Editing 19: Bret Weinstein - The Prediction and the DISC/lang-it

'''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.

'''Bret:''' Yeah, so let me say it this way. If you have a damage to a tissue cut on your arm or something, the cells on both sides of that cut suddenly become aware that there is a problem, a gap, because the can't hear a neighbor on one side of them and their natural reaction is to start growing into the gap until they can hear a neighbor which is the sign to stop. If you imagine that something like that is occurring in every tissue, or almost every tissue, the problem is that that means that every tissue in your body for which that story is about right, is in danger of having damage from radiation or whatever, turn it deaf to its neighbors. A single cell that has turned deaf to its neighbors will suddenly start replicating, and if it is deaf to its neighbors, then there's no message that it's going to hear that's going to tell it to stop. So that thing, imagine any cell in your body just taking off and growing and growing and growing—

'''Eric:''' Okay, this is terrifying. What you're saying to me is, is that if I'm comprise 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 in the lens of your eye because the nucleus has been removed, but any other reasonable cell is potentially your assassin, because it's mitosis process might completely go rogue.

'''Bret:''' It can run away.  

'''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 loved to talk about—

'''Bret:''' Yep.

'''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 him 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.  

'''Eric:''' Got it.  

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

'''Eric:''' Yep.

'''Bret:''' Is adaptive to protect you from cancer—

 

'''Bret:''' Yes, and that what selection does is it balances these two competing forces to give you as much vigor and longevity as it can.

'''Eric:''' So all of the other diseases and insults and things that I can die from sort of start to fade away. And at the complete core of biology, in this theory, there are two things that I can't get away from, one of which is death by immortality, and the other one is death by recursion limit.  

'''Bret:''' That's it.  

'''Eric:''' It's a very elegant thing. And now the problem is, is that there's all this weird attended complexity that you had to deal with.  

'''Bret:''' Right

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

'''Bret:''' So when I went into the literature, what I found was that people had played around in the neighborhood, but that there was a particular fact which blocked every attempt to make sense of what was going on. And the fact was that rodents were understood to have ultra long, hypervariable telomeres. And I didn't know what that meant at first, but the more I looked into this possibility, the more I realized that dozens of longstanding problems would be solved if my hypothesis was true, but that my hypothesis couldn't be true because basically mice have long telomeres in short lives. Why is that? And I banged my head on the table for a couple of weeks trying to figure out what was going on.  

'''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, 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?  

'''Eric:''' Right.

'''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:''' Mus musculus, which is the common one. What shocked me was that it turned out all the mus musculus that were being used in labs across the country, and in many cases, farther afield than that were coming from one place, which I had no idea. There was one—

'''Eric:''' I remember getting a phone call when you said, what do you know about the [https://en.wikipedia.org/wiki/Jackson_Laboratory JAX Lab]?

'''Bret:''' The [https://en.wikipedia.org/wiki/Jackson_Laboratory JAX Lab] in Bar Harbor Maine, right? They seemed to be the source of everybody's mice. And so it began to be—it was a possibility I could not shut down in my mind, that there was something about what was going on at the JAX Lab that had resulted in the mice that were being sent out to all these other labs—

'''Eric:''' Is it that they were representative animals—

'''Bret:''' Right, these are a model organism. 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—

'''Eric:''' Well, it's unbelievable because the consequences, I mean, look, I have not even heard whether anyone has said, “Yeah, we did that, we screwed that up.” But it is, like, your favorite model organism for mammalian trials being screwed up by a central facility. Because also there's this weird thing where medical people very often stop taking into account evolutionary theory because they treat that as “Well, that's that class I took in college or the beginning of graduate school.”

'''Bret:''' Right. So I began to focus on this question and I did something that was the right thing to do, but I did it in a way I will forever regret. I found somebody who was represented in the literature, who I regarded as very well versed. They made sense to me, their papers. Her name was [https://en.wikipedia.org/wiki/Carol_W._Greider Carol Greider]. Carol Greider is now a Nobel Laureate. She was not at the time. She was the co-discoverer of the enzyme [https://en.wikipedia.org/wiki/Telomerase telomerase], which is the enzyme that elongates telomeres, when that occurs—

(01:14:01)

'''Eric:''' With the famous and co-Nobel recipient—she was the student of [https://en.wikipedia.org/wiki/Elizabeth_Blackburn Elizabeth Blackburn].

'''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.  

'''Eric:''' You’d have to go out into the woods.

'''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'd done it Discovery J'accuse— the mice, you know, I remember, you were over the moon.  

'''Bret:''' I still am! I still can look at this email and it is the moment at which I realized, A, there's no way I'm kidding myself about how well I understand this.

'''Eric:''' Right.

'''Bret:''' Right? That prediction was—

'''Eric:''' How old are you?  

'''Bret:''' Now? Or then?

'''Eric:''' No, when you get this email.

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

'''Eric:''' Okay. So over 20 years ago.  

'''Bret:''' Yeah. So I get this email, and—

'''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—

'''Eric:''' Okay, either you are a dirty dog liar—

'''Bret:''' Right

'''Eric:''' And I was there at the time—

'''Bret:''' Yeah.  

'''Eric:''' Or, so we're both dirty dog liars about this particular story—

'''Bret:''' Or—

'''Eric:''' Or, one of the great moments in evolutionary theory, which is—and let me just curate this, because I'm not a biologist, but I think I can more or less get this—because it's a breeding protocol that is the alteration in the evolutionary landscape for these laboratory mice, and because it's acting on a non-protein coding region, the adaptation to a change in the breeding protocol can be extremely rapid. It doesn't have to undergo some sort of completely crazy typical Darwinian story about random mutation and some of them being retained and others being rejected.  

'''Bret:''' It's even better than that. The creatures are presumably—so we haven't gotten to what the breeding protocol has to do with this—but the creatures are built in some sense to detect how dangerous their environment is, and to the extent that the level of extrinsic danger changes, their telomeres respond quickly so that they are better adapted to the environment. So, they're built to detect the environment and then what is actually a strict matter of market forces.  

'''Eric:''' Okay, so there are no predators in this environment.

'''Bret:''' No predators in this environment.

'''Eric:''' And we're not killing them particularly early based on their skills. So environmental insult is sort of absent.  

'''Bret:''' Environmental insult is more or less absent. What we are doing is imposing an economic rule on breeding so that we can maximize the rate at which we turn mouse chow into mice, which is obviously economically the right thing to do, if you're selling mice to all these labs, you want to produce as many mice as cheaply as possible. So producing as many mice as people—

'''Eric:''' The genius of the market!

 

'''Bret:''' It's the genius of the market.

'''Eric:''' There you go.  

'''Bret:''' So in order to produce as many mice as cheaply as possible, what you do is you don't breed animals past eight months. They breed faster when they're younger because of senescence. And so you don't breed older mice. You throw them out and you replace them with younger mice who breed faster. What that effectively did was it eliminated the selection against cancer, and it turbocharged the selection in favor of youthful vigor

'''Eric:''' Well let me see if I get this—in general, almost all cancers, like, cancer of the germline happens early in life, but all the other cancer, in general, is much more common later in life.  

'''Bret:''' I gotta pause. I realize I forgot to tell you one thing Carol told me in my first phone call with her that’s vital.

'''Eric:''' Sure.

'''Bret:''' In addition to telling me that there was something funny about mus spretus, she told me that, consistent with the hypothesis that I was conveying to her, that all mice die of cancer. She said, “If you let them live long enough, and then you do the necropsy, you find cancer of one kind or another”, and that was perfectly consistent because they had these wildly long telomeres and no cancer protection. That would be the prediction of the hypothesis—

'''Eric:''' That’s an extrapolation—it's not really all mice. It's all mice that we see in the lab, which happens to be the mice that are ordered.  

'''Bret:''' Right. She was still speaking from the mindset of somebody who thought that the mice she was getting in the mail representative representative of mice in the wild.  

'''Eric:''' Got it.  

'''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:''' Yeah.  

'''Bret:''' The reason that the breeding protocol has this weird effect, is that when you throw out the mice at eight months of age, you eliminate selection against cancer, you turbocharge selection in favor of—

'''Eric:''' Sorry, when you throw out the mice, for breeding purposes, at eight months of age.

'''Bret:''' Right,

'''Eric:''' Okay.  

'''Bret:''' When you throw them out for breeding purposes at eight months of age, you are increasing the importance of their early life breeding, and you are discounting anything related to their ability to fend off cancer because they don't live long enough in that period of time to get cancers that kill them. And so what has happened, according to this hypothesis, is that the mice that have longer telomeres have driven out the other animals from the colony. The trait of having long telomeres has swept through the colony and the telomeres have been elongated to an absurd degree, creating animals that do all die of cancer. And interestingly enough, another thing that's evident from the literature is that if you look at their tissues, their tissues do not age in the way that a normal mammal’s tissues age, they remain young.  

'''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.  

'''Bret:''' Yes, radical effectively indefinite capacity to repair, which is going to come back in this story in the worst possible way. So—

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

'''Bret:''' Me too, I go years sometimes without thinking deeply about it.

'''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:''' This came from you, but I want to mention your coauthor’s name.  

'''Bret:''' Yeah. Debbie Ciszek.  

'''Eric:''' Okay.  

'''Bret:''' And Debbie was an excellent coauthor, strong contributor to the paper. Anyway, we put together over the course of a year, I took a break from, effectively, my real dissertation work, and wrote a paper. Dick thought it was a fantastic paper. He was blown away by it—

'''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:''' The number one guy in the world.

'''Bret:''' The number one senescence guy at the evolutionary level in the world, and he writes a beautiful recommendation letter for this piece. We're going to send it to Nature. George Williams tells Nature, you need to take this piece very seriously. We send it to Nature and they send it back with one of their absurd form letters that says that “The nature of the article is such that it's probably not—

'''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?

'''Eric:''' On what planet?  

'''Bret:''' On what planet do you turn down his recommendation to look at something about senescence? So, anyway, I get back this rejection, and I have purposefully not shown Carol Greider the paper in preparation, which I am afraid she might've read some way. The reason I didn't show it to her was because I wanted to preserve her independence as a reviewer for the paper. I was hoping, because I still thought she was an ally of mine, I was hoping that Nature would send it to her to review, and that she would look favorably on it, especially since it was, you know, very clear that she had done—

'''Eric:''' It was her lab that made the confirmation.  

'''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.  

'''Eric:''' That’s a hell of a delta.  

'''Bret:''' Where are you going to publish it so that I can cite it—

'''Eric:''' Right.  

'''Bret:'''In my paper, which is the natural thing to do. And she says, “we're not going to publish it. We're going to keep the information “in house.” That was her phrase. I was too young to understand what the hell she was talking about.

'''Eric:''' I'll be honest, I'm 54 and I don't quite understand it myself.  

'''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 any 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:''' Right. So—

'''Eric:''' I mean, this is not just a question of academic interest—

'''Eric:''' Because these mice are used for medical testing.  

'''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 it—

'''Eric:''' Do you still have that copy?

'''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.

'''Eric:''' No but you haven’t told this in enough—

'''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 gerontology. 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.  

'''Eric:''' So the only way they would have known about this would have been from Nature or from Dick, or—

'''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 gerontology. 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:''' If it’s a small field.

'''Bret:''' Yeah. So they read the acknowledgements of my paper, which are now on alert about Carol. I have to thank her in the paper for the work she did, but I'm now on alert that she's gone strange on the subject matter of this paper, and so I've broken her out separately in the acknowledgements. I don't want to be as gracious to her, because she's being hostile to me.

'''Eric:''' Right.  

'''Bret:''' But I don't want to not acknowledge her, so I acknowledge her separately. Experimental Gerontology then—I am 99% sure—sends the paper to her as the reviewer. She pans it. Absolutely brutal critiques, just pages and pages and pages of them. They are not high quality critiques. I could go through every single one.  

'''Eric:''' Don’t bother, this is a podcast, just—

'''Bret:''' No, I can't do it here, but I could have then—

'''Bret:''' But I didn't know what to do because she was in line for a Nobel Prize, that was well understood. I didn't want to accuse a leading light of the field of,

'''Eric:''' Okay, this is exactly why I got angry with the beginning of the podcast, you moron. No, no offense. You were in line for a Nobel Prize. You didn't. I mean, I'm sorry. There is an aspect of this about giving away your power, before you’ve even accumulated—you don't even have a PhD at this time.

'''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.

'''Bret:''' Right. So I sit on the review for too long, not knowing what to—

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

'''Bret:''' I don't know how to handle it.  

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

'''Bret:''' He wasn't equipped for the modern era. He wasn't equipped for molecular biology.  

'''Eric:''' That's true.  

'''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—

'''Eric:''' It makes no sense according to regular protocols.  

'''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.  

'''Bret:''' Right.

'''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.

'''Bret:''' Recent invasive problem that has no justification for existing in light of the fact that—

'''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:''' Keep the world from learning about your work—

'''Eric:''' Because peer review is what happens— real peer review is what happens after you've passed the bullshit thing called peer review.  

'''Bret:''' Yes. Okay, so the paper was accepted by Experimental Gerontology. They went on to publish it.  

'''Eric:''' This is called “Life’s Slow Fuse”?

'''Bret:''' No, “Life’s Slow Fuse” was the title as sent to Nature, and I changed the title because I did not want to compromise the story—I didn't want to confuse the story.

'''Eric:''' The original submission was called “Life’s Slow Fuse”.  

'''Bret:''' Right.

'''Eric:''' We probably have a copy of that somewhere?

'''Bret:''' Oh, of course.  

'''Eric:''' All right. Then the Experimental Gerontology paper, what is it called?  

'''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:''' By insult, what you mean is cellular necrosis?  

'''Bret:''' Damage. Yeah. What this would cause us to do is release drugs onto the market for human use that are highly toxic across the body.

'''Eric:''' Wait a second—if the mouse standard was the last standard—

'''Bret:''' Well, no, even if it's not the last standard, because—

'''Eric:''' Well, it’s important to say this—

'''Bret:''' The problem is, I mean, you can imagine how hard it is to test on large, slowly reproducing animals.  

'''Eric:''' Well, and the ethics of testing on humans is very—

'''Bret:''' Absolutely.

'''Eric:''' —restricted, so mice is the last cheap place—

'''Bret:''' It's the last cheap place—

'''Eric:''' —to get large N data.  

'''Bret:''' Not only large N, but it's the one place that you can make the following move. You can imagine that in many circumstances the accelerated lifespan, the accelerated life cycle of mice allows you to see long term damage as it would accrue in humans on a very short timescale. That doesn't work with monkeys. It doesn't work with human patients. It works with mice, maybe, but in the case of mice with ultra long telomeres, those insults will be invisible.  

'''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 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:''' Yeah, I mean if you took a drug and it knocked 15 years off your life on average, that might not show up in any notable way in a short term study.

'''Eric:''' If there was pressure to—

'''Bret:''' Right. And nobody is going to want to let drugs, you know, you don't want to wait 40, 50 years to find out what happens to these patients. So what we do is we make the assumption that if we give large amounts of a drug to an animal that lives a very short life, we will see those effects early. And if the animal happens to have ultra long telomeres, you won't see those effects early. So, it's a perfect storm for causing us to release drugs that should never have been released into public.  

'''Eric:''' Can you think of one?

'''Bret:''' Oh, I sure can. [https://en.wikipedia.org/wiki/Rofecoxib Vioxx], for example. So Vioxx was discovered to do heart damage, right? Heart damage. How do you, why do we know that it's heart damage? Well, the thing about hearts, for reasons we can get into maybe another time, hearts have a very low capacity for self-repair, right? That's why they're vulnerable to heart attack.

'''Eric:''' Not much turnover.

'''Bret:''' Not much capacity for repair, and not much turnover. Now, there's an adaptive reason for that, but hearts don't repair themselves very well in a healthy person. And when they fail, it's hard to ignore, right? If somebody who's 30 has their heart fail, there's questions asked, right? So anyway, Vioxx was released into the public having passed drug safety testing.

'''Eric:''' This isn’t the only system that doesn't have a lot of mitosis, like for example, neurons.

'''Bret:''' Neurons don't have a lot, cartilage doesn't have a lot.  

'''Eric:''' Got it.

'''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,

'''Eric:''' If they get brain cancer, it tends to be glial—

'''Bret:''' It’s glial cells, exactly. So the tissues that have very low capacity for self repair do tend to wear out and they don't tend to get cancer, which is exactly one of the predictions of my paper.  

'''Eric:''' Right.

'''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:''' Yikes

'''Bret:''' Right. There's all of these cases of drugs that were released and then later understood to do heart damage. Now my claim is they don't actually do heart damage. They do cellular damage and the heart is the most conspicuous.  

'''Eric:''' Yeah, yeah, yeah, yeah. Geez. This is like another layer of this thing.  

'''Bret:''' It's like a huge fucking nightmare, right? Because—

'''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:''' Yep.

'''Eric:''' —but if you know a lot of weird facts about what you think are just mice, or something about hearts, you can't put together what is going on. The idea that ambient damages only manifest in the heart because that's the one system—you know, or the neural system—that, like, really doesn't have a lot of mitosis.

'''Bret:''' So, well, piece of advice to anybody who finds themselves in remotely similar waters. The signal that you are on the right track is that stuff starts canceling. Complexity in the story, which has accumulated because something was missing, starts disappearing in the story. You begin to take on a model. Anyway, so yes, we've got a situation where we've got a bunch of drugs mysteriously producing heart damage.

'''Eric:''' K, so now you've got a paper that's out. You've got a real world application. You've got a theory coming out of evolutionary theory. It's making a molecular prediction.  

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

'''Eric:''' One of the world's leading labs has confirmed the prediction.  

'''Bret:''' Yup.

'''Eric:''' Where are we now? What year is this?  

'''Bret:''' God, well, let's see. The paper came out

'''Eric:''' And my recollection—and, just to be horrible about this—is that your fucking department at the university of Michigan, which has some great people, is also holding you back and enervating you year after year by not allowing—because this is groundbreaking stuff. This is Nobel quality work, at least one or two times over, in my opinion. I could be wrong. I'm biased because I'm your brother, but what concerns me here is that you are not comfortable with what this story really might be.  

'''Bret:''' No I— Look, it's not mine to judge. I'm very proud of this work and the work—

'''Eric:''' But the problem, Bret, is that Jerry Coyne and Richard Dawkins did not know that Dick Alexander, Leonard Hayflick, and George Williams were all on this thing, because that community had broken down.

'''Bret:''' You know, the irony is, I sent a letter to Dawkins when this was going on, asking for his help, and he sent back a letter saying, “This is very interesting. It's not my area of specialty. You should talk to [https://en.wikipedia.org/wiki/W._D._Hamilton Bill Hamilton].” And I was in the process of writing a letter to Bill Hamilton on Dawkin’s suggestion, at the point that Bill Hamilton came back from Africa having—he was pursuing a remote hypothesis about humans having accidentally unleashed AIDS into the world with a polio vaccine. But anyway, so—

'''Eric:''' Bill Hamilton, I'm sorry, not everybody's going to know—this is the guy who came up with inclusive fitness?  

'''Bret:''' Yes. He was one of the great geniuses of evolutionary biology in the late 20th century.  

'''Eric:''' He was held back by John Maynard, right?  

'''Bret:''' I don't know that story. I, you know—

'''Eric:''' I think Maynard is interviewed on Web of Stories where you—

'''Bret:''' Maynard Smith.  

'''Eric:''' Yeah, sorry. Yeah. Maynard Smith. Right.  

'''Bret:''' Yeah.  

'''Eric:''' And Maynard Smith talks about like, you know, “It was very unfortunate. I didn't really understand who he was.” You should check it out. It's pretty amazing.  

'''Bret:''' Well, as long as we're doing this, years after this story had cooled—

'''Eric:''' Yeah.  

'''Bret:''' —I ran across a paper from John Maynard Smith that, I now don't remember exactly what its nature was, but it appeared to predict my whole story.  

'''Bret:''' Right? And John Maynard Smith was dead. I couldn't contact him. I really wanted to say, “Oh my God, you nailed it.” Right. But anyway, so I was in the process of writing to Bill Hamilton to get his help. You know, he was sort of on a par with George Williams, and he went into a coma on his trip back from Africa having contracted malaria. And then there was, I think complication with the aspirin that he took or something. And he never woke from his coma and he died, tragically. So he never got the letter, and who knows what he would've done.  

'''Eric:''' Okay, but look, that's a tragic and interesting story, but Hayflick was positive towards you. Williams was positive towards you and Dick Alexander. Those were the three that blew me away. That's a huge amount of firepower.

'''Bret:''' That’s a lot of firepower, and it wasn't enough. But, here's the punchline to the story, effectively. At the point that my paper is out—

'''Eric:''' Right.  

'''Bret:''' —and it very directly alleges the danger with these drugs being released when they're not safe, and the drugs have started emerging and turning out not to be safe, and the government is now really interested in what's going on, the government puts together a FDA commission to study the question of—the book that they put out, literally a book that they put out, at the end of their study is called The Future of Drug Safety

'''Eric:''' I hope it’s a Blue Ribbon panel.

'''Bret:'''It's not exactly clear what it was. What is clear is that you can search the manuscript of this book. Nowhere does it mention “mouse”—

 

'''Bret:''' It doesn't mention antagonistic pleiotropy. It doesn't mention the genus “mus”. It doesn't mention “telomeres”. It's not in there. It's alleged in the literature in broad daylight that this is what is causing the problem, and—

'''Eric:''' Now you're—see, this is the Vampire Effect, where you don't exist if nobody reacts.  

'''Bret:''' Right. And, so I start going to members of the press, I think, “This is a huge goddamn story. Somebody is going to make—

'''Eric:''' “Oh my god, you’re self promoting!”

'''Bret:''' —career on it”, and I call up members of the press, and it's always the same, right?

'''Eric:''' Always the same.

'''Bret:''' It’s always the same. They're very excited about this story.  

'''Eric:''' No, they’re initially, the reporter—

'''Bret:''' The reporter is excited.

'''Eric:''' Yep

'''Bret:''' And then the reporter—

 

'''Bret:''' They talk to someone, and then either they stop returning your calls, or they say, “I'm sorry, the story doesn't hang together”. It's again and again and again.

'''Eric:''' Yeah.

'''Bret:''' And there's just nothing you can do.

'''Eric:''' Remember what I said about the Distributed Idea Suppression Complex

'''Bret:''' Yeah. And the people who man it don't even know what they are. For most of them, they don't know what role they're playing.  

'''Eric:''' Look, you see the same thing with like string theory because none of the reporters are actually string theorists, so they're dependent upon this. You saw this with this woman alleging that she had the Epstein story three years earlier, but that the editors said, well, we might lose access to the baby pictures of the Royal grandchildren like, you know, you're seeing this with catch and kill. There's this, I mean, I want you to take this seriously. You're just showing a part of what I'm calling the DISC, the Distributed Idea Suppression Complex. We have 50 years of such stories, and it happens that in our family, three out of four of us created such a story trying to get a PhD. And the idea for me is that every time you have to go into some closed system, like, there's a committee meeting or there's a blue ribbon commission or there's a peer review process, or there's a, what do they call them, the panels—study groups, for grants. That's where the DISC lives. We know that it's localized to the things that protect the integrity of science. It's an autoimmune disease, where what we have is an ability to stop highly disruptive ideas from getting a hearing in the general population of experts, by virtue of the fact that a carefully chosen group of experts can stop publication. Because look, if you're wrong about this stuff, there's a cost. It's not, it's not cheap.  

'''Bret:''' No, I mean, in fact, it would have been career ending. I'm pretty sure, had I been—

'''Eric:''' I don't know that it would be career ending if it was done in good faith, but you know, this is my, my problem with this is that you're sitting on one of the great scientific stories—I would say that I've ever heard. But you know, I'm sort of, kind of saying, “Well, Bret, what happens next?” You know, obviously I know a lot of this stuff. I've forgotten it, but I lived this with you and this is, I can vouch that this is more or less the order of events as it was taking place, as we didn't understand what was happening.  

'''Bret:''' So I have to go through the final Carol Greider chapter. In order for this story to fully make sense,

'''Eric:''' Where the Nobel Prize is given?  

'''Bret:''' That's the very tail end.  

'''Eric:''' Make sure you include that.  

'''Bret:''' Okay. So at the point that my relationship with Carol is changing its tenor and she is becoming hostile and I'm not clear on what's going on, I contact her and I discover through talking to her that she and Mike are about to publish their paper on the long telomeres of laboratory mice.  

'''Eric:''' So this is the Delta between a wild type and laboratory mice.  

'''Bret:''' Yeah. And I'm shocked because she's told me they're keeping it in house and instead they've got a paper that there, she says in final revisions there that day submitting their final revisions to nucleic acid research with their paper. And I say, Carol, can I see the paper? And she says yes. And she sends me a manuscript, not the pre-print of the paper. She sends me a manuscript of the paper, no acknowledgements, no figures. And I contact her and I say, can I see the acknowledgements and the figures? She sends them to me, and I contact her and I say, “Carol, I'm disturbed. This was my hypothesis that you were testing. I should probably be an author on this paper, but at the very least I need to be an acknowledgement in this paper so that I can go back and point to it and say that was”—

'''Eric:''' It changes everything. That it was a prediction. It wasn't just something that was stumbled upon.  

'''Bret:''' Absolutely.  

'''Eric:''' Yeah.  

'''Bret:''' And her response is, “I have been through my email and I see no evidence of the communications you are talking about.” Now, when I said at the beginning that—

'''Eric:''' You had called her.

'''Bret:''' I had called her.

'''Eric:''' Holy Shit.

'''Bret:''' That was my error.  

'''Eric:''' This is such fucked up. I mean, I don't swear a lot in this program.  

'''Bret:''' Yeah.  

'''Eric:''' But this is such fucking academic, petty, stupid ass bullshit. This is like one of the great stories of all times.

'''Bret:''' One of the great stories of all time, maybe, and human life hangs in the balance on this one.  

'''Eric:''' No kidding.

'''Bret:''' Right. Okay. So Carol does get awarded the Nobel prize, Carol Greider, Elizabeth Blackburn and Szostak. Szostak, who mentions at the point that the Nobel Prize is awarded that he was shocked as all hell to get a Nobel Prize because his work was so deep in the history of telomeres that he just didn't expect it. And suddenly—

'''Eric:''' No, I should say, I want to be very clear, right. All of these people have made fantastic Nobel-worthy discoveries.  

'''Bret:''' Totally.

'''Eric:''' There's zero allegation that these people—

'''Bret:''' Weren't deserving. No,  

'''Eric:''' Absolutely.  

'''Bret:''' No. And they, you know, Carol and Elizabeth got their Nobel prize for the discovery of telomerase, which is a huge, huge progress. So anyway, I don't deny that they were worthy of this prize. What Carol Greider does with her Nobel lecture, right. Nobel lecture being the biggest lecture a scientist will ever give, the lecture that—

'''Eric:''' And filmed.

'''Bret:''' And filmed—is she delivers a paper in which she very oddly has now embraced my entire set of hypotheses about the effect. She has come over from the comparison between the paper of mine that she panned and said didn't make any sense. She is now a total convert to the idea that senescence across the body is being caused by Hayflick limits that are telomere based.  

'''Eric:''' Okay, and this is the first public incident that we know of in which the delta between the negative comments on your paper, which is not an anonymous peer review.  

'''Bret:''' We have it in an envelope from her.  

'''Eric:''' Got it. And it's immediately after the Nobel prize that the wisdom of that line of thinking is embraced.

'''Bret:''' Right. But there's more to the Nobel lecture. So she spends her Nobel lecture on what is admittedly a very beautiful presentation of the connection between telomeres and senescence. She goes through tissue after tissue, says cirrhosis of the liver is what happens when you have short telomeres and your liver, etc. She goes through tissue after tissue. She projects the data, the blot actually from the paper with Mike Hemann, the paper that I should have been a coauthor on, she projects it on the screen, but she does some weird freaking dance, where she, instead of describing the long telomeres of laboratory mice as a major bug in the system, she describes it as a happy accident, effectively, because it allows us to test certain things like, “Oh, isn't it delightful that they have long telomeres?” And it's like, what the hell are you doing? There is so much riding on correcting this and you're presenting it like it’s just a bonus. And she, in her presentation, she's got several experiments that I did not know she had run that I had suggested to her and I said, you know, things like, “Carol, do you have any idea if a cell has many different telomere lengths, is it the shortest telomere that controls how many reproductions a cell can do?” She's run that experiment. Interesting. Low and behold, it's the shortest telomere. It's a good guess. But anyway, so, she goes through this. There's no mention of me, there's no mention of the actual implications of the the long telomeres for things like science and safety testing and all of that. And I can't seem to raise the issue of the safety question with anybody. Right? At best, I get journalists who are interested until they call somebody, and the somebodies on the other end, I know what they say. They say “everybody that mice aren't great models”. In fact, there's a paper out there that says something like the mice lie. It's not about this issue. It's just about the fact that mice aren't a perfect match. The issue in question could be solved. It could be addressed thoroughly. And, for all I know, once the JAX Lab figured out what they were doing—

'''Eric:''' They could change the protocols.

'''Bret:''' For all I know they quietly have fixed this and there was a private, you know, I've heard that there was a private meeting in which they decided—

'''Eric:''' Look, this is the thing.  

'''Bret:''' Yep.  

'''Eric:''' You see something like this in statistics, everybody knows that most distributions that are bell-shaped are not normal. Right?  

'''Bret:''' Yup.

'''Eric:''' And on the other hand, we all use normal distributions, and as a result, there are lots of things that at one level everybody knows—

'''Bret:''' Yep.  

'''Eric:''' But don't percolate down to the important layers in which we test things. And I don't know where, like you and I have never been able to fully put together, cause we're not molecular researchers and I'm not even a biologist. How important are these results? How robust are they? Has there been a change? This is a quiet world at some level.  

'''Bret:''' It's a quiet world. But I think what I have concluded, yeah, working backwards from the phenomenology of the field and how it reacts to this problem, is that there's a tremendous amount resting on failing to acknowledge the error. Even though the error was obviously an honest error to begin with, they would rather sweep it under the rug. I mean, imagine you've got all these knockout mice, right? These knockout mice, there's a major investment in them. It takes a lot of work to knock out a particular gene.  

'''Eric:''' No, dude, you've got a central, you've got a single point of failure—

 

'''Bret:''' Right.  

 

 

 

'''Eric:''' This is like an era. This is like a centralized irreproducibility crisis.

'''Bret:''' Yes, it's that bad or worse.  

'''Eric:''' Okay.  

'''Bret:''' And, and you know what happens if, let's say somebody hears this podcast and they check into it and they find out, lo and behold, this story is true.  

'''Eric:''' Yeah.  

'''Bret:''' Well now the FDA has a problem.  

'''Eric:''' What would, wait, wait a second. I don't want to get too far out over our skis. We have enough listeners that people will get a chance to hear an unbelievable story. And if there are things in the story that are not true or misremembered or unkind or there've been changes or maybe we don't really fully understand how the drug testing works. I'm open and I, and I want to be very clear, and I want this in the podcast, I'm open to the idea that the most straightforward implications of the story are subject to adjustment. However, having lived the story, I can say that this was an egregious story at multiple points, with conflicts between the evolutionary community, the biomedical community, the professional publishing community. This is a terrible story, and it's also an amazing and beautiful and wonderful story. And you know, I felt really lousy at the beginning of this podcast goading you and prodding you. But I am so bored of you, no offense, as the guy who stood up to the funny kids at Evergreen, and you know, we know what's in the heads of these people. If you're at Evergreen, you're not that good.  

'''Bret:''' Yep.

'''Eric:''' Right. And that was like, this is the, I just want to be open about it.

'''Bret:''' No, I look, I appreciate it, and I'm glad to have this story out. The story has many different layers of meanings. I know, I remember where I was when I finally sat down to watch Carol Greider's Nobel lecture and I had one of the oddest experiences of my life. I was actually in a hammock watching her lecture, watching her present my hypothesis without my name anywhere on it, and then she projects this image from her paper with Mike Hemann, and I was flooded with two simultaneous emotions that are just completely incompatible. Right? I've never felt anything like it. I was absolutely elated to see my work projected on a Nobel stage, right? That changed me.  

'''Eric:''' You know I called the horse and rider problem?

'''Eric:''' The point of the official complex of science is to knock the rider and take the horse, where the horse is the theory and the rider is the attribution.

'''Bret:''' Well, this was it. I was elated and livid simultaneously, and I can still almost feel what it was almost like my body was trying to figure out one half supposed to feel one thing and the other feels the other? But, this story has many levels of importance. Personally, it gave me the ability—I was already, as you are, very good at not being persuaded by the fact that everybody else disagrees with you, that that has an implication. Every great idea starts with a minority of one and you have to be able to endure being alone with a great idea in order to advance the ball significantly. This story was so extreme and so clear in the end that it just left no doubt. And I must say, I don't know how young students can arrange to confront materials so that if they're really good, they get a clear demonstration like this, that they're really good. So they know to keep going.

'''Eric:''' Bret, look, I think you're selfish, and I don't mean to be horrible about it. I think that the story is an inspiration. I've lived the story with you. I have my own version of the story where instead of it being the slide from the paper of Grider and Hemann, it's equations that are known as the Sieberg-Witten equations. And you see what you did, with somebody else putting, you know, putting it up on a board, it starts to change the field, and you suddenly say, you mean I'm not an idiot? Right? And what I'm claiming is that the next layer of this is, “Well, why don't you just submit a paper? If you have ideas, submit a paper, submit a paper, submit a paper.” Who is this fucking suppose to fool?  

'''Bret:''' Well, right, and this, this—

'''Eric:''' I mean, I just, I think the idea is that if you have a seat on the exchange, you know that by submitting a paper, your paper will get reviewed because you have, you present a credible threat. It doesn't occur to you that what you're saying is effectively like “let them eat cake”, to somebody whose paper is going to be reviewed by the person who's, like, holding them back.  

'''Bret:''' No, this is exactly—when Jerry Coyne came at me with, you know, “Bret doesn't understand his, his explorer mode stuff is, is nonsense”. And then Richard Dawkins echoed it “Bret doesn't understand natural selection. And, you know, if he did, he'd submit a paper.” My feeling is, I lived this story, and you're going to pretend that there is even a mechanism to get a proper hearing?  

'''Eric:''' Look, here's my proposal proposal. All right?