Particles of Thought

SEAN: Loss is really common when we look through evolution. I mean, look at things, the creatures that are kind of marked by loss. One of my favorite groups are snakes, right?

HAKEEM: Oh, no legs.

SEAN: Where are those legs, right? Well, they became burrowing creatures, a whole lifestyle. So they evolved from lizards. So they evolved from four-legged animals, but you have this whole group of animals, they just ditched their legs, right? Ditched their ears too.

HAKEEM: Oh, geez.

SEAN: Yeah, no ears on snakes either, right?

HAKEEM: Right.

SEAN: So yeah, loss is pretty common. At the same time-

HAKEEM: So snake are pretty efficient.

SEAN: Snakes are pretty efficient.

HAKEEM: They just reduced themselves to a tube with muscles.

SEAN: To a tube, they're a tube, yes, with great muscles. But they've been doing a lot of inventing venomous snakes.

HAKEEM: Venom, yeah.

SEAN: Venomous snakes have been incredibly creative in the last 30 or 40 million years, inventing all sorts of venom toxins to take down their prey, and that's another example we see throughout the animal kingdom. Independent examples, you know about spider venom, you know about bee venom, you know about scorpion venom, you know about venomous jellyfish and stuff, all independent inventions of venom.

HAKEEM: Wow.

SEAN: So these are new molecules that get invented. Invention's gone on a time, but that helps those animals get their supper, and that's a really powerful force in evolution. If you have a way to get your prey, you have a way to get food, this is like evolution almost in fast-forward.

HAKEEM: So language for humans is like venom for the other animals, right? Because we can cooperate and hunt these [inaudible]

SEAN: In our culture today, language is very much like venom. Yeah, I think you're making that analogy. But yeah, venom is a special power that these animals have, and it's vital to essentially their daily being. Language is something we came up with, walking on two legs and language, pretty big inventions, you bet, and vocalization to make that language.

HAKEEM: So let's dig a little bit deeper into these transitions. So we have the transition of vertebrates going from sea to land. So sometimes I come up with a crazy idea, it makes sense to me, and then I look it up later. So my crazy idea I came up with was, hey, we have a tube that goes from our mouth to our butt. We're all worms. We just evolve this extra stuff around the tube. But then I went and looked where did vertebrates come from, and the story was something about some filter feeder that decided not to become a adult, and in this larval stage, it was like a little tadpole, and it became the first chornate that eventually became something like a lamprey and then a backbone and then onto land. It's an amazing story.

SEAN: It is an amazing story. Yeah, those early stages of backbone creatures, a little harder to trace. Again, it's how good is the fossil record. As we get a little bit later, the fossils are great. The fish record and then the fish to transition to land record, thanks to some brave paleontologists out there who've gone to the far corners of the world, we have a lot richer fossil record now than we did just say 25 or 30 years ago.

HAKEEM: Really?

SEAN: Yeah. Oh yeah, oh yeah. No, we see this in much better detail than we had.

HAKEEM: Wow.

SEAN: Yeah. So I think probably the breakthrough fossil was something called Tiktaalik discovered by Neil Shubin.

HAKEEM: Wait, TikTok.

SEAN: Tiktaalik, Tiktaalik. No, no, it had nothing to do with the social media app. It has to do with Inuit language. It was out of honor to the Inuits it was named Tiktaalik. This was a fossil discovered in the Arctic that is just... if you had to draw a transitional fossil between fish and four-legged animal, this is it, right?

HAKEEM: Wow.

SEAN: This is what you essentially dream up, and it's sort of a composite, or if you have... we call them fish and tetrapods, four-legged animals, tetrapods, you could say Tiktaalik is a fishapod. Before I go into the detail, let me just give you the significance of this, the big picture significance. When Darwin wrote the Origin of Species, he knew that his theory had a lot of predictions, and one of those predictions was that there should be intermediate creatures out there between the great groups of animals. But he didn't have any. I mean, he was essentially staking his theory, and he in his book he admitted, he said, "If these aren't found, my theory would be crushed."

HAKEEM: Well, that's great science. He presented his old falsifiable prediction.

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

HAKEEM: That's so good, yeah.

SEAN: Now, amazingly, two years after the Origin of Species, somebody found this creature out of a quarry in Germany called Archaeopteryx, you may have heard about, which had reptile characteristics and bird characteristics. It was a beautiful fit for Darwin's theory. It was 150 years, almost 150 years later, that Neil Shubin and his colleagues, after a lot of searching, find this creature in the Arctic that has transitional features. Its eyes are more on the top of its head as though it's kind of looking up as opposed to looking side to side a little bit, but there's changes taking place in its limbs. And so to come to land, the fish lifestyle has to change quite a great deal. It needs those limbs to bear the weight of the animal because it's up on all fours as opposed to floating in water, those articulated digits as opposed to just a flipper that you could imagine is clumsy. If we look at things like seals on land, they don't look that agile, right?

HAKEEM: Right, right, yeah.

SEAN: Okay. Right? If you have a much more mobile paw-

HAKEEM: So it had digits?

SEAN: Yeah, it had the skeletal makings of the digits. That's what we see in Tiktaalik because it's a transitional creature. It's not a full-fledged walking around tetrapod, but it's heading in that direction. That's what we can see about it. It has a neck that can move relative.

HAKEEM: Oh, fish don't have necks.

SEAN: No.

HAKEEM: Yeah.

SEAN: It's got a neck. How about that, right?

HAKEEM: Wow.

SEAN: So those are sort of the giveaways of it's definitely not a fish, it's not a full-fledged walking four-legged animal, but you can see it heading that direction. That's why it's such a remarkable... what we call these transitional fossils because it's really marking a big transition between two groups. We're not talking about between two species. We're talking about fish to four-legged animals, one of the big transitions.

HAKEEM: Right, right, right. If I could just insert here, when people criticize evolution, they want to disbelieve it, they will point out, they say, "Oh, we see microevolution, yes, but not microevolution." So what you're describing is what they would describe as macroevolution, evidence of macroevolution.

SEAN: Yeah, you're seeing the big transitions between the big groups, the big classifications, the big categories, in this case of animals, you're seeing these transitional forms. So I'm just describing you the features of this creature that sort of tell you a little bit about its lifestyle and how's it different from a fish and how's it different from a four-legged animal. But the evolutionary process is also what's going on. How do you change your body? How does the body evolve? Now this is a really interesting area. Again, 50 years ago, couldn't have said much, and that's because the process of development, the process of making an individual from an egg to a complete individual was a black box. I mean, we could watch it maybe under a microscope, watch a frog egg develop or something like that, but we were just spectators. We were just seeing-

HAKEEM: So you're talking about at the process of egg, the embryo?

SEAN: Yes, all the way to animal, all the way to whether it's juvenile or adult animal. That process, we could watch it with-

HAKEEM: I guess what I'm getting at with that question is is all of this baked in at those very earliest stages? Because we talk about how humans have gills in the womb when we first start and this sort of thing, but ultimately we become a full-fledged human at some point.

SEAN: That's right. That's right. So that developmental process, let's just take a second to appreciate this because it's almost like it's an everyday process going on around us. You mentioned frog eggs, you see a frog egg in the pond, that's about to be one of the most spectacular pageants that exists on earth. The making of a complete individual from a single-celled egg is remarkable. I've watched it millions of times, never bored me once.

HAKEEM: Still remarkable.

SEAN: Still remarkable, and of course, anyone who's gone through having children and you sort of imagine all those stages, and if you're watching the ultrasound, you're like, "Oh my gosh, look at this whole being that's coming together that's going to be this remarkable thing." So I think if we just appreciate that and we say this has got to be also one of the most complex things we can imagine, yet it's everyday. Whether it's a tree from an acorn or whether it's an elephant from an egg, every day this is happening on earth is this process of development. We really didn't have much insight into it until, I'm going to say about beginning about 40 years ago we were able to start to understand what was going on, what were the chemical changes taking place in an egg that would start to shape tissues, organs form, and start to say, "Okay, here comes the creature."

This was a huge revolution in biology to understand development. Why is development important from an evolutionary point of view? Because it's changes in development that give you different kinds of creatures. That's the process. If you're going to make a creature with a longer neck or shorter limbs or whatever, that's all going to happen in that process of development. So the actual process that's being tweaked with in evolution is the process of development. So if you want to understand how evolution works, you got to know how development works. That's a decision actually I made as a young biologist. I said, "Okay, I want to know how evolution works," I became a developmental biologist first. I wanted to understand the embryonic development process, and by understanding that what that meant was what are all, for example, all the genetic ingredients, what's necessary to make a complete creature for it to all go right.

As I said, you see the smile on my face because it is spectacular. It's amazing. I think a lot of people who wrestle with evolution, they're like... it seems hard, it's hard to imagine how you get from a fish to an amphibian or something like that. Well, let me tell you, it's hard to imagine how you get from a single-celled egg to an adult human with 37 trillion cells.

HAKEEM: Right, yeah.

SEAN: Okay?

HAKEEM: I mean, we basically start off as liquids.

SEAN: Yes, exactly. But we can see it, and this is the thing, we can see it with our own eyes, and we just can't see evolution with our own eyes. It happened in the past, it's buried in the rocks, et cetera, et cetera. It's kind of hard for us. It's an incredible amount of time.

HAKEEM: Exactly.

SEAN: But whether it's a day, a week, a month, or nine months, we can watch development of creatures, and now we can go in there and we can tinker with it, we can understand how exactly this thing unfolds. That's a remarkable set of insights that's [inaudible]

HAKEEM: How do you do that in the lab? Do you have certain species that... like how to use mice quite often?

SEAN: Yeah. We have to give credit where credit is due, and the big catalyst for understanding development is the fruit fly.

HAKEEM: It's always the fruit fly in the mouth.

SEAN: The fruit fly, yeah. Well, let me tell you, the fruit fly baby paid my mortgage, okay? So that's why we got to give credit where credit's due. A fruit fly, the advantage of the fruit fly, very short life cycle, just a couple weeks or so, you can keep a lot of them in a small amount of space, and they're cheap to keep, but they are complex animals. So you have a little tiny animal like that. It builds all these kind of tissues. It's got wings, it's got limbs, it's got a little heart, it's got a brain, it's got eyes. So we can watch the development of these creatures and we can change what's happening in development.

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

SEAN: Egg, larva, pupa, adult, yeah.

HAKEEM: So are you scanning the larva and looking at the insides?

SEAN: Sure, we can put all those stages under microscopes and see what's happening. But what gave us power was genetic approach to it. So what a genetic approach is, we deliberately induced mutations in fruit flies and started studying the interesting flies that would come out. So something like one of the most famous fruit flies was fruit flies that instead of antenna have legs on their head.

HAKEEM: Oh geez. That doesn't sound very useful.

SEAN: No, but it's a laboratory mutant, except for it was incredibly useful as a laboratory mutant because those are fully formed legs in the place of antenna. You start thinking, "How do you put legs in the place of antenna?" And then you map where those mutations are and it goes to a single gene, and that gene turns out to be a gene that orchestrates a big part of development.

HAKEEM: So let's talk process. Is it the case you blindly make a genetic change, you see what the outcome is, and then you go back and look at the genome?

SEAN: Bingo. Exactly. And you're picking those flies that are interesting, right? You're saying, "Well, maybe I have a fly that changes eye color." I go map where that happened. But in this case, I take a fly that has legs on the top of his head and I say, "What happened?"

HAKEEM: So let me ask you a question there. So in astronomy, which I know a lot more about, one of the ways that you discover exploding stars and moving objects like asteroids is you do an image subtraction and everything that remained the same disappears and the only thing that remains is what changed. Is it like that with DNA?

SEAN: Logically, it's very similar to that. To a geneticist, it will map the mutation because it can figure out where in the genome the changes happened, and you can do that at sort of a low level of resolution, sort of chromosomal level and say, "I think it's in this part of the chromosome." Now with DNA sequencing tools, we can just sequence the animal and go, "There it is right there. That's the change." The parent didn't have it, this has [inaudible]

HAKEEM: Wait, that's easy for you to say, man. When I look at images of these DNA sequences, I just see like barcodes, I just see dots.

SEAN: Yeah. Well, we need help with computers to sift through all that DNA. But yeah, we can now pinpoint mutations just sequencing DNA. If you take an animal that doesn't have the change, that has antenna in the right place, and the animal that has the legs on top of its head, you can see the difference. Couldn't do it in 1983 when I got into the game.

HAKEEM: Got it.

SEAN: Didn't have those tools. We've got those tools now. So it was a longer march to discovery in those days. But those discoveries were really important is it taught us that there was a small subset of genes. So the fruit fly has maybe 14,000 genes, something like that. There was a small subset of genes that kind of orchestrated development, had a really outsized impact on development, and if you messed up one those genes, weird things happen, like there were genes that you'd wind up with half the number of segments. So if you've looked at insects, you've also looked at a lobster on a plate, whatever it is, it's segmented, right? It's got some segments of the thorax, it's got segments in its abdomen. So there are genes that in the fruit fly, you mess them up it comes up with half the number of segments. Or there are genes you mess them up, it has no eyes.

HAKEEM: Oh wow.

SEAN: So you got an eyeless fly, an adult fly with no eyes. Well, why was that helpful? Well, we map the gene for eyeless, it tells us the gene that's necessary to make an eye. And then this is a different trajectory this conversation's going to go on. And then you know what blew our minds? Humans have that same gene, and when you mutate in humans we don't have eyes.

HAKEEM: That's what I was going to ask. Does it translate to other species?

SEAN: Yeah. No one expected that.

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

SEAN: That's right. Exactly. That's the correct inference, and that blew... no one expected that. You think of a fruit fly anatomy, human anatomy. Look, I had a PhD. I was going off to do this work, and my mentor said, "You work on fruit flies, you're walking off the edge of the earth because nothing you're going to find has anything to do with making furry animals like us." That was the bias that existed across the world. And then a little small group of people studying fruit flies like, "Hey, look at this gene. Hey, look, you got it too, we got it too. Oh my gosh. Mess that up, we don't have eyes either."

HAKEEM: So what about limbs? So like the legs on the head, so fish have fins, arthropods have limbs. So they have some common ancestor for which the limb gene exists that you could manipulate?

SEAN: Exactly. Actually shown in my lab.

HAKEEM: No way.

SEAN: That common limb bearing... yeah.

HAKEEM: I came too late to get authorship or acknowledgment.

SEAN: Yeah, 1997. If you got to my lab in '96, you would've done it. Again, surprised us because the dogma at the time was these limbs were all independently invented, right? Because a fly walking leg is a hollow structure it's walking around on, and our limbs are got a bone in the center and all that kind of stuff. But essentially as appendages that stick out from the main body, those instructions go all the way back 500 million years, and these are just unfolding differently in you and I from a fruit fly. So the fruit fly was a passport to the whole animal kingdom.

HAKEEM: Wow.

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

HAKEEM: It paid off.

SEAN: But it also, besides now allowing us to study development in all sorts of creatures, it allowed us to study evolution because then we find these body-building and body-patterning genes. Again, it's a small subset of genes that are sort of devoted to that. A lot of genes, they just kind of run the physiology of normal cells. But there are genes devoted to sort of sculpting the body. They affect the number, the size, the shape, the color of body parts, and that's the stuff that's really interesting in evolution. So then we started studying things that look different, either insects versus other kinds of arthropods or maybe just butterflies versus fruit flies, how do you get spotted wings and things like this, and then we're starting to figure out, oh, how do you make something new. The general rule, I'll just give you the breakthrough, the general rule is that basically you take old genes and you use them in new ways.

HAKEEM: Okay. Okay.

SEAN: Isn't that a simple statement?

HAKEEM: That's a very... no new creation necessary.

SEAN: God, if I had known that I could have gone on Wall Street and skipped my whole career in biology. But it turns out it was a much better journey. Yeah, and this is also telling us why these genes have been preserved for hundreds and hundreds of millions of years is they get used in new ways in different creatures.

HAKEEM: Speaking of which, we mentioned how we found this evidence of Neanderthal DNA in humans and Denisovan DNA in humans, but we have even more viral DNA in ourselves, right? So is that a result of viral infections happening in the animal across its evolution or was it all early?

SEAN: Oh, no, no, it keeps happening. Yeah, yeah, yeah, yeah, yeah, yeah. So we will see these vestiges essentially of viruses spreading through DNA. We see this in all sorts of lines of evolution, and it can happen anew all over.

HAKEEM: Well, it first came to my attention when there was a recent mention of a discovery that the sheath of our nerves which allows fast, long-range nerve signal transmission was inherited from a virus. So talking about... I don't see how a virus needs that.

SEAN: Yeah, yeah. But we hijacked that genetic information and repurposed it in a new way, and this is what I mean, this sort of repurposing, this sort of co-option. So we might take animal body-building genes and use them in a new way, and that's in fact how a butterfly put spots on its wings. Have you've seen beetles with really big horns?

HAKEEM: Yes, yeah, yeah, horned beetles

SEAN: Okay, they've taken limb-building genes and they're activating them on their head and making these appendage-like things on their horns as examples. But we also, we hijacked that viral material and we use it for... it's just material to be used and reused.

HAKEEM: What about spots and stripes, stripes and spots? What was that originally?

SEAN: Well, spots, the spot-making program in a butterfly actually uses a little bit of the limb-building program, but it turns it on really late. So if you're just building, if you've got the embryo and it's just really an insect embryo, they often would look like little mini-footballs, like a little bit of an oval without any shape or form, no specific tissues, whatever. When you activate the limb program then, you build limbs and you build the basic limbs of that body. But days and weeks later when you have the pupa and you've already made limbs, you've already made the wing, turn that limb-building program on in the wing, connect it to the pigmentation program, so you make a new connection, and you build a pattern of spots.

HAKEEM: That's a whole new realm you just introduced into this conversation. It's not just turning genes on and off. Now you can connect them.

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

HAKEEM: Wow.

SEAN: So you could take the same... I'll just give you this thought experiment. Take 14,000 genes and I think I can build a fruit fly, a lobster, a crab, a dragonfly, and a butterfly out of those same 14,000 genes. I don't need any new genes. All I have to do is just keep change their wiring.

HAKEEM: What?

SEAN: That's the big discovery. That's the big discovery. Yeah.

HAKEEM: Holy cow.

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

HAKEEM: So the genes are like Lego bricks.

SEAN: That's right.

HAKEEM: You can build different animals with those.

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

HAKEEM: Wow.

SEAN: Yeah, yeah, yeah. And then we see that that toolkit, those Lego blocks-

HAKEEM: You just gave me a lot of homework. I've got a lot of thinking to do now.

SEAN: All right. Well, good.

HAKEEM: That is pretty awesome.

SEAN: But hopefully it's a little anchored, it's a little anchored. But then you say, "Okay-"

HAKEEM: Well, I need to know more.

SEAN: "... that toolkit's been preserved through 500 million years." We've got it. Earthworms have it. Elephants have it. Sea urchins have it.

HAKEEM: That same 14,000 set?

SEAN: Well, they've got the same, yeah, the number varies. We've probably got 20,000.

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

SEAN: Yeah. So there's a core body-building set. There's a core kind of physiology set that just has to... to run cellular metabolism, that's probably, I don't know, I'm going to say 5, 6,000 genes just to do what every cell needs to do. In us, a couple thousand body-building and body-patterning genes, and then the rest maybe... we have genes for immunity, big number of genes involved in immunity, adaptive immunity to deal with infections. So there are inventions that have come along. Our immune system is far more sophisticated than what you find in animals without backbones, for example. A lot of mammals I said are good at smelling, so are insects. They got a lot of the same smell receptors and stuff like that. So you see expansions and contractions in some of these capabilities as lifestyles change, but there's sort of a core body-building and a core set of cell physiology genes that you'll just find across the whole animal kingdom.

HAKEEM: Hey, everyone, if you're loving this podcast, please go ahead and like us or leave a comment and also make sure to subscribe so you never miss an episode. Your support means everything and helps us reach more curious minds like yours. Now back to the show.

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

SEAN: Oh yeah.

HAKEEM: Sounds like a European band or something, right?

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

HAKEEM: Oh, okay.

SEAN: Got shortened to evo devo for the rhyme with a little bit of a play on the devo thing. But I've really been describing to you evolutionary developmental biology because what that's saying is the devo part is that changes in development are what give us anatomical changes in evolution, okay?

HAKEEM: And by development you mean embryonic development?

SEAN: Yes. So it's changes that happen during the process of making a creature are what will give you different appearing creatures. So if you're going to have changes in your anatomy, those are taking place during the process of development.

HAKEEM: During construction.

SEAN: During construction, exactly. So there must be some instructions that have changed that change the construction so you get a different kind of animal. So evo devo, yeah.

HAKEEM: From instruction to construction.

SEAN: That's right. That's right. So it changes during the process of construction. So all evo devo means is that... and it really focuses on changes in form, changes in that three-dimensional form, how to even describe creatures. I'm trying to understand the evolutionary changes in development. That's what an evo devo scientist does.

HAKEEM: Okay, so here, tell me this then, Mr. Smarty-Pants Science Evo Devo Guy, could you take embryonic Hakeem and stick a needle in me, change instruction, and I now have fangs and venom?

SEAN: Yep.

HAKEEM: Oh, what?

SEAN: Now I'm going to say in principle.

HAKEEM: In principle.

SEAN: I wouldn't say it's impossible. There's probably a little bit of knowledge that we would need to bill for. But when you know the program for making teeth, and we know a lot about it, and when you know how you might be able to sort of modify that a little bit to make it elongated tooth with a central canal which is a fang, then we could tweak that, right?

HAKEEM: Wow.

SEAN: And then we know how to make venom, yeah.

HAKEEM: Wow. That's what I wanted to get into, man, because making this molecule, venom, it is such a mysterious thing to me. I was like, "How would that even come about?"

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

HAKEEM: So let me ask you a question about that then. I'm sorry to interrupt.

SEAN: Oh no, anytime.

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

SEAN: Well, everybody's got their own instruction book. Sometimes some chapters have been torn out and left behind, and some have some new chapters, but they have a lot of instructions in common because they have their animalness in common. They have a lot of cell biology in common which even is deeper than animals, that they got cell biology that's in common with fungi and bacteria and plants and stuff like that. So there's some common parts of the code book, there's some unique parts. But that code book which was, again, not accessible to us, starting to become accessible in the early 1980s, and then today, oh my goodness. I mean, the speed and the costs involved is now almost trivial-

HAKEEM: Wow.

SEAN: ... where it used to be too expensive or impossible.

HAKEEM: Geez.

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

HAKEEM: You're having a good time.

SEAN: We are having a great time. We're having a great time. And so what we do, a lot of science is detective work. You're playing hunches, you're trying to look around, you're trying to find those clues, et cetera, and kind of DNA science these days is exactly detective work. You're saying, "Okay, I've got this creature here that doesn't have this capability, I got this creature here that does have this capability, and I'm looking around to try to figure out what does it have that it doesn't have." If I compare, for example, non-venomous animals, take a lizard or something like that to venomous snakes or non-venomous snakes to venomous snakes, I can see exactly what's going on when I look in the right place in the genome. That's telling us that what's happened is, again, this co-option thing, taking something that was used for some other purpose and repurposing it.

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

HAKEEM: So how does this begin before... I'm sure it doesn't start out as full-blown fang with venom gland.

SEAN: They bite.

HAKEEM: So the chemical's just being secreted in their mouth and they bite, and they somehow get some specialized-

SEAN: Yeah, yeah, probably components of saliva, yeah. Imagine the way these animals were first taking down their prey was they're biting and holding on. Now biting and holding on is kind of dangerous. You can go for a bad ride and get really roughed up. So you can imagine the ability to strike and then sit back while the prey dies is a little bit safer attack mode, right?

HAKEEM: Right.

SEAN: So if you can deliver something in your prey during that initial bite that will subdue it, then there you go. And so we've got a lot of enzymes in our mouth, we got a lot of enzymes in our saliva. And so what venom evolved from was some basic capability of having digestive enzymes and things like this in our saliva, and instead of just sort of those things passively getting transferred during a bite, through this modified tooth, a fang, a delivery apparatus that could deliver a more potent wallop of that kind of stuff.

HAKEEM: Wow. Wow.

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

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

SEAN: Now that's an apparatus that then does the job, and when we look at the venom components... and these are fascinating sorts of things. I got so many stories, I'm running my head saying, "Which one should I really tell you?" But I'll tell you one that's really striking it, and one of my students is studying right now, so I don't know, the reputation Australian snakes have, right? We've probably heard Australia's dangerous-

HAKEEM: Oh yeah. As we're having this conversation, I was sitting here thinking about the box jellyfish, which is another [inaudible], yeah.

SEAN: Yeah, another one, yeah. So on land, they had a couple snakes called brown snakes and taipans.

HAKEEM: Oh, yeah, the taipans, yeah.

SEAN: And they make me nervous, and I like snakes, and here's the deal.

HAKEEM: Have you been bitten?

SEAN: I've been bitten by non-venomous snakes, yeah. I got an old buddy that he had a great saying which was, he said there were two kinds of snake enthusiasts, those who'd never been bitten, and those who'd been bitten a lot.

HAKEEM: So there's no in-between.

SEAN: If you remember where that comes from.

HAKEEM: Oh yeah.

SEAN: Yeah, because, okay, you can piece that together. Anyway.

HAKEEM: Oh, I get it.

SEAN: Yeah, yeah. So, taipans and brown snakes, they're remarkably toxic. So ounce for ounce of their venom, one of the most toxic things on the planet. What have they done? And this is just to give you a picture of what's the strategy of venom. If you look at what their venom does to the prey blood, you can watch it in a test tube, it will clot like that. What they've done is they've taken two clotting proteins, proteins that we normally use to clot our blood in response to injury, pack them into their venom gland, they inject them into prey, and that blood clots like that.

HAKEEM: Gee.

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

HAKEEM: Wow.

SEAN: So they've taken proteins that are used inside the body and then using them kind of outside their own bodies onto prey, and that's the strategy of the venom. So you'd think, "Venom, wait, what is this kind of special substance, et cetera?" No, it's using existing proteins in a new way, right?

HAKEEM: Wow. Yeah.

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

HAKEEM: Do the prey respond with evolutionary changes to exist with the venom?

SEAN: Oh, brilliant, brilliant. It's an arms race out there. It's an arms race out there. And we see-

HAKEEM: So they are?

SEAN: Yeah, we see this all over the world, when prey are being preyed upon by venomous creatures, they're evolving all sorts of mechanisms. Some of those are... well, they're all sorts of levels. So the targets of the venom toxins are evolving. There's a lot of pressure because if you can be less susceptible, then that means maybe you got a better chance of surviving a bite or a bite that's sub-lethal, is not as hazardous, that sort of thing. It's going on all... it's remarkable. The joy to an evolutionary biologist, or you might say the purpose of an evolutionary biologist is studying this, is that those arms races going on, meaning that there's pressure for the predator, for the venomous animal to keep coming up with more and more potent venom, and there's pressure for the prey to keep coming up with ways to evade that venom. So you sort of have evolution and fast motion going on on both sides.

HAKEEM: Wow.

SEAN: It makes the evolutionary process... we just have more stuff we can dig into when it's happening on that kind of timescale. So it's measure, countermeasure. That's why we refer to them as arms races, obviously from the human analogy. It's all over the place. You go out west, there are rodents that are resistant to rattlesnakes.

HAKEEM: Oh wow.

SEAN: There are snakes that feed on rattlesnakes that are resistant to rattlesnakes.

HAKEEM: So here's a question. So we develop anti-venoms, from the movies I've watched, we typically make the anti-venom from the venom.

SEAN: Yes.

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

SEAN: God, you got great questions. Nobody's done it yet, but I think that's the new opportunity. Now that we've learned enough, this is actually something my lab works on, now as we learn enough about the natural defense mechanisms, we can exploit them. So what we did... anti-venoms got started in the late 19 century. At the same time, we were making like anti-toxins for things like diphtheria toxin and tetanus toxin and stuff, and what we'd do is we would immunize an animal like a horse with these toxins or venoms, take the blood of that horse, we'd refine it, and that would be the product we would give people who if they had tetanus or if they got bitten by a snake. So that's a 19th century analogy.

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

SEAN: That's right. That's right, and given that, and we use antibodies today. I mean, half the drugs that we use today are monoclonal antibodies that we make in a lab that we give people for everything from cancer to eczema or whatever, that sort of thing. But these natural defense mechanisms, some of them look really, to me, they look really, really potent and broadly acting. I think there are going to be some anti-venoms coming out of this new branch of knowledge from the way the prey defense mechanisms work.