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Introduction
The current in-vogue thing to do for most longevity companies is to go for partial cellular reprogramming. As in, fill a cell with the necessary transcription factors for long enough to reduce epigenetic noise, restore mitochondrial dysfunction, and so on, but not long enough to completely change the cells identity. I’ve written about the promise there before, it’s definitely an exciting field.
So, when I first met Alan— who told me that he was a longevity researcher — last October, I naively assumed he was also on the reprogramming train. But he told me that he was investigating something a bit different. His pitch was that, instead of reprogramming the cell to fix age-related damage, what if you just protected it from (genetic) insult first? It’s an obvious idea, but one that I’d never really deeply considered. He sold me on the concept, and I was very curious to hear what he’d do next to push it forwards.
A few months after our chat, he spun up a company to pursue this line of thinking: Permanence Bio, which develops molecules that stabilize/protect the genome. They are just about eight months old, but there are already some exciting results coming out. I’m a sucker for people doing ‘contrarian research in consensus fields’, and I immediately knew I wanted to have Alan on the podcast. He graciously agreed and, during my trip to SF last month, we sat down and talked for a few hours.
In this episode, we talk about why DNA protection is so important, what indications is it useful for, how to mentally conceptualize the idea of a molecule ‘stabilizing’ a genome, what it was like to raise money for a company pursuing such an out-of-distribution thesis, and lots more.
Finally, Alan has a really great blog (something I mention in the video), and I wanted to attach a much longer article he’s written about the topic here.
Timestamps
[00:00:00] Teaser clip
[00:01:39] Introduction
[00:07:32] What is Permanence working on?
[00:11:48] What does DNA protection actually look like?
[00:27:12] Why is DNA protection not focused on as much?
[00:41:03] The utility of epigenetic clocks
[00:46:47] Do you need multimechanism approaches for longevity?
[00:51:58] Longevity outside of DNA protection
[00:55:57] What's going on inside of Permanence?
[01:05:54] How could Permanence fail?
[01:09:03] How do you stay optimistic?
[01:10:26] Why work on aging?
[01:15:26] What are you bearish on?
[01:19:12] Weirder types of aging beyond 110
[01:21:37] How did you decide on DNA protection and what else would you have done?
[01:25:27] What was it like raising money?
[01:31:48] What do you think of past cancer prevention trials?
[01:34:12] What does good wet-lab talent look like?
[01:37:02] What does your information diet look like?
[01:40:06] What's it like going from research to being a CEO?
[01:42:20] What happens after cancer prevention for Permanence?
Transcript
[00:00:00] Teaser clip
Alan: The fascinating thing is that a lot of organisms have mechanisms for preventing DNA damage. If you look at epigenetic clocks and how they measure aging, you can create an epigenetic clock that measures aging consistently across tissues and cell types. That was Steve Horvath's big finding in 2013. But if you take his clock and you apply it to sperm cells, it's always off. The sperm cells either don't seem to be aging or are aging 70% slower than every other cell type.
Abhi: This is something common with germline cells, right?
Alan: Yeah, exactly. Oocytes have similar things, although oocytes sort of cheat a little bit. I think there's a really cool paper that showed they just turn off part of the electron transport chain and so they kind of get into this hibernation stage. But sperm don't get to do that. They have to keep dividing, they have to stay alive, they have to stay metabolically active, and yet their genomes don't seem to age nearly as much as other cell types and tissues.
Escaping humans a little bit, there are these deep-sea bacteria that live in temperatures that are crazy high and very damaging to DNA. They create small molecules that protect the genome. Of course, there's the naked mole-rat story too, where they have these long lipids that protect DNA from damage. So it's not like an unthinkable idea. We're not building something that has never existed before. I think we are just taking the best parts of everything and seeing what we can translate into humans.
[00:01:39] Introduction
Abhi: Today, I'll be talking to Alan Tomusiak. He has a PhD in the Biology of Aging from the USC Buck Institute and is currently founder and CEO of Permanence Bio, a longevity startup developing genome-stabilizing therapeutics. Today, we'll be talking about DNA protection mechanisms, why preventing somatic mutations will be extremely important for longevity treatments, and much more. Welcome to the podcast, Alan.
Alan: Thank you. It's amazing to be here.
Abhi: So I think my first question is to set the broad picture of what we'll be talking about today. One of the theses for the field of longevity at large that you seem to be really interested in is that protecting the genome is of far higher importance than almost any intervention we can do. You have a really great blog post that walks through all the reasons you believe this, which I'll attach to the description of this video, but I'd love for you to just give that as a recapitulation.
Alan: Yeah. On a high level, there's no such thing as a more important or less important part of aging. I think almost any biologist who's working in the field of aging will tell you that all of the hallmarks of aging exist. I think the one dimension where genome stability has a certain degree of primacy isn't the question of what is the order of events. So you have different hallmarks of aging. You have extracellular matrix breakdown, mitochondrial breakdown, genome stability, and epigenetic alterations. But the question is more, it's not so much which of these is most important to aging, but which happens first. When you're 20 and 30, what are the first things that go wrong that lead to the other things? What is the sequential order here? In that case, it seems to me, from everything that I've seen, that genome stability stability seems to be a first thing that breaks down.
There are a few different areas from which you can look at this. For example, one Twitter thread that I want to write at some point is looking at every single hallmark of aging and how a genetic defect in each hallmark of aging looks like aging. For example, there are people out there who have a mutation in elastin. You can ask, if you have a mutation in elastin, how much does that look like aging? Of all the progeria, the accelerated aging disorders, every single one of them has a mutation in some DNA repair or some genomic maintenance gene. So I think that's how I think about it. I think about it less in terms of what is the most important, and more in terms of what is the causal relationship and what is the most causal upstream factor for aging.
Abhi: When I say important, I do mean that there's this base layer upon which all the other hallmarks of aging seem to derive some sort of causal link. If you have some somatic mutation, it causes this hallmark of aging. Is it correct to think of it that way, where somatic mutations genuinely are the cause for the six other hallmarks?
Alan: I'm very careful about saying genome instability. Somatic mutations on their own are a very controversial field. To what extent somatic mutations, specifically a change in the DNA code versus damage happening to DNA and then all the downstream effects of that. As an example, the somatic mutation field used to be one of the most dominant theories of aging. More recently, there's been a lot of work showing that there are individuals out there with certain mutations in a polymerase enzyme that leads to far higher rates of somatic mutations. They do not look like they have accelerated aging. Specifically, I think it's polymerase epsilon, and they have a 15 times higher basal somatic mutation rate in the colon. Sure enough, they get a lot of cancer, but they don't age faster.
There are still ways that you can think around this. I wouldn't say the somatic mutation theory of aging is dead necessarily. There are people who, you know, there are certain papers that are really compelling, showing there are selective mechanisms. In clonal hematopoiesis, you have that advantage of certain somatic mutations that then leads to aging-like phenotypes. There was recently a very fascinating paper that came out looking at chronic kidney disease, and in mice, they show that somatic mutations lead to defects in, I want to say the laminin gene, that then leads to dysfunctional senescent cells that look a lot like aging cells. But I think overall, the state of the evidence right now doesn't quite support the fact that somatic mutations are the cause of aging. I would say it's one factor upstream. The way that I think about it is that you have DNA damage that then leads to somatic mutations, which leads to cancer, but you have DNA damage that leads to other things, including epigenetic loss of information, and that is more concretely an aging phenotype.
Abhi: One potential mistake I've been making is I'm equating genome instability with somatic mutations. Is that incorrect? Is there actually some nuance there?
Alan: There is a lot of nuance. I'm thinking, is there a way to rephrase genome instability? Because a lot of people will say, "Oh, genome instability, mutations," but genome instability means a lot of things. Even on a meta-level, thinking about the 3D architecture of the DNA, that changes so much. Senescent cells will just throw out DNA from the nucleus into the cytosol. That is definitely genetic instability; that's not a mutation. It's not sure whether it's a controlled process or not, but telomere attrition is a form of genome instability in its own way. You can think about abasic sites, crosslinks, double-strand breaks. All of these things are derived from genome instability, but they're not mutations. So I would take it one step higher level than looking at mutations specifically.
I do care a lot about mutations. I think mutations are incredibly important from the point of view of preventing cancer. For what I'm working on right now, to some extent, mutations are a good enough proxy for genome instability because at the end of the day, genome instability and mutations both cause cancer very directly. Therefore, if you prevent one, you're fine. But I think if we're thinking on a bigger level in terms of aging, it's not quite somatic mutations. I think it's one step higher.
[00:07:32] What is Permanence working on?
Abhi: So the primary lens by which Permanence is working is trying to prevent somatic mutations from occurring in the first place?
Alan: I would say so. Of course, if you can prevent other types of DNA damage... as an example, one thing that comes from genome instability is inflammation. A cell picks up the fact that the genome is damaged and then it releases all sorts of different factors that lead to aging, but also cancer creation. I would say mutations are a very, very useful readout for us, specifically because it's also relatively easy to measure, and it's a binary thing. You have a mutation or you don't have a mutation. How many mutations do you have? It's relatively easy to interpret. If you protect the genome, then you shouldn't be getting as many mutations. But it's one of many things that we care about.
Abhi: For Permanence, you guys are building chemical treatments to prevent the genome from undergoing mutation. Could you walk me through the general lines of medicinal chemistry reasoning when developing these sorts of things? What are the primary directions you've historically seen in the field and where do you think the field is going?
Alan: That's a very good question. Where the field is going or has been going is finding ways to boost DNA repair. I think that's by far the most common thing. What people have looked at is they found all sorts of different natural compounds that improve DNA repair, and certain drugs that seem to increase the fidelity of DNA repair. I think that's been by far the most common way in which people have gone at the problem. We're doing things a little bit differently in that we're trying to actually prevent the damage. Instead of trying to improve repair, we're seeing if we can just stop the DNA from being damaged originally. In my mind, this is going down the key theme of how upstream can you go. The most upstream way of preventing genome instability is to prevent the damage in the first place.
Abhi: It feels like at least some of the sirtuin stuff was concerned with trying to boost natural DNA repair mechanisms. It doesn't seem like it actually worked out particularly well. One, is that correct? And two, why do you think it is the case that boosting existing DNA repair mechanisms hasn't empirically worked all that well, or have they actually worked well?
Alan: That's a very good question. There's a lot of interesting work in this area. The sirtuin story is definitely a compelling one. Most recently, the DREAM complex story out of Bjorn Schumacher's lab is very, very exciting. I think the biggest challenge for everyone building in that field is that DNA repair is so intrinsically tied to cell cycle state or cell cycle arrest. If a cell knows that it is about to divide a lot, then there are certain mechanisms that it turns on in terms of DNA repair and certain ways that it turns off. If you're boosting DNA repair a lot, that is a pretty clear signal to a cell that it should probably not be dividing because clearly there's damage happening.
The most direct example outside of the therapeutics realm is looking at p53 mice, where if you turn up p53 in mice, the idea was, "Oh, you prevent cancer because elephants have like seven copies or whatever." The result is that these mice are actually less healthy. They do get less cancer, but to my understanding, they have hematological deficiencies because the cells that should be dividing a lot are not dividing because they're recognizing, "Oh crap, there's a danger signal here." That's just across the board, no matter what DNA repair complex you look at, there is definitely some tie to cell cycle state and stress state. I think that's been the main reason why it's been tricky. I don't think that it's impossible. For example, a number of companies now are thinking, "Well, if you look at cells that are already out of the cell cycle, what if you specifically boost DNA repair in neurons? Would that work?" I think that's pretty interesting. We haven't seen a big success yet, but we very well could.
Abhi: You are going the opposite route, well not the opposite route, but the route of trying to prevent the mutations from happening in the first place rather than fix mutations that have already occurred.
Alan: Precisely.
[00:11:48] What does DNA protection actually look like?
Abhi: What's your mental model for thinking about what protection actually looks like?
Alan: The fascinating thing is that a lot of organisms have mechanisms for preventing DNA damage. If you look at epigenetic clocks and how they measure aging, you can create an epigenetic clock that measures aging consistently across tissues and cell types. That was Steve Horvath's big finding in 2013. But if you take his clock and you apply it to sperm cells, it's always off. The sperm cells either don't seem to be aging or are aging 70% slower than every other cell type.
Abhi: This is something common with germline cells, right?
Alan: Yeah, exactly. Oocytes have similar things, although oocytes sort of cheat a little bit. I think there's a really cool paper that showed they just turn off part of the electron transport chain and so they kind of get into this hibernation stage. But sperm don't get to do that. They have to keep dividing, they have to stay alive, they have to stay metabolically active, and yet their genomes don't seem to age nearly as much as other cell types and tissues.
Escaping humans a little bit, there are these deep-sea bacteria that live in temperatures that are crazy high and very damaging to DNA. They create small molecules that protect the genome. Of course, there's the naked mole-rat story too, where they have these long lipids that protect DNA from damage. So it's not like an unthinkable idea. We're not building something that has never existed before. I think we are just taking the best parts of everything and seeing what we can translate into humans.
Abhi: To create a mental model of the system, you have this nucleotide and phosphate backbone, and you have potentially reactive oxygen species kicking nucleotides out. You have the background radiation of the universe damaging the nucleotides. What are these phospholipids in naked mole-rats or any of these other DNA protection mechanisms physically doing to the DNA to prevent the damage from occurring in the first place?
Alan: It depends. There's a whole spectrum. Some of them don't interact with DNA at all. A lot of these compounds are just basically very powerful antioxidants that exist inside of a cell. The downside is that you need a very high concentration of them to do anything. You can imagine a cell is very big, and the amount of distance that a reactive oxygen species takes to actually hit the DNA is very, very tiny. So you have to be either very lucky or you have to have a very high concentration of antioxidant to see an effect. Or you have to localize it to the right place. Some compounds are very directly DNA binding, so they will change the 3D structure of the DNA in order to make it more resilient against damage. Or they'll compact it in some ways. Again, you kind of need high concentrations of the compound for that. But for a lot of these, especially bacteria, that's the interesting mechanism.
Abhi: Potentially a dumb question. If DNA is compacted into chromatin, is it more resistant to damage or less resistant to damage?
Alan: It's more resistant.
Abhi: Okay. I guess that makes some intuitive sense. On one hand, you could perhaps build better antioxidants. On the other hand, potentially you find some ways to stabilize the phosphate backbone, or interact with the chromatin in some way. What is the primary axis of variation and what is something you think is the most important thing to poke at?
Alan: This is a very complicated answer. I'm looking at it from both a top-down and a bottom-up angle. The top-down angle is not even thinking scientifically, but thinking about indications. For example, if you have a human disease, which human disease can you treat such that a genome-stabilizing compound will be effective? That's what landed me on cancer prevention. Cancer is a very debated topic to what extent genome stability is relevant to aging, of course. I'm on the side that it's very, very important. But for cancer, it is not disputed. Cancer seems to be largely driven by mutations and inflammation. If you could prevent mutations, then there's a lot of cancers that you can stop almost entirely. That became a bit of a no-brainer. Plus, the sheer impact that you could have on people by modulating and improving DNA repair for cancer prevention is huge. We're kind of driven by that as well.
Abhi: When you were developing DNA protection molecules, how are you actually testing that whatever protection you're conferring to the molecule actually works? Is it just deep sequencing of single cells or is there some other proxy measurement you use?
Alan: Everything. This is where Permanence Bio really stands out and what we're doing is very special. The biggest challenge in the genome stability and DNA repair space has been figuring out how you screen and test things. If you just blast cells with an enormous amount of radiation and see which ones survive, the hits that you get are not DNA repair-related. They're hormesis proteins that shut down the cell and protect it from doing anything. They completely shut down the cell cycle, they completely shut down everything. So how do you tune an assay to tell you the genome protection mechanism, but not anything else?
People look at gamma-H2AX a lot. For listeners who don't know, when there's a double-strand break, there's a little marker on a histone nearby where the cell tags it. That tag is a sign that there's damage happening here, and that recruits a ton of DNA repair machinery to go to the area. We screened a whole bunch of compounds in the beginning, basically trying to compare the things that we're developing versus the best in class that other researchers have found. We found that some of the best DNA repair molecules are not only not hits, but they actually increase the gamma-H2AX signal. For example, nicotinamide, which is very well known to be a very good DNA repair booster, I think canonically accepted as such, and we see a 20% increase in gamma-H2AX signaling after we induce damage in a cell. You'd immediately think, "Oh, that's terrible. That means that you're actually increasing DNA damage," but you're not. You're actually improving signaling. That's also a good thing.
The long way around to getting to your question is that we're doing a lot of things. Gamma-H2AX is one of them because if we can actually reduce the damage, then we reduce the damage signaling. Therefore, that's good. We're also looking at broader things. We're experimenting with hematopoietic stem cells. They're very genomically unstable. In the bone marrow, there's a very small percentage of oxygen, so it's very easy for them to exist there. As soon as you take them out of the bone marrow, suddenly they're exposed to a ton of oxygen, so their genome instability jumps up. If you have a compound that can, for example, improve genome instability in hematopoietic stem cells, they should be able to grow better. You should be able to see a whole bunch of different flow markers that indicate the cell is in a healthier state, and they should remain high even as the cells are dividing in these unnaturally high oxygen conditions.
There's also a diversity of insults that you can do. People like radiation a lot because that's fairly direct, but of course, the type of damage that you're seeing with radiation is not the type of damage that you see with formaldehyde, which is not the type of damage that you see with H2O2, which is not ENU. So what we're trying to do is a whole battery of things at the same time and then see if we can get hits in everything.
Abhi: Is there a way to discretize different types of DNA damage, or is it kind of all on a spectrum and it's hard to categorize what is what?
Alan: This is also a very good question. I think there are two ways to do it. One is you have insults that you know should be causing mostly one type of damage. There are very good papers that have mapped out every single type of DNA damaging drug and roughly what type of DNA repair mechanism it's impacting. So you can just screen across, let's say, six or seven insults and say, "Hey, which one of these seven is our compound most effective against?" The only downside to that approach is that a lot of these will not be very specific. Some will damage one but also another mechanism, but it's very efficient. The other way you can go about it is you have some cells and then you knock out their ability to repair one type of damage. Then you cause general damage and then you see to what extent your compounds can rescue those particular cell lines. I think both approaches are good. We're leaning more on the first.
Abhi: Is there a particular cell type that you're most interested in working on, or is Permanence Bio really spread across many different cell types?
Alan: It has to be many different cell types, especially for cancer prevention. What I've noticed is that there's a big distinction between how slow-dividing cells, non-dividing cells, and fast-dividing cells deal with DNA damage. As an example, I mentioned earlier that there are people out there with a disease where they have a mutation in a polymerase that then leads to a 15 times higher mutational burden. You mostly see that mutational burden in the colon and very fast-dividing cells. They primarily have very high rates of colorectal cancer. In contrast, if you mess up another genetic pathway that leads to DNA repair in humans that leads to Cockayne syndrome, they don't get colorectal cancer at all. Instead, it's a major neurological disorder. These are mostly impacting non-dividing cells, so it's mostly autoimmune and neurological. Werner syndrome impacts a third batch of DNA repair, and there you see slow-dividing cells get messed up. These patients have something that looks a lot like diabetes. Their skin starts to look wrinkled, and it's the most physiologically accelerated aging-looking model that I've ever seen. So we need to be effective against many different cell types and many different types of damage.
Abhi: How should I think about DNA damage not in the context of environmental insults, but in inherent genetic defects in an individual? The example that I'm thinking of is someone who has a BRCA mutation and is unable to repair double-strand DNA breaks. Do you imagine something like what Permanence Bio is doing is amenable to fixing that problem, or if there is a genetic defect that is causing DNA damage, is that a trickier problem to fix?
Alan: No, we think about that a lot, mostly because when we think about clinical strategy. If we want to go big picture for cancer prevention, to run a cancer prevention trial in the general human population without stratifying populations at all, that's somewhere north of a hundred million dollars and five years and tens of thousands of patients. Looking at individuals who have a high risk of cancer is absolutely something that we're deeply interested in. There are sort of gradations here. You mentioned BRCA carriers have a much higher risk of breast cancer. We also have thought a lot about Lynch syndrome, where these patients have a 70% lifetime risk of colorectal cancer. So that's an even higher risk of cancer. Then there are more rare or ultra-rare diseases like Fanconi anemia, where they're guaranteed to have cancer. As we're thinking about our path to clinic, we'll very likely want to start at these higher-risk patients and then gradually move on to lower-risk patients to prevent cancer in them as well.
Abhi: The larger question is, are there some forms of DNA damage that aren't amenable to these protection mechanisms, or are all forms of DNA damage amenable to DNA protection?
Alan: In theory, you can only get DNA damage by virtue of having some insult that causes DNA damage. Some are trickier than others. The main one that we think a lot about from the point of view of this question is replication stress. Is replication stress inevitable? Or is it purely dependent on polymerase fidelity? If it's only polymerase that can cause or contribute to replication-mediated DNA damage, then DNA damage protection mechanisms are not going to do a whole lot. It's going to have to be, at that point, some sort of gene therapy or some sort of interesting drug that boosts DNA polymerase fidelity. But aside from that, no, I think DNA damage is pretty central and will impact everything.
Abhi: There are some scenarios in which learning some aspect about a certain drug modality is fine to do in an in vitro setting because it transfers pretty well to in vivo settings. I think one common example people use is that you don't typically need to worry too much about antibody toxicity, so it's fine to test in vitro, and it'll probably translate in vivo. With DNA repair mechanisms, what is the situation like? Is in vitro usually perfectly fine to test everything in, and you expect that it'll translate pretty well, or are you primarily testing in animals and even then there are worries that it might not work across species?
Alan: That's a very good question. I think you learn a lot from cells. For example, especially from the point of view of things that could go wrong. Things that could go wrong with DNA repair, a lot of them have to do with cell cycle arrest, as I mentioned. There's this deep, entrenched talk between not replicating and doing DNA repair. You can do experiments in rapidly dividing cells, activated T cells, hematopoietic stem cells, you name it, in a cell culture model. That will be really, really informative as to whether or not you'll see that kind of problem in the mouse. So there are a lot of things that are going to be helpful.
Others, less so. My big questions are kind of like the ones I asked before. Are there certain types of cancer that are going to be more amenable to treatment than others? That's hard to tell unless you test against every single type of cell in an in vitro model.
Abhi: I've always been a little bit curious, and again, potentially a very, very dumb question, how well does in vitro cancer mirror real-life in vivo cancer? What are the big distinctions there? What are you not accounting for, and what are you accounting for?
Alan: The immune system is the big thing that you miss. That's the toughest one. I kind of mentioned before, cancer is largely described by two things: inflammation and mutations. By doing an in vitro model, unless you have a very sophisticated organoid model, you're missing the inflammation part.
Abhi: But does the immune system still matter for the problem of DNA damage protection?
Alan: Oh, absolutely. There are even cases where, let's say that you don't prevent mutations at all, but you modulate the immune system's response, and you have a huge effect. One thing that people, even I, have thought a lot about is autoimmune disorders. A lot of those are driven by genome instability, but they're not driven by genome instability because the cells themselves are dysfunctional. They're theorized to come from the cell sending out dangerous signals to the immune system, which then comes in and floods and causes chronic inflammation. So the actual DNA damage and mutations barely matter. It's just this overactive immune system cycling that is causing the issue there.
[00:27:12] Why is DNA protection not focused on as much?
Abhi: Speaking a little bit big picture, you make a pretty strong case for why preventing DNA damage is really important. But it does feel like historically the longevity field at large has not focused on this particular subfield and has focused a lot more energy on, I think, largely epigenetic reprogramming and also lifestyle changes, like eating less and exercising. Why do you think epigenetic reprogramming has been given the spotlight, and why has this particular subfield of yours been kind of left to the wayside?
Alan: Epigenetic reprogramming is really, really exciting because it promises reversing aging. If you're already pushing your later years and you want to live, especially if you're motivated by living forever, epigenetic reprogramming is one of your very few choices. The field of replacement is coming out that's becoming more and more exciting, where the idea is you just replace body parts. But reprogramming, I think, is the most mature field that has that idea of, "Okay, maybe you can do something right now and then live forever." There's this whole concept of longevity escape velocity. If you're going to hit that, you probably need something that will reverse aging, especially for the people who are already older. That's the biggest reason why reprogramming is exciting.
In addition to a few mouse experiments that I think were really, really compelling. The biggest reason why genome instability is toughest to reach, and we think about this a lot in terms of clinical strategies, is that prevention in general is hard. Prevention is expensive. Prevention takes a long time. By definition, it is very hard to do. Most genome instability diseases are going to be inherently prevention-oriented because in most cases, once the genome instability has already occurred, either through mutations or inflammation, it is not something that you can reverse. Maybe you'll slow down the progression at best, but you're not going to reverse it by preventing more damage. The damage is already there.
You can think about this in the simplest form, like Huntington's. If you already have the crazy high somatic expansion, if you already have a lot of copies of HTT—Huntington's is caused by an expansion of a region in this gene called HTT—then preventing more expansion isn't doing anything for you because you already have all that. Most of the thinking around how you treat genome stability relates to prevention, and prevention is just so much tougher to do.
Abhi: If I think about what the major prevention drugs are, I'm thinking of anti-hypertensives and statins. But even then, those aren't a close analog to this because they have pretty easy biomarkers to tell quickly how well this is working or not. Is there any drug class in history you can point to as what you think the parallel journey for Permanence is going to look like?
Alan: Statins are actually a great one. The most direct are vaccines. That's the easiest, right? There are two drugs approved for cancer prevention. One of them is Gardasil, which is the HPV vaccine. There's one other cancer prevention drug that exists to my knowledge, and that's Tamoxifen. They showed that Tamoxifen is effective as a breast cancer treatment, but then there was a huge study that showed it can also prevent breast cancer. The clinical path has already been set. Statins, GLP-1s, these are actually very similar to what we're trying to do in that they were originally approved for very narrow indications, for people who are at very high risk of a disease. Then gradually, as people saw that they were also safe and effective across a whole broad range of different indications, they gradually label expanded. It's the same thing that we see here in cancer prevention where we'll probably start out with people who are at very high risk of disease and try and prevent them from getting cancer. But then slowly, as these drugs are shown to be safe and working in more and more people, we just expand.
Abhi: I'm curious, for Tamoxifen, I was not aware of that. Do we know what's going on there? Does it have a DNA protection mechanism, or is it doing something else entirely?
Alan: I can speculate. What's known is that Tamoxifen modulates the estrogen receptor signaling. That's also why it's a drug that prevents breast cancer. The conventional wisdom for breast cancer prevention is that in women, you have this idea of a pre-cancer, where it's not quite cancer yet, but estrogen signaling can help push it over the edge. If you block that signaling, then you prevent it from going over the edge into being cancer. That's why it's preventing cancer.
With that being said, there's a lot of fascinating overlap between estrogen receptor signaling and DNA repair. There are only hints of it out there. As an example, if you look at GWAS hits for the age at which a woman undergoes menopause, almost every single hit is a DNA repair gene. It's strong; these are massive effect sizes. There's one very common variant in the GWAS hit where if you have it, you undergo menopause a year and a half earlier or a year and a half later, regardless. There's a very strong correlation, a link between estrogen signaling and DNA repair.
Abhi: Does this imply that if you're a woman and you're above 40 or 50, you should be on Tamoxifen?
Alan: Probably not. To be honest, I'm not knowledgeable enough in that field. Menopause itself may or may not be estrogen receptor signalling mediated.
Abhi: I'm curious, and related to this whole cancer tumor thing, do you imagine that DNA protection chemicals would also help in preventing cancer from adapting to whatever therapy you throw at it? Or is there something about cancer that's a little bit weird, and these methods may not necessarily work for the cancer itself?
Alan: Yeah, I've thought about this a lot: can you prevent cancer progression? In fact, there's a very interesting study done with nicotinamide, which I mentioned earlier as a pretty good DNA repair drug, in terms of preventing, I want to say, secondary malignancies from a melanoma treatment. It was effective. It worked. The patient population was 400 patients in each arm. The trial was a year and a half, and they showed that sure enough, if you give patients who had melanoma once, you have a 30% decrease in the risk of a second malignancy two years later. I think it'll depend a little bit on the cancer. Some cancers are known for getting a lot of mutations throughout the course; some cancers don't. For a lot of cancers, progression is more defined by immune cell exhaustion than it is by adaptation of the cancer itself. So I think it is going to depend a little bit on the specific cancer type.
Abhi: Do you think the first indication for Permanence is going to be for stopping the progression of existing advanced cancer or for preventing cancer from occurring in the first place amongst some high-risk population?
Alan: Probably the latter.
Abhi: Why not the former?
Alan: The former is exciting. When I think about indication selection, I think about reasons you could fail. If there are patients out there who are going to get cancer and we have a drug that should prevent mutations, and they're getting cancer from mutations, then it should work. If we fail, then that means that our drug just didn't work. That is a very clear indication. If the indication is prevention of progression, progression can happen for a lot of different reasons. I would hate for our drug to work really nicely and prevent mutations and then that not impact the endpoint.
Abhi: There are a lot of reasons a patient could die for reasons unrelated to mutations. What were the other things on the table for indications other than cancer?
Alan: We've thought a lot. If you look at which drugs right now are genome-stabilizing or antioxidants, for example, things that prevent damage, to my knowledge, there are two indications right now that people are pursuing. Epsilon Edavarone is a drug for ALS, and neurological diseases are very well known to have DNA damage as a driving mechanism. ALS was interesting to us, especially because there's already been a clinical success for an antioxidant there. Dry AMD, currently the main treatment, or not even treatment, but the main way that you prevent that is through this cocktail of antioxidants. When we think about what is something that we can move into where we see there's already success, there's already a path, those two stand out because that's been done before.
From there, there are other indications where there's a very clear causal link to genome stability. I cited Huntington's before. Alzheimer's is looking increasingly interesting, and kidney disease, where there isn't currently a beaten path, but genome stability is clearly related to progression or initiation of the disease. Those were interesting. I think the main thing for us was mission alignment. Our vision is to do cancer prevention and longevity. What a lot of longevity companies, I think, run into is that the way that you treat a disease ends up looking a lot different than the way that you address longevity. What I mean by that is that, let's say that you have a drug that you want to put in as a cancer therapeutic, and you think that it also has a pro-longevity mechanism. The downside to that is that the way that you think about a cancer therapeutic is very different from a safety point of view. For example, you can dose extremely highly if you have a cancer therapeutic because otherwise the patient will presumably die. That is not something you can do for longevity. You want to have the lowest possible dose where there are no side effects and the patient's just healthier.
When I think about overlap with the mission of doing something that's pro-longevity, cancer prevention is really well aligned. Similar to longevity, in cancer prevention, what you're trying to do is prevent a new disease from occurring. You want something extremely safe. You want something that you can take orally. You want something you can take for a very long time. You want something that has minimal drug interactions with every other drug. In terms of just thinking about the problems that we're solving on one path versus the other, they're basically the same problem. We like that as a case, but of course, we could go into multiple programs. I don't think we're married to only doing cancer prevention.
Abhi: On the topic of actually taking the drug itself and it systemically going throughout your body, if you do go with the cancer route, do you imagine your drug will be injected at the site of the cancer? In the case of taking the drug to prevent cancer in the first place, you have this systemic application of the therapeutic. Where do you want the therapeutic to get into most? Do you want it to get into hematopoietic stem cells? Do you want it to get into muscle cells? Where is the primary place that you think is important either for longevity or for cancer?
Alan: It really depends on the indication. For example, if you look at xeroderma pigmentosum patients, they have an extremely high risk of cancer. It's a really rare disease that's mostly caused by sun damage. You really, really, really need the drug to get into the skin. For Fanconi anemia, these are patients that are mostly getting hematological disorders and squamous cell tumors. In that case, you want it to get to the bone marrow, but you also kind of want it to get everywhere. If you're thinking about more common diseases, Lynch syndrome, that's the colorectal cancer I mentioned earlier. You need it to get to the colon. So it really depends on the indication in question.
Abhi: To some degree, when you say the indication for Permanence Bio is cancer, it's probably going to be more specific than just cancer. It's going to be like a very specific organ, for example.
Alan: In the beginning, I imagine it's going to be a lot more specific.
Abhi: Do you think we'll ever get to the point of having this systemic negative 10% reduction in cancer across all types of cancer because of genome-stabilizing drugs? Some context for this question: I know that for at least epigenetic reprogramming, different cells reprogram at different rates. There's this weird problem where if you want to reprogram a neuron, you need to almost go slower in the reprogramming process versus a muscle cell. Is there something akin to that for genome stabilizers where different cell types need a different level of dosage?
Alan: That's a good question. On a very, very high level, yes. The cells that are going to be accumulating a lot of mutations tend to be the ones that are dividing a lot. You want to get into your bone marrow, you want to get into the colon. From that point of view, yes.
The other thing is, and this is both a blessing and a curse for us, when I mentioned that we have this cancer prevention/longevity alignment, one of the biggest things for us is safety. We need a drug that is fine in everything. If it gets into any cell type, no matter where it works, it should still work. That's very, very important. And that's why we're testing so many different cell types, because if we find out that we're working in four cell types but we're toxic in the fifth one, we just cannot pursue it.
[00:41:03] The utility of epigenetic clocks
Abhi: You did a lot of research on epigenetic clocks during your PhD, but from just scrolling through your Twitter feed, you're pretty pessimistic on the overall utility that they can provide. I'd love to hear your take on the current state of things in the field and perhaps on biological clocks more generally.
Alan: I've been thinking about this a lot lately. I think clocks are very promising, perhaps not right now, but probably very soon, from a clinical biomarker point of view. So looking at, "Hey, we have this intervention, we give it to patients, what do the clocks say after two years?" I think there's a primary challenge there in that a lot of these clocks are difficult to interpret, but I think slowly the field is solving that problem and their power, the clocks are getting strong enough that they have real meaningful predictive power for functional endpoints that would just take too long to get to using a conventional trial format. I'm very bullish on that front and excited to see where that goes.
That's especially helpful for prevention. What would be nice is if we had a compound that is not only cancer-preventing but also longevity-extending, and you can tell that with a biomarker off the blood that you trust, so you don't have to run the full, long cancer prevention trial. From a prevention point of view, I think biomarkers and clocks are a godsend. As basic research tools, they're also very helpful. Most of my PhD was trying to use epigenetic clocks to understand to what extent aging is a mechanism of cells getting old and not working versus a mechanism of the system collapsing.
The place where I think I'm a little bit more pessimistic is in direct-to-consumer, like an individual person takes a clock. I'm not sure to what extent that is very actionable and it doesn't seem very accurate. A lot of the technical noise there is higher than anything that you could possibly impact. Unless you have the money to buy a hundred of these things, there's not a whole lot of value that you get out of buying a genetic clock off the internet. I've never done my own tests. That's where I'm pessimistic. But in terms of where the field is going with the biomarkers of aging consortium and looking at clinical trials, I'm very, very excited.
Abhi: How much does the biological clock you use matter based on which therapeutic you're throwing at the problem? I imagine for the Retro and Altos of the world, who are all epigenetic people, epigenetic clocks are the most useful for them. Are they also useful to you, or are there some genome-stabilizing clocks that you're more interested in?
Alan: That's a cool question. I think we're getting to a point where you could actually use mutational burden as a clock. We are getting there. We're not quite there yet, but I think within the next two or three years, we'll start seeing that. I think what's most exciting are the systems clocks.
Abhi: What are those?
Alan: Basically, there are I think five papers out now, but there's a flurry of them. So far, everyone's been mostly looking at epigenetic clocks in terms of blood. You take someone's blood sample and then that tells you their epigenetic age. But the question is, you're not—there's not just one dimension to aging. There are 60-year-olds out there who have perfectly healthy lungs, but they have a failing heart, or vice versa. The question was, can we use epigenetic clocks or proteomics clocks to understand to what extent someone's at high risk of a certain type of disease for a specific tissue or organ? Those are exciting. When you're thinking about diseases, those are very, very good because let's say that you have a drug that's supposed to improve sarcopenia, well, maybe the muscle clock is going to be the most effective at predicting how well the trial will go a year before you hit the endpoint.
Abhi: Let's say you meet a hundred people, all of whom are 110 years old. Do you suspect there is a primary protective mechanism that all of them have, or is it likely very heterogeneous among them?
Alan: That is a good question. There's this saying in the longevity field that I like a lot, which is, "If you want to live to be 90, what do you do?" And the answer is, "Oh, you should diet and eat well and exercise and sleep and do all these healthy things." And if you want to live to 110, what do you do? It's, "Have parents that live to be 110." If you look at 110-year-olds specifically, I think it is a genetic improvement in genome stability. I think that the aspect of aging that fixes your lifespan is likely mostly genome-stabilizing. That would be my prediction. There's some evidence to support that. People have found there is a variant in, I believe, (SIRT6), which is a known genome-stabilizing protein, and that is enriched in people who live a very long time. But I think there aren't even enough individuals to really have a strong enough study to predict that.
Abhi: I suppose an easy way to study this is to look at the average mutational burden of some sample among these hundred people who live to be 110. Is there some reason that is not a trustworthy number, or is it just that we don't have enough samples?
Alan: We do not have enough samples.
[00:46:47] Do you need multimechanism approaches for longevity?
Abhi: Somewhat related to this, it feels like longevity startups in general have pursued singular mechanistic hypotheses at a time. Some groups are pursuing only replacements, some groups are pursuing only epigenetic reprogramming, and you're pursuing DNA stabilizing stuff. It has long felt to me that aging almost wants to occur, and so if you plug one of the seven holes that cause aging, the pressure on the remaining six holes will simply intensify. Is this an accurate mental model of aging as a concept? And two, do you imagine you'll be forced to move into other therapeutic areas for longevity, or is genome stabilizing a really good base to start off on?
Alan: My own mental model is almost the opposite. People have shown that a lot of these hallmarks of aging, these aging dysfunctions, feed off each other. If you remove one, you'll probably actually release the tension off a lot of the other ones. As an example, inflammation leads to dysregulated nutrient sensing because suddenly your immune cells are eating all of the different nutrients that other cells should be getting, which then causes mitochondrial stress. Mitochondrial stress induces genome instability, which leads to telomere attrition. If you just didn't have the inflammation in the first place, probably the other ones would be a lot better off too.
I definitely share the core sentiment that there are a lot of longevity companies that focus on one thing. Even when we think about genome instability, I think by the time that someone's quite older, let's say 85-plus, doing genome instability alone isn't going to be enough. In fact, I'm not sure to what extent you'll see a big effect. That's kind of why we're focusing on this prevention angle, because the hope is that early on, the primary thing that's affecting you as you age is genome instability. So the earlier you treat that—for example, inflammation is not that much of a thing when you're 25 or 35 or 45 or 55. It only becomes a real hallmark of aging past the age of 65. It probably doesn't make sense to prioritize genome-stabilizing drugs for someone who's 85. At that point, I would probably hit the other hallmarks. But for someone who's 30 or 40 or 50, absolutely, that would make a huge difference.
Abhi: A very, very dumb question. When we talk about a cell's ability to repair its own genome, can that happen hours after the insult has taken place? Or is it kind of like the repair mechanism is only available a few seconds after the damage has been done, but after that the information is lost?
Alan: That's a very interesting question. It depends. The concrete answer is all of it. What I mean by that is there are stem cells out there, quiescent cells that get DNA damage that just sit there with the DNA damage for months. Because if they're not doing anything, that doesn't really matter. But as soon as they emerge from quiescence, suddenly they turn on their DNA repair machinery. They open up their DNA, all the DNA repair proteins come in, fix all of it, and so on and so forth. Versus there are certain types of damage, like a double-strand break, you better fix immediately or the cell is going to immediately become senescent and then die.
Abhi: The more specific question I'm asking is, you say if you're 80, we probably don't have anything to offer you. But can you not imagine that if you upregulate their DNA repair mechanisms and allow them to go through this rough period of cells not dividing because they permanently think they're in a permanent repair state, and then you give them the genome-stabilizing drugs, do you think there's anything there, or is it just like their cells have been through so much information loss that isn't recoverable?
Alan: The way I think about it is, my mental model of aging is like a boulder rolling down a hill. In the beginning, there's not a whole lot going on. The boulder's not moving very fast, and at the bottom, it's going at full speed. Trying to reverse entropy is tough. Inherently, that's just a fact of nature. Biology does have mechanisms for doing it, and that's kind of what the reprogramming field is pursuing, this idea of returning back to a natural state. It's just very, very hard.
You could definitely imagine some synergy, like a reprogramming therapy plus a genome-stabilizing therapy to kind of push someone back and then keep them there. I definitely can't say that we will have things to offer for people who are very advanced in age. Plus, if you stabilize a genome, there are just certain diseases that elderly people get that could be very helpful, like autoimmune disease, as I mentioned earlier, or Alzheimer's or something. It's just much harder at that stage.
[00:51:58] Longevity outside of DNA protection
Abhi: Outside of genome-stabilizing drugs, what is the second most promising area of longevity therapeutics that you're most bullish on?
Alan: I like reprogramming, but everyone likes reprogramming. I think just in general, hematopoietic stem cell treatments excite me.
Abhi: What is that exactly? What are you actually doing to those cells?
Alan: I mentioned earlier the replacement field is very big, and so I'm thinking about hematopoietic stem cells. If you were to take a human body and you were to replace something in them, and you were to weigh the cost trade-off of how hard is it to replace, how difficult would the surgery be, versus the maximum possible impact that could have in terms of rejuvenating that organ or that system, that's where I'm really excited about bone marrow and hematopoietic stem cells. They're responsible for your entire immune system. They're responsible for your entire blood system, and they're in a very relatively small niche in a relatively small part of your body. So if you could actually replace all of them, which is feasible, or at the very least, theoretically very feasible, then the benefit that you would see would be huge because you just rejuvenate your entire systemic circulation.
Abhi: Going back to this group of 110-year-olds, do you imagine that the vast majority of them have extremely detrimental somatic mutations in their hematopoietic stem cells, or is it kind of like if you're prone to having mutations in that area, you're probably not going to live to be 110?
Alan: The second one. There have been studies looking at this. There have been studies done on people who are centenarians and looking at their immune systems, and their immune systems are weird. As an example, there's this relatively rare subpopulation of cells in younger people or even elderly people, just everyone in general that isn't one of these crazy centenarians, called a cytotoxic CD4 T cell. CD4 T cells are usually helper cells, so in some ways, it's an oxymoron; they have cytotoxic helper cells. They have cells that kill and also help. This is a very rare cell type. It's weird, it's grossly understudied. People don't know what it does. It probably helps against cancer is one of the theories. It's a very understudied cell type. Turns out that there are people who are 105 years old where something like 30% of their T-cells are this bizarre, weird cell type that is maybe 0.01% in a healthy individual. Those people tend to live longer. They're enriched in these supercentenarians.
That could mean a lot of things. It could mean that they have a mutation or some genetic variation that leads, that makes them more predisposed towards having this cell type. It could mean that every other cell is just so vulnerable that they die off and this one weird cell type survives, so there could be a selection bias. It could be that as they age, they got a mutation in their hematopoietic stem cell system that led to them producing more of this very beneficial cell type. None of it's known, but the hematopoietic system does weird stuff in very old people.
Abhi: Is there anywhere else in the field of longevity where among the people who live a really long time, there's something unique going on about them biologically and it isn't just that they're better at doing the normal things that everyone can do?
Alan: Nothing immediately comes to mind.
[00:55:57] What's going on inside of Permanence?
Abhi: What is currently going on inside of Permanence? Obviously, we have discussed your thesis at length, but I'd love to hear about any details that you're able to share about what's going on inside.
Alan: A lot of it's what I've shared already. A lot of testing, a lot of screens, a lot of assays, just looking at the battery, ordering every single best genome-stabilizing thing that we could find and then putting them head-to-head and then doing some iteration on those and trying to improve them. Different cell types, different tissues, different types of damage, just doing the whole battery of assays. I think our first thing is just to look wide, what general patterns do we see? What are the most effective things in what disease models do certain types of compounds perform the best? As we kind of build up a database, as we build up a knowledge base internally, then that is going to be putting us towards specific compounds. We've gotten some incredibly exciting results lately where we have something proprietary that seems to be outperforming the best of the best that we've tested. So we're starting mouse studies, and that is a very, very exciting thing, especially a cancer prevention study because doing a cancer prevention mouse study is a lift. It takes a long time. So what we are doing a lot is asking, "What is the best model? How do we screen this? What do we look at? What do we model? Where do we look at mutations?" The details of how do we turn something that looks really compelling in cell assays into something three steps closer to being a drug that we can give to patients.
Abhi: When it comes to designing these DNA-stabilizing molecules, I tend to think of molecules and proteins as attaching to some cellular receptor. One way you can conceptualize how well this is going to work as they transfer from a mouse to a monkey is how structurally conserved this receptor is. Is there an analog to that in the DNA protection world?
Alan: Not really. It depends. Broadly speaking, yes. I kind of mentioned there were a few other genome stability companies that are looking at hitting things like DREAM or sirtuins or whatever. From that point of view, yes, you're still going to be titrating binding, you're still going to be finding, hopefully, the best possible binder that is going to be attached to this particular thing. If you have something that's mopping up damage, not really. You still have to do your dose curves to figure out what is the minimum dose that leads to the best improvement, but your readouts tend to be less biophysical, like "enzyme plus compound, how do they bind?" and they tend to be a lot more functional, of "you have a cell, how is it reacting molecularly to damage to this compound? Is it staying alive? What does it look like phenotypically?" and so on.
Abhi: When you're quantifying how well a particular molecule is working, is it kind of a binary yes or no on these functional assays, or is it a very wide spectrum?
Alan: It's a wide spectrum. The biggest thing that we're thinking about right now in terms of assay design is how do we get the cleanest separation between the things that we're testing? Some types of damage are just going to kill everything, and some types of damage are going to do nothing. You can't see a difference between your compounds. But how do you hit that sweet spot where you can see that some things are working but others aren't?
Abhi: The way that I've been conceptualizing DNA protection mechanisms is that they affect, for a given cell, the entire genome all at once. Is that a correct way of viewing it, or is it often the case that you want to protect specific segments of the genome at a certain point?
Alan: It depends on the mechanism, it depends on the drug. Some really do not do anything next to histones and they only have an effect on open areas of DNA; other ones, vice versa. If you're improving DNA repair, then certain types of DNA repair mechanisms are more involved in certain parts of the genome than others. So I think it's going to be very molecule-dependent.
Abhi: I imagine, just given what you've said about the DNA protection field, it feels like it's almost certainly relatively immature compared to most other longevity fields. As such, I imagine Permanence as a company is in an area where there's relatively little established ground for what empirically works, what theoretically works, etc. Have you learned anything that you can share about preventing DNA damage that perhaps runs a little counter to how biologists might naively think about the problem?
Alan: Yes. I will say that we're very lucky. In some ways the genome stability field is nascent, in some ways, it's very old. The idea that DNA damage is tied to aging is something that a lot of thinkers have thought on before. There's just an incredible number of people who have developed antioxidants and mouse models. I mentioned that we're screening the drugs that we're developing against the best in class. Every single one of those things that we're testing against was developed by teams of people trying to find the best possible protecting agent against something. There is a lot that we've learned from everything and everyone that has come before us in the cancer prevention space, in the genome stability space, and in the aging space.
In terms of what is something that's counterintuitive and different that we're doing, I think it is really the recognition that different types of damage lead to different effects in different cell types. I think there's been a very common trend of, "We're going to take some fibroblasts, we're going to look at gamma-H2AX, and just hope, cross our fingers and know that's going to translate to everything." I don't think that's how it works. I think what we've learned, where our intuition was and that has absolutely panned out in our assays, is that you need to look at a lot of different things to get a very big picture view of what DNA damage is doing and how you can prevent it.
Abhi: And there's no functional readout that you can trust above everything else.
Alan: Right.
Abhi: What is the most exciting internal result that you're currently seeing and why do you consider it exciting?
Alan: I mentioned this earlier. It's just the fact that we're seeing some proprietary compounds just work across everything. What I was really scared of, and this was absolutely possible, is that we would have four types of DNA damage that we would be screening to protect against, and then you would have like three compounds that would work for one, three that would work for two, three that would work for three, and three that would work for four, and then none of them would overlap. The fascinating thing is that we do actually see that with some of the control compounds. We're screening nicotinamide, we're screening astaxanthin, which is this incredibly powerful antioxidant that algae that salmon eat produce. To my knowledge, I think it's one of the most powerful antioxidants that has ever been known. We were screening a whole lot of different genome-stabilizing compounds, and we do see that in some of them where they're really effective in like two out of four or three out of four, but they're really harmful in the fourth one or something. I'm really excited to see that we have potential compounds that we want to move into mice that are helpful in everything. They're not necessarily number one in everything, but they're high up there in everything, and that's good.
Abhi: When you're designing these molecules at Permanence, how do you select the molecule in the first place? If there's no cellular receptor that you think, "I have this ligand that's binding to this one epitope," and you're inside this world of, "I want to bind to this backbone," or "I want to bind to the chromatin," what's your mental process for selecting these molecules in the first place?
Alan: A lot of things. We have a hypothesis for what makes a really good genome-stabilizing drug. We are hoping that that hypothesis is correct and is backed by literature. It is a little bit contrarian. We're testing out whether or not that hypothesis pans out in our cell screens and in other screens that we're doing. So far, it seems to. Given that it works, then the question is, can we improve upon that mechanism? We're doing a lot of things for that. For example, we're doing some first-principles AI prediction algorithms to see, given that this is our hypothesis, can we create new compositional matter that does that particular hypothesis better?
Then there's a second layer of AI that we have where the idea is every single assay that we have that is finalized and every single result that we get for every single compound, we feed that all into a massive database. The plan is in the next three months to go, "Okay, now that we have this huge amount of data and structural data on all these families of compounds, can we actually generate something new that a really powerful medicinal chemist could not have thought of?" We'll get there as well.
Abhi: When it comes to Permanence's usage of AI, the way that you phrased it implies that it's primarily LLM-based and not molecular models. Is that correct?
Alan: We do both.
Abhi: When you're using these molecular models, are you taking the DNA and trying to find something that binds to the DNA, or am I conceptualizing it incorrectly?
Alan: I'll not tell you. But it's very cool. I wish I could. I genuinely wish I could.
[01:05:54] How could Permanence fail?
Abhi: I think it's helpful to think about ambitious companies in terms of the bets they're taking because I think it's difficult to do ambitious things without taking a bet on where the future is going. Clearly, it is known that DNA damage prevention is important and that there are mechanisms that help prevent or fix it. What do you think is the bet that Permanence is making, or phrased differently, if Permanence completely fails, what do you suspect the reason is?
Alan: The clinical trials will be tough. The clinical trials for cancer prevention have been done, but they're all difficult and they all are expensive and they take a long time. The upside is massive, both in terms of good for humanity but also in terms of market. There are little weird things that can go wrong. For example, one of our advisors is Professor Dr. Sir John Burn. He's an absolutely incredible man. He has run the world's longest cancer prevention trial ever, clocking in at 20 to 25 years. He ran the CAPP series of trials, which were basically testing aspirin for preventing colorectal cancer in patients who have Lynch syndrome. Five years into the trial, they wanted to look at actually preventing colorectal cancer, but they had some secondary endpoints, and one of those was whether it could prevent polyps because polyps are on the path to progression of becoming colorectal cancer. Five years in, they saw no decrease in polyps whatsoever. They were really hoping that this polyp result would work because you don't want to wait until patients get cancer, because that's going to take another five years and be a mess. They almost killed the trial at that mark because they didn't see any decrease in polyp count. They let the trial run another 15 years, and the result was a 40% decrease in colorectal cancer in the patients who were taking aspirin versus the patients that weren't.
The bet that we're taking is that there's not going to be something ridiculous that falls out like that. A lot of clinical trials, especially ones that go long, tend to fall apart for reasons that have very much nothing to do with the mechanism or being wrong on the core biology, but just something else like that. That's where we're the most worried, I would say.
Abhi: Would you imagine the length of whatever clinical trial you run would be five years, 10 years, even longer?
Alan: Definitely not 10. It's got to be less than five. It's a little bit of a math problem. The more patients you have, inherently the less long it takes, but the more expensive it is. The more highly cancer-predisposed patients you have, also the shorter it takes and the fewer patients you need. We probably don't want to run a cancer prevention trial that lasts longer than three years. There are some cancer prevention progression trials that we can do in as little as one or two. But it's going to be a long clinical trial for sure.
[01:09:03] How do you stay optimistic?
Abhi: Working in the longevity field seems like an excellent way to grow pessimistic as to anything working out at all. You've posted also in the past on Twitter about how it is a shame that the ambition of the field has dramatically lessened than what it was 10, 20 years ago. How do you personally stay motivated in such an extraordinarily difficult field to work in?
Alan: It is just so worth doing. I got into the longevity field because I used to work in the late-stage cancer field, and I was just made aware of the idea that the way that we set up our healthcare system, the way that we treat patients, is that we wait until they get a very serious disease, and then we hope to bring them back from it once they're at the brink. Most of these drugs are operating on very specific mechanisms that don't help anything else. The promise of the longevity field is that you can actually modulate something that's way upstream of everything. It could prevent not only one disease but nearly every disease. What else is worth doing? As far as time immemorial, people have been having this idea of how to extend lifespan. It's the most effective revolution of healthcare that we can imagine. I think it's worth fighting for.
[01:10:26] Why work on aging?
Abhi: I mentioned in your introduction that you did a PhD at the USC Buck Institute of Aging, which is obviously an aging institute. Walk me through the journey leading up to getting the PhD. What made you realize you wanted to spend a significant fraction of your life working on this?
Alan: I used to work at Arsenal Bio. I think that's where I got my intellectual start. Arsenal Bio is a CAR-T and cell therapy company that has incredibly advanced technology in that particular space. My job was improving screening. The question that I would come into work every day thinking is, "Okay, here is a way that we can test 10 ways of improving a CAR-T to kill a cancer cell better. How do I make that a thousand ways in two months?" That was a very fun problem and it taught me a lot about the importance of the details in screening. One of the biggest values that Permanence has is that we think about screening and testing things for genome stability in ways that are, in many ways, better than other people. That came from my time at Arsenal Bio, where I was really enmeshed in that screening mentality.
The thing that led me to aging was, I looked at all of that and I saw they're doing incredible work and are incredible people, but could we have prevented that cancer in the first place? There's a personal overlap there in that the very same time that I was at Arsenal Bio, my father was experiencing cancer, and he passed away from cancer right before I started my PhD. Strangely enough, he had the signs of melanoma for a decade prior to it actually becoming malignant and then eventually killing him. I thought to myself, "Why do we wait so long? Why are we developing therapies that you can only introduce into patients once they're already six months away from dying? Why can't we go more upstream, and what is more upstream than aging?" I was like, "I've got to do aging."
When I thought about aging, I was like, "Okay, where do I go? Do I start a company immediately? Do I go into VC?" I realized that the aging space was very confusing and it was very hard for me to see what was the signal, what was the noise, what was real, and what wasn't. It felt worth it for me to spend years of my life on a PhD to figure that out. So I went to the Buck and I loved my time there.
Abhi: I haven't looked too much into the Buck. Do they have a pretty dogmatic thesis on what the causes of aging are and how to fix it, or is it pretty freeform and they don't take any particular stance?
Alan: No, not at all. That's the beautiful thing about the Buck, and that's the beautiful thing about the PhD program. Almost every single day, we would have conversations with my colleagues in the cafeteria or somewhere, just chatting about what aging is, what is the best way that you can interface with it. We had this program called "Think and Drink," where we literally just got wine, oftentimes with a relatively well-known person in the aging space, and just debated and lobbed questions at them, thinking about what aging is, how we can intervene here, and what's the best thing that we can do. We hosted the Buck Student Aging Symposium. We had our own in-house conference where we had speakers and presenters. So there is no particular thesis I think the Buck has. They're a little bit more healthspan-focused than lifespan-focused. They lean more on how can we live better, still longer, but on the living better aspect as opposed to the mortality crowd. But in terms of scientifically and intellectually, that was a place where all opinions were accepted.
Abhi: Do you feel that DNA protection mechanisms were covered well during your time at the Buck, or was that an area that they could have focused on more? How you've described this so far does feel like a relatively, even though the field has existed for a long time, it's taken a bit of a backseat to other fields. Does Buck give a very holistic overview of all the available approaches, or does it really focus on the things that feel the most promising in the last five years?
Alan: It's definitely much more all-encompassing. I'll say that there's no concrete genome stability lab at the Buck, for example, or a genome stability center. But genome stability pops up all the time. As an example, the research the Buck is really well-known for is this work in the senescence field. Of course, how does a cell become senescent? A whole variety of things, but genome stability is one of the main drivers of senescence. So you had a lot of people—postdocs, students, PIs—working on understanding genome stability in the context of senescence. Ditto, I was working with Dr. Eric Verdin, mostly focusing on immunology, but what drives a lot of immune dysfunction? What drives clonal hematopoiesis? That's mutations. So, wherever you look, whether you're primarily focused on genome stability or not, it always comes up.
[01:15:26] What are you bearish on?
Abhi: What is a subfield of longevity research or longevity therapeutic research that you don't personally think there's that much promise in, or perhaps is the furthest away from being in the clinic?
Alan: Those are two very different questions. The furthest away, on the most radical side of aging, there's this idea of doing whole-body replacement or even BCI, but from an extreme angle of you just chop off the body and have mind upload. That's super far away. I think a lot of people are excited about that field because they come into it from an engineering mindset. I think there's a very high representation of engineers who are really excited about replacement because they see it as an engineering problem. The reason why I think it's a long ways away is it's not an engineering problem, it's actually a biology problem that is masquerading as an engineering problem. If you talk to a doctor about how you would replace a spine, that is just a whole other beast. That is not an engineering challenge yet; it is very difficult medically and scientifically. Not to say that we won't get there and not to say that maybe that's the most promising path towards immortality for the individuals who are mortality-oriented, but it is a very long way away.
Abhi: What about the former question of something you view as not very promising?
Alan: I've been bearish on—there is very little evidence that thymic involution drives aging.
Abhi: I have no idea what that is. That's a brand new word to me.
Alan: Thymic involution. The first organ to age—this is also a debatable field; people will argue about what the first organ to age is—I will say the first organ to age is the thymus. You start to see the thymus falling apart even as early as the age of five. The thymus is really, really important. The thymus is where all of your naive T cells spawn from. The thinking is, if you've run out of naive T cells and you don't have the organ that creates naive T cells, then it's clearly going to negatively impact immune function. The downside is that there have been studies that have been done on patients who have had a thymus removed early, even as early as five years old, and it doesn't seem to really impact aging a whole lot. I think the reason why is that you make a lot of T cells and humans are pretty big, so as a result, you have enough T cells to last you past where you would naturally die.
I once chatted with someone, and he said, "Thymic involution would be a serious problem if we live to 150." There are a number of problems like that in aging where if we solved aging up to 150, then you suddenly get a whole new suite of problems. It seems like thymic degeneration is one of them. I'm less excited about ways to bring the thymus back.
Abhi: Purely because it's a problem—it's like an overpopulation on Mars problem. It's not something you expect to be an issue for a very long time.
Alan: That's what the literature says to me. Of course, the contrarian argument is that having more naive T cells is always better. So if you had more new naive T cells as opposed to old naive T cells, then that would be beneficial. But naive T cells also don't age a whole lot. So I've had a hard time with that.
[01:19:12] Weirder types of aging beyond 110
Abhi: This is interesting because I've long wondered, let's say we solve all six to seven hallmarks of aging, and we get to the 110 mark. Thymic degradation is the first thing I've heard of as where it really starts to be a problem. Is there something else that is like an end-game boss with regards to aging that only rears its head long past the natural lifespan?
Alan: In the immune space, that's the only one I can think of. I'm trying to see if there's anything else that also comes up, and nothing immediately comes to mind. I think the more time goes on, the more the extracellular matrix plays a role. You just have a lot of extracellular matrix proteins that have a certain half-life, and that half-life is measured in many decades.
Abhi: Do those turn over?
Alan: That's the thing. It's complicated. A lot of them do, but when they get turned over and get replaced, they get replaced poorly. Over time, you see problems with elastin, but the problem is that it's not even an end-game boss because you start seeing these problems even when you get to be 80, 90, 70, 60. We wrinkle, and a lot of that is ECM problems. I wouldn't say that's an end-game boss, but it becomes increasingly hard to deal with, I think, the older we get.
Abhi: Do you imagine that stuff like epigenetic reprogramming and DNA protection can only go so far and the final longevity treatment will be replacement? Is that how people in the longevity field generally think about it, or are there people who are full on "epigenetic reprogramming is all you need," "genome stabilizing is all you need," and if you have this in sufficient quantities, you will live to be 200, 300?
Alan: I think almost everyone thinks that it's going to be a combination of things. It also depends on the age. Again, if you're super old, if you're pushing your nineties, then probably replacement/reprogramming is the way to go. If you're in your twenties, then you're better off preventing aging and doing genome stability work. So there are a lot of ifs involved in there.
[01:21:37] How did you decide on DNA protection and what else would you have done?
Abhi: You've mentioned in the past that you decided on DNA damage prevention relatively early in your career. I think it was something you happened upon while you were at the Buck Institute. Was there some less-discussed approach to longevity that you were really wondering about and thinking that you should start a company in, or was DNA damage prevention the main thing you were curious about?
Alan: The way in my mind that I broke this problem down was as a healthspan or a lifespan problem. If I was trying to optimize for how do we make people who live better, longer, do you emphasize "live better" or "live longer"? Genome instability is harder, but I think it'll do both and it also will extend maximum lifespan. If we're thinking purely from the healthspan angle, I'm just very excited about targeting inflammation. BioAge has a LRP3 drug that I'm very, very excited by. I think that one of the primary reasons why people feel bad as they age is because of chronic inflammation. If there's one lever that I would pull to address that, it would be that inflammation side, especially innate inflammation.
Abhi: What would an alternative universe Alan have worked on that is perhaps not even in the longevity space at all? Is there such a thing?
Alan: There is. Conceptually, I love oncolytic therapies. This is coming back from my CAR-T world background. I love CAR-Ts. Again, Arsenal Bio was a great time, but you always have this antigen escape problem. If you train a T cell to recognize a single thing on a cancer cell and then kill it, then the cancer can just not make that thing, and then the CAR-T is not particularly effective. But there's the concept of oncolytic viruses. For everyone who's not familiar, you just take a virus or a bacteria and you put it inside of a tumor, and that leads to a number of things happening. One is that you kill the tumor itself using your virus, but the other thing is that your immune system sees the threat and it wakes up. It turns a cold tumor into a hot tumor because suddenly it sees not only is there a bacteria or a virus that's attacking the tumor cell, but suddenly there's also a tumor cell, and it only starts to recognize that once there are other immune signaling threats happening there. As a more generalized cancer therapy, I'm incredibly excited about that field, even though clinically it's been a little bit of a mess.
Abhi: I have heard a lot about this particular side of oncolytic therapies. Why do you think it has been such a mess?
Alan: It's just so hard to—you're toggling three things at the same time. If you have a virus that is too good, that is incredibly effective at killing the cancer cells but then doesn't get recognized by the immune system, then the tumor can kind of adapt to it and then the immune system never gets turned on and the virus slowly dies. You deal with your primary malignancy, but you don't do anything with the secondary malignancies because the immune system doesn't recognize the threat. If you have a virus that isn't strong enough and is too safe, then you don't have an effective therapy. If the virus is very effective and not safe, then you start seeing actual side effects in patients where you not only have cancer but you now have a very serious infection, which is also not good because cancer patients have notoriously not good immune systems. Dialing all of those to be the right level of safe, effective in terms of turning on the immune system, but also effective enough in terms of actually killing the tumor cells has proven to be very difficult. I think a lot of companies have worked on this and it's still a very promising field, but it's going to take some iterating, I think.
[01:25:27] What was it like raising money?
Abhi: I'd like to talk to you about your process of raising money for Permanence. Permanence sits in this place of not having a clear parallel to any existing therapeutic that's out there. At the same time, I also see a lot of VCs saying that they want new targets, but the people who are developing new targets often struggle with raising money. I'd like to hear about your fundraising journey and whether that was an issue for you.
Alan: I think there's a little bit of a difference between the tech world and the biotech world in this regard. In the biotech world, people have tweeted about this all the time and posted on LinkedIn of, "Look how many PD-1 drugs there are now, look how many TIGITs and CTLA-4s." Because biotech VCs, especially on the East Coast, really care about validation. They want to have something that they trust will work simply because every stage of the biotech/biopharma process is so expensive. You want to de-risk as much as you can, especially from the beginning. It's difficult to go to a biotech VC and fundraise on something very fundamentally new because it's just technical risk on top of personal risk.
For tech VCs, the way that tech has been so successful, you hear about the power law a lot. The idea is 95% of things will fail, 5% of things will be incredibly successful and become unicorns. You really only need to bet on—if you have a VC fund and you bet on 99 things that go to zero, but you bet on one thing that is a 1,000 to 10,000x, then you've returned your fund 10 times over, so you're very happy. The appetite towards risk is extremely different in the tech world. Biotech VCs have been incredibly helpful and were very useful in terms of, "Hey, look, here are the things that we would want to see when we invest eventually." But early on, it was the tech world that was the most helpful to me because what they saw was, "Hey, there's a guy who's trying to prevent cancer. There's a 95% chance it's not going to work because it's a very difficult journey, and that's entirely valid, but there's a 5% chance that it succeeds and you prevent all of cancer." That is going to be massive. It's worth investing in. So I think leaning into that was very helpful for me and was how I managed to fundraise.
Abhi: The way that I've heard one tech VC actually describe the biotech VC world is that the managing partner at these firms looks at what the top 20 pharma chiefs of science are interested in and just does aggressive M&A to try and find the people to invest in who will appeal to one of those 20. Do you imagine that whatever Permanence produces will eventually be acquired by a big pharma, or will you take this drug to the finish line?
Alan: That's a good question. We'll see. The way that I've always presented it, especially to investors, is that there are different paths that Permanence Bio could take. Our dream is cancer prevention. Our dream is longevity too, to prevent disease as early as possible. At this stage, that is a hard sell and I am contrarian enough to try my best to do it. It seems like we have some early success and hopefully, that success continues. So long as we can see success moving into cancer prevention, we want to be the number one cancer prevention company.
There is a world out there in which genome-stabilizing drugs turn out to be very effective for a whole variety of different diseases. I mentioned dry AMD and maybe ALS. But the cancer prevention thing is just too much of a lift. In that case, we'll have a very effective drug against, insert acute indication here. Maybe we'll get acquired, and that can be more of the strategy. But I think so long as cancer prevention is on the table, we want to do it.
Abhi: When you were raising for Permanence, how difficult was it to tell the story at first?
Alan: Very. There was a huge shift between how the narrative played out. The challenging aspect was that I came from a PhD for three years and then did VC for a very brief period of time and then dove right into building a company. That PhD mentality, even the kind of conversation we're having now, it's hard to unwind. You have to unwind it when you're trying to raise for a company, especially among tech investors. I remember my first pitches, the first narratives I had were like, "Oh, you know, aging and genome instability are really important in aging, and if you can prevent genome instability, then you can prevent other forms of hallmarks of aging that then leads to other diseases." Boy, everyone was bored immediately.
So what I pivoted into instead was focusing on the cancer prevention aspect because people really thought that was interesting and different and unique, and it had a huge potential upside. The narrative became much more into, "Cancer is a function of mutations and inflammation. No one's targeting that mutations aspect. We can. We know how." So let's just do that. Let's build drugs that prevent mutations and then we prevent all of cancer. That was a really compelling story.
Abhi: Was it a matter of removing the science and not explaining the exact specifics of it? How important was that? How much did tech investors practically care that you're doing one modality versus another modality?
Alan: It's both. I think it's both making the vision grander. It seems weird, right? Because cancer prevention is theoretically a less grand vision than longevity, but longevity means a lot of things to a lot of people.
Abhi: It's kind of a squishy definition. It's like you can put whatever you want inside. Cancer is a little bit more definitive.
Alan: Cancer prevention specifically is a much more defined big goal. Then, taking the science down a notch from genome instability—I mean, even the first 10 minutes of our conversation today was like, "What do you mean by genome instability?" It's this whole thing. But instead, just "mutations." Focusing on mutations because people know what that is and everyone can agree on a definition of what a mutation is. I think that grounded it for a lot of folks.
[01:31:48] What do you think of past cancer prevention trials?
Abhi: Why do you think the existing cancer prevention trials, or the past ones, have failed?
Alan: It really depends on which ones. There's a very long cancer prevention history, and to be honest, I'm only familiar with some of it. For example, people very early on realized that aspirin is very effective at being a chemopreventive agent. Big pharma also realized that aspirin seems to prevent cancer by pretty significant margins, specifically colorectal cancer. Aspirin has a few less-than-ideal side effects, especially at high doses. What a lot of big pharma companies did was they were like, "Okay, let's take aspirin and then improve its targeting, I want to say its COX-1 or COX-2 targeting, but one of the two specifically, and then improve that angle to make it a safe thing and then really target that one mechanism, and then that will be the best ever cancer prevention drug that will be like aspirin." The sad thing is, and this is still, I think, very controversial, there isn't a clear answer, but from reading the literature deeply, it seems like aspirin prevents cancer through a weird off-target mechanism. So pharma, having spent hundreds of millions, possibly even billions of dollars into cancer prevention, improving these drugs for a mechanism that was incorrect, the appetite just died after that because there was a lot of investment and a lot of hype and a bunch of failure, but they were just going after the wrong thing. So I think that's part of the reason.
Abhi: When was that? Early 2000s? Do you think we're coming back into the cycle of people being really interested in cancer prevention, or is it still a little bit outside of the Overton window?
Alan: It's coming back. The first-ever, I want to say, the first-ever cancer prevention conference was hosted a year ago. The second one is actually happening, I think, possibly right now in the UK. More and more people are thinking about it. The big boon here is that we're getting the technologies to measure genome stability coming online. Of course, there's Alex Cagan's big paper looking at aging and somatic mutations with aging and showing there's a crazy strong correlation between how quickly a species gets mutations and its lifespan. That technology just didn't exist even five or 10 years ago. The fact that the tools are coming online to develop these drugs, to measure these things, the biomarkers in the blood exist now, I think it's bringing a lot of fresh air into cancer prevention.
[01:34:12] What does good wet-lab talent look like?
Abhi: Permanence Bio, I think, just hired its first person, at least according to the LinkedIn post. You posted a job posting, and last I checked, it seemed to be offline. I assumed you hired someone. If so, congratulations. I'm curious, what were you looking for in a founding scientist, the first few employees?
Alan: Details. The main thing that is challenging about cancer prevention and genome stability, I would say, is how do you set up these assays? How do you measure mutations? That is, if you've looked at a whole-genome sequencing pipeline specifically looking at DNA mutations, it is complicated. Every single little enzyme that you use, the steps that you use, the read depth you analyze it at, all of that matters so, so much. We brought on our first hire, Carlos, who I knew from my PhD. He's the smartest guy that I knew in the PhD program, and I felt very lucky that he offered to join. He's got such an eye for these particular details. He knows exactly, "This experiment failed. I'm going to test these four things and that's going to make it work." Detail orientation, I think, helped a lot.
Abhi: What do you think leads to that? Is it just extremely high conscientiousness, a lot of past experience, very high fluid intelligence, or something else entirely?
Alan: Obsession.
Abhi: Obsession with getting things correct, obsession with the field as a whole, or what is it exactly?
Alan: It's more of that engineering obsession of how do you solve a puzzle, how do you troubleshoot this thing and make it work.
Abhi: Do you think there is such a thing as 10x wet lab biologists?
Alan: Yes. Easily. Yes. Absolutely.
Abhi: And you think it comes down to this detail-oriented approach?
Alan: I think it comes down to probably two things. One is the detail orientation. I think that helps a lot. There are a lot of scientists who can spend a lot of time and effort on something that, because of the details, fails. But it's also about asking the right questions. I think probably asking the right questions is the more important part of that. It's so easy to spend, especially because biology just takes so long, months, if not years, beating your head against the wall for something that, in the end game, doesn't really matter. The people who I think have been incredible scientists are the ones who see a gap that they can solve and they figure out how to solve it.
[01:37:02] What does your information diet look like?
Abhi: What does your information diet look like? If I scroll through your Twitter page, you often post links to papers that are completely unrelated to the field that you're working in, but you find some way to connect it and you say, "Hey, this is super relevant for DNA protection mechanisms." Do you spend relatively little time reading papers in your own immediate field and instead search for "alpha" in other fields, or is it a mix?
Alan: It's a mix. I think this is also more of a deeply personal thing and not my philosophy towards life in general, which is to surround myself with things that I like. To a large extent, we are a product of our environment. To what extent can you surround what you see and what you experience with the kind of person that you want to be? My Twitter is actually a really good example of that. I follow a relatively small number of people, and for everyone that I follow, all of them talk science. That is their main thing. There are a number of people that I would feel awkward not following because they're like a close friend or something, and they've posted other stuff. In which case, every single person that I have there that doesn't post on science, I mute. So my Twitter feed, and I never go into the "For You" tab, I only go into the "Following" tab. When I scroll Twitter, I only see scientific papers, scientific discussions, maybe some founders, and now kind of more oriented in that direction, biopharma discussions as well. Just surrounding myself with that knowledge.
With regards to papers, I have Google Scholar alerts for cancer prevention, lifespan, DNA repair, kind of everything that I'm interested in there. I also try to surround myself with people who think about these things a lot. I'm part of a genome stability journal club group chat on WhatsApp where it's just like 30 people who are all obsessed with genome instability. We meet once a week to discuss some paper. We literally had that today. I spent an hour debating whether or not mitochondrial DNA mutations are a causal driver of aging and what the evidence for that is right now. A lot of my other communities are also oriented in a similar direction. So it was just a non-stop input stream of relevant information.
Abhi: I know at least one person in the pure machine learning world who says that a lot of the best papers of today are worth reading, but the best papers of 30 to 40 years ago are also worth reading, and no one is reading those. Is there something akin to that also in your space where you read papers from the eighties and nineties, or are they not super relevant?
Alan: They're very relevant, but I think much more from a—I've found a lot of joy in reading old theory of biology or theories of aging papers. I've been trying to dive into those less now that I'm very much heads-down operational, but still, thinking about how people saw things big picture is pretty important, especially as we go into, I start to sound very old now, but as we go into a world where everything is sped up, going back to a time when people thought very big picture, I think, is helpful.
[01:40:06] What's it like going from research to being a CEO?
Abhi: You went from three years of doing research in your PhD and I imagine also your time at Arsenal, and I imagine you did some research during your undergrad. I imagine your day-to-day is not too much bench work research and is more being a CEO. What's that transition been like?
Alan: It's both. It's the best of both worlds. My day-to-day is I come into work at 9:00 AM and then I take my meetings from 9:00 AM until 1:00 PM, and then I put on a lab coat from 1:30 until 10:00 PM and then I do science. So it's both, actually. It's a beautiful mix of both. I think it's both things that I feel very comfortable in. I love operating and I love science, and at least for this period in Permanence Bio's history, which I think will probably not last a whole lot longer, the best use of my time, the most alpha I can bring to the organization, is in my scientific knowledge. Right now, I'm still harnessing that. I imagine two years from now that's going to be much less the case and it's going to be mostly CEO hat.
Abhi: You guys are roughly eight months old, I think. Is that correct? Incorporated in October, so eight months. At some point, I imagine you're going to have to make a decision of whether you want to be the full-time operator versus the full-time scientist or the full-time CSO of the company. Do you know if you're leaning one way or another?
Alan: I think much more the CEO hat than a CSO hat. I think I'm very good at vision, like seeing and connecting the dots between, "We have a vial of a hundred micromolar of some compound that we want to test in some assay," and seeing how the dots connect towards how can we prevent cancer in the general human population. I think that is kind of, exec coaches like to say, the "zone of genius." The zone of genius that I think I have is I can connect those dots, and I think that's very hard for a lot of other folks. I'm a pretty good scientist, but I wouldn't even—I think there are a lot of very, very, very good scientists out there who are much better than I am that I would love to hire and bring on. I don't think I'm as needed there.
[01:42:20] What happens after cancer prevention for Permanence?
Abhi: Big picture view, and I think this is the last question that I'm going to ask. Over the next 10 years, let's say whatever Permanence is working on works really well for a specific type of cancer, do you imagine you'll keep poking away at improving, like moving whatever therapies you have into other subtypes of cancer, or would you switch to a different indication entirely?
Alan: We'll follow the data. If our assays show that it's really powerful in some acute disease model, then we've got to do that. But if it doesn't, then yeah, just keep moving into cancer.
Abhi: Cool. Thank you for coming onto the show, Alan.
Alan: Thank you so much. This was a lot of fun. Hours of yapping on my favorite topic, so thank you so much.
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