The Pomp Podcast - #495 James Peyer on Longevity and Curing Cancer

Episode Date: February 18, 2021

James Peyer, PhD is the Founder and CEO of Cambrian Biopharma, a Distributed Drug Discovery Company developing therapeutics targeting the biology of aging. Cambrian builds, finances, and manages a pipeline of therapeutics. In this conversation, we discuss the nine hallmarks of aging, molecular damage, how to add healthy years to your life, prevention vs reversal of diseases, and distributed drug companies.  ======================= Exodus is an absolute game changer in the crypto wallet space, and we’ve teamed up to offer an exclusive discount for you, as listeners of the podcast. Sign up for Exodus today using my promo code http://exodus.com/pomp This is a no brainer for both newcomers and crypto heavyweights - go sign up today.  ======================= With over 5 Million users, Crypto.com is the easiest way to buy, and sell over 90 cryptocurrencies. Download the app at Crypto.com and get $25 with my code: POMP. When it’s time to spend your crypto, nothing beats the Crypto.com Visa Card, which pays you up to 8% back instantly, with no annual, or monthly fees to worry about! Get $25 when you download the Crypto.com App today using the code “POMP”  ======================= Download the top-rated DraftKings Sportsbook app NOW and use promo code POMP when you sign up to Hammer the Over on Sunday night’s basketball game when LA takes on Denver. For every ONE THOUSAND people that bet the over in Sunday’s game, the line will decrease by one point. Yes, this is your2 chance to improve the odds of the over hitting, so tell your friends and family, this is a team effort! Hammer the over and improve your odds of doubling your money. That’s promo code POMP.… for a limited time, only at DraftKings Sportsbook! =======================

what's up everyone this is anthony pompliano most of you know me as pomp you're listening to the pomp podcast simply the best podcast out there let's kick this thing off james pyre is the founder and ceo of cambrian biopharma a distributed drug discovery company developing therapeutics targeting the biology of aging cambrian builds finances and manages a pipeline of therapeutics. In this conversation, we discuss the nine hallmarks of aging, molecular damage, how to add healthy years to your life, prevention versus reversal of diseases, and distributed drug companies. I really enjoyed this conversation with James, and I hope you do as well. Before we get into the episode, though, I want to quickly talk about our

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All right, let's get into this episode with James. I hope you enjoy this one. Anthony Pompliano is a partner at Morgan Creek Digital. All opinions expressed by Pomp or his guests on this podcast are solely their opinions and do not reflect the opinions of Morgan Creek Digital or Morgan Creek Capital Management. You should not treat any opinion expressed by Pomp as a specific inducement to make a particular investment or follow a particular strategy, but only as an expression of his opinion. This podcast is for informational purposes only. All right, guys. Bang, bang. I've got a very special treat for you today. I've got James here. Thank you so much for doing this. Thanks for having me. This is going to be fun.

Absolutely. Let's just jump right into your background. We're going to talk about all kinds of crazy stuff today but uh just kind of give people context in terms of what you've done previously and kind of what got you into the longevity space absolutely so yeah james pyre um i started my career as a scientist so i did a phd um focused on the stem cells in the blood worked on leukemia worked on stem cell transplants then uh knew that i wanted to get into drug discovery um so switched um consulted for some big pharma companies for a while launched a vc fund which was the first vc fund to focus on longevity um or to build companies around around this longevity topic and then now for the last couple years we just came out of stealth a few days ago

um i i teamed up with a co-founder christian engermeyer to start this company called cambrian which is we call it a distributed drug discovery company or a disco focused on aging. I got into this space actually really early in my life when I was a teenager. My grandfather was dying of cancer and I was a hotshot, kind of arrogant, know-it-all and tried to learn whatever I could about his disease. And I came to this really depressing conclusion, which is that we were treating all the diseases of aging like cancer wrong, that we were waiting for these diseases to happen to us and only then trying to use medicines to unwind them. And that was fundamentally the wrong way to approach these diseases, that we should instead understand them, try to attack them

before they appear, and only then could we cure them. And so I've been spending my entire life chasing that idea. So let's get into a little bit, when we talk about disease, there's a lot of people who just say, hey, we get older. Of course, that happens to everyone. I think that the conversation is changing a little bit to this idea of aging is a disease. But I want to break down what exactly is happening as you age and why there's a growing portion of people who believe that we can actually treat that, prevent it, delay it, all these different aspects. And so first, let's maybe start with the nine hallmarks of aging. I know that you guys have done a ton of work of identifying these and explaining them and kind of elaborating on it. But what does it

mean when you talk about the nine hallmarks of aging? Yeah. So I think this is really the right place to start. So the nine hallmarks of aging are basically nine different types of molecular damage that build up in our bodies as we get older. And so, you know, we don't just, you don't just get cancer, right? The moment, you know, it doesn't just appear. It happens over a very long period of time where different aspects of our bodies are breaking down little by little. In the case of cancer, you have DNA mutations that accumulate one after the other, creating an evolutionarily selective pressure for some cells to out-compete others until you kind of, you know, run this cycle long enough that you have this uncontrolled tumor. But the damage that starts all of this

that are mutations in our DNA that happen randomly, even in our 20s and 30s that are constantly happening way before we get cancer. And there are nine of these types of damage that include chronic inflammation that happens just more and more as we get older, buildup of aggregates like the aggregates that cause Alzheimer's disease. But there are more than just amyloid and tau aggregates that are building up all the time. And the machinery that we have, the recycling mechanisms for chewing up those aggregates degrades over time as our cells and our tissues get older. And so there are this group of scientists in this emerging field called geroscience, right? The study of what makes us age have mapped out way more than nine particular

mechanisms, but they fall into these nine categories that we call the hallmarks of aging, which define the different types of damage. And what we've been able to do with those nine categories, which were only kind of distilled into a single thesis about seven years ago to 2013, 2014, what we've been able to do since then is you pick one of those types of damage and you tweak it, right? Either preventing it from building up or removing it from an already aged animal. And we see this amazing thing happen, which is you can take a mouse, for example, tweak one of these hallmarks of aging, and it just lives longer and healthier than it ever would in the past. So instead of living, you know, for a mouse, like two and a half years, it's living three or more

years instead. And instead of getting sick at two years, so that it dies at two and a half years, It's only getting sick at, you know, two and a half or close to three years. And that change is fundamentally what gets me excited about this space. Because that would mean, you know, if we could translate that into human biology, like it would be way better than like a magical cure for cancer or something like that. As far as like the number of extra healthy years of life we could distribute to the population. We can talk about that a little bit more. Yeah. So what I want to talk about is just at a very high level, when you talk about molecular damage, just explain that very quickly for people, because I think that that's somewhat table stakes in the scientific community and the longevity community, but there's a lot of people who won't understand what that actually means. Sure. So we're all just collections of cells. Cells are bags of fat containing water, protein, DNA, and other molecules, right?

And the molecules that make up our bodies are changing dynamically all the time. And so we're constantly being assaulted with, you know, UV rays from the sun or crap that we put into our bodies that we eat, or even just like random changes as we get older, where like the bags that are our bodies are not designed to live or to function forever in an unchanging state. And as these different environmental and natural impacts affect our cells and our tissues, things change over time. So let me try to do a better job of explaining what molecularly we mean here, right? And I think that would actually help to maybe touch on the nine hallmarks of aging really, really briefly, just so we know what we're talking about. at Cambrian, we separate these into three categories of changes that we think of as like changes inside the cell. So I already mentioned in cancer, we have mutations to the DNA, but also as our cells divide the ends of our chromosomes called the telomeres, which

you and some of the listeners may have heard of, they get shorter every time a cell divides, right? And so that's another kind of molecular damage in a way, because our cells are becoming less able to do more divisions every time they divide. So then there's also inside the cell a loss of what's called epigenetic information. So this is some of the markers on top of the DNA that change which genes are expressed in which cells at which time. And the more information is lost there, the less well the cells perform the job that they're supposed to do. Then we have a second category of like whole cellular level dysfunction. So cells themselves can become old and dysfunctional. We call this cellular senescence, where they were supposed to die, but actually fail to do so. And they operate, they start operating in this different program that spews inflammatory cytokines. So basically inflammatory molecules out into the environment. And they can cause quite a lot of havoc, even if you only have one out of every hundred cells being in this senescent state.

Um, and similarly, another kind of like whole cellular level dysfunction, we have the power plants in our cells, the mitochondria that make energy, those start working less and less well over time as our bodies get older. And so those might, the, the, the power plants can become dysfunctional and there's a few different types of molecular damage that can make mitochondria not work well. So this is kind of a second theme of cellular level dysfunctions. And then the final theme is tissue level dysfunctions. So we have stem cells in our tissues that are trying to regenerate, especially when we're young, regenerate injured organs. Our liver is super good at regenerating. For example, our bone marrow, our immune systems are super good at

regenerating. But as we get older, the stem cells that are fueling all of that, they get worn out over time and and they are able to regenerate less and less well um another one that's in this kind of like organismal level or you know whole tissue level is uh the topic of chronic inflammation um so long-term chronic inflammation does horrible things to a tissue it turns it from being very flexible and regenerative to what we call fibrotic. Basically, we become more and more like a scar as we get older, not just on our skin, but in all of our tissues. And so we're spending a lot of time thinking about this increased scarification that happens not just in our skin, but in our liver, in our kidneys, our hearts, our lungs as we get older and what

molecular tools we could use to reverse some of that, to make our tissues more flexible, more able to regenerate instead of hardening up. So that gets into a little bit of scientific detail, but hopefully gives a sense of like the types of damage that we're thinking about in this geroscience field. Yeah. And what's so interesting about this, I think that there's a sequence that people may or may not understand, which is that a lot of this molecular damage happens in what most would consider your healthy years, and then it actually shows up, you know, 10, 20, 30 years later. And so maybe talk through a little bit of like that sequencing around the when the damage happens, but then also like when it shows up and how that's

not actually happening simultaneously, in most cases. Exactly. I think that that's the key to understanding this whole field is that when, like, when someone is diagnosed with a disease like alzheimer's let's say that that alzheimer's diagnosis is it's like not the start of the disease it's one inflection point of a really long process that's been happening in that person um and and so what this field of aging biology or geroscience is helping people think about is that if we can understand all of the damage that's building up 10 years, 20 years, 30 years before what we call a phenotypic effect, right? So before someone is actually losing their memory or unable to walk or unable to eat or something like that that can happen to a patient with

Alzheimer's or in the case of cancer before you see a big tumor that's metastasizing. If we can understand that damage in the 10, 20, 30 years leading up to it, measure that damage and then use a biomedical intervention to either stop it or reverse it before we get a disease, then it's a much easier problem to solve than it is to try to react to a disease once it's already happened. And I actually have like a kind of nerdy scientific example that I like to use to think about this. So as a VC in bio, we invest in companies like cancer companies, for example right and one of the ways that drugs are tested in cancer companies is you give a mouse a tumor and then try your experimental treatment to see if the mouse can clear out its tumor right

and so it's you know pretty standard practice you're giving mice mice cancer curing the cancer and then you can like use that as a justification for trying it in humans later but as a vc one thing that we all do is we make sure in these mouse models of cancer that before we try our experimental treatments that the mouse has been injected with a tumor and the tumor has like grown big and scary enough that, you know, it's going to be hard for the treatment to clear out that tumor. Because if you treat the mouse too early when the cancer is just developing, we know that almost every anti-cancer treatment works really, really well. And you get like 100% cure rates, but that doesn't then translate into good results for patients, human patients that have

advanced tumors. And so it's this fascinating situation to me, and I guess a bit nerdy here, that we're turning the thinking on its head, where a lot of the VC and investment thesis in how we think about mouse models has been, how do we make sure we can replicate advanced stage human disease in the mice so that the mice that we're treating look more like the patients that we're treating? That's one way to think about this investment thesis. But this geroscience hypothesis almost turns it on its head, which is like, if we know a way that we can cure cancer almost every single time, why don't we start thinking about how we treat our human patients in the way that works almost every time in our mouse models.

And I think that that kind of flipping of the script is one of the powerful ideas behind this. One of the most fascinating things to me in all of this was when I learned about Brett Weinstein and kind of a lot of the controversy around the mice and the shortening of telomeres and kind of how a bunch of the mice came from the same place. And without getting super into detail

about that whole situation, you can go Google it. but it really just showed that like, hey, this is still science. And if you don't get kind of a bunch of stuff right, the conclusion can be inaccurate. And so this whole idea of like, what's the framework you use, right? Do you try to replicate the human disease in a mouse and then go ahead and address it? Or do we just figure out how do we cure mice? And then should we bring that to the humans is a fascinating way to kind of look at it. What I want to talk about next is this idea of healthy years. And Christian and I have talked a ton about this. And I think that a lot of people, when they think of longevity, they just simply say, okay, well, if the average human lifespan

is 77, 78 years, whatever it is now, how do we get that to 80? And then how do we get that to 85, 90, 100? And that makes sense because you just want to live more years. But actually, there's a difference between living for an extra 20 years at the healthy or unhealthy state of a 90-year-old versus living an extra 20 healthy years that might actually be more like what you feel and how you operate at 45, not actually feeling the effects of older age until maybe you're 65, and then being able to kind of capture those healthy years. So talk a little bit just how you think about healthy years versus maybe non-healthy years and why it's so important to focus on the former rather than the latter. Yeah. And I think you nailed our thesis

right off the bat there, which is if we only extend the unhealthy period at the end of life, we're doing a disservice rather than a service to the population at large. So anything that's worth doing has to extend the number of healthy years. And that's our ultimate readout. So whenever we talk about it, we actually avoid the term lifespan altogether, unless it has the term healthy put before it. Or, you know, I think the most popular term among people in our field is actually to talk about it in terms of health span, as one word, or my favorite, again, kind of wonky term, which is qualities, the quality adjusted life years, where this is kind of how insurance companies think about quantifying human life happiness, that cross product.

And so the positive news here is what we've seen both in humans as our lifespans have risen from 35 at 120 years ago at the start of the 1900s to close to 80 now. Um, we've seen as human lifespan has gone up, human healthy lifespan has also gone up dramatically, obviously, because we're dying of these chronic and horrible diseases like cancer and cardiovascular disease and Alzheimer's. Now there is a tail period of unhealthiness that most of us experience at the end of our lives. Um, but, but in humans, we have been able to extend that healthy lifespan portion out

very significantly. And in mice and other model organisms that we've been able to use drug interventions to extend the healthy lifespan of those animals, you're basically never able to increase just the unhealthy portion of life. Because one of the conclusions, or I guess the assumptions from this damage theory of aging, is that once you've got a critical amount of damage that's going to send you kind of tumbling downhill, which will ultimately result in the organism's death, you can't undo that hill from that inflection point. So it's a much simpler idea to extend the time before you reach that turning point that starts you tumbling downhill. And so when I talked a little bit about the mouse life extension earlier, the way that essentially all of these treatments work is you extend that healthy period, and then the period of decline that ultimately ends in the death of the organism actually stays fairly constant. Because once you've reached that big threshold, then there's almost just nothing you can do, and it's a matter of time. Got it. Let's think through a little bit.

there's multiple, I think, schools of thought around prevention, reversal, and then maybe I'll just call it treatment, right? Like you're already kind of old and we're just going to make it as painless as possible and as enjoyable as possible. How do you look at those three buckets, right? Kind of prevention, reversal, or treatment? And is one better than the other? Is it kind of, no, we need to do all three at the same time to get the best outcome? Just what's the framework to use to think through that? It's a really good question that we could probably spend an hour talking about to give justice. But I will put it in kind of almost like an easiest to hardest term, sort of terms, where prevention is always scientifically the easiest thing to do.

But from a treatment perspective, both getting drugs approved through the regulatory system, like the FDA, but also in choosing which patients to treat, prevention is the hardest. So scientifically easiest, practically the most difficult. Treatment is scientifically, in some ways, the hardest. It's much harder to unwind these diseases after they've already appeared. But from a regulatory perspective, it's much easier because that's how our healthcare system is set up today. It's set up to be reactive, waiting for someone to get sick, and then now we know we can approve a drug to see if it can shrink your cancer or something like this.

But the sad reality is that we haven't developed enough drugs that can work that well in a lot of people. So if you look at the past 75 drugs that have been approved to treat cancer over the last 10 years, the average amount of extra time a cancer patient gets when they go on to one of these drugs is about two and a half months of extra life, right? Not a huge bonus for the fact that we're spending hundreds of billions of dollars a year conducting clinical trials and cancer therapy. And so it's not zero progress at all. And there's tons of good discoveries being made, but it's just such a scientifically harder problem than prevention. um and then the the final one around reversal like this is in some ways you know in some contexts you could think of reversal as treatment um and so let's say in the context of cancer reversal probably isn't an option uh right like once you've got a cancer you can't just like reverse the damage that caused the cancer from being there because if you would

it would just be a treatment for the cancer. So reversal is really something that you have to think about in a tissue specific or a disease specific sort of way, where it's like, before you have something that's going to definitely kill you, but when there's still time to undo the damage. So it kind of sits somewhere in between treatment and prevention. And so I'll give like a couple of examples here. Like, let's say I'm getting into my 70s or 80s, and my muscles are becoming way weaker, right? And my bones are becoming way weaker. So, this is now already happening to me. I'm getting less robust. And we could try to use a therapy to strengthen my muscles, to strengthen the structure of my bones so that I don't continue to get more frail,

Kind of like resetting me back to the point where I was in my 40s or something along those lines. From a scientific point of view, that's harder than the prevention aspect, but not as hard as trying to put me back together once I've had a fall in my late 80s and my hip is shattered. and then from a regulatory perspective it actually looks a lot like the prevention part because again when we're weakening but we haven't been diagnosed with a major disease the FDA kind of looks at all of that in the same in the same way and so a lot of what we focus on is this reversal and prevention ideas and we kind of bundle those together into one way of thinking about like medicines that we can use before a true disease happens. That's either preventing damage from building up or reversing it once it's there. That's the same category for us.

Everything you're talking about is incredibly complex. And there's a lot of really, really smart people working on it. And there's a lot of people who are doing it for what I'll call kind of the right reasons in terms of they want to make a difference. They want to increase life. They want to have people live healthier lives. There's also people who are doing it from a for-profit kind of perspective. And profit is kind of the number one thing that they're focused on. I don't think, neither do I think that you nor Christian believe that those two things have to be mutually exclusive.

Like I actually think that there's a world here where you could take a capitalistic perspective and the capitalism or the pursuit of profits actually drives revenue, which then can be reinvested to further kind of the health impact and probably is the most sustainable model that we've seen so far. But you guys have a spin or kind of a variation of how to finance a lot of this work. And one of the things that I think is fascinating to me is that most of the people in this space come from the science side, right? They look at it from a very scientific perspective and there's a constant cat and mouse game. How do I get funding? How do I get a grant? How do I get some level of financial kind of backing so that I can actually spend time both mentally and

kind of with resources to actually make an impact. You guys are looking at this in kind of this drug discovery company model. So maybe talk a little bit about this DISCO, D-I-S-C-O that you guys talk about a lot, and then talk through what are the variations or changes that you think of from financing perspective that should lead to kind of a better outcome and a more kind of sustainable platform yeah so there's there's a lot of threads that i can pick up from there um but but maybe before we jump deep into the the disco model i want to just emphasize one of the pieces that you're talking about around like doing this for the right reasons kind of how drug discovery in general works um because there are you know a few different ways that people have been doing this

And I think that, as you articulated, the biggest problem for folks trying to think about developing a drug for anything is the funding question, that a lot of drugs that start clinical trials ultimately end up failing, and that those failures are usually very expensive to figure out because it takes, you know, tens or even hundreds of millions of dollars to run a phase one, then a phase two, and then a phase three clinical trial. We've seen that with the COVID vaccines that everyone has paid attention to. These are incredibly expensive human experiments to run. And so one of the cool things about the pharmaceutical industry as it exists in the free market for all of its flaws, and it has many, is that once you start going down a path that's going to cost $100 million plus to get you from an idea stage to an approved drug, that at the end of that, it really never makes sense to start to say like, oh, well, this is just going to be for one small group of people, right? That you actually want to get those drugs to as many people as possible at the right price.

And so there's this old joke in the pharma industry that it takes a billion dollars to make your first pill, and it takes a fraction of a penny to make your second one. And what that means for supply and demand curves is that when a medicine is applicable to a large fraction of the population, it drives the price way, way, way down. And so the closest thing that exists today to what we would think of as one of these geroprotective or age-slowing drugs is actually the drug Lipitor. So these statins that reduce cholesterol, that's the closest equivalent to what's been on the market so far.

And those drugs at their highest point never cost more than $4 or $5 a day, right? And it was the most profitable drug of all time because it reached so many people. And so when we think about doing this for the right reasons and kind of like mixing and matching of the profit motive with drug development, I think there is actually kind of a positive story there. So I just wanted to pick up on that thread. The second piece that you talked about as it relates to how we fund drug development today, we've actually been in this really interesting, quiet revolution where two things are changing a lot in science. And the first part is that universities and academic research scientists, because of all

of the genetic sequencing tools and like advances in chemistry, advances in genetics that have been happening. So you can do so much more now in a university lab than you could 20 or 30 years ago as far as making a drug. And so almost all, like the majority of new drugs are actually discovered at universities, spun out into biotech companies, and then are eventually acquired by big pharmaceutical companies that do the late stage clinical trials. Because this is working so well. On the flip side, the big pharma companies are actually powering down their R&D and relying more and more on gobbling up through M&A these small research companies, right? And so the intersection of those two things means that there's tons of good ideas inside of academia

that need to do the research and development work to prove to a big pharma player that their idea is worth a damn. And so they're constantly fighting for funding. And so the VCs, the funders have kind of become the gatekeepers in this. And you have this really kind of messy mixture of like CEOs coming into a biotech company, pitching a VC to try to get funding, and then getting a little bit of data, pitching more VCs, bringing more in until you can kind of like finally roll a big enough snowball to get absorbed by a pharma company. But it's really messy. It involves a lot of hype generation and a lot of who you know sort of conversations. And ultimately, what we've seen is that it can get disconnected from the value of the underlying science. And so when

Christian and I came into this field, what we wanted to do was build an organization that could have this scale to take a lot of different shots on goal so that some of them would ultimately succeed. And then at the individual asset development level, make our decisions exclusively based on the quality of the science, not on how hyped it was or what the last valuation was or who had invested before. And so with Cambria, we've been able to absorb almost 15 different projects that started at universities into our umbrella. And now we can continue to resource the ones that are working with more and more money to kind of get them into clinical trials. And if an idea fails, like that's a tough message to deliver to that team. But it's better for us

as the ultimate, like the organization that's footing the bill to make that decision early, instead of trying to pull more and more capital and like hype it up and hype it up, try to get it out the door and then have it ultimately fall on its face. And so that's a bit of a lecture on this. And we can go deeper or stay at a higher level as how this model works. But changing those incentives around so that I can talk to my ultimate investors and not have to sell them a bill of goods around how this one technology is going to change the world, but instead say, hey, look, we have this thesis around how we're going to create this new category of preventative or proactive medicines targeting

the hallmarks of aging. And if you believe that this hypothesis has merit to it, we're going to take enough shots on goal to get one, two, three, four things working. And we don't need every single project to ultimately be the golden goose. I think that's a very powerful idea. Absolutely. And so you guys recently came out of stealth. You've been working on this for, I think, about two years or so. What can you share in terms of who some of the investors are and kind of how you guys have been funded to date?

Yeah, so Cambrian is a biotech company, not a VC fund, right? So we actually have attracted investors that are traditional company investors. Started this together with Christian Angermeyer, who runs a Pyron investment group, who's also behind a few other really interesting projects, including one called Atai that is commercializing all of the psychedelics for use in mental health disorders and actually running clinical trials in those. So Christian is the biggest single investor in Cambrian. But then we've also attracted a really, really good group of other folks. I can't talk about all of them, but among them are Future Ventures, which is Steve Jurvetson and Mariana Sayenko's fund. Steve was one of the early

investors and on the board of Tesla and SpaceX. And they are just really far thinkers about what the future is going to look like, have been huge supporters. Mike Novogratz, who is really big in the crypto space, as well as doing a ton of other smart investments, also involved in the psychedelics work. Brent Saunders, who's the former CEO of Allergan, which was acquired for 50 plus billion by AbbVie, is really interested in this space. And then a biotech specific VC based out of Baltimore called Catalio also participated with us. So we've got this kind of like cool group of eminent tech investors, entrepreneurs, some folks from the crypto world, kind of like all coming together to, to support this mission for Cambrian. Um, and we've raised 60 million so far. Um, but

I've, I can say kind of like on this, not off the record, but like not on paper sort of format that, that I've had the, uh, the luxury of being able to turn down about three times as much money as we've accepted, um, which is a really cool place to be. Absolutely. And so part of this is obviously financing is an important part of the drug development and kind of distribution. And you've got a recent announcement, Sensei, and there's been a kind of a public market angle to this. So maybe talk a little bit about what exactly is Sensei? How does that fit into the Cambrian model? And then talk a little bit, whatever you can share in terms of the public market. Yeah, absolutely. So Sensei is a cancer

vaccines company that we started working with right when we started Cambrian. That was had already completed a phase one clinical trial and needed funding to start its phase two clinical trial. We partnered with them around that. Before touching a little bit on like what their product specifically does, I want to put it in the context of like why this fits in Cambrian. And so every program that we put together has to have two features. The first feature is that it has to target one of our hallmarks of aging. And if it targets one of the hallmarks of aging, we think it can ultimately be used as a preventative or either a prevention or reversal therapy somewhere down the line. But the key is somewhere down the line. It has to also, on the other hand,

be able to be built as a real biotech company that can deliver short to medium-term value for investors today within the existing regulatory environment. And so what got us excited about Sensei is that these guys had figured out how to make a cancer vaccine that you could give to patients with an already established cancer. They would kind of like do some sequencing, kind of measure some of the genes that were overexpressed in that tumor, make a cancer vaccine that could boost the person's immune system to attack the cancer cells, and it was working, right? And we don't have to go too much into the specific details, but basically, at the, you know, not the 30,000-foot level, but at the 1,000-foot level, in order to turn your

immune system on to attack cancer cells, you need to trick it into thinking that the cancer cells are virally infected. And so what these guys have done is they've taken a hollowed out virus that normally infects bacteria, doesn't affect human cells, and layered cancer proteins on top of it, injected it into a person. That person's immune system noms on that bacterial virus with the cancer proteins, first realizes, oh, hey, I've been like, it looks like there's a viral infection here. What should we respond to? And as it chops up all of the different pieces, It shows the immune system all of these cancer proteins, which then as the immune system starts to look around the body for like where these quote unquote virally infected cells are, it finds all the tumor cells. And that is kind of like something that people in the cancer immunotherapy field have been trying to do for 15 years.

And I haven't seen done as successfully until I met Sensei and discovered their platform. So that's kind of like how this works. But the really cool thing about this is in addition to treating people with stage four metastatic cancer, people who have no other options left, which is the people that Sensei has been treating right now and actually been able to help a substantial fraction of them, we think. in addition to that the platform has this really cool potential which is i don't know uh how much you and your listeners have paid attention to some of this stuff like there's this thing called a liquid biopsy um that's been developed just in the last couple of years which is like before you could even detect a tumor in your body you can start detecting like single cell single tumor cells circulating in the blood. And people have been able to pick up, oh, can we use advanced

sequencing techniques to find those tumor cells in the blood? And so in the longer term, we could imagine using this vaccine technology not just to treat people with no hope left, but to actually go in for regular checkups to see if there's any little bits of tumor cells in our body, vaccinating ourselves there before we even detect a tumor to prevent a tumor from happening. And then even in the long term, to use a technology like this the same way that we have HPV vaccines to prevent cervical cancer. Why couldn't you do this with other proteins to prevent lots of different types of cancers? It is very theoretically possible. And it's just a matter of building a platform that's both powerful enough and we think safe enough to justify doing that. And so that's where Sensei's long-term vision is. So that's, yeah, a little bit of an overview there of what got us excited about it. And talk a little bit about the public market aspect to it and why that's so important. Absolutely. So I talked a little bit already

about this kind of change in supply and demand, right? As university spin-out programs and these small biotech companies have become the wellspring from which all new medicines arise. And so the natural history of these companies goes in one of two different directions. Either they get gobbled up by a big pharma company, or they raise a bunch of funding and can kind of go it on their own, which usually involves a path into the public markets. And especially since COVID, with clinical trial data being on the front page of the New York Times and the Wall Street Journal every day, regular investors have started to get biotech so much more than they did in the past. And they're able to make informed decisions about what's working and what's not by looking at these clinical stage biotech companies. And so the IPO market for biotechs has exploded in the last couple of years. And so by bringing Sensei public, we can do a couple of things. Number one, we've been able to resource its clinical program so that it can get all the way into what's called a pivotal trial, right?

The trial that would give it the ability to approve a drug all on its own with the money that we raised from IPO investors, which often is just like a much higher number because once you're publicly traded, those investors aren't stuck with an asset that they don't want, right? They can sell off their shares later if they want to. And then the second benefit is that from Cambrian's perspective, it was really valuable for us to take this affiliate company of ours into the public markets, because it's kind of a validation for the way that we source, resource and build assets for our whole portfolio. So we were able

to take this company that had, you know, a little bit of data, but like, was right at a point where we could accelerate it dramatically by getting involved and generated nearly $600 million of value in a year and a half, a little bit more by pushing the gas on this one asset. And that value is now validated in the public markets because this is what people are freely trading the stock at. And that's a cool place to be. What do you think is the biggest lesson that you've learned over the last two years that would surprise people? The thing that you didn't expect or the thing that you didn't understand, but now you look back and you say, hey, here's the one learning that i've had that uh that would be just absolutely fascinating for people to

understand it's a really good question so i think the thing that's probably been most surprising to me throughout all of this is just how segmented and like and fractured the drug development ecosystem is where like the university professors really can't even speak the same language as the guys at the pharma companies who are ultimately developing drugs. And there's such a wide gap of data and understanding there that the folks who are coming into the middle to fill in this gap and actually build biotech companies that bridge this gap, it's way, way wider than I expected. And let's see if I can put this a little bit more concretely with a story here. So, and maybe I think it's useful to get into just like a little bit of the detail around this.

So, in order to get a drug approved, right, we talked about the three phases of clinical trials, but you also need to run all of these safety studies before you go into humans. And you have to validate that your drug is working in a million different ways. And when I was a PhD student working in the lab on mice, I didn't know and wasn't taught a single one of these things that had to be done, right? It was all about, could I generate some interesting discovery that I could publish about in a paper and get it in some journal and then move on to the next thing that would be the next discovery? And so now that I'm in the middle here, I see that there's about 500 experiments that need to be done from that first observation, which gets covered in the New York Times or whatever, like, oh, wow, we've made this huge discovery in mice.

There's about 500 things that then need to be done before someone at a pharma company will say, oh, yeah, it looks like you have something really interesting here. and figuring out what those 500 things are and building the right teams together of chemists and toxicologists and pharmacologists and patients and all of these other people that have to come together to think about how we formulate this drug and how we treat it and how we've tested it in all the right ways. It's such an operation. And so that's really why this process, this process is so expensive to go from university to, to ultimately getting a clinical ready product, but also why there's so much opportunity for companies to add a ton of value there, because there really is this, you know, really ripe landscape for, for picking great

ideas out of universities. And if you can be that translation engine, both translation in the literal sense of like being able to speak the language of the, of the folks who will ultimately be working with you, but also, you know, translating the discovery from the mouse stage to the human stage. It's just a great business that's adding a lot of value to the healthcare system. What's the biggest obstacle or challenge, right? Obviously, you're an optimistic person. So am I. So is Christian. I think that we generally have confidence, given who the backers are, what you guys are working on, that there's a lot of progress that'll be made here. But what would the argument of the detractors be or kind of what would be the identification of what those

obstacles and challenges are? So the biggest obstacle for us, like as I have my eye on the next decade of what we need to do, is establishing the regulatory paradigms to do prevention. When we value Cambrian right now, it's entirely based upon what we can do with the drugs that we have in the existing regulatory regime, which is essentially entirely reactive. And so the biggest challenges that we're thinking about now are how do we create the pile of data that we're going to need to convince the regulators that we have to work with? And to the FDA's credit, they've been open to having a conversation with us on this. But how do we create the pile of data that will allow us to say, hey, we have this drug, it works in cancer, or it works in some rare childhood disease, we want to see if it can slow down aging, and actually get them to say yes.

Because the way that the FDA works now is they would allow us to run a trial for slowing down aging or preventing multiple diseases. But if you and I started taking – you start taking the drug, I start taking the placebo right now, it'll take 30 or 40 years for us to know whether it worked or not. And even if you start treating people in their 60s, it would still take 10 or 15 years whether you would know if it was working or not. And so what we need to do is find the right tools, like what was done with cholesterol and these statin drugs, where people could come in and say, oh, you have high cholesterol. Let's put you on the drug. If your cholesterol goes down, we can actually approve the drug already, get it out into the market, get it into people's hands, but then follow up those patients for another 10 years to see if they actually get fewer strokes, actually get fewer heart attacks. we have to do the same sort of thing here, but that's just something that doesn't exist in the aging space yet. And we're going to be working very closely with the FDA, but also with other countries who are excited about exploring this kind of transformational technology. Before I go to kind of the rapid fire questions to wrap up, what's the message to people,

right? When they would think of Cambrian, when they think of the work that you're doing, what is that one thing that you want them to walk away for remembering or kind of what that mission is? So what I would say here is that the 1900s in medicine were defined by our conquest of our biggest human predators at the time, which were viral and bacterial diseases. And the combination of vaccines and antibiotics led us into a new era where now our biggest predators are age-related diseases, heart disease, cancer, Alzheimer's, et cetera. And the way that we conquered those diseases in the 20th century is going to be applicable to how we conquer the age-related diseases in the 21st century by understanding what causes them before people completely break

down from those diseases and devising treatments to, in some cases, proactively, and in some cases, at the very early stages of the disease, use the power of medicine to reverse them. And that's how, in this century, we're going to overcome today's biggest predators. It's a transition from being reactive to proactive that's going to happen at some point this decade, and we want to be on the cutting edge of eliciting that transition. That's fantastic. I always ask the same three questions to everyone before I let them go. And you get to ask me when to finish up. The first is, what is the most important book that you've ever read? So my pick one, probably Richard Dawkins, The Selfish Gene. I think that is for me,

I almost tell people it's the grounding of my philosophy in some ways to understand how the logic of evolution really works. And it's been incredibly impactful to me in thinking about this topic of aging and longevity. Because we have to remember that evolution isn't here to serve us, our bodies that are thinking and doing interesting things. We have all evolved to serve our genes on an individual level. And the fact that we are able to think about the universe and have fun conversations like this one is an evolutionary accident in a lot of ways. And so we have to take responsibility

if we want to preserve what we have here, kind of like taking that into our own hands. So I would say, yeah, Selfish Gene with an honorable mention to a book called The Origin of Wealth by Eric Beinhacker about how markets work with the same mathematical principles as the biology of evolution. I love that answer. Second question, a little bit more personal, brought to you by our friends over at Eight Sleep. They've got a thermoregulation bed that essentially allows for you to make it hotter or colder. I'm a really, really cold, get deep sleep and not feel much better. But I used to only sleep five or six hours. Now I sleep like eight or nine. What's your sleep routine and kind of how's that evolved over the years?

so i'm also sleep cold kind of guy sleep sleep cold but with like a nice blanket um and and i try to go to bed at the same time uh every single night i go for like seven and a half to eight hours of sleep for me although eight to nine i definitely like i think there's a lot of evidence that getting up into that range is way better for you um and yeah and then i guess without taking too much time, my sleep has evolved quite a lot over my life. When I was a grad student, I tried to, you know, before a lot of this sleep research was done, I was trying to actually shorten my sleeping hours to get more done in the lab. And I got so, I became such an asshole to people when my sleep was getting down to like five or six hours a day that I abandoned

it and spent two years during graduate school operating on a 28-hour circadian rhythm where I sleep for eight hours and then stay up for 20 and had six days in a week instead of seven so i was up at like really weird uh weird hours and you know that was great when i wasn't dating anybody and didn't really have any friends and just needed to be working in the lab uh but but now i'm trying to be a little bit more disciplined i love the uh the experimentation with sleep uh i've even tried I think they call it the everyman sleep schedule, which is like four hours of sleep, but split into an hour and a half and then a couple of 30-minute naps and the whole thing. Polyphasic sleep, I think, or something like that. The third question is more fun.

Aliens, are you a believer or a non-believer? I think that they have to be out there. The Drake equation is a very compelling reason to think that there are other life forms out there. It's just a matter of finding them. um i as a as a i don't know fun little experiment in college at some point a group of friends and i were thinking about alternative answers to the the fermi paradox right which comes out of the drake equation basically like do all evolved civilizations destroy themselves and i actually think that there is we don't have to get deep into this but i think that there is another

compelling explanation, which is because we've scanned so little of the sky for radio transmissions and these other things, there is a possibility that interstellar travel is just not often worth it, right? And that it's just so far and getting up to close to light speeds is so freaking hard that even very advanced species end up just hugely colonizing their own stellar neighborhoods. but not expanding like what Isaac Asimov once said, a ball of flesh expanding at the speed of light, that that just doesn't happen even for very advanced civilizations. So I'm a future optimist and an alien believer. I'm right there with you. They exist. We probably won't engage with them during our lifetime. Everything we look in the sky is a million years old. So we'll see.

Depends how long our lives are, I guess. very very true uh what's the one question you have for me to uh to wrap up so the question that i think i would ask you is as you think about the future of technology and you ask yourself like what are the most important changes that are going to happen to our civilization in the next 30, 40, 50 years? How do you rank the biggest impacts between automation of work, changes to the monetary system, climate change, as well as medical innovations? How do you think about ordering those things in terms of their impact? That's an impossible question. I don't think I could rank them in terms of magnitude of

significance. What I could say is, can I paint a picture of where I think the world's going? And of course, this gets labeled as the sci-fi Silicon Valley view of the future. But I like to joke all the time and say, well, technologists are right. And so I think that when you get bioengineered humans that are augmented by technology and computing power, either externally or internally, you get a ton of automation. Automation includes robotics, all the way down to literally streaming payments and digital assets like tokenized stocks, bonds, currencies, commodities, etc. You get a multi-planetary species that involves travel both domestically, internationally,

and multi-planetary. And then I think that what we're going to see is a drastic shift in the world to clean renewable energy and to electric vehicles. You just go down the line. All of this stuff that everyone's all excited about. Like, yeah, sure. It takes longer than we probably wanted to take, uh, but it's all going to happen. Um, and I think that the part that probably people are underestimating the most is how disruptive the disruption actually ends up being. And then also to, uh, we like to think about, you know, humans are geniuses. We're going to build all this stuff. Uh, but I actually think one of the craziest, uh, most exciting, um, innovations is going to be as we disrupt ourselves, right? Meaning that, uh, when you start thinking about,

longevity and people living longer, healthier lives. When you start to think about an augmented human, literally with the brain-computer interfaces, when you start to think about just what carrying a supercomputer in our pocket did, well, imagine when that is reduced friction and things like AirPods and what that has empowered. And so I think that it's just like, we're headed in the right direction. What's more important than the rest? It's all interconnected. right um and so i think that uh you know just people who are pessimists i'd like to say you know pessimists are losers um because they basically are betting against innovation they're betting against progress and i just tend to think that that's a really really bad

side of the trade to be on totally fair although as someone who has a few pessimists on my team i uh i love the counterbalancing effect no they're losers tell them if you're a pessimist you're a loser. Now, as much as I joke around about that, I think that, uh, you know, it really is you, yes, you do need some people with kind of rational belief. Uh, but I like to remind people that, uh, being rational doesn't mean you have to be a pessimist. Like you can be a rational optimist. Uh, if you kind of think like the Matt Ridley view of the world. I was going to say great, another great book that would be in my top five as far as recommendations. Yeah. And I, so I think Matt's just done a great job of kind of, you know, look, being rational is important.

Being an optimist is important, but the whole idea of being a pessimist, especially somebody who hangs their hat on being a pessimist or somebody who is, you know, I like to say a lot, a multi-time violator of pessimism. If you just, every time you see something, you're pessimistic, then, you know, it's just like, hey, man, jump over on the other side of the river. This side is a little bit more fun. And I think that rational optimism is the way to play the game. Awesome. Well, thanks for answering that, Pop. this is fun. Absolutely. Listen, James, thank you so much for doing this. I think people are really, really going to enjoy this. Obviously, I'm a huge fan of what you and Christian are

building here. And I think that longevity and a lot of the work is just super important to the human race, if you will. So thanks so much for all the hard work. And I appreciate you taking the time to have the conversation. We'll have to do it again in the future. Okay, fantastic. Look forward to that.