19: Bret Weinstein - The Prediction and the DISC: Difference between revisions

'''Bret:''' I've noticed I have the ultimate Marcia Marcia market problem.  

'''Eric:''' All right. Bret, this is not the story of your career and your life. What happened is that you got stuck at the university of Michigan for a very long period of time, because you made people very uncomfortable. What he's saying in that letter of recommendation is that you wrote four different theses, so far as I can remember, and they were on widely different topics. Furthermore, here's an interesting one: no one that I know of, despite the amount of discussion that's been spilled in ink over Evergreen, has put you together with the hero of a book called The Tapir’s Morning Bath, that appeared years earlier.  

'''Eric:''' Right? It never shows up. And then you're also the recipient of the Golden Gazelle award, I think of the National Organization of Women, for standing up to ZBT at the University of Pennsylvania. And you got ejected, effectively, from an Ivy League school due to threats of physical violence for standing up for black women being exploited by white men. I mean, like, then you're like the, the field assistant and main student as an undergraduate of another legendary evolutionary theorist, Bob Trivers. And somehow, you know, Richard Dawkins is treating you as a guy who isn't really his equal. “You're not really a major theorist. You're very confused and you need to learn more about the extended phenotype” and all this kind of nonsense. And you're so polite that you're not even just, I dunno, I think you're out to lunch. No offense.  

'''Bret:''' Okay.  

'''Eric:''' Okay. Now Dick Alexander is a legend in evolutionary theory because it's very hard to use evolutionary theory to make predictions that can be verified in the world. It's sort of this loose amorphous collection of techniques and viewpoints. And people sometimes think it's not even a theory because it doesn't seem to be predictive.

'''Bret:''' But he was absolutely correct. There is a moth that has this beautifully long tongue. It's a Sphingid Hawkmoth, one of these sort of hummingbird-esque moths, and anyway, yeah, it's one of the major predictions, demonstrations, that evolutionary theory actually can be used to predict phenomena that you haven't been able to observe.

'''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—

'''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—

'''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:''' 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.  

'''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.

'''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:''' 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:''' 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.  

'''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.

'''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:''' Yeah. I mean it's, you, you did that.

'''Eric:''' Okay. I want you to talk to me about that story, and because I lived it 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.

'''Bret:''' Yup. All right. I'll try to do a short version of it.

'''Eric:''' Okay.  

'''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 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—

'''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—

'''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 at 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—  

'''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.  

'''Bret:''' Fitness enhancing traits, at some cost 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 to experience 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.

'''Bret:''' The Antagonistic Pleiotropy Hypothesis for senescence. We knew that it was right because it predicted so many phenomena in nature that we could readily go out and measure. And this is again where the phenomenology versus mechanism comes in.  

'''Eric:''' Okay.  

'''Bret:''' So selection sees their late life more easily than it sees a small __?__ .

'''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 happened.

'''Eric:''' Which is bizarre.  

'''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.

'''Bret:''' Yeah, I think, I think that's well said. So anyway, I left the room feeling like I had just glimpsed something so important, kind of, you know, I wondered could it be right and I started to just do the first bit of library research to figure out whether somebody else knew what I knew or—

'''Eric:''' So I'm not even sure that you fully said it. I want to make sure that I'm even clear on it and I'm going to, I think I'm right, but correct me if I'm wrong. What you're saying is, “What if the Hayflick limit is a protection against dying from immortality at a cytological level,” that some cell gets a dream of immortality that it shouldn't have because, let's say, it's a somatic cell, and it says, “Okay, I just want to keep dividing and dividing and dividing.” Nature knows how to do this, and that immortality, which sounds good at first, is actually called cancer. And so in computer science we would say, okay, you've introduced a recursion limit into a while loop or a for loop to make sure that you don't have a resource leak, which is what a tumor is.

'''Eric:''' Okay, this is terrifying. What you're saying to me is, that if I'm comprised of let's say 30 trillion cells, and I view them as each let's say subroutines, any subroutine that is not denucleated, right? Like this wouldn't happen in the lens of your eye because the nucleus has been removed, but any other reasonable cell is potentially your assassin, because its mitosis process might completely go rogue.

'''Eric:''' Okay.  

'''Bret:''' And so the rather elegant and very simple idea is that there would be a hard limit so that any cell that had become damaged, so it started down this path, would just simply run into the number of cell divisions it was allowed in a lifetime and it would stop.  

'''Eric:''' So like, the moles on my face that some of my less couth commenters love to talk about—

'''Eric:''' Are effectively attempts to kill me that may have stopped. And that the perimeter where they stop is where the Hayflick limit took over and said, “This cell line must die so that the patient will live?”

'''Bret:''' Yeah. The name I gave them was “prototumor,” and the idea is a prototumor is a patch of cells arrested at their Hayflick limit because they had become unregulated. If you go to the dermatologist and you say, “What do I look for?” You know, they tell you certain things to look for. So a round patch of cells that suddenly becomes irregular in shape?  Well that's what would happen if you took one of those cells and gave it a second mutation and it started growing again.  

'''Bret:''' Right. So anyway, the idea that a limit on cellular reproduction—

'''Eric:''' So it was like stem cells, versus germ, versus ...

'''Eric:''' Figuratively

'''Bret:''' Yes, maybe even literally on occasion. But the question was-I began to wonder if there was something wrong with the idea that mice had long telomeres. Sometimes, like in Hayflick's case it turned out that a bunch of people were copying some wrong result, and so it seemed like a lot of people had seen it, but only one had. And I checked, was it true, that there was some-that everybody was parroting one study that said mice had long telomeres?  

'''Bret:''' It turns out lots of people had tested it. Mice have long telomeres like 10 times the length of human telomeres. It just didn't fit. So finally, it occurred to me that it was possible that what was going on-I discovered something in trying to figure out what they meant by “mice”. Right? There's a lot of species of mice, but all the mice that we use in the lab, with rare exception, are from one genus, and often from a particular target species.  

'''Eric:''' So you were focused, if I recall correctly, on mus spretus  

'''Bret:''' Right. These are model organisms. People were just using mice because mice were a convenient mammal, but they're all coming from one place, and it began to occur to me that that one place was not just a source of mice in the sense that we might think it, it was actually a selective environment that was impacting those mice. And when I dug deeper, it turned out that the mice had all-they were descendants of a long lineage that had lived in captivity under conditions at the [https://en.wikipedia.org/wiki/Jackson_Laboratory JAX Lab]. And at some point I realized that the most likely thing going on was that there was something about this environment that had wildly elongated the telomeres of these mice. And that was simultaneously an unbelievable idea, but the only one I could think of that made sense of everything I had seen. And so—

'''Bret:''' [https://en.wikipedia.org/wiki/Elizabeth_Blackburn Elizabeth Blackburn]. Exactly. She was her student and they shared the Nobel prize with [https://en.wikipedia.org/wiki/Jack_W._Szostak Szostak]. In any case, her work seemed good to me. I called her up, cold, you know, I went into the Insect Division Office, and I sat down at the phone. I called her, I said, Carol, you don't know me. I'm a graduate student at Michigan. I'm an evolutionary biologist. I'm racking my brains trying to understand something. Can you tell me, is it possible that mice don't have ultra long telomeres? That it's only laboratory mice that do? And she said, huh. That’s really interesting. I'm pretty sure that mice have long telomeres universally. But it is odd that if you order mus spretus instead of mus musculus and you order from European suppliers, the lengths are very different than what you get if you order mus musculus from the JAX Lab. I said, Whoa.

And she said, yeah. That’s really interesting. And then she said, I can't remember if it was the same phone call or if we had a second phone call, but she said she was gonna put her student, her graduate student, [https://biology.mit.edu/profile/michael-t-hemann/ Mike Hemann], who I think is now at MIT, on the project, and he was going to do a little work to figure out whether there was anything to this. And Mike did some work. They sourced some different strains of mice that were, they were actually not wild mice. Wild mice would have been the right test, but she couldn't get wild mice for obvious reasons.  

'''Bret:''' Right, exactly. And so she got several different strains of mice that had just been in captivity much less time. She actually got one strain of mice that was treated very differently in captivity. But nevermind. She put her graduate student on it, and he measured their telomere lengths. And I get this excited email. [https://biology.mit.edu/profile/michael-t-hemann/ Mike Hemann] sends me any email that says effectively, “Whoa! The hypothesis is true, mice have short telomeres!” Right? Now—  

'''Eric:''' I'm sorry, this is like as close to a ‘who dunnit’ discovery-J'accuse-the mice, you know, I remember, you were over the moon.  

'''Bret:''' When I got that email it was 1999? 98? Something like that?

'''Eric:''' By the way, that puts you at about 30. You're at the beginning of your career, and you—in this story, you've just predicted that—

'''Bret:''' It's a stunning coup for a graduate student. And, it wasn't in my advisor’s wheelhouse, so it was clearly my own work. And, I mean, Dick was great about not blurring those things, but—

'''Bret:''' Okay, so let me clear up why the breeding protocol—and I should say, that-It is the breeding protocol that is causing this? That part, I would say, is still a hypothesis. It has not been directly tested by anybody; but, what I would say is that many hypotheses were tested in the aftermath of the discovery-that lab mice have bizarrely long telomeres, and wild mice don’t-and no other hypothesis has stood up to scrutiny. So it is the last hypothesis standing and I'm all but certain that it will turn out to be true.  

'''Eric:''' So there's one aspect of aging, but that there's a far darker interpretation of what you've just said, if I'm understanding you—correct me, I’ve never taken a class in biology, but I lived this adventure with you—those tissues have, at a histological level, the level of how cells are organized, the possibility of radical histological repair.  

'''Eric:''' This is like a-I mean, I just forget how great of a—

'''Eric:''' Without telling the story. Alright.

'''Bret:''' Yeah. Okay. So the story now gets kind of ugly. I recognize I've got all the pieces of the puzzle necessary to tell the story correctly. I have taken on a coauthor, we've found the literature necessary to do it in proper scientific form.  

'''Eric:''' Well I remember the revisions, and I remember this was like, I mean, if I think about what's on the line, like this combines one of these freak situations where you're using evolutionary theory to predict something, and in this case it's at the level of molecular biology, so with Darwin's orchid it's a tongue, and with Dick's thing, its behavior in naked mole rats. This thing is actually at a molecular level, and, it couldn't be more important if mice are going to be the major system in which we are going to test drugs, which are highly sensitive to what? Histological repair.

'''Bret:''' Yup. It's so profound on several different levels that I'm super energized about getting this into the world. It's transformative. Dick looks at the paper, he says, “This is fantastic.” He puts me through the ringer to get it really tight. We get it tight. We send it to George Williams, the—

'''Eric:''' Of limited interest—

'''Bret:''' -to their readers. And we're, you know, I mean, we had a good laugh about that. You know, it's cancer, it's senescence—

'''Eric:''' Dude, it's so bad. Like, this is a response that indicates either malfeasance, or an Eliza program, or the janitor ended up responding who didn't know any bio—

'''Bret:''' It’s the craziest thing, and you know, the cherry on top is that they're turning down George Williams’ recommendation? Like, how cra—do they know who he is? Like, what? Where?

'''Bret:''' Yeah. And I, oh, another thing I forgot, I asked her at some point, something that now rings in my ears—I asked her, Carol, you've now got this result about, no, actually lab mice have long telomeres, but wild mice have short telomeres. That's a big result.  

'''Bret:''' Well, it's so heartbreaking. What she has effectively done is decided, “I could publish this result”

'''Eric:''' And then everyone would have it.

'''Bret:''' It would be huge, but then I'm on a level playing field with everybody else. If I don't publish this result—

'''Eric:''' I have a stream of papers I can get at.

'''Bret:''' Then I can start predicting other results. Nobody will know how I am doing that thing. I will look like a super genius. And so, holding it “in house” is a mechanism for a whole slew of papers.

'''Eric:''' to be, to be 100. You can afford to bend over backwards and not make inferences. Let's say the following, holding it in house is a seemingly inexplicable decision in science, but for the fact that it fits at least one story of this kind, which is that it is consistent with wishing to publish a stream, rather than the source of the information that would allow you—so you can either do one discovery or you can do a stream of predictions and that makes a certain amount of sense, given the ruthlessly competitive grant-winning environment. And we don't know exactly what happened, but there is no world that I know of in which you're allowed to hold back that kind of information, because, in part, of what's on the line.  

'''Bret:''' Not even that. It's medical testing, but it's also all of the science relative, at least, to cancer, senescence, wound healing—all of the science that is stacked on these mice that is contingent on their function relative to their tiers is all compromised. You're letting year after year of this stuff accumulate. It's malpractice at an incredible level. So, I don't know that she has turned on me, but I call her up, and I say, “Carol, we are stunned to find that our paper was turned away without review from Nature—“

'''Eric:''' Without review.

'''Bret:''' Without review. We need your help. Can I send you the paper and have you look at it? And she says yes. And I sent her the paper and she sends back the paper with an unbelievable number of intense criticisms that are not sensible. She pans the paper, does not believe a word of it—  

'''Bret:''' I have that paper, I have that paper with her handwriting. I believe I also have the FedEx envelope in which she sent it to me. But she hates the paper, and I have now forgotten a bit of the sequence. But as I am attempting to fix this up for another journal—oh, here's a, sorry, I hate to tangle this story, but it's important to get it right.

'''Bret:''' I haven't told it in a very long time. After the rejection from nature, after Carol has seen the paper, and said it's cruddy, I get a letter I don't expect from a journal I don't—I know it exists, but I'm not super familiar with it, Experimental Gerontology. Experimental Gerontology says, “We are the editors of Experimental Gerentology. We have heard a rumor of your work. We're very interested. Would you be willing to submit a version to our journal?” and, oh, this is happening prior to Carol looking at my paper and panning it.  

'''Bret:''' I'm pretty sure I know, based on what they-again, I was too young to sort out really what they were saying, but they indicate that they're fans of antagonistic pleiotropy, so what happened was George Williams, having heard that it got rejected, contacted some friends of his and was like, you should really take a look at this. So I begin the process of revising it. I've shown it to Carol, she's panned it. I send the revised version to Experimental Gerentology. They send it out for review. As you know, review is blind. You don't know who your reviewers are, but you can often tell who they are. It's not as obscure—  

'''Eric:''' No, okay?

'''Bret:''' I'm just saying, at the time, if you mentioned her name, people would say, “Oh yeah, her Nobel Prize is one of these years.” Right? So my point was, I was in the awkward position—I didn't understand what I was supposed to do. I didn't want to send back a review that said, “I don't know who the person is who reviewed this, but they don't understand the material, and all of their critiques suck,” because I didn't want to accuse somebody who was that powerful of not getting it.

'''Eric:''' I mean, here's the problem. What do you do? You don't actually have evidence in the hard form where like you have got videotape, but on the other hand, these are small worlds. This, all of this is preposterous.

'''Eric:''' Well you don't know how to play the game!

'''Eric:''' I'm sorry, but, like, I had no advisor? Your advisor was not equipped for the modern era.  

'''Bret:''' I finally settle on a strategy that I can live with and I send back a note. I send back the review and my note says, “I don't know why, but this entire list of critiques is not high quality. If you would like to point me to any of the critiques in this list that you would like me to address, I am more than happy to do it, but I don't think it makes sense to address the entire list,” and as I recall it, I hit send on the email, and within minutes, maybe it was an hour, I got back a response: “Your paper has been accepted for publication,” which blew me away because I—

'''Bret:''' Right. It makes no sense, because, clearly, they're supposed to send it out for review. The reviewer is supposed to say whether it's supposed to get published. The reviewer said it shouldn't be published. I said, “I refuse to address these critiques unless you ask me to.” The editors have overridden the reviewer. They understood the reviews were cruddy. They needed me to say that in order to justify the move that they wanted to make. They knew the paper was good and the review was crap. So they effectively overrode normal peer review. Was my paper peer reviewed? Well, it was by the editors who were experts.

'''Eric:''' Let me jump in. Peer review is a cancer from outer space. It came from the biomedical community, it invaded science. The old system, because—I have to say this because many people who are now professional scientists have an idea that peer review has always been in our literature and it absolutely motherfucking has not.

'''Eric:''' Okay? It used to be that the editor of a journal took responsibility for the quality of the journal, which is why we had things like Nature crop up in the first place, because they had courageous, knowledgeable, forward thinking editors. And so I just want to be very clear, because there's a mind virus out there that says “peer review is the sine qua non of scientific excellence, yada, yada, yada, bullshit, bullshit, bullshit”. And if you don't believe me, go back and learn that this is a recent invasive problem in the sciences.

'''Eric:''' Well, no, not only does it have no justification for existing. When Watson and Crick did the double helix, and this is the cleanest example we have, the paper was agreed should not be sent out for review because anyone who is competent would understand immediately what its implications were. There are reasons that great work cannot be peer reviewed. Furthermore, you have entire fields that are existing now with electronic archives that are not peer reviewed. Peer review is not peer review. It sounds like peer review. It is peer injunction. It is the ability for your peers to keep the world from learning about your work.

'''Bret:''' “The Reserve Capacity Hypothesis,” which is a much less catchy title, but, nonetheless, the paper-I'm very proud of how it's written. People read it who were not expert, could understand it. The abstract is extremely clear, and it ends with the clear point that, because we have unearthed, we have predicted, and Carol Greider has shown, that wild mice telomeres are short, and the telomeres had been elongated by captivity, that there is a clear danger that the mice we are using for drug safety testing are biased in an egregious way. And the bias would look like this: a mouse that has very long telomeres has an indefinitely large capacity to replace damaged tissue, and, it has a vulnerability to cancer that is preternaturally high. So, we may be overrating—if we use these mice, we may be overrating the danger of causing cancer, and vastly underrating the danger of toxicity. And, in fact, one of the things—so, the point was you give a mouse who's got an effectively infinite capacity to replace its tissues, a toxin, and either the toxin is so deadly that it dies right away, but if it doesn't die right away, it just eats up the insult. So those animals would lead us to release drugs—  

'''Eric:''' Let's just, I want to back up because I think this is a really important part of the story. What you're saying is that if you take an organism that has an expected, let's say, 40 year lifetime, it's very expensive timewise to say, “We ran this experiment and found that there was no immediate damage that was visible, but towards the very end of their lives we saw a marked increase in morbidity,” or-

'''Bret:''' Your eye cells don't. Now note, all of the tissues I've just mentioned, when's the last time you heard about anybody having, you know, cancer of the cartilage, of their knee, cancer of the heart,

'''Bret:''' Okay. So Vioxx is known to do heart damage. That created a big scandal because how the hell did it get through drug safety testing? It turns out a lot of drugs have done this. We've seen it with Gleevec, Fen Phen, Arithromycin. Your doctors probably still doesn't know that Arithromycin does heart damage—

'''Eric:''' Well, but it's this thing about, like, perseverance and disagreeability. You've got all sorts of things that sound like something that invalidates the theory, and then it’s sort of theories upon theories that allow you to see the original simplicity of the idea. I see the original idea is very simple—

'''Bret:''' Yup. Successfully predicts mouse telomeres.  

'''Bret:''' Yup.