YouSaid · the spoken record

Jacob Kimmel

lines on the record: 109
first: 2025-08-21
most recent: 2025-08-21
sittings or episodes: 1
sources: podcast

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“Environment I want to sense to perform some function. And then I have some sort of payload that I deliver. Carti's engineer, the first of those and leave the second exactly the same as the immune system does. So they engineer, go recognize this other antigen that you wouldn't usually target some protein on the surface of a cell, for instance, and then deliver the payload you would usually deliver if it was infected by a virus or if you saw that it was foreign in some way, whereas cancer cells usually don't actually look that foreign. Most of their genes are the same genes that are in your normal genome, and that's why it's hard for the immune system to surveillance.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Not literally every single cell. I'll like asterisk it there. So, for example, T cells don't go into your brain. You don't have, they can, but it's generally a pathology when they get in there. So it's not like literally every cell, but almost every cell in your body is surveilled by the immune system. So there are very, very few what we call immune privileged compartments in your body. It's things like the joints of your knees and your shoulders, your eyeball, and your brain, basically. There might be a couple other ways. I think the ear probably falls into that category. A funny way of thinking about this is all the gene therapy people using viruses, they want to deliver to the immune-privileged compartments because their drugs are immunogenic and they're limited to a very, very small set of diseases. So in a way, it's like the shadow of all the diseases you can't address with viruses is what you can address with cells. And given the complementarity between them, it's like, okay, you can probably cover the entire body. And so they can't literally go everywhere. But I think your analogy to the CAR-T work is very apt as well, where you can think about that two-component system. I've got some detection mechanism for the”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“With in terms of encoding all your logic. So I think that's ultimately how delivery will get solved. We've got many, many stepping stones along the way. But if I could clone myself and work on an even riskier endeavor, that's probably what I would do.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Particular areas of the body that we want to find, and then some sort of payload delivery system. I can deliver some arbitrary set of things. And I imagine if we were to rip von Winkle ourselves into 2100 and wake up, the way we will be delivering these nucleic acid payloads is actually by engineering cells to do it to perform this very ornate function. Those cells might actually live with you. You probably will get engrafted with them, and they might persist with you for many years. They deliver the medicine only when the environment within your body actually dictates that you need it. And so you'll actually won't be seeing a physician every time this medicine is active, rather you'll have a more ornate, responsive circuit. The other exciting thing about cells is that they're big and they have big genomes. And so you actually have a large palette to encode complex infrastructure and complex circuitry. So you don't need to limit yourself to the very small RNAs you can get in that might encode a gene or two or in our case a few transcription factors. You don't have to limit yourself to this tiny AAV genome that's only a few kilobases. You've got billions of base pairs to play.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“And then deliver some important cargo there when some set of events happens. How do I find a specific place and only near those cell types release my cargo? And really the problem was solved by the immune system. So we have cell types in our body, T cells and B cells, which are effectively engineered by evolution to run around, invaginate whatever tissues they need to. They can climb almost anywhere in the bodies. There's nowhere they can't get access almost. And then once they sense a particular set of signals and they've got a very ornate circuitry to do this, they run basically an AND gate logic, they can release a specified payload. And right now, the way our genome sets them up, the payload they release is largely either enzymes that will kill some cell that they're targeting or kill some pathogen, or some signal flares that call in other parts of the immune system to do the same thing. So that's super cool. But you can think about it as a modular system that evolution's already gifted us. We've got some signal and environmental recognition systems, so we can find”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“If you think about viral vectors, no matter what, they're always going to be some amount of mutagenic. You're always going to have your immune system trying to fight them off. You can play tricks. You can try and cloak them, etc., etc. But they're always going to have some toxicity risk. They also don't go everywhere. It's not that we have examples of a single viral species that infects every cell type in the body, and we just need to engineer it to make it safe. We would have to also engineer the virus to go to new cell types. So there's some limitations there. LMPs likewise have some problems. They can go to tons of cell types. That's what largely we're working on. We're super excited about it. But there are some physical constraints. They just have a certain size, and they have to get from your bloodstream out of your bloodstream toward a given target cell, and they have to not fuse into any of the other cells along the way. So there's a whole gamut they have to run. Ultimately, I think we're probably going to have to solve delivery the way that our own genome solved delivery. So we have this same problem that arose during evolution, which is how do I patrol the body, find arbitrary signals in the environment?”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“You have only one? I have any controversial opinions. One of them is that I think both of these probably in the limit will not be the way that we're delivering medicines in the year 2100”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“So, I think both of those methods are super promising. Again, if nothing else emerged for decades, we'd still have tons and tons of problems as a therapeutic development community to solve even using just those. I do think I have one sort of very controversial opinion, which people can roast me for later. You have one?”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Another prominent way people go after this is using viral vectors. The basic idea being viruses had a lot of evolutionary history and very large population sizes. They've evolved to get into our cells. Maybe we can learn something from them, even better Trojan horses. So one type of virus people use a lot is called NaV. Those AAVs carry DNA genomes, and so you can get genes, whole genes into cells. They've got some packaging sizes. You can think of it kind of like a very small delivery truck, so you can't put everything you want into it. They can go to certain cell types as well. And then on top of just where do you actually get the nucleic acid to begin with, you can engineer the sequences a bit. And that basically allows you to add like a notgate on it. You can make it turn off the nucleic acid in certain cell types, but you're never going to use the sequence engineering to get nucleic acid into cells where it didn't get delivered in the first place. So you can sort of start broad with your delivery vector and then use sequence to narrow down to make it more specific, but not the other way around.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“And I think the field is making a lot of progress on being able to target various different cell types with lipid nanoparticles. So even if nothing else worked for the next several decades, I think companies like ours would have more than enough problems to solve. And with the cells that we can actually target.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“How do you deliver stuff? How do you get them in there? So I think there are many ways one could imagine solving it. I'll sort of like narrow the scope of the problem to saying, I think delivering nucleic acid is a pretty good first order primitive. Ultimately, the genome's nucleic acids, the RNAs that come out of it are nucleic acids. So if you can get nucleic acid into a cell, you can drug pretty much anything in the genome effectively. You can reduce this problem to asking, how do I get nucleic acids wherever I want them to any cell type very specifically? So today there are two main modalities that people use, both of which have some downsides. The first one that we've touched on already is lipid nanoparticles. These are basically fat bubbles. And by default, they get taken up by tissues which take up fat like the liver, and they can be used sort of like Trojan horses. So they can release some arbitrary nucleic acid, usually RNA, maybe encoding your favorite genes, in our case transcription factors, into this all types of interest. You can play with the fats, and you can also tie stuff onto the outside of the fat, like you can attach a part of an antibody, for example, to make it go to different cell types in the body.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Have a particular sequence, they bind to it, and often they just like stop it from working by glomming a big thing onto the side. So those are too big to get through the cell membrane, so then they can't actually get to a TF or do anything directly. So we take these bank shots. What changes that today, and why I think it's pretty exciting, is we now have new nucleic acid and genetic medicines, where you can, for instance, deliver RNAs to a cell that can get through using tricks like lipid nanoparticles. You wrap them in a fat bubble, looks kind of like a cell membrane. It confuse with a cell, put the mRNAs in the cytosol, you can make a copy of a transcription factor there, and then it translocates the nucleus the same way a natural one would and exerts its effect. And likewise, there are other ways to do this using things like viral vectors. But I think we've only very recently actually gotten the tools we need to start addressing transcription factors as first class targets rather than treating them as like maybe some ancillary third-order thing that's going to happen.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Traditionally, we use what are called small molecule drugs, where they're defined just by their size. The reason they have to be small is they need to be small enough to wiggle through the membrane of a cell and get inside. Then you run into a challenge, which is if you want to actually stick a small molecule between two proteins that have a pretty big interface, meaning like they've got big swaths on the side of them that all sort of line up and form a synapse with one another, then you would need a big molecule in order to inhibit that. And it turns out that TF's binding DNA is a pretty darn big surface. And so small molecules aren't great at disrupting that and certainly even worse at activating it. So small molecules can get all the way into the nucleus, but they can't do much once they're there. They're just too small. And then the other classic modalities we have are recombinant proteins. We make a protein like a hormone in a big fat. We grow it in some Chinese hamster ovary cells. We extract it. We inject it into you. This is how, for instance, like human insulin works that we make today, or you make antibodies. Antibodies produced by the immune system. These run around and find proteins.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Have that, for instance, inhibit a particular cytokine that might bind a receptor, or they block that receptor directly, or maybe they hit a certain signaling pathway. Ultimately, the way that they're exerting their effect is then downstream of that signaling pathway, some transcription factor is either being turned on or not turned on, and you're using different genes in the cell. And so we're kind of taking these crazy bank shots because we can't hit the TFs directly. So that sort of begs the question, like, why can't you just go after the TF directly?”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Reservoir within human cells. So it's just one example offhand. Then there are a number of other pathogens, and unfortunately I don't have quite as much molecular detail on some of these, but they will interface with other parts of the cell that eventually result in transcription factor translocation to the nucleus and then transcription factors being active. This actually segues a little bit to your second question on why aren't there more medicines targeting TFs. In a way, I think many of our medicines ultimately downstream are leading to changes in TF activity, but we haven't been able to directly target them due to their physical location within cells. And so we go several layers upstream. If you think about how a cell works in sensing its environment, it has many receptors on the surface. It has the ability to sense mechanical tension and things like this. And ultimately, most of what these signaling pathways lead to is to tell the cell, use some different genes than you're using right now. That's often what's occurring. And so that ultimately leads to transcription factors being some of the final effectors in these signaling cascades. So a lot of the drugs we”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Hep C can both do this sort of like latent sort of behavior. And so HIV is probably the most pernicious of these. And one way it does it is this gene called TAT actually interacts with NFKB. NFKAB is a master transcription factor within immune cells. Typically, if I'm going to horribly reduce what it does and some immunologists can crucify me later, it increases the inflammatory response of most cells. They become more likely to attack given pathogens around them on the margin. And so it'll turn on an F-kappa B activity and then uses that to drive its own transcription and its own life cycle. And so I can't remember quite all the details now exactly of how it works. But part of this circuitry is what allows it to in some subset of cells where some of that upstream transcription factor machinery in the host might be deactivated. It goes latent. And so as long as the population of cells is infecting always has a few that are like turning off the transcription factors upstream that drive its own transcription, then HIV is able to persist in this latent”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Yeah, yeah. Why don't we have a million of these pills? Okay, I'll try and take those in stride, and they're pretty different answers. First answer is there actually are pathogens that.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Yeah, or Eddie Chang has found like positional encodings, probably exist in humans using neuropixels. If you haven't read these papers, oh, yeah. So he implants these neuropixel probes into individuals. And then he's able to talk to them, look at them as they read sentences. And what he finds is that there seem to be certain representations which function as a positional encoding across sentences. So they fired a certain frequency and it just increases as the sentence goes on and then resets. And so it seems exactly like what we do when we train large language models where you've got some function.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“We love this. I don't know about your audience, but you will. You can kind of think about it like, you know, if you think about how attention works, like queries, keys, values. TFs are kind of like the queries, the genome sequences they bind to are kind of like the keys. Genes are kind of like the values. And it turns out that structure then allows you to very efficiently in terms of editing space. You can change just one of those embedding vectors, in this case one of those sequences, and get dramatically different performances or total outputs. And so I do think it's kind of interesting how these structures recur throughout biology, you know, in the same way that the attention mechanism seems to exist in some neural structures. I think it's kind of interesting that you can very easily see how that same sort of querying and information storage might exist in the GLA.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“I don't know about that, but if I can give you, I'll give you like a real cringe analogy that sometimes I deploy, but it requires a very special audience. I think you'll probably be the one who fits into it.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Evolution's levers upon the broader architecture of the genome. And so by pulling on those same levers that evolution has gifted us, there are probably many useful things we can engender upon biology.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Yeah, yeah, in a way. And to think, why would transcription factors, maybe this is getting a little bit too gigabrained about it, but why is the genome even have transcription factors? What's the point? Why not just have every time you want a new cell type, you engineer some new cassette of genes or some new, totally de novo set of promoters or something like this? I think one possible explanation for their existence rather than just an appreciation for their presence is that while having transcription factors allows a very small number of base pair edits at the substrate of the genome to lead to very large phenotypic differences. If I break a transcription factor, I can delete a whole cell type in the body. If I retarget a transcription factor to different genes, I can dramatically change when cells respond and have hundreds of their downstream effector genes change their behavior in response to the environment. And so it puts you in this regime where transcription factors are a really nice substrate to manipulate as targets for medicines. In some ways, they might be like”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Changes at the level of sequence at a given time. Evolution needs a substrate where in order to function effectively, these small changes can give you relatively large changes in phenotype. Otherwise, it would just take a very long time across evolutionary history for enough mutations to accumulate in some duplicated copy of the gene for you to evolve a new TF that does something interesting. And so I think we're actually in most cases in biology, due to that evolutionary constraint. Small edits need to lead to meaningful phenotypic changes in a relatively favorable regime for generic gradient-like optimizers. It would be maybe a little bit overstating to say evolution is using the gradient, but there is a system kind of like, if you've heard of evolution strategies where basically the way you optimize parameters is you can't take a gradient on your loss, so you make a bunch of copies of your parameters, you randomly modify them, and then you compute a gradient on your parameters against your loss. And so you can take a gradient in that space. That's kind of how I imagine evolution is working. And so you need lots of those.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Yeah, yeah, that would be very much my contention. And one piece of evidence for this is that's the way the development works. It's kind of a crazy thing to think about, but you and I were both just like a single cell, and then we were a bag of undifferentiated cells that were all exactly alike. And then somehow we became humans with hundreds of different cell types all doing very different things. And when you look at how development specifies those unique fates of cells, it is through groups of these transcription factors that each identify a unique type. And in many cases, actually, the groups of transcription factors, the sets that specify very different fates, are actually pretty similar to one another. And so evolution has optimized for being able to just swap one TF in or swap one TF out of a combination and get pretty different effects. And so you have this sort of like local change leading to local change in sequence or gene set space leading to a pretty large global change in output. And then likewise, many of these TFs again are duplicated in the genome. And because mutations are going to be random and they're inherently small”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Like math on the back of a napkin in order to just screen through all of those, you would need to do many orders of magnitude, more single cell sequencing than the entire world has done to date cumulatively across all experiments. And so it's just not tractable to do exhaustively. And so that's where actually having models that can predict the effect of these interventions comes in. If I can do a sparse sampling, I can test a large number of these combinations, and I can start to learn the relationship of what a given transcription factor is going to do to an age cell. Is it going to make it look younger? Is it going to preserve the same type? I can learn that across combinations. I can start to learn their interaction terms. Now I can use those models to actually predict in silico for all the combinations I haven't seen, which are most likely to give me the state I want. And you can actually treat that as a generative problem and start sampling and asking which of these combinations is most likely to take my cell to some target destination in state space. In our case, I want to take an old cell to a young state, but you could imagine some arbitrary mappings as well. And so I think as you get to these more complex problems that don't”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Way is the bar for a medicine achieved in his laboratory discovery. You can't just have 0.001% success and then wait for the cells to grow a whole bunch in order to treat a patient's disease or make their liver younger, make their immune system younger, make their endothelium younger. You need to actually have it be fairly efficient across many cells at a time. And so because of this, we don't have the same luxury Yamanaka did of taking a relatively small number of factors and finding a success case within there that was pretty low efficiency. We actually need to search a much broader portion of TF space in order to be successful. And when you start playing that game and you think, okay, how many TFs are there? Somewhere between 1,000 and 2,000 depends on exactly where you draw the line and developmental biologists love to argue about this over beer, but let's call it 2,000 for now. And you want to choose some combination. Let's say you guess it's like somewhere between one and six factors might be required. The number of possible combinations is about 10 to the 16. So if you do an”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Just make the old ones cancer and then they'll grow. Yeah. Dorkash, you've solved it for me. So there's no trivial way that you can tell whether or not you've succeeded. You actually need a pretty complex molecular measurement. And so for us, a real key enabling technology, and I don't think our approach would really have been possible until this emerged was something called single-cell genomics. So you now take a cell, rip it open, sequence all the mRNAs it's using. And so at the level of individual cells, you can actually measure every gene that they're using at a given time and get this really complete picture of a cell state, everything it's doing, lots of mutual information to other features. And from that profile, you can train something like a model that discriminates young and aged cells with really high performance. It turns out there's no one gene that actually has that same characteristic. So unlike in Yamanakis case where a single gene on or off is like an amazing binary classifier, you don't have that same feature of easy detection of success in aging. The second feature is, as you highlighted, we can't just turn these into cancer cells. Success doesn't amplify. And so in some”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“So now we look at those key features of the problem and we pick any other problem we're interested in. I'm interested in aging, so that's the one I'm going to pick for explanation. How difficult is it to measure the likelihood of success or whether you've achieved success for cell age? Well, it turns out age is much more complicated in terms of discriminating function than actually just comparing two types of cells. An old liver cell and a young liver cell prima fascia actually look pretty darn similar. It's actually quite nuanced the ways in which they're distinct. And so there isn't a simple trivial system where you just like label your one favorite gene or you can just”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“If the cells were not growing and they were not proliferating like mad, you probably would never be able to detect that you would actually found anything successful. It's only because success is easy to measure once you have it, and even being successful in very rare cases, one in a million, amplifies, and you can detect it, that this, I think, was amenable to his particular approach. So in practice, what he would do is dump these factors or this group of 24 minus some number eventually whittling it down to four. He would dump these onto a group of cells. And over the course of about 30 days, just a few cells in that dish, like a countable number on your fingers, would actually reprogram, but they would proliferate like mad. They form these big, what we call colonies because it's like a single cell that just proliferates and forms a bunch of copies of itself. They form these colonies. You can see with your eyeballs by holding the dish up to the light and looking for opaque little dots on the bottom. You don't need any fancy instruments. And then you could stain them with this particular stain and they would turn blue based on the genetic reporter he had.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“The second really key feature of the problem is this notion that those cells he's converting into amplify. They divide and grow really quickly. So in order for you to find a successful combination, you don't actually need it to be efficient almost at all. The original efficiency Yamanaka published, the number of cells in the dish that convert from somatic to an induced pluripotent state back into a stem cell is something like a basis point or a tenth of a basis point. So like 0.01, 0.001%”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Thing. So, he's starting with fibroblasts. You can look at them under a microscope, and you can see their fibroblast just based on how they look. And then the Celsius reprogramming toward are embryonic stem cells. So these are tiny cells. They're mostly nucleus. They grow really, really fast. They look different. They detach from a dish. They grow up into a 3D structure. And they express some genes that will just never be turned on in a fibroblast by definition. So actually how he ran the experiment was he just set up a simple reporter system. So he took a gene that should never be on in a fiberblast, should only be on in the embryo, and he put a little reporter behind it so that these cells would actually turn blue when you dumped a chemical on them. And then he ran this experiment in many, many dishes with millions upon millions of cells.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Wish it were so easy. You're entirely right. Shiny Yamanaka was able to do this with a relatively small team, with relatively few resources, and achieve this remarkable feat. So it's entirely worth asking, why can't a similar procedure work for arbitrary problems in reprogramming cell state, whether it be trying to make an egg cell act like a young one, disease cell act like a healthy one? Why can't you just take 24 transcription factors and randomly sort through them? So there were two features of Shinya's problem that I think make it amenable to that sort of interrogation that aren't present for many other types of problems. And this is why he's such a remarkable scientist. Most of science is problem selection. You don't actually get better at pipetting or running experiments after a certain age, but you do get better at picking what to do. And he's amazing at this. So the first feature is that measuring your success criterion is trivial in the particular case he was investigating. He's starting with somatic cells that in this case were a type of fiberblast, which literally is defined as cells that stick to glass and grow in a dish when you grind up a tissue. So it's like sounds fancy, but it's a very, very simplistic.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“But you can also use that same information to check for a number of other pathologies that might develop. Did I make this T cell hyperinflammatory in a way that would be bad? Did I make this liver cell potentially Neoplastic proliferate too much, even when the organism's healthy and undamaged. And you can check for each of those at the level of gene expression programs and then likewise functionally before you put these molecules in a human, you actually just functionally check in an animal. You make an itemized list of the possible risks you might run into. Here are the ways it might be toxic. Here are the ways it might cause cancer. Are we able to measure deterministically and empirically that that doesn't actually occur?”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“For instance, at the level of a transcriptome, but simultaneously, you might be changing that cell's type or identity. So Shinyamanaka, a scientist to Woman Nobel in 2012 for some work he did in about 2007, discovered that you could just take four transcription factors. And actually, just by turning on these four genes, turn an adult cell all the way back into a young embryonic stem cell. It's a pretty amazing existence proof that shows that you can reprogram a cell's type and a cell's age simultaneously just by turning on 4 genes. Out of the 20,000 genes in the genome, the tens of millions of biomolecular interactions, just four genes is enough. That's a shocking fact. And so we actually have known for many years now that you can reprogram the age of a cell. The challenge is that simultaneously you're doing a bunch of other stuff, as you alluded to. You're changing its type, and that might be pathological. If you did that in the body, it would probably cause a type of tumor called a territoma. So we measure not only at the level of the genes a cell is using, do you still look like the right type of cell, or do you still have you still a T cell? If not, that's probably pathological.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Sequencing all of the mRNAs, which are really the expressed form of the genes being utilized in the genome at a given time, you see that each cells use different genes. Can I revert them back to a younger state? Colloquially we call this looks like assay. Can I make an old cell look like a young one based on the genes it's using? And maybe more importantly, we go down and drill to the functional level and we measure, can I actually make an age cell performance functions, its object roles within the body the same way a young cell would? And these are the really critical things you care about for treating diseases. Can I make a hepatocyte, a liver cell in Greek, function better in your liver so it's able to process metabolites like the foods you eat, how it's able to process toxins like alcohol and caffeine. Can I make a T cell respond to pathogens and other antigens that are presented within your body? These are the ways in which we measure age. And so we need to ensure that not only does the combination of TFs that we find actually have positive effects along those axes, but we then want to also measure any potential detrimental effects of that emerge. So there are canonical examples where you can seemingly reverse the age of a”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Oh, how I wish it were straightforward. No, it's very likely. Each of these transcription factors binds hundreds to thousands of places in the genome. And one way of thinking about it is if you imagine the genome is sort of the base components of cell function, then these transcription factors are kind of like the basis set in linear algebra. It's different combinations and different weights of each of the genes. And so most of them are targeting pretty broad programs. And there are no guarantees that aging actually involves moving perfectly along any of the vectors in this particular basis set. And so it's probably going to be a little tricky to figure out a combination that actually takes you backward. There's, again, no guarantees from evolution that it's just a simple reset. And so it's actually a critical part of the process that we run through as we try and discover these medicinal combinations of transcription factories we can turn on is to ensure that they not only are making an age cell revert to a younger state, we measure that a couple different ways. One is simply measuring which genes those cells are using. They use different genes as they get older. You can measure that just by”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“What has now become relatively apparent is that the epigenome can degrade with H. It changes. The particular marks that tell your cells which genes to use can shift as you get older. This means that cells aren't able to use the right genetic programs at the right times to respond to their environment. You're then more susceptible to disease. You have a less resilience to many insults that you might experience. And our hope is that by remodeling the epigenome back toward the state it was in when you were young right after development, that you'll be able to actually address myriad of different diseases whose one of strong contributing factors is that cells are less functional than when you were at an earlier point in your life. So we're going after this by trying to find combinations of these transcription factors that are able to actually remodel the epigenome so that they can buy into just the right places in the DNA and then shift the chemical marks back toward that state when you are a young individual.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Yeah, so we're working on something called epigenetic reprogramming, which very broadly is using genes called transcription factors. I like to think about these as sort of the orchestra conductors of the genome. They don't perform many functions directly themselves, but they bind specific pieces of DNA, and then they tell which genes to turn on, which genes to turn off. They eventually put chemical marks on top of DNA on some proteins that DNA surrounds. And this is one of the answers, this particular layer of regulation called the epigenome. It's the answer to this fundamental biological question of how do all my cells have the same genome, but ultimately do very different things. Your eyeball and your kidney have the same code, and yet they're performing different functions, and that may sound a little bit simplistic, but ultimately I think it's kind of a profound realization. And so that epigenetic code is really what's important for cells to define their functions. That's what telling them which genes to evoke from your genome.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“I think that's correct. I don't think that there is a single monocausal explanation for aging. I think there are layers of molecular regulation that explain a lot. For instance, I have dedicated my career now to working on epigenetics and trying to change which genes cells use because I think that explains a lot of it. But it's not that there is some upstream bad gene X and all we have to do is turn that off and suddenly aging is solved. And so I think the most likely outcome is that when we eventually develop medicines that prolong health in each of us, it's not going to fix everything all at once. There's not going to be a singular magic pill, but rather you're going to have medicines that add multiple healthy years to your life, years you can't otherwise get back, but it's not going to fix everything at the same time. You are still going to experience for the first medicine some amount of decline over time, and this gives you an example of if you think about evolution as a medicine maker in this sort of anthropomorphic context, why it might not have been selected for immediately.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“You can arrange genes in the human genome by homology to one another. And what you find is even in our current genome, even without having the full historical record, there are many, many genes which are likely resulting from duplication events. One trivial way that you can check this for yourself is just go look at the names of genes. And very often you'll see something where it's gene 1, gene 2, gene three, or type 1, type 2, type 3. And if you then go look at the sequences, sometimes those names arise from like they were discovered in a common pathway and they have nothing to do with each other. A lot of the time it's because the sequences are actually quite darn similar. And really what probably happened is they evolved through a duplication event and then maybe did some swapping with some other genes. And you ended up with these quite similar, quite homologous genes that now have specialized functions. So it's like when evolution has a new problem to solve, it doesn't have to start from scratch. It starts from like what was the last copy of the parameters for encoding a gene that is getting close to solving this, okay, let's do a copy paste on that and then iterate and fine-tune on those parameters as opposed to having to start.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Number of edits, for instance, in trim 5 alpha for this particular phenomenon we're talking about for memory, but it's in the tens. It's not that you need massive kilobase scale rearrangements. It's actually a fairly small number of edits. And basically, you can just align the sequence of this gene in New World versus Old World monkeys and then for humans. And you find there's a very high degree of conservation.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“It's not that the base rate goes up. It's not like DNA polymerase is more erroneous or that you're just like doubling it. It's not like, oh, well, I've got two copies. That is true, but I don't think it's the main mechanism. One of the main mechanisms that just makes it difficult for evolution to solve a problem is that if a mutation breaks a gene or somewhere along the path of edits, imagine there are three edits that take a host defense gene from restricting SIV to restricting this new nasty PT endogenous retrovirus. Well, if one edit just breaks the gene, two edits just breaks the gene, three edits fixes it, it's really hard for evolution to find a path whereby you're actually able to make those first two edits because they're net negative and net negative for fitness. And so you need some really weird contingent circumstances. Through duplication, you can create a scenario where those first two edits are totally tolerated. They have no effect on fitness, you've got your backup copy, it's doing its job. And so even though the mutation rate is low, some of these edits actually aren't that large. I'm going to forget.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Might be null. I've got two copies of the gene. I can have lots of mutations in it accumulate. Nothing bad really happens because I've got my backup copy, my original. And so that you can end up with drift.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“I think a great explanation for understanding a lot of evolution and how you're able to actually adapt to new environments, new pathogens is that gene duplication is possible. And this explains a whole lot. If you look at most genes in the genome, they actually arise at least at some point in evolution from a duplication event. So that means you've got gene A, it's performing some job, and then some new environmental concern comes along. Maybe it's like a lack of particular source of nutrient, maybe it's a pathogen challenging you. And maybe gene A, if it were to dedicate all of its energies, so to speak, you were to mutate it to solve this new problem, could be adapted with a minimal number of mutations. But then you lose its original function. So we have this nice feature of the genome, which is it can just copy and paste. And so occasionally what will happen in evolution is you get a copy-paste event. Now I've got two copies of gene A, and I can preserve my original function in the original copy. And then this new copy can actually mutate pretty freely because it doesn't have a strong selective pressure on it. So most mutations...”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“I'm going a bit beyond my own knowledge here. So I want to say my strong hypothesis would be yes, I can't point to direct evidence today. There are some examples of this where, for instance, bacteria that fight off viruses that infect them, bacteriophages, have things like CRISPR systems. And you can actually go and look at the spacers, the individual guide sequences that tell the CRISPR system which genome do you go, where do you cut. And you find some of these guides that are very ancient. It seems like this bacterial genome might not have encountered that particular pathogen for quite a while. And so you can actually get sort of an evolutionary history of what was the warfare like, what were the various conflicts throughout this genomic history, just by looking at those sequences. In mammals, where I do know a bit better, we do have examples of this, where there is this coevolution of pathogen and host. Imagine you have some anti-pathogen gene A fighting off some virus X.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Something like antibiotics, and it's necessary to maintain that same mutation rate in population size in order to maintain the competition. Even if our human genome stumbled into making an antibiotic, most pathogens probably would have mutated around it pretty quickly.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“My bacteria evolves a new evasion mechanism, the fungus that occupies the niche will evolve some new antibiotic. Part of why there is this competitiveness between the two is they both have very large population sizes in terms of number of genomes per unit resource they're consuming. There are trillions of bacteria and a drop of water that you might pick up. So there's trillions of copies of the genome, massive analog parallel computation. And then at the same time, they can tolerate really high mutation rates because they're prokaryotic. They don't have multiple cells. So if one cell manages to mutate too much and it isn't viable or it grows too fast, it doesn't really compromise the population in the whole genome. Whereas for metazoans like you and I, if even one of our cells has too many mutations, it might turn into a cancer and eventually kill off the organism. So basically what I'm getting at, and this is a long-winded way of getting there, is that bacteria and other types of microorganisms are very well adapted to building these complex metabolic cascades that are necessary to make”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Why didn't humans have all their own antibiotics? Yeah, it's actually an excellent question that I haven't heard posed before. So we think about where do antibiotics come from? To your point, we could synthesize them. They're just metabolites largely of other bacteria and fungi. You think about the story of penicillin, what happens? Alexander Fleming finds some fungi growing on a dish and the fungi secrete this penicillin antibiotic compound. And so there's no bacteria growing near the fungi. And he says he has this light bulb moment of, oh my gosh, they're probably making something that kills bacteria. There's no prima fascia reason that you couldn't imagine encoding an antibiotic cassette into a mammalian genome. I think part of the challenge that you run into is that you're always an evolutionary competition. There's this notion of what's called the red queen hypothesis. It's an illusion to the story in Lewis Carroll's Through the Looking Glass where the red queen is running really fast just to stay in place. So when you look at sort of pathogen host interactions or competition between bacteria and fungi, they're all trying to compete for the same niche. What you find is they're evolving very rapidly in competition with one another. It's an arms race.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Lambdos are dialed toward infectious disease resilience more effectively, then you can construct an argument for yourself. And so I think really when you start to ask, why don't we live forever? Why didn't evolution solve this? You actually have to think about an incredibly contingent scenario where both the positive selection is there, the negative selection is absent, and you have a lot of our evolutionary pressure going toward longevity to solve this incredibly hard problem in order to construct the counterfactual in which longevity is selected for and does arise in modern man and in which we are optimal. And so I think that puts human aging and longevity and health really in this category of problem in which evolution has not optimized for it. Ergo, it should be, relatively speaking, relative to a problem evolution had worked on, easy to try and intervene and provide health. And I think in many ways the existence of modern medicines, which are incredibly simplistic, we are targeting a single gene in the genome and turning it off everywhere at the same time. And yet the fact that these provide massive benefit to individuals is another”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Lots of forces constraining population size as well. One of the dominant sources of selection on the genome is really prevention of infectious disease. And it seems like when you study the history of early modern man, infectious disease is actually what shaped a lot of our population demographics. And so there's a lot of pressure pushing for those step sizes, those updates to the genome, really to be optimizing for protection against infectious disease rather than other things. And so even if you imagine that maybe the arguments on the former and the first and the second of these possible positive selection being absent for longevity and potentially some negative selection existing, you could, I think, construct a reasonable argument for why humans don't live forever, why the genome hasn't optimized for that, simply based on these optimization constraints. You have to imagine not only that the positive selection is there and the negative selection is absent, but that when you think about sort of the weighted loss term of all the things the genome is optimizing for, that the weight on longevity is high enough to matter. And so even if you imagine it's there, if you simply imagine that the”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source