SIO448: How To Build A Dinosaur

Transcript

This transcript was generated automatically and may contain errors — the audio is the record.

0:00:16 Thomas: Hello and welcome to Serious Inquiries Only. This is episode 448. I'm your host Thomas Smith, and I'm so excited to bring you today's episode. We're going to be joined by Dr. Eric Jaffe. He's someone who submitted out the expert form way back when, and his proposal is absolutely delightful. Think I had referenced Jurassic Park at at some point. And he said he would love to take me up on my offer to talk about the science behind Jurassic Park and how to properly build a dinosaur.

Now, I'm actually going to read this from his proposal because it's something we actually kind of skipped over just due to how the conversation went. Says, "I enough, the proper way to build a Dinosaur is to manipulate the development of a chicken." Says DNA only lasts 10 ,000 years, and the mosquito plan is so stupid on like 10 levels. Sad to hear that the mosquito plan might not be a good plan. I'm still going to hold out hope. But Dr. Jaffe would like to take us through how you might actually build a dinosaur, and along the way just teach us a ton about biology and evolution. It's astounding. It's so fascinating to me each and every time I learn anything like this. It just feels impossible in a really cool way, though. Was just a lot of fun. I can't wait for you to hear it after this break, of course, which you can avoid by going to patreon.com/seriouspod, pledging as little as a dollar.

You can avoid the ads and get extra stuff. We have a Seriously Awful Movies coming your way this month, and the Hangouts, there's lots of cool stuff. So please consider becoming an supporter. Patreon.com/seriouspod. With that said, let's build a dinosaur, huh?

0:01:53 Thomas: Joined by Dr. Eric Jaffe. How are you doing today?

0:01:56 Eric: I'm doing well. How are you doing?

0:01:58 Thomas: I'm going to resist the urge to just say dino DNA. It's my favorite thing. I love Jurassic Park. I love the dino dna, the Mr. DNA character. And I'm so excited to talk about building a dinosaur with you. Do we get to actually build one?

0:02:11 Eric: That's actually in the process. There's about a 10 -year research project that we're going to talk about, and they actually released an update last year. So there is no dino yet, and we are going to talk about Mr. Dino DNA because, like you, Jurassic Park is kind of my Genesis story, and there's lots of things that did great for paleontology and science, and then a lot of misconceptions, both in that movie and lots of other movies, that I would like to to use this kind to unpack?

0:02:26 Thomas: I can't wait. Well, first, you want to give listeners a little introduction to who you are and kind of what you do?

0:02:43 Eric: Sure. My name is Eric Jaffe. I mentioned, I first started my science journey at about three and a half years old when I convinced my mom to let me see Jurassic Park because I love dinosaurs. And ever since then, I've wanted to build a dinosaur. I'm probably the only person that saw that movie and thought it's still a great idea. And so I started reading a lot of books about how to build dinosaurs and stuff like that. And And to be honest, and we'll get into it, it's not really viable to do it the way Jurassic Park did. But there was this great paleontologist at the time called Jack Horner, and he published this book, How to Build a Dinosaur. And we're going to use that as the framework. But that's really what jumped into my knowledge or my interest in science. So I joined a graduate program led by a mentor, Dr. Lee Niswander.

Did have a fossil dinosaur in her office when we first met, though, which is part of why I knew that it would be a great fit. So I joined that lab because I wanted to turn chicken wings back into those three -fingered claws that dinosaurs are well known for. And when I got there, she had a giant fossil of Archaeopteryx, the first bird that many people credit as being kind of the most basal that we call a bird species.

0:03:07 Thomas: Yeah.

0:03:49 Thomas: Basil?

0:03:49 Eric: And so I thought this was a great fit. Basal is like that original form, right? If you think of like Mammals, right, the basal mammal would be like those tree shrews that that were walking around that later diverged and became all of the wonderful mammals we see today.

0:03:54 Thomas: Oh, okay. Right. Like earliest thing that we kind of identify as that sort of species or whatever, that sortof subgroup.

0:04:09 Eric: Exactly. That is the perfect definition of basil, not the herb.

0:04:12 Thomas: Interesting. Yeah. Yeah, have a lot of ideas for recipes based on your interest. You know, we got chicken wings. We got we got basil.

0:04:20 Eric: Oh, dinosaur barbecue is about to get a new name, right?

0:04:21 Thomas: Yeah. Well, one of the things I love about Jurassic Park is like, I, I love when sci-fi gives you something that seems at least plausible, you know, not that I thought like tomorrow we're going to be able to build dinosaurs. But I love that story. It's like, oh, cool. That's it seems kind of interesting. And it's funny that like so that that became a little bit of a of a quest of yours, like a genuine more than just like, oh that's a fun story, like why aren't we having dinosaurs now, give me dinosaurs yesterday, I want pictures of dinosaurs, get me pictures of monsters and you bang your desk.

0:04:47 Eric: Exactly. Now in mind, this is before I knew that there were billions of dinosaurs flying around Earth at the time, because obviously, as we will get to the punchline eventually, birds are in fact living dinosaurs. So when we really say the dinosaurs went extinct, we're really talking about non-avian dinosaurs, those dinosaurs that weren't our true birds. But yeah, so I wanted to build a dinosaur, and I went to that lab, and I found out she wasn't actually working on dinosaur building research anymore, so I instead had to settle for doing what we call live imaging. Exactly.

0:04:57 Thomas: Uh, Like ever since The Lost World came out, it kind of ruined that for us, I don't really like anymore. Sorry.

0:05:29 Eric: And she realized that a lot, lot of the genes involved in neural tube closure are much more easily relatable to cancer, where all the science funding is. So if you want another peek behind the scene, you always want to hunt those cancer genes.

0:05:35 Thomas: Oh, fair enough. Fair enough. Yeah. Fault people for wanting to research cancer for sure.

0:05:43 Eric: But So started researching kind of how we sew our brain and spinal cords together, which is actually very similar to the things you would need to do to build a dinosaur. And that's actually what I would really love this conversation to be about is why it's not really about finding dino DNA. It's using the DNA we already have and treating the human body or the, in this case, the chick embryo as like a ball of clay that you can sculpt and kind of use a very simple but diverse toolkit to find all of the different forms that make animals what they are.

0:06:17 Thomas: Wow. The dinosaur was the dino DNA we've made along the way is what you're saying. It was all the dinosaur wasn't inside us all along.

0:06:24 Eric: Well, it's inside the bird all along. Unfortunately, we actually diverged way before dinosaurs. Have you ever seen those when you were growing up? Did you ever see those those dinosaur toys that had like the legs off to the side and the giant sail on its back?

0:06:25 Thomas: Okay. Yeah, not inside us. Gotcha. Ah, I don't think so. I can't think of what that would be. Wow,

0:06:42 Eric: Some of your listeners might. That dinosaur is actually not a dinosaur. That is one of the first things that put us on the road to mammals called Dimetrodon.

0:06:52 Thomas: Dimetrodon. Hold on, maybe I got gotta google this right now. Dimetrodon.

0:06:55 Eric: You might recognize it.

0:06:56 Thomas: No way I'm spelling that right. Oh, the big old lizard with the big, like, sail, wind sail thing.

0:07:03 Eric: Exactly. Now that probably looked a lot less like a lizard than a lot of our old toys did and probably looked like a dinosaur and probably a lot more mammalian than we gave it credit for.

0:07:03 Thomas: Huh.

0:07:12 Eric: Because those things were kind of not true reptiles. They were already starting that process of becoming what we think of as mammals. So the mammal evolution is actually much longer than we're thinking. And the bird evolution is actually much larger. But you're right. The story is the DNA we made along the way.

0:07:28 Thomas: Well. Know, there's, um, mean there's millions and hundreds of millions of years and it's like, there's, of my favorite factoids, you know, that I learned in like 2007 that I still find amazing is like, like the distance between Triceratops and, you know, and T -Rex is like more than the distance between T -Rex and now or something in terms of time. And it's like, I get that. Oh That's right. And it's like crazy to think about that much time. So I was always under the impression that we were at this time, mammals were like the little, like almost rat-like things that were kind of crawling around under the dinosaurs. When is this guy, when is this like big old wind sail thingy, I like, he do not look at all mammalian, but like you say, maybe they were, you, the police sketch artist was racial profiling a little bit. It's like it's definitely a dinosaur.

0:07:45 Eric: It's a stegosaurus, but yes.

0:08:13 Eric: Yeah. So really important thing to remember, right? Don't get soft tissue and fossils a lot of time, right. So it's actually very hard to know. This is why a lot of dinosaurs, it's called shrink wrapping, they look very skin tight, right? They don't look like they have a lot of fat and muscles. That's because artist reconstructions until very recently failed to take into account all that musculature, all those fats, all those extra features that don't preserve well. But with Dimetrodon, it is actually interesting. He was before the dinosaurs. So, or at least with

0:08:13 Thomas: Yeah. Oh. Really. With

0:08:44 Eric: The early dinosaurs, he was actually part of the Triassic period, which is before the the dinosaurs got going, there was actually probably another mini asteroid in the Triassic period, that early Mesozoic one, that knocked out those, what we call synapsids, those early mammal-like reptiles, and left a lot of room for dinosaurs to then expand and fill out a bunch of niches along with some of their crocodilian relatives.

0:08:45 Thomas: Early Time I've How Have I never heard this? Is this like a theory, or how is that, like, how firm are we on this? This, I love the idea that like a meteor, or whatever, an asteroid, asteroid, meteor, which would asteroid, which meteor, meteor.

0:09:21 Eric: I believe it's an asteroid until it reaches Earth, and then it's a meteor, if I remember right.

0:09:26 Thomas: There's something like that. Meteor takes out the mammals and the dinosaurs are like, ha, sucks to be you. And

0:09:33 Eric: Synapses would be a little more accurate, but yes.

0:09:36 Thomas: Some hundreds of billions of years Later, it's like, ooh, oh, how the meteor table has turned, Mr. Dinosaur. I've never heard that before.

0:09:44 Eric: Because a lot of people think of evolution, this is one of the big things I'd actually like to Kind of Unpack in this episode is people think evolution is like this linear process, right? Building towards the future. That's only because we have hindsight to look at layers of fossils stacked on top of each other where it tells a coherent story. But really, evolution is a series of starts, stops, and the main thing that frames everything is changes in the environment. So as changes to the environment happen, different animals will be primed to succeed and different animals will not be.

0:09:48 Thomas: Mm. -hmm. Yeah. Mm. -hm, right.

0:10:15 Eric: But those aren't going to build in a progressive way because the environment is just as capricious as everything else. So some days you'll have, well, it's because it's one of the smaller of the big extinctions. So you've obviously got the dinosaurs and then you have what we call the Permian extinction, which if you really want a wild one, that's one we don't fully know the cause of, but almost 96 % of all life on Earth got wiped out at the end of the Permian.

0:10:15 Thomas: I Just Literally Hadn't Heard about this meteor Is all I'm saying. I take all your point on that, but yeah. Real When When is this? Wow.

0:10:42 Eric: This is right before the Triassic. So that period of time had a little bit of a rough go at things.

0:10:45 Thomas: I Need Like a, you know, like BC idea, like before dinosaur, after, before dinosaur era, after dinosaur era. I don't know when this is, but like, okay, somewhat pre-diet. So there was a massive die-off of some kind and we don't know what that was. Is that the one? I know there's one where they're like maybe it was a super volcano that like covered the whole earth in ash. Is

0:11:06 Eric: Yep, that's a possible explanation. And actually, the super volcanoes are also heavily implicated in that end Cretaceous extinction along with the asteroid. So Like, you would not have wanted to live in that end Cretaceous period, right up to the asteroid hitting. Minus, know, the asteroid itself was a, we can talk about it, but it basically hit with the force of a hundred billion Hiroshima's and It turned the entire planet into a literal hellscape for that day. That's bad enough, but there was probably what called the Deccan Traps, which are these volcanic complexes in the Indian subcontinent that were like sporadically going off for millions, hundreds of thousands of years before, that was just poisoning the atmosphere.

0:11:14 Thomas: Someone's got to Talk to them, right?

0:11:29 Thomas: Geez.

0:11:47 Thomas: How is anything living?

0:11:48 Eric: That is honestly a question I have. And the real answer is just like the great Ian Malcolm said, life finds a way.

0:11:55 Thomas: All right, so where were... so, so you're thinking this thing, and it seems like the Google image results are not up to date, uh, there, like, more current renderings, because that has been a thing with dinosaurs over the years. It's been crazy to see how our understanding of them has changed and how much all of my knowledge is still based on coloring books from the 90s. And It's like, no, they had freaking feathers. And I'm like, man, I don't like that. I would prefer they didn't, if it's not too much trouble. I'd rather the dinosaurs didn't have feathers. But I think that's a losing battle. I think it seems like they may have had feathers. Just, just a question of like, well, there's more meat on it. There's more chunk. And that is what makes, made it more mammalian looking versus if reptiles do somewhat have that kind of tight skin to the bone look, right? I mean, is that like a defining feature of what makes a a reptile? Sure.

0:12:16 Eric: No, but what it would really be, and this is a little bit above my main content knowledge, I'm less in paleontology and more in developmental biology, but it has to do with the way that the jaw is structured. So a big way to identify particularly the mammal lineage is in their jaw and dental structures. So the jaw and mental structures of these Dimetrodons, these synapsids are way more similar to mammals than they are to diapsids and other reptiles. So diapsid and other rep tiles would be your snakes, your lizards, your crocodila morphs moving forward and things like that. That divergence happened 300 million years ago. Now those dimetrodons are not mammals, but they also aren't reptiles, they're their own kind of thing. And that's actually another thing that I would like to talk about is that we have labels for things, right, right? And they are useful. Labels are not reality in biology. Biology is kind of these continuous gradients that overlap with each other and make everything super messy.

0:12:52 Thomas: Mm. -hmm. Hmm Hmm. Okay. Yeah. Yeah. Mm. -hm, totally.

0:13:44 Eric: And then we just decide to pick a time and go, that's no longer blue -green, it is blue, right? It's no long blue -greens, it's green. But at no point, if you look at a color gradient, would you actually be able to say, this is the pixel that's blue, this the pixel is green. It

0:13:50 Thomas: Yeah. I Love it, I think I talked about this the other day on something, I don't remember what, but I do love that thought experiment of like, if we had every single creature alive at once, like for all time, you would, you make species, like there's so many, you know what I mean, like, it's just, it's exactly what you're saying, where it's, it's all gradual change, but with the benefit of hindsight, we can kind of put these labels on things. But I do really appreciate that, that fact about, um, uh, evolution is that like, it really is a lot of it is like, well, it's not quite this. It's not quite this. Now, is this, uh... the Demetrodon, are you saying that that's not quite a mammal? It's not quite a reptile because it's like our last common ancestor of both, or...

0:14:36 Eric: So it's already after the divergence. The last common ancestor of both would be a little further back. But it isn't quite the mammal because it doesn't have mammary glands, right? It doesn't produce live young. It doesn'T do all of those things that we kind of treat as mammals. That comes a couple 100 million years later or so. The main point is, at that point, they've already started to be completely segregated in their gene pools.

0:14:38 Thomas: Okay. Ah, Hmm.

0:15:01 Eric: So they're going to have their own rates of mutation, their own ecological niches that they're gonna start to fulfill. And they're not really going to keep mixing their genes together. Whereas everything that's still a common ancestor of dinosaurs and crocodiles, for instance, have the ability to still split off, right. Right. And then by the Triassic, you have those synapsids, those mammal -like reptiles, which is a slightly outdated term, because again, they're not really reptiles. You have your diapsids your normal turtles, your lizards, you Have amphibians, but the two main players in the Triassic when the dinosaurs are first getting started, are those crocodilomorphs, those crocodilian archosaurs, and

0:15:01 Thomas: Hmm. And Comcast.

0:15:39 Eric: Then dinosaurs.

0:15:40 Thomas: Oh, no. Okay. Sorry.

0:15:42 Eric: Oh, if you look up a crocodilomorph, picture like a a crocodile where like they are lifted up off the ground. They are like 20 feet long. They have giant, giant jaws, even bigger than before. If you look up something like called a pastasuchus, you will be frightened.

0:15:42 Thomas: They owned everything. Yeah. Hmm. Yikes. Even the name is scary. Okay, I'm sure I have distracted you from our building of a dinosaur. How did we get onto this part of it?

0:16:03 Eric: I actually like that we went on the segue because it does get to the main point. In the same way that species and, you versus non -mammal is a fuzzy concept, it's a fuzzy content to go from dinosaur to bird, I think Most of us know that birds, dinosaurs evolved from dinosaurs, but I don't think a lot of us know that birds are actually dinosaurs themselves, and that the way we generally code evolution now is what we call cladistics. And right? The difference from that is you probably remember normal taxonomy, right, where you have like species and genus, right.

0:16:07 Thomas: Okay, good. Love it. Hmm, sure.

0:16:36 Thomas: Yeah, interesting.

0:16:37 Eric: So you'll have like your mammals are one, I think it's class, right, and then you have reptiles in another class or order. I forget which one. And then you keep going down hierarchically. Way we do it now is slightly different. We don't really get hung up on those boundaries and borders. Instead, we say, how related are you in evolutionary time? And we group people based on how related you are in evolutionary time and when you started to diverge and no longer share those common ancestors. So everything is based on kind of, if you start from that population of bacteria and ocean vents, right? Theoretically, and this is slightly wrong, but you could think of us as bacteria that have really lost the plot, right?

0:17:16 Thomas: Yeah?

0:17:16 Eric: Because some population of bacteria swallowed a mitochondria, became eukaryotic, and then became animal cells, eventually.

0:17:23 Thomas: Right. And the bacteria from today looks at us and is like, ugh, disgusting. I can't believe.

0:17:28 Eric: Oh, they think we're completely uncultured. It's the way Europeans look at Americans, pretty much. Kind of what I want to first make the point of, is species is already a fuzzy thing. And so when when we say we're building a dinosaur, people are going to say, well, you didn't actually build a dinosaur because you're not taking Velociraptor DNA. You're not taken T -Rex DNA, but that's already missing the point of biology. The reason you want to build a dinosaur is because you can reconstruct a hundred million years of evolution in the lab, right? You can show those key genetic changes that happen that take you from that really scary T -REX, well not a T -rex, but a a celesaur, which is a bipedal dinosaur, into the sparrows, the bird, the chickens, the geese that we all see every day.

0:17:31 Thomas: But without the fun of thinking this was a real dinosaur that was around. Okay.

0:18:17 Eric: But I would argue it's even more fun because what you really learn in that process is you can make any animal very, very weird, very, very quickly. Because people think of evolution, right, as like an RPG game where you pick up these these new adaptations, these new features by getting like a level up, right? And those new features help you navigate the environment. Evolution actually works much more subtly than that. You're typically not getting a lot of really new genes. Instead, you're getting a difference in the way those same genes over time are expressed, particularly in time and place, and in particular in the development. And as you change when and where those genes are expressed, you're going to to end up with different types of tissues and different types of structures. But you're not just like adding on a new arm. Instead, what you're doing is you're taking the genes that promote limb development, for instance. And you're saying if I add it to another spot, it will eventually grow another arm, but you're nicht adding new genes to make that extra arm. You're using the genes you already existed, if that makes sense.

0:18:26 Thomas: Sure. Yeah.

0:19:19 Thomas: I've always wondered, because I know nothing about it. I'm always wondered just looking at, I don't know, what seems to be the the basic math of what anything is, this DNA, well it's got a DNA math, it's a different code, and whatever, it always has felt like, well, couldn't you just like make the code for stuff, like where does it get so complicated that it's hard to just do that, like why, if this is the way you're talking about it, seems like something that could have been done a long time ago. What's the, what's the complicating factor, uh.

0:19:50 Eric: Okay, let's peel back some of that complexity. I'm going to start with a very simple question. You ever watched like CSI or any of those crime shows? When isolated the DNA, they would always identify the person, right?

0:19:58 Thomas: Back in the day, sure, all Right, yeah, you match it, right.

0:20:07 Eric: Would never say like, this is their skin cells. This is their liver cells, right. Think about that. The liver and the skin in your body have the exact same DNA, right there, liver cells and your skin cells are very different looking, right, they do very different things, they They need to express very different genes, right? And that's where evolution builds in the complexity, is the when and where. So what they do is, in eukaryotic organisms, and when I say eukarya, I mean not bacteria, cells that have nuclei with chromosomes in linear forms, right, multiple chromosomes often. They do, is they have a three -dimensional architecture to them, right. We often think of cells as those diagrams from freshman biology, but they're really like these complicated 3D metropolises with proteins

0:20:12 Thomas: Okay, yeah, yeah. It's so fascinating.

0:20:38 Thomas: Yeah. Hmm.

0:20:57 Eric: And vesicles and all these things moving around, right? DNA is no different. It's not just the sequence of DNA. In fact, your body doesn't read ACTG, Right, what those actually are, are protein nitrogenous bases with different shapes, right, different structures to them. And that causes the chemistry to react differently. So all that DNA does is it changes what we call the configuration of chromosomes, it will add different chemical groups to different base pairs, different nitrogenous bases, and it will make it more or less easy for different proteins at different times to access those genes, right? So let's say you have a gene that you really need turned on. What you'll do is you'll have this process usually called acylation, where you add a small carbon group onto that base pair, or in a key part of that chromosome, that will change the a three-dimensional architecture of how that chromosome is folded and kind of open up that gene so that DNA polymer or RNA polymerase, which is the thing that turns it into RNA and then protein, can access the gene.

0:21:07 Thomas: Jesus.

0:22:02 Thomas: Christ, no, I'm back to this, is impossible, never mind, life's actually not possible, I'm sorry. None of none of that

0:22:06 Eric: My boss used to always say it's amazing that any baby is ever born.

0:22:08 Thomas: No. It's impossible, it can't be done, I, I, new episode, this is wrong.

0:22:14 Eric: But here's where it gets even more fun. It's about to sound super complicated, but it's actually somewhat simple.

0:22:14 Thomas: Oh. It already did. You You had said a bunch of words that nobody understood. But yeah.

0:22:20 Eric: So what's going to get it simple in the pure logic. There's about six signaling pathways, right? Like six things that form a set program. You can think of this as like when you roll out a bill, right, in law, you're not just setting up one thing, right. You're setting up a infrastructure program along with a system of, you know, ways to implement that program .You have to have construction workers and training program for the workers that are going on that infrastructure, right? Exactly. Our cells have a bureaucracy to them.

0:22:36 Thomas: Okay. Okay. Bureaucracy. Oh, wow.

0:22:54 Eric: So what they do is they set up a couple of molecules and they put them in opposition to each other.

0:22:55 Thomas: No wonder I can't get anything done. Sorry. What?

0:23:05 Eric: Call these morphogens, right. Say I want to make my hand the same way a bird would want to made their hand, right, set up couple of different molecules. In one part of that developing limb bud, like a little paddle that will become your hand, you put this gene called sonic hedgehog. And yes, that's the actual name of the gene. You have sonic hedge hog in one corner, right? Sonic hedgehog is going to recruit a set of proteins called transcription factors at the end of its signaling.

So it tells all the cells like we're in the sonic hedgehawk protocol, And right. It's going to tell those cells, you need to produce these proteins called transcription factors. What transcription factors are, are proteins that recognize certain sequences of DNA. Those pieces DNA are not the thing that will become the protein. They're the thing that lets the protein be made to begin with. And so those transcription factors will only bind that piece of DNA when they're told by Sonic Hedgehog.

And that happens at particular times and places in the embryo. That will tell the cells that I need to start producing these genes, and it will give the cells those properties and traits the gene will turn into protein, right?

0:24:10 Thomas: If you say so. Yeah, this is so beyond anything I understand. But I mean, the principle that's going on is, it crazy to think of the fact that all our cells, you're saying basically all our selves have like the same DNA in them, but somehow we're not all one cell. Bell. We're not all one kind of thing. And it is like trying to understand parse through the words you're using is a little bit difficult for me, but fundamentally that what's going on is you're describing the process by which whatever fundamentally makes us, us or us, the species we are, whatever translates into like these things actually building different physical structures and stuff, right?

0:24:26 Eric: Exactly.

0:24:52 Eric: Exactly. Can I try one more analogy for you?

0:24:54 Thomas: Sure. I love analogies.

0:24:56 Eric: Let's say you have a recipe, right, you have the ingredients listed, you have the steps, right. You can take those ingredients and recombine them in a bunch of different ways, right? Analogy I always bring with my students, as I'm now a high school biology teacher, is, right, is the Taco Bell menu. They have about six or seven key genes that they recombine in a bunch of different ways to give you gorditos versus tacos versus burritos, right?

0:24:57 Thomas: Now Now we're talking.

0:25:25 Eric: And basically, yeah,

0:25:25 Thomas: And then the Crunchwrap Supreme rules the animal kingdom. I get it.

0:25:29 Eric: So basically, all that's happening is Sonic Hedgehog tells you, I need these ingredients cooked in this way at this time for this order of steps, right? Your liver cells may produce a different signaling thing that will tell you, you can still use some of these ingredients, but now I need them expressed at this time in a different place and in different locations. And what that does is it sets up what we call gradients, Morphogenic right? Gradients.

0:25:56 Thomas: So you're going to stick to the Sonic Hedgehog thing? Going stick to that, huh? What the hell is that? Somebody just name something for fun?

0:26:04 Eric: Is one of those regulators. Sonic Hedgecock tells you this is the recipe we're making. We are treating our bread as a funnel cake this time and we're deep frying it.

0:26:12 Thomas: So So who's responsible for that being named that?

0:26:16 Eric: That was a graduate student. So back in the day, there was a lot less kind of standardization of names. And there was two related proteins that were found in hedgehogs, right? Was desert hedgehog and Indian hedgehog. And they were found to do similar things. They helped regulate what genes turned on when, as we were building our bodies. Graduate student found a related one and he was a big fan of Sonic. So he said the the first two were named after hedgehogs. I'm going to name this one after a hedgehog. It just so happens that Sonic Hedgehog is a really, really major player.

0:26:50 Thomas: Geez. Thing I can't I believe I've never heard before. Have I never, I, it looks like you made a Wikipedia page to support this lie you're telling. And I see it. It's right there. But yeah, Sonic Hedgehog is it just turned out that like this student happened to discover something that was important, named very widespread in using it to describe stuff.

0:27:08 Eric: It's very important because it's one of those six or seven, what we call morphogens, and I'll describe that in one second, but they're one of Those six or 7 types of molecules, types of we produce that really control a lot of stuff, right? It's actually formed a problem because if someone has a sonic hedgehog mutation, it comes with a lot body disformity.

0:27:31 Thomas: Wow.

0:27:32 Eric: And if you're a doctor, the last thing you want to tell a patient is the reason your kid has these birth defects is because of a mutation in sonic hedge hog, because the tone doesn't match the phenotype.

0:27:40 Thomas: Oh boy. Like, yeah, but we're a Nintendo family. There's no way.

0:27:46 Eric: Exactly. But like that's been a huge controversy. But so we have sonic hedgehog, right? Let's say you have sonic hedge hog right by what will eventually become your thumb, right. And it's telling all the cells right by where you're going to become a thumb.

0:27:57 Thomas: I'm sorry. I gotta stop you. You have Sonic Hedgehog. What does that mean? You have... You're expressing...

0:28:02 Eric: Means you're expressing it. So remember how like liver cells and skin cells don't always look the same. Reason why is they're not used. This is is going to sound like that we only use 10 % of our brain thing, but this one's actually true. We only use some percentage of our genome at any given time, right? You don't want all your genes expressed at once because a lot of your genes are responding to specific things, right.

0:28:05 Thomas: Sure. Right. Sure. That makes sense, though. Yeah. For sure.

0:28:25 Eric: don'T want a stem cell gene in your brain cells. You DON'T want a brain cell gene and your stem cell. Does that make sense?

0:28:31 Thomas: Yeah, but what's... So, I was interpreting the sonic hedgehog thing is like a kind of a tool that builds, I... This is so hard for me, I understand, sorry, um, it's a thing that your body makes and puts places. What...

0:28:42 Eric: Yes, everything we're going to talk about this genetic toolkit kit are things that your own body will make and produce.

0:28:43 Thomas: Okay. Okay. Like in utero and then you always have it, or is it like always happening? Hmm.

0:28:53 Eric: You don't always have it, right? You only have your your proteins, your genes when those genes are being expressed. So Sonic hedgehog is very tightly regulated in time and place, particularly in embryonic development. The genes we're going to be talking about are really big players in embryomic development and then less necessary in adult tissue, because you're not making these large shapes and sculptures in adult tissues, right? Your hand is largely your hand by the time you're born.

0:29:00 Thomas: Hmm.

0:29:23 Thomas: Okay, so once... once you already born, it's more about like you're just kind of maintaining and regenerating what you already have, in a way, versus when you're in... It's like, well, obviously, big things have to happen pretty quickly. Is that kind of what you're saying?

0:29:36 Eric: Exactly. One of the major shifts as we go from stem cells to adult tissue is our stem cells are constantly dividing and constantly what we call differentiating, right. You can think of them as like, they're the college students, right, they're finding themselves, they're trying to find their identity. They're constantly trying to reproduce, right? That's our stem cells. But once you grow up and you start to have kids, you're settling down, right, you are kind of in your routine, You right. Are not as adventurous. You're largely doing the thing you were born to do, right.? stem cells are how do we find it? And those morphogens like Sonic Hedgehog is that really great professor that puts you on to the thing that you were borne to do.

0:30:02 Thomas: Yeah, for sure. This is a very good analogy.

0:30:20 Thomas: Okay, that's a great analogy. I'm liking this. This makes sense now.

0:30:23 Eric: Now here's we're going to get a little more complicated. So let's be in our limb bud. We're going to use that as an example because it's a big part of building a dinosaur, right?

0:30:26 Thomas: Okay. Sorry, what? BNR what?

0:30:32 Eric: A limb bud, which is basically the thing you make in your body before it becomes your arm, leg or hand, right. Yeah, like the little paddles, if you've ever seen like a picture of a sonogram, those little padtles when the embryo still looks like an alien, right, that limb bud will eventually be your five fingers. Right by the thumb, the cells there, because it's going to be hundreds of thousands to millions of cells in that bud, right? The cells right in that bottom corner are going to express the morphogen sonic hedgehog, right. At the back towards like where your wrist will eventually Be, you're going to use another one of those proteins, right, in that case, it's gonna be, I believe it's Wnt signaling, signaling, which the names aren't as important. The main thing is like, recognizing that we have two of these signals now, right?

0:30:39 Thomas: Limb bud. Oh, gotcha. Okay, yeah, yeah. Yeah, sure, sure. Yeah, yep, mm -hmm, mm, nah, I'm bad, nevermind. Sorry, it's not real. It's not happening. This is impossible.

0:31:30 Eric: Picture it like a, have you ever like seen like a matrix of like weather patterns where like, you have one storm system going into the other? Or actually wave interference patterns would be a better way to put it. Have you ever seen wave interference patterns?

0:31:37 Thomas: Mm -hmm. Yeah, oh, there you go. Yeah, yeah, sure of course I have. Yeah, what are you talking about?

0:31:44 Eric: Right? These morphogen gradients are like interference with waves, right.

0:31:49 Thomas: But what's crazy is somehow that all ends up being roughly, roughly speaking, a very high percentage of the time with humans, it is just that is going to be a hand. Like, how the, how the fuck does that work? That's impossible. There's

0:32:02 Eric: Very, very Very slowly is how that works.

0:32:03 Thomas: No way. Because You start as a lump of something and then you got all these little differentiating, whatever you're talking about, and it knows to make the certain amount of, you know, like five fingers and make that's, never mind, I, every time I learn more about this, I'm like, it's not true, it's fake, fake news. It's

0:32:22 Eric: Can be honest? Biology is a little bit of, I say this with my students all the time, it's turtles all the way down.

0:32:28 Thomas: It's crazy.

0:32:28 Eric: There's, it layers in these different regulations. It's a little hard to pinpoint other than what we call maternal RNA. So when you're very first born, right, and you're just that single cell that's trying to establish like an an up -down, what we call anterior -posterior rostral caudal, which is your head to your toe, your mom gives you a couple of pieces of RNA, which will eventually become protein, that kind of turns on the lights and gets everything organized.

0:32:42 Thomas: Mm hmm. Yeah.

0:32:58 Eric: And then from there, everything just starts falling into place because you have those morphogenic gradients. So what the maternal RNA does is sets up those first sets of gradients, and like let's say you have one RNA that's what we call localized, right? It's located at the left side of the cell and another RNA that'S located on the right side, right. They're going to start to produce proteins that establish the identity of those two poles of yourself.

0:33:26 Thomas: Yeah.

0:33:26 Eric: And then from there, as the cells divide, as you go from one cell to two cells, they know which were the initial morphogens that clued them in, right? They know which maternal RNA they were on a team with. It's kind of like when you have an icebreaker game and you divide people up by one and two and send them off to each side and they go, "Now team one and team two." You have that initial sorting.

0:33:27 Thomas: Wow. Yeah. So cool. Yeah. Yeah. It's it really just shows the power of like iteration, you know, like incremental change, because I know it's not exactly the same. But if you just think about like, OK, what did a computer look like in 1980? And what does it look like now? You know, our phones like is like that's magic. Like, there's no way someone in 1980 could possibly fathom what just so complicated now. And I know it's a little different because you have, you know, a top down, you know, people trying to actually design stuff, but you also have a way shorter timeline.

So over time using evolution, you know, evolutionary forces is kind of that, quote, unquote, designer in a way to use a problematic term, but still, I'm showing like how powerful can be to iterate on top of whatever iteration, you know, like it gets so powerful so quickly that it's amazing to consider. Like what you just said is just, just, fantastical. Like there's no way to even, if you actually think about it, it is like, this is unbelievable that this happens and that it happens every single day times a gazillion. Like it is just reliably, this This is like easy for biology. Life is like, no, this isn't even hard anymore. We just make a perfect like embryo exactly, almost how we should every single time with very few mistakes, relatively speaking to how complicated it is. And it's like crazy. I can't, it's, it'S beyond description.

0:34:27 Eric: It is truly awe-inspiring, although I do think the metaphor kind of muddies how hard it is. Don't get me me wrong, it is immensely hard, right? But when we say things like, you know, it's reading the DNA and using that information, right, we think of it the way humans do, where we make a ton of mistakes in reading, and like, our brains are working as a middleman. But keep in mind that all of this is the laws of physics and chemistry, right. There's no actual labels on these things. So in many ways, these things are constrained in what they can do so that they can only do the right things, Right! You're absolutely right about that iteration. And I'd actually take it one step further. I actually think if you took one of the luminaries in the field from the 1950s and explained to them the logic of modern computers, they would say it's the exact same principles.

0:35:29 Thomas: Yeah, exactly. Yeah. Yeah. Right.

0:35:57 Eric: It's just been refined. And that's what evolution is. The reason why we have two arms and two legs is because the fish we evolved from had two fore fins and two hind fins, right? The body plan is what we were dealt with. And evolution doesn't really stray too far. It just, again, uses those same six or seven molecules in development to set up new locations and new structures. And then from there, you can get really incredible stuff. So for instance, we were talking about the hand, right.

0:36:07 Thomas: Yeah. Yeah. Yeah.

0:36:29 Eric: Have those different gradients, right? So you have three major players in the hand. You have Wnt, W -N -T, which is kind of like Sonic Hedgehog. You have Sonic Hedgehog, and then you have Fibroblast Growth Factor, FGF. Those three things are all trying to do the same thing. Fibroblast, it's like a skin stem cell kind of thing.

0:36:43 Thomas: Fibroblast? What? Are These More Like weird names that people gave stuff, or what is the, like, why is It called fibroblast? Okay, are

0:36:50 Eric: Yes. Fibroblast is, blast is like the suffix for cell. And then fibro, my guess is, and this is complete speculation, is because they're skin cells, they would be filled with with a lot of fibrous proteins. So it may be that fibroblast refers to the way those filamentous networks stretch out in the cells in a microscope. That would be my guess.

0:37:10 Thomas: You saying fibroblast this whole time? That's Okay, fibroblast is what I heard, because that's A word Yeah Gotcha No Yeah, still Weird, but makes more sense. Okay, thank you. They

0:37:13 Eric: Fibroblast, yes, like blastoise. Oh no, sorry, fibroblasts, like a blastocyst is, yes. So that FGF, that sonic hedgehog, and that wink, They right? All want to do the same thing. They all wanna turn on their cells and turn on their gene programs, right? So that they get the identity.

0:37:35 Thomas: Get the identity. Sorry, say that, what, explain That

0:37:38 Eric: Yeah, they all want to have their identity win, right, they want their genes to be expressed that the cells look like that.

0:37:38 Thomas: Uh Oh Gotcha, okay. Okay.

0:37:45 Eric: But As you can imagine, if you have all three of these signaling factors very close together, and they're reaching across the tissue, eventually, they're going to run into each other, right. At the bottom of the hand, where Sonic Hedgehog very powerful, you are going to get a lot of cells that follow that sonic program, right? Right next to where FGF is being expressed, the sonic hedge hog is far away and weaker, but the FGf is very strong, right? So those ones are going follow more of an FG f program. And the ones by the wind signaling are going following the wind program. Everything in between is going to be a balance between those three as they diffuse fuse across a gradient.

0:38:05 Thomas: Yeah. Yeah, that makes sense.

0:38:27 Eric: And that's how we get our different zones of our body, right? Those set up like this is going to be this program, this is gonna be that program. And they generally tell your body to either make certain properties. So if I'm making skin cells, I'm gonna make a lot of that kind of like what we call actin and other kind of rope like proteins. But if I am a brain cell, I am gonna make myelin sheath, right. I am going to make a a lot membrane. I'm going to to increase my surface area so I can transduce those signals down to the brain, right? So depending on where you are and what signals you're getting, your cells are going to change their structure and function and are very closely related. So as you change that structure, as you change that form, you're going to chance the function.

0:39:11 Thomas: It's Just it's mind-blowing, and it's also crazy to think about, like, how it has worked on top of itself to where mutations need to be stuff like mutations need to be something in order to actually, obviously, affect some sort of change down the line, they have to be like, you know, beneficial in some way, right? Or at least that's kind of the basic, very basic level. But like thinking about that at that tiny level, you like, where, where does that happen? Hard to put into words what I'm trying to say. But thinking about how some some sort OF mutation at some tiny level can then at the, at the higher level, um, a broader level, like effect, some sort of change is just weird to think about. Like, I don't even, how does it even work?

0:39:33 Eric: Yep.

0:39:57 Eric: So let's actually, let's unpack that real quick. Ready? So we're Still in the limb bud, right. If I'm a dinosaur, those those combinations of FGF, Wnt, and Sonic Hedgehog are slightly different than the combinations in strength in the chicken, right? And so it's going to tell certain parts of that limb bud, these cells need to grow more, other cells need to die, right. And so the cells in between the fingers, for instance, are going to die by a thing called apoptosis, whereas other cells are going to keep growing, right, as you grow that tissue out, you're going to get either their longer and longer claws, longer and longer wrists, right? It's that establishment of the tissue and then forcing them to either grow or die that's going to change the architecture, and then you will get really big changes. But it starts from those small changes that direct other things.

0:40:00 Thomas: Okay.

0:40:47 Thomas: It's so crazy.

0:40:48 Eric: You want me to give you one that's a little more simple when talking about evolution?

0:40:48 Thomas: I no, reaction is just an awe reaction. It's, it's uh, obviously no matter no matter what anyone thinks of how complicated this is, which it definitely is, there's no better theory. Like, the idea that you could look at this and be like, well, never mind, God did it. It's like, okay, well please tell me the process by which God came to exist. Like that sounds more complicated, definitionally more complicated. So not as though I think like, obviously this didn't happen, but it's just this feeling of Like, I know this is real and how it works and how it happened throughout evolutionary history, but it's so fucking impossible, like it just seems so crazy. It's this really interesting feeling, but I love it. I love learning about this stuff because it's just mind-blowing to think about.

0:40:55 Eric: It really is incredible, yeah.

0:41:20 Eric: Great. Well, and that's where the time and the numbers really do the a heavy lifting, right? Because it really isn't dramatic, right. It's maybe, maybe you get half an inch longer on your claw, right, but There's still variation and random mutation that won't make that every time, right? Maybe If your parents had that mutation in Sonic Hedgehog, you will get that same thing and be slightly longer in your claw, right.

0:41:40 Thomas: Yeah. Yeah. Mm. Mm-hmm, yeah. Mm. Mm-hmm, sure.

0:42:00 Eric: Because you're going to survive maybe 0.1% of the time more often than someone with half an inch shorter claw, you are 0.1% more likely. You individually have about the same odds, but when you multiply that difference in odds by a million, then it becomes powerful. So it really only does work with that heavy lifting. And to really quickly touch on that God thing, I would actually say this is pretty definitive proof against creation, because this is not the system you would do, right?

0:42:12 Thomas: Yeah. Right. Yeah. Absolutely. That's What I Mean. Oh, Of

0:42:30 Eric: System you would do is what we were talking about before, where it's an RPG game. And if you wanted to to give them a new feature, you would just give them the item that they needed. This is a way more complicated to do it.

0:42:30 Thomas: Course. Course. Yeah, absolutely. I personally, I mean, maybe it's just my own bias, but I love the kind of the computer programming analogy because it really, the power of iterating on top of iterative is just really, really fantastic.

Like you but I'm not an expert, but just as a little bit of a hobbyist and interested in it, it's love I love learning about basic computing and programming early on and things like, OK, how did you make a little screen in which, you you could just barely make some difference in voltages and make different little, you know, black and white on a screen? And how did you turn that into like, all make this be a representation of numbers.

And then, of course, we have the binary code to go with like what goes into that. That. So we'll display a one here when it's got this value, et cetera, et cetera. So there's all these little building blocks, but then what, what over time is you shortcut it. So it's like, okay, we've solved that problem of like, here's how we get a basic little tiny number display, you know?

And there's that cool, there's a name for it, but I forget what it is, but that sort of like scoreboard type number display where it's really easy to display all the numbers, like the classic alarm clock, it's like all like lighting just writing different segments. That's a really cool solution to that. And then once that's solved, it's like, okay, well now we have kind of a short code of how to do that. And you're not having to reinvent that every time.

And now it's like, let's just call the little subroutine that does that. It's like we need to display the number three. Okay, bam, done. And it's a bazillion versions of that on top of each other where when you consider them individually, you're like, this is breathtaking.

I don't know how this could possibly be working and yet it's just the power of iterating like you just yeah no we've solved that problem and then now that's forever a little subroutine that we can use and multiply that times a million and you get this you know you of duty it's like just like ridiculous, ridiculous, complex, amazing stuff, yeah.

0:44:28 Eric: Exactly. And that's what your body is doing, right? They go, we need a little bit of notch signaling here. We need a Little Bit of Sonic Hedgehog signaling here, we our hox genes, which are things that kind of give us our top to bottom identity, right? Like where we are from our head to our toe. All of those genes are turning on at different points. Each one is just regulating their own thing using the same logic that all of the other ones are doing. Then they just come together.

0:44:53 Thomas: Right.

0:44:53 Eric: I've got to be honest, though, as you were talking about that, I was actually recently playing the game Baldur's Gate 3, and I'm using it with mods. And I'm always amazed that people are able to go into the computer code, change a couple of numbers, and now a completely different character is on the the screen like to me that's just as mystifying going from that binary to that rich vivid and textured world It It Is yes The

0:45:08 Thomas: Yeah. Yeah. It's Very Similar Though Because You Have a you have a series of like little subroutines, it's like, okay, well, this will be the hitbox of this character or whatever. Like this will determine that, and you can change the visual representation, and maybe that changes the hit box. Like it's very, it sounds like the it, the principle is very similar.

0:45:30 Eric: Principle is very similar as, like you were explaining, I was like, this is actually an analogy I'm going to steal and use with my students from now on, but

0:45:36 Thomas: Yeah, it definitely needs polishing, but yeah, for sure.

0:45:39 Eric: Are some times where you do get the rpg loop box and Those are pretty dramatic things, and I'm gonna explain briefly how that one comes, and then we can start to put it all all together and go from dinosaur to bird. So the one way that you can get really dramatic changes without that sculpting and more by adding on the new Lego piece is your genes are selected for because they're usually pretty necessary.

0:45:43 Thomas: Hmm. Mm-hmm.

0:46:04 Eric: But once in a while, you get what we call a gene duplication event. And that's when that gene, because of a mistake during either DNA replication or the way the chromosomes get pulled apart during meiosis, because you may know this, but you have one of each chromosomes, right? One from your mom, one from your dad. Means by definition, you're only giving one of your two chromosomes to your kid, right.

0:46:28 Eric: Before you produce your sperm or your egg, your chromosomes, your pairs of chromosomes have to divide and they get segregated such that like you're either giving the mom version of your chromosome or the dad version of your Chromosome to your kids, right, that happens, sometimes the chromosomes get stuck together and an extra piece of one of those chromosomes can get onto the other one. That will cause that gene to be duplicated. And the reason why that's so important is go all the way back to prehistory, right? And you are a cave person trying to cut meat so that you can eat it, right.

You're going to use a sharpened stone that you've turned into a knife, and right, you're going probably hold it with your hand and and you're going to cut the meat with your knife, right? You can't turn that knife into something else yet because you need it to cut them. Right. But then you get another rock that you turn into a knife because you're like, my hand keeps slipping and it's not really efficient. I'm going to stab the meat in place and I'm going to use the second knife to cut.

0:46:20 Thomas: Mm -huh. Uh-huh, yeah. Right. Mm -hm. Okay. -mm. Okay.

0:47:26 Eric: Right? So now you have one knife that's stabbing and one knife. That's cutting the knife that stabbing no longer needs to do its job as a knife that cuts though, right? So now you don't need that sharp, long edge. You need a point, right.

0:47:36 Thomas: Okay. -hum.

0:47:40 Eric: Maybe that knife will be even more effective at holding it in place, if you Have multiple points stabbing the steak, right.

0:47:46 Thomas: You're talking about the invention of a fork.

0:47:49 Eric: Right, that's what evolution is. It doesn't create a fork out of nothing. It takes the knife that wasn't necessary. And now that's no longer under selective pressure. Pressure, right? It's now free to experiment and find different structures and different functions. That's the way we generally get the RPG type item in evolution as opposed to the more subtle sculpting.

0:48:11 Thomas: Like, so repurposing something for a new function, function maybe?

0:48:15 Eric: Exactly. But usually that happens after either the original function is no longer necessary or you get one of those gene duplication events. So now you've got an extra copy to play around with, right.

0:48:24 Thomas: Like A Duplicate Yeah Wow Interesting. Do

0:48:26 Eric: That would be one way that we will.

0:48:28 Thomas: We know, like, examples of that, or is it just a general principle that, sure,

0:48:32 Eric: Are definitely examples. I don't know any off the top of our head, but gene duplications played a huge role in human evolution, which happened very, very quickly, relatively speaking. Even more interesting one, and you've probably heard of this one from a bunch of creationist debates, is chromosomes can also do stuff like fuse together, right? And that will affect the way those genes are expressed. So humans have one less pair of chromosomes than chimps because two of our chromosomes fuse together. And we can actually pinpoint exactly where in the chimp DNA the two two chromosomes fused together, which is really cool. The main point is the logic of evolution is you're not creating new stuff. You're taking the stuff you have that's no longer under pressure. And now you're able to experiment. All we're going to put this all together for the dinosaur. Ready?

0:48:35 Thomas: Yeah Yeah Well Gotcha Well All

0:49:17 Eric: So we have these basic logics, right, we can either get a gene duplication that gives us a new trait, or we have those morphogenic gradients that can shape our our body into different structures at different times and places during embryonic development, right? And you look at the difference between a non -avian dinosaur and an avian dinosaur, our birds, and let's say a velociraptor, right?

0:49:40 Eric: Major difference between those is a velocaraptor has, like, a teeth and a jaw and a bird has a beak, right. Velociraptor has an elongated tail and a chicken or a bird has a shortened tail that ends in a structure we call a pygostyle. Velociraptors had three claws. Birds had wings, right? Of those changes come from differences in the way those six or seven signaling molecules affect the rest of the embryo and the downstream, what we call transcription, the expression of other genes in development.

So if you want to take a and turn it back into something that looks like a velociraptor, all you have to do is find the cells during the time of tooth development. And instead of seeing the protein that inhibits teeth growth, right? Because something in the chicken embryo is telling what we call bone morphogenic protein, right, the thing that can usually promote bone growth, which is similar to Sonic Hedgehog, another one of those gradient -based molecules.

Another one of those signaling molecules is telling that BMP, that bone morphogenetic protein, not to be expressed in right? But if you turn on that BMP, now it will be able to grow teeth again, right. You take the tail, there's certain signaling interactions that tell it we are no longer growing our tail invertebrate, we are stopping that and we are developing that structure called the pygostyle.

But if vous boost something that is inhibiting or is promoting that that stopping of the tail growth, and instead let the tail keep growing, you're basically removing the signaling molecule that's telling it, stop, stop. So now you've got a chicken with the same DNA, but just by changing the way those signaling molecules are expressed, we now have teeth and we now have a tail.

You then go into the limb bud and you tell that Sonic Hedgehog, that FGF, that wind signaling, we don't want to do it this way. We want to change slightly when and where we're expressing and the zones that we're expressing. Maybe we turn off wind signaling in a certain spot and a certain time.

Maybe мы turn on Sonic Hedgehog again at a certain point in a certain time, and that will cause the shape and the structures that are produced in all those places to go back into the more dinosaur form instead of the chicken form. So the real key, the reason we haven't done it yet, is we need to find exactly which genes are responsible once we've turned on and off those signaling molecules, and when and where those genes are important.

Once we've identified those genes and know when and where, then it's just a matter of making those changes at the right time and place in chick development. And you can do that by changing certain sequences of the DNA that are less about what protein will be produced, and more the packing slips. So the way I always explain to my students is your gene has two major parts.

It's got the part that codes, the part that will make the package, the protein, and then it's got what we call regulatory sequences. And that's where those transcription factors, those signaling molecules will bind in effect that basically are the packing slip of the protein. They say when and where it's going to be shaped. And so by changing those packing slips, you're changing not the protein itself, but the structures those proteins will create.

0:49:40 Thomas: Right Yeah So that answers my question as to, like, why this is so complicated in terms of, it's not just like, oh, let's punch in the code for dinosaur, that's, it's like, there's seems like there's this these complicating factors of like precise timings and locations, and whatever, of when, where this thing is going to be, um, or expressed, to to change different things. And yeah, it just sounds like that's a very, that opens up the landscape of possibilities by a lot, to have that many variables introduced, to to able to, um, different, um, different things in utero, I guess. And so, so I guess looking at it from that perspective, it makes sense that it's not as simple as just like, well, let's just punch in this little like dinosaur code and then that'll make a dinosaur.

0:53:37 Eric: It's why I always hate in in the movies when the, I don't know if you watched Jurassic World, but like when the Dominus Rex was running havoc and it was camouflaging, they were like, well, it's got cuttlefish DNA, so I guess it can camouflage. But that's not how DNA works. It's not like it's like, oh, I've recognized cuttlefish and now I have all the properties of the cuttle fish, right?

0:53:48 Thomas: Yeah. Stupid. Yeah.

0:53:57 Eric: What they're really saying is they were stupid enough to put in the precise protein in cuttle fish DNA that produces that camouflaging pigment. And it's the same with the way we would build our chicken. First, we have to find what things do what, and then we make the changes. But if you just make changes, you're not going to know when and why those changes worked. So what you typically do when you want to identify when and what to do is you do what's called a mutation screen. And that's where either through what we now use as CRISPR, radiation, what we call silencing RNA RNA that can turn off genes, is you basically target every gene in the genome, right?

Now, a lot of genes will cause, when you turn them off, will cause the embryo to die immediately, they're not going to really be viable. But some of them will have the mutation, the phenotype that you're looking for, right, so you scan those hundreds of thousands of embryos, right, you go, okay, this one is no longer growing a tail, right. This one is growing a a tail. Which are the genes that are turned off in this one that's making it not grow a tail? The problem there is, as we talked about, yes, we know that there are those six or seven main regulators, right? Each of those turn on hundreds of genes at one time. So knowing which of those genes is the putative gene that is really cooking the meal, so to speak, is the real key. I

0:54:12 Thomas: Yeah. Right.

0:55:21 Thomas: So you're not closed into making a dinosaur? Is what you're trying to tell? We don't have today.

0:55:24 Eric: Will say, I speak for them, but Jack Horner, I think last year, actually did send out a tweet that they have figured out the way to extend tail growth, the way to grow teeth in chicken, and the way to fuse those digits back into a wing -looking thing. So they are pretty much there, because one of the major things you don't have to do, as we talked about in the beginning, is we actually don't have to figure out feathers or any of that. The feathers are actually part of the dinosaur body plan, at least proto feathers.

0:55:25 Thomas: There's no dinosaur today.

0:55:51 Thomas: Yeah. Yeah.

0:55:57 Eric: So like, instead of the more complicated ones, they would have things. But a lot of what we call the par avian dinosaurs, the mani raptors, your velociraptors, you're micro raptors your troodontids. If you watch dinosaur train, they will have true panaceous feathers, the feathers that birds have.

0:56:16 Thomas: Don't know what any of that is. Sorry. No, I don't want it. But, but yes, interesting. And, We're way over time, but that is so fascinating. I feel this forever. Um, is there anything that you wanted to get to that you didn't get to? Um,

0:56:27 Eric: Think the main thing that if I could stress to people, as they think about evolution, think about biology in their everyday life, is you really want to remember that we don't want to think of biology like Gattaca, where your gene is like a series of letters and things that you want to read like a book. You want to thinking of it as more of a simple set of logical principles, as you were saying, that iterates over time.

0:56:45 Thomas: Yeah. Hmm.

0:56:52 Eric: And I think once you get to that, combined with population, biology will make a lot more sense for a lot more people.

0:56:59 Thomas: Got it. Well, this was a lot of fun. Um. There anywhere, uh? You want to send people or anything to learn more? Do you have any, uh., you know, online presence you want to tell people about?

0:57:09 Eric: I have zero online presence.

0:57:10 Thomas: Love it.

0:57:11 Eric: This is my first time doing anything like this. I don't have any social media because I have 10th grade students and I do not need anyone going into my socials.

0:57:16 Thomas: There you go. That sounds like the way to be. This was an absolute pleasure. I appreciate it. Maybe we can find another way to carry on the discussion in directions. It is a little technical and difficult, but I think you did a great job. I appreciate you trying to dumb it down for us. Dr. Eric Jaffe, thanks so much for joining us today. That was fun.

0:57:41 Eric: Thank you and I'd love to come on again.