For listeners who aren't familiar, tell us about NewLimit. What are you and the team building?

NewLimit is working on a new type of medicine based on an idea called epigenetic reprogramming. And we're trying to do something a bit unique with those medicines as well, which is add happy, healthy years to the median American's life, as opposed to treating very narrow populations as traditionally defined as specific diseases.

If we look at the basic building blocks of the science, you've described epigenetic marks as the control flow of the genome. What goes wrong with those marks as we age, and how is what you and the team are working on aiming to fix that?

I'll start with just introducing a bit of what these marks are. Every cell in your body has the same DNA, which is something that almost all of us learned fairly early in life. But if you sit and think about it for a second, it's actually pretty profound to then recognize that all of the cells in your body are nonetheless doing very different things. Your eyes do different things than your kidneys and your tongue and your liver. And really what controls that diversity is that on top of your DNA code, which is the same everywhere, you have these epigenetic marks that tell your cells which genes to use at which times. Just as you alluded to, the analogy I often reach for is that they're like control flow in software. When a user hits an application, not every line in the code base runs at the same time. Depending on the context, you navigate through different code paths, and cells are very similar in that way.

So as you age, unfortunately, what happens is those marks can get, for lack of a more rigorous technical term, messed up. They begin to change in such a way that your aged cells no longer use the right genes at the right time. And that means that they're less functional when called into action, when you face an environmental insult or an infection, or many of the other challenges that meet us with age. And so your incidence of not just one or a couple diseases, but nearly all possible pathologies that affect us, increases rapidly and concomitantly, all at the same time, because your cells are losing function.

I want to take a step back and talk about longevity science, because it hasn't been an area that a lot of scientific R&D dollars have been invested into, and it seems like the tide might finally be starting to shift. Why is that? Were there scientific unlocks over the past few years that enable a company like NewLimit to exist, or something else?

I think both are true. The problems of aging biology are much more nascent than the problems in some other therapeutic areas, as we'd call them in the business, different types of diseases or challenges you might treat. And so it requires really ambitious founders and capital partners to embark on trying to solve them, period, regardless of the technology unlocks.

And then likewise, there are discoveries and tools that have emerged over just the past decade, really, that make a company like NewLimit possible. Two are really critical for us. On the technology side, there's the ability to profile individual cells, so we can take a cell from a human or an animal, profile all the genes it's using at the same time, and then learn a lot about whether some intervention we've made, some potential medicine we've treated that cell with, made it look like a younger version of itself in a way that we think might be therapeutic. Before that technology emerged, the number of experiments you could imagine running here, the number of interventions you might imagine testing, was fairly small. It was very hard to test hypotheses.

The second key unlock for us was modern AI tooling. The types of interventions we're thinking about use combinations of special genes called reprogramming factors that run around on your genome and rewrite those epigenetic marks we had a chance to talk about earlier. Because it involves combinations, the number of potential medicines we could test is about 10 to the 16th, which is a stupidly large number, so to speak. It's about 10,000 times as many stars as are in the Milky Way. So no matter how clever you are, you just can't do all those experiments. What these modern AI tools allow us to do is take what we know from searching a subset of that space and then be really rigorous in prioritizing which experiments we actually go run in the real world. Even with all these fancy single-cell genomics tools, we're still many, many orders of magnitude from exhaustively searching the space. And so using those models allows us to prioritize in a way that really wouldn't have been tractable for humans. For us, that's really the confluence of technological trends that has gotten us excited about the biology.

There's another key piece here as well, which is that the biology we're working on, epigenetic reprogramming, had its earliest existence proofs a couple decades ago with the advent of something called pluripotent reprogramming. Take an old cell from a mouse about to die, and you can turn on just a few of these special reprogramming factor genes, turn that old cell back into a young cell, and then turn that into a mouse with a whole normal life ahead of it, really resetting the age of that cell with a pretty simple four-gene manipulation.

It wasn't until about 10 years ago that it was demonstrated there are some hints you might be able to decouple two things happening in that process. In that classic discovery, you change a cell's age and its type at the same time. Take an old cell, make it a young stem cell. That's really cool in a lab, but that's not a medicine. I don't want to turn you into a bag of young stem cells. That probably wouldn't be very beneficial. And so there were some hints about 10 years ago that you might be able to reprogram just age without reprogramming type. I say hints because no one knew for sure. What we've been working on at NewLimit is testing new combinations of these special factors to figure out whether we can decouple those two things. And we're happy to say today that we have evidence that makes us believe that really is possible and might allow us to unlock therapeutics going forward.

Do you think you could not have started this company without what has happened in the AI landscape over the past three to five years?

I definitely think that's true, maybe going back even further than three to five years. Something like going back a decade to the AlexNet moment in deep learning is the original takeoff point, the hinge point in that curve of intelligence as a function of flops over time that I like to think about. Prior to that moment, it wouldn't have been tractable for biologists using the classic tools to search a hypothesis space this large.

The advent of molecular biology, the discipline a lot of modern drug developers were originally trained in, is premised on the notion that there are a small number of very important genes. You can break one of them at a time, and that'll teach you how biology works. That mentality took us really far, actually. It helped us create many of the medicines we enjoy today. But unfortunately, biology is more complicated than that, in the same way that even a car, or famously in one article, a radio on your desk, involves multiple parts interacting together, and ripping one out at a time can't really explain how the full ensemble is performing at once.

So I think these modern ML tools give us a way of observing how the systems behave overall in aggregate, and then making predictions about what might happen next. Without those tools, searching the types of medicines we're thinking about, combinations of very complex genes, just wouldn't be tractable. You'd have to be absurdly lucky to maybe discover something like we've discovered today using these models to help recommend what we should do.

You're starting with alcohol-related liver disease, specifically with mRNA delivered via lipid nanoparticles. Out of everything you could work on, why start there?

The first is that it is most tractable, once we discover that set of factors we talked about, these special reprogramming factors, to turn those into a medicine by delivering them as mRNAs. These are actually normal genes that exist in your genome, and that's the way your body uses them. It makes mRNA from your DNA, that makes some proteins, and then that goes on to reprogram your epigenome. So once we get a list of what those TFs are, it's actually pretty straightforward to turn them into a drug using mRNA medicines, which is a really incredible technology that's also only about 10 years old.

Now, the reason for using lipid nanoparticles is that it's one of the very few ways we've found to safely, transiently, and repeatably dose something like an mRNA into a human. And one special fact about the liver, which helps explain why we chose it as one of the first places to go, is that part of its job in your body is to scavenge all of the fat from your bloodstream and pull it up into your special liver cells, which are called hepatocytes, which is unfortunately just Greek for liver cell. So if you wrap mRNA in a tiny fat bubble, which is really what a lipid nanoparticle is, that means tiny fat bubble in scientist language, then by default, your liver is going to pull that in. I like to think of it as a Trojan horse. You can get whatever RNAs you'd want into the liver just by wrapping them in fat.

That means that if we can get reprogramming factors into the liver, a really great place for us to start is to look at challenges that emerge in patients as a result of their liver aging. If we can make their liver younger, effectively, by reprogramming those hepatocytes back to a youthful state, can we actually provide benefit to them? Alcohol-related liver disease is one really interesting opportunity where, unfortunately, patients today have almost no therapeutic options. When you're diagnosed, there really aren't any treatments available other than liver transplant, and liver transplants are unfortunately incredibly limited. So for many people, they get diagnosed and it's effectively a death sentence. This is an area where, even for a new medicine like reprogramming, we think we can provide a lot of benefit to these patients who might not otherwise have that opportunity.

We also think their disease resembles some of the problems that develop in all of us as we get older. So if we're able to find efficacy there, we think it means we'll be able to expand out to other indications. This is very similar to how medicines like the GLP-1s, Wegovy and Ozempic, that many people are familiar with were originally developed. They didn't originally start as obesity or weight loss medicines. They started as medicines for diabetes. And after showing efficacy in that smaller population, who saw a lot of benefit from it early on, you can start to expand to broader and broader pools. Our hope would be that a medicine like that could eventually address something like metabolic syndrome, which is a challenge that emerges in about half of all people as we get older. We start to get heart attacks, diabetes, and strokes more frequently than we'd hope to. So we imagine if you could make the liver younger, you'd start to address that really common challenge as well as this much more specific one we're starting in.

What might be the second or third parts of the body you would look to expand to? And beyond that, when we think about human healthspan versus lifespan, which is something you all have talked a lot about, which area of the body do you think will be most high-leverage for extending healthspan versus simply lifespan?

We've already identified a couple of other tissue systems we're going after. We have programs in the immune system and immunology focused on T cells. These are one of the special cell types that recognize pathogens when they invade your body. They both directly attack the pathogen and also send a call out to the rest of the immune system to bring the whole army marching in to combat it. As you age, these cells lose function, and it leads to an increased susceptibility to infectious diseases and also cancers, because people don't recognize. We actually all develop tiny cancerous outgrowths quite often, but your immune system protects you and clears them. And as we age, one reason that many hypothesize we start to develop more cancers is that we lose the ability to surveil ourselves and clear these out before they become more challenging. The immune system is actually everywhere in your body. It's not just one special tissue in one special portion. It's inside every other tissue. So there's a lot of evidence to suggest that a healthier immune system would benefit you in myriad different ways, not just when you've got an infection.

Similarly, the next cell type we're working on is actually the endothelial system. Folks might not know what an endothelial cell is, but we've all heard of veins, arteries, and capillaries. It turns out endothelial cells are basically the building blocks around the walls of all those blood vessels. I like to think of them as the pipes in your body. There's the famous Al Gore (Ted Stevens) quote that the internet's a series of tubes. Well, you're a series of tubes that are endothelial cells. And it turns out these cells are constantly breaking down and rebuilding themselves, but as you get older, they lose the ability to rebuild. So you start losing these over time, and you're no longer getting the amount of blood flow and delivery that you need to all your other tissues.

This leads to a number of challenges. A couple of prominent examples: in your kidney, it can contribute to chronic kidney diseases, which are really difficult to solve. Actually, 7% of all Medicare spending is just dialysis, which is a truly massive number when you think about the amount of money that goes into trying to just symptomatically treat that one problem. It contributes to cardiovascular disorders. And one shocking one many folks don't realize is that it's a contributor to cognitive decline, because as the endothelium breaks down, things get into your brain that aren't supposed to be getting in there. It's suggestive in animal models that that's part of the reason we encounter many neurological challenges as well.

So those are a couple of areas where, to your framing, we hope that by providing benefit in that one tissue system, because these systems are inherently in every part of your body, you're going to see a much larger knock-on benefit. And we can imagine adding healthy years of life rather than just the weeks or months that might result from treating one narrow or more specific disease.

Jacob, thanks so much for joining today. I think you and the team are, number one, doing some incredibly special work. But number two, and I think most importantly, if you're successful, I'm looking forward to living in a world where many age-related conditions are preventable, and thinking about the implications of what that means socially and economically. It's a great future ahead. So I appreciate you joining. Congrats again, and thanks for taking your time today.

I appreciate it.