Mind & Matter
Mind & Matter
Evolution & Animal Development: How Nature Builds & Changes Bodies | Sean B. Carroll

Evolution & Animal Development: How Nature Builds & Changes Bodies | Sean B. Carroll

Download, watch or listen to M&M episode #138

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About the Guests: Sean B. Carroll, PhD is an evolutionary developmental biologist at the University of Maryland, who recently stepped down as VP of Education at the Howard Hughes Medical Institute. He is the author of many popular science books, such as "Endless Forms Most Beautiful."

Episode Summary: Nick and Dr. Carroll discuss developmental biology & genetics; evolutionary biology; genetics, genome size & genetic mutation; animal diversity; snake venom; human brain evolution; and more.


Full AI-generated transcript below. Beware of typos & mistranslations!

Sean B. Carroll 4:31

double duty there is both VP of science education and head of the studio 13 years as VP six years has had a studio that was incredibly busy and you cannot sustain that for infinity. Yeah. I thought it was time to step back and I had my lab here I was going every Friday to the lab but I thought this is I kind of feel like I'm refilling you know the well now back in science for A few months enjoying reading and joining daily conversations about research in the lab. Now still still have a hand in the film storytelling, but I'm not responsible for the production. So I am i I'm in a good place. Okay, great.

Nick Jikomes 5:20

What's How big is the lab now?

Unknown Speaker 5:23

Eight people?

Nick Jikomes 5:24

Oh, that's that's like, that's a good size, I think. Yeah. Yeah.

Sean B. Carroll 5:28

So enough for things to be happening and not so many that I'm overwhelmed and, you know, stretched stretched too thin. So yeah,

Nick Jikomes 5:36

what? Well, just for background, for people who don't know you, what do you study generally? And then can you just give give us a snapshot of some of the projects you're working on right now?

Sean B. Carroll 5:46

Yeah, the central question that's guided thinks for a long time is the origin of novelty, where new things come from, in the course of evolution. And that's really things that are sort of qualitatively novel that either it's body parts that do something new, or molecules that do something new, or give some sort of capability to an organism didn't have before. And I've decided to focus a lot of energy on the origin of steak Venom's and their toxins. Because the fundamental reason why that's interesting venom is had been invented multiple times in the animal kingdom, you know, spiders and scorpions and octopi, and snakes and all that kind of stuff. We've come up with Venom's independently many times. And the question is, where did those things come from are those sort of normal body proteins that you've sort of hijacked to do something new, or you really have this evolutionary stage something together that didn't exist before. And in snakes in particular, there's lots of just the history of snakes, which is under appreciated, how they've sort of invaded continents, brother relatively recently, in evolutionary terms, and flourished, radiated and all sorts of species. They're, they're really under appreciated as models of evolution.

Nick Jikomes 7:07

And, you know, one of the things I want to talk about first with you is, you study evolution, obviously, we're going to talk about a lot of evolution stuff, I can remember being, you know, 17, high school student, and I knew what evolution was in the abstract, you know, at the level that you learn about in high school biology, I know that I knew at the time, you know, millions and millions of years go by the DNA mutates, known things emerge. But it was all kind of abstract. And it wasn't until I read your book, endless forms most beautiful, that things kind of collected became much more concrete and just easy to intuit. And I think the reason for that is just, if you are trying to understand evolution, it makes it a lot easier if you first understand something about how bodies are built in development. And then you realize, oh, if I just sort of tweak this process, you know, it just makes everything a lot more blockable, I think to the mind. Yeah, so

Sean B. Carroll 8:05

we can all appreciate we all develop from an egg, right to single celled egg made all these body parts. So, you know, changes in anatomy, or due to changes in development, and you can appreciate with all these different processes going on, you know, a little tweak, here, a little tweak there can can make a pretty big difference. And, you know, we had no access to understanding those tweaks, you know, really until the 1980s. So that this interested biologists for a really long time, but we couldn't make it concrete until the 80s and 90s. And, and really get into to the the actual mechanism of how bodies are built and how they change. And that, that I think that changed a lot of things for the way we could talk about evolution. Evolution has, you know, evolutionary science has a big theoretical history, there was a concrete history that Darwin gave us, but there was a big theoretical period of, okay, you know, how to small changes add up to be big things, but we just couldn't get to the concrete. And I think a lot of people including me, need the concrete, I want to look at creatures, I want to look at parts of those creatures. I want to know why those parts matter. And they're, you know, and the world they live in. And I want to know how those parts change. And then I've got that it's like, I got a full description, you know, of the owner's manual, of

Nick Jikomes 9:24

how things work. Yeah. And I think part of what you're referring to there is, you know, there's literally, you know, between Darwin and you are Darwin and you know, the 1980s developmental biology. You know, there are decades and decades of research happening, but a lot of that was basically applied statistics, and it was the math to figure out in the number crunching to literally calculate like, Okay, if you've got this much time and this much DNA, yes, you could, you can account for things, but it was literally like math, and it wasn't like mechanistic biology. Yeah, it was.

Sean B. Carroll 9:54

It was math man. It is heavily mathematical models, brilliant people. I mean, you know, especially in it The 20s and 30s. But realize that, you know, a lot of that math came before we had the double helix of DNA. It's not till 1953 that really the world sort of understands that, you know, what the genetic material is, there was scientific evidence that it was DNA from some years earlier. But that was not kind of widely understood. And it was really the structural model of DNA that we said, Okay, here's the molecule that transmit the infant information generation to generation. And it was instantly obvious to Watson and Crick, how mutation happened, it was a change in the sequence of bases. And that would change the characteristics of organisms. Now we have concrete for the genetic material. And we know that evolutionary change must be due to changes in genetic material. So we really just couldn't put, you know, that kind of foundation underneath Darwin until we were able to look at the stuff that's changing and evolution.

Nick Jikomes 10:56

And, you know, one of the things I want to ask you about here, when I first started learning some of these key facts, I remember being blown away. And the question I'm going to ask you is, how many genes does a human being have? And I want, I want you to put them in historical context for us by telling us, how many genes do we do we know we have today? And what was the thinking? Before we actually did the Human Genome Project and actually could look and see. Yeah, so

Sean B. Carroll 11:25

the question of how many genes any creature has that was, that was a question I got sort of a front row seat to because the technology for sequencing DNA sort of sprang up just as I was hitting graduate school, that was then starting to be applied on a larger and larger scale. But there was still a good decade and a half, before between sort of being able to sequence a gene and being able to sequence a genome, the entire genetic complement of an organism. And I would say, for most of that time, well, there are several, I'm going to start with this as sort of like several biases that I can, I can recall, because I was exposed to all of them, biases in human medicine, biases in biology, but a huge human bias about human biology, that somehow we must be the most complicated, right? Now, you would be better situated than I am to comment on that from a neurobiological point of view. But from a genetic point of view. There was an anticipation that, you know, we would be, you know, genetically more complex than any creature on the planet. Well, it took a while to get to that answer. But, you know, the first picture we got was probably a VP of bacteria. And those are sort of on the scale of four or 5000 genes essentially, you know, run the metabolism and physiology and in bacterial cells. And then it took a while to get to animals, like the fruit fly Drosophila, or the nematode worm center epididymis. And in those cases, were probably getting into the ballpark 13 14,000 genes, something like that. And, and then the question would be, what would humans have? And there were, well, one of my, one of my heroes, Jacque Munno, I think I have them on tape somewhere, you know, there's a video recording them somewhere, this is in the 60s, just extrapolating because we knew that of the size of the amount of DNA in a human cell, that humans might have 2 million genes. And for a while there, I think the number that I heard circulating might be like 100,000 genes, so still, you know, far more than other animals or whatever. And I remember having this discussion with a really prominent fruit fruit fly researcher who had who had a good grip on things. And he said, Well, Shawn, you know, what do you think? And I said, it's not going to be much more than a flyer where, you know, 15 20,000, bingo, yeah, maybe it's 20,000. But it's not any more than a mouse or something like that. So, you know, first of all, that kind of, you know, vanquishes, our genetic, you know, specialty in our specialness genetically. But it really underscores something that is, you know, is fundamentally interesting to me about evolution, which is how you build diversity with essentially the same toolkit of genes. So you don't need more genes to make more different kinds of creatures. So you can use the same genes you got just in myriad different ways. So many ways, sort of the, you know, the leveling of the playing field for humans to Dabbagh similar genetic complement as mice, and now chickens and even fruit flies, was to also tell us that we shouldn't be thinking that the number of genes dictates the complexity of a creature, but it's, it's how genes get used that are the real source of diversity. And that is a major meshes that then emerged in research that was directly comparing Different animals were built and, and what the what the genetic machinery involved was. Yeah,

Nick Jikomes 15:05

so just just the simple observation that we don't have that many more total genes than a fly. And we've got comparable numbers too. And sometimes even less than, you know, creatures that we would basically universally agree are simpler than us, that tells you that, yes, it's about how you use this stuff much more than it is the amount that you have. Right? And, you know, obviously, you're going to tell us a lot about the how you use it part of it. I want to build up a little bit of vocabulary for people. So when we talk about genes, what exactly are we talking about in the DNA in terms of like protein coding sequences versus other stuff?

Sean B. Carroll 15:42

Yeah, so let's, um, let's do a little, little accounting. So basically, we've got 23 pairs of chromosomes, okay? A chromosome is a long molecule of DNA. A gene is a segment of that molecule of DNA that has some information that gets used in in cells. So you know, if we might say maybe, on average, there might be 1000 genes per human chromosome. I'm averaging things out a little bit. So an individual gene is going to take up a certain amount of linear space on a molecule of DNA, that gene, a segment of DNA, in order for it to then contribute to the physiology or development of an organism, it's going to have to be used to it as instructions to make proteins. And there's an intermediate in that, which is it's first transcribed into RNA, all this language, all this cryptographic language, by the way came from, you know, the discoverers, who are all had kind of a post world had a world war two background, right. So the, the gene is transcribed, right? So you make this intermediate transcript, and that transcript is translated decoded into making protein using genetic code, sort of, like, you know, a code book or, you know, think of things like the Rosetta Stone.

Nick Jikomes 16:59

I never actually thought about that, that. The discoverers here, were sort of operating in the the Oppenheimer era.

Sean B. Carroll 17:06

Yeah, yeah, they're coming out well, and you know, Crick, who is probably the is definitely the most brilliant theoretician in biology, Crick worked for the Admiralty in World War Two, you know, so all these folks, a lot of these folks had, if not a direct World War Two background, they were of the era just coming right out of World War Two. So they had this, you know, code books and transcripts and translations and decoding and deciphering all that language was, was there. But anyway, the point is, is that when we think about a gene, we're really talking about a stretch of DNA, a linear sequence of DNA, four letters, might take up 1000s, and 1000s of letters, maybe even 100,000 letters for a gene. But still, it's a discrete segment of DNA. And that information is in a stepwise process transcribed, and translated into the making of proteins. And proteins are linear chains of molecules called amino acids, but those proteins do essentially all the work in our bodies. They're the things that carry oxygen, they're the things that fight off invaders, they're the things that digest our food, et cetera. And really, to operate a cell just to do the work of any old cell looks like you probably need five or 6000 genes working. So some of the genes we have are specialized to various cells, we have genes that, as I said, to carry oxygen, they're in our red blood cells, genes, they're active in our red blood cells, genes that fight off invaders are active in our white blood cells, genes that transmit electrical signals, those are in our neurons. So genes that build bone, proteins that build bones, those are, of course, going to be in cartilage and bone. So you know, we've got a lot of things that are specialized, but we also have a cord that we share with almost everything on the planet, to just do basic metabolism up.

Nick Jikomes 18:45

And so yeah, so things like, you know, literally making ATP making energy or how the basics, the fundamentals of how cell divides things that every single cellular creature has to do.

Sean B. Carroll 18:56

Absolutely. And this stuff is deep. So we can see that that stuff is shared way back that's shared throughout. And there's many things we share with bacteria. There's lots of things we share with simple unicellular creatures. And so we know that stuff goes back. In fact, the genetic code we use is exactly the same genetic code that a fly uses that a bacterium uses, etc. So the genetic code is universal, or universal with respect to planet earth. But that tells you that stuff is old. But that machinery for doing all that stuff has been around a very long time, and every cell needs it.

Nick Jikomes 19:30

And when we say, you know, we often we often talk about genes with respect to proteins, like a gene encodes a protein. If you look at all, if you look at the whole genome, roughly speaking, what percentage of the letters are the code to make proteins versus other?

Sean B. Carroll 19:50

I think in the human eye, I'm not going to give you a precise figure because it's kind of left my aging brain. It's probably on the order of like 2%

Nick Jikomes 19:59

Okay, so But quite quite a small amount, it's

Sean B. Carroll 20:01

not a small amount. So there's tons of stuff, tons of other DNA in our cells not devoted to encoding proteins.

Nick Jikomes 20:10

And you know, the term, I used to hear that term a lot more, I don't hear it as much today. I've also probably tuned it out, because I do know what still gets used is junk DNA, you know, and I think the idea historically, you can correct me if I'm wrong on the details is, you know, the Human Genome Project came out, we started looking at the actual code more, we realized, okay, we only have x number of genes, we only have, you know, 2%, give or take of the genome devoted to encoding proteins. And so there's all this other junk DNA, what is junk DNA, and this is that term even makes sense today. Now,

Sean B. Carroll 20:45

that's a bad term because it lumps and we don't want to lump we don't want to lump it was appreciated. And this is, you know, it's kind of an inconvenience to biologists. And it's kind of aesthetically not pleasing. But there's reasons why genomes can accumulate pretty large amount of like repetitive DNA. So there's, we get exposed to agents, like some viruses and insert DNA and our Insert DNA into our genomes, there's processes going on where DNA can get amplified. And that doesn't mean that DNA necessarily contributes to how our cells perform, or anything that we do. So we know, humans, I'll just use humans as an example. There's not a say a lot of pressure to kind of prune out DNA. So you can sort of think of it as like, you know, kind of like the garage or some storage shed, you've got, you know, stuff can pile up there, whether you're using it or not, over evolutionary time, it can pile up. But in that garage, or that storage, shed, there are some useful tools, and there's still a small percentage. So if we, it's better to sort of talk about the coding fraction, which is small, there's a non coding fraction, which is very large. But some small part of that coding fraction is, is also crucial machinery that governs how genes are used. And I think the best category to sort of describe these are things like genetic switches, these are sequences in the DNA that the way they operate in the process of turning genes on and off. And so it's not all junk, right? Not the non coding DNA is not all junk, there's a part of that non coding DNA, that it's crucial to the whole choreography, of which genes get turned on and off in your cells and in which cells and which what times in the development of an individual. That stuff was really hard to find. Okay, so that I can give you sort of a historical reason why junk has, you know, kind of held on first people found, and then some other species, like some amphibians, there's a massive amount of DNA that doesn't encode anything. And people are like, you know, John, yeah. But because there's a universal genetic code, it's very easy for our computer programs, to identify stretches of DNA that encode proteins. Easy as can be. It's not easy to identify among that other DNA, which stuff operates in some important function in which stuff is just going along for the ride. Which stuff is just that, you know, that stuff in the car in the garage or the storage? Shed?

Nick Jikomes 23:24

It is some combination of both. Is that Is that true?

Sean B. Carroll 23:27

Yeah. Oh, for sure. Yeah. So so that had to be that has to be figured out experimentally, there's no kind of computer program that will tell you, this segment of DNA exactly operates this way. So it was longer to realize that probably about in the human, I'm gonna say about 3% of the DNA is devoted to orchestrating how that 2% of the DNA gets used. And all that stuff is really important. That's what orchestrates you know, that's how you put ahead in the right place and make the right number of red blood cells and, you know, a lots of other choreography of of how genes get used.

Nick Jikomes 24:05

One, I want to give people a sense that there's different there's different types of genes and coding different types of proteins. And so one distinction that I think is useful is, you know, there's a lot of genes that encode proteins that do like the every day, housekeeping physiology stuff of the cell, so enzymes chop up certain, you know, nutrients, or, you know, carry oxygen around or whatever. They're, they're, they're doing the the daily operations of the cell, right? And then there's other proteins and one example of a class would be transcription factors. So, what are transcription factors and how do they differ from say, like enzymes?

Sean B. Carroll 24:44

Alright, so transcription factors are proteins that govern the activity of other genes, and some transcription factors, while some of them may govern the activity of, you know, 500 or 1000 genes or more. So, if you want to think sort of hierarchical terms, you sort of any medical metaphor you want, you know, these are sort of the generals and the other genes are sort of the soldiers. But a smaller number of genes probably in the human, you know, might be on the order of 1000 or so. So it still might be 5% of our genes encode transcription factors. But these transcription factors, turn other genes on and off. Often they work in combination. So some of the some of the biological specificity and fine tuning comes from these transcription factors working in combinations. But if a transcription factor affects the activity of say, four or 500 other genes, so let's say for example, the body is building a muscle, there's a whole lot of stuff that you got to turn on. To give that muscle its property of muscles, the fibers that are in the muscle, the way energy gets used by the muscle, the way the muscle recovers after exertion, the anatomy of the muscle, there's all sorts of stuff that has to go on. And so there's a muscle specific genetic program, and there's a few transcription factors sort of in charge of that program. So those are really hierarchically speaking, sort of, you know, top of the hierarchy, genes, and their genes way, way, way will say, you know, at the bottom of the hierarchy that essentially just carry out some job in the in the differentiated cell, the final muscle cell, you know, some enzyme reaction or something like that, that cycle something in the, in the muscle cell. And you know, that's not, that doesn't influence other genes, it's carry out an important job, but it's essentially at the terminal end of the circuit is the terminal end of the hierarchy. So however you like to think about, I think hierarchies are probably a good way to think about it, you can imagine these genes or these transcription factors are so important, because they do so many things. And then we realize they're so important, the easiest way to demonstrate that is to knock them out. So biologists have all sorts of tools for knocking genes out whether that's, for example, in experimental animals, like fruit flies, or worms or mice, we can also do it in cells and culture and stuff. And we can show drastic, dramatic, sometimes catastrophic effects, when these transcription factors are altered, because whole batteries of things don't happen when those transcription factors are altered.

Nick Jikomes 27:18

So in startup speak, it would be like you've got some genes that are individual contributors, like they're doing day to day tasks, they know how to do that one thing, and that's kind of all they do wherever you find them. And then there's managers that are telling them where to go and when to do what they

Sean B. Carroll 27:33

do, right. And some of these genes are kind of like executive vice presidents actually control a lot of the managers. Yeah, there's a, there's a hierarchy to this logic. And when things get changed way up in the hierarchy, the biological impacts are dramatic.

Nick Jikomes 27:53

I want to start talking a little bit about, you know, keeping some of this stuff in mind, and we'll connect the dots for people, but I want to give people a sense for some of the basic principles by which animal bodies are put together. And, you know, one of the things that that you're gonna teach us is, you know, even when you talk about something like a fly compared to a human, you know, remarkably, there are a lot of shared principles there. But you know, let's think about flies and bugs and insects first, because when you look at them, their bodies are. There's, there's literally segmented, right, like you can think of a millipede, it's got a bunch of these, almost like Lego blocks, pieces put together. Where does this sort of segmentation and modularity that we see in something like an insect come from in terms of this genetic toolkit?

Sean B. Carroll 28:42

Well, it gets set up very, very early in the development of the insect embryo, I mean, the best studied embryo being the fruit fly embryo. But I think to start to paint a picture for listeners about this, I like to think so a lot of a lot of embryos started out there, they're spherical, they're close to spherical and shape, sort of think about a globe. And I like to think about longitude and latitude. And, and poles, right, so you know, so think of something spherical, it's got a north and a south pole. Right? It's got that equator. But along that there's, there's all sorts of longitude. And of course, there's all sorts of latitudes marked out north to south. As a body is built, essentially, there has to be information as to what to build it and all these positions. So at a certain degree, longitude and latitude, that might be where the eyes are gonna go. A certain degree longitude and latitude, that may be where some appendages are going to go. And if you make this fully three dimensional on the inside, that's where you're going to put muscles and guts and all this other kind of stuff. So this three dimensional spatial information is really important in development. And you also have the aspect of time you're going to do some things before other things, right? It's almost like building a house. You realize you're gonna lay the foundation before you you No, paint the drywall in the kid's room, right? Same thing and building an animal body, you're going to lay out some of the basic foundation, sort of this grid work. And then you're going to start filling in with specific body parts specific organs in particular places. So segments are this very repeated pattern that lots of animals have. So insects belong to this group called arthropods. And if you think about, you know, crabs and lobsters and other favorite things like that, or or butterflies and millipedes, they have these segmented bodies, we do to the obvious part of our segmentation, if you look along our backbone, right, so we have cervical vertebrae, we have thoracic vertebrae, we have sacral, lumbar, vertebrae, etc. We are segmentally organized as well. So this and so both animals, both insects, and humans, have an organization of head to tail, right, we know the head goes in front, that's where the brains and the eyes go, right. And at the back end goes the, you know, where the waist comes out, right. So there's a lot of polarity, there's a lot of spatial information in a creature and all that has to be set up. And so segmentation, this major feature that you can see, so obviously, in insects, but it's also there in us, that's going to get set up early, because at different positions along that main segmented axis, that front to back axis to the animal, other things are going to form, you know, ribs along your backbone, for example. All that all that information has to be set up in an insect, the insect is laying out there's three main sick parts of an insect, we all know it from either from biology class, or from just looking under a magnifying glass, it's got a head, right, and that's got the mouthparts and the antennae and stuff like that on it, it's got a thorax, that's where the walking legs and the wings are. It's a winged insect, and it's got an abdomen, and often that abdomen is segmented it may or may not have anything sort of coming off of it. So in building an insect, you sort of laying out head, thorax, abdomen, and then within that a segmented pattern because the thorax has multiple segments, the abdomen has multiple segments, etc. So that sort of modularity is is a really common feature in the animal kingdom is that bodies are made of repeated bits. And then those repeated bits get specialized. So what gets built on the thorax of a insect, you know, our wings go their antennae go on the head. So there's a whole process for putting for laying out the basic body plan, and then for putting the various specific features in the right place on the developing body.

Nick Jikomes 32:45

And I would imagine, like, you know, when we think about the the managers, and the individual contributors in genetic terms, early on, right, there's gotta be, there's gotta be proteins in every cell, from the beginning that do like the most essential basic stuff. But then I imagine, right, there's, there's some period of time as development is proceeding where you're eventually going to start specializing, you're going to make things like neurons and skin cells. And they're going to have special proteins that most of the other cells don't have. But it's going to take time to get those on. And in between, you've got some kind of cascading temporal logic by which these other transcription factor things are orchestrating those changes,

Sean B. Carroll 33:32

right? So you've got transcription factors, setting up these main body axes, the front of the front to back and the top to bottom. So we know for example, that, you know, what's biologists will use the terms dorsal and ventral but dorsal is our back, ventral is our stomach side, right? So different things happen on that, that part of our body from the other side of our body, you know, think about a deer, right? It's colored differently on its back than it is on its ventral surface, front to back. So these transcription factors are setting up these regions of the body. And certain transcription factors are responsible for what goes on in a particular region. Those those managers are saying, Okay, I'm part of the head program here, or I'm part of the thorax program here. I'm part of the lumbar program here. And, again, those things have to happen earlier, and they have to go right, because when they go wrong early, you can imagine it's a cascade of disaster. So, you know, essentially think about birth defects, that sort of birth defects, we would probably never even see because they Strophic its enviable, right, you just you build, you don't build a viable animal when these things go wrong early.

Nick Jikomes 34:42

So these, yeah, some of these key genes, these master regulators, that would mean that, you know, if they mutate, it's catastrophic. The other cut well, actually, let me back up a second. So, you know, we think about all of animal diversity Flies, worms, bugs, humans, birds, everything. They're all very different. But they've all got head and tail. So there's that polarity there that you mentioned, they've all got some kind of body symmetry left and right, top and bottom, all this stuff gets set up. Maybe, you know, cuz I don't want to go too, too into the weeds and like the molecular details, but why don't why don't I just ask you like, let's take polarity, we all have a head and tail all animals do. How does the embryo know which side the head is on?

Sean B. Carroll 35:29

Yeah. So it gets set up differently, it's, it's sort of funny, like there's not a universal rule for how it gets set up in some animals and say something like a fruit fly, there's information there in the egg, the egg is pretty big. And actually, so as the egg is developing in the mother, in the female, there's information being laid down, the way that cell is forming, there's information laying down, that are ready, essentially, is specifying polarity in the cell. And the polarity in the cells becomes the polarity of the embryo. In other species, for example, where the sperm fertilizes the egg, starts to set up that information. So the egg is kind of agnostic. And then where the the point of sperm injury happens, can set things in motion. So you need something to create an initial asymmetry, it may be built into the egg before it's fertilized that maybe once the egg is fertilized, but once you have that initial asymmetry, and cells start dividing, that means you have the st, you'd have different information across the egg, you have something that's localized, you have more some stuff in one place than you have in another place. And that chemical difference, can set in motion, a whole cascade of things that can really then distinguish those different regions of the body from each other. I think if you just hopefully, that's a decent enough verbal description, again, without getting into molecular details you need and it's some kind of initial asymmetry that then cues, a whole bunch of events that happen after that. And the molecules that are involved in these asymmetries. You know, we've gotten our hands on all these things, they, they do spectacular things, we can manipulate them. So if we put those molecules in a different place, you know, you can make some pretty freaky looking embryos. And that's a good way to test it, you understand how things work. But that spatial information in the embryo is really what that means is there are chemicals in the form of proteins that are distributed asymmetrically. Early on, and those asymmetries are elaborated upon in building bodies.

Nick Jikomes 37:34

So you know, maybe you can imagine a perfectly spherical egg, and it doesn't know which side has had which is tails to perfect sphere, but the sperm enters at some point on that sphere. And maybe there's a chemical on the sperm, and it's so it's highly concentrated where the sperm the egg, physically touch, and then there's a diffusion gradient that goes away from that point, and the head is like that point and the tails, then the other point.

Sean B. Carroll 38:01

And it could also be something inside the egg that reacts to that and says, Okay, this is a change is now taking place at this point in the egg, that's going to be sort of my North Star, that's going to orient the whole egg and things are going to happen from there. So it can be sort of a physical change, that then triggers a chemical change, a cascade of chemical changes. So different animals use different mechanisms, it turns out kind of a little bit, there's kind of a variety of logic out there. Yeah, a variety of mechanisms that's out there. But I guess

Nick Jikomes 38:30

the principle here is some initial asymmetry is set up, that polarity then starts to get built in and elaborate it on. And to put it in a very coarse way, you've got these cascades of different transcription factors and proteins to get turned on. And at different points along that embryo, they get turned on sort of in different combinations. And then ultimately, that's what's going to get you one segment being unarmed versus a leg versus or whatever.

Sean B. Carroll 38:56

And people may start thinking, Well, you know, how do you make How do you make those distinctions? Well, these transcription factors also talk to each other essentially. So some transcription factor, for example, may turn off other transcription factors. So you sort of get zones of exclusion. So you start setting up finer and finer, you start with very coarse, I guess the best way to describe it is course to find delineation so that you start with very coarse, okay, this is the front, this is the back, this is the top, this is the bottom. But that course, sort of map becomes much more finer scale as time unfolds. And it's all sorts of mechanisms, including sort of crosstalk between these transcription factors that are saying, Hey, I'm active over here, stay out of my zone. And then that next thing is active in another zone. And it's and it's talking they can set up these you know, very restricted pattern, very restricted zones within the animal were different things are going to happen both along the main axis, including into the body because we also need to know what to think there's a lot of songs about this from the fifth These are what have you got to know, you know what goes on the outside and what goes on the inside, right? You want you want a gut running through the middle, not on the outside of the animal you want, you know, skin on the outside, you want to put a skeleton in the right place. So it's three, it's, you know, three dimensional information.

Nick Jikomes 40:15

And I would imagine, so like, as we start to think about like, okay, you know, we get some sense for how the body is put together. And we've got, you know, we can talk about transcription factors and the mechanisms that underlie that, immediately, you know, in as we're talking about this, you can start to intuit I think that, okay, if I'm now going to start think about evolution, and think about how mutations tweak this developmental process to create a new type of animal, it becomes pretty clear and pretty intuitive. I think that, okay, if I mess with the, the sequence of one of these master regulators, that's probably going to be catastrophic. So I'm gonna break everything because right from the beginning, things are gonna go wrong. And then that gets you thinking about constraints. In what type of genes and and where the gene, can you start to get mutations that that tweak what the animal looks like,

Sean B. Carroll 41:06

right? So let's give some concrete examples about that sort of catastrophic argument. So, you know, we know that whether you want to think about humans or mice, or fruit flies, or whatever, we know, what happens when these genes are rendered, non functional. And generally, it's a very obvious and terminal effect, you could be missing whole parts of the body, you can be missing whole organ systems, you can be missing entire appendages, things like this, okay? So that's, that's what we mean by the scale of what can what can be disrupted when these things are missing. But when you think about, let's just think about, you know, four legged animals. So you think about the bodies that you see out there, and you think about, oh, you know, giraffes with their longer necks, you know, or, you know, something with maybe shorter limbs or something with a longer body or a shorter body and things like this, you're like, they kind of all look like the same sort of animals been bent through a funhouse mirror, right? You know, kind of elongating this or shortening that or whatever, though, that kind of the basic outline is there, but what's changed is the portions of things. And you have to do that in a way that's viable. Right, these things, these evolution is a matter of, you have to tinker while the engines running, right? You don't do these things are not designed from the ground up, like they build cars. at Ford, right, you have to tinker while the engines running. And what we appreciate now is that subtle changes in where these genes are turned on how many cells are turned on in subtle changes in the subordinate subordinates that they regulate? These are the kinds of changes that are happening in the course of evolution. Not, you know, not in one step wholesale rearrangement. Those big, big changes generally aren't aren't very viable. But subtle changes in size, subtle changes in the relative position of something. That's what you see happening. How do you do that? Well, you don't, you don't have to tinker with the transcription factor as a protein itself, you tinker with the subtle aspects of space and time? Well, I turned it on in a few more cells, or I leave it on longer, and those are those cells divide longer, that's going to change the size and shape of something in a in a viable way. That's the sort of stuff that variation is is made of. So how are what kinds of mutations have those properties? Those are generally mutations in the switches. Those are mutations in the non coding parts of DNA, that influence this choreography of how these genes work in space and time. And they're not catastrophic. And furthermore, these mutations, these switches in individual gene, say one of these top regularity genes, it might itself have 10, or 20 switches associated with it. So no mutation in one switch has no effect on the other switches. So if you think about a gene, for example, that might be involved in building bone, it might have a switch that turns on very late, say, for example, in the elaboration of the fingers, okay. Well tinker with that, and you might be changing the width and length of fingers. But you're not changing the backbone, you're not changing leg length or things like this, right? So it gives fine tuning control over the proportions of body parts and the compositions of body parts. Yeah, the action, the evolutionary action in terms of the evolution of anatomy, the evolutionary action is in the switches that control this choreography. It's not actually in the proteins themselves. And that was that was we probably may need to get into that. Maybe not. But that was sort of a breakthrough and thinking for evolutionary science, because until then people were really thinking about how proteins change.

Nick Jikomes 45:07

Yeah. And I liked the I liked the funhouse mirror analogy that you brought up. It reminds me, you know, it's commonly like a textbook, you know, when you start talking about evolution and homology, and how the basic structures are often shared across distantly related organisms, you know, you might see the picture of the human arm and hand next to the whales fin and the bats wing. And even, you know, even as a, you know, even as a young student, you can appreciate, oh, yeah, like, it's the same basic set of pieces and the same geometric arrangement. But one, this piece is longer and this creature and shorter and this creature, and it sounds like what you're saying is, you can get there slowly. And little by little over time by just saying, Okay, turn on this protein a little bit more, or leave, leave it on a little bit earlier, whatever. And those are all coming from mutations in these non coding switches. Yes, yes. Yeah.

Sean B. Carroll 46:02

And whereas if you actually mess with the transcription factor, you might be missing the limb altogether.

Nick Jikomes 46:08

Yeah. Yeah. And that would also, I guess, kind of make sense of why so much of the genome isn't protein coding sequences, so you actually have a large palette to play with to do this fine tuning.

Sean B. Carroll 46:19

Right. And that's what's evolved. I mean, I mean, I think, let me give you let me just give you another example of sort of how to think about this. We of course, we're thinking about our bodies, we're most familiar with our bodies added, right, we all change, etc. But one way to drive home that the role of these switches is think about a caterpillar and a butterfly. Okay? Same species, right. We've all seen a beautiful monarch, Caterpillar, pick your favorite butterfly, whatever, I'll just pick a monarch, most people have seen him, right? That caterpillar is living a certain lifestyle, as it crawls up that plant and it's feeding on that plant. And you know, what it's eating, what it's doing, et cetera, doesn't have wings, yet, anything like that. And then it goes through this incredible transformations metamorphosis, into a butterfly migrates to Mexico, right? Those that's essentially two animals from the same genome. This caterpillar with an obvious segment of body, it even has little little legs on the abdominal segments, and several the abdominal segments, no wings, and then the beautiful butterfly with wings, you know, that that flies away. So same genome, same genes in that animal. But a certain program takes it so far to be a caterpillar, another program kicks in, in making the butterfly that shows you the power of regulation, it's all the same DNA in that creature. And essentially, it's almost like getting two entirely, you're getting two entirely different lifestyles out of one genome. And that's all about the choreography. So we don't have such, you know, incredible transformations. But I think it's a very helpful way to think about how such different things can be built using the same set of genes. A caterpillar and a butterfly is probably the most dramatic thing I can think of probably the most visually appealing.

Nick Jikomes 48:17

And it's it's easy to think about mutations and some of these master regulator genes that set up and orchestrate this whole developmental process. It's easy, it's easy to imagine how mutating them can be catastrophic, because everything downstream is affected. But are there ways in which they can actually lead to functional mutations that are dramatic? And here I'm thinking about, you know, some of the stuff that you can tell us about in terms of the identity transformation of tissues? Or how do we think about the fact that okay, at some point, you know, the centipede and millipede actually got more segments? Well, what's the genetic basis for actually changing the identity of something or creating more units?

Sean B. Carroll 49:02

Well, people are working on this, this is still a, this is a pretty lively area of research, this is getting into some of those subtleties, but if you think for example, about you may not have appreciated just how different crustaceans are from each other. But if you like Adium, you can sort of appreciate you know, shrimp and lobsters and crabs are, are are different, but they all have a really sort of some similarities and body design. But what makes a lot of them different is the number of different kinds of segments what's devoted to what how many segments carry legs, how many segments carry swimming, appendages, etc. Clearly, evolution is playing with the number and kinds of for example, appendages and these creatures, right, the number of guides and segments and what they and what they bear. So somehow, there's while there's that commonality, you still a crab is a crab and it's not a lobster, right? So you gotta go way back in time to when they had a common ancestor and realize they've gone there. separate ways. So what we know is as the embryo is being set up, there is a battery of about nine genes, eight or nine genes that are that are specifying what's going to happen along that main body axis, the head, the thorax, the abdomen, and the territories they lay out, can be subtly modified. So if you sort of think I'm going to give Okay, here's another analogy. I hope everybody goes with it. I gave you the globe and longitude and latitude. Now, it's Super Bowl Sunday, think of a football field. All right, and you got the yard lines, the 100 yard lines, okay? Well, you can imagine that if I just say, let's divide those up into the 1010 yards, divisions, that if you say, well, the you know, the zero to 10 is different than 10 to 20 is different than 20 to 30, different than 30, to 40, etc. But now, if, as you're setting up this field, you know, there's an interaction that allows that 30 to 48 is to spread to 42. Now, 42 gets shortened to just, you know, 42 to 50, you've just changed the proportion between two segments, just a little little ticker, well, then what's going to happen in those segments is going to be different. And it's these, it's the territories that gets set up that are occupied by these master regulators that are being tinkered with, early in development. So by shifting the relative I'll just call them territories of these of these genes, you can dramatically modify and sort of sculpt the animal to be different, and you don't get it overnight. Okay, we can do things in the laboratory and make really big changes. But that's kind of evolution can't can't deal with it, like the one of the most famous mutations in fruit flies, is a mutation that transforms the antenna into legs. That's a, you know, it's a nice little trick in the laboratory, you will not find flies in the wild, with legs coming out of their head, because they need those antenna to find their way in the world. Okay. But it shows that that's how we started to know that we were dealing with this stuff that govern what happened in any individual body part. But so we just want to imagine how you get this sort of diversity. It's by tinkering with the layout of the body plans, think of the body plan, almost like a little bit of a blueprint of what's going to happen, where you're tinkering with the layout of the body plants of these creatures. And if you've, you know, and I did, I gave you an example of things like arthropods, but maybe an obvious one in our group of animals and vertebrates, backboned animals, I mean, think about a snake. Some people don't like to think about snakes, I like to think about snakes, I look at snakes, and I just see novelty all over the place. So they've lost their limbs, snakes evolved from a limbed ancestor. So that tells you some big changes can happen. Right. And we know what's happened many times in lizards independently, we're legless lizards have evolved from limb to ancestors, all those are burrowing creatures. So a burrowing lifestyle is facilitated by losing these limbs. So you can obviously slip into nooks and crannies and things like that. So snakes have lost limbs relative to their ancestor. And we know, in fact, some of the very specific genetic changes that happen in the snake are in the switches that build limbs. So you didn't knock the genes out themselves, you change the switches, so that that program for making the limbs did not happen. That's been clearly shown, experimentally. So that's a pretty big change when you think about limb versus unlimited. And, you know, I certainly would have predicted it 25 years ago, and thankfully, the research has been done, I can say, yes, it's a change in the switches, shuts the limb program off. And that's how you get a limb listening.

Nick Jikomes 53:55

Yeah. And so, you know, we've started to talk about mutations. And sometimes they can be catastrophic in the sense that the embryo is not viable, the final animals never even built to even test it out in the wild. Sometimes, it might be built, but the animal just can't survive well. So if you get that logically not going to do well. Yeah, like if you're the fly, who's got the mutation that changes your antennae and two legs, maybe you can run around for a little bit, but but you're not going to be able to find food until you die. This now gets us to the concept of natural selection. Right? And I've got a bunch of questions here about sort of evolution, per se. Now that we've gotten a little bit of a background here in the developmental genetics, but let's just start off with the basics. What exactly is natural selection? And in your experience as an educator, what are some of the major misunderstandings, people that trip people up with natural selection?

Sean B. Carroll 54:47

I like to think of natural selection as really just being competition between forms. Okay, so that and this is the way that the two great discovers the same believe evolution Darwin and Wallace thought about it, they saw nature as a battlefield with with competition going on out there, and those that would have a slight advantage. For some reason, let's suppose they could run a little faster or handle a few more offspring, they do better than than other individuals. And all that means is that nature is the agent determining winners from losers. So let's just say winners from second place. Third place, fourth place. It's not I say total losers, but it's a range. So it's a competitive process out there in terms of which forms do better than others, and do better means they might live longer and have more offspring. Because it's also essentially, if you don't have any young, it's a moot point, because that's the end of the line. So that's natural selection is really about the future generations descended from those individuals. Doing well. So I think natural selection is is best to think of as a competitive process. And what that means is it's favoring those things with a slight advantage. And it's describing those things with a slight disadvantage, or however slight it might be, if it's a catastrophic disadvantage, it's, it's no race at all.

Nick Jikomes 56:15

And the currency for success here is simply reproductive output. Yep. Yeah, cuz you can, you can live forever, you can be big and tough and strong and get away from predators. But if you don't leave the next generation behind you, then then your lineage goes, right. And those

Sean B. Carroll 56:31

things that give you an advantage, they have to be heritable as well. So if you've, If all you've done is acquire wealth by building a real estate in New York, you know, but your children are, nevermind, I'm not gonna go there. Okay, so anyway. So these are things that you acquire in life don't matter, it's what you're able to pass on through through genes that matter. So that's natural selection. And I think the most common misconception is that in some way, the organism is willing itself to that. Superior State, that advantageous state. So let's just take let me take like one of the simplest examples, one of my favorite examples, is the story of the rock pocket mouse, and the Desert Southwest. So basically, these mice generally occur in to coat colors, dark and light. And when you look at the distribution of those mice, when you go out and catch them in the field, most of the mice you find on dark rock. So this is an area's for example, where there's been a lot of volcanic activity. There's dark lava rock, you find dark mice on the dark rock and you find light mice under like Sandy, Sandy rocker, sandy desert flora. And that in that pattern of distribution, is actually due to the activity of predators, the mice have no idea what color they are getting, but visual predators, owls, snakes, etc. When you have a color mismatch, those mice snake stick out, and they're picked off. So essentially, it's the action of natural selection by the predators that is that is shaping the distribution of these creatures. And you think okay, being dark on dark rock gives you an advantage, in fact, immeasurably much larger, large advantage selective advantage. Being light on light background gives you a strong advantage. But the mice have no influence, they have no influence over the mutational process that makes them light or dark. That is entirely a random throw of the genetic dice. This is the hardest thing for people to get about natural selection is the creature has no agency in what's going to happen. mutations happen at random, they affect body characteristics at random. And whether or not that's advantageous or disadvantageous, depends upon the conditions in which the animal finds itself. So if you're a light colored mouse, and you happen to pick up a mutation that makes you dark, that's advantageous. If you happen to stroll over under some dark rock. It is dis advantageous if you stay on Sandy's on on the light colored sandy soil. And you can think vice versa. It's the conditions that you're living under. And if you think oh, well, up on that dark rock, there's that lava rock as it as it breaks down. It's a nice substrate for plants to grow. It's you know, it's richer, and there'll be more food up there in the rock and I want to go, I want to get up on that food. I need a dark mutation. The mouse has no agency and becoming darker. Whether it's dark is entirely dependent upon things that happen in DNA that are not under its influence. So this sense of agency that somehow creatures can you know, will or drive themselves to adapt It's probably understandable why our brains might think that way, because we'd like to modify our behavior to do that. But that's just not the way nature works. The genetic lottery is random. And whether or not something's advantageous or disadvantageous, depends upon the conditions that creatures find themselves.

Nick Jikomes 1:00:20

And so yeah, the conditions, you know, the the natural world that the animals embedded in, is what's doing the selecting, that's where the agency is, so to speak. And what it's selecting for are forms that are able to survive long enough to reproduce, so that the light mouse on the dark Raava lock is gonna get picked off before it has a chance probably to reproduce. But then the other thing that comes into play here that's interesting is the, the sort of reproductive act itself. So the interaction of say, the males and females of a given species, and here's where you start to talk about sexual selection. So let's just start with a simple definition. What is sexual selection? And how is it similar to and different from natural selection?

Sean B. Carroll 1:01:02

So sexual selection, again, another Darwin insight is that there's all sorts of characteristics that seem to affect reproductive success. And they could be, for example, things used most obviously, would be in things involved in courtship display. So the idea would be that you can think of all sorts of species where males are in competition with other males, or they're trying to get the attention of females. And so whether it's, you know, a dance, or whether it's the size of their horns, or whether it's a chemical musk, they put on themselves or whatever, there's all sorts of competition out there. For a mate, very, very often. Male competition for female and the females making the decision as to what's going to happen. Pretty, pretty common in the in the animal kingdom. And those traits under sexual selection, boy, they can evolve pretty rapidly, and they can get very, very, as Darwin call them sort of exaggerated, right? I mean, the peacocks tail. I mean, holy smoke, what an extravagance right. Some of these horns, right on, you know, are antlers on animals, I mean, ridiculous size, you know, it takes a lot of energies to build those things, and to hold the neck up, etc. But that's because the mating game is where a lot of the actions that so as you're sort of dialing in here, we talked about natural selection. Sexual selection is essentially a form of natural selection. But it helps us sort of focus on in on the, on the mating game on the reproductive contest. You know, when you think about the structure of all sorts of things where a male might have, you know, 15, or 20, females in a harem, and competing with other males, that's a big competition as to whether or not that males genes are spread, make it into the next generation. And this This is competition has been going on probably for as long as the animal kingdom has been in existence.

Nick Jikomes 1:02:54

When I think about the pocket mouse example, with the light in the dark rock environments, that one makes sort of complete sense, okay, the dark boss is going to blend into the dark background, the light moss is going to blend into the light background. This enables them to evade predators long enough to be successful in the rest of their life and find a mate. When I think about sexual selection. Sometimes, I also get a sort of complete feeling to my sense of understanding as to why these ornate structures evolve, but sometimes I don't. So let's look at an example of each. And this is, by the way, this is a genuine question I have, I don't actually know if this is in the literature, anyone's got a good explanation for this one. If I if I look at something like a white tailed deer, then I think about the males competing with their antlers. If I just go, Okay, I accepted the female wants the one that's going to win the fight, it makes sense for why they're going to have bones that grew out of their head, and the one with the bigger, better antlers is going to win win the fight. That one's intuitive, even though it's it's hard, it's heavy to carry around, it's serving a clear purpose. And that's a literal battle. When I think about something like a peacocks tail, it's from the outside looking in, I see a hindrance to survival, the animals going to be slower, it's going to be harder to fly. My question is really, why do we know anything about where that female preference actually comes from? What are the females selecting for that's going to help their offspring in a case like that? Well,

Sean B. Carroll 1:04:22

I don't really know that if we we have really, you know. Watertight evidence, I think the thinking is that females are, you know, are generally dialing in on these characteristics as some sign of, for example, male health. So it may be simpler when we think about say, for example, certain birds that might have head feathers. And some of these colors and birds are you the birds can see in the ultraviolet. They're actually colors that we may not be able to perceive. But you know, things like zebra finches and stuff like this and well studied that it will reflect to some degree male health, the overall condition of the male. And that sort of reflects. Now again, we're sort of this we're coming up with a rationale that sort of reflects that it's been able to access food, it's doesn't have any obvious body defects, you know, things like this. So in some ways, it's, you know, that's showing this is a way of saying, you know, I'm so well fed, I'm so well traveled, essentially, that I built this magnificent tail, and oh, don't you want a piece of my genetic material. That's sort of that's sort of the rationale. There's trade offs, that what you're talking about, exactly, it's invested energy in making this tail. It's, in the case of the, you know, animals, locking horns, there's not only just the energy of building the horns, but of course, there's tremendous energy involved in combat and things like this. And of course, as you know, a lot of males, and a lot of species die younger, right? I mean, male lions, same thing, right? You know, then they get, they get kicked out of the pride, they go off and die by themselves, et cetera. So you can have a lot of fun with this, sort of looking at the males is essentially, you know, just sperm on two or four legs. And, you know, as long as the job gets done, it doesn't really happen doesn't matter what really happens to the male. So, you know, the males job is, is sort of think about it, you know, the males job is to is to procreate. And these are essentially these flashy, sort of almost luxury items, that's evolved to sort of be, you know, symbols of success symbols of health surrogates, because you can't really, you know, the female can't know that, that males got sperm, it's,

Nick Jikomes 1:06:57

it's, it's potentially like a genuine display of what you might otherwise fake. So if you've got the biological resources to make the peacocks tail, it says that while you've obviously been around long enough to be able to allocate and acquire resources, enough that you've got a bunch of leftover to make these cool feathers. And

Sean B. Carroll 1:07:15

there's a trade off. I mean, so often in biology, there, we can see there's a trade off even bested resources there, it may make you slower, it may make it easier for some predator to find you and track you down, etc. But in this straight off the mating game, the imperatives of the main game are outweighing the drawback of, you know, being grabbed by a leopard or whatever it might be.

Nick Jikomes 1:07:40

I also want to ask you about you know, when we talk about evolution, you know, we were just talking about how mutations are random. You know, the animals aren't choosing or wheeling their adaptations into existence, it really is a genetic lottery, you can't control which which base pairs are going to mutate generation to generation. And yet, you know, we've talked about some important constraints here, like, the catastrophe that comes from mutating certain genes in certain places, means that that variation sort of never even starts the race and never even sort of enters the picture out of mutations, you can play around with more so that there's constraints on where mutations can accumulate in the genome. And there's also the phenomenon say, of convergent evolution where, you know, obviously, evolution is somehow coming to the same kind of adaptation over and over and over again, and a really repeatable way. And so my question is, you know, with this element of random mutation, is there a predictability to the evolutionary process? And how predictable is it? Well,

Sean B. Carroll 1:08:44

that's a superb question, I think we're definitely getting getting down in the in the kind of center in some of these sort of beautiful black boxes that only recently, I think we can sort of shed light on. So we can't predict where a new mutation is going to happen. In an individual, these are distributed throughout the genome. It's a, it's just a probability process. But given a sizable population, knowing that individuals are born with new mutations, we can estimate that for example, you know, give me 50,000, new newly born, you know, mice from from Sandy parents, I might see a black offspring in there, right? Because I know how many genes can give me a black fur coat. I know how many mutations might be able to give me that. So I can, I can kind of come up with the math of this. This might be a one in 50,000 event, this might be a one in 10,000, event, et cetera. So we can at least predict sort of a probability that something might might happen. But give me the conditions. So for example, give me hundreds of square miles of desert where over the last 1000 or 2000 years there's been all sorts of eruptions and lava flows. Let me go in and look at the mouse populations of those black rats, what I'll find is I'll find over and one part of find certain mutation that makes this mice black. And I'll go to another population, and I might find the different mutation that made those mice black. So they've arrived at the same solution, sort of the imperative their conditions, right, the conditions have said, dark mice are going to do better on dark rocks, they may or may not have gotten there through the same mutation kind of kind of depends on the nature of the trait that you're talking about. How, how easy or how likely is it for the same mutations to happen?

Nick Jikomes 1:10:38

But there will be a lot of traits for which there are many mutational paths that can get you to the same outcome. Yeah,

Sean B. Carroll 1:10:44

I think path is a great way to use that the almost sort of think like, actually, this is this goes almost a century, probably a century back in evolutionary thinking, that if you think about, you know, a mountain range, and you're going to, you know, climb that mountain, how many paths are there up that mountain, how many different trails could you possibly take, if you're trying to get to the same place, which is sort of peak fitness, dark mice on dark rock, and there's more than one way up, nature will find a way to take more than one way up. Now, if one way up is many, many steps. And the steps in between are no advantage. They won't take those long way. Well, that goes long and complex routes, it still needs a route that gets you there. But it's beautifully satisfying. Both cases where we see the same mutation happened independently. Many times over, where we see maybe different mutations in the same gene happen independently. But also sometimes we see, essentially, species execute the same advantage or achieve the same advantage in almost entirely different ways. I see lots of these examples in snakes. We actually just just think about animals, for example, that that snakes have to get their toxins into your bloodstream, okay? Well, there's all sorts of groups of snakes across the world that have evolved over time. And it turns out that they're often messing with your blood coagulation. There's more than one way to mess with blood coagulation. But sometimes instincts independently come up upon essentially the same solution. There's, you know, ways to make your blood pressure go down, there's, there's independent ways to come up with that. And there's sometimes independent inventions that they use the same way. And then think about blood feeding animals think about ticks and vampire bats and things like this. They want to keep your blood flowing, when they're sucking, right, are leeches, right. So totally different groups of animals feeding on say, for example, a mammal, and they've got to put enzymes in there that stop that prevent your blood from coagulating, so that they can keep the bloodmeal going. So when we look at strategies like that ecological strategies, you know, I'm a snake, I want to get a toxin through your bloodstream, or I'm a vampire bat, I want to feed on your blood. These are lovely topics I'm sure that your audience is enjoying. But rest assured that we start to understand what's been tinkered with an evolution, we can often see similar, if not identical solutions being come up with by different animals. And that tells us how strong the conditions of selection are that things will arrive at similar or identical solutions, given similar conditions of selection.

Nick Jikomes 1:13:32

I see. One of one of the more interesting concepts that I was introduced to in some of your writing was, you know, classically, before the dawn of molecular biology, if you wanted to understand evolution and natural history, you had to understand, look at physical macroscopic things like go dig bones out of the dirt and go, Oh, wow, there, there used to be these things called dinosaurs, and we can see their bones, looking at things at that scale. But after the molecular revolution, you could look at genomes, you can look at the actual molecules, the base pairs of DNA and stuff inside of organisms. And you could go fossil hunting in the genome, so to speak. And one of the coolest concepts that I read in one of your books was the idea of fossil genes that you can actually see the evidence of evolution by looking at the genome of an organism and seeing like, Okay, this, this animal once had this, that or the other protein. How do fossil genes work? And what are maybe one or two examples of this type of thing?

Sean B. Carroll 1:14:34

Yeah, this is I'm glad you appreciate it. I always thought was so cool when I spied this when we started to have this power, and to look into genomes, and then realize there was a history in there. And I'll take my favorite example is this so every animal with a backbone on the planet has red blood cells that used to carry oxygen, except a little group of fish in Southern Ocean fit off the shelf of Antarctica, called ice fish that are transparent and have no red blood cells. Okay? So it's and it's probably no more than like a dozen or so species. Alright, so of the millions and millions of species of vertebrates that have ever lived on this planet in the last 400 plus million years, they're the only ones we know of that have gotten rid of red blood cells. And we know we got rid of them. Because we have all sorts of red blooded relatives, we know these ice fish. But when we look in the ice fish DNA, we can see the genes for the protein that carries oxygen, the genes for hemoglobin are fossils. The code is there are pieces of the code are there but it's broken, it's screwed up. And so what these fossil genes are, is they're they're like genetic text where we can recognize, hey, it's like you've got, you've got that stretch of DNA, if you like, if you think about text, it's like you've got the page from the book there. But there's typos and deletions and stuff like that, it says, at one point, and it's it had it had an ancestor that had intact text, and we can infer that from other species, but it's decayed. Now it's mutation has started to erase that gene. In these animals 100, we've got hundreds we know, we got some significant number of fossil genes in us a lot of species are carrying this around, because they've shifted lifestyles, a fish that used to live in temperate, an ancestor lived in temperate waters, relied on hemoglobin to carry oxygen, it turns out that there's probably a disadvantage to having red blood cells when you're living at almost minus two degrees Celsius in as ocean waters. And in fact, also there may be iron is limiting, and you need iron for hemoglobin to work. And so you don't have a lot of iron in the diet, it's a liability. It's been selection has favored the animals that have lost the red blood cells. And when you look in their DNA, they can no longer make this this hemoglobin, which is just, you know, the, it's a fossilized gene in there, it's almost intact, but it's got enough breaks to it, that it tells us no longer operational, but essentially, it's like a vestige of, of ancestral life sometimes tells you a lot about the about the ancestor. And we've got these in our genome, and all sorts of species have them all over their genomes. And it's a way another way to look back in time and say, Well, that was a piece of code that worked in some ancestors, and still may be working today and some close relatives, but in this lineage in this group of creatures, no longer working because something's changed about its conditions of life. And now this thing is either not needed, or it's a liability.

Nick Jikomes 1:17:52

So So you mentioned that we we have a lot of I mentioned, every species is going to have some fossil genes, because they've all got some history. Humans have fossil genes, we have a number of them. Are there any patterns to the fossil genes that we have? Are there any themes, like certain classes of proteins that that we've lost?

Sean B. Carroll 1:18:12

We've got a big number of fossilized olfactory receptors. Okay, so here's the thinking about that. So one of the biggest gene families we know about in mammals are encode proteins that help us detect odors. And it's a very rich family. And if you look at things like mice, or dogs, it may be I think it may be close to 1000 members in the family. But you look at humans, hundreds of them are fossilized. What's going on? Well, the best way we can rationalize this is you know, we're great apes, our closest relatives of the old world, great apes. That's the only group of mammals on this planet that has full color vision. So our ancestors evolved full color vision, and full color vision, we actually and you know this, because, you know, neurobiology that we've devoted a fair amount of our brain to our visual system. And we navigate the world in color. And we make maps of the world in color. And we identify foods to eat or foods not to eat, you know, using color that other mammals can't. So the thinking is that we've shifted to more visual. We rely more on a visual senses to make our way in the world than say, imagine a mouse scurrying around the ground that that can't see very far can't see very far ahead. And it's finding its way in the world using its its sense of smell. So that's a case where a lifestyle change becoming more visual meant. We've left behind a fair amount of the olfactory system and that's we also can see genes that are involved in building some of the anatomy of our olfactory system are fossilized genes. So we've, we've discarded a bit of our, the olfactory capabilities of our ancestors, living a more visual lifestyle. But when we look at other mammals, living a very olfactory lifestyle, don't have color vision, those genes are intact, kind of a beautiful story is,

Nick Jikomes 1:20:22

yeah, I mean, it all fits together very nicely, it really does make a lot of sense. Obviously, we still use the sense of smell. But I mean, you can just Intuit, you know, comments in a common sense terms we don't use or smell like a dog or a bear does. And it's very, very easy to imagine, based on what you just said that, although we can smell a lot of smells, a lot of odors, the repertoire of potential smells is probably more limited for us than it is to them, analogous to the way that their their color spectrum is more limited in terms of what we

Sean B. Carroll 1:20:51

can detect all sorts of hues of color that they can't, and they can detect all sorts of ranges of smells. And we can't, which is why you got all those dogs in the airport.

Nick Jikomes 1:21:02

I want to ask you about the speed of evolution. You know, normally when you talk about evolution, you're talking about very, very large stretches of time, millions of years to get new species and things like this thinking about the dinosaurs and very, very, very long stretches of time. The question I essentially want to ask you is, and I think I would like to use humans here as an example. But there's probably lots of other examples we can use. How fast can evolution work? What is the speed of evolution? Or the speed limit of evolution? And what are maybe some examples of of the more recently evolved things that have sprung up in human beings that help us get that speed limit?

Sean B. Carroll 1:21:43

That's a great question. I still think we're all wrestling with this. And we need examples to learn from but I'll start with human. And then I and I may just kind of then bounce around a little bit to sort of disperse some, some thinking maybe some some visual examples that might occur and listeners heads. Well, if you look at a human, you know, the most impressive thing of a modern human relative to some of our bygone ancestors is brain size. It's not overrated. It's maybe underused, but it's not overrated. So from the period of about two and a half million years ago to let's say, maybe a million to 800,000 years ago, brain volume in humans tripled in size. That is a spectacular change. When you take into account what that means in terms of capability, all that neural capacity, when you take into account how much energy it takes to run the brain. That's a that's a pretty big commitment to that. Now, you might say three fold increase in size and a million and a half years, maybe that's you might you know, for for brain that may not be that impressive. I can't tell you. If I was trying to say, you know, how much has like horse body size changed per million years? Or do we have a good sense of how much Wales changed in a few minutes, you know, gigantism in Wales, I think it's a relatively recent phenomenon. I think some people maybe have some kind of peg on the time there. So I don't want people to take away from this and go, Oh, Sean, thanks, three fold is spectacular. And it's the top of it. But it's impressive because of the body structure we're dealing with. And obviously, all the impact that has on lifestyle. And not only is that mount if you want to know about the speed limit of evolution, and I can't tell you whether the brain could have evolved any faster than that. But the why the brain probably evolved in that period is really interesting, which is we're in an ice age. I understand it the first ice age and 300 million years on the planet. Ice Ages are a really weird time. Ever since the asteroid hit the Earth 66 billion years ago, the Earth has been pretty warm. And in fact, in the, for millions of years after that asteroid impact, you know, the Earth was green from pole to pole, you did not have any ice at the poles. You only started getting ice, for example, at the South Pole probably 30 some odd million years ago. And then the freezing over of the Northern Hemisphere, and then the the advance of the ice sheets and then the retreated, the ice sheets, all that kind of stuff that kicked in two and a half million years ago. In Africa, it's not so much a story of cold and warm. It's a story of wet and dry. And our ancestors, by two and a half million years ago had invented tool use. So stone tools, primitive tools, but if you look at the next million and a half years, that stone toolkit got much more sufficient educated, you know, somewhere in there, maybe on the more recent side of it came the use of fire. Fire obviously allowed us to control some of our habitat less to cook our food, cook our food, you get more calories out of it. You know, we became a technological ape, essentially, in that million and a half years or so. And, you know, quite obviously, we're still technological apes. So, that brain size increase, you know, it was profound for our lineage. Obviously, it's been profound for the planet. And the closest causal link we could say is it's the Ice Age, and that you're living under this is regimes of shifting climate wet and dry, and the ape that can control its habitat, the ape that has a little more cognitive ability, in terms of finding food, or whatever it might be doing a little bit better. And so a big brained apes did a lot better. Yeah, so

Nick Jikomes 1:26:03

So basically, you can get in terms of sort of a gross anatomical change, and a very, very important one, one that basically defines our species. You can go from something about the size or not much bigger than a chimpanzee brain to a modern a human brain and about a million years. Yeah, maybe you can do it faster. But that's how long it actually took in our lineage. What about so what about what's what's like an example of like, something that's happened so recently, in evolutionary terms that it hasn't actually spread to everyone yet? An example that I can think of here would be like the lactase persistence story? Yeah. Yeah.

Sean B. Carroll 1:26:40

So I think, to my knowledge, the ability to utilize the milk sugar lactose of all twice in humanity. You know, I'm not totally up to date, Nick, on the literature, I'm thinking this is in the last six to 10,000 years. So it's going to correlate with the use of livestock, and obviously, harvesting, you know, milk from livestock, hasn't spread to everyone. That's why some of us are lactose intolerant. But that that's, that's a great example of a trait that clearly came along, I think, was civilization, and domestication of livestock hasn't spread throughout the population all the way. But,

Nick Jikomes 1:27:23

like, 1000s of years, and as a matter of a few 1000 years, is a few 1000 years, you can see change, like that spread to a lot. A lot of the population. Yeah, yeah.

Sean B. Carroll 1:27:33

I also think somebody told me, we don't think there are many, well, hey, just look at skin color. Okay, so probably the big migration out of Africa, that's people, the world probably started 60,000 years ago, all of us who are fair skinned who are light skinned, that's a big change from our African ancestors. It's not that has to do with being in northern climates, that you have to have less melanin in order for vitamin D, to enter the skin and the way we need it, we rely on it for a lot of body functions. So you know, that that change in pigmentation is going to be within the last X 1000 years. And you can also see that, that, you know, different grades of pigmentation exist in humans, you know, across the world, relative to latitude and an altitude. So you can, you know, those are some examples of of traits that that have definitely changed in geologically recent humanity. Yeah. What, um,

Nick Jikomes 1:28:39

what's what's guy? I mean, I haven't followed this area of science, you know, as closely as I used to, what's what's what's one or two? What are what are two things going on in evolutionary biology right now where people are making progress, and and we're probably going to get some answers to some interesting questions we didn't know about before.

Sean B. Carroll 1:28:56

I think I think probably the things that that, that people hear about and that are interesting, are essentially paleo genetics. So, you know, this is where archaeology now has met genetics and our ability, which, you know, didn't start till, you know, late 80s, early 90s, that we started getting DNA out of museum specimens and starting to analyze it. But this is ratcheted up to, you know, phenomenal, high resolution, high speed work, and the ability to look at specimens 1000s, many, many 1000s of years old, both human human pathogens that are associated with humans, humans, livestock, etc. This I think is, you know, archeology and anthropology are in a both a renaissance and perhaps you know, sometimes an uncomfortable revolution because ideas have been around for a while are being tested with new methodology. And but whether you want you're interested in you know, plagues that swept humanity and may have changed the course of history and Europe or changed, in fact, the since the ancestry of humans because you had some plagues that are pretty large scale and add a pretty big impact on, on who the survivors were understanding the origin of pathogens. I think those are, I think that's an area in in, in sort of a human evolutionary studies that is on fire and in terms of the amount of work going on, and the potential there for, I think, just that findings that help us stitch together our own history, I'd say, particularly from like, the last 10,000 years. I think everybody's familiar that's been gone for a while this, the genealogy studies have been there, you know, where did you come from? We're a country, obviously, of immigrants, and everyone's interested in where their ancestry goes. But we're talking about a little deeper time, a little more complex changes, you know, adoptions of various technology who introduced which animals were which crops were, you know, what, what's the story of humanity of the last 10,000 years? And I think that and and people are going through graveyards and bogs and everywhere to try to, you know, to try to get specimens to tell that story. Interesting.

Nick Jikomes 1:31:15

Yeah. So just basically the story of, you know, there's the story of deep human history. So like, this fungi problems of the world looking at, you know, Neanderthals and ancient extinct lineages of humans. But there's also like the more modern historical record of how did people move around in Europe and bring sheep to this place in that place, and all that stuff? Yeah.

Sean B. Carroll 1:31:35

And you know, who domesticated horses and all that sort of stuff. So I think the last 10,000 years where we know, this is where crops were domesticated livestock were domesticated, we imagined that the people that were doing that had interesting advantages in terms of, you know, food resources. And then of course, you had just waves of people moving around the globe, and, and well, not with great abandon, and it did depend on modes of transportation at some point. But, of course, these these events were, you know, human population was much smaller, you know, you can imagine that some of these infectious diseases that we may have encountered, as we entered new areas, may have, you know, devastated human populations. So I think the story of the last 10,000 years is going to be, you know, a whole a whole, the synthesis of paleo genetics and archeology and anthropology is, is underway. And I don't know if the dust will ever settle. But for a while here, it's it. I just think it's a really fertile period.

Nick Jikomes 1:32:45

is another interesting question I have for you is, what is the relevance of the study of evolution beyond just the academic interest we have in knowing the story of ourselves? In particular? Is there any, is there any advantage that would be had by say, a medical student or a physician and understanding something about human evolution and evolutionary biology that would actually enable them to be a better healthcare provider?

Sean B. Carroll 1:33:16

Yeah, I think so. In fact, there's this whole realm called evolutionary medicine and there's a, there's groups that get together across the nation who get together on those who are essentially zoom seminars, to try to sort of use evolutionary knowledge from a from a medical perspective. I'll take the low hanging fruit here, okay. You know, we had this pandemic, did you hear about this last couple years ago, etc. I mean, everything about how that virus was evolving, and it's evolving under the intense selective pressure of our immune systems, both our immune systems as it responds to infection and our immune systems as it's responding to vaccination. And it was really important to try to figure out, just, you know, how far and fast could COVID evolve? And in what directions and still be COVID. Right? It's, you know, still be essentially dangerous. And so scientists, for example, we're studying this spike protein that's on the surface of the virus. That's what's in the vaccine. So, to understand the arms race, I mean, this is for evolutionary biologist, I think some of the most interesting situations are what we would describe as these arms races. And that arms race is describing, you know, its predator prey, its host pathogen, these examples. It's where evolution is. TVs, another metaphor is on steroids. It's essentially it's in fast. It's in very fast motion, because there's such strong selection, and there's a Counter Strike and in the case So the virus, it's got a very rapid replication cycle. So it's spitting out variants, you know, in every individual. Yep. Multiply that by the 10s of millions of people's infecting. And you're getting a huge experiment going on with this virus, right? So arms races are just really interesting. That's a different way to put the COVID story. But what we're trying to learn was you remember you were talking about which mutations were viable, right? What's the mutational path. So the virus for example, it's mutating, as it mutates, it's, it's spitting out all these variants, remember, at random, it just, essentially, you just have all these viral variants, it's spitting them out. Our immune system is clearing out the ones that can recognize so of course, the ones that it can't recognize, because I hadn't seen it before, those of the escapers that are then seeding the new variant that we're all worried about. But this process, we, the virus still has to be able to infect cells, it still has to be able to recognize the protein on human cells that it uses to get into our cells. So it's changing the spike protein under the pressure of our immune system, we can only change it in certain ways and still get inside ourselves. So this is the things that we've been talking about in this conversation, what mutations are advantageous, what mutational pathways are permissible to the virus, what things won't work, because it will cripple its ability to infect cells, you know, game over. And when you when this is run for years, against the immunity of the globe, you know, we weren't Trix does COVID have, right? So we hope it's kind of exhausted self, in terms of what it can come up with that our immune system hasn't seen yet. You were just asking, you know, why would a knowledge of evolution be helpful? You know, HIV was a totally different story. Some of you know, people may be too younger, kind of remember all that. But HIV has an incredible mutation rate, perhaps 10,000 times the mutation rate of something like our own cells. So that means in an individual infected with HIV, that individual has a whole spectrum of HIV variants. That's why and then the insidious thing about the HIV virus is it attacks the immune system, it attacks the very system that we use to counteract the virus. So that arms race, and that's why it's such a deadly virus is that arms race is, is that virus essentially escapes the immune system is destroying it. And so the capability, obviously, of the infected person to respond at subsequent waves of variances, is thwarted. So you know, these are battle with infectious agents, and, you know, take malaria, in Africa, whatever. These are large scale public health battles. And I think to understand mutation variation, the pathways of mutation, our adaptive immune system, you know, people may not appreciate that, but why our immune system reacts to these things, we actually rely on a mutation and selection mechanism in our immune system. This could be another 15 minutes of this podcast that people don't want to hear. But our immune system is amazing. Because in fact, our countermeasure is to generate all sorts of immune molecules using mutation. somatic mutation, as mutation only takes place in our immune cells, to generate all sorts of variants to try to counter punch, the variation we're experiencing from a pathogen,

Nick Jikomes 1:38:51

you're talking about the way our bodies produce antibodies. Yeah, the

Sean B. Carroll 1:38:54

way we produce antibodies, and people may not appreciate that what we do in making antibodies, our body can make billions of different antibodies, using only a few 100 genes. So I repeat that, again, because everything we've been talking about is like a gene encodes a protein, right? But the way antibodies are stitched together, and because of certain mechanisms that are particular to antibodies, is that using just a few 100 pieces of antibody genes that can be assembled and all sorts of different ways, the body can make billions of different kinds of antibodies. And for that, we should be thankful, which is why essentially, we will mount an immune response against virtually anything we're exposed to. Right. And that's, that's the story of our group of vertebrates is that you know, 400 million years of vertebrate evolution has given us a pretty impressive immune system, which is, you know, a, a very alert, very responsive system for counter attacking foreign agents that we've never seen before in the body. It's a really dramatic and meaning you talk about, you know, what should a physician understand about evolution? Well, when you understand that our own adaptive immune system runs on the principles of evolution, in a fight against all the infectious agents that could ever exist in the world, including new ones that are evolving as we speak, I think I think a knowledge of evolution seems really sensible to have, if you're gonna go into the field of medicine.

Nick Jikomes 1:40:23

I do want to ask you a little bit about the snake the snake venom stuff, just because it's so interesting. It's so I don't think you quite said this, but I was detecting that maybe snake venom has evolved independently in different lineages multiple times. Can you maybe give a survey of the different types of venom and what we know about what what the venom is actually,

Sean B. Carroll 1:40:41

toxin. So different groups of snakes have come up for wisdom, different toxins, but so snake venom is old it may be it's very likely that essentially lizards came up with venom meaning something in a secretion that was delivered specifically in into prey and to help immobilize the prey. But different groups of snakes have kind of gone wild with this idea. So if we work on rattlesnakes, they're easily accessible to us. Maybe hopefully, well familiar to listeners probably not too familiar to listeners, their close relatives in this country are copperheads and water moccasins, they belong to the same large family. Those snakes are largely very often hemorrhagic in their nature, so they disrupt hemostasis so they cause hemorrhaging cause a drop in blood pressure, lead to tissue damage, when they bite humans. They're very effective at subduing prey. And this is, obviously venom is first about subduing prey. When we get invaded by a snake and has no intention of eating us, that's a that's a defensive bite. But if but there are rattlesnakes that are very neurotoxic, and that will cause respiratory arrest very quickly. So particularly in the desert southwest, things like the Mojave rattlesnake, are something to be alert to. There's also some populations of snakes, even here in the in the east, that also have neurotoxic capability. Looking around the world, you know, probably the Australian snakes are most famous for this. Maybe that's partly biological reality, partly Steve Irwin. But so the snakes we have here that I just described are called pit vipers. There's things called elap IDs in Australia. That most toxic venom we know of, and a snake is a in an Australian snake called a TaiPan. Interestingly, depending upon its prey type and can kill in different ways. But one way it it kills is essentially exhausting your coagulation system very quickly. And it's come up with toxins that are in fact components of the blood coagulation system, that it has co opted into the venom gland. So it injects those into its prey, and wrecks its clotting system I

Nick Jikomes 1:43:12

see. So it's almost like taking its own blood clotting proteins, scrambling them and then injecting that into another,

Sean B. Carroll 1:43:19

not even that scrambled. It's essentially saying that you take some there are certain physiological proteins, things that control blood pressure, things that for example, control clotting. Yeah, that when injected into prey in some quantity,

Nick Jikomes 1:43:34

yeah, if it's concentrated, it's just that a dose that super physiologic toxic

Sean B. Carroll 1:43:38

is toxic, so So something that has a normal physiological function, you know, working in harmony with everything else, and the snake's body, put an event on gland deliver it, and it's a payload into prey. Well, that's essentially giving away for example, the probably the main concept here is that when I say Well, where did these toxins come from? They're coming from normal physiological proteins, that it just turns out some subset of them when expressed in the venom gland and delivered through that hypodermic needle that is a fang subdue prey. And it's an arms race with prey because prey themselves have certain defenses, they, they you could select for prey that have certain countermeasures. Some of those countermeasures might be things in their bloodstream that will soak up toxins. It might be variation in some of the things that the toxin hits, say, for example, parts of the nervous system. So we know that this predator prey relationship between snake and prey is one of these evolution, arms races that's going on. So that's part of the reason why we wanted to study it. evolutionary biologists like to study things that have changed. So snakes have come up with new weapons and re have come up with countermeasures and And that's a rich area for understanding, you know that this dimension of evolution, the origin of novelty, and coevolution of venom and anti venom measures.

Nick Jikomes 1:45:13

How long ago? A lot of what we were talking about in the beginning, you know that that was me kind of pulling up the past our past. Because I read your book, endless forms most beautiful. When I was in high school that came out in what 2005? Yeah, yeah.

Sean B. Carroll 1:45:31

And Nick,

Nick Jikomes 1:45:33

also was, Sean is one of the few people Sean is one of the few living people on planet Earth. Who knows what I look like without facial hair. Fun fact.

Sean B. Carroll 1:45:42

There's very few people on planet earth who know what I look like when I facial hair, because I've had it since I'm 18. So I'm a lot older than you now, buddy. Yeah.

Nick Jikomes 1:45:51

And where are you at now? University of Maryland, Maryland. Okay. And so are you focused mostly on the snake venom stuff now? Are you still doing flying?

Sean B. Carroll 1:46:00

No, in the lab moved here from the University of Wisconsin about six years ago. And I thought we should, you know, I should take on new things. I've done that in the research lab over the course of, oh goodness, now 36 or 37 years and leading a research team. I felt satisfied with what we had done in developmental and understanding, body part development, I felt satisfied with what we contributed to understanding the evolution of form. And I thought, let's get to biochemical novelty, let's get what's going on. And the idea is not so much to solve the snake mysteries unto themselves and say, here's what snakes did. It's the general question of how does how does novelty arise? What? Well, how does a snake come up with put a clotting protein into its into its venom? What are those genetic steps? what's permissible? Why those proteins and not others? So it's understanding more of the general logic and rules surrounding the evolution of novelty using snakes, because it's just a rich set of examples that we can get, right? And we understand the ecological significance of what's been invented.

Nick Jikomes 1:47:16

All right, Shawn, I don't want to take too much more your time. We've already talked about a lot of interesting areas, is there anything that you want to reiterate or go back over from what we set or just sort of hammer home for people in terms of you know, how they should think about evolution, or maybe where they can go to learn more about some of the stuff we were describing?

Sean B. Carroll 1:47:35

Well, if they're interested in a little more how this stuff works, you mentioned endless forms most beautiful, there's also a book I wrote called The making of the fittest, but I'm going to, I'm going to take that door you just opened. And I'll just say, what's sort of what's on my mind when I talk to people about evolution these days. And I gave you a little piece of it, and I'm gonna throw this out there and just see if any of it sticks, and maybe a listener can offer a comment. I think we kind of need a new origin story. You know, if you take an evolutionary biology class, or you know, or God knows what you might be exposed to, and you're gonna start four and a half billion years ago, et cetera, et cetera, et cetera. I really think when you look around the planet, I think the most significant event I can think about is that asteroid that hit 66 million years ago, that was a reset button. And it's, and it's so changed the world, changed it from the age of reptiles, open the door to the age of mammals, our ancestors, mammals took off, they got bigger than they'd ever been very quickly, they'd been around 100 million years, alongside the dinosaurs, they got bigger than they'd ever been. All these groups we know and love of the different kinds of mammals evolved, probably a pretty short period of time, maybe 10 million years after the asteroid. But you know, three quarters of the species of the planet were wiped out in that in that mass extinction. And, to me, it's sort of like an eraser, an eraser and a reset button. And I think of it as part of the beginning of our origin story, because if it hadn't happened, you and I wouldn't be having this conversation. If it hadn't happened, mammals wouldn't be dominant on Earth, we wouldn't have primates etc. And the world we see out there, which the groups that rebounded birds from a very small number of ancestors that flourished and the types of birds there was essentially a bird radiation, a frog radiation, a mammal radiation after this snakes, my little favorite group, snakes are a small part of the story before that. These groups of snakes I'm talking about a lot of their action has happened in the last 20 or 30 million years, the invasion of Australia, the invasion of North America, the radiation to all these types that's pretty young as evolution goes. And then humanity, and I said, Well, there's another big event, which is the Ice Age, a really peculiar, really odd geologic period. And I don't need to spend your time going into why the Ice Age kicked in, but let's just say it was some really interesting geology behind that. And without the Ice Age, you don't get the technological apes that have podcasts and talk over zoom. So the origin story is to sort of think about the geological and biological events, without which we would not be here. Most of which was discovered in the last 50 or 60 years. Yeah, it couldn't have told this story to our grandparents didn't know it. In fact, couldn't have told them much about DNA either. Okay. So so the the explosion of scientific knowledge is massive. I think there's a, there's a very concrete narrative, we can say about our kind of mammals, primates, humans, what what are the contributing conditions to all that? And that's the kind of thing I think that whether you're, you know, an artist, or, you know, a business owner, or a lawyer, this is this is the piece that this is what biology has to offer you. And some other things too, but the part that I think you should have is some picture of the planet you're living on and how humans got here. And there's been lots of stories about humans total over the millennia. But the one that we can tell in the last 5060 years, including our ancestors out of Africa, remember that that was only solidified really 1959. So there's, it's a, it's an incredible achievement of humanity, to understand how we got here, and it beats any other story that someone tried to tell me a long time ago when I was a little kid. And I think this is I think this is a big thing that evolutionary biology has to offer. So that's, that's what I'm throwing out there.

Nick Jikomes 1:51:53

All right. Well, Sean Carroll, thank you for your time.

Sean B. Carroll 1:51:55

Thanks, Nick.

Mind & Matter
Mind & Matter
Whether food, drugs or ideas, what you consume influences who you become. Learn directly from the best scientists & thinkers about how your body & mind react to what they're fed. New episodes weekly. Not medical advice.