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, an evolutionary biologist and Chief Scientific Officer at Colossal Biosciences, about the science and ethics of de-extinction. Dr. Shapiro explains that Colossal has already produced living direwolves — grey wolves with 20 targeted genomic edits derived from fossil direwolf DNA — and is actively working on the woolly mammoth, dodo bird, and thylacine (Tasmanian tiger). She argues that de-extinction and conservation are not competing priorities but use identical tools and technologies, with high-profile species like the mammoth generating the investment and enthusiasm needed to develop synthetic biology tools that can also prevent living species from going extinct.
The conversation extends into human genomics, covering Neanderthal DNA in modern humans, embryo selection, CRISPR-based medicine, and the first child cured of a genetic disease using a bespoke base editor. Dr. Shapiro also addresses the regulatory, ethical, and ecological frameworks Colossal uses, including advisory panels with local stakeholders, care reports for each target ecosystem, and staged release protocols.
Key Takeaways
FULL TRANSCRIPT
Species Concepts, Taxonomy, and What Makes a Species
Andrew Huberman: Welcome to the Huberman Lab podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr Beth Shapiro. Dr Beth Shapiro is an evolutionary biologist. She was a professor at UC Santa Cruz and an investigator with the Howard Hughes Medical Institute before leaving to become Chief Scientific Officer at Colossal Biosciences. Her work at Colossal is focused on what is called de-extincting species such as the woolly mammoth, the dodo bird, and the direwolf — meaning bringing them back to life. But that entire initiative is also about species preservation more broadly and how genomics can be used to improve the global ecosystem. In this episode, we discuss what it means to use ancient DNA to bring back extinct species, which then led us to a broader discussion about genetic engineering in human health — both of which, by the way, are happening right now. So this is not just a projection into what's coming in the future. As you'll see, Dr Beth Shapiro is truly a one-of-a-kind thinker. Today you'll learn the science, the ethical implications, and the positive potential of using genetics to de-extinct species and using genetic selection and genetic tools to change humans. And no, Dr Beth Shapiro is not planning to bring back dinosaurs. Today you'll learn why.
Dr Beth Shapiro, welcome.
Dr Beth Shapiro: Thank you.
Andrew Huberman: Longtime fan of your work.
Dr Beth Shapiro: Same.
Andrew Huberman: Love animals. Love stories about animals that aren't around anymore. I've heard that you're going to bring back the woolly mammoths, 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 and so on. 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? And like — is my dog, a bulldog mutt, as different from a Chihuahua as they really seem? 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 we have Linnaeus who 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 unfortunate reasons, or fun reasons, or whatever — but a lot of time working on bison. And 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 for the first time animals they'd never seen, 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 Llama 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: 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: Fair point.
Andrew Huberman: Mine 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.
Dr Beth Shapiro: Yeah, right. A guest on this podcast said that — an animal expert from the Karolinska.
Andrew Huberman: That makes so much sense.
Dr Beth Shapiro: She said in Scandinavia it's actually — she claims, and I believe her — that it's illegal to neuter a male dog unless there's a health reason.
Andrew Huberman: In Scandinavia and 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, we don't want to digress too much. But my dog doesn't try to mate — I didn't see my previous dog try to mate with cats or even Chihuahuas.
Do you think Neanderthals and humans are a different species?
Dr Beth Shapiro: I don't know. But I want to know if we are all the same species. This is an edgy topic, right? But 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. 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 — and we can maybe get him on here separately — but feel free to steal his thunder in any way that 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 — if we start there with what's going on with Neanderthals — is we now know, based on studying DNA both from Neanderthals that used to be alive and a different lineage of human called Denisovan. We call it this because it was first isolated, again by Svante Pääbo's research group, from a tiny little finger bone that they found in a cave — Denisova Cave in Russia. That's why they're called Denisovans. 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 our ancestors — Homo sapiens, anatomically modern humans, everything you want to call them — 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 this point. So again, species concepts are just what we make of them. And today most people have somewhere between 2 and 5% of their DNA that is 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, Ancient DNA, and Human Evolution
Andrew Huberman: Many questions about this. First of all — and try not to laugh — the silhouette diagram that we've seen of apes gradually in time sequence working their way to bipedal and upright. When we see that diagram, is that substantiated by the fossil record?
Dr Beth Shapiro: It is. Yes. We know that the lineage that eventually became us evolved in Africa. We can trace ancestry back to primates and then to apes 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 bone and it's 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. And 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 I can get DNA from that, 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 that bone is 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 that are 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: Do you think Neanderthals and humans are a different species?
Dr Beth Shapiro: I don't know. But what's interesting is that we now know, based on studying DNA from Neanderthals and Denisovans, that there were multiple different lineages of human-like people alive at the same time, and they interbred. So if they were a different species, they were violating the biological species concept. Species concepts are just what we make of them.
Andrew Huberman: Humans and Neanderthals diverged somewhere 300 to 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.
Dr Beth Shapiro: I know — they're terrible names, right? You want a different name for this.
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 were able to go back. 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 that bear's ancestors at some point 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. And 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 because of that interbreeding roughly 20,000 years ago.
Andrew Huberman: Wow.
Dr Beth Shapiro: Yeah. So in that case, half a million years had gone by, they're really adapted to different habitats, and yet they can interbreed. But what's most interesting, and I think is relevant to your question, is that those hybrid bears only ever live and survive as brown bears. We see no evidence of brown bear DNA getting into polar bears. And it's especially interesting because 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, so 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. So why is it that since bears live with their moms, all the brown bears 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. So it is just adaptation that means that admixture doesn't work. Even though there's no problem with the sperm and egg mixing and the animal is born, they cannot survive as polar bears, and so polar bear stays separate from brown bear in that way.
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 not get shaken off by the bull very easily. The floppy face is associated with lack of pain receptors. There's 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, of course, the females can't give birth because the birth canal just doesn't allow for it.
Dr Beth Shapiro: Right.
Andrew Huberman: Humans realized this pretty quickly and they learned cesarean section. So I could imagine a situation — although I don't tend to think like this today — 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. And 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. And not much smaller in most cases.
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 cesarean 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 cesarean birth.
Andrew Huberman: So I like to think you would have survived anyway. But 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 now humans, maybe it's been bred out, but there were humans walking around who are not completely Homo sapiens. Or is it not possible? I don't know what's known about hip size or anything like this. But it is true that humans and our archaic cousins Neanderthals interbred and that people walking around today have Neanderthal DNA.
Dr Beth Shapiro: Two to 5% you said.
Andrew Huberman: Two to 5%. What's interesting about that — and it touches a little 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 for people — that pretty much all of it could get passed on and live in healthy humans today.
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. And a lot of change happens in 3 to 5 million years in your DNA. Some of it is useful, some of it is what makes us human, and most of it is just not — it's just changed because of copying errors during cell division. That's how we're different. Every child that's born has about a hundred differences compared to their parents because of copying errors in the process of making the sperm and making the eggs. So 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. I found that interesting. Is there any evidence that the Neanderthal genes are quote-unquote vigor genes — that they allow for more durability in human males or females?
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 anything that is 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. And this has been a really interesting thing to learn when you think about Neanderthal DNA. There are a couple of things that have come out. There are genes that are 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 makes people feel more or less pain. I remember there was a trial of people in Colombia where they got to feel pain in some way and there's a Neanderthal gene associated with this. But most of the really interesting ones have been immune-related genes. During the pandemic, one of the first alleles that was discovered to be associated with bad outcomes of COVID was a gene that came from Neanderthals. It was a Neanderthal-derived gene that was at something like 50% frequency — way above the 3% average frequency — in Asian populations, and it made people more susceptible to the virus entering your lungs. Presumably it only became that high frequency because it was protective against some other disease that was circulating in the past, but the trade-off was that it made people more susceptible to COVID. There was another Neanderthal-associated allele that was actually protective against COVID. So I think 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 and see how their immune systems and genes have responded to exposure to things like this. It's really fascinating.
Andrew Huberman: My red-headed friends like to claim that they have more Neanderthal and therefore more vigor and pain resistance. So I'm guessing the study probably said more pain resistance. We have pain experts on here that verify that red heads tend to require more anesthesia on average. So that tracks. But were Neanderthals — were a lot of them gingers?
Dr Beth Shapiro: Yes. This comes from studying MC1R, a gene that's 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 just 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 on Earth had a lot more green-eyed people?
Dr Beth Shapiro: I think 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, and so people want a mate that has blue eyes. I really think eye color was sexual selection.
Andrew Huberman: Probably. 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
Dr Beth Shapiro: Geneticists are so much fun because they're willing to just go there.
Andrew Huberman: I was going to ask you this question later, but I'll ask now because it relates to what we're on to. We tend to think of our lives in the time bin of our lives — roughly 100 years if we're lucky. But 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 always curious about this. How do you pick the problems that you choose to work on? We'll talk about de-extinction, but why the woolly mammoth? Why not get the Florida panthers rebooted completely? Maybe why not both, right? But in terms of where to focus — like why bring back things from way back when as opposed to maybe 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: That's a very complicated set of questions. I think I'll start with what is motivating, and I think what's motivating is what drives the selection of the species. It's funny — 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. What are you going to do? How are you going to choose a species to bring back? And 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. It's hard to know how old it is in that time range because there's not a really clean way of dating something within that range, but it's old. Dinosaurs went extinct more than 66 million years ago. So that's far outside of where we're going to get recoverable DNA. That's because the skeletons are fossilized — they've turned into rock. 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 through three processes. UV light — we know about this, it's why we wear sunscreen when we go outside. UV light hits your DNA and it actually breaks it. When we're alive, we have proofreading enzymes that will 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 on the shelf 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 they stay that way for a million years, like this mammoth bone that we were able to recover DNA from. But if you die in a very hot, wet, swampy place like Mauritius, where the dodo lived — another one of the species that we're working on at Colossal — there's very little chance you're going to be able to recover DNA from any of the fragments on Mauritius Island. I have tried with 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. But one is good enough to get some sort of template for what you're going to do. 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.
Andrew Huberman: Or bring back something really nasty that knocks out a bunch of other species.
Dr Beth Shapiro: Yeah, 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. And 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 that 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 always throwing at our natural ecosystems.
Andrew Huberman: Could you give me an example of that? If you were to bring back woolly mammoths, I'm guessing that's not going to save the Amazon forest. But what probably is going to do something useful?
Dr Beth Shapiro: Yeah. So if you think about what large animals, large herbivores, do in their ecosystem — they turn the soil by walking around, they knock down things. Elephants knock down trees. Mammoths probably lived places above the tree line, so that wasn't what they were doing, but they were distributing 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 have 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 that they've brought in from Canada, and wild horses, and several species of deer and muskox. And they've seen that having the animals on the landscape that 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 of the surface of the dirt. In the absence of these animals, the snow stays on the surface, and snow is a very efficient insulator. So 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 there are some parts that are moist and wet, and other parts that have been exposed and are dry and colder, and you get broader diversity of plants coming back where these animals are. So they are essentially recreating their ecosystem just by being there.
The Dodo, Bird Reproductive Biology, and Condor Parthenogenesis
Andrew Huberman: Okay, so you're picking — you don't have to pick a species, but you've got to pick something if you know two or three, right? I can't say we're going to bring back everything from a given era. So we 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 a bird de-extinction program, because all of the tools that we are developing for de-extinction are the same tools that we can use to use synthetic biology to modify the genomes of living species and help them avoid becoming extinct. The kit that we're building — from multiplex genome engineering to cellular rejuvenation to iPSC cell technologies for wild animals to even learning the link between particular letters of the DNA sequence and what those letters actually do to cause an animal to look the way that it does — all of that is applicable across the board. So the stack that 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. And so I wanted a program that was going to help us develop technologies for birds.
So why did we pick the dodo compared to any other bird for the first one? 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 also 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. There are skeletons that we can piece together using the many bones in Mauritius that do not have any DNA in them based on my very best tries.
Andrew Huberman: You didn't choose to bring back like a 75-foot-long python. Thank goodness.
Dr Beth Shapiro: There might be virtue in doing that. Although I think there are plenty of pythons in the Florida Everglades right now.
Andrew Huberman: I'm not a snake fan. No disrespect to the snake lovers. But talk about bird developmental genetics for a second. A few years ago, I saw something about two female condors being able to reproduce.
Dr Beth Shapiro: It actually wasn't two female condors reproducing. It was one female condor just having an egg all on her own.
Andrew Huberman: Yeah. 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." That was the reaction. But 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. So the separating of the cells 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? Yes. I mean, it's very cool, and very clear the way you described it how that could happen, because you need the two sets of chromosomes. So both sets came from mom in this case and only mom. 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 all the genes that everyone healthy walking around has — you and me — have genes that only came from our mom and only from dad. And 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 some things. And you also 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 — those 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 till 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? I'm not talking about the actual act of sex. I'm talking about whether somehow sperm and egg met, or whether there was something more like the condor you were just describing, where the females were able to reproduce through these unusual meiotic events.
Dr Beth Shapiro: Sex has evolved a bunch of different times on the tree of life, and different ways of doing sex have evolved. So we have this XY process where the males are what we call the heterogametic sex — the males have an X and a Y and the females have two X's and they don't have a Y. But birds do it differently. They have the WZ system, and it's the females that have the two different chromosomes, the males that don't. 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: Yeah, there are communities online that actually believe this kind of stuff for humans. There are 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? Unless you use 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. Can you actually determine the XX or XY of the sperm?
Dr Beth Shapiro: They can do that now. You can select. It's because the Y chromosome is teeny tiny compared to the X, and 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 how things of different weights spin out to different depths, you can bias the likelihood that you'll get a Y-carrying sperm or an X-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.
Mammoth Genomics and the De-extinction Process
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. Let's use the woolly mammoth — it's a fun one. Birds are complicated. As a developmental neurobiologist in my past, the bird stuff gets tricky.
Dr Beth Shapiro: Birds are really tricky. Some birds are trickier than others. 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.
Andrew Huberman: Germline — the sperm and eggs.
Dr Beth Shapiro: Sperm and eggs. And this chromosome 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 mini microchromosomes 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. So with the woolly mammoth — it was a mammal.
Andrew Huberman: Yes. Right. Okay. And you know that because — I mean, people can say "well, duh" because people normally think, oh, it has fur, must be a mammal, 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. And we can assemble those genome sequences using a computer and then compare them to other animals that are alive today. And 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.
Andrew Huberman: Okay. So if you get the sequence of DNA from a mammoth, you know this is the complete genome. And I think a lot of people probably don't realize that your complete genome is represented in most all of your cells. There are rare exceptions. 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 and so on.
Dr Beth Shapiro: That's the epigenome.
Andrew Huberman: Right. But the menu is there.
Dr Beth Shapiro: The menu is there.
Andrew Huberman: Are you growing up DNA in a laboratory that is the mammoth sequence?
Dr Beth Shapiro: So this is what comes, I think, 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 Jurassic Park or they've thought about this movie. What happened in Jurassic Park — and I should just say it was not a documentary, so let's not get carried away — what happened was scientists found mosquitoes preserved in amber, stuck a needle into those mosquitoes, sucked out a bit of stuff that happened to be blood and had dinosaur DNA, and then they had 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. So 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 in terms of percentage similarity of DNA?
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.
Andrew Huberman: Yeah. I mean, there's some statistic online that we're 85% the same as a banana or something like that. A lot of our DNA is — I don't know if that's true. 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. And this gets back to the idea that you brought up in the beginning about a species concept. This is one of the most common things that we hear. If you are going by a strictly genetic species concept — where you're saying that a species 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. The genetic species concept is an idea that was proposed to classify organisms that evolve over a very long evolutionary, bifurcating phylogenetic tree process, where accumulation of changes is over many generations over a long time. 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.
I'm going to just push back a little bit on this, because what I don't want is for this sort of definitional gatekeeping to really take over and become the whole story. It's important, it's a question, but it's a narrow one. And I think it crowds out the real discussion about what it is that we're doing, how the technologies that we're developing can be applied to ecosystem health to help stop species from becoming extinct, 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. And thinking that those places — like we were talking about with humans — are the places that are important to make a mammoth a mammoth. And that is where I'm going to focus my energy in bringing back a mammoth, which will be an elephant that is capable of living in the habitats that a mammoth lived in. Mammoths will have to live in habitats that exist today and tomorrow. So the mammoths will have to be genetically capable of living with the pathogens and the microbes and the food sources and the microbiome that the elephants that will birth them can survive in today.
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 I want to be very clear — I'm not arguing for species gatekeeping here. That's not what I do. I own a mutt after all. It's 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, right?
Andrew Huberman: I think like all things media and Hollywood, 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.
Dr Beth Shapiro: 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."
Andrew Huberman: You're a scientist and I am too. My dad's a theoretical physicist. He was involved in chaos theory. He's been a guest on the podcast. I remember when Jurassic Park came out, he didn't dislike it, but the part where he kind of rolled his eyes was the description of chaos theory in there and what it means. In Hollywood, they love to use the example of like a butterfly flaps its wings in Patagonia and then this thing happens to the barista in Brooklyn. People like to bridge those concepts and they think, "Oh, that's so cool." It's sticky, as we say. But he was rolling his eyes. He's like, "Okay, that's not how these things work." For people that are experts in the area, it can be a little grating at times. But the public, I think, is open. In my experience, if they just have the knowledge in hand, the way you described it, great.
The Direwolves: Romulus, Remus, and Khaleesi
Dr Beth Shapiro: So our direwolves — they have 20 edits that we picked, and we sequenced genomes from fossil direwolves. We learned from those genomes what genetic changes made those animals bigger, more robust, 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. It wasn't like, oh, we're going to take a couple of genes from the direwolf and throw them into this other wolf and create what we call the direwolf. If I were to look at the direwolf and a grey wolf side by side, is the direwolf larger?
Dr Beth Shapiro: They are. On average at the same age, they are 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, with some fidelity, bring back these extinct traits so that the animals can eventually be released. Now, we're not planning on rewilding direwolves — we will study the animals and learn about the effect of their genes on their lifespan. But for the other animals, the ultimate goal is to eventually have populations of free-living animals as they would like to. And so we want to understand how healthy they are, how they're going to interact with the habitat that's there. And we want to make sure that because we with synthetic biology have the power to engineer them in a very deliberate way, 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 — the same 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 that we saw in direwolves, but close enough to where we would need to do the edits — can lead to oculocutaneous albinism. So blindness or deafness in these dogs. And we decided that because we're not changing the whole genome — they have to be safe on a grey wolf genetic background — we wouldn't make the trait that way. It just wasn't passing the bar of animal welfare safety. And so instead, we brought back the 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. So we used the edits that we know are safe because they exist in living dogs.
Andrew Huberman: Oh, that's cool.
Dr Beth Shapiro: 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 in some location?
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 bit on the specially goofy side, but she's the best. She's adorable.
Andrew Huberman: Do you feel safe interacting with them?
Dr Beth Shapiro: Oh, no. We have interacted with them, but the people who work with them a lot — that they know — feel safe interacting with them. But as they got older, it was very clear that they're wild animals. These are not domestic dogs. Remus is a little bit less skittish than Romulus. He will eventually, if you sit in the middle of where they are, 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 like 120 lbs, which is big for a grey wolf.
Andrew Huberman: Yeah. 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. Some can be skittish, some can be calm.
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: Except for Chihuahua. They're just terrible. I'm just kidding. No, it's okay. We had Cesar Millan on the podcast. He'll be the first to say that in almost every decade in the United States, there was the demonized dog breed. It was actually German Shepherds post-World War II.
Dr Beth Shapiro: Then it was Dobermans.
Andrew Huberman: Same reason. Then it was the bulldog, the English bulldog — which, having had English bulldogs, is hilarious to me. I went to Georgia, so that's never going to be my least favorite. And then now it's pit bulls. And statistically, actually, I think most bites come from chows.
Dr Beth Shapiro: And that's a particular variant you can imagine. Color is one of the things that's best understood, especially 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 it is that causes the thylacine to have the stripes that it has, or causes the particular types of hair development that happen on a woolly mammoth? These are all huge open problems in evolutionary biology that I get to work on every day in my job.
Andrew Huberman: Clearly you have the right job. 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 and intermediate 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? And you're like, no. First of all, no, because 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 resources it needs.
Andrew Huberman: The Jurassic Park thing again — they break out, right?
Dr Beth Shapiro: But also, you can't do that. We exist in the regulatory environment of anywhere that these animals are. It's not that we're some crazy scientists on an island like in Jurassic Park. 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.
Ecosystem Restoration, Gene Drives, and the American Chestnut
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 challenge with any of these genetically modified organisms is that the chestnut tree is one of these stories like the passenger pigeon — 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 and it contains a little quarter-size plastic container, just thin, in an envelope. It had a little note and it said "free seeds for gardening." And I started fishing around on the internet. It turns out massive amounts of seeds were being shipped from China and sent here. Now, this isn't a conspiracy — if you look at this, there was this sort of attempt to just put new populations of plants. Maybe it was all benevolent. And my friends, one of whom is down at Santa Cruz — some plant biologists — they were like, "Whatever you do, do not put that into the ground outside, because these things travel. Birds eat them, birds poop, and then stuff grows." And 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. Is 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 release direwolves, they would compete with grey wolves. And grey wolves are already having enough trouble trying to find a way to survive. So there's no ecological need to release direwolves into the habitat, and we can use them to study these things.
But if you think about what you just said — 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, and we changed ecosystems by going into them and getting rid of all the largest animals that were there 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. And 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.
We've also been moving stuff around forever. We have English birds all over the place here and in New Zealand that were brought by people because they liked them. And 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 things happening, multiple species in an ecosystem that are 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 there. 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: 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 something absolutely essential, which is 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 that are built from local people. We have the Tasmanian advisory panel that has politicians, and people who grow forests to log them, and people who work with the animals, and scientists and conservation biologists. 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. And 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 mean, 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 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. And I got emails from my colleagues at universities who said the undergraduates were coming into their ecology classes and their sociology classes, their anthropology classes. Some of them were mad and some of them were 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. And 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. It makes people happier and healthier. And I love that I get to talk about it and do this hard science — like really hard science — with a bunch of smart people every day.
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. So we have this thing called IVF, where people can make embryos and select what are deemed at this point healthy versus unhealthy. So people are doing genetic selection in humans through technology, right? People don't really stop too often and think, oh yeah, 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. And 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 that was 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 kind of more of a eugenics experiment. That was the idea. And it was very interesting how this emerged — not in the general public, but 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: Yeah. 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 this guy? He's blacklisted. And it turns out it was the latter, right? The Chinese government said, yeah, we're going to shut down his lab, he's going to be punished. I don't know what's happening — if he's running experiments or if he's in prison or what's happening. But this was so interesting, right? Because since then, there's 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." And so some of these companies are geared towards ruling out disease, others are geared towards trying to optimize for the best possible outcome. Right now, this gets people riled up because it's very expensive at this point. 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. And 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. I think 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 it before we can decide if we're curious about something. So there's initial pushback. But we are doing genetic selection on humans by choosing our mates, and it makes us uncomfortable even to think about that. But 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 what are you at, and it's different in different cultures — height is relatively easy and we know that it's heritable. So 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 the ancient human DNA that in Europe at least — where there are a lot of very tall people in Northern Europe, the Dutch are extremely tall — 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 it 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 that we created for them, 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: It's wonderful that you're doing public education on these things, because I think people really need to understand that there are well-meaning scientists who are not just trying to figure out "what would happen if." And I think it's clear that there are going to be more things like this, so we have to navigate forward with that — similar to AI. It's not going anywhere, just like smartphones aren't going anywhere. And the question is what is the best use of this, the safest uses, and where can it evolve our thinking and our lives in really unforeseen positive ways.
Dr Beth Shapiro: 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. This was a child that was born with a urea cycle deficiency. His blood was building up 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. And then it was a collaboration between academia, industry, the 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 that you need to do to make sure that it's safe, and then gave him a CRISPR medicine — 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: Right. That's what's so funny. I mean, why is that not playing God in the same way that anything is playing God? I think we play God every day. And 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 actually 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.
Black-Footed Ferrets, Cloning, and Genetic Rescue
Andrew Huberman: Can I ask you about ferrets?
Dr Beth Shapiro: You can.
Andrew Huberman: And I also want to talk about stuff that lives underwater. That ecosystem has all sorts of issues that it needs to deal with. Humans probably have to intervene really quickly or we're going to be in trouble. So ferrets — they're not rats, they're carnivores, great binocular vision, great hunters. But a few years back, the black-footed ferrets were almost extinct. My understanding, which might be wrong, 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, and that 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. So 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. Because mating of close relatives is bad for genomes — you get homozygosity. You get genes that are too similar, and then if you have most mutations that are recessive alleles, if you get genes that are very similar between brother and sister, you're likely to have two recessive alleles and you get bad mutations, deformities, sterilities. It's a very interesting thing that throughout all species, inbreeding is bad.
Dr Beth Shapiro: To a point. The Channel Island foxes that you talked about — this is 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. And they have almost identical genomes. They have almost no genetic diversity and they are perfectly healthy.
Andrew Huberman: Wow.
Dr Beth Shapiro: Now, I don't know if something happened to that habitat — if they wouldn't be able to survive because there's no diversity, or if a disease came in, they would all be susceptible rather than some versus not.
Andrew Huberman: And that's a very protected region. I know that because my college girlfriend was an environmental studies major and they used to go out there. It's very protected. You can't just take a boat and stomp around those islands.
Dr Beth Shapiro: But it's fascinating. In general, my understanding is that breeding 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. So what's the deal with these black-footed ferrets? Because it's an example of this dynamic tension between trying to reestablish a population and wanting enough genetic diversity.
Yeah. And it's also a great example of how we can use multiple tools that we have for genetic rescue simultaneously to help a species. I should say that the Black-Footed Ferret Project is not something that 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 and they're doing really fun work.
The story is that the prairie dogs, which black-footed ferrets eat, were a real pain in the butt for farmers. And 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. And so 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. And 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 they were like, "We want this because it's kind of cool. What is this?" And the taxidermist was like, "I'll be back." And he went and called somebody and was like, "I think we have this extinct species here." And it was proven that it was a black-footed ferret. So there was a population that 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 that they could find in the wild. And I believe one of them was Scarface, who is the one that 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 hearing this look them up.
Andrew Huberman: Don't get one as a pet. Trust me.
Dr Beth Shapiro: 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. The one is what you mentioned — there's not that much genetic diversity. There were a handful of founders in this population, all of them 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. So 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. You don't need the Yamanaka factors — you just need the egg to do this. So it becomes a cell that starts to divide and become all the different types of cells that make up an animal. So I think in 2020, Elizabeth Ann was born. Elizabeth Ann was 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. I can't remember. Ferrets have this induced ovulation thing too — they have a kind of funny reproductive biology. 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.
Andrew Huberman: That's another reason you don't want to have a ferret as a pet.
Dr Beth Shapiro: Well, definitely not a black-footed ferret. I had a pet ferret many years ago and I don't — you were going exactly where I'm going. A domesticated ferret. It was not the black-footed ferret. 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 as 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 the 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 dire wolf 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: Yeah. Okay. They didn't come out ferocious. No, they were putting in a plug for them. Wolf pups here — extremely adorable.
Dr Beth Shapiro: Yes, I bet. Everyone loves a baby animal.
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 or something, 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: Yeah, 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.
Andrew Huberman: I think about that sometimes because I have two Labradors and so my house is permanently coated in at least one layer of dog shed hair. We're so comfortable as humans to modify species for our immediate convenience, but sometimes that's obviously detrimental to entire populations. You're talking about reintroducing species that have not been there in a long time, or expanding their numbers. I would like to think that with AI or other modeling tools you could make predictions — not perfect, but better predictions. Like, let's model the mosquito population, the swamps, the seasons, the quoll population. You can model as many things as you're aware of. 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 who are 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 be able to narrow down the window of what edits might be reasonable to make. We're doing other things too. 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. And it involves conversations with local stakeholders and conservation biologists and people who are thinking about it from all sorts of different perspectives. So it's absolutely, as you say, 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: Yeah. Along those lines, I predict in probably 3 to 5 years, not 10, the technology we were talking about earlier — of mutating the HIV receptor, that sort of thing — will be very commonplace in the context of fertility. I mean, 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: Right. You know, 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: You mean gene editing ourselves.
Dr Beth Shapiro: Gene editing ourselves. Yeah.
Andrew Huberman: And now we're talking more about public perception, scientists, and implementation, and where those intersect. And I think that one thing that I've learned is that a lot of it is about the delivery method. So when we hear about gene editing and you're taking a cell and putting it in a dish — or even ICSI, what you described before, 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 with very few healthy sperm, where you can take a healthy sperm and put it in the egg.
Dr Beth Shapiro: Yeah. I think people are comfortable with it now because it's been around for a while.
Andrew Huberman: It's this thing with every new technology — you have your first reaction of "is it scary?" before you let yourself be curious. I mean, in a different conversation but one that is relevant — you know, I get asked about peptides like every five minutes these days. And not the peptides of the GLP sort, but what's happened in the health space is that the GLP drugs have destigmatized and taken away needle phobia by putting the needle on a pen. And so now people are like, "Which peptide should I take?" No one's saying, "Is there a capsule version anymore?" That was a big thing. It turns out it's the hypodermic part, not the needle, that freaks people out. The needle kind of freaks people out, but people have no problem taking a pen and going. But they don't like using a plunger and a needle. So now needle phobia has plummeted and people are willing to explore things — some of which there's good data on, some of which there's like no data. It turns out that something this couldn't have been predicted — there was this other thing that was getting in the way. It wasn't really the thing about taking the peptide. It really was the delivery method. We saw this with computers, right? 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.
Dr Beth Shapiro: Same thing with brain-machine interface. As long as people think you need to drill into the skull or put something behind the ear, 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, just a little bit.
Andrew Huberman: Would you like to pet a direwolf?
Dr Beth Shapiro: I would love to pet a direwolf, especially the little ones. 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 — I realize this is going to terrify people. I'm a biologist, but okay. So describe to me an artificial womb and what that looks like.
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. And 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 and it's super quiet. There are these preemie babies, some of which are very preemie. Some have issues and some don't. Some are just early, which is an issue of its own kind. But the NICU technology has come a long, long way. It's far from perfect, but 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 that are 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 people are excited about.
De-extinction, Conservation, and the Red Wolf
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 someone — the principal of Alpha School — come 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. Then they go learn how to farm, start businesses. The public reaction was 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 there is to figure out the best way to educate humans and then wick it out to everybody. But there has to be this pioneering spirit, and that's always going to stimulate concern. There's going to be the haves and have-nots thing in people's minds. 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 a lot of times the assumption — that oh, you're doing this just for your own self-interest. It's all financially driven. And what about the starlings that need our help right now? There's always this "what about the things that need our help right now? Why are we doing this?" And I don't have any great solutions for you on this, but I think that public education is clearly a big part of it. And I think the humanizing it at the level of who's doing it — like it's very clear that you love biology, it's very clear that you like hard problems in biology, and it seems like you're not afraid of but rather enjoy the fantasy positive outcome part of it. It's not all doom and gloom. I mean, this example works for me — hopefully it works for you. 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 excited about the problem, to evolve this thing that we call life on Earth.
Dr Beth Shapiro: Sure. And 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, ideas, excitement, enthusiasm, excitement 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, which is the most endangered species of wolf in North America — an endemic wolf that is 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: Have you heard about our red wolves?
Dr Beth Shapiro: No. They were announced at the same time though. So all these people who are like, "You should be doing this instead of that" — pay attention. We are.
Andrew Huberman: They saved the ginger wolves. I love it. Yeah. There's something that I think people need to understand about scientists — and probably technologists too — which is the person matters. The person doing the work has to be really, really drawn to, almost obsessed with, the project. Because you could sort of ask, for any scientist, there are a lot of scientists working on kind of pedestrian stuff. I used to review a lot of grants for NIH and you go, "Eh" — sometimes those will get funded, sometimes not. But that's the kind of science that certain people do. They want to turn a crank. And then there are certain scientists who really want to be out on that really 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 — I don't know him, but you can't really draw him off target by saying, "Hey, why aren't you working on curing cancer?" And so I think 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. I mean, I'm stating the obvious, but I think from the inside I relate.
Dr Beth Shapiro: Also, 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.
Andrew Huberman: It's so interesting. People love to tell other people what to do. But I will say there are people out there — I know this because of this podcast — there are people out there who are enchanted by biology, who are enchanted by what you've told us today, who are excited about these species and can imagine the positive outcome. And some of them are young and some of them are old, but God bless the young ones, because they're the ones — it only takes a few of them in a certain area of science to really move things forward, as you know. So where are the public education efforts outside of podcasting and whatnot? Like, 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 bits out for the world, targeting different audiences with different types of information. We work with a lot of podcasters and we work with other teams of people making documentaries and films. We publish papers using the traditional old-school 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. So we're trying lots of different methods of communicating. 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.
Dr Beth Shapiro's Origin Story
Andrew Huberman: So in junior high, high school, graduate school — were you sitting there thinking, I'm in a department of zoology at Oxford University, and there's a picture of some old dude on the wall — this is how I felt when I went to Cambridge, like, that's Darwin's house — and there are two ways to be in that kind of environment. Like, "Whoa, that's so-and-so and there's this history," or, "We can do this all much, much better." Because I get the sense that you like to break the mold. But I don't want to lead the witness here. So what were you like as a kid and in graduate school? Were you thinking this whole zoology thing feels kind of steeped in old stuff and I want to break it open?
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 at the University of Georgia. 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 sort of coastal dynamics on the coast. 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 was like, I already know how to be a journalist. I'll just learn how to be a scientist. And so I started taking science classes.
I ended up going to Panama, living on a place called Barro Colorado Island, and studying parasitoid wasps. It was 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 this proposal of a project that 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? Like, if we inbreed, we'll get rid of all that bad stuff that's accumulated, 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. This is going to be great. Help me apply for these scholarships." And 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 the Rhodes. 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: So I got a Rhodes and 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 was like, I'm in.
So that's my origin story. And I think it is because it was new, because it was an opportunity to bring together lots of different disciplines that otherwise really hadn't been thought of together. I got into de-extinction because everyone who works in ancient DNA is asked, as the first question whenever they publish a paper, "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. I've never been dinosaur-obsessed. I can think of many more animals and human diseases that to me are more interesting. But 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 a bit. And so it's a matter of awe, of interest. I think it's the size and scope — they make us feel small.
Andrew Huberman: People don't like to feel small, but mammoths make us feel small too, I think, but in a way that we can appreciate.
Dr Beth Shapiro: Yeah, 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.
Andrew Huberman: You should come see them.
Dr Beth Shapiro: As a biologist, I got it. This is not like taking some human cells from the cortex and putting them into a mouse cortex — those are cutesy experiments. Frankly, I thought those experiments were more derivative. They didn't really inform anything in my opinion. But what you guys did, I thought was really cool. And then as I started learning more about what you're trying to accomplish — like 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. I didn't even get into the fact that 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.