- Could you take embryonic Hakeem, stick a needle in me, change instruction, and I now have fangs and venom?

- Yep.

(both laughing) (pulsating music) - Sean Carroll, welcome to Particles of Thought.

- Thanks for having me.

- Yeah, I'm so happy to have you here, man.

So you are an evolutionary biologist and you study the evolution of new species coming into existence.

And when I hear that, I think about us humans.

We've changed a lot in a very short period of time.

What are we going to evolve into and when?

(Sean laughing) - Boy, wouldn't we like to know.

- Yeah.

- It's hard to predict the course of evolution, because there's a lot of ingredients that go in.

For most of the story of life on Earth, the Earth changes and life changes along with it, and we're creatures of that.

We're kind of creatures of the ice age.

But then we started to control our own environment and that's now where, we're kind of in a whole different realm.

I would say, because we get across the globe relatively easily, we mix with each other very easily, I think our future is going to be one big, kind of intermixed population.

That's real different from the past when we had a lot more isolation, people on islands, people living in high altitude, all that kind of stuff.

That makes us all look more different.

I think in the future, that gene pool is all mixing, so maybe we're going to be a little more similar to one another, but I don't see any superpowers coming out.

- No.

- I'm just hoping we don't lose what we already got, which is libraries, the scientific method, little things that help us cope.

- Well, according to Stan Lee, we evolve into Homo superior and we do have superpowers.

Before we get too deep into the conversation, we're using terms and sometimes we say phrases all the time which makes us think we know what we're saying, but actually we don't.

I've experienced this in my field with the phrase Big Bang, and I think when people hear a word like evolution, a lot of people go, "Monkeys to humans."

Right?

"Not happening."

Let's go into what evolution really is and how it really works.

- Sure.

Evolution is change over time.

That's it.

Just let that settle for a second.

That's all it really is.

Change over time.

So you can think about those two things.

What do we mean by change?

Well, that's change in appearance, change in the properties of something, right?

And time, time's a big ingredient.

And time is really the hard thing for people to get their heads around, and Darwin really appreciated this, because in his day, where the entire mindset was one of creation or essentially instantaneous creation of things, he had really two big challenges which was to get people out of that mindset, to understand that natural processes were sufficient to explain what you saw in the world, and that there had been immense amounts of time available to do it.

And these were big scientific gaps, right?

And even Darwin who thought, oh, maybe the world was as much as 300 million years old, I mean, he was off by a factor of 10, right?

There was a lot more time than even Darwin realized, okay?

So let's just start with change over time and we can break that down in any direction you want.

How does the change happen, and then, small amounts of time, big amounts of time.

The degree of change is somewhat going to be proportional to time.

But things can change rapidly.

If things on Earth have changed rapidly, you'll see rapid evolutionary change.

If the Earth is fairly stable, you'll see relatively gradual evolutionary change.

- Oh, interesting.

Interesting.

Yeah, because I know there is that geological time that's called the Boring Billion just before the Cambrian explosion, so does that mean that geologically things were boring, so life was boring?

- No, well, I mean, I think any geologist sitting here would say, nothing's ever been boring about the planet because the planet has changed tremendously, especially things like oxygen levels, which means the metabolism of life has changed a lot.

I think the boring comes from just our perspective which is life was really small.

Life was microbial for those billion years, right?

- I see.

- So if you visited Earth from somewhere else during that billion before the Cambrian, you kind of look around and you go, "Okay, I see some algae, I see some bacteria.

Next."

- Yeah, it's not a, yeah.

- But we're animals, so we get excited by bigger things, right?

And animal evolution really kicks into high gear in the Cambrian.

And then when life gets to land, of course, then you get plants and trees and all this sort of stuff in the world that's much more familiar to us.

So that perspective depends upon maybe what kind of creature you are.

If you were a cyanobacterium a billion and a half years ago, the planet was wonderful.

It was paradise.

- Yeah.

Now it's kind of... - Now, I got to share it with all these clowns, yeah.

- And feed them their oxygen.

So the idea of new species evolving, like it's pretty obvious when a species goes extinct, there's no more of them.

How do you know when a new species has become?

- This is a great question.

This is a tremendously great question.

I think we kind of grow up getting species, a concept of species sort of very static and very, as though these are categories that are very cleanly delineated and that's it, and there's no mixing or anything like that.

But that's not the case.

In fact, I just saw in the news, it's a really cool story about the green jay and the blue jay, green jay from Mexico, blue jay is familiar to us here in the United States.

Hybrids have been observed in Texas.

And the hybrid doesn't exactly like either parent.

So when these groups can come in contact, even though we would've called them separate species, you can get hybrid forms.

- Okay.

- That's not like a cement wall necessarily between one population and another.

It can be a leaky barrier.

Now let's go to the speciation process itself.

When it's happening, how can you tell when something is split into two?

Because you got to realize that those populations are probably so difficult to distinguish from each other.

So if you take something like a mountain range or a river that might, a lot of species form because of isolation between populations.

- Right, yeah.

- So let's back up a little bit about process and say, all right, mountain ranges, or you look on different islands or something like that.

So if you start out with two populations that are really similar, and given time there's been isolation between them, they live on opposite sides of some kind of barrier, how do you know when there's different species?

- Yeah, what does that switch flip to?

- And it's not a switch because, A, I tell you it's a leaky barrier, and second of all, it depends on time.

And is there a little bit, is there just a little bit of intermingling between them which will sort of keep those barriers lower?

So we humans, we like to classify things.

It's useful to classify things as species, but we don't want to give people a hard and fast idea that these things are sort of some kind of absolute, totally self-contained population because they can mix.

And then in that process of speciation, it's a gradual separation of populations one into two.

So speciation is splitting.

One becomes two.

And that's happening all over the tree of life, right?

- Yeah.

- And it may be driven by different conditions that the two populations experience.

So maybe think about maybe up a mountainside, the things that are adapting to maybe, you know, near or above the tree line are different than those that are living below the tree line, and eventually they sort of divide.

We can see that happening with things like insects and all that.

But no biologist can walk in and say, "Well, this is the day.

This is the day that speciation happens."

It's a gradual change.

And for some population, say animals, it might be a two-million-year-long process of essentially becoming so distinct that there's no going back.

- You just gave me a movie in my mind, of an experiment, where you have these, you take one species separated on two islands, then you have generations of scientists observe them, and then you can say, "Aha!

On July 8th, 2027."

But even if you were to do that, would you do it based on taking two members and seeing if they mate?

Would you figure out that they were different species by looking at their genetics?

How would you figure that out?

- I think, functionally, we'd say two things.

If they wouldn't mate, okay, then that's it, they're separate.

There's no putting things back together if they won't mate.

Or if they mate and their offspring are inviable or infertile, then that's it, okay?

But often the case is going to be, and my prediction is this.

Let's say we'll do this with two birds on islands.

It's kind of been done a few times in nature, right?

And those scientists are on those islands a long time, 10,000 years, 50,000 years, a hundred thousand years.

I think when you do that experiment, they're still going to mate and their offspring are still going to be viable, 200,000 years, 300,000 years, 400,000 years.

Somewhere maybe half million years, million years, okay, now maybe they start to, their behaviors are different enough they're not going to mate, or they're genetically distinct enough that if they do mate the offspring aren't viable.

So that's the long gradual ticking of the clock, and what do we mean by ticking of the clock is that under isolation, mutations happen in populations, traits change a little bit, et cetera.

So eventually either behavior or biology may be different enough that you can't mix them back together again.

But there's a long window where things are permeable, right?

- Yeah.

- You started out with a question about us.

And one of the most mind-blowing discoveries in the last 20, 25 years was the Neanderthal contribution to Homo sapiens.

- Right, right, yeah, yeah.

- So for a long time we thought, "Okay, here's our species.

We're different from everything else."

Right?

- Yeah.

- But now we know, there's a little bit of Neanderthal in most of us, right?

- Yeah, and Denisovan.

- Yes, exactly.

So it's a much more complex history than just split, split, split.

The convenient picture of the tree of life is you just keep splitting species one in two, one in two, some go extinct, some keep going, et cetera, et cetera.

But those splits, they come back into contact.

- Ah, that's right.

- And why do they come back into contact?

Well, they come back into contact because we have a changing Earth.

Think about the ice ages here.

How many times in North America ice sheets have covered North America?

So that's going to drive life- - South.

- into refugia.

Into places that aren't ice-covered, and things are going to be mixed, and then the sheets retract again and things spread back out again.

And this population's on one side of the Rockies and that population somewhere else, and then here comes the ice again, back in.

So with a changing planet, you're going to have populations driven apart and populations driven back together again.

So speciation is, we'll just call it sloppy.

- Yeah, and not only that, we have a- - It's not a clean cleaving of one into two.

- Yeah, and the other thing that you just pointed out how these geological changes drive that, and since the time of Homo sapiens sapiens having civilization, we've been pretty stable.

We haven't had major geological upheavals like super volcanoes and ice ages hitting us.

So what we think now is a normal is not really a normal.

- Yeah, it's in a short little interval, right?

- Yeah.

- I mean, civilizations that last 10 or 12,000 years, or at least farming and domestication and all that kind of stuff, right?

- Exactly, yeah.

- But our species is 300,000 years old.

- Right, so they saw it.

- They saw some serious stuff, and they've been through a bottlenecks.

I mean, we may have been down to, I don't know, maybe 1,200 breeding pairs.

- That's what I've heard, yeah, around 900,000 years ago we were down to like 1,300.

- Yeah, under some climate duress.

Let that be a lesson to us all.

- It lasted about a hundred thousand years.

But it also talks about our resilience.

We made it through that and we got a lot more technology than those hippies, right?

I mean.

- Yes, we do.

We absolutely do.

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So there have been a lot of transitions that have occurred over life, these stories that we hear, right?

Going from land to air, animals going from sea to land and back to the sea.

There was even this idea that humans were water monkeys.

Remember that idea?

- Yes.

Occasionally comes up in seminars I give, but- - Oh, no way!

Yeah, yeah.

So how do these transitions happen and how long do they take?

If a tetrapod is going to become a whale or seal and then you have animals like otters that are somewhere in between, how does that?

- Well, it's the paleontologist, so that's a different branch than myself.

I'm not a fossil hunter.

You've had a really- - So that's where that story is written is right in the- - Yeah, that story's in the fossils and I think it's reasonable to think, I think the estimate, let's look at a big one.

Let's look at back-boned animals coming to land.

So fish to land, right?

Going from fin to limb, walking on limbs.

That takes longer.

And a lot of speciation events.

You don't just go from being a fish to an amphibian in one step.

You don't go from being ground-dwelling to flying in one step.

Roughly speaking, from the fossil record of various things, I'd say 10, 15, 20 million years to execute a change like that, because there's a lot of anatomy changing.

If you look at all the remodeling of the skeleton and you're going from something that's very flippery to something that we think is a little more digity, yeah, takes a while.

But the paleontologists are out there looking for the fossils that sort of mark that transition, and this has been, again, really an exciting time.

It's been a golden age for paleontology the last 30 years or so.

- Well, it makes me think of the animations you see.

The animation show a little fish and then they come up on the land and then they transform into an amphibian and then they transform into a reptile.

- Yeah.

- Each of those steps is- - It's sped up, yeah, but we know there are creatures that will live in the shallows and then maybe do a little air breathing when they're in the shallows, and you can start to imagine because other things are happening.

It's not just the limbs that are changing, for example.

You got to remember they got to breathe air, so they got to go from gill to lung.

How long do you think- - Yeah, so a lot of change- - that takes?

- will happen simultaneously.

- Yeah, lot of things are changing.

And then probably you're seeing the position of the eyes and the head changing from maybe being out here to being up top or being facing forward.

- What I learned recently was the limbs that splay out to being directly underneath.

- Yeah, you got to support because you come, gravity is different, right?

You come on to land, you got to support that whole body, whereas you're floating water otherwise.

- How does it happen then?

So all of these changes of gill to lung, fin to limb, and I would imagine if you are in water, then there are some sort of balancing act with salinity that your body has to undertake.

- Exactly.

Physiology is changing, et cetera.

Yeah, yeah, yeah, yeah.

- So how do those- - Diets going to change, right?

The whole thing, right?

What you're going to eat is going to change, the whole thing, right?

Yeah.

In fact, it might be food that's driving you onto land, right?

Sometime in scarcity you start finding, there's stuff on land you eat.

- Or you are the food.

Let's get out of here.

- Absolutely.

Let's get out of here.

- Like the flying fish or something, how does that evolve?

- So things are driving things.

- But what drives that from the inside?

So the story of evolution is, you have some advantage to become an adult and reproduce so you pass that trait forward.

- That's right.

- And so there's going to be some variation in that trait across that species.

So is it the case that it's very slow, although it's fast to you, or does it happen that these mutations are occurring and then the mutation occurs and, "Hey, look!

We've suddenly made a leap!"

- It's not very leapy, you know?

I think a hundred years ago, we entertained the thought of things could move in jumps like that, but it's really not like that.

When we really break down these transitions, it's a lot of anatomy that's changing, that's a lot of physiology that's changing.

And it's happening in increments.

And the increment isn't like, oh, this generation is 1% better, the next generation is 2% better.

That's even pretty fast.

There's going to have to be a lot of concerted changes, and we also see when these things are happening, lines go extinct.

You can see something kind of getting there, but that branch doesn't make it.

It's something else that does better and is a more direct ancestor to what we finally see on land and things like this.

So it's a process ridden with extinction, because in 10 million years, there's a lot of extinction.

Probably most species only last a million years or two.

- Oh wow.

Well, wait a minute.

So there's two ways to go extinct, right?

- I just want to get this picture.

It's not a one-way street.

That line that starts to make its way onto land, that's like a super lineage or something like that.

It's going to experience extinction as well.

Branches are going to die off, et cetera.

It's a messy process.

- So what about something like a mental change?

So apes going from Australopithecus to Homo habilis and now you're making tools and you're designing tools and you come up with multipart tools.

How does that?

- That's a great one.

Boy, wouldn't we love to know a lot of those details, right?

But look, what we do know, two and a half million years ago or so, we're starting to make tools.

That's fine motor skills, right?

And we're living a more visually-driven lifestyle.

So one thing you can see relative to other mammals is that our visual system is we dedicate a fair amount of brain space to visuals and, for example, less to scent.

So if you compare it with mammals that may make their way along the ground, even our favorite companions like dogs, et cetera, they're devoting a lot of brain space and a lot actually of genome to the things that are going to help them smell their way through the world.

We're kind of seeing our way through the world.

- So is this because we're upright?

Because you made this relation to the ground.

- We're upright, so we're away from odors as much, because if you're living close to the ground and if that's where your food is and you're trying to find scent trails, that's where your mates are, right?

So just, I mean, whether you think of a rodent or a canine or something like that, close to the ground, kind of smelling its way through the world.

Look, we use dogs to detect things.

They're so much better at it than we are.

Well, they've got a bigger repertoire of receptors for smell, and they devote more of their brain space to detecting these smells.

Well, we've adopted a different lifestyle.

We've actually given up a lot of the capability for smell that existed in more distant ancestors.

You can ask me later how we can see some of those vestiges.

And we're living a more visual lifestyle and the great apes have full-color vision.

So we're in a- - Is that unusual?

- Very unusual.

So other mammals don't have it, okay?

So there was an evolution, I'm going to go 25, 30 million years ago, where we picked up another light receptor in our retinas, but it connected to our brain.

So we can distinguish, for example, red, green, blue.

Well, really useful when you're grazing on leaves in the jungle and you can tell the ripe ones from the unripe ones, et cetera.

So we see in full color.

As I said, we're a more visual species and we've traded off that sort of smell-driven, olfactory-driven lifestyle.

And so when you say about change, this is manifested in all sorts of ways.

In the brain, how much is dedicated to visual processing versus olfactory processing.

In the genome, a mouse or a dog might have a thousand genes for scent reception.

We've inactivated hundreds of them.

You can actually still see them in our genome.

So in other words, we know they were there in our ancestor, and these are little fossil texts.

They're like little redacted texts, almost there, but with mistakes in them that have accumulated over time.

It's a really cool way to sort of look back at our past is that there are fossilized genes in our DNA and that's telling us about lifestyles of our past ancestors.

- So if by some alien invasion or something like that, we find, oh, we better keep your head below four feet off the ground, we still have that ancient genome in us to go back to smelling the- - Yeah, we'd have to do some repairs, which, of course, now we have technology to do those repairs to change our own DNA.

But yeah, the lifestyle of creatures and the lifestyles of their ancestors, this is something again that we sort of didn't imagine decades ago, is that in DNA we can see the vestiges of the past, may not be used anymore, but some of that text is still there in the DNA, and it's a really cool clue to look back and say, "Well, what were our ancestors doing that we're not doing anymore?"

- Well, what about conversion evolution?

So there are many species that fly.

So we have insects flying, we had flying reptiles, we have flying mammals.

So all of these created a wing of some sort, not necessarily the same physics with each one.

- No.

- So how does a wing, so I'm a tetrapod, but now I feel like I need to fly.

How do I go from being me with arms to me with wings?

- Well, they've all done it differently.

So pterosaurs, the dinosaur you're referring to, and birds, which of course were also flying reptiles essentially, and bats, the anatomical details are all different now.

They all had to create this, they had to create some kind of surface to catch air.

- Is it genetic?

The part of the gene that activates these?

- They've all done it differently.

- They've all done it differently.

- Okay, but they've all modified their forearm.

So they've all worked with this, but where they've made the webbing, essentially to create that wing surface, is different.

So you can sort of do this out more on the hand.

You can sort of create maybe a, and I got to think of my details a little bit and I'd have to almost check this, but bats, birds, pterosaurs, and this is why we know they're all independent inventions, is that when you look at the design of the wing, they're using different pieces of the forearm anatomy to create that wing surface.

You're inventing a wing, you're working from a similar starting point, but it turns out they engineered three different pathways, bats, birds, and pterosaurs to make wings.

Now the origin of novelty, the general thing that I'm interested and lots of evolutionary biologists are interested in is, okay, well, that's cool to look at the finished wing and go, "Wow, look at that pterosaurs, amazing!

Bats, amazing!"

But how does that even happen?

- Yeah, how do you get there?

- Okay, how do you get there?

This is a question that, it's really central to evolutionary biology.

It worried Darwin from the start, because he'd look at these things and he'd say, "Well..." His description of evolution was this very incremental process, and if you think about something like an eye or a wing, well, what good is half a wing, or what good is half an eye, right?

So how do you get there?

So you have to start thinking about, maybe it was first a little bit of membrane, it was a gliding surface, before you had powered flight, right?

We think about things that glide, like there's squirrels that glide.

There's snakes that glide for goodness sakes, right?

- Oh, geez, yeah.

- So we have to either think our way through what the value of sort of intermediate stages would be, and of course the paleontologists are trying to help us by actually finding the fossils that tell us what these intermediate stages looked like.

So that transition from fin to limb looks pretty good.

To wing is a little bit tougher, like bat wing, I mean those are tough fossils to find, like bat fossils or bat relatives and things like that.

We've got tons and tons of bird fossils, which I think, and we got a pretty good story about feather evolution, because we think, here's another thing I'll just jump into.

When we think about feathers, we think about flight.

But you may now know from finding dinosaurs that didn't fly but had feathers, oh, feathers came before flight.

So let's think about that one for a second, right?

Because, again, humans come in and we think like engineers.

We think, "Okay, I want to get up in the air.

How do I get up in the air?"

We design it, but that's evolution.

- No.

- No, no, evolution has to kind of improvise its way there, right?

And feathers are just a great illustrator of the evolutionary process, because they weren't there first for flight.

They were probably there for either insulation, maybe a little bit of display, maybe a little bit of camouflage, et cetera.

But as you start making these flaps or whatever, now you got something out there that can catch the air and then you start to evolve flight feathers.

- You're like, "Hey."

- So feathers are a great illustration of this thing of often in biology there's this process we call co-option.

We use something that first existed for some other use and co-opted into another purpose.

So evolution has to work with the materials that are already there.

It doesn't get to invent them from scratch.

In fact, evolution doesn't work from scratch.

It always has to work on the pre-existing materials, and so it, over time, fashions a way.

- Not even via mutation?

Not even via mutation you can't?

- Oh no, no, mutation is it.

So mutation is the fuel that gives you- - No, I mean like, could you, for example, have a mutation where suddenly your kid is born and it has feathers?

(Hakeem laughing) - That's a big step.

- Or a feather-like... - You could have a kid, it's more about, if you already had, for example, if you already had some kind of feather-like structure, yeah, you could have a kid with feathers all over, okay?

- Right, yeah, yeah.

- But to create a feather out of nothing is tricky.

- It's not going to happen.

What about getting rid of something?

Because if we look at the transition from fish to land animals for vertebrates, the fish probably had a dorsal fin.

So where'd that dorsal fin go?

- Stuff goes away all the time.

That's a great question.

That's a great question.

Because we often think about evolution being this process of accumulation of new stuff coming.

We're getting rid of stuff all the time.

You may notice, where's our tail?

- Yeah, exactly.

It's gone.

- Right?

Right, it's gone, right?

Because all our relatives did have tails, right?

- Right.

- So we've stopped that part of the developmental process.

We have the capability to make a tail, but we don't make it, okay?

- Right.

- So this goes on in evolution all the time is the loss of stuff.

- That is more common, you think?

Is it more common to lose than to repurpose?

- Yeah, I'd probably stick my neck out and say that, that loss is going on all the time.

Because as conditions change, it's essentially a case of use it or lose it in evolution.

- You think there's some efficiency principle underlying our design or the design of animals?

- Yeah, yeah, because either making that body part comes at some cost or operating that body part comes at some cost.

So if it's not contributing to performance, then here's the logic, mutations that start to inhibit its formation or reduce its size or whatever, those things are either of no cost to us or they're actually beneficial because we're not wasting energy building things that don't affect our performance.

So these things go away.

They go away over time.

So evolution, we can't plan for the future, right?

So we didn't hang onto our tails just in case we might need them, okay?

Right?

- Yeah, yeah, yeah.

- It can't wait.

It can't change that.

It's all sort of being weighed in the moment.

So things that enhance our performance or are important to performance, we retain.

That's that natural selection happening.

But things that don't affect performance, survival, reproduction, et cetera- - Get rid of it.

- those things go away.

Yeah, yeah.

So loss is really common when we look through evolution.

I mean, look at things, the creatures that are kind of marked by loss.

One of my favorite groups are snakes, right?

- Oh, no legs.

- Where are those legs, right?

Well, they became burrowing creatures, a whole lifestyle.

So they evolved from lizards.

So they evolved from four-legged animals, but you have this whole group of animals, they just ditched their legs, right?

Ditched their ears too.

- Oh, geez.

- Yeah, no ears on snakes either, right?

- Right.

- So yeah, loss is pretty common, at the same time- - So snakes are pretty efficient.

- Snakes are pretty efficient.

- They just reduced themselves to a tube with muscles.

- To a tube, they're a tube, yes, with great muscles.

But they've been doing a lot of inventing venomous snakes.

- Venom, yeah.

- Venomous snakes have been incredibly creative in the last 30 or 40 million years, inventing all sorts of venom toxins to take down their prey, and that's another example we see throughout the animal kingdom.

Independent examples, you know about spider venom, you know about bee venom, you know about scorpion venom, you know about venomous jellyfish and stuff, all independent inventions of venom.

- Wow.

- So these are new molecules that get invented.

Invention's gone on a time, but that helps those animals get their supper, and that's a really powerful force in evolution.

If you have a way to get your prey, you have a way to get food, this is like evolution almost in fast-forward.

- So language for humans is like venom for the other animals, right?

Because we can cooperate and hunt these- - In our culture today, language is very much like venom.

Yeah, I think you're making that analogy.

But yeah, venom is a special power that these animals have, and it's vital to essentially their daily being.

And yeah, language is something we came up with, walking on two legs and language, pretty big inventions, you bet, and vocalization to make that language.

- So let's dig a little bit deeper into these transitions.

So we have the transition of vertebrates going from sea to land.

So sometimes I come up with a crazy idea, it makes sense to me, and then I look it up later.

So my crazy idea I came up with was, hey, we have a tube that goes from our mouth to our butt.

We're all worms.

We just evolve this extra stuff around the tube.

But then I went and looked where did vertebrates come from, and the story was something about some filter feeder that decided not to become an adult, and in this larval stage, it was like a little tadpole, and it became the first chornate that eventually became something like a lamprey and then a backbone and then onto land.

It's an amazing story.

- It is an amazing story.

Yeah, those early stages of backbone creatures, a little harder to trace.

Again, it's how good is the fossil record.

As we get a little bit later, the fossils are great.

The fish record, and then the fish to transition to land record, thanks to some brave paleontologists out there who've gone to the far corners of the world, we have a lot richer fossil record now than we did just say 25 or 30 years ago.

- Really?

- Yeah, oh yeah, oh yeah.

No, we see this in much better detail than we had.

- Wow.

- Yeah, so I think probably the breakthrough fossil was something called Tiktaalik discovered by Neil Shubin.

- Wait, TikTok?

- Tiktaalik, Tiktaalik.

No, no, it had nothing to do with the social media app.

It has to do with Inuit language.

It was out of honor to the Inuits it was named Tiktaalik.

This was a fossil discovered in the Arctic that is just, if you had to draw a transitional fossil between fish and four-legged animal, this is it, right?

This is what you essentially dream up, and it's sort of a composite, or if you have, we call them fish and tetrapods, four-legged animals, tetrapods, you could say Tiktaalik is a fishapod.

Before I go into the detail, let me just give you the significance of this, the big picture significance.

When Darwin wrote the Origin of Species, he knew that his theory had a lot of predictions, and one of those predictions was that there should be intermediate creatures out there between the great groups of animals.

But he didn't have any.

I mean, he was essentially staking his theory, and he in his book he admitted, he said, "If these aren't found, my theory would be crushed."

- Well, that's great science.

He presented his old falsifiable prediction.

- Absolutely, and this is what made the Origin of Species one of the most remarkable scientific works ever is because he analyzed explicitly all the weaknesses of his own theory, like where's the evidentiary holes.

- That's so good, yeah.

- Now, amazingly, two years after the Origin of Species, somebody found this creature out of a quarry in Germany called Archaeopteryx, you may have heard about, which had reptile characteristics and bird characteristics.

It was a beautiful fit for Darwin's theory.

It was 150 years, almost 150 years later, that Neil Shubin and his colleagues, after a lot of searching, find this creature in the Arctic that has transitional features.

Its eyes are more on the top of its head as though it's kind of looking up as opposed to looking side to side a little bit, but there's changes taking place in its limbs.

And so to come to land, the fish lifestyle has to change quite a great deal.

It needs those limbs to bear the weight of the animal because it's up on all fours as opposed to floating in water, those articulated digits as opposed to just a flipper that you could imagine is clumsy.

If we look at things like seals on land, they don't look that agile, right?

- Right, right, yeah.

- Okay.

Right?

If you have a much more mobile paw- - So it had digits?

- Yeah, it had the skeletal makings of the digits.

That's what we see in Tiktaalik because it's a transitional creature.

It's not a full-fledged walking around tetrapod, but it's heading in that direction.

That's what we can see about it.

It has a neck that can move relative.

- Oh, fish don't have necks.

- No.

- Yeah.

- It's got a neck.

How about that, right?

- Wow.

- So those are sort of the giveaways of, it's definitely not a fish, it's not a full-fledged walking four-legged animal, but you can see it heading that direction.

That's why it's such a remarkable, what we call these transitional fossils because it's really marking a big transition between two groups.

We're not talking about between two species.

We're talking about fish to four-legged animals, one of the big transitions.

- Right, right, right.

If I could just insert here, when people criticize evolution, they want to disbelieve it, they will point out, they say, "Oh, we see microevolution, yes, but not macroevolution."

So what you're describing is what they would describe as macroevolution, evidence of macroevolution.

- Yeah, you're seeing the big transitions between the big groups, the big classifications, the big categories, in this case of animals, you're seeing these transitional forms.

So I'm just describing you the features of this creature that sort of tell you a little bit about its lifestyle and how's it different from a fish and how's it different from a four-legged animal.

But the evolutionary process is also what's going on.

How do you change your body?

How does the body evolve?

Now this is a really interesting area.

Again, 50 years ago, couldn't have said much, and that's because the process of development, the process of making an individual from an egg to a complete individual was a black box.

I mean, we could watch it maybe under a microscope, watch a frog egg develop or something like that, but we were just spectators.

We were just seeing- - So you're talking about at the process of egg, the embryo?

- Yes, all the way to animal, all the way to whether it's juvenile or adult animal, that process, we could watch it with- - I guess what I'm getting at with that question is, is all of this baked in at those very earliest stages?

Because we talk about how humans have gills in the womb when we first started in this sort of thing, but ultimately we become a full-fledged human at some point.

- That's right.

That's right.

So that developmental process, let's just take a second to appreciate this because it's almost like it's an everyday process going on around us.

You mentioned frog eggs, you see a frog egg in the pond, that's about to be one of the most spectacular pageants that exists on earth.

The making of a complete individual from a single-celled egg is remarkable.

I've watched it millions of times, never bored me once.

- Still remarkable.

- Still remarkable.

And, of course, anyone who's gone through having children and you sort of imagine all those stages, and if you're watching the ultrasound, you're like, "Oh my gosh, look at this whole being that's coming together that's going to be this remarkable thing."

So I think if we just appreciate that and we say this has got to be also one of the most complex things we can imagine, yet it's everyday, right?

Whether it's a tree from an acorn or whether it's an elephant from an egg, every day this is happening on Earth, this process of development.

And we really didn't have much insight into it until, I'm going to say about beginning about 40 years ago, we were able to start to understand what was going on, what were the chemical changes taking place in an egg that would start to shape tissues, organs, form, and start to say, "Okay, here comes the creature."

This was a huge revolution in biology to understand development.

Why is development important from an evolutionary point of view?

Because it's changes in development that give you different kinds of creatures.

That's the process.

If you're going to make a creature with a longer neck or shorter limbs or whatever, that's all going to happen in that process of development.

So the actual process that's being tweaked with in evolution is the process of development.

So if you want to understand how evolution works, you got to know how development works.

That's a decision actually I made as a young biologist.

I said, "Okay, I want to know how evolution works," I became a developmental biologist first.

I wanted to understand the embryonic development process, and by understanding that, what that meant was, what are all, for example, all the genetic ingredients, what's necessary to make a complete creature for it to all go right.

As I said, you see the smile on my face, because it is spectacular.

It's amazing.

I think a lot of people who wrestle with evolution, they're like, it seems hard, it's hard to imagine how you get from a fish to an amphibian or something like that.

Well, let me tell you, it's hard to imagine how you get from a single-celled egg to an adult human with 37 trillion cells.

- Right, yeah.

- Okay?

- I mean, we basically start off as liquids.

- Yes, exactly.

But we can see it.

And this is the thing.

We can see it with our own eyes, right?

And we just can't see evolution with our own eyes.

It happened in the past, it's buried in the rocks, et cetera, et cetera.

It's kind of hard for us.

It's an incredible amount of time.

- Exactly.

- But whether it's a day, a week, a month, or nine months, we can watch development of creatures, and now we can go in there and we can tinker with it, we can understand how exactly this thing unfolds.

And that's a remarkable set of insights that's- - How do you do that in the lab?

Do you have certain species that like, how to use mice quite often?

- Yeah, we have to give credit where credit is due, and the big catalyst for understanding development is the fruit fly.

- It's always the fruit fly in the mouth.

- The fruit fly, yeah.

Well, let me tell you, the fruit fly baby paid my mortgage, okay?

So that's why we got to give credit where credit's due.

A fruit fly, the advantage of the fruit fly, very short life cycle, just a couple weeks or so, you can keep a lot of them in a small amount of space, and they're cheap to keep, but they are complex animals.

So you have a little tiny animal like that.

It builds all these kind of tissues.

It's got wings, it's got limbs, it's got a little heart, it's got a brain, it's got eyes.

So we can watch the development of these creatures and we can change what's happening in development.

- So I'm assuming it's happening in like a egg, pupa type transitions.

- Egg, larva, pupa, adult, yeah.

- So are you scanning the larva- - Sure.

- and looking at the insides?

- We can put all those stages under microscopes and see what's happening.

But what gave us power was genetic approach to it.

So what a genetic approach is, we deliberately induced mutations in fruit flies and started studying the interesting flies that would come out.

So something like one of the most famous fruit flies was fruit flies that instead of antenna have legs on their head.

- Oh geez.

That doesn't sound very useful.

- No, but it's a laboratory mutant, except for it was incredibly useful as a laboratory mutant because those are fully formed legs in the place of antenna.

And you start thinking, "How do you put legs in the place of antenna?"

And then you map where those mutations are and it goes to a single gene, and that gene turns out to be a gene that orchestrates a big part of development.

- So let's talk process.

Is it the case you blindly make a genetic change, you see what the outcome is, and then you go back and look at the genome?

- Bingo.

Exactly.

And you're picking those flies that are interesting, right?

You're saying, "Well, maybe I have a fly that changes eye color."

I go map where that happened.

But in this case, I take a fly that has legs on the top of his head and I say, "What happened?"

- So let me ask you a question there.

So in astronomy, which I know a lot more about, one of the ways that you discover exploding stars and moving objects like asteroids is you do an image subtraction and everything that remained the same disappears and the only thing that remains is what changed.

Is it like that with DNA?

- Logically, it's very similar to that.

To a geneticist, it will map the mutation because it can figure out where in the genome the changes happened, and you can do that at sort of a low level of resolution, sort of chromosomal level and say, "I think it's in this part of the chromosome."

Now with DNA sequencing tools, we can just sequence the animal and go, "There it is right there.

That's the change."

The parent didn't have it, this has- - Wait, that's easy for you to say, man.

When I look at images of these DNA sequences, I just see like barcodes, I just see dots.

- Yeah, well, we need help with computers to sift through all that DNA.

But yeah, we can now pinpoint mutations just sequencing DNA.

If you take an animal that doesn't have the change, that has antenna in the right place, and the animal that has the legs on top of its head, you can see the difference.

Couldn't do it in 1983 when I got into the game.

- Got it.

- Didn't have those tools.

We've got those tools now.

So it was a longer march to discovery in those days.

But those discoveries, what were really important, is it taught us that there was a small subset of genes.

So the fruit fly has maybe 14,000 genes, something like that.

There was a small subset of genes that kind of orchestrated development, had a really outsized impact on development, and if you messed up one those genes, weird things happen, like there were genes that you'd wind up with half the number of segments.

So if you've looked at insects, you've also looked at a lobster on a plate, whatever it is, it's segmented, right?

It's got some segments of the thorax, it's got segments in its abdomen.

So there are genes that in the fruit fly, you mess them up it comes up with half the number of segments, right?

Or there are genes you mess them up, it has no eyes.

- Oh wow.

- So you got an eyeless fly, an adult fly with no eyes.

Well, why was that helpful?

Well, we map the gene for eyeless, it tells us the gene that's necessary to make an eye.

And then this is a different trajectory this conversation's going to go on.

And then you know what blew our minds?

Humans have that same gene, and when you mutate in humans we don't have eyes.

- That's what I was going to ask.

Does it translate to other species?

- Yeah.

No one expected that.

- So that means that the eye-making gene preceded the split.

- That's right.

Exactly, that's the correct inference, right.

And that blew, no one expected that.

You think of a fruit fly anatomy, human anatomy.

Look, I had a PhD.

I was going off to do this work, and my mentor said, "You work on fruit flies, you're walking off the edge of the Earth, because nothing you're going to find has anything to do with making furry animals like us."

That was the bias that existed across the world.

And then a little small group of people studying fruit flies like, "Hey, look at this gene!

Hey, look, you got it too, we got it too.

Oh my gosh, mess that up, we don't have eyes either."

- So what about limbs?

So like the legs on the head.

So fish have fins, arthropods have limbs.

So they have some common ancestor for which the limb gene exists that you could manipulate?

- Exactly, actually shown in my lab.

- No way!

- That common limb bearing.

Yeah.

- I came too late to get authorship or acknowledgment.

- Yeah, 1997.

If you got to my lab in '96, you would've done it.

Again, surprised us because the dogma at the time was these limbs were all independently invented, right?

Because a fly walking leg is a hollow structure it's walking around on, and our limbs are got a bone in the center and all that kind of stuff.

But essentially, as appendages that stick out from the main body, those instructions go all the way back 500 million years, and these are just unfolding differently in you and I from a fruit fly.

So the fruit fly was a passport to the whole animal kingdom.

- Wow.

- Nobody saw it coming, but I'm smiling because I took the leap, and as they say, it has paid off handsomely.

- It paid off.

But it also, besides now allowing us to study development in all sorts of creatures, it allowed us to study evolution, because then we find these body-building and body-patterning genes.

Again, it's a small subset of genes that are sort of devoted to that.

A lot of genes, they just kind of run the physiology of normal cells.

But there are genes devoted to sort of sculpting the body.

They affect the number, the size, the shape, the color of body parts, and that's the stuff that's really interesting in evolution.

So then we started studying things that look different, either insects versus other kinds of arthropods or maybe just butterflies versus fruit flies, how do you get spotted wings and things like this?

And then we're starting to figure out, oh, how do you make something new?

And the general rule, I'll just give you the breakthrough, the general rule is that basically you take old genes and you use them in new ways.

- Okay, okay.

- Isn't that a simple statement?

- That's a very, no new creation necessary.

- God, if I had known that I could have gone on Wall Street and skipped my whole career in biology.

But it turns out, it was a much better journey.

Yeah, and this is also telling us why these genes have been preserved for hundreds and hundreds, of millions of years is they get used in new ways in different creatures.

- Speaking of which, we mentioned how we found this evidence of Neanderthal DNA in humans and Denisovan DNA in humans, but we have even more viral DNA in ourselves, right?

So is that a result of viral infections happening in the animal across its evolution or was it all early?

- Oh, no, no, it keeps happening.

Yeah, yeah, yeah, yeah, yeah, yeah.

So we will see these vestiges essentially of viruses spreading through DNA.

We see this in all sorts of lines of evolution, and it can happen anew all over.

- Well, it first came to my attention when there was a recent mention of a discovery that the sheath of our nerves which allows fast, long-range nerve signal transmission was inherited from a virus.

So talking about, I don't see how a virus needs that.

- Yeah, yeah.

But we hijacked that genetic information and repurposed it in a new way.

And this is what I mean, this sort of repurposing, this sort of co-option.

So we might take animal body-building genes and use them in a new way, and that's in fact how a butterfly put spots on its wings.

Have you've seen beetles with really big horns?

- Yes, yeah, yeah, horned beetles.

- Okay, they've taken limb-building genes and they're activating them on their head and making these appendage-like things on their horns as examples.

But we also, we hijacked that viral material and we use it for, it's just material to be used and reused.

- What about spots and stripes, stripes and spots?

What was that originally?

- Well, spots, the spot-making program in a butterfly actually uses a little bit of the limb-building program, but it turns it on really late, okay?

So if you're just building, if you've got the embryo and it's just really an insect embryo, they often would look like little mini-footballs, okay, like a little bit of an oval without any shape or form, no specific tissues, whatever.

When you activate the limb program then, you build limbs and you build the basic limbs of that body.

But days and weeks later when you have the pupa and you've already made limbs, you've already made the wing, turn that limb-building program on in the wing, connect it to the pigmentation program, so you make a new connection, and you build a pattern of spots.

- That's a whole new realm you just introduced into this conversation.

It's not just turning genes on and off.

Now you can connect them.

- You can connect them, right.

So there's this whole, I'll say the software, which is how the genes are connected in development, and it's those changing of connections that's a big part of the evolution of anatomy.

- Wow.

- So you could take the same, I'll just give you this thought experiment.

Take 14,000 genes and I think I can build a fruit fly, a lobster, a crab, a dragonfly, and a butterfly out of those same 14,000 genes.

I don't need any new genes.

All I have to do is just keep change their wiring.

- What?

- That's the big discovery.

That's the big discovery, yeah.

- Holy cow.

- It's not the genes you have, it's how you use them, and how you use them is these connections between the genes.

- So the genes are like Lego bricks?

- That's right.

- You can build different animals with those.

You can build different animals out of the same genes, yeah.

- Wow.

- Yeah, yeah, yeah.

And then we see that that toolkit, those Lego blocks- - You just gave me a lot of homework.

I've got a lot of thinking to do now.

- All right.

Well, good.

- That is pretty awesome.

- But hopefully it's a little anchored, it's a little anchored.

But then you say, "Okay-" - Well, I need to know more.

- "That toolkit's been preserved through 500 million years."

We've got it.

Earthworms have it.

Elephants have it.

Sea urchins have it.

- That same 14,000 set?

- Well, they've got the same, yeah, the number varies.

We've probably got 20,000.

- So would it be the case that if you look at species that evolve later, they would have the, so there's a sort of core set and then you add or manipulate?

- Yeah, so there's a core body-building set.

There's a core kind of physiology set that just has to run cellular metabolism, that's probably, I don't know, I'm going to say five, 6,000 genes just to do what every cell needs to do.

In us, a couple thousand body-building and body-patterning genes.

And then the rest maybe, we have genes for immunity, big number of genes involved in immunity, adaptive immunity to deal with infections.

So there are inventions that have come along.

Our immune system is far more sophisticated than what you find in animals without backbones, for example.

A lot of mammals I said are good at smelling, so are insects.

They got a lot of the same smell receptors and stuff like that.

So you see expansions and contractions in some of these capabilities as lifestyles change, but there's sort of a core body-building and a core set of cell physiology genes that you'll just find across the whole animal kingdom.

- Hey, everyone, if you're loving this podcast, please go ahead and like us or leave a comment, and also make sure to subscribe so you never miss an episode.

Your support means everything and helps us reach more curious minds like yours.

Now back to the show.

So I want to bring up a word that I heard, a concept, and I looked it up when I first heard it, and it was when I was preparing to have a conversation with you, but I've since forgotten, and the phrase is evo devo.

- Oh yeah.

- Sounds like a European band or something, right?

- So somehow what happened was, this is called evolutionary developmental biology.

- Oh, okay.

- Got shortened to evo devo for the rhyme with a little bit of a play on the devo thing.

But I've really been describing to you evolutionary developmental biology because what that's saying is the devo part is that changes in development are what give us anatomical changes in evolution, okay?

- And by development you mean embryonic development?

- Yes, so it's changes that happen during the process of making a creature are what will give you different appearing creatures.

So if you're going to have changes in your anatomy, those are taking place during the process of development.

- During construction.

- During construction, exactly.

So there must be some instructions that have changed that change the construction so you get a different kind of animal.

So evo devo, yeah.

- From instruction to construction.

- That's right.

That's right.

So it changes during the process of construction.

So all evo devo means is that, and it really focuses on changes in form, changes in that three-dimensional form, how to even describe creatures, right?

I'm trying to understand the evolutionary changes in development.

That's what an evo devo scientist does.

- Okay, so here, tell me this then, Mr.

Smarty-Pants Science Evo Devo Guy, could you take embryonic Hakeem and stick a needle in me, change instruction, and I now have fangs and venom?

- Yep.

(both laughing) - Oh, what?

- Now, I'm going to say in principle.

- In principle.

- I wouldn't say it's impossible.

There's probably a little bit of knowledge that we would need to bill for.

But when you know the program for making teeth, and we know a lot about it, and when you know how you might be able to sort of modify that a little bit to make it elongated tooth with a central canal which is a fang, then we could tweak that, right?

- Wow.

- And then we know how to make venom, yeah.

- Wow, that's what I wanted to get into, man, because making this molecule, venom, it is such a mysterious thing to me.

I was like, "How would that even come about?"

- The general idea here is this, all these characteristics we're talking about, all these creatures that fascinate us, right, the instructions for making them are in the DNA, and that book has been blown wide open to us, right?

- So let me ask you a question about that then.

I'm sorry to interrupt.

- Oh no, anytime.

- Does every animal have all of the instruction book or is it later animals have all of it because they have everything that came earlier?

- Well, everybody's got their own instruction book.

Sometimes some chapters have been torn out and left behind, and some have some new chapters, but they have a lot of instructions in common because they have their animalness in common.

They have a lot of cell biology in common which even is deeper than animals, that they got cell biology that's in common with fungi and bacteria and plants and stuff like that, right?

So there's some common parts of the code book, there's some unique parts.

But that code book which was, again, not accessible to us, and starting to become accessible in the early 1980s, and then today, oh my goodness, I mean, the speed and the costs involved is now almost trivial, right?

- Wow.

- Where it used to be, too expensive or impossible.

- Geez.

- So yeah, I mean, we can look at any animal with genome.

- You're having a good time.

- We are having a great time.

We're having a great time.

And so what we do, a lot of science is detective work.

You're playing hunches, you're trying to look around, you're trying to find those clues, et cetera, and kind of DNA science these days is exactly detective work.

You're saying, "Okay, I've got this creature here that doesn't have this capability, I got this creature here that does have this capability, and I'm looking around to try to figure out what does it have that it doesn't have."

And if I compare, for example, non-venomous animals, take a lizard or something like that, to venomous snakes or non-venomous snakes to venomous snakes, I can see exactly what's going on when I look in the right place in the genome.

And that's telling us that what's happened is, again, this co-option thing, taking something that was used for some other purpose and repurposing it.

And so what's basically happening is that snakes are taking proteins that have been used inside the body to do something normal, they're making them, usually in significant amounts, in a gland, and putting them into prey through that fang, and they're putting sort of abnormal amounts of either the same or a modified protein into that prey and usually disrupting one of two things, in things like venomous snakes, they're either messing up blood hemostasis like clotting and heart rate and blood pressure, or the nervous system.

They're stopping the nervous system, so for example, respiratory arrest.

- So how does this begin before?

I'm sure it doesn't start out as full-blown fang with venom gland.

- They bite.

- So the chemical's just being secreted in their mouth and they bite, and they somehow get some specialized- - Yeah, yeah, probably components of saliva, yeah.

And imagine, the way these animals were first taking down their prey was they're biting and holding on.

Now biting and holding on is kind of dangerous.

You can go for a bad ride and get really roughed up.

So you can imagine the ability to strike and then sit back while the prey dies is a little bit safer attack mode, right?

- Right.

- So if you can deliver something in your prey during that initial bite that will subdue it, then there you go.

And so we've got a lot of enzymes in our mouth, we got a lot of enzymes in our saliva.

And so what venom evolved from was some basic capability of having digestive enzymes and things like this in our saliva, and instead of just sort of those things passively getting transferred during a bite, through this modified tooth or fang, a delivery apparatus that could deliver a more potent wallop of that kind of stuff.

- Wow, wow.

- So you can sort of feel that transition from a bite, hold on, with some kind of weak saliva to strike, sit back, very potent venom delivered and let it do the job.

- This sounds somewhat like what you described earlier where you connect genes, but now you're connecting a saliva gland to a tooth-formation gland, and now they become a single system of venom.

- Now that's an apparatus that then does the job.

And when we look at the venom components, these are fascinating sorts of things.

I got so many stories, I'm running my head saying, "Which one should I really tell you?"

But I'll tell you one that's really striking it, and one of my students is studying right now.

So I don't know, the reputation Australian snakes have, right?

We've probably heard Australia's dangerous- - Oh yeah.

As we're having this conversation, I was sitting here thinking about the box jellyfish, which is another, yeah.

- Yeah, another one, yeah.

So on land, they had a couple snakes called brown snakes and taipans.

- Oh, yeah, the taipans, yeah.

- And they make me nervous, and I like snakes.

And here's the deal.

- Have you been bitten?

- I've been bitten by non-venomous snakes, yeah.

I got an old buddy that he had a great saying which was, he said there were two kinds of snake enthusiasts, those who'd never been bitten, and those who'd been bitten a lot.

- So there's no in-between.

- If you remember where that comes from.

- Oh yeah.

- Yeah, because, okay, you can piece that together.

Anyway.

- Oh, I get it.

- Yeah, yeah.

So, taipans and brown snakes, they're remarkably toxic.

So ounce for ounce of their venom, one of the most toxic things on the planet.

What have they done?

And this is just to give you a picture of what's the strategy of venom.

If you look at what their venom does to the prey blood, you can watch it in a test tube, it will clot like that.

What they've done is they've taken two clotting proteins, proteins that we normally use to clot our blood in response to injury, pack them into their venom gland, they inject them into prey, and that blood clots like that.

- Gee.

- So it's essentially instantaneous stroke and loss of blood pressure, prey down.

- Wow.

- So they've taken proteins that are used inside the body and then using them kind of outside their own bodies onto prey, and that's the strategy of the venom.

So you'd think, "Venom, wait, what is this kind of special substance, et cetera?"

No, it's using existing proteins in a new way.

- Wow.

- Right?

- Yeah.

- And you can see, when you already have that protein that can clot blood, it's just a matter of making more of it and delivering it in a new way into another creature in an unregulated way, so that creature, that creature balances blood clotting very carefully.

You just overwhelm it so it clots instantly.

- Do the prey respond with evolutionary changes to exist with the venom?

- Oh, brilliant, brilliant.

It's an arms race out there.

It's an arms race out there.

And we see- - So they are?

- Yeah.

We see this all over the world, when prey are being preyed upon by venomous creatures, they're evolving all sorts of mechanisms.

Some of those are, well, they're all sorts of levels.

So the targets of the venom toxins are evolving.

There's a lot of pressure because if you can be less susceptible, then that means maybe you got a better chance of surviving a bite or a bite that's sub-lethal, is not as hazardous, that sort of thing.

It's going on all, it's remarkable.

The joy to an evolutionary biologist, or you might say the purpose of an evolutionary biologist is studying this, is that those arms races going on, meaning that there's pressure for the predator, for the venomous animal to keep coming up with more and more potent venom, and there's pressure for the prey to keep coming up with ways to evade that venom.

So you sort of have evolution and fast motion going on on both sides.

- Wow.

- And that allows us to, it makes the evolutionary process sort of, we just have more stuff we can dig into when it's happening on that kind of timescale.

So it's measure, countermeasure.

That's why we refer to them as arms races, obviously from the human analogy.

It's all over the place.

You go out west, there are rodents that are resistant to rattlesnakes.

- Oh wow.

- There are snakes that feed on rattlesnakes, that are resistant to rattlesnakes.

- So here's a question.

So we develop anti-venoms, from the movies I've watched, we typically make the anti-venom from the venom.

- Yes.

- Do we ever use the prey's mechanism to create anti-venoms?

- God, you got great questions.

Nobody's done it yet, but I think that's the new opportunity.

Now that we've learned enough, this is actually something my lab works on, now as we learn enough about the natural defense mechanisms, we can exploit them.

So what we did, anti-venoms got started in the late 19th century at the same time, we were making like anti-toxins for things like diphtheria toxin and tetanus toxin and stuff, and what we'd do is we would immunize an animal like a horse with these toxins or venoms, take the blood of that horse, we'd refine it, and that would be the product we would give people who if they had tetanus or if they got bitten by a snake.

So that's a 19th century analogy.

- So you're using that animal's immune system that has been exposed.

- That's right.

That's right.

And given that, and we use antibodies today.

I mean, half the drugs that we use today are monoclonal antibodies that we make in a lab that we give people for everything from cancer to eczema or whatever, that sort of thing.

But these natural defense mechanisms, some of them look really, to me, they look really, really potent and broadly acting.

And I think there are going to be some anti-venoms coming out of this new branch of knowledge from the way the prey defense mechanisms work.

- So given how advanced we are with our capabilities, I wonder why there's a certain capability that we don't have, and here's what that is.

I constantly hear about researchers going to the Amazon, finding some plant or animal that creates some novel molecule that's useful for us.

But why can't we say, "Oh, here's a problem we have.

I'm going to use my computational powers to calculate what molecule I need to deal with that problem, then I'm going to synthesize that"?

So instead of searching for it in nature, take on that role ourselves, but in a direct way.

- We do both.

We really do both, and I'll give an example.

So for example, we have so much better control of AIDS now than we did in the beginning or even the middle of the AIDS crisis, and a lot of those drugs are designed by humans out of thin air.

We're saying, "Okay, I need to design a drug that's going to fit into a pocket of an enzyme and shut that thing down," and we design that on computers and we make it in the lab, and then we test it, and there you go.

- Oh wow.

- So that's drug design sort of from scratch.

We do it.

- Okay.

- At the same time, nature has had millions and millions and millions of years to work on some of these things and come up with sometimes pretty complicated chemistry, a lot of antibiotics, et cetera, those aren't things that a chemist would synthesize just in their spare time someday, right?

They're fancy-looking molecules when you first look at them and you're like, "Yeah, nature's has come up with it," and sometimes they're made by sort of longer pathways, lots of chemical modifications, because those arms races that have been happening between, say, a fungus and bacterium in the soil, oh my gosh, those are so old.

So let's exploit what nature's been tinkering with for millions and millions of years, while we also- - And when say millions and millions, you mean tens of millions and hundreds of millions.

- Tens of millions and hundred of millions of years, et cetera, yeah.

I mean, a great example of that, underappreciated story is the first statin.

- What is a statin?

- Statin.

Everybody's- - Staten Island?

- No.

People aren't staying.

- That's where the Wu-Tang Clan is from.

- People are on statins to control their cholesterol.

- Oh, right, yeah, yeah, yeah, yeah.

- The first statin came from a fungus because a Japanese researcher, I'm going to say back in the early '80s, thought, "You know, if I can stop the cholesterol metabolism, if I can get involved with cholesterol metabolism, I could really benefit, for example, cholesterol levels in humans.

Well, I'm betting that somewhere out there in nature that's a strategy that some fungus used to stop an invader."

And he screened like 6,000 strains of fungi.

- Wait a minute, how did he make that connection, human cholesterol, a fungus stopping bacteria?

- Yeah, well, it was kind of the same strategy people use to find antibiotics.

A lot of these things are fungal products are antibiotics.

So he thought, "There must be like an antibiotic I can use for cholesterol."

Because cholesterol is used in making membranes, he thought, "Okay, that might be a target that fungus would use."

I think he screened like 6,000 strains of fungi, and that launched a drug revolution.

- And he found what?

- The first statin.

And once you got the first statin, you got the first principle, and then the chemist came along and they said, "Okay, we'll modify this.

We'll modify that.

We'll make this a little more potent.

We'll make this a little easier on the stomach," whatever.

But the first statin was pulled out of nature.

So there's two strategies going, use nature if you can.

I feel the same way with anti-venoms.

These animals have had tens of millions of years to work on these defense mechanisms.

Let's exploit that knowledge, while at the same time, the laboratory, we can also use our, we got ever more powerful tools for designing drugs.

- So you want to do both.

- We live in a time where we can do both, we do do both, and let the competition begin.

Because very often in drug development, there's a first generation where you didn't have something, then you have something.

But this was true for AIDS.

I mean, you had to take so many different pills and they were so big and there were side effects and all that stuff.

So over the years, what you work on are more potent drugs operating off those first principles, less toxic, more convenient to take.

It's the same thing going on with weight loss drugs right now.

- Right, right.

- You know the root of this weight loss- - Yeah, Ozempic and such.

- Yeah, you know the root of this?

- No.

- The root of this- - Tell me.

- It's the Gila monsters.

- What?

No way.

- Yeah.

This is a discovery.

The weight loss drugs are based on a discovery made in Gila monsters.

So reptiles can go a long time between meals.

- Yeah, yeah.

- How do they do that?

How do they control their body physiology in these long periods?

- They're cold-blooded.

- No, they're doing a little more than that.

So the lead to what became Ozempic and Mounjaro and all that kind of stuff were discoveries in Gila monsters.

- Wow.

- This is why when you talk to biologists, we plead for the support of basic research because the more we learn about how nature works, we come up with new ideas of how to, for example, intervene in human medicine.

And if it weren't for people studying how Gila monsters regulate their physiology in the long gaps between meals, we wouldn't have these weight loss drugs which we now start to understand are helping cardiovascular health, liver health, all this kind of stuff, and we're going from injectables, because you're watching the evolution of the drug making to now oral which is a lot more convenient, easier for compliance, we're all also reducing side effects, et cetera.

It's the same story being told, a lead from nature, a first in class drug, then the collective human creativity gets involved, and we come up with things that are more potent, safer to take, et cetera, et cetera.

- Well, tell me this then.

Tell me have we crossed the threshold as a species.

Because one of the things that was pretty impressive is how fast we developed a vaccine for this pandemic that we just had.

- It was amazing.

- So is it the case now that we've reached a threshold in our understanding of chemistry and biology that we have freed ourselves from the possibility of extinction from bacterial and viral pandemics?

- It's a great question.

Obviously, we know this has some pretty profound implications right now.

- Well, I mean, we do get better, we do get better.

- I would yes, we've gotten better.

And in my lifetime, I'm stunned.

I'm stunned by the rapidity of innovation.

Things have gone faster farther than I ever could have imagined.

Scientists are optimists.

You have to be an optimist to be in this game.

So even my most optimistic projections of where we might be, we're far and far beyond that, okay?

So I would say yes, if we're on our toes, our combinations of vaccine development, drug development, et cetera, yeah, I think we can handle- - Basic research.

- I think we can handle what's coming down the pike.

Obviously, what we're experiencing right now is that we're having a little bit of societal struggle of exactly how those things are prioritized and who's doing it, and we've got a lot of misinformation out there about, well, actually what happened and what's safe and what's effective, and things like that.

So we're struggling a little bit on the information side of it, but on the scientific prowess side, we're in great shape, or we're in potentially great shape, I should say, and that's why it's, massive layoffs in the scientific community are worrisome, and obviously we don't want to get into the politics of that, but let's get into the reality of that.

That has to do with our capabilities, right?

- Yeah.

- There was a scientist at NIH, because you get Corbett, who was happened to be studying what turned out to be a relative of COVID-19.

She was studying actually something called a Middle Eastern Respiratory Syndrome virus, MERS, and this has never touched our shores or anything like that, or never gone pandemic, okay, but it was a problem in the Middle East, and I believe it was transmitted by camels.

And she was studying this spike protein on that virus when along came this report from Wuhan of what became COVID-19.

So she and her collaborators had knowledge, basic knowledge about this family of viruses, and these spike proteins, and this- - Right, and these spike proteins are on the extremity of the virus that allowed the- - Right.

And it was a vaccine target for her for MERS, and she could immediately translate that knowledge that had taken her years working on MERS and go, "Okay, I got something new here.

Activate the toolkit."

So we happen to be in a fortunate position that there was some basic knowledge about this kind of obscure family of viruses, right, and we could activate it, and then we activated again this knowledge of mRNA vaccines which had not really been put to the test on a large scale.

So what I thought would've happened post-COVID is that we would've also filled the shelves.

Mostly we've got PAXLOVID.

My wife had it last week because she had COVID.

- Oh geez.

- I thought we'd have more antivirals on the shelves by now because what the pandemic, which was based on this particular family of viruses that COVID belongs to, is we didn't have anything ready to go.

Like for flu, I'm going to say, my understanding is we've got about four flu drugs to go.

So if an influenza virus gets out of control right now and we don't have a vaccine, we do have drugs, and that might keep people at work and people in school, et cetera.

So not having a drug was a big challenge of COVID, and I would've thought we'd gotten ahead of that now, and we would try to have essentially ready-to-go antivirals in the case of some other outbreak.

This is something I'm a little worried that we didn't fully implement the lessons of COVID, because while it takes time to get to a vaccine, if you have some off-the-shelf drugs society can keep functioning while we essentially treat people that have the virus.

But we had no treatment for COVID.

We had no specific antiviral treatment for COVID.

So we've got to do a little more both imagination and sort of infrastructure to be well-prepared.

So going back to your question of have we crossed a threshold, I think it's probably within our reach, but we haven't grasped it yet, and that's just sort of a societal challenge of investing the resources and saying, "Hey, we want to have a shelf of antivirals to throw at whatever comes down the pike next."

- Got it.

So the other question I have is, connecting this to evolution, is there a way to predict, oh, we see that these viruses are likely going to evolve in this way in the future, or is there a way to identify the vulnerabilities we have biologically and say, "Oh, we might want to plug this hole"?

- Yeah, brilliant question, brilliant question.

So this question of predicting the course of evolution, particularly in microbes, bacteria and viruses, it's a really fertile ground, and there's some just brilliant people working in this area and are tools.

So once you see something like the spike protein and you say, "Okay, how does that spike protein, how does it work in gaining access to our cells?"

Because it's the route in, and then we're vaccinating against it because we're trying to block that.

But then as we vaccinate against it, or as we make antibodies against it in the course of infection, that puts pressure on the virus to change.

So how many different ways can the spike protein change and escape our immunity and get inside our cells?

So this is the sort of thing, this is an arms race.

- It's the arms race, yeah.

- This is our immunity against the virus.

People are plotting out that arms race and trying to get ahead of the virus and say, "Okay, the virus has how many routes open to it?

What do we need to do to anticipate and block off all those routes?"

So for example, people are working on what they hope would be a universal COVID vaccine.

So you wouldn't need strain by- - Stop all of them.

- Stop all of them, and it's essentially just blocking out all paths.

Right now, the vaccines are changing season to season because the virus, as it runs the gamut and then can't find any more people to infect, that's the pressure to evolve, to do something new.

So we think about universal vaccines, and that requires anticipating what the virus could be doing, what that virus could be doing in the future.

Same with flu, same with other sorts of things.

We also have problems on bacteria because we've kind of emptied the microbial arsenal, the antibiotic arsenal at bacteria, and there's serious concerns about our ability to deal with some of these bacteria that have evolved- - Superbugs.

- Superbugs that have evolved resistance to most of our arsenal.

So a lot of innovation is needed there because, I mean, the hard thing about scientists, again, we're optimists.

COVID even exceeded our imagination societally.

I never imagined something effective as this.

- Well, some people were unhappy.

Some people were unhappy with our vaccine because I feel like they were like, "Oh, I thought the vaccine meant you weren't going to even get it."

But that's not how it turned out, you could still get it.

And then the people are leaning on, "But natural immunity, we should do natural immunity."

- Yeah.

- So this brings me to the question of the role of chance, because nature does it by chance.

It does runs all these experiments.

We are more directed, but we don't have all those years and chance.

So talk a bit about the role of chance in evolution.

- It's huge.

Well, this is a big topic, underappreciated, I think, and chance in our lives, chance in how we get there, how we even got here.

So we can stay down at the scale of things like viruses, et cetera, well, they're changing by chance mutations, and what happens is is that the conditions sift out the winners and the losers, right?

So the mutations that affect the spike protein, that disable it so it can't infect, well, we never see those mutations because that virus can't get anywhere, right?

- Right.

- But those mutations that change the virus in a way that evade our immune systems and it can still infect cells, guess what?

- We see those.

- We know those are going to happen, for sure, okay?

So basically the mutational process is like generating random lottery tickets.

And the conditions sort out which ones are the winners and losers, and of course the losers we just never see.

The losers are just filtered away.

They don't get a head start at all.

This is the evolutionary process at its basic root.

Mutations take place all the time.

Every human is born with 30 to 50 mutations that didn't exist in Mom or Dad.

- Oh wow.

- Single changes in the text of our DNA, that just happened because it's actually built in to the DNA itself.

It's not a bug.

It's a feature of DNA.

We understand that chemistry of DNA is such, that there are going to be changes in DNA in every generation, and we pick up about 30 or 50.

- So is that more fundamental than life, it's really chemistry and physics?

- Yes.

- Yeah, and so it- - It's the basic chemistry.

It's a, sorry.

It's a little shift in the position of a hydrogen in a DNA base.

- Wow.

- And that's going to happen.

That's sort of flickering as a matter of physics.

And when it happens and gets locked in in one position, we call that a mutation.

So that's happening.

That's just built in.

There's going to be, now, when you say 30 or 50, like, "Oh my goodness."

But those are spread among three billion bases, and most of the time they're just landing nowhere.

- Nowhere.

Having no effect.

- No effect whatsoever.

But every now and then, of course, they're going to have an effect, either to just change us in a little way, make us a little different from Mom and Dad.

Of course, sometimes they have consequential health effects.

But that mutational process is going on all the time.

It's going on in all creatures and all this, and without it we'd have no biodiversity at all, right?

Life would be unchanged.

- It's interesting because even in my field of cosmology, it's these random quantum fluctuations that gave rise to everything until now.

- Well, this is where DNA meets your world is that there's random fluctuations in DNA that are the root of mutation.

- So fluctuations are the sort of like opportunity and possibility.

- Yes.

- That's what, yeah, yeah.

- Yes, yeah, it's going to give you both spots on butterflies and cancer.

- All right.

- I mean, cancer is a, cancer is a genetic disease.

It's due to mutations taking place in cells that then cause the normal process of controlling cell multiplication to run amok.

So we got to understand the era we're living in now.

The reason why we're sequencing the DNA of people's tumor samples is that's powerful information, that says your breast cancer is different than somebody else's breast cancer, and let's take now what we know about the genes that are mutated in breast cancer, drugs that we've developed that target some of those mutations, and prognoses that we develop based on the behavior of tumors that have those mutations.

So this is powerful knowledge to understand mutations and what's going on.

It's revolutionized oncology, hopefully to longer, better lives.

I mean, mutation has a negative connotation, and when I bring up disease and cancer, there is it.

But of course, it is the fuel of evolution, and that's why it's so important for us to understand it, both in health and disease.

- Wow, wow.

Man, Dr.

Carroll, this was amazing.

Thank you, sir.

- It was a blast.

- You are welcome to come back anytime because who doesn't have questions about life?

- You bet.

Thanks so much.

- Thank you, man.

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