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.
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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.
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This week’s episode of Mindscape is sponsored by the Techmeme Ride Home podcast, by Indeed job site (http://indeed.com/mindscape), and by Azlo banking (http://azlo.com/mindscape).
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0:00:01 Sean Carroll: 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, an 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.
0:00:27 SMC: 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, ’cause I saw that, I think it was Time magazine had a story about the 30 scientists under 30 years old or something like that who 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 did 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 was another person with my name.
0:01:09 SMC: 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 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.
0:01:50 SMC: And this makes perfect sense. 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.
0:02:33 SMC: What we’re going to talk about is musings on the bigger picture of evolution, that his cutting-edge work with 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 a genomic population finds itself in versus the role of random chance. And what Sean wants to do is to emphasize the role of random chance; 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.
0:03:16 SMC: 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, 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.
0:03:51 SMC: So while I have you here, let me remind you that we have a web page for the podcast, preposterousuniverse.com/podcast. I recently wrote a blog post, there’s a separate blog on my website, so preposterousuniverse.com/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 that I could possibly take, but I do take them sometimes. I have 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 there you can read about what those reasons are in the blog post. So check that out, preposterousuniverse.com/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 before the episode actually airs, it’s actually published, Ian Robinson on Twitter suggested that I interviewed Sean B. Carroll.
0:05:00 SMC: 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.
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0:05:36 SMC: Sean B. Carroll, welcome to the Mindscape Podcast.
0:05:39 Sean B Carroll: Hi, Sean, thanks for having me.
0:05:39 SMC: I’m wondering if I just should just said Sean Carroll, 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 universes.
0:05:54 SBC: Well, and I always say you’re the one that understands the cosmos, so you’re better at math, how about that?
0:06:00 SMC: But you’re better at experiments, you have a lab, right? You get your hands dirty.
0:06:05 SBC: Yes, I do. Well, I get other people’s hands dirty, but I’ve dirtied my hands over the years, that is true.
0:06:10 SMC: Yeah, we age into a part of our lives where we get other people’s hands dirty. 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 read it, buy it right now as they’re listening.
0:06:23 SBC: Yeah, sure. It’s in all sorts of formats, 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.
0:06:32 SMC: That’s pretty good. But you come at this as an evolutionary biologist who got interested in the role of chance and what it plays. 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?
0:06:49 SBC: Right, yeah.
0:06:51 SMC: 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?
0:07:04 SBC: Well, that was really 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 curiosity and love for animal form. I like butterflies and snakes and leopards and all that, which I think a lot of biologists do, and I always wanted to know the hows and wise, 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 to crack the science of how any animal form is built, and that’s the arena of developmental biology. And in the course of doing that started making discoveries that surprised us as much as anybody else, and that led to this term, this field called evo-devo of, it’s really trying to understand the evolution of form through the lens of the making of animal body.
0:07:58 SMC: 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. 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.
0:08:16 SBC: 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, 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 in 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 the mysteries of how do 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.
0:09:07 SMC: Yeah, and it’s a fascinating idea, because I think that probably 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 blueprints or something like this. So we have the idea that somewhere in our DNA, there’s just a little road map 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.
0:09:31 SBC: 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 anatomists’ view, that let’s look at 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.
0:10:26 SBC: 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.
0:10:53 SMC: Yeah, so you’re saying that, basically, there are some genes that make legs and among other things, and how you control how those genes turn on and off depends whether you get an insect leg or a human leg.
0:11:05 SBC: 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 100 legs, as in a millipede. So we quickly got into the machinery that was really making the key differences, 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 the recipe for a fly and the recipe for a mouse and the recipe for a worm, slowly but surely and separately from each other, but really we kind of discovered a passport to the whole kingdom.
0:11:41 SMC: Yeah, and it’s amazing to me, because it’s not only that very different species now have this toolkit of gene, but they’ve been around, I want to say almost forever, but at least for a very, very long time in developmental history. Evolutionary history.
0:11:57 SBC: That’s absolutely true, yes. 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 documents the various ways these things have been repurposed and tinkered with to shape this incredible variety of life that we love.
0:12:24 SMC: Well, yeah, 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. What are the implications of this discovery for how we think about natural selection or how species evolve?
0:12:42 SBC: Well, the biggest implication, I think, of evo-devo is, I’m going to get into 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’ve got to start picturing, kind of imagining DNA. And DNA, the way it’s… Our chromosomes are made up of DNA, and genes are encoded in segments of DNA.
0:13:19 SBC: And when you think about DNA, and you think about genes, if you could sort of take a quick snapshot of your DNA or my DNA, those genes would stand out like islands in 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 that’s 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.
0:14:00 SBC: Because to build one body, you have to orchestrate the turning on and off of genes in time and space, and it’s 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-devo 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.
0:14:46 SBC: And so that’s a huge mechanistic insight, and I think a 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.
0:15:01 SMC: So maybe to put this in context a little bit, 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 the code for proteins, etcetera, 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.
0:15:41 SBC: 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, you know, 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, they’re sort of the genes that launched a thousand post-docs, are these genes that when mutated, for example, transformed the antennae of the fruit fly into legs or give the flies a second set of wings.
0:16:18 SBC: And when you see these striking appearances and you say, how can you do that? And it’s a single… You’ve altered a single gene, it makes… You’re just too damn curious, you’re just like, “I’ve got to figure out what that… What’s going on.” And I was one of those post-docs. 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 when we dug into those things and 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 bean bag genetics, of just studying formal genetics by crossing one fly to another, that’s when we really could get at these questions. And when we did, the science flourished in an amazing way.
0:17:05 SMC: So how does this all fit in with the idea of levels of selection? Richard Dawkins famously popularized the phrase “the selfish gene,” and I’m not sure if I have 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, we can argue about that, but I think that a lot of people think that what gets selected are sort of traits like, oh, you want your neck to be longer, so you evolve a 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, 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?
0:17:54 SBC: 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 maybe we had a gene for building our pinky and a different gene for building our thumb, 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, every toe; in fact, they might be involved in building other parts of the skeleton.
0:18:27 SBC: So you didn’t have anatomy that said that there was sort of like a three-dimensional map of the body that correlated 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, 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?
0:19:12 SBC: 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 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 exists at all or not. So we first had to change our thinking about sort of where would sort of be the hot spots of evolution in DNA, so the genes, the actual protein coding parts of these genes are very stable and can be evolutionarily conserved for hundreds of millions of years, but the switches are very tinkerable, alterable in the course of evolutionary time.
0:19:54 SBC: 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 or 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 the creatures live in that generally determine whether or not a longer neck or a shorter neck is more favored or a longer digit or a shorter digits is favored.
0:20:25 SBC: 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, those things originally arise without any consideration of consequences, 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 has 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.
0:21:04 SMC: 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. There certainly have been claims that we should say that at this point in the history of the development of biology, we’re no longer Darwinian natural selection people, we have a new synthesis… I guess, no, the new synthesis already happened. What do we call it now? What is the attempt to say that we’ve moved beyond the traditional Darwin paradigm? The extended synthesis?
0:21:38 SBC: Well, you know, yeah, I think it’s also our mechanistic understanding. I think that 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 formal descriptions 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, we had a fairly… Let’s just say only a 10,000 foot view of evolution. And so I think it’s more about the richness and depth of our understanding rather than conceptually have really, really thrown much out that we had before? I don’t think so.
0:22:23 SMC: Okay, so there is that. I know because I’ve interacted with people that emotions get very heated when we say, 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?
0:22:43 SBC: Well, I think there’s some uncontroversial things there. For example, Darwin never imagined things like symbiosis or let alone endosymbiosis, so that we know that some huge things in evolution, like chloroplast in plants and mitochondria in us, evolved by the merger of different creatures. 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 certainly found phenomena that were not in the Darwinian playbook, but we can celebrate those things. Darwin did not have to be a clairvoyant to all things that would ever be discovered in nature.
0:23:19 SBC: Now, 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. He had to come up with a way to sort of explain what kind of process could be at work that would shape the diversity of the world. And he came up with this analogy to breeding, to domestication, or what we call artificial selection, that… 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 an intelligence, so that people could get the idea that things can change. And that was the first thing that he had to overcome. The thinking of the time was that species were immutable, that they were divine creations from God and created in their current form and unchanging, so he had a pretty difficult paradigm he had to dislodge first.
0:24:25 SBC: 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 a very same idea. And that was a huge step forward. He didn’t know, he explained that there would be differences in a population and that natural selection would 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 in thinking about evolution, to the point almost where natural selection sometimes is almost synonymous with evolution.
0:25:10 SBC: And this I’m going to say is missing a big piece of the picture, because the big piece of the picture, both mechanistic ally and philosophically, is the role of chance in generating that variation. It wasn’t of interest to a lot of people for a long time, ’cause 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 sort of this dominant idea, but really the idea that 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, my awe and regard for Darwin will never be diminished, it’s just amazing what his intellectual contributions are, but he just couldn’t get there. It was before the time we could get at it.
0:26:06 SBC: But I would say… I mean, you’ve had Daniel Dennett on the show, and Dennett really talked about, for example, natural selection and evolution as 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, it’s because chance is the engine that gives us all this variation, and without that engine, you don’t have evolution at all, and yet it’s fundamentally a random mechanism, so I’ll let you pick through that and decide where you want to go with it.
0:26:49 SMC: No, 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 off-handedly that a certain process didn’t seem to fit the traditional Darwinian way of thinking. And 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 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 things, there’s a whole bunch of subtlety about 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.
0:27:50 SBC: Absolutely, and we should all rejoice in that, the science is still growing, or else the last few generations of evolutionary biologists didn’t need to exist. But it’s been, if anything, 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 us discarding much. I think this is a growth and expansion narrative and not replacing something.
0:28:37 SBC: And if anything, 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 that makes the whole evolutionary process run. And when you have a chance process, and we can see just how chancy that process is now, you understand that there’s nothing in charge. A point that I make in the book is we now understand we can capture some of these mutational events now in a way that thanks to great biophysics work, we can capture the moment of spontaneous mutation and realizing, when you understand, for example, that one of the bases of mutation is a subtle chemical shift, just the movement of a proton in a base, which happens as a fundamental matter of physics, you realize that mutation is a feature, not a bug, in DNA.
0:29:41 SMC: Oh, yeah.
0:29:41 SBC: Mutation is something… It’s due to the intrinsic characteristics of the chemicals that make up DNA, it’s inescapable, but now we understand that, 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 far afield from the Darwinian concept.
0:30:00 SMC: Yeah, no, I like that way of putting it. 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.
0:30:17 SBC: Yeah, and you had Neil Shubin 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 his books too. He makes the great point that’s emerged from paleontology, this has been a heyday for paleontology as well. And I mean, Darwin would just be salivating if he could sit around with a hundred paleontologists, because this was… 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 one form to another, but there were none existing in 1859 that we could point to.
0:31:00 SBC: And these days, the fossil record is so much richer, but what have we learned from the fossil record? Neil will tell you that it’s a natural thought, for example, that when you see feathers on birds, you think they evolved for flight, but no, the paleontologists can tell us, nope, they evolved 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, no, fish invented them for buoyancy in the water.
0:31:29 SBC: 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 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 evolved for. And as a molecular geneticist, I can tell you there’s all sorts of beautiful stories in our DNA about how this process works. And so 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.
0:32:17 SMC: Yeah, so let’s get into the role of chance, which you properly are emphasizing here. 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 emphasizing.
0:32:43 SBC: Absolutely, and I think that chance, it’s just… I want to acknowledge, there was a really influential book by a person who had a huge influence on me, I never met him, Jacques Monod, in 1970, called Chance and Necessity, and this rocked the philosophical world. This was a bestseller in France, I think, second only to Love Story at the time, but 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 Monod, coming from French tradition and one of his friends when he, as was a scholar, was the writer Albert Camus, and they shared, I think, some pretty deep conversations. Monod 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.
0:33:48 SBC: Monod passed away six years later. I think 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, we can 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 up-to-date in 2020, and not just at the deep molecular level, but including the geological and planetary level, ’cause 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.
0:34:39 SMC: Well, you mentioned Jacques Monod and also Albert Camus. 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 idea.
0:34:55 SBC: Yeah, I gotta tell you, Sean, that was one of the greatest adventures of my life. Okay, yes, it took me to Paris frequently, but I met incredible people, and what drew into their story, there were some… Monod 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 talked about as being a bona fide genius. And at the same time, he was incredibly, as they said in France, engagé 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.
0:35:32 SBC: So the book is… 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 Monod a great deal with his early works like The Myth of Sisyphus. But in turn, when Camus met Monod and Monod 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, 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 what I mean by thrilling, it was every time a new nugget emerged, whether that was in a letter from an archive or an anecdote or a new interview of somebody I got to meet who knew one or the other, it was just for me, a kid from Toledo, I never imagined I’d be talking to people who had those life experiences.
0:36:53 SMC: 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, just… 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 get that, a different part of your brain being tickled a little bit, right.
0:37:14 SBC: 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 I said, I’m writing this book about Jacques Monod and Albert Camus, I mean, I’m running a lab, I had some other duties. And you do get the look of, he’s gone off the deep end…
0:37:33 SMC: I have gotten that look, many times.
0:37:33 SBC: You won’t hear from him again. But viscerally, 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 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, in that every time I met a gap, I had to figure out, well, is there any way I could figure out what had happened in this time, or 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 a paleontologist gets when they see a possible for the first time.
0:38:19 SMC: 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 could see why that would resonate with a biologist who emphasized the role of chance in the development of life, but also the existentialists wanted to say, we can make choices, we have some autonomy that lets us guide our lives. How did that fit in or did it fit in with Monod’s point of view?
0:38:50 SBC: 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, Nazism and Stalinism and Fascism and all this, that all the European isms, let’s just say that were going on, or Eurasian isms, that these were all empty, that they were empty promises of some kind of utopia, and the same with religion, that that was the promise of a better afterlife, right?
0:39:37 SBC: 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, this is the life we’ve got, and now how do you make the most of it? And I know for lots of scientists that really resonated, Camus was very much… Well, he was read by everybody, but he was very much embraced by a number of scientists, and that’s because he was throwing off all this 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 this is some of the things you got into in your book, The Big Picture, if you have a naturalist’s 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 use our time best? And I think this is the question that the journey of life is all about.
0:40:31 SMC: Well, in a world where accidents happen and chance plays a large role, maybe you can say more about what Monod’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, or did that only come in later?
0:40:55 SBC: 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, yeah, okay, Chuck, where does this variation come from. And 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?
0:41:18 SMC: Sure.
0:41:18 SBC: So you have to kind of extract it there, and I think it took a while, and it took the rediscovery of genetics, and then it really took understanding from geneticists of the early 20th century that mutations arose at random. They could see that 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 discover the randomness of mutation, the random assortment of chromosomes, all that, sort of the basic rules of genetics through more thorough science in the first part of the 20th century. But then when you look at the genetic code, which 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 base in DNA changes this protein, which changes this trait, now you’re looking at the fundamental root, the fundamental basis of evolution, or as the way Monod put it, the root of all innovation in the biosphere.
0:42:21 SBC: 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 an 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.
0:42:51 SMC: And when we say a word like random, it doesn’t mean there’s no structure there at all, like we throw it a six-sided die, we can, even though it’s a random number, the chance that the number 1 comes up versus numbers 2-6 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?
0:43:21 SBC: 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 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 any individual egg where the mutations are going to be. But there’s going to be, 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 spread throughout three billion base pairs of DNA…
0:44:03 SMC: Let me just pause 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, that’s… Is that what we’re saying?
0:44:18 SBC: That’s right, that’s right. So each of us is born with changes in our DNA that are different from our parents at the level of about… 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 it’s a three billion base pairs of DNA to copy, there are typos, and those typos are really just the fundamental matter of the physics that I was talking about. So this is going to go on all the time. The distribution of those mutations throughout the DNA is… And I’m just going to use that, that first approximation argument, is 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.
0:45:17 SBC: 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. That process of selection in 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, etcetera.
0:45:58 SBC: 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 it… 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.
0:46:18 SMC: What were the chances?
0:46:18 SBC: So each of… 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?
0:46:37 SMC: Yeah, it’s a big number, ’cause I know how exponentials work, but I think that what probably I don’t know is in a strand 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.
0:46:54 SBC: Yeah, well, we’ll first start with this combination, so it’s over 70 trillion from one couple. So this means the genetic deck is being shuffled a lot in nature and in humanity, right? And then secondly, yeah, not every gene is going to have a variant 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 in three billion, that’s three million bases that differ between you and I and between any two unrelated individuals in the population. So there’s a lot of variation out there and that all has occurred and it continues to occur every generation with the occurrence of new mutation. So the randomness part of this is that there’s no intention here, there’s no filter, mutations happen at random, and basically life sorts them out.
0:47:54 SMC: And 30, 20 or 30 mutations out of three billion base pairs actually sounds like a small number, but I remember talking with David Baltimore recently, and you know, viruses can use RNA or combinations of RNA and DNA to carry their genetic information and they will mutate much more rapidly, so in some sense, is it too much to think that that 20 or 30 per generation is optimized? Do 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?
0:48:31 SBC: Yeah, I think that’s a good way to think about it. There’s a concept in genetics called the genetic load and 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.
0:49:07 SBC: 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 a month or two than the virus that person was originally infected. So there’s a lot of evolution taking place 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, ’cause 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 the mutational load with adaptability.
0:49:56 SMC: And I need to ask this, is it true that we can think of these mutations as honest to goodness quantum mechanical fluctuations?
0:50:06 SBC: 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 tautomers, so these are chemically slightly different forms in this case, the bases, which I’ll just shorthand, say A, C, G and T, which are adenine, cytosine, guanine, and thymine. These bases, the hydrogen on the larger ring goes through transitions that are… 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 at one one-thousandth of a second, so a given base might be in what we call the common keto form, about 999% 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 machine re-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.
0:51:29 SBC: 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 a biophysicist use as a quantum flip, and it’s an inherent nature of the basis that endowed DNA with its properties.
0:51:46 SMC: Well, a famous thought experiment in biology is, if we could play the tape backwards, if we could start back with whatever an initial conditions life had and let everything go, how similar would it be? And now it seems that I’m going to say that if you believe in the many worlds 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.
0:52:09 SBC: 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, more… 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 and that tectonics and asteroid impacts and all sorts of other things 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’d get dinosaurs and humans that many times.
0:53:01 SMC: Yeah, no, I think that there’s an 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, every card-carrying modern biologist will admit that there is randomness in the mutation, but I guess some would argue that when those mutations come out as organisms, 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.
0:53:34 SBC: Yeah, look, and that’s the phenomenon of convergence, and you might say, 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 I think the truth is fun to explore, not the truth, I can’t say the truth, both poles are fun to explore because there’s no doubt that evolution repeats itself, and when we find very similar circumstances, if you find animals living, say, in a dark habitat in caves, no doubt you’ll see the same independent mutation 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.
0:54:18 SBC: 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, fish, mice, whatever you want to think about, if you have large enough population, you will… Basically, this random mutation mechanism will sample most of the possible mutations in the DNA of that organism, and so it may happen upon the same solution repeatedly, and this has been well documented by simple to study organisms like viruses, but even out there, as I said, mice in the deserts of the American Southwest living on lava outcrops, they repeatedly do the same sort of evolutionary tricks. Bacteria living in our guts exposed to antibiotics keep coming up with the same mutations, so we can see evolution repeat itself, but you just have to 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.
0:55:23 SBC: But when you start way back, 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.
0:55:43 SMC: 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, 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 the 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.
0:56:21 SBC: 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, where 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 the 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 of… Sometimes more than a billion years, they do show properties of being optimized, so that it’s very hard to make a more efficient enzyme to, say, detoxify alcohol, because organisms have had a long time to play with that substance and they’ve probably happened upon the best solution.
0:57:14 SMC: That’s too bad.
0:57:15 SBC: 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 are 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 get my alcohol story…
0:57:53 SMC: 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 and scotch, but that’s okay, we have to live with the constraints of the 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.
0:58:21 SBC: 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, the ocean was a very different habitat post-asteroid, the land was a very different place. Competition is 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 variance and for things that might have had a really tough time in a more… In a well-populated forest or in a more densely populated ocean. So the regime, the competitive regime changes.
0:59:01 SBC: 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 paleontologists 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 Lyson and 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.
1:00:00 SBC: 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, co-existing alongside dinosaurs, but dinosaurs were… 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 a 50-fold increase in maximum body size among the mammals. So quite clearly take away the big… 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.
1:00:51 SBC: And so 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 a big disruption like that, ecological opportunity, one of my favorite paleontologists, there are many, but Andy Knoll at Harvard, has framed it, something along the lines of sort of when 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.
1:01:42 SMC: And so it does… When you sort of think of it in those terms, the asteroid impact being a very obvious one, the role of chance comes to the fore, right, not just the mutations in our genes, but 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 lead.
1:02:08 SBC: Yeah, this is the unfortunate series of events, you’re referring to cancer, for example.
1:02:13 SMC: 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.
1:02:22 SBC: Cancer is the obvious one, because it shows up in the clinic and then we study it and we really understand cancer as a genetic disease. Yeah, so that process of random mutation, which is the source of all that beauty and diversity and complexity in the biosphere and all of human diversity, 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.
1:03:07 SBC: So in the book I… We’re just trying to get people to appreciate that this phenomenon of random mutation impacts lots of things. 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 it’s going to affect a very… All of us, it’s going to affect our families and individually it’s going to probably affect 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 second-hand 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.
1:04:09 SBC: So that knowledge of cancer being a genetic phenomenon is also power. And in the last 20 years, we’ve developed a lot of counter-measures to deal with the mutations that arise in our body in the course of our lifetime, but I did… We come into this world an accident, and many of us are going to exit due to one of these accidents.
1:04:30 SMC: 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 living in conditions of uncertainty, but one of my favorite examples, I think I’ve mentioned this in the podcast before, but it’s my podcast, no-one’s going to stop me from mentioning it again, is when you talk about life expectancy, there’s a million different websites you 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 as I’m going to probably live to 90 and then die.
1:05:06 SMC: But I did find one website that actually also… And I’ve lost it now and it kills me ’cause I can’t find it again, but it actually took the probability, right, so rather than just saying your expected value is 90, it knew what the tails were, and it would randomly generate a number from that distribution, you can click a button again and again. And I think that 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 knowing that you’re going to live to about 90 on average is interesting, but much less relevant than the fact that you could die within years, that’s absolutely possible.
1:05:48 SBC: Absolutely, and this should be the realm of psychology, and I think we can all benefit from the insights of psychologists, ’cause of course we’re playing all sorts of games with ourselves to deny that, there’s a lot of cognitive distance around death and we’re also… Everyone’s struggling to figure out, well, how do we use the time we have, 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, what do you say about somebody who dies young, and everyone’s crushed. Everyone’s absolutely crushed. And the minister talked about life being a gift, nice, but a gift of 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 thoughtful, and you’ve dealt… You dealt with this in your writings, Camus dealt with this, so many people have dealt with this.
1:06:50 SBC: Yet, I think what you’re getting at is that we have lots of games we play with ourselves to sort of deny our own death and to just put it out of our minds, it’s sort of understandable, but, and if you… And then you can imagine… 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, etcetera, 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. And we all look for some wisdom anywhere we can into that. I by the way, and I mention this in the book, I looked at comedians, that’s what I get my psychology and philosophy from.
1:07:32 SMC: Well, 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 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, that we always tend to say, well, if this happened, why did that happen, and I’m going to find the reason, I’m going to fix it or whatever. And I forget who it was, it might have been Steven Colbert, considering your idea that it’s comedians who are the wisest here, but he says whenever anyone tells him, 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.”
1:08:28 SBC: Yeah, exactly.
1:08:28 SMC: But a lot of things don’t, and it’s very hard to craft a vision of life that accepts that things happen without explicit reason.
1:08:37 SBC: Right. Well, there it is, Sean. I think there it is, which is why we have so much of the mythology that we have. It’s understandable, people are trying to think, why would we think about the afterlife? Well, that’s a very pleasant and comfortable, comforting thought, and why you can create so much story around all that, it’s very hard and difficult, very difficult to deal with. The finite nature of life, life is great, but Ricky Gervais, I quote it in the book, you know, he just says, look, this is a holiday. We didn’t exist for 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.
1:09:18 SBC: Now, there might be, 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 and their time, there’s actually some compassion and empathy that comes for that that might surprise people who are believers and who would think that religiosity is important, 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.
1:10:01 SMC: It is, and I don’t claim to have fully figured out it myself. Have you heard about the discourse in philosophy circles around moral luck, the idea of moral luckiness?
1:10:11 SBC: No, I don’t know that. Sounds fun. Go for it.
1:10:13 SMC: It is fun, because in the real world, 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 ’cause 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 the same punishment to everyone who does exactly the same things, but that’s hard to do, it’s certainly not what we actually do in life, like coming to terms with this is even harder in real life than it sounds at first glance, I think.
1:11:00 SBC: No, but I think these are really exciting discussions to have, and in some ways, they’re unfortunately probably had in 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 diss religion, I grew up in… I was educated, 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 a supernatural, supreme being overlooking each of our lives, that sort of inhibits exploration of other ideas that might actually be really constructive for how we live our lives. And so I just hope that as generations pass that there’s just more exploration of moral luck and the meaning of life without an afterlife.
1:11:52 SMC: Well, to borrow a phrase, you are preaching to the converted when you say that. But maybe to close up here, I think it’s been a great conversation and we 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 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. So 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 decided to become a movie producer.
1:12:36 SBC: Stories. So the same reason for writing books, same reason for you and I having this conversation, 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 in 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 concoct scenes out of their imagination that I just couldn’t possibly imagine how they did that. And so I’m comfortable… Well, not comfortable, but let’s just put it this way, 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, it travels very well around the world, and of course, many of us seek out stories in film form so, you know, the brass tacks truth for two writers like you and I, is that 100 or 1000 times more people will see the film version than read our books.
1:13:39 SBC: 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 a head of a documentary studio, Inside Philanthropy, to work with lots of filmmakers and to support the work of lots of filmmakers, and I think science stories, we need more of them out there in the world. And it was another big motivation is that is to help science with its place in our culture by telling more science stories and trying to reach some audiences that would not otherwise tune in for a story about science.
1:14:23 SMC: Yeah, I mean, tell me what 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 provides some good for the world, then find a way to get involved with that, and that sounds like what you’ve done.
1:14:39 SBC: Yeah, thanks, Sean. It’s not that different, honestly, than teaching. It’s certainly as pedantic as teaching, it’s just you’re sharing stories with the world in a form… Science has to compete with every other form of story in our world, right. And people voluntarily choose to listen or pay attention or not, so science has to realize that we’re a storytelling animal in a storytelling world, we have to tell our stories and we have to move people. I think the biggest sort of shortcoming I find among scientists is that we think that if people only knew what we knew, only knew what was going on in our heads, the world would be fine. And maybe that’s true, but you gotta 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. We’re very much sort of cerebral beings as scientists, but 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.
1:15:49 SMC: Present company excepted, of course, when it comes to reading the books, but…
1:15:53 SBC: Yeah, absolutely, of course. But I’ll tell you this, as 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 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 different media, they each serve their important purposes, but I am acknowledging that film might just be a little more popular.
1:16:29 SMC: It’s possible that it does, and then… 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.
1:16:50 SBC: Thanks, Sean, it was a lot of fun.
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That was interesting, informative and delightful. Clearly, the more Carrolls the better. But it added about three more books to my neverending reading list. Oh well 🙂
I had learned a lot from S. B. Carroll’s book on evo-devo and I will rush to read this one. I wonder how you measure/quantify “chance” and show that it plays a “large” role.
Best,
Stéphane from Paris
P.S. Has anyone found the website which calculates the distribution of your remaining life years and not only the average expectancy? Actuarial tables are made for insurance companies which (reasonably) care mainly about the latter. But the former is much more informative for an individual.
Another most interesting discussion, thank you! I once heard Werner Arber discuss the numbers relative to genetic diversity – what is mathematically possible versus what evolution has had time to try. He estimated how many cells there were in every organism that had ever lived on earth for the past 2 billion years and assumed one base pair change in every gene, every hour in every cell. A very large number. So – how many times has evolution tried out every possible gene of 1kb over 2 billion years?
5x10E30 bacteria; 10E31 virus; 7x10E25 human cells etc. Less than 10E40 total cells on earth
2 billion years has 17.52x10E9 hours
100,000 gene coding sequences per cell
So – 10E55 gene mutation hours in 2 billion years
However, for a single gene of 1000 base pairs, encoding a protein of 333 amino acids, the number of possible DNA sequences is 4E1000 = 10E602. The number of amino acid sequences possible is 20E333 = 10E433. So – how many times has evolution tried out every possible gene of 1kb over 2 billion years? Approximately none. Would we evolve again if we did a do-over? Not much chance. Or maybe I am missing something.
I did my own estimate of how much of the earth’s surface would be needed to plant one rice seedling of every possible combination of all the known alleles in the rice gene pool. My estimate was that we’d need a google squared earths to do that. In other words, even without any new mutations, we can’t possible sample every combination of alleles that already exist before the sun burns out and the universe is dark. 🙂
Terrific episode. Just finished “A Series of Fortunate Events” based on the episode. Thoroughly enjoyed the book; nice use of Kurt Vonnegut quotes.
One of your best podcasts yet. Fantastic job
54:00: something I have wondered about ever since my undergrad theoretical physics days (so 35 years and counting): Is the probability of life evolving on earth both probability 1 and probability 0 under the many-world’s interpretation? Probability 1 because somewhere in the evolution of the wave function we get a path that has life (we have an existence proof of this :). But probability 0 because “almost all” the probability mass of the wavefunction today is over earths in which nothing happened. My guess is this is true but I’d be really curious whether our host or any guest could shed light on this. If true, it probably explains why we seem to be alone in the universe. We are alone, because the universe is simply not large enough for two astronomically unlikely events to have occurred. Or more precisely, the fraction of the wavefunction in which there is life at more than one place in the universe is a vanishingly small relative to the fraction with life in only one place, which in turn is vanishingly small relative to the fraction with no life.
Of course another consequence of an affirmative answer to the 0/1 probability argument for life under MWI is that “replaying the tape” from sufficiently early in earth’s history leads to nothing almost surely. Not even simple organisms.