Episode 8: Carl Zimmer on Heredity, DNA, and Editing Genes

0:00:00 Sean Carroll: Hello everyone and welcome to the Mindscape Podcast. I'm your host, Sean Carroll, and today we're gonna be talking about heredity. This is, of course, a very old idea, the idea that there's something inside us, some properties, some features that get passed down through the generations. So we inherited something from our ancestors, and we send something down to our descendants. Back in the day, there used to be the thought that royal blood was handed down, that the right to be the king, or the queen, or the emperor, depended on who your parents were. I suppose there's still countries in which that is the case. But we know a lot more about how heredity really works now than we used to. We know that all of our cells have a little molecule in them called DNA, and that DNA is a little code, it's a chain of letters, A, G, C, T. That the arrangement of those letters tells us what makes up who we are, or at least, there's a simplistic version of it where you think of DNA as kind of like a blueprint, that if you knew what the DNA was, you could predict exactly what the organism was going to be, maybe even what kind of food they would like or what kind of occupation they would have later in life.

0:01:10 SC: Today we know it's a little bit more complicated than that. There's more going on than just our DNA to make up who we are, not only nature versus nurture, but even the nature part is very complicated. There's epigenetics and development factors, there's mitochondrial DNA, there's the expression of different parts of the genes that we have. And so we're in a very, very rapid state of evolution, as it were, in terms of how we think about how heredity works. These days you can get your genome sequenced, you can send it into a company, pay some money, and they'll tell you something about your genetic heritage. On the horizon, we see the ability to edit genes, we can do it in some ways now and the ability to do that for human beings probably is not very far away. So it's natural to imagine, can we design what the next generation of human beings is going to be like? Can we design the animals and plants that make up the rest of our ecosystem?

0:02:08 SC: These are important questions as well as fascinating ones. So we have today, Carl Zimmer, as our guest. Carl is one of the very best science writers working out there. He's been working and writing about this area of genetics and heredity in DNA for a very long time. You may know Carl through his blogging or his Twitter account, his New York Times column, or you may have heard him on NPR. Now Carl has a major new book out called She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity. It's a door stopper. It's a big one, but it's full of fascinating individual human stories, as well as the deep science behind what we know about heredity. So we're gonna talk about how heredity works, what we do and don't know about it and, most importantly, where the new knowledge that we're gaining every day might take us. It seems very plausible that what we're learning these days might dramatically change how we think about being human beings. So, let's go.

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0:03:26 SC: Carl Zimmer, welcome to the Mindscape Podcast.

0:03:28 Carl Zimmer: Hey, it's great to talk to you.

0:03:30 SC: So now, we've known each other virtually, at least online, since the early halcyon, salad days of the blogging world, right? Didn't... Isn't that how I got to know you, reading your blog, and you read mine?

0:03:41 CZ: Absolutely, yeah, back when blogs were the future.

0:03:44 SC: Blog, yes. Now we're in the future and no one writes blogs anymore.

[laughter]

0:03:49 CZ: They delivered us here.

0:03:51 SC: Exactly, the future is a journey. We've been through the future, now we're in the post-future. So, I couldn't help... You've written this gigantic, magisterial book about heredity, inheritance, She Has Her Mother's Laugh, and the subtitle, of course, The Power, Perversions, and Potential of Heredity. And while reading it, I can't help but think, as a physicist, "My goodness, how lucky I am that what I do for a living doesn't really matter to people's lives." This is a kind of science that everyone has feelings about, does that come through in your work?

0:04:26 CZ: Oh, I think that everybody clings to heredity in a profound way. And I see that when I give talks about my book. I have learned to keep my prepared remarks fairly short, because people just have tons of questions, and the questions come from the fact that we use heredity to define who we are, and also what is our connection both to the past and to the future. You can't ask for anything more intimate than that.

0:04:58 SC: Yeah, so the future in terms of our children, our descendants, you mean?

0:05:04 CZ: Sure, absolutely. And also, what if we tamper with the heredity of other species, then what is left after we're gone? Well, heredity will carry on those sorts of changes into the future.

0:05:18 SC: So I think everyone who is involved in this conversation right now knows a little bit. We're not entering and we're not telling people something that they've never heard before, that there's something called DNA in our cells that carries some information. So let's try to remember what it was like before we knew that. People still had an idea of inheritance and heredity and things being passed down through the blood, even before Darwin and Mendel came along.

0:05:48 CZ: Right. It's hard to reconstruct the way people fought in the past, especially when they didn't use the concepts and the words that we use today. And yeah, we can start to get some clues about it just by looking back and trying to piece together. For example, there were ideas about blood, as you say. We still use the word 'blood' to talk about what we really mean by genes. There's blue blood, for example. Blue blood is something that is like, well, you come from a blue blood family. In other words, somehow like that is inherited down through the generations, your status. The irony is, of course, that the phrase actually comes from a particular time and a particular place. It was in Spain in the 1500s when people in Spain were trying to distinguish themselves from Jews and Muslims. So this is where... And this is where the whole issue of race comes from. Literally, the word race starts to be used in Spain in this way. And so...

0:07:02 SC: When are we talking? What century, you said?

0:07:04 CZ: 1500s. 1400s and then to 1500s. And the... So the idea with blue blood was that, if you were racially pure, then someone could see your veins through your translucent skin. And so you can get these ideas about how in Western society, there were these ways in which we started to define ourselves as being made up of something that was being passed down through the generations. But really, it wasn't until the 1800s that people like Charles Darwin actually framed it as a scientific question. Like, okay, there's something, something molecular, that is being passed down through the generations and explains why people have these traits that seem to run in families. So what is it?

0:08:07 SC: Yeah. Darwin wouldn't have said the word molecular, but we know what you mean. There is something that is being given from parents to children. But without genes, without DNA or anything like that, with this basic idea that we inherit from our mothers and our fathers, did anyone ever wonder about the fact that why aren't we always just exactly halfway in between our mothers and our fathers in every trait? There clearly seem to be variations around that. Did people in pre-Mendel and DNA worry about this fact?

0:08:38 CZ: Yeah, they could see for themselves that these patterns of heredity were not simple. They really puzzled over them. Mendel was just in a long line of people who were scratching their heads. And these were plant breeders. These were animal breeders. In the 1700s, someone named Bakewell in England became legendary because he created a new breed of sheep, and he did it by carefully breeding different kinds of sheep together and coming up with these rules of his own for how to breed them. And it was an incredible accomplishment, because people would breed animals and their offspring would be all sort of a mess. They would be all this variation when, if you're breeding animals, you want them all to be the same. If you want a particular kind of meat from an animal, you want them all to have that same taste. You want a kind of wool, you want the same wool. So it was a huge puzzle and struggle, and the stakes were enormous. By the 1700s and 1800s, countries were actually looking at breeding, in other words, heredity, as part of their national wealth. If you could breed new crops and new livestock, you were going to make your country rich.

0:10:05 SC: I love the practicality of it, it reminds me of how thermodynamics, which can be a very abstract and theoretical subject, arose from trying to get better steam engines. This is definitely an era where there's a give and take between people with boots on the ground trying to make better products and trying to understand the world better as scientists.

0:10:27 CZ: Yeah, it is interesting, because we assume that everybody must have thought about heredity the way we do and wondered about it the way we do, 500 years ago or 1000 years ago, but they just didn't. And it wasn't really until some practical questions drove people to really think carefully about this. And the other people, in addition to breeders, were psychiatrists. In the early 1800s, particularly in France and also, in some extent, the United States and elsewhere, psychiatrists were trying to understand madness. Then they were struck by the fact that, when they would do questionnaires for their patients, their patients often had people in their family or more distant relatives, who also were institutionalized, or maybe they had something that seemed like a form of madness. And so they said, "So, is this a hereditary disease? And if so, how on earth could this be passed down through the generations?" And so, Darwin actually read a lot of psychiatry when he was developing his own ideas about heredity.

0:11:46 SC: So this connection between heredity, and intelligence, and madness, and thought, was there from the very very beginning?

0:11:54 CZ: Yeah. A lot of the things that we're talking about right now, people were talking about 150 or 200 years ago, with just as much loudness and passion and conflict.

0:12:09 SC: Maybe not just as much, 'cause now we have Twitter and they didn't have that there, so that's an amplifier that they didn't have.

0:12:14 CZ: Yeah, but they had pamphlets.

0:12:16 SC: Pamphlets.

0:12:18 CZ: Yeah. A lot of the stuff would get circulated in things like pamphlets, where... You'd get a new pamphlet every day. I feel like Twitter is just an extension of the old traditions of pamphlets.

0:12:31 SC: So maybe blogging is the past, more than the future.

0:12:34 CZ: There you go. I don't know where podcasting fits in now.

0:12:37 SC: So then, we did get to genetics, to real genetics, to Mendel. Mendel, by the way, I have to always say this. I went to an Augustinian University, Villanova, and Augustinians have a slight inferiority complex compared to the Jesuits, who are wonderfully, intellectually, have this wonderful intellectual tradition. But we have two really important Augustinians in history. One was Gregor Mendel and the other was Martin Luther. So they weren't always the best Catholics, but they did affect the world in an important way. So Mendel, among other things, he helped pinpoint this discreteness of heredity, that there could be like, you get this feature or you don't. So there must be somehow, it wasn't just a blending of your two parents, there was some piece of information, a quantum, a physicist would call it, that's being handed down through the generations.

0:13:33 CZ: Right. Mendel didn't call them genes. Sometimes the terms he used get translated as factors. So, there would be some factor that was in a plant. And there was an almost mathematical beauty to how these factors combined in new offspring and then produced a trait. So just an example that people may recall from high school is that peas can be wrinkled or they can be smooth. And if you cross two wrinkled pea plants together, you're gonna get nothing but wrinkled peas. If you cross two smooth peas together, you might get nothing but smooth peas and then the next generation after that, smooth peas and smooth peas forever. On the other hand, if you cross a smooth pea and a smooth pea together, you might be surprised to suddenly have a quarter of the peas being wrinkled. And... So the fact is that that wrinkled factor can hide because it's what we would now call... Well, actually Mendel called it too, recessive. So yeah, so that was the first recognition that there was this... There was this thinking about heredity when these two distinct parts, the invisible factors that get carried on through the generations and then what you see, what scientists called the phenotype.

0:15:08 SC: And then we started finally figuring it out. We're moving quickly through the history here, 'cause I wanna get to the modern world, but it wasn't 'til 20th century that we were able to identify these genes as being carried by this wonderful molecule, the DNA. And Watson and Crick, etcetera. And by that time, correct me if I'm wrong, but there was already this new synthesis of genetics and evolutionary biology, natural selection, Darwin. And so the DNA was just figuring out, not just, but it was figuring out what the mechanism of that was.

0:15:44 CZ: Yeah. That's a beautiful distillation of 80 years of really rough science. Yes, exactly, yeah. People had known about DNA, really, since the 1800s, but they were like, "Huh, what is this weird stuff?" And...

0:16:01 SC: Sorry, just to make that very clear, they knew that there was a molecule called DNA.

0:16:07 CZ: Exactly. If you pulled apart cells, you would find different components. So you would find some molecules that are known as proteins that all had a similar chemical composition, and then you would find this stuff that they called nucleic acid. And people just didn't really know what it was for. And actually, even in the mid 1900s, a lot of people thought proteins were what genes were made of. And it took some elegant experiments to demonstrate, no, actually, if you transfer DNA from one microbe to another, you transfer that trait, the proteins don't matter. And so then, once we figured out the structure of DNA, then all of a sudden, we can get down to the molecular details of how genes make heredity possible. In other words, that it's almost like genes are like texts. They're made up of these units, where they're like letters made up from a four-letter alphabet and we have over three billion letters in our DNA, and change the letters, or cut and paste chunks of text, and you get changes to us. And those changes can be passed down if the DNA is being faithfully copied.

0:17:37 SC: Right. And so, three billion base pairs in the human DNA, and... But we talk about only having like 20,000 genes. So I'm gonna ask every biologist I ever talked to on the podcast to explain this, 'cause it took me a long, long while to get it right. But explain the relationship between the base pairs in the DNA and what we call genes.

0:18:02 CZ: Yeah, it's kinda messy, but biology is messy.

0:18:07 SC: Yeah.

0:18:12 CZ: So the way that people traditionally think about genes is a stretch of DNA that encodes a protein. And so, every protein is encoded by a gene, it is true, although sometimes you get proteins that are made by combining genes together and all sorts of stuff we don't need to get into. But in any case, we have, as you say, 20,000 of these protein-coding genes. And they only make up about 1% or so, 1 or 2% of the human genome. So then the big question is, "Well, what's all the other stuff?"

0:18:54 SC: Yes.

0:18:54 CZ: Yeah. So some of it, maybe 10% of it, has functions of its own. So actually, some of them are also genes, it's just that they don't go the full process towards making proteins. You have thousands of genes, we don't know how many that actually encode RNA molecules.

0:19:25 SC: Okay.

0:19:26 CZ: So you may be used to thinking of RNA as part of the process to make protein. You got a gene made of DNA...

0:19:30 SC: Right, so RNA... Yeah, go ahead.

0:19:33 CZ: You got a gene made of DNA, you make a copy in RNA which is a single-stranded version of DNA, basically, and then you use that RNA as a template for building proteins out of a different set of molecules called amino acids. And that's true, but it turns out that sometimes our cells will make an RNA molecule, and then that's it. And not only that's it, but that RNA molecule has a really important job to do. For example, in women, women have two X chromosomes, they need to keep one of them shut off or they're gonna basically poison themselves with too many proteins from the X chromosome.

0:20:14 CZ: Men only have one X chromosome. So there are these RNA molecules that basically wrap around the X chromosome, one of the X chromosomes in women, and silence it. And so we know that at least some of these RNA molecules play an important job. Those are more genes, but that still leaves you with a lot of the rest of the genomes. So some of that DNA is really important as genetic switches for turning on and off genes elsewhere in the genome. And then the rest, a lot of it is probably what scientists would scientifically call junk. A lot of them are dead genes, they're genes that have mutated and just are useless now, and we just carry them along. Some of them are actually, descend from viruses. So viruses infect our DNA and make copies in the cells that get passed down and just spread all over our genome and bulk it up with all sorts of stuff that we don't actually use. So it's...

0:21:25 SC: They also could be codes that were injected by aliens, millions of years ago to be activated, some point in the future, right?

0:21:33 CZ: Yeah, right. Now, I haven't seen the papers on that yet, but maybe you've seen a pre-print, I haven't seen...

0:21:39 SC: I'm giving you jewels here Carl, you should write the paper.

0:21:41 CZ: Yeah. All right. I'm gonna have the scoop of the century.

0:21:45 SC: But it's a good reminder that we're not intelligently designed. The cell is kind of a mess that has been put together over billions of years, and DNA doesn't care that its job is to encode genes into proteins, it does whatever it wants to do, or whatever it needs to do, to make things function. Some of the DNA is making proteins, some of it's making RNA that will do something, some of it's just going along for the ride 'cause it keeps getting copied all the time, right?

0:22:12 CZ: Yeah, it's hard to believe, but the cell is a lot sloppier than we think of it as being. A lot of DNA actually, is used by our cells to produce RNA molecules, and then the cell just immediately shreds all that RNA, because those were just accidental. They were just not... They didn't really have any function. So you can have junk DNA shooting off RNA molecules, but they don't serve any purpose. The cell just manages this chaos by having certain proteins that go around and say like, "Are you supposed to be here?" And if not, then they just shred 'em and just recycle it to make more RNA molecules. So yeah, if you really get to know cells, intelligent design becomes laughable.

0:23:12 SC: Okay. We have this idea that the coding parts, there are parts of the DNA, stretches of DNA, many, many base pairs at once that will code into a protein. There's probably an informal and incorrect idea, I'm sure none of our extremely sophisticated and well-educated Mindscape listeners would have this idea, but some people might think that there's a direct map from a gene to a trait, to how big our nose are, what color our hair is, or how charismatic we are, but it's more complicated than that, right?

0:23:49 CZ: For the most part, yeah, it is more complicated. It's good to learn about Mendel in high school, but I do think that it's gonna be important for schools to take students beyond Mendel, now that people are getting their DNA tested by companies like 23andMe. You can't really understand those test results if you're just relying on pea plant experiments.

0:24:16 SC: Right.

0:24:18 CZ: Your blood type, sure, it's like there's one gene, and there're different versions of the gene that can determine your blood type. Okay, no problem, but for most of the traits that we actually really care about or think about, and even seemingly simple ones like height, they are influenced by many, many, many, many, many different genes. And so that... Yeah, you can't say that, "Oh, I have... Do I have the tall gene?" It's just meaningless.

0:24:54 SC: So we brought ourselves up to about, as you infer, imply, the level of high school biology, what people remember, we have a DNA, we pass it along. And I think that even if there's some complicated non-linear map from the genes in our DNA to our traits, people still have this idea that basically there's a molecule, the DNA, and from the molecule, that's us, that just makes us. But we know a lot more than that now also. There's various ways in which the thing that we turn into is more than just what's encoded in our DNA, in any straightforward way, is that an accurate statement?

0:25:33 CZ: Yeah, yeah, definitely. It's funny, if you say to someone, "Oh, you have two eyes, you must have gotten your two eyes from your parents." They're gonna look at you funny like, "What? That doesn't make sense." And the fact is that you did get your two eyes from your parents, but when we talk about "Oh, you got this, you got that from your parents," we're really more interested in the things that are different between people, so that we can say like, "Oh, you are tall, and your great Uncle Birdie was tall, so you must have gotten it from him." Even though, of course Birdie is off to the side, whatever. My point being that, we just get confused about what it is that we're talking about when we talk about these traits.

0:26:31 CZ: And the fact is that you might be tall like your Uncle Birdie is tall, sure, partly because of the genes you inherit, but maybe you and your Uncle Birdie also had the privilege of growing up in a affluent society, an affluent family, you had good diets, you got medicine when you were a kid, and so that you had the opportunity to grow to be tall. Because the fact is that, all over the world, the average height of people is several inches higher than it was a century ago. And that's not because we are now inheriting a different set of genes, it's just that in that respect, the world got to be a better place. And so you have to take into account the combined influences of genes and environment, or actually as Shakespeare once called it, nature and nurture.

0:27:36 SC: We'll get there, but I think that even at the level of nature, even at the level of our inheritance, our genetic inheritance, I'm learning about from your book, among other places, how complicated that is. For example, the idea of mitochondrial DNA.

0:27:54 CZ: Right.

0:27:55 SC: We have these little genetic stowaways in every single one of our cells, and we hand them down to subsequent generations.

0:28:01 CZ: That's right, that's right. Yeah, even if you just limit yourself to genes, heredity can be a lot more complicated and strange than we learned about. Mitochondria, we have dozens or hundreds of them in every cell, and we depend on them for our survival. They're the little factories that generate fuel for our cell, using oxygen and various nutrients to build fuel that we then burn. They do lots of other stuff too. So, they're great...

0:28:36 SC: The powerhouse of the cell.

0:28:40 CZ: Yeah, absolutely. And the weird thing about them, well, several weird things. One is that they've got their own DNA in them, that's aside from the DNA that's tucked away in the nucleus. So they've all got their own DNA, and if you look at a cell, you can actually watch mitochondria divide on their own, and they make new copies of their own DNA for those new daughter cells. And you might say, "Whoa, that doesn't make sense, that sounds like bacteria." And I was like, "Yeah, guess what, they're bacteria. Exactly." About 1.8 billion years ago, when we were single-celled, the ancestors of mitochondria somehow ended up inside of our cells in maybe some symbiotic relationship, like cleaner fish that go inside the mouths of bigger fish, and then they became basically permanent residents, so that they couldn't live outside of our cells anymore.

0:29:39 CZ: And as if that wasn't weird enough, when a sperm approaches an egg, it's swimming furiously, and it's using that mitochondria to generate that fuel to swim. So the only way it can get to an egg is to use its mitochondria, and then it reaches the egg, and it jumps in its chromosomes, but then it also destroys its own mitochondria. It just rips them apart.

0:30:09 SC: So both the sperm and the egg have separate mitochondria from dad and mom?

0:30:14 CZ: Right. And the sperm do not deliver their mitochondria into the egg.

0:30:19 SC: Lazy bastards.

0:30:21 CZ: Well, it's puzzling because when you look at our chromosomes, we are a 50-50 split between our parents. But you look at our mitochondria, it's all mom, just all mom.

0:30:35 SC: So mitochondrial inheritance is not sexual reproduction?

0:30:41 CZ: Exactly, exactly. For some reason, we keep out one of the parents from that process. And it's interesting 'cause what that means is that your mitochondria is extremely similar to your mother's and your grandmother's, and so on, and so on, and so on. Because with your chromosomes, in every generation, the pairs of chromosomes, they shuffle some of their DNA together.

0:31:12 SC: Right.

0:31:13 CZ: And so they swap pieces in this process called meiosis. And so after several generations, your chromosome number two doesn't really look all that much like your great, great, great, great grandmother's chromosome two. But mitochondria, basically the same. And so they're really powerful for tracing genealogy, for example. You can say like, "A-ha, well, this person has to be the child of this woman." There's just no two ways about it. And yeah, it's a... Scientists who are just looking at the basic questions about heredity are like, "Why is this? Why would the sperm not give the mitochondria? Why is it only the mother's?" And there are some interesting theories about it. One theory is that if you have two batches of mitochondria inside a person coming from different people, they're going to not play well together, that they're gonna operate differently and that could actually cause problems. And there's some...

0:32:30 SC: That makes sense, when meiosis happens, meiosis is the splitting of the cell into a little sexual reproduction cell. We split our genome in half and then they're gonna recombine with the half from the other parent, and the mitochondria aren't participating in that process. It's dad's mitochondria and mom's are just there separately, and they might come into conflict, like you said.

0:32:56 CZ: Right, right. It's interesting, we think of mom and dad's genes as playing nicely in our own genome, but there are conflicts between the genes in our parents, evolutionary conflicts.

0:33:17 SC: Sometimes there's conflicts between our actual parents too.

0:33:20 CZ: Yeah, and now think about it inside our DNA. Sometimes, they'll be like dad's genes are maybe driving kids to grow faster, because that's good for the father's long-term evolutionary benefit. The mother meanwhile, if mother has to carry the children, has to be pregnant, too much growth is actually... Can really drain her resources, and may mean that she has fewer children over her lifetime. And so you will actually find that the man's copy of a gene is turned on, a woman's copy is turned off inside the child. So it's like this tug of war going on.

0:34:05 SC: Sure.

0:34:05 CZ: Just to try to... That finds this optimal thing. And then sometimes you actually find there are genes, or pieces of DNA that basically just totally break Mendel's law completely, and just override that 50/50 split between which chromosome ends up in an egg or a sperm. This was illustrated with a discovery once of certain kinds of flies, certain strains of flies, where they would almost always produce daughters. And scientists were like, "What's going on here?" And it turned out that there was a gene that was basically hijack, it was sitting on the female chromosome in flies, and was basically, ensuring that these flies did not have any sons, because if they were just daughters, that wouldn't spread this gene further, the ultimate selfish gene.

0:35:09 SC: Well this makes sense. Maybe it makes sense, maybe I'm leaping ahead too far, but we have this game theoretic way of thinking about not just the struggle to survive as organisms, but we can, in the selfish gene way of thinking, think of it as the individual genomes trying to pass themselves down. And mom has a genetic set of information and so does dad, and they both wanna win. And in human beings, in mammals, there's this rough equilibrium that we've reached where children are 50/50 male and female, but that's certainly not universal across the animal kingdom, there's a different equilibria you might imagine reaching where the struggle plays out in different ways.

0:35:54 CZ: Sure, and actually, there are some animals that adjust the ratio of their offspring, just depending on what their environment looks like. There are birds that, in effect what they're doing is looking around and saying, "I think I need a lot of daughters to stick around and to help me raise my other chicks." And voila, incredibly, they produce more daughters than sons. And then there are other situations where they produce more sons than daughters, and then the sons fly off.

0:36:29 CZ: We like to think about... We like to take biology and put it into categories and try to come up with absolutes, Mendel's observations become Mendel's Law, or males and females become these absolute categories that you could never have any exception to. We keep doing that. I think we just have brains that really like categories, but heredity just does not work like that. And yeah, there are some patterns that repeat themselves a lot, but a lot of times, those patterns are this sort of a stable balance produced by competition that works out into this almost like a detente.

0:37:23 SC: Well, I talked with Alice Dreger in episode three of the podcast, and we talked about intersexuality and how the fact that the idea there's two sexes, that's a convenient fiction. It's very useful, it's a good approximation but if you're gonna try to be a little bit more careful, there's a whole bunch of stuff in between, in different ways you can be in between. And this reflects... I think that philosophically, this is just a really important point that you're bringing up, that we organize the world, we human beings, for our comprehension because it's easy for us. But as we try to be more and more accurate, all those complications are gonna become more and more relevant to a better understanding.

0:38:00 CZ: Yeah. And I notice that a lot of times, people will justify these absolute categories by saying, "Well look, like this is just nature. This is biology, you have to just accept biology." And I was like, "Whoa, you wanna talk about biology? Let's take a little tour, shall we?"

0:38:18 SC: Through my 600-page book on inheritance.

[laughter]

0:38:21 CZ: Absolutely, absolutely. The fact is that heredity itself works very differently in a lot of different organisms. And the irony is, this is one reason why Mendel was forgotten, actually. So this is... One of these incredible ironies is that Mendel studied peas and he was like, "Oh my gosh, look at this mathematical thing that's happening." And he wrote to one of his mentors and his mentor is like, "That's interesting. I'm not sure what to make of this, but why don't you see if you can replicate this? If this is what you say it is, then you ought to be able to find it in another plant, right?" So Mendel, I guess, agreed with that, and he went and studied another common garden plant and it turned out that this other one, hawkweed I think, I forget the name now, it doesn't reproduce in the neat sexual way that peas do.

0:39:29 CZ: It has pollen. Pollen is sort of like the plant equivalent of sperm. They have male and female gametes, and you have to have fertilization. But in these other plants, once fertilization happens, the ovules, the eggs as it were, just basically, just kick out any male DNA, they don't use it. They do meiosis within their own genes, and so they're like clones except that they're shuffling their DNA with every generation. Boom, those lovely 3 to 1 patterns that Mendel saw with peas, they're just not there at all when he looks at another species and then it's like, "Huh." And you imagine if he had picked another species that was very neat about... Worked like peas did, that he might have gained more traction, but no, he was forgotten for basically 50 years.

0:40:33 SC: It's good to know that the deflationary role of mentors has not changed in academia over the centuries, that's... I think I've done that to my students sometimes. I love the idea that mitochondria as important as they are, these stowaways, they're basically living their own lives. They're handing down their own genetic inheritance and it's part of what makes us who we are and so forth. Are there other examples of that? I know that we carry around a whole microbiome, a whole set of little monocellular organisms that function in us, but my impression is that we build those up throughout our lives, we don't actually get those from mom and dad.

0:41:13 CZ: Well, that is a big question right now. And there're people who are trying to really nail it down at the moment. Because it is true that you pick up microbes every day, you're picking them up off your keyboard and your doorknob, and you're shaking hands, or you're having yogurt. We're just swimming through a microbial ocean.

0:41:41 SC: And by "you," you don't mean me in particular, you mean all of the listeners out, it's not my keyboard that is worse than average, right?

0:41:48 CZ: Well, I've heard things. No. The thing is that we also know that there are lots of species that passed down certain microbes as faithfully as they do their own genes, my favorite example is cockroaches.

0:42:12 SC: Okay.

0:42:15 SC: Cockroaches actually depend on one species of bacteria to help them to eat food, because the bacteria can actually make some of the compounds they need for proteins out of their food. The cockroaches don't have the genes to do it, so they totally depend on these bacteria. In fact they actually build special little organs for these bacteria to live in and the bacteria actually embedded inside the cockroach's own cells in this organ. And when it comes time for the female to produce her eggs, something incredible happens. Some of these cells that carry these microbes, they just start crawling, and they make their way through the cockroach's body to the cockroach's eggs. And then they open up, and they basically deliver these bacteria into the eggs. And so, after these eggs get fertilized by a male cockroach, then the cockroach is born with these bacteria ready to go, just like we are with our mitochondria.

0:43:18 SC: Biology is very scary.

[laughter]

0:43:23 CZ: It's mind blowing. The best book on all of this is Ed Yong's book, "I Contain Multitudes". For me, what interests me in particular about this, is to think about this as another form of heredity, another channel of heredity. It's like you got your own "genes" but then you have these bacteria.

0:43:48 SC: Yeah.

0:43:48 CZ: Now we don't have anything quite like that except for mitochondria that we know of.

0:43:51 SC: That we know of.

0:43:52 CZ: But... Right. But maybe there is something like heredity in the way that some of our bacteria end up inside of us. Scientists are trying to figure out, for example, are human embryos sterile when they're in the uterus? The evidence is not clear. What is clear is that as a baby moves through the birth canal during delivery, it gets slathered in bacteria and some of that bacteria goes into its gut and there are certain forms of bacteria that the mother encourages to grow in the birth canal. And not only that, but the mother's milk contains bacteria as well, as well as bacteria food, in other words, sugars in the milk that babies can't digest themselves, but bacteria can. There is a debate right now whether there might be certain species that are being put into babies early on and define our own species that way.

0:45:05 SC: It's a very romantic picture you are painting. The miracle of childbirth is [laughter] so enhanced by your scientific understanding, it's really great.

0:45:14 CZ: It was, but it raises some very practical medical questions. Caesarean sections are exploding in countries like the United States, and so those babies are not getting that exposure. And so there's a question, well, does that matter? Can you still pick up those species just by being handled by your parents and other people or does that... Not getting that seeding at the beginning, is that a problem? Because if your microbiome isn't quite right when you're young, that can lead to problems throughout your life, your immune system may not work properly, for example.

0:45:55 SC: Is it still thought to be true that the number of unicellular organisms in our microbiome is more cells than human cells in our body?

0:46:05 CZ: Actually no.

0:46:07 SC: I heard rumors that that had gone away, that thought.

0:46:10 CZ: Yeah, yeah. I and other people had... When we'd write about the microbiome, we always say your microbes outnumber your own cells by 10:1 which is always fun to say.

0:46:24 SC: It is.

0:46:26 CZ: It turns out probably not to be true. It's probably more like 1:1.

0:46:33 SC: Okay.

0:46:34 CZ: We have about 37 trillion cells of our "own" human cells. It might be around the same, I don't know, 30, 40 million bacteria. I don't... That doesn't count the viruses and the fungi and all the other fun critters that are living inside of us. The final number of the full microbiome might be higher, but it's not a 10:1 thing anymore.

0:47:01 SC: But a body, a biological body is a complicated open system. It's a ecosystem all by itself, it's a... We're a little bus that is carrying around a whole world of little critters talking to each other and evolving, and doing their own things.

0:47:19 CZ: Yes, but it's not a totally random collection of critters, the same species and the same strains tend to turn up again and again in people. Your microbiome is gonna be different than mine, but not too differently. And so if you look at human microbiomes compared to a chimpanzee's, they're gonna be a lot more similar to each other than chimpanzees are, and it seems like we have filters.

0:47:55 SC: Right.

0:47:55 CZ: So not everybody gets a seat in the bus.

0:47:57 SC: And then, there's also the idea that we're learning more and more that just the information in our DNA, even just getting back to the genetic part of inheritance. There's more to it, there's more to how we pass information down, there's the whole story of epigenetics and so forth. I hear that you're advocating that people take epigenetic yoga classes so they can pass down new things that they learned to their children, is that right?

0:48:27 CZ: Many people are saying that. No, I...

[laughter]

0:48:31 SC: I hear people saying it, yeah.

0:48:32 CZ: Yeah, right, right. No, I think you should take epigenetic yoga if you like it, but don't think that your kids are gonna be better for it.

[laughter]

0:48:42 SC: But the idea is that we can learn something and pass it down, right?

0:48:46 CZ: Yeah, that we could have an experience that alters how our genes work and that alteration can get passed down to future generations. That's the crux of epigenetics and heredity. And it's tricky and I explored in my book, and there's definitely good evidence for it happening in plants. It's good evidence for it happening in little tiny tiny worms. When you get to mice, there's a very tantalizing experiments. For example, there is one experiment where scientists would expose male mice to a certain odor and then give them a shock, and then they learn just to associate the odor with the shock. And then they took sperm from the mice and used it in in vitro fertilization and then produced mouse pups. And it seems like the mice in the next generation responded oddly to that same odor. And so the claim was that somehow that learned memory, that learned association about that smell got passed about down to the mouse pups. When that paper came out, the journal put Lamarck on the cover.

[laughter]

0:50:14 SC: Remind us who Lamarck is, Mr. Lamarck.

0:50:17 CZ: Mr. Lamarck. Right, Lamarck was a French biologist, who preceded Darwin. He was most active in the early 1800s and came up with his own theory of evolution which depended a lot on what's known as the inheritance of acquired traits. And so he had a classic example that giraffes stretch their neck to reach leaves. There's some nervous fluid that causes their necks to get a little bit longer, you can think about that like building up muscles. And then those giraffes would pass down that longer neck to their descendants, and so then over many generations, the giraffes would adapt to their environment by getting a longer neck. And so, the claim, I guess is that, well mice are adapting to their environment, by learning about the risks that they face and that their offspring are inheriting that knowledge.

0:51:29 SC: Right.

0:51:31 CZ: So that's the basic idea.

0:51:32 SC: And how would this work at a molecular level for the mice? Is it pups? You call them mice pups, mice babies or puppies?

0:51:39 CZ: Pups. They're pups.

0:51:39 SC: Okay. Good. I learned something. So it's a matter of obviously, the DNA are not being altered, as you smell something, your DNA is still your DNA, but somehow, there's information being passed down to the next generation that is not in the DNA, somehow in the chemical make up of what goes into making a little puppy.

[laughter]

0:52:04 CZ: Yeah, yeah, I don't think... If you call them mouse puppies at a biology conference, people will probably look at you funny.

0:52:12 SC: You think that people will see through me and not realize I'm not a biologist?

0:52:15 CZ: There's an impostor in our ranks. There's a cosmologist, get him out. We know that genes are attended to by lots of molecules in the cell. Genes just don't take care of themselves. And so there are proteins for example, that will clamp on to genes and they can essentially shut them down. There are other places that proteins latch on to DNA and they can switch on a gene. You can coil DNA around spools and then basically anything that gets coiled up, any gene just can't be used to make a protein, 'cause it's just all tucked away. And those changes can be very long lasting, like when a cell divides, those same controls will in effect be inherited by the two new cells. So that's why your skin cells, when they divide, they make skin cells, they don't make brain cells, or tooth cells or something. We know that epigenetics really matters a lot, there's no question about that. And so the question is, could these kinds of processes change the way that genes are being used? And then, could those changes, those proteins and those coils or whatever, get passed down through the generations? We don't know.

0:53:54 SC: Yeah. We don't know.

0:53:56 CZ: The mechanism for it, it's... Especially for mammals, it's hard to figure out how the mechanism would actually work. And you look at a mouse experiment, all the critics of this kind of research who says like, "Whoa, so you're telling me that there's this change that is happening in the mouse's brain, the daddy mouse's brain, and that somehow... Then that is getting communicated into daddy mouse's sperm, and then somehow, that is then making its way through fertilization, through the development of an embryo, through the development of a brain. And then somehow, it's getting plugged back into the brain in the same circuits that daddy had been altered." And a lot of scientists just say, "Whoa, that doesn't make any sense at all."

0:54:47 SC: Right. But this is something that's being studied, we'll try to figure it out.

0:54:51 CZ: Yeah, but in the meantime, there's epigenetic yoga. [laughter] There are literally, psychiatrists who will help you to undo the epigenetic trauma probably that your grandparents passed down to you. This has totally saturated pop culture, and I don't honestly know how it happened because epigenetics is messy, and complicated, and the language is totally inscrutable. And yet, when I give talks, half the questions I get after the talks are, "What about epigenetics?"

0:55:23 SC: Look, I'm writing a book about quantum mechanics, so the idea that crazy abstract ideas are going to be hijacked by popular culture is not foreign to me.

0:55:31 CZ: Any tips?

0:55:33 SC: Well, quantum epigenetic yoga might be a best seller, right? There you go.

0:55:36 CZ: Oh, my God. That's it, that's it.

0:55:39 SC: Throw dark energy in there, and we'll be buying yachts any moment.

0:55:43 CZ: Okay, we need to... We need to patent that idea right now. Author the book...

[overlapping conversation]

0:55:47 SC: Okay. I will edit this out of the podcast, so no one hears it, and steals our great idea. [laughter] It sounds like though, even in principle, if you handed a computer, a complete list of the three billion base pairs in our DNA, the GCTA letters in our alphabet, a computer with perfect knowledge, that would not be enough to predict what the organism would look like. It would be missing the mitochondrial DNA, it would be missing all sorts of chemical signals that could be passed down through the body. It sounds like we're learning how much of the organism is predicted by that, probably a lot, but certainly not the whole thing.

0:56:30 CZ: Yeah. In a way, this is one of those deep questions in the history of biology. How much of an organism is basically determined at the very beginning? And how much of an organism's end result is just the emergence through development? And as always, the answer is both, but it's complicated in the sense that there are a lot of things that you can predict based on DNA. Those predictions are not like... I can't predict what color of shoes you're wearing right now, today based on your DNA, Sean. But I bet if I looked at your DNA, I could get a pretty good idea what your eye color is. And I might be able to make some very crude predictions about the influence of your genes on your height. I couldn't tell you how tall you are, 'cause I don't know if your parents fed you properly.

0:57:42 SC: Right.

0:57:43 CZ: But there are things that you can predict out of DNA. But then there's this, the DNA makes... The cells make proteins or molecules from the genes, and the cells are talking to each other, and they're taking in cues from the environment. Cells are migrating through the body, and all sorts of crazy stuff is happening, and the genes are responding to all of that. And that is how we end up the way we are. So yeah. If someone... I had my genome sequenced. I'm sure nobody could make any predictions about me from that.

0:58:23 SC: Right. I do want to... That's right. I remember this from the book. So when you say you had your genome sequenced, so you're special here because you really had the full-blown treatment. If people do ancestry.com or 23andMe or any of these things, they get a little bit of information about their genome, but they do not get a list of three billion ACGTs, right? They get some sub-knowledge of that. Do you actually have a print out of all three billion base pairs in your DNA?

0:58:56 CZ: I do not have a printout. I have a hard drive.

0:58:58 SC: Okay. Metaphorical. I was being metaphorical.

0:59:02 CZ: Yeah. Well, well, if I printed it out, it would fill up dozens and dozens of books, and that would be a fun art project, but...

0:59:12 SC: You can use a small font, it's okay.

0:59:16 CZ: Yeah, right. And it would be kind of hard to do a search function on that.

0:59:18 SC: That's true.

0:59:19 CZ: So I prefer to have it on that hard drive because then, I can take it to scientists and say, "Okay, let's play around with this data here which just so happens to be my genome, and show me how you discover things in human genomes by analyzing this sort of data." And it's been a fascinating experience. But it is a very different thing than getting your DNA sequenced from a place like 23andMe. What 23andMe or Ancestry does is they do something called genotyping. Basically, they look at maybe a million markers, a million spots in... Throughout your genome, and they try to... They look at to see, well, which variant do you have at that particular spot? And so, it's kind of a high level survey of your genome, but you can learn an awful lot. One of the reasons you can learn an awful lot is because we tend to share similar stretches of DNA. So if you've got a string of variants all in a row, chances are that that whole segment of DNA is identical to somebody else that has those same variants.

1:00:36 SC: Right.

1:00:36 CZ: And so you can infer a lot about what's in between those markers. When you get your whole genome sequenced, that means that you're trying to figure out as best as you can, every single letter in your genome, and with that you can discover all sorts of deeper things about your genome.

1:00:58 SC: Well, and one of the deeper things you could discover is that you are susceptible or even almost inevitably going to have some disease that might affect you at a certain time of your life. And so there's this question of what do we want to know? If you could... The philosophers would come in and instantly say, the version of the question to ask is, "If you could know you were going to die on exactly a certain day, would you want to know that? Is that information you want?" Some much cruder version of that might be available through this, looking at our genomes.

1:01:33 CZ: That information is really only available to a small fraction of the people who get their DNA genotyped or get their genome sequenced, because the genes that really have a strong impact on your health, let's say, we're talking about genes that cause Huntington's disease, or genes that raise your risk dramatically of getting early onset Alzheimer's, genes that dramatically raise your risk of getting certain forms of cancer, these are rare. Natural selection is not fond of these genes.

[laughter]

1:02:18 SC: For obvious reasons.

1:02:20 CZ: Therefore, they're rare. When I got my genome sequenced, the first part of it was doing it... I did it as part of a conference, and I think there were like 40 people who were going to this conference who also got their genome sequenced. They weren't getting the raw data but they were getting these interpretations from clinical geneticists. And there were like 40 of us, and if I recall correctly, maybe like five people were told, "Okay, we're gonna sit down with a genetics counselor, and make some plans for you to talk to your doctor because there's something you need to know about."

1:03:02 SC: How is your life insurance plan looking?

1:03:04 CZ: Yeah, right, right. For the rest of us, it was like "Man... " You don't have anything that really jumps out, is what they would say. There's nothing where it's like, "Hey, that gene, that's big trouble." Now, I have plenty of genes that have been associated with raising my risk of this disease or that by some modest amount, but that doesn't mean that I'm gonna die of any of those diseases. I also have variants that lower the risk for certain diseases too.

1:03:36 SC: Right.

1:03:37 CZ: And so... And that's... That is going to be how most people are going to... Most people are gonna find when they get their DNA sequenced. And it's going to be... I'm concerned that people not make one of two mistakes. One mistake is to be angry and irritated that they didn't find anything in their genome, it's like, really?

1:04:12 SC: My genome is much more interesting than you're making it out to be, yes.

1:04:15 CZ: Well, this isn't a status thing, it's not like you wanna go to the doctor's office and get terrible news, it's not like you feel like... You should feel happy if they say, "Oh no, you're fine, see you later." And also, the flip side of that is that sometimes people will get in these reports or maybe do their own research and discover they have a gene that is associated with some disease, let's just say like colon cancer, and they say, "Oh my God, that's it, I'm gonna die of colon cancer." No, no, no, you have to dig down that extra level and say, "What exactly did this study find?" Did it find that people who had this variant had a slightly higher risk of this disease? And also, how big was this study? A lot of these studies when they're preliminary, is just like a hundred people, they're tiny. And tiny studies are often wrong. So there are plenty of mutations that were thought originally to cause diseases that we now know do not. So you gotta think about all these things when you're looking at these results. And that gets back to me, and how I feel that our high school, grade school genetics has just gotta step up its game, because these things are not just abstractions that you learn about in high school and never think about again. People are getting these results in their email inbox.

1:05:51 SC: Right. But also, isn't it maybe an antiquated worry, because, recently I bought new running shoes. So, I went to the Nike website, and they let you actually customize your own shoes, like what color is the front, and what logo is on the bottom and stuff like that. So, within a couple of generations, we'll have the website for doing that for our babies. Right? We'll just be able to pick what different features we want them to have, edit the DNA, and get whatever baby we want.

1:06:22 CZ: I am sure that there will be people who are offering that, if the laws allow. I don't think that you will get the baby of your dreams, I think your baby will just be your baby, and will be subject to all the vagaries of experience and biology, and all the rest of it. But we already have all sorts of companies out there that are offering really dubious claims based on looking at your DNA. They'll looked at a few variants, and they'll say, "A-ha, here's your special exercise program," or "Here's your special DNA diets" or... There's even a company that's called Vinome, I don't know if you've seen them?

1:07:13 SC: No.

1:07:13 CZ: They will recommend wine to you, based on your DNA.

[laughter]

1:07:21 SC: Sorry, how do you spell that? I actually have to look this up. What is this called?

1:07:24 CZ: Yeah, please do. V-I-N-O-M-E, Vinome.

1:07:28 SC: Alright. It could be a podcast sponsor down the road, I like it.

[laughter]

1:07:33 CZ: Well, yeah. You may not wanna play this episode. Because when I saw a video for it, I just thought, "Well, this is... Wait, is this The Onion? This can't be real." But it was. And all these companies seem to be doing, as far as I can tell, is looking in the scientific literature, and saying like, "Oh, here's a variant where people who had it tended to report a stronger sensation for bitter tastes than people who didn't." And then going from that to saying like, "Here, take this Pinot Noir." And with exercise, it's a very similar thing. Yeah, sure, there are genes that are associated with all sorts of aspects of exercise, the power in your muscles, or how much oxygen you take in, and so on. And I'm sure that there is a genetic element to great athletes being great, but when I got my genome sequenced, the company that gave me that first layer of results before I took matters into my own hand, they... Actually they said like, "Your muscles are built for power." I was like...

[laughter]

1:09:00 SC: Sorry, I do not mean to laugh. I was laughing at something completely separate, that was happening here in the room.

1:09:04 CZ: Yeah, I'm sure, I'm sure. No, it's okay, Sean. You've met me and anybody who's met me knows that my muscles are not built for power, it's just not the case. But what they were doing is they were just looking at this one variant, and these limited number of studies, and not taking into account all the other genes that influence our muscles, many of which we don't really understand. So, I do worry about letting folks like that, who run these companies, do the same thing with designing babies.

1:09:43 SC: Well, tell us a little bit though about CRISPR, and the reality of gene editing. It is something that is brushing at us very, very quickly, right?

1:09:52 CZ: Yeah, yeah. I only became aware of CRISPR maybe six years ago or something. And I can remember thinking... At first I was sort of puzzled by it, because actually CRISPR was... It's a natural thing. What it is, is it's basically an immune system for bacteria. They make molecules that can essentially store information about viruses, and then use that information to create new molecules that could zero in on particular stretches of virus DNA, and cut it. And I thought, "Wow, that's cool, microbes never cease to amaze me." But then some scientists said "Well, we could use that, and we could maybe cut whatever DNA we want." And lo and behold they could, they could zero in on particular stretches of DNA, and make cuts, and then substitute in new DNA. And all of a sudden, they had this very powerful new molecular tool at their disposal. Scientists use CRISPR all the time now to do experiments.

1:11:08 CZ: They might say like, "We wanna know which genes in a cancer cell are essential for it to survive as a cancer cell?" So, they will just use CRISPR to systematically cut out every single gene in individual cell lines, and just see which ones survive as cancer. You just couldn't do that before. And so the impact is unbelievable. And then people are starting to say like, "Well, can we use this to alter the genes of crops, or of animals?" And the answer is "Hell, yeah."

1:11:48 SC: Sure.

1:11:50 CZ: And so the next step is, well what can we do for people? And one of the things you can potentially do for people, is treat hereditary diseases. So, if someone has sickle cell anemia, you take some of their bone marrow cells out, the stem cells are... Can make blood. You tweak their DNA so that they can now make hemoglobin that they need, the proper kind of hemoglobin, 'cause sickle cell anemia is caused by a misshapen kind of hemoglobin, and you put the cells back into people, and they make healthy blood cells, that's the hope. And there are clinical trials that could start very soon on that. And then, the big frontier, the one that understandably everybody gets excited and scared about is, what if you could use these on embryos and change genes in embryos, and then you are creating an inherited change that will be passed down through the generations?

1:12:55 SC: Right. Yeah, they're gonna do it, right? It's gonna... So, there's no... I have a kind of an extremist point of view on this. Because people say, people raise this question that you just raised, "Can we genetically edit what's going on in the embryo and therefore change what the person is gonna be like?" And there's a sort of instant reluctance, right? It's like, "Well, of course, that would be bad, or at least it might be bad, we should think about it, and we should really be very careful." But I'm not quite sure where the reluctance comes from other than a sort of squeakiness, a sort of feeling that we're messing with nature. And what I suspect is that some people will feel that way, some people will not feel that way, and it's absolutely 100% gonna happen. And 100 years from now, the idea of just making a baby by randomly picking half of the DNA from mom and half the DNA from dad, and hoping for the best will seem hopelessly barbaric.

1:14:00 CZ: Well, you and I are gonna have to hope that life extension, anti-aging drugs advance really quickly so that we can make a bet and see if it pans out.

1:14:13 SC: Yeah.

1:14:14 CZ: But I have thought about these scenarios a lot. Partly, they're just fun to think about and it's what science fiction writers do so well. And I... There are a lot of questions I have. I'm not as sanguine, maybe is the word, as you are in the sense that... So for starters, like CRISPR. CRISPR is indeed revolutionary but it's turning out to have some problems because it's based... People call it gene editing, but it's editing that involves chopping DNA, and that is a pretty radical thing to do to DNA, and cells don't like it. The cells actually have all sorts of defenses against chopping up DNA because it can lead to all sorts of damage that can ultimately cause a cell's descendants to become cancerous, for example. And not only... So, there are concerns about just how safe CRISPR would be in terms of creating a line of cells you'd wanna put in your body through CRISPR. You don't wanna put in cells that are gonna be more prone to cancer, that's problem number one. Problem number two, there's a recent study that showed that sometimes when scientists try to cut one particular segment of DNA out, they cut out a long stretch that includes that particular target. And so, you might be cutting out pieces of DNA that you really need. And maybe when the DNA is getting repaired, it gets kind of shuffled around in ways that could be a problem.

1:16:18 CZ: So, okay. So there's the safety issue and then also, there's kind of the logistics issue. If you're saying like, "Oh, this is barbaric," so you're imagining a world where... Are you imagining a world where all, say nine billion people all get in vitro fertilization? In vitro fertilization is a very difficult, drawn-out process right now. It could get a lot better in the future, but maybe not. Maybe there is some inherent sort of limits to this. It's not... So my point is CRISPR... It wouldn't be CRISPR... You wouldn't have... CRISPR alone would not deliver you into that science fiction future, you'd have to have all sorts of other advances in reproductive technology and stem cell research, and all the rest of it before this could even be possible. But I have talked to biologists who say, "We're gonna look at CRISPR like vaccination in the future."

1:17:29 SC: Right. Yeah. So I think... I get absolutely the fact that it's not within the next five years or 10 years, right? We will have to extend our lives if we're gonna see this thing come true. And I'm also not sanguine in the sense that I think that it's not going to be unalloyed good. I look at this editing of our children's genomes as some... It's a technology, it's like cars or Twitter. There's gonna be good parts about it or bad parts about it. I just think it's inevitable. I just think that it's like we have jumped off of a pier into the ocean, and as we fall in, we're debating, "Should we get wet or not?" And that's just not a debate that is very reasonable to have.

1:18:09 SC: We can have other debates, "Should we swim for shore? Should we try to climb back up the pier? Should we fight off the sharks?" But I think it's going to happen, and people are gonna be trying to alter their children's intelligence and skin color and size of their noses and everything, and I think that we're kind of dropping the ball a little bit on dealing with what the implications of that really are gonna be.

1:18:33 CZ: Well, I guess the question becomes, if people really are going to try to do this if they can, that... Should we pass laws to prevent that? Or, do we have... Do we put regulations in place to allow certain uses of it for certain things? And then really you're shifting from a scientific question to a social or a political one.

1:19:02 CZ: For example, with... We're dealing with that right now, actually. People don't realize it, but genetically engineering humans has already begun because we were talking about mitochondria before. So mutations can cause mitochondria to become defective, and so women can pass down defective mitochondria to their children and you can get these mitochondrial diseases which can be quite devastating. And there are all sorts of different ones that emerge from faulty mitochondria.

1:19:37 CZ: So some years ago, people thought, "Well, what if we were to do a transplant, an egg transplant? Take the DNA and the nucleus of an egg and put it into a donor egg that has good mitochondria in it. Obviously, you'd take out the nuclear DNA out of the egg, donor egg first. But anyway, so basically now you have an egg that has the mother's nuclear DNA, the chromosomes, and another woman's mitochondria, and then fertilize that. People call that three-parent babies [laughter] which is unfortunate, but it stuck. Anyway.

1:20:14 SC: And again, yeah, well...

1:20:15 CZ: We can debate about what it means to be a parent, but...

1:20:16 SC: Yeah.

1:20:18 CZ: But in any case, in the United States, that has been banned. There's no way that's gonna happen in the United States. There's no way there's gonna be research or evaluation of it. Forget it. That is dead in the water right now. And there was a case of a doctor in New York who had done some research on this, who actually went to Mexico to treat a couple who, the mother had a mitochondrial disease. And so they... And Mexico doesn't have any laws one way or the other about it. So they did it kind of on the... Secretly.

1:21:02 CZ: And... But meanwhile in Britain, they talked about this very quite explicitly and had discussions in Parliament and they said, "You know what? These diseases are so devastating, and we feel that this combination of mitochondria from one woman and chromosomes from another woman, we're okay with that. We don't think that violates our human dignity and we're going to allow this to go forward under a lot of regulation." And so, there's a university in Britain that has gotten the license. They're open for business. And so they will start... Probably babies will start being being born soon through this technology. So I wonder, what's gonna happen with CRISPR?

1:21:50 SC: Right.

1:21:51 CZ: Will it be the American version, total ban? Will it be the Mexico version, like it's all kind of on an unregulated black market? Or is it going to be out in the open, carefully, explicitly regulated under the guidance of government?

1:22:11 SC: Well, and I think that's... I'm being a little intentionally provocative here because I think that people are... There's a tendency for people either to just sort of ask rhetorical questions and leave them hanging without quite answering them, or there's this other tendency which we in the United States love so much is just to ban it first and ask questions later. For something like designer babies, if it does become possible, and obviously, there's enormous scientific technical hurdles to getting there, but I could easily imagine that it's banned here, and so, okay, someone sets up a clinic in Mexico or the Cayman Islands or whatever and rich people go there and design their babies and poor people can't do it.

1:22:51 SC: Or even if it doesn't get banned anywhere, like you alluded to earlier, there's just, "Okay, you can do it. It costs a $1 million." That's just how much the effort is going to require. And so that's a kind of inequality, socially, that is going to be hard to deal with. It's a little bit... It hits home in a way, the ability to make sure all your children are tall and beautiful that other kinds of inequality might not.

1:23:19 CZ: I have a problem with these arguments against CRISPR based on inequality, because they all make it sound like we are living in a paradise of equality today.

1:23:33 SC: Wait, what? We're not?

1:23:36 CZ: If you are concerned about inequality, like it's time to get started now, because it's not as if genes are the only thing that can influence the success of children later in life, and...

1:24:00 SC: Sure.

1:24:00 CZ: So... And this raises... I do think that this also raises difficult questions, because if you say, "Okay well, it's wrong to let parents use CRISPR to make their children... " Let's say, "Tall and beautiful," or whatever you want to dream that you could do with CRISPR. I don't think that would happen, but let's just pretend you could do that. Anyway. Okay, so what about all the other advantages that children of wealthy parents have that help them to get ahead in life? Do we make those illegal? Should SAT prep classes be banned?

1:24:42 SC: Yeah. No, I think this is very real, but I still think the analogy is not quite perfect. I get it and I think that we are a terrible society at treating people equally right now, though that point is very, very well taken. But in America, at least, people grow up with this idea that someday, no matter where you come from, you could be a millionaire or you could be President, but no one grows up with the idea that 20 years from now my DNA will be better. So it's this kind of obvious, in your face, difference between people, which I suspect people will react to very viscerally.

1:25:18 CZ: I agree and I think part of it is that... Part of the problem here is that we think of genes as being the absolute definition of who we are. It's not. But we also think about heredity in the sense that these kids will then pass down these traits to their kids and so on, and that really strikes a chord I think, because, like I was saying before, heredity is such a profound thing to us in terms of how we define ourselves. And so to be tampering with heredity seems like one of the great transgressions, and that I think colors our discussion of this. And you can see this in the debates people have.

1:26:12 CZ: Scientists who developed CRISPR actually have, just in the past few years, had a series of international meetings to figure out like, "Well, what's right, what's wrong, what should we do with this?" And the overriding issue, it seemed, was what is this gonna do to heredity? Which is so striking to me, because it really tells you where our concerns are located. And I think it's a good question, but on the other hand I just... I don't... Some people say like, "Oh, we're gonna turn ourselves into two separate species." You'll have the rich people who can afford CRISPR who will become their own species, and the poor people will become a different species. It sort of reminds me of The Time Machine by HG Wells.

1:27:03 SC: It's very HG Wells. Yes. Exactly. That's right.

1:27:05 CZ: You know what I'm talking about.

1:27:07 SC: Yeah.

1:27:10 CZ: But, people just don't work that way, animals in general don't work that way. People have sex, lots of sex, and people don't respect these sort of arbitrary boundaries when they're having sex. Whatever genes might get introduced into some rich person will either disappear entirely from the human gene pool eventually, 'cause that's what happens to most gene variants. Or will just kinda diffuse around all over the world after a while, because of just the way that people have kids together. So I just find some of these science fiction scenarios that people are talking about as if they're real ethical questions to be silly, frankly.

1:27:58 SC: I think actually, so I'm gonna go on the other side. I think that even if they're wildly unrealistic and not mapping out the future, I am glad people are envisioning the craziest, most extreme scenarios, I think will help us, sort of, be prepared a little bit for the brave new world yet to come.

1:28:14 CZ: Well, no but, you have to then... But, okay, yeah we can talk about these scenarios, but then we have to take the next step and say, "Well, okay, but here are the basic facts of science that tell you that this is not even something worth considering."

1:28:31 SC: Sure.

1:28:33 CZ: For example, I wrote an article for The Times recently about studies on DNA and the link between genes and how long you stay in school. There is a connection there. We don't really know why there's a connection there. It may have to do with genes that influence certain things in our brains, or maybe even our parents' brains, we don't know. But there's an association there. It's interesting, it's worth studying, and you can actually look at these million variants in people's DNA and actually come up with a score, a sort of education score, which sounds very fancy, like, "Oh well, I could use that to test some kindergartener." And say like, "You're never gonna make it to college so we're just gonna put you over here in this track and you just be content with your lot."

1:29:26 CZ: And that would be a ridiculous thing to do because this score it only predicts a small amount of the variation in how people do in school. So chances are that your score would be very wrong. So lots of people with a high genetic score who drop out early from school. There are a lot of people with a low genetic score who go into grad school. It's just one variable among several. So for people to say like, "Oh, okay, well, clearly we're gonna have this future where everybody's fate is predetermined." Well, "No, no." And it's not a scenario worth talking about just because of the basic statistics of what we're talking about. So I'm all for talking about scenarios, but you have to be willing to throw some out.

1:30:19 SC: No, I completely agree on that. That idea that you just said about predicting people's educational attainments based on their DNA makes no sense to me. It's like taking a pre-season power poll in some sports league and then saying, "Well we don't need to play the games now, we figured out who's going to win." But, playing the games actually matters also. So Carl Zimmer, or as we say around here, Carl "built for power" Zimmer, thank you very much for a wonderful conversation. It's always great to talk to you.

1:30:49 CZ: Oh, it was good talking to you again, Sean.

1:30:50 SC: Alright, bye bye.

1:30:53 CZ: Bye.

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