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I think what organisms are doing is partly through their social choices, effectively choosing which genes they will allow to survive. That's what Waddington is doing too. Social selection. Social selection, yes. How? Well, who you mate with, for example. Why do we marry anybody? Isn't that why we do it? This is perfectly Darwinian, what you're talking about. Yes, absolutely, I agree. Darwin was a Lamarckian. Now, I think what we need to do here is to get another element into this because I think what you're really worried about is how can it be that the body can actually change the genome? And that's the big question. Now, the reason we know that it can is that we know it controls it. That's the first step. So let's see first of all how that can be done. I have two very important colleagues who have done the work I'm going to describe, so I'm going to credit them. Dick Chen worked with me as a graduate student way back in the 1960s and is now working at the University of New York and has done part of the experiments I'm going to describe. And Anand Parekh, who is a physiologist in the same department as me in Oxford. And what they've done is absolutely beautiful. They've asked the question, you see, it's the relevant question that I think Richard is asking. How can it be that the surface of the body or of a cell, it might be that it's a unicellular organism, then it would be the surface of the organism. How can it know, how can its nucleus know that there is a need to change? And we now know how that can be done. What they've shown is best described by imagining first of all that a single nucleotide is about the size of my fist, and it's situated in the nucleus. Let's put that in the center of the cell. If we did that, on that scale, the surface membrane of that cell would be way up in Scotland. How on earth can it be that a signal through a receptor on the surface can influence the nucleus? And we now know how that can be done. What they both found doing different experiments in different cells was that calcium coming through protein channels in that surface membrane using the same metaphor way, way up there in Scotland, creates a calcium concentration in a small subspace underneath the membrane, and that high calcium triggers a chemical reaction that produces a messenger. And that messenger gets attached to some extremely important proteins in the cell. Those proteins are called tubulins, and the name suggests what they do. They form tubes. Literally, there are tube trains in cells. And I'm not joking, because what happens is those tubulins run all the way through from one edge of the cell to another. They have little motors on them, little molecular motors, and they can attach a messenger molecule to the motor. And what then happens is phenomenal. They literally walk along the tubulin. It takes just a few seconds to go from that surface, imagine on this scale way up there in Scotland, to the nucleus. What does it do? In those experiments, it changes the gene expression levels in the relevant genes that matter for that particular function. Now, the only thing that's missing here, and I'm sure Richard will pick this up very quickly, so I'll say it myself, is that those are very recent experiments, done 2016 and more recently, 2018, I think it was. Anyway, the important point is that we don't yet know how that induces genome change, and I really mean actual change in DNA. And yet we know also that those processes must be able to do that, because we can show that. Let's take a tumor developing your body, and it's a bad situation. You're beginning to get metastasis. So the doctors get out the radiotherapy and the chemotherapy, they attack it and try to destroy it. What happens? The tumor cells themselves tell the genome to increase the mutation rate. How can they do that? Precisely by the kinds of mechanism I've just described, because the mutation rate is under the control of what is happening in the body as a whole. What then happens is phenomenal.

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It happens in your immune system all the time. It happens in bacteria all the time, because they change their genomes in response to antibiotics. And what they do is very simple. You remember that difference between one in 10 to the four and one in 10 to the 10? That depends, as I said, on the cell. Having these repair mechanisms, the proofreading mechanisms, but you see they can be downregulated. That process can be downregulated. And what that does is to produce literally millions of new DNA sequences. That can then be selected. Now the selection, and I agree, there is a kind of natural selection here within the organism. Now the question is very simple. Do those new sequences get to the germline? You bet they do. And that, I'm afraid, is where I think the big hole in theory lies. Because once you can do that, you can get what, for example, Zhang and his colleagues have shown in a paper published in 2018. I can send all these references to anybody who sends me an email. So if you're worried about whether I'm telling the truth, just send an email and I will send you the reference. What they showed was that a small non-coding RNA, that's a little bit of technology, but a new sequence generated by the organism can pass to the germline cells, which become eventually, of course, the eggs and the sperm. And what that will do is then tell the next generation to inherit the metabolic characteristics that were conveyed by that. I'm sorry to say this, because I know this is a dirty word amongst most evolutionary biologists, but Lamarck is back. Very simple. Oof, all right. By the way, the walking mechanism is simply beautiful. It is, absolutely. See films of it, it's absolutely uncanny. At one point, Dennis, I thought you were confusing gene expression, which of course is obvious. I mean, it happens all the time. No, it didn't confuse them. With germline changes. I said we don't, that's why I went on to explain how those changes can then be communicated to the germline. That's an extremely important distinction. Indeed, yeah. There's no dispute whatever about certain genes being turned on in some cells and others in other cells. That's what embryology is all about. However, what Dennis went on to say is that there's evidence that it actually gets into the germline. And Lamarck is back. Well, if Lamarck is back for an indefinite number of generations, I'm impressed. If it's only for a couple of generations, I'm not. But let's suppose that it is for a larger number of generations. If that's true, then I would have to revise what I say to include any change in the germline then now becomes admitted into the charm circle of replicators. And that's fine. Well, it would, yes. I doubt it. I know you do. But I don't want to be dogmatic about saying that the DNA in the existing germline is all that ever was. If on some other planet and maybe on this planet, it's true, the germline can be altered, then that's fine. The broad church of the selfish gene can embrace that. As I say, I doubt it. Yes, okay. Yes, but look, Richard, I think one thing to perhaps make clear to the audience is this is happening in everybody in this room because we had the pandemic that arrived with coronavirus. Now, of course, we've fortunately developed vaccines against the virus and that's been our great saving grace. But what would have happened anyway with a lot of people dying, of course, would have been that our immune systems would have done exactly what we're describing. That is, they would have used that mechanism for hypermutating, that is mutating extremely quickly to produce millions of new DNA sequences. And then that is used to be what then gives you the immunity, the acquired immunity, obviously. Now, what Richard is questioning is, okay, maybe that can occasionally be passed to the germline and we don't know that yet, whether an immune response can be passed to the germline and I would readily say we don't know that yet. But what is important is Richard's point about how temporary it is. Now, it's very important indeed, and I agree with Richard about the importance of temporariness or permanence.

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Because it seems to me that what these mechanisms give is the option for the evolutionary process to as it were try it out If there's an environmental change That makes it very difficult to survive and all organisms are under stress and they alter their genomes and pass some of that even temporarily on to the next generations What the next generations can do is to find out whether they do experience that change environment or not If they don't then it's great that it's temporary You don't have to alter the main genome if it is more or less permanent and goes on for many Generations then how can it get assimilated in the genome? Conrad Waddington showed how to do that way back in the 1950s Incidentally his book the strategy of the genes has been rightly Republished in 2014 so you can buy it again. It was published in 1957 He did beautiful experiments on fruit flies. He induced changes with very tiny gentle persuasion as it were from either heat or ether or some other Experimental techniques in which he could as it were persuade a few of the fries to show a new Characteristic and he actually determined how many generations would you have to continue to do that in order for it to become? Assimilated into the genome. It's about 14. It's not very long Now what he was showing is what he called genetic assimilation I think it was a great mistake that Waddington was ignored by the evolutionary biologist. That's a shame The Waddington effect was actually selection and it was not the mark by him Well The the the flies that didn't respond correctly to the heat shock. Yeah died. Yes, that's right So it was selected what it was Darwinian. I'm agreeing with you It only looked like the mark may be the only point in the evening where we totally agree that was selection Yes, I absolutely agree I'm agreeing with you what Waddington was doing was a simulation of a Lamar can experiment for quite a different reason And I think it comes back to your opening question to to me Do you still hold to the idea that it's agency that organisms have rather than the DNA? Now I do because you see I think what organisms are doing is partly through their social choices Effectively choosing which genes they will allow to survive. That's what what incest do you shot? Social selection. Yes, how I mean Well who you mate with for example, we're back to Darwin's idea of sexual selection Well, we are the social selection. So ideas why why drag Lamar can then I? Think that's Lamar kian Because it's part of the use within the social context. You see what what landmark was insisting on Was the idea that use and disuse was itself something that could be inherited and I think this is something Of course, it starts culturally but it becomes something that can be inherited through the fact that you are as organisms choosing the Characteristics that you want to survive in the later generations. Why do we marry anybody? Isn't that why we do it? But Dennis you're I mean the this this is perfectly Darwinian what you're talking about Yes, absolutely. I agree and Darwinian Darwin was a Lamar kian I'm not joking. No, you're not. No in 1868 he published his theory of gemmules Which is precisely the thing we've now discovered as the Erechter cellular vesicles today So I absolutely agree with you Richard Darwin was indeed a Lamar kian. I'm a good Darwinian You're a sixth edition Darwin Darwin in the sixth edition of the origin of species did flirt with Lamar kism. That is true That's a historical fact, but it's not a very important biological fact. Oh, I think it's extremely important. Okay, well No, seriously Richard because he he he collaborated with this is not very well known He collaborated with physiologists in the last 20 years of his life between 1872 and 1882 he collaborated with my predecessor as the chair of physiology Burden Sanderson and he collaborated with his student George Roman is in a very simple set of experiments because you see took Lamar kian ism so seriously that he invented this theory of gemmules and I better just very briefly explain what that is He realized as Richard is beautifully explained that you've got to explain how it can be that the body

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can in its changes due to use and disuse communicate any of that to the germline. Otherwise all of that information as Richard beautifully expressed it earlier on would be lost. So how can that be communicated? He couldn't see what could possibly do that so he invented an idea. And he admitted it was an idea which was that tiny particles put out by the cells themselves which he called gemmules would be able perhaps to pass through the bloodstream down to the germline. That was his way of explaining there could be soma to germline expression. But he readily admitted at the time this was just a hypothesis because he couldn't see them. Now with 19th century microscopy indeed you could not. The 20th century microscopy and 21st century microscopy even better we've been able to do so. And the experiments are simply beautiful. Just go online and ask to look at extracellular vesicles made evident by labelling molecules fluorescently so they literally glow green, yellow, red or whatever it might be. It enables you to know this is this particular RNA, this is this particular DNA and so on. And that escapes the limits of light microscopy. You can actually resolve down to very tiny particles indeed. They're called extracellular vesicles. Those have been shown experimentally to be passed to the germline. That's how the RNAs and DNAs, the new RNAs and DNAs get to the germline. So I think that if he was alive today I think Charles Darwin would be praising and cheering the discovery of extracellular vesicles. They are his gemmules and they carry out the function that Darwin proposed. Now why did he spend the last 20 years of his life collaborating with George Romanes is because he actually thought this must be right. So I don't think it's trivial that Darwin was a Lamarckian. Okay I think I do think this is actually quite misleading. What Darwin's gemmules were supposed to be about was investigating the current state of the body and passing it on to the next generation. So the gemmules were going all around the body and they were detecting changes in the body. The sort of classic Lamarckian examples like the blacksmith's arms getting muscular and the giraffe's neck stretching and things like that. Lamarck thought that those were inherited. Darwin in his later years thought they were too. And Darwin's gemmules were going around the body in the bloodstream and picking up information about the current state of the body, the modified state of the body, the acquired state of the body, and going to the germline, going to the gonads and imprinting the information into the germline. Now that is a very radical idea. It's precisely what the extracellular vesicles are doing. Well yes but they're not, it's nothing to do with blacksmith's arms. They may be doing something if you're right about the immune system. You seem to be suggesting that what happens is that when the immune system reacts to an infection like COVID and we become immune to it, that immunity gets passed on. No, I did not say we're not yet sure about that. I know you did and I'm glad you said that. What we are sure about is that other things are passed on. Metabolic disorders are passed on and sexual preference are passed on. Well sexual preferences in what way are passed on? It's passed on in plenarians and that's been demonstrated. Again, all of these references, I'm very happy for people to email me and ask for them, but that's been shown very recently by Toker and his collaborators in work in Israel. And I think that is actually a 2021 reference. And how many generations? Well what they're showing, okay, come back to the point I made about temporary and permanent. Because you see, temporary is actually an advantage if you don't yet know from an evolutionary perspective whether the change is valuable or not. I think it's great you see that epigenetic changes and temporary alterations of the germ line are not necessarily passed on through many, many thousands of generations. Because if the change in the environment is really temporary, you don't want a permanent response. So I can see the evolutionary logic of doing it in that kind of way. You keep it soft until it needs to become hard and then you let it become hard. You let it then become assimilated into the genome.

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Well, that's fine. I mean, that's coming back to the Waddington effect in a way. To some extent, yes. I think this is why I said that Waddington was badly ignored. Or sometimes called the Baldwin effect. Sometimes called that. Yes. But I think what's happened today is that we actually now know the precise mechanisms by which it can happen. We know the molecular biology of it. We know the cellular biology of it. So what I'm saying is it's time for evolutionary biology to catch up. I mean, if I may ask in that case, how long would it need to be? I mean, you've asked a few times. I'm really taken by this sort of temporal thing. How long would it need to be to have an effect, do you think? In order to be evolutionarily interesting, then it needs to be something that we see as a change in the gene pool. And changing the gene pool would be... I mean, I can't put an actual number of generations on it. But it's not a proper Darwinian change if it's just... For example, there's evidence that starvation effects can... Yes, I was going to ask about that next, yes. And these are, as it were, epigenetic effects are changes in the... As the embryo develops, changes in the expression of genes in different parts of the body. So in liver cells, certain genes are turned on. In kidney cells, other genes are turned on. Muscle cells, other genes are turned on. Those are epigenetic effects. Now, there is some evidence that those epigenetic changes can be inherited into next generation, and possibly the grandchild generation. That's not a proper gene pool change. Yeah, I think Richard is right on that. But what we would need to do is to look at the effects after billions of years. And that's exactly what the Human Genome Project did in its Nature paper of 2001. Remember, I referred to figure 42 of that paper. You see there the evidence that those genomes were changed by moving great chunks around in the genome. It's not time, I guess, to go through the detail of that. Yeah, unfortunately not. But that's fairly clear evidence that it must have happened during evolutionary time scale. It's obviously also important to say that increasingly with modern technologies, people are starting to look at sort of the genomes of other humanoid species. Indeed. And looking into the past to sort of get more information on perhaps what our more recent ancestors look like. And it might be quite interesting to sort of see whether or not those pieces of data can add to this conversation in due course. What bothers me is, is Dennis is saying Lamarck is back. Because in order for Lamarck to be back, it seems to me we would need to have something more like the blacksmith's arms effect, where an adaptation, and I mean there are plenty of adaptations that happen in lifetime. Your muscles develop when you use them. It would be wonderful, maybe on some other planet it happens, that when your muscles develop, when you get a suntan, when you're... all sorts of adaptive changes like that get inherited. And that's what Lamarck was suggesting. And I think to say that Lamarck is back is going to give a misleading impression, because people will think you're saying that something like the giraffe effect, the blacksmith's arms effect. I think what I... very precise it is that the inheritance of use and disuse is now evident. That's the way I would... Well, is it? I mean, you're not going to go out and say that adaptation, as we see it in the field, as animals develop camouflage, as animals develop stronger bones as they use them, stronger muscles as they use them, that would be a proper Lamarckian effect. That would be a real adaptive change as a consequence of use and disuse. Thank you for your attention.
