What happened in Jurassic Park was scientists found mosquitoes preserved in amber. They stuck a needle into those mosquitoes preserved in amber. They sucked out a bit of stuff that happened to be blood and it had dinosaur DNA. And then they had the little dancing DNA thing tells you about how they piece it together and you can see the little pieces of dinosaur DNA lining up next to each other and then there's holes and they fill in those holes with frog DNA, which was a weird choice even at the time because we already knew that birds are dinosaurs, right? So why they picked frogs? Well, I don't know. Anyway,
Maybe they talked to Richard Harlan at Berkeley or something. That's another biology joke. Look it up.
Not actually how we're doing this. What we're doing is somehow easier than that because we know that Asian elephants are the closest living relative of mammoths. We also can, by sequencing a bunch of Asian elephant DNA and sequencing a bunch of mammoth DNA, we can see that they already have almost exactly the same genome sequence.
How similar?
They're about 99% similar. It depends on how you calculate the percentage and things like that.
As a point of reference, how similar are we to the chimpanzees in terms of percentage similarity of DNA?
In that counting, it's about the same.
But some people might say we don't look anything like chimpanzees.
Well, 99 just sounds like so similar, like you're going to get the same thing.
Yeah, well, there, I mean, people calculate this in lots of different ways. There's some statistic online that we're 85% the same as a banana or something like that. Like a lot of our DNA is, I don't know if that's true, right?
Is the goal to recreate the ancient mammoth or is it to create a pseudo-hybrid of the ancient mammoth?
The goal is to think about a mammoth in terms of what it does and what it looks like. And this gets back to this idea that you brought up in the beginning about a species concept. You know, this is one of the most common things that we hear. If you are going by a strictly genetic species concept where you're saying that a species, an organism is classified just by some threshold of similarity, sequence similarity to something else, that's the only way you can call it that thing. That isn't what we're doing in de-extinction. That's not what anyone doing synthetic biology is thinking about when they're designing or engineering things to solve problems, engineering animals or engineering plants to solve problems that we have in the future. The genetic species concept is an idea that was proposed to classify organisms that evolved over a very long evolutionary bifurcating phylogenetic tree process where accumulation of changes is over many generations over a long time. Our mammoths, our dire wolves are not created by that process. And so that concept really doesn't apply. I think that's where a lot of the disinformation comes. I'm going to just push back a little bit on this because what I don't want is for this sort of definitional gatekeeping to really take over and become the whole story. It's important. It's a question, but it's a narrow one. And I think it crowds out the real discussion about what it is that we're doing, how the technologies that we're developing can be applied to ecosystem health to help stop species from becoming extinct, even as synthetic biology for human medicine. So we're not trying to make something that is identical to a particular individual that used to be alive. Our mammoths are millions of letters of DNA code different from each other. So even which one to use would be an open question. Instead, what we're doing is focusing on where all of those mammoths are the same as each other, but different from elephants. And thinking that those places, like we were talking about with humans, those are the places that are important to make a mammoth a mammoth. And that is where I'm going to focus my energy in bringing back a mammoth, which will be an elephant that is capable of living in the habitats that a mammoth lived in. Mammoths will have to live in habitats that exist today and tomorrow. So the mammoths will have to be genetically capable of living with the pathogens and the microbes and the food sources and the microbiome that the elephants that will birth them can survive in today.
When you mentioned species nomenclature gatekeeping, I have a feeling this is based on the publicity around the direwolf.
Yes.
Okay. I just, I like to just address things very directly. I want to be very clear. I'm not arguing for species gatekeeping here. That's not what I do. I own a mutt after all.
It's not even that. It's that somehow this idea of what we should call it based on this very specific definition of you can only call it this if it's some threshold genetic similarity is noise. It's not an important part of the conversation. I mean, it's a part of the conversation and it's one that we can have, but if people don't want to call it a direwolf, just don't, right? It's like...
Well, I think like all things media and Hollywood, you know, I think Jurassic Park did an amazing service to science and the excitement around these concepts, but probably did a disservice as well by embedding in people's minds that the idea is to bring back the exact same animal.
But didn't we just say that these dinosaurs were some dinosaur DNA and a whole bunch of frog DNA? Nobody looks at them and goes, 'Oh, they're not a dinosaur.'
Well, you're a scientist and I am too. Actually, it's funny that you mentioned this because my dad's a theoretical physicist. He was involved in chaos theory. He's been a guest on the podcast. I remember when Jurassic Park came out, he didn't dislike it, but the part where he kind of rolled his eyes was there's a description of chaos theory in there and what it means. And in Hollywood they love to use the example of like a butterfly flaps its wings in Patagonia and then this thing happens to the barista in Brooklyn, you know, and people like to bridge those concepts and they all, that's so cool. Like so, it's sticky as we say, but he was rolling his eyes. He's like, 'Okay, that's not how these things work.'
Yeah. And so for people that are experts in the area, it can be a little bit grating at times. But the public, I think, is open, right? And my experience in doing what I do is that the public, if they just have the knowledge in hand, and the way you described it, great. So our direwolves, they have 20 edits that we picked. And we sequenced genomes from fossil direwolves. We learned from those genomes what genetic changes made those animals bigger, more robust, light-colored in coat. And then we engineered those changes into a gray wolf genome to recreate the direwolf. If it looks like a direwolf and it's able to fill the niche of a direwolf, I'm happy to call it a direwolf.
So the direwolf was a very interesting choice. Clearly, you were successful in creating this animal. Sounds like you were very intentional in picking which genes. It wasn't like, 'Oh, we're going to take a couple genes from the direwolf and throw them into this other wolf and create what we call the direwolf.' If I were to look at the direwolf and you said a gray wolf?
Yes.
Side by side, is the direwolf larger? They are. On average at the same age, are there any other features that are visibly different? Or are the other features more adaptive in terms of gut and ability to live in certain environments and this kind of thing?
They're muscular. The fur is longer and more full, and it's also light-colored. I think it's an important thing to understand about how we're selecting these because we are very deliberate about what we're doing. And it's both because we want to with some fidelity bring back these extinct traits so that the animals can eventually be released. Now, we're not planning on rewilding direwolves. We will study the animals and learn about the effect of their genes on their lifespan and...
But the other animals, the ultimate goal is to eventually have populations of free-living animals that the local people are stewarding as they would like to. And so we want to understand how healthy they are, how they're going to interact with the habitat that's there, and we want to make sure that because we with synthetic biology have the power to engineer them in a very deliberate way, that we can do that in a way that's safe. So, the hair color is a really interesting example of this and the strategy that we use. So, when we sequenced the genomes of the fossil dire wolves, we found that they both had variants, the same variants in two genes that would have made them have light-colored coats. But, in living gray wolves and dogs, variants in those genes, not the same ones that we saw in dire wolves, but close enough to where we would need to do the edits that you have some concern that you would have bystander edits that might cause a problem, can lead to oculocutaneous albinism. So, blindness or deafness in these dogs. And we decided that because we're not changing the whole genome, they have to be safe on a gray wolf genetic background, we wouldn't make the trait that way. It just wasn't passing the bar of animal welfare safety. And so instead, we brought back the dire wolf light-colored coat using different edits that we know are safe in a gray wolf background because there are light-colored domestic dogs and gray wolves. So, we used the edits that we know are safe because they exist in living dogs.
Well, that's cool.
So, we were able to engineer, using all the tools of synthetic biology, this light-colored coat that is the dire wolf light-colored coat, but using a path that we know is safe. And this is the way that we think about all of our projects. We have to take an Asian elephant and turn it into a woolly animal. That trait requires changing not just the structure of the hair, but of the skin itself. We have to make room for more follicles, sebaceous glands, different approaches to be able to support that woolly coat, right? And we need to be able to do that in a way that results in a healthy animal because these are very long-lived animals. It takes 22 months for gestation, they reach sexual maturity at 14, and it's a lot of work.
So, how many direwolf wolves are walking around right now in some location?
Right now there is Romulus and Remus and they're almost 2 years old and...
Male and female or male and...
Romulus and Remus are boys and Khaleesi is a girl. She is about 18 months old or so.
Is the intention to mate them?
No, they're too closely related. We're stopping them using hormones. So, rather than to...
But they live together.
Castration. They live together. She was reared by herself. The boys had each other and she had just her. So, she's a little bit on the like... I mean, you would never look at these animals and say this is the way a wild wolf behaved. They were hand-reared, right? But she's a little bit on the specially goofy side. But she's the best. She's adorable.
Safe interacting with them?
Oh, no. We have interacted with them, but the people who work with them a lot that they know feel safe interacting with them. But as they got older, it was very clear that they're wild animals. These are not domestic dogs. Remus is a little bit less skittish than Romulus. He will eventually, if you sit in the middle of where they are, he will eventually kind of sniff around and maybe come near you. Romulus wants nothing to do with you. Which is funny cuz they're identical twins, but they're slightly different interacting with people. But it's very clear that these are wild. They're so huge, right? So...
Yeah, how big are they?
I don't have the latest measurements on how big they are. Of course, it's seasonal for all these different things. But I know that they were at some point they were at least like 120 lb, which is big for a gray wolf, yeah.
So, everything you just said about these direwolves, would you also say about gray wolves? Like you wouldn't want to be alone with one. Some can be skittish, some can be calm. Like you...
You know, I have good friends who are somebody you should think about having on. Actually, if you're interested in dog behavior and what we've learned about domestic dogs. I know you have a dog and it's very exciting. Eleanor Carlson is at the Broad Institute and at UMass and she's done a lot of work with wolf-dog hybrids and then also with domestic dogs and trying to map genes to behavior and all these things and basically showed that breed stereotypes are just not real and that you really can't map genes to behavior except for Chihuahuas. They're just terrible. I'm just kidding.
No, it's okay. We had Cesar Millan on the podcast. He'll be the first to say that in almost every decade in the United States there was the demonized dog breed. It was actually German Shepherds post World War II. Then it was Dobermans. Same reason. Then it was the Bulldog, the English Bulldog, which having had an English Bulldog is hilarious to me.
I went to Georgia and that's never going to be my least favorite dog.
And then now it's Pitbulls, right? And statistically actually I think most bites come from Chow. At least my uncle who's a vet tells me that, but Chow owners, I met some nice Chows. The blue tongue is pretty cool.
And that's a particular variant. You can imagine, yeah, there's a, there's color is one of the things that's best understood I think especially in domestic dogs cuz so many genomes and all these things have been mapped. And that's part of what we have to do in all of these cases is how do we figure out what it is that causes the thylacine to have the stripes that it has or causes the particular types of hair development that happen on a woolly mammoth. These are all huge open problems in evolutionary biology that I get to work on every day in my job.
Yeah, clearly you have the right job. So you have these three dire wolves. They're not mating. Is the plan to make more of them, to mate them? What's the ultimate goal and intermediate goal?
We will have another pack so that hopefully they will all be born, more of them at the same time, so that's the plan eventually. It's not our priority right now. We're working on other species, but what we'd like to do is have another pack in the space where we are so we can really better understand the impact of the animals on ecosystem. This is really the next rational logical step in any de-extinction project. I often hear rumors that what are you doing? You're just going to take an elephant and make a mammoth and just release it into Alaska? You're like, no. First of all, no cuz it's going to be so hard to make that first mammoth that I'm going to want to make sure that it is safe and cared for and has access to all the things that it needs.
Park thing again. It's that they break out, right?
But also, you know, you can't do that. We exist in the regulatory environment of anywhere that these animals are. It's not that we're some crazy scientists on an island like in Jurassic Park. You know, we work here. We have IACUC protocols and if you're doing anything that is releasing animal outside, you're under the regulatory purview of a whole bunch of different agencies.
