Instant Genius - The Science of De-extinction

Episode Date: August 24, 2023

When an animal is extinct that means we’ll never see the likes of it again, right? Well, not quite. Not if biotechnology and genetic engineering company Colossal Biosciences have anything to say about. A few years ago the company launched with the bold aim of bringing animals such as woolly mammoths, dodos and Tasmanian Tigers back from extinction. In this episode we catch up with Ben Lamm, founder and CEO of Colossal Biosciences. He tells us all about how the ambitious project got started, how they plan to bring back extinct animals and why we might being seeing baby mammoths sooner than we think. Learn more about your ad choices. Visit podcastchoices.com/adchoices

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When you want savings, not surprises. It matters where you stay. Hilton, for the stay. This podcast is sponsored by name, audio and focal. Streaming has made music more accessible than ever, but true listening is about more than ease. It's about quality. British audio experts name audio,

alongside French acoustic specialist, focal combine handcrafted tradition with cutting-edge innovation and high-end materials delivering digital precision with analog warmth so you can experience exceptional sound at home music just as the artist intended visit name audio.com to learn more and welcome to instant genius a bite-sized master class in podcast form i'm jason goodja commissioning editor at bbc science focus magazine when an animal's extinct that means we'll never see the likes of it again right well Not if genetic engineering company colossal biosciences have anything to say about it. A few years ago, the company launched with the bold aim of bringing animals such as woolly mammoths,

dodoes and Tasmanian tigers back from extinction. In this episode, we catch up with the company's founder and CEO, Ben Lamb. He tells us all about how the ambitious project got started, how they planned to bring back extinct animals, and why we might be seeing baby mammoths sooner than we think. This is, dare I say, quite an interesting project. let's go back to the sort of the beginning, the inception of this. How did it all come together? So my background is in working with much smarter women and men to work on interesting projects, right?

So I've been in gaming, I've been in AI, I've been in satellite software, and I actually reached out to George Church for the purpose of building a synthetic biology software platform, leveraging AI. That's what I want to do. Now, we actually got to do that with Form Bio, our first technology spent out from colossal. But I reached out to that, and I'm just really curious. And I'm always interested to talk to really smart people. I was talking to George. I asked him, what else who's working on?

He started talking about neuro regeneration. He started talking about multiple Xediting. And then he started talking about leveraging CRISPR and a bunch of his other tool sets to bring back proxies for extinct species and de-extinct these genes that have been lost to time and build technologies for conservation and human health care along the way. And, you know, it wasn't a conventional pitch, but I was pretty excited at that moment and didn't sleep that night and thought, I got to go meet with this guy. So you mentioned there, like proxies. We'll get onto that in a moment. But let's have a look at the hit list of the

animals that you've got. It's quite a lineup. So we've got Wully Mammoth, the Thylacine, or sometimes known as the Tasmanian tiger, and the dodo. How did you go about choosing these animals? Well, the mammoth was easy, right? Because George had been working on it for eight years. We had 54 mammoth genomes to build the assembly from. George had been working on IPSCs and elephants. George had been identifying edits in that. So having George as a co-founder in wanting to help with elephant conservation, that was a no-brainer, right? Right after launch, we got introduced to Andrew Pass, through Best Shapiro, one of our scientific advisors and lead paleogenesis. We got introduced to Andrew Pass. We've been working for 15 years on the thylase.

So he's kind of like George, subject matter expert on the thylacine, didn't have the funding, didn't have the technologies, but really knew the computational biology side of the thylacine and the whole desirid family. That's the family of marsupials that the thylacine sits within. So that was kind of a no-brainer to work on that one because the problems on the thylacine are exactly inverse as that of the mammoth, meaning that if you simplify the process down to getting DNA and doing the analysis, doing the editing, doing the editing, doing the. gestation. Mammoth is hard because you have to assemble it even though there is a lot of it you have to assemble it. The editing is easier than that at the thylosine, but then the

gestation's 22 months versus 13 and a half days. So the same kind of a million process except the challenges in terms of complexity were inverse. So when you look at things, I'm a systems designer and so when you look at things from a systems lens

and you look at kind of that system's design, having a complementary project that's almost inverse really helps when you're trying to kind of build something that can be more applicable to a system. And then lastly, we have Beth and she loves the Dodo. She can work on the Dodo for a long time. We made a lot of progress on our mammalian work. And our investors asked if we had more capital, could we start an avian genomics group? And arguably, the Dodo is the symbol of manmade extinction. So it was a natural, it was a natural species. So you mentioned there that George, which has got multiple mammoth genomes.

So how do you go about gathering those? You know, where do you get them from? It's not obviously the animal's been extinct for such a long time. Yeah, so in certain cases it's easier. Some species are easier than others. George, and then there were some published mammoth genomes, and then George had a collection of genomes. He and Arianna Hussili,

who is our head of biological sciences at Colossol, and our mammoth lead actually went to Siberia, went to Yakuts, and it actually went out on an expedition I'm going to remember with the Explorers Club, so I'm pro-scientific expeditions. And so went out to the country and actually brought back samples. And then we worked very closely also with other top mammoth researchers. So 44 of our 54 mammoth genomes came from Louva Dahlin in Sweden.

He's incredible. And he's one of our scientific advisors. And so really it's been this collaboration of, as you know, ancient DNA is highly fragmented. So it's been this collaboration between museums, research. searchers and field work that is required to give enough DNA that you can start to build reference material. Okay, so let's have a look at the sort of meat of the de-extinction process then. So we've got our genomes. We've got our mammoth genome, our phylocein genome. What happens next? The overall process, and this is probably the most simplified, this is a massive simplification of it.

But once you have your assembled reference genome of your ancient DNA or even a partial gene, you compare that to the closest living relative on the family tree. So in the case of the mammoth, that's the Asian elephant, it's 99.6% the same genetically as a woe mammoth. In the case of the thylosine, it's actually the fat-tailed dunnard, which is a small marsupial carnivorous mouse. So not the size of a wolf, much smaller. And then you go through, use a process called computational biology, and you start to understand what are the differences of the genomes.

And then when you start to define different genes or different coding regions that are different, you then dive deep into what is that gene do, how does it express, what are the phenotypes or physical attributes that are created from that? And then you also do literature reviews. Other scientists are doing this in dogs and many other species. So then you start to do literature review. And then you take all that collective knowledge together to then have your gene list. And that's when you actually start genetic engineering.

use a combination of DNA synthesis where we can actually build out chunks of DNA. You can swap that into the genome. You can use CRISPR or you can knock pieces of DNA out. You can even use individual single nucleotide changes. And what that means is you think about DNA as a ladder that's twisted, those little rungs of the ladder, you can even change that as well, right? And so you can change so many things with kind of this suite of tools. A lot of times it's just called CRISPR, but that's only one of the mini tool sets that we use.

And then once you have edited cells, you use a process called cloning or somatic cell nuclear transfer where you actually move the nucleus or center of the cell into that of an egg cell. And then you gestated it through that closest living relative. So in the case of the mammoth, that's the Asian elephant. Yeah, so you mentioned just going back to this idea of proxies, which you mentioned earlier. to make this clear, they're going to be thylacine-like animals or mammoth-like

animals rather than an exact copy of an ancient mammoth or a thylacine. Yeah, so we're not trying to, we are not trying to clone those exact species. You can't, right? Because you just, you don't have living cells. You cannot clone

corrupt dead cells. You just, it's just not, it's not scientifically feasible. And so, you know, I was on a call or on a podcast a couple weeks ago and someone said, well, it's not really a dodo, it's a silly looking pigeon. And I don't want to break hearts and minds and confuse

people, but a dodo is a silly looking pigeon. A dodo is a pigeon. A mammoth is a elephant, and a thylacine is a desirid, right? And so fundamentally our goal is to de-extinct the core genes in kind of phase one that represent the core phenotype or physical attributes that made that animal unique that have gone extinct and have been lost to time and then fundamentally help that in those core attributes of that species that help solve that ecological void, right? And so those are our goals. And so with that, you know, if our quote-unquote silly pigeon has the de-extincted genes that made a dodo a dodo and it looks indistinguishable to you and me, and it serves its purpose, which is slightly different from that of the thylasean or me.

That for us is what we're looking to do. You know, for us, you know, I don't, like people also use the term hybrids, but all species are effectively hybrids. That's how you get new species. So as you say, they're using gene editing techniques to sort of give these animals the qualities that they'd need in order to fill in the part of the ecosystem that has been left by the extinction of these certain animals. could you perhaps end up with some unintended qualities from editing the genes that you're not looking for?

No, that's a great question. A lot of that's called some of that's called off-target effects. Like when you make a gene edit, sometimes it's not precise, and then can it lead to other issues downstream in the genome? It's a great question. And so we actually spend a lot of time doing functional and molecular assays and tests on individual different tissue types, as well as at the molecular cellular level. And so we spent a lot of time in the testing phase before we ever went to produce the animal. And so, for example, most people don't know this.

I didn't know this before I got into this. But that shaggy coat on a mammoth is actually five different types of hairs. It's not just one long hair. It's actually five different types of hairs controlled by this network of genes. So we're spending a lot of time on that because it's such an important core phenotech or physical attribute to the mammoth. And then we spend a lot of time on that. testing in themselves, testing kind of like what the proteins are things that come from

the expression of those genes to ensure that it's successful. And then we even test some of these in mice, right? And so we want to be very, very thoughtful in the process to ensure that we are making edits that not only will result in the phenotype, but won't have any of those off-target effects. And so we've actually achieved over 97% efficiency, which is nearly unheard of in gene So kind of taking this idea to almost breaking point, would it be possible then to create an entirely new species? Yeah, so I think the world of DNA synthesis, right, which we play in, right?

Where we're doing more editing. So a lot of times people will compare us to Jurassic Park, believe it or not, people have seen that movie. And I like to tell them it's kind of like a reverse Jurassic Park, right? Because in Jurassic Park, they were taking broken dino DNA and putting and frog DNA in it. We're, think of us exactly the opposite. We're taking an existing elephant genome in the Asian elephant that we know it works and produces an elephant and then just changing the individual genes that represented those core physical attributes that cold tolerance that made a man with the mammoth, right?

And so it's kind of like reverse. Like we're not trying to fill in holes. We have a complete genome and we're just tweaking it. That's at least how I think about it. I do think that the world, so it's mostly editing is what we're doing. with a lot of AI and a lot of computational biology behind it. What's interesting is the whole notion of DNA synthesis. And that's where we are synthesizing or building on our independent of the genome,

different pieces of fragments of DNA that then we are inserting back into the genome. Long term, whether it's colossal or some other company or a myriad of many companies, I think that we will, we as humanity, will achieve full DNA synthesis where we can actually build out and essentially print an entire genome. Right now, I think it's hard. It depends on where you want to draw the lines for a new species. I mean, and that gets into the whole GMO versus species conversation with the IUCN and specifically the species survival commission, which is like the U of the species.

They define species as a new animal that evolves naturally in nature, right? And so how does genetic engineering apply to that? But I do think through the power of gene editing synthetic biology and in DNA synthesis, we will be able to engineer whether they're new species. At a minimum, we are engineering traits right now that also have massive applications to human health care. Think about as like drought-resistant cattle or cattle that produce less methane, right, that affect the atmosphere. And so I really think that we're in that, in this kind of like phase of genetic engineering with animals that's, you know, more about genetic reconciliation.

I do think that we will be able to do true directed evolution in the coming decades for sure. No one goes to Hank's for spreadsheets. They go for a darn good pizza. Lately, though, the shop's been quiet. So Hank decides to bring back the $1 slice. He asks co-pilot in Microsoft Excel to look. look at his sales and costs. Help him see if he can afford it.

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for more information. So let's move on from there then. So we've got our genome, we're happy with it. What do we do then? How do we go on from that stage to create a in the viable embryo. Yeah, so once you have that viable cell where you feel like all the edits, you've gone through the different functional testings, you feel very confident in the success of those edits. You also resequence it.

There's a lot thing you do in that process to ensure that you got what you need. You do a process called somatic cell nuclear transfer, most famously known by Dolly, the sheep, right, where they took the nucleus or kind of brain, of the cell of a somatic cell, which is all the cells in your body, except those of the germ cells, which are what you pass on through sperm and egg. And you take that nucleus out and you put it into that of a germ cell or an egg cell. So then you essentially have a fertilized

egg that you can stimulate and start to grow and then transplant into a surrogate species. So the surrogate species would be the fatale Dunant or the Asian elephant. Yes, that's correct. Now, once again, all these projects, so I kind of talked about the differences between the mammoth and phylocein. But specifically on the dodo, what's interesting is we actually, the gestation is much easier because we're just using a chicken as our surrogate and laying eggs. But what's harder is on the front of it, you can't just go get somatic cells or egg cells and we can't do cloning in birds yet. So what we have to do is we have to use a process. of editing what's called primordial germ cells, the precursors to those sperm cells. And so what's really interesting for us is that it's a different set of tools that we have to cultivate and develop,

which have different applications than some of the mammalian editing we're doing. So one thing that I find interesting that I don't think I've heard people talking about much is, so say we've got a young proxy woolly mammoth, how do we raise it? You know, because there's no sort of woolly mammoth mother to take care of it. There's no woolly mammoth herd for it to grow up in to learn how to be a woolly mammoth.

You know, what's the plan once we've got a viable living? Yeah, that's a great question. So we brought on a team that falls at our chief animal loss or our animal husbandry group. And we work very closely with Elephant Havens, Save the Elephants, International Elephant Foundation foundations, all the top elephant conservation groups. And we actually announced, I think it was about a month ago, some of the work that we're doing, I think we shared the story with CNN, but we share the work that we're doing in elephant with elephant havens, which is the largest group in Botswana that's dealing with exactly what you just hit on, which is orphaned elephants, understanding herd dynamics. Elephants will sometimes even adopt dogs and everything into their herds. They're pretty interesting. They're amazingly social animals, right? And so what's interesting for us is really understanding years before we have MAMIS,

what is that herd dynamic need to look like? How do we track her, how do we understand that social behaviors, not just for them to survive, but to thrive. And so we're leveraging a combination of AI tools, computer vision, and genetics to look at these populations that elephant havens is actually working with right now with African elephants. We're also doing a similar project with another group that will be. announcing soon so that we can really understand not just herd dynamics but herd integration between

an orphaned elephant and that of the herb. So doing that now is really important, right? Because to your point, the first mammoths, their mothers will effectively be, you know, Asian elephants, right? Now, over time, they will be, you know, hopefully will, you know, we were successful breeding populations and over the right amount of event timeline. I think we'll have, you know, hopefully mammoths raising mammoths. But in the short term, to your point, it's going to be Asian elephants that are raising their offspring being the first man. So you mentioned early on in our conversation that this project has long-term ecological purposes or motivations. So could you tell me a bit about that, please? Yeah, every project that we're working on have different implications, right?

So the Dodo was an egg-laying species on the ground, and obviously a flightless bird. So we're already working with the Mauritian government teams with the Ben Mauritius to look at. Part of what led to the extinction of the dodo wasn't just mankind eating them, which is sometimes what they get this terrible reputation for being stupid. And that man just ate them, right? Which we don't really know. What we do know is that the Dutch and others introduced invasive species to Mauritius, certain types of monkeys, pigs, and rats that ate the ground laying for its eggs. right, on the ground. And so we've seen this in other species like the cockapoo and New Zealand and whatnot. So in the case of the dodo, the ecological impact to it is really us as humans,

working with other humans being in Mauritius to remove those invasive species to get that land back ready to take dodoes, as well as that kind of downstream effect that we get for other non-invasive species of Mauritius. With the thylosine, there's a problem. process called tropic downgrading. So we've seen, we've seen this in Yellowstone with the reintroduction of wolves, we've seen this time and time again that when you remove a keystone species, a lot of times specifically a predator, you had this tropic downgrading effect where all of those mid-level species overpopulate, some of them get sedentary. A lot of them get, like in the case of the Tasmanian devil, they get sick with disease. And so most predators,

It's easier to be an herbivore than a carnivore. Carnivores have to go out and hunt. That's expending energy. If you're not successful in that haunted kill, then you've lost energy that now you have to re-expend on the next attempt. So it's very hard to be a predator. People think it's easy, but it's actually pretty hard compared to being an herbivore. So in that, a lot of times they look for the weak or the small or the sick.

And so many predators actually thin out herds of these sick and dying weak or old, right? So it's really, really great. The removal of the thylosine has nothing has replaced it in that ecosystem. And then last, certainly not at least, but the mammoth, you know, the Arctic tundra used to be this incredibly vibrant location that was full of life and full of biodiversity, had a much faster nitrogen oxygen cycle, had Arctic grasses that had about a. two to three times albedo effects with light reflection back to space, or much more carbon, we're about six times more carbon efficient than the tiger forest that were there. And so there's been extensive modeling showing that,

that's shown up in peer-review scientific papers, that with the reintroduction of coal-tolerant megafauna, like they've done in Siberia, implies testing part, they've actually found, with the right population density of these animals, they've been able to lower ground temperatures by up to eight degrees, which is really important when you go into those summer months, you know, you're starting at a colder

place. Like, we are all talking about the 1.5th century tipping point, but there's more methane and carbon stored in the Arctic than anywhere else on the planet. So it's really, really important that we do that. So different projects that we're working on have different ecological impacts. They also come out from a different way. It's really important for us as a company to work with ecologists, conservationists and NGOs, as well as local landowners, governments, and indigenous people groups to ensure that it's not a project that people are just excited about, but it's a project that from day one people are collaborating with us on. Yeah, well, I think maybe what some people might say is this is very interesting, you know, it's all fascinating stuff, but you know,

why are we concentrating our time and our effort and our money on de-extincting animals when there are lots of endangered animals in the world that we could potentially put effort into saving? No, it's a great point, and we should not stop saving critically endangered species. But the challenge is that traditional conservation is fighting a losing battle. We are going to lose up to 50% of all biodiversity between now and 2050. There's not enough money, to your point, going to. into conservation. We are actually new money into conservation. We didn't go to big philanthropic donors and the Gates Foundation and all the people that donate into conservation. We went to

technology investors because we're building a technology stack that has an application, not just conservation and the extinction, but also to human health care, right? And so all of the technologies that we're making that have an application to conservation were open sourcing, giving to the world for free. Right. And so we want to arm the next wave of conservation and conservationists with newer tools that they need in this fight because protecting land is not enough, right? Like we can't just protect land. We've seen that like even if you stop poaching, even if you can create the right

breedable population dynamics for an endangered species, we see time and time again that like look at the wildfires in Australia. even if you do everything right. We are also, man's also affecting the climate, so we're going to continue to have these massive, you know, events. There was a hurricane this week in Los Angeles, which is insane. And so we're going to continue to have these accelerated and bigger events from a climate perspective.

So wildfires, for example, in Australia, are going to continue. And so even if you do everything right, protecting that land, that whole biodiversity could get wiped out with the wrong wildfire. we saw that a couple years ago. So if we could actually biobank these species create ways to create more of them in the lab, well then you're starting to build sustainable populations and preserve population genomics,

which isn't currently being done. Okay, so just sort of one more question then before I let you go, which I think a lot of people will want to know the answer to. You know, how long do you envisage this project taking? You know, what's the time frame? When are we going to be seeing the first de-extincted animal? So here's what I'll tell you. I'll tell you three things.

Number one, we have a goal of 2028 for our first mammoth calves. That's our goal. We feel very good about that goal. It's still a few years out, but we feel good about it, right? There's a 22-month gestation. That's just nature. We've got to work with it until we don't. Number two is I will say that thylaseans have a 13 and a half day gestation.

So much shorter. And the third thing I'll say is I think it's highly likely you'll see an animal before the mammoth. So there's some framing for you, if that's awful. Thank you for listening to this episode of Instant Genius. Brought to you from the team behind BBC Science Focus. That was founder and CEO of colossal biosciences, Ben Lamb. The current issue of BBC Science Focus magazine is out now. Pick up a copy where of you buy your favourite magazines

or downloaders on your preferred app store. You can also find us online at sciencefocus.com. This podcast is sponsored by name, audio and focal. The texture and emotional depth of music can be lost through digital sources or poor signal. Name Audio believes you can have digital precision with analogue warmth. Alongside French acoustic specialist vocal, Name creates high-end audio systems combining innovation with craftsmanship, so you can listen to music, just as the artist intended.

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