Why Cryopreservation is No Longer Science Fiction with Until Co-founder and CEO Laura Deming

0:00What if you could take someone who is on their deathbed and find some way to hibernate them until the critical cure for their disease comes online. and the ability to freeze time for humans. I didn't actually think that was something you could go work on, so apparently it is. Our long-term goal is reversible whole body cryopreservation for medical hibernation. But in the near term, what we work on is reversibly cryopreserving single human organs to help transplant patients get organs more efficiently. Making time not a variable changes the whole paradigm. One thing I love about the field of cryopreservation is I think the problem speaks for itself.

0:31Water expands when it warms ice. That's just hard for your tissue to take without substantial damage. And the cool thing is that there's sort of a temperature below which ice formation stops happening. So basically if you can traverse and you can get below that without ice formation, then you're good. We already reversibly cryopreserved tissue, including human tissue, all the time. And we do it for very long time periods. There are kids who were literally cryopreserved for 30 years as tiny embryos. And so the main question is not, is this possible to do it all? It's, is it possible to scale up?

0:59Given that's true, why don't you think it's been worked on?

1:08Hi, listeners. Welcome back to No Priors. Today, I'm really excited to be here with Laura Deming, previously the founder of the Longevity Fund, and now the co-founder and CEO of Until. We're going to talk about how Until is progressing the frontier of reversible cryopreservation, or freezing, living things, and waking them back up, beginning with human organs progressing to small animals and hopefully making progress on the whole body. It sounds like science fiction, but we'll talk about some of the scientific challenges, where we are today, and the implications if this is possible. Thanks so much.

1:43Welcome, Laura. Laura, thanks so much for doing this. Yeah, thanks for having me. I've been so looking forward to this since our Pantheon Watch sessions. We're talking about upload and the nature of consciousness. But one thing that you don't know is that my like very long ago wished for technologies that I wanted to exist were telepathy and like upload and the ability to freeze time for humans. I didn't actually think that was something you could go work on. So apparently it is. How do you end up working on that or being interested in longevity at all? There's two different questions. So I come from a longevity background, but in my mind, like reversible cry preservation is applicable a bit outside of that as well.

2:22I don't know. I mean, I think I'm really obsessed with areas that feel like they should be worked on, but aren't. And, you know, when I was a kid, I think naively just growing up, that seemed really obvious for longevity. And it's really surprising to realize that it's not the case that most people are working on that explicitly as a goal. And in fact, I think longevity and aging occupy this weird realm where because they're not explicitly diseases in a way that's fully socially recognized yet, they're not seen as valid to work on. But like that's not really for, I think, technical reasons on some level.

2:56It's more for like classification reasons because like, you know, you can extend the lifespan of like sort of many different organisms using technology and how much can do that in humans. We have no idea. And, you know, it could be very small technology, but sort of like I think longevity is interesting because it feels like an area where there's a social blind spot around something. And I find those very interesting. Perhaps I was just I'm sure this is true. not very observant as a school-aged child, but I don't think I even understood aging was like a concept that I should consider at all. And so how did you end up thinking about it in any depth?

3:31I grew up in a pretty odd setup. So, you know, I was in New Zealand, I was homeschooled. I didn't really have a, like, I didn't go to a normal biology class. I was kind of, you know, by myself in the house. I imagine you like staring at a field of sheep and then being like, Someday we're going to get old. I should do something about this. Yeah, that would have been the farm that we had for a little bit. But I remember one thing that really stood out to me was at some point when I was a kid, I was thinking about how long people in my life were going to live and how old they were. And for some reason, it made a lot of sense to me that everyone should live until they were 10 years old and then die immediately at 10 years old.

4:05Like that seemed like some hypothesis. I didn't really know how old people were. And so working backwards, I was like, oh, my dad must be like, you know, maybe eight and my mom's younger than him. So like maybe seven. But I think one thing that was really striking was realizing that we don't all live until a certain age and then we die. In fact, we don't know what determines how long we live. That was very interesting, right? This idea that like, if we all live until 10 years old and then we die immediately, I would feel much more confident with the idea that longevity is some kind of imalleable, hard limit.

4:33But the idea that there was uncertainty about that. It's really interesting. And it's sort of like, what are the factors behind that uncertainty? So I'm going to fast forward through a bunch of like lab work you did and going to MIT and being a Teal Fellow. Like why a longevity fund? Me just being very literal, like at the time that I was interested in longevity, I think if you ask the average person in the field, like what's the big problem? Most people would say, well, we just can't get enough funding for our projects. And so that's the big problem. And I just took that literally like when I was a teenager.

5:02So I want that problem. Yeah, I was like, I should just get a lot of money to like help push longevity drugs forward. And the name for that happened in venture capital fund, but it definitely wasn't working downstream of the idea of venture capital. Like that came after this idea of like just getting money for projects that should have money and didn't. You did this for a number of years. What triggered the like sort of change in how you were going to spend your attention to cryopreservation? I think just like cryopreservation is one of the coolest. it like i think it's not like to pardon the pun but i think it's one of the coolest most interesting like best problems ever like i think like i mean if from so many different angles like i think you've heard such counterfactual impact like if you're obsessed with like just technical delight like just rush your like technical interest and diversity and um it's like a lot of technical parts of the problem and then also i think from perspective of social impact like i'm just it was just it's such an interesting problem from like how it's perceived and then like what are the different factors of that it was like zero to one it was like the i remember just seeing the problem clearly for the first time.

6:00I mean, a lot of the people in my life, I think, had been aware of it, but I just, it took me so long to really, I think, see it clearly for myself. But then it was just like zero to one of like, this is the only thing that I could imagine pouring the next decade of like my work into. That was after I kind of done kind of the first set of work with the fun. I was kind of like thinking like, what is the next like big thing? With your co-founder Hunter, was it like an immediately obvious, yes, we should work on this together? He's one of the few people where if I ask him a question, like he'll come back the next day and give me an answer.

6:32He's literally thought through from first principles, like what the correct answer is. I remember at some point I realized that he'd written a doc on the principles of craft preservation. Most people would write that from the literature or citing different sources at various levels of granularity. Hunter went back and re-derived fundamental laws of stat and mech as part of like, this is what you should know in craft preservation doc. I really admire how much he builds up from like really simple models to try to create coherent like technical pictures that are more complex. He's like the most fun, interesting, best person to work with ever for sure.

7:07And it wasn't a hard sell. Like we should go work on this problem in particular. It was not a hard sell, but it was not an interesting way. So I think one thing that I like love about the field of cryopreservation is I think it's very compelling. like if you like hard like it's one of those things where if you like the problem speaks for itself and so I remember telling Hunter about it in our first call and he basically was like oh I don't buy it he told me later that he didn't tell me in the call but then he went off and thought about it for a couple days and like really thought about like what we knew about ice formation like did you know some like basic back of the envelope math and came back and he was like oh wait this seems like actually if he's or like this seems like it's in their own impossibility in a way that is very different from my initial intuition.

7:51And that sort of like conjugation is just so interesting to me. Maybe it's useful to zoom out and just say, like, what is the goal of UNTIL? I would think about our goal as trying to create a new form of critical care. The example that I would give that is sort of the core of the company is there's some years where certain diseases such as like metastatic melanoma go from being, like sort of in a single year, like metastatic melanoma went from being something that you had like a six to nine month prognosis, like less than a year of expected survival to with like, you know, new combination immunotherapies, you might have a decade plus of expected survival or like 50 % of people sort of surviving over a decade, you know, without getting sort of death from melanoma.

8:32In fact, there was a story to have other things at that point. The tagline is like single years can make the difference between a patient dying of maternal illness and like living long enough to make the critical cure. But right now, like there's no way to press pause on their biological time. Like what if you had an ambulance for the future, right? Like, what if you could take someone who is on their deathbed and, you know, find some way to, you know, just sort of hibernate them basically until the sort of critical cure for the disease comes online. And like, you know, in this context, we're not talking about necessarily decades or kind of like, you know, much longer than that.

9:00Initially, it's just kind of in the context of like when there's a window where you could you could imagine like a critical trials being done for a drug that were they eligible for it could make a huge difference for their disease. To give an example of the need to, it's like my sort of co-founder's father-in-law had this happen to him in the sense that he got sort of advanced cancer that would have been treatable or addressable by a therapy that came out basically a couple of months after he was no longer eligible for the therapy. And he like missed, you know, the critical clinical trial by like, you know, a couple of months.

9:33And so it's sort of like that level of urgency that like someone in that position shouldn't have to, you know, miss a critical therapy because there's a couple of month difference in like when they got their sort of disease and when the therapy came available. And from a just like product perspective, that means you need to do whole body cryopreservation. Yeah. So so like to give context on technically how we think about this problem. So our long-term goal is reversible whole body cryopreservation for medical sort of hibernation. But in the near term, what we work on is reversibly cryopreserving single human organs to help transplant patients get organs more efficiently.

10:10I want to come back to like all of the technical challenges here and where we are and what you think the next milestones are. But because you describe it in the context of medical use, like I'm going to be honest, as a kid, I was like, well, I want to be able to freeze time because I want to be able to go to Mars too. or you said because you've worked on longevity with this perspective, like aging is, you know, it could be considered a disease, a health state we should work on that is credible medical science. So how do you think about those other use cases? So an interesting thing when you start to think about like actually applying this technology is sort of what's the experience of the person, not just kind of technically for the disease, but socially.

10:49So like one of the number one reasons most people wouldn't do medical hibernation, and especially that it wouldn't be like for the most part of recreational thing, is that, you know, I think a lot of people view themselves in part defined by their social context. So like when you say recreational thing, you mean because like you just you think of that as going to Mars as a recreational use case. Oh, no, sorry. I think this case what I'm thinking of is, you know, some people might imagine that they would love to skip into the future just to see what happens, you know, and maybe, you know, like have their same amount of number of years of life, but like have the future shifted by some amount of time.

11:20Yes. But the number one reason that most people wouldn't do that and are also just, you know, very wary of the idea of hibernation for themselves is, you know... I can't take everybody with me. Yeah, exactly. It's this idea that, like, you kind of define yourself by the people around you. And so I think, like, you know, those kinds of use cases, like going to Mars, those are all kind of things that could happen and could happen with or without or, like, sort of could happen, will work for hibernation technology for certain, like, definitions of mind. But I think the thing that a lot of people will face is just, like, this question of, like, is it worth, you know, traveling so far to give up my current social context?

11:51and that will put a limit on like how much people want to use this for like i think there's like a real cost that that kind of you incur and so it's in my mind it only makes sense for like really serious use cases initially um where like you literally would die if or like you know because yeah because you're kind of putting on the line like your current like all of your current social reality and like how that will evolve without you versus like you know this other thing that you might want but i mean a lot of people might want to go to mars you know that context which is i think i'm a little yeah the cost is pretty significant it's very hard to know what we want though like a lot of people might make that decision whether or not you know their ultimate happiness is higher.

12:22Maybe you can just break down how you think about the challenges scientifically, right? Versus I think to maybe even Hunter's original reaction, like sounds like science fiction. I don't know if you can go work on that thing. And so if it's, you know, crystal formation or whatever the set of challenges and what sequence you think you should solve them. I see. Yeah. Maybe I can just give a series of facts that I think together sort of make the problem super interesting. So one fact is that ice formation is a stochastic process. So if ice just formed unilaterally in any given material past a certain point of temperature, like, you know, just like go from zero to one, it's like 100 % ice, like that might be kind of hard to think carefully about technically.

13:09but ice sort of forms through a process of random nucleation and then extension. And this is cool because you can modulate the rate of nucleation and extension to then modulate the probability of ice formation. And because it's probabilistic, if you can do that well enough and you can sort of spend minimal time in the temperature range where ice can nucleate, then that gives you a shot at sort of preventing a lot of ice formation. So like the number one tagline would be like avoid ice at all, avoid as much as possible. There may be some, like I think some people might be working on technologies to cryopreserve with some sort of like ice formation, but we're focused on regimes where you're basically trying to avoid as much ice formation as possible.

13:51Just for the non-biologists, you know, ice formation is bad because it breaks all the cell membranes. Yeah, so ice formation is bad because ice expands, water expands when it forms ice. And that's just hard for your tissue to take without substantial damage. So you want to avoid ice formation. And the cool thing is that there's sort of a temperature below which ice formation stops happening. So basically, if you can traverse, let's say, you know, going below zero degrees or less through to around minus 130, and you can get below that without ice formation, then you're good. And the interesting thing is at that point, you're good for quite a long time.

14:28So there have been human embryos that were reversibly cryopreserved for, the latest record was over 30 years, and then rewarmed and sort of viably used to create pregnancy. And then, you know, sort of like there are kids who were literally cryopreserved for 30 years as tiny embryos. And so that's the last thing, which was very surprising to me, which is that like we already reversibly cryopreserved tissue, including human tissue, including cold body human tissue at that very, very small, like, you know, a couple hundred cells stage. all the time. And we do it for very long time periods, which I honestly like, what have first principles been stuck on?

15:04Is this possible to do at all? Is it possible to scale up to a large, complex biological system that has a lot of vasculature, where you're dealing with different material properties, where you have to think a lot about like perfusion and how to sort of diffuse chemicals in and out and how to like get heated out quickly enough. So the idea that you could pause all molecular motion and then randomly restart it and even a cell would survive that, you know, like from first principles to me used to seem crazy. But we know that works. It's like, wait, wait, wait, we just, we already like scientists just tried it and it worked.

15:30And so now the problem is like scaling that up and doing it in a way that's compatible with like, you know, tissue health. Yes. I think one of the things that was most wildly surprising to me, like being in your lab a little while ago, is how much it looks like people were working on what I'd consider to be like engineering problems around like, oh, how do we get something to warm quickly and safely enough versus let me go work on this therapeutic? Yeah. So actually, I feel like there's this part of the problem that I've been trying to explain externally for a long time. Every time I try to explain it, I think it comes off as like not specific or something, but it is actually one of the core reasons why I think the problem is interesting to work on, which is that like you can trade off like engineering difficulty and biological difficulty to a non-zero degree.

16:16Like not 100%. You can't just use engineering to solve the problem. You absolutely have biological questions. And like those questions could come out in the negative for some of these cases. So like that's not saying you can just make an engineering problem, but like you can make your life easier on the biology front by building better engineering tooling. And the fact that that's possible is a huge deal. Like that is that is not true for most problems in biology. And it gives you a lot of leverage on the problem. This is probably interesting to maybe only like 5 % of people watching this. But like I think that I'm obsessed with this idea like temperature is such a beautiful conceptual tool, right?

16:46It's like temperature as an idea, something that in physics took like took physicists hundreds of years to come up with. it links like molecular motion to a high like a single high level measurable parameter and just tuning temperature like sort of tells you about almost like the relative passive time of like molecules at the nanoscale like that's that's a highly non-trivial sort of conceptual lever to have on a problem and in biology one of the biggest problems is like it's really hard to find powerful conceptual levers on sort of like for like nanoscale um for for manipulating like the nanoscale that have anything approaching that degree of sort of leverage.

17:23Basically, what that gives you is like you can apply a lot of theoretical sort of a lot of theoretical toolkit used in physics to model parts of this question in ways that are actually useful. And it is just not true that you can use like equations from physics to think usefully about almost any other problem in biology. There are plenty of questions like medical devices, like in a context where you're talking about like changing the course of terminal illness, which this one is interesting because this doesn't mean I will change it, but like it gives you the possibility of some more time. I think it's one of the most important things to understand about the problem.

18:00I don't understand how to explain it in a way that is clear, but I think it's like one of the most important things to understand about the problem. Yeah. Maybe if I think about actually applying it like just very concretely to what you are doing, like if it is challenging from a, you know, organ preservation biology perspective to have a organ reheated or sorry, rewarmed like evenly throughout, then maybe the thing to do is to like change the surface area to volume ratio of like your heating device or distribute the heat in different ways without like changing your understanding of the biology, but just with new devices and technologies that you invent from the engineering perspective.

18:39Like that actually seems like a very simple example. I realize you're implying a like more fundamental view of like why temperature is just such a interesting framework to be working on from both an engineering perspective and a biology perspective. And there's like tradeoffs where you put your effort here. But I think that's actually that's something that like didn't did not occur to me at all coming into your lab and learning more about until I was like, oh, it's actually like a to some degree much simpler problem than I understood to the point of like, well, if you can just reduce and preserve, reduce and increase temperature in these ways that are perfect through this organ is going to work.

19:19Right. Yeah. So let me restate that and then give one caveat just to make sure that I can do it correctly. So a way that you can talk about the trade-off between engineering and biology is that with engineering, you can modulate cooling and rewarming rate to certain extents. And then that can then change how much what we call a crop-tractive agent or kind of chemical that modulates ice formation you add to the system. And you want to minimize the concentration of that crop-tractive agent. Basically toxic. Exactly. And so as you increase cooling and rewarming rate, aka spending therefore minimal time in kind of the dangerous zone of ice formation, you can correspondingly decrease the concentration of carbon content that you're putting in.

20:00But if you could instantaneously cool and rewarm, then you wouldn't have to put any CP in. But that's not something that we're default assuming is feasible for a large system. So there's still always going to be a component of biology, aka like how tissue responds, especially from a toxicity perspective, to like a new chemical agent. And where are you now in this progression? Like, should I think of it as like, there's a kidney and then it seems like quite a large jump to a small animal, but maybe it's not. Yeah. So we work on the two in parallel. So we both work on scaling up preservation and rewarming technologies to kind of human organ scale.

20:37And also in parallel, we work on a sort of whole rat reversible hibernation and translating technologies over from sort of what we learn on the kidney side into the rat context, as well as doing things specifically for rat. When you started the company, did you have a timeline in your own mind? So I think initially I was like, we could maybe make some progress and hopefully make some good products. But like the idea of full body cry preservation felt like that would be really far out if that was possible. I mean, I think I definitely still wouldn't put like a near-term on it, but I feel like we have a much clearer roadmap, at least to get to begin to get there.

21:15And the first steps seem faster than I would have imagined, if that makes sense. Like, but the big unknown to get to whole body reversible is the brain. It's unclear, like the brain can withstand a lot of change and does withstand a lot of different types of damage or change with age, for example. But it's unclear whether like what kind of injury the brain could sustain in the context of like a whole body of recore preservation protocol and then like what level of fidelity it's possible to do. So like that, that to be clear is a big unknown on the neuroscience side. How do you recruit and like lead in a company that has like, let's say, an unclear like timeline around a really big scientific goal like that?

21:58Like in terms of both finding people that are the right fit, motivating them. And how do you think about urgency in that context? I mean, I think we have a pretty clear timeline for our first product, which is like get a reversibly cryopreserved. So basically transplant patients today surprisingly frequently miss organs that are on route to them because there's a timing problem. So like, you know, organs expire very quickly after they become available from a donor. That's very unfortunate. Yeah. And it's crazy because it's like they're like one of the most precious resources we know of. And yet like people regularly charter private jets.

22:31It's like you're putting a surgeon on a private jet to go pick up an organ, get it back to the patient in time. And you're doing all that at the last minute and scheduling the patient for surgery at the last minute. So the patient has to wait within a two-hour radius of a transplant center with a pager on them or a notification device at all times. And so the first product that we're aiming towards is just being able to pause time for the organs. So you can take as long as you need to get the organ to the patient. And that's very near term. That's not long-term ethical. That's like we're aiming to get that into prequel studies and into the clinic as quickly as possible.

23:00So I think it helps to have a very concrete goal that clearly is relevant to a long-term goal, right? I think another thing that was inspired us about that product was like, if we're at all talking about whole body reversible cryopreservation and we can't make a dent on that problem, like - There's no version of not going through it. Yeah. It's sort of the same sort of like, if you're serious, that should be doable. And if like, you can't do that, then like, you're not the company to like do the long-term thing. So that was nice for us to like, have a very clear benchmark for ourselves of like, you know, are we correct that this is attractable technology on that scale?