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

1. 0:00 – 1:08

   Cold Open

   1. LDLaura Deming0:00

      What if you could take someone who is on their deathbed and find some way to hibernate them until the sort of critical cure for their disease comes online?

   2. SGSarah Guo0:08

      The ability to freeze time for humans. I didn't actually think that was something you could go work on, so apparently it is.

   3. LDLaura Deming0:14

      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, like, the problem speaks for itself. Water expands when it forms ice. That's just hard for your tissue to take [chuckles] 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 cryopreserve tissue, including human tissue, all the time, and we do it for very long time periods. There are kids who were literally cryopreserved for thirty years as tiny embryos, and so the main question is not, "Is this possible to do at all?" It's, "Is it possible to scale up?"

   4. SGSarah Guo0:59

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

   5. LDLaura Deming1:02

      Um. [upbeat music]

2. 1:08 – 1:53

   Laura Deming Introduction

   1. SGSarah Guo1:08

      Hi, 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. Welcome, Laura. Laura, thanks so much for doing this.

   2. LDLaura Deming1:45

      Yeah, thanks for having me.

   3. SGSarah Guo1:47

      I've been so looking forward to this since our Pantheon Watch sessions. We're talking about upload and the nature of consciousness,

3. 1:53 – 6:20

   Why Laura Focused on Cryo Preservation and Longevity

   1. SGSarah Guo1:53

      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, to, to freeze time for humans. I didn't actually think that was something you could go work on, so apparently it is.

   2. LDLaura Deming2:09

      [chuckles]

   3. SGSarah Guo2:10

      How do you end up working on that or being interested in longevity at all?

   4. LDLaura Deming2:14

      There... There's two different questions. So yeah, I come from a longevity background, but in my mind, like, um, reversible cryopreservation is, is applicable a bit outside of that as well. I don't know. I mean, I, I think I'm really obsessed with areas that feel like they should be worked on but aren't. Um, and, you know, when I was a kid, I think naively just growing up, that seemed really obvious for longevity. Um, and it's really surprising to realize that, you know, it's not the case that most people, like, are working on that explicitly as a goal, and in fact, that, like, it's, it's kind of... Like, I think longevity and aging kind of occupy this weird realm, where because they're not, like, 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, I think, technical reasons on some level. It's, it's more for, like, classification reasons because, like, you know, uh, you, you can extend the lifespan of like, uh, sort of many different organisms using technology. Um, and, and how much you 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.

   5. SGSarah Guo3:17

      Perhaps I was just, I'm sure this is true, uh, not very observant as a, uh, you know, school-aged child, but I don't think I even understood aging was, like, a concept that I should consider at all. [chuckles]

   6. LDLaura Deming3:28

      [chuckles]

   7. SGSarah Guo3:28

      Like, and so how did you end up thinking about it in any depth?

   8. LDLaura Deming3:31

      I grew up in a pretty odd setup. So, you know, it was in New Zealand. I was homeschooled. Um, I didn't really have a... Like, I didn't go to a normal biology class, so I was kind of, you know, by myself in the house.

   9. SGSarah Guo3:43

      I imagine you, like, staring at a field of sheep and then being like-

   10. LDLaura Deming3:46

       [chuckles]

   11. SGSarah Guo3:46

       ... "Someday we're going to get old. I should do something about this." [chuckles]

   12. LDLaura Deming3:50

       Yeah. No, that would've been the farm that we had for a little bit, but I, I remember one thing that was, that really stood out to me was, um, at, 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 ten years old and then die immediately at ten years old. Like, I just, uh, that, like, that seemed like a simple 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-

   13. SGSarah Guo4:11

       [chuckles]

   14. LDLaura Deming4:11

       - 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, you know, know, like, what determines how long we live. Like, that, that was very interesting, right? This idea that, like... Ex- Almost, like, if we all lived until ten years old, and then we die immediately at ten, like, I would feel much more confident in the idea that, like, longevity is some kind of inalienable, like, hard limit. But the idea that, like, there was uncertainty about that, it's just really interesting, and then sort of like, what, what are the factors behind that uncertainty?

   15. SGSarah Guo4:39

       So I'm going to fast-forward through a bunch of, like, lab work you did, and going to MIT, and being a Thiel Fellow. Like, why a longevity fund?

   16. LDLaura Deming4:48

       Me just being very literal, like, at the time that I was interested in longevity, I think if you asked 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, [chuckles] like, when I was a teenager, so I signed up.

   17. SGSarah Guo5:03

       "I want no problem."

   18. LDLaura Deming5:03

       Yeah.

   19. SGSarah Guo5:04

       Yeah.

   20. LDLaura Deming5:04

       I was just like, " Literally, 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-

   21. SGSarah Guo5:14

       Yeah

   22. LDLaura Deming5:14

       ... this idea of, like, um, just getting money for projects that should have money and, and didn't.

   23. SGSarah Guo5:19

       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?

   24. LDLaura Deming5:26

       I think just, like, cryopreservation is one of the coolest... Like, I, I think it's [chuckles] not, not, like, to, to pardon the pun, but I think it's one of the coolest, most interesting, like, best problems ever. Like, I, I think, like, it, I mean, if... From so many different angles, like, I think you're versus counterfactual impact. Like, if you're obsessed with, like, just technical delight, like, just raw, sheer, like, technical interest and diversity, and, um, and just, 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 f- I remember just seeing the problem clearly for the first time. I 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. Uh, that, that was after I'd kind of done kind of the, the, the first set of work with Fund, and was kind of, like, thinking of, like, what is the next, uh, like, like, big thing?

4. 6:20 – 7:55

   Bringing on Co-Founder Hunter Davis

   1. SGSarah Guo6:20

      With your co-founder, Hunter, was it, like, an immediately obvious, "Yes, we should work on this together?"

   2. LDLaura Deming6:26

      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 where he's literally thought through from first principles, [chuckles] like, what the correct answer is. Like, I remember at some point I realised that he'd written a doc on, like, the principles of, like, you know, cryopreservation. Like, most people, you know, like, like, would write that from the literature or kind of like citing different sort of, um, sources at various levels of granularity. Hunter went back and, like, rederived fundamental laws of stat mech as part of, [chuckles] like, this is what you should know in cryopreservation doc. Like, I, I, I really admire how much he builds up from like, like, uh, like, really simple models to try to create coherent, like, technical pictures that, that are more complex. He's, like, the most fun, interesting, best person to work with, um, ever, for sure.

   3. SGSarah Guo7:08

      And it wasn't a hard sell, like, "We should go work on this problem in particular"?

   4. LDLaura Deming7:11

      It was not a hard sell, but it was not an interesting way. So I, I think one thing that I, like, love about the field of cryopreservation is I think it's very compelling, like, if you like har- It, like... It, it's one of those things where if you, like, the problem speaks for itself. And so I remember telling Hunter about it on our first call, and he basically was like: "Oh, I don't buy it." He, he told me later [chuckles] that. He didn't tell me in the call.

   5. SGSarah Guo7:34

      [chuckles]

   6. LDLaura Deming7:34

      But then he went off and thought about it for a couple of 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 fuse," or like, "This seems like it's in the realm of possibility in a way that is very different from my initial intuition." And, and that, that sort of, like, conjugation is just so interesting to me.

5. 7:55 – 10:10

   Until’s Goal

   1. SGSarah Guo7:55

      Maybe it's useful to zoom out and just say, like, what is the goal of Until?

   2. LDLaura Deming7:58

      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 are some years where certain diseases, such as, like, metastatic melanoma, go from being... Like, like, sort of i- 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, y- you might have a decade-plus of expected survival or, like, fifty percent of pe- people sort of surviving over a decade, um, uh, you know, without getting sort of, uh, death from melanoma. In fact, they were starting to die of other things at that point. The tagline is, like: Single years can make the difference between a patient dying of terminal 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. It's like, what if you had an ambulance to the future, right? Like, what if you could take someone who is on their deathbed and, um, you know, find some way to, you know, just sort of hibernate them basically until, um, the sort of critical cure for their disease comes online. And like, you know, a- and in this context, we're not talking about necessarily decades or kind of like, you know, much longer than that. Initially, it's just kind of in the context of, like, when there's a, a window where you could, you could imagine, like, a critical trial is being done for a drug that, were they eligible for it, could make a huge difference for their disease. To give an example of, like, the, the need, too, it's, like, my, um, uh, sort of co-founder's, uh, father-in-law, um, had this happen to him in the sense that he, he got a sort of advanced, uh, cancer that, that would have been treated... or treatable or addressable by a therapy that came out, um, basically a couple of months after he was no longer eligible for, um, the therapy. And he, like, missed, you know, the critical clinical trial by, like, you know, a couple of months. And so it's sort of like that level of urgency that, like, someone in that position shouldn't have to, um, you know, miss a critical therapy because there's a couple-month difference in when, like, when they got their, uh, sort of disease and when the therapy became a- available.

   3. SGSarah Guo9:47

      And from a, um, just, like, product perspective, that means you need to do whole-body cryopreservation.

   4. LDLaura Deming9:54

      Yeah. So, so, like, to give context on technically how we think about this problem, so our, our long-term goal is reversible whole-body cryopreservation for, you know, medical, uh, sort of hibernation. Um, but in the near term, what we work on is reversibly cryopreserving human, single human organs to help transplant patients get organs more efficiently.

   5. SGSarah Guo10:09

      Um,

6. 10:10 – 12:22

   Other Use Cases for Cryo Technology

   1. SGSarah Guo10:10

      I wanna 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 s- y- you describe it in the context of medical use, like, I'm gonna be honest, as a kid, I was like: Well, um, I want to be able to freeze time because I wanna be able to go to Mars, too. Or you, you said, um, because you've worked on, uh, uh, longevity with this perspective, like, ageing is, uh, you know, it could be considered a disease, a health state we should work on, um, that is credible medical science. So how do you think about those other use cases?

   2. LDLaura Deming10:39

      So an interesting thing when you start to think about, um, like, actually applying this technology is, is sort of what's the experience of the person, not just, um, kind of technically for the disease, but socially. So like, 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, a recreational thing, is that, you know, you... I think a lot of people view themselves as in part defined by their social context. So, like-

   3. SGSarah Guo10:59

      When, when you say recreational thing, you mean because, like, you, you just, you think of that as, uh, going to Mars as a recreational use case or a-

   4. LDLaura Deming11:07

      Oh, oh, no, no, sorry.

   5. SGSarah Guo11:08

      Oh.

   6. LDLaura Deming11:08

      I, I, I think in this case, what I'm thinking of is, you know, some people might imagine that they would love to skip into the future-

   7. SGSarah Guo11:13

      Oh, yes

   8. LDLaura Deming11:13

      ... just to see what happens, you know?

   9. SGSarah Guo11:15

      Yeah.

   10. LDLaura Deming11:15

       And maybe, you know, like, have the same amount of number of years of life but, like, um, have be future shifted by some amount of time.

   11. SGSarah Guo11:20

       Yes.

   12. LDLaura Deming11:21

       But the number one reason that most people wouldn't do that and would... and are, and are also just, you know, very wary of the idea of hibernation for themselves is, you know-

   13. SGSarah Guo11:28

       I can't take everybody with me.

   14. LDLaura Deming11:29

       Yeah, exactly. It's this idea that, like, you, you kind of define yourself by the people around you. Um, and so I think, I think, like, you know, those kinds of use cases, like going to Mars, and like, th- those are all kind of things that could happen and could happen with or without hiber- or, like, sort of, um, could happen, will require hibernation technology for certain, like, definitions of mine. Um, but, but I think the, the thing that a lot of people will face is just, like, this question of, like: Is it worth, you know, travelling so far to give up my current social context? And that will put a limit on, like, how much people wanna use this for... Like, I, 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 case, use cases initially, um, where, like, you literally would die if, or like, you know, but, but because, yeah, 'cause you're, 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 wanna go to Mars, even in that context, which is I think I'm a little... Yeah.... the, the cost is pretty significant.

   15. SGSarah Guo12:14

       It's very hard to know what we want, though.

   16. LDLaura Deming12:16

       [chuckles]

   17. SGSarah Guo12:16

       Like, a lot of people might make that decision whether or not, you know, their ultimate happiness is higher.

   18. LDLaura Deming12:21

       It's fair. [chuckles]

7. 12:22 – 15:36

   Scientific Challenges in Cryo Tech

   1. SGSarah Guo12:22

      Maybe you can just break down how you think about the challenges scientifically, right? Versus, um, 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."

   2. LDLaura Deming12:34

      Yeah.

   3. SGSarah Guo12:35

      Right? And so if it's, you know, crystal formation or, um, uh, whatever the set of challenges and what sequence you think you should solve them.

   4. LDLaura Deming12:43

      I see, yeah. M- maybe I can just give a, a, a series of, of facts that I, I, I think together sort of make the problem super interesting. Um, so, so one, one fact is that, um, ice formation is a stochastic process. So if, 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, a hundred percent ice, like, I-- That, that might be a kind of hard to think carefully about technically, but ice sort of forms through a process of random nucleation and then extension. And this is cool because you can, uh, modulate the, like, sort of nucleation, 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, um, sort of spend minimal time in the temperature range where ice can nucleate, um, 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 costs, [chuckles] or, like, sort of 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.

   5. SGSarah Guo13:51

      Just for the non-biologists, you know, ice formation is bad because it breaks all the cell membranes and-

   6. LDLaura Deming13:55

      Yeah, so i- ice formation is bad because ice expands- water expands when it forms ice, and, um, that's just hard for your tissue to take [chuckles] without substantial damage. Um, so you wanna avoid ice formation, and the cool thing is that there's um, there's sort of a temperature below which ice formation stops happening. Um, so basically, if you can traverse, uh, let's say, uh, you know, going below zero degrees or, or less through to around minus one thirty, um, and you can get below that without ice formation, then you're good. And the interesting is, is at that point, you're good for quite a long time. So, um, uh, there have been human embryos that were reversibly cryo- that were, you know, cryopreserved for, uh, the latest record was over thirty years, and then rewarmed and sort of viably used to create pregnancy. And then, you know, sort of like there, there are kids who were literally cryopreserved for thirty years-

   7. SGSarah Guo14:44

      Mm-hmm

   8. LDLaura Deming14:44

      ... as tiny embryos. And so that's the last thing, which was very surprising to me, which is that, like, we already reversibly cryopreserve tissue, including human tissue-

   9. SGSarah Guo14:52

      Yeah

   10. LDLaura Deming14:52

       ... including whole-body human tissue at that-

   11. SGSarah Guo14:54

       [chuckles]

   12. LDLaura Deming14:54

       - very, very small, like-

   13. SGSarah Guo14:55

       Right

   14. LDLaura Deming14:56

       ... you know, in a couple hundred cells stage all the time.

   15. SGSarah Guo14:59

       Mm-hmm.

   16. LDLaura Deming14:59

       And we do it for very long time periods, which I, I, honestly, like, would have first principles been stuck on, like, is this possible to do at all? Is, is it possible to scale up-

   17. SGSarah Guo15:06

       Mm-hmm

   18. LDLaura Deming15:06

       ... to a large, complex biological system that has a lot of vasculature, um, 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 heat 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.

   19. SGSarah Guo15:26

       But we know that works.

   20. LDLaura Deming15:26

       Yeah, it's like, it's like we, we just- we already, like-

   21. SGSarah Guo15:28

       Yeah

   22. LDLaura Deming15:28

       ... scientists just tried it, and it worked. And so now the problem is, like, scaling that up and doing it in a way that's compatible with, like, you know, tissue health.

   23. SGSarah Guo15:35

       Yes.

8. 15:36 – 20:18

   Using Engineering Principles to Solve Biological Problems

   1. SGSarah Guo15:36

      I think one of the things that was most, uh, wildly surprising to me, like, being in your, um, 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-

   2. LDLaura Deming15:50

      Yeah

   3. SGSarah Guo15:50

      ... quickly and safely enough?" Versus, uh, uh, "Let me go work on this therapeutic." Yeah.

   4. LDLaura Deming15:56

      Yeah. So, so, 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.

   5. SGSarah Guo16:15

      Mm-hmm.

   6. LDLaura Deming16:16

      Like, not, not a hundred percent. Like, y- 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-

   7. SGSarah Guo16:22

      Mm-hmm

   8. LDLaura Deming16:22

      ... some of these cases. So, like, that's, um, not saying you can just make an engineering problem. 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, five percent people watching this, but, like, I, I think that I'm obsessed with is just the idea, like, temperature is such a beautiful conceptual tool, right? It's like temperature as an idea is 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 passage of time of, like, molecules at the nanoscale. Which, 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, it, it's really hard to find powerful conceptual levers on sort of, like, for, like, nanoscale, um, for, for manipulating, like, the na- the, the nanoscale, that, like, have anything approaching that degree of sort of leverage. Basically, what that gives you is, like, you can apply a lot of theoretical, sort of, um a, a, a lot of theoretical toolkit used in physics to model parts of this question in ways that are actually useful. And it, like, 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 places like the, in the, in the context of, like, medical devices, but like, um, in a, in a, i- in a context where you're talking about, like, changing the course of a terminal illness, um, which, which, this one is interesting because this doesn't even allow to change it, but, like, it, it gives you the possibility of, of sort of more, more time. I think it's one of the most important things to understand about the, the problem. I don't yet understand how to explain it in a way that is clear, but I, but I think this is, like, one of the most important things to understand about the problem.

   9. SGSarah Guo18:05

      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, y- 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, um, new devices and technologies that you invent from the engineering perspective. Like, 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, um, interesting framework to be working on from both an engineering perspective and a biology perspective, and there's, like, trade-offs of where you put your effort here. But I, 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," um, to the point of, like, well, if you can just reduce and preserve temp- reduce and increase temperature in these ways that are perfect through this organ, it's going to work, right?

   10. LDLaura Deming19:20

       Yeah. So, so I, uh, let me restate that and then give one caveat, um, just to make sure that, um, like I, I hear correctly. So a way that you can talk about the trade-off between engineering and biology is that, like, with engineering, you can modulate cooling and to, and rewarming rate, just to some, to cer- to certain extents. And then, that can then change, like, how much, uh, what we call a cryoprotective agent or kind of chemical that, um, modulates ice formation you add to the system.

   11. SGSarah Guo19:45

       Mm-hmm.

   12. LDLaura Deming19:45

       And you wanna minimize the concentration of that cryoprotective agent so that you have-

   13. SGSarah Guo19:49

       Because it can be toxic.

   14. LDLaura Deming19:50

       Exactly.

   15. SGSarah Guo19:50

       Yeah.

   16. LDLaura Deming19:51

       And so as you increase cooling and rewarming rate, a- aka spending, therefore, minimal time in kind of the danger zone of ice formation, you can, uh, correspondingly decrease the concentration of cryoprotectant that you're putting in. But if you could instantaneously cool and rewarm, then you wouldn't have to put any CPA in, but that's, that's not something that, uh, we're default assuming is feasible for a la- a large system. Um, so there, 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.

9. 20:18 – 21:48

   Scaling Up Cryo Preservation

   1. SGSarah Guo20:18

      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-

   2. LDLaura Deming20:28

      [chuckles]

   3. SGSarah Guo20:28

      ... but maybe it's not?

   4. LDLaura Deming20:29

      Yeah, so we work on the two in parallel. Um, so we, we both work on scaling up cryopreservation and rewarming technologies to a kind of human organ scale. And also, in parallel, we work on a sort of whole rat, uh, reversible hibernation, uh, and translating technologies over, um, from sort of, um, what we learn on the kidney side into, into the rat context, as well as doing things specifically for, for rat.

   5. SGSarah Guo20:53

      When you started the company, did you have a timeline in your own mind?

   6. LDLaura Deming20:56

      Uh, so I, I think initially I was like, we could maybe make some progress and hopefully make some good products, but, like, the idea of whole body cryopreservation felt like that would be really far out if that was possible. I mean, I, I think it... I, I, I definitely still wouldn't put, like, a near-term timeline on it, but it, it, I feel like we have a much clearer roadmap, at least to get, to begin to get there, and the first steps seem faster than, than I would've imagined, um, if that makes sense. Like, but the, the, the, the big unknown to get to whole body reversible is the brain.

   7. SGSarah Guo21:24

      Mm-hmm.

   8. LDLaura Deming21:25

      Um, it's unclear, like, like, the brain can withstand a lot of change and does withstand a lot of different types of damage or, or change with age, for example, um, but it's unclear whether, like, what kind of injury the brain could sustain in the context of, like, a whole body reversible cryopreservation protocol, and then, like, what level of fidelity it's possible to do. So, like, that, that, that, to be clear, is a big unknown on the neuroscience side.

10. 21:48 – 25:02

    Leading and Recruiting at Until

    1. SGSarah Guo21:48

       How do you recruit, uh, and, like, lead in a company that has, like, let's say, an unclear, like, timeline around a really big scientific goal like that? Like, in terms of both finding people that are the right fit, motivating them, and how do you think about urgency in that context?

    2. LDLaura Deming22:04

       I mean, I think we have a pretty clear timeline for our first product, which is, like, get, uh, reversibly cryopreserved or... So, uh, basically, transplant patients today surprisingly frequently miss organs that are en route to them because there's a timing problem. Um, so, like, you know, organs expire, um, very quickly after they become available from a donor. Um, and-

    3. SGSarah Guo22:23

       That's very unfortunate. [chuckles]

    4. LDLaura Deming22:24

       Yeah. [chuckles] And, and it's crazy 'cause, like, they're the, they're, like, one of the most precious resources we know of, and yet, like, people regularly charter private jets. You know, like, it's like you're putting a surgeon on a private jet to go pick up an organ-

    5. SGSarah Guo22:34

       Yeah

    6. LDLaura Deming22:34

       ... get it back to the patient in time.

    7. SGSarah Guo22:35

       Yeah.

    8. LDLaura Deming22:35

       Like, 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, like, a two-hour radius of a transplant center with a pager on them or, like, a notification device at all times. And so the first product that we're aiming towards is just, you know, being able to pause time before the organ, so the patient doesn't... So, you know, like, you can take as long as you need to get the organ to the patient. Um, and that, that's very near term, like, that, that's not long-term technical. That's, like, we're aiming to get that into, like, preclinical studies and into the clinic as quickly as possible. So I think it helps to have a very concrete goal that clearly is relevant to our long-term goal, right? I think another thing that was inspiring to 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- [chuckles]

    9. SGSarah Guo23:12

       There's no version of it not going through it.

    10. LDLaura Deming23:14

        Yeah. [chuckles]

    11. SGSarah Guo23:14

        Yeah.

    12. LDLaura Deming23:15

        It's one of those things where like, it's like-

    13. SGSarah Guo23:16

        Yeah

    14. LDLaura Deming23:16

        ... if you're serious, that should be doable. And if, like, you can't do that, then, like, you, you're not the company to, like, do the long-term thing. So that, that was, it was nice just for, for us to, like, have a very clear benchmark for ourselves of like, you know, it... Are we correct that this is a tractable technology on that scale?

    15. SGSarah Guo23:29

        I guess, like, is it, is it a challenge or to, to lead beyond that? Because everybody understands the company has a, a broader mission, or is it just focus on step one?

    16. LDLaura Deming23:38

        I, I, I, I think, I think there, there, there's the, the possibility that's difficult, but I, I, I think right now I feel good about sort of our ability to communicate around that, which is like, I think if we were like, "It's 100% possible to do whole body reversible cryopreservation, there's no question, we're certain," um, like, then we would just be bullshitters, and then we, like, we wouldn't be able to recruit. Because it's, you know, there, there's a lot of technical risk, and there's a lot of uncertainty between here and there.

    17. SGSarah Guo23:58

        Mm-hmm.

    18. LDLaura Deming23:58

        But I think what we can accurately expose the models that we use to think about the problem, um, you know, like, why, why we think that this is at all p- like, possibly in scope and, like, you know, what we're testing to, you know, sort of try and get closer to there.... and I, I think the problem is interesting enough that, you know, some of the hunters, sort of like really good people, tend to be skeptical at first because there's an intuition that it shouldn't work. But then, like, they'll see a lot of data very quickly, where it's like, "Wait, I wouldn't have thought that was possible intuitively, but that seems to be possible, and so, like, let me think about this from first principles." I- I think you want-

    19. SGSarah Guo24:27

        What's another data point that you think matters besides, like, embryos can be frozen?

    20. LDLaura Deming24:31

        Embryos can be reversibly cryopreserved.

    21. SGSarah Guo24:33

        Yeah.

    22. LDLaura Deming24:33

        Um, and there's, uh, work from the existing cryobiology community, um, so from John Beschas' group and then predated by that, um, s- also, you know, Greg Fahy, he has done excellent work, um, sort of looking at reversible cryopreservation in kidneys and showing, like, you can reversibly cryopreserve a kidney, rewarm it, put it into a rat that does not have another kidney, and that rat returns to normal function after about a month.

    23. SGSarah Guo24:50

        Mm-hmm.

    24. LDLaura Deming24:51

        So it's sort of like, you know, e- even just on the whole mammalian organ scale, like, this is not a problem that's entirely out in the wilderness. It's something that, like, um, is even academically tractable right now.

11. 25:02 – 27:14

    Why Hasn’t Cryo Tech Been Worked On More?

    1. SGSarah Guo25:02

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

    2. LDLaura Deming25:04

       Um-

    3. SGSarah Guo25:04

       I realize I'm asking an answer for other people, but I'm like, well, that's very odd.

    4. LDLaura Deming25:09

       Yeah, I mean, I, I, I think even the field of, like, organ reversible cryopreservation really s- had trouble for a while attracting the resources that would be required to, to scale it, and it... I, and I, I really give a lot of credit to the field pioneers, like, you know, Greg. You know, he's just an incredible example of somebody who fought tirelessly to make this field a reality and sort of make vitrification a thing that people were taking seriously and, you know, like, like, through a long period where I think it just wasn't kind of something to, to focus on. But I don't know how to put it, but like, in venture, like, I think my whole, my whole job sort of, it... in that part of my life is, like, picking trends that, like, sort of feel like, oh, this, this thing is f- just feels weird, or it seems kind of hard to think about, but technically, like, there's nothing kind of that corresponds to that.

    5. SGSarah Guo25:50

       Mm-hmm.

    6. LDLaura Deming25:51

       And I think, like, for example, like whole body reversible cryopreservation, like, now it's seen as just much more kind of reasonable, but whole body reversible cryopreservation, definitely an area where I, I think there's just, like, so much possibility for conflation with, like, really extreme... Like, like, it's, it's, it's, um, it's hard to talk about it rationally. People either, like, love it and they love it so much that they won't question it, or-

    7. SGSarah Guo26:07

       Mm

    8. LDLaura Deming26:07

       ... it's like they're worried that thinking about- that associating with it is a little bit too science fiction for kind of where it might be optimal for them to be focused. And so I think, like, I'm, I'm kind of dancing around some things that, like, are still a bit antimimetic around it, but yeah.

    9. SGSarah Guo26:23

       The, the study of longevity has become much more mainstream over the last five years or so, um, uh, both academically, um, and, uh, in terms of consumer interest, right? And I think those two things are linked. Um, do you hope that happens with cryopreservation?

    10. LDLaura Deming26:41

        Aging becoming something that, like, a, one of the, the best... Like, someone who seems one of the best, like, next-generation professors chooses to work on without shame or fear of, like-

    11. SGSarah Guo26:52

        Mm-hmm

    12. LDLaura Deming26:52

        ... not getting a grant is great. That part of aging being mainstream is great, and, like, I definitely hope that that happens for cryopreservation, specifically also for cryopreservation of, like, a variety of tissues, including, like, neural tissue, um, and including, like, things related to, um, whole-body work. Not exclusively, but, like, like, you can basically... That tho- those topics are, are, like, um, seen as something that you're- like, it's fine to work on.

12. 27:14 – 29:06

    Making Time Not a Variable in Organ Transplants

    1. SGSarah Guo27:14

       Maybe, uh, just, like, if you go to paint a picture of, um, organ transplantation is transformed by, you know, until, like, in what ways? Like, how do you think that will change, um, either what type of care patients can receive, or even do you think that has any impact on how people think about, um, the, uh, the speed of medical research?

    2. LDLaura Deming27:38

       I think the thing that feels the most compelling for me is just, like, the experience of the transplant patient. It's really, I think, constricting. It's like you're waiting for a life-changing surgery, and you have no idea when it will even be scheduled. You know, and you can't go on vacation or really leave, like... And you have to, like, move. You, you have to be, like, close to the place where you will get surgery, and you can't leave a certain radius of, like, travel distance to that place for fear of losing out on your life-changing surgery. Like-

    3. SGSarah Guo28:04

       Mm-hmm

    4. LDLaura Deming28:04

       ... that is such a, um-

    5. SGSarah Guo28:06

       Yeah, surgery center house arrest.

    6. LDLaura Deming28:07

       Yeah. [chuckles] Yeah, that's such a crazy proposition, and then I also think, um, you know, right now for matching, it's like everything's done at literally the last minute. It's like someone dies, an organ becomes available, and, like, you're just kind of calling around, trying to find, like, what patient is available to get this organ, and you don't have that much time to make the optimal match, right? It's sort of like, like, who can get to the hospital? [chuckles]

    7. SGSarah Guo28:25

       Yeah.

    8. LDLaura Deming28:26

       Who's high on the list?

    9. SGSarah Guo28:26

       Yikes.

    10. LDLaura Deming28:27

        Um, and so I think just, like, one, uh, sort of transplant surgeon that, that we've been working with, the way he described it was just like, "Just making time not a variable changes the whole paradigm." I don't think that will happen overnight, obviously, but, like, I think the dream would be that, like, everyone in the ecosystem has the time they need to, like, you know, make the best possible decisions, sort of, like, do things in a way that feels the best for them. You know, like, a surgeon doesn't have to stay up overnight the same day that they flew out to get the organ to do this, the surgery. You know, they, they can, like, wait sort of until it's, like, the best time, um, for them, instead of doing it, like, literally, you know, like, as soon as they land, like, they go into operation. Like, that, that, it just... It's sort of something that when you really think about it, it's like, it's amazing that... I mean, it's incredible that, like, everyone is operating this way right now.

13. 29:06 – 30:47

    Changing How the Molecular World is Depicted

    1. SGSarah Guo29:06

       Maybe to close up, if we broaden the scope a little bit, uh, are there other problems that are in, let's say, biology, medicine, science, technology, that you think are, like, worth working on and interesting and perh- perhaps feasible, but people are not looking at as much as they should be? Y- you know, maybe not even making a value judgment, but that you're curious about.

    2. LDLaura Deming29:28

       Aesthetically, I'm, I'm just really curious about, like, how to represent the molecular world in a way that people can understand and engage with. Like, I think it's just such a cool and beautiful thing.

    3. SGSarah Guo29:35

       Mm.

    4. LDLaura Deming29:35

       It's like a kind- It's like, you know, we were talking about kindergarten-like worlds earlier. It's like this beautiful kindergarten, like, um, feels in my mind, very colorful, even though it's, like, not literally, um, sort of place to play around, and I think most people experience it as, like, flat triangles and squares in a biology textbook, where it's like, you know, there's an arrow between, like, this triangle-

    5. SGSarah Guo29:48

       Yeah

    6. LDLaura Deming29:49

       ... and this triangle. It just, like, doesn't make any conceptual sense, and it's, like, confusing and annoying, and so I'm just, like... I, I personally am really curious about, like, how to represent the molecular world in a way that is really compelling and feels super exciting.

    7. SGSarah Guo29:58

       From an education perspective.

    8. LDLaura Deming30:01

       I think it is artistically cool if it's educational, but I think it's, it's more just because I think it's so beautiful. It's like if you've never seen a tree, it's like-

    9. SGSarah Guo30:07

       Mm-hmm

    10. LDLaura Deming30:07

        ... being able to see a tree. It's like, that would be so great, right? [chuckles] You know, it's like this complex fractal thing, and all this, like, light falling through the, the sort of tree branches, and I, I think, like, the molecular world is like that. It's just, it's a kind of view that's not made accessible to most people. Um, it's hard to conceptualize, and you have to, like, do some amount of studying to sort of, like, build the world in your mind correctly.

    11. SGSarah Guo30:23

        I look forward to finding that art. [chuckles]

    12. LDLaura Deming30:24

        [chuckles]

    13. SGSarah Guo30:25

        Thanks, Laura.

    14. LDLaura Deming30:26

        Thanks for having me. [upbeat music]

    15. SGSarah Guo30:29

        Find us on Twitter, @NoPriorsPod. Subscribe to our YouTube channel if you want to see our faces. Follow the show on Apple Podcasts, Spotify, or wherever you listen. That way, you get a new episode every week. And sign up for emails or find transcripts for every episode at no-priors.com.

Episode duration: 30:47