TTT020 Unveiling age-defying proteins - Mark Allen - Elevian

9:44PM Apr 29, 2023

Speakers:

Jonathan

Forrest Meyen

Announcer

Mark Allen

Keywords:

protein

work

aging

animals

started

humans

disease

age

blood

studies

effects

measure

treat

patients

alzheimer

people

approach

life

mice

treatment

Aging is malleable. That your destiny in terms of your health span, so your quality adjusted years of life, is under your control that this approach to therapeutically target aging makes a lot of sense. And it's worthy of investment, of our tax dollars going into it, of investment dollars going.

Welcome to Tough Tech Today with Meyen and Miller. This is the premier show featuring trailblazers, who are building technologies today to solve tomorrow's toughest challenges. Welcome to Tough Tech Today.

There has been evidence that when it comes to mice in the laboratory, putting the blood of young mice into old mice has caused them to grow biologically younger. While the opposite is also true. Putting the blood of older mice into younger mice has caused the young ones to grow biologically older.

We're here with Dr. Mark Allen, a physician who also co-founded the pharmaceutical company Elevian to explore the implications of this phenomenon to see if is there a way to commercialize therapies for humans experiencing aging related diseases such as stroke, diabetes, and obesity.

We sat down with Mark just ahead of their $40 million Series A funding round in late 2021. And they are now on track to be conducting human trials this year. Mark and his team are using a recombinant growth differentiation factor, which is something that we really want to double click into what that is. Welcome, Mark. Tell us about Elevian.

Well, thank you. It's pleasure to be here. Jonathan, Elevian is a biotech company that's working on new medicines that target the aging process. So if you think about this, aging is the number one risk factor for most chronic diseases. And not just chronic diseases, but all forms of debilitation that we don't have even disease labels for that occurs later in life. And most pharmaceutical products, most medicines, target individual diseases. The problem with that approach is to the degree that those drugs work, they only work for that disease, and not for all the other diseases that catch up to us and attack us as we age. So to put a fine point on that, if we were to eliminate cancer, just eradicate it from this planet, which would be a wonderful thing to do, it would only increase the average lifespan by two to three years. And it would more than double the incidence of Alzheimer's disease and many other age related diseases, which would continue to attack us. So an alternative approach is instead to target various aspects of the aging process itself. So the underlying cellular-molecular mechanisms that we see occur with aging. And by doing that we have the potential to treat and prevent many different age related diseases at the same time. Now, this is not just science fiction. We're doing this in the lab. And we're seeing remarkable results in animal models that we're in the process of bringing to human clinical trials.

So can you give me an example of like the effects that you're seeing on these animals? Like are they actually living longer? Are you seeing a reduction in disease?

So, all this research started with my scientific co-founders working at the Harvard Stem Cell Institute. And they discovered this protein called GDF11. That very little was known about this protein at the time of their initial discovery. So it's a circulating factor that that is identical across all mammals. And they're orthologs that go back to earlier species. So you know, really key part of the evolution of life. And this factor, by some measures decreases inactivity with age, and they estimated what it would take to replenish this protein to its youthful levels via daily injections of a recombinantly produced version of the protein. By recombinant, I mean that it's produced using biotechnology. We can dive into that and how that's done. But when they gave daily injections of this protein to aged animals, they were able to effectively rejuvenate those animals so they seed that the heart, the skeletal muscle, the brain, the metabolism reverts in many ways to a youthful state. This is really exciting. Now, there appear to be many different things that are happening, but we think the most prominent effect is a regeneration of the vasculature, the blood vessels. And, you know, some really interesting things about our blood vessels, you know, we normally think about our veins, and our arteries, you know, things that we see and hear about, but the capillaries are much, much longer when you think of the quantity of them. They're everywhere. A lot of them are so thin, that just single cells flow through them. And they're there between many, many different cells throughout our bodies. And I heard a statistic that if you were to take all of your blood vessels, all of your arteries, veins and capillaries, and line them up end to end, in a healthy young adult, it would wrap around the Earth, one person would wrap around the earth two and a half times. Now, when you're a middle aged person, it's about half that... now you think about that...

Okay, do they just collapse and close off?

Yeah, they start to close off. So you know, we talk about this a lot in terms of some of the effects to it, you see the effects on atherosclerosis, on your arteries themselves hardening and becoming inflamed, and sometimes clotting down. You know, in your veins, sometimes you see these problems. In veins and varicose veins, people talk about pain there. But you know, the microscopic capillaries, as they start to deteriorate, now you're no longer bringing nutrients to much of the tissues of your body, you're no longer taking out waste. And some of those nutrients are just food to the cells, right. But some of them are also growth factors, healing factors that are flowing through our circulation. So if you think about this, if we're just to... the only effect was just on the vasculature, right? Just that affects the entire body. So what we see quantitatively, this is also published by one of our co-founders is we've studied the effects of the vasculature most in the brain, and in the brain, it's about a 50% reduction in the quantity of the vasculature in the old animals, the old rodents, and when we give GDF 11, for four weeks, it restores the vasculature to a youthful state, in terms of the quantity of the vasculature, but also we see quality improvement to the vasculature as well. So we see very quickly an improvement in blood flow, initially in neurogenic regions of the brain where new neurons are forming, and then over four weeks to the entire brain. Now, that effect, we see a lot of other effects. So we see the activation of stem cells... okay, so neural stem cells, we see the activation of other stem cells throughout the body, as well. So we see in the skeletal muscle, we see a much faster healing response. So you guys know this: when we age, the rate at which we heal goes dramatically down. So you get a cut, or a scrape or muscle injury, like when we were young, it'd heal in like a few days. I just had a scrape on my leg, it took like three weeks to heal. You know, so this when we give GDF11 to these animals, they heal at the same rate as a youthful animal from skeletal muscle damage. So you see these really incredible effects. So now that rejuvenative effect, right? You know, where you see this broad effects in aged animals. That's really cool and really, really exciting: it has long term potential in humans. But there's no clinical path for that. Okay, you can't just treat aged people. Aging is not recognized as a treatable disease. It's not reimbursable. So instead, we have to look at, strategically, how do we get the product to market. And it's by treating one disease at a time and getting approval for one disease. And so strategically, when you think about this, you know if we were to go after even an aging, let's say a disease prevention type of indication, a clinical trial for that would be really long and really expensive because you'd have to recruit patients that are well into the trial, treat them for some indefinite period of time until they potentially get illness or not. So it'd take many, many patients and a long time. So instead, we look at what's the worst possible disease that has a terrible status quo. So basically, it has no good treatment. And where we could treat for the shortest possible duration to see clinically meaningful effects. And so we looked, when we started working on this, our co-founders had done several studies in different areas. And then based upon their work, other groups started picking this protein up and doing studies in different areas... so we saw, there's quite a bit of data already out there. And we really begin to analyze this as a commercialization strategy. So what would it take to prove out for a given disease, and the way this works is, you first have to prove it out in animals, then in an end, but when I say prove that you have to prove two things, number one is efficacy, that it actually works to reverse a disease. Number two is you have to prove safety. Okay? And then you reverse that in humans. So first, in humans, you prove safety, then you prove efficacy.

So you've already told me what the secret sauce is? How do you.... you know with this particular protein, how do you protect your invention?

Because I mentioned so little was known about this protein at the time of our cofounders' discoveries that they patented, with Harvard University and their research collaborators, they patented quite broadly in a couple of different categories. So number one is the use. So you cannot patent a natural protein. Right. So you can't patent the protein itself, you can't get a composition-of-matter patent so that nobody else can study it. But what you can do is you can patent methods of use of the protein. And so they patented methods of use to treat a broad range of different age related diseases. So disease, the heart, of the brain, of the skeletal muscle, the metabolism. Okay, so kind of effectively the most common diseases. So that's one category. And then another category is new compositions that modulate this protein. Okay, so a new composition, a molecule that doesn't exist yet. And a way that you might increase the production of GDF11, increase its activity levels, or keep it from being broken down, pulled out of circulation. So lots of different strategies there. So our first generation as a company, our first-generation product, is the natural protein. And we're already working on next generations as well that can... the goal there is... I mean there is some goal of, you know, extending patent life so that we have that, but the bigger goal is to provide a product that is more convenient and cost-effective than the natural protein. So the problem with a natural protein is that a protein has to be injected. It's broken down by the gut. So now there are lots of technologies that people are working on to allow us to ingest proteins, or take them in different ways, inhale them, transdermal, encapsulate them so that you can take them or.... there's lots of technologies like that, but you don't want to use a new technology at the same time you bring a new molecule into humans. So that's one way to ultimately get this but into a more convenient form. That wouldn't necessarily be cost effective, unless you make lots of technology, inventions, along the way. I'm sure we will, but the other is to identify different ways of, for example, engineer the protein to make it last longer in circulation... longer half life, or find another molecule that prevents its breakdown for example: that's a strategy that we have right now that have some interesting molecules that fit in that category.

This is a long haul kind of project. I mean from the original publications back maybe 2005 with who would become your cofounders on this kind of project and publications in publications like Nature, Science, Cell, publications, or Proceedings of the National Academy of Sciences and the list goes on. These are amazing publications. And there's a long trail of them. So what was the process that then sort of got you engaged on it: like saying, you know, maybe we're on an inflection point to start to commercialize this or steer this out of the auspices of say Harvard Labs to make it own standalone entity as a Elevian.

Yeah, yeah. So great question. So yes, indeed. Our Elevian scientific cofounders have been working on this path for a couple of decades. And the seminal discovery of this protein itself. So you know, the first discovery.... actually, let me go back and explain it like this. So we know that the way our body works changes with age. Okay, very clear to everybody. Our genes don't change with age, our DNA does not change. Okay? Minus very rare cancers. So what changes is the expression of different genes. Okay, and that expression of the different genes... the hypothesis is tha would result in different proteins, or at different levels of different proteins between young and old. And so that was really the core thinking is. There were, back in 2001 of our cofounders, Professor Amy Wagers wrote a Nature paper that showed that circulating factors can regulate aging. So they used a model called parabiosis. And these are pretty famous studies now, where they can join the circulatory systems of young and old mice. And they left those animals together, so the bloods flowing freely between the two animals for four weeks straight. And they found after four weeks that the old animals had a biological reversal of aging, by many different measures. So kind of like GDF11, I told you, so their hearts, their brains, their skeletal muscle, their metabolism. So it appeared biologically to look as a younger state. And interestingly, the young animals exposed to old blood had accelerated aging, by many measures. So, you know, this implicates circulating factors that are sending messages back and forth. So they then went on a hunt. So Amy Wagers got a professorship at Harvard, and working at the Harvard Stem Cell Institute. And she continued this research asking the question, how do circulating factors change with age, by trying to measure their concentration levels. And so it's really interesting, they say that there's some 20,000 different proteins that we have, and a lot of those proteins, with most of them, we still have no idea what their function is. It's really interesting... there's much more that we don't know, than that we know. So what scientists have done is they've... and most of these, by the way, we haven't even been able to measure them. Until recently, they circulate in such minute concentrations, we just didn't have the technology. So they used the latest technologies that were available and a new technology that was available to measure proteins at levels that we could never measure before. And they identified out of that work, a few different proteins that change with age and one of them being GDF11. And we know in that work, that it's actually measuring a combination of a couple of different proteins, GDF11, and a closely related protein called GDF8 that circulates in much higher concentration than GDF11. And so when they looked at this data, there's, as I mentioned, very little known. What was known was what happens if you knock out these proteins in the embryos of mice. And so, you know people talk a lot about this CRISPR gene-editing technology, it's a new easier to use gene-editing technology, but we've had gene-editing technologies for a long time. And a little bit more crude. And so what scientists have been doing is they've been saying, okay, this protein is the same between humans, it's in humans. And by the way, we've been measuring what we've been sequencing genes for a long time and sequencing RNA even before we were sequencing DNA. And so they say, okay, we don't exactly know what this is, but we've identified this particular gene, and it's the same or similar in a mouse in the case of GDF11, it's the same in the mature domain of the protein. And so let's knock it out in the embryo of a mouse and see what happens to the mouse. Okay, so they did this with both GDF8 and GDF11. So, you know, from a protein biochemistry perspective, these two proteins are in a category of proteins called TGFβ, a superfamily of proteins they call it, that have to do with growth and differentiation. So they know they're critical for those purposes.

So the GDF11 and the GDF8, they're sort of sibling proteins. So far they're sort of showing up in levels that seem to suggest that they somehow have something to do with the aging process, or a lack of aging process, right?

GDF11, much more with many different things. GDF8 seems to be specific to muscle. So let me explain that.

Oh so they knocked out one or the other.

So they knocked out one or the other. So going back. This is 20 years ago now. So scientists knocked out GDF8, and the animals make it to term, they're viable, and they're hyper muscular.

So it means the animals are alive.

They're alive, but they appear to have normal phenotypes. When we say phenotype, that means kind of everything about the body, how it looks, what it looks like molecularly. But it's hyper muscular. And you've seen humans that are just naturally muscular. So a lot of those humans have variants of GDF8 that produces less GDF8. And they've created horses, they've created cows, they've created dogs with GDF8. Knockouts. And they're hyper muscular. So they, as a result of those studies, a number of different pharma companies started to work on creating drugs that would knock down GDF8 to treat various muscle diseases. Right? Makes sense. So muscle grows, when you have no GDF8; if we knock it down, maybe it will help a muscle to do so. So the GDF11 shares 90% amino acid sequence homology to GDF8: so very, very close. But has very different behavior in embryonic knockout, and now we know also in post-birth. So when you knock out GDF11, by contrast, the animal makes it to term but dies upon birth, with malformed kidneys, spleen, pancreas, vertebra, retina. So it's essential for life. Now, before this, these studies, you know, you think, oh, maybe they're similar or the same protein. But clearly, they're very, very different. And GDF11 circulates in about 20 times lower concentration than GDF8. So really interesting data there. So that was basically what was known. And so then they do this study, they find that GDF... at that time, they thought it was just GDF11. But now we know, some combination of these proteins goes down with age. And when they replenished it via daily injections, it basically reproduced the parabiosis model, the parabiosis model that used young blood to rejuvenate the aged animals. You saw very similar effects when you use just GDF11. Now, this is remarkable, because in our blood, circulating our blood are hundreds, potentially more than thousands, low thousands of different proteins. And one protein can produce this regenerative effects of young blood. It's like, really, really incredible.

That's then, in some ways, sort of corroborates what the studies, I think, circa 2014, where it was Alzheimer's patients would be receiving plasma infusions from young... like 18 year old patients and seeing if that would help to halt or reverse the Alzheimer's development. Right? Yeah, is that sort of like the idea?

Yeah. So one approach to those parabiosis experiments is to say... one approach that we took is to say, what are the proteins that are causing this effect? And let's create a drug or drugs out of those proteins. Another approach is to say, let's just take young blood and let's use young blood as the therapeutic, right?

So are your Silicon Valley tech giants really harvesting the blood of kids? Well, it sounds like there's some science behind it.

Yeah... there's some science behind this. So let's put this into perspective. There are people working on this too. And there's some very credible science and there's some non-credible science, let me say that. So the concept to... let's go to a clinic, and let's inject ourselves with... you know, let's get some blood transfusions of young blood. It's a real big stretch based upon the science. So the parabiosis model, the animals have a continuous transfusion of young blood for 24/7 for four weeks, right? So the concept that you could get a few units of blood and reproduce those effects is it's just not based on science. So you know, that that's really the issue now, perhaps....

So if I'm in an accident or something like a car accident and need some blood from the folks who have donated, I shouldn't be worried that... I mean I should be worried about my life and being patched up, not so much whether I'm getting blood from an 18 year old or a 70 year old that... in the scheme of things it's such a minut amount, it doesn't matter.

Yeah, the factors that you need, the red blood cells that you need that are lost, and the plasma that you need, it doesn't matter if it comes from a young or an old. So there are these factors that circulated in much, much lower concentrations. So if you were to take, for example, GDF11, and you were to try to extract it from the blood, it circulates in such minut concentrations that you'd hardly get any. So it's just not an effective way... so before we had this recombinant technology to manufacture proteins, we used to extract proteins from the blood of animals. So the first treatments for diabetics, you know, insulin... we would extract that insulin from pigs. So it takes six pigs, you have to kill them, and extract their blood to treat one diabetic patient for a year. So it's not an effective way. So the whole industry of biotech was created around this concept of recombinant protein manufacture. So we identify what the gene is, of the protein that we want, we insert that gene into a virus, we then transfect, it's called, a cell. So the virus comes in and inserts its gene into the DNA of the cell. And now that cell starts to manufacture the protein. And we use cells that are immortal, that can continue to divide forever. So sometimes use bacterial cell or in our case we use, it's called a CHO cell, which stands for Chinese hamster ovary. That's kind of funny, so CHO cell. So we use a CHO cell, we insert a whole bunch of copies of the gene into the cell. And then the cell... we grow the cell in vats with media, so a liquid that feeds the cell, and the cells started making the protein and excrete it out into the liquid. And then we pull the liquid off, and we purify it and we pull the protein out of the liquid. That's the process for manufacturing. So that created this whole industry of biotech, and it's now being used for many, many, many different purposes. But you know, the first companies like Genentech and Amgen that started using this for things like insulin initially, a growth hormone and other factors. So we're doing the same thing with our protein.

It's pretty wild. I recall hearing about... with like, say horseshoe crabs as being sort of a.... their blood is a weird blue color. And I think it has a recombinant factor in it that makes it really great for sort of its antibacterial, and there's rapid healing. And so that sounds like then to me—I'm not an expert, of course, on recombinant growth factors—that these kinds of proteins are potentially sort of unlocking a lot of this kind of healing or in some ways superhuman kind of abilities where extra muscular or were able to withstand the aging process in a perhaps more graceful way though perhaps unnatural way. Is that...?

Yeah, well, so that's certainly our hypothesis, right? In a hypothesis that we created that the company from, and we just need to prove that out and prove that all these incredible effects we're seeing in animals translate to humans. Now, there's no question that proteins can make really excellent therapeutics, there's tons of proteins that, you know, as a category, I've heard that it's actually more revenue than any other modality of drugs than even small molecules, you know, which is what we what become pills, oral pills. So, you know, examples are insulin growth hormone as I said, but there's Epogen, which stimulates growth of red blood cells, there's things that stimulate growth of platelets, there's albumin. So there's many, many different recombinant proteins that are out on the market. So it's a very, very proven modality. And it's a modality that, you know, if you make a high quality manufacturing where it is effectively identical to the protein in humans, then because the body's already seen it, it's more likely to be safe. Now, it certainly if you put too much of anything, including oxygen or water, you're going to start to see toxic effects. We see the same thing with GDF11. We put too much—too much of anything is not good. But at the right range, where we're seeing these therapeutic benefits and safe. So I wanted to go back, I realized I didn't answer your question, like how did this whole thing come to be? And so kind of two ways. So I talked about our cofounders and their path in coming to understand and learn about this, and then publish it. And so my path, I'm trained as a medical doctor, prior to that in applied physics. And I then... so being a medical doctor, it's a noble profession, you're helping people. That's what it's about. But it's also a frustrating profession because there's no scale, there's no leverage to it, to me. You can only help people one at a time while you're working. So I always looked at this as, how can I scale? How can I help many, many more people, and even when I'm gone? And it's by creating some product, right? And so while I was going through my medical training, I created one of the first web-based expert systems to help doctors diagnose and treat patients better, using basically the world's best knowledge, and I left halfway through my residency, which was in emergency medicine to start this company called Corticon, to create this product. And so I ran that company for 12 years, had a successful exit with that. And then I, after the exit, I left with, I guess, enough money to really step back and think about what I wanted to do next and went right back to that same question. How do I help people at scale? And it's where I started. One of the very first things I did when I stepped back was I took this the digital curriculum from Peter Diamandis and Singularity University, around exponential thinking. And it's really interesting. It's now part of something that's called Abundance 360, Abundance 360 Digital, this curriculum and....

I smile because because he was a graduate of my lab at MIT, one of our famous graduates.

Another reformed physician, medical doctor, that's doing other things. Really, really phenomenal guy. So Peter created this postgraduate university, Singularity University, that teaches exponential thinking. And so what exponential thinking is, is it's using exponentially improving technologies to solve different problems. And so what's the first exponentially improving technology is a computer chip, semiconductors. So semiconductors—and we think of it as Moore's Law, you know—are improving in price performance, doubling every year and you think about the difference between doubling of, you know, if you take 10 steps, he moved 10 steps forward, if you take 10 exponential steps, you move 1000 steps forward, move that to 20, it's a million. Move that to 30. It's a billion. So it's, it's really a whole different way of thinking, and our brains don't think exponentially. But if you start to think exponentially, and you get on the ride of exponentially improving technologies, all of a sudden, problems that for all of humanity, we couldn't even... maybe we can imagine... I should say, in science fiction. But all of a sudden, they become solvable. And they talked about in that curriculum, one of the problems being aging, longevity. And, you know, as a medical doctor, I had never thought about that. It's not the way that they talk about it at all. They talk about it's a natural phenomenon, there's these different diseases that you would target. But the concept of targeting aging process, like, "oh, my God, that's what I want to do." And so right at that time, so this is 2016, not that long ago. These reports out of academic labs were starting to come out where we are successfully, scientists, successfully extending the healthy lifespan of model species by, in the case of worms, it's ten times the natural lifespan of a worm, by one gene change and caloric restriction. Ten times their natural lifespan. And very similar changes in mice two times their natural lifespan. Now, mice and us share 98% similar genes. Like it's remarkable. So you think about that, if we can translate that to humans. Wow. Right, it changes humanity. And so I, immediately when I read about this was like, this is what I want to do. I announced it to my network, and just started getting introduced to people and just went back to like reading, picked up every single journal article that I could, and I hadn't read a journal article in a while. So like, getting back into that kind of scientific analysis and then going to conferences, meeting the scientists. And then I met other entrepreneurs interested in this space, other investors interested in the space, and started looking at different projects. And with my medical degree, my success as an entrepreneur, I got introduced to a bunch of people. And so it looked at a lot of things. And I looked at this from two different perspectives initially. I was like, well, first of all, the concept that I really want to get across this audience is aging is malleable. Okay, there's no question about it. Not chronological age: you cannot do anything about that number, right? But your biological age is absolutely malleable, right? There are things that you can do that accelerate your biological age, like smoking, like being sedentary, like eating a bunch of sugar, or overeating. And there are things that can actually reverse your biological age, actually improve it. And so this is... and you know, exercise, mindset, proper nutrition, getting sleep. Okay, so really, really important.

So that's the low hanging fruit for and it's maybe conventional wisdom... maybe not conventionally applied well.

Exactly.

That if we do that we get like 80% of the way or something, and then it's this long tail of some really far-out ideas, like what Elevian is working on that could provide a bit of a boo boo repair, if we weren't leading such a healthy lifestyle, or if we really wanted to just keep it going longer and having that quality of life. That's what Elevian could support.

Yes. Absolutely, absolutely. So, I'm convinced. So looking at just the lifestyle interventions, I would like to work with somebody who would be interested in doing this analysis, but I'm pretty convinced that there is more benefit and quality-adjusted years of life. If we just did that, certainly in the United States, then probably the entire healthcare system which by the way, that's a misnomer, is not a health care system. It's a sick care system. You go and use it when you're sick. So there is like vaccines and stuff.... there is some preventative but much more of the spending in the US has to do associated with sickness. So that's kind of number one. But you're absolutely right, Jonathan, is that the... if you were to do all of that right, there still seems to be some natural cut-off that, you know, everybody dies by 120 if you did everything right, just the species. And but if you did everything right, probably what would happen is you wouldn't get sick. And all of a sudden you just die.

Then does that mean that treatments like Elevian... and there are sort of other companies that their technological approaches that are working on this. Is there the risk then that this becomes something that's only accessible to kind of the rich, who are sort of so focused on staying alive, and they have the means to do that? Or is there another way that a reimbursement model that makes it work differently than that?

Oh, yeah. So we're very focused on making this reimbursable for specific diseases. So I'll share that approach. And then I'll come back to this question. So our approach, as I said at the beginning, is to find a disease that we could treat that is reimbursable, if it had a good treatment, right? And sometimes easiest thing is to find something that already has a reimbursable code, and then you just make it better. So what what we did with a whole bunch of choices, you know, if you look at all the organs that I mentioned, the effects and there are more like it has positive effects on the lungs, for example, on the kidneys, on the liver. So when you take a look at that, and we did from from different perspectives. So from that perspective, is it going to be reimbursable? What does the commercial opportunity look like? Are there great drugs that work super well? Well, we wouldn't want to try to go there, initially. So by looking at that, we identified this area of stroke as a really compelling first application. So stroke is across the globe, the number two cause of death, and the number one cause of long term disability. So, there are two types of stroke. There's clots, which we call ischemic strokes, and bleeds, which we call hemorrhagic strokes. And you can't tell the difference between these two from the clinical presentation. So both, we say that you see facial drooping, sometimes semi-paralysis of the body, sometimes difficulty speaking. And so the only treatment is for clots, and it's to break down the clots and has to be given within the first few hours. And if you give that treatment to somebody who's had a bleed, you could cause them to bleed more and kill them. So you have to rush the patient to the hospital, get imaging of the brain to differentiate what type it is. And then if it's a clot, you give them the clot busting treatment. So because of that time window, all in the best hospitals in the cities in the United States, only about 20% of patients get that treatment, and about half of them don't see any improvement. Now half of them see this miraculous improvement: you know, you're paralyzed, and all of a sudden, you're not, because we open up that flow before the cells die. But most of stroke patients, the bleed patients and the clot patients have that permanent brain death. It's an infarct to the brain. Now, after that initial period, there is no treatment, right? There's rehab. Now what's interesting, though, is there is some degree of spontaneous recovery. So some patients really seem to recover, but they still have that infarct in their brain, they still have dead cells. So there's plasticity in the brain, there's ability to relearn, right? And throughout our lives, we know this: you can learn new things, that's plasticity of your brain. Right? So what GDF11 appears to do when we give this to animals that have had a stroke. For only a few days, we give them this: it significantly improves their ability to recover. So the animals we see and we're looking at motor function animals, yeah... they're harder to measure other things. We look at motor function, so the animals are bascially half paralyzed when we give them the stroke. There's a small degree just like in humans of recovery, in the natural animals when we give them vehicle, so we give them... we still inject them, but without the drug in the liquid. And then we give them drug and it's a massively improved recovery. And in some cases, you can't even differentiate from normal function. So we see this very fast within two weeks in these animals. We repeated these studies and study after study, we see... a really good news is... what you don't want is there's only this one magical dose for this and it only works here. We see it across a broad range of doses, we see it starting at different time windows, right? And we see it in both ischemic stroke, clots and bleeds. Because it's not working on breaking down a clot. It's working on improving the vasculature. So it's working on helping the brain grow new vasculature to effectively heal itself.

So it's like making the vasculature that was only like wrapping around the Earth once... we're making it starting to wrap around the Earth more times, going back to an earlier analogy, but how much we have?

You got it. Exactly.

That's super awesome. And reassuring that we're seeing this in the mice model. But then, I'm sure you get asked this a lot is: okay, when might we be able to see this being demonstrated in a human? And then the bigger question is, when might this be more widely available? Is this something that could be a treatment for my mother or for me? Or do I have to wait to my kids are of age before this would be a treatment?

That's a great question. But I want to answer your prior question first, which is, so if this translates, the effects that we see in animals, if these translate into humans, this would clearly be reimbursable, every person who's had a stroke would get this covered by insurance, right? So now, how do you get it there? So what are the steps from where we are, how long is it going to take? Now unfortunately, it is a long and expensive process to get through clinical trials. So the clinical trials themselves are, if we're lucky, and do everything as well as we can, about six years long, more likely, eight years, possibly ten years. And we're still about a year and a half from starting our first clinical trial. So right now our steps as a company. So I mentioned we've developed this manufacturing process to make the protein; we need to scale that. We're now making the protein research scale at our lab and our bench.

So the artisanal manufacturing of it.

You got it?

So like a homebrew.

Yeah. So we need to move that to big commercial scale and in an audited process. And then we take that drug, and we have to repeat our safety studies with that drug. And then we can go into humans. So those are the steps that we're in the process of doing right now.

I want to go back to kind of your life experiences just real quick, because we've had, now we've had three biotech startup CEOs, three of them actually had a successful exit in a different industry, before getting tired of spending their time on the beach and deciding, alright, we need to go do the next big thing and change the world. So it's interesting that your story was, you know, somewhat along those lines. I mean, when you had your first exit, did you plan on an early retirement and get restless? Or did you always knew you were just waiting for the next thing?

I don't think that I'm ever gonna like retire and sit on a beach? I can't sit on a beach. Like, I go to a beach and I go kiteboarding or swimming. Now, I do like to enjoy myself. Right? So I like to have the work-life balance. So even now today, like when I ran my first startup at the beginning, I was just working... like I was trained from being... you know, the training you have as a doctor... you're working.... a lot of times you don't sleep at night, you just work all night long. And I started to put my software team to that pace and they're like, Mark, you're gonna kill us. I mean, we could do this maybe every once in a while as a sprint. We can't live like this. Like, you know, you're right. But I still kind of drove myself like that. But so after I saw sold my company, then I sold it. And I worked for the acquirer for a little bit. Now I had a work-life balance. And so I kind of learned that and like, you know what, anything I do, I'm going to have a good work-life balance, I'm going to work hard, but I'm not going to work 100 hours, right? I work 60 hours. And then also I want to incorporate like, the other thing for me is it's not like... life in harmony, life in flow, is when you can't differentiate your work from your play, you get so much pleasure out of your work. But you can't differentiate. I love what I do. I love learning about what I do. Working with our scientists. Now, the actual lab work: there's a certain people that are super good at that. And I'm not. I recognize I'm not. I don't have the patience for that, itself. But I love to think about the experimental designs, I love to talk about the results and like, oh, wow, that's interesting. And, you know, just follow the science. And I love to think about the commercial path. I love to think about, how do I translate all this incredible science in a way that that investors can understand, in a way that the public can understand? And, you know, strategy, how do you build a business? All this stuff I love doing like, it's, again, it's as cool to me as going kiteboarding like to do this stuff. Right? So that's really key. And I expect to continue to do that forever. Right? I never want to be not doing that.

So once you solved aging, what do you think's going to be your next challenge?

Well, I think that solving aging is a long term challenge. So I don't think we're gonna get there overnight with a silver bullet. So I do think... all the evidence is, from our initial hypothesis, that GDF11 plays this important role in the aging process, like we are ticking off the risk, we are validating this hypothesis, and coming up with the right ways to bring this to market and getting investors support, so we're making that work. It didn't have to work as it's working today. So it's really, really cool that it is. But even we get GDF11 to the market, and we start to even use it to prevent disease, nobody thinks that this one protein replenishing is going to make us live forever. So I don't think that it's a silver bullet like that, so I think we'll continue to work on ways to tick away. It's like cancer, right? We've been working on cancer and had a huge push of money and spending from the time of Nixon initially started. Right. And now we're at a point where we have really effective treatments for a number of different types of cancers. But we haven't eradicated from the planet yet. Ultimately, we will. I think we will. But it just takes a long time. Now we need to have that same push on aging. And this approach of aging, instead of like... the NIH has this all wrong. You know, the NIH has all this money going toward Alzheimer's. So they've a National Institute of Aging, and guess where like 80-90% of the money goes to... Alzheimer's! Um, it's possible. It's possible that...

By then, it's already too late, right?

Exactly. Billions and billions have been spent and nothing's worked. So you know, that instead I really hope that they start to shift their spending toward companies like Elevian and approaches like it... not just companies, but approaches that target more generally the aging process and can prevent Alzheimer's and many other different diseases. And so like GDF11 itself, we've done some studies and we show some effects in Alzheimer's. And there are other people that have published some results. But we're not going there. Because again, I think it may be intractable.

For all our listeners, or viewers who are like, well, I heard about the anti-aging, age-defying creams and lotions have been around forever. Like why don't I just lather that on. I see Jennifer Aniston always promoting her creams and things. So this is really something that's important to disambiguate is that it's, well once the skin is an organ and there are lotions and creams and things that helped make that look less like a crocodile. But that with what Elevian and it's sort of a cohort of approaches are going for is sort of from the inside out, that it's going to be able to help make you have... not just look like you have like shiny smooth skin or whatever you want, but being able to really feel like you're as you are in your brain. Like where I hear people who are getting up into their more senior years who are saying like, I feel like mentally I'm like 30, like I've always been, but my body just feels like it's not keeping up. And so Elevian would be able to help with that, right? To move that goalpost a little farther out in a good way.

That's right. That's right. So you know, the term anti-aging is typically applied to that industry that is targeting your skin, most of them not being the part of the medical industry. You know, you buy a lot of that over the counter, and it works, right? Takes out wrinkles, makes your skin look better. But it's only your skin, the rest of your body and your internals continue to age. Now GDF11, interestingly, also works on your skin. So Avon did a collaboration with one of our scientific cofounders, Lee Rubin and published this and showed that GDF11 injected systemically has about the equivalent effect on the skin as the best skin products, the best positive control out there ,we say, which is the best existing gold standard product. So really pretty incredible. That's a nice little side effect. And we're not going after.... since there's good skin products, we're not trying to come up with a pharmaceutical product that requires prescription that would affect your skin. But it's a nice, as we say, an off-target effect. You know, if you treat stroke, and your skin looks better, that's not too bad.

One sort of like five year old kind of question is we mentioned like GDF11, GDF8, what does this look like? Because I'm kind of picturing like a primordial goo that's in a petri dish, and that that's what we want inject. What does this look like at the bench when you're making it?

Well you can't see it. It's a teeny, teeny little protein. You can see it when it aggregates together. So, if you put it in too high of pH, then it starts to clump up together, and you can see it as cloudiness. But you know, a part of the trick of you formulate in such a way that it doesn't clump up. That's part of the technology, and part of the IP that we've created.

So it's kind of like a sea monkey.

Yeah, now what you do see is... so we have... to see things that are molecular level, what we do is we tag them in such a way that we can then read them. So we tag them in some way with fluorescent signaling a lot of times. So we develop these bioactivity assays, where we give GDF11 and we see when it binds receptor, because it turns on this fluorescent tag, and then we can measure the light emitted. So that's part of our quality control of the protein is to see if it actually if the cell actually turns on that light. That approach of lighting things up with fluorescence is a very common approach to measure. You have to build those assays, right. But it's very common approach of how you measure things, that are microscopic.

But we also might have some collaborations, you know, future collaborations between some of our Tough Tech teams. So we have Nautilus Biotech, that is doing proteomics, so they've got a device and some AI techniques to actually dig into the structure of different proteins. And we recently talked to New Equilibrium Bioscience and they're doing a lot of modeling and AI to kind of investigate different proteins that could be useful so maybe everyone will get linked up and help each other out. It's a fascinating industry.

We have a ton of collaborators, and we're looking for more collaborators and now we're starting to manufacture a surplus of this protein, which is really expensive. So before we started to manufacture, you could buy it from research suppliers that are making every protein known to man. But it's super expensive. And so it prohibits people from studying, just the expensive patents. So now we're making a lot and so we're looking for collaborators, you want to study it and so you know this particular disease model, you want to study it and we can partner up together and look at different diseases. So really just excited to share and explore and collaborate.

And I think that brings us to the time on the episode. We did want to give you one last opportunity to give words of advice or pitch anything for your company, if you're looking for new scientists or something, the time's yours.

Sure, so I have a couple of messages that I want to convey. I want to come back to this point that aging is malleable, that your destiny in terms of your health span, so your quality-adjusted years of life is under your control. You have to do the right things, it starts with your mindset. I think it's fundamentally the most important thing. So your mindset, your thoughts create emotions, which create these proteins in your body that either can create chronic stress and age you or create good feelings that can help to heal you. And the right mindset allows you to do the other correct things: exercise, nutrition, go to sleep at the same time and wake up, have good routines, right? So super important to understand. And then number two, understanding that aging is malleable, that this approach to therapeutically target aging makes a lot of sense. And it's worthy of investment, right of our tax dollars going into it of investment dollars going into and so... it's very expensive to bring a drug to clinic, so we're constantly raising money. So you know, if you guys are accredited investors, reach out to me. We have a lot of great investors and support, join the ride of the company, be a part of this, understand where it's going and so that's really the core message that I want to convey. And I want to thank you all very much for your interest in this topic.

Thank you so much for joining us for this episode. Forrest and I would appreciate if you checked out what Dr. Allen and his team are developing, and it would also be great if you'd liked, subscribed, or left a positive note about Tough Tech Today. Your feedback is important for us. Our next episode is the third in our series on biology. Until next time, stay tough.