0:00
So our direwolves, they have 20 edits that we picked and we sequenced genomes from fossil direwolves.
Search this video
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We learned from those genomes what genetic changes made those animals bigger, more robust, light colored in coat and then we engineered those changes into a greywolf genome to recreate the direwolf.
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You know, I often get the question of why are you thinking about bringing extinct species back to life?
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Why aren't you thinking about helping living species not become extinct?
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And the answer is we are doing both. It is the same tools.
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It's the same technology. It's the same needs.
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And when we excite people with the idea of mammoths and dodos and thyloines, we get more engagement and enthusiasm and investment in developing the technology that we can use to stop living species from becoming extinct.
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>> Welcome to the Huberman Lab podcast, where we discuss science and science-based tools for everyday life.
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I'm Andrew Huberman and I'm a professor of neurobiology and opthalmology at Stanford School of Medicine. My guest today is Dr. Beth Shapiro. Dr.
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Beth Shapiro is an evolutionary biologist.
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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.
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Her work at Colossal is focused on what is called deextincting species such as the woolly mammoth, the dodo bird, and the direwolf, meaning bringing them back to life.
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But that entire initiative is also about species preservation more broadly and how genomics can be used to improve the global ecosystem.
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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.
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So, this is not just a projection into what's coming in the future. As you'll see, Dr.
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Beth Shapiro is truly a one-of-a-kind thinker.
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And 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.
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Beth Shapiro is not planning to bring back dinosaurs.
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And today, you'll learn why.
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Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford.
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It is however part of my desire and effort to bring zero cost to consumer information about science and science related tools to the general public.
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In keeping with that theme, today's episode does include sponsors.
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And now for my discussion with Dr. Beth Shapiro. Dr. Beth Shapiro, welcome. >> Thank you.
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>> Longtime fan of your work. >> Same. >> Love animals.
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Love stories about animals that aren't around anymore.
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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 blackfooted ferret.
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I'm a big fan of muselids, of which ferrets are.
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We're going to talk about all of that today, including the ethical implications and so on.
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But I have a very basic question, which is how do you decide what a species is?
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Because you have a degree in zoology.
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I always wanted to get a degree in zoology but a few years ago we got this thing called DNA sequencing.
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We can look at ancient DNA can look at skeletons.
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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 phoggenetic trees.
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So, what have we learned that you think people might appreciate understanding about taxonomy and like a is my dog as a bulldog mut [clears throat] as a Chihuahua?
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Are they really the same species? >> Right?
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That's a really fascinating way to put it.
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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.
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Species is a a human concept.
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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.
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In order to share something, we have to know what to call it.
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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?
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what is a species? probably when you learned about species in biology class when you were in middle school you learned about Ernst Mar's biological species concept >> kingdom film order genus species like this kind of thing clay you >> know that's the taxonomy right so we have a lanaeus came up with this idea of
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doing taxonomy right so here's an interesting taxonomy story I've I've spent a lot of my career working on bison for unfortunate reasons probably or fun reasons or whatever but a lot of time working on bison and bison were called buffalo buffalo right we think of American bison as buffalo it's the same
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thing the same thing but bison is the taxonomic name that was given to American buffalo by Carl Lanaeus because when Europeans were going around the world and finding for the first time Europeans had seen all these different animals if they saw a big animal that looked like it would make a good coat that was called a boof coat they called
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it a buffalo or a buffalo right so we have African buffalo buffalo, an Asian buffalo, an 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, or at least there was the idea that they would. But
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But taxonomists found this to be very disturbing.
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We want to know what animal we're talking about when we say the buffalo.
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And so this is why Carlaeus comes up with this scheme.
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The American bison, the American buffalo is called bison bison.
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In fact, the plains bison is called bison bison bison.
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That's a genus and a species and a subspecies that are all the same thing.
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>> That's the Latin name bison bison bison. >> Bison bison bison.
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>> It's almost as humorous as I think it's gorilla gorilla for the gorilla.
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>> Gorilla gorilla and llama llama.
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That's one of my favorites, too. >> Love it. >> Anyway, taxonomy.
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So, we have these taxonomic ways of thinking about things and that sorts everything into your deep evolutionary history.
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But species concepts are what people use to try to say, okay, I have this animal.
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Is it in the same species as this other animal or a different species from this animal?
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And the species concept that you probably learned Erns May is the biological species concept which says if they can breed and their offspring are fertile then they're the same species >> which seems like a good place to start.
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>> It's a good place to start >> because even in my understanding from my fly biologists friends is that you can't mate Drosophila with another species of fly and get a fertile offspring.
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So even among flies, there's some restriction.
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And what's wild is that flies and mammals of all sorts seem to know.
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Like they actually don't try to mate in most cases.
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They don't try to mate with other species, which is fascinating in its own right.
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>> Beg to disagree there.
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I mean, if you seen your dog tries, your dog probably tries to mate anything it comes across.
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>> Just hit seven [laughter] months.
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I've not seen him hump a single time. He's still intact.
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This time I'm keeping my dog intact.
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We can talk about the reasons for that. Health reasons.
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I might get him a vasectomy.
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People we never talk about this, right?
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You can keep your dog intact and just give him a vasectomy if you don't want them to breed. >> Right. Yeah. Right.
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A guest on this podcast said that an animal expert from the Karolinska.
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>> That makes so much sense.
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>> She said, you know, 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.
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In Scandinavia and Australia the inverse is true.
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Of course they're upside down, but we'll forgive them for that.
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But yeah, they need their hormones for proper brain development, right?
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and we worry about them running around and breeding.
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There is this thing called the vasectomy which is actually less invasive a procedure than the the full neuter.
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Anyway, we don't want to digress too much but my dog doesn't try and mate I' I didn't see my previous dog try and mate with cats or >> or even Chihuahua, you know.
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>> Do you think Neanderls and humans are a different species? >> I don't know.
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But I want to know if we are all the same species.
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This is an edgy topic, right?
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But if humans I mean if if it's somewhat based on nomenclature and if there's enough genetic variation out there is it the case that people that 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.
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I'm not trying to cast any hierarchy.
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They could just be different.
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So you're referring to a different species concept which is the genetic spec species concept where an organism is classified based on some threshold of sequence similarity and that is a species concept that is as valid and valuable a species concept as the biological species concept which says you can't interbreed.
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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.
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But if you live in Texas, you're a Texas panther.
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We're going to call you different species.
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Biology doesn't care about your species concept.
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Your species concept is something that you have adopted to have a conversation with another person about a particular topic.
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>> Educate us on this Neanderthal piece.
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>> Educate us on this Neanderthal piece. I know this is a a topic very close to home given that your husband works on these issues and we can maybe we'll get him on here separately but feel free to steal his thunder in any way that that you feel >> uh my husband Ed Green was part of
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spontabo's group when they were assembling the Neanderl genome and so he spent a lot of time thinking about Neanderl I think what's interesting from a species concept if we start there with what's going on with Neanderls is we now know based on studying DNA both from
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Neanderls that used to be alive and a different lineage of human called uh Denisven we we call it this that was first isolated again by Swonte Pabo's research group from a tiny little finger bone that they found in a cave Denise of a cave in Russia that's why they're called Denisvens we know that there were
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multiple different species or lineages or whatever you want to call them of humanike 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
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They met groups of Neanderls and they bred with them.
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So if they were a different species, they were violating the biological species concept at this point.
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So again, species concepts are just what we make of them.
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And today most people have somewhere between 2 and 5% of their DNA that is from this ad mixture event, this hybridization event between anatomically modern humans dispersing out of Africa and the Neandertols that were already in Europe.
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>> Many questions about this.
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First of all, and try not to laugh, the silhouette diagram that we've seen of apes gradually in sort of time sequence working their way to bipeedal and upright.
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When we see that diagram, is that substantiated by the fossil record? >> It is. Yes.
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Um, we know that the the lineage that eventually became us evolved in Africa.
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We can trace ancestry back to apes and then to primates or primates and then to apes and then eventually to us.
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The fossil record in Africa is very fragmentaryary.
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One thing that's really been really fun about working in ancient DNA is the field of paleo anthropology is pretty contentious because there are so few bones that are 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.
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And maybe they're right and maybe they're not.
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And they're smart and they've been thinking about these things and they compare it to all the other bones. So there's a lot there.
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What's brilliant about ancient DNA is that if I can find a little pinky bone in a cave in Denisa, right?
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And I can get DNA from that.
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I know that my bone has ancestors, right?
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If I have a bone that might be somewhere on that lineage to human evolution, I don't know that that bone has descendants.
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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.
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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 because there was breeding between these lineages because they could and because I think that if they can they do.
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15:27
Because if you took the far ends of the spectrum of the, you know, the old world primate, you know, apes and then the upright human walking, my assumption is that let's just say you used artificial insemination that you wouldn't actually get viable reproductively competent offspring from those.
15:42
But at some point, you know, two different species, again, it's a nomenclature or two, some at some some point, but two non- genetically similar, I don't want to say identical because they're not twins, right?
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So, I don't have a language here, forgive me, but you can get breeding across species and get reproductively viable offspring.
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That that has to be the way this happened, right?
16:04
It couldn't have just been through spontaneous mutations that suddenly took animals from quadripeds to bipeds.
16:10
No, this is a very long and slow evolutionary process.
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It's actually a really good question and I think it's an open question in evolutionary biology and it's probably different.
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Evolution does happen because of random mutations that accumulate in a genome.
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And if you think about what might happen if two lineages are isolated from each other for a really long time and in different habitats, say this lineage is adapting to the habitat that's it it's in.
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Maybe it's, you know, very rainy and there's a lot of water and there's a lot of floral plants and over here it's drier and there's really scrubby plants.
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There's different selective environments and as mutations arise in that genome, different ones will go to fixation.
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The size of the population also matters.
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If a population is really small, even mutations that arise that are bad can become fixed in that population just because the population is small and it just happens by chance.
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And so over time these two will become more and more different from each other.
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So what happens when they come back in in contact with each other?
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I think it will really depend on what those mutations that arose over that time was.
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It could be that there's a very short evolutionary time but a mutation has arisen that means the sperm can't fertilize the egg or the egg can't subdivide properly if you have a hybrid ancestry.
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Or it could be that nothing really has happened over a really long evolutionary time and ad mixture can happen.
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>> Humans in the anderls diverged somewhere 300 to 500,000 years ago.
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That's not very long ago in evolutionary time.
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Brown bears and polar bears diverged about half a million years ago.
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And we know that they can readily interbreed and do whenever they overlap in habitat.
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Yeah, they're called grer bears or pizzly bears depending on which direction.
17:58
I know they're terrible names, right?
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You want a different name for this really >> especially if you're a bear. [laughter] >> Yeah.
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>> But that's been happening throughout their evolutionary history.
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We can see this because using ancient DNA, we were able to go back.
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We found um a polar bear off the coast of Alaska that probably lived more than 100,000 years ago.
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And it had ancestry that we see in brown bears everywhere in the world, suggesting that that bear's ancestors at some point or that bear's descendants had hybridized with brown bears and that DNA got passed around.
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We know that during the last ice age, there were polar bears that got trapped on the ABC islands in southeast Alaska.
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And when brown bears expanded from the mainland, they interbred with those polar bears.
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And brown bears all alive in North America today have polar bear ancestry.
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That is because of that interbreeding 20,000 years ago or so. >> Wow. >> Yeah.
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So, in that case, a half a million years had gone by.
18:51
They're really adapted to different habitats and yet they can interbreed.
18:55
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.
19:06
We see no evidence of brown bear DNA getting into polar bears.
19:09
And that is again because of how evolution has worked.
19:16
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.
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Polar bears are induced ovulators.
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So the presence of a male will call them to ovulate, cause them to ovulate.
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So you can imagine situation where a brown bear wakes up from hibernation, goes on to polar bear habitat to scavenge for food, comes across a polar bear female, induces ovulation and they mate.
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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 her because of the size difference and difference in what they're doing.
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So why is it then that since bears live with their moms, all the brown bears that we see that have polar bear ancestry are brown bears, not polar bears?
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We were working with some polar bear biologists when we were doing this analysis many years ago and their hypothesis was simply that if you have brown bear ancestry, you don't have perfectly white fur and you cannot successfully hunt seals.
20:12
So it is just adaptation that means that that ad mixture doesn't work, right?
20:18
So 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.
20:30
>> 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.
20:42
So in the dog world, it's well known that the English bulldog, which has a big head, small hips, is the byproduct of many crossings, but it's basically the bullmastiff and the pug.
20:57
And this was an attempt to generate an animal with a short snout so it could clamp down for bull baiting, which fortunately is an illegal sport now, and to clamp down and not get shaken off by the bull very easily.
21:08
>> Uh the floppy face is associated with lack of pain receptor.
21:10
There's a bunch of things in the bullmastive lineage that they want, but they wanted a low center of gravity, so they took the pug.
21:16
But when you cross them, of course, the females can't give birth because the birth canal just doesn't allow for it, >> right?
21:22
>> Humans realize this pretty quickly and they learn cescareian section.
21:24
So, I could imagine a situation, although I don't tend to think like this today.
21:28
don't tend to think like this today. I'm imagining a situation where homo sapiens and some other non-hom homo sapien humanish species were having sex sometimes getting pregnant but the babies would always die because the birth canal and that structure of the
21:44
pelvis wasn't quite right to allow the head size through which you know there a lot of I hear a lot of arguments that you know humans sort of optimized for just enough space so that the large humans you know we love to talk about how big our brains are right could pass through but no larger and and not much smaller in most cases. >> One of the reasons that giving birth is
22:01
>> One of the reasons that giving birth is one of the ways that women have died in our evolutionary history. >> Right.
22:06
And and cesareian sections I probably have changed human evolution in that sense as has a aseptic you know conditions and things like that. >> Absolutely.
22:13
For me my child was cesarian birth. So >> right.
22:16
So, I like to think you would have survived anyway, but the um 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.
22:28
The the mother survived as well and then that DNA, you know, propagates so that there are now humans, maybe it's been bred out, but that there are or were humans walking around who are not completely homo sapien or is it not not possible?
22:44
I don't know about what's known about hip size or anything like this, but but it is true that humans and our archaic cousins Neanderls interbred and that people walking around today have Neanderl DNA.
22:57
>> 2 to 5% you said >> two to 5%.
22:58
What's interesting about that and it touches a little bit on the adaptation component that you you raised is that I think most people or a lot of people have heard this number.
23:07
We have 2 to 5% Neanderl DNA.
23:09
less well understood is that it's a different 2 to 5%.
23:13
Like the 2% Neanderl that is in my genome is different from the 2% or maybe 5% Neanderl that's in your genome is different than the next person.
23:25
>> So it could be heart, liver, skeleton and uh spleen for me and it could be some other constellation for you. >> Could be anything.
23:31
And if we were to go around the world today and pick out all of the pieces of Neanderl DNA that exist in humans today, we would put together more than 90% possibly more than 95% of the Neanderl genome just from people who are alive today.
23:48
And that tells us that most of the Neanderl genome was not maladaptive for people that pretty much all of it could get passed on and live in healthy humans today. >> Interesting.
24:01
We don't know what happened in the other direction, right?
24:03
We we see Neanderl bones and there hasn't really been any evidence of humans admins with Neanderls.
24:10
There has been evidence of hybrids between Neanderls and Denisven.
24:15
This is really one of the most exciting things that ancient DNA has been able to contribute, I think, to understanding human disease and human medicine and what it means to be human.
24:21
Because before we had the Neanderl genome, if we wanted to know what in our DNA makes us human, we would have to compare all the humans that are alive today with our closest living relative, which is a chimpanzeee or a bonobo.
24:34
So there's 3 to 5 million years of time between when we shared a common ancestor.
24:40
And a lot of change happens in 3 to 5 million years in your DNA.
24:45
And some of it is useful and some of it is what makes us human.
24:49
And most of it is just not.
24:49
It's just changed cuz copying errors during copying cells and that's what happens.
24:56
That's how we're different.
24:56
Every child that's born has about a hundred differences compared to their parents because of copying error in the process of making the sperm and making the eggs that made that kids.
25:04
So when we got the Neanderl genome, that 3 million to 5 million year long branch leading to us was shortened to 300,000 to 500,000 years by an order of magnitude.
25:16
So now if we want to know what it is that makes us human, we have a much smaller list of mutations or variants that we can look at.
25:26
And because we now know that 95% say of the Neanderl genome exists in people today, we've narrowed that list down even further to that other 5%.
25:34
What's going on in that 5% of the genome where no living person has Neanderl DNA?
25:40
That is where the stuff that the baby had to have the human version in order for that baby to survive.
25:48
And that's where we look to see what it is that made us human.
25:53
>> A few years back when 23 and me and these other uh companies started making genomics in humans easier and more affordable.
26:00
A lot of guys boast about Neanderthal DNA being vigor genes whereas women try and downplay the amount of Neanderthal DNA that they have when they get their results.
26:10
I found that interesting.
26:11
Is there any evidence that the Neanderthal genes are quote unquote vi vigor genes that they allow for more durability of human male or female?
26:21
>> It's an interesting question.
26:21
If you just look at that 2 to 5% of nano DNA that we all have, most of it is not anything that is under selection.
26:26
So you see it at about 3% frequency or so in different populations.
26:32
What is interesting is when a piece of Neanderl DNA is suddenly much more common in a population of humans because that would suggest I got some DNA from my Neanderl ancestry and that bit of DNA suddenly made me more fit because I had that bit of Neanderl DNA.
26:48
I was able to survive and have more kids than everybody else and so it increases in frequency compared to average.
26:53
And this has been a really interesting thing to learn when you think about Neanderl DNA.
26:57
There are a couple of things that have come out.
27:00
There are genes that are common in Latin American populations that come from Neanderls that predispose to type 2 diabetes.
27:07
There is another gene that I think was again in a Latin American population that makes people feel I can't remember if it was more pain or less pain, but it did have to do with pain sensation.
27:17
And I remember there was a trial of people in Colombia where they got to feel pain in some way and there's a Neandertol gene associated with this.
27:25
But most of the really interesting ones have been at inimmune related genes during the pandemic.
27:30
One of the first alals that was discovered to be associated with negative risk or bad outcomes of COVID was a gene that came from Neanderls.
27:40
So it's a Neandertol derived gene that was at something like 50% frequency.
27:45
So way above the 3% average frequency in Asian populations.
27:51
And it it made people more susceptible to the virus entering your lungs.
27:54
And presumably it only became that high frequency because it was protective against some other disease that was circulating in the past.
28:01
But the trade-off of that is that it of course, you know, made them more susceptible to CO.
28:08
There was another Neanderl associated alil that was actually protective against CO.
28:11
So I think our ancestors have been subjected to different diseases and pandemics and things that have happened throughout life and we see the traces of that in in ancient DNA.
28:22
We can now go into graveyards in Europe and 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 to things like this. It's really fascinating. >> Wow.
28:39
My red head friends like to claim that they have more Neanderthal and therefore more vigor and pain resistance.
28:47
So I'm guessing the study probably said more pain resistance.
28:48
It we have pain experts on here that verify that indeed on average >> that red heads tend to require more uh anesthesia on average.
28:57
So that tracks but were neanderthalss were a lot of them gingers. >> Yes.
29:03
This comes from studying at MC1R a gene that's associated with the red melanin. mammoths as well.
29:06
They had I mean you can see mammoth you can see mammoth mummies with the actual hair and you can see that they're kind of I don't know if it's because they all bleached to red, but there definitely is a um some evidence from their genome that they had reddish colored hair. Yes. >> Interesting.
29:21
Maybe we could just briefly talk about eye color.
29:23
Is it true that all blue-eyed people descended from a single blue-eyed human at one point?
29:29
This almost sounds like some eugenics thing, but that's not why I'm asking.
29:33
Um, you also see a lot about how true greeneyed people are are quite rare.
29:36
Was there a time when the population of humans on Earth had a lot more greeneyed people?
29:42
>> I think all of the colors, if you if you look at um African populations mostly, it's like me, dark eyes.
29:46
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.
29:53
I mean, people like things that are different and unique and so people want a mate that has blue eyes and stuff.
29:58
really think that that it was selected for it.
30:01
>> Probably eye color was was sexual selection.
30:02
I I don't know what other benefits blue eyes could have other than looking very, you know, stoic and cool as you're like trying to hunt down something on them.
30:11
[laughter] >> Oh, geneticists are so much fun because they're they're willing to just go there.
30:17
I was going to ask you this question later, but I'll ask now because it relates to what we're on to now.
30:20
You know, we tend to think of our lives in in the time bin of our lives, you know, roughly 100 years if we're lucky, right?
30:28
You know, at this stage of human evolution for about 100 years, maybe 80, maybe, you know, if we're fortunate, 90, [clears throat] 100.
30:34
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.
30:42
>> I'm always curious about this. I know you have to make your coffee in the morning and do every and you know manage your life like anybody else in in the today and in the week and in the month and in the year but do you do you sit back and think of all the different tens and hundreds and thousands and millions
30:57
of years that I could focus on I'm going to focus at this time bin right it's a it's an interesting way to live now I'm just curious how you pick the problems that you choose to work on because we'll talk about deextinction but you know why the woolly mammoth why not like get the Florida Panthers rebooted um completely. Maybe why not both, right? But in terms
31:17
Maybe why not both, right?
31:17
But in terms of just, you know, where to focus, like why bring back things from way back when >> as opposed to, you know, maybe we could name a few species that uh disappeared in the last 200 years.
31:29
I'm guessing there are >> quite a few. >> Yeah.
31:33
>> You know, how do you pick?
31:33
And when you're making that decision, what's guiding it at the ethical level?
31:37
What's guiding it at the practical level?
31:40
like what what really are you trying to accomplish?
31:43
Cuz the stuff about humans is fun place to play and put in the backdrop. We'll return to it.
31:47
But your work's really focused on the extinction. >> Mhm.
31:51
>> And like dinosaurs are one option.
31:54
Woolly mammoths are another.
31:54
And you know, just making sure that we don't lose any species that we've got right now.
31:59
Also seems like a very very important indeed noble pursuit.
32:04
>> Yes, there's that's a very complicated set of questions there.
32:06
Um, I think I'll start with what is motivating.
32:12
And I think what's motivating is what drives the selection of the species. In fact, it's funny.
32:17
I I wrote a book a long time ago now called How to Clone a Mammoth.
32:22
And the first chapter was how to pick a species.
32:23
What are you going to do?
32:25
How are you going to choose a species to bring back?
32:26
And there are technical, ethical, ecological, and social reasons to pick any of the species that you can. Technical.
32:36
These are the easiest, right?
32:39
We can't bring a dinosaur back to life because we don't have dinosaur DNA.
32:41
The oldest DNA that we have ever recovered from a bone is from a mammoth bone.
32:46
A mammoth's bone probably dates to around 1 to2 million years ago.
32:52
>> 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 time range, but it's old.
32:57
Dinosaurs went extinct more than 66 million years ago.
33:01
So, that's far outside of where we're going to get recoverable DNA.
33:03
And that's because the skeletons just don't >> they're fossilized.
33:07
They've turned into rock, right?
33:09
So >> there's there's no shred of DNA left. >> Yeah.
33:12
As soon as an organism dies, the DNA in its cells starts getting chopped up into smaller and smaller and smaller fragments until eventually there's nothing left.
33:21
This is really by three processes. UV light. We know about this.
33:25
It's why we wear sunscreen when we go outside.
33:27
But the UV light hits your DNA and it actually breaks it.
33:29
And 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.
33:36
But that is an energy requiring process.
33:39
And after you die, there's no more energy.
33:41
So the breaks from UV accumulate.
33:43
Freezing and and thawing is water molecules expand and will physically break the DNA fragment.
33:51
So that's bad for DNA preservation.
33:51
And most importantly, just microbial decay.
33:56
The fungi, the bacteria that get into an organism when it's decaying.
33:59
and chew it up to transform that carbon and nitrogen into the next generation of organisms, right?
34:06
And so that process is slower in some environments than others.
34:09
Exactly in the same way that your sandwich will rot faster if you leave it in the sun versus in the shelf versus in the fridge versus in the freezer.
34:19
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.
34:28
like this mammoth bone that we were able to recover DNA from.
34:30
But if you die in a very hot, wet, swampy place like Maitius, where the dodo lived, it's another one of the species that we're working on at Colossal.
34:38
Very little chance you're going to be able to recover DNA from any of the fragments that are on Maitius Island.
34:44
And I have tried like hundreds of bones from Maitius.
34:47
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.
34:55
So you have to have a wellpreserved sample that you can get DNA from.
35:00
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. Right?
35:08
So many of them will help you to do that.
35:10
But one is good enough to get some sort of template for what you're going to do.
35:13
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 deextinct.
35:23
and then the first species to be re-extinct >> or bring back something really nasty that knocks out a bunch of other species.
35:33
>> Yeah, you have to understand the role that that animal played in the ecosystem and whether that niche is still available.
35:39
I mean, ecosystems don't live in a vacuum just waiting for something to come back.
35:44
And in some cases, there's a real ecological driver for the species that we're focusing on.
35:50
We feel like there is a real ecological role for these species to play.
35:53
That these ecosystems are destabilized because of extinction.
35:57
And by bringing back these key ecological interactions, we can make those ecosystems more robust and more resilient in the face of all the crap that people are always throwing at our natural ecosystems.
36:10
>> Could you give me an example of of that?
36:12
So, if you were to bring back woolly mammoths, I'm guessing that's not going to save the Amazon forest.
36:16
But what what probably is going to do something useful based on what you just said. >> Yeah.
36:21
So, if you think about what large animals, large herbivores do in their ecosystem.
36:26
They turn the soil by walking around. They knock down things.
36:32
Elephants knock down trees.
36:32
Mammoths probably lived places above trees, so that wasn't what they were doing, but they were distributing seeds and nutrients.
36:38
Have you heard of Pletoine Park?
36:40
This is up in northeastern Siberia.
36:42
There are these two scientists.
36:44
It's actually Sergey Zimov who's a Russian Academy scientist and his son Nikita.
36:46
They've been running this park up in northeastern Siberia for a long time.
36:50
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.
37:01
And they have bison that they've brought in from Canada and wild horses and several species of deer and muskox.
37:08
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 verocity.
37:17
So these animals, they have to eat during the winter.
37:23
So in order to find food, they scrape the snow off of the surface of the dirt.
37:29
In the absence of these animals, the snow stays on the surface and snow is a very efficient insulator.
37:36
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.
37:48
With the animals, you get a a mosaic landscape where there's some parts that are moist and and wet.
37:53
there are other parts that have been exposed and they're dry and colder and you get broader diversity of plants that are coming back where these animals are.
38:02
So, they are essentially recreating their ecosystem just by being there.
38:08
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39:20
So, you're picking, look, you don't have to pick a species, but you got to pick something if you know two or three, right?
39:27
I can't say like we're going to bring back everything from a given era.
39:30
So, >> so we did technical, ethical, ecological.
39:35
I think another answer is what is going to make an impact right when I joined Colossal, we didn't have a bird program, but I really wanted there to be a bird deextinction program because all of the tools that we are developing for deextinction 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.
40:01
And so the kit that we're building from multiplex genome engineering to cellular rejuvenation to iPS 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. Right?
40:21
All of that is applicable across the board.
40:24
So the stack that we're building for de-extinction for synthetic biology stack applies to synthetic biology for conservation.
40:29
So when I joined Colossal and there wasn't a bird program, they had launched the mammoth program which is a placental mammal and the thyloine program or Tasmanian tiger that's a marsupial mammal.
40:41
But birds are among the most endangered species on the planet and it is not possible to clone birds using sematic 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.
40:57
So while that process is really pivotal and integral to our mammoth and thyloine and the other mamalian project, it's just not possible to use it for birds.
41:06
And so I wanted a program that was going to help us develop technologies for birds.
41:11
So why did we pick the dodo compared to any other bird for the first one? >> Cool beak.
41:17
It comes down to that which I also think is a really important part of talking about this project and it's the idea of awe of being excited about something.
41:30
We get kids drawing animals that drawing mammoths and bioines and dodos and sending them to us all the time.
41:36
Ben has put them in frames up around some of them are good.
41:38
The dodo with its sort of rounded top beak also and the way the eyes are typically drawn.
41:46
It also has a kind of cartoonish friendly toucan Sam type of look.
41:51
>> Well, it was in Alice in Wonderland.
41:52
Most of what we know about the dodo is from cartoonish drawings of this animal.
41:56
There are some and of course there's skeletons that we can piece together using the many many bones in Maitius that do not have any DNA in them based on my very best tries.
42:05
>> You didn't choose to bring back like a 75 foot long python. Thank goodness.
42:06
Oh, but there may be virtue in doing that.
42:11
>> There might [clears throat] be.
42:11
Although I think there are plenty of pythons in Florida Everglades right now. >> I'm not a snake fan.
42:15
No disrespect to the snake lovers.
42:17
But talk about uh bird developmental genetics for a second.
42:21
Not to scare anyone away, but hang in there.
42:24
A few years ago, I saw something that um two female condors can reproduce. >> Crazy, right?
42:31
>> And this, of course, for >> it actually wasn't two female condors reproducing.
42:34
It was one female condale just having an egg all on her own. >> Yeah.
42:39
And because of the socopolitical implications, this got people in well, we're from Northern California pretty excited.
42:45
They were like, "Okay, we don't need men after all." Right.
42:47
That was the That's always That was the You know, >> that's funny cuz what I heard was life finds a way.
42:52
So, how did one female condor, who we trust her when she says that she never mated with a male condor or a female condor, we believe her, was able to reproduce.
43:05
>> My scientific explanation is that meiosis didn't fully separate and she ended up having a fertilized egg or >> we should explain meiosis.
43:12
So the separating of the of the >> of the cells during 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 [clears throat] chromosomes.
43:26
So when normally in normal reproduction, 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, they're fertilized.
43:36
The resulting eventually embryo has two copies, one from mom and one from dad.
43:40
In this case, there was no sperm.
43:43
There was an egg that had both copies, probably because of a mistake during meiosis.
43:47
Like, they didn't separate out properly and that was able to develop full term.
43:52
>> Was the offspring viable? >> Yes.
43:55
>> What's weird about that? Yes.
43:55
I mean, it's very very cool and and um very clear the way you described it how that could happen because you need the two sets of chromosomes.
44:04
So, both sets came from mom in this case and only mom.
44:06
from mom in this case and only mom. But in humans where that happens uh and it does happen on certain chromosomes these homozygosity effects they happen under certain conditions like there are these paternal or maternal imprinted conditions like praater willy syndrome where paternal DNA gets kicked off and
44:22
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 that all the genes that everyone healthy walking around out you and me and have genes that only came from our mom >> and only from dad. And so if you get two
44:42
And so if you get two copies from mom of a chromosome or two copies from dad, you end up with like pretty severe deficits in brain development and other things >> and some things.
44:52
And you also could never be a boy because the one gene that turns on that cascade of male development is called SRY.
44:58
It's on the Y chromosome.
45:00
So without that gene, you would never be a boy.
45:03
You would always be a girl.
45:04
Tricomemes where you get two copies from mom and one copy from dad.
45:08
Those can also be bad because of different levels of gene expression >> is down syndrome.
45:12
>> Down syndrome is tricome 21 and there are a few other tricomemes that are >> compatible with life.
45:17
Try 21 is the most common one because those people can live obviously with some challenges additional challenges because the additional chromosome but they can live full lives till relatively middle age. Right?
45:29
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?
45:36
I'm not talking about the actual verb sex.
45:38
I'm talking about the repro like somehow sperm and egg met but or there was something more like the condor you were just describing where the females were able to reproduce through these kind of unusual [clears throat] myiotic events.
45:52
>> Um I think because well obviously sex has evolved a bunch of different times on the on the animal or the tree of life, right?
45:58
And so different ways of doing sex have evolved.
46:01
So we have this XY process where the males are what we call the heterogimedic sex.
46:07
So the males have an X and a Y and the females have two X's and they don't have a Y. But do it differently.
46:13
They have the WZ and it's the the females that have the two different chromosomes. The males that don't.
46:19
And then there are, you know, 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.
46:29
And so, >> yeah, there's like there are communities online >> I've learned that actually believe this kind of stuff for humans.
46:34
There all these theories about how to get a male or female offspring based on position of intercourse, temperature, location, food.
46:42
None of it beats chance, >> right?
46:45
>> right? Um >> or if you really want ixxie right which is 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 >> can you actually determine the XX or XY
46:58
of the sperm and they can do that now you can do it >> you can select so you can do true sexual selection >> you can and it's because the Y chromosome is teeny teeny tiny compared to the X and so you can centrifuge them and because they're smaller they sort out. >> Got it. So you can spin sperm around. >> Got it.
47:13
So you can spin sperm around. Don't do this at home.
47:15
And then based on how the different things of different weights basically spin out to different depths.
47:20
And so you can bias the likelihood that you'll get a XY carrying sperm or an XX >> caring.
47:27
>> Or you can use cloning like we are at Colossal and like we're thinking about in synthetic biology where you actually know the sex because you're starting with an actual sematic cell, a tissue cell of that animal instead of using a sperm and an egg.
47:39
>> So let's talk about that.
47:39
And before we do that, we should probably do a brief developmental neurobiology lesson.
47:43
You beautifully told us what meiosis is.
47:45
You know, sperm or egg, you have 20.
47:48
Well, in humans, it's 23 chromosomes.
47:50
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, right?
47:58
And so, in these other species, I guess you know how many chromosomes there are.
48:02
And I must use the woolly mammoth or the cuz it's a fun one.
48:06
Birds [clears throat] are complicated.
48:07
As a developmental neurobiologist in my past, the bird stuff gets tricky.
48:10
Reptiles >> birds are tricky and there's really tricky.
48:14
>> Some birds are trickier than others.
48:14
I did not know until I joined Colossal that there are some birds that have a what's called a germline restricted chromosome which doesn't exist in any of their cells except for the germline.
48:26
>> Germ line or the sperm and eggs. >> Sperm and eggs.
48:27
And it comes into being this chromosome just in the germ line and then it disappears. >> Wow. >> I know. Biology is amazing.
48:33
The birds have these like mini mic chromosomes that are a pain to assemble.
48:37
And if you're sequencing DNA from an extinct species where the DNA fragments are really short and you have to do it by taking each one of those really short fragments and trying to figure out where on a whole genome it goes best on a computer.
48:51
We don't actually do it with our with like a tweezers or anything like that.
48:54
But >> yeah, the birds are really cool animals, but they from reproductive biology standpoint, it's it's tricky.
48:59
So with the woolly mammoth was a mammal. >> Yes. >> Right. Okay.
49:04
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.
49:13
So you know it's a mammal because there's evidence of lactation.
49:16
How are you deeming it a mammal >> using its genome.
49:19
So we've been able to sequence whole genome sequences high quality whole genome sequence sequences from multiple mammoths that date to the last million and a half years.
49:28
And we can assemble those genome sequences using a computer and then we compare them to other animals that are alive today.
49:37
And we know that the closest living relative of a mammoth is an Asian elephant.
49:41
And in fact, mammoths and Asian elephants are more closely related to each other than Asian elephants are to African elephants.
49:47
So mammoths are nested within the elephant family, most closely related to Asian elephants. >> Okay.
49:55
Okay, so if you get this the sequence of DNA from a mammoth, so you know, okay, this is the complete genome.
50:00
And I think a lot of people probably don't realize that your complete genome is represented in most all of your cells.
50:05
There are rare exceptions.
50:05
It's just that not all those genes are expressed, which is why you get a hair cell versus skin cell versus heart cell and so on.
50:11
>> That's the epigenome, >> right? But the menu is there. >> The menu is there.
50:15
>> Are you growing up DNA in a laboratory that is that that is the mammoth sequence?
50:19
>> So this is what comes, I think, from Jurassic Park.
50:21
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.
50:30
And what happened in Jurassic Park, and I should just say it was not a documentary, so let's not get carried away here, right? Okay.
50:38
[laughter] What happened in Jurassic Park was scientists found mosquitoes preserved in amber.
50:44
They stuck a needle into those mosquitoes, preserved an animal.
50:47
mosquitoes, preserved an animal. They sucked out a bit of stuff that happened to be blood and it had dinosaur DNA and then they had the little dancing DNA thing tells you about how they piece it together and you can see the little pieces of dinosaur DNA lining up next to
51:03
each other and then there's holes and they fill in those holes with frog DNA which was a weird choice even at the time because we already knew that birds are dinosaurs right so why they pick frogs I don't know but anyway they >> talk to Richard Harland at Berkeley or something that's another biology joke. Look it up. Look it up.
51:20
>> But that's not actually how we're doing this.
51:22
What we're doing is somehow easier than that.
51:25
Because we know that Asian elephants are the closest living relative of mammoths.
51:29
We also can by sequencing a bunch of Asian elephant DNA and sequencing a bunch of mammoth DNA.
51:36
We can see that they already have almost exactly the same genome sequenced. >> How similar?
51:42
>> They're about 99% similar.
51:42
It depends on how you calculate the percentage and things like that.
51:46
As a point of reference, how similar are we to the chimpanzees in terms of percentage similarity of DNA >> in that counting? It's about the same.
51:55
>> But some people might say, "We don't look anything like chimpanzees."
51:59
>> Well, >> 99 just sounds like so similar, like you're going to get the same thing. >> Yeah.
52:02
Well, there I mean, people calculate this in lots of different ways.
52:05
There's some statistic online that we're 85% the same as a banana or something like that.
52:09
Like a lot of our DNA is I don't know if that's true. Right. Yeah.
52:12
Is the goal to recreate the ancient mammoth or is it to create a a pseudo hybrid of the ancient mammoth?
52:19
>> The goal is to think about a mammoth in terms of what it does and what it looks like.
52:24
And this gets back to this idea that you brought up in the beginning about a species concept.
52:28
You know, this is one of the most common things that we hear.
52:31
If you are going by a strictly genetic species concept where you're saying that a species an organism is classified just by some threshold of similarity sequence similarity to something else.
52:42
That's the only way you can call it that thing.
52:44
That isn't what we're doing in deextinction.
52:46
That's not what anyone doing synthetic biology is thinking about when they're designing or engineering things to solve problems.
52:54
Engineering animals or engineering plants to solve problems that we have in the future.
52:57
The genetic species concept is a an idea that was proposed to classify organisms that evolve over a very long evolutionary bifurcating filogenetic tree process where accumulation of changes is over many generations over a long time.
53:13
Our mammoths, our direwolves are not created by that process.
53:18
And so that concept really doesn't apply.
53:21
I think that's where a lot of the the disinformation comes.
53:24
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 it's important.
53:34
It's it's a question, but it's a narrow one.
53:36
And I think it crowds out the the real discussion about what it is that we're doing, how the technologies that we're developing can be applied to >> ecosystem health to help stop species from becoming extinct, even as synthetic biology for for human medicine.
53:51
So we're not trying to make something that is identical to a particular individual that used to be alive.
53:58
Our mammoths are millions of letters of DNA code different from each other.
54:02
So even which one to use would be an open question.
54:07
Instead, what we're doing is focusing on where all of those mammoths are the same as each other >> but different from elephants.
54:13
And thinking that those places, like we were talking about with humans, those are the places that are important to make a mammoth a mammoth.
54:20
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.
54:33
Mammoths will have to live in habitats that exist today and tomorrow.
54:35
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.
54:49
When you mentioned um species nomenclature gatekeeping, I have a feeling this is based on the publicity around the dire wolf. >> Yes. >> Okay.
54:58
I just I like to just address things very directly. I want to be very clear.
55:01
I'm not arguing for species gatekeeping here. Uh that's not what I do.
55:05
I have I own a mut after all. >> It's not even that.
55:07
It's it's that um somehow this idea of what we should call it based on this very specific definition of you can only call it this if it's some threshold genetic similarity is noise.
55:18
It's not an important part of the conversation.
55:21
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?
55:26
Like, >> well, I think like like all things media and Hollywood, you know, I think Jurassic Park did an amazing service to science and the excitement around these concepts, but probably did a disservice as well by embedding in people's minds that the idea is to bring back the the exact same animal.
55:44
>> But didn't we just say that these dinosaurs were some dinosaur DNA and a whole bunch of frog DNA?
55:49
Nobody looks at them and goes, "No, they're not a dinosaur."
55:52
>> You're a scientist and I am, too.
55:54
Actually, it's funny that you you mentioned this because my dad's a theoretical physicist.
55:57
He was involved in chaos theory.
55:58
He's been a guest on the podcast.
56:00
I remember when Jurassic Park came out, he didn't dislike it, but the part where he kind of rolled his eyes was there's a description of chaos theory in there and what it means.
56:07
And in Hollywood, they love to you use the example of like a butterfly flaps its wings in Patagonia and then this thing happens in the to the barista in in Brooklyn, you know, and people like to bridge those concepts and they think, "Oh, that's so cool."
56:21
Like, so it's it's it's sticky, as we say.
56:23
But that's but he he was rolling his eyes.
56:25
He's like, "Okay, that's not how these things work."
56:29
And so for people that are experts in the area, it can be a little bit grading at times.
56:32
But the public, I think, is open, right?
56:35
in my experience in doing what I do is that the public if they just have the knowledge in hand and the way you described it great.
56:40
So, >> so our direwolves, they have 20 edits that we picked um and we we sequenced genomes from fossil direwolves.
56:48
We learned from those genomes what genetic changes made those animals bigger, more robust, light colored in coat and then we engineered those changes into a greywolf genome to recreate the direwolf.
57:02
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.
57:08
>> So, the direwolf was a very interesting choice.
57:10
Clearly, you were successful in creating this animal.
57:14
>> Sounds like you were very intentional in picking which genes.
57:16
It wasn't like, oh, we're going to take a couple genes from the direwolf and throw them into this this other wolf and create what we call as the direwolf.
57:23
>> If I were to look at the direwolf and a you said a greywolf. >> Yes.
57:29
Side by side, is the direwolf larger?
57:32
>> They are >> on average at the same age.
57:33
Are there any other features that are are visibly different or the other features more adaptive in terms of gut and ability to live in certain environments and this kind of thing? >> They're muscular.
57:42
The fur is uh longer and more full and it's also light colored.
57:48
I I think it's an important thing to understand about how we're selecting these because we are very deliberate about what we're doing and it's both because we want to with some fidelity bring back these extinct traits so that the animals can eventually be released.
58:02
Now, we're not planning on rewing direwolves and we will study the animals and learn about the effect of their genes on their lifespan. >> Yeah, sorry.
58:09
[laughter] But the other other animals, the ultimate goal is to to eventually have populations of freeling as as they would like to.
58:19
And so we we want to understand how healthy they are, how they're going to interact with the habitat that's there.
58:24
And we want to make sure that because we with synthetic biology have the power to engineer them in a very deliberate way that we can do that in a way that's safe.
58:32
So the hair color is a a really interesting example of this and the strategy that we use.
58:36
of this and the strategy that we use. So when we sequenced the genomes of the fossil direwolves, we found that they both had variance, the same variance in two genes that would have made them have light colored coats, but in living
58:52
greywolves and dogs, variance in those genes, not the same ones that we saw in direwolves, but close enough to where we would need to do the edits that you have some concern that you would have bystander edits that might cause a problem, can lead to oculaneous albinism. Um, so blindness or deafness
59:06
Um, so blindness or deafness in these dogs.
59:10
>> And we decided that because we're not changing the whole genome, they have to be safe on a greywolf genetic background, we wouldn't make the trait that way.
59:19
It just wasn't passing the bar of animal welfare safety.
59:22
And so instead, we brought back the direwolf light colored coat using different edits that we know are safe in a greywolf background because there are light colored domestic dogs and greywolves.
59:34
So, we used the edits that we know are safe because they exist in living dogs. >> Oh, that's cool.
59:39
>> 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.
59:47
And this is the way that we think about all of our projects.
59:50
We have to take an Asian elephant and turn it into a woolly animal.
59:55
That trait requires changing not just the structure of the hair, but of the skin itself.
1:00:00
We have to make room for more follicles, sebaceous glands, different approaches to be able to support that woolly coat, right?
1:00:06
And we need to be able to do that in a way that results in a healthy animal because these are very longived animals.
1:00:13
Takes 22 months for gestation.
1:00:15
They reach sexual maturity at 14 and it's a lot of work.
1:00:20
>> So, how many dire wolf wolves are walking around right now in some location?
1:00:24
Right now there is Romulus and Reheis and they are almost two years old.
1:00:30
And >> male and female or male?
1:00:31
>> Romulus and Remis are boys and Klesia is a girl.
1:00:33
She is about 18 months old or so.
1:00:37
>> Is the intention to mate them?
1:00:38
>> No, they're too closely related.
1:00:38
We're stopping them using hormones.
1:00:40
So rather than >> But they live together. >> They live together.
1:00:44
She was reared by herself.
1:00:46
The boys had each other and she had just her.
1:00:48
So she's a little bit on the like I mean you would never look at these animals and say this is the way a wild wolf behaved.
1:00:54
They were hand reared, right?
1:00:55
Um, but she's a little bit on the specially goofy side, but she's the she's the best. She's adorable.
1:01:01
>> Do you feel safe interacting with them? >> Oh, no.
1:01:03
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.
1:01:11
These are not domestic dogs.
1:01:11
Remis is a little bit less skittish than Romulus.
1:01:15
He will eventually, if you sit in the middle of where they are, he will eventually kind of sniff around and and maybe come near you.
1:01:21
Romulus wants nothing to do with you, which is funny because they're they're identical twins, but they're slightly different interacting with people, but it's very clear that they these are wild.
1:01:28
They're also huge, right? So, >> yeah. How big are they?
1:01:32
>> I don't have the latest measurements on how big they are.
1:01:34
And of course, it's seasonal for all these different things, but I know that they were at some point they were at least like 120 lbs, which is big for a grey wolf. >> Yeah.
1:01:41
So, everything you just said about these direwolves, would you also say about grey wolves?
1:01:46
Like, you wouldn't want to be alone with one.
1:01:47
Some can be skittish, some can be calm.
1:01:49
like you >> you know I have good friends who are somebody you should think about having on actually that if you're interested in dog behavior and what we've learned about domestic dogs and I know you have a dog and it's very exciting.
1:01:59
Ellen Carlson is at the Broad Institute and at UMass and she's done a lot of work with wolf dog hybrids and then also with domestic dogs and trying to map genes to behavior and all these things and basically showed that breed stereotypes are just not real.
1:02:13
The that you really can't map genes to behavior except for Chihuahua. They're just terrible. I'm just kidding. No, it's okay.
1:02:19
We had Caesar Milan on the podcast.
1:02:20
[laughter] He'll be the first to say that in in almost every decade in the United States, there was the demonized dog breed.
1:02:28
It was actually German Shepherds post World War II.
1:02:32
>> Then it was [clears throat] Doberman's. >> Same reason.
1:02:33
Then it was the bulldog, the English bulldog, which having had English bulldog is hilarious to me.
1:02:38
>> I went to Georgia, so that's never going to be my least favorite. >> Right. Exactly.
1:02:41
And then now it's pitbulls. Right.
1:02:42
And statistically, actually, I think most bites come from chow.
1:02:46
>> At least my uncle who's a vet tells me that.
1:02:48
But um chow owners I met some nice chows.
1:02:50
The blue tongue is pretty cool.
1:02:52
>> And that's a particular variant you can imagine.
1:02:54
Yeah, there's a there's color is one of the things that's best understood I think especially in domestic dogs.
1:02:59
There's so many genomes and all these things have been mapped.
1:03:03
Um and that's part of what we have to do in all these cases is is how do we figure out what it is that causes the thyloine to have the stripes that it has or causes the particular types of hair development that happen on a woolly mammoth.
1:03:16
These are all huge open problems in in evolutionary biology that I get to work on every day in my job.
1:03:23
>> Clearly you have clearly you have the the the [laughter] right job.
1:03:24
So you have these three direwolves. They're not mating.
1:03:29
Is the plan to make more of them to mate them?
1:03:32
What's what's the ultimate goal and intermediate goal?
1:03:36
>> We will have another pack so that hopefully they will all be born more of them at the same time so that that's the plan eventually.
1:03:43
It's not our priority right now.
1:03:44
We're working on other species.
1:03:46
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.
1:03:52
This is really the next rational logical step in any deextinction project.
1:03:56
I often hear rumors that what are you doing?
1:03:58
You're just going to take get an elephant and uh make a mammoth and just release it into Alaska? And you're like no. Um first of all, no.
1:04:07
cuz it's going to be so hard to make that first mammoth that I'm going to want to make sure that it is safe and cared for and has access to all the >> Jurassic Park thing again.
1:04:16
[laughter] It's that they break out, right?
1:04:19
>> But also, you know, you can't do that.
1:04:21
We exist in the reg regulatory environment of anywhere that these animals are.
1:04:25
It's it's not that we're some crazy scientists on an island like in Jurassic Park.
1:04:29
You know, we we work here.
1:04:31
We have Ayakok protocols and um if you're doing anything that is releasing animal outside you're under the regulatory purview of a whole bunch of different agencies.
1:04:39
I don't know if you saw but the very first geneedited organism created specifically for the purposes of conservation ecosystem restoration was deregulated by the USDA this week.
1:04:52
It's the American chestnut tree.
1:04:54
And the challenge with any of these genetically modified organisms that we have which we're creating synthetic [clears throat] biology uses a tool to make these things better.
1:05:02
The chestnut tree is one of these stories like the passenger pigeon where the American chestnut was the most prolific tree across the eastern forests of North America all the way through 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.
1:05:28
But it took a decade and a billion trees died.
1:05:33
>> This scares me for a variety of reasons.
1:05:35
A few years ago, this would be 2016, 17, I got this strange envelope in the mail to my residence. Do you know about this?
1:05:43
No, but I'm >> So there was a So I was living in the East Bay, California, and I get this envelope and it contains a little kind of like looks like a small quarter size plastic like container just thin an envelope and I had a little note and it said free seeds for gardening.
1:05:57
Oh >> and I was like this is really odd and I started you know fishing around on the internet.
1:06:03
Turns out the idea was that massive amounts of seeds were being shipped from China and sent here.
1:06:07
Now, this isn't a conspiracy, right?
1:06:09
Like, if you look at this, there are these this is sort of attempt to just kind of like put new populations of plants and maybe it was all benevolent.
1:06:17
And my friends, actually, one of whom is down at Santa Cruz.
1:06:21
Yeah, I know some plant biologists.
1:06:22
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 gets grows.
1:06:30
And this is how you can decimate important populations of trees and plants."
1:06:34
It was the first time I really thought about vegetation on vegetation warfare.
1:06:38
Is that what is actually what was happening?
1:06:40
Is it was this the Chinese trying to do this? We don't know.
1:06:43
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, you know, into the dog park.
1:06:56
>> I wouldn't put the wolves out because if if we release direwolves, they would compete with greywolves.
1:07:00
And greywolves are already having enough trouble trying to find a way to survive.
1:07:03
And so there's no need there's no ecological need to release greywolves into the habitat and so we can use them to study these.
1:07:08
But if you think about what you just said, right, I I think >> people we as a lineage have been messing with the evolution and of the stuff around us for as long as we've existed, right?
1:07:24
Initially just by driving things extinct. Not deliberately, right?
1:07:26
like just like maybe this wasn't a deliberate attempt to >> have some plants that would out compete other things, >> but we did and we changed ecosystems by going into them and and getting rid of all the largest animals that were there because we were hunting them.
1:07:40
I'm thinking about, you know, our ancestors in, you know, 50,000 years ago in Australia, 30,000 years ago in Asia, and then we domesticated things and and now we we conserve things.
1:07:51
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.
1:07:58
But that's not what we're doing.
1:08:01
We are deciding how many of them get to live, what they get to eat. We vaccinate them.
1:08:05
We protect them from predators.
1:08:06
We 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.
1:08:12
And we've also been moving stuff around forever.
1:08:17
Like we have English birds all over the place here and in New Zealand that were brought by people because they liked them, right?
1:08:23
They liked them where they were.
1:08:25
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 you're claiming a particular slice of history as the thing that is better than everything else.
1:08:38
And I think it's more important to think in terms of robustness.
1:08:42
And you said, well, go back to the beginning.
1:08:45
You you said something about how when we have multiple things happening, multiple species in in an ecosystem that are all doing different things, you end up with more biodiversity and richer environments.
1:08:57
When there's an overlap in ecological nest, there's some redundancy there.
1:08:59
And that redundancy is really good for that ecosystem because it means that bad stuff can happen and it can weather that bad stuff.
1:09:09
So maybe we shouldn't always think in terms of bringing in something new is bad.
1:09:14
>> I should have planted the seeds.
1:09:14
No, I'm totally on board what you're saying when I um >> I don't mean to plant the seeds.
1:09:18
I just >> No, no, no, no.
1:09:20
I'm totally totally on board with what you're saying.
1:09:21
It it touches on an important theme that we've certainly never discussed on this podcast, but is very relevant to today's discussion and that people should think about, which is, you know, who gets to decide.
1:09:31
It's interesting because there's both a kind of like massive ego inserted into the notion that like we know best about everything in including the other all the other species of plants and animals.
1:09:41
That's obviously not true.
1:09:41
But also that we don't have anything to contribute in terms of our own evolution that is I mean look here you're a human being bringing back species of past and some people might think scary other people might think fantastic.
1:09:56
I think why it's hard for people to wrap their head around these things and they default to thinking about oh it was better in the past is because a most pe people never experienced that they have no concept.
1:10:07
no concept. I think there's a great book that I had to read years ago called uh the good old days they were terrible about we hear the good old days and you hear about all like the dysentery the lack of antibiotics like but we tend to look back and say oh that was it must have been so nice back then everything buolic and beautiful and you forget all the the the dark side of that
1:10:23
>> but the other one is that we don't have a window into the future >> right >> and so you know I went to school in Santa Barbara and one of the first things you learn there is that there are all these species of fox that are out on the the Anakappa island and and Santa Rosa Island and all these islands that the Schumash brought out there on boats, but no one says they don't belong there. They say there's this incredible
1:10:41
They say there's this incredible biodiversity out there, which is why it's protected, why we don't have, you know, a lot of tourists walking around out there. We want to protect that.
1:10:47
But humans brought those out.
1:10:49
But the fact that it was Native Americans and it was and it was some time ago leads to our percept like it was good, right?
1:10:55
And so the idea that we would remove them, no, we need to protect them.
1:10:59
And that makes total sense to me, but it's a default psychology that I think is driving a lot of the quote unquote ethical conversations around this because we don't have a window into the future.
1:11:08
So let's say these dire wolves, you make more of them.
1:11:11
I can get totally on board the idea that then they're wildlands that they are roaming that then they're serving other populations of animals and plants.
1:11:20
There's new interactions that are that are benevolent interactions that are pro-evolution as opposed to devolution.
1:11:25
I think the challenge for people is we don't know what that looks like and it feels like there there too many variables to understand.
1:11:32
So I'm just wondering how you wrap your head around that when you're talking to people about what you do and and when you're thinking about what you do.
1:11:41
>> I'm thinking in terms of helping ecosystems to become more resilient.
1:11:43
We know, for example, because of what happened in Yellowstone, the impact that restoring the top predator of an ecosystem that had been removed can have.
1:11:55
The grey wolves that were reintroduced into Yellowstone, the population of animals that they ate had become too large and they had eaten away at all of the shrubbery.
1:12:04
And so putting the greywolves back in Yellowstone cascaded all the way down that ecosystem ladder to changing the way the rivers were flowing because the plants were growing back now along the edges of the rivers.
1:12:17
The thyloine, which is the Tasmanian tiger, this is the second species that Colossal declared as one of our de-extinction targets.
1:12:24
Um the thyloine was the top predator in Tasmania.
1:12:28
And Tasmania today has problems because that top predator is missing.
1:12:36
Have you heard about or seen the awful pictures of the Tasmanian devil facial tumor disease?
1:12:42
>> Yeah, this came up um on a few podcasts ago because we had Jared Rudder who's a another Hughes biologist where some mitochondria and we're talking about they're no transmissible cancers, but these Tasmanian devils um have wound induced cancer-like problems.
1:12:54
So they fight, they scratch each other up, they get cancers, and that that population is suffering as a consequence.
1:13:03
>> And they're so closely related to each other that they can pass them between each other.
1:13:07
>> Oh, so it's the genetic similarity that allows that to happen.
1:13:10
>> The point is that I Yes, this is terrible.
1:13:12
But if [clears throat] we had had the top predators, those sick individuals would have been weeded out of that population and we might not have this problem.
1:13:20
So you can see restoring that ecosystem.
1:13:24
And also I'll get back to, you know, I often get the question of why are you thinking about bringing extinct species back to life?
1:13:30
Why aren't you thinking about helping living species not become extinct?
1:13:35
And the answer is we are doing both. It is the same tools.
1:13:38
It's the same technology. It's the same needs.
1:13:44
And when we excite people with the idea of mammoths and dodos and thyloines, we get more engagement and enthusiasm and investment in developing the technology that we can use to stop living species from becoming extinct.
1:13:57
There's a really great story.
1:14:00
Our colossal Australia partners have been working on a project to try to stop the northern qual from becoming extinct.
1:14:07
Have you ever heard of familiar with the qual? Most people won't. >> It's qu L l. So it's a little guy.
1:14:12
They're adorable little cute >> carnivorous marsupials and they eat >> amphibians.
1:14:18
And in Australia, there is an introduced amphibian called a cane toad that is toxic. It's toxic to dogs.
1:14:27
When dogs eat them, they die.
1:14:27
It's toxic to everything.
1:14:29
When a qual eats a cane toad, it dies. And that's terrible.
1:14:31
And there is a very strong chance in the next few decades the northern qual is going to become extinct.
1:14:39
However, there is a synthetic biology solution to this and it's one that has actually already been made, right?
1:14:46
There are mammals that eat toxic toads that live on the other side of the planet even that eat cane toads, right?
1:14:53
And they have a single letter change that changes one amino acid in one gene that allows them to eat that toxic cane toad and not die.
1:15:01
Our Australia, Colossal Australia partners have made those changes in a coal.
1:15:05
And when you measure in a dish, the ability of that toxin to break down the cane toad, that single letter change to that qual's genome could allow that qual to avoid becoming extinct, but to eat cane toads, which currently nothing really can in Australia.
1:15:22
So now we can see the real benefit of this massive comparative biology framework.
1:15:29
I know which gene it is that I need to change.
1:15:31
The stack that allows us to develop the tools to be able to make that change and just that change and then show that that's the only change that's there.
1:15:38
You've made what [clears throat] you wanted to do and then put that in a living animal can stop a species from becoming extinct.
1:15:45
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1:17:23
As someone who does a lot of public science health education interaction, I there there are a couple things that get the public really worried and that they need reassurance on.
1:17:31
Honestly, I think it dates back to the pandemic.
1:17:35
>> There's a lot of distrust about scientists.
1:17:37
There is this belief that some scientists are only concerned with themselves.
1:17:41
themselves. M it's an important myth in my opinion to dispel the idea that most scientists are not what I believe them to be which is they're trying very hard to get answers right to do good for the world including other species and it they're not so careerist that they're
1:17:57
willing to overlook that independent of the IRB boards and the thing that the the constraints that force them to to do that but that is the era we're living in right so I think that some people think more now in terms of you know scientists
1:18:10
are like doing stuff because they And this has parallel conversations about AI where people are think like hey like have we really thought this one through and people are are scared but I totally agree with with what you're saying and I want to talk about two species to try
1:18:23
and highlight this and how it can be done right because I I think it's clear that you're trying to do this right [snorts] which means for the the best possible outcomes for humans and other species and the first are mosquitoes >> and the second are humans. Most people
1:18:35
Most people don't care about mosquitoes, but some years ago, I started paying attention to mosquitoes because your very own Howard Hughes director now, I think Leslie Bosall, works on the old factory system of mosquitoes and other insects.
1:18:49
And turns out bugs find mates and find things to suck blood from and etc.
1:18:54
by odors and pherommones, but odors.
1:18:58
And so there this idea, oh, mosquitoes have malaria.
1:19:02
This wasn't Leslie's idea, but it was like, um, mosquitoes have malaria.
1:19:05
let's just get rid of all the the mosquitoes, >> right?
1:19:08
>> And the biologists were like, "No, you can't do that cuz then the birds are going to suffer cuz they eat the mosquitoes." And on and on and on.
1:19:13
I mean, this stuff can really domino.
1:19:14
And it sounds like a great idea. It's a terrible idea.
1:19:19
>> Or let's just make mosquitoes that can't reproduce.
1:19:21
That's a great way to do it, right?
1:19:24
Or let's just do an half of them, right?
1:19:26
There were these ideas just kind of thrown out there that with genetics, you can do that.
1:19:29
You just release a few of these little suckers into the wild and there is the potential that they mate and proliferate and just enough to eradicate a population or half a population.
1:19:38
It's harder to do than that.
1:19:40
So people didn't know this was like being explored, but smart people put the brakes on it.
1:19:44
So let's talk about mosquitoes.
1:19:46
Like it they clearly carry pathogens that harm people, but they're also important for ecosystems, vitally important for certain ecosystems.
1:19:54
So, how do you think about plucking out a node in an ecosystem like a species or introducing a a species back into an ecosystem and thinking about the ramifications?
1:20:06
It's hard to model behavior in one species, let alone interactions between species.
1:20:09
How do you wrap your head around that with the maybe the mosquito would be a I hope a simple example of this.
1:20:17
>> Mosquitoes are a hard one and I think that they do cause a lot of death and disease, but not all mosquitoes.
1:20:22
So the you know only certain species of mosquitoes carry malaria and deni and other diseases that are known to affect people.
1:20:31
And also those mosquitoes have much higher population density because of the way that people have built our towns than they would have had in natural ecosystems.
1:20:42
So for something like a mosquito that is extremely overpopulated and carrying a devastating disease, I would think that there actually is reason to think that it is safe in an ecosystem to at least bring that population back down to a size that it would have been in a natural ecosystem.
1:20:58
A lot of problem with mosquitoes is because people leave just tubs of water or water that isn't circulating out and they lay a billion eggs and then you have many more mosquitoes.
1:21:07
That's not true in the Arctic.
1:21:09
In the Arctic there's a bazillion mosquitoes and no people and it's really miserable.
1:21:11
That's uh I've spent a lot of time in my life.
1:21:13
>> Yeah, I heard you describing that elsewhere and it sounds horrible.
1:21:16
Someone I do not like mosquitoes.
1:21:16
I don't like mosquito bites.
1:21:18
And I get it like at first blush and like get rid of all the mosquitoes, but it's a lot more complicated than that.
1:21:24
>> Maybe engineer mosquitoes that they can't carry the disease rather than engineer the mosquitoes to be dead.
1:21:28
I mean, there are ways that I think we can use synthetic biology and gene drives as the thing you were getting at where you release something that is created by a synthetic drive into the wild and then it passes on to the next generation.
1:21:39
I actually think that gene drives are an incredibly powerful way that we have at our fingertips where with the appropriate safety measures and care in place, we should think about how we might deploy these tools.
1:21:51
You can make a gene drive so it only lasts for a fixed number of generations.
1:21:56
And also because they tend not to make things reproduce, there is incredibly strong natural selection against them.
1:22:02
Anything that breaks a gene drive and lets something reproduce is going to be favored in a population, right?
1:22:07
Um, so gene drives are going to be difficult to get to persist and there are many switches that we could build into them to make them last for a short period of time.
1:22:15
But there are some species that have taken over and you talk about your plants that you got in in this part of the world.
1:22:24
There's cheat grass everywhere and it's highly flammable and it grows along the roads and it's Mediterranean in origin.
1:22:29
And the only way we are ever going to get the cheat grass down enough to be able to let the native California grasses come back is if we get rid of the cheat grasses for a few generations.
1:22:40
And >> do you think this is one of the reasons there's so many fires?
1:22:43
>> They're very flammable and they also don't have very um deep roots.
1:22:44
So in California, it's very dry, right?
1:22:49
California native grasses have much deeper roots and so they stay green longer.
1:22:52
So they're sequestering carbon and they're not as flammable for longer into the season.
1:22:55
these these shallow rooted Mediterranean grasses dry out super quickly.
1:22:59
So as soon as it's fire season like it is now, they're ready to go, right? And it's not just here.
1:23:03
It's all across the western part of North America. And this is a problem.
1:23:06
And it's a problem because it causes huge amounts of damage to forest ecosystems, huge amounts of property damage when fires take off and they're out competing these grasses.
1:23:16
This is a situation where I would say, let's think about how we might safely deploy something like a gene drive that can remove something or at least tamp something down enough to allow that ecosystem to become again once again more robust and resilient.
1:23:28
As far as you know, what do we think about adding things back into an ecosystem?
1:23:36
This is one of the reasons that every de-extinction project or every species transllocation project is staged and thoughtful.
1:23:44
When people moved Texas panthers into Florida in the mid 1990s to try to stop Florida panthers from becoming extinct, they had developed crooked tails and cowicks and crypt orchidism.
1:23:56
Their testicles didn't descend and they were going to become extinct.
1:24:00
This was an inbreeding depression.
1:24:02
There were only a few individuals, so they only bred with individuals they were related to. There was no choice.
1:24:07
You bring in the Texas panthers and the panthers recovered.
1:24:09
All of these diseases disappeared for a short period.
1:24:13
Now they're inbreeding again because the population is cut off from Texas and so they'll have to keep doing it.
1:24:19
We have to be the stewards of these ecosystems that we're creating. But that's in our power.
1:24:23
We can do a ton of analyses about potential risks and rewards of what might happen when we modify an ecosystem.
1:24:32
And we do it all the time.
1:24:35
Sometimes to good ends and sometimes to bad ends.
1:24:37
What we can't do, and I think this is sometimes where the conversation gets lost, is if you look around, we see habitats around the planet that are suffering because of changes that people have made.
1:24:55
Within those habitats, there are species that are teetering at the edge of extinction.
1:25:04
And the only strategy that they have to survive is natural selection, evolution and natural selection.
1:25:08
The rate of change of these ecosystems is too fast for that to work.
1:25:13
for that to work. If we say these technologies that we have whether it's transllocations or assisted reproduction or genetic modification and synthetic biology and deextinction if we say that those technologies are too risky we are accepting the outcome of doing
1:25:33
nothing which is also a decision and I think that's where a lot of times the conversation gets lost doing nothing is not not deciding doing nothing is saying we accept the fact that we are going to have a future that is less biodiverse than the present. >> It's amazing how people are perfectly
1:25:50
>> 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 to a potentially better outcome.
1:26:04
I think it gets back to this issue of trust in scientists and it also raises the question of who decides.
1:26:11
I'm very opinionated about this when it comes to public health policy.
1:26:13
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 right >> people need to hear from a group including the denters in that group >> and why they arrived at a particular decision >> I should be clear for all of the species
1:26:35
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 people who are
1:26:49
scientists and conservation biologists and we have regular meetings with all of our different advisory groups to talk about what the future might look like well before we have a philyloine to be able to to release anywhere. Our MOA
1:26:59
Our MOA project is led by the Nitahu Research Center in South Island of New Zealand.
1:27:06
And these Maui people are the people who will be the long-term stewards of the MOA.
1:27:10
And the decision about how many to make, which MOA to make, where to release them, how to release them, it's it's their decision um in consultation with other people who will be impacted by this.
1:27:20
And I think that's really important.
1:27:22
The other thing that I think we do well is this, right?
1:27:23
I mean, I am not a scientist hiding up in an ivory tower somewhere.
1:27:30
I'm here talking to you and talking to as many people as I can to tell people all about what we're we even get yelled at for this.
1:27:37
Why is Colossal always talking about what Colossal is doing?
1:27:40
Well, would you rather we not tell you?
1:27:41
I mean, >> I think the education piece is the critical piece.
1:27:44
I think it's great that Colossal is doing this. >> I mean, it is true.
1:27:48
I I think we are all desperate for 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.
1:27:59
And there are a bunch of people who were like, "Wow, I can't believe you learned from a bone and actually use the tools of synthetic biology to engineer extinct traits into a living animal and now you have living direwolves." Right?
1:28:10
And there were people who were scared of it and people who loved it.
1:28:13
And there were a bunch of people who said the word extinction and synthetic biology for the very first time in their lives.
1:28:20
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.
1:28:30
Some of them were mad and some of them were excited, but they were talking about it.
1:28:34
And they were talking about it as if they had some agency in the world that they were inheriting.
1:28:39
And we hear that from middle schoolers and high schoolers.
1:28:43
And I think that is really something tremendous about what we're doing.
1:28:46
People need to feel excited and positive and they need to feel awe.
1:28:52
And when I saw the direwolves for the first time, that's what I felt is genuine awe, right?
1:28:57
And there's something about that that just makes the world a better place.
1:29:02
It makes people happier and healthier.
1:29:04
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.
1:29:10
As long as we're waiting into deep water here, let's talk about the really deep water, uh, which is humans.
1:29:18
>> Okay, >> so we have this thing called IVF >> where people can make embryos and select what are deemed at this point healthy versus unhealthy.
1:29:28
So people are doing genetic selection in humans through technology, right?
1:29:31
People don't really stop too often and think, oh yeah, you know, how is that disrupting the human ecosystem in any different number of ways?
1:29:40
But a few years back there was a a guy in China actually who had been a postoc at Stanford who decided to use gene editing to modify the genome of some babies disrupted the HIV receptor and there are two stories about this.
1:29:53
I don't know which one is true.
1:29:55
One story is that they did it for benevolent reasons to prevent these babies from getting HIV from an either an infected parent or to just protect them against >> father was HIV positive.
1:30:06
The other story that was running in parallel was that there was that this uh modification uh might have some impact on hippocample or other brain circuit function that might make them hyper intelligent in one dimension.
1:30:20
So this was kind of more of like a eugenics experiment. That was the idea.
1:30:23
And it was very interesting how this emerged.
1:30:25
Not in the general public, like that was interesting in its own right, 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.
1:30:39
>> Yeah, I remember this.
1:30:39
It was Antonio Regalado broke the story about a week before the big crisper conference. >> Yeah.
1:30:44
There were these emails that suddenly came out and and it was very clear like people were kind of tap dancing around this guy like what's going to happen to him?
1:30:49
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 like he's he's blacklisted and turns out it was the latter right and the Chinese government said yeah we're going to shut down his lab he's going to be punished
1:31:07
>> I don't know what's happening if he's running experiments or if he's in prison or what's happening but 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 nonIVVF babies and I have people coming up to me saying, "Hey, guess what? [clears throat] We just got to screen
1:31:28
[clears throat] 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 which of them is going to be this and which one and that."
1:31:38
And so some of these companies are geared towards ruling out disease, >> right?
1:31:43
>> Others are geared towards trying to optimize for best possible outcome.
1:31:48
Right >> now, this gets people riled up because it's very expensive at this point.
1:31:50
So that has other implications, >> right?
1:31:54
>> And it's easy to say, oh well that's like eugenics.
1:31:56
But when people select who assuming they do it voluntarily who to have children with, they're selecting on the basis of a number of features.
1:32:06
some physical, some emotional, some resource related, some cognitive, you know, and so >> there's a lot of this happening happens in the animal kingdom and in humans it's happening now at the level of genetic sequencing.
1:32:20
And I think we're headed for big discussions about ethics about changing quote unquote ecosystems, >> right, >> through genetic selection of humans. It's started. It's happening.
1:32:29
There's a really fascinating story that comes partly out of ancient human DNA literature and speaks directly to this this idea that I think we feel uncomfortable with things.
1:32:39
We feel comfortable with new technologies initially because there's kind of this reptile brain thing going on where first we have to decide if we're scared of it before we can decide if we're curious of something, right?
1:32:48
So there's initial push back there.
1:32:50
But we are doing as you say genetic selection on humans by choosing our mates and it makes us uncomfortable even to think about that.
1:33:03
But here is a relatively benign example to show that that's true and it has to do with human height. Right?
1:33:11
So we know 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 and so that's hard but height is relatively easy and we know that it's heritable.
1:33:25
So we know that there's bits in your DNA that can mean that you're tall or short.
1:33:30
I'm 5t tall, so I didn't get any of the tall genes, right? I'm little.
1:33:32
But we know now by looking at the ancient human DNA that in Europe at least where there's a lot of very tall people in Northern Europe, right?
1:33:40
The the Dutch are extremely tall.
1:33:42
I remember going >> going to the Netherlands and imagining that I was going to be like speciating there where I would be walking in between people as they were above me, you know, like but like driving a tiny car where with a lot of big trucks on the highways and anyway, that's kind of what I feel like when I walk around in the Netherlands.
1:33:56
>> The Dutch are very tall, very kind, but very tall. >> Very tall.
1:33:58
But we know that a lot of these genes were first introduced into Europe with the step people at about 4,700 years ago at the Yam Nia and that originally they were migrating and for a long time we thought that people were just getting taller because of environment.
1:34:12
They were learning more about health.
1:34:14
They're learning more about what they should eat.
1:34:15
And yes, there is some truth to that.
1:34:16
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.
1:34:29
It's it's not in other parts of the world, right?
1:34:31
And so there is human genetic selection for a trait that we can visibly see that makes people look different from each other.
1:34:38
That isn't because somebody's picking an embryo and a sperm in a dish.
1:34:42
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.
1:34:49
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 we pick, we engineer to have different traits because they have different roles in the society because we have created the roles for them in society. We created them.
1:35:11
They were once greywolves.
1:35:11
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.
1:35:20
And this idea that one generation might do something to take that away from the next generation just sits really uncomfortably with us.
1:35:30
uncomfortably with us. It's wonderful that you're doing public education on these things because I think people really need to understand that um there are well-meaning scientists who are not just trying to figure out you know what would happen if and I [snorts] think that it's clear that there are going to
1:35:44
be more things like this right and so we we have to navigate forward with that similar to AI it's not going anywhere just like smartphones aren't going anywhere and and the question is what is the best use of this the safest uses and where can it evolve our our thinking in our lives in really unforeseen ways in unforeseen positive ways. >> We're really only just beginning to see
1:36:03
>> We're really only just beginning to see this.
1:36:05
I mean, you know the story of baby KJ, the first child who was cured of a genetic disease using the tools of synthetic biology.
1:36:13
This was a child that was born with um ura cycle deficiency.
1:36:18
He his blood was building up in ammonia.
1:36:20
And because people 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 academic industry NIH the children's hospital Philadelphia where he was born this huge collaboration came together took six months designed a base
1:36:44
editor crisper base editor to target his particular cells come up with a delivery mechanism to get it into his liver, do all of the testing that you need to do to make sure that it's safe, and then give him a crisper medicine, a bespoke crisper medicine as a six-month old kid, three times, and he is cured of this disease and will live a normal life. >> Amazing. And no one accuses those >> Amazing.
1:37:04
And no one accuses those doctors of playing God, >> right? That's what's so funny.
1:37:08
I I mean, here I guess we're sort of exploring in the background like what what establishes >> why is that not playing God in the same way that anything is playing God?
1:37:17
I think we play God every day and you know and in Judaism there's actually the idea that you're supposed to take care of the natural world out there.
1:37:26
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.
1:37:34
When we took a greywolf 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.
1:37:44
as we took tacente and turned it into corn.
1:37:48
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.
1:38:01
These are all decisions we make that fall into that category of exerting human influence on the world.
1:38:07
But the world today is a human world.
1:38:09
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 for it.
1:38:18
And we need to just deal with that and get better at it.
1:38:21
Use the tools at our disposal.
1:38:25
>> Can I ask you about ferrets? >> You can.
1:38:27
>> And I also want to talk about stuff that lives underwater.
1:38:29
That ecosystem has all sorts of issues that it needs to deal with.
1:38:34
Humans probably have to intervene really quick or we're going to be in trouble.
1:38:37
So ferrets, they're not rats, they're carnivores, great binocular vision, great hunters.
1:38:41
But a few years back, the blackfooted ferrets were almost extinct.
1:38:45
My understanding, this might be wrong, was that it was that the prairie dog population got out of control when the numbers of blackfooted ferrets were were diminished.
1:38:56
And as a consequence, the grasslands were being eaten up like crazy.
1:38:59
And that had all sorts of downstream negative [clears throat] consequences.
1:39:02
So it was important to reestablish the blackfooted ferrets, not just cuz they're cute.
1:39:05
And my understanding is that it was one ferret Scarface who sired like 300 litters [laughter] uh or more and they were able to resuscitate or at least partially resuscitate the population.
1:39:16
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 uh one male siring all these all these litters since you get a bunch of kits and they're mating.
1:39:31
But mating of close relatives is bad for genomes for reasons that sort of emerged earlier is you get homozygosity.
1:39:38
You get genes that are too similar and then if you have most people dominant alals, you know, where you only need one copy, okay, uh that's a separate matter.
1:39:47
But when normally many mutations, you need two copies recessive alals.
1:39:51
But if you get genes that are very similar between brother and sister, you're likely to have two recessive alals and you get bad mutations and >> you can get deformities and sterilities and low IQ.
1:40:00
It's a very interesting thing that throughout all species inbreeding is bad >> to a point.
1:40:07
The the island foxes, 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.
1:40:26
And they have almost identical genomes.
1:40:29
They have almost no genetic diversity and they are perfectly healthy. Wow.
1:40:33
Now I don't know if something happened to that habitat if they wouldn't be able to survive because there's no diversity of if a disease came in they would all be susceptible rather than some versus not.
1:40:44
>> And that's a very protected region.
1:40:44
I know that because my college girlfriend was environmental studies major and they used to go out there and it's very protected.
1:40:51
You can't just like take a boat and like stomp around the those islands. >> But it's fascinating. It is fascinating. It is fascinating.
1:40:57
In general, my understanding is that reading with close relatives is bad. Really bad.
1:41:01
Certainly for humans, which is why in Iceland and Scandinavia, there's these incredible genetic records dating back to when there were fewer foreign opportunities to mate with pe foreigners, right?
1:41:11
We were going to [laughter] be blunt about it.
1:41:14
So, what's the deal with these blackfooted ferrets?
1:41:16
Because it's an example of this a dynamic tension between trying to reestablish a population and wanting enough genetic diversity. >> Yeah.
1:41:25
And it's also a great example of how we can use multiple tools um that we have for genetic rescue simultaneously to help a species.
1:41:31
I should say that the Blackfooted Ferret Project is not something that I was personally involved with.
1:41:36
This is a project that's been a collaboration of US Fish and Wildlife and the San Diego Frozen Zoo and Revive and Restore, which is a nonprofit conservation organization.
1:41:43
I was on their board for a long time and they're doing really fun work.
1:41:46
But the story is interesting.
1:41:48
The story is that the prairie dogs, which blackfooted ferrets eat, were a real pain in the butt for farmers.
1:41:54
And so they wanted to get rid of prairie dogs.
1:41:56
And so they set out all these ways of just trying to kill a whole bunch of prairie dogs.
1:42:00
And it killed a couple of prairie dogs, but it killed almost all of the blackfooted ferrets in instead.
1:42:04
And so we ended up with a situation where blackfooted ferrets were nearly extinct in the wild.
1:42:11
People brought them into captivity, but they could not figure out how to get them to breed in captivity.
1:42:15
And eventually the last captive animal died and then the last wild animal died and they thought the species was extinct.
1:42:21
It was actually on the I think it's the class of 1966 the first list of endangered species when the endangered species act first passed.
1:42:29
Blackfooted ferret was but then like a decade later Shep the family dog of a family that lived outside of Matitzi Wyoming killed a blackfooted ferret while it was out one night.
1:42:41
And the the story is that the family took it in to a taxiderermist and they were like we want this cuz it's kind of cool. Like what is this?
1:42:48
And the dude was like uh uh I'll be back.
1:42:49
And he went back and called somebody and was like I think we have a you know this extinct species here.
1:42:56
And it was proven that it was a blackfooted ferret.
1:42:58
So there was a population that persisted around Matiti Wyoming.
1:43:02
people started studying this population again and they went and they collected a whole bunch more individuals, brought them into captive breeding and knew more about this.
1:43:12
It was a real international push to figure out how to make these animals breed in captivity.
1:43:16
But then they noticed that the animals in the wild started to get sick and in a last stitch effort to save them, they went and collected every individual that they could find in the wild.
1:43:25
And I believe one of them was Scarface who is the one that eventually like bred with everybody and ended up having a bunch bunch of diversity. scarf face.
1:43:33
He had a scar on his little blackfooted ferret little. They are so cute.
1:43:36
I recommend everyone who's hearing this.
1:43:38
Look them up like pictures.
1:43:40
>> Don't get one as a pet. Trust me.
1:43:42
>> So, this is a successful captive breeding program and every year they can release about 500 blackfooted ferrets into the wild.
1:43:48
But there are two problems.
1:43:51
The one is what you mentioned and that is that there's not that much genetic diversity.
1:43:54
There were a handful of founders in this population.
1:43:56
All of them were from the same population near Matiti, Wyoming.
1:44:00
So they're already closely related to each other and over time the amount of diversity in that population is going to decline.
1:44:06
So a few years ago this collaboration of organizations got together and said there's a solution to this.
1:44:14
In the frozen zoo in San Diego there are tissue samples from that original captive breeding population unrelated to the individuals that were in Matiti Wyoming.
1:44:27
So different genetic diversity.
1:44:27
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 blackfooted ferret.
1:44:44
>> So, revert them to stem cells. >> Not in this case.
1:44:46
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, which is kind of like reverting, but you don't need the Yamanaka factors.
1:44:57
just need the egg to do this.
1:44:59
So, it becomes a cell that starts to divide and become all the different types of cells that make up an animal.
1:45:04
So, I think in 2020, Elizabeth Anne was born.
1:45:06
Elizabeth Anne was the first clone of 40-year-old tissues from an animal that had lived decades earlier.
1:45:14
She was not reproductive, unfortunately.
1:45:16
She was never able to have offspring >> by behavior or there was some biological wiring issue.
1:45:22
>> There was some wiring issue.
1:45:22
Her ovaries weren't releasing the eggs or something. I can't remember.
1:45:26
spirits are are have this induced ovulation thing too.
1:45:28
They have a kind of funny funny I mean to us it's funny to them it's perfectly normal >> but they did make another one and from the same line and that animal has reproduced and there were offspring from that that can be able to be introduced.
1:45:41
So so here we have a solution to introducing genetic diversity into a population that had lost genetic diversity on the path to extinction.
1:45:50
But there's another problem, and that is that the thing that's actually killing the blackfooted ferrets in the wild is plague. >> Bubonic plague. >> Plague. Yes.
1:46:01
>> That's another reason you don't want to have a ferret as a pet.
1:46:04
>> Well, definitely not a blackfooted ferret.
1:46:05
[laughter] I mean, the the European I you don't want to send me off on a thing.
1:46:08
I had a pet ferret leave many years ago and I don't you were going exactly where I'm going. >> Domesticated ferret.
1:46:14
It was not the It was not the blackfooted ferret.
1:46:16
Domestic ferrets are not susceptible to plague and that susceptibility must have some genetic underpinning.
1:46:26
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 blackfooted ferrets and make them resistant to plague.
1:46:41
So, not only use cloning, a form of genetic rescue, but then also synthetic biology to create animals that are able to survive in this habitat despite that people have mucked with that habitat in a way that makes their survival hard.
1:46:54
We can use these same tools for for lots of different things.
1:46:58
We have a project related to our dodo project with the maritian pink pigeon.
1:47:02
Another >> is it actually pink? >> It's pink. It's very pink.
1:47:03
Um, >> when you pick cool animals to wear, you're like woolly mammoth, dodo bird, pink pigeon.
1:47:08
pink pigeon. you [laughter] like you know you guys know how to you know uh get >> part of part of it right dire wolf you know [laughter] and the direwolf thing my understanding is that it was also on the heels of like the game of thrones popularity so that that was like a piece if you weren't going to make a dragon you might as well make a very large wolf
1:47:23
because it has these kind of connotations >> when I was working on the first direwolf genomes in way before I was involved with colossal but the very first time we published direwolf DNA we were desperate to sync the publication with some editor in some you know science journal to the Game of Thrones coming out, we were like, "We can get this genome done. Surely they'll be they'll want our paper
1:47:42
Surely they'll be they'll want our paper because then they can have some press attention to the dire paper."
1:47:46
We never got the DNA finished in time to do that.
1:47:50
It was the so poorly preserved.
1:47:50
They lived in warmer parts of the world and so it was really hard to find samples that had high quality DNA to be able to get.
1:47:59
It was a fun project though. >> Were the babies cute? >> Yes. >> Yeah. Okay.
1:48:02
[laughter] They didn't come out ferocious. Yeah.
1:48:03
No, they were putting a plug in for them. Wolf here. Extremely adorable. >> Yes, I bet.
1:48:10
Everyone loves a baby animal.
1:48:13
>> Well, that's how we got dogs.
1:48:13
I'm pretty sure they were hanging around outside cleaning up after us.
1:48:16
Um, giving us a little bit of advantage cuz if something scary came like a giant cave bear or something, they would howl and we would our ancestors would know.
1:48:24
But I'm pretty sure that that was just commensal.
1:48:26
We could have lived for a long time with them living around us and us living around them.
1:48:32
>> But I think their puppies were cute.
1:48:34
Yeah, you make a really good point.
1:48:34
I mean, you know, this notion like the the eyes of the getting rounder like in the in dog breeds, you know, because people like them.
1:48:42
I mean, all the doodle breeds, the hypoallergenic breeds, they don't have fur.
1:48:46
>> I think about that sometimes cuz I have two Labradors and so my house is permanently coated in at least one layer of dog shed hair fur.
1:48:51
[laughter] We're so comfortable as humans to uh modify species for our immediate convenience, but sometimes that's obviously detrimental to entire populations.
1:49:04
You're talking about reintroducing uh species that have not been there in a long time or or expanding their numbers.
1:49:09
I would like to think that with AI or other modeling tools that you could make predictions, not perfect, but better predictions about, okay, let's model in the mosquito population, the where the swamps are, what the seasons are like, what the qual population looks like, and you could put you can model as many things that you're aware of.
1:49:33
There's no graduate student, no matter how brilliant, or professor, no matter how brilliant, that can mathematically model all the different influences of all these different plant and animal species.
1:49:42
But my but AI can run it 24 hours a day, 7 days a week.
1:49:46
>> 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.
1:49:51
I think this is totally within the realm of feasibility.
1:49:55
feasibility. It's big foundational model but I I know there are groups of people who are working on this for for smaller systems like individuals to think about human medicine how what happens in this system this particular organ system if you perturb it in this way and using AI
1:50:10
to be able to narrow down the window of what edits might be reasonable to make and what might others I mean we're doing other things we have a completely independent group of people that make what we're calling our care reports which are deep dives into the ecosystems where we would releasing any future deextinct animal. We we release these when we have them
1:50:28
We we release these when we have them with the blue buck.
1:50:30
We have a blue buck 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.
1:50:38
And it involves conversations with local stakeholders and conservation biologists and people who are thinking about it from all sorts of different perspectives.
1:50:46
So, it's absolutely, as you say, critically important to think hard before doing things, >> but also be willing eventually after you understand as best you can what that risk was. >> Yeah.
1:50:58
Along those lines, I predict in probably 3 to 5 years, not 10, the technology that we were talking about earlier of of mutating the HIV receptor, that sort of thing will be very common place in the context of fertility.
1:51:11
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 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.
1:51:28
No, nobody wants a a harder life for their child, >> right?
1:51:32
You know, it could also come I I I've thought about this when my my last book is called Life as We Made It.
1:51:36
And it's all about how we've been messing with the species that we encounter for as long as we exist.
1:51:41
In the last chapter, I think about how we might turn our editing technology on ourselves.
1:51:45
Um, really asking the question, what is it that will push us over that edge? Right?
1:51:52
>> One of the possible scenarios is that we have a, you know, a pandemic, a crisis, and we learn that there are certain people who have a particular genetic variant that means that they will die.
1:52:03
And suddenly the most morally reprehensible thing that we could imagine doing becomes the actual only ethical solution.
1:52:10
And that is the thing that pushes us over the edge.
1:52:14
>> You mean so you're talking about more people dying or rescuing that through a through gene editing >> gene editing ourselves. Yeah.
1:52:20
>> And now we're talking more about public perception scientists and implementation and and where those intersect.
1:52:24
And I think that one thing that I've learned is that a lot of it is about the delivery method.
1:52:30
delivery method. So when we hear about gene editing and you're taking a cell and you're putting in a dish and you're or even Ixie what you described before like you know um the in in a dish of you basically injecting a sperm cell into a into an egg as opposed to running a sperm race right people are a little more comfortable with that than they are
1:52:47
like the Ixie it's like this one we're taking this one already because you're biasing an outcome in a strong way right 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. >> Yeah. No, I think people are comfortable >> Yeah.
1:53:05
No, I think people are comfortable with it now because it's been around for a while.
1:53:09
>> It's this every new technology you have your first is it scary like why do I hate this before? Let me be curious. >> Yeah.
1:53:15
I mean in a in a different conversation but one that is relevant.
1:53:18
You know, it's fortunately we're not talking about it today, but you know, I get asked about peptides like every 5 minutes these days.
1:53:23
And not the peptides of the GLP sort, but what's happened in the health space is that the GLP drugs have dstigmatized and taken away needle phobia by putting the it's still a needle, but it's on a pen.
1:53:36
And so now people are like, "Which peptide should I take?"
1:53:39
I'm like, "How do you get it?"
1:53:39
No one's saying like, "Is there a capsule version anymore?"
1:53:42
That was a big thing, right?
1:53:44
And now if you're like because it turns out it's the hypodermic part, not the needle that freaks people out.
1:53:47
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, right?
1:53:54
So now people needle phobia has plummeted and people are willing to explore things that some of which there's good data on, some of which there's like no data and people are pinning themselves all over the country, right?
1:54:06
And so it turns out that something this couldn't have been predicted that there was this other thing that was getting in the way.
1:54:12
It wasn't really the thing about taking the the peptide that may or may not have enough data.
1:54:17
There are a lot of data on the GLPS, but it really was the delivery method.
1:54:22
We saw this with computers, right?
1:54:24
They were big clunky things.
1:54:24
You had everyone had to use the same one.
1:54:27
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, right?
1:54:32
>> Same thing with brain machine interface.
1:54:33
As long as people think you need to drill into the skull or put something a wire behind the ear, pretty soon this will be non-invasive, >> right?
1:54:39
And then people aren't thinking about, oh, it's going to control my brain.
1:54:42
So the big fear wall tends to come down to zero through these things that are hard to predict.
1:54:48
And it's often a combination of the messaging and kind like like maybe everyone should pet a dire wolf just once, just a little bit.
1:54:59
>> Would you would you like to pet a dire?
1:55:00
>> I would love to pet a dire especially the little ones.
1:55:01
But you know, >> you should come visit us in the lab and you'll see some of the really cool stuff we're doing.
1:55:05
The artificial wombs, our really cool artificial eggs.
1:55:07
You know, there's a >> you have artificial wombs.
1:55:11
>> We have one of >> I realize this is going to terrify people.
1:55:13
I'm a biologist, but Okay, so describe to me an artificial womb and what that looks like.
1:55:17
>> Right now, we're thinking about about mice, right?
1:55:18
So, 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 with mammoths.
1:55:29
We need a way to be able to birth multiple mammoths simultaneously without using elephants.
1:55:36
Elephants should be allowed to make elephants, right?
1:55:39
>> And so we'll need to build the technology to do this.
1:55:41
But building that technology is also an opportunity to build technology that can really help people and can help other species, but really thinking mostly about people.
1:55:51
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.
1:56:03
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?
1:56:11
Or if a baby needs surgery, but you can't really do it inside, have a safe way to have that baby come out.
1:56:17
These are all technologies that are will be feasible in the future that are motivated by deextinction. How crazy is that? >> It is wild.
1:56:25
One one of the most incredible things that I've witnessed is a a niku.
1:56:30
It's a different form of what you're describing, but it's incredible.
1:56:34
Like you go in these places and it's room upon room and it's super quiet and you know they try and keep it dark and there I mean like these are artificial wombs so to speak, right?
1:56:42
These are so preey babies and some of which are very preey.
1:56:46
Some have issues and some don't.
1:56:48
Some are just early which is an issue of its own own kind.
1:56:50
But the niku technology has come a long long way.
1:56:55
It's you know far from perfect but that's essentially what you're talking about right? >> Yes.
1:56:59
a more sophisticated NICU where the we've learned so much more because of the complimentarity 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.
1:57:22
I mean, it's a 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.
1:57:38
>> There seems to be a theme lately in my life where people come on this podcast and they're talking about revolutionizing education.
1:57:42
We had someone uh the principal of Alpha School come on here.
1:57:46
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. >> Cool.
1:57:54
I need that >> two hours a day.
1:57:55
Then they go like learn how to farm, start businesses.
1:57:57
It was interesting that public reaction is very divided on that.
1:58:01
People say great and then other people say, "Oh yeah, but it costs a lot so it's only for rich kids."
1:58:06
And it turns out they're starting scholarship programs.
1:58:07
And but the idea there is to figure out the best way to educate humans and then wick it out to everybody.
1:58:14
But so but there has to be this pioneering spirit and that's always going to stimulate concern and there's going to be the halves and have nots things in people's minds.
1:58:21
I think about your work in in a different but similar vein where being a pioneer is hard because you have to tolerate people saying and and a lot sometimes the assumption that oh you're doing this just for your own self-interest.
1:58:35
It's all financially driven and what about the you know what about the starings that you know need our help right now.
1:58:42
There's always this like what about the things that need our help right now. Why are we doing this?
1:58:45
And I don't have any great solutions uh for you on [laughter] this, but I think that public education is clearly a big part of it.
1:58:51
And I think the humanizing it at the level of who's doing it.
1:58:55
Like it's very clear that you love biology.
1:58:57
It's very clear that you like hard problems in biology.
1:59:00
And it's very clear that if I may, it it seems like you ra you're not afraid of but you rather enjoy the the fantasy positive outcome part of it.
1:59:10
It's not all doom and gloom. I mean this is similar.
1:59:12
This example works for me.
1:59:15
Hopefully it works for you.
1:59:17
You know, like Elon wants to go to Mars and I have guests on the podcast that say like no, he should be curing humanity here.
1:59:23
And and I I told that person that's like telling you know the Metallica they should be the Grateful Dead.
1:59:30
They we need individuals who are thinking in a different way steeped in really good ethics and are excited about the problem to evolve this thing that we call life on earth. >> Sure.
1:59:40
And I'm I'm good with that if people say to me, "Oh, why are you working on this?
1:59:43
You should be curing cancer."
1:59:45
Those are two different although you know there's things you know what quit this I don't know you but quit this and go cure cancer.
1:59:50
Well, I mean, we are learning things from elephants, for example, that we have to know about and that is actually relevant to curing cancer, but that's not our main I'm not focusing on curing cancer.
2:00:01
But people who say you should do this instead of saving living species, I I just really have to push back on that. We are doing both.
2:00:07
There is not enough money in conservation. There just isn't.
2:00:13
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.
2:00:24
I mean, why why is this not embraced?
2:00:27
Why is it always the well, you must not be doing that, right? >> We are doing that. the direwolves.
2:00:32
When we announced the direwolves, we announced that we had cloned red wolves, which is the most endangered species of wolf in North American, endemic wolf that again is living in a very small population, captive breeding in the Carolinas.
2:00:46
We had colleagues Bridget von Halt um who works at who's at Princeton, who had discovered a population of coyoteike animals that have a bunch of redwolf ancestry, some on the order of more than 75% redwolf ancestry.
2:00:57
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 be able to clone and generate our direwolves.
2:01:13
Have you heard about our red wolves? >> No.
2:01:15
They were announced at the same time though.
2:01:17
So all these people who are like you should be doing this instead of this, pay attention. We are.
2:01:23
>> They saved the ginger wolves. I love it. Yeah.
2:01:26
Yeah. There's something that I think people need to understand about scientists and probably technologists too but that's not my uh area which is the person matters like the person doing the work has to be really really drawn to almost obsessed with the project because you could sort of ask like for
2:01:44
any scientist there are a lot of scientists working on kind of pedestrian stuff in my opinion used to review a lot of grants for NIH and you go like eh sometimes those will get funded sometimes not but but that's the kind of science that certain people do they want to turn a crank and then there are
2:01:58
certain scientists who really want to be out on that like really cutting edge and they have to be obsessed with the question otherwise you get nothing in the same way that I think Elon's pretty obsessed I don't know him but with this going to Mars thing and I don't think he he's got a bunch of other stuff going on
2:02:13
clearly but you can't really draw him off target by saying hey why why aren't you working on curing cancer or building I guess he is building flying cars so the example of musicians to me just works like you you can't get Metallica to play the Grateful Dead happily. They're just not going to do it. It's
2:02:27
They're just not going to do it.
2:02:27
It's not in their spirit.
2:02:29
It's not in their their soul to do it that way.
2:02:30
And so I think that like we have to accept this about people and the people who move things forward.
2:02:38
Like Howard Hughes, the very Howard Hughes, right?
2:02:39
He liked his aircraft, right? He liked you.
2:02:41
You can't convince people like, "Oh, you should be saving the coral reefs."
2:02:44
Someone else should be saving the coral reefs, but they need to be obsessed with coral reefs.
2:02:49
I mean, I'm stating the obvious, but I think from the inside I relate. >> Yeah.
2:02:54
Also, people shouldn't [clears throat] feel bad about not being able to do everything.
2:02:56
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.
2:03:03
You're not going to make an impact.
2:03:05
So, >> it's so interesting.
2:03:06
People love to tell other people what to do.
2:03:07
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, that are enchanted by what you've told us today, that are excited about these species and can imagine the positive outcome.
2:03:24
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.
2:03:32
So, where are the public education efforts outside of podcasting and whatnot?
2:03:37
Like, how many people are at Colossal?
2:03:40
>> There are about um 120 scientists and then there's, you know, other other people involved.
2:03:45
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.
2:03:53
We work with a lot of podcasters and we work with other teams of people making documentaries and films.
2:03:59
We publish papers using the traditional old school peer review process.
2:04:04
We post some papers on the archive if we think it's important to get the information out faster before peer review.
2:04:10
So, we're trying lots of different methods of communicating.
2:04:13
And of course, I go out and talk to people and I'm a National Geographic explorer.
2:04:19
So, I do I take part in the National Geographic live series.
2:04:20
So I've gone and just talked to communities about, >> you know, conservation and genetic rescue and deextinction and a future that can be both biodiverse and filled with people.
2:04:31
>> 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 what how I felt when I went to Cambridge.
2:04:41
I'm like, that's Darwin's house or like there are two ways to be in that kind of environment.
2:04:48
like whoa that that's so and so and there's this history or was it 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 kind of lead the witness here.
2:04:59
So what were you like as a kid and in graduate school?
2:05:02
Were you thinking, you know, this this field, this whole zoologology thing feels kind of steeped in old stuff and I want to break it open or Yeah.
2:05:12
[clears throat] Like maybe just tell us a little bit about your mindset in in uh these kinds of >> my origin story.
2:05:16
I think I always disappoint people with my science origin story.
2:05:20
I went to the University of Georgia as a broadcast journalism major.
2:05:24
I had worked for the local TV station in the corner of Northwest Georgia where I grew up.
2:05:29
I was on air >> in the mornings.
2:05:31
I did local cutins on headline news at 24 and 54 after the hour.
2:05:35
When I went to the University of Georgia, I was actually the news director of a local radio station that was there, which was not particularly well aligned with being a freshman at the University of Georgia.
2:05:44
We'll just say I was living in a dorm that had a shared bathroom and we would 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.
2:05:53
Do you remember these from the '9s? Like the >> Yeah.
2:05:56
So, I had an opportunity to take a class after my freshman year and it was an honors program class and it was geology and archaeology and it was a nine-week class and we started off on the east coast and learned about minerals, identifying minerals and and the sort of coastal dynamics on the coast.
2:06:16
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, right?
2:06:27
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 sites and anthropological sites and saw the impact of people on the ecosystem and the impact that we had on those people.
2:06:43
And I thought, this is the kind of story that I want to tell.
2:06:47
Maybe I want to be a science journalist instead of just a regular journalist.
2:06:52
The idiocy of people who think they're an expert because they've done something for a few years.
2:06:55
I was like, I already know how to be a journalist.
2:06:56
I'll just learn how to be a scientist, right?
2:06:57
And so I started taking science classes.
2:06:59
I ended up going to Panama, living on a place called Barrow, Colorado Island, and studying parasettoid wasps and wasn't doing anything related to genetics or really evolution.
2:07:10
and it was ecology, population ecology.
2:07:12
And I met somebody there who was starting up a lab in Edinburgh.
2:07:17
And [snorts] I thought he was really smart and interesting.
2:07:20
We put together this proposal of a 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.
2:07:29
So the question was, is the switch to inbreeding something that is intended to purge your genome of those delletterious alals like the Channel Island foxes?
2:07:39
like if we inbreed, we'll get rid of all that bad stuff that's accumulated.
2:07:41
Then we can go back to outreing. >> It's a pressure test. >> Yeah.
2:07:45
So, we designed this experiment.
2:07:45
I went back to the University of Georgia.
2:07:48
I was like, I'm going to go to Edinburgh.
2:07:49
This is going to be great.
2:07:50
Help me apply for these scholarships. And they said, cool.
2:07:52
Because I couldn't afford to go, you know, overseas for grad school. And I said, cool.
2:07:55
You can you can apply, 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.
2:08:02
So, I applied for the Marshall scholarship to go to Edinburgh >> and the roads.
2:08:07
And I did not get a first round interview for the Marshall.
2:08:10
So ended up not obviously being able to go to Edinburgh, but I got a road scholarship. So I ended up at Oxford.
2:08:18
>> So you are a true I think you're our first road scholar, you know.
2:08:19
[laughter] >> So I got a roads I ended up at Oxford.
2:08:22
I had no idea what I wanted to do or who I was going to work with.
2:08:27
And I met on my first few days there this guy called Alan Cooper who was a Kiwi.
2:08:32
He was setting up an ancient DNA lab.
2:08:34
This was one of the few labs at the time that was going to be built to be able to process these old samples.
2:08:41
And I was really excited about the idea of ancient DNA because it brought together geology and paleontology and storytelling.
2:08:50
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 or how the environment changed with rapid warming out of the last ice age.
2:09:04
And I was like, "This is the science I want to do." Plus, it was brand new. Nobody was doing it.
2:09:10
There were a couple of dinosaur DNA papers that had been published and proven to be false.
2:09:13
And it was really an opportunity to bring stuff together that hadn't been done before and just do something entirely new.
2:09:19
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.
2:09:26
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 you know otherwise really hadn't been thought of together.
2:09:38
I got into deextinction because everyone who works in ancient DNA is asked as the first question whenever they publish a paper.
2:09:49
This is you're working in ancient DNA.
2:09:51
We're doing stuff that's high-profile.
2:09:53
We get high-profile papers.
2:09:53
It's it's normal in science for this thing to happen.
2:09:57
You get interviewed by somebody from the media and the first thing they want to know is, "So, what does this mean about how close we are to bringing dinosaurs back to life?" Every time. Every time.
2:10:06
>> I'm more concerned about the blackfooted ferrets.
2:10:07
Frankly, [laughter] >> when I was researching my my second book, I was using the New York Times Wayback Machine, which is amazing.
2:10:13
Love the Wayback Machine.
2:10:15
And [snorts] I was reading the very first article about the very first ancient DNA publication in 1984.
2:10:23
Researchers from Berkeley in what was called the extinct species study group had managed to isolate using molecular cloning because this was precr days >> a tiny little fragment of DNA from the skin of a preserved quaga which is an extinct type of zebra >> and show that it was related to a zebra.
2:10:43
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.
2:10:52
It really set off all of the the stuff that became the dinosaur DNA days of ancient DNA.
2:10:56
The >> lead to forensics in >> all of the forensic stuff. Yeah.
2:10:59
All that came came out of this, too.
2:11:01
But when the journalist interviewed Alan 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.
2:11:13
>> The dinosaur question. Yes.
2:11:15
>> I mean, it is true that if you walk into the life sciences building at Berkeley, there's a T- fullsize T-Rex skeleton there. It's very cool.
2:11:20
People love the I've never been dinosaur obsessed.
2:11:22
I I can think of many more animals and human diseases that to me are more interesting, but this is like the why don't you cure cancer thing. So, >> yes.
2:11:31
Well, but I think we get to mammoth because as soon as people hear that and understand that we can't have dinosaurs because there's no dinosaur DNA, they they tend to settle on mammoth.
2:11:39
Either mammoth or saber-tooth cat.
2:11:40
Those are the two things that that we get after that.
2:11:44
But I think it's just because they're big, you know, it's it's this big thing.
2:11:47
We know they're extinct because our ancestors hunted them.
2:11:51
>> We know they're relatively recent.
2:11:51
We can imagine what they looked like.
2:11:54
They're in popular culture a bit.
2:11:54
And so it's a matter of of awe of interest.
2:11:57
it's a matter of of awe of interest. I think it's the size and scope that is uh they make us feel small and >> people don't like to feel small but mammoths make us feel small too I think but in a way that we we can appreciate >> yeah there's something about the psychology around this in terms of public perception and the dinosaur thing
2:12:14
I'm going to go with that people want the best for our species and other species on average they're a little scared based on for reasons that make perfect sense to me based on what they know and 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
2:12:31
I thought the direwolf thing was super cool. I still do.
2:12:35
>> You should come see them. >> I got it.
2:12:37
I'm not saying that I'm, you know, I, as a biologist, I got it.
2:12:38
As a, you know, developmental biology, I was like, I got it.
2:12:42
This is not like taking some human cells from the cortex and putting them into a mouse cortex.
2:12:46
Like those are cutesy experiments.
2:12:48
Frankly, I thought those experiments were more like cutesy derivative.
2:12:52
They didn't really inform or anything in my opinion.
2:12:54
But what you guys did, I thought was really cool.
2:12:58
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.
2:13:06
So, thank you for doing what you do, for continuing to do what you do.
2:13:08
I didn't even get into the fact that you walked away from a fully thriving lab in academia, Howard News Investigator, which is this thing that very few attain. and so to do this.
2:13:19
So clearly you're on a mission and I I have every anticipation that it's going to work out and work out for the best for animals and for people.
2:13:26
I'm excited to see what you guys do.
2:13:29
>> Thank you for the opportunity [clears throat] to have this conversation.
2:13:31
>> Yeah, it's a lot of fun for me.
2:13:31
I rarely can I talk about ferrets, woolly mammoths, dinosaurs, and uh human gene editing all in one conversation. Thanks so much. >> Thank you. >> Appreciate you.
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