Bringing Extinct Species Back to Life | Dr. Beth Shapiro | Andrew Huberman Transcript

Andrew Huberman interviews evolutionary biologist Dr Beth Shapiro on de-extinction, genetic engineering, and ecosystem restoration

Andrew Huberman speaks with Dr Beth Shapiro, Chief Scientific Officer at Colossal Biosciences, about her work bringing extinct species back to life.

Summary

Andrew Huberman interviews Dr Beth Shapiro, evolutionary biologist and Chief Scientific Officer at Colossal Biosciences, about the science and ethics of de-extinction. Dr. Shapiro explains how ancient DNA is used to identify the genetic changes that defined extinct species — such as the woolly mammoth, dodo bird, thylacine, and direwolf — and how those changes are then engineered into the genomes of living relatives using synthetic biology tools. She reveals that three living direwolves already exist, created by making 20 targeted edits to a grey wolf genome based on fossil direwolf sequences. The conversation broadens into the use of the same genomic tools for conservation of living species, including a project to make the northern quoll resistant to toxic cane toads through a single gene edit, and the cloning of black-footed ferrets to restore lost genetic diversity. Dr. Shapiro also addresses the ethical dimensions of genetic engineering in humans, drawing parallels between de-extinction work and emerging technologies in human medicine, including the first child cured of a genetic disease using a bespoke CRISPR base editor.

Key Takeaways

FULL TRANSCRIPT

Species Concepts, Taxonomy, and What Makes a Species

Andrew Huberman: Dr Beth Shapiro, welcome.

Dr Beth Shapiro: Thank you.

Andrew Huberman: Longtime fan of your work.

Dr Beth Shapiro: Same.

Andrew Huberman: I love animals. I love stories about animals that aren't around anymore. I've heard that you're going to bring back the woolly mammoth, the dodo bird, and that you might have already done something to contribute to the proliferation of the black-footed ferret. I'm a big fan of mustelids, of which ferrets are. We're going to talk about all of that today, including the ethical implications. But I have a very basic question, which is: how do you decide what a species is? Because you have a degree in zoology. A few years ago we got this thing called DNA sequencing. We can look at ancient DNA, we can look at skeletons. People have done that for a long time, and my understanding is that it's completely revised the understanding of the relationship between different animals and the number of branches in these phylogenetic trees. So what have we learned that you think people might appreciate understanding about taxonomy? Like, is my dog — a bulldog mutt — as a Chihuahua, are they really the same species?

Dr Beth Shapiro: That's a really fascinating way to put it. And I think the most important thing that most people probably don't think about is that biology doesn't care what species you are. Species is a human concept. We have this incredible proclivity to want to put things into boxes so that we can talk about them, so that we can have conversations or share stories or share memories. In order to share something, we have to know what to call it. That's one of the reasons language has been so fundamental to the evolution of our species and our social structures.

So, what is a species? Probably when you learned about species in biology class in middle school, you learned about Ernst Mayr's biological species concept.

Andrew Huberman: Kingdom, phylum, order, genus, species — that kind of thing. Taxonomy.

Dr Beth Shapiro: Right. So Linnaeus came up with this idea of doing taxonomy. Here's an interesting taxonomy story. I've spent a lot of my career working on bison — for various reasons — but a lot of time working on bison. Bison were called buffalo, right? We think of American bison as buffalo. It's the same thing. But bison is the taxonomic name that was given to American buffalo by Carl Linnaeus, because when Europeans were going around the world and finding all these different animals for the first time, if they saw a big animal that looked like it would make a good coat, they called it a buffalo. So we have African buffalo, Asian buffalo, and American buffalo, and they are not related to each other at all if you look at their DNA, but they all have the same name because they all made a good coat at some point.

But taxonomists found this very disturbing. We want to know what animal we're talking about when we say "the buffalo." And so this is why Linnaeus comes up with this scheme. The American bison, the American buffalo, is called Bison bison. In fact, the plains bison is called Bison bison bison — that's a genus and a species and a subspecies that are all the same thing.

Andrew Huberman: That's the Latin name — Bison bison bison.

Dr Beth Shapiro: Bison bison bison. It's almost as humorous as Gorilla gorilla for the gorilla.

Andrew Huberman: Gorilla gorilla and Lama glama. That's one of my favorites too.

Dr Beth Shapiro: Anyway — taxonomy. So we have these taxonomic ways of thinking about things, and that sorts everything into your deep evolutionary history. But species concepts are what people use to try to say: okay, I have this animal — is it in the same species as this other animal, or a different species? And the species concept that you probably learned, Ernst Mayr's biological species concept, says: if they can breed and their offspring are fertile, then they're the same species.

Andrew Huberman: Which seems like a good place to start.

Dr Beth Shapiro: It's a good place to start. Because even in my understanding from my fly biologist friends, you can't mate Drosophila with another species of fly and get a fertile offspring. So even among flies, there's some restriction. And what's wild is that flies and mammals of all sorts seem to know — they actually don't try to mate with other species in most cases, which is fascinating in its own right.

Andrew Huberman: Beg to disagree there. I mean, your dog probably tries to mate anything it comes across.

Dr Beth Shapiro: Just hit seven months. I've not seen him hump a single time. He's still intact. This time I'm keeping my dog intact. We can talk about the reasons for that — health reasons. I might get him a vasectomy. People never talk about this, right? You can keep your dog intact and just give him a vasectomy if you don't want them to breed.

Andrew Huberman: A guest on this podcast — an animal expert from the Karolinska — said that in Scandinavia it's actually illegal to neuter a male dog unless there's a health reason. And in Australia the inverse is true. But yeah, they need their hormones for proper brain development, right? And we worry about them running around and breeding. There is this thing called the vasectomy, which is actually less invasive a procedure than the full neuter. Anyway, my dog doesn't try to mate. I didn't see my previous dog try to mate with cats or even Chihuahuas.

Dr Beth Shapiro: Do you think Neanderthals and humans are a different species?

Andrew Huberman: I don't know. But I want to know — if it's somewhat based on nomenclature, and if there's enough genetic variation out there, is it the case that people we call people are actually divergent enough in terms of their DNA that two people are not necessarily both Homo sapiens? That there's some Homo sapiens with an asterisk? I'm not trying to cast any hierarchy — they could just be different.

Dr Beth Shapiro: So you're referring to a different species concept, which is the genetic species concept, where an organism is classified based on some threshold of sequence similarity. That is a species concept that is as valid and valuable as the biological species concept, which says you can't interbreed. If you're interested in conserving species, you might use a geographic species concept that says: if you live here, you're a Florida panther, but if you live in Texas, you're a Texas panther — we're going to call you different species. Biology doesn't care about your species concept. Your species concept is something that you have adopted to have a conversation with another person about a particular topic.

Andrew Huberman: Educate us on this Neanderthal piece. I know this is a topic very close to home given that your husband works on these issues — we can maybe get him on here separately — but feel free to steal his thunder in any way you feel.

Dr Beth Shapiro: My husband Ed Green was part of Svante Pääbo's group when they were assembling the Neanderthal genome, and so he spent a lot of time thinking about Neanderthals. I think what's interesting from a species concept standpoint is that we now know, based on studying DNA both from Neanderthals that used to be alive and a different lineage of human called the Denisovans — we call them this because they were first isolated by Svante Pääbo's research group from a tiny little finger bone found in a cave called Denisova Cave in Russia — we know that there were multiple different species, or lineages, or whatever you want to call them, of human-like people that were alive at the same time. And we know that after people moved out of Africa to colonize Europe, they met groups of Neanderthals and they bred with them. So if they were a different species, they were violating the biological species concept at that point. Species concepts are just what we make of them. And today most people have somewhere between 2 and 5% of their DNA from this admixture event, this hybridization event between anatomically modern humans dispersing out of Africa and the Neanderthals that were already in Europe.

The Fossil Record, Hybridization, and Ancient DNA

Andrew Huberman: Many questions about this. First of all — the silhouette diagram we've seen of apes gradually in time sequence working their way to bipedal and upright. Is that substantiated by the fossil record?

Dr Beth Shapiro: It is. We know that the lineage that eventually became us evolved in Africa. We can trace ancestry back to apes and then to primates, and then eventually to us. The fossil record in Africa is very fragmentary. One thing that's been really fun about working in ancient DNA is that the field of paleoanthropology is pretty contentious, because there are so few bones out there that if someone finds a partial fragment of a jaw with a piece of a tooth in it, they can use that bone to completely revise what we think has happened in human evolutionary history. Maybe they're right and maybe they're not.

What's brilliant about ancient DNA is that if I can find a little pinky bone in a cave in Denisova and get DNA from it, I know that my bone has ancestors. If I have a bone that might be somewhere on that lineage to human evolution, I don't know that that bone has descendants. I don't know that it's part of our actual family tree or if it's another one of the dead ends that went in a different direction and eventually became extinct. But that is one of the coolest things about being able to sequence one of these bones — because now you know what it is, and now you can line it up against all the DNA from all of the people alive today and discover things like: we all have ancestry from breeding between these lineages, because they could, and because I think if they can, they do.

Andrew Huberman: It's interesting, right? Because if you took the far ends of the spectrum — the old world primate apes and then the upright walking human — my assumption is that even with artificial insemination you wouldn't get viable reproductively competent offspring from those. But at some point, two non-genetically identical species can get breeding across species and get reproductively viable offspring. That has to be the way this happened, right? It couldn't have just been through spontaneous mutations that suddenly took animals from quadrupeds to bipeds.

Dr Beth Shapiro: No, this is a very long and slow evolutionary process. It's actually a really good question and I think it's an open question in evolutionary biology, and it's probably different in different cases. Evolution does happen because of random mutations that accumulate in a genome. If you think about what might happen if two lineages are isolated from each other for a really long time and in different habitats — say this lineage is adapting to a very rainy environment with a lot of floral plants, and over here it's drier with really scrubby plants — there are different selective environments, and as mutations arise in that genome, different ones will go to fixation. The size of the population also matters. If a population is really small, even mutations that arise that are bad can become fixed just because the population is small and it happens by chance. So over time these two lineages will become more and more different from each other.

What happens when they come back into contact? I think it will really depend on what those mutations were. It could be that there's a very short evolutionary time but a mutation has arisen that means the sperm can't fertilize the egg. Or it could be that nothing really has happened over a really long evolutionary time and admixture can happen.

Humans and Neanderthals diverged somewhere between 300,000 and 500,000 years ago. That's not very long ago in evolutionary time. Brown bears and polar bears diverged about half a million years ago, and we know that they can readily interbreed and do whenever they overlap in habitat. They're called grolar bears or pizzly bears, depending on which direction.

Andrew Huberman: Especially if you're a bear.

Dr Beth Shapiro: But that's been happening throughout their evolutionary history. We can see this because using ancient DNA, we found a polar bear off the coast of Alaska that probably lived more than 100,000 years ago, and it had ancestry that we see in brown bears everywhere in the world, suggesting that at some point its ancestors or descendants had hybridized with brown bears and that DNA got passed around. We know that during the last ice age, there were polar bears that got trapped on the ABC islands in southeast Alaska. When brown bears expanded from the mainland, they interbred with those polar bears. Brown bears alive in North America today all have polar bear ancestry from that interbreeding roughly 20,000 years ago.

What's most interesting and relevant to your question is that those hybrid bears only ever survive as brown bears. We see no evidence of brown bear DNA getting into polar bears. And it only really happens in the direction where the mom is a polar bear and the dad is a brown bear. Polar bears are induced ovulators — the presence of a male will cause them to ovulate. So you can imagine a situation where a brown bear wakes up from hibernation, goes onto polar bear habitat to scavenge for food, comes across a polar bear female, induces ovulation, and they mate. The other way around — where a polar bear male finds a seasonally ovulating brown bear female — probably wouldn't happen because the timing of overlap wouldn't be right, and also he would probably kill her rather than mate with her because of the size difference.

Since bears live with their moms, all the brown bears we see that have polar bear ancestry are brown bears, not polar bears. The hypothesis from polar bear biologists we were working with was simply that if you have brown bear ancestry, you don't have perfectly white fur and you cannot successfully hunt seals. It is just adaptation that means that admixture doesn't work in that direction. Even though there's no problem with the sperm and egg mixing and the animal is born, they cannot survive as polar bears.

Andrew Huberman: I'm going to bring up dogs again, but in the back of my mind is a conversation about humans and this question about different species of prior to Homo sapiens or Homo sapiens and nearby species having reproductively competent offspring. So in the dog world, it's well known that the English bulldog — which has a big head and small hips — is the byproduct of many crossings, basically the bull mastiff and the pug. This was an attempt to generate an animal with a short snout so it could clamp down for bull baiting, which fortunately is an illegal sport now, and to clamp down and not get shaken off by the bull very easily. The floppy face is associated with lack of pain receptors. There are a bunch of things in the bull mastiff lineage that they wanted, but they wanted a low center of gravity, so they took the pug. But when you cross them, the females can't give birth because the birth canal doesn't allow for it.

Humans realized this pretty quickly and learned Caesarean section. So I could imagine a situation where Homo sapiens and some other non-Homo sapiens humanish species were having sex, sometimes getting pregnant, but the babies would always die because the birth canal and the structure of the pelvis wasn't quite right to allow the head size through. There are a lot of arguments that humans sort of optimized for just enough space so that the large human brain could pass through, but no larger.

Dr Beth Shapiro: One of the reasons that giving birth is one of the ways that women have died in our evolutionary history.

Andrew Huberman: Right. And Caesarean sections have probably changed human evolution in that sense, as has aseptic conditions and things like that.

Dr Beth Shapiro: Absolutely. My child was a Caesarean birth.

Andrew Huberman: I could imagine a mutation that was an adaptive mutation where suddenly this other species — which maybe had a smaller pelvis — a female could deliver this child live, the mother survived as well, and then that DNA propagates. So there are or were humans walking around who are not completely Homo sapiens. But it is true that humans and our archaic cousins the Neanderthals interbred and that people walking around today have Neanderthal DNA.

Dr Beth Shapiro: Two to 5%, as I said. What's interesting about that — and it touches on the adaptation component you raised — is that most people have heard this number: we have 2 to 5% Neanderthal DNA. Less well understood is that it's a different 2 to 5%. The 2% Neanderthal that is in my genome is different from the 2% or maybe 5% Neanderthal that's in your genome, which is different from the next person's.

Andrew Huberman: So it could be heart, liver, skeleton, and spleen for me, and some other constellation for you.

Dr Beth Shapiro: Could be anything. And if we were to go around the world today and pick out all of the pieces of Neanderthal DNA that exist in humans today, we would put together more than 90% — possibly more than 95% — of the Neanderthal genome just from people who are alive today. And that tells us that most of the Neanderthal genome was not maladaptive — that pretty much all of it could get passed on and live in healthy humans today.

What's interesting is we don't know what happened in the other direction. We see Neanderthal bones and there hasn't really been any evidence of humans admixing with Neanderthals from the Neanderthal side. There has been evidence of hybrids between Neanderthals and Denisovans. This is really one of the most exciting things that ancient DNA has been able to contribute to understanding human disease and human medicine and what it means to be human. Because before we had the Neanderthal genome, if we wanted to know what in our DNA makes us human, we would have to compare all the humans alive today with our closest living relative, which is a chimpanzee or a bonobo. So there's 3 to 5 million years of time between when we shared a common ancestor. A lot of change happens in 3 to 5 million years in your DNA.

When we got the Neanderthal genome, that 3 to 5 million year long branch leading to us was shortened to 300,000 to 500,000 years — by an order of magnitude. So now if we want to know what it is that makes us human, we have a much smaller list of mutations or variants to look at. And because we now know that 95% of the Neanderthal genome exists in people today, we've narrowed that list down even further to that other 5%. What's going on in that 5% of the genome where no living person has Neanderthal DNA? That is where the stuff is that the baby had to have the human version of in order to survive. And that's where we look to see what it is that made us human.

Andrew Huberman: A few years back when 23andMe and these other companies started making genomics in humans easier and more affordable, a lot of guys boasted about Neanderthal DNA being vigor genes, whereas women tried to downplay the amount of Neanderthal DNA they had when they got their results. Is there any evidence that the Neanderthal genes are vigor genes — that they allow for more durability?

Dr Beth Shapiro: It's an interesting question. If you just look at that 2 to 5% of Neanderthal DNA that we all have, most of it is not under selection. So you see it at about 3% frequency or so in different populations. What is interesting is when a piece of Neanderthal DNA is suddenly much more common in a population of humans, because that would suggest that bit of DNA made someone more fit — they were able to survive and have more kids than everybody else, so it increases in frequency compared to average.

There are a couple of things that have come out of this. There are genes common in Latin American populations that come from Neanderthals that predispose to type 2 diabetes. There is another gene — again in a Latin American population — that has to do with pain sensation. But most of the really interesting ones have been immune-related genes. During the pandemic, one of the first alleles discovered to be associated with bad outcomes of COVID was a gene that came from Neanderthals — a Neanderthal-derived gene at something like 50% frequency in Asian populations, way above the 3% average. It made people more susceptible to the virus entering the lungs. Presumably it only became that high frequency because it was protective against some other disease circulating in the past. There was another Neanderthal-associated allele that was actually protective against COVID. So our ancestors have been subjected to different diseases and pandemics throughout life, and we see the traces of that in ancient DNA. We can now go into graveyards in Europe and actually isolate plague from dirt and from bones from people who died of plague, and look at how their immune systems and genes responded to exposure to things like this.

Andrew Huberman: My red-headed friends like to claim that they have more Neanderthal and therefore more vigor and pain resistance. Were Neanderthals a lot of them gingers?

Dr Beth Shapiro: Yes. This comes from studying MC1R, a gene associated with the red melanin. Mammoths as well — you can see mammoth mummies with the actual hair, and there definitely is some evidence from their genome that they had reddish-colored hair.

Andrew Huberman: Interesting. Maybe we could briefly talk about eye color. Is it true that all blue-eyed people descended from a single blue-eyed human at one point? And was there a time when the population of humans had a lot more green-eyed people?

Dr Beth Shapiro: If you look at African populations mostly, it's dark eyes. I think that's probably the ancestral state, but there are lots of different eye colors that have evolved and I think they're selected for. People like things that are different and unique, so people want a mate that has blue eyes. I really think eye color was sexual selection. I don't know what other benefits blue eyes could have other than looking very stoic and cool as you're trying to hunt something down.

Choosing Which Species to Bring Back

Andrew Huberman: As somebody who studies long periods of time and what's happened to our species and other species across long periods of time, I'm curious how you pick the problems that you choose to work on. Why the woolly mammoth? Why not get the Florida panther completely rebooted? Maybe why not both, right? But in terms of where to focus — like why bring back things from way back when as opposed to species that disappeared in the last 200 years? How do you pick? And when you're making that decision, what's guiding it at the ethical level? What's guiding it at the practical level? What are you really trying to accomplish?

Dr Beth Shapiro: I think I'll start with what is motivating, and I think what's motivating is what drives the selection of the species. I wrote a book a long time ago now called How to Clone a Mammoth, and the first chapter was "How to Pick a Species." There are technical, ethical, ecological, and social reasons to pick any of the species that you can.

Technical — these are the easiest, right? We can't bring a dinosaur back to life because we don't have dinosaur DNA. The oldest DNA that we have ever recovered from a bone is from a mammoth bone that probably dates to around 1 to 2 million years ago. Dinosaurs went extinct more than 66 million years ago. That's far outside of where we're going to get recoverable DNA. The skeletons are fossilized — they've turned into rock — so there's no shred of DNA left.

As soon as an organism dies, the DNA in its cells starts getting chopped up into smaller and smaller fragments until eventually there's nothing left. This happens by three processes. UV light — we know about this, it's why we wear sunscreen. UV light hits your DNA and actually breaks it. When we're alive, we have proofreading enzymes that come and fix your DNA so you don't get cancer every time you go outside. But that is an energy-requiring process, and after you die, there's no more energy. So the breaks from UV accumulate. Freezing and thawing — water molecules expand and will physically break the DNA fragment. And most importantly, just microbial decay. The fungi and bacteria that get into an organism when it's decaying chew it up to transform that carbon and nitrogen into the next generation of organisms. That process is slower in some environments than others — exactly in the same way that your sandwich will rot faster if you leave it in the sun versus in the fridge versus in the freezer. DNA will preserve for longer in the cold Arctic where things are rapidly buried in frozen dirt and stay that way for a million years, like this mammoth bone we were able to recover DNA from. But if you die in a very hot, wet, swampy place like Mauritius, where the dodo lived, there's very little chance you're going to be able to recover DNA from any of the fragments there. I have tried — hundreds of bones from Mauritius. We have a great dodo genome, but it's from a bird that went to Europe alive on a ship and is part of the collection at the Danish Museum of Natural History.

So you have to have a well-preserved sample that you can get DNA from — ideally many of them, because you want to know what are the DNA changes that made a mammoth a mammoth instead of another type of elephant. You probably should know what caused that species to go extinct in the first place so that you don't bring something back that becomes the first species to be de-extincted and then the first species to be re-extincted. You have to understand the role that that animal played in the ecosystem and whether that niche is still available. Ecosystems don't live in a vacuum just waiting for something to come back. In some cases, there's a real ecological driver for the species that we're focusing on. We feel like there is a real ecological role for these species to play — that these ecosystems are destabilized because of extinction, and by bringing back these key ecological interactions, we can make those ecosystems more robust and more resilient in the face of all the pressures that people are throwing at our natural ecosystems.

Andrew Huberman: Could you give me an example of that? If you were to bring back woolly mammoths, what would that probably do that's useful?

Dr Beth Shapiro: If you think about what large animals, large herbivores, do in their ecosystem — they turn the soil by walking around, they knock down things, they distribute seeds and nutrients. Have you heard of Pleistocene Park? This is up in northeastern Siberia. There are two scientists — Sergey Zimov, who's a Russian Academy scientist, and his son Nikita. They've been running this park up in northeastern Siberia for a long time, and they've been really interested in understanding what happens when you restore all of the species that used to live on the tundra to the tundra ecosystem. They have bison brought in from Canada, wild horses, several species of deer, and muskox. And they've seen that having the animals on the landscape they've fenced off actually causes the plants to come back with more veracity.

These animals have to eat during the winter, so in order to find food, they scrape the snow off the surface of the dirt. In the absence of these animals, the snow stays on the surface, and snow is a very efficient insulator. It traps the summer heat in that frozen sediment, causes the sediment to melt faster, and when the plants come back, it's a particular type of plant that can live in that moist sediment. With the animals, you get a mosaic landscape where some parts are moist and wet, other parts have been exposed and are dry and colder, and you get broader diversity of plants coming back where these animals are. They are essentially recreating their ecosystem just by being there.

The Bird Program, the Dodo, and Reproductive Biology

Andrew Huberman: So you did technical, ethical, ecological. I think another answer is: what is going to make an impact?

Dr Beth Shapiro: Right. When I joined Colossal, we didn't have a bird program, but I really wanted there to be one, because all of the tools that we are developing for de-extinction are the same tools that we can use to modify the genomes of living species and help them avoid becoming extinct. The kit we're building — from multiplex genome engineering to cellular rejuvenation to iPSC technologies for wild animals to learning the link between particular letters of the DNA sequence and what those letters actually do to cause an animal to look the way it does — all of that is applicable across the board. So the stack we're building for de-extinction applies to synthetic biology for conservation.

When I joined Colossal, they had launched the mammoth program, which is a placental mammal, and the thylacine program — the Tasmanian tiger — which is a marsupial mammal. But birds are among the most endangered species on the planet, and it is not possible to clone birds using somatic cell nuclear transfer — the process that most famously brought us Dolly the sheep — because we don't have access to the egg cells at the right stage. So while that process is really pivotal and integral to our mammoth and thylacine and other mammalian projects, it's just not possible to use it for birds. I wanted a program that was going to help us develop technologies for birds.

Why did we pick the dodo compared to any other bird? It comes down to awe — being excited about something. We get kids drawing mammoths and thylacines and dodos and sending them to us all the time. The dodo with its sort of rounded top beak and the way the eyes are typically drawn — it has a kind of cartoonish, friendly, Toucan Sam type of look. It was in Alice in Wonderland. Most of what we know about the dodo is from cartoonish drawings of this animal.

Andrew Huberman: You didn't choose to bring back like a 75-foot-long python. Thank goodness.

Dr Beth Shapiro: Although there might be virtue in doing that. Though I think there are plenty of pythons in the Florida Everglades right now.

Andrew Huberman: Talk about bird developmental genetics for a second. A few years ago, I saw something about two female condors reproducing.

Dr Beth Shapiro: Actually, it wasn't two female condors reproducing. It was one female condor just having an egg all on her own.

Andrew Huberman: And because of the sociopolitical implications, this got people in Northern California pretty excited. They were like, "Okay, we don't need men after all." How did one female condor — who we trust when she says she never mated with a male or female condor — manage to reproduce?

Dr Beth Shapiro: My scientific explanation is that meiosis didn't fully separate and she ended up having a fertilized egg. We should explain meiosis. During the very early phase when you're making eggs or making sperm, you're trying to duplicate your cell, but instead of that, you make two versions of the cell that only have one copy each of your chromosomes. So when normally an egg that has one copy of the set of chromosomes and a sperm that has one copy of the set of chromosomes come together and are fertilized, the resulting embryo has two copies — one from mom and one from dad. In this case, there was no sperm. There was an egg that had both copies, probably because of a mistake during meiosis where they didn't separate out properly, and that was able to develop full term.

Andrew Huberman: Was the offspring viable?

Dr Beth Shapiro: Yes.

Andrew Huberman: What's weird about that? I mean, it's very cool and very clear how that could happen because you need the two sets of chromosomes. So both sets came from mom in this case. But in humans where that happens — and it does happen on certain chromosomes — these homozygosity effects happen under certain conditions. Like there are these paternally or maternally imprinted conditions like Prader-Willi syndrome, where paternal DNA gets kicked off and you have two copies from mom, which doesn't sound like a bad thing unless there are things on the paternal chromosome that are required for development. And the reverse also happens — like in Angelman syndrome, I think it is. So if you get two copies from mom of a chromosome, or two copies from dad, you end up with pretty severe deficits in brain development and other things.

Dr Beth Shapiro: And you could never be a boy, because the one gene that turns on that cascade of male development is called SRY. It's on the Y chromosome. So without that gene, you would never be a boy — you would always be a girl. Trisomies, where you get two copies from mom and one copy from dad, can also be bad because of different levels of gene expression.

Andrew Huberman: Down syndrome is trisomy 21.

Dr Beth Shapiro: Trisomy 21, and there are a few other trisomies that are compatible with life. Trisomy 21 is the most common one because those people can live — obviously with some additional challenges because of the additional chromosome — but they can live full lives into relatively middle age.

Andrew Huberman: Is there a way of looking back at the ancient DNA of different species and knowing if they reproduce the way we imagine they reproduce?

Dr Beth Shapiro: Sex has evolved a bunch of different times on the tree of life, and different ways of doing sex have evolved. We have this XY process where the males are what we call the heterogametic sex — males have an X and a Y, and females have two X's. But birds do it differently. They have the WZ system, and it's the females that have the two different chromosomes. And then there are alligators and crocodiles, and they do sex determination based on the temperature at which the egg is sitting during a very critical period during development.

Andrew Huberman: There are communities online that actually believe this kind of stuff for humans — all these theories about how to get a male or female offspring based on position of intercourse, temperature, location, food. None of it beats chance, right?

Dr Beth Shapiro: Or if you really want ICSI — the process by which you take an egg and you take a particular sperm that you know whether it's carrying the Y chromosome or not, and use that to fertilize the egg.

Andrew Huberman: Can you actually determine the XX or XY of the sperm? They can do that now?

Dr Beth Shapiro: You can select. You can do true sexual selection. It's because the Y chromosome is teeny tiny compared to the X, so you can centrifuge them and because they're smaller they sort out.

Andrew Huberman: So you can spin sperm around — don't do this at home — and then based on different weights, basically spin out to different depths. So you can bias the likelihood that you'll get an XY-carrying sperm or an XX-carrying sperm.

Dr Beth Shapiro: Or you can use cloning, like we are at Colossal, where you actually know the sex because you're starting with an actual somatic cell, a tissue cell of that animal, instead of using a sperm and an egg.

Andrew Huberman: So let's talk about that. And before we do, we should probably do a brief developmental biology lesson. You beautifully told us what meiosis is. In humans, it's 23 chromosomes, so you only have half so that they can meet in conception and then start to divide and create more cells that become the embryo. In these other species, I guess you know how many chromosomes there are. Birds are complicated. Some birds are trickier than others.

Dr Beth Shapiro: Birds are really tricky. I did not know until I joined Colossal that there are some birds that have what's called a germline-restricted chromosome, which doesn't exist in any of their cells except for the germline — the sperm and eggs. It comes into being just in the germline and then it disappears.

Andrew Huberman: Wow.

Dr Beth Shapiro: I know. Biology is amazing. The birds have these little micro chromosomes that are a pain to assemble. And if you're sequencing DNA from an extinct species where the DNA fragments are really short and you have to figure out where on a whole genome each one goes on a computer — the birds are really cool animals, but from a reproductive biology standpoint, it's tricky.

Andrew Huberman: So the woolly mammoth was a mammal. You know that because — well, people might say "duh, because it has fur" — but that is not necessarily true, right? You have monotremes and all this other stuff. So you know it's a mammal because there's evidence of lactation? How are you deeming it a mammal?

Dr Beth Shapiro: Using its genome. We've been able to sequence high-quality whole genome sequences from multiple mammoths that date to the last million and a half years. We can assemble those genome sequences using a computer and then compare them to other animals alive today. We know that the closest living relative of a mammoth is an Asian elephant. In fact, mammoths and Asian elephants are more closely related to each other than Asian elephants are to African elephants. So mammoths are nested within the elephant family, most closely related to Asian elephants.

How De-extinction Actually Works — Not Like Jurassic Park

Andrew Huberman: Okay. So if you get the sequence of DNA from a mammoth, you know: this is the complete genome. A lot of people probably don't realize that your complete genome is represented in most all of your cells — it's just that not all those genes are expressed, which is why you get a hair cell versus a skin cell versus a heart cell.

Dr Beth Shapiro: That's the epigenome.

Andrew Huberman: Right. But the menu is there. Are you growing up DNA in a laboratory that is the mammoth sequence?

Dr Beth Shapiro: So this is what comes from Jurassic Park. And this is why I love talking about Jurassic Park — because I think everybody has an idea of how we're doing this because they saw that movie. What happened in Jurassic Park — and I should just say it was not a documentary — was that scientists found mosquitoes preserved in amber, stuck a needle into those mosquitoes, sucked out a bit of stuff that happened to be blood with dinosaur DNA, and then there's the little dancing DNA thing that tells you about how they piece it together. You can see the little pieces of dinosaur DNA lining up next to each other, and then there are 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. Why they picked frogs, I don't know.

But that's 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, and by sequencing a bunch of Asian elephant DNA and a bunch of mammoth DNA, we can see that they already have almost exactly the same genome sequence.

Andrew Huberman: How similar?

Dr Beth Shapiro: They're about 99% similar, depending on how you calculate the percentage. As a point of reference, how similar are we to chimpanzees?

Andrew Huberman: In that counting, it's about the same.

Dr Beth Shapiro: But some people might say, "We don't look anything like chimpanzees." Well, 99% just sounds so similar, like you're going to get the same thing. There's some statistic online that we're 85% the same as a banana or something like that. A lot of our DNA is shared across life.

Andrew Huberman: Is the goal to recreate the ancient mammoth, or is it to create a pseudo-hybrid of the ancient mammoth?

Dr Beth Shapiro: The goal is to think about a mammoth in terms of what it does and what it looks like. This gets back to the idea you brought up at the beginning about species concepts. This is one of the most common things we hear: if you are going by a strictly genetic species concept — where you're saying an organism is classified just by some threshold of sequence similarity — 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.

Our mammoths, our direwolves, 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 from. I want to push back a little on this because what I don't want is for this definitional gatekeeping to really take over and become the whole story. 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 we're developing can be applied to ecosystem health to help stop species from becoming extinct, and even to 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. 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 they'll 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.

Andrew Huberman: When you mentioned species nomenclature gatekeeping, I have a feeling this is based on the publicity around the direwolf.

Dr Beth Shapiro: Yes. And 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 of 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 have, but if people don't want to call it a direwolf, just don't. Like, 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.

Andrew Huberman: 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, "No, they're not a dinosaur."

Dr Beth Shapiro: You're a scientist and I am too. My dad's a theoretical physicist. He was involved in chaos theory. I remember when Jurassic Park came out, he didn't dislike it, but the part where he kind of rolled his eyes was the description of chaos theory in there. In Hollywood, they love to use the example of a butterfly flapping its wings in Patagonia and then something happens to the barista in Brooklyn. People like to bridge those concepts and they think, "Oh, that's so cool." So it's sticky, as we say. But for people that are experts in the area, it can be a little grating at times. The public, though, in my experience, is open. If they just have the knowledge in hand, they get it.

The Direwolves — What Was Done and Why

Andrew Huberman: So tell us about the direwolves.

Dr Beth Shapiro: Our direwolves have 20 edits that we picked. We sequenced genomes from fossil direwolves. We learned from those genomes what genetic changes made those animals bigger, more robust, and light-colored in coat, and then we engineered those changes into a grey 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.

Andrew Huberman: 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. If I were to look at the direwolf and a grey wolf side by side, is the direwolf larger?

Dr Beth Shapiro: They are more 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. It's both because we want to bring back these extinct traits with some fidelity so that the animals can eventually be released — and we will study the animals and learn about the effect of their genes on their lifespan — but also because we with synthetic biology have the power to engineer them in a very deliberate way, and we want to make sure 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. When we sequenced the genomes of the fossil direwolves, we found that they both had variants in two genes that would have made them have light-colored coats. But in living grey wolves and dogs, variants in those genes — not the same ones we saw in direwolves, but close enough to where we would need to do the edits — can lead to oculocutaneous albinism, meaning blindness or deafness in these dogs.

We decided that because we're not changing the whole genome — they have to be safe on a grey wolf genetic background — we wouldn't make the trait that way. It just wasn't passing the bar of animal welfare safety. So instead, we brought back the direwolf light-colored coat using different edits that we know are safe in a grey wolf background, because there are light-colored domestic dogs and grey wolves. We used the edits that we know are safe because they exist in living dogs.

So we were able to engineer, using all the tools of synthetic biology, this light-colored coat that is the direwolf 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. 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. It's a lot of work.

Andrew Huberman: So how many direwolves are walking around right now?

Dr Beth Shapiro: Right now there is Romulus and Remus, and they are almost two years old.

Andrew Huberman: Male and female, or male?

Dr Beth Shapiro: Romulus and Remus are boys, and Khaleesi is a girl. She is about 18 months old or so.

Andrew Huberman: Is the intention to mate them?

Dr Beth Shapiro: No, they're too closely related. We're stopping them using hormones. They live together. She was reared by herself — the boys had each other and she had just herself. So she's a little on the goofy side, but she's the best. She's adorable.

Andrew Huberman: Do you feel safe interacting with them?

Dr Beth Shapiro: We have interacted with them, but the people who work with them a lot — the ones 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, kind of sniff around and maybe come near you. Romulus wants nothing to do with you — which is funny because they're identical twins, but they're slightly different in interacting with people. It's very clear that these are wild. They're also huge.

Andrew Huberman: How big are they?

Dr Beth Shapiro: I don't have the latest measurements, but I know that at some point they were at least around 120 lbs, which is big for a grey wolf.

Andrew Huberman: So everything you just said about these direwolves — would you also say about grey wolves? Like, you wouldn't want to be alone with one?

Dr Beth Shapiro: You know, I have good friends — somebody you should think about having on, actually, if you're interested in dog behavior and what we've learned about domestic dogs. Elinor Karlsson is at the Broad Institute and at UMass, and she's done a lot of work with wolf-dog hybrids and also with domestic dogs, trying to map genes to behavior. She basically showed that breed stereotypes are just not real. You really can't map genes to behavior.

Andrew Huberman: We had César Millán 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. Then it was the English bulldog — which, having had English bulldogs, is hilarious to me. And then now it's pit bulls. And statistically, I think most bites come from chow chows.

Dr Beth Shapiro: Color is one of the things that's best understood in domestic dogs. There are so many genomes and all these things have been mapped. And that's part of what we have to do in all these cases — how do we figure out what causes the thylacine to have the stripes 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.

Andrew Huberman: So you have these three direwolves. They're not mating. Is the plan to make more of them, to mate them? What's the ultimate goal?

Dr Beth Shapiro: We will have another pack so that hopefully they will all be born more of them at the same time — 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 the ecosystem. This is really the next rational logical step in any de-extinction project.

I often hear rumors: "What are you doing? You're just going to get an elephant, make a mammoth, and just release it into Alaska?" No. First of all, 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 right things. Also, we exist in the regulatory environment of wherever these animals are. We're not some crazy scientists on an island like in Jurassic Park. We work here. We have IACUC protocols, and if you're doing anything that involves releasing an animal outside, you're under the regulatory purview of a whole bunch of different agencies.

I don't know if you saw, but the very first gene-edited organism created specifically for the purposes of conservation and ecosystem restoration was deregulated by the USDA this week. It's the American chestnut tree. The American chestnut was the most prolific tree across the eastern forests of North America until the early part of the 20th century, when a disease was introduced — believed to be on an import of a Chinese chestnut tree — that caused a fungus to get into these trees and they all died. It took a decade and a billion trees died.

Andrew Huberman: This scares me for a variety of reasons. A few years ago — this would be 2016, 2017 — I got this strange envelope in the mail to my residence. I was living in the East Bay, California, and I get this envelope containing a little quarter-size plastic container in an envelope with a little note saying "free seeds for gardening." I started fishing around on the internet. It turns out massive amounts of seeds were being shipped from China and sent here. My friends, one of whom is down at Santa Cruz — plant biologists — were like, "Whatever you do, do not put that into the ground outside, because these things travel. Birds eat them, birds poop, and stuff grows. This is how you can decimate important populations of trees and plants." It was the first time I really thought about vegetation-on-vegetation warfare. Was that actually what was happening? Was this the Chinese trying to do this?

Dr Beth Shapiro: We don't know. But what is very important is that anytime you plant something, you actually want to talk to the people who understand how different ecosystems of plants coexist. In the same way that you wouldn't put your wolves out into the dog park.

I wouldn't put the direwolves out because if we released direwolves, they would compete with grey wolves. And grey wolves are already having enough trouble trying to find a way to survive. There's no ecological need to release direwolves into the habitat, so we can use them to study these things.

But I think we as a lineage have been messing with the evolution of the stuff around us for as long as we've existed — initially just by driving things extinct. Not deliberately, right? Like maybe this wasn't a deliberate attempt to have some plants that would outcompete other things, but we did change ecosystems by going into them and getting rid of all the largest animals because we were hunting them. I'm thinking about our ancestors in Australia 50,000 years ago, in Asia 30,000 years ago. And then we domesticated things, and now we conserve things.

When people think about conservation, a lot of people have this idea that it's this beautiful thing where you're just leaving everything alone. But that's not what we're doing. We are deciding how many of them get to live, what they get to eat. We vaccinate them. We protect them from predators. I'm not saying that is bad, but I think it's naive to say that it's not us determining what the future of these animals are. And we've also been moving stuff around forever. We have English birds all over the place in New Zealand that were brought by people because they liked them.

I think it's a mistake to imagine that the only good ecosystem is the one that you know right now, because you're claiming a particular slice of history as the thing that is better than everything else. I think it's more important to think in terms of robustness. When we have multiple species in an ecosystem all doing different things, you end up with more biodiversity and richer environments. When there's an overlap in ecological niches, there's some redundancy, and that redundancy is really good for that ecosystem because it means that bad stuff can happen and it can weather that bad stuff.

Andrew Huberman: I'm totally on board with what you're saying. It touches on an important theme that people should think about, which is: who gets to decide? There's both a kind of massive ego inserted into the notion that we know best about everything, including all the other species of plants and animals — that's obviously not true. But also the idea that we don't have anything to contribute in terms of our own evolution. I think why it's hard for people to wrap their head around these things and they default to thinking "oh, it was better in the past" is because most people never experienced that — they have no concept. And we don't have a window into the future. So let's say these direwolves — you make more of them, they're roaming wildlands, they're serving other populations of animals and plants, there are new benevolent interactions that are pro-evolution. The challenge for people is we don't know what that looks like and it feels like there are too many variables to understand. How do you wrap your head around that when you're talking to people about what you do?

Dr Beth Shapiro: I'm thinking in terms of helping ecosystems to become more resilient. We know, for example, because of what happened in Yellowstone, the impact that restoring the top predator of an ecosystem that had been removed can have. The grey wolves that were reintroduced into Yellowstone — the population of animals that they ate had become too large and had eaten away at all of the shrubbery. Putting the grey wolves back in Yellowstone cascaded all the way down that ecosystem ladder to changing the way the rivers were flowing, because the plants were growing back along the edges of the rivers.

The thylacine — the Tasmanian tiger — was the top predator in Tasmania. And Tasmania today has problems because that top predator is missing. Have you heard about the Tasmanian devil facial tumor disease?

Andrew Huberman: Yeah, this came up on a podcast a few weeks ago. We had Jared Rutter on — another Hughes biologist — where we were talking about transmissible cancers. These Tasmanian devils fight, they scratch each other up, they get cancers, and that population is suffering as a consequence.

Dr Beth Shapiro: And they're so closely related to each other that they can pass them between each other. If we had had the top predators, those sick individuals would have been weeded out of that population and we might not have this problem. So you can see restoring that ecosystem would help.

And I'll get back to this: I often get the question of why are you thinking about bringing extinct species back to life? Why aren't you thinking about helping living species not become extinct? And the answer is we are doing both. It is the same tools. It's the same technology. It's the same needs. And when we excite people with the idea of mammoths and dodos and thylacines, we get more engagement and enthusiasm and investment in developing the technology that we can use to stop living species from becoming extinct.

There's a really great story. Our Colossal Australia partners have been working on a project to try to stop the northern quoll from becoming extinct. The quoll — Q-U-O-L-L — is a little carnivorous marsupial. They're adorable. And in Australia, there is an introduced amphibian called a cane toad that is toxic. It's toxic to dogs. When a quoll eats a cane toad, it dies. There is a very strong chance in the next few decades the northern quoll is going to become extinct.

However, there is a synthetic biology solution to this. There are mammals that eat toxic toads on the other side of the planet that eat cane toads, and they have a single letter change that changes one amino acid in one gene that allows them to eat that toxic cane toad and not die. Our Colossal Australia partners have made those changes in a quoll. And when you measure in a dish the ability of that toxin to break down, that single letter change to that quoll's genome could allow that quoll to avoid becoming extinct — but to eat cane toads, which currently nothing really can in Australia. So now we can see the real benefit of this massive comparative biology framework. I know which gene it is that I need to change. The stack that allows us to develop the tools to make that change — just that change — and then show that's the only change that's there, and put that in a living animal, can stop a species from becoming extinct.

Genetic Engineering in Conservation and Human Medicine

Andrew Huberman: As someone who does a lot of public science education, there are a couple of things that get the public really worried and that they need reassurance on. I think it dates back to the pandemic. There's a lot of distrust about scientists. There is this belief that some scientists are only concerned with themselves. It's an important myth to dispel — the idea that most scientists are not what I believe them to be, which is: they're trying very hard to get answers right and to do good for the world, including for other species. And they're not so careerist that they're willing to overlook that.

But that is the era we're living in. Some people think scientists are doing stuff because they can, and this has parallel conversations about AI where people are thinking: have we really thought this one through? I want to talk about two species to try to highlight how this can be done right. The first are mosquitoes, and the second are humans.

Most people don't care about mosquitoes, but some years ago I started paying attention to mosquitoes because your very own Howard Hughes director — Leslie Vosshall — works on the olfactory system of mosquitoes and other insects. Turns out bugs find mates and find things to suck blood from by odors and pheromones. And so there was this idea: mosquitoes have malaria, let's just get rid of all the mosquitoes. And the biologists were like, "No, you can't do that because then the birds are going to suffer because they eat the mosquitoes." This stuff can really domino. Or let's just make mosquitoes that can't reproduce. There were these ideas thrown out there that with genetics, you can do that — you just release a few of these into the wild and there is the potential that they mate and proliferate and just enough to eradicate a population. It's harder to do than that. Smart people put the brakes on it. So let's talk about mosquitoes. They clearly carry pathogens that harm people, but they're also important for ecosystems. How do you think about plucking out a node in an ecosystem like a species, or introducing a species back into an ecosystem, and thinking about the ramifications?

Dr Beth Shapiro: Mosquitoes are a hard one. Not all mosquitoes carry malaria and dengue and other diseases that are known to affect people. And also those mosquitoes have much higher population density because of the way that people have built our towns than they would have had in natural ecosystems. So for something like a mosquito that is extremely overpopulated and carrying a devastating disease, I would think that there actually is reason to think it is safe in an ecosystem to at least bring that population back down to a size that it would have been in a natural ecosystem. A lot of the problem with mosquitoes is because people leave tubs of water or water that isn't circulating out, and they lay a billion eggs and then you have many more mosquitoes.

Maybe engineer mosquitoes so they can't carry the disease, rather than engineer the mosquitoes to be dead. There are ways that I think we can use synthetic biology and gene drives — the thing you were getting at, where you release something created by a synthetic drive into the wild and then it passes on to the next generation. I actually think that gene drives are an incredibly powerful tool that we have at our fingertips where, with the appropriate safety measures and care in place, we should think about how we might deploy these tools. You can make a gene drive so it only lasts for a fixed number of generations. And also because they tend not to make things reproduce, there is incredibly strong natural selection against them. Anything that breaks a gene drive and lets something reproduce is going to be favored in a population. So gene drives are going to be difficult to get to persist, and there are many switches that we could build into them to make them last for a short period of time.

But there are some species that have taken over. There's cheat grass everywhere here, and it's highly flammable and it grows along the roads and it's Mediterranean in origin. The only way we are ever going to get the cheat grass down enough to let the native California grasses come back is if we get rid of the cheat grasses for a few generations.

Andrew Huberman: Do you think this is one of the reasons there are so many fires?

Dr Beth Shapiro: They're very flammable, and they also don't have very deep roots. California native grasses have much deeper roots, so they stay green longer. They're sequestering carbon and they're not as flammable for longer into the season. These shallow-rooted Mediterranean grasses dry out super quickly. So as soon as it's fire season, they're ready to go. And it's not just here — it's all across the western part of North America. This is a problem because it causes huge amounts of damage to forest ecosystems and huge amounts of property damage when fires take off. This is a situation where I would say: let's think about how we might safely deploy something like a gene drive that can remove something or at least tamp something down enough to allow that ecosystem to once again become more robust and resilient.

As far as adding things back into an ecosystem — this is one of the reasons that every de-extinction project or every species translocation project is staged and thoughtful. When people moved Texas panthers into Florida in the mid-1990s to try to stop Florida panthers from becoming extinct, the Florida panthers had developed crooked tails and cowlicks and cryptorchidism — their testicles didn't descend — and they were going to become extinct. This was inbreeding depression. There were only a few individuals, so they only bred with individuals they were related to. You bring in the Texas panthers and the panthers recovered. All of these diseases disappeared for a short period. Now they're inbreeding again because the population is cut off from Texas, so they'll have to keep doing it. We have to be the stewards of these ecosystems that we're creating.

We can do a ton of analyses about potential risks and rewards of what might happen when we modify an ecosystem. And we do it all the time — sometimes to good ends and sometimes to bad ends. What we can't do — and I think this is sometimes where the conversation gets lost — is look around at habitats around the planet that are suffering because of changes that people have made, see species teetering at the edge of extinction, and say that the only strategy they have to survive is natural selection. The rate of change of these ecosystems is too fast for that to work. If we say these technologies — whether it's translocations or assisted reproduction or genetic modification and synthetic biology and de-extinction — if we say that those technologies are too risky, we are accepting the outcome of doing nothing. Which is also a decision. And I think that's where a lot of times the conversation gets lost. Doing nothing is not not deciding. Doing nothing is saying we accept the fact that we are going to have a future that is less biodiverse than the present.

Andrew Huberman: It's amazing how people are perfectly happy to allow the negative default outcome to emerge even though it's the consequence of humans, but they are wary of humans intervening toward a potentially better outcome. I think it gets back to this issue of trust in scientists, and it also raises the question of who decides. I'm very opinionated about this when it comes to public health policy. I think what the pandemic taught us — regardless of where people sat on vaccines and lockdowns — if nothing else, it taught us that you can't have one person be the spokesperson. People need to hear from a group, including the dissenters in that group, and why they arrived at a particular decision.

Dr Beth Shapiro: I should be clear: for all of the species that we're working on, we have advisory panels built from local people. We have the Tasmanian advisory panel that has politicians, people who grow forests to log them, people who work with the animals, scientists, and conservation biologists, and we have regular meetings with all of our different advisory groups to talk about what the future might look like — well before we have a thylacine to be able to release anywhere. Our moa project is led by the Ngāi Tahu Research Centre in the South Island of New Zealand. These Māori people are the people who will be the long-term stewards of the moa. The decision about how many to make, which moa to make, where to release them, how to release them — it's their decision, in consultation with other people who will be impacted by this. And I think that's really important.

The other thing that I think we do well is this — I am not a scientist hiding up in an ivory tower somewhere. I'm here talking to you and talking to as many people as I can to tell people all about what we're doing. We even get yelled at for this. "Why is Colossal always talking about what Colossal is doing?" Well, would you rather we not tell you?

Andrew Huberman: I think the education piece is the critical piece. I think it's great that Colossal is doing this.

Dr Beth Shapiro: When the direwolf story broke and there was a small subset of scientists who were just yelling at me that I wasn't allowed to call it a direwolf, there were also a bunch of people who were like, "Wow, I can't believe you learned from a bone and actually used the tools of synthetic biology to engineer extinct traits into a living animal and now you have living direwolves." And there were people who were scared of it and people who loved it. And there were a bunch of people who said the words "de-extinction" and "synthetic biology" for the very first time in their lives. I got emails from colleagues at universities who said undergraduates were coming into their ecology classes, their sociology classes, their anthropology classes — some of them mad and some of them excited, but they were talking about it. And they were talking about it as if they had some agency in the world that they were inheriting. We hear that from middle schoolers and high schoolers. And I think that is really something tremendous about what we're doing. People need to feel excited and positive and they need to feel awe. And when I saw the direwolves for the first time, that's what I felt — genuine awe. And there's something about that that just makes the world a better place.

Human Genetic Engineering — IVF, CRISPR, and Baby KJ

Andrew Huberman: As long as we're wading into deep water here, let's talk about the really deep water, which is humans. We have this thing called IVF where people can make embryos and select what are deemed healthy versus unhealthy. So people are doing genetic selection in humans through technology right now. People don't really stop too often and think: how is that disrupting the human ecosystem in any number of ways?

But a few years back there was a guy in China — actually a postdoc from Stanford — who decided to use gene editing to modify the genome of some babies. He disrupted the HIV receptor. There are two stories about this. One story is that they did it for benevolent reasons to prevent these babies from getting HIV from an infected parent. The other story running in parallel was that this modification might have some impact on hippocampal or other brain circuit function that might make them hyper-intelligent in one dimension. So this was more of a eugenics experiment. And it was very interesting how this emerged. There was this short moment of about a week where it wasn't clear if this guy was going to win a Nobel Prize and be celebrated or was going to be put in prison.

Dr Beth Shapiro: Yeah, I remember this. It was Antonio Regalado who broke the story about a week before the big CRISPR conference.

Andrew Huberman: There were these emails that suddenly came out and it was very clear that people were kind of tap-dancing around this guy — like, what's going to happen to him? Do I want to be associated with this and glean some of the benefit, or is he going to be demonized, in which case I want nothing to do with him? And it turns out it was the latter. The Chinese government said they were going to shut down his lab and he was going to be punished.

Since then, there have been no fewer than four major companies launched for deep sequencing of embryos, both from IVF but also non-IVF babies. And I have people coming up to me saying, "Hey, guess what? We just got to screen these embryos and we were told which of them is going to have the highest IQ and which of them is going to be tallest." Some of these companies are geared towards ruling out disease. Others are geared towards trying to optimize for the best possible outcome. This gets people riled up because it's very expensive at this point, so that has other implications. And it's easy to say, "Oh well, that's like eugenics." But when people select who to have children with — assuming they do it voluntarily — they're selecting on the basis of a number of features: some physical, some emotional, some resource-related, some cognitive. So there's a lot of this happening in the animal kingdom, and in humans it's happening now at the level of genetic sequencing. And I think we're headed for big discussions about ethics about changing ecosystems through genetic selection of humans. It's started. It's happening.

Dr Beth Shapiro: There's a really fascinating story that comes partly out of the ancient human DNA literature and speaks directly to this idea. We feel uncomfortable with things initially because there's kind of this reptile brain thing going on — first we have to decide if we're scared of something before we can decide if we're curious about it. But we are doing genetic selection on humans by choosing our mates, and it makes us uncomfortable even to think about that.

Here is a relatively benign example to show that that's true, and it has to do with human height. Unlike IQ, which is very difficult to pin down — which bits of your genome mean IQ, and IQ is measured by what, and it's different in different cultures — height is relatively easy and we know that it's heritable. We know that there are bits in your DNA that can mean that you're tall or short. I'm five feet tall, so I didn't get any of the tall genes.

But we know now by looking at ancient human DNA that in Europe — where there are a lot of very tall people, particularly in Northern Europe — a lot of these genes were first introduced into Europe with the steppe people at about 4,700 years ago, the Yamnaya. And originally we thought that people were just getting taller because of environment — they were learning more about health, learning more about what they should eat. And yes, there is some truth to that. But height in Northern Europe has kind of plateaued now, and people have reached what seems to be the tallest you can be with this set of genes that exist in people today. But it is there. It's in Northern Europe. It's not in other parts of the world. And so there is human genetic selection for a trait that we can visibly see that makes people look different from each other. That isn't because somebody's picking an embryo and a sperm in a dish.

So we would be naive to imagine that genetic selection doesn't happen, that it hasn't happened throughout our evolutionary history, or that we can control it. But I think what offends us about it — this innate reptilian brain part of us — is that while we don't care that a Chihuahua and a boxer are engineered to have different traits because they have different roles in society — we created them, they were once grey wolves — we like to think of people as not having niches to fill, as having some freedom of choice, to be able to pick what they want to do and what they want to be. And this idea that one generation might do something to take that away from the next generation just sits really uncomfortably with us.

Andrew Huberman: We're really only just beginning to see this. You know the story of baby KJ, the first child who was cured of a genetic disease using the tools of synthetic biology?

Dr Beth Shapiro: This was a child that was born with a urea cycle deficiency. His blood was building up in ammonia. And because scientists had done a ton of research on this particular condition and really understood a lot of what was happening, they were able to identify the cause of this genetic disease. Then it was a collaboration between academia, industry, NIH, and the Children's Hospital of Philadelphia where he was born. This huge collaboration came together, took six months, designed a base editor — a CRISPR base editor — to target his particular cells, came up with a delivery mechanism to get it into his liver, did all of the testing needed to make sure that it's safe, and then gave him a bespoke CRISPR medicine as a six-month-old kid, three times. And he is cured of this disease and will live a normal life.

Andrew Huberman: Amazing. And no one accuses those doctors of playing God.

Dr Beth Shapiro: That's what's so funny. I mean, in Judaism there's actually the idea that you're supposed to take care of the natural world out there. So you're actually playing human in this case instead of playing God when you're using the tools available to you to make the world and the people around you better and healthier. When we took a grey wolf and decided we were going to let its puppies live in our campsite as hunter-gatherers 30,000 years ago, we were making a decision that impacted another species. As we took teosinte and turned it into corn. Every decision that we make about which populations of species to protect and which not to protect — to decide to allow corals to have this genetic modification so they can survive in the habitat that we changed, by introducing cane toads — these are all decisions we make that fall into that category of exerting human influence on the world. But the world today is a human world. And the species that live today and thrive today are those that have figured out how best to do that in the niches that we have created. And we need to just deal with that and get better at it. Use the tools at our disposal.

The Black-footed Ferret — Cloning, Genetic Rescue, and Plague

Andrew Huberman: Can I ask you about ferrets?

Dr Beth Shapiro: You can.

Andrew Huberman: A few years back, the black-footed ferrets were almost extinct. My understanding was that the prairie dog population got out of control when the numbers of black-footed ferrets were diminished, and as a consequence, the grasslands were being eaten up like crazy, which had all sorts of downstream negative consequences. So it was important to reestablish the black-footed ferrets, not just because they're cute. And my understanding is that it was one ferret — Scarface — who sired like 300 litters or more, and they were able to resuscitate or at least partially resuscitate the population. I'm curious which elements of that recollection are false, and also whether or not there's any concern about diversity given that it was one male siring all these litters. Mating of close relatives is bad for genomes — you get homozygosity, you get genes that are too similar, and if you have normally recessive alleles, you're likely to have two recessive alleles and you get bad mutations, deformities, sterilities.

Dr Beth Shapiro: The Channel Island foxes that you talked about earlier are a really fascinating example of a population that was so small for such a long time and lived in a pretty steady environment with no predators that they went through that bottleneck where all of those bad mutations were expressed and purged from the population. They have almost identical genomes — almost no genetic diversity — and they are perfectly healthy. Now, I don't know if something happened to that habitat whether they wouldn't be able to survive, because there's no diversity. If a disease came in, they would all be susceptible rather than some versus not.

Andrew Huberman: That's a very protected region. You can't just take a boat and stomp around those islands.

Dr Beth Shapiro: In general, inbreeding with close relatives is bad. Really bad. Certainly for humans, which is why in Iceland and Scandinavia there are these incredible genetic records dating back to when there were fewer opportunities to mate with foreigners.

The Black-footed Ferret Project is not something I was personally involved with. This is a project that's been a collaboration of US Fish and Wildlife, the San Diego Frozen Zoo, and Revive and Restore, which is a nonprofit conservation organization. I was on their board for a long time.

The story is interesting. The prairie dogs, which black-footed ferrets eat, were a real pain in the butt for farmers. So they set out all these ways of trying to kill a whole bunch of prairie dogs. And it killed a couple of prairie dogs, but it killed almost all of the black-footed ferrets instead. We ended up with a situation where black-footed ferrets were nearly extinct in the wild. People brought them into captivity, but they could not figure out how to get them to breed in captivity. Eventually the last captive animal died and then the last wild animal died, and they thought the species was extinct. It was actually on the first list of endangered species when the Endangered Species Act first passed.

But then, like a decade later, Shep — the family dog of a family that lived outside of Meeteetse, Wyoming — killed a black-footed ferret while it was out one night. The family took it to a taxidermist and were like, "We want this — what is this?" And the taxidermist called somebody and was like, "I think we have this extinct species here." It was proven that it was a black-footed ferret. So there was a population that had persisted around Meeteetse, Wyoming.

People started studying this population again and collected a whole bunch more individuals, brought them into captive breeding. It was a real international push to figure out how to make these animals breed in captivity. But then they noticed that the animals in the wild started to get sick, and in a last-ditch effort to save them, they went and collected every individual they could find in the wild. I believe one of them was Scarface, who eventually bred with everybody and ended up having a bunch of diversity. He had a scar on his little black-footed ferret face. They are so cute. I recommend everyone look them up.

So this is a successful captive breeding program and every year they can release about 500 black-footed ferrets into the wild. But there are two problems. One is what you mentioned — there's not that much genetic diversity. There were a handful of founders in this population, all from the same population near Meeteetse, Wyoming. So they're already closely related to each other, and over time the amount of diversity in that population is going to decline.

A few years ago, this collaboration of organizations got together and said: there's a solution to this. In the Frozen Zoo in San Diego, there are tissue samples from that original captive breeding population — unrelated to the individuals that were in Meeteetse, Wyoming. So different genetic diversity. If we could use cloning — the tools that we will use to make mammoth, that we used to make our direwolves, that most famously was used to make Dolly the sheep — we can take those skin cells and turn them into a living black-footed ferret.

Andrew Huberman: So revert them to stem cells?

Dr Beth Shapiro: Not in this case. You just take an egg that you've harvested from another one and you inject the cell into the egg, and the proteins in the egg itself can do that epigenetic reprogramming. It becomes a cell that starts to divide and become all the different types of cells that make up an animal. So in 2020, Elizabeth Ann was born — the first clone of 40-year-old tissues from an animal that had lived decades earlier. She was not reproductive, unfortunately. She was never able to have offspring.

Andrew Huberman: By behavior or there was some biological wiring issue?

Dr Beth Shapiro: There was some wiring issue. Her ovaries weren't releasing the eggs or something. But they did make another one from the same line, and that animal has reproduced and there were offspring from that that can be introduced. So here we have a solution to introducing genetic diversity into a population that had lost genetic diversity on the path to extinction.

But there's another problem, and that is that the thing that's actually killing the black-footed ferrets in the wild is plague.

Andrew Huberman: Bubonic plague?

Dr Beth Shapiro: Plague. Yes. Domestic ferrets are not susceptible to plague, and that susceptibility must have some genetic underpinning. So if we can figure out what that is — and there are several hypotheses that different teams are working on right now — we could use the tools of synthetic biology, genetic engineering, to edit the genome of these black-footed ferrets and make them resistant to plague. So not only use cloning — a form of genetic rescue — but then also synthetic biology to create animals that are able to survive in this habitat despite the fact that people have mucked with that habitat in a way that makes their survival hard.

We can use these same tools for lots of different things. We have a project related to our dodo project with the Mauritian pink pigeon.

Andrew Huberman: Is it actually pink?

Dr Beth Shapiro: It's pink. It's very pink.

Andrew Huberman: When you pick cool animals to work on — woolly mammoth, dodo bird, pink pigeon — you guys know how to get attention. And the direwolf thing — my understanding is that it was also on the heels of the Game of Thrones popularity, so that was a piece of it. If you weren't going to make a dragon, you might as well make a very large wolf because it has these connotations.

Dr Beth Shapiro: When I was working on the first direwolf genomes — way before I was involved with Colossal, but the very first time we published direwolf DNA — we were desperate to sync the publication with Game of Thrones coming out. We were like, "We can get this genome done. Surely they'll want our paper because then they can have some press attention to the direwolf paper." We never got the DNA finished in time to do that. It was so poorly preserved. They lived in warmer parts of the world, so it was really hard to find samples that had high-quality DNA. It was a fun project though.

Andrew Huberman: Were the babies cute?

Dr Beth Shapiro: Yes.

Andrew Huberman: They didn't come out ferocious?

Dr Beth Shapiro: No. Extremely adorable.

Andrew Huberman: Well, that's how we got dogs. I'm pretty sure they were hanging around outside cleaning up after us, giving us a little bit of advantage because if something scary came like a giant cave bear, they would howl and our ancestors would know. But I'm pretty sure that was just commensal. We could have lived for a long time with them living around us and us living around them. But I think their puppies were cute.

Dr Beth Shapiro: You make a really good point. This notion of the eyes getting rounder in dog breeds because people like them — all the doodle breeds, the hypoallergenic breeds. We're so comfortable as humans to modify species for our immediate convenience, but sometimes that's obviously detrimental to entire populations.

Andrew Huberman: I would like to think that with AI or other modeling tools you could make predictions — not perfect, but better predictions — about, okay, let's model the mosquito population, where the swamps are, what the seasons are like, what the quoll population looks like. There's no graduate student or professor, no matter how brilliant, that can mathematically model all the different influences of all these different plant and animal species. But AI can run it 24 hours a day, 7 days a week.

Dr Beth Shapiro: This idea of digital twins — can we create a digital twin of an ecosystem and then perturb it in lots of different ways and see what happens? I think this is totally within the realm of feasibility. It's a big foundational model, but I know there are groups of people working on this for smaller systems — like individuals — to think about human medicine: what happens in this particular organ system if you perturb it in this way, and using AI to narrow down the window of what edits might be reasonable to make.

We have a completely independent group of people that make what we're calling our CARE reports — deep dives into the ecosystems where we would be releasing any future de-extinct animal. We release these when we have them. With the bluebuck, we have a bluebuck CARE report that people can read to figure out what we've thought about in terms of the impact to the ecosystem over short, medium, and long term. It involves conversations with local stakeholders and conservation biologists and people thinking about it from all sorts of different perspectives. So it's absolutely critically important to think hard before doing things, but also to be willing eventually — after you understand as best you can what that risk is — to act.

Andrew Huberman: Along those lines, I predict that in probably 3 to 5 years, not 10, the technology of mutating the HIV receptor — that sort of thing — will be very commonplace in the context of fertility. If we knew a certain constellation of disease genes inevitably led to a disease or a high probability of disease, and there was a way to use gene editing to rule those out once that had been established a number of times, I'm willing to bet even outside the Bay Area that people would want that. Nobody wants a harder life for their child.

Dr Beth Shapiro: It could also come — I've thought about this. My last book is called Life as We Made It, and it's all about how we've been messing with the species that we encounter for as long as we exist. In the last chapter, I think about how we might turn our editing technology on ourselves, really asking the question: what is it that will push us over that edge? One of the possible scenarios is that we have a pandemic, a crisis, and we learn that there are certain people who have a particular genetic variant that means that they will die. And suddenly the most morally reprehensible thing that we could imagine doing becomes the actual only ethical solution. And that is the thing that pushes us over the edge.

Andrew Huberman: And now we're talking more about public perception, scientists, and implementation, and where those intersect. I think that a lot of it is about the delivery method. When we hear about gene editing and you're taking a cell and putting it in a dish — or even ICSI, where you're basically injecting a sperm cell into an egg as opposed to running a sperm race — people are a little more comfortable with that than they are with ICSI. It's like: this one we're taking because you're biasing an outcome in a strong way. You're not letting the system decide. But people are okay with this if, for example, you have a man with a very low sperm count or very few healthy sperm, where you can take a healthy sperm and put it in the egg.

Dr Beth Shapiro: I think people are comfortable with it now because it's been around for a while. Every new technology — you have your first reaction of "is it scary?" before you can be curious. I mean, in a different but relevant conversation: the GLP drugs have destigmatized needle phobia by putting it on a pen. And so now people are like, "Which peptide should I take?" It turns out it was the hypodermic part, not the needle, that freaked people out. The needle kind of freaks people out, but people have no problem taking a pen and going. Now needle phobia has plummeted and people are willing to explore things that some of which there's good data on and some of which there's like no data. It turns out there was this other thing getting in the way. It wasn't really the thing about taking the peptide — it really was the delivery method.

Andrew Huberman: We saw this with computers. They were big clunky things. Then all of a sudden you turn it into a phone that's also a camera and the next thing you know, you kind of forget that it's a computer. Same thing with brain-machine interface. As long as people think you need to drill into the skull or put a wire behind the ear, there's resistance. Pretty soon this will be non-invasive, and then people aren't thinking, "Oh, it's going to control my brain." So the big fear wall tends to come down through these things that are hard to predict. And it's often a combination of the messaging and — maybe everyone should pet a direwolf just once.

Dr Beth Shapiro: You should come visit us in the lab and you'll see some of the really cool stuff we're doing. The artificial wombs, our really cool artificial eggs.

Andrew Huberman: You have artificial wombs?

Dr Beth Shapiro: We have one of —

Andrew Huberman: I realize this is going to terrify people. I'm a biologist, but — okay, describe to me an artificial womb and what that looks like.

Dr Beth Shapiro: Right now, we're thinking about mice. The idea is: if we're going to have hundreds of mammoths, we're not going to get there by having a hundred Asian elephants pregnant for 22 months with mammoths. We need a way to be able to birth multiple mammoths simultaneously without using elephants. Elephants should be allowed to make elephants.

So we'll need to build the technology to do this. But building that technology is also an opportunity to build technology that can really help people. I have a friend who was diagnosed with breast cancer during her pregnancy and she had to make a decision about not starting the therapy until she gave birth, or taking a giant risk with the baby. What if we could just take the baby out and be able to put it in a place and have it completely develop, and then she could start the treatment a couple of months earlier? Or if a baby needs surgery but you can't really do it inside — have a safe way to have that baby come out. These are all technologies that will be feasible in the future that are motivated by de-extinction. How crazy is that?

Andrew Huberman: It is wild. One of the most incredible things that I've witnessed is a NICU. It's a different form of what you're describing, but it's incredible. You go in these places and it's room upon room, super quiet, they try and keep it dark. These are artificial wombs so to speak, right? These are preemie babies, some of which are very preemie. The NICU technology has come a long way. That's essentially what you're talking about, right?

Dr Beth Shapiro: Yes — a more sophisticated NICU where we've learned so much more because of the complementarity of understanding how genes map to phenotypes and being able to use all of the genetic resources available to us from all of the people, and learning about epigenetics, and building this technology that builds on what we understand about the developmental process. We are facing a future that I think is really exciting and spectacular, maybe a little bit scary, but I think as long as we keep talking about it and having conversations about it way before it's possible, we can get to a place that people are comfortable with and excited about.

Origin Story, Public Education, and the Mission of Colossal

Andrew Huberman: There seems to be a theme lately in my life where people come on this podcast and they're talking about revolutionizing education. We had the principal of Alpha School on here — kids spend two hours a day on their iPad learning from an AI tutor that knows exactly what they need to fill every gap in their knowledge. The public reaction is very divided. People say "great," and then other people say, "Oh yeah, but it costs a lot so it's only for rich kids." And it turns out they're starting scholarship programs. But the idea is to figure out the best way to educate humans and then wick it out to everybody. There has to be this pioneering spirit, and that's always going to stimulate concern.

I think about your work in a different but similar vein, where being a pioneer is hard because you have to tolerate people saying — and sometimes the assumption is — "Oh, you're doing this just for your own self-interest. It's all financially driven. What about the starlings that need our help right now?" There's always this "what about the things that need our help right now?" I think public education is clearly a big part of it. And I think humanizing it at the level of who's doing it — it's very clear that you love biology, you like hard problems in biology, and it seems like you rather enjoy the fantasy positive outcome part of it. It's not all doom and gloom. This example works for me: Elon wants to go to Mars, and I have guests on the podcast that say, "No, he should be curing humanity here." And I told that person that's like telling Metallica they should be the Grateful Dead. We need individuals who are thinking in a different way, steeped in really good ethics, and are excited about the problem to evolve this thing that we call life on Earth.

Dr Beth Shapiro: I'm good with that. If people say to me, "Oh, why are you working on this? You should be curing cancer" — those are two different things. Although we are learning things from elephants that are actually relevant to curing cancer, but that's not our main focus. But people who say "you should do this instead of saving living species" — I really have to push back on that. We are doing both. There is not enough money in conservation. There just isn't. The idea that we're developing tools that are immediately applicable to existing conservation problems, using new funding, new resources, bringing in new investment, excitement, enthusiasm from students — why is this not embraced? Why is it always "well, you must not be doing that"?

We are doing that. When we announced the direwolves, we announced that we had cloned red wolves — the most endangered species of wolf in North America, an endemic wolf living in a very small population, captive breeding in the Carolinas. We had colleagues — Bridgett vonHoldt, who's at Princeton — who had discovered a population of coyote-like animals that have a bunch of red wolf ancestry, some on the order of more than 75% red wolf ancestry. And so we've cloned these wolves as a means to introduce new red wolf genetic diversity into the existing red wolf population, using the same toolkit that we used to clone and generate our direwolves.

Andrew Huberman: They were announced at the same time though. So all these people who are like "you should be doing this instead of this" — pay attention. You are.

Dr Beth Shapiro: There's something that I think people need to understand about scientists — and probably technologists too — which is that the person matters. The person doing the work has to be really, really drawn to, almost obsessed with, the project. There are a lot of scientists working on kind of pedestrian stuff. But then there are certain scientists who really want to be out on that cutting edge, and they have to be obsessed with the question, otherwise you get nothing. In the same way that Elon is pretty obsessed with going to Mars. You can't really draw him off target by saying, "Hey, why aren't you working on curing cancer?" We have to accept this about people and the people who move things forward. You can't convince people, "Oh, you should be saving the coral reefs." Someone else should be saving the coral reefs, but they need to be obsessed with coral reefs.

Andrew Huberman: People shouldn't feel bad about not being able to do everything. If you think about the amount of time that you have in your life, if you try to do 10 things instead of one thing, you're going to get way less done. You're not going to make an impact.

So where are the public education efforts outside of podcasting? How many people are at Colossal?

Dr Beth Shapiro: There are about 120 scientists, and then there's other people involved. We have a huge social media team who put a lot of science content out for the world, targeting different audiences with different types of information. We work with a lot of podcasters and with other teams of people making documentaries and films. We publish papers using the traditional peer review process. We post some papers on the archive if we think it's important to get the information out faster before peer review. And of course I go out and talk to people — I'm a National Geographic Explorer, so I take part in the National Geographic Live series. I've gone and just talked to communities about conservation and genetic rescue and de-extinction and a future that can be both biodiverse and filled with people.

Andrew Huberman: In junior high, high school, graduate school — were you sitting there thinking, "I'm in a department of zoology at Oxford University, and this whole thing feels kind of steeped in old stuff and I want to break it open"? Or were you thinking, "Wow, that's Darwin's house"? What were you like as a kid and in graduate school?

Dr Beth Shapiro: My origin story. I think I always disappoint people with my science origin story. I went to the University of Georgia as a broadcast journalism major. I had worked for the local TV station in the corner of Northwest Georgia where I grew up. I was on air in the mornings. I did local cut-ins on Headline News at 24 and 54 after the hour. When I went to the University of Georgia, I was actually the news director of a local radio station, which was not particularly well aligned with being a freshman. I had to be at work at 4:00 in the morning to write and cut the news so I could be on the drive-time show.

I had an opportunity to take a class after my freshman year. It was an honors program class — geology and archaeology. It was a nine-week class and we started off on the east coast and learned about minerals, identifying minerals and the coastal dynamics. We drove across the country, sleeping in national parks, drove up the west coast, drove back across the country, and learned about the formation of the national parks, the landscape that is the US. And I thought to myself as I was watching this — you could see the scars on the landscape from glaciers, and we went to all of these archaeological and anthropological sites and saw the impact of people on the ecosystem and the impact that we had on those people. And I thought: this is the kind of story that I want to tell. Maybe I want to be a science journalist instead of just a regular journalist.

I started taking science classes. I ended up going to Panama, living on a place called Barro Colorado Island, and studying parasitoid wasps — not doing anything related to genetics or really evolution, just ecology, population ecology. And I met somebody there who was starting up a lab in Edinburgh. I thought he was really smart and interesting. We put together a proposal of a project I could do as a PhD student where we were going to study the type of wasp that switches back and forth between inbreeding and outbreeding. The question was: is the switch to inbreeding something that is intended to purge your genome of those deleterious alleles — like the Channel Island foxes — so that if we inbreed, we'll get rid of all that bad stuff that's accumulated, and then we can go back to outbreeding?

Andrew Huberman: It's a pressure test.

Dr Beth Shapiro: Yeah. So we designed this experiment. I went back to the University of Georgia and said I'm going to go to Edinburgh. They said, cool, but you have to apply for all of the scholarships that we have for our honors program people together because it's just one big package. So I applied for the Marshall scholarship to go to Edinburgh, and I did not get a first-round interview for the Marshall. So I ended up not being able to go to Edinburgh, but I got a Rhodes scholarship. So I ended up at Oxford.

Andrew Huberman: So you are a true — I think you're our first Rhodes scholar.

Dr Beth Shapiro: I ended up at Oxford. I had no idea what I wanted to do or who I was going to work with. And I met on my first few days there this guy called Alan Cooper, who was a Kiwi. He was setting up an ancient DNA lab. This was one of the few labs at the time that was going to be built to be able to process these old samples. And I was really excited about the idea of ancient DNA because it brought together geology and paleontology and storytelling. If I'm reading DNA sequences from entire ecosystems that used to be alive, I can tell a story about how the environment changed when people first arrived, or how the environment changed with rapid warming out of the last ice age. And I was like, "This is the science I want to do." Plus, it was brand new. Nobody was doing it. There were a couple of dinosaur DNA papers that had been published and proven to be false. And it was really an opportunity to bring stuff together that hadn't been done before and just do something entirely new. And he told me that if I joined his lab I could go to Siberia, and that was enough for me. I signed on the line.

I got into de-extinction because everyone who works in ancient DNA is asked, as the first question whenever they publish a paper, whenever they get interviewed by somebody from the media: "So, what does this mean about how close we are to bringing dinosaurs back to life?" Every time.

Andrew Huberman: I'm more concerned about the black-footed ferrets, frankly.

Dr Beth Shapiro: When I was researching my second book, I was using the New York Times Wayback Machine, which is amazing. And I was reading the very first article about the very first ancient DNA publication in 1984. Researchers from Berkeley in what was called the Extinct Species Study Group had managed to isolate — using molecular cloning, because this was pre-PCR days — a tiny little fragment of DNA from the skin of a preserved quagga, which is an extinct type of zebra, and show that it was related to a zebra. So the scientific finding was not that illuminating, but the fact that DNA survived after death — this was the first discovery of that. So it was a big deal. It really set off all of the stuff that became the dinosaur DNA days of ancient DNA. And all of the forensic stuff came out of this too.

But when the journalist interviewed Allan Wilson as the very first ancient DNA researcher, publishing the very first ancient DNA paper, he got to be the first person to ask the dinosaur question.

Andrew Huberman: The dinosaur question. Yes.

Dr Beth Shapiro: I mean, it is true that if you walk into the life sciences building at Berkeley, there's a full-size T-Rex skeleton there. It's very cool. People love the dinosaurs. I've never been dinosaur-obsessed. I can think of many more animals and human diseases that to me are more interesting. But this is like the "why don't you cure cancer" thing.

Andrew Huberman: Well, I think we get to mammoth because as soon as people hear that we can't have dinosaurs because there's no dinosaur DNA, they tend to settle on mammoth. Either mammoth or saber-tooth cat. Those are the two things that we get after that. But I think it's just because they're big. We know they're extinct because our ancestors hunted them. We know they're relatively recent. We can imagine what they looked like. They're in popular culture. And so it's a matter of awe, of interest.

Dr Beth Shapiro: People don't like to feel small, but mammoths make us feel small too — in a way that we can appreciate.

Andrew Huberman: There's something about the psychology around this in terms of public perception. And the dinosaur thing — I'm going to go with that people want the best for our species and other species on average. They're a little scared, for reasons that make perfect sense to me based on what they know and what they don't know. For that reason and many other reasons, I'm just grateful that you'd come out here and talk about this stuff today and that you're doing what you do. I thought the direwolf thing was super cool. I still do. And as I started learning more about what you're trying to accomplish — repair ecosystems, make better ecosystems — I'm all for progress. So thank you for doing what you do, for continuing to do what you do. You walked away from a fully thriving lab in academia, Howard Hughes Investigator — which is this thing that very few attain — to do this. So clearly you're on a mission, and I have every anticipation that it's going to work out and work out for the best for animals and for people. I'm excited to see what you guys do.

Dr Beth Shapiro: Thank you for the opportunity to have this conversation.

Andrew Huberman: Yeah, it's a lot of fun for me. I rarely get to talk about ferrets, woolly mammoths, dinosaurs, and human gene editing all in one conversation. Thanks so much.

Dr Beth Shapiro: Thank you. Appreciate you.