Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas - 117 | Sean B. Carroll on Randomness and the Course of Evolution

Episode Date: October 5, 2020

Evolution is a messy business, involving as it does selection pressures, mutations, genetic drift, and the effects of random external interventions. So in the end, how much of it is predictable, and how much is in the hands of chance? Today we're thrilled to have as a guest my evil (but more respectable, by most measures) twin, the biologist Sean B. Carroll. Sean is both a leader of the modern evo-devo revolution, and a wonderful and diverse writer. We talk about the importance of randomness and unpredictability in life, from the evolution of species to the daily routine of every individual. Support Mindscape on Patreon. Sean B. Carroll received a Ph.D. in immunology from Tufts University. He is currently the Andrew and Mary Balo and Nicholas and Susan Simon Endowed Chair of Biology at the University of Maryland, Vice-President for Science Education at the Howard Hughes Medical Institute, the Executive Director of HHMI Tangled Bank Studios, and Professor Emeritus of Genetics and Molecular Biology at the University of Wisconsin. His new book, A Series of Fortunate Events: Chance and the Making of the Planet, Life, and You, explores the role of chance in the development of life. Web site HHMI web page Google Scholar publications Tangled Bank Studios Talk on The Serengeti Rules Amazon author page Wikipedia Twitter

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Limited lubrication warranty for lifetime engine protection. Other conditions apply, including enrollment and receipt requirements. See pensoil.com slash warranty for full details and turn. Hello, everyone. Welcome to the Mindscape podcast. I'm your host, Sean Carroll. And today, special treat, our guest is also Sean Carroll. But not because it's a solo episode, not because I'm the only one talking. We have another Sean Carroll here today on the podcast. This is Sean B. Carroll. And honest to goodness, another person with the same name as me, different middle initial, who is a world famous biologist, who would have thought. There's a lot of Sean Carrolls out there, as it turns out. I first heard of the other Sean Carroll. When I was a graduate student, I was walking down the road in Harvard Square, and I stopped at the out-of-town news newsstand because I saw that, I think it was Time Magazine, had a story about like the 30 scientists under 30 years old or something like that were going to change the world. And so, of course, as a joke, I opened it up looking for myself. Now,

I knew perfectly well. I was not on that list. You don't get on those lists without being told, but also in no sense that I deserve to be on that list as a graduate student. But to my surprise, there I found my name, and I realized that, oh my goodness, there's another person with my name. But the podcast is not going to be a whole bunch of jokes about us having the same name. Sean Carroll, the biologist, is actually a leading figure in the field of Evo-Devo, the idea that evolution is coupled with development of organisms. You know, you might remember from high school biology the idea that your DNA, encodes information that is carried over to RNA in the transcription process, and then the RNA goes

off and makes proteins that do functional things in your body. That's a true story, but it's very far away from being the entire story. Much of your DNA does not code for proteins at all, but it nevertheless serves a purpose in turning on and off other DNA strands that actually do cause proteins to be formed. And this makes perfect sense. You know, the DNA in a skin cell in your body is the same DNA as in a blood cell or a brain neuron, but of course they develop in very different ways. And this has important ramifications for evolution. In fact, interestingly, it's not just the DNA that can evolve in some sense. The chemical environment that a fetus grows up in in the womb can affect how its genes are expressed and that can even be passed on to subsequent

generations. Maybe not that far. Maybe it doesn't last forever. It's a contentious area. We talked a little bit about this with Carl Zimmer on the podcast a while ago. But in fact, we're not going to mostly talk about that with the other Sean Carroll today. What we're going to talk about is musings on the bigger picture of evolution, that his cutting-edge work studying fruit flies and other aspects of the Evo-Devo story have led him to really think about what evolution is, how it works, and in particular the long-running debate about to what extent evolution is an algorithm, that picks out the best adaptations for whatever situation denomic population finds itself in,

versus the role of random chance. And what Sean wants to do is to emphasize the role of random chance. You know, both adaptation and randomness are very important, but they have different aspects that are important in different ways at different times for different kinds of things. So this led him to not only think about randomness in the course of evolution, but randomness from other things that impact on the course of evolution like when an asteroid hits the Earth.

You know, that actually has a very important impact on evolution, even though it has nothing to do with mutations in our DNA or anything like that. So that's the story we're going to dive into today. We're going to talk about chance and randomness and unpredictable events and the huge role they play, both on the evolution of life on the large scale and even on individual lives here on Earth. So while I have you here, let me remind you that we have a web page for the podcast, preposterousuniverse.com slash podcast. I recently wrote a blog post. There's a separate blog on my website. So preposterousuniverse.com slash blog.

I wrote a blog post about what I look for when people suggest potential podcast guests. I'm not limiting myself to guests who only have the same name as me or anything like that. So I actually love getting suggestions. I rarely take them just because there's a limit. I get way more suggestions than I could possibly take, but I do take them sometimes. I've gotten very, very good guests out of people who I never would have heard of, but someone suggested them. And a lot of people suggest people who I would never pick for one reason or another, and they're, you know, you can read about what those reasons are in the blog post.

So check that out, preposterousuniverse.com slash blog. If you want to drop some suggestions, who knows, I might actually pick somebody. In fact, as I'm recording this, which is a few days, a few days, before the episode actually airs, it's actually published, Ian Robinson on Twitter suggested that I interview Sean B. Carroll. So, Ian, you're going to think that I did this because you suggested him, but in fact, we recorded the actual interview a couple weeks ago. Anyway, Sean B. Carroll is not only a leading scientist, he's an amazingly good communicator and writer, as you will learn very quickly in the course of this interview. I encourage you

to check out his books. And with that, let's go. Sean B. Carroll, welcome to the Mindscape podcast. Hi, Sean. Thanks for having me. I'm wondering if I should have just said Sean Carroll, and that would have confused people even more. But I'm very glad that we're having this chance to talk. We've known about each other for a very long time. And as I always tell people, you're the one with the beard that makes you the evil twin by the rules of science fiction universities. Well, and I always say you're the one that understands the cosmos.

So you're better at math. How about that? I think that, but you're better at like, like, experiment. You have a lab, right? You mean, you get your hands dirty. Yes, I do. Well, I get other people's hands dirty, but I've dirtied my hands over the years. That is true. Yeah, we age into a part of our lives where we get other people's hands dirty. So, but let me, I mean, you've written a book. Tell people what the title of the book is so they can rush out to read it or even, you know, read it by it right now as they're listening. Yeah, sure. It's in all sorts of formats, if whether you like to read or listen. So it's called a series of

fortunate events, chance and the making of the planet, life, and you. That's pretty good. So, but you come out of this as an evolutionary biologist who got interested in the role of chance and what it plays. So I definitely want to get into that. But your first book, or at least your first trade book, I don't know if you have, I think you have textbooks and things like that, right? Do you have a textbook? Right. Yeah. So your first trade book was Endless Forms Most Beautiful, which is about the extremely hot and sexy topic these days of Evo Devo, Evolutionary Developmental Biology.

So what was the theme of that book? Well, that was really, you know, my first sort of mature passion in science that as I became an independent scientist and thought about what I wanted to do, I was really driven by, you know, curiosity and love for animal form, you know. I like butterflies and snakes and leopards and all that, which I think a lot of biologists do. And I always wanted to know, you know, the how's and wise, you know, how did all this diversity evolve? And the path to that was long for both science. and for me personally, because we had to first sort of crack the science of how any animal form is built. And that's the arena of developmental biology. And then the course of doing that, started making discoveries that surprised us as much as anybody else. And that led to this term called this field called Evo-D-Vo of it's really trying to understand the evolution of form through the lens of the making of animal body. Okay. So in particular, I think that there are implications in a sentence like that that are perfectly clear for you, but maybe not for the audience.

I mean, there's a story to be told about what genes matter and what they do, right? That is a little bit of a shift from the traditional paradigm. Yeah, so think about it this way. So the making of an individual form is that process of going from egg to adult, and that's development. So to get different kinds of looking adults, you know, imagine the entire array of the animal kingdom, changes have to happen in that process. So we want to understand what kinds of changes happen in that process of building animals that give us different types. To do that, we had to get into that inner machinery, which is really the genes that are involved in building bodies and body parts. And that was really the heyday starting in the 1980s of developmental biology, where we started cracking sort of the mysteries of how to animals sort out what's going to be the front end, what's going to be the back end, what's going to be the top, the bottom, right left. And it all started with identifying what we call this genetic toolkit for development, a relatively small number of genes that are involved in building bodies. Yeah, I mean, it's a

fascinating idea because I think that probably we're, most of us are fooled by not knowing a lot of biology and maybe knowing a lot about, or at least thinking we know about, you know, blueprints or something like this. So we have the idea that, you know, somewhere in our DNA, there's just a little roadmap for all the different parts of our bodies, and you just have a one-to-one correspondence, there, but the reality turns out to be a little bit more nuanced. It's both simpler and more complicated at the same time. So let me try to unpack that. The simpler part, the great and thrilling discovery, and I was really close to it, so it was, I can really tell you it was thrilling. The expectation in, say, the early 1980s, before we had a glimpse of any of these genes was that really like the building

of a human and the building of an octopus or a insect had nothing to do with each other. that things were so different. And that was really kind of the anatomous view that, you know, let's look at the, you know, the structure of these creatures and, gee, they look so different. But what was amazing, and this all came out of studying the fruit fly, which has been sort of the great workman of geneticists for decades, was that when the first genes were identified in fruit flies that built fruit fly bodies, we quickly discovered those very same genes are in us and in virtually every other animal in the kingdom.

And they're used in very similar ways, and they're even organized in similar ways in the DNA. And nobody, nobody expected that. I've never met anyone who claimed they expected that. And so that's the simpler part, that there's a common toolkit. Then it sort of phrased the next question, well, if everybody's got all this in common, how do you make differences? And that's what I really spent a lot of my research time on, was working from a common toolkit. How do you build different kinds of animals? Yeah.

So you're saying that, I mean, basically there are some genes that make legs, and among other things, and like how you control how those genes turn on and off is depends whether you get an insect leg or a human leg. That's right. And where you turn it on and off also depends whether you get six legs as in an insect or eight legs as in a spider or a hundred legs as in a millipede. So we quickly sort of got into, you know, the machinery that was really making the key differences in the major differences in the way. animals are built. And so that happened just so much faster than anyone expected because everyone thought we were going to have to work out sort of the recipe, you know, for a fly and a recipe for a mouse and a recipe for a worm, you know, slowly but surely, you know, and separately from each other. But really, we kind of discovered a passport to the whole kingdom. Yeah. And it's, it's amazing

to me because it's not only that different, very different species now have this toolkit of gene, but they've been around, you know, I want to say almost forever, but at least, for a very, very long time in developmental history, evolutionary history. That's absolutely true, yeah. So at least a half billion years, for these genes to be shared among such different animal types as sea urchins and butterflies and humans, birds, they've been around a half billion years. So pretty much everything we see in the animal fossil record, you know, sort of documents the various ways these things have been repurposed and sort of tinkered with to shape this incredible variety of life that we love.

Well, yeah, I mean, I'm going to encourage the audience also to buy that book, Endless Forms Most Beautiful, that you wrote, to hear about the Devo side of things. But let's dig into the evolutionary side of things. I mean, what are the implications of this discovery for how we think about natural selection or how species evolve? Well, the biggest implication I think of Evo-Devo is, I'm going to get into a mechanism for a second because I've told you there's this common toolkit and kind of the analogy to carpentry or whatever is somewhat intentional in that just as a carpenter can fashion very different things out of the

same materials these genes can fashion very different forms out of pretty much the same set of materials how does it do it and to think about that you got to start picturing kind of imagining DNA and DNA the way it's organized our chromosomes are made up of DNA and genes are encoded in segments of DNA. And when you think about DNA, you kind of, and you think about genes, if you could, if you could sort of take a quick snapshot of, you know, your DNA or my DNA, those genes would stand out like islands and sort of a sea of, well, we might say junk, things that are not genes, things that don't encode things that do work in the body. So genes that encode proteins and proteins are the things that do the work in the body. That's a relatively small part of our

DNA. There's another part of our DNA been much harder to see, much harder to figure out where it is. And that's the DNA that's used like switches for turning genes on and off in time and in space. And understanding those switches became central to understanding the evolutionary puzzle you just described. Because to build one body, you have to orchestrate the turning on and off of genes and time and space and sort of a very elaborate choreography. To build different kinds of bodies, you have to tinker with those switches. You have to tinker with where they're turned on, how many places they're turned on and when and how they're turned off. And so getting at those switches, which was experimentally more difficult, but evolutionarily, very rewarding, that's one of the big insights of Evo-Divo is to understand that while the genes are very similar between animals, the things that they encode that make these proteins that do the work are very similar among animals, nearly identical between chimpanzees and humans. But how they're used is different. And those differences are wired into the switches that are littered throughout our DNA.

And so that's a huge mechanistic insight and I think, you know, pretty profound biological insight that you can make lots of different things from a common toolkit. But the action, the evolutionary action is outside of those genes in the parts of DNA that regulate how they're used. So maybe to put this in context a little bit, you know, Darwin comes along with the theory of evolution by natural selection. But he didn't know about genes, much less DNA. And then we figured out that there were genes and Mendel and others, although there's a history of who. paid attention to who. And then we figured out there was DNA and, you know, they coded for proteins, et cetera. So I take it, you're going to correct me if I'm crazy here, that there was this picture that the things that were being selected on by the forces of natural selection were these genes

that were coding for protein. And maybe the Evo Devo story changes that a little bit because the genes that switch on the other genes are equally or more important. Yeah, and it's the switches themselves. So I think that's a true history. And I think part of the way science grows, as you well document, is that sometimes things are just not within our reach, let alone our grasp. And things were outside of Darwin's reach and things were outside the reach of early 20th century biologists. And really, until we could clone DNA, until we could look at individual genes and say, okay, here's a gene. And in the case of the fruit fly, the sort of the genes that launched a thousand postdocs are these genes that when mutated, for example, transform the antennae of the fruit fly into legs or give the flies a second set of wings. And when you see

these striking, you know, appearances and you say, you know, how can you do that? And it's a single, you've altered a single gene. It makes, it's just, you know, you're just too damn curious. You're just like, I got to figure out what that, what's going on. And I was, I was one of those postdoc. When I learned about these mutations that could change body parts like that, I said, well, you know, what the heck kind of gene is under there? And that, that, when we dug into those things, and it had the tools, finally by the late 70s, early 80s, to analyze the DNA that was the genes themselves, as opposed to just studying genes, sort of what's called kind of beanbag genetics, of just studying formal genetics by crossing, you know, one fly to another. That's when we really could

get at these questions. And when we did, you know, the science, you know, flourished in an amazing way. When New Yorker magazine asked Mark Zuckerberg how he gets his news, he said the one news source he definitely follows is TechMeme. For three years and nearly 800 episodes, the TechMeme Ride Home has been Silicon Valley's favorite tech news podcast. The TechMeme Ride Home is a daily podcast only 15 to 20 minutes long, and every day by 5 p.m. Eastern, it's all the latest tech news. But it's more than just headlines. You could get a robot to read your headlines. The TechMeme Ride Home is all the context around the latest news of the day. It's all the top stories, the top

posts and tweets and conversations about those stories, as well as behind-the-scenes analysis. The tech meme ride home is like TLDR, Too Long Didn't Read, as a service. The folks at TechMeme are online all day, reading everything so they can catch you up. So listen to the one podcast anyone who's anyone in Silicon Valley listens to every day. Search your podcast app now for Ride Home and subscribe to the TechMeme Ride Home podcast. So how does this all fit in with the idea of sort of levels of selection? I mean, Richard Dawkins famously popularized the phrase the selfish gene. And I'm not sure if I had the right conception of this, but what I took that to mean is that in some sense, I mean, there's the selfishness of it.

Okay. But we can argue about that. But I think that a lot of people think that what gets selected are sort of traits, right? Like, oh, you know, you want your neck to be longer, so you evolve. all the longer neck, but there's not just a bunch of switches or dials inside the organism that says length of neck and things like that, right? There are genes, and you might have genes that do or do not do what you want, and a gene that does what you want might also have other effects. So how did that change our picture of selection and adaptation? Yeah, let me get to selection and adaptation in a second,

but first it had to change our picture of exactly how anatomy was encoded. In other words, How did you, what was the relationship between physical anatomy and genetics? And you might have thought, for example, that, you know, maybe we had a gene for building our pinky and a different gene for building our thumb. Right. And maybe a different gene for making our toes, right? Well, we started to learn through developmental biology that actually the same genes were involved in building every digit, you know, every toe.

In fact, they might be involved in building other parts of the skeleton. So you didn't have anatomy that said, you know, that there was sort of like a three-dimensional map of the body that correlated, you know, sort of beautifully onto the DNA. What you had was these sort of circuits that were used again and again in different times throughout the building of the body to do very similar operations. Then you'd have to say, well, how does this evolve? Because here's the trick. The trick is if you damage one of these genes, the actual sort of protein coding part of the gene, because it has so many jobs, it's catastrophic. Right. You know, it's what we would call a birth defect. In fact, the animal might not be viable at all.

So how do you tinker with the genetic information in a way that's viable, in fact, even novel, and doesn't have this cost, this dramatic cost? And this is the other really important discovery of this regulatory DNA, these switches, is that these switches act independent of each other. And so you actually have fine-tuned control of sort of, you know, for how long a given gene is active while you're building a certain digit, as opposed to really kind of crude control of just whether that gene, you know, exist at all or not. Yeah. So we first had to change our thinking about sort of, you know, where would sort of be the hot spots of evolution in DNA. So the genes, the actual protein coating parts of these genes are very stable and can be evolutionarily, you know,

conserved for hundreds of millions of years. But the switches are very tinkerable, alterable in the course of evolutionary time. So back to your question about selection and adaptation. it means that not a huge change in sort of our classical thought that there's variation. So if you're thinking about evolving a longer neck or a longer finger, whatever it might be, that there's variation in a population because there's genetic variation that gives you slightly different outputs of, say, digit length or neck length. And really, it's external circumstances. It's the environment that creatures live in that generally determine whether or not, you know, a longer neck or a shorter neck is more favored or a longer digit or a shorter digit is favored. So we're right that selection occurs really at the level of traits because those traits really determine performance in nature.

But you're also the real basis of evolution is changes in DNA, which are down at the molecular level. And those changes, which we'll get to, you know, those things originally arise without any consideration of consequences, right? They're arising at random. And so really nature is filtering which mutations can make it or not. So I don't think Evo-Devo's really overturned our fundamental thinking about selection and adaptation. I think it's just made us think much more precisely about where evolution is taking place at the genetic level and how that relates to traits. I mean, maybe this is a good place since I have you here.

Let's broaden our scope a little bit, not just to books you've written, but to this broader question about how to think about evolution, right? I mean, there have certainly been claims that we should say that at this point in the history the development of biology, we're no longer Darwinian natural selection people. We have a new synthesis. I guess no, the new synthesis has already happened. What do we call it now? What is the attempt to say that we've moved beyond the traditional Darwinian paradigm? The extended synthesis? Yeah, I think it's also our mechanistic understanding. I think that some of my, there's different words floating out there. I'm most sympathetic to what some of my colleagues say sort of the

functional synthesis. I think we had form. description, you know, for maybe the first half of the 20th century of what species are and sort of understanding how species get made. But until we could crack the genetic code, until we could look under the hood at how traits evolve, you know, we had a fairly, you know, let's just say only a 10,000 foot view, you know, of evolution. Right. And so I think it's more about the richness and depth of our understanding rather than, you know, conceptually have we really thrown much out that we had before? I don't think so. Okay. So, I mean, there is that, I mean, I know because I've interacted with people, that emotions get very heated when we say, you know, are we just improving upon the

existing paradigm of natural selection, or do we truly have a different conception now that we know a lot more about the multitude of things that go into these kinds of consideration? Well, I think there's some uncontroversial things there. For example, you know, Darwin never imagined things like symbiosis or let alone endosimbiosis so that we know that some huge things in evolution, like chloroplasts and plants and mitochondria in us, evolved by the merger of different creatures. You know, that's a very non-Darwinian thing, but it's now well established, controversial when first proposed, but now very well established and accepted. So we've certainly found phenomena that we're not in the Darwinian playbook, but, you know, we can celebrate those things.

I mean, Darwin did not have to be a clairvoyant to all things that would ever be discovered in nature. Now, you know, in terms of people getting heated, I think, let me, this somewhat goes towards the theme of the current book, but let me tell you something that I think is fair to say historically. Darwin's baby really was natural selection. Yeah. He had to come up with a way to sort of explain what kind of process could be at work that would shape, you know, the diversity of the world. And he came up with this analogy to breeding, to domestication, or what we call artificial selection. It was brilliant. It's how he started the origin of species. He explained using pigeon breeds. That really what breeders do with birds or cattle or dogs or whatever is very similar to what nature does, albeit more slowly and without, you know, in intelligence.

So that people could get the idea that things can change. And, you know, that was the first thing that he had to overcome. The thinking at the time was that species were immutable, that they were divine creations from God and created as they, in their current form and unchanging. So he had a pretty difficult paradigm. He had to dislodge first. He had to get people used to the idea that things could change naturally. And so natural selection really was his brain child.

And Alfred Wallace came up with the very same idea. And that was a huge step forward. forward. He didn't know. He explained that there would be differences in a population and that natural selection would, you know, favor some over others. But he didn't understand the basis of that variation. If he did, we might have a little different Darwinian theory, a little bit different picture. So my personal point of view, Sean, is that natural selection has dominated a lot of the discussion and thinking about evolution, to the point almost where natural selection sometimes is almost synonymous with evolution. And this I'm going to say is missing a big piece of the picture.

Because the big piece of the picture, both mechanistically and philosophically, is the role of chance in generating that variation. Right. It wasn't of interest to a lot of people for a long time, because there was no way to get at it. If you couldn't see into the mechanisms of genes, well, you just kind of took it as a given. And so natural selection was much more interesting. And natural selection was, you know, sort of this dominant idea. But really, the idea, idea that, you know, order comes from randomness and randomness is chance mutation. This is a huge idea. Not something Darwin could have given us. He pointed at chance a bit in his writings. He had some good instincts about it like he had with many things. I mean, I'm, I'll, you know,

my awe and, you know, regard for Darwin will will never be diminished. It's just amazing what his intellectual contributions are. But he just couldn't get there. It was, it was before the time we could get at it. But I would say, I mean, you've had Daniel Dennett on the show. And, you know, Dennett really talked about, for example, you know, natural selection and evolution is this acid, this universal acid that could dissolve through so many things speaking philosophically. And I'd actually, if Daniel was here today, I'd say, I think you've got to think about chance, because chance is both mechanistically so important. And it's also philosophically so important as to why people get so upset about evolution is because chance, chance is the engine. that gives us all this variation. And, you know, without that engine, you don't have evolution at all.

And yet it's fundamentally a random mechanism. So, yeah, no, I think. I'll let you pick through that and decide where you want to go with it. No, I mean, this is great because this is one of the reasons why I want to get things very, very clearly on the table is I had Stuart Bartlett on the podcast a few weeks ago. And he is an origins of life researcher. And he mentioned offhandedly that a certain process, you know, didn't seem to fit, you know, the traditional Darwinian way of thinking. And, you know, I asked him to explain what

he meant by that. But actually, after we were done recording, he said, you know what, people are going to get confused by that. We should just delete it. Because, you know, I think that there's a viewpoint out there that the opposite, the alternatives are Darwin or God, right? And I think that what people don't appreciate is that within the scientific, naturalistic, biological way of doing thing. There's a whole bunch of subtlety about, you know, how evolution broadly construed actually works. And like you just said, Darwin got a lot of it and he got a lot of it right and he got some major insights. But of course, we keep adding extra stuff that Darwin didn't know about. Absolutely. And, you know, we should all rejoice in that. I mean, you know, the science is still

growing or else, you know, the last few generations of evolutionary biologists didn't need to exist. But, you know, it's been, if anything, you know, my good fortune has been to be living through a new golden era of evolutionary biology because our access to the genetic code, our access to being able to precisely map the relationship between genetic change and changes in traits has made it so powerful to interrogate all sorts of questions in evolutionary biology. So, of course, I hope we're discovering some new and worthwhile things. But boy, I don't find it. discarding much. I think this is a growth and expansion narrative and not, you know, replacing something. And if anything, you know, when I want to elevate the role of chance when we think

about the evolutionary mechanism, I'm really just saying historically natural selection has been the dominant narrative. Doesn't mean natural selection is important. Of course it's important. But don't overlook chance mutation because that's the fuel, right? That makes the whole evolutionary process run and when you have a chance process and we can see just how chancey that process is now, you understand that there's nothing in charge. A point that I make in the book was we now understand we can capture some of these mutational events now in a way that, you know, thanks to, you know, great biophysics work, we can capture sort of the moment of spontaneous mutation and realizing when we understand, for example, that one of the bases of mutation,

is a subtle chemical shift, just the movement of a proton and a base, which happens as a fundamental matter of physics, you realize that mutation is a feature, not a bug in DNA. Oh, yeah. Mutation is, it's something, it's due to the intrinsic characteristics of the chemicals that make up DNA. It's inescapable. But now we understand that, you know, really down to the level that I think would satisfy a physicist.

And so we're only getting richer and deeper. I don't think we're getting, you know, far afield from the Darwinian. concept. Yeah, no, I like that way of putting it. I mean, we haven't overturned much of what Darwin said, if anything, but we've broadened and enriched the number of things that are going on, which, like you say, what else should we expect? This is how science works, right? We discover new things. Einstein didn't have the last word on gravity after all. Yeah, and you had Neil Schubin on earlier in the year, and Neil's a very good buddy of mine, and his new book, Some Assembly Required. I get a commission on Neil's books, too. You know,

He makes the great point that's emerged from paleontology. This has been a heyday for paleontology as well. And, oh, I mean, Darwin would just be salivating if he could sit around with 100 paleontologists because this was, you know, he really had geology in his bones. And he was so thrilled by fossils. And when he wrote the origin of species, he proposed that there should be intermediate forms connecting sort of one form to another. But there were none existent in 1859 that we could point to.

And these days, you know, the fossil record is so much richer. But what have we learned from the fossil record? Neil will tell you that, you know, it's a natural thought, for example, that, you know, when you see feathers on birds, you think they evolve for flight. But no, the paleontologists can tell us, nope, they evolve for something else first in the dinosaur lineage, not for flight. And if you look sort of by so many innovations, lungs, you'd think, oh, that's for breathing on land.

Nope. Yeah. Fish invented them for buoyancy in the water, you know? And this is the joy of being a biologist, which is you have these notions, which are totally understandable, I think very human notions. But then you have to put them to the test. And the more data you can get, the more evidence you can get, it's actually when you overthrow some of your sort of convenient notions that you feel like you've really learned something. And paleontologists are learning that almost everything that we see as a novelty has some precursor that it

wasn't first for whatever we think it was, you know, evolved for. And, you know, and as a molecular geneticist, I can tell you there's all sorts of, you know, beautiful stories in our DNA about, you know, how this process works. And so, you know, that's, that's the joy of it, as I said. I think there's lots of revelations to happen because we still, I think, think we're looking at only part of the iceberg. Yeah, so let's get into the role of chance, which you, which you properly are emphasizing here. I mean, you mentioned Dan Dennett, and he also likes to say that we should think of evolution as an algorithm. And I know what he means, and it's true in a sense, but I think that a lot of people in their minds, they conflate algorithm with deterministic algorithm.

And you can have algorithms that involve random numbers as well, and that's a crucial role in evolution. That's what you're sort of emphasized. Absolutely. And I think that, you know, chance, it's just, there was, so I want to acknowledge, I mean, there was a really influential book by a person who had a huge influence on me. I never met him. Jacques Minot in 1970 called Chance and Necessity. And this rocked the philosophical world. I mean, this was the bestseller in France, I think second only to love story at the time. This was France, after all. But I mean, it did well in England and Germany. And to a degree, it was still highly covered here in the United States. And Minot, coming soon for a French tradition and had one of his

friends, as he was a scholar, was the writer Albert Camus, and they shared, I think, some pretty deep conversations, Minot felt that biology was uncovering some new truths, some new facts that had not yet sort of registered in the philosophical realm. And so this is 1970, and he wrote chance and necessity and really pointed out that this chance-based mechanism in DNA had profound implications for how we think about ourselves. So, you know, it got some traction. You know, Minot passed away six years later, I think, you know, the idea of chance is very prominent in Dawkins' writings, like the Blind Watchmaker, which is a brilliant book. But I still feel it's kind of slipped out of common discussions about evolution. And now that we can really see that chance mechanism and

sort of catch it in the act, what a missed opportunity. So I sort of wanted to lean in and bring sort of our new understanding of chance, you know, up to date in 2020. And not just at the deep molecular level, but including the geological and planetary level, because we've been startled to discover all sorts of things that have changed the direction of life on Earth. Probably most familiar to the audience is the asteroid impact 66 million years ago, and we realized that accidents have had a huge role in what's happened on this planet. If you're a business that needs to hire people, you know how difficult it can be to not only find the right people, but sorting through everyone to hire the right people. Indeed.com

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will see it fast. Try Indeed out with a free $75 credit at Indeed.com slash mindscape, This is their best offer available anywhere. So go right now to Indeed.com slash mindscape. Terms and conditions apply, of course, offer valid through December 31. Well, you mentioned Jacques Mono and also Albert Camus, and it would be a mistake not to mention that you wrote a kind of joint biography of them. It's a wonderful story of this biologist and existentialist philosopher finding sympathy in each other's ideas. Yeah, I got to tell you, Sean, that was one of the greatest adventures of my life.

You know, because it, okay, yes, it took me to Paris frequently, but I met, I met incredible people. And what drew me to their story, there were some, Manoa was an incredible biologist and all sorts of people I interviewed who knew him well. It's one of the few people I've ever heard anyone talk about as being a bona fide genius. And at the same time, he was incredibly, as they said in France, in his time. He was a member of the French resistance. He had some very harrowing experiences during World War II, as did Camus. That was clearly a bond between the two men when they met after the war. So the book is, you know, it's about their adventures, both sort of physical in the real world, because they both dealt with what was going on in society at the time, whether it

was defeating the Nazis or exposing Stalinism for what it was, or human rights or reproductive rights, whatever it might be, they were fully involved. And so I think that made for me an exciting story to tell. But intellectually, they were clearly on the same wavelength. And Camus had influenced Minot a great deal with his early works like the myth of Sisyphus. But in turn, when Camus met Mano and Mano had these insights into the workings of life, I think that was very exciting for Camus. So that book and as I said, the people I met in telling that story was, you know, it was a heck of a ride. So you can't see me smiling at the moment. But every time I think of my experience of putting that book together. I was absolutely on one of the most exciting. And when I mean by thrilling,

it was it was every time a new nugget emerged, whether that was in a letter from an archive or an anecdote or a new interview, somebody I got to meet who knew one or the other. You know, it was just for me, a kid from Toledo, never imagined I'd be talking to people who had those life experiences. Well, it's so much fun to, as a sort of senior researcher, let's put it that way, do a very different kind of research, right? You know, just not, you're not in the lab, in this case, you're not solving equations, you're doing kind of historical, biographical work, and it's just a thrill to, you know, get that a different part of your brain being tickled a little bit, right? Yeah, the rush is very similar. I've tried to explain this sometimes to folks, because when people

found out when I was writing the book. And, you know, I said, I'm writing this book about Jacques Beno and Albert Camus, you know, I mean, I'm running a lab. I had some other duties. And, you know, you do get the look of, you know, he's gone off the deep end. I've gone that. I've heard from him again. Many times. But, you know, viscerally, the thrill is, the thrill is very similar to a great result in the lab. The storytelling is very similar. You're trying to knit together a narrative. And nothing tells you about holes, you know, in a scientific story or holes in a real world story as when you try to tell it and realize, oh my gosh, I can't connect these two dots. And so for me, the process of researching that book is very much like working on a scientific

problem and that every time I met a gap, I had to figure out, well, is there any way I could figure out what it happened in this time or, you know, who could tell me or where would the documents be? And when you find those things, when you find the missing links in the historical record, I think it's the same thrill of paleontologist gets when they see a fossil for the first time. And it's a very interesting connection because the existentialists absolutely wanted to emphasize the lack of any overarching purpose or teleology or reason for us to be here. So you can see why that would resonate with a biologist who emphasized the role of chant in the development of life. But also the existentialists wanted to say, you know, we can make choices, right? Like we have some autonomy that lets us guide our lives.

How did that fit in or did it fit in with Minot's point of view? Absolutely. And I think the experience of the war had a huge impact. Although Camus best sort of formulated his outlook by about 1942 and published it in the middle of the war and had to race south from Paris with a manuscript in the trunk of his car, I think especially coming out of the Second World War, which of course for France was the second traumatic experience really in a generation, that all these, you know, Naziism and. Stalinism and fascism in all this, that, you know, all the European isms, let's just say that were going on or Eurasian isms, that these were all empty, right? That they were empty promises of some kind of utopia. And the same with religion, that that was a promise of a, you know, a better afterlife, right? Not this life. Something better was coming later. And I think for people who had been through

the trauma of World War II, Camus was so refreshing because he was basically saying, you know, this is the life we've got. And, you know, now how do you make the most of it? Yeah. And I know for lots of scientists, that really resonated. Camus was was very much, you know, well, you know, he was read by everybody, but he was very much embraced by a number of scientists. And that's because he was going off all this sort of political mythology or religious mythology and just saying, hey, this is the one life we've got now. Now, how do you deal with that? And, you know, this is some of the things you got into in your book, big picture. You know, if you have a naturalist view of the world, then you have to confront that this is it. So how do we live with each other and how do we, you know, how do we use our time best? And I think this is, you know, this is the question that the journey in life is all about. Well, in a world where accidents happen and chance plays a large role, I mean, maybe you can say more about what Minot's actual contribution was there, because I guess my naive version of evolution was that even as early as Darwin, we thought that the changes from generation to generation

had a random component. Was that always there? Did that only come in later? That came in later. I mean, you can find sort of forensically, Darwin is toying with the idea of chance at a few times in his work, not just origin of species, but later, because people had to say, okay, Chuck, where does this variation come from? And, you know, he had to kind of shrug his shoulders. And since, of course, he was getting resistance for other reasons. Everything he couldn't explain was seen as a weakness, right? Sure. So you have to kind of extract it there.

And I think it took a while and it took sort of the rediscovery of genetics. And then it really took understanding, you know, from geneticists of the early 20th century that, you know, that mutations arose at random. They could see that if, you know, if they were looking for a white-eyed fly among thousands of flies. They didn't know which one was going to be born with white eyes. It seemed to pop up at random. And so really we had to get, we had to kind of discover the randomness of mutation, the random assortment of chromosomes, all that, sort of the basic rules of genetics, you know, through more thorough

science in the first part of the 20th century. But then when you look at the genetic code, which wasn't, you know, was not discovered until the early 60s, and you realize there's a universal genetic code in every organism. And now you can map how a change in one, you know, one base in DNA changes this protein, which changes this trait. Now you're, now you're looking at, you know, the fundamental root, the fundamental basis of evolution, or as the way Minot put it, you know, the root of all innovation in the biosphere. Yeah. And that, I think it just took a while. I think we needed to have DNA. We needed to have a genetic code to say these things with much force. And then I think we needed other things like Evo-Devo to say them with even greater force in terms of understanding

thoroughly the connections between random change at the atomic level and change at a organismal level and change at a population level. So now I think we have that sort of seamless continuity throughout all those scales in life. And when we say a word like random, it doesn't mean there's no structure there at all, right? Like we throw it a six-sided die. Even though it's a random number, the chance that the number one comes up versus numbers two, three, through six is only one-sixth. And so when you say that there are mutations in DNA that are random, like how well do we understand the probability distribution of what's going to happen at every step in these kinds of process? It's still a really active field. I think that when we talk about

random and we can say more, and I think we can back it up more, let's put it that way, that random means in a couple of ways. I think it's really important. And as you're drilling down here, that we do get a little more disciplined about our use of the word. But it means if you look across DNA, mutations are going to occur, and there's an unpredictable nature of that. We don't know in any individual sperm or individual egg where the mutations are going to be. But there's going to be 20, in a human egg or sperm, there's going to be 20 or 30 new mutations that weren't in mom or dad.

They're going to occur, you know, spread throughout 3 billion base pairs of DNA. Let me just pause to, to, to, to say that because that's, I didn't actually catch that number before from, I must have skipped over it in your book. So every new baby comes with over a dozen new, brand new mutations. Is that what we're saying? That's right. That's right. So each of us is born with changes in our DNA that differ, that are different from our parents at the level of about, well, probably we're carrying about 40 or 50 mutations that weren't there in mom or dad. And we got probably a few more of those from dad than we did from mom. But yeah, there's new mutations in every generation. And this is because

when you copy DNA, every time you copy DNA, there's going to be mutations that are going to happen. Just, you know, it's a three billion base pairs of DNA to copy. There are typos. And those typos are really just a fundamental matter of the physics that I was talking about. So this is going to go on, you know, all the time. The distribution of those mutations throughout the DNA, is, and I'm just going to use that first approximation argument, as random. They're unpredictable. They're spread throughout. If you have a large enough sample, you can see that lots and lots of different places are collecting mutations. It doesn't mean that every base has exactly the same probability of changing, but to a first approximation, the distribution of those mutations

are random. And here's the real important thing. The mutations occur without any let's just call it a consideration of their consequences. Some of those mutations may be deadly. Some of those mutations may be meaningless. They're going to occur no matter what. It's, that process of selection and life is going to sort out the fate of those mutations. So those mutations arise regardless of their potential impact on the organism. That has to get sorted out in that individual's life or in their offspring's life, et cetera. So that's one level of randomness. There's lots of other randomness in that which chromosomes you inherit from your mom or dad involves a random sorting process. And here's a number that's in the book. So if let's you and I play a little game, especially since

we both have the name Sean Carroll. This might be a fun one to play. What were the chances? So each of our moms and our dad, 23 chromosomes contributed through the sperm. Our mom's 23 chromosomes contributed through the egg. So you and I each have 46 chromosomes. But now let's think of our siblings. How many genetically unique siblings, Sean, could you and I each have from the same set of parents? Yeah, it's a big number because I know how exponentials work. But I think that what probably I don't know is in a strain of human DNA, probably many of the genes are just, or many of the base pairs are just exactly identical in every bit of human DNA. And some others vary. So that one I don't know.

Yeah. Well, we'll first talk with those combinations. So it's over 70 trillion from one couple. So this means, you know, the genetic deck is being shuffled a lot in nature and in humanity, right? Yeah. So, and then secondly, yeah, not every gene is going to have a variant, you know, as you look through DNA. But over time, there's a lot of variation that's there. You and I differ by about one base in every, well, our Irish ancestry might make us a little more closely related.

But differ about one base out of a thousand. But, you know, in three billion, that's three million. bases that differ between you and I and between any two, you know, unrelated individuals in the population. So there's a lot of variation out there. And that, you know, all has occurred. And it continues to occur every generation with the occurrence of new mutation. So the randomness part of this is that, you know, there's no, there's no intention here. There's, there's no filter. Mutations happen at random and basically life sorts them out. And 30, 20 or 30 mutations out of 3 billion base pairs actually sounds like a small number. But I remember talking with David Baltimore recently,

and viruses can use RNA or combinations of RNA and DNA to carry their genetic information, and they will mutate much more rapidly, right? So in some sense, is it too much to think that that 20 or 30 per generation is optimized, like that we have the chemistry that gives us enough robustness to carry off, to send down genetic information through the generations, but also enough looseness that we can mutate and find new happy features? Yeah, I think it's a good way to think about it. There's a concept in genetics called the genetic load or mutational load. And the idea is if we had a very high mutation rate,

you would have too many deleterious mutations per generation, and you'd obviously have a real problem in terms of getting to the next generation. Too few mutations, and of course nothing changes at all, and your adaptability is very constrained. The mutation rate is selectable. So in viruses that often carry their own machinery for replicating, something like HIV, the human immunodeficiency virus that causes AIDS, that mutation rate is about 10,000 times higher than what you and I are talking. And this is the selection at work there is that this is what helps that virus evade the immune system.

And this is why there's no AIDS vaccine 40 years later is because the virus is mutating so much that really the virus in an individual human is pretty different after, you know, a month or two than the virus. virus that person was originally infected. So there's a lot of evolution taking place at that, you know, at the individual virus level. And that's, so if you figure maybe four or five orders of magnitude difference across genetic things, I won't call them living things, because viruses are not living per se. But yeah, so there's even variation in the mutation rate. And you can think that that has been tuned by selection in terms of balancing sort of the mutational load with adaptability. And I need to ask this.

Is it true that we can think of these mutations as honest to goodness quantum mechanical fluctuations? I think it's the right way to think about it. You're talking if you want to do chemistry for a second, and it's explained in the book. Bases come in totemers. So these are chemically slightly different forms. In this case, the bases, which I'll just shorthand say ACG and T, which are adenine, cytosine, guanine, and thionine, these bases, the hydrogen on the larger ring goes through transitions that are, you know, it's really just the movement of a proton on that ring. and thus it's now been measured that that sort of shape shift occurs at a frequency about one one thousandth of a second. So a given base might be in what we call the common keto form about 99.9% of the time, but 0.1% of the time it's in the enol form.

And if that is the form it's in when the copying machinery passes by, the wrong base can be inserted. And now you've got a mutation. Now there's ways because also that base. will flip back. There's then ways for the cellular machinery to recognize that mismatch and excise it. So there's proofing mechanisms that improve the fidelity of copying DNA by several orders of magnitude. So there are correction mechanisms we have, but nonetheless, a small percentage slip through. But you're absolutely right. This is a quantum mechanical phenomenon. And I think one of the scientists, I remember using the term a quantum flip, that might be a word that a biologist or biophysicist use,

a quantum flip, and it's an inherent nature of the bases that endowed DNA with its properties. Well, a famous thought experiment in biology is if we could play the tape backwards, right? If we could start back with whatever initial conditions life had and let them go, how similar would it be? And now it seems that I'm going to say that if you believe in the many world's interpretation of quantum mechanics, there will be a different world where every different set of mutations came true, and somewhere out there all the different possibilities have been tried. Well, it's a great thought experiment. I think you, and a sampling of different biologists, they'll probably lean to one way or the other.

There are some folks that see the tape as replaying more accurately, you know, more, you know, replaying itself, more accurate, more, I want to try to say maybe with more fidelity, repeating itself, maybe evolution repeating itself more, and others seeing less so. I probably tend towards the less so, partly because I also think you have to deal with all the external sort of physical circumstances of the world. that, you know, tectonics and asteroid impacts and all sorts of other things have, you know, have wreaked havoc on the process of the evolution of life. And so, yeah, I think that thought experiment for me is you'd get a different world. And I don't know if we get dinosaurs and humans, you know, that many times. Yeah. No, I mean, I think that there's a interplay going on here between the randomness of the generation of the mutations and then they're selected for, right? This is what Darwin actually emphasized the fact. So I guess there are, every biologist, you know, every card

carrying modern biologist will admit that there's randomness in the mutation. But I guess some would argue that when those mutations come out as organism, some will inevitably thrive and some will not. And that's why we will see more or less similar behavior if we did run the tape backward again. Yeah, look, and that's the phenomenon of convergence. And you might say, you know, this, this argument was made especially famous by Stephen J. Gould in his book Wonderful Life, and countered by Simon Conway Morris in Life's Crucible, two paleontologists. And, you know, I think the truth is fun to explore. Not the truth. I can't say the truth. Both polls are fun to explore because there's no doubt that evolution repeats itself. And when we find very similar circumstances, you know,

if you find animals living, say, in a dark habitat in caves, no doubt you'll see the same independent mutations selected for again and again. If you find things living in deep water, you'll find some of the same things selected for again and again. So there are external circumstances, external conditions that will essentially create the same selective regime. And you can think that if you have a large enough population of whatever you want, you know, fish, mice, whatever you want to think about, if you have large population, you will, basically, this random mutation mechanism will sample most of the possible mutations, you know, in the DNA of that organism. And so it may happen upon the same solution repeatedly. And we, this has been well documented by sort of simple to

study organisms like viruses, but even out there, as I said, you know, mice in the deserts of the American Southwest living on, you know, lava outcrops, they repeatedly do the same sort of evolutionary tricks. Bacteria living in our guts exposed to antibiotics, keep coming up with same mutations. So we can see evolution repeat itself, but you just have to kind of drill down a little bit to say, well, if I've really presented very similar circumstances to a highly, to a large population of individuals with a pretty significant pool of mutations to draw from, you will draw the same lucky card repeatedly. But when you start way back, you know, a billion or two billion years ago when life is unicellular and you say, okay, I'm just going to run this whole thing again, there are so many

factors that enter the course of life, that it's difficult for me to think that you're going to get T-Rex and Neanderthals out of that again and again. Yeah, that does make sense to me. But I think also, and you have alluded to this, but let's highlight it a little bit. You know, most mutations in the world that we live in now, where species are fairly mature and have found their niches and so forth, most mutations are going to be bad, right? Like we've kind of optimized to some extent, and the chances of getting a really good mutation that we hadn't already tried are relatively small. But at a time like 66 million years ago, when an asteroid just hit and wiped out a lot, there were a whole bunch of unoccupied niches, and the chance to let

your experimentation run wild was much greater. Well, I think intuitively, that's, again, that's a very interesting question and a very interesting arena to explore. Now, let me take the first part where you said, you know, were things sort of species mature and in stable habitats, Will most mutations be deleterious? Well, actually, most mutations aren't deleterious anyway, because they just land in parts of DNA that don't matter. But if you land in a part of the DNA that matters, what you're, I think, intuitively right about is, and this is probably best illustrated by things like enzymes. So enzymes that do the work in the body that convert one chemical to a different chemical form, a lot of these enzymes have been around for hundreds of millions, sometimes more than,

you know, a billion years. They do show properties of being optimized. So that, It's very hard to make like a more efficient enzyme to say detoxify alcohol, okay? Because organisms have had a long time to play with that substance and they've probably happened upon the best solution. That's too bad. Now, if an organism finds itself in a high alcohol environment, what it does is instead of evolving an enzyme that is more proficient at converting that alcohol, it makes more of that enzyme.

And it makes more of that enzyme through mutations that enable it to make more of that enzyme. So there's still adaptive mutations to be had, but qualitatively, they're a little different. They're not so much about changing the properties of a very ancient enzyme. They're about changing how much you make in a given circumstance. So I think you're intuitively right there in terms of sort of things being well-tuned. On the other hand, and there was the second part of your question, which I've now forgotten because I had to give my alcohol story. I know. You made me sad to think that There's not some mutation waiting out there to be discovered that will make us able to drink a lot more good wine in scotch. But that's okay.

You know, we have to live with the constraints of laws of physics. But the other point was we have these accidents of history that have nothing to do with biology, like the asteroid hitting the Earth, that sort of reset a lot of the environments. And then maybe the experimentation has a little bit more room to play in. Great. Yeah, thanks. Sorry. Yeah, I think that's also a very constructive way to think about things. and that when new opportunities present themselves,

and certainly after the asteroid impact, with three quarters of plant and animal species, killed off. You know, the ocean was a very different habitat post-asteroid. The land was a very different place. You know, competition's different. And you think about sort of, for lack of a better word, organisms establishing a beachhead. Well, in that competition,

there might be a lot more room for variants and for things that might have had a really tough time in a more, in a well-populated, you know, forest, or in a more densely populated ocean. So the regime, the competitive regime changes. A real straightforward example, and I love this story. This was just published last year. The asteroid story is, it's a gift that keeps on giving,

is what I would say, Sean, because while we probably all heard the outlines of it and relived in one way, cinematic or otherwise, that asteroid impact, what happened after that has been harder for pale and to get at. And that just has to do with few exposures on the surface of the earth of that critical, say, first million years after the asteroid impact, particularly exposures on land. But scientists at the Denver Museum of Science and Nature, Tyler Leeson, Ian Miller struck paleontological gold just outside of Denver a few years ago. And it was published in science last year. And actually, we made it into a film called The Rise of the Mammals. When they discovered a treasure trove of remarkably preserved, extraordinarily well-preserved mammals spanning that first million years of recovery on Earth. And what you see among those mammals are that mammals got much bigger very

quickly than they ever did before in Earth's history. So mammals had been around for probably 100 million years coexisting alongside dinosaurs, but dinosaurs were the, you know, they were the big, they were the big land animals on the planet. Well, dinosaurs are killed off. They're very vulnerable to the collapse of the food chain. Some small mammals survive, which probably were not more than a pound or two in body size. And then they take off. And within a few hundred thousand years, you're seeing a 40 or 50-fold increase in maximum body size among the mammals. So quite clearly, take away the big, you know, I'd say, I'm not going to say the bullies. That's putting characteristics to dinosaurs I don't really want to put on them. But that dominant animal that was

really keeping mammals in a much smaller niche, take away those dinosaurs and the mammals exploded. there was no room. There were no place for those mutations that would make mammal bodies bigger during the dinosaur era, but take away the dinosaurs. And now those mutations allowed us allowed mammals to explore all sorts of body forms. So I think we have good understanding that, you know, a big disruption like that, ecological opportunity. One of my favorite paleontologists, there are many, but Andy Nold at Harvard has framed it something along the lines of sort of when, you know, genetic potential meets ecological opportunity. And these big upheavals on the surface of the earth present ecological opportunity.

And then all that genetic potential can flower. And that's what I think we see with the rise of the mammals. I think that's what we see in the Cambrian explosion, which is following another mass extinction. The very famous Cambrian explosion, probably the easiest explanation for it, is the opening of ecological opportunity. You know, I often talk about entropy and friction and dissipation. and these are concepts that are important not only for cosmology or for living organisms, but also for small businesses. How do you like that segue there? Pretty good, huh?

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the asteroid impact being a very obvious one you know the role of chance comes to the fore right not just the mutations in our genes but like the fact that our environment is changing in unpredictable ways the other point you make in the book is that even within individual lifetime there are things happening in our bodies that are a little bit random and unpredictable that end up playing a huge role in the lives we leave.

Yeah, this is the unfortunate series of events. You're referring to cancer, for example. For example, yeah. I mean, I presume that a whole bunch of aging and other disease kind of things have similar features, but cancer is the obvious one, the big one. Cancer is the obvious one because, you know, it shows up in the clinic and then we study it and we really understand cancer is a genetic disease. So, yeah, so that process of random mutation, which, you know, that process of random mutation,

which is the source of, you know, all that beauty and diversity and complexity in the biosphere and all of human diversity, you know, which we celebrate, well, but it is a fact of life that when we copy DNA mistakes get made. And some of those mistakes, if they land in certain places in the genome, in certain genes, can alter the properties of those cells. And if those cells acquire a growth advantage relative to their neighbors, and particularly if more mutations hit that might either enhance that growth advantage or shield those cells, for example, from the immune system, well, then now you have the beginnings of cancer. So in the book, I'm just trying to make people to appreciate that, you know, this phenomenon of random mutation impacts lots of things. You know,

I think there's some things that are more joyful. And I think I say when I get into the cancer chapter, you know, oh boy, I'm not sure anybody was going to be too enthusiastic about reading this. But, you know, it's going to affect the very, you know, all of us is going to affect our families and individually it's going to probably affect, you know, half of us at some point in our life. So understanding that cancer is a genetic phenomenon brought on by random mutations, but that we can do something about the probability of those mutations. So cigarette smoke contains mutagens. So we can decrease our chances of mutations that hit our lung cells by either not smoking and not inhaling secondhand smoke, or I'm going to go golfing later this afternoon, and as a lightly pigmented

Irishman, I have to put on my sunscreen or I'm gambling with the mutations in my skin cells. So, you know, that knowledge of cancer being a genetic phenomenon is also power. And, you know, in the last 20 years, we've developed a lot of countermeasures to deal with the mutations that arise in our, in our body in the course of our lifetime. But I did, you know, We come into this world an accident and many of us are going to exit, you know, due to one of these accidents. Well, I think it's part of facing up to the random nature of life. And it's a truism that human beings are not very good at conceptualizing randomness. I did a whole podcast with Maria Konnikova about poker and, you know, living in conditions of uncertainty.

But one of my favorite examples, I think I've mentioned this on the podcast before, but it's my podcast. No one's going to stop me for mentioning it again is when you talk about life expectancy, there's a million different websites you can. can go on to and calculate your life expectancy. And they always give you a number, right? Like, you'll probably live to be 90. And I think that people conceptualize that is I'm going to probably live to 90 and then die. But I did find one website that actually also, and I've lost it now, and it kills me, because I can't find it again.

But it actually took the probability. Right. So rather than just saying your expected value is 90, you know, it knew what the tails were, and it would randomly generate a number from that distribution. You can click the button again and again, and I think we don't appreciate how broad that distribution is. Like, I got plenty of times when I was dying before the age of 60, and plenty of times when I lived to be over 100. And that knowing that you're going to live to a Brout 90 on average is interesting, but much less relevant than the fact that you could die within years. That's absolutely possible.

Absolutely. And this, you know, this should be the realm of psychology, and I think we can all benefit from the insight. of psychologists because, of course, we're playing all sorts of games with ourselves to, you know, deny that, right? There's a lot of cognitive dissonance around death. And we're also, everyone's struggling to figure out, well, how do we use the time we have? You know, in that unknown amount of time, one of my dear friends from childhood died young in his 40s. And I sort of feared in the religious service, you know, what do you say about somebody who dies young, you know, and everyone's crushed, right? Everyone's absolutely crushed. Sure. And the minister talked to

about life being a gift, nice, but a gift of, of, you know, unknown quantity, unknown, unknowable what quantity you get. So think about how you're going to spend it. And I found that to be a very secularly friendly eulogy and, you know, thoughtful. And, you know, you've dealt, you dealt with this in your writings, you know, Camus dealt with this. So many people have dealt with this. Yet I think, you know, what you're getting at is that we have lots of games we play with ourselves to sort of deny her own death and to just put it out of our minds. It's sort of understandable. And if you, and then you can imagine all the, you know, how many movie plots have there been about people knowing they're going to die the next day? Or if they don't do this,

they're going to die at a certain time or an asteroid is coming and we only have so much time, et cetera, and how people behave. But we've got to figure out what to do when we don't know how much time we've got left. Yes. And, you know, we all look for some wisdom anywhere we can, into that. I, by the way, and I mentioned this in the book, I looked at comedians. That's where I get my, that's where I get my psychology and philosophy from. Well, I mean, I think that you very effectively convey this idea in the book. And this is one of the reasons why it's a great book worth reading, is that not only do you do biology and so forth, but you're not afraid to talk about the ramifications of these ideas for how we live our lives and how we think about our lives. And, you know, there, Among the things that the human brain is not good at, among probability being one of them, but another one is just accepting that some things happened without a reason, right? That we always tend to say, well, oh, if this happened, why did that happen? And I'm going to find the reason. I'm going to fix it or whatever.

And, you know, I think, I forget who it was. It might have been Stephen Colbert, you know, considering your idea that it's comedians who are the wisest here. But he says, whenever anyone tells them everything happens for a reason, he pushes them down the stairs and then he says, I bet you can understand the reason why that just happened. But a lot of things don't. It's very hard to craft a vision of life that accepts that things happen without explicit. Right. Well, there it is, Sean.

I think there it is, which is why we have, you know, so much of the mythology that we have. It's understandable. I mean, people are trying to think, you know, why would we think about the afterlife? Well, it's a very pleasant and comfortable, you know, comforting thought. And wow, you can create so much story around all that. It's very hard to difficult, very difficult to deal with, you know, the finite nature of life. I mean, life is great. But Ricky Jervais, and I quote it in the book, you know, he just says, look, this is a holiday.

We didn't exist for, you know, 14 and a half billion years. And now we exist and we get 80 or 90 years if we're lucky. You just make the most of it. Now, there might be a, and then you've got to think about, okay, what does make the most of it mean? But at least it's, I think it's healthy psychologically. I think it's also really constructive in terms of how you choose to spend your days is to say, look, you know, accept that this is it. And I think that kind of puts a premium on your time. I also think it makes you put a premium on other people's lives in their time.

There's actually some compassion and empathy that comes for that. That might surprise people who are, you know, believers and who think that, you know, religiosity is important. And that that's essential to sort of a moral life. But no, I think when you realize that everybody else also is constrained to one life, that it might make you a more empathic and compassionate human being. It's possible. It is. And I don't claim to have fully figured it out myself.

Have you heard about the discourse in philosophy circles around moral luck, the idea of moral luckiness? No, I don't know this. I mean, they point out it is fun because, you know, in the real world, you know, you have a few too many drinks and you hop in your car and you try to drive home, right? And that's against the law and you can be pulled over and punished for that. But if you happen to run over someone as you pass through a red light because you were drunk driving, just by chance, the punishment is enormously greater than if you just drove home while inebriated, even though your actions were the same.

The punishment is not because it depends on completely random things. And so how do we deal with that? And you might say, well, okay, just give you. the same punishment to everyone who does exactly the same things, but that's, it's, that's hard to do. It's certainly not what we actually do in life. Like, coming to terms with this is, is even harder in real life than it sounds at first glance, I think. Yeah. No, but I, I think these are, these are really exciting discussions to have. And in some ways, you know, they're unfortunately, probably had a too narrow a circle, right, that I think if we were not so dominated by religious

ideas, and I don't mean to, I don't mean to dis-religion. I grew up and I was, I was, I was, is educate, thank goodness, I was educated, for example, in a Catholic high school that if that had not existed, I don't think we'd be having this conversation today. But I do think that to dominate the idea that there is, you know, a supernatural supreme being overlooking each of our lives, you know, that sort of inhibits exploration of other ideas that that might actually be really constructive for how we live our lives. And so, you know, there's, I just hope that, you know, as generations past, that there's just more exploration of moral luck and, you know, the meaning of life without an afterlife. Well, to borrow a phrase, you are preaching to the converted when you say that.

But, I mean, maybe to close up here, I think there's been a great conversation and, you know, we've at least reminded people about the important, or the fact that there's a lot about what's going to happen in our lives that is not either purposeful or predictable. But Camus, if we can conjure him up here, might have said that, you know, we can bring some meaning to our lives by taking actions. So you do that, among other things, besides being a biologist and a writer, you produce movies. And I just want to give you a chance to explain to the audience out here why in the world, when you clearly have enough on your plate, you've decided to become a movie producer? Stories. So same reason for writing books.

Same reason for you and I having this conversation. You know, we're telling stories. But film is such a powerful vehicle for stories and especially for science films, sort of taking people on an adventure and immersing them an experience that they might not otherwise have. And I'm also, I had some interesting early experiences with filmmakers and I was really intrigued by their craft because I've seen filmmakers, you know, concoct scenes out of their imagination that, you know, I just couldn't possibly imagine, you know, how they did that. And so, you know, I'm comfortable, well, not comfortable, but let's just put it this way. I, you know, I try to write stories on paper. When I've seen them translated to film, there's just other dimensions that open up. And also film, you know, it travels very well around the world.

And, of course, many of us seek out stories in film form. So, you know, the brass text truth for two writers like you and I is that a hundred or a thousand times more people will see the film version than read our books. Sure. Right. So there was a little bit of pragmatism, but it's also the excitement of telling stories in other forms. And when it goes well, it's also a very collaborative craft. And the combination of visual imagery and music and all this can be just such a powerful, memorable experience. And so I've had the opportunity through the position I have now as the head of a documentary studio inside of philanthropy, you know, to work with lots of filmmakers and to support the work of lots of filmmakers.

And I think science stories, you know, we need more of them out there in the world. And it was another big motivation is to help science with its place in our culture by telling more science stories than trying to reach some audiences would not otherwise, you know, tune in for a story about science. Yeah, I mean, tell me what do you think. But to me, if you can find an activity that, on the one hand, is just a lot of fun to do. But on the other hand, also provide some good for the world, then, you know, find a way. way to get involved with that. And that sounds like what you've done. Yeah, it's, thanks, Sean. It's not that different, honestly, than like, teaching. I mean, it's, it's certainly not as, it's not, you know, as pedantic as teaching. It's just, you're sharing

stories with the world and a form, look, you know, science has to compete with every other form of story in our world, right? And people voluntarily and, you know, and choose to listen or pay attention or not. So science has to realize that we live in a, you know, we're a storytelling animal in a storytelling world. We have to tell our stories. And we have to tell our stories. And We have to move people. You know, I think the biggest, you know, sort of shortcoming I find among scientists is that, you know, we think that if people only knew what we knew, you know, only knew what was going on in our heads, the world would be fine.

You know, maybe that's true. But you've got to motivate people to want to know a little bit more about what we know. And you have to bring it in a form that is engaging and inspiring and emotional. You know, we're very much, you know, sort of cerebral beings as scientists, but, you know, we are we're an emotional species. And I think it's that combination of storytelling and visuals and music and things like that that can arouse that and be a much more intense experience for people than, dare I say, reading a book. Pressing company, except of course, when it comes to reading the books. But yeah, absolutely,

of course. But books are, I'll tell you this as a, having made a lot of films, books are a great place to start because writers have often fleshed out a lot of story threads that are great places for filmmakers to pick up. So it's a, it's a necessary process. It's also books are generally a lot more, a lot deeper and broader than films are. Films have to sort of keep up their pace and cannot wander into some of the dimensions that a book can. So they're, they're different media. They, they each serve their important purposes, but I am, I am acknowledging that film might just be a little more popular. It's possible that it does. I mean, you know, but there's an important role for a complex ecosystem of ways of communicating.

And one thing I've discovered is that having the ability to listen to someone's voice provides people a connection with them they wouldn't otherwise have, which is why it's so great to have people like you here on the podcast. So Sean Carroll, thanks very much for appearing on the Mindscape podcast. Thanks, John. It was a lot of fun.