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Show Notes
This is a ~1 hour interview with the great Denis Noble (https://en.wikipedia.org/wiki/Denis_Noble), who made seminal contributions to understanding the heartbeat and went on to contribute exciting and counter-paradigm ideas in physiology, evolutionary theory, causation, and other aspects of biology.
Some of classic Denis Noble writing:
https://www.univ.ox.ac.uk/book/the-music-of-life-biology-beyond-genes/
https://www.cambridge.org/core/books/dance-to-the-tune-of-life/721483A1B5BB01E837BC8A8435E52710
https://www.ncbi.nlm.nih.gov/pubmed/35871280
https://www.ncbi.nlm.nih.gov/pubmed/30384641
https://www.ncbi.nlm.nih.gov/pubmed/23386960
Aastha Jain: https://www.linkedin.com/in/aasthajs/ and https://www.livelongerworld.com/
CHAPTERS:
(00:00) From Reductionism to Systems
(08:06) Neo-Darwinism Under Scrutiny
(20:35) Genetic Versus Epigenetic Information
(30:21) Life, Purpose, and Textbooks
(41:28) Causality, Controversy, and Speciation
(57:09) Philosophy, Networks, and Medicine
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Transcript
This transcript is automatically generated; we strive for accuracy, but errors in wording or speaker identification may occur. Please verify key details when needed.
[00:00] Denis Noble: Great to see you too, Mike. Is it Aastha?
[00:05] Aastha Jain Simes: It's Asta. Just as you said it. It's like Asta la Vista.
[00:11] Denis Noble: So it sounds like a flower to me.
[00:16] Aastha Jain Simes: Like a flower.
[00:17] Denis Noble: Yes, we have Asta. It means.
[00:20] Aastha Jain Simes: Oh, it means faith in Hindi.
[00:23] Denis Noble: I learn about languages all the time. What are we talking about today?
[00:35] Michael Levin: We're talking about a few things, and it's an incredible pleasure to have you here. Denis is one of my heroes from the very earliest work. So it's great to be able to talk about these things. Aastha will have some questions. I want to talk about some of your ideas around, of course, top-down causation, evolution, beyond molecular determinism, and then maybe getting to some of the Eastern thought towards the end. But Aastha, why don't you go first?
[01:13] Aastha Jain Simes: Thank you so much again, Professor Denis. I really enjoyed your book, "Dance to the Tune of Life." I think it's such an eye-opening book. One thing you mention in the book is why neo-Darwinism is a reductionist approach to biology and is, for all practical purposes, incorrect. Instead, you're advocating for a more integrative systems approach. I want to ask you: you say that you started from a reductionist camp when you were studying ion channels and cell membranes, where you did pioneering work. Did some of your work studying ion channels inform the approach you take to systems biology now?
[02:03] Denis Noble: It does, but realizations came later. Among the physiologists I was working with at University College London, I was regarded as doing close to the most reductionist account of a biological process you could have: single channels in membranes enabling processes to occur. It seemed investigating the processes there, representing them by sets of differential equations, was automatically a very reductionist approach compared to those who are looking at the effects of hormones on a system as a whole, those who are looking at the whole gastric system, those looking at the whole immune system. You can begin to see why that was characterized by others largely, but accepted by me at the time, that this was effectively a reductionist approach. It was later that I came to realize that if you understand that all of that is integrated through the cell surface voltage, which is a global property of the cell, you are not being reductionist at all. You're actually saying the accumulation of all of that movement of charge is contributing to that electrical phenomenon. Therefore, in the end, what you're doing is talking about a higher level of causation than the components of the cell. That's why in the end I came to see it as being a top-down process. It wasn't the way I viewed it when I first published in 1960. I would have been shocked if somebody told me then, "You are the most non-reductionist physiologist possible." That would have deeply shocked me then. It doesn't shock me now. I see the Hodgkin cycle, which is that interaction between the electrical global property of the cell membrane and the individual components of the ion channels, as being one of the prime examples of a global property influencing the molecular properties.
[04:52] Aastha Jain Simes: Say there's a young researcher who comes to you and says, Professor Denis, I am looking at ion channels and their role in cancer. I also want to take the systems-level approach. Would you say that it's okay to recognize the cell voltage and the voltage of cell membranes as a global property and then apply that with the more specific reductionist approach? What advice would you give to combine the two approaches?
[05:23] Denis Noble: You have to combine the two. I don't reject the reductionist approach. You need the upward causation from the individual molecular components as well as the constraints from the global property of the cells, tissues, organs and so on. I incorporate it into what I see as inevitably a multi-level approach to causation in biological systems. I am still at heart, therefore, a reductionist in the sense that I want to calculate how those ion channels contribute to the function they contribute to, but at the same time recognize that they are constrained not only by the particular potential of that cell, but also through connections between the various cells, the properties from a global point of view of the whole tissue and then of the whole organ, and so on. You cannot, for example, understand a cardiac arrhythmia like a ventricular fibrillation at the level of a single cell. You have to understand how waves of re-excitation can travel around the ventricle, and that depends on very many things. The particular fibre structures that occur in the ventricle of the heart, which pathways are likely to be good and which not, and the variations in the ion channel mechanisms that give rise to differences in the duration of the electrical event in different parts of the heart all contribute. That is beautifully orchestrated to try to prevent re-excitation, which is to say that the very structure of the heart, the density of ion channels varying from the base of the ventricle to the tip, and how those changes are orchestrated, is itself a way of trying to prevent those arrhythmias. So once you see all of that, you naturally see, in that case, an organ-level constraint of the molecular processes, which means you just can't understand a ventricular arrhythmia just from the reductionist viewpoint.
[08:06] Aastha Jain Simes: Maybe now's a good time to talk about some of the flaws you think with neo-Darwinism, because that seems to take a very reductionist approach, only looking at molecules in DNA. What would you say is wrong with neo-Darwinism?
[08:25] Denis Noble: Let me clarify that a little bit. It's got so many assumptions about molecular biological processes that I think are simply incorrect. Number one, it claims, as Dawkins does in his books and as many of the more, there are different varieties of people who favour the modern synthesis, as it is often called. Some are very much neo-Darwinists, some are less so. But taking in a broad way, one of the critical claims is that DNA can replicate itself like a crystal. That was introduced by Erwin Schrödinger in 1942. He didn't know the genetic material would be DNA, but he did know it would have to have been at a molecular level in order for there to be enough information to be transmitted down the generations. At that time, physicists were using X-ray crystallography to understand the structure of very big molecules. I remember watching Dorothy Hodgkin here in Oxford at the time when she was working on insulin and then later on penicillin and working out the structures of those complicated systems by using X-ray crystallography. What that led Schrödinger to do was to say there's no problem about reproduction of the molecular sequence of whatever the genetic material is. We now know it's DNA. It's just that, as we now realize, the base pairs come to join each other up together as the system unravels and forms a new pair of DNA molecules. Up to a point it does. That point is known to be accurate to about one in 10,000 base pairs. If you and I wrote an article and there was only one typo in a 10,000-word article, we'd be very pleased. But this is nowhere near enough. For a DNA sequence of 3 billion base pairs there would be at least half a million errors at the rate at which self-replication can occur. What happens? The cell orchestrates a system of cut-and-paste enzymes, which come in and work systematically, going along the loops of the DNA as it's unravelled and then put back together and correcting all of those errors. That's a system property. We don't know how to reproduce that outside a living organism. I would say to the neo-Darwinists, DNA does not self-replicate; it can't, and it needs a living cell to do so.
[11:51] Denis Noble: And indeed, outside a living cell, if you put all of my DNA, as Richard Dawkins told me two years ago in a debate with him, "Dennis, we could inscribe your DNA in blocks of granite, the C's, G's, A's and T's, and we'd keep those blocks of granite for 10,000 years, and then we'll be able to recreate you." I said, no, you can't. Why not? Where would you get my mother's egg cell as it was in 1936? You can see the point here. It led people to a very simplistic idea that from DNA, you could automatically recreate a person, an organism, exactly as it is in its first incarnation, if you like. We can all be reincarnated as many times as we wish. I don't think even the Buddhists would accept that was the way they were going to do it, if they do it at all. So I think there's the first break, it seems to me, in the neo-Darwinist mold. DNA simply does not replicate like a crystal. You have to have a living organism to enable it to do so. The second one is this lovely thing called the Weissman barrier. That's the idea that the germ cells in the future, egg and sperm, are protected from any changes in the body. Darwin never agreed with that. He actually introduced a theory which he couldn't prove at the time. He admitted he couldn't prove it. He invented the idea that the body naturally transmits information from its cells to the germline to enable information to be passed on to the next generation. He was ridiculed for that idea by Wallace, one of his co-discoverers of the theory of natural selection and by Weissmann. Weissmann particularly, just after Darwin's death in 1882, in 1883, he proclaimed the necessity of the Weissmann barrier. That is, there's no way in which cell, tissue and organ properties can be transmitted to the germline. We found the vesicles that do that. For around 20 years now, we've known that all cells in the body are pouring out tiny packets that give a snapshot of many of the control molecules that are concerned with the metabolism and other processes occurring in those cells. Those vesicles have been shown to transmit down to the germline, to carry RNAs, even DNA, to the germ cells. So I think the Weissman barrier is not any longer a barrier. Now, I forgot what the third one was, but I have around 3 molecular biological mechanisms that the neo-Darwinists assume that just don't work when you work them through. Those are two of them, and I'm sure during this conversation I'll remember the third.
[15:17] Michael Levin: Could I ask, Dennis, on that last point, are you emphasizing that there is a parallel heredity mechanism functioning alongside DNA in terms of these vesicles? There are other cytoplasmic components, cytoskeleton, and are you emphasizing the idea that once you've passed on that material, it can actually get integrated into the genome and then also pass along the conventional route? How important is that aspect?
[15:50] Denis Noble: Yes, both can occur. We know that because we have a huge amount of our DNA — more than the DNA involved in protein coding — that's come from viruses. It's clear that incorporation of new DNA from other organisms into the germline has occurred many times during evolution. So we can say there's both occurring. Epigenetic inheritance, which would be RNAs determining how much of a gene is expressed, will be transmitted down through the germline, and there's the possibility of actual new DNA being incorporated into the germline. We need to emphasize another major point. We have to give space for future experiments that characterize this in greater detail to occur. Even major standard evolutionary biologists now accept epigenetic inheritance. Futuma did so last year in a review article he published. He's one of the big textbook writers from the modern synthesis point of view. His textbook, called "Evolution," is 600 pages long. He has now accepted that we have to take into account epigenetic inheritance in addition to DNA inheritance. We now need to make it possible for people to get grants necessary to pursue these ideas in more detail than has been done. The reason is simple. The point is this. We can follow with fluorescent labeling of RNAs, DNAs and proteins. We can follow around two, three, four, perhaps more molecules at the same time, but that's a tiny fraction of what any vesicle can contain. It's tedious work. You have first of all to decide which molecules you're going to label with fluorescent labels, and you're limited in the number you can label with different colors of fluorescence if you're going to identify those molecules in the vesicles. That's the only way you can visualise the vesicles because they're too tiny to be visualised by standard microscopy. Labelling with fluorescent dyes is about the only way we can easily identify what molecules have been passed down from the vesicles to the germ cells. But that's restrictive, because there will be millions of different molecules in a single vesicle. Being faced with only being able to label three or four of those is tedious, because we can't make out the differences. People investigating those processes are going to have to be given the funding and the space necessary to do it. It's very important to do it. It will be tedious and take time to really work out. I interact now with a whole group of around a dozen younger academics trying to get the funding for the experiments they want to perform. They say that most of their grants are rejected. The reason is simple: rejection is often on the basis that the proposal disagrees with standard theory. We have to break out of that mindset.
[20:35] Michael Levin: Denis, in your estimate, a ballpark, what percentage of the information that is used by an organism, let's say embryogenesis onwards, is genetic versus all other sources put together? What would you guess as a breakdown?
[20:55] Denis Noble: I guess.
[20:57] Michael Levin: How much do you think is actually in the primary DNA sequence versus all the other epigenetic stuff that can exist?
[21:08] Denis Noble: I don't think we really know. Even if you just ask the question, how does a developing embryo from the earliest stages, initially 2, 4, 8 and 16 cells, eventually gastrulate into a three-dimensional object? How do all of those differentiations occur into what in the adult may be around 200 different types of cell distinguishable by the protein concentrations, the variations, therefore, in gene expression? Clearly, that is enormous as a range of variation. We're talking about, in some cases, cells with long fibrous tissue that can form a nerve cell compared to a liver cell, which is focusing on metabolism. And so I would say the epigenetic inheritance that has to occur there and how it occurs must be contributing a very large fraction indeed to the differentiation process. But what do we know at the moment? We know that the cells do start to differentiate, and that as they go from being stem cells to being specific types of stem cells and then finally into the adult cells, all of that is orchestrated by epigenetic processes. It seems to me that the potential information there is at least as great as the 3 billion base pairs of DNA. I don't know how to calculate it, really. Some time ago I published a paper on what I called the analogue and digital information in single cells. The digital information in DNA is easy to compute. You've got 3 billion base pairs. You can convert that into a binary form and get an idea of the total amount of information with the analog information, which is the structure of it all. An egg cell is an exceedingly complex structure with all of the organelles inside the cell as well as the cell itself. You can represent it at almost any degree of information if you convert that into digital information. At an individual molecular level, you could imagine computing it all digitally, but that's too fine a grid to be useful at any reasonable grid density for determining the total amount of analogue information. I think it's easy to show, and I have shown, that the total amount of information can easily exceed the 3 billion base pairs of DNA. But then, how do you do the comparison? One is analogue, the other digital. It's never going to be possible to come to a precise way of representing the comparative influence of those forms of inheritance.
[25:11] Michael Levin: One thing that makes it hard to quantify is that we have to first agree on what the observer is that's interpreting the information. It's easy for DNA because we've decided that it's the specific base pairs and the groups of them that matter. And so that's what we quantify. But in these other scenarios, we have to first say what the actual observable is that the rest of the biological system is interpreting as information. And probably many of them overlap. So that makes it much harder. I wasn't even trying to quantify the information. I was imagining the biology textbook from 50 years from now. Let's say it's 1,000 pages long. Now the question is, how many of those pages are about DNA and all the DNA-associated material? Where is the emphasis? I like to try to think forward.
[26:09] Denis Noble: That's not too difficult to answer, Mike. They're going to be at least equal. That's my best guess. Sometimes those textbooks will have to be written to take that into account.
[26:26] Aastha Jain Simes: I'm curious when you say that it probably lies in some of these epigenetic processes. Do we know or have theories on what the epigenetic processes entail, some of the more specifics of what they include?
[26:42] Denis Noble: The original definition of epigenetics was Waddington in the 1950s. He saw it as a general constraint on the actions of individual genes by the organism as a whole. He didn't have the concept of epigenetics that we have today, which is that of marking particular parts of the DNA with methylation or other processes, and the marking of the histone molecules, both of which can alter DNA expression.
[27:40] Aastha Jain Simes: I was asking more if we know some specifics of what epigenetics and epigenetic processes may include. Maybe one piece of it is, say, ion channels and bioelectricity. Maybe there's another component of it?
[27:56] Denis Noble: I would say it's occurring everywhere. Wherever there is a need to alter gene expression, it's epigenetics that will do it. When I exercise, for example, I am telling my muscles to make more actin and myosin. I'm not telling them deliberately. I'm exercising. I know that will tell the relevant cells to grow more of those proteins. So it seems to me that this must be ubiquitous, that it's like a continuous rain of epigenetic effects on the organism and its cells, not just an occasional intervention that we might think about. I take the view that at base, the DNA information, that's the sort of hard inheritance, if you want to call it that, with the epigenetic being sometimes described as soft inheritance. That's the basic, which without which there wouldn't be the proteins that we make anyway. That's straightforward. This bit of DNA codes for this protein. That's fine, and we can quantify that pretty accurately now. But the epigenetic processes are not like that. They're almost continuously variable. It depends, in my case, how often I go to my dance club tutor and get trained in prancing around the dance hall. I do that as often as I can now because I'm trying to look after my health. The point I'm making is that this will vary enormously from individual to individual. I usually feel that the epigenetic changes are far and away the bigger ones.
[30:21] Aastha Jain Simes: I know both you and Mike agree that DNA is not the blueprint for life. It doesn't have the code for life. I'm curious then, do you think there is a code for life somewhere else, perhaps in some of the epigenetic processes, or is that not fair to say?
[30:42] Denis Noble: No, I don't think of it that way. I think life itself is the creator of life. Now, you might think that's a bit of a get-out, and I understand that. But at the same time, I think we've got to recognise that living organisms have certain properties that are just almost by definition true of them. They have purposive behaviour, they have the ability to alter what their DNA is doing, possibly even altering their DNA. Immune systems are doing that all the time. When we get invaded by a new virus, we quickly create new DNA to enable an immunoglobulin to tackle that new virus. So I would say that not only is life definitively capable of purposive behaviour, but that it's definitively capable of altering what it is doing. That's difficult, philosophically speaking, isn't it? So much so that when you read Futuma's textbook, of his 600 pages, he has only one page which is devoted to philosophical issues. And the statement on that page is quite straightforward. There is no room for purposive behavior in science. Full stop. Any justification of that statement? No. Any thinking that there might be a philosophical need for a justification of that and to at least say, is that characteristic of life or not? No, not at all. It's as though these people are thinking in a philosophical vacuum, to my mind anyway. And I've already commented on Futuma's book. It's got many other errors, complete misrepresentation of what Lamarck thought. But there's another aspect of the story there. The more I have studied the texts, including the textbooks, but also some of the more popular texts like Jerry Coyne's "Why Evolution Is True", Richard Dawkins's many books on "The Selfish Gene" and similar ideas, and the various editions of John Maynard Smith's "The Theory of Evolution", which was a standard text to many people as I was growing up, the more I see that there is almost an agreement amongst them all to rule certain things out of court, that you cannot even talk about them. So you cannot talk about Lamarck because he was totally wrong.
[34:13] Denis Noble: They make the mistake of attributing to Lamarck the theory of his great opponent in Paris all of those years ago, Georges Cuvier. I've researched his work to that degree. First of all, I don't trust them on what they say about the history of their subject, and in particular, what they say about Lamarck. He was not a man favoring the idea that there was some special energy in life. He's often presented that way, as though "le pouvoir de la vie" is what he expressed in French, "the power of life." He was a materialist. Even I am not a materialist in the same sense as Lamarck, but the idea of attributing to Lamarck a kind of form of spiritualism, I think, is just way outside the range of what people should say about Lamarck. I'm about to try and publish articles on Lamarck that say all of this, and I think on the major principles of evolution, he and Darwin were not in serious disagreement. That's the extraordinary conclusion I've come to. But there's a major fact about the textbooks. I've also carefully studied the four editions over 40 years of John Maynard Smith's book, "The Theory of Evolution." He wrote that because he was not himself originally a biologist. He was an engineer trained to build aircraft. That's what he did during the Second World War: design aircraft from an engineering perspective. He wrote "The Theory of Evolution" in order to teach himself biology. I think of all the textbook writers or popular book writers, because I suppose "The Theory of Evolution" is more like a popular book than a textbook. Many people have used it as a textbook. It's interesting to see the process of a very clever thinker. John Maynard Smith was a very clever thinker about evolution. He came so close at various points to disowning the modern synthesis, but he never made that switch. What he did was to say, "I don't agree with Weismann." So he never accepted Weismann's barrier idea. He certainly did not think that epigenetics was a mere will-o'-the-wisp, something that was not very important. When it came to questions like, "Does DNA replicate like a crystal?" he went along with the standard story. He had never appreciated the difficulties with the concept that DNA replicates like a crystal. That is characteristic of nearly all neo-Darwinists and the modern synthesis. I therefore think that it's time we rewrote textbooks. I'm discussing with one of my own associations, the International Union of Physiological Sciences, how that might now be done, because I think it's necessary.
[37:46] Michael Levin: So Dennis, we've talked about a number of ideas. Which do you think is really the most fundamental? If you had one thing that you could wave a magic wand and get people to change their mind about one thing, what do you think is the most fundamental thing to get things going in a better direction? Is it the causality? Is it the purposiveness? What is the one thing at the top of it all that you would like to change?
[38:16] Denis Noble: I would say, Mike, that rewriting the textbooks is the most fundamental thing because that's what people learn from. If you don't teach the various developments that have occurred that are outside the range of the modern synthesis, then generally speaking, you won't have people looking to do the work that would be necessary. So I'm reluctant to try and put my finger on the major thing to do now. What I've done instead, Mike, is to gradually accumulate a dozen younger people around me, not to work under me. I'm not asking them to do my work. I'm trying to encourage people to think in ways that the textbooks haven't really taught them to think. And I find that very exciting. I leave it to them as a new generation to define what you're asking for, what would be the most important thing to do. I probably can't tell them that anyway, even if I wanted to, because as I look at the ways in which research has changed in biology, even over the last 20 years since I retired from an official position in my university, it's changed out of all recognition. Who now pokes? Who pulls tiny tubes over a Bunsen burner to create a one micron electrode to try to stick it into a cell that's reluctant to take it anyway. This is how I started recording from single bikini fibres in the heart way back in 1960. I'm out of date on the various techniques that are now possible. The fluorescent microscopic techniques are beautiful but limited because there's only a limited number of molecules that you can label at any one time. And how are we going to deal with that kind of problem when we want to work out all of these questions about epigenetic inheritance, what passes down from the body to the germline? I would feel my role is to encourage others to think out of the box, but I'm certainly not going to aim to say what I think is the most important thing to do. I'm rejecting the question, Mike, aren't I? But I think I've learned enough now to know that people like me looking back on it all are not the best people to judge where it should now go.
[41:28] Michael Levin: I agree completely as far as the details of where it goes. In your work and in your writing, you've emphasized a couple of really fundamental changes of perspective that have so many trickle-down effects if they were more widely recognized. The incredibly important role of goal-directed activity in biology, the top-down causation, the work on no privileged level of causation. These are incredibly fundamental ideas that make you see biology in a new way, and that then inform all the specific things that you may do later.
[42:12] Denis Noble: Yes. I'm very firm on what I say about those general principles. I look forward very much to a day when. A lot of time has been wasted. I say that advisedly. When I helped to organise a meeting in 2016 at the Royal Society here in England. It was a joint meeting with the British Academy, which is the Academy of the Humanities and Social Sciences, particularly including the philosophers. We built it as a discussion meeting on what we call new trends in evolutionary biology. I was subjected to the most extraordinary attempt to get that meeting cancelled. We went through the standard committees of the Royal Society and the British Academy to organise a discussion meeting. Twenty-one other fellows of the Royal Society, so those are top people in the field, wrote to the president of the Royal Society: "This meeting is organised by Dennis Noble; it should not occur. Full stop." I spoke with the chair of the committee that approved the meeting, and his position was in something of a difficulty anyway. His committee had approved this meeting with enthusiasm. In the end, when I said to him, "There's no problem, John, you can invite them, they can come to the meeting," he agreed. It's an open meeting. Nothing's to stop anybody coming and talking at the meeting. We're open to adding further speakers to the meeting, but that is not what they wanted. It took nearly a year to sort that out. It was a complete waste of time in the end because the meeting occurred almost as a gladiatorial confrontation. That is not how discussion meetings work. We discuss when we have an agreed basis for discussion. We can't manage if people are coming simply to ridicule the other side.
[45:10] Denis Noble: I think that's a great shame and I think it's a big blot on the landscape of academia here in the UK that happened. The meeting, incidentally, went ahead and produced a good publication by Interface Focus. There was, in one sense, no problem in the end. But the bitterness that that generated has never gone away. I regret that. I think we do our best science when we respect each other's views and ideas. We don't do it when what you're faced with is more like a gladiatorial confrontation. Since that time, the attempts to denigrate people like me have almost disappeared. I think there's now more — there is a greater realization that there is an important case here. I spent nearly three months earlier this year interacting with a Forbes journalist, Andrea Morris. It was three months of interactions because she was doing what a top journalist should do, probing every single major idea and assumption in what I was saying to test it to destruction, almost. What she did in the end was extraordinary. She rearranged all of that into a coherent video, which accompanied her Forbes article. What I found from that interaction was if you've got the opportunity to take somebody who's quite naive, she knew there was a big argument. She knew that there was major disagreement. She probed and probed until she got down to two things, really. First of all, I think your major discussion, your major difference from the other side is you think purposive behaviour in organisms is a characteristic of organisms, and they don't. She was quite right on that, of course. But in addition to that, Andrea, there are about three major processes at the molecular biological level where I think they've got it completely wrong. I went through the ones I did earlier: the self-replication of DNA, which simply does not happen in long DNA genomes, and the existence of the Iceman barrier. I'm afraid I've forgotten what the third one was. I'm sure it'll come back to me when this meeting is over.
[48:10] Aastha Jain Simes: It probably is.
[48:15] Denis Noble: There is epigenetic inheritance. I think that may be the prime basis of speciation. The main point of evolutionary biology is to explain speciation. That's what Darwin thought. That's why he called his book "The Origin of Species." But he never thought he had answered the question of the origin of species. Why not? He didn't think he had because, as he well knew, artificial selection had led to new varieties, but never to branching speciation. He realized that the reason they got their varieties was that they were preventing interbreeding. So he understood that for speciation to occur in a branching way, there would have to be something that stops the interbreeding. In the Galapagos Islands, he knew what was happening. The islands are separate. So you could get branching speciation through a particular finch species developing in a different direction on different islands. He realized the rest of the world is not like that. You've got to have some mechanism by which the interbreeding can be stopped. An interesting physiological fact: many epigenetic changes can influence the reproductive likelihood. It's a very sensitive thing. It can be a psychological change in that variety of the organism that leads to them not wishing to mate with their former colleagues. Or it can be actual physiological changes in the reproductive system. That may not happen often, but you don't need it to get branching speciation, which is what I think has happened. I think that epigenetic changes may well have led speciation, but that's speculation. I can't prove that. I put the idea into an article I did last year. It's up to other people to find out whether it's possible to prove one way or the other. It may be very difficult, because we'd have to do what has been done in the case of the Galapagos, which is to follow particular species over many generations. That has been done with the birds on the Galapagos, with Mike Skinner's work looking at how far apart the different finches on the different islands have grown and how many of those changes were epigenetic and how many were hard DNA. The interesting thing is both, almost equally. That itself doesn't prove that the epigenetic changes led the DNA changes, but it's possible that is the case. I'm good at throwing ideas out. I'm not so good at doing the experiments that could now prove them.
[51:57] Aastha Jain Simes: Wouldn't modern synthesis also say that it's random mutations that lead to speciation?
[52:04] Denis Noble: What do you also say to that? On its own, I don't think it can. Random mutation, other than, for example, controlled mutations such as the immune system controlling the rate of mutation in the B cells. Other than that, random mutation is an exceedingly slow process. One of the points I put to Richard Dawkins two years ago was, Richard, I agree with one of your calculations. He said, which one? I said, you calculated how long it would take for monkeys typing away randomly on a typewriter to create a particular sentence in English. 'Me thinks it looks like a weasel,' 28 characters. He calculated that it would take billions of years to happen, just by chance, unless somehow the system knows when a monkey had got the right key in the right place and could hold it. He realized that couldn't be the way it's done because the holding cannot be totally random. Now, I think that natural selection with random mutation is a background process and must occur. So I don't deny that natural selection in that sense occurs, but I do say that it will be exceedingly slow. Other processes, epigenetic included, have sped up the process. You can see that from the first comparisons between genomes in 2001, when the Nature paper on human genome sequencing was published, together with a comparison with organisms from yeast through flies, worms, higher organisms, and finally human. And what you find is the two categories of protein that were studied in that way, the chromatins and transcription factors, have grown by accretion of whole domains of functionality. The modern versions of those proteins, the latest in the evolutionary process, are vastly more complicated with many more domains with particular structures that enable them to be receptors, channels.
[54:35] Denis Noble: It's impossible to see how that could have occurred by chance. I think there must have been processes during evolution that enabled organisms to rearrange their genomes under stress. Barbara McClintock showed that over half a century ago when she was investigating corn. We've known about this kind of way of speeding the process up for very many years. She eventually got the Nobel Prize for mobile genetic elements in 1983 when she was aged 81. Was she then taken seriously? No. It has not led to people seriously taking into account what the sequencing of the human genome has shown in comparison with other genomes: rearrangements of the domains have occurred during evolution. That's not point mutation by point mutation. It's taking whole chunks and reassembling them. In my days it was bits of Meccano. Today it would be bits of Lego. Giving a child a construction kit. If he's already got stuff that's reformed, pre-formed bridges, pre-formed tunnels, a child will get there to build a new structure very quickly. If he's got to work with the tiny original Lego bricks, it will take ages. There's the difference.
[57:09] Michael Levin: Since we're heading towards the end, I wanted to see if you want to say a couple words. I know that you have a lot of interest in various kinds of Eastern thought and approaches to these bigger questions. I'm curious what you want to say about that and how that interest dovetails or informs or is informed by the biology you've been doing and the philosophy of biology you've contributed to?
[57:35] Denis Noble: Yes, I think it's been unfortunate that philosophy and science have diverged. I've interacted with some very good philosophers and they have succeeded over the period of time in which I've interacted with them. Anthony Kenny is one of them, Alan Montefiore, another, Charles Taylor, another. What they have contributed is not new discovery, that we shouldn't expect of philosophers, clarity of thought. And for Fatuma, for example, to write, purpose has no use in science. It seems to me, without any justification, without any discussion of what it would mean for an organism to be purposive, which I think is largely the anticipatory process of knowing what other organisms are doing and be able, nimble enough and quick enough to react. I see nothing as a problem in that in science. We now talk of building AI systems that can do that and giving them the intelligence to do it. Why don't we think that it must be characteristic of living organisms? I've come to many of the positions I've come to, Mike, through what I see as important philosophical mistakes made by the reductionists. First of all, for denying there's any other way of looking at a living system, that it must always be through reductionist analysis. And there is no philosophical basis for that. There's certainly no philosophical basis for dismissing the idea that organisms, cells, tissues, organs, and so on, naturally constrain the molecules within them to do what they do. And that doesn't seem to me to be particularly controversial. It must happen. But it is in essence also a philosophical point that you cannot have a complex system without levels of interaction. And once you've got levels of interaction, you've got downward as well as upward causation. I don't know whether that answers the point. I've always been fascinated by some aspects of philosophy since being a student and being introduced by the philosopher Stuart Hampshire many years ago at University College London, where I was a student, who introduced me to Spinoza. Now, Spinoza was the main opponent of Descartes, and that's very interesting because in Descartes, you can see the beginning of the Weissman barrier. He wrote, if I knew what was in that sperm, I would be able to predict the organism. That is very much the idea that from the DNA you would automatically predict the organism. Spinoza very clearly said no. It was in a letter that he wrote to the Royal Society in 1663 or five, I can't remember exactly now, Concypium armus yamsi placate, conceive, if you will, a little worm in the blood. This little worm would understand the interactions between the particles of the blood, but he would have absolutely no idea that the function of the blood was to circulate. It is a statement of the principle of seeing the whole, not just the parts. Now, in those days, a scientist and a philosopher was not a separate person. And I suppose what I am saying is I largely regret that the two have diverged.
[1:02:06] Aastha Jain Simes: I don't know if we have some more time.
[1:02:13] Denis Noble: Up to you, Austin. I'm endless. I have time.
[1:02:20] Aastha Jain Simes: I don't know if Mike does.
[1:02:22] Michael Levin: I got plenty of time, but I don't want to over-text Dennis. If you've got another question, go for it.
[1:02:29] Aastha Jain Simes: More practically speaking, I know you stress the importance of studying functional networks. I'm wondering, for people who want to apply this toward curing disease and therapeutic potential, maybe you can touch on why it's important to look at functional networks in biology for that.
[1:02:56] Denis Noble: Very important indeed. I like that question. And I think we need to get back to what we were doing before the genomics revolution. What we did then was to study the networks and ask the question at a network level, what could modify this functionality? My own work around 30 years ago indicated that sufficiently clearly to a pharmaceutical company, Servier in France, that they spent a considerable amount of time looking for chemicals that would be able to interact with an HCN1 protein. That's a channel protein that conducts both sodium and potassium, which was one of the mechanisms that we found in the heart underlying rhythmic activity. And what we showed was that if you could produce a drug that could block that mechanism, you would only produce roughly a 10 to 20% change in frequency; it would slow the heart just a little. Even better, it would slow it most when exercising with a lot of adrenaline because then the effect is larger. And that's exactly what they did. They produced ivabradine, which is a drug doing precisely that. It helps people who need their heart rate to be reduced, particularly during exercise. Otherwise, they're more likely to have heart attacks because of ischaemia and associated problems. I think that came from a systems analysis. So did some of the early work of Jim Black, which was largely on gastric treatment and related to pH. It was, as he always admitted, largely a functional analysis that led him to several major drugs that he developed during that period, way back in the 40s, 50s, 60s. He always said, "You've got to get back to that kind of analysis." At the DNA level, I don't think it will work. That's been shown recently. There's a paper by Hingorani and colleagues from University College London, published last October in the British Medical Journal. What they looked at was the ability of polygenic scores — adding together all the contributions of particular genes to a given function — to predict that function, because a single gene doesn't do it. So the next idea is to say, add a large number of gene effects together, all their association scores.
[1:05:39] Denis Noble: Ask the question, does that predict? It doesn't. It's a very important paper, October 2023 in the British Medical Journal. What that tells us is that that's too low a level at which to see the functionality. I think we've got to get back to network analysis and what we were doing before the genomics revolution, reasonably well, it seems to me. But that's a very important question. I would love to see us move back to that kind of approach. Look for ways in which one might cure Alzheimer's by restoring function up here. Don't bother about whether or not you can do it from a DNA level. You probably can't, but somehow try to restore the function. People are trying to do that now with the idea of possibly creating stem nerve cells that could replenish the brain's function. Who knows whether they will succeed? It seems to me that going deliberately for restoring function might be a better way to proceed. Do we need to succeed? Yes, we do. Those illnesses are now creating in aging populations a cost to health services that is beyond what we can afford. There are too many of us, me included, living a long life and, in the end, forming a burden to the rest of society. We haven't focused on those diseases. We haven't succeeded in getting the cures for them, and we need to do so. I don't think you could ask a more important question.
[1:08:24] Aastha Jain Simes: Perfect. I think that's a very important point to end on because it also puts it in practical perspective for people: why is it that we're not able to solve so many diseases by just focusing on DNA and genes, and what could we be doing instead, which is important to everyone?
[1:08:43] Denis Noble: And that Hinkarani study is quite stunning. The problem is there are some associations, but there are many that are false positives. It's rather like looking at a drug and whether it should be approved for treatment by the FDA and using exactly the same criteria. What they showed in effect is the polygenic scores are almost useless. What's happened to 23andMe? They're collapsing. Why? Because it isn't predictive and they know it.
[1:09:30] Michael Levin: Dennis, thank you so much. This was great. Awesome.
[1:09:32] Denis Noble: Okay. My thanks. Sorry about this cough, but it'll disappear by tomorrow, I'm sure. I'm always very positive about these things. Thank you so
