EP 141 Ben Lamm (Founder & CEO, Colossal Biosciences) On The Breakthroughs Making De-Extinction Actually Possible

30:39Yeah. The thing I think is sometimes hard to understand is like the more stuff you're trying to change in a single cell, the more chances it goes wrong. Yeah. The more chances it goes wrong, causes breaks, causes unintended consequences, like off-target effects. It's also the higher probability that the cell just, I mean, you're hitting the cell, right? Think about it. You're punching the cell. And it's just like a CRISPR-driven? It's a combination. So CRISPR is one from a knockout perspective. We're doing single, we're doing some, using some of the work. We've got licenses to the base and prime editing from the Broad and from David Liu's lab.

31:15And so we're using a combination of all these tools, and then we're packaging all of it in different ways. And I think one of the things that's interesting about Colossal is our packaging and our delivery mechanisms are creating very high degrees of efficiency with how we're delivering. So you get, yeah, we can make some numbers up, but you got your cell line. Yeah. You make a bunch of edits. You hope, obviously, that the edits work. But then you screen all the edits. And then you screen after the edits. You screen all the edits. And then one of the things that we do is we then do, we do full gene sequencing, right, on all the edited cells.

31:49and then once we go through the uh somatic cell nuclear transfer or cloning process once we train once we transfer the nucleus we then resequence them all which which is a lot of fertilized yeah roughly yeah fertilized yeah fertilized new cell yeah yeah so you're so step by step basically like you've got your cells the the gray wolf cells yeah you've got a bunch of cool technology to go and edit them that is actually very hard to do successfully at any scale because you just get like errors and issues along the way making 20 edits is is not an easy thing to do without something going wrong. There's only one other group that's ever done 20 edits that we've seen.

32:24I mean, maybe there's one that we haven't seen that's made 20 edits and they were just, they were random knockouts. So they weren't really what we call precision editing. They weren't like, let's change this letter to this letter. Or like, take this whole thing out and swap a new piece of DNA in, which is like a big change. We've actually done over 100 KB swaps, which is crazy. It's a very long swap. very long swap so it's got to be real precise of like where do you start and where do you stop and there's a bunch of like new technologies let's call it that allow you to do this i mean 10 years ago impossible 10 years ago yeah probably probably impossible yeah it's the timing as well yeah and what's the big change in the like what do you think has allowed this so i'd say i'd say there's the the the three things one ai and ai and access to compute is definitely like this would be impossible without that for us which part of it so all the all of the dna synthesis work uh would be impossible all of the comparative genomics work some of the ancient dna assembly we've built some proprietary tools around to like know what to change and the analysis there yeah we actually we actually have a tool that's pretty cool so we use we do a lot of interesting things when you come from a software background you try to oh we'd solve everything with software right not here no i no but i but i i naively thought that so everything you know it's like you have software hammers, everything looks like a software nail.

33:41So, but we have done some pretty cool stuff. Like we have one thing that is not interesting to probably anyone else, but we now, we fed it enough data over enough editing with different types of editing modalities that we can now effectively say, we're going to go make this change in this part of the genome, which is the best tool. And it tell, it actually relevance ranks the tools for us and what we should use, which will, which, which have the highest likelihood of less off target effects. Yeah, those, I assume the answer would be the actual editing technology to like go into the cell, into the nucleus and swap DNA in the spot that you want is reasonably new.

34:16Yeah, it's reasonably new, like last five years. So to do, maybe you could do like a single base pair swap. But people are still doing that. I mean, people are claiming victory, which is great. I'm all about this. For a small knockout, for just a single change, like people are doing that all the time. Like, you know, like when one of the negative feedbacks we got when we launched the Woolly Mouse Project, which I would say is pretty objectively cute project. They, one of the feedbacks was like, well, people have made eight changes into miles. And I was like, not at once. Yeah, individually. Yeah, they've done it over eight generations of miles, right?

34:50And so we like, these are the things that I, and I think that I believe that, I don't know what the current upper limit is. I don't. Changes. I've changed. Yeah, before something and it just goes wrong. We're just doing, we're doing, we're hollering it so well that we're doing 50 plus edits right now. And so this goes back to your point of risk, right? Like one of the feedbacks that we got on the classification of direwolves was like, why didn't they make a thousand changes? It's not going to make, on a percentage basis of three and a half billion base pairs, guess what? It may not matter. It's not going to make it more direwolf and it's not going to change the phenotypes anymore.

35:29So the physical attributes, it's not going to make it look more like a direwolf. and it's not going to make it more dire well from a percentage basis right and and all you're doing is is doing more you're just creating more risk for what so that you can show the strength of genome engineering well i can show that in a cell i don't have to take the risk with a live animal so in the new cell you take some of them you sequence them you make sure you didn't have off-target issues meaning like hey we thought we were going to edit this thing and we did but oh well we also edited over here yeah because dna is complicated and it's not as simple as just like it doesn't work that way.

36:00And so the notion of off-target can be really bad. Yeah, exactly. Either because it just makes the cells not viable. And so that's where we spend a lot of money and time on sequencing. We kind of like... Yeah, but it's belts and suspenders, right? I think when you're doing not just cell work but your goal is to have living, healthy animals, I think you have a responsibility to do that. And so people are like, oh, you raised so much money. It's like, well, when do we have to build a whole system? Two, we have to have the best people in the world. This technology is really expensive. Oh, and by the way, like we're adding in layers of safety protocols throughout the whole thing.

36:37Because the last thing we want is some like, you know, stillborn animal or something because we made the wrong change and we didn't screen for it. Yeah, you get a wolf with mental issues or behavioral issues or physical issues. I mean, that happens all the time. I won't say which one, but there is a zoo in the United States that recently had a stillborn giraffe that had multiple heads and multiple legs. And they weren't gene editing. That's just biology. Biology goes wrong, right? It's not perfect. And so I think we have a responsibility when we're taking in that forced evolution, right, that we need to actually overprotect to ensure that the things we're doing won't have negative impact.

37:16By the way, and this is probably a longer conversation for another day, but the whole biology goes wrong thing, I think, is for normal people who aren't in science day to day, which was me as of three years ago. Now I get it a little bit better. But you forget that the ability for biology to go wrong is also what enables evolution in the first place. And so you need a little bit of like, nope, that's not good. That's not good to catch the one that is. That advances the ball for the disease. All right, so you get the, you get, let's call it like the clean new DNA. The cells you're super stoked about.

37:48Now you got to get them into, essentially, you could think, I think of it as kind of like into like an egg, right? If you will. Yeah, it's a great way to look at it. So this is the same thing that we did. We as Humanity Not Colossal did with Dolly the Sheep, right? Only they were using like archaic tools like Jim and stuff together. We use a combination of robotics. We actually have a laser drill. We have a whole system that uses computer vision to drill into a hole into the outer shell so that we're not just hitting in mammary like literally physically just jamming the you take the whole nucleus out and pop it in yes so we take the whole and we cut it's pretty interesting what can you explain that one and like kind of simple i mean yeah dumb it down but so so instead of like like before we like with like they would have needles uh and kind of kind of blunt instruments that are just like jamming the nucleus to extract the dna we aren't doing that so we actually cut a hole in the outer shell, the Zona Palooza, we go in, we actually fabricate our own, we actually fabricate our own removal devices as well, because there was nothing that could do exactly what we wanted to.

38:49And different species have different things. Like, for example, we needed to build a one made out of quartz. It was the only way that we could do, get into the, get past the Zona palooza in uh that we vibrate at an insanely high frequency uh to get into the zone of palooza for marsupial cells and it sounds weird because you're like oh big giant elephant little tiny marsupial but their outer shell is insanely hard that that we hit it as hard as we could with a laser and wouldn't even burst wouldn't open yeah so it's crazy so we do that we and we take out that middle kind of brain and then we put it into that of an egg cell where we kind of do the exact same process and reverse suck it out and kind of make space for it and then we drop it and then essentially you have a an embryo right you have a precursor to to an embryo which is pretty which is pretty and you take that and implant it back into a gray wall so you grow it so you grow it in uh in culture for a little bit right so once you get to a little bit further you put it we use domestic dogs dogs we put them in in domestic dogs so like it's actually the actual growth what what percentage of the from like the actual embryo to growth is in the dog versus in the in the lab oh 99 percent and the dog and the dog yeah and in that we do weekly ultrasounds we do yeah it's pretty involved and why do a dog versus a wolf well wolves are endangered yeah and so oh really yeah and so you and so one of the things that colossal we do have a 17 person team to get we can talk about this get weirder in a minute we um we have a 17 person team working on artificial worms so long term we'd love to grow everything exogenous like through kind of uh uh actually our development systems but um short term we're still using surrogates right and so we have to get good at uh for many reasons at uh interspecies somatic sonic co-transfer so well yeah if you're growing i didn't realize they were extinct or not extinct endangered yeah and so you've got to go to like a slightly adjacent species to grow in that whole process anything in there where you felt like this is just insanely complicated we couldn't do it and you figured it out i assume there's tooling and oh So yeah, it's all like, I mean, delivering the number of edits is really hard.

40:52Getting culture conditions is really hard and different projects have different issues. So, so for example, um, you, you do a different process with birds and do mammals. Cause there's not a clear way to do a semantics on like do the cloning stuff in birds. So you have to use generational birds. So you actually, instead of editing like, um, uh, uh, stem cells, you are, or editing like EPCs with the wolves, we're editing what's called primordial germ serial cells, the precursor to egg and sperm. But just to get the culture, like this is the media, it's like getting just the media conditions for those, what they're called PGCs to grow outside of a bird body is insanely hard.

41:30It's only been done publicly in chickens. We're very close to having it done in pigeons because dodos were pigeons. And so it's very, very hard just to get the media conditions correct on that stuff. So we have to innovate across the entire spectrum. But once again, it's not like we know, like when you do reprogramming, we know of cellular reprogram, we know that there's a cocktail of transcription factors. We just have to get the right cocktail. On the surrogate side, like how do you ensure a cross-species compatibility of the surrogate? So we typically use the egg cell from that species, right?

42:04And so the further genetic distance you get, you could run into mitochondrial rejection issues of the, not of the parent, but of the host, of the host egg, right? And so we use - Of the dog in this case. Of the dog in this case. And so one of the things that we are working on in addition to artificial wombs is we are working on, and we're not there yet on artificial wombs and we're not there on this other concept, but we are working on a universal egg concept of like, how do you map, how do you have like, which I think has weird, interesting applications to mitochondrial health applications outside of Colossal, but how do you map and change mitochondria, basically have a universal egg that you could accept any type of nucleus in it and you have a low probability of mitochondrial rejection.

42:51Like the simplest form of an egg that you possibly can that will be transferable, the primitives of an egg. So the wolf shows up. And now I assume there's like a whole bunch of optimization work to make sure that, you know, the throughput and the yield, if you will, this whole process just like inches up and up because you're probably wasting money in a lot of areas. I mean, the biggest thing now for us is, I'd say the two biggest areas for us from an innovation perspective that we are is delivering DNA. How do we expand DNA synthesis and delivery? How do we also deliver multiplex more and more edits at a high degree of efficiency?

43:29Because we can screen in the sequencing. That allows us to know what we did wrong, right? Why do you think you need more edits? I mean, the wolf looked pretty wolf-like. I mean, it looks just like a daryl. Yeah. So at least at this stage, morphological. I mean, they're 85 pounds right now and they're six months old, right? As a typical wolf is like 75 to a hundred pounds, right? So we're on the trajectory, the wolves grow for about 18 months. We're on the trajectory for these to be 140, 150 pounds, which is roughly what dire wolves were. So, um, and then, and also the snap, everything they're stock here.

43:58If you go look at a five month old, if you go to the internet, look at a five month old wolf puppy, you look at ours, you're like, yeah, those don't look the same. You can like, ours look like linebackers, the linebackers of the, of the wolf world. Um, well it's just different species, right? So like on the thylacine or Tasmanian tiger, there's 70 million years of genetic divergence between the thylacine and the fat-tailed donor, which is – it's a marsupial carnivorous mouse. We're turning a marsupial mouse into a carnivorous wolf. Well, it's not a wolf, but it's a wolf-shaped body. So different species are going to require more edits essentially.

44:29Yeah. And so now the better we do at Comp Bio, we think that it's about 500 edits for craniofacial morphology. So we get that hypercarnivorism skull. Like the thylacine is a super hyper, it was a super hypercarnivore. So it's about, we think it's about 500 edits, which we've made in one cell line, which is great. But some of the work on sizing and some of the patterning could be more. And so I think the thylacine project, it's hard to say, but it'll be thousands of edits. Maybe a controversial question. So business model for a second, right? And obviously there'll be some pieces of this, which is like we made a technology.

45:07It's cool. And we spun it out. We spin it out. So we spun out three companies so far, a computational biology platform for human healthcare, a company called Breaking, which is a plastic degradation company. So we've accelerated, there's a microbe that makes this enzyme that literally breaks the chemical bonds of plastics. And so that's why we call it Breaking. And that's now, we've raised capital for both those businesses. We spun out another company we haven't announced yet that's valued at way over$100 million, which is great. So Spin Out Technologies is one. And each of those carry their own unique esoteric risks of lots of startups.

45:39You've got to, the jack has to work. You've got to scale it. Someone has to pay for it. Yeah. Someone's a run. I don't want to. Yeah. Find a CEO. Yeah. But on the core. I try to stay on the board as little time as possible. It's also a lot of work. Yeah. On the core business itself, do you view this as like people will actually buy the wolves as pets? I mean, they're not going to buy a woolly mammoth as a pet, I don't think. So we got a tremendous amount of ask for everyone ranging from the request on the woolly mouse were ranging for kids' pets, school pets, large household named, I don't want to route them, but museums want them.

46:16We've even had some museums reach out and say, well, mice don't live forever. Can we taxidermy? I'm going to put them in a display. And so we've gotten all kinds of those types of requests, right? We get the apparel request. We get all these types of requests. I do think that there are lots of people that would love to buy our animals. That is not our business model. Our business model, we're learning. If you ask us when we started, it's like non-existent. If you asked us two years ago, it was technology spin outs because we thought, hey, we can create enough option value that if you innovate across all these things and if we can deliver thousands of edits with zero off target effects, that company alone is worth$100 billion.

46:51Just that spin out. Your cash runs out, which is the challenge in that model, right? Because you've got core cash. and you spend them out yeah you spend them out and then they need their own money they need their own money we don't we don't take we don't fund them right they they got oh i just mean without like a core revenue no without core attitude yeah yeah so so we are kind of raising money so that that's that that was kind of model one um there's a huge economic driver and you probably heard about carbon credit scene the carbon credit model right yeah mostly fraud but yeah just like crypto like crypto like i well no i mean well i would argue crypto is more of a religion than a currency, but that's another argument.

47:25I meant more like a lot of the carbon credit businesses. No, no, no. I mean, they're not like them are fraudulent. Yes. And so just like the early days of crypto, but what you've seen in that market, a couple of things that you've seen in that market. One is you've seen this move to biodiversity credits because it's highly trackable versus like, so that's like saying there's now been studies that have been peer reviewed. This is an elephant in Gabon has this annual ecosystem restoration and carbon impact, right? So you have people that aren't like, hey, like the fraud that you're talking about is that people are like, oh, like, I'm gonna go buy a bunch of forest and I'm gonna keep all the animals alive.

47:58And they like wink at you. And then it's like, that's where the trillion dollars of carbon. Like, here's this forest, we didn't cut down. And yeah, the forest never existed in the first place, or they did cut it down. It's been wrought with that. But what you found is that if you look at like, you know, the Paris Agreement, 66 % of people's agreements say that they have to move to nature based solutions, like rewilding, like some of these things. So if you look at things like rewilding elephants, If you look at kind of like the total economic value, and I'm not talking about anyone that's currently monetizing it, but from peer reviewed papers shows that there is over five hundred billion dollars of value that's being added to the African.

48:38And they take into ecotourism, take all these things into it to protect, to essentially protect the forest elephant, which is critically endangered. And so what we're seeing, if you look at now, PwC entering the game, you see TPG raising$9 billion fund around this. You see, who else did it? Oh, Lloyd's of London is now certifying it. You're now seeing people saying, yeah, this market was nascent. Lots of people running around. But here's the other thing. We know that ExxonMobil and we know that in this extractive economy that we live in, we know that like Sumitomo Corporation, Mitsubishi, in strip mining and where do you think lithium comes from?

49:15and doesn't magically grow on trees, right? And so synthetic biology does not solve the house plant that makes lithium a problem, right? No. And so - Nor is it likely given that - Nor is it very, very likely. And so I think that those companies, whether it's social pressures, ESG, or government regulations like in the EU, they have to buy these offset credits, right? And so regardless of where the market was, there's now this maturation of the market. So for us, it's a perfect market timing because a lot of these pioneers got arrows in the back, which is great. Now you've got people that are actually coming in and having to certify and really understand it.

49:51So if we can go in and say, hey, we're going to return the thylacine back into Tasmania. We think the tropic cascading effects could be this. Let's go measure it. Let's bring in ecologists and conservationists. Let's then bring in Lloyd's. Let's certify it. And then let's also get government subsidies for - This is the most progressive left business model I've ever heard. I love it. Yeah, it's interesting. So we have both sides of the aisle. Yeah, we're very - So it's not a domestic safari that's like really expensive to visit because that I think I would go for that. Everyone would go for that, right?

50:20And so. Is that like an ethical consideration? I mean, like a fancy zoo sounds awesome. Yeah. I mean, look, I am not. Five-star hotel. Sounds great. Yeah, yeah. Singita brings you. No, but two things. Like if you look at like on the eco-tourism front, like we talked to the Ministry of Tourism from Mauritius where the Dodo was. and he's like, you're going to 5X our tourism, right? And I said, well, look, we would love for you to give us land that goes on our balance sheet. We would love to get the carbon and biodiversity credits that we can go sell, that we can get certain that we can, that isn't just like, hey, we promise you there's Dodo's there, it's wink, wink, but like, let's actually measure it.

50:58Let's have third-party verifications. Let's go sell it. And the other thing about the carbon and biodiversity market is based on the sexy factor, like the credits try to add a higher value, right? Because ExxonMobil wants to show that they're doing stuff with like, you know, alternative things like ethanol or algae, right? So they do trade at a higher premium. So if we can do all that, and then if we can say, oh, well, let's have a Four Seasons or a One and Only or a Mon, be there and they do an ecolodge and we get a cut of that, then that's great, right? But also the local people get a cut of it and whatnot.

51:28And if it causes people in Mauritius to clean up the environment and remove the invasive species that led to the dodo's demise, then that's a win also for conservation. And so I think that you can find a way to put a value on nature. Don't you remember forever people were like, well, if we charge$100 ,000 to kill a lion, then we're putting a value. That was like the argument for like hunting lions. But regardless of how you feel about hunting, what they were right about is if an animal has some value, it isn't just seen as some random animal that doesn't have value, someone will at least think about that, right?

51:59And so if we can do it in the opposite way where you're not killing them, you're encouraging them to have an ecosystem function. I think that's pretty interesting. um and to your zoo question we're not against zoos like we we think like people like the aza and people that have great zoos like san diego zoo they do a lot of stuff for conservation they do really good stuff we we work and collaborate with some of them on different projects you know i think that bringing back extinct species just to put them in zoos seems like a weird optics yeah it's to be what one business line of you know many yeah i was gonna go to to maybe but But we think that we really do believe the restoration work, the biodiversity credits, where we think it's going to go is certified nature credits plus ecotourism.

52:40We think that's billions of dollars in ARR for us. I mean, the tourism appeal is likely massive, right? And government subsidies. Yeah. Human embryo editing. We are not doing that. I assume someone's brought it up. Yeah, we do have that question. So the reason I ask is, you know, theoretically, and tell me where I'm wrong, a lot of the underlying technology is to do like safe editing here there's no reason why those technologies don't also apply to editing it goes into germline editing right and there's a general on the germline side yes yes yes so i would say that um so colossal does not work on anything that is human uh neanderthal like precursor to human or um non-human primates just there's just like We already get enough, you know, In-Q-Tel as an investor.

53:30We get a lot of conspiracy stuff already, right? We don't need more of that, right? So we're like, there's enough for us to do. We're not going to do some of that stuff. And then if there's applications to our technologies, whether it's artificial wounds or multiplex editing or computational biology, we'll spin those out. Other people can go through the FDA. They can do all that process. That's not our problem, right? We can benefit from it, but that's not our problem. All of the technologies that we're developing, you know, the work that we, we're also looking at different delivery mechanisms.

53:56So outside of doing somatic cell nuclear transfer for what we're doing for the cloning, we did micro injection in embryo for for the woolly mice. So we actually are editing. So we're delivering a way that also doesn't create chimeras. So you're actually getting all the delivery in. So it's really cool tech. And so all of that could be applied to embryo editing. We aren't doing that. At what point like the prioritization in all of this is probably an interesting thing. of there's there's probably i don't know how many novelty animals you can work on i don't know if that's the right phrase yeah just like continuing to do stuff that's sick and like would get me excited about it but at some point the dodo is like a little bit more racked or has more practical considerations how do you think through the the pr side versus the practicality side the three are three like flagship projects right mammoth thylacine and dodo all have apple thousands Tasman tiger, have applications to rewilding and to ecosystem restoration, right?

54:56So those are our three flagship projects, the highest staff projects are the ones we're working on the most, number one. Number two is we pair each one of those with the critically endangered species, right? So with elephants, it's the mammoth, it's the pink pigeon with the dodo, and it's the northern quoll with the thylacine. And what's interesting is like, you know, while we made three direwolves we also we use that same epc technology to clone four red wolves there's only 15 red wolves left in the wild it's the most endangered wolf in the world and it's the only wolf that's only endemic to america and you think you can grow it in a dog i already have we have i have four there's four i have four red wolves yeah is that public or yes probably yeah just no one cared that's amazing yeah so in uh i guess as you think i shouldn't say that no one cared in a relative number.

55:45We did increase by 100 ,000 fold Google searches because I'm a data guy, so I look at all the data. And there were 7 billion media hits alone on Red Wolves. And there was, I think, 398 or 498 stories on just Red Wolves. So people cared, but there's 180 billion impressions on Dire Wolves. So relatively speaking, they didn't care as much. But then a week later, after we were on the Today Show, a week later, the Today Show just ran a special on Red Bulls. I don't think they would have done that without us. So we are building technologies to help conservation, right? Because another business line that we're finding, while we open source, I mean, open source software is a great example, right?

56:28So you build a community, you build some tech, you build a community, you do it, people use it and whatnot, that's all great. But then you have the enterprise use cases, right? Where you've got someone like Microsoft or someone saying, hey, cool, this is cute. Our developers have used this technology. We love your technology. We don't want our developers to implement this for the Department of Defense. We need you guys inventing the technology. You guys need to do it, right? So a lot of these open source communities will then have their private instincts. So while we open source all of our technologies for conservation, so like, you know, we're cloning red wolves.

56:55We're open sourcing all of that technology to make it more efficient, better for cloning. You know, I think we could productionize endangered species, which I think is an interesting concept. So how do we get species off the endangered species list because we're actually recovering them? You know, we're not just saving their habitat, which is... Saving their habitat is critical and it has to be done. So this isn't a replacement for this. This is an and. But then how do we also make more of them? But now governments are coming to us on a new business line where they're saying, hey, we're using all we love some of the papers you put out.

57:22We love some of the concepts or our team to work on. But this one government, for example, has a specific type of cat. And they were like, we want we need to get to 50 breedable females. Well, it's going to take them at their best rate based on the male to female ratio that they, their breeding cycle, the male to female that are born. It's going to take them 23 years to get there. It's going to cost about$300 million to get to their 50 genetically diverse females. We can do that because we can select for females. We can engineer in genetic diversity. We can do that in three years. And if they paid us$100 million, we'd still be making a fortune on that$100 million.

58:00So we could save them hundreds of millions of dollars. But more importantly, we can save them. We could deliver a better product as we can engineer in more genetic diversity. And we can do it in two years. Isn't preservation versus de-extinction pretty separate in terms of potential implications? Bringing back more red wolves. We know how they do in the wild. We know generally why they've decreased in number versus bringing back a woolly mammoth. I guess we don't... Do we know why they went extinct? And do we know the implications of bringing them back into the wild? So it's a great, it's a great question.

58:32We know a lot about rewilding because we know, and we know rewilding works because we've done it. It's a very systematic process that has indigenous people groups, private landowners, governments, you know, local private landowners. So it's a very stage gated process. Like nobody just like, you know, like in the Yellowstone Wolf rewilding, right? No one just made a bunch of wolves and opened the gates and like cross their fingers, roll the die, right? Like no one did that. It's a very thoughtful stage gated process where you're in a managed care facility, you're in less managed care, you're in less Spanish care and then eventually the wild, right?

59:00So that's a very measured process that I think's well documented and it's very inclusive of the community to do that. So we do know, there's also been studies that show what the reintroduction of cold tolerant megafauna back into the Arctic looks like and how it revitalizes the ecosystem and kind of makes this mosaic landscape, which is actually really good for adding biodiversity, flora and fauna, as well as carbon sequestration. And so we know all that because there's been people that have done this and tested it, obviously not with mammoths, but other species. So I will say that, you know, from a conservation perspective, you know, we think that this is not a replacement for these technologies.

59:38This is just a new set of tools like biobanking, genetic engineering, engineering and genetic diversity, cloning. These could all just be new tools in the tool belt because it's forecasted that we're going to lose about 50 % of all biodiversity between now and 2050. So we need new tools. We as the world are failing loss of biodiversity. Why no non-human primates? Monkeys, essentially. Yeah, I mean, it's just one step closer, right? Like, what, we're going to make giant epithecis? Like, that's everyone, it seems to be a fan favorite. It's like a small King Kong. It's like, we're not going to do that.

1:00:12The use case, actually, I'm curious about, and we can talk offline about it, actually, is in animal testing for new therapeutics, for new drugs. Yeah. um and do you think that ai and do you think ai will get to the point from a simulation design perspective that it can simulate all of that no not even close i would i would put that at 50 plus years i i think it's one of the hardest things because the data to know yeah on an animal what what happens in a live bot like human system animal system is insane there's no data people i i i'm a hundred percent with you like fusion and so many other technologies are so much closer than that yes yeah i think that's a i think that is a very very hard problem so when i read these things about oh well ai and you're eventually gonna be able to do simulation design i was like i think you're gonna be able to do local simulation design but i don't think you're gonna be able to do it on a system model a full system model i mean one of my co-founders at curie he because i was asking these same questions of like you know why can't we do it with computers as like yeah and and at one point he said to me you know uh a petri dish is not a human yeah and i think like just that And a mouse model is not a human.

1:01:15A mouse model is not a human. You know, a monkey is not a human. You see all that in these therapeutics, so. Yeah, and all the training data for a lot of these biology systems are on a Petri dish, which is a piece of plastic. Yeah. And so it's as close as we can get to a human, but it's not a live system. It's like, you know, a cell and a piece of plastic. Yeah, yeah. It's not representative. I totally agree. So when you look at animal testing, if you think about, we would call them non-human primate testing, right? So it's essentially monkey testing. It is an absolutely required step for many new drugs.

1:01:44I bet you could build a large language model for a large animal model for non-human primates. Well, I think the non-human primate thing that could be really interesting with the editing side of this is you want non-human primates that have human-like disease. Yep. Because that's going to give you a better data set. Yeah. And the way you can give a non-human primate disease post-birth is limited. Yep. versus if you could edit and grow in an HP that is more likely to develop X, Y, and Z disease. And while that sounds rough from an animal standpoint, it saves human lives. Because now you can actually test and get more predictive data on a marine planet.

1:02:27You also don't have to have infinite cycles of that. It's a somewhat contained loop where it's like, you do enough, you get enough training data that you feel confident, at least in this species of monkey that you can apply. Maybe give a literal example, like some cancer. I mean, the one that I would, now we don't know what cause, from what we can tell, you cannot give a monkey an NHP, Alzheimer's, or dementia at this point. At least no one's figured out how to do it. I mean, in theory, you could kind of like try and have them live forever and see if they naturally develop it, but you can't. You can't give it to it artificially.

1:03:00Can you monitor to the point of showing signs? They die too fast. uh and like that's an oversimplification but basically they don't get it they don't get it and so and you can't give a mouse dementia uh and so when you're developing a new dementia drug or a new alzheimer's drug the only point in which you get any real data on whether this thing works is when you put it into a person yeah and that could be a hundred million dollars just to get to that point and the chances of it working are really low because there's no feedback loop right like there's no ability it's also a long feedback loop isn't it well you have to wait for the human uh so it's even longer than you think um and so you you know you test it in in in cell lines you test it in mice but like it's not really predictive we need the woolly mouse of uh oh this is gonna sound insane but like if you had a non-human primate edited so that it develops something like dementia or alzheimer's well not great for the primate great for the people because now you can get feedback on your new potential drug faster and cheaper.

1:04:03And it's not like 5 % faster and cheaper. It's like 90 % faster and cheaper. Or zero to never cheaper or faster. I mean, the amount of things that we simply don't do or don't test because getting a drug into a human for Alzheimer's and dementia, essentially clinical trials is so expensive and time consuming that you just, it's not worth it. What do you think about, it's just an absolute tangent, but what do you think about the whole notion that like Alzheimer is type 3 diabetes? I mean, there's a lot of cool theories. I think the reality of biology, it's probably all of the above would be my guess, but like, what do I know?

1:04:45I mean, this is the single most complicated organ in the history of the world, right? The human brain. We barely understand how it works. So like, what drives this kind of stuff? It could be like nine things all at once. wouldn't it be nice to be able to study it in a monkey? And that would accelerate research faster. So that's why I was asking about it. And it's not just self-service and dementia, but there are probably edits you could make, and now I'm speaking a little bit out of my ass, but I bet you there are edits you could make in a monkey that are predictive of disease. Yeah, I mean, you're seeing that with PGT testing.

1:05:19Like I just had a kid and we used Orchid Health to look at where they actually do full genome sequencing. And so outside of the specific, you know, major things people screen for and specific things we were screening for, there was also a, they also kind of give you this, it's somewhat, I don't know if it's controversial, I think not everyone subscribes to it, but they give you a distributed kind of like bell curve of like, of what you could have predisposition, what your child could have, or that embryo could have a predisposition to, including early on-site Alzheimer's and others and things like diabetes and whatnot.

1:05:56So you're at least understanding, because to your point, we don't know all of the things, but at least we know that there are specific genes and specific mutations that create a higher likelihood within environmental factors. Yeah, it's great. It's just to drug it is an incredibly challenging thing. I'm glad I don't have to make that decision because we made this decision not to be in therapeutics because I think those are really hard decisions, right? I think from where I – do I think that people should explore all ways to make human life better? If you've ever had anyone that has gone through dementia or Alzheimer's, you don't wish it on your worst enemies in the world.

1:06:30So you don't. You don't. And so if there are ways to achieve it, I think that's something that we should – we as humanity should – if we achieve longevity, escape velocity, but we don't solve that, well, then what's the point? What's the point? Logan just wants to base at it so his kids are Knicks fans. Yeah, exactly. Is there a Knicks gene somewhere? He's already watched two games in five days of life. So he's moving along pretty well in this fandom. Yeah. Playoff basketball. Best place to start. I'm curious, like you bump into religious zeal. You bump into regulatory considerations. Like you're sort of in the Petri dish, I guess, to use a cute term of like society's third rails.

1:07:10It feels like in so many different ways. Not to mention the PR storm that you guys get caught up in or benefit from, depending on the day, probably. Actually, before direwolf, we were at 98 % positive or neutral feedback. Is that right? Crazy. Wooly mouse, people love it. Well, even before that. Mammoth, I see you, don't know, yeah. Yeah. And if you extract out, because we, once again, data, if you extract out classification of direwolves, 98 % positive also. And what was it that was the direwolf that just sort of set off such a storm? Can't call a direwolf. It was really just that. It was that simple.

1:07:40Semantic argument, yeah. Silly argument. I think the look too it's a very like just the look of it gets national attention because it's folklore right like they're in Game of Thrones and others which I think it just causes people to be interested in it maybe I guess more so than the what was it the Red Wolf was it a step function in PR too as well like did it just reach a different we kind of got fucked because we we spent a lot of time with what we do is hard and it's complicated right we spend a lot of time educated like sometimes we get these these articles where the most annoying was we launched our foundation.

1:08:16So we make all these technologies available for conservation. We then open source all of that technology. We then also pick a species that we help. So for example, the number one killer of elephants in the world is a herpes larva, E-H-V. 20 % of elephants. More than poaching, human elephant conflict combined. It's terrible. We have actually worked with Baylor College of Medicine, some of these AZA accredited zoos, to actually get in, they're in trials in elephants that's conferring resistance using an mRNA approach that we helped design. You're vaccinating elephants. Yeah, but check this out. It's great.

1:08:52If Colossal does nothing else and we just saved, we'll save more if that works, which it is, against the number one strain of EHV. I think there's five strains, but this is the one that takes like 75%. It kills baby elephants too. It's like fucking awful. That alone will save more elephants than all elephant conservation combined, right? And so we have to deal with, So even with all of that, right? You know, most people, like there's still articles out there that like we launched. We then launched the foundation. We raised$50 million separately for the foundation just to fund other people to use our tech because maybe you don't have the money that you want to use our tech, but you don't have labs or whatever.

1:09:23So we'll fund you to do it if it's helping a species or if you're developing new tech as long as it's open source. So we're doing all that, right? And then like we launched that in London and CNN was one of our launch partners. Then we launched the woolly mouse in one of the lines in the same article by the same journalist is like they should do stuff for conservation i was like but you you know we do stuff for conservation because we launched our foundation with you yeah um and so so there's always an education thing and the the problem with with uh colossal times is it's highly nuanced right like everyone's busy every our every pr company or every like media company is looking for clickbait and so it's like you know dire like there was an article that was like george r mark George R.R.

1:10:05Martin hasn't finished the last book of his Song of Nice series because of Colossal. That's literally the title. There was another title in Bloomberg, right? So the launch title with Bloomberg was Colossal brought back direwolves because we spent 20 hours with Bloomberg. They got deep in the science. They really understood it. And their result was, oh, yeah, we're not going to argue classification. This is a direwolves closest approximate thing. We're going to call it direwolves. Same thing with time. Same thing with New Yorker. Same thing with many others. but then what happens is then you get wave two which is all the click baby stuff which is like oh there was actually an article that was one of my favorite titles by someone else at bloomberg uh later that's like the terror uh colossals uh direwolves and terrorists uh have one thing in common it's like that's the weirdest so you're starting to get stuff like what was that by the i didn't read the i don't read the articles yeah there's billions of articles what's a bigger risk for the business uh funding and they're not mutually exclusive i guess but funding or pr I think neither.

1:11:02I really don't. I think there's a huge app. We've been very fortunate. We have a huge appetite for funding. We're not announcing new funding at this time, but publicly to this date, we've raised$435 million. I think that's highly likely to change in the future. Yeah. So you have more than enough interest on the funding side. There's unlimited interest. And you don't worry then about - And the PR side isn't, the PR thing is really just about education, not persuasion, right? Because we take this attitude, like some of our biggest critics in the world, like my chief science officer, best career, number one ancient DNA expert in the world.

1:11:37She joined the, cause she was the most, one of the most negative person when we left, when we started the company and we just reached out to her. You know why? She's the number one, she's number one in her field. So regardless of whether she likes us or not, we would be fools not to reach out to her. So we've had that attitude, right? We, we don't have an attitude. Are we ever going to fix the clickbaity stuff? No. Yeah, but I guess the question I was more getting at is the clickbaity stuff can often lead to derivative consideration on the policy side. That might be - We work really closely. It's a great question.

1:12:05We work with both sides of the aisle. You said that we had the left. Well, I was joking about the carbon credits. Yeah, yeah. But what I'm saying is we work with both sides. One of the things that we found on the Hill is that loss, regardless of how people feel about climate change and some of these other things, loss of biodiversity is a bipartisan issue. Everyone agrees losing animals is bad. They may have different motivations behind it, but nobody, neither side seems to really want to lose animals, right? So like we have a great relationship with the left. We have a great relationship with the right.

1:12:33We, we, uh, you know, the Department of Interior and Secretary Burgum, uh, of this administration acknowledged our work and, um, you know, thought this one of the most innovative things that's ever happened, uh, which is a really kind statement. And also said that the technologies that, that de-extinction technologies now need to be a tool in conservation. Now that was weaponized in the press and said, oh, well now, now we don't have to save species. He's like, that's not what he said. Trump's pick for, you know, I'll give you another business model. Maybe this works, maybe it doesn't. But, you know, while I agree, a lot of groups are interested in like keeping animals around.

1:13:05Yeah. There's obviously a bunch of like environmental review for rare species that we find on some like giant development. And we spend three years arguing about like whether we care about the species and the development doesn't happen, which harms people. Yeah. Right, it makes houses more expensive. Could you work with developers to say, look, you find some rare species that you need to protect, we'll just make more of them and move them elsewhere? So that's the argument that I think was weaponized by, so part of, we got, Washington Post wrote, by other people's standards, not mine, a moderately unfair thing, because something like that, that exact example was brought up in a cabinet meeting, right?

1:13:47And that was just a discussion, right? I view it as it's okay to have these conversations. And the response to that was, that means we don't need the Endangered Species Act. Nobody's saying that we don't need it. Like, Colossal believes you need the Endangered Species Act, right? But at the same time, there are certain times where you take, there's been numerous cases where there's been a population of frogs. They put a rodent. They're now two populations of frogs. And this population is smaller. They are now classified as two different species because there's a geographic species definition. There's one of your Baskin-Robbins 31.

1:14:18one. And so there's a difference. So what I think a better model is to that is we should, regardless of why we're losing species, we do need to protect habitats. And we know that current conservation works, which doesn't work at the speed of which we're eradicating species. So I think we have to continue to protect land, right? Even at some cost to humans. So I think we have to do that. And I think we just have to balance that, right? And then at the same time, we also have to look at what are opportunities for us to also biobank species because no matter how good we are at conserving land, there's going to be some trade-off to humans where land development is going to move forward, land development is not going to move forward.

1:14:58So we have to biobank everything because we know overfishing and all these other things are going to continue to eradicate some of our species. So I think that having, like we have insurance policies for everything, yet, you know, like the government and military is like one of their number one things is like readiness. How ready are they for a conflict? It's like one of the core metrics that the military judges itself on. Why don't we have that for biodiversity? And so sometimes I'm a very big advocate for having like the seed vault in Northern Europe for species. Like we need bio vault, a nationalized bio vault program.

1:15:28But then people say, well, then you're just trying to build an insurance program so that we can do with everything in species. And that's not what we're saying. I think this is an and conversation, not an or conversation. I mean, you could make the argument that if this technology works at at any scale but it's expensive totally it's time consuming so is endangered species yeah uh you know i think that argument of like but if you can productionize endangered species and you can put and you can and you can conserve land and do if you can take modern conservation and layer on the ability to move the productionize yeah then that's that could be a win for everybody right and and i think what sometimes people what people recently have said was well if you can productionize endangered species then you don't need the land is like, that's not what we're saying.

1:16:08That's not, you know, other people say that. That's not, I can't control the world of what they say or what they choose to interpret the technologies. It's kind of like for a while where everyone hated computer vision because people were in China were using computer vision to segregate populations based on specific profile. Like, yeah, that's bad. But that doesn't mean computer vision's bad or facial recognition's bad. That means it was bad. It was a bad application of that technology. And so I do think though, if we can, like if we can get animals off the endangered species list, because we have one conserved land done existing.

1:16:39Maybe it's the same land. Maybe it's different lands, right? But if we can conserve that land and do modern conservation and then productionize and make 1 ,000 or 2 ,000 or however many you need red wolves that have engineered in genetic diversity so that they have a population that won't go through a bottleneck, that should be a win for everybody. Yeah, then you don't need the actual endangered species act in the long run or you just need it in certain geographical areas. But you still need to protect species because you're going to have areas both foreign and domestic where people don't care right i think like we all care right but it's like we all want to figure out the car the hard uh thing is always figuring out human progress and in our oh to be clear i don't care i don't i get why people care i i don't believe in the endangered species acts i think nature takes species extinct and has been doing it for four billion years we have been accelerating it right and so i will say but so are you know like lions accelerated the you know i would say humans are on a different pace that's just how it works earth has survived you know we go up and we go down i think it's forced extinction uh i get why people care i don't but i'm saying what i'm saying is is regardless of what you're i i think there's i think that if every i think if both sides of the argument open the aperture and look at technological solutions look at exists like what currently works we know conserving land works we do know that works.

1:17:58Yeah, 100%. But we also know that sometimes conservative land can come at a cost. So where are the balances? And I think those are important questions. But what I have found, the only decisiveness I found on the biodiversity topic is this is like, is that we have different, there's different opposing views on on how to save them. But generally speaking, people are mostly in favor of figuring out how to save them. And what we're saying is, we are not the solution. we're just one new tool so throw our throw our tool in this whole conversation and see how it happens yeah you guys with the right land could pull it off there's but it is still i will tell you and once again i run the de-extinction company right i will tell you it is way more expensive at least today to bring back a species uh than to just say hey let's keep it alive here it is it is It is more expensive.

1:18:48From a regulatory standpoint, are there things that you've bumped up against that are just feel nonsensical? And if you could wave your magic wand or do something, it's like, gosh, this is just rooted in 1900s prohibition. I think there's different things. We work very closely with all the organizations. We're very transparent about it. The intelligence community is an investor in the business. uh north dakota is an investor in the business we have other states that uh have expressed north dakota like pension yeah they're uh economic and commerce development fund um and then um there's other uh vehicles within the united states government that's interested in supporting the efforts right we work closely with fish and wildlife so we're working with all these different things right i think that you know i do think that sometimes there are things that could be changed in and accelerated um you know one thing in particular is there was this moratorium for a long time on GMOs.

1:19:47Now we aren't creating genetically modified organisms for consumption, even though we do get asked if people could eat our mammals, which is weird. Um, but I do think that, that, that we, we got that question quite often when we launched. It's kind of a great question. I mean, whether you want to do it or not, it's an interesting question. So I understand the need from a USDA and an FDA perspective to look at the classifications of, uh, uh, uh, genetically modified organisms for consumption. But for example, So we aren't doing this, but let me give you an answer that goes straight to regulation.

1:20:18The FDA has historically taken the stance that if anything has a edit and it should be treated as a drug, right? Well, okay, well, man, I'm going to go through clinical trials. And the other thing is like, there's a process. We're not in the cattle industry, but there are people that are in the cattle industry. And a lot of times they have a pretty unhumane model of dehorning cows because when they put them, they're not like running around like Yellowstone National Park, right? When they put them in these large things, they have horns, they spear each other, that leads to infection, that leads to disease, that can create all kinds of bad stuff downstream for human healthcare, that can kill off the cattle.

1:20:52It's really, really bad. So they dehorn them, right? Which is a pretty inhumane process if you really, really look at it. But in the whole, it's good for the herd, but it's not good for the individual animal. But there's actually some researchers that have identified making, I think it's either one or a couple edits that make it where they just don't grow horns, right? Way more humane for the cows or whatever. But I'm not in it, but from my conversations with people that are in that field, that hasn't gotten through because it's classified as a drug. Well, that's silly. We have been doing genetic modifications to animals and plants for years.

1:21:26We've just done it inefficiently, and we've been doing it the old-fashioned way of crossbreeding. Crossbreeding, yeah. Crossbreeding, yeah. And so I would say we're just doing, to your forced evolution perspective, we're just doing it way more efficiently. Can you get the cows that don't release methane? You know, there was a study. We were, I don't know where this went. There was a study that happened in Australia where they were trying. I don't know where this went. So I'm only giving you a half truth on this. But marsupials give different levels of milk because so much of the gestation happens outside.

1:21:54So they give you like high fat. Then they give you like 2%. And then they give you like skim. So the marsupial body is incredible. So the moms produce these different tiers of milk, which is really cool. And so there was a study. I don't know if it went anywhere. we didn't work on it but one of our Australian partners at the University of Melbourne told me about this where they actually were trying to figure out how you engineer that into cows so that you could have like 2 % milk cows oh the one I always think about is cow farts which everyone laughs at but it's like a greater contributor to emissions than you know climate change yeah because you need the cows and they fart methane and there's a lot of cows I mean there's a ton of super ones probably like that but what about the religious element of like playing God and altering.

1:22:39I think, I think we have a pretty, once again, I, we, we try to engage with everyone, right? You know, so we go on the most conservative shows, we go on the most liberal shows. We try to be pretty bipartisan and, and, and, and pretty inclusive, right? We've got some of the strongest atheists behind us. We, we also have some of the strongest, you know, Christians and people from various religions and Jews. So for us, I think that, you know, we have attack that and this goes to you're probably where you fall it's like we've been playing god for quite some time like we were eradicating for us we're overfishing the ocean we're polluting shit we're like like i take drugs is that a form of playing god like i i like i like i lower my cholesterol with a shot twice a year or twice a month so does that does that mean that we screen human embryos for disease already yeah i did that with my son so it's like so is that a form of playing god i built a distributed uh uh risk matrix for uh embryo selection for our kid and we chose him because he came out on top from a weighted average that i made yeah so um based on apologetic risk scoring right so it's a um so i think we do that all the time right and it's like you know i view it as you know there's not enough money going into conservation we open source all the time we look i look at this is like a free research and development arm for conservation right like we're doing all this stuff as industrial and human application and other things that we'll make a lot of money on.

1:24:01We do think we'll make money from an ARR perspective on rewilding and carbon credits and biodiversity credits at ecotourism. But separately, we're just giving all this stuff away from conservation. So anyone that's been in research and development knows it's a huge fucking R and a very small D, right? Very little goes actually into development. So we're burdening that cost and risk for the entire community. And so I think that we're definitely not going to do everything right, but I think that we're trying to do everything and work with critics that are at least informed to the point that we can get where, you know, people are excited about it.

1:24:33But the playing Godwin doesn't come up as much as I think one would think. We get asked the question, do you get that question a lot? But for the most part, I think people realize that, you know, the intentionality behind what we're doing. Like if we weren't open sourcing stuff for conservation and we're just like, yeah, we're just making whatever we want F off, then I could see how that could... I found that logic can be totally orthogonal to sentiment oftentimes. Yes. Yeah, that's a great point. It's really cool. I mean, just leaving the business model stuff aside for a second, just the underlying technologies to do this without like, you know, insane failure rates up and down the stack are going to be used in a bunch of other settings as you guys, you know, bring the tech to market.

1:25:13So it's very cool. And it's much harder to do with ancient DNA than existing. So we're making the tools like super hardened. Yeah. So thanks for doing this. Yeah. Thanks for having me. This is awesome.

1:25:26Thank you.