Editing 19: Bret Weinstein - The Prediction and the DISC/lang-it
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'''Eric:''' Okay. | '''Eric:''' Okay. And you know, Darwin famously couldn't, for example, like, I don't know how much I've talked about this in the open, but my favorite Darwin book is the one he wrote after [https://en.wikipedia.org/wiki/On_the_Origin_of_Species Origin of Species], which is [https://en.wikipedia.org/wiki/Fertilisation_of_Orchids On the Various Contrivances by Which British and Foreign Orchids are Fertilized by Insects]. It makes absolutely no sense as a title, I think that's what's so funny about it. But because orchids are so highly speciated, it turned out to be the perfect place to explore the consequences of evolution. And he couldn't figure out my favorite, I don't know whether it's clade or a group— | ||
'''Bret:''' Clade | '''Bret:''' Clade is pretty safe. | ||
'''Eric:''' | '''Eric:''' Yeah, clade of orchids, the [https://en.wikipedia.org/wiki/Ophrys Ophrys] system, which is just unbelievable because it mimics the pollinators, the female of the pollinator species using pheromones and some sort of replica good enough to fool males into copulating with the lower pedal of an orchid— | ||
'''Bret:''' | '''Bret:''' A 3D replica of the female that smells like her. And it just so happens that when the male lands on it to copulate, he gets these pollen packets glued to him, and then he screws up and makes the same mistake at another flower and delivers— | ||
'''Eric:''' | '''Eric:''' Well, he may, he may or may not | ||
'''Bret:''' | '''Bret:''' Put it this way— | ||
'''Eric:''' | '''Eric:''' Only the ones that screw up twice get to fertilize. | ||
'''Bret:''' | '''Bret:''' The reason that it gets glued to him is that it has worked enough times for this strategy to have been so beautifully refined. | ||
'''Eric:''' | '''Eric:''' Right. So Darwin saw that there was this mimicry going on, but he couldn't put it together. He spent pages and pages not getting it. So I think it's very funny. So he predicts some things, but he can't predict something else in a very closely related system. Okay. Fast forward, Dick Alexander comes out with a crazy prediction, which I still don't fully— I mean, it's just amazing that he made it— where he says, I bet that you will find the kind of behavior we associate with wasps and bees, which is in this clade called Hymenopteran ants of [https://en.wikipedia.org/wiki/Eusociality eusocial] breeding patterns and organization, but in mammals that will live underground. | ||
'''Bret:''' | '''Bret:''' So, I think, the way this story actually worked, he didn't say you will find it— | ||
'''Eric:''' | '''Eric:''' Or, you could find it. | ||
'''Bret:''' | '''Bret:''' What he said is, in principle, there's no reason that a eusocial animal has to be an insect. That in fact, you could get such a thing in a mammal. And then he predicted—I forget how many characteristics there were—but he named some large— | ||
'''Eric:''' | '''Eric:''' So we should say that there's something funny about the system of ants, bees, wasps, which is that they've got this very strange [https://en.wikipedia.org/wiki/Haplodiploidy haplodiploid] chromosomal characteristic. Do you want to say a word about that? Cause that makes the prediction more— | ||
'''Bret:''' | '''Bret:''' Sure. So it has long been understood that the [https://en.wikipedia.org/wiki/Hymenoptera Hymenoptera] behave in this incredibly cooperative fashion, which effectively all of the workers of the colony forgo reproduction in order to advance the reproductive interests of the queen. And it was late discovered that actually their genetic system is unlike our genetic system, and that males have basically half a full complement of genes. They have enough greens to function, but they have half the female complement of genes. And, for reasons that are mathematically slightly complicated and require a chalkboard, the females are more closely related to the daughters produced by their mother than they would be to their own offspring, their three quarters relatives to her offspring. And there they would be 50% relatives to their own offspring. | ||
''' | '''Eric:''' Spot on. | ||
'''Eric:''' | '''Bret:''' So, they are actually evolutionarily favored by very standard mechanisms. Once you understand the crazy genetics underlying the thing, they are favored to engage in behavior where they forgot reproducing and fostered. | ||
'''Eric:''' So, once you understand the chromosomal difference of the system, it is far less surprising that it would behave as a loosely coupled, in some way—don't overreact—unified organism, which is distributed. That there are ways in which the hive behaves as a superorganism, and there are ways in which it does not. | |||
(00:45:40) | (00:45:40) | ||
'''Bret:''' | '''Bret:''' Yeah. Well, all I want to say is, I'm not sure how clear we have the story with respect to what precedes what— it's completely plausible that the behavior precedes the evolution of the genetic system. | ||
'''Eric:''' | '''Eric:''' Right. | ||
'''Bret:''' | '''Bret:''' And I actually, frankly just don't know where that research stands at the moment. We have found many other insect systems that have various versions of this. Interestingly, though, the termites are not hymenopteras. | ||
'''Eric:''' | '''Eric:''' Right. | ||
'''Bret:''' | '''Bret:''' And the termites engage in this behavior— | ||
'''Eric:''' | '''Eric:''' Termites are eusocial, but they're not haplodiploid. | ||
'''Bret:''' | '''Bret:''' They’re eusocial, they behave very much like ants. | ||
'''Eric:''' Okay. | '''Eric:''' Okay. | ||
'''Bret:''' | '''Bret:''' But they don't have the strange genetic system, proving that the behavior can evolve even in the absence of this genetic system— | ||
'''Eric:''' | '''Eric:''' Well, the reason I bring this up is that if you look at, for example, Prince Peter Kropotkin, the great anarchists theorist, he was obsessed by finding analogs in nature of preferred human structures. And so it's very simple to say, why can't we work together the way an ant colony all works together? And then there's a counter to that, which is, well, they have different chromosomal structures, and then you say, well, but yes, but that's a kind of a cheap way of achieving eusociality. There are other ways of—so through this crazy kind of investigation, we get to Dick Alexander, who, and I think you're quite correct, says there is nothing prohibiting us from finding a mammalian species that exhibits ant- and wasp-like behavior. And it would be likely to have these characteristics, it would live underground, in a— | ||
'''Bret:''' | '''Bret:''' Yeah, underground, I believe eating tubers, was on the thing. It was a crazy list. And you know, my understanding from, from Dick—Dick is now unfortunately dead. He died a couple of years ago. But my understanding from him was that he didn't actually expect to find such an animal. He was speaking very abstractly, just completely theoretically. And at the point that he unleashed this idea, it may even have been in a talk, rather than a paper. The information made it back to him, actually—what about [https://en.wikipedia.org/wiki/Naked_mole-rat naked mole-rats]? They match your characteristics, and study reveals then that actually they are eusocial, they behave very much like ants, bees, wasps, termites, et cetera. | ||
'''Eric:''' | '''Eric:''' And this is like one of the great moments in modern science. | ||
'''Bret:''' | '''Bret:''' I really think it is. It's certainly the moment that people who know who Dick Alexander was, reference as sort of the high watermark because it's comprehensible. You know, Dick did a lot of things. He was very interested in people and other things, but this particular demonstration was so, it would be impossible to have predicted such a thing and have gotten lucky. He had to have understood some things that were extremely deep in order for that to have worked out. And so, yeah, it's really, I don't know of another example in evolutionary theory of a prediction that clean, of something that obscure. | ||
'''Eric:''' | '''Eric:''' I know one. | ||
'''Bret:''' | '''Bret:''' Oh yeah? | ||
'''Eric:''' | '''Eric:''' Yeah. I once heard a story about a graduate student who predicted that the breeding protocols of laboratory rodents would compromise the laboratory system in terms of its relationship to so called “wild type” versions of the same species. So you have the bred rodents and you have the wild rodents, and that they would be distinguished by virtue of the fact that the non-coding nucleotide sequence at the end of the chromosome, known as “[https://en.wikipedia.org/wiki/Telomere <span title="A telomere is a region of repetitive nucleotide sequences at each end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Over time, due to each cell division, the telomere ends become shorter. They are replenished by an enzyme, telomerase reverse transcriptase.">telomeres</span>]”, would be wildly different in length if the prediction were true from pure evolutionary theory. | ||
'''Bret:''' Wow. | '''Bret:''' Wow. | ||
'''Eric:''' | '''Eric:''' Yeah. | ||
'''Bret:''' | '''Bret:''' Yeah. Yeah, that story that didn't happen exactly the way you said it, but you know, it's been a lot of years, and it takes a second to get back there. | ||
'''Eric:''' | '''Eric:''' Yeah. I mean it's, you, you did that. | ||
'''Bret:''' | '''Bret:''' Yeah, I did that. | ||
'''Eric:''' | '''Eric:''' And that story, unfortunately, has not really been told, and it is, in some sense, your central origin story as a biologist. | ||
'''Bret:''' | '''Bret:''' It's a pretty good one, and it definitely changed the way I saw myself in a way that has been very productive. | ||
'''Eric:''' Okay. | '''Eric:''' Okay. I want you to talk to me about that story, and because I lived with you, I know that it happened, and I know that it got buried, and I know that it's part of what I'm calling the Distributed Idea Suppression Complex because, quite frankly, you were not the only person who was a part of the story, and the story had to die because it said something, which is that the power of your theory was sufficient to predict, from first principles, a manifestly observed and surprising result, within molecular biology, from pure evolutionary principles. | ||
(00:50:47) | (00:50:47) | ||
'''Bret:''' | '''Bret:''' Yup. All right. I'll try to do a short version of it. | ||
'''Eric:''' | '''Eric:''' You know, this is long form podcasting, and you tell—however long the story is, I guarantee you when people finally figure out that it may be that the rodents that we've used to test drugs on, let's say, might be compromised, and compromised in a way that would be potentially extra permitting of potential toxins in the form of pharmaceuticals. I think that it's going to be fascinating. And it's going to repay the study that it will take to understand the story. The floor is yours. | ||
'''Bret:''' | '''Bret:''' All right, so let me just set the stage a little bit. Evolutionary biology has— | ||
'''Eric:''' | '''Eric:''' But, do me a favor. | ||
'''Bret:''' | '''Bret:''' Yeah. | ||
'''Eric:''' | '''Eric:''' You can get into a very patient careful pedagogical mode. This is an exciting story. Tell it the way it actually occurred. | ||
'''Bret:''' | '''Bret:''' I'm going to tell it the way it actually occurred. And I'm going to be careful. I'm going to try not to be—there are parts of it that were for a very long time kind of emotionally fraught. But anyway, I think I remember it well enough to do a sparse but complete version. | ||
'''Eric:''' Okay. | '''Eric:''' Okay. | ||
'''Bret:''' | '''Bret:''' Evolutionary biology has long been biased in the direction of abstraction. Rather than thinking about mechanism, that is to say we deal in the phenomenology of things. We talk about gross patterns that we see in nature rather than talking about the fine detail of what drives them. That has been changing in recent decades, but it has a long history, and it comes from a very mundane place. That mundane place is that we just haven't had the tools to look, for example, inside of cells and we haven't been able to read genomes. You know, we could have been able to read a gene here and there at great expense, but the ability to peer into genomes is pretty new. The ability to peer into these molecular pathways is pretty new. So anyway, there's a historical bias in evolutionary biology against mechanism and in the direction of phenomenology. I have never been particularly fond of that bias. I have always been interested in [https://en.wikipedia.org/wiki/Mechanism_(biology) mechanism]. I'm interested in the phenomenology too, but I've always kept my foot in the door with respect to mechanism. And as an undergraduate, I took lots of mechanism classes. I took a development class at the time, developmental biology was in my opinion, a bit stuck. It is now unstuck in a very dramatic way. But anyway, I took a developmental biology class. I took some or immunobiology. And anyway, I was armed with these things in an environment in evolutionary biology where most people were not, most people were in the phenomenology. And one day I happened to be in a seminar. Dick Alexander was running a seminar for graduate students, and a student was there who was very out of place. He was studying cancer, and he, on a lark, decided to take an evolution seminar that looked good to him in the catalog, and it wasn't right for him. And he gave a talk at some point, and his talk was on his work with cancer and frankly, because all the other people in the room were evolutionarily oriented, nobody was really tracking what he was saying. But what he said struck me like a bolt of lightning. He said that in the realm of cancer research, people were looking at telomeres, which are these repetitive sequences at the ends of chromosomes. And they were toying with the possibility that the fact that these telomeres shorten every time a cell divides, that that is providing a resistance to tumor formation. Very straightforward—counter counts down, and that would prevent— | ||
'''Eric:''' | '''Eric:''' So just for the audience that maybe needs a tiny refresher, we're taught in general that DNA is a string of letters called nucleotides, A, C, T and G, and that, in general, three of those that are adjacent to each other form words called codons. And for every word there is an amino acid or an instruction to stop coding for amino acids. So this is the instruction tape that tells us how to string together amino acids into proteins to make machines, molecular machines. This is some weird different thing, where the region of DNA could be interpreted as coding for a protein, but in fact might be instead just counting how many nucleotides are at the end. So it comes across as a counter. | ||
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'''Bret:''' | '''Bret:''' It's a little better. It was known not to be a coding sequence. It wasn't a useful sequence. So what you had is a bunch of DNA at the ends of chromosomes that were just repetitive, and the length of the number of repeats varies. And the number of repeats correlates with basically how many times the cell can divide before it refuses. This being interpreted as a cancer prevention thing made perfect sense. But the reason it struck me like a bolt of lightning was that I was well aware of the existence of tumors and their implication in something entirely different. What they had been implicated in, as far as I was aware, was something called [https://en.wikipedia.org/wiki/Hayflick_limit Hayflick limits], which were the tendency of perfectly healthy, happy cells to grow and grow and grow and grow in a Petri dish, until they hit some number of divisions and then to stop without apparent dysfunction. So— | ||
'''Eric:''' | '''Eric:''' So this was the theory of [https://en.wikipedia.org/wiki/Leonard_Hayflick Leonard Hayflick]? | ||
'''Bret:''' | '''Bret:''' Yup. It was the discovery of Leonard Hayflick, who basically overturned the prior wisdom about cells, which was that they would grow indefinitely as long as you kept feeding them and making an environment that was conducive to division. So I don't exactly know why that result had been misunderstood at first. Maybe somebody had a cancerous cell line and so they got the wrong idea and it just spread, but Hayflick checked it and it turned out to be false. It turned out there was a number of cell divisions that healthy cells would go through, and then they'd stop. The mechanism was not obvious to Hayflick, but later it became clearer and clearer that the mechanism was these sequences at the ends of chromosomes which shorten each time the cell divides. And the implication was that, potentially, this was a cause of what we call [https://en.wikipedia.org/wiki/Senescence “senescence”]. What in common parlance would often be called “aging”, the tendency to grow feeble and inefficient with age. If your cells are each in a cell line and that line has a fixed number of times that it can replace itself before it has to stop, then some point your repair program starts to fail. And that repair program, failing across the body, looks like what you would expect aging—aging follows the pattern you would expect if cell lines one-by-one stopped being able to replace themselves. So— | ||
'''Eric:''' | '''Eric:''' We know that there's a special sort of a, I don't want to call it cell line cause you keep correcting me for every tiny mistake I make in speech. But, if we divide our body into two kinds of cells, soma and germ, where germ lines are that which has a hope of immortality through reproduction, then it's the [https://en.wikipedia.org/wiki/Somatic_cell somatic cells] that have finite limits on their ability to undergo mitosis and cellular repair and whatnot. | ||
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'''Bret:''' | '''Bret:''' And the [https://en.wikipedia.org/wiki/Germline germline] can't because if it did, your lineage would go extinct as a result of small— | ||
'''Eric:''' | '''Eric:''' Small addendums. | ||
'''Bret:''' | '''Bret:''' So it's the soma, the parts of your body that don't go on to produce babies, that have this effect. The reason it struck me like a bolt of lightning was that I was aware of another very elegant piece of research done by a guy named [https://en.wikipedia.org/wiki/George_C._Williams_(biologist) George Williams]. George Williams had finally— | ||
'''Eric:''' | '''Eric:''' One of the greatest of modern— | ||
'''Bret:''' | '''Bret:''' One of the greatest modern evolutionary biologists. I actually knew him a bit too. He is also now gone, unfortunately. But George Williams had laid out in a beautifully elegant paper, the evolutionary theory of senescence. It is an absolutely elegant argument that says that, in a lifetime there are, well, let's start somewhere else. A creature is built of parts and traits. It has a relatively small [https://en.wikipedia.org/wiki/Genome genome] and a relatively high complexity. At the time it was thought there might be 100,000 genes or something and you have maybe 30 trillion cells with a ton of complexity. In order to get that small number of genes to dictate how to produce a creature that complex, the genes are doing multiple things. | ||
William's point was when a gene has multiple effects, what we call a [https://en.wikipedia.org/wiki/Pleiotropy pleiotropy], those effects may be good or bad. If effects are good early in life— | |||
'''Eric:''' | '''Eric:''' By good we mean contributing to fitness— | ||
'''Bret:''' | '''Bret:''' Fitness enhancing traits at some costs late in life, then they will tend to be accumulated by selection. And the reason for that is because, well, there are two ways to think of it, really. If a negative trait occurs very late in life, then a large number of individuals who have the gene for that trait will not live long enough to experience the harm. So if it came bound to a positive thing early in life and you're dead before the late life harm accrues, you got away with it. Right? So William's point was, he was building on earlier work of Medawar, but let's skip that for the moment. | ||
His point was, because of tradeoffs, you will have lots of traits that are good early and bad late. Selection sees the early traits much more clearly than it sees the late traits, and it prioritizes them because of the discounting that arises because so many individuals aren't around to experience the late-life harm, and if they are around experienced the late-life harm, a lot of their reproduction is behind them anyway. So they count less. Selection counts more early in life. And this timer starts at the moment of first reproduction, the usual moment of first reproduction for your species. So this was a beautiful hypothesis, and it was beautifully articulated with many predictions, which is the way really good work is done. And we knew, at the point that I was entering graduate school, we knew that the hypothesis was right. It was a theory. | |||
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'''Bret:''' | '''Bret:''' And the reason that we knew it was real, | ||
'''Eric:''' | '''Eric:''' The hypothesis is the [https://en.wikipedia.org/wiki/Antagonistic_pleiotropy_hypothesis Antagonistic Pleiotropy Hypothesis]. | ||
'''Bret:''' | '''Bret:''' The Antagonistic Pleiotropy Hypothesis for senescence. We knew that it was right because it predicted so many phenomenon in nature that we could readily go out and measure. And this is again where the phenomenology versus mechanism comes out. | ||
'''Eric:''' Okay | '''Eric:''' Okay. | ||
'''Bret:''' | '''Bret:''' We know that creatures that are poisonous or have a shell that protects them or can fly away from danger, are disproportionately long-lived for their size. Small creatures tend to live shorter lives than large creatures. But if you can fly, then you're off the line of the other creatures of your size. So for example, their small bats who have been recovered after 30 years in the wild. So creatures that have special protections have disproportionate longevity. This matches William's hypothesis, because it is their ability to fly away from danger that makes the likelihood of their experiencing late-life costs go up. | ||
'''Eric:''' | '''Eric:''' Yep. | ||
'''Bret:''' | '''Bret:''' So selection sees their late life more easily than it sees a small Creek. | ||
'''Eric:''' | '''Eric:''' I just want to say something. This is a podcast. It's an unusual podcast and we can talk science and I'm thrilled, but we always have our colleagues in our minds when we're talking to a general audience and the colleagues are always in a “gotcha” mode. Well, you forgot about this. You didn't mention that. I'm even interjecting little bits because I want to make sure that you're immunized from all the bullshit that the academics, so I just want to make a general statement, which is we can come back and get into any level of specificity that somebody wants to, if they want to take you down, I don't care. What I'd love to do is to tell the story with enough punch that people understand what happens. | ||
'''Bret:''' | '''Bret:''' So we're about to jump into the meat of the matter. The theory of antagonistic pleiotropy was well established, but in four decades of research on the genome, nobody had found a gene that matched it, so that we knew that this explanation was right, but we couldn't find the genes that caused it. The mechanism was missing. So, anyway— | ||
'''Eric:''' | '''Eric:''' Does that mean, to be a gene, it has to be protein encoding? | ||
'''Bret:''' | '''Bret:''' Yeah. Anyway, I knew this assertively, I was well familiar with William's paper. At the point that I saw this talk on cancer and I knew already about the question of senescence, everything came together. This was obviously the answer, where the missing pleiotropy was. Well, the missing pleiotropy had to do with a telomere, which wasn't exactly a gene. It was genetic, it was DNA, but it wasn't a gene, but it was perfectly capable of producing exactly the effects that we see in senescence across the body, tissue— | ||
'''Eric:''' | '''Eric:''' So a counter, and not a protein, could be the answer. | ||
'''Bret:''' | '''Bret:''' Right. Now, I saw this instantly at the point I heard this talk, I raised my hand, and I tried to articulate what was so obvious in that moment, and I couldn't compel a single person in the room. They couldn't even understand what I was trying to say— | ||
'''Eric:''' | '''Eric:''' Which is bizarre. | ||
'''Bret:''' | '''Bret:''' It was bizarre. I mean Dick was in the room and you know, Dick was very broad-minded and I just couldn't make it clear. | ||
'''Eric:''' | '''Eric:''' Look, let me just interject something, and you can correct me if I'm wrong, but my impression of it is that it was a very simple idea attended to by an outrageous amount of irrelevant complexity that had to be very carefully pried off of the central idea. | ||
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