The Story: From Woolly Mice to De-Extinction w/ Ben Lamm

Welcome to tech Stuff. This is the story. Each week on Wednesdays, we bring you an in depth interview with someone who has a front row seat to the most fascinating things happening in tech today. We're joined by Ben Lamb, an entrepreneur and the founder and CEO of Colossal Biosciences. By now, you might have heard of the company's wooly mice, fluffy creatures with the same type of fur as the

I learned in this process that in the next twenty five years, half of species will either be extinct or be at least threatened with extinction. So I thought maybe there was an opportunity to build a company that we could develop tools to help conservation, hopefully inspire kids and give people excited about science through something that was like truly a moonshot and like the Apollo Days.

CEO Ben Lamb has a background in tech entrepreneurship, but became interested in the extinction after meeting the renowned geneticist George Church and having a pivotal experience in his own life. Ben Lamb, thank you so much for joining on tech stuff.

Hey, thanks so much for having me.

So we're going to talk about Willy mammoths and Willie mice and dire wolves and gene editing and fa but I kind of want to start with you and your drive to create arguably the most engaging, live scientific experiment ongoing in the world. So my question is why this science project and why this mission for you?

Yeah, so my background is in just building technology companies with much smarter women and men than me, and I met this guy, George Church. He's the head of genetics at Harvard and he'd actually invented a lot of these

Right.

And one of my employees, my chief strategy officer, was fantastic. His name was Greg. He passed away of a sudden cardiac event. And it causes you to really kind of you reconsider your priorities, and especially when with someone that you've known for fifteen years. You're flying back from NASA one night joking about UFOs and the next morning you're talking to his wife and widow right, and so you know those moments where mortality and reality hits you. I

You had that moment of how much time might I have left? And the time I do have left is more of a blessing than I may have considered. Therefore, how do I want to spend it? I remember, I think before twenty twenty, reading about George Church and reading about the Wooly memmoth project and being fascinated by it, but how did you catch this de extinction bug? In other words, going not just from the mammoth but to this larger project you're working on mount.

So I had met George and was fascinated by the fact that this person that's at the top of their field had told.

Me that we have all the tools to do this. This is really a.

Function of funding, and if we could bring the right people together with the right focus and the right funding, we had the technologies to make extinction a thing of the past. But over time, if we can make them more efficient, well then that has massive ripples into conservation, into human healthcare.

So he told me that.

In twenty nineteen, I just kind of went back to my day job and I was interested.

Maybe I'd fund his lab, maybe I'd work with him.

But then after I went through this introspection period, I was like, well, worst case scenario, this is a massive failure, and I'll just go back to making software. And then what George was right about was there are no real science gits. We have all of the tech in some form or fashion, and so we really these are in some cases innovation problems. And I think that with AI and automation, we're seeing scientific discoveries slowly moving from scientific

What do you actually mean by the extinction? And was there an accepted definition or if you kind of created to concept it on with George.

So, the extinction is a made up word, right, like a stinction of the word the extinction. You know, we learned from Jurassic Park and whatnot. It's become one of these these just part of the nomenclature. And up until this year, Wikipedia defined the extinction as engineering a species

For extinct organism that's been dead for quite some time.

Right, we thought that just engineering something that look like an extinct species is kind of like phoning it in, and so we came up with this idea that the definition of the extinction was flawed, and so we really wanted to focus on how do we bring back loss diversity, lost genes, how do we ensure that it has the core phenotypes or physical attributes, but are also are there opportunities for enhancements?

Right, So I guess you're thinking beyond using genetic engineering to make animals that look like extinct animals, but actually trying to bring back extinct genes or re express extinct genes, and then in turn trying to see if any of them can be used to solve genetic problems that are found in species today.

So I'll give you one example of that is like EEHV, which is the number one killer of elephants, specifically Asian elephants, but it kills about twenty percent of elephants every year.

More than poaching, more than anything.

We're working with Baylor College of Medicine and others to actually eradicate this disease, and we've actually have a MR and A based vaccine that's being tested right now in elephants and is conferring resistance, which is awesome for existing elephants. But here's the deal, mammas are actually closely related to Asian elephants. They are African elephants, and they were susceptible to eat.

We know that.

And so if you can engineer in resilience at EEHV, why wouldn't you.

I really want to talk about the wooly mice and the dire wolves. I was at south By Southwest this year as you were, and I think the release of the wooly mouse. I've never seen a conference being taken by storm, or not just a conference, I mean the whole internet, frankly, as the release of.

The wooly mouse, I think you saw the direwolves, and.

Then and then you saw the dire wolves, which, yeah, which were an apex predator. When it came to hype that said, it's a little uncanny to talk about animals as though their product releases. But hold my hand and walk me through this. You guys are trying to make the wooly mammoth, a species that existed and then went extinct thousands of years ago, and in that process you make an entirely new creature, which is the wooly mouse. Why mice? Why not just work on the mammoth?

So one we wanted to test our Indian pipeline two.

We want to ensure that if your I didner find phenotypes or physical attributes that you believe will be engineered that have been lost to time in the Asian elephant lineage, but engineered back into that lineage from the mammoth. And you want to confer cold tolerance, hair color, hair texture, hair thickness, wave length. Your three options, or you make a mammoth, right, But going back to an ethics perspective, like if you have better ways to test it, let's test it there.

The second is you grow organoids, which this sounds.

Frankenstein, It's super cool, though, is we actually create stem cells, program them into organoids, and we actually grow mammoth hair in little follicles and dishes, so it's alive, so we.

Know it's working.

But that's still not a complete animal model, right, And so taking that same into end pipeline, applying it from the specific variance from mammoth to the mouse specific variance.

In terms of the gene that expresses as hey, you can mention the mammoth headed gene to the mouse head.

Gene exactly exactly when we did this for the mouse, It's like there's two hundred million years of genetic divergence between an ELpH in the mouse, and so I believe it's irresponsible and unethical to just shove it in, cross your fingers and see what happens, right, because why would we do that, right, Because we're really trying to test if the pathways and the edits express the phenotypes or

Twenty days versus twenty two months because the gestation period of the mouse versus an elephant correct correct.

And we found that we get healthy wooly mice with the exact predicted phenotype that all of our modeling showed. And so it's a much faster, easier, and more ethical way to test. And then the only unintended consequence is that they were objectively cute and they took the Internet by storm. We thought it was interesting and we thought it proved our endo end process works really well.

We did in one month, by the way, which I think no one seemed to write or care about.

But that's amazing and most people at the time, we made eight edits and seven genes. And what most people think is that sometimes the number like eight doesn't sound like a big deal, but when you're dealing with genome engineering, and most people were making an edit in one generation of a mouse, making an edit in the next generation of mouse, and so that they were stacking eight generations to get to eight edits, right, And so we did it all with one multiplex delivery in one shot with

Where we edit the cell and then move the nucleus.

And then we wanted to test our monoclonal screening process at the end to ensure that all the sequencing. So Colossal does a lot of extra steps. Probably the most people would in our.

Boat this just to make sure you don't make Frankenstein woody mice switch it, which have horrible illnesses and which are in pain and one of those things exactly.

So none of these technologies are perfect.

Right.

You know, before the Wooly Mouse and before the Dire Wolf, people were making like one, maybe two edits at a time that weren't what are called linear repeats.

We neither the same edit over and over again.

Right, there's thousands of those, but those are just copies of the same thing. Right, But making a lot of edits all over the genome with ninety plus percent efficiency and not creating what's called off target effects or unintended consequences is what you're talking about. It's really really hard, and that's where I think Colossal is really succeeding. But still you want to screen, and so we sequence, and so think about like sequencing is.

Reading the DNA.

We read the DNA at every step and that's insanely computationally heavy and it's exanely costly.

But here's what we know.

The embryos that we transfer, we know one hundred percent of them are healthy. And so we're certified by American Humane Society. And we don't do it because that certification, but we do it because we care about conservation.

We care about animal welfare.

And so the reason why we have successfully birth, you know, animals with no unintended consequences, is because we do it before the editing, during the editing, after the after the embryo creation.

And I think that's really really important.

But practically functionally, how much closer to the wooly mice take you to the wooly mammoth? Have they knocked off? Three months? Six months a year?

So they don't speed up anything. They're just a validator.

It's like, oh, okay, well this is behaving exactly as we were predicting, and so this is a validation step. So we're all the edits that we made the woy mouse. We've already made the mammoth equivalent of them in Asian elephant cels. We just haven't taken them to term right, So I'd say less likely that it will speed up the project, more likely that it means that we aren't getting the project wrong.

When we come back. What Ben says is the first the extinct species, the dire wolf, stay with us. So the Woolli mice were a validator, but the dire wolves were, at least as far as you're concerned, the first the extinct species.

Yes, I think the dire wolves were the first extinct species brought back. The will mice never existed, so we can't classify them in that category.

And the dire wolf this species that went extinct about ten thousand years ago. I guess it was kind of reintroduced into the popular imagination, at least by George R. R. Martin in the Game of Thrones series, which I know you're a fan of. But can you tell me what it was like to see these die wolves coming into existence, being born? Holding them?

Yeah, it was highly emotional.

So I was on FaceTime while they were being born, so I was actually in London.

I remember exactly where I was.

Your hearts palpitating, You feel like like you want everything because everything healthy is.

I was like, it's like when you have your first child, was like to they have the right feet.

And when they came out, they were white, which you know wolf when they're born they're all black or gray dark gray, like super dark gray, so that was an early indicator.

They were much larger.

They're about forty percent larger than normal wolf puppies. So I didn't because I'm not an animal veterinarian, like, I had no value add I actually waited until they were about five weeks.

And then I got to see them.

So and when I saw them the first time, I got I mean, I still do, I get chill bumped, I teared up.

It's very very emotional.

And what's been interesting is even people that aren't as attached specifically to the Extinction or specifically to Colossal, they have a very similar response. And it awakened something in you. The importance of the moment isn't lost on you. I remembered one of the first people I showed the how video that became very very popular on the internet.

You're talking, of course, about the YouTube video of the die Wolf Pops Howling. Who did you show it to?

Peter Jackson.

Peter's a dear friend and he's director for Lord of the Rings and he's an investor in Colossal, And so I was in his living room with his partner fran I hooked up old school like HDMI to my laptop. I said, I got to show you something, and I showed it to him. He was overwhelmed. It's a very very surreal experience.

I can only imagine. Ben, this is the Tech Stuff podcast. So I just want to make sure, I do have the tech right. I actually wrote down seven bullet points for myself about the the extinction process, which includes the use of generating tools like CRISPA. But I wonder if you could sort of let me know if I've got the steps right. Starting with step one, which is you go out and find as much DNA as you can of an extinct species.

Yes, and that can come in the form of some researchers already have it on their hard drives, sometimes from museum specimens.

Sometimes it's expeditions.

Digging through permafrost.

I mean, yeah, you go.

Into the permafrosts, you go into caves, but it's really a global collaborative effort. It's you're in the sub basement of a museum talking to a researcher at some university that's sent their whole life sequencing it.

To You're actually out in a cave or in the Arctic and whatnot. It's pretty cool.

Okay, So now I'm going to go through steps two to five. You take the sample from the field back to the lab and sequence the DNA. Then you cross reference to DNA with other samples from the extinct species. Then you build as complete a genome as you can of the extinct species using AI, and then you cross reference with that genome with all living animals to find the closest living relative.

That is correct, But on that last parts to those don't exist either, so you actually have to go build the reference genome for the closest living relative. There's not like a database of all life on Earth.

So you have a hypothesis about what the closest living relative might be and then go and build that genome in parallel. Then yeah, okay, yeah, Then you identify the key genes that you need to edit in the living species to make it genetically closer to the extinct.

Species exactly right.

Then you use CRISP gene editing to edit the embryo of the living species.

So this is where it kind of forks a little bit.

So we use a combination of I think it's better to classify it as genome engineering tools. One of the things that colossals I think done a really good job of is figuring out, we actually built an AI model for this, what is.

The right tool for the right job.

And with that our system actually now recommends what combination of tools in what order, and how that guide design should be packaged to deliver the highest levels of efficient see AI for us.

Has been a game changer in how we then deliver the edits.

So then you've made the edits, you go to an embryo.

Sorry, you've got to cell.

Okay, And then so the next step is to do the same thing they do with Dolly the sheep, which is sematic cell nuclear transfer. So you've got two types of cells, germ cells and sematic sels. Germ cells are like egging sperm. Somatic cells are everything else, right, So

Two big criticisms.

One is only two that's incredible, fantastic.

We only have an em no. But one is that it's not really the extinction if you're just changing a few phenotypes. In other words, you justanging the appearance of an animal to look more like an animal that was extinct. Some people accuse you guys of doing that. On the other end of the spectrum, some people say, no, you're

So I come from software, right is predominantly my background in some space hard mostly software. And if you can build something to achieve a function that's got three hundred lines of code, and then you've got something that can do it in seven lines code, every great programmer will take you to the second one because there's less room for error, there's less things to troubleshoot, it's cleaner, it runs fast, it's more efficient.

There's a million reasons to do that.

We spend a lot of time and a lot of money on compute AI comparative genomics, because no matter how good you get at this, we're still in the world of discovery. I do think, as I mentioned, it will move to the world of strictly engineering and the entire idea of genotype of phenotype expression. What genes cause different things to do different things that result in a physical attribute of an animal is.

The great medical question of our age.

It's a huge medical question, right, And that is the core of what we were doing at Colossal, right. And so you know, I would argue that we're a genetic engineering company and a genotype of phenotype company at our core. And so when you can do that, and you know, if you look at a species, if you ask me if you could just make a couple changes to the elephant, you know, and it wasn't informed in any way by mammos, but you just made like a hairy elephant.

I wouldn't consider that the extinction. I wouldn't.

But if you can take data like true data from a mammoth and it can tell you what are the genes that were fixed over time that really drove these phenotypes, and you can either engineer in those exact variants which we did in the direwolf, and potential enhancements that are in the world of synthetic biology to produce those phenotypes that are informed by ancient DNA, that's the extinction.

And so what's.

Interesting to me is all the people that saw Jurassic Park and say it's a movie about dinosaurs, but then don't want to call my direwolf direwolves. It's like, well, you're just a fucking hypocrite because those are either genetically modified frogs and birds with dino DNA in it, or their dinosaurs.

Right.

And so this is a semantic question. It is not a scientific question. It is a human construct that we're putting on this. And so going to your second.

Question, the accusation that you're playing gold, you know.

I think that we play God every day, and I think that taking cholesterol medication is a form of playing God on a personal level.

It doesn't mean you shouldn't do it.

I think the idea of cutting down the rainforest or overfishing the ocean is playing God. So if you think of if you define playing God is interfering with the natural order.

To Jennifer's point, we do that all day long.

So why not do it in a way that helps us develop technologies for human health care, inspires kids, and can help with conservation. Because every conservationist will tell you that while conserving land and protecting species is the primary focus of conservation, which by the way we agree with. We think that's where everyone should just spend ninety nine

But there may be a day in humanity's future.

And I'm an eternal optimist, so I hope I'm wrong on this, even though im running.

At the Extinction Company.

There could be a day in human history where there is a species that we lose in the near future that we have to bring back. You know, not to get too Star Trek four on you, but who knows. We may have to bring back blue whales, not to appease some drone from an alien planet like in Star Trek, but to potentially help with ocean currents and the phytal plankton turnover in the nutrient cycling in the oceans. Right, we don't know, and I think that having these technologies

Just to play Demod's evocat though. I mean, the dire wolves are living on the enclosure, going to breed. What will be different in future about animals that you bring back? How will they be integrated in a way that these tibles on being to the real world.

So they could breed. They are physiological capable of breeding. We use different cellions as with male and females, right, and then you know they are to your point, secure expansive ecological preserve.

But what isn't these days? Like what is truly the wild?

This Kruger National Park is six million acres in Africa that's fully fenced with lots of biodiversity.

Some would consider that the wild. It's still a park.

Right, So these animals, I assure you you know, they've got ten full time people that take care of them. They're on two thousand acres of a yellowstone like environment. They live quite quite well, but our long term goal with all of our species is to put them back into the wild in collaborations with indigenous people groups, private landowners, and governments. Right, So those are very long term processes. I won't say that we have a clear date that we could put dire wolves back in the wild, but

There's a lot that goes into this, right.

So, like one of the projects we just announced was in partnership with Yellowstone is using AI for bioacoustics for wolves, so we understand migratory patterns, so we understand different call patterns, so we understand things, right, Because you know, the best thing that humans can do is figure out how we

No, and I like what you said earlier about some of these secondary benefits like the vaccine for the elephants. I know there are tons and tons of others, including you know, potentially bacteria to eat, ocean plastic. We've talked at the beginning about mortality, and then we talked a lot about de extinction. So I just want to close with this question. If you had a Chillncee to read your obituary and you're happy with it, how do you complete the sentence? He did this because.

He did this because others were too afraid to do it.

What do you mean by that?

I think that making change is hard, and I think it requires determination, it requires thick skin. I think that some of the biggest and boldest things have had a perspective of abundance, and it's also a not zero sum game. And I think that's important because I think right now, sometimes when you work on new things, it's scary and it's hard, and I've been criticized a lot. You know, I've been a very long term supporter of developing technologies

But it's okay, because at.

The end of the day, I am convicted in what I'm doing and I'm not afraid to do it because I truly believe that we need these technologies for conservation, and I think we need to also do big, bold things that will inspire the next generation so that we have more scientists and astronauts and fewer influencers.

Thank you, very very well said, Thanks so much for having me for tech Stuff. I'm most velocian. This episode was produced by Eliza Dennis and Tori Dominguez. It was executive produced by me Kara Price and Kate Osborne for Kaleidoscope and Katrina Norvel for iHeart Podcasts. Jack Insley mixed