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0:00:00 Sean Carroll: Hello, everyone, and welcome to the Mindscape podcast. I’m your host, Sean Carroll. And as I’m recording these words we are in the middle of a proto-pandemic with the coronavirus, the COVID-19 disease that is happening because of this. I’m certainly not an expert in viruses or pandemics or anything like that. And this episode is not about viruses or pandemics, but it is about evolution. And this is part of why we get pandemics is because all these little microbes, bless their hearts, they keep evolving clever new ways to deal with us even if it hurts us in doing it. And it turns out, when you go into the details, that we human beings sometimes take advantage, as you’ll learn in this podcast. Human DNA has a certain fraction that is just borrowed wholesale from virus DNA in cases where we encountered a virus and we didn’t just combat it, we absorbed it, or at least absorbed part of it.

0:00:57 SC: It’s part of the whole question of how transitions happen in evolution. When Charles Darwin first invented the idea of natural selection, he had the idea that it was more or less gradual, right? That there were slow changes, minor changes, and some of them would catch on, develop and grow, others would be less successful, but we do see examples of major transitions. Whether they happen quickly or not is a complicated thing, but there are transitions, like the first flight, right? The first animals that could actually fly and develop wings, or the first climbing onto land on the part of aquatic animals. So this has always been a question for Darwinian evolution, how does that happen? How does a fish develop the right organismal abilities to live on and flourish on dry land? It’s not teleological, evolution is not based on goals toward future success. So the fish can’t think to itself, “I would like to be able to get up and get that yummy food up on land, let me develop some feet and some lungs and the ability to do that.”

0:02:08 SC: So today, we’re talking to Neil Shubin, who’s a quite well-known evolutionary biologist, he is a Distinguished Service Professor of Organismal Biology and Anatomy at the University of Chicago, very well-known, of course, for being one of the co-discoverers of Tiktaalik, the fossil that represents a crucially important transitional stage, the transitional stage precisely from being a fish swimming in the water to being an amphibian, living mostly on land. It’s a little fish-like thing that has the basic very primitive versions of feet and hands, and the ability to breathe air and so forth. So Neil has some evolution of his own in the research that he does, mostly from going out there and hunting fossils and doing paleontology and learning about the evolution of life on that macro scale to being in a lab and doing molecular biology, understanding how changes in DNA, both the actual coding for proteins, but also how the DNA we have is regulated and expressed can lead to these major transitions in evolution. I mean, what actually happens in the DNA of a fish to turn it into something that can climb about on land.

0:03:21 SC: It’s an extremely exciting field, because it’s one of these things where obviously, we’ve learned a lot, but there’s still a lot left to learn. And as we discuss at the very end of the episode, it’s a rapidly changing field, in part because we are developing the ability to make these changes in DNA ourselves. So what used to be more or less gradual changes in how organisms functioned can be very, very rapid because now we can have teleology, we can actually plan what might happen next. So it’s a fun episode. Neil is a wonderful science communicator. He’s the author of a book called Your Inner Fish, which tells how things that are still in your body right now were first developed in the context of when our ancestors were in fact fish. And he has a new book coming out literally tomorrow as this episode is being released called Some Assembly Required: Decoding Four Billion Years of Life from Ancient Fossils to DNA, about these major transitions in evolution and how we are learning about them through studying DNA. So, let’s go.

[music]

0:04:40 SC: Neil Shubin, welcome to the Mindscape Podcast.

0:04:42 Neil Shubin: Great to be here.

0:04:43 SC: We’re going to be talking about evolution, natural selection, Charles Darwin. I want to let everyone know right from the start, the official Mindscape podcast position is that evolution is real, and we’re not going to be discussing whether or not evolution happened versus creationism or anything like that. I hope that’s okay with you.

0:05:00 NS: Yeah, I didn’t do that in the book either, so that’s good.

0:05:02 SC: Yeah, that’s not why we’re here. You can go to other places for that. But given that evolution is real, given that Darwin was roughly speaking right, there’s certainly a lot of work to be done in figuring out exactly how it happened. Is that a fair way of stating it?

0:05:20 NS: And that’s good news because that keeps people like me employed. And what’s happened recently is just… We’ve had game-changing technologies, both for the ways we analyze fossils, both in molecular biology and computation, that really changed things. And so many of the questions that Darwin had, and many of the ideas he had are still relevant, but, boy, are we learning new things.

0:05:42 SC: Yeah, yeah, and it’s always one of those things where when you solve one problem, you open up multiple new problems and multiple new puzzles. And I think that people who are not embedded in the scientific process might feel like there’s just more and more puzzles that you guys are inventing [chuckle] whereas it’s actually there’s more and more knowledge being gained at the same time.

0:06:00 NS: Yeah, sometimes you actually get to ask new kinds of questions, more powerful questions in many ways, more precise questions, maybe more global questions. The questions never stop, they just change, and as we gain answers we can new questions.

0:06:00 SC: Yeah, so you have a new book coming out called Some Assembly Required: Decoding Four Billion Years of Life from Ancient Fossils to DNA, congratulations on that.

0:06:00 NS: Oh, thank you so much.

0:06:00 SC: And you’ve written a couple of other books, your sort of break out one was Your Inner Fish, about the discovery of… I always say Tiktaalik, but I’m told that’s the wrong pronunciation.

0:06:00 NS: Well, that’s actually right in some quarters, but we say Tiktaalik.

0:06:00 SC: Tiktaalik, okay.

0:06:00 NS: Yeah, so if you go to the Inuit, it’s an Inuit word, an Inuit name, it would be Tiktaalik.

0:06:00 SC: Oh, really, Tiktaalik.

0:06:00 NS: But Tiktaalik is what we’ve been saying. Yeah.

0:06:00 SC: Oh, I’m definitely going to stick with the Inuit way, if that’s okay with you.

0:06:54 NS: Definitely.

[chuckle]

0:06:54 SC: So let’s, we’ll tell that story a little bit, but first just to put things in context, one of the things that you still want to understand if you’re a good natural selection evolutionary biologist is the question of missing links and big transitions in evolution. I mean, the joke is that whenever you find a missing link you’ve created two more missing links because you now have one species in between two other ones, but this is a good puzzle for biology. Is that right?

0:07:19 NS: Oh, it’s a wonderful one. And in fact, it’s the one that drew me into the field and in realizing that, that’s how this book came about, was realizing how important those questions are, the great transitions in evolution and some of the misconceptions that we have, all of us, about those transitions, missing links being one of them.

0:07:36 SC: So what sense, is there a slogan that says the idea of missing links is itself a misconception?

0:07:43 NS: Well, there should be…

[laughter]

0:07:45 NS: As somebody who’s been… Who has claimed to have found a missing link and other people have purported it that Tiktaalik is. But the reality is evolution is a hugely branching tree, it doesn’t take a straight-on path. And when we talk about links which there are, number one, they’re found, they’re not missing. But number two, the path of evolution is often very unpredictable, it has lots of twists and turns and goes backwards and forwards and it’s not a straight path, a linear ladder, it’s a hugely branching bush of change that goes in many different directions.

0:08:21 NS: So the missing link concept, I mean, the part of it that’s right is link, is there are links among species, but what underlies that narrative, however, is the assumption that evolution acts as a ladder of progress, of change, of one form inexorably giving rise to another that’s, that looks sort of like, that looks the same but different. There are aspects of that that are true, but it’s that linear narrative that I think we’re finding as we study fossils and genes as really doesn’t hold up.

0:08:49 SC: Yeah, and your book certainly does a good job of explaining the messiness of it all, which is… Like you say, full employment for scientists, so that’s good.

0:08:56 NS: Yeah. It’s a beautiful messiness. The mess is the message, and so we can get into that but it’s… That’s half the fun of this, you know, so.

0:09:03 SC: That’s why people should become physicists instead of biologists, it’s way cleaner. Biology is way too messy.

0:09:08 NS: Yeah, we’re a total… We’re a total mess.

[laughter]

0:09:11 SC: So one of the very most obvious links that one might want to fill in, whether you call it a missing link or not, is between fish and land dwellers or amphibians or whatever, and that’s where Tiktaalik comes into the story. So why don’t you tell us just the wonderful human story of you and your team discovering that and what it all meant.

0:09:31 NS: Well, it began, as I describe in the book, actually, it began in my second year at graduate school. I was… I didn’t know what I wanted to do for my PhD, I knew I wanted to study evolution, but I thought maybe I want to study mammals or I don’t know, I didn’t know. And so I took a survey course on evolution and like each week was a different greatest hits in the history of life, you go from one great transition to the next and the professor showed this beautiful slide of a fish on one end and an amphibian or tetrapod, a limbed animal on the other with an arrow connecting them and then it was like kind of what we knew about that transition from water to land. I remember looking at that slide thinking, golly, I want to work on that problem and I want to find fossils that do it. And so, you know, with colleagues, we set off on a multi-year quest to find an intermediate between a fish that lives in water and limbed animal, tetrapod that lives on land and we know, we’re used the rules of paleontology, we didn’t invent new methods here.

0:10:25 NS: We were using sort of the tried and true perspectives of field paleontology, which goes as follows, in simplified form. If you want to find a key intermediate fossil, say a transitional fossil, say between say fish and tetrapods or between birds and reptiles or reptiles and mammals, whatever, you look for places in the world that have three things. You look for places in the world that have rocks, that hold rocks of the right age to answer whatever question interests you, so if you’re interested in the fish to limbed animal transition, you’re going to be looking at rocks about 380-375 million years old or so. You’d look for places in the world that have rocks of the right type to hold fossils. Obviously, not every kind of rock does that, and as a geologist you start to learn the catalog of environments and rocks that are likely to preserve the best fossils. That’s as much art as science, by the way and a lot of induction there.

0:11:17 NS: And then the third part is you look for places in the world that not only have rocks of the right age or the right type but the rocks that are exposed and accessible, it makes total sense, right? You don’t want rocks that are buried 12 miles underground or that are in the side of Mount Everest or in a politically unviable place, a war zone, you need accessibility. And so those are the filters, right? So, the world’s a big place.

0:11:38 SC: So the point with that last one being that erosion and plate tectonics, etcetera, are constantly exposing new layers and so are you going to go for… Look for the layers which have the kind of rocks that you want.

0:11:50 NS: That’s correct. That’s correct. And so you can actually go to geology libraries, which is what we did in the ’90s, or do it online and you can get aerial photos, you can get geological maps that give you the kinds of rocks in a country’s border, you can dig out papers on the local geology to find out what kind of rocks are there and you can put all this information together. So that’s what we were doing in the ’90s, looking for rocks of the right age, about 375 million years old and so forth. Our first gig was in Pennsylvania, because my first job was outside Philly… Was at the University of Pennsylvania in Philadelphia and I grew up there as well and so I knew the place and I also knew that there is a lot of Devonian aged rock in Pennsylvania throughout the state.

0:12:31 NS: So it became… The first part of our hunt was looking at the Devonian age, again, 365-375 million year old rocks in Pennsylvania. And it turns out… We didn’t have a lot of exposure, so we worked on road cuts when PennDOT, Pennsylvania Department of Transportation, would come in to build a new road, we’d get in there and look at the rocks and that was amazingly successful. It really was. We started finding early tetrapods, early limbed animals, we found all kinds of fish. It was just a remarkably productive program.

0:12:51 NS: But my colleague in this, Ted Daeschler, who was a student at the time and now a colleague, who works on all this stuff with me. We realized we had a problem, we were in rocks that were too young to answer the question. We wanted to find a fish with limb, with a fin with limb bones inside it, that had a head like a limb of a tetrapod, like a flathead not a conical head like a fish, that had a neck or things like that, and we weren’t finding a lot of that, so we were in rocks that were way too young to answer the question. So back to the drawing board, and so it turned out one thing led to another and we settled on a region of rock up in the Canadian Arctic, that extends from about 1500 kilometers from Melville Island in the west to Ellesmere Island in the east.

0:13:45 NS: And perfect, I mean, rock 375 million years old, rock that was produced in ancient rivers and streams much like the Amazon Delta today, it’s in the Canadian Arctic, by the way, that tells you how different, how much the world’s changed, and then rock that was exposed by ice and water and so forth. So we had all our variables maximized at this spot. So starting in 1999, we began expeditions there and…

0:14:11 SC: Slightly more exotic than the hills of Pennsylvania.

0:14:13 NS: Yeah, quite a bit. You’re taking a team of six people. There are polar bears up there. It’s daylight 24 hours a day. We’re 300 miles from the nearest village, which has 170 people at that 80 north latitude, I mean, it’s pretty extreme. And for those reasons, it took us a while to be successful. A season up there would be about four weeks. And so we started in ’99, did four weeks then, 2000 did it again. And each year we made a little progress, but we never really found what we were looking for until 2004. We had found a layer with lots of fish bones in it. And we’re digging this layer, I’ll never forget this day in my life. It was like July 17th, 2004. We’re in this layer, cracking rocks, finding fossil fish, nothing we’d be talking about.

0:14:58 NS: But my colleague, one of my colleagues in the pit with me, cracked a rock and said, “Hey, Neil, what’s this?” And I came over, and I looked at it, and as soon as I saw that, I knew we had found what we had spent six years and lots of money and lots of sprained ankles looking for. And what it was, was a snout of a fish, clearly had fish bone. The texture was classically fish. It was clearly the front of a skull, but it was clearly a very flat skull. And so early limbed animals have flat heads. We were looking for a flat-headed fish. So I said, here’s a flat-headed fish looking right out at me in the rock. [laughter] So lot of celebration.

0:15:31 NS: So we ended up removing the whole thing. It was about four feet long, a little over a meter, and then pulled it out. And then, as we did that, we found four more of these things. And since then we’ve found about 20. So they’re not at all rare. And then, we got these things back to the lab, and the rock was removed grain by grain. And first, we saw it had a fin. Great. But then we saw inside it had a humerus, an upper arm bone, had a radius and ulna in there. It had a wrist. It had even things that that might compare to digits, fingers and toes.

0:16:02 SC: Things most fish don’t have.

0:16:04 NS: Yeah, and but in a fin, clearly it had fin rays. And this thing clearly had a shoulder that was part fish, part limbed animal, it had that sort of setup, yet it had scales, yet it had fish-like bones in the skull. So it was a real mosaic between characteristics of fish and limbed animals. And it was an animal that had lungs and gills, had fins with limb bones inside. It was exactly what we were looking for. And it tells us a lot about how this transition from water to land happened. It’s real physical evidence of that. And it wasn’t lost on us that this was when we were working on this fossil initially, it was 2000… We found it in 2004. We did most of the work in 2005 and ’06, illustrating it. There were trials going on where people were suing to teach intelligent design creationism in schools. And here we had on our desks, these fossils, it was quite the time.

[laughter]

0:16:51 NS: As you can imagine.

0:16:53 SC: Presumably, they would just say, yeah, you glued together a fish with a salamander or something like that, right?

0:17:00 NS: Yeah, well, but we actually recorded us taking it out. This was just… And the wonderful thing is that about this example, I love using it to teach, not only because it’s a huge part of my life, is that we used the tools of evolutionary biology, of geology and stratigraphy, of historical geology to make a prediction. We didn’t go randomly to the Arctic, and we didn’t just stay there. And we stayed there for six years. We stayed there for a reason is we felt we had a very strong prediction that the odds were in our favor if we stuck with it long enough that we would be successful. And yeah, and that’s what happened.

0:17:37 SC: It’s a predictive science. It’s not merely a matter of history.

0:17:41 NS: That’s correct. And you can put the odds in your favor by knowing a lot about the evolutionary history of the groups you’re interested in, the dating and ages that those fossils first appear, and then knowing a lot about the environments that creatures likely lived in. Once you do that, then you can make your predictions, and that’s the toolkit.

0:18:00 SC: And just that you sort of skipped over one thing, which I think is absolutely fascinating. So once you’ve found the rocks you want to look at, then you go up there for years on end. What is the actual process of looking through the rocks for a fossil like? I can imagine I’d be walking through rocks for a long time and not see any fossils. Part of it is just you have a trained eye, but there’s probably more to it than that.

0:18:24 NS: Well, it’s getting a trained eye, definitely, there’s a couple of things that fit together. One is you train your eye, and if you were to come on an expedition with us, you’d first get there, and you’d think we were magicians. We’d be picking up rocks all over your feet. And but after a few days you’d do it yourself, that pattern recognition system that we all have kicks in. It takes a few days, but you learn it. And whenever I go to a new place, I have to learn how to find new fossils, each rock, kind of rock is different. But what we do is, you get up in the morning, and we have geological maps, we have our aerial photos, we have a good knowledge of what kinds of rocks are exposed everywhere around us, so which hills hold which kinds of rocks. So we decide in the morning which rocks we want to visit. So we’ll walk to those, and we’ll literally follow layers for miles, looking for bones that are weathering out on the surface.

0:19:14 NS: And it’s just painstaking. You gotta stick to it. And once we find something that’s weathering, then we’ll… If it looks good, we’ll dig out the layer, try to find the layer the fossils are coming from, and if it’s any good, we’ll put a whole team on removing the fossils in that layer. That’s essentially what happens and so, success. But is success what matters here? What matters is developing that eye, developing a knowledge of the geology of the rocks you’re working on, being really patient.

0:19:31 SC: Yeah, I think that’s… [laughter]

0:19:31 NS: There’ll be whole days, whole weeks where you’re not finding stuff, but you got to stay on point. And sometimes that’s not easy. If the weather’s lousy, if you’re stuck in the Arctic and you want to get home. There’s lots of other psychological things that kick in as well that you have to think about up there. But all those are variables that are related to success.

0:20:03 SC: We’ve done the experiment. I have gone to Wyoming and Montana with your colleague, Paul Sereno, digging for dinosaurs. And I’m just not really very good at distinguishing the rocks from anything else.

0:20:16 NS: Well, I got news for you. I was no good either when I was in graduate school. The first expedition I went on was like 1983. My first year in graduate school, I was invited to look for fossil mammals, which are really small. I was an utter disaster, to the point where one of the senior people told me, “You don’t have a future in this, kid. Just stick to the theoretical side.” [chuckle] By the way, I had never camped before that.

0:20:38 SC: Yeah, okay.

0:20:38 NS: I was just such nerd. This all was new. But then I decided I wanted to do it. And just like anything in life…

0:20:43 SC: You can learn, yeah.

0:20:44 NS: Make a decision, you can learn it. Exactly.

0:20:46 SC: And I love the fact that the book that you wrote about this was not just, hey, we found a transitional organism between fish and amphibians, but the fact that the relics of that transition are still within us today, right? That’s what it really means to have our Inner Fish. And it’s a reminder…

0:21:04 NS: Oh, yeah.

0:21:04 SC: That the transitions are gradual and continuous from very early times to right now.

0:21:11 NS: That’s correct. The conceit of that book was… You know, that fossil was just a way point. But really once you start to look at anatomy and development and molecular biology, what you start to see is there’s billions of years of artifacts, of billions of years of history inside our own bodies. And you see that in the genome, you see that in ourselves, you see that in our tissues, our organs. You look at our skulls, limbs and so forth, we can see layer after layer of evolutionary history inside of us. So that was the story that I told in Inner Fish. And that was a really an extension of a lot of the teaching I did, because at the time I was also… At the time we discovered Tiktaalik, I was teaching human anatomy to medical students here in the University of Chicago Medical School. It enabled me to connect the dots in the way I probably wouldn’t have done in the same way previously.

0:22:00 SC: I think that hiccups were my favorite example, right? Can you explain why we have hiccups?

0:22:04 NS: Yeah. Well, we have hiccups. It’s basically a spasm of the phrenic nerve. One theory that came out from some folks in Canada a few years ago, was the idea that that response, that is a very calibrated, stereotypical response of nerves firing and muscles firing, and in consequence that there’s a pattern inside our central nervous system that causes that pattern to occur. That pattern occurs naturally elsewhere in the wild. In one place where we see it is in frogs and tadpoles, which use a form of a hiccup and that neural response to actually breathe with water. And so what we’ll see is there’s these antecedents that we see in other animals for things that we think are distinctively human, when in reality they’re not.

0:22:50 SC: Yeah. So we can get into exactly sort of the purpose, I think, of… The main theme, let’s call it that, of this podcast, which is, this is, that Tiktaalik does represent a major transition from one way of life to another. Can you just say a little bit for people who don’t know anything about… What was its motivation for climbing up onto land? And how did that really work? It seems like something that if you’re just under water and have a happy life there, that climbing up to a different, poisonous environment is not your first idea.

0:23:21 NS: Well, it helps to compare water and land. There’s probably not one reason, there are probably many. But if you look in the Devonian and what lived in the water at that time, you had big fish, you had small fish. But pretty much all of them were carnivores, they were all predators. So it was a fish-eat-fish world. And by the way, you wouldn’t have wanted to swim in these Devonian streams. There were 15-foot long predators filling the crocodile kinda niche. Giant predators with teeth the size of railroad spikes. So, yeah, it was a very predator and competitor-intense world in the water. But if you look at land at that time, there are plants on land, there are invertebrates, there are food sources on land, there are a few competitors and certainly no predators. So any trait that would allow a creature to avoid the water, get away from the predators and the competitors into the mudflats and to land would probably be favored, because there was a world of opportunity with foodstuffs on land without competitors or predators.

0:24:20 NS: There are probably lots of other reasons as well. Things like Tiktaalik and its cousins in the Devonian were not fully land-living. They were living in the shallows and the mudflats. So there’s a continuum between these environments as well. So lots of reasons, but those… There are lots of good reasons to get out of the water. You could think about it. If it’s a fish-eat-fish world, there’s lots of strategies. You can get big, ’cause big fish eat little fish. You can get armor, which a lot of fish do, or you can get out of the way. Get out of there. [chuckle] I think our distant ancestors were the ones who got out of there.

0:24:52 SC: But it’s not Lamarckian. You can’t as a fish say, “Boy, there’s a lot of yummy food up there on land. I think I will turn my fins into feet,” right? There have to be all of these little transitions.

0:25:03 NS: No. That’s exactly right. That’s a really good point. It’s not that. It’s actually, it’s natural selection and that’s with some assembly required. The new book really is about in showing how that happens. So when you think about the water-to-land transition, it actually exemplifies other great transitions as well, in showing one really important thing. That is, pretty much every trait that we associate with one of the great revolutions in the history of life, say, limbs or arms and the invasion of land, lungs and the invasion of land, feathers and the origin of flight, walking on two legs and the origin of humanity. Pretty much every trait that we associate with a revolution is not associated with that revolution. It came about millions of years before.

0:25:49 SC: Right.

0:25:50 NS: And that’s the big thing. One of the quotes that leads off the book is one of my favorite ones from Lillian Hellman, who lived a fairly hard life, and she said, “Nothing, of course, ever begins when you think it does.” That is a great motto for thinking about evolutionary change. Nothing begins with… It always begins well before.

0:26:01 SC: It’s always repurposing something else, right?

0:26:01 NS: It’s repurposing. It’s repurposing and then modifying and then repurposing again. Co-opting, duplicating, merging. It’s all these things. It’s tinkering in some very profound ways and we get to see glimpses of that tinkering in the fossil record. We could see the pathway it took. But when we look at genes and we look at development, we look at molecular biology, we begin to see the mechanisms behind that kind of tinkering and repurposing, which is really fabulous stuff.

0:26:37 SC: So I can imagine, it might have been much harder for that fish to climb up onto land if it didn’t have fins in the first place, or flippers, flippers, is that what you are saying?

0:26:46 NS: Yeah, it had a sort of a flipper-like limb with… It basically had a shoulder, it had an elbow and it had a wrist and it had part of the fin that… The terminal end of the fin that could serve as a palm. This is a fish that can do a push-up, that can even walk in funny ways and, by the way, this fish also had lungs. So you can imagine that these fish with all this gear living in water, walking on the bottom of the water, maybe in the mudflats, it was already set up to jump into land when the need happened and to refine those structures and to modify them and repurpose them in new ways.

0:27:16 SC: I think maybe to the people who are not experts, the fact that it had lungs is even more impressive and surprising than the fact that it could develop feet, because as long as you have flippers, you can imagine morphing them into feet, but if you breathe through gills, why do you also have lungs?

0:27:32 NS: Yeah, that’s great. And so this is actually something that was discovered in the 1830s. We’ve known this forever; yet, if you talk to people they always say, “Well, lungs arose when… Of course, they’re related to living on land.” No, they’re not. They originally came about in creatures living in water and we’ve known that since Napoleon’s expeditions to Egypt in the early 1800s and ever since. And what people started to do is they discovered in dissecting new kinds of fish that they saw in Africa or in South America or in Australia, they found that some fish have lungs, real lungs that are exactly like ours in many ways. And in fact, if you look at a lot of fish, a lot of fish have a air sac that is connected to the gut tube or related to the gut tube in development, and in some of those fish that sac becomes lungs; in others that sac becomes a swim bladder which they use for buoyancy.

0:28:29 NS: So this air sac presence in fish is really ancient and, in fact, an air sac that functions as a lung is ancient still, so what is it doing? Well, in critter, in fish that have lungs, they have both gills and lungs, and more often than not they’re using their gills. They’re sitting in water just like any good old fish and breathing, right? But the oxygen concentration in water can vary a lot, it can vary a lot from month to month, season to season and so forth. And so there are times when the oxygen content of water is not sufficient to support an animal’s life and what they’ll do is in those cases they’ll go to the surface and actually gulp air into their lungs and then go back down.

0:29:15 NS: And so lungs are sort of an accessory organ that allow fish to exploit water that has variable oxygen concentrations throughout the year. And there are lots of strategies that fish have to do this, some have lungs and others breathe through their skin, still others will vascularize parts of their mouth and use that as a respiratory organ. So there’s lots of little different indentions that happen in evolution to allow fish to breathe air. Air breathing in fish is very, very common, but lungs are a very ancient one, and so our distant relatives who originally took the first steps to walk on land, they didn’t need to involve lungs, they already existed.

0:29:54 SC: Is it safe to say that the lungs always came from swim bladders or air sacs or something like that? Was there some prior purpose that it developed?

0:30:02 NS: Yeah. It’s safe to say that the lungs actually originally rose as a, developmentally as an out-pocket of the gut tube, so during development of the tube that forms the gut, it develops there, and then it out-pockets, forms an out-pouch and in some fish that pouch becomes lungs, in others it becomes swim bladders, so they’re related developmentally, but the whole thing is, it’s the common developmental process that gives rise to both. And pretty much all fish have one or the other.

0:30:27 SC: Yeah, good, and I… This is a good segue. Thank you for doing my work there, because one of the lessons of your book is that one of the major sort of resources for doing this repurposing is tinkering with our development, right?

0:30:41 NS: That’s right.

0:30:42 SC: There’s this famous but slightly exaggerated idea that ontogeny recapitulates phylogeny. Tell us that story a little bit and maybe we can work salamanders in there at some point, because the salamander stuff was just amazing.

0:30:54 NS: Yeah, it’s really cool. So ontogeny recapitulates phylogeny, a lot of us learned it in high school. I did. I learned it in junior high and it was like a little jingle we’d all sing in like the third week of evolution or something like that.

[laughter]

0:31:07 NS: And as most people know, it’s this notion that, an older notion, that claims that during the course of development going from egg to adult through the different stages of embryology. Organisms, creatures would track their evolutionary history, so if you look at a mammal, it would go through a fish stage, an amphibian stage, a reptile stage and so forth, and this was right after Darwin wrote the Origin of Species. Ernst Haeckel, a great German biologist, really promulgated this theory, pushed it along, and there are other versions of recapitulation as well. There was one that actually came out before Darwin and that basically said that creatures look most similar as embryos, they tend to get look very different as adults. That’s actually a much more modern concept, even though it’s the older one in many ways. Anyway, these were very foundational concepts. It turns out that, I think biology is a world of exceptions particularly for ontogeny recapitulating phylogeny and there are so many exceptions.

0:32:12 SC: You should probably tell us what ontogeny and phylogeny are.

0:32:15 NS: Yeah. Sorry about that. So ontogeny is another word for development, phylogeny is another word for evolutionary history. So development tracks evolutionary history, that’s what ontogeny recapitulates phylogeny basically means, in English, development tracks evolutionary history, and so that… But that was a very dominant theory, worldview, for a period of time. It turns out to be wrong though there are cases where it does that. So there are some cases where we do see in individual traits that the development will track evolutionary history, but it’s certainly not true as a law of nature, like Haeckel and his contemporaries proposed.

0:32:58 SC: So it does seem to be true that in the embryos, etcetera, of various species you see features that are in common with very, very different species, presumably because of our common ancestry.

0:33:10 NS: That’s correct. So we see a ton of that. In fact, that’s… We see so much common in development, and that’s… When you look at an early embryo of a fish and a human, you’ll find an enormous number of similarities in the skull bones, in the digestive system, in the expiratory system, and so forth. But it’s not like we track evolutionary history, it’s just that we begin from a common stage of development, more or less, or our early stages of development tend to be much more similar is kind of the idea there. But the relationship of development embryology to evolution has long been a source of fascination for scientists in my field. It’s really, the embryo has always held this special place, because you think about it, here I am studying evolutionary history, and I’m looking at great transformations in the history of life, but what happens in development? Great transformations happen every hour.

[laughter]

0:34:03 NS: You go from… You know, right? Organs appear out of… You begin as a single cell. Then the cell doubles and doubles and doubles and doubles, and eventually you get germ layers, these different layers that form different tissues of the body, and then the heart emerges, and the central nervous system emerges. These things emerge over time. And part of the fascination which I felt as a graduate student, when you’re looking at an embryo, you’re looking at an organism being built. It’s a really beautiful thing. And when we can compare the embryos of different creatures, say, a fish and a mammal, you begin to see how… You can begin to explain the differences between them by differences in the way they’re built, right? And that’s a very powerful way to look at evolution.

0:34:49 SC: Which reminds me, I wanted to ask a little bit more about the history of Darwin. I know this is out of order, but that’s okay. Darwin correctly gets credit for natural selection, etcetera. But there were ideas floating around that species evolved in some very generalized sense without necessarily all the mechanisms of random mutation and natural selection, right?

0:35:14 NS: Oh, that’s correct. The notions of evolution were around before Darwin. You mentioned Lamarck, he was before Darwin. Darwin’s own grandfather, Erasmus Darwin, had a notion of evolution. And in fact, when Darwin was working on his theory of evolution, other people were coming up with it at the same time, Alfred Russel Wallace and a few other people independently. So yeah, the idea has been out there. And in fact, many of the ideas we use in an evolutionary concept originally came about in… Before Darwin. So this notion about embryos being very similar, more similar to one another than adults, that was something that was pre-Darwinian, and in a lot of concepts.

0:35:52 SC: Yeah, that’s what I wanted to get at. That’s just amazing to me. So, they already that idea even.

0:35:57 NS: Oh, yeah. See, they were really trying to explain diversity. Someone said my new book is trying to explain diversity. How do we know? How do we explain and understand the diversity of life we see on our planet, right? Well, people have been after that for a long time before Darwin, it’s just they weren’t using natural selection as a mechanism. They saw the work of a creator, but they were looking for order and rules underneath diversity, that explained it. And a lot of those ideas that they developed in the pre-Darwinian context, actually, apply very well in the evolutionary one.

0:36:31 SC: Did anyone have the idea that God did it and it was designed, but God’s plan involved species changing over time from something simple to the incredible diversity we see today?

0:36:46 NS: The… I’m not aware of that particular view, ’cause one of the challenges for that… Some listener probably would know it. I don’t. However, one of the challenges for that was to accept that you’d have to accept that species are imperfect, and they go extinct. And the concept of extinction was a relatively new one in biology, believe it or not. It has its own history. But it really wasn’t until soon before Darwin that people really accepted the reality of extinction. So if you don’t have extinction and if species are perfect, then it’s hard to have a notion of evolution. And so, the idea of extinction was itself part… The understanding of extinction was really essential for Darwin and other approach… And other people’s perspectives on evolution as well.

0:37:36 SC: So there was still some picture that nature was a perfect kind of setup and there was no reason for it to change over time. And that was part of the cultural change that Darwin rode in on.

0:37:44 NS: That’s correct.

0:37:48 SC: Yeah.

0:37:48 NS: And that was the dominant world view. But these folks, then, many of them who make it into the book, were really looking for order and diversity, rules and diversity. What explains why a fish looks the way it does, and a human? And they were trying to do it in a world where these species are fixed and not changing. But in doing that, they devised tools, conceptual tools that we use today. And one of them is this notion called homology, where again it has pre-Darwinian roots, but it translated very well for Darwin, the idea that you can compare similar structures in different species. That you can compare a vertebra from a fish, to a reptile, to a bird, to a human, and you can compare the same vertebra among these different things. That was a notion that came up in the pre-Darwinian world, but yet, Darwin basically put a mechanistic… A material spin on it, basically saying the reason why he can do that is because these things share an evolutionary history together.

0:38:42 SC: Got it. Good. So this is an appropriate time to bring in the salamanders, ’cause I think this is just a wonderful example of how… There is a connection between development and evolution.

0:38:54 NS: Yeah, salamanders, I love salamanders. So did part of my PhD thesis on salamanders. I just love them, and then I did my postdoc on them. I didn’t grow up as a kid who loved herps, reptiles and amphibians and stuff, but as a graduate student, I just fell in love with these little creatures and they just have such a history. So one of my favorite stories is Auguste Duméril, who was a professor at the Museum of the Natural History in Paris. He and his dad were experts, academician experts on reptiles and amphibians. And this is a time of discovery, sort of in the mid-late 1800s, right after Darwin, about 1864 or so, and so Duméril would get shipments of critters from expeditions around the world that folks found and they’d want him to figure it out.

0:39:41 NS: Well, one day he gets a box with, I think, six salamanders inside, and these are from Mexico. And he looks in the box, and the folks sent it to him because Darwin just published his theory. And these salamanders that he was sent, they had an aquatic tail, big fleshy lobe tail, they had external gills, they were fully aquatic, and they sent them to Duméril thinking, “Well, here’s a living missing link,” right? This is kind of like a creature that maybe will tell us something about how fish evolved to walk on land. So, Duméril…

0:40:14 SC: Did they know about salamanders at all in Europe at the time?

0:40:18 NS: Yes they did, yeah, ’cause there are European salamanders. So they knew quite a bit about them, just their local species, but this from Mexico was weird because it had… This is a giant adult fully… Full adult with all these aquatic features. So he’s like, “Oh, this is great.” So he put them in his menagerie, and salamanders are easy to care for, you can actually leave them alone for long periods of time. And that’s exactly what he did. And he came back after a period of time, and he went back to his box, and he looked in his box, and he saw his fully adult salamanders that were aquatic with external gills, but then there was a whole another type of salamander there. Fully adult, reproducing, big, with no external gills, a fully terrestrial body. No aquatic lobe-y tail, no external gills. He looked at it and was like, “These are two different genera, okay. Something happened in that box.”

0:41:05 SC: Not just species, yeah.

0:41:06 NS: Yeah, it’s like this was a magic box. Well, he was a scientist, he didn’t follow the magic reasoning, so he said, “Well, what is going on here? Something amazing happened.” It’s almost like he put gorillas in the cage, came back and found chimps and gorillas the next year. It was like that kind of thing. So he did his homework and he started to study their embryology and he found that this difference is really a simple shift of development, and it showed how a simple shift of development can bring about changes across the entire animal. So what happened is… During the normal life cycle of one of these salamanders, they have an egg, they hatch from the egg, they swim around in water with external gills and fleshy tails that are like a fin, and then at some point in their life they swim around as aquatic larvae, right? And then they get bigger and bigger and bigger and bigger and then eventually at some point in their life, they undergo metamorphosis and metamorphosis hormone is triggered, thyroid hormone, and they lose the external gills, the tail changes, the head changes, all that good stuff.

0:42:13 NS: And what Duméril realized, as well as some other people at the time, was what happened in his box is the salamanders, the aquatic salamanders reproduced, but their offspring underwent metamorphosis which those other ones didn’t. And so there was a… The trick there is whether you undergo metamorphosis or not, which can be triggered by external cues in these species. So it’s really remarkable, he was able to show… And this was a huge insight, that a subtle change in development, maybe just changing thyroid hormone and metamorphosis, can have changes across the body, and two animals can look entirely different as a result of that.

0:42:52 NS: So that work was really foundational in the sense that what it did is it turned people on to thinking about, “Well, what kinds of subtle changes in development can bring about some of these huge changes in the history of life that Darwin was talking about?” And it turns out one simple way is just to change the timing of developmental events, extend development, stop it early, that sort of stuff.

0:43:13 SC: Yeah, it’s amazing to me because, just be super clear, that other form that did undergo the metamorphosis is completely land-based. It doesn’t look like it has any aquatic paraphernalia at all, is that correct?

0:43:27 NS: That’s right, that’s correct. Yeah, so I mean, the body looks totally different, right? And the way it feeds is totally different, the whole thing. And it’s a really just a subtle change in the level of hormone at one time of development. And so that…

0:43:37 SC: And also the fact that it can just get stuck in that pre-metamorphosis stage and still flourish, it’s a perfectly working salamander but it’s an aquatic salamander.

0:43:46 NS: Oh, yeah. And by the way, it really is full of the critters living in water.

0:43:50 SC: Yeah.

0:43:51 NS: So, and think about that. Here the whole water-land transition happens in one animal through the course of its life.

0:43:55 SC: Yes, that’s an easy [0:43:56] ____.

0:43:56 NS: That’s why development’s interesting, right? And here I go study fossils and look at this guy. So, but that’s really amazing because then the hunt is on. Well, what kind of changes to development can bring about the evolutionary changes we see?

0:44:09 SC: Yeah.

0:44:09 NS: And again, it’s these changes of timing, developmental events, it’s now we know it’s a lot of molecular changes and how genes are controlled, turned on and off during development. That’s been such a powerful and powerfully important tradition in my field of biology, this relationship between development and evolution. It’s its own sub-field now.

0:44:30 SC: Yeah, but you’ve already now mentioned something that is crucial to this story. As good as the 19th century was about figuring out all sorts of weird things about animals, these days, we have information about DNA and genes that is really changing the whole way we think about the story.

0:44:48 NS: That’s correct, and so the predicate for all this were people like Duméril, who were studying the embryos, who were studying the bodies. But the game changer for us is really the advent of molecular biology and its power to explain. And it gives us a whole new set of tools to approach these classic questions. And some of the biggest discoveries started… Well, again, they have predicates as well. But the 1980s and 1990s were quite a remarkable time where molecular tools were getting powerful enough and cheap enough and could be applied to a number of different species that we began to see the relationships between genes and development in the embryo. How genes control that development and how changes to genes can bring about changes to development and ultimately changes to evolution. So that has been incredibly important and incredibly powerful. And some of those initial discoveries were game changers for me in my own growth as a scientist. I had trained to be a paleontologist, and I was studying how to find fossils, the techniques that led to the discovery of Tiktaalik, right?

0:45:57 NS: But I remember back in the ’80s, there were a bunch of papers that were being published, and I was made aware of them by a fellow graduate student, and showing that we were seeing in flies, genes that build the bodies of these animals. Genes that control why a wing is in one part of the body and an antenna is in another part of the body. And that was exciting enough. But what was even more exciting was later papers showing that these genes aren’t present only in flies, but versions of these same genes are present in salamanders, frogs, worms, mice and people. That there’s a common toolkit. Versions of the same genes are doing similar things in many different creatures. And for me, that was glimmers of a new biology, and for a lot of people it was glimmers of a new biology in the ’80s. And so that’s when I decided to add the molecular biology toolkit to my own repertoire as a scientist.

0:46:54 SC: And we don’t think that that’s convergent evolution, we think this is just a set of genes that have been with us a long time.

0:47:00 NS: Oh, my gosh, yeah. These are ancient genes. And these ancient genes aren’t the same, but they evolved in the distant past of animal life. And then there have been rounds of where these genes have been duplicated, modified, repurposed; just like structures, genes are repurposed. So there’s rules we see for the evolution of anatomy, they apply very well to the tinkering, the re-purposing, the co-option, the duplication. All these things that we see in the evolution of structures, they happen at the level of genes. So these genes are ancient, but they’ve also witnessed a lot of changes. Flies have only one set of these genes. We have four. So, they’ve duplicated over time. They’ve gained new functions and more complexity over time, that kind of thing.

0:47:40 SC: I’m sure that the ’80s and ’90s were great, but I don’t want to skip over all the really charming early technologies that were there for thinking and measuring genes and their differences and so forth. Yeah, I guess I’ll let you pick your favorite stories from the book. But the idea of putting little molecules in a gel and pulling them across with an electromagnetic field to see how heavy they were. ‘Cause I think that these days we’re spoiled, and people probably think, “Well, just look at the DNA and figure out what it says.” But they didn’t have that ability back then in the ’50s, let’s say.

0:48:13 NS: No. One of my favorite stories is Sumo Ono. Ono was a researcher at the City of Hope, California, and he was interested in genetics, hugely interested in genetics. And ’cause he loved horses, and he found he couldn’t train… That there’s only so much you can train horses. He said if a horse is no good, it’s no good. It’s all about the genes. So because of that love of horses and his knowledge of them, he decided to study genes. And so he designed one the greatest techniques. So he looked at chromosomes, right? Chromosomes sit in the nucleus, and chromosomes are bundles of DNA. And he wanted to see, can he characterize differences among species by looking at differences of their chromosomes? This is in the ’40s and ’50s, and he didn’t have much technology at his fingertips. What he had was a microscope, and he had a camera, and he could develop pictures with that camera.

0:49:13 NS: So what he did was he took pictures of different species. He took salamanders, he took rhinos, he took people, he would just get cells, right? Cell samples from zoos and he would look at the nuclei, and look at the chromosomes in the nuclei. So he’d take pictures of all these things. And what he did was lowest technology possible, he took pictures of the chromosomes, printed out the pictures, cut them out and weighed them. So he would basically take pictures of the chromosomes of a salamander, cut them out and weigh them, and then take pictures of the chromosomes of a human, cut them out and weigh them. And he used those weights as proxy for the amount of DNA in the cell. Okay?

0:49:55 SC: Better make sure the zoom was the same in both pictures, right?

0:50:00 NS: Yeah, [chuckle] well, what he found was that the salamanders have 10 times more genes, chromosomal stuff, than humans. And he was one of the first persons using this low-tech technique to show that the amount of genetic material in the nucleus, and what we know now is the amount of DNA in the genome, is unrelated to the complexity of the organism.

0:50:22 SC: Yeah, I was going to say, that’s not possible because aren’t we way more superior to these little salamanders? How come they have so much more genetic? [laughter]

0:50:29 NS: Well, I don’t know about superior, they could flip their tongue in a millisecond, some of these things. So that’s pretty superior. Depends how you measure it. But yeah, we’re much more complicated in a lot of ways, cognitively and so forth. And yeah, he found that that’s unrelated to the amount of genetic material in the cell. So he was one of the first people to show that the amount of genetic material in a cell is unrelated to a critter’s complexity. He looked at plants like lilies, they have an enormous amount of that. Yeah, so that was a huge surprise.

0:50:54 NS: And then he was able to look at those chromosomes, because you can add dye to the nucleus, and you could begin to see the chromosomes with little stripes on them. He began to see when he looked in detail at the stripes. It looked like whole sections of stripes were just repeated and duplicated. Like somebody took a Xerox machine to the chromosome of a salamander and just duplicated whole chunks of it. So he came up with a notion of, with all this low technology stuff, that the idea was that perhaps one of the major sources of innovation for new genetic material in evolution is gene duplication, is duplicating old genes. So that’s a great way of co-opting and repurposing. And so that turns out to be a very profound discovery, ’cause the more we look at gene sequences we can now sequence genes in an afternoon.

0:51:45 NS: We begin to see just how important that is that there are whole gene families which might contain hundreds of genes all related to each other by history, rounds of duplication in their history. We see that in tissue over and over again. I just love that story, because here’s a person who had a great idea, found a very low-tech way to test it and opened up a whole new field of research.

0:52:09 SC: Yeah. No, it gives hope for the ingenuity of scientists and interesting to speculate about how we’ll be equally ingenious in the years to come.

0:52:20 NS: One hopes.

0:52:21 SC: But, good. So let’s get down to brass tacks about the genes and how they work. So we assume we know the basic story, but an important part of the story that you tell in Some Assembly Required is that of course we have genes… That is to say, we have segments of our DNA, the code for proteins and then the proteins go and do useful things in our body. But then there’s other parts of the DNA that are regulating when the genes are switched on and switched off and there’s also junk DNA. How does all that fit together and how does it play into the story of major transitions?

0:52:56 NS: Yeah, okay. Just to set the stage. DNA sits in the nucleus of all of our cells. And in each cell there’s about six feet… So if you have a strand of DNA, if you would unwind it, it’s about six feet long, sitting inside the nucleus. It’s packed super tightly. Think about that. We have about four trillion cells. If you put all our DNA end-to-end, of all our cells, stretched it out and laid end-to-end, it would go almost to Pluto. Think about just how much genetic material is in our bodies and how tightly packed it is in each cell. It’s kind of mind-blowing. Now, when we think of DNA, the DNA is a sequence of bases, so it’s a gene sequence, sits in a double helix and it’s packed really tightly.

0:53:40 NS: There’s a part of the DNA that contains the information to make a protein. That’s the protein coding part. But there’s a whole other parts of this that does other things, some of which we’re still grappling with. But to give you a little perspective, the gene part of our genome, that part that makes proteins, is only 2% of our genome. [chuckle] Genes only make up about 2% of our genome so the protein coding part, the part that contains the information to make the proteins is just a tiny fraction of the genome. The rest of it kinda controls the activity of those things.

0:54:19 SC: Is that completely true or it is also true that some of it is just kind of wasted space?

0:54:25 NS: It could be. Yeah, it could be wasted space or it could be space we don’t know its function yet. See, a lot of the activity of DNA is related to its dynamism, how it opens and closes, forms loops in on itself. And so those space or regions could have lots of importance in terms of the overall geometry of the DNA, but the individual sequence might not matter as much. Who knows?

0:54:45 SC: Okay. That’s interesting.

0:54:46 NS: But there’s still a bit of a mystery, still quite a mystery for us and, boy, there’s a lot of ink spilled on debates around that, too.

0:54:53 SC: Yeah.

0:54:55 NS: You think about it this way. If you take… The cells in our body pretty much all have the same DNA inside them. What’s different is they’re making different proteins, so the cells in the retina of our eye, compared to the cells in the skin of our fingertip, they have the same DNA inside them, but the DNA in the retina cells is making proteins that builds and keeps a retina functioning. The cells inside the tip of our finger have the same DNA, but the genes that are active are the ones making the skin tissues. The proteins that give skin tissue its properties. So what’s different here is which genes are turned on and off in each kind of cell, in each kind of tissue. So it’s not the DNA per se that’s utterly different, it’s what’s controlling their activity.

0:55:43 NS: People have really since the, I’d say, the mid-late ’80s, really focused on that. What are these genetic switches, what controls whether a gene is turned on and off? And once we know that, is that a big player in evolutionary change? And it turns out yes, yes and yes. Understanding these switches is so important not only to understand what makes issues different in health and disease, but also to understand evolution, to say, well, it’s not like you have a new protein coding gene, it’s you have the same gene, it’s just you’re turning it on and off in different places and different times in development. So it all comes back to development and what these genes are doing in development. And if you’re turning on genes and turning them off in different times and places, you can make really big changes.

0:56:28 SC: Is it possible to explain to us at the molecular biology level how the information encoded in one set of the DNA actually does turn on and off the other sets of DNA?

0:56:43 NS: Yeah. So you have the protein coding gene and lying next to it is usually a little sequence that when something attaches to that sequence, some very important things attach to that sequence, it’ll turn the gene on or turn it off depending on what the nature of that little section is. So it all comes down to molecular keys that come in. So basically, one part of the genome might fold over to touch that switch and if it does that, it activates the gene. There are lots of little triggers that would control these things. But you have to think about this as a very dynamic chemical landscape where proteins and other factors are being made.

0:57:26 NS: And as they do that, they’re attaching to these different switch sequences in the genome, which then control the activity of the gene. It’s three-dimensional structure. You have the genome opening and closing. So when the genome is closed, it’s not making proteins, so it’ll open up in areas where proteins are made. So first it has to open up. So there’s that dynamism at the level of the genome. Then certain sections have to come in and touch these switches, actually connect to them to activate the genes. So there’s a whole Rube Goldberg kind of set of activities that have to happen for a gene to turn on.

0:57:43 SC: Does the three-dimensional structure differ from one kind of cell to the other?

0:57:43 NS: It can, yeah, very much so. In fact, that’s a very active field of research right now in molecular biology is understanding these three-dimensional changes. It’s really gotten very big is, is now we can see the genome. We could begin to map it, we begin to see it at work and what surprises everybody is just how utterly dynamic it is and how very important this three-dimensional structure really is.

0:58:31 NS: And there’s lots of mysteries here. We know there’s a lot we don’t understand ’cause it’s filled with puzzles. But one thing we do understand is just how these changes can affect evolution and that is pretty clear, that is if you change a switch, you’re going to change the ability to make a new… You’ll be able to make some new things in evolution, a new tissue, a new protein and so forth.

0:58:52 SC: And that fits in with the connection with development, because obviously development is all about deciding which kind of cell I’m going to be, and where I’m going to fit in and therefore, what kind of, what parts of my DNA are going to be useful.

0:59:04 NS: That’s right, and it’s basically if you think about the genome of an organism, it’s basically forming a recipe for a development. You’re changing the ingredients, you can change the genes, you can change the process, which is these switches. And what you do is subtle changes to these things. And then the embryo can have large consequences to anatomy, to evolutionary history, just like we saw with salamanders. And so what we can now do is look at that at the genetic level.

0:59:31 SC: So does this help explain some features of major transitions? Does it make it easier to understand how major transitions can happen once we understand this picture of certain coding areas of the DNA and other regulatory or expressive regions of the DNA?

0:59:48 NS: Oh, very much so. It can show, for instance… And it’s kind of getting back to one of the themes we talked about earlier with the fossil record, is that you really don’t have to often invent whole new things to have great transitions happen. A lot of great transitions might not involve as much new genes as it would involve using old genes in new ways, so using genes that exist, but you’re changing when and where they’re active.

1:00:11 NS: So again, it’s like the raw material for these transitions exists before the transitions themselves. You have the genes, you’re just using them in new ways. That’s part of it. There are cases where lots of new genes come about, but using old genes in new ways turns out to be a very profound part of these great transitions. We see that over and over again.

1:00:29 NS: The other thing that is getting renewed attention which is really fascinating and we see this over and over again, we see this in the origin of new biological inventions, but we also see it in the human technological realm, is that one thing that’s very common is multiples, that is, you’ll see the same, I’ll call it evolutionary invention, appear independently in different species at the same time, that is the same solution to a problem appears independently in different creatures that are not directly related to one another. So it means it’s happened separately.

1:01:03 NS: And one of the reasons why that may happen is if organisms, if creatures have the same set of genes functioning in the same ways, it makes similar outcomes more likely, right? So this notion that you could have parallel evolution or independent evolution of the same structure is something that’s gaining renewed intention from the molecular realm. Because if organisms have similar genes and they’re using those genes in similar ways, then they might produce the same kinds of mutations independently, that natural selection can work on. So it’s not random.

1:01:33 SC: Because they’re building on some sort of common starting point. They’re not just, like you say, not just randomly choosing crazy things.

1:01:40 NS: That’s right, if you have a recipe to make cupcakes, there’s only certain ways you can change that recipe and have it still be recognizably cupcakes. So yeah, and you hit upon the same… If different people are making cupcakes with the same recipe and playing with it in different ways, they may come up with the same kind of cupcakes independently.

1:01:57 SC: So this helps explain certain examples of convergent evolution?

1:02:01 NS: It does, very much so. Convergent evolution can happen for lots of reasons. So first is, and a very common reason is common adaptive solution. If creatures are going to fly they’re going to need some sort of wing, right? And you see that over and over again. And you see white color patterns appearing independently in polar animals, that kind of stuff. But the other reason why these sorts of, that pattern may happen is, again, common recipes, common genes. That sort of, common recipes to build bodies, common genes, that sort of thing.

1:02:31 SC: And does it help explain this puzzle that’s always there in evolution? What I think of as the statistical mechanics of mutations, like most mutations are presumably really bad. [chuckle]

1:02:43 NS: Yeah, most are not so good, but doesn’t take many beneficial ones to really take off. So, a beneficial mutation can gain traction very, very readily. But we talk about mutation being random. It’s really not random, right? It’s only random with respect to predicting the future. Just because a creature may need to walk on land in 100 million years, doesn’t mean it’s going to come up with mutations to do that. So it’s not random with respect to the needs of the organism in the future.

1:03:15 NS: But I mean, it’s random with respect to… Excuse me. It’s random with respect to that, but it’s not random with respect to everything else. Certain mutations are more common than others, based on what happens in the genome. Certain mutations are more likely to be beneficial than others, based on what happens in the genome and in development. Yeah, so when we talk about random it has to be very specific about it, it’s random in respect to predicting the future, it’s not random.

1:03:43 SC: Well, you talk in the book about the idea of hopeful monsters and how they kind of got you in trouble as a graduate student, if I read that correctly?

1:03:48 NS: Yeah, it got into trouble with Ernst Mayr in a very big way. Yeah, he really… So I used to have tea, so one of the great gigs of my graduate student life was… I don’t know how this happened. I was not a great graduate student, but Mayr took a shine to me, Ernst Mayr, this great eminence and the new synthesis of evolutionary biology. He was a huge eminence. He was about in his mid-80s at the time, and had a lot of history and he loved history of science and philosophy of science, and he was there during one of the pivotal times in our field. And for some reason took a shine to me.

1:04:18 NS: He used to invite me for Thursday teas up into his office on the fifth floor of the Museum of Comparative Zoology at Harvard and I made the pilgrimage there every Thursday, and I was up in the bird collection, it smelled like mothballs and there was this old creaky floors and Mayr would sit in his chair and just wax about great people in the field. And then he always encouraged me to come with a book, a paper, a question to stimulate it. So I came one day with this book called The Material Basis of Evolution, which was a recent reprint, it had an introduction by Steve Gould that just came out a couple of weeks before, a month before. And I brought it up to Mayr to see what he… “Look at this new thing. What do you think of Gould’s preface?”

1:05:00 NS: And he just turned beet red and shot me this glare like, “Kid, I’m going to eviscerate you.” He went to his filing cabinet, came back with his papers. He says, “I wrote Animal Species and Evolution in response to page 95 of this piece of crap.” And he threw it down at me, this yellow reprint by Goldschmidt, which laid out the theory that you can have major evolutionary transitions in one step in one mutation, so-called macro mutations. Now, I knew Goldschmidt was a bit of a whipping boy at the time. But I wanted to talk to Mayr about what he thought about it, that kind of thing. Oh, boy, yeah, I was just… It was something else. So, Goldschmidt’s idea, the one that got me so in trouble with Mayr… By the way, the teas did continue. I’d think that… Yeah.

1:05:46 SC: It was a famously contentious place, Harvard Evolutionary Biology, right?

1:05:50 NS: Oh, but… I’m sorry?

1:05:52 SC: Harvard Evolutionary Biology seems like a famously contentious place. There were big personalities that…

1:05:56 NS: It was, yeah, at that time, yeah, ’cause you had EO Wilson and Steve Gould at the time, Richard Lewontin, Mayr. Yeah, so I had to navigate that a little bit. Anyway, so I did so pretty much unscathed, anyway, so the idea was that Goldschmidt proposed, he studied development and he studied genes. He said, look, subtle changes in development can yield big effects. So hey, the first bird hatched out of a reptile egg. He said, basically, one mutation. One set of mutations, you got a bird out of a reptile, and that was not well-received, for good reason. There were a lot of reasons why that theory was bound to fail, but it’s reappeared in different ways over the years. But it really is not a very viable theory, that despite the fact that you can find mutations that will do big things to the animals, it just turns out that those big mutations are almost exclusively lethal. It’s really the small mutations that are most likely to be beneficial, so it’s the accumulation of these.

1:06:57 SC: So, sorry, that is the current way of thinking that, in fact, it is the accumulation of tiny things that is much more driving the engine of evolution.

1:07:06 NS: Yeah, but that accumulation can happen pretty quickly and over geological timescales. It does, the geological timescales I deal with are in the millions, hundreds of thousands to millions to tens of millions of years. We’re talking about… Accumulation of these mutations can happen much, much, much faster than that, particularly knowing ways the genome can change.

1:07:26 SC: Well, I was going to ask this about the issue of missing links. When you’ve begun such a transition, there’s no teleology, you’re not aiming for some target, but once you’ve sort of been able to enter a slightly different ecological niche, is it true that then the rate of evolution is faster for species like you than those that are happily in their equilibrium and, therefore, there are fewer records of those in the fossils?

1:07:53 NS: Oh, that’s a interesting point. There are cases where creatures enter a new zone, like ecological zone, and the evolutionary rate takes off, but there are other cases where it’s a delayed fuse where something happens and that diversification, the explosive diversification doesn’t happen till much later, and we really don’t know why that happens. That’s a bit of a puzzle, why you might have that. Yeah, so that’s still very much an open question.

1:08:17 SC: Okay. I always like to give the undergrads and graduate students out there in the audience problems to work on, so that sounds… It’s always good to find the open questions.

1:08:26 NS: Oh, we got lots of those.

1:08:28 SC: Yeah, exactly.

1:08:29 NS: That’s what it makes it fun, definitely.

1:08:30 SC: Well… And so, there’s also… You already mentioned this, I think, very briefly, but let’s link it in back in here now that we’re talking about the transitions at the molecular level, the idea of genes jumping from one animal to another, and being borrowed, like you tell the stories of how viruses, virus genes got embedded in other people’s genes. I think this is something obviously that is not part of the classic story of molecular biology and evolution.

1:08:58 NS: No, it’s amazing. So when you look at a human genome sequence, we have sequenced, we could sequence genomes now pretty quickly, right? When you look at a gene sequence, what you find is, in humans, about almost 10%, about 8% of our genome, of our entire genome are defunct viruses. Viral sequences that no longer function, but they’re there. It’s like a fossil graveyard, a graveyard of ancient viruses that attacked our genome, became part of our genome, but then got knocked out.

1:09:34 SC: Every time I talk to a biologist, it’s very important that they creep out the audience at some point or another, and so…

1:09:39 NS: Oh, that’s my goal here. I mean, my goal is to creep everybody out. And think about it, it gets even creepier still when you think that, okay, only 2% of our genomes are our genes, but 8% are like defunct viruses.

1:09:53 SC: Yeah.

1:09:53 NS: But there’s also something else that’s really amazing about this. So viruses are, as we know, which is very relevant in today’s world, viruses are… We live in a balance with viruses, right? They’re continually infecting us and our internal mechanisms, whether it’s our immune system or our genome, are trying to knock them out, are trying to disable them, but there’s something else that’s happening as well, and this is something that’s pretty new and it begins with… There’s a researcher who I talk about in a book, Jason Shepherd, at the University of Utah, he’s a neurobiologist, he’s not interested in viruses. He’s an MD, though. He studied his microbiology, but he’s interested in memory, and his research in memory led him to a gene called Arc, A-R-C, ’cause Arc is a gene that is involved in memory and people, mutations in that are associated with dementia, schizophrenia. Mutations in Arc and mice mean that they lose their memories. They can do a maze, but the next day, they forget their solution.

1:10:51 NS: And so, he’s studying Arc, that’s his thing, because he cares about neurodegenerative diseases in memory. And he’s studying Arc and he’s studying, when you study a gene, you’re going to study its protein, so he looks at the protein that Arc made, and he pops it under a microscope after some effort. It turns out he saw these spheres, these spherules, and he’s like looking at them thinking, “I’ve seen these spherules before,” in his microbiology class in medical school, the capsules that look like the virus, HIV, the virus that causes AIDS. He says, “Wait a minute, this looks more like a virus than a memory protein.” So, he runs down to the next building to talk to people, AIDS experts. He doesn’t tell them what is on the slides, says, “Identify this for me.” These AIDS experts look at the… The HIV experts look at the slide and they say, “Oh, that’s HIV, the virus,” ’cause they just didn’t… “Nope, its Arc, the memory gene in people,” and they’re like, “What”? Well…

1:11:46 SC: Do not trust biologists bearing gifts.

[chuckle]

1:11:49 NS: Yeah. So what happens is, what Jason Shepherd showed in his lab and some others as well, is that what Arc is, is it’s an ancient virus that invaded a distant ancestor of people. And that virus, instead of being knocked out by the genome, it was domesticated, it was repurposed. It was like, “Sorry. You got a new job. You’re no longer going to infect us. You’re going to make a protein that’s going to be used in memory.” And what’s relevant here is that capsule that is made by HIV and Arc helps the information, the genetic… The capsules made to protect the genetic information of the virus, as it goes from cell to cell, so it makes HIV very effective in going from cell to cell. But that’s exactly what makes the Arc gene effective in making memories, it goes from neuron to neuron. So this virus was put to work, was re-purposed, if you will, by our distant ancestor, the genome of our distant ancestors, just how we don’t know, but it was, to play a role in memory. And we’re finding that in all kinds of other genes too and genes that make the placenta, the proteins that make the placenta, some of those genes were originally viruses that invaded the genome. So it turns out…

1:12:58 SC: It’s all about re-purposing, that’s all evolution ever does.

1:13:01 NS: It’s re-purpose. Yeah, it’s either take something from something else and repurpose it or repurpose your own genome. And, it’s mergers and acquisitions. It’s claiming things as well as your own.

1:13:11 SC: Yeah.

1:13:11 NS: And so it’s a real wild world. But these viruses are not only threats, but they’re sources of genetic information, genetic novelty, they are sources of new genetic stuff that occasionally have made a very big difference in our evolutionary history. And that’s one thing that within the last decade has become, under much clearer focus, and it’s pretty, really remarkable.

1:13:33 SC: And we should probably distinguish, because probably many people have heard the story that you relate in the book about Lynn Margulis and the mitochondria, and so forth. And that’s sort of, we absorbed little tiny organisms and made them part of ourselves. But mitochondria have separate DNA, this, what we’re talking about now is actually sticking segments of virus DNA into our DNA strands, right?

1:13:55 NS: Yeah. So what a virus does right, there are lots of different kinds of viruses and there’s many different ways that this happens, but typically a virus will enter, and then it goes into the genome of its host and then commandeers the genome to make more copies of itself. It’s like the ultimate parasite. It goes in there, makes copies of itself, takes it over, takes over the machinery, makes more copies of itself. And there it goes. So what happens is, sometimes the host can take over the virus, or knock off the virus, but also take it over to do new things. And that’s what we’re seeing in some of these cases. So the viruses can be the source of genetic novelty, right, new stuff as well. Yeah. It’s pretty amazing.

1:14:34 SC: And I don’t know of how much you followed the controversies over at what point do we stop calling this Darwinian evolution? Obviously, Darwin said a lot of true things. And then there is this new synthesis with genetics and so forth. But the idea that we simply do sexual reproduction and some of our DNA base pairs get mutated but otherwise we just hand them on, is way over-simplified. And so at what point do we call it a new theory versus just little tweaks on the old theory?

1:15:08 NS: Yeah, it’s hard to say. So you think about when Darwin did, though. Darwin, The Origin of Species, the first edition was 1859. There was no knowledge of genetics whatsoever.

1:15:18 SC: Yeah.

1:15:19 NS: Okay. We didn’t know anything. Mendel didn’t come till much later, let alone a knowledge of DNA. Yet that theory he proposed, before genetics, didn’t make sense under the kind of inheritance that they thought then.

1:15:33 SC: Yeah.

1:15:33 NS: So, in fact, some of the most trenchant criticisms of Darwin were about that and how and without a… There was no knowledge of genetics, was no knowledge of heredity. It was really hard to think about how these changes can be sustained over time, though he did use artificial selection or artificial breeding experiments as well in his argument. But you know, it’s a good point. We have moved far beyond, but we’re staying very much in the center of Darwin. Natural selection is still the major mechanism of evolution. Common descent is still the major pattern we see in the history of life, albeit with some exceptions where you have information being traded among species. When we talk about Darwin, we’re really talking about not just a body, a theory, but a profound shift.

1:16:18 NS: The Darwinian revolution was a profound shift in the way we see the natural world, how it came about, and our relationship to it. So, when we think about Darwinian biology, I kind of refer to it in those ways, in terms of the fruits of the Darwinian revolution. Yeah, yes, and no, we’re still using some of Darwin’s ideas. One of the main ideas in the book is actually a Darwinian one, the idea of repurposing the idea that structures arise in one form originally, and then they change function later on. But it’s just amazing to me. I read the book. I did a deep dive back into several of the editions of Darwin, different editions in preparation for writing Some Assembly Required. And I was struck by so many things. I was struck by what a great way he was able to marshal evidence, how he used it, what a great writer he was. Not only in producing evidence but some of his prose, it’s just really beautiful. I just would sit there and read it over and over again. It was just amazing stuff. Just what a remarkably talented human being.

1:17:15 SC: Yeah, we’re lucky because of that. Because not all scientists are like that, but he did have the ideas and was able to convey them in an especially compelling poetic way. So that’s nice.

1:17:24 NS: Yeah. So beautiful. It really is and at every level, at the intellectual level as well as the aesthetic one.

1:17:28 SC: Yeah. Alright, so I think that we’re able to get some payoff here. So all of this understanding of genes and expression and regulation and so forth. Tell us how this explains how fish can develop hands?

[laughter]

1:17:42 NS: Well, my lab works on that. And, so you know, in the summer we go out to find fossils. And the rest of the year we’re working on the DNA of extant fish. So, working on mice, people were able to identify a series of genes and regulatory elements, elements that control the activity of those genes that are deeply involved in making wrists and fingers and mice and people and everything that has wrists and fingers. And you can identify those genes, and when, they showed, for instance, that if you, say, make a mouse lacking these genes, the mouse has a humerus, a radius and ulna but no wrist and digits. If you mark the cells that, where these genes are active, they’re in the wrists and the digits. So these genes are wrist and digit genes, they’re necessary for the wrist and digit. Not necessarily sufficient, there are probably other ones as well, but they’re necessary.

1:18:36 NS: So my lab, as well as a bunch of others, have asked the question, are these genes present in fish? The answer is yes, we’ve known that for a while. And if so, are these genes involved in fish fin development? And, again, if so, what are they doing in fish fins? So that’s what we’ve been looking at. Well, it turns out, to make a very long story short, this was a 10-year research program of my lab, longer than Tiktaalik actually, the search for Tiktaalik. That was six years. This was 10.

[laughter]

1:19:06 NS: But the essential idea is that many of the genes that make the wrists and digits of mice and people and birds and so forth, are present in fish. And they’re making a terminal strip of tissue in those fins. And that terminal strip of tissue gives rise to the fin rays, those, the spicules of bone that you see. If you look at a trout, when you look at its fins, it looks clear in the terminal end of the fin with little rays inside their little bony rods. It makes those rods.

1:19:41 NS: And so what’s remarkable here is that there is a common tool kit to make appendages as different as people, mice and fish, fins and limbs, that those genes are there, that they’re active and that in all species, they’re active in making the terminal end of the fin. What’s different is, there’s a switch in fish that turns those cells where those genes are active into fin rays, whereas in us and mice and others, it makes fingers and toes.

1:20:16 NS: So what we’re able to see is that there’s a common history, a genetic history, of limbs and fins, and that the differences among them aren’t as much in entirely new genes, but it’s in using those genes in new ways and modifying their activity in different ways. So there’s a case where molecular biology has given us insights that we might not have had otherwise. ‘Cause if I was just looking at anatomy, I would never compare fingers and toes with the fin rays of fish.

1:20:46 NS: But there’s a clear-cut developmental connection between them. And so now what we’re doing and some other labs are looking at, okay, well, what controls whether you have a finger or a fin ray? What are the molecular controls that control how you make those different kinds of tissues? So as we open the whole thing is it’s, when you have answers, like we had with this research, now we can ask whole new kinds of powerful, more precise questions. So these answers now set us up for a whole new set of experiments which we’re doing now.

1:21:14 SC: And do you go in, is this by going in and zapping some of the genes to kill them off or keep them going longer or, and seeing what kind of organism results?

1:21:24 NS: Yeah. So what we do is, we could take the genes from a mouse and put them in a fish and you can see what they do. We could take the fish genes and put them in a mouse and see what they do in that new environment. It turns out they function very well. I could take a shark gene from the fin and put it in a mouse, some of these genes from a shark and then put them into a mouse. And it does perfectly fine. Likewise, the mouse one in the shark.

1:21:47 NS: So we can make these swaps. We can also knock these genes out. We can use CRISPR-Cas genome editing, go in there and just knock these genes out and delete them. We can add factors as well. So yeah, it’s a real house of horrors here. [laughter] We could do it all. But what it shows is, quite literally, that there is a deep connection among creatures. Nothing is more… I still find it amazing that we could take a fish gene and put it in a mouse and it functions just fine in the limb of a mouse, whereas in a fish, it works in its fin. That, in a nutshell, just shows you just the deep connections among all life on our planet.

1:22:27 SC: Are you a fan of the SyFy channel’s TV show, Sharktopus?

1:22:33 NS: No. I haven’t seen it yet, I’m afraid.

1:22:34 SC: I think that should be your next project in the lab.

1:22:36 NS: I think, I do so. Yeah. I’m surprised they didn’t call me to consult.

1:22:39 SC: Well, we’re at the end of the podcast here. So now, we can let our hair down and speculate a little bit. We’ve learned a lot about how major transitions happen in real evolution. You’re opening, I don’t want to call it Pandora’s box but at least, a whole door onto a new landscape of things where we can make major evolutions in our labs. Is this going to be a frontier over the next hundred years where we’re not just figuring out how evolution happened but designing organisms for human purposes?

1:23:15 NS: It’s already happening. You have people growing organs in dishes, tissue engineering, for clinical purposes as well. We already have people who use computation and a knowledge of evolutionary history to resurrect proteins that were present 400 million years ago and test their activity. No. We can reconstruct ancestors, at least at the biochemical level. We can modify development at the embryological and developmental level, and in the genetic level as well.

1:23:47 NS: And we can begin to mimic certain stages of evolution. Sometimes, that’s helpful. Sometimes, it’s not. But we’re definitely in this brave new world where we can manipulate things as well. The big game changer has been, obviously, genome editing, the CRISPR-Cas gene editing, which applies to so many species. It’s remarkably effective, but it’s also remarkably cheap. So a lot of issues with boredom when you’re in a big lab.

1:24:13 NS: Yeah. And that’s been a huge game changer for us. I have a colleague here in Chicago, Joe Thornton, who’s literally resurrecting ancient proteins to understand how enzymes originally came about. And he uses knowledge of evolutionary history and computation to make predictions about what those proteins looked like. And then he makes them in the lab and tests their activity. And we can tweak genes right now to test, can we make a limb bone in a fish fin? I have a colleague from Harvard who did just that with a mutant he found and showed that fish fins have the ability to make limb-like bones. So really remarkable stuff. It’s definitely a brave new world.

1:24:54 SC: Yeah, so the answer is yes, we will be seeing… It’s just the beginning of all this, and people talk about regulating it and so forth. And my rough feeling is that once you can do something, someone out there is going to do it and so remixing all sorts of organisms and their organs is going to be a major frontier.

1:25:14 NS: I think so. I think what will drive it obviously would be clinical, making new kinds of tissues that can help in regeneration. Regeneration is a big thing, too, being able to re-build organs too, and that’s… People are pushing the limits of that as well.

1:25:29 SC: Well, okay, so for the very last question, let’s return a little bit back to reality. And we talked about how fins can turn into hands and so forth, but the other obvious question is human beings. We’re very similar to other primates, but we do have these big brains. I recently saw a claim, which then I think I saw people arguing against, but the claim was that there are mental capacities, cognitive capacities that chimpanzees are much better at than we human beings, short-term memory kinds of tasks. And the claim was that we have, I don’t want to say intentionally, but we have sacrificed that part of our cognitive capacities in order to develop language and linguistic capacities. Is this kind of trade-off a big part of what turns other primates into we smart and sexy human beings?

1:26:24 NS: [chuckle] I don’t know the answer to that, but trade-offs are a very huge part of human history. There’s trade-offs in terms of the structure of our brain. There’s trade-offs in terms of the structure of our adrenal system, our ability to walk. The trade-offs of just being human are huge, because there are costs to being human. We suffer certain kinds of conditions that are not seen in other creatures. Our ability to talk, for instance, I’m just shifting it from the cognitive piece, ’cause I know less about that, honestly. But our ability to talk comes at a huge trade-off, so it wouldn’t surprise me that cognitive issues do as well. So for instance, we are the only animals that suffer a particular kind of dangerous sleep apnea, and the reason for that is we have a very flexible back of our throat and a set of neural circuits that play a huge role in our ability to make sounds. So our ability to make sounds for language comes at a giant cost, because it sets us up for certain kinds of sleep apnea, which can be quite dangerous.

1:27:25 NS: But that’s true for almost every part of the human, the human body, whether it’s our walking on two legs, whether it’s having huge brains that consume an enormous amount of energy, whether it’s having cognitive capacities to make language that are trade-offs from other kinds of cognitive capacities which we might have had. Trade-offs are a part of being an extreme organism like we are, we’re highly optimized in certain ways, and that optimization comes at a cost because of the inherent nature of trade-offs.

1:27:52 SC: I guess I already said this is last question so I lied, but I just had a podcast with Martin Rees, where we talked a little bit about the prospects for post-humanity and how in different environments and so forth, we might evolve in different ways, like people living on Mars might have different skeletal structures or something like that. Is it completely crazy for an evolutionary biologist to look at human beings and say, well, here are things we could improve, here are things that we could intentionally change that would make us better, like get rid of backaches or something like that?

1:28:27 NS: Oh, yeah, definitely. In fact, our relationship to the microbial world we can change. When you think about, we’re just beginning to come to grips with our relationship to the microbial world, and that relationship can sometimes hurt us, but most of the time it’s essential for our lives, and that’s something that as we look forward, that’s something that is going to be incredibly important to think about. But no, you can look at any part of our body and then say, well, jeez, that’s something that needs to change going forward. But a lot depends on the operative environment that we find ourselves living in.

1:29:02 NS: So the environment today, yeah, you could say certainly that there are certain aspects of our bodies, that in this modern environment, that we’re kind of disconnected from. We have an evolutionary history in one environment, yet many of us are living in built environments now that are very different. And we have a sedentary lifestyle. So our whole metabolism is sort of ill-equipped to… We evolved from highly active ancestors, and most of us are relatively sedentary.

1:29:33 SC: Less active. [chuckle]

1:29:35 NS: You are, when you think about the leading causes of death, cardiovascular disease, cancers, and so forth, these are all parts of the trade-off of being human and living in our modern world, right? And so I could think of a whole host of things that would need to change. We are susceptible of all kinds of cancers that are a product of living in our modern world and a product of living after 50. And so, yeah, I could give you a list of many things to change based on where we’re living now, and I can give you even a longer list if you’re telling me we’re going to be living in bases on Mars or terraforming somewhere or whatever.

1:30:10 SC: Well, good, it’s good to know that we’re members of the last generation of purely organic human beings.

[chuckle]

1:30:16 NS: One part iPhone, actually. I’m actually merged with the device.

1:30:19 SC: Well, we were born organic. We’ve deteriorated over time. Alright, Neil Shubin, thanks, that was a fascinating conversation. Thanks for being on the podcast.

1:30:29 NS: Thanks for having me, appreciate it.

[music]