Listener Questions #35: Genetics (featuring Dr. Benjamin de Bivort)

Daniel and Kelly answer questions about innate behaviors and what it means to "decode" a genome with help from Dr. Benjamin de Bivort. See omnystudio.com/listener https://omnystudio.com/listener for privacy information.

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Daniel Whiteson?

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• 2:15Kelly Weinersmith?

  What does it mean to decode DNA? And having done it, what can you really say?

• 2:21Daniel Whiteson?

  Is DNA coding for innate behaviors more like a blueprint or a recipe? How does DNA result in a web by a spider or honey from a bee?

• 2:31Kelly Weinersmith?

  Can instincts be transferred? And how do we know? Could gene manipulation give me a rooster's crow?

• 2:39Daniel Whiteson?

  Whatever questions keep you up at night, Daniel and Kelly's answers will make it all right.

• 2:44Kelly Weinersmith?

  Welcome to another listener questions episode of Daniel and Kelly's Extraordinary Universe. This is episode number 35, featuring Dr. Ben de Bevore.

• 3:07Daniel Whiteson?

  Hi, I'm Daniel. I'm a particle physicist and I'm not a biologist.

• 3:12Kelly Weinersmith?

  Hello, I'm Kelly Weider-Smith. I am a biologist, but I am not a geneticist. And I did kind of try to avoid genetics a little bit when I was in grad school.

• 3:24Daniel Whiteson?

  Why is that? To me, genetics has so much mathematical underpinnings. It's like, maybe the math is part of biology. Oh, wait, am I answering my own question?

• 3:33Kelly Weinersmith?

  I am insulted. I, so I actually, I went into ecology because I loved that it had math.

• 3:42Daniel Whiteson?

  Right, differential equations, yeah.

• 3:43Kelly Weinersmith?

  That's right, that's right. And what, you know, I was taking stochastic differential equations over in the math department with the math PhD students when I was working on my masters. I like the mathy stuff.

• 3:53Daniel Whiteson?

  Awesome, all right. So then what's your objection to genetics?

• 3:57Kelly Weinersmith?

  You know, it was changing pretty quickly. What I was, here's, here, bottom line, I'm not good at the PCR machine. And so I just, it was like magic. And I just felt like I couldn't do genetics in the lab. And so I just kind of veered away from it a little bit. I'm not a lab person, I think.

• 4:18Daniel Whiteson?

  You're more of a farm person, aren't you?

• 4:19Kelly Weinersmith?

  I'm more of a farm person or like. Experiment like a behavior experiments kind of person. I'm just, I'm not good with the pipette. That's as we've discussed before.

• 4:27Daniel Whiteson?

  All right. So then my question to you today is, are you doing genetic experiments on your farm? Are you breeding some new variety of goats?

• 4:36Kelly Weinersmith?

  Oh.

• 4:37Daniel Whiteson?

  Or something similar?

• 4:38Kelly Weinersmith?

  Uh, you know, I, I have had a lot of discussion with the people I got my goats from about like, oh, you know, dude, which of the goats on your farm, like which ones had mothers that produced a lot of milk and had good teeth placement and had good, uh, you know, stuff like that. And so.

• 4:54Daniel Whiteson?

  I'm sorry, I have to ask, what is good teeth placement and what is bad teeth placement?

• 4:59Kelly Weinersmith?

  Well, I, well, so, so it's like a combination of like, you know, are they placed like, you know, far from the legs? So it's easy to like, get a good hand. And then, you know, are they like long? So you can get your hands around them because you're like, your fingers cramp if it's just like your thumb and your pointer finger, you know, you want them to be nice, you know, long and you want them to have a big hole. So a lot of milk comes through with each squeeze and, uh.

• 5:23Daniel Whiteson?

  Good for human milking then, not for kid suckling?

• 5:26Kelly Weinersmith?

  Human milking, I feel like that gives me a different visual picture, but good, good for, uh, easy for the human. Easy for the human who is doing the milking. Yes, indeed.

• 5:40Daniel Whiteson?

  Wow. Fascinating.

• 5:41Kelly Weinersmith?

  That's right.

• 5:42Daniel Whiteson?

  All right. And is that factoring into your decisions about these goats futures?

• 5:46Kelly Weinersmith?

  Uh, you know, I will tell you that we, you know, we've talked about Lottie's prolapse a number of times on this, uh, this podcast, uh, but that tends to be genetic. And so Lottie's kids will not be bred, uh, because we don't want to pass that trait on. And so any little dudes that she had will become what they call Weathers, which means we're going to finally get a goat named Carl Weathers, which we're excited about. And, uh, if we have any boys would, uh, and then if, if we have girls, then we're just gonna, they'll be, they'll all be pets. So anyway, this is, this is factoring into some decisions on our farm, but, uh, we're getting a little off track because we're.

• 6:27Daniel Whiteson?

  No, we're not. We're talking about how genetics influence organisms.

• 6:31Kelly Weinersmith?

  That's true.

• 6:31Daniel Whiteson?

  She's the topic of today's episode, isn't it?

• 6:33Kelly Weinersmith?

  Yeah, no, you're, you're right. You're right.

• 6:35Daniel Whiteson?

  And because of your famous discomfort for genetics, you called in a ringer, didn't you?

• 6:39Kelly Weinersmith?

  I did. Yes. Right. And not just any ringer. We are a big enough podcast that the ringer we called in is a Harvard geneticist. We got Dr. Benjamin Debevoire. He's a professor at Harvard in the Organismic and Evolutionary Biology Department and the Center for Brain Science. He studies evolution and behavior where he asks questions like, why do genetically identical individuals behave differently from one another? And I am super excited that we got him on the show. And so today we're doing, is this supposed to be a listener questions episode? There were some parts where I felt like, I can handle this because, so, you know, while I said, I kind of tried to avoid genetics.

• 7:23Kelly Weinersmith?

  I did get a degree in animal behavior. So I didn't like avoid genetics entirely. And so today we're gonna like, jump between a conversation that you and I had with Ben.

• 7:36Daniel Whiteson?

  Yep.

• 7:37Kelly Weinersmith?

  And then me answering some questions because I'm not completely incapable. I'm just maybe a little bit nervous about genetics. And so, but I'd like to preface this with any mistakes that are made when I'm just talking on my own. Those are my mistakes, not Ben's mistakes. But yeah, we're gonna jump between a conversation that we had with Ben and, you know, me trying to hold my own on genetics and we'll just see how it goes.

• 8:01Daniel Whiteson?

  All right. Whenever you feel uncomfortable, just mash that Harvard genetics button.

• 8:05Kelly Weinersmith?

  That's right. That's what I'm gonna do. And our trusty and amazing audio guy, Matt, will come up with the sound for us. We love you, Matt. Okay, so let's go ahead and start this episode by bringing Ben on the show. And it turns out that in addition to enjoying puzzles, skiing, sailing, fossils, minerals, mushrooms, and games, Ben enjoys super forecasting.

• 8:29Daniel Whiteson?

  Super forecasting?

• 8:30Kelly Weinersmith?

  Super forecasting. And he was a super forecaster for the Good Judgment Project. So we are going to jump in to our interview with me asking Ben a question about super forecasting. Matt, bring us to the conversation with Ben.

• 8:47Kelly Weinersmith?

  What does it mean to be a super forecaster?

• 8:49Speaker 06

  Yeah, so this is the idea that with a little bit of reasoning and reading the news, people can make reasonably accurate predictions about future geopolitical events. It's a set of skills that have been monetized of all things, like, and now there's like betting markets where you can make forecasts about elections and...

• 9:13Kelly Weinersmith?

  And were you working on the betting markets? Or you were, what were you doing?

• 9:18Speaker 06

  No, this was in a earlier stages where this kind of, these techniques were the object of academic research. And so there was a research team out of University of Pennsylvania. Phil Tetlock and Barbara Mellors were the lead investigators. And it was a research project for DARPA, of all things. You know, the government certainly has an interest in knowing what will happen politically in the future. And their first result had been that random people do better than so-called experts, pundits, at predicting future events.

• 9:57Kelly Weinersmith?

  Okay.

• 9:58Speaker 06

  And then their main finding, when I started to be involved, was that you could aggregate the predictions of amateurs, use the wisdom of the crowds to make more accurate forecasts. And then they ran these studies and I was just a study subject, testing variables like prediction markets versus forums as a sort of discussion venue for making predictions. So testing some theories about efficient markets producing the best estimates. And then I ended up being good at it and being sort of categorized as a super forecaster, which meant that they used us as one experimental group for some further studies and put us head to head against people from the intelligence community who had access to classified information.

• 10:43Speaker 06

  So there were sort of four or five studies that came after those initial results.

• 10:48Daniel Whiteson?

  And so do you think the CIA has like tapped your living room to hear your dinner conversation so they can tap into your insight about the future of the world?

• 10:56Speaker 06

  That's right. They've just activated the microphone on my phone.

• 10:59Daniel Whiteson?

  Exactly.

• 10:59Speaker 06

  Not that they don't think it's for everyone.

• 11:04Kelly Weinersmith?

  All right. Well, I know who I'm gonna call the next time I need to know how an election turns out.

• 11:10Daniel Whiteson?

  Wait, I can't believe I didn't ask him what's gonna happen in the midterms.

• 11:14Kelly Weinersmith?

  Oh, my gosh.

• 11:15Daniel Whiteson?

  I'm dying to know.

• 11:15Kelly Weinersmith?

  Well, I guess we're just gonna have to wait and see. Or maybe we can bring him back for a midterms episode.

• 11:22Daniel Whiteson?

  I also should have asked him whether his fondness for mushrooms helps or hurts his ability to forecast elections. But maybe I held my tongue because that's not the kind of question you ask a Harvard geneticist.

• 11:33Kelly Weinersmith?

  Yeah, maybe. And frankly, that could have been a whole episode of questions about super forecasting, but we need to get back to genetics.

• 11:41Daniel Whiteson?

  Yes, we do.

• 11:42Kelly Weinersmith?

  And since many of us learned the, you know, the basics of genetics and translation and transcription when we were in like sixth grade, I felt like maybe I could tackle that topic. And so let's give it a shot.

• 11:57Daniel Whiteson?

  All right. So Kelly, explain to us, how does this all work? How's information stored in DNA? And then how does that turn into me and you and mosquitoes?

• 12:06Kelly Weinersmith?

  Okay, right. Unfortunately, it does turn into mosquitoes sometimes. All right, but let's, I'm gonna try to keep this as like simple and jargon free as possible. So the way information is stored in DNA is that it's stored in a series of letters. These letters are A, T, G, and C. We're not even gonna say the names because Daniel's gonna get annoyed if I start using the names.

• 12:28Daniel Whiteson?

  Because there's no information in the names. It's just cognitive burden for your listener.

• 12:33Kelly Weinersmith?

  And that's why you never say muon or anything on the show. It's what I appreciate your consistency. And so.

• 12:43Daniel Whiteson?

  Muons do sometimes change the letters in DNA, actually.

• 12:47Kelly Weinersmith?

  Oh.

• 12:48Daniel Whiteson?

  So it's relevant. Cosmic ray radiation.

• 12:50Kelly Weinersmith?

  Wow, wow. Does it change like an adenine to a guanine?

• 12:56Daniel Whiteson?

  It changes a something to a something else.

• 12:58Kelly Weinersmith?

  Okay.

• 12:59Daniel Whiteson?

  But I think of these four letters as sort of like quaternary code. You know, like binary is zero or one, trinary is zero, one or two. This is like a digit that has four possibilities. Is that the right way to think about it?

• 13:10Kelly Weinersmith?

  Yes. Yeah, yeah. It's a digit that has four possibilities. And then for each location, and those locations are many, you can have any of these four digits. And the way they're sort of set up is kind of like. A rope ladder is how I think about it. And so you've got like a rope on one side, sort of holding everything together. And then you have rungs. And on the left side, you've got like, you know, an A, a C, a G, an A, a T, T, T, and stuff like that. And then on the other side, you essentially have the exact same information, but it's flipped. And so to hold the ladder together, the rungs snap together.

• 13:52Kelly Weinersmith?

  So instead of being just like one ladder that goes all the way across, you get two pieces that snap together. And to get them to hold together, you need to have the opposite letter to essentially make them like molecularly strong enough to hold together.

• 14:07Daniel Whiteson?

  And so in this sense, they're not exactly just like four letters, right? Because they have this opposite relationship.

• 14:13Kelly Weinersmith?

  That's right.

• 14:14Daniel Whiteson?

  Like if it was zero, one, two, and three, like I couldn't tell you three is opposite to one. But here they have this additional relationship.

• 14:21Kelly Weinersmith?

  That's right. Yes. Yeah. So I should have earlier been like, you're wrong. I missed my chance.

• 14:29Daniel Whiteson?

  Or you'll get many more.

• 14:30Kelly Weinersmith?

  Or yeah, that's right. Or no, you're right, plus complications, because it's biology. So, uh, all right. So, so across from an A, you always get a T. And across from a T, you always get an A. And across from a C, you always get a G. And across from a G, you always get a C. So anyway, the As and the Ts always teamed up. The Cs and the Gs always teamed up on this rope ladder. And so you get this rope ladder system. The way you usually find it configured is that the rope ladder sort of like twists. And so like, if you imagine, uh, you've got like your sibling on the rope ladder and you really want to like get them dizzy, you sort of twist it at the bottom. And then you let it go and your, your sibling sort of goes sort of flying as it untwists.

• 15:13Kelly Weinersmith?

  Can you imagine what that looks like when you twist it?

• 15:16Daniel Whiteson?

  So, yes.

• 15:16Kelly Weinersmith?

  Okay. So when it's twisted, it looks like what's called a double helix. If you get your sibling off, so it'll twist the right way. And if you keep twisting and twisting and twisting and twisting and twisting, it gets really, really tight. And that's how we store it in your nucleus. Okay, so that's the way it's usually stored, but you can't really do anything with it when it's stored up like that. So now, say you want to do something with it. Say, for example, you would like to use some of the information that is stored in one of those genes. Say, maybe you want to make a particular protein that is coded for in one of those genes. The next thing that happens is called transcription. So you start unwinding that messy ball of stuff that you've got.

• 16:01Kelly Weinersmith?

  And now you unzip and you start opening up that rope ladder. So remember how I was saying like you've got the As that are matched with the Ts? You've got the Cs that are matched with the Gs? Now you've got something that goes in and it sort of separates all of those things. And so now your rope ladder is in two different pieces. And now you've got RNA that goes in and it also matches up Cs with Gs and Gs with Cs. But now instead of matching up As with Ts, it matches up As with Us. This is a point that you really don't need to understand. Biology is weird. I don't necessarily know that biochemists know why biology decided to add a U instead of a T here, but it's fun, right?

• 16:46Kelly Weinersmith?

  It depends. It had to be something different at this stage.

• 16:51Daniel Whiteson?

  Because it was all about to make sense to me and then you threw in the U.

• 16:54Kelly Weinersmith?

  That's right, that's right.

• 16:55Daniel Whiteson?

  And you weren't even kind enough to use a U spoon. You just threw it right at us.

• 16:59Kelly Weinersmith?

  That's right, that's right. I know, I'm so sorry. I really loved your joke the other day, as long as it's not a me spoon. So anyway, so, and so now you've got essentially a copy of what you had before, but it's like an inverse copy with Us now instead of Ts. But anyway, so now you've got this copy, right?

• 17:19Daniel Whiteson?

  And so so far, the DNA has been tightly stored. It's got information in it, though we don't yet know like how to read that information or what it means specifically. It's just like some set of code tightly bound. Then you've unwound it and now you're using the RNA to somehow read that. And then it's going to get us to building proteins that make up me and mosquitoes. Is that where we are?

• 17:40Kelly Weinersmith?

  Uh, yeah, that's where we are.

• 17:42Daniel Whiteson?

  Okay.

• 17:42Kelly Weinersmith?

  Yeah, I mean, like, evolution knows what that stuff does, but...

• 17:46Daniel Whiteson?

  Yeah.

• 17:46Kelly Weinersmith?

  But I haven't told you. Yes, yeah, that's right. That's right. Okay. So, all right, so now you've got RNA that has like an inverse copy of the information. And it now is going to travel out of the nucleus and out into the like watery outside of the cell. It's going to find an organelle, like a little organ. I think you called it an organito in a previous listener questions episode. And I will always think of them as organitos now.

• 18:15Daniel Whiteson?

  They're so little and cute.

• 18:16Kelly Weinersmith?

  I know, it's a little organito and called a ribosome. And at the ribosome, you're going to have what's called translation, where essentially you are going to translate this information from RNA into proteins. And so now each of those three letters are coding for an amino acid. And amino acid is just a little building block for a protein. So each of those three letters is going to become a chunk of a protein. And so at the ribosome, you just get one amino acid chunk connected to another amino acid chunk, connected to another amino acid chunk. And you get all of these chunks together and you get this long string

• 18:59Kelly Weinersmith?

  that is going to fold up to become a protein. And these proteins are essentially like what makes up all of your body. It makes up the mosquitoes, it makes up your hair, it makes up, you know, all of the stuff, your, the hormones that, you know, that make you do the things that you do and whatnot. Okay, so now you've got this long string of amino acids. And we've now talked about what is usually thought of as like the central dogma, which is that, you know, you've got this information, it's stored in DNA and then gets copied with RNA and then that RNA gets turned into proteins. But we're going to now talk a little bit about how those amino acids get turned into proteins that then get folded up in a very particular configuration

• 19:40Kelly Weinersmith?

  because Daniel and Ben had a really interesting conversation about how that stuff folds up on itself. And so we're going to jump back to our conversation with Daniel and Ben so that we can talk about protein folding. So we're pressing the interview button and we're heading back to our conversation with Ben.

• 20:01Speaker 06

  We can say that amino acids are compounds. They have nitrogens and carbons. If you take protein powder, it's going to be rich in amino acids. Monosodium glutamate is a salt of glutamate, which is an amino acid. And there are about 20 of these amino acids, which get pieced together in different sequences to make proteins. And they have different chemical properties. And by assembling them in the right combinations, in the right sequences, you can get that protein to fold into the correct shape. This is a bit like origami, where, imagine like origami where you don't have an instruction

• 20:45Speaker 06

  guide with a paper. It's just that the paper has certain properties of like, you know, one side has a certain kind of stickiness and it wants to fold up to the next part of the origami. And these are the so-called like electrostatic properties of these amino acids, where the ones which like to hang out with water will tend to hang out together and the ones that try to avoid water get pushed together. And so by developing the right sequence of amino acids in the protein, it ends up adopting a particular 3D shape and its function within the cell comes from that shape that it has.

• 21:20Daniel Whiteson?

  And so is this the process we here refer to as protein folding? That you've put together these amino acids and then they somehow make themselves into this 3D machine?

• 21:30Speaker 06

  That's right.

• 21:31Daniel Whiteson?

  And how much of that is understood? Like if you start from a DNA sequence, how hard is it to predict what protein it's going to turn into?

• 21:40Speaker 06

  Yeah, well, I would say for a few decades, we've had a good conceptual understanding of it. So there's different levels of protein folding organization. So one thing that happens is, you know, there's interactions between the one amino acid and the next one in its sequence. You know, these would be like the individual folds, maybe you'd make in the origami analogy. And You know, so there are certain shapes that proteins have within them, you know, alpha helices, beta sheets, you know, gamma turns, all these things. And this has to do with kind of local interactions. That's sort of the lowest level of protein folding. Then there's a question of how do those local structures fold together to form domains within the protein?

• 22:24Speaker 06

  So maybe if we're making an origami crane, like the head and the neck is the domain and the wing is a different domain. So how do we get the head and the neck out of individual folds? And then how do the head and the neck relate to each other to give the shape of the overall body to the protein? And then there's interactions beyond that. So proteins interact with each other to produce complexes, you know, in the same way that the different parts you'd put into an engine, you know, like the carburetor and the manifold or whatever. These are different elements, but they work together to produce the grand function of the object. Proteins are the same. You might make one protein. This is mixing metaphors, but you have, you know, different origami pieces come together

• 23:06Speaker 06

  to make a, you know, origami scene. And that's, those are the sort of bioactive complexes that run the cell.

• 23:14Daniel Whiteson?

  So does that mean that we can predict it or we roughly can predict it?

• 23:18Speaker 06

  Oh, sorry, yes. So we had this nice conceptual framework about these hierarchical levels and we could in the past do some predictions about like when you would see an alpha helix emerge. This could be done computationally. And then it was considered a great mystery how you produce the overall shape, that sort of grand conformation of a whole protein molecule. But then the, the great insight four or five years ago was AlphaFold. This is a machine learning based prediction tool for protein folding, which is trained on data from, you know, thousands of protein sequences that were figured out by experimental methods.

• 23:58Speaker 06

  And now for certain categories of proteins, particularly ones that are freely floating within the watery portions of a cell, we can get a quite good prediction of its conformation just from its sequence. It required the tools of machine learning to get there. So. You know, like all kind of AI, machine learning methods, you can have an effective tool at making that prediction without understanding all of the relationships that the model has learned in order to make that prediction.

• 24:31Daniel Whiteson?

  So my understanding is that these techniques rely on a bunch of examples. As you say, we had an example of here's the DNA and we know what the protein is. Here's another example where we know the DNA, we know the protein. And machine learning essentially learns a mapping from the DNA to the folded protein. But as you say, knowing how to do it or knowing how to generate an answer doesn't always yield an insight. Have we been able to pick apart AlphaFold in any way and learn something about the fundamental biochemistry? Or is it completely a useful black box?

• 25:01Speaker 06

  My understanding, it's more in the useful black box because it's fairly recent. And when we get these ML objects, you know, I would say like the one I encounter more in my own research is simulations of neural networks and brains, more than these biochemical simulations. These objects have a comparable complexity to the biological object you're trying to study. So you can switch from studying the cell to switching the simulation of the cell. But in some ways, you use the same empirical approaches. You know, you snip off certain parts of the network or you perturb it in different ways and see how it alters the prediction. But it can be similarly hard to gain insight about how these

• 25:46Speaker 06

  tools make their predictions as it can be to understand how the biology happens. So I would say that's ongoing. The extraction of principles out of these tools is ongoing.

• 25:59Kelly Weinersmith?

  All right, Daniel and I are back from our fascinating discussion about protein folding. And we're ready for our first listener question.

• 26:09Daniel Whiteson?

  All right, and this question comes from Matthias and it's about the dire wolf episode.

• 26:18Kelly Weinersmith?

  Kelly here. We didn't hear back from Matthias in time. That's okay. We all get super busy sometimes, so I'm gonna read their question here. "Hi, Kelly and Daniel. I have a biology question. I'm listening to the Dire Wolf episode, and I have a question about DNA. What does it mean to decode DNA? I've read, for example, that the human genome is decoded. What exactly does this mean? What do we know when it's decoded? Do we know to change the hair color, you'd need to change those X parts in this specific way? I'm guessing not. Thanks, Matthias."

• 26:57Kelly Weinersmith?

  Okay, right, so this is a great question. And so I looked through a bunch of different sites to try to figure out what "decoded" means. And frankly, it meant different things depending on what site I was looking at. I feel like decoded is just kind of a word that means like, we kind of figured it out.

• 27:21Daniel Whiteson?

  I think the fuzziness in my mind is, does decoded just mean we did that first step, the part that RNA is doing where we said like, oh, it's an A, and then a G, and then a T, and then a C? Which already is cool, because like, we didn't know that, right? We didn't know what the sequence was for a particular human. Or does it mean we took the second step of saying, and we know what this T is for, and we know what this G is for, and we know how it all builds together to make your eyeball? Which part of it have we done? What do we mean by decoded?

• 27:49Kelly Weinersmith?

  Yeah, so as far as I could tell, decoded is not really actually a technical term. Like, when I was looking, I saw it used to mean something like, we now know the string of A's, C's, T's, and G's. Like, we figured out the sequences of those letters that make up the human genome. Or we know that the DNA has been transcribed into RNA, and we know what the sequence is in the RNA. So that's the stage where it was copied.

• 28:15Daniel Whiteson?

  Right.

• 28:15Kelly Weinersmith?

  Or that the RNA has been translated into amino acids, and now we know what the sequence of amino acids is. And so we decoded it into the protein. And so now we kind of know what the protein sequence is. And so I saw it used for each one of those three steps.

• 28:32Daniel Whiteson?

  And as Ben has explained to us so nicely, those are big differences, right?

• 28:36Kelly Weinersmith?

  Yeah.

• 28:36Daniel Whiteson?

  Just knowing the sequence is very different from knowing the proteins, right? There's a huge leap there.

• 28:41Kelly Weinersmith?

  Yeah, huge leap. But then the second part of the question was, when something has been decoded, what do you know? And what do you know depends a lot on what you knew before you did the decoding. So for example, if you got somebody's genetic sequence and they wanted to know, you know, hey, my mom had Huntington's disease, do I have Huntington's disease? And you decoded the sequence of their genome and you had all this background information, you could tell them if they were likely to get Huntington's or not, because we know all this background information. And so if you have the sequence, then you know a lot of information.

• 29:26Kelly Weinersmith?

  But if you went to an alien planet and they happened to use the same ATGC system that we use and you got the sequence, you might not know anything. I mean, maybe you'd get lucky and they were, they had a lot of the same genes that we had. But like, you'd have to do a lot of work to figure out what those sequences mean and what those genes are doing. And so just having the sequences doesn't really tell you where the genes are, what those genes do, what the proteins do. And so you need a lot of background information. So with the dire wolf example, because we know what a lot of those genes do in wolves, just having the sequences meant we could find a lot of genes.

• 30:09Kelly Weinersmith?

  And we knew what a lot of the proteins do because we know what they do in wolves or we know what they do in closely related mammals. So we can use a lot of information from other organisms to infer a lot.

• 30:20Daniel Whiteson?

  I see. So it's like somebody gives me a map of a brand new house I've never seen before, but I know what a bathroom looks like and I know what a living room looks like. I'm not a complete alien and so it helps me navigate to the bits I need.

• 30:33Kelly Weinersmith?

  That's right, yes. But just getting a genetic Sequence from, you know, an organism that we've never seen before, totally unlike anything else, you'd really know nothing. So when we, yeah, the first genetic sequence we ever got, we were probably like, oh, okay, we can do this. But what does it mean?

• 30:50Daniel Whiteson?

  I remember the sense when we were working on the Human Genome Project that once we had this, so many things were going to be unlocked. We would finally have a map to this incredibly powerful territory. Do you think that that came to fruition afterwards? Or do you think that was a little bit of a disappointment?

• 31:06Kelly Weinersmith?

  So when Zach and I wrote the chapter on precision medicine for Soonish, my sense was that there was quite a bit of disappointment right after we got the human genome, that there weren't a lot more problems that were solved immediately after that. But I do feel like over time, as we've learned a lot more things and put a lot more pieces together, we have been able to solve more things. And I was talking to someone the other day about like the human connectome, where they're trying to like, find the connections between all of the, you know, nerves in the human brain. And I was like, come, I mean, do we ever learn anything helpful from all of this stuff? And their take was that I was being a wet blanket. Surprise. And they were like, no, I do feel like out of all of these pieces of information,

• 31:51Kelly Weinersmith?

  more, you know, a more complete picture is emerging. And we are starting to be able to solve more problems. And yeah, and they felt like I was being negative, which I probably was. Because come on.

• 32:04Daniel Whiteson?

  So I think Matthias is asking essentially, how useful is this? What does knowing this information mean? Does it just mean we have the letters and who cares? Or does it mean we now understand everything? And I think you're saying it's somewhere in between. It's more than we just have the letters, but it's definitely not that we understand everything about what it turns into.

• 32:23Kelly Weinersmith?

  Yeah, yeah, I mean, I think it's context dependent. With the dire wolf, we probably knew quite a bit, given the context we had for wolves. And if it's about humans, we probably also know quite a bit. But, but yes, it's, it is probably somewhere in between. You don't know everything. It depends on what you knew before you got the sequence.

• 32:40Daniel Whiteson?

  Right.

• 32:41Kelly Weinersmith?

  Okay, so let's take a break. And when we come back, we are going to talk to Ben about what percent of our genes are associated with behavior.

• 32:59Speaker 07

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• 33:28Speaker 03

  Hey, it's Covino and Rich Davis from Covino and Rich. Buy smart, drive for less, and trade for more. That's Toyota affordability, and it starts with a great deal on an off-road ready Tacoma or half-ton Tundra, two of Toyota's most capable and longest-lasting trucks. Combining power for work, tech for adventures, and style in between. Built on reputation for quality and reliability, Toyota trucks are known for holding their value, which can mean big savings when it's time for your next Toyota. So get a great deal today and great value tomorrow. Shop toyota.com for more. Toyota, let's go places. I'm Malcolm Gladwell, host of Smart Talks with IBM. I spoke with Dr. Lara Jayhai of Cleveland Clinic about how advanced computing is helping

• 34:12Speaker 03

  shorten the path from medical discovery to treatment. The moment that there is a compound that someone in a lab thinks it would be effective to treat a certain disease, it takes about 10 to 13 years from that moment to when that drug is on a shelf for a patient. A big part of that gap could be computationally solved. Better simulation of compounds, designing drug trials that are more efficient, that would finish faster. That was the motivation to bring computational tools and technology closer to biomedical researchers. Learn more about how Cleveland Clinic and IBM are using AI and quantum computing

• 34:55Speaker 03

  to revolutionize biomedical research at ibm.com/smarttalks. Hi, I'm Jenna Oshkowitz. You might know me from Glee. This is At the Table, the food allergy podcast, a show about

• 35:09Speaker 02

  Food, connection, and what it really looks like to live with food allergies. Each episode, we hear stories from real people like Daniel. People would always think I was lactose intolerant, so I just kind of shortened my explanation to I'm deathly allergic, in a big way that defined a lot of my childhood. And while there are challenges, there are moments that remind you you're not alone. One of the best guys that I dated, he made a point to memorize all my food allergies. So join us and hear their stories and more, because living with food allergies isn't just about what you can't eat, it's about still having your seat at the table. Brought to you by Genentech and Novartis. Listen to At The Table, the food allergy podcast

• 35:52Speaker 02

  on America's number one podcast network, iHeart. Follow At The Table and start listening on the free iHeart Radio app today.

• 36:10Kelly Weinersmith?

  Okay, we're back. And in the third segment of today's episode, we're going to be talking about innate behaviors. And so we wanted to start this second segment by asking Ben about what percent of our DNA is associated with behavior. And then I sort of hijacked the conversation because I've always been really interested in what percent of our DNA does nothing at all. And so I went ahead and asked him that as well. And so let's dig back into our conversation with Ben. Ben Button.

• 36:44Kelly Weinersmith?

  So how much of our DNA is associated with behaviors? This is probably like an impossible thing to know for sure.

• 36:51Speaker 06

  Yeah.

• 36:51Kelly Weinersmith?

  And maybe you have to be kind of hand wavy, but like, yeah, what percent of the human genome is associated with what ends up being a behavior?

• 36:58Speaker 06

  A huge amount. And part of this is that genes have many, many functions each.

• 37:07Speaker 06

  So a gene might be involved in coordinating heart rhythms and blood circulation. And you might say, well, that doesn't have to do with behavior. But we also know that cardiac health has a huge amount to do with like the behaviors and organism exhibits. That gene could also be used to pattern the heart during development and used in a different context to pattern neural development. So genes get redeployed in different contexts, in different organs, at different times, all across the body. And so they have many phenotypes. And depending on sort of how sensitively you measure behavior, I honestly think if you picked a random gene and disrupted it, there would be a high chance that you could

• 37:52Speaker 06

  observe some effect on probably any behavior you look at, right? It's sort of this all to all mapping of genes and phenotypes when you have a sensitive enough instrument to measure it.

• 38:03Kelly Weinersmith?

  How are we not getting more Nobel Prizes, Ben? Everything depends on this.

• 38:08Daniel Whiteson?

  It's all the particle physicists are pushing you guys out.

• 38:10Kelly Weinersmith?

  That's right.

• 38:11Speaker 06

  There's a lot to figure out and in other fields, too. So they can, they can get some prizes.

• 38:18Daniel Whiteson?

  Such a nice answer. Oh, my God.

• 38:21Kelly Weinersmith?

  So when I was in undergrad, I remember there was this headline that some really high percent of our DNA does nothing. And is that, do we still think that's true? Or does it have a function now? And if it does nothing, why do we still have it?

• 38:37Speaker 06

  It's complicated. I think that's going to be the theme of these answers. So, you know, a lot of that comes from experiments where you, so there's kind of theoretical arguments of when we take a genome and we look at what kind of annotations we've given to it, segment by segment.

• 38:55Kelly Weinersmith?

  What does annotations mean?

• 38:57Speaker 06

  Annotations means, um, like, okay, so you, you have a genome and you put it into a sequencer and you get that raw ATGC sequence and it's billions of base pairs or hundreds of millions. That's the genome sequence. Then there are processes by which you can take that sequence. And these days, for the most part, computation Assign some meaning to different regions of that sequence. So imagine if you've got a book written in a language and in a script you're sort of unfamiliar with, you can see what the symbols are and what their sequence is. But to get meaning of, oh, well, this is a chapter. And, you know, this is this part of the plot and this is referring to a character in the story.

• 39:40Speaker 06

  That's applying meaning to this sequence of symbols.

• 39:43Kelly Weinersmith?

  Great.

• 39:44Speaker 06

  You know, these days, this is done drawing on the sort of vast body of molecular biology research that's been done already. To say, oh, I'm, you know, I'm looking at this sequence of symbols. And it it looks really similar to this one I've already seen in some other organism. And so I can make the prediction that it's referring to a certain biological process. And we know things about, you know, how RNA polymerase, which is the enzyme that does transcription, that converts DNA into RNA, recognizes the places in the genome where it should start to make a new RNA molecule. Like, we know something about the sequence character that are those transcriptional start sites.

• 40:28Speaker 06

  So we can, the computer can go through and look at all those symbols and say, you know, I have found 20,000 transcription start sites. And I know something about the sequences based on homology. So this is like shared characteristics by common descent. So the fact that the sequence looks the same in one organism as another allows us to kind of transfer our knowledge from the one organism into the one that we're trying to characterize. So you get predictions about function that come from this annotation process. And part of the notion that there's a lot of functionless DNA is that much of this of the genome is not assigned a function through this annotation process.

• 41:10Speaker 06

  The fraction of the genome which encodes for genes and proteins is small compared to the total genome. It's very species by species, but, you know, in humans, I think it's like two and a half percent or something like that is is genetic and protein coding.

• 41:27Kelly Weinersmith?

  And the rest, over 90%, we don't know what it does?

• 41:30Speaker 06

  Well, we we know many things that it does, right? So, you know, I've talked about proteins being redeployed in different contexts during development. So and and in adulthood. And the rules for how you reuse a protein in different contexts, in what cells do you turn it on or turn it off? Those are given in the regulatory regions. So regulatory regions are a large part of that remaining 90%. And they provide the kind of context information about when do you deploy a gene? But then there's a whole bunch of intergenic stuff, which is probably non-regulatory. Maybe or maybe not. And this is where the sort of crux of that debate is.

• 42:11Speaker 06

  And, you know, some people will say that a segment of DNA has a function. If I can assign any kind of biochemical response or characteristic to that sequence. So, you know, DNA, in addition to just kind of encoding abstract information, is this physical object, right? It, you know, it has a certain length and it, it gets folded up to fit into a cell. And one of the ways in which you can like measure a, a biochemical impact or effect of a certain segment is to say like, if we got rid of it, can we measure something different about the cell?

• 42:49Kelly Weinersmith?

  Okay.

• 42:50Daniel Whiteson?

  Exactly.

• 42:50Speaker 06

  And so, you know, it turns out in many cases you can get rid of it and you can measure that something has changed. Like that, that physical molecule now packs differently into the cell. Uh, as an analogy, like imagine I've got 200 feet of yarn and I need to kind of like squeeze it into a baseball or something like that, right? That's probably approximately the density of DNA in the nucleus. And like the exact kind of folds you get, there are some consistencies from cell to cell and some of it is going to be random. But, you know, the sequence matters for how it folds. And so is that a function? Maybe, you know, it's a separate question of like, how meaningful is it to the organism?

• 43:35Speaker 06

  And the folks who are on the skeptical side and say, there's a lot of junk DNA will look and say, yeah, you measured a biochemical impact of perturbing that sequence, but it didn't change the fitness of the animal. It still continues to live fine in the lab, even though you disrupted it. So it's disposable in that sense. It's junk in that sense.

• 43:54Daniel Whiteson?

  The way I think about it is I look at like somebody who has a messy office, like Kelly's husband Zach, and I wonder like. Is it necessary that he has like, you know, a Doritos bag on the floor and a pile of, you know, random stuff in the corner? Maybe that's essential for him to make his hilarious comics. If you cleaned it up, maybe he wouldn't be able to do his job. It's like participating in some indirect way, right? Is that a fair way to think about it?

• 44:17Speaker 06

  Yeah, I think that is fair.

• 44:21Kelly Weinersmith?

  On so many levels, that's fair.

• 44:23Speaker 06

  Picking up the Dorito bag is gonna have, maybe have a measurable impact. Like, maybe, you know, a different snack bag replaces it because you changed it. But again, like, the overall fitness of the operation may not be impacted that much. There is kind of another category, and these are like the selfish DNA elements. And, you know, so a substantial portion of our DNA, and I may need a fact check on this, maybe it's like 10%, something like that, is these repetitive sequences that are these sort of ancient viruses that are still present in our DNA. They copy and paste themselves through their own active and passive processes, producing more copies of each other, of themselves

• 45:05Speaker 06

  within the DNA. It's very likely these are not advantageous to people, but are the result of their own evolutionary process that plays out within our genome. It probably adds a little bit of a fitness drag. So it's like a little bit costly for each cell to replicate those selfish DNA elements. But they also get co-opted through evolution to, you know, offer useful value to the genome. So it's not obvious that you could get rid of them without impacting fitness.

• 45:37Kelly Weinersmith?

  Can you give us an example of a useful thing, like a way we've co-opted a virus?

• 45:41Speaker 06

  Yeah, like that information could be used for scaffolding. There's this phenomenon of telomeres. So more jargon. I'm sorry. Okay, so DNA, we haven't talked about chromosomes, but these are the, like, when you take a single molecule of DNA from N to N, that is a chromosome, right? And in diploid organisms, so in organisms that have two copies of all their chromosomes, which include humans, we have 46 of these chromosomes in each nucleus. So it represents 23 different chromosomes present in two copies each. And when we reproduce a chromosome,

• 46:24Speaker 06

  imagine proteins kind of marching along that sequence of DNA, making another copy. They have this, this kind of awkward property that the machinery that replicates the DNA has a particular size. Let's just say it's like measured in the length of DNA nucleobases. Let's say it's like 50 bases wide. So the core enzyme might be kind of in the middle of that 50 base wide object. So it has trouble like getting to the end of the DNA. Cause it like, it'll fall off before the sort of core enzyme can copy the final trailing sequences of, at the end of that chromosome molecule.

• 47:08Kelly Weinersmith?

  Okay.

• 47:09Speaker 06

  Right. It's like, we're, we're into analogy. So it's like, if a road is a mile long and a car is eight feet long, the last like three or four feet of the road can't be used by the car because it's gonna like, it's gonna fall off and ground itself when that first tire goes off the end of the road. Right. And so if the car was making more road, it would produce a road that's like six feet shorter than the last road. And the next time you copy it, it's going to be six feet shorter than that. And the next time it's six feet shorter than that. So one of these kind of ancient viral mechanisms, it's thought, has provided this set of sequences,

• 47:50Speaker 06

  which just get grown onto the end of chromosomes. So that the copying machinery has some distance it can run past the useful protein coding region of the genome, but without missing the end. And these are called telomeres. And it's thought that they're derived from ancient viruses. So, you know, there's a sort of a self replicating dynamic there. Telomeres tend to make more telomeres. In some sense, it's wasteful, but it has been co-opted in the sense of now it provides this like buffer to the replication machinery.

• 48:25Kelly Weinersmith?

  I didn't realize that telomeres were co-opted viruses. That's pretty cool. Daniel and I are back for a moment. So yes, I got us pretty far off track there talking about-

• 48:37Daniel Whiteson?

  Following your curiosity about this extraordinary universe.

• 48:39Kelly Weinersmith?

  Yeah, okay, thank you, thank you. I appreciate your support. Uh, but let's, let's get a little bit back on track here. One of the main things we brought Ben on the show to talk about was genetics and behavior. And Ben runs a fruit fly lab looking at genetics and behavior in fruit flies. And so let's jump back into our conversation with Ben and ask him about what he studies in his lab. Ben, interview button pressed.

• 49:09Kelly Weinersmith?

  So you study fruit flies. What kind of behaviors in the fruit flies do you study?

• 49:12Speaker 06

  Well, we're interested abstractly in variation in behavior, right? So why do individuals behave differently? Why do species behave differently? And we pick and choose behaviors based on their utility and answering other kinds of questions. So we study a lot of different behaviors in the lab. We look at spontaneous walking behaviors. Do animals tend to turn left or right? For example, we look at temperature preferences. Do they like to hang out where it's warm or where it's cold? We look at odor preferences. Do they like the smell of bananas versus apples? We look at learned behaviors. So if we give them training associations to say that a particular odor proceeds getting shocked, and then they will learn to avoid that odor.

• 49:57Speaker 06

  We look at how that varies across individuals. So the, you know, the, the choice of the behavior is motivated by the kind of question we're asking. When we ask questions about the genetic basis of behavior, we love to take advantage of the experimental tools that are available in fruit flies. These are, these are animals that folks have been studying in the lab for over a century. And there's this great legacy of tens of thousands of different kinds of flies that have different genetic variations and alterations. And it's basically a Lego toolkit for designing experiments. Like if I want to manipulate the activity of a single neuron to see how does that impact a behavior?

• 50:44Speaker 06

  Odds are good that there's a tool sitting out there to target that individual neuron and do a specific manipulation to it. So you can kind of mix and match these genetic reagents.

• 50:54Daniel Whiteson?

  Sorry, how many neurons does a fruit fly have? It's not as simple as a worm that has like a hundred, right?

• 50:59Speaker 06

  A fruit fly has about 150,000 neurons in its head and another 50,000 to 70,000 in its ventral nerve cord, which is like its spinal cord.

• 51:10Daniel Whiteson?

  And so out of that huge number of neurons, you can target an individual one? They have like names? This is like, this is Jack and there's a similar one in every fruit fly that like does the same thing?

• 51:20Speaker 06

  Yes, essentially. Maybe the slight caveat on that is much of that count of 150 central, 150,000 central neurons is in the optic lobes where, you know, the animals have a retina which has like 800 facets. It's a compound eye, so it sees the world through 800 different lenses arranged in this hemispheric array. Each of those like points of visual orientation in the visual world has a whole sort of computational circuit that's downstream of it. So there are, there are sort of computational units that are repeated 800 times and it might

• 52:00Speaker 06

  be hard to target, you know, Omatidium 735 versus 734 with a different genetic reagent because those are just set up through the development of the eye to be repeating units. And they, there's not much genetically that distinguishes, you know, a neuron performing one computational element at one of those positions from the next position over. But within the central brain where there's less kind of just sort of copy paste of the neural circuit template, the way there is in the visual system, then yes, it's, it's more or less like you're saying that there's a neuron you can find across individuals and we have ways to access it genetically.

• 52:44Daniel Whiteson?

  I think that's really fascinating because it already suggests that like the structure of, of the brain is determined by the genome. I know a little bit about the fly Randomly because one of my oldest friends worked on the connectome, Mala Murthy at Princeton.

• 52:59Speaker 06

  Oh, yeah.

• 53:00Daniel Whiteson?

  And so it's incredible to me that like so much of the structure of the brain is determined at the gene level. I think a lot of people imagine that like your brain just sort of like turns out this way or that way. Obviously, my brain is different from Kelly's brain. Fruit flies must have individuality also, but essentially it sounds like you're telling me they're basically robots.

• 53:18Speaker 06

  Well, I'll start by doing a shout out to Mala. And Mala and I are recently co-authors on a new connectome, which is the first example of a nervous system where we have the brain and the ventral nerve cord still attached to it.

• 53:33Daniel Whiteson?

  Cool.

• 53:33Speaker 06

  And we've done the electron microscopy reconstruction of all of the central nervous system from a single animal.

• 53:39Kelly Weinersmith?

  Awesome.

• 53:40Speaker 06

  Well, yes, so the notion that you can find the same neuron across individuals definitely supports this intuition that they are robot-like and that they're all identical. And that's part of the compelling paradox for us of why do genetically identical flies raised in standardized environments behave differently from each other? Especially when the components of their brains are the same in this way. You know, we think that the details matter and that there is individual variation in how the neurons connect to each other. There also is some variation animal to animal in the cell type composition. So for example, as part of the olfactory system, which is how the animals smell,

• 54:23Speaker 06

  you have a layer of cells out in their nose, essentially it's their antenna. And they all send their axons so that like neurons convey information from their input side, which is their dendrite side, to the output side of the neuron, which is the axon. So that's how they send information to other parts of the brain. The olfactory cells in the antenna send their axons into the brain to deliver odor information into the brain. And the sort of the neuron that comes second in that hierarchy after those.

• 54:59Speaker 06

  Neurons that are in the antenna that directly sense the molecules. The next neuron that comes in the next layer is a thing called a projection neuron. And projection neurons pool the information from all of the olfactory neurons that express a single odorant receptor. So they are sort of signals of how much signal am I getting from the environment in a particular signaling channel for the presence of odors, let's say. Generally, there might be two projection neurons for a particular category of olfactory receptor neuron. But we've seen in these kinectomic studies where you take a brain and you dissect it

• 55:39Speaker 06

  and reconstruct neurons very precisely with electron microscopy, that sometimes there's three, or sometimes there's one. So you can address them all genetically, and you can find that same corresponding projection neuron from animal to animal, but sometimes there's a variation in exactly how many there are. And then there's the variation in how they connect differently into the neural network of the brain. And this is where we think a lot of the magic happens of individuality, is that it's in these variations in the connections. Another way to think about this is that like DNA is providing this set of blueprints for the animal to build itself during development, right?

• 56:21Speaker 06

  You know, flies lay eggs, and then, you know, those eggs are allotted a certain amount of nutrient to use to grow. And they use the energy in that nutrient to produce cells and pattern their body by implementing the instructions that come in the DNA. But just the same way that if you had some IKEA instructions on how to build a house, if you implemented it twice, you'd probably get slightly different outcomes. You know, you would lose some bolts, and you'd make do with some other fastener. Or the board is slightly warped that you install, and so everything is shifted by a few millimeters. You know, you just wouldn't expect that the process of going through all those mechanical steps produces the same object in the end.

• 57:05Speaker 06

  And that's where we think the sort of detailed differences in the wiring of the brain. Are producing this variation in behavior.

• 57:12Kelly Weinersmith?

  So the projector neuron, sometimes you have one, sometimes you have three. And we think that's not because of like a mutation that

• 57:18Speaker 06

  Yeah.

• 57:19Kelly Weinersmith?

  results in three. It's because

• 57:21Speaker 06

  That's right.

• 57:21Kelly Weinersmith?

  Mistakes are made along the way. A fastener was missing. The board was warped.

• 57:25Speaker 06

  It's, it's very reasonable to think it might reflect a mutation. So animals in all, creatures in all circumstances acquire mutations. It's, it's inevitable. It happens even in the lab. But you can test this. So you can, you know, you can take that individual, which happened to only have two or had two instead of three, let's say, or had three instead of two and made it to another individual that had three instead of two and ask, do their progeny show this? Do they show that they also have three projection neurons? And they don't. So traits in this kind of category seem to have low heritability, at least in, in the context of our lab studies.

• 58:07Speaker 06

  So that's saying that there was not a genetic difference between the animal that had three projection neurons and the one that had two, because otherwise it would have passed that trait on to its progeny.

• 58:20Kelly Weinersmith?

  And Daniel and I are back.

• 58:23Kelly Weinersmith?

  Okay, so that perfectly sets up the questions that we have from the listeners for the last segment of the show. And so when we get back, we will jump into those listener questions.

• 58:42Speaker 07

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• 59:13Speaker 03

  Hey, what's up? This is Kelvin Washington from The I Couple with Rob Parker and Kelvin Washington. Buy smart, drive for less. And trade for more. That's Toyota affordability. And it starts with a great deal on off-road-ready Tacoma or half-ton Tundra. Two of Toyota's longest-lasting trucks, combining power for work, tech for adventures, and style in between. Built on a reputation for quality and reliability, Toyota trucks are known for holding their value, which could mean big savings when it's time for your next Toyota. So get a great deal today and a great value tomorrow. Shop toyota.com for more. Toyota, let's go places. I'm Malcolm Gladwell, host of Smart Talks with IBM. I spoke with Dr. Laura Jayhai of Cleveland Clinic

• 59:57Speaker 03

  about how advanced computing is helping shorten the path from medical discovery to treatment.

• 1:00:03Speaker 07

  The moment that there is a compound that someone in a lab thinks it would be effective to treat a certain disease, it takes about 10 to 13 years from that moment to when that drug is on a shelf for a patient. A big part of that gap could be computationally solved. Better simulation of compounds, designing drug trials that are more efficient, that would finish faster. That was the motivation to bring computational tools and technology closer to biomedical researchers.

• 1:00:37Speaker 03

  Learn more about how Cleveland Clinic and IBM are using AI and quantum computing to revolutionize biomedical research at ibm.com/smarttalks.

• 1:00:50Speaker 07

  Hi, I'm Jenna Oshkowitz. You might know me from Glee. This is At the Table, the food allergy podcast, a show about food, connection, and what it really looks like to live with food allergies. Each episode, we hear stories from real people like Daniel.

• 1:01:05Speaker 02

  People would always think I was lactose intolerant, so I just kind of shortened my explanation to I'm deathly allergic in a big way that defined a lot of my childhood.

• 1:01:16Speaker 07

  And while there are challenges, there are moments that remind you you're not alone.

• 1:01:21Speaker 02

  One of the best guys that I dated, he made a point to...

• 1:01:25Speaker 07

  Memorize all my food allergies. So join us and hear their stories and more because living with food allergies isn't just about what you can't eat. It's about still having your seat at the table. Brought to you by Genentech and Novartis. Listen to At The Table, the food allergy podcast on America's number one podcast network, iHeart. Follow At The Table and start listening on the free iHeart radio app today.

• 1:01:58Kelly Weinersmith?

  And we're back. We've been talking about genes and behavior with Ben de Bivore from Harvard. We've chatted about how genes are associated with behavior in lots of ways. And I remember when I was in grad school, we used to hope that we were going to find like a gene that was associated with a behavior and that there would be like this one gene that would break everything open. But over time, it actually looks like in lots of cases, it's like tens or maybe hundreds of genes that are influencing behavior like, and each one has like a small effect on the behavior. And it's not quite as easy as we were hoping. And that might also be why I ran away screaming from genetics a little bit because it was more complicated than I thought.

• 1:02:40Kelly Weinersmith?

  But one of the nice things about studying fruit flies is that you can actually kind of start to get a handle on things. And so Ben was talking about how in fruit flies, we know where essentially the neurons are going to end up. And we know like what genes are influencing where the neurons are going to end up. And because he works on this model organism, they can kind of get, they can kind of pin down the links between genes and neurons and behavior. And so with that background information in mind, let's go ahead and listen to questions that we got from listeners. And we actually got these questions after the initial interview we did with Ben. And so I sort of pieced this episode together after that interview because I was like, oh, this, these need to all go together.

• 1:03:21Kelly Weinersmith?

  So anyway, let's listen to the question from Jim and the question from Mark about innate behaviors. Here we go.

• 1:03:29Speaker 06

  Hi, Daniel and Kelly. I've always read that DNA isn't so much a blueprint for an organism as it is a recipe. By analogy, you make chalk chip cookies. The directions don't say exactly where to place each chip. Instead, they just say add so much of this, add so much of that, stir it so many times, put an oven at a certain temperature for so long, and then a cookie like thing comes out at the

• 1:03:50Speaker 03

  That makes sense to me for how the body plan unfolds and how cell structures can self-assemble. I can even understand how a brain can form mostly as a blank slate and that subsequent experience will prune the network to develop a human brain. But the question I've always had is this: innate behaviors require something more like an exacting blueprint than a recipe. Do we know how DNA can code the development of these innate behaviors with such precision? Looking at spiders, it's wired to know how to navigate the world, avoid predators, select a good place to build a web, build the web, wrap up the food, find a mate, all with a small amount of DNA. From an information theory point of view, I'm a programmer type, it seems like the amount of information which is encoded in that network must take a large part of the spider's DNA.

• 1:04:35Speaker 03

  So what's the trick? How does nature pull that one off? Do developmental biologists know? And thanks for all you do. Hello, Kelly and Daniel. This is Mark in Honolulu. I would like to learn about instinctive versus learned behavior. My questions include: how much of a human's behavior is instinctive compared to that of, say, a baboon, or a goose, or a frog? Exactly where in an organism are the instructions stored? In individual genes? Are they similar to a computer programs if-then commands?

• 1:05:14Speaker 03

  Could gene manipulation be used to transfer instincts between organisms? Insert a rooster gene in me and a crow in the morning? I'm curious. Is my curiosity instinctive or learned? Thank you.

• 1:05:31Daniel Whiteson?

  Oh, wow. These are great questions. And I imagine the answer is, we don't know, or it's complicated, or it depends, or some mixture of those?

• 1:05:39Kelly Weinersmith?

  Yeah, it was a mixture of them. And also, the answer involves me banging my head on the table a lot. And it was like, oh, these are big ones. All right, so where to start? Let's, let's start by, but, but actually, let me back up and say, these are great questions. They're just questions that are like, not super straightforward to answer.

• 1:05:59Daniel Whiteson?

  So let's start by defining. Exactly what we mean by innate behavior. And why is that a useful distinction?

• 1:06:04Kelly Weinersmith?

  Yeah, so these are behaviors that you do without needing to learn them. And so, as the listener pointed out, like, so, you know, spiders are born. And then often what happens is they, you know, like they hatch out of their egg. They release a string, a web out of their rear end. That web gets picked up by the wind. They move away from their mother. They never see her making a web. And they just know how to make their own web on their own.

• 1:06:35Daniel Whiteson?

  That moment when spiders like fly using their web, that's so cool.

• 1:06:39Kelly Weinersmith?

  It is so cool.

• 1:06:40Daniel Whiteson?

  Incredible.

• 1:06:41Kelly Weinersmith?

  There was a day when the light was just right. And I actually saw some of them, I think it's called ballooning. I saw some of them like just moving past me. And they're so tiny. And I was like, you're all are starting your lives. Good luck. And it was just, I don't know. It's very cool, very cool that they can do that.

• 1:06:58Daniel Whiteson?

  But your point is they've had no parenting.

• 1:07:00Kelly Weinersmith?

  That's right.

• 1:07:00Daniel Whiteson?

  And so they're out on their own. They can only rely on their innate behaviors, what they come programmed with.

• 1:07:05Kelly Weinersmith?

  That's right, yes. And so the question is, how the heck do they do that? And that is kind of amazing because different spiders make different kinds of webs. You know, like if you've seen a black widow, they make these webs that just kind of look like a mess on the ground. Or then there's orb weaving spiders. And then there's humped trash line spiders, which are some of my favorite spiders. We've got those on the farm. What a great name for a web. But anyway, they have, you know, they all have their own unique web that they know how to make without anyone teaching them how to do it. And so how does that happen is the question? And for a lot of these, the answer is, I like, I don't think we know. So I started my search with, how do spiders know how to make their webs?

• 1:07:49Kelly Weinersmith?

  And I wasn't able to find a link between like, you know, this gene creates these neurons, creates this web building behavior. I mean, I was able to find like videos where they, they watched the different steps that the spiders take to make their webs. And so they were able to break it down into like, okay, first the spider goes and they like. Like find all of the different attachment points in an area. And then they randomly like connect all of the different attachment points. And then they start doing circles to like connect all of those things. And so they're like trying to break it down into steps. And you need to know those steps because each one of those steps might have a different like neural circuit connected to it.

• 1:08:29Daniel Whiteson?

  Yeah.

• 1:08:30Kelly Weinersmith?

  And so breaking down the steps is the first step.

• 1:08:34Daniel Whiteson?

  But it doesn't tell us how the spider knows the step.

• 1:08:37Kelly Weinersmith?

  That's right. Right. And so I, I, and then maybe I missed it, but I wasn't, I don't think that in spiders, we have worked out. Like, you know, how the genetics of web building at the innate level. But in organisms like fruit flies, we have a little bit more information. And so some of the behaviors that have been looked at in terms of like innate behaviors are like sex differences. So for example, often what happens is that like, you know, very soon after eggs are fertilized. It's clear if an organism is going to become genetically male or female. And so you get like the production of, you know, sex organs and those sex organs start producing hormones.

• 1:09:22Kelly Weinersmith?

  And those hormones start impacting the development of the brain. And male brains and female brains will, uh, in some cases develop differently. And they'll start developing different neural circuits. So different connections between different neurons and different parts of the brain. Some brain regions will be bigger or smaller than other brain regions. And then when they reach sexual maturity, these neural circuits will essentially come online. So for example, in fruit flies, the males have very specific stereotypical like dances they'll do for the females to try to attract them. That they don't need to learn. They just know how to do them because they have these neural circuits that get activated when they become sexually mature. And females have very stereotypical responses to the males.

• 1:10:06Kelly Weinersmith?

  Usually they reject them initially is how I read it. And so the answer is that, you know, these, these innate behaviors are things that are essentially coded in genes. And then that impacts. Neural circuits in the brain that then get turned on at the right time when the individuals are older. And so I think it was Mark that had a question that was like, how is the information for these behaviors stored? And I think the answer is that it's stored in the genes and in the connections between nerves in the brain.

• 1:10:42Daniel Whiteson?

  Wow.

• 1:10:42Kelly Weinersmith?

  And then Jim, who's a programmer, had a question about, is this more like a blueprint or more like a recipe?

• 1:10:50Daniel Whiteson?

  Yeah.

• 1:10:50Kelly Weinersmith?

  And, you know, metaphors always fall apart when you're talking about biology, you know, they just capture some aspect of the system that you thought was helpful when you developed the metaphor. But when you dig in, maybe you discover the metaphor isn't perfect. But this sounds more blueprinty than chocolate chip recipe-y to me, you know? It's like, when we were talking to Ben about where the neurons are, it sounded like he knew exactly where the neurons are, for the most case. Like, it was very specific. So, like, yes, sometimes you're missing a screw, and it doesn't go exactly the way you thought it was going to be. And so he was talking about how sometimes you think you're going to get one neuron in one place, but instead you get two. You know, as someone who has

• 1:11:33Kelly Weinersmith?

  tried to follow blueprints and has messed up a lot, has ended up with like, things not exactly where they thought they were going to go, I can, I can definitely understand that. But, but this sounds more blueprinty to me.

• 1:11:46Daniel Whiteson?

  It seems like that's the only way it could work. I mean, if you just have some sort of like, general instructions, like sprinkle in chocolate chips, you're not going to get the same web across spiders that are in the same species, right?

• 1:11:58Kelly Weinersmith?

  Yes. Yeah, that's right. But, but on the other hand, you do need some flexibility. So like, when I was talking about how they were documenting the different steps that were taken in web, web building. So like, you know, when, when a spider goes to build a web, they don't always have the exact same connection points, you know? So they like, if they're building a web in a tree, there's going to be branches at different spots. And so they need to be flexible in where the web is going to start, you know? So it's not always going to be exactly the same. And so they, they need to be flexible to some extent. So, you know, maybe they always need five connection points, and that's like five chocolate chips or something. And so like, it's, it's somewhere between, I think,

• 1:12:41Kelly Weinersmith?

  a blueprint and a recipe, in that you do need to be a little bit flexible. Because you don't know, you're not going to have exactly the conditions you want, probably.

• 1:12:53Kelly Weinersmith?

  But I've got another example that's a little bit more concrete, maybe, and might help us think through this a bit. And this example was inspired by the question, could gene manipulations be used to transfer instincts between organisms? And I took the word instincts to actually mean something more like innate behaviors.

• 1:13:13Daniel Whiteson?

  So this is like, can you take the spider web instinct out of a spider and put it in a person? And then they can crochet that same web or something?

• 1:13:21Kelly Weinersmith?

  Yeah, and so I think that when you are trying to make big jumps like that, the answer is probably no. Almost certainly, absolutely no, because a lot of these behaviors are controlled by many, many genes. And so I think if you, you can't transfer lots of different genes without messing the system up.

• 1:13:40Daniel Whiteson?

  Right.

• 1:13:41Kelly Weinersmith?

  But if you have two closely related species that differ for something that's like on a gradient, maybe you can transfer some things around. And so an example that I like is that there are prairie voles, whose Latin name I won't say for Daniel's sake. And they're monogamous. And actually, from here on out, we'll just call them the monogamous voles. And then there's polygamous mountain voles. And so there are voles where they pair up for a long time. They raise kids together. And if you put them in cages in the lab for 24 hours and they breed, they will form a strong pair bond. They'll huddle together. And if you give them a choice between some other

• 1:14:24Kelly Weinersmith?

  vole in the lab or the partner that they mated with yesterday, they'll keep choosing the partner they mated with yesterday.

• 1:14:30Daniel Whiteson?

  How long does it take to form that bond?

• 1:14:32Kelly Weinersmith?

  24 hours.

• 1:14:33Daniel Whiteson?

  24 hours?

• 1:14:34Kelly Weinersmith?

  Yeah.

• 1:14:35Daniel Whiteson?

  First date and done, huh?

• 1:14:36Kelly Weinersmith?

  Well, you know.

• 1:14:39Kelly Weinersmith?

  24 hours and they are bonded, but the polygamous voles, you put them together for 24 hours, doesn't really impact how, which partner they choose the next day. If you give them a choice between the one that they were with for 24 hours the day before, or a new one, the males like, oh, hey, someone new, that's awesome. And like, if they're out in the wild, they like diversity of partners.

• 1:15:04Daniel Whiteson?

  So these are two different instinctive behaviors, monogamy or polygamy?

• 1:15:08Kelly Weinersmith?

  Yes, in, in, in voles that are closely related. And so what we think is happening here is, we think that this has to do with what's happening with vasopressin. So vasopressin is a neuro peptide, it's like a hormone in their brain. I'm not going to go into too much detail, but it's a hormone that we think it binds to receptors in a certain part of their brain, and it gives them a reward for affiliating with a part, a particular partner.

• 1:15:35Daniel Whiteson?

  Interesting.

• 1:15:36Kelly Weinersmith?

  And the monogamous voles have more of a receptor in a certain part of their brain. So we think that when they are bonding with this one particular partner, they feel better. So being monogamous just gives them a bigger reward. And so they want to stay with that one partner because just being with that one partner makes them feel better. Whereas the polygamous male gets less of a reward hit for being with that one partner. And so they sow more wild oats.

• 1:16:05Daniel Whiteson?

  So they're all just narcissists, though. They're all just doing what feels good.

• 1:16:09Kelly Weinersmith?

  Aren't we all?

• 1:16:17Daniel Whiteson?

  We're all just voles, deep down, I guess.

• 1:16:19Kelly Weinersmith?

  We're all just obeying our instincts, perhaps. But anyway, so this was an experiment that was done in like 2004 by Limital. And what they did was they manipulated the receptors in the polygamous voles, and they increased the number of receptors in their brain in that particular area. And the polygamous voles that had more receptors in this particular part of their brain became more monogamous. And so by tinkering with the receptors, which we think the number of receptors is genetically coded for by having these regions in the genome that say, make more of the receptors. You are able to make a polygamous bull more monogamous.

• 1:17:03Kelly Weinersmith?

  And so I think that you can change innate behaviors, whereas the innate behavior in this case is a tendency towards monogamy, by just tinkering with something like the number of receptors in the brain. Does that make sense?

• 1:17:16Daniel Whiteson?

  Yeah, that does make sense.

• 1:17:17Kelly Weinersmith?

  So I don't think that you could do something like make a human crow like a rooster at the crack of dawn, because moving a couple genes from a crow to a human is unlikely to have exactly the desired effect, because we have a totally different neuronal background, like totally different connections in our brain. It just wouldn't do the same thing. But if you have closely related species and you're just like moving dials up and down a little bit, you can probably do some tinkering. Does that make sense?

• 1:17:46Daniel Whiteson?

  Yeah, that's fascinating. I think that solving this puzzle will really help us understand how the brain works, how it's put together, how it's essentially programmed by evolution. I think it'd be fascinating to figure out which things are hardcoded, which things are learned, if there's some fuzziness in between. I mean, like reverse engineering any system is always fascinating.

• 1:18:07Kelly Weinersmith?

  Yeah, absolutely. And then one of the questions was how much of human behavior is instinctive relative to a baboon, a goose, a frog, et cetera? And to your point, first of all, it's hard to even bin some of these behaviors. So things like aggression in males is to some extent innate, because males are more likely to be aggressive than females. And part of that is from the programming that happened when they were a fetus. But then also, some of it is learned from the outcome of fights that they have when they're younger, and that tinkers with how aggressive they'll become when they're an adult. And so it's hard to bin some of these things as innate versus learned, because sometimes it's a mix of both of them.

• 1:18:50Kelly Weinersmith?

  So if we can figure out how much of this stuff is hardwired versus how much of it is learned, I think we're going to find that a lot of it is both. And some of that might help answer this question about like... You know, do humans have more hardwired behaviors relative to a goose or a frog? I don't think anyone has tried to like rank those things because so many of these behaviors probably fit in more than one box. And it's just kind of hard to do all of that stuff. But, you know, in general, I think we'd love to learn more about how behaviors are tied to genetics, although I have to also say that when you start talking about how behaviors are tied to genetics in humans, it becomes especially fraught.

• 1:19:31Kelly Weinersmith?

  And it, you know, very quickly becomes, yes, a difficult topic to talk about for a variety of reasons. Uh, and I'm backing off.

• 1:19:40Daniel Whiteson?

  Smart.

• 1:19:41Kelly Weinersmith?

  And that's why I've stuck with fruit flies and voles. So let's go ahead and see what Jim and Mark thought about those answers.

• 1:19:47Speaker 06

  Thank you, Kelly, for doing all that research into what I think is a really fascinating topic. Like most good answers, it raises even more questions than it answered. I guess I'll submit those later for a subsequent episode. Thanks again for all you do, and I look forward to hearing the rest of the episode.

• 1:20:03Speaker 03

  Thank you, Daniel, Kelly, and Ben. I now have a better understanding of innate behavior. We are fortunate to live on a planet with an enormous variety of life forms and behaviors. Let's continue to explore and learn more about this world. And while we're at it, the universe.

• 1:20:22Kelly Weinersmith?

  Okay. And it wouldn't be an episode of Daniel and Kelly's Extraordinary Universe where we have a guest if Daniel didn't have an opportunity to ask our guest the alien question. So let's jump to our interview with Ben and see what he thinks about aliens. Boop.

• 1:20:42Kelly Weinersmith?

  All right. Is it alien question time, Daniel? Go for it.

• 1:20:46Daniel Whiteson?

  How universal do you think our system of encoding information in DNA or some DNA like molecule is? If we're about to land on an alien planet and dig into alien life, what do you expect to find as the molecular basis of heredity on an alien planet?

• 1:21:04Speaker 06

  I would, I, this is putting my forecaster hat on.

• 1:21:07Daniel Whiteson?

  Yeah.

• 1:21:07Speaker 06

  I would say. I would very much go with like a uninformativ prior here and just say fifty fifty on DNA. You know, I, I think there are some first principle reasons that RNA will play a important role in early life. It's relatively easy to make as things go. It's reactive. It can do all these enzymatic functions. You know, then whether you sort of find a way to stabilize RNA or find a different stable hereditary biopolymer or stumble into DNA, maybe that's a bit of a contingent matter for each independent origin of life. But I, you know, I think it's

• 1:21:52Speaker 06

  quite plausible that you would stumble into DNA more than once. I think you'd have a pretty radically different genetic code. I, I think the, the mapping of codons onto amino acids feels extremely arbitrary. So maybe, you know, that sort of second step might be different. But yeah, DNA seems plausible.

• 1:22:12Daniel Whiteson?

  Fifty percent is high. Yeah, that's a big number. I mean, this, if there's a lot of life out there, then that's, that's a lot of DNA.

• 1:22:18Speaker 06

  Well, that's right.

• 1:22:19Daniel Whiteson?

  I'm not disagreeing. That's, that's awesome. And maybe if I can ask you a more philosophical question, if personality is controlled or strongly influenced by genetics, what does that say about our responsibility for ourselves and our choices and who we are? If I'm a jerk, is that my fault if it comes from my parents because they were jerks and they passed it on to me? Can I take credit for being a nice guy because it's just in my genes? How does this inform our feeling about ourselves and our sense of responsibility for our, our behavior?

• 1:22:53Speaker 06

  You know, I, I think you can have robust ethical frameworks, whether the universe is deterministic or random or has free will in some sense. You know, like if, if we believe

• 1:23:06Speaker 06

  One of the evolved purposes of punishment or positive rewarding is to alter behavior and improve the sort of overall fitness of behavior. These things can happen in a deterministic framework, right? And, and they can happen in a framework that accommodates free will. So I think that you can uncouple these questions. I do think that just as in the sort of psychological domain, there's something slightly liberating about not having to explain personality variations in these deterministic, genetic or environmental frameworks. It just, I think it sometimes takes the burden off of people in explaining the way they are

• 1:23:50Speaker 06

  to just say, no, there's not really a good reason. It's just dumb luck and we don't have to think about it beyond that. We don't have to attribute it to something, our, some quality our parents had or some childhood experience. So I think it sort of lightens the load in that sense. But ethically, I, I think it's, it's a, it's a different axis. It doesn't, doesn't talk to that deeply.

• 1:24:12Kelly Weinersmith?

  Thanks so much for being on the show, Ben. We had a lot of fun learning about genetics.

• 1:24:16Speaker 06

  Happy to do it. Thank you all for having me.

• 1:24:24Daniel Whiteson?

  Thanks, everybody for listening. Please go and do us a favor and rate the show on whatever podcast app you're using. It really helps people find us.

• 1:24:32Kelly Weinersmith?

  Daniel and Kelly's Extraordinary Universe is edited by the amazing Matt Kesselman.

• 1:24:37Daniel Whiteson?

  He really is a wizard. You can also find us online on Blue Sky, Instagram and X, D and K Universe. Come engage with us.

• 1:24:47Kelly Weinersmith?

  You can email us at [email protected]. We really do want to hear from you.

• 1:24:53Daniel Whiteson?

  And you can find our website, www.danielandkelly.org, where you'll also find an invitation to join our Discord where everybody comes and talks about the amazing universe.

• 1:25:04Kelly Weinersmith?

  And we also have the most amazing moderators. This is an iHeart Podcast. Thanks for joining us.

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