Particles of Thought

SEAN: 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.