The World’s First De-Extinction? George Church on Bringing Back the Dire Wolf

WALTER ISAACSON: Thank you, Christiane. And Professor George Church, welcome back to the show.

 

GEORGE CHURCH: It’s great to be here again. 

 

ISAACSON: We woke up this week to headlines that weren’t about tariffs or stock market crashes, but something really interesting, which is the dire wolf, kind of made famous in Game of Thrones, after 10,000 years of extinction has sort of been brought back to life by a company you co-founded. Explain what a big deal that might be.

 

CHURCH: Yeah. We’re trying to develop technologies that will help with various conservation efforts for prevent, preventing species from becoming extinct. And if they, if they just go over the line for a couple of days, not give up on them, maybe bring them back. In this case it was more than a couple of days. It was more like 12,000 years, but you get the idea. So the technologies are based on things like, you know, CRISPR and rewilding and sequencing of ancient DNA.

 

ISAACSON: When you say it re it relies a bit on CRISPR, that’s the tool that you help pioneer that allows us to cut DNA in very specific places. And eventually you can sort of fix it and change the DNA. Explain how you did that with this, the dire wolf.

 

CHURCH: So more than just cut. So sometimes when you cut, you just make a mess. These were all very precise. These are 20 very precise edits. And so this is a kind of a, you know, milestone where we’re seeing exponential improvement in our ability to be precise and many of them at once. So by, and a lot of the precision is thanks to work for my colleague David Lou, also a Harvard professor, to, where you can change one base at a time very precisely. Or we can substitute in big chunks of DNA, which is another thing that we’re developing.

 

ISAACSON: You just mentioned David Liu, the Harvard professor, and he just won the breakthrough prize for what’s called base editing and prime editing, which means you can actually insert certain genes you want. Did you do that when you tried to recreate the dire wolf?

 

CHURCH: Yes. We have, we’re using both base editing and prime editing for various projects at Colossal.

 

ISAACSON: And one of the things about it is that you haven’t really cloned the wolf. Explain the difference between what you did and cloning.

 

CHURCH: Well, so we used cloning as part of the process. But what we, what we didn’t do was, you know, find some magical sample where the, where the nucleus of a cell has survived. Instead what we do routinely for almost all the species that we work on, or all the, all the ancient DNA that we work on, is the DNA is highly degraded, and we read it with modern techniques into a computer, and then from the computer we synthesize it and then put it into a cell, and then we will take the nucleus from that cell and move it into an embryo in a surrogate, in this case a dog, and, and then create wolves. So the, it, there is cloning as a little piece of it but mostly, the magic comes from multiplex precise editing.

 

ISAACSON: You know, it was almost 30 years ago when Dolly the sheep was cloned. I remember we put her on the cover of Time Magazine. It was gonna be a big deal. How come cloning hasn’t really become that big of a deal?

 

CHURCH: Well, I think, I think it’s like a lot of things in our life. It is a big deal, but just nobody notices it. So for example, we use cloning to also create pigs for, which are compatible with human transplants. The most recent transplant patient was a kidney done at Massachusetts General Hospital January 25th of this year. So this, that’s due to cloning as well. And there are many agricultural uses as well. So it is a real thing. It’s just become so accepted that we take it for granted.

 

ISAACSON: But could we really clone our pets, our children, ourselves?

 

CHURCH: Well, I think it’s not generally considered ethical in part because it hasn’t been through FDA approval, but for, but for deeper reasons than that to do, to do human beings. And it’s not necessary, moreover, but yes, pets are done, and agricultural species are done, and transplants are done that way. So it makes its way into human bodies, but only via transplants.

 

ISAACSON: Explain to me the dire wolf thing. It, what you did was you edited gray wolves to have lots of the DNA and traits of the extinct dire wolf. But are these really dire wolves or are they gray wolves with some of the traits edited in?

 

CHURCH: Well, it, so the whole species definition is intentionally blurry in the endangered species act, in all sorts of definitions. It’s a mixture of what can breed with what, what can, you know, what has you know, different, different physical traits and so forth. And also you can, you can literally speciate with as little as one change, but there’s millions of changes within a population. Millions of differences, say between you and me, but none of those are species levels of differences ’cause I think most people <crosstalk> would argue you and I are the same species.

 

ISAACSON: So this is a dire wolf, you would say.

 

CHURCH: I think that this is much more recognizable as a dire wolf than any other kind of wolf. We also brought back, we also, sorry, did clone a red wolf which is an endangered species, probably the most rare wolf in the world. And that’s most certainly a red wolf.

 

ISAACSON: And you were able to exactly clone –

 

CHURCH: Even though it was quite the different population.

 

ISAACSON:  As you know better than anybody on the planet, genes can have unintended consequences and effects, including even in this one with the genes you did to get the gray wolf to have a white coat could also cause deafness and blindness. Explain that to me.

 

CHURCH: Right. So the, so this was a case where we didn’t do it in order to be simple. We made our life a little more complicated in order to be kind to the first generation of dire wolf. We wanted to make sure we didn’t accidentally put in an allele that could cause the kind of sensory problems that’s been associated with one of these alleles that we found. So we did a substitute allele. We’re looking for functional de-extinction where they can, you know, fill a particular ecological niche. Anyway, we chose an unnatural allele at that one. But most of the 20 alleles that we changed there was no compromise between the health of the, of this, of the new species or, and the, and the the alleles that we chose.

 

ISAACSON: We’ve talked a lot, you and I, about the woolly mammoth. That’s sort of the goal in some ways of your de-extinction company. Tell me how that’s going.

 

CHURCH: Well, the real, the real goal of Colossal is developing technology that can be used freely by, for conservation efforts and, and with, with lots of other applications to human health and so forth. The mammoth is more challenging because than both the mouse and the wolf that we’ve done, because those two have very short generation gestation periods. So as little as 20 days for the mouse while the elephant is 22 months. Also because they’re endangered species. And one of the things we’re trying to do is give them new land. We have, there’s more complexity to getting access to their, the tissues and and the land that they will go on to. So that’s, we knew from the beginning that was gonna be slow, and that’s why we picked other species to work, work out our technology and show the world that we, you know, are semi competent.

 

ISAACSON: Let me ask you the Jurassic Park question, which is, what could go wrong, reintroducing species like this into the wild, and is there some regulation or self-regulation?

 

CHURCH: There’s plenty of regulation. So and this applies to the pigs that I’ve referred to as well, the FDA regulates safety and efficacy, both for the animal and, and in, if in the case of transplants for the human being, there’s a lot of regulations there. There’s the Environmental Protection Agency and their equivalents in other countries. And that’s, and there should be. I, I’m, we’re delighted to be working with this. There’s also considerations of, you know, local populations, indigenous people. I think we have a lot of support there, but we’re not rushing into this. We’re not moving them on the you know, public land until we’ve had a very broad conversation and consensus.

 

ISAACSON: What would happen if the dire wolves that you’ve sort of recreated just went out into the wild someday? Would everything be all right? Or could there be a problem?

 

CHURCH: Again, I wouldn’t rush to do that. I, we, right now they would probably be capable of breeding with a variety of other species, what are called species, but species, like I said, is a broad term, and it, and there’s not sharp edges to the breeding. We could make them so that they don’t interbreed. We could even make them so they couldn’t leave the enclosure that they’re in, which is now 2000 acres, which is quite generous. But yeah, it remains to be seen what could go wrong. I, just because we can’t think of something right at this minute, doesn’t mean that we stop looking for and engaging all kinds of ecologists and developmental biologists, and so forth to think out of the box as to what could go wrong before we do it.

 

ISAACSON: Your company that you co-founded has a $10 billion or more valuation. Explain to me what is the revenue stream? What do you envision?

 

CHURCH: I think that from the beginning that the, what the investors were looking for and, and was new technologies. And in fact, that’s already happening. We’ve spun off form bio which is a computational biology company, which has been instrumental in all the things that we’ve been talking about today. This conversation. We’ve also, in the process of making gametes, we’ve spun off a product that’s the first FDA approved phase three trial for an IPS derived cell. I mean, the jargon there, sorry, is that, is IPS is a very important source of stem cells that is making its way into multiple medical products. But this one jumped to the front of the line enabling maturation of eggs in IVF clinics. So that’s something that we had both veterinary and human use. And there’ll be, there’ll be many more. I’m sure.

 

ISAACSON: When you and I last spoke on this show about five or six years ago, you talked about artificial intelligence being important in what you’re going to do. Explain how that was relevant here and what you’re doing with it.

 

CHURCH: Well, so back then it was just beginning to show that its value. I mean, I think a lot of people had seen it coming and a lot of people hadn’t. But today, it’s undeniable. And I think one of the major applications of AI, even more amazing than art and language I think, is its application to protein design. This was recognized in this year’s Nobel Prizes and in particular, my good friend and colleague, David Baker has been doing this. And five of my recent startups use, have used it routinely in combination with large libraries. And we’re using it essentially everywhere now for diagnostics, for therapeutics, for the kind of work that we’ve been describing here on wild animals. It really is very helpful. I mean, so far, it definitely depends heavily on collaboration with humans and the creativity and out of box thinking and perspective and ethics of humans. But it’s a tremendous time to be a scientist.

 

ISAACSON: You’ve spoken about using gene editing tools you’ve pioneered, including CRISPR, base editing, the things we talked about that David Lou just won the Breakthrough Prize for, in order to recreate extinct species. Could you create new species, ones that never existed before? Would that be a good idea?

 

CHURCH: You asked, I mean, two questions. Could you, and is it a good idea? I think it could be done, technically, and it could be a good idea if you want to have a species that has a particular niche. But you want it to immediately not interbreed with another species. And I think that could be very easily done. And it’s one of the research projects in my lab is to figure out how to do that in as humane way as possible.

 

ISAACSON: Give me an example of what you are thinking about in the lab.

 

CHURCH: Well, there, there a few examples of where you can get speciation with a single mutation. For example, the ality of snails causes speciation and multiple, it’s been observed multiple times. You can get inability to produce fertile offspring if you have multiple reciprocal translocations in the chromosomes. These are things that allow it to breed with itself, but not with the, not with the species that it came out of. So those are two example, but there are many more behavioral changes can happen with single mutations and so forth.

 

ISAACSON: How many companies, by the way, have you co-founded?

 

CHURCH: I’ve co-founded 50, 49 or 50. And it’s I’ve helped with a few, quite a few more.

 

ISAACSON: By co-founding that many companies. You’re sort of the poster child for why American science has been so innovative and entrepreneurial ever since the end of World War II, which is, there’s a funding of basic research at universities, and the people who do it find ways to translate that from the bench and the lab to the bedside of a patient, for example, and to turn them into companies. Are you worried that the cuts in federal support for basic research is going to end that 70 year boon that we’ve had in the United States?

 

CHURCH: Well, I worry about everything. I think in this particular case, I read something recently today that there is a proposal for five $15 billion for biotech, specifically, so we can be competitive internationally. I don’t know whether that will arrive or not, and whether it will sufficiently support basic science, but I completely agree with, I think what you’re saying, is that basic science has been important to almost, well, essentially everything that we’ve been talking about here and many others. And increasingly it goes very quickly from basic science to applications. Although it doesn’t need to, I think we need to be flexible in our support of this. But it’s inspiring. You, no matter how dire, sorry to use the word the economic reports can be to see the, you know, new breakthroughs having impact on healthcare and other aspects of our life, I think gives us new hope.

 

ISAACSON: George Church, thank you so much for joining us again.

CHURCH: Thank you.