where they're going to die without a transplant in weeks. We're going to have two therapeutic signals very quickly and that will guide us. Now, if this doesn't work,

Obviously, it's better to know if it doesn't work a lot quicker than if it does, like a five-year clinical trial, like some of our colleagues have done in other types of senolytic drugs. So this is what I think sets us apart from everybody else, is we have a team that's second to none. We have Boris Reznik, my business partner, who had a nine-figure exit

in software, then he had a nine-figure exit with me in selling off the contract research organization. Together, we must have done at least 200 clinical trials. Know everybody in the field. We have Vicarious, who's the chief medical officer, who came from Pfizer. And we have Russell Kaufman on our board. Russell Kaufman is at Papa's Ventures. He was the dean of Duke Medical School for like 15 years. So we have a team and we're operating, we have an excellent team that's extremely conservative,

But yeah, we have the passion and the agility to move quickly. So far, we're completely funded by ourselves. We've all had multiple exits. So we have not gone through the traditional funding routes that have different problems. We definitely will go through the traditional funding routes, but we believe we've been able to

secure a nice piece of the company for ourselves as we go with this. And we have not had to succumb to other pressures that usually startup companies have. You know, we've been able to intellectual freedom to pursue a lot of these approaches and to move quickly. And, you know, we've had approaches that didn't work. And because we are a small team, we have the funding, we can launch a project and kill a project very, very easily. So that's why we were poised for success.

One last question that just came back to mind. It's said that cancer cells are metabolically different. They don't do oxidative phosphorylation. They do fermentation. And since you said that senolytic cells are part of the outside structure of some tumors, what about their metabolism? Do they do oxphox or are they doing fermentation? And maybe they could be targeted where you're giving your therapy and at the same time, the person is on a ketogenic diet to starve the body of sugar and the

and maybe suppress the metabolism of the senolytic cells as well as the cancer cells and make this more efficacious? I don't know. That is a very, very good question. I imagine that there would be some. The short answer is I don't know. This is one that I saw before. Long-term ketogenic diet accumulates age cells. A ketogenic diet can contribute to cellular senescence, which can damage organs. You see, this is the issue. I mean, with these kind of things, you have to sit down and study. Maybe in the short term it would work, and then it backfires, who knows.

Well, you know, let me tell you, it's kind of like the whole vitamin C story. And, you know, the vitamin C story, I don't know if you know the name Neil Reardon. Neil Reardon is a big offshore stem cell guy. He traded Mel Gibson, Tornado.

Tony Robbins and Neil and I collaborated in the past. He's a good friend. Neil's father, so the vitamin C story is Linus Pauling did his clinical trial where he showed just with, I think it was 20 grams a day or something, some high amount of vitamin C. He showed response in some end-stage cancer patients. And when the study was repeated at Mayo Clinic, and they repeated it two times,

It failed. Completely different results. Neil Reardon's father, Hugh Reardon, who was one of these alternative medicine and nutritional guys, he's like, hey, I wonder if there's a difference between IV and oral vitamin C. And this is before they discovered the pumps.

See, what it is, is you have different pumps in your gut. So no matter how high concentration you eat orally, once you reach a certain level, the body's going to pump it out and you just cannot achieve that concentration in the bloodstream. The concentration needed to kill cancer by vitamin C can only be achieved by intravenous administration.

Neil Reardon's dad published this about 25 years or 30 years ago, and the paper did not receive much attention. Then in the Proceedings of the National Academy of Sciences, a physician, a PhD from the NIH, his name evades me now, he published it, he did the whole workup, and he showed black and white

intravenous vitamin C kills cancer cells in vitro at those concentrations and in vivo in animal studies. There's a story where I try to say is, unless you sit down and read the literature carefully and have certain angles, you just don't know what to believe. This ketogenic stuff where, you know, we just Googled it right now, it says ketogenic diet increases senescent cells. Well, you know what?

Maybe they're looking at the wrong senescent markers. Maybe it's some kind of twisted animal study that means nothing. I agree with your general hypothesis that there is metabolic alterations. There has to be. I mean, these guys completely change who they are. I'll tell you something else. There was a really cool study about chelation therapy. Chelation, the chelating agent, dexapherz, I can't pronounce it, it starts with a D. That one has selective cytotoxicity to senescent cells. So there is definitely a lot we have to learn. And, um,

The oncologic, the anti-cancer effects of ketogenic diet are well-published. The ability of ketogenic diet to increase sensitivity to chemotherapy is well-published. And yeah, there's just a lot to know. And I think that's what makes, along your lines, my God, what if there's a selective strain of microbiome?

Now, here I'm destroying my ability to get IP on this. What if there's a selective strain of microbacteria that selectively infect senescent cells? I mean, you've seen this cancer. The lady you interviewed, I'm sure she told you, there's a whole bunch of bacteria that selectively grow in cancer cells. What about cellulitic bacteria? My friend Boris Miniev, who published with us, they have a company that in clinical trials is a

NYSE trained a company called Kalili, and they are infecting cancer cells. They're actually, what they're doing is they're putting the senolytic virus in a stem cell. The stem cell goes into the cancer, releases the senolytic virus, but the senolytic virus by itself has proclivity only to tumor tissue and does not do anything to healthy tissue. So is there such a thing as a

central lytic virus. I bet you that there is. So there's a lot of fascinating, and I think, Richard, this is what makes life fun, living especially in the times we live in now, because right now, we are at the edge, at the dawn of a revolution, with a convergence of

AI, and look, I know everybody's talking about AI. I think AI is going to make a lot of people stupid because I know a lot of people don't stop thinking and they just put everything on the damn AI. But if you use AI, if you use it the proper way, I think the potential literally is unlimited with the thought. You know, if you just think about it,

If you think about the explosion of information, when I was in graduate school, if I wanted to see the effect of one treatment on one gene, so let's say, for example, I wanted to give interleukin-7 to hepatocytes. I want to see what it does to, let's say, cytochrome P450, the detoxification enzyme. I would have to sit there and do a northern blot where I would purify the mRNA and then mix it in with a probe.

and do the gel, and it would take several days. With the advent of micro DNA chips and microarrays and with Illumina in San Diego, you can look at the whole gene expression and the whole human being in one hour after you do one treatment. So this is the thing. The revolution, you know how that song says the revolution will not be televised? This revolution has not been televised, and that's where podcasts like yours are so important.

Because they educate people on how fast. It's not just a thing about the public versus the biotech people. The biotech people also do not, because when you are in science, what they teach you during your graduate school is you have to focus, focus, focus. I remember when I was a graduate student, my professor, Dr. Kim Singar,

We were at the first science conference. My first science conference was with him because I went to the first science conference when I was like 17. But when I was with him, so I was maybe in my 21, I go, you know, Dr. Singhal, what I want to do in my life is that this was the American Association of Immunology meeting. I'm an immunologist.

And I said, what I want to do in my life is I want to get to the point where I can walk down these posters and I can have a meaningful conversation with anybody in here. That's how much immunology I know. And he got mad at me. He said, Thomas, that's the most naive thing that's come out of your mind. And I'm like, why, Dr. Singel? And he's like, you need to focus. Well, I'll tell you, Richard, I might not be a lot of things, but one thing that I really am proud of now, 48 years old, is that when I do go to the American Association of Immunology meeting, I walk down and

I can't say every poster I understand, but at least one and two, I at least understand well enough to have a discussion because what has happened is that science as a whole has become...

a lot easier to understand in a way. And sure, we are inundated with new cytokines every day, but patterns are emerging. And that's my bottom line. Patterns are emerging. So for example, there's certain, we knew that there's different cytokines, different chemical signals associated with an inflammatory state. Now we know that there's mass-regulated proteins that bind to the DNA

and they somehow activate all of these things. There's a material basis. We also know, through the advent of stem cells, that if you knock out one of these transcription factors, it relates to a specific phenotype. So it's no longer where there's correlations, but now we have a lot of cause and effect stuff. You know, for example, like,

like FOXP3. FOXP3 is the master regulator of T-regulatory cells. T-regulatory cells are the ones that control for autoimmunity. They help maintain a healthy pregnancy. They stop autoimmunity. They promote cancer. The FOXP3, we knew about these cells, but we didn't know what they were or what controlled them. There were genetic mutations in people that some people would just get this crazy autoimmune disease and nobody knew what caused it because, you know,

Usually autoimmunity, you have like diabetes that's killing the pancreas. But this one has a full-body autoimmunity. So they found a gene that encoded something that looked like a protein that binds DNA. In parallel, they found a similar gene in mice and the scurfy mouse. Scurfy mouse, I can't pronounce it. Then at the same time, the guy in Japan, Simon Sakaguchi, found that the T cells that specifically block activated T cells, they have a protein, and the sequence of that protein looks like that gene. That's how immunologists...

found out there's one gene that encodes FOXP3. FOXP3, if you put it in a cell, it makes a cell a T-regulatory cell. And so the bottom line, the bottom line is we're living in an age of convergence. And even though it's extremely complicated and, you know, I find it,

I say on the one side of my mouth, I say I can walk around the American Association of Immunology and look at all the posters. But if you look at my Twitter, this is why I tweet, because the Twitter is me walking through those same postal sessions. You know, you sit down there and you just type in Journal of Experimental Medicine and you just see what are the newest papers that the Twitter is me taking notes. So anyway. Okay. Well, very good, Tom. What's the best way for people to follow up your company and your efforts? And, you know, it sounds like Twitter...

Maybe the best place to hear from you. Twitter is the best. It's at Exosome, E-X-O-S-O-M-E. It's not extracellular vesicle. It's not expensive enough. Good one. I used to have the domain name. I used to have the domain name, exosome.com. My Twitter name is at Exosome. So yeah, thank you for coming. If you like this podcast, please click the link in the description to subscribe and review us on iTunes.

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