The Engine That Built Life. Nick Lane - #541

Please join my mailing list here 👉 https://briankeating.com/yt to win a meteorite 💥 Nick Lane joins Brian Keating to argue that life is not information running on chemistry but energy in motion—showing how a single ancient metabolic “transformer” predates genes, powers mitochondria, shapes aging and cancer, constrains alien life, and reveals why today’s AI excitement echoes a solution biology discovered billions of years ago. 00:00 — Defining life vs. death; membrane potential as the boundary between living and dead 00:50 — The title “Transformer” and parallels between AI transformers and biochemical transformation 03:22 — Schrödinger’s What Is Life? and why defining life is intrinsically slippery 06:25 — Why the Krebs cycle sits at the center of metabolism 08:45 — The reverse Krebs cycle, CO₂ fixation, and links to cancer metabolism 11:35 — Mitochondrial membrane potential and the electrical field that powers life 15:00 — Reverse Krebs cycle vs. Calvin cycle and the evolution of carbon fixation 18:00 — Endosymbiosis: origin of mitochondria and chloroplasts 30:02 — Metabolism before genes; CO₂ + hydrogen and prebiotic chemistry 59:49 — Rapid-fire Q&A: RNA world critique and big open questions in origin-of-life research ------------------------------------------------------ ➡️ Follow Nick Lane 🌐 Website: https://www.nick-lane.net 📚 Transformer: The Deep Chemistry of Life and Death: https://nick-lane.net/books/transformer-the-deep-chemistry-of-life-and-death/ Join this channel to get access to perks like monthly Office Hours: https://www.youtube.com/channel/UCmXH_moPhfkqCk6S3b9RWuw/join 📚 Get my books: Think Like a Nobel Prize Winner, with productivity tips from 9 Nobel Prize winners: https://a.co/d/03ezQFu Focus Like a Nobel Prize Winner, with life-changing interviews with 9 Nobel Prizewinners: https://a.co/d/hi50U9U My tell-all cosmic memoir Losing the Nobel Prize: http://amzn.to/2sa5UpA The first-ever audiobook from Galileo: Dialogue Concerning the Two Chief World Systems: Ptolemaic and Copernican https://a.co/d/iZPi9Un Follow me to ask questions of my guests: 🏄‍♂️ Twitter: https://twitter.com/DrBrianKeating 🔔 Subscribe https://www.youtube.com/DrBrianKeating?sub_confirmation=1 📝 Join my mailing list; just click here http://briankeating.com/list ✍️ Detailed Blog posts here: https://briankeating.com/blog 🎙️ Listen on audio-only platforms: https://briankeating.com/podcast #universe #podcast #briankeating #intotheimpossible #science #astronomy #cosmology #cosmicmicrowavebackground #intotheimpossible #briankeating Learn more about your ad choices. Visit megaphone.fm/adchoices

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:01Speaker 00

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• 1:25Brian Keating?

  Tell me, Nick, what is life?

• 1:28Speaker 04

  Well, I can't tell you. If you get an answer from someone, it'll be a bad answer.

• 1:34Brian Keating?

  Seems like it might be easier to answer the question, what is death?

• 1:38Speaker 04

  Death is really easy. You lose your membrane potential permanently. That's it. We are burning rocket fuel.

• 1:45Brian Keating?

  Nick Lane, thank you for joining us all the way from London, I presume.

• 1:49Speaker 04

  I am in London, yes.

• 1:50Brian Keating?

  Very good. I've been wanting to do this interview for years now. This is a real treat for me and my audience. And I want to start with something that, you know, I came to, maybe you were presciently aware of this before you wrote the book, or when you were writing the book, as you often are, that the letter T in GPT would take over the world. And it does stand for transformer in ChatGPT, generative pre-trained transformer. Nick, were you ahead of the curve when you wrote this book in 2022, 2021, when you were writing it?

• 2:19Speaker 04

  I'd love to say I was, but I wasn't really. It became very clear when I was writing it. So, yes, I was pleased with the title. But the title goes back, actually, some, some years before that. And at that time, it was not so much common, common usage at all.

• 2:34Brian Keating?

  Well, we'll talk about the title of the book, the cover design of the book. But I do want to talk about the, the, at least the transformer aspect of it, you know, in, in the world of AI, which is, you know, kind of eating the world, transformer, you know, is this, is this mechanism by which information flows through a system, doesn't get absorbed or, you know, consumed, kind of acts like a catalyst in some way. And I saw a lot of parallels between the transformer that you speak about, which is, we're going to talk a great deal about, the Krebs cycle, mitochondria, and so forth. But what are the parallels between, you know, transformation of information that these GPTs do have in common with the humble mitochondria and the humble Krebs cycle?

• 3:21Speaker 04

  Um, I, I think I would take that as a broader question on the role of information in biology, maybe. And it's something that troubles me, actually, quite a lot, because I don't know, I mean, you can probably correct me here, but it seems to me that in terms of Shannon entropy, in terms of informational entropy and so on, there isn't quite an equivalent in there to the way that molecules interact with each other through chemical interactions. So really, when I'm talking about a transformer in, in biochemistry, it's the way that molecules are transformed from one into another. And a lot of that depends on the chemistry. And of course, there's information that underpins the whole thing. A lot of that information,

• 4:05Speaker 04

  in the end, is in chemical entropy, is in the, is in the physical interactions between molecules. So I don't know, honestly, I don't know, to what extent. There's really, there's really a commonality there.

• 4:17Brian Keating?

  Yeah, it seems like these systems do things, but maybe they don't understand what they're doing. I mean, if you look at the neural network architecture and then thinking about the Kreb cycle, you know, it's and, and, you know, we're kind of giving away what, what the book is about. But, but the Kreb cycle is this, you know, thing that, you know, my ninth graders, you know, are learning about right now. But, uh, but in, in reality, it's, it's really so powerful and it has so many important implications for, as you said, life, entropy, et cetera. But I'd, I'd like to maybe start with, uh, you know, a link between physics and, and biochemistry, which is the great question posed by the Nobel laureate Erwin Schrödinger. What is life? So I've got an expert, so, so tell me, Nick, what is life?

• 5:01Speaker 04

  Ah, well, I can't tell you. It's one of those funny questions that you, if you get an answer from someone, it'll be a bad answer. And I, I, I work mostly on the origin of life and, and most people will say to you immediately, well, so, so how do you define life? What is life? What are you trying to explain here? Uh, and it's one of those very slippery, very frustrating things that's hard to define. If you define it, I mean, there's, there, there's a working definition from NASA, which goes back some years now, uh, which is something along the lines of life is a self-sustained chemical system capable of undergoing Darwinian evolution or words to that effect. And I have a personal problem with the word self-sustained because obviously we're sustained

• 5:45Speaker 04

  by the environment and these are smart guys who wrote that. They know what they mean, but they're at least they're deflecting away from the importance of the environment. It's a disequilibrium in the environment that powers all work in, in biology. So there's that. And then again, there's, there's, there's people who say, well, uh, you know, a rabbit by that definition is not alive. Only a pair of rabbits would be alive because you require a pair of rabbits to undergo evolution by natural selection. So it's a working definition. It doesn't work very well. And what we're really trying to explain is a continuum. And where do you want to draw a line across that continuum? By going from very simple prebiotic chemistry at the origin of life

• 6:29Speaker 04

  through to complex machines, cells with machines and genes and all the rest of it. And that's not a phase transition. I think a lot of physicists would love to see it as a phase transition. It's actually a long evolutionary distance. And it's difficult to kind of say, at this point, it's now alive. You could say, at this point, it now has the potential to be alive. But you could say that about almost any point. So I think it's actively unhelpful to have a definition.

• 7:01Brian Keating?

  Yes, it's a rare anti-intellectualism wins the day in that case, Nick. So, you know, I first encountered the Krebs cycle, you know, I think it was 40 years ago. I mean, today is, you know, I'm 54, so it must have been when I was a freshman. And, you know, I remember some vague diagram and, you know, I'm really bad at bio, Nick. I mean, when I dissected the frog in biology class, it somehow lived and like screamed out in pain.

• 7:27Speaker 04

  Oh, no, ouch. It would put you off biology for life.

• 7:32Brian Keating?

  But I remember vaguely the circular diagram with labels and hard to pronounce things, the cholates and AOPB and all these other things. But tell me, what is that kind of, there must have been something magical that really thrilled you to this almost erotic level that you have with the Krebs cycle?

• 7:51Brian Keating?

  What is that simple diagram hide? And I'm going to put some animations and diagrams in the video. What does that diagram hide? Where's the magic, as Stephen Hawking said? What breathes fire into the cycle?

• 8:02Speaker 04

  Well, it's not the cycle itself so much as if you imagine all of metabolism, you see a map of metabolism and what you're seeing is really a network diagram with lots of nodes and lots of edges. And the edges are enzymes catalyzing reactions. Those enzymes are encoded by genes. And so there's a tremendous Amount of genetic information encapsulated in one of those. And pretty much all of them are linear pathways. And, and sitting right at the heart of this is, is the Krebs cycle. It's the cycle which is kind of connecting, it connects to respiration. It connects to energy generation. It connects to, you know, life and death in that sense. It's right at the heart of how these things work. And it's a cycle.

• 8:45Speaker 04

  And Krebs, actually, he discovered about three cycles, if not four cycles. So he had a, he, he, he must have seen things in circles. But most of them are fairly trivial and small things that most people wouldn't talk about. Right at the heart of every metabolic map you'll ever see is the Krebs cycle. And anybody who does biochemistry at university sees, you know, on the wall of every lab and pretty much every office of the, you know, the prof who you think, wow, I'd like to be like them. Um, you know, they've, they've got a metabolic map and there's the Krebs cycle at the middle of it. And you think, you know, being, being young and naive, you think, oh, I wonder why it's a circle? Why is it a cycle? What's going on there? There's so many ways into it. Um, you know, people like Harold Morovitz, who was a biophysicist.

• 9:29Speaker 04

  He had a lovely quip, energy flows and matter cycles. He saw that as a kind of physics way into questions like the origin of life. Even Morovitz, when he spent, you know, 20 years writing about a lot of that, hadn't for a long time registered that the Krebs cycle, what it's doing is pulling out CO2 from organic molecules, pulling out hydrogen, and then it's feeding the hydrogen to oxygen to be burnt in respiration. So it's effectively, we are burning rocket fuel. Um, and that's what's keeping us alive. Uh, but, but what you're not taught in university is that that cycle, which is kind of spinning around, pulling these things out, burning them, if it goes the other way, pulls in carbon dioxide, pulls in hydrogen and makes organic molecules and drives growth.

• 10:14Speaker 04

  Yeah, I would, I never knew that. Now it turns out that, well, what's going on with cancer? Cancers are cells that are growing. What's happening with the Krebs cycle? Oh, they've just turned around and they're, they're fixing CO2 and growing. Um, and they're not interested in the energy side of things. What they're interested in the molecules they need to make copies of themselves. And so it, the reason I started writing the book was that I have really two labs. One of them is working on the origin of life. And the other one is working on how mitochondria work in, actually in fruit flies as it happens. Um, and I realised after a while of kind of not really. Having too much overlap between the labs, but they were both trying to measure Krebs cycle intermediates using methods like mass spectroscopy.

• 10:56Speaker 04

  And I kind of thought, well, there's something, something important about this. It's there at the origin of life, it's there in why fruit flies, you know, these life, life history traits, like how fast do you age, how fertile are you, you can look at that kind of thing in fruit flies, and there's a relationship between them. You, you, you invest more in growth, in sexual maturity, you age faster and die faster. And it's all in the end about how do you wire your Krebs cycle to the rest of metabolism. So it, it feels like it's really dusty, old, kind of GCSE in the, in the UK, kind of, you know, high school biology that you'd rather forget.

• 11:39Speaker 04

  But actually, it's, it's really tapped into the, the way that biology works right across the board, from the way that we age to the origin of life. And that was what the book was about.

• 11:47Brian Keating?

  Yeah, it seems like we professors or scientists, our, our job is to take the most fascinating things imaginable, the greatest script possible, and make it so mind-numbingly boring that it fits on a poster, like periodic table of the elements. That's some of the most magical scientific discoveries in quantum mechanics and atomic, that the Greeks would have killed for thousands of years ago. And, and we just like memorize it and then, and then find it to be, you know, a source of great angst and frustration. But, you know, I kind of wondered about, you know, and I, I have a tendency towards teleological, you know, kind of fantasies, but, but how does the Krebs cycle know, you know, whether it should be producing, you know, turning carbon into energy or a structure or a waste product? And how does it know which, which way to spin the flywheel?

• 12:31Brian Keating?

  I mean, after all, if you, if you just have the, you know, your motor and you try to turn it into a generator, but you don't, you know, you do it randomly, it's not going to be useful for either generation or motive for. So how does it know what to do to turn carbon into energy, structure or waste product?

• 12:46Speaker 04

  It's embedded, and it's embedded in our own case in the mitochondria. And the way that we actually burn food, but burning hydrogen stripped out of the Krebs cycle intermediates is very funky indeed. We effectively split the hydrogen into the electrons and the protons, and we then have a current of electrons in the insulated membrane to oxygen. And that current of electrons powers the extrusion of protons across the membrane. So then you end up with a potential difference across the membrane, which is, you know, it's about 150, maybe 200 millivolts. The membrane is incredibly thin. It's about five nanometers, so that's five millionths of a millimeter thick. So that gives you a field strength of about 30 million volts per meter if you were down,

• 13:30Speaker 04

  shrunk next to that membrane. And that's pretty colossal. That's like a bolt of lightning. And that's what's keeping us alive. Now, so which way does the Krebs cycle go? It's got a pump against that. It's got to pump protons against that. So it's pushing back at you all the time. And if your pumps are not so efficient, you can't pump against that pressure. And if you can't pump, then you can't oxidize the Krebs cycle. If you can't do that, then it starts to go the other direction. So it's really all about the efficiency of your machinery, but also if you don't have any oxygen, you can't pass the electrons on to oxygen. If you don't have the hydrogen, the food, if you're starving, you can't do that either.

• 14:13Speaker 04

  So there's actually, it's an integration between the metabolism of your system and the outside world and, you know, how much oxygen is there? How much food do you have and so on? How good is your machinery? So the direction it goes depends on all of that.

• 14:31Brian Keating?

  And in the, we'll get to the mitochondria in just a bit, but you also talk about the parallels between the Krebs cycle and the Calvin cycle, which I understand from my local high schooler, you know, is sort of the, the plant world analogy of the Krebs cycle. Is that, is that an oversimplification?

• 14:53Speaker 04

  Slightly, but basically plants use a different cycle for fixing CO2. That's the Calvin cycle or the Calvin Benson cycle. I go into some of that history. I mean, there were some fairly unlikable people linked with all of that. But the Calvin Benson cycle, it's kind of a very odd cycle. It seems to have been hitched on to metabolism relatively recently. And the story of how it was discovered is actually really fascinating. It goes back to the 1940s and to the early discovery of 14C, so radioactive carbon, and incredibly beautiful but rather dangerous experiments done during those war years

• 15:38Speaker 04

  in San Francisco or Berkeley. So that kind of nailed eventually how plants fix CO2 and convert it into sugars in the end. But they started out, I mean, there were a whole bunch of papers. The one that they finally nailed it was number 24 in a series of papers that they basically, the first 23 had all been incorrect, which is a nice insight into how science works in itself. And so this, but the reason they were incorrect was they kept finding Krebs cycle intermediates. And so they thought that there was something going on with the Krebs cycle. Well, later on, it turned out that there, you know, this reverse Krebs cycle was discovered. That was by the 1960s by the time the reverse Krebs cycle was discovered.

• 16:22Speaker 04

  And that took quite a long time to get through. But basically, the reverse Krebs cycle fixes CO2 as well and about four times more effectively than the Calvin cycle. But if you have any oxygen around, the whole thing kind of just grinds to a halt and doesn't work.

• 17:04Brian Keating?

  At the heart of the cell that is doing this transformation is mitochondria. In plants, you know, you have the chloroplast. Am I thinking about that correctly, that they're sort of the analog? So you make the case, a very powerful case, you know, not for the first time, but you describe how it's believed that mitochondria were some sort of, you know, pre-existing bacteria related to bacterial, or what's the A word, F? I forget, anyway.

• 17:33Speaker 04

  Well, the alpha proteobacteria, I think.

• 17:35Brian Keating?

  That's right. So, and then they were ingested by the first eukaryotic cells. Do I have that right?

• 17:42Speaker 04

  Yeah.

• 17:43Brian Keating?

  More or less, or that's sort of prevailing wisdom. Did a similar thing happen with plants that, you know, chloroplast were just floating around like bacteria or some other?

• 17:51Speaker 04

  So chloroplast derived from cyanobacteria, so that's another type of bacteria, which are relatively large, complex bacteria with big genomes as bacteria go. They're still small compared to eukaryotes. So eukaryotes are us, we are, plants are, and things like amoeba and fungi and so on, they're all eukaryotes. And we all have our DNA in a nucleus, we've got big cells, lots of DNA, lots of stuff going on. And bacteria generally are much smaller and in their, in their kind of structure, in their morphology, they're much simpler. So the cell that acquired what's called an endosymbiont, which is to say a cell within

• 18:33Speaker 04

  a cell, well, that was not a eukaryotic cell. That was an archaeon, which is a group that look a lot like bacteria. There's still some debate about what kind of an archaeon it was. It was, there's a group discovered about 10 years ago called the Asgard's. We know it's within those Asgard's. Exactly how much variation there is within that group is debatable. But basically it was a relatively simple cell. It didn't have, I would say it didn't have a nucleus, it didn't have an endoplasmic reticulum, it didn't have endomembrane systems. There was actually a paper in Nature about a month ago saying, oh yes, it did, it had those things. I don't agree with that paper, but

• 19:14Speaker 04

  that's another story. Anyway, it was a, it was a, an archaic cell, it acquired mitochondria and it went on to become eukaryotes as we know them. So the chloroplast was acquired by some, some kind of fully fledged eukaryotic cell, probably what's called a phagocyte, so a cell that goes around engulfing other cells for, for dinner. And, so it was another example of an endosymbiosis, but it didn't transform the whole structure of eukaryotic cells in the way that mitochondria did. What it did do was transform the entire atmosphere

• 19:54Speaker 04

  of the earth, because cyanobacteria, they produce oxygen, but they do it on a small scale in comparison with algae and plants and so on. And it's partly a genome thing. As soon as you've got a large eukaryotic genome, you can do all kinds of interesting symbioses, like with lichens, for example, or with fungi for, for, for the roots of plants, roots of trees and things. And so suddenly you can, you're so much more effective at capturing CO2 and pumping out oxygen as a waste product, that photosynthesis transformed the planet, but it didn't transform cell structure in the way that mitochondria did.

• 20:33Brian Keating?

  So in that sense, the, you know, the, our ancestors are mitochondrial based life predated the, the plant kingdom, which, which was kind of surprising to me, because it seems like, you know, the chicken or egg problem here is whether or not you have Glucose or some, you know, material to metabolize in the mitochondria. But a lot of glucose we get from ultimately from photosynthetic processes, right? So how do how do biochemists reckon with that?

• 21:02Speaker 04

  Yeah, I mean, remember that we're we're talking about single cells, critters mostly here. So the first eukaryotes probably for a billion years or more were single cells, things living in the sea. The first algae is a little difficult to know, but maybe half a half a billion years after the the first eukaryotes. So, you know, 500 million years afterwards, maybe longer than that. It's a, you know, we we have molecular clocks, but those molecular clocks are difficult to calibrate. And they can be out by literally hundreds of billions of years. So it's, you know, a lot of these dates are pretty uncertain because we don't have a particularly great fossil record. We do have fossils, but they're not great.

• 21:42Speaker 04

  So just for the first few billion years of life, most cells are, you have things like methanogens, which are growing from CO2 and hydrogen, hydrogen's just bubbling out of the ground. Cells can live from hydrogen sulfides. Cells can live from iron dissolved in the oceans. There's all kinds of things that will donate electrons that you can use for food in effect. We get electrons from food. And and there's all kinds of things you can use, which is not oxygen, as an electron acceptor. So nitrate, you can put electrons onto nitrate, it becomes nitrate. You can put them onto nitric oxide, you can put them onto sulfate, you could put them on to rusty iron, onto ferric.

• 22:23Speaker 04

  You know, cells are astonishing, bacteria are astonishing, that they can grow from pretty much anything. But there's a principle in common, and that's you take electrons from somewhere and you dump them onto something else. And that's respiration. And we do a limited form of respiration. We take the electrons from food and we put them onto oxygen. And that's what we do in our mitochondria, but bacteria do exactly the same thing. E. coli lives that way. And it can do a whole bunch of other forms of respiration. And then there's lots of bacteria can do photosynthesis. And some of those, the cyanobacteria, produce oxygen as a waste product.

• 22:59Brian Keating?

  Hmm.

• 22:59Speaker 04

  So there's a whole amazing history of the planet. And, and you know, I suppose at first, first level, life arose maybe four billion years ago, eukaryotes maybe two billion years ago, animals about half a billion years ago. The Cambrian explosion was 550 million years ago or thereabouts. And land plants around 400 million years ago. So it's not the order you'd think. And it's, there's long, long gaps. You know, you've got two billion years before you have complex eukaryote cells and another one and a half billion years before you get to animals. Then another couple of hundred million years before you get to plants and so on.

• 23:42Brian Keating?

  And then we get the DoorDash. Yeah, that's, yeah. So before we judge the book by the cover, which is some conceit that I have to engage in. When we look at the Krebs cycle, the bidirectionality seems so prominently important. Is that sort of its killer app? Or I mean, does the Calvin cycle have a reverse Calvin cycle? I mean, are there other, is that truly a unique facet of the mitochondrial expression?

• 24:09Speaker 04

  The reversibility of it is not unique. Pretty much every pathway in biology can go in both directions. But most things have been regulated a lot. And you may stop it going in both directions through kind of genetic interference one way or another. The Krebs cycle, I suppose the thing that's unique is it really is, it's right at the center of what living is. You're burning, you're stripping the electrons out of food and you're burning it in oxygen. The Krebs cycle is, is the molecules you're stripping those electrons from. So you're one step removed. And if you stop that from happening, you die within a minute or something. Turn it the other way around and you're, you know, you're, you're taking electrons

• 24:53Speaker 04

  from hydrogen or wherever and you're, you're, you're making organic molecules from them. And it's right, it's the heart of metabolism. The Calvin cycle in plants is kind of tacked on at the edge. You can almost independently regulate it. You can switch it off at night, doesn't affect your metabolism. Whereas the Krebs cycle.

• 25:13Speaker 04

  You're either making things with it, even in us today, it's the source of pretty much, you know, the precursors for amino acids to make proteins out of, for sugars, and eventually nucleotides to make DNA out of, fatty acids to make membranes out of. It's all coming from these Krebs cycle intermediates. So the directionality and the centrality, it's not so much that nothing goes both ways, but it depends on this pushing pressure back from the membrane potential. So we've got this strange system, and that's right at the heart of the system, this strange system where you're always pumping protons across the membrane to generate an electrical

• 25:57Speaker 04

  membrane potential, which is pushing right back at you.

• 25:59Brian Keating?

  Seems like it might be easier to find, you know, answer the question, what is death by the anti Schrodinger than what is life?

• 26:07Speaker 04

  Yeah, I mean, from that point of view, death is really easy. You lose your membrane potential permanently, that's it.

• 26:12Brian Keating?

  That's right. You're dead. And by the way, I had a breakthrough recently, one in the discovery of the solution to the problem of which came first, the chicken or the egg. Are you ready for it, Nick?

• 26:24Speaker 04

  Go on.

• 26:25Brian Keating?

  The way to find out which came first is you order a chicken and an egg on Amazon, and you see which comes first. That's almost better than my kid's dad joke, which is that you biochemists, you know, boffins, have recently discovered that you inherit diarrhea from your parents. Have you ever discovered that or heard this before, Nick?

• 26:44Speaker 04

  I hadn't heard that before, no.

• 26:46Brian Keating?

  No, because it runs in your genes. All right, Nick, now we're gonna do what you're not supposed to do.

• 27:05Brian Keating?

  If you told me, you know, when I was taking high school bio, that I would be, you know, enthralled by a book about the Krebs cycle and, and other things like fruit flies, which we have to get to, I know you love your fruit flies. Um, I would have said you're nuts, but this is such a great book. The audio book is wonderful, even though you didn't read it, uh, it's still, uh, quite, uh, mellifluous and, and wonderful. Nick, would you mind showing us the book cover that you have there and then helping us judge it? Tell me the origin of the title, the subtitle, and that mysterious cover artwork. Go ahead, please.

• 27:35Speaker 04

  Well, the title, uh, I mean, you really don't want Krebs cycle in the title, do you? So you've got to try and think what's, what, what are you trying to get at here?

• 27:49Speaker 04

  Transformer goes back, you know, I wrote the proposal for this book probably in about 2015 or something. So it was before I really knew anything very much about, um, ChatGPT or anything like that. Um, so I, you know, I was really thinking more of a, trying to come up with a way of what is, what is it doing in words that are interesting and will perhaps grab attention. You know, there was a Lou Reed song Transformer that, that was in my mind. Um, there was the films on Transformers. Uh, my kids had watched those kind of things. So, you know, there were other, other cultural references to it. So it was more of a play on those things. I, I mean, I wish I could say that, yeah, it was all, it was the T in,

• 28:32Speaker 04

  uh, in GPT, but, uh, it wasn't really. The deep chemistry of life and death. Why the word deep? I mean, I added the word deep very deliberately to try and, the word chemistry, a lot of people find really off putting. Deep is a very ambiguous word. What do I mean by that? I almost don't mean anything by it. It can be deep in the sense that some of this stuff is deep in the oceans, deep in the sense that it's deep. Deep in the way that biochemistry works, deep intellectually in the sense that there are, there are kind of currents going through there, but really the word, the reason it's there is precisely to offset the word chemistry in, give a sense that I'm, I'm looking for something which is intellectually meaningful here, rather than, you know, a lot of words

• 29:16Speaker 04

  in chemistry. And then the, the image, well, the image was, was not selected by me at all. That came from, from the publisher who I, I'm terrible. I've forgotten the name of the artist, but it, it was not intended for this kind of thing at all, but it's, it gives the sense of almost evolution, starting with the kind of the dot at the top and it's kind of evolving towards greater complexity. It's a cycle. It's, what's the thing you call it in physics as well as, as a sense of the cosmos in there. So kind of cosmological meaning in there. And there's a sense of fluidity to the whole thing as well. And

• 30:00Speaker 04

  again, I was trying to capture the sense that biochemistry is all about movement and fluidity and change and transformation. So it captured all of those things really beautifully. And I, I thought, looks rather graceful.

• 30:17Brian Keating?

  Yeah. And it sort of has this persistence without consumption that, you know, a good catalytic process should have. I mean, it's same color. It's bulbous curve of linear. I do really find it quite mesmerizing. As I do the claim that you make in the book, which is something to the effect that the Kreb cycle might have existed before genes existed. So when you say metabolism comes first, what, what are you saying? Are you saying that life popped into existence fully formed? Or you're saying chemistry itself had some organization, some teleology? What's going on?

• 30:49Speaker 04

  I mean, chemistry does have organization. Yes. Would you call it teleology? That's an interesting question. I wouldn't see it in those terms, but it's very close to those terms. If you start with CO2 and hydrogen.

• 31:04Speaker 04

  And you can coax them into reacting, you will get carboxylic acids. And if you get, if you add another CO2 onto that, then you will have a double bonded oxygen on the first carbon, which is quite reactive. And that will tend to react with things like ammonia and then you have alpha amino acids. So there's a lot of, which are the ones that biology uses. So there's a lot about the chemistry of CO2, which says, you look at this molecule and think about which bits of this molecule are going to react. And you can say, okay, you know, this bit's not going to be very reactive. This bit's going to react. What's it going to react with? What's around? Well, it could react with these things. And then you get another molecule that looks like it's in biochemistry. Okay, this is also reactive.

• 31:49Speaker 04

  What's it going to react? Which bit's going to react? So, so what I was trying to do was, was kind of introduce kind of the principles of the chemistry of molecules as to why they would react and, and, and show that you, you go straight into metabolism that way. So yes, there is information there. It's thermodynamic information really about the reactivity of molecules. Where does all that thermodynamic information come from? That's where you're into the teleology side of it. What I would like to say, and this is a, this is an overclaim because it's not been demonstrated to be true, but it's, it's what I would love to be the case, is that you start

• 32:32Speaker 04

  with CO2 and hydrogen and you, and you get the driving forces right and you will get flux through all the metabolism as we know it, right the way up to the nucleotides that make up DNA and RNA and so on. Catalyzed by simple things like metal ions.

• 33:14Speaker 04

  And some of these molecules from within metabolism can catalyze some of those reactions. So you have effectively autocatalytic loops and feedbacks and so on that way. And that you'll amplify the whole thing up to metabolism as we know it without any genetic information whatsoever. So that's a big claim. Some of it's true, which is to say, we know from the lab that, you know, three, four, five steps along these pathways often, often works. You get the biochemical intermediates along those pathways. But the bigger claim that you start with CO2 and you get nucleotides coming out is not yet understood, not yet demonstrated in the lab.

• 33:51Brian Keating?

  And one of the things that really jumps out in the book is the, you know, kind of role of thermodynamics and the, and the physical properties, which is red meat or white tofu, if you're vegan to a physicist. The, the notion of thermodynamics, you know, to me then couples with the, some of the work done by my friend, you know, past guest and upcoming future guest Jill Tartar of the SETI Institute. She's talked about extremophiles and done a lot of work on that. Hydrothermal vents enter the story in your book as well. So for somebody who's just encountering the notion of thermodynamics, energy flow and hydrothermal vents, what makes those environments so special and so pertinent to, to the work that you do and your colleagues are working on?

• 34:35Speaker 04

  Um, I mean, a couple of things. One of them is it's they, they are continuous flow environments. You've got a continuous, you know, hydrothermal fluids going through that system. And if you think about us, we, we have a cardiovascular system. We have a continuous delivery through the bloodstream pumped by the heart of stuff, food and oxygen to our mitochondria. So we have a continuous flow and a hydrothermal vent is, is the closest thing you can get to something like that, that doesn't have a cardiovascular system. You've got stuff delivered to you from both the oceans being sucked in and from the hydrothermal system being effectively blown out, mixing within that system.

• 35:16Speaker 04

  And, and so continuous reactivity is as if you have a cardiovascular system which is continually reacting things. So how do they react? They're not very reactive, neither hydrogen or CO2 is particularly reactive, but you've got a structure in there that looks a lot like, you know, a honeycomb of cells, cell like things. It's not just a big central chimney. You've got, you've got this. It's kind of labyrinth of pores that are cell-like in their structure. And the ocean waters, we think, would have been acidic. The fluids are alkaline. And so we have natural proton gradients with a kind of a topology from the outside to the inside that's reminiscent of how our own cells and how our mitochondria work.

• 36:00Speaker 04

  So you've got two things going on here. You've got the continuous flow, the continuous reactivity, and a cell structure which is likely to drive their reactions. You also have this structure includes minerals, iron, sulfur minerals, things like that, which, again, we use in our own biology to drive this reaction between hydrogen and CO2. So these environments have basically got everything you need, in principle, to turn gases into living things.

• 36:31Brian Keating?

  Is that the origin of the seemingly inescapable or sine qua non, this pH gradients? Can you talk about that as a physicist? I'm fascinated by these things. So what's generating the pH gradients, besides just bubbling out hydrogen sulfide or whatever? I mean, is that enough for early life, perhaps, to glom onto? Or do we need more?

• 36:55Speaker 04

  Well, it's an interesting question. I mean, I mentioned already what's happening in your mitochondria is you're stripping, you've got a current of electrons going from food to oxygen, and that's powering the extrusion of protons across the membrane. So now you've got a difference in proton concentration and charge between the outside and the inside. And that's effectively what you have in these hydrothermal systems. It's not really charge in this case, because the charge is balanced, but a difference in protons between the outside and the inside. So the question is, well, what could that do? We know that we use them in biology, and we know that you have them here. But they can't be used to rotate ATP synthase, which is what we do in our own mitochondria.

• 37:40Speaker 04

  We don't have any genes, we don't have any molecular machines, we don't have those things. What could they do in a purely inorganic world? And that is physics, that's just down to things like the Nernst equation, which is really about what's the reduction potential of hydrogen? How reactive is it? It depends on pH. And same for CO2. If there are protons involved in a in a redox reaction, so a reaction which is transferring an electron from here to here, if you're also transfer, if a proton is involved in that, then the redox potential will shift by around about 60 millivolts per pH unit. So if you've got an outside which is, say, pH 4 or 5 or something, and an inside which is pH 11,

• 38:23Speaker 04

  then you're dealing with a difference which is, which is, you know, half a volt or something like that. It's quite a substantial, it's quite a substantial difference. What's it going to do? Effectively, if you if you think about hydrogen, it puts its electrons onto something else. It's actually not particularly reducing. It doesn't want to do that. It doesn't want to push its electrons onto other things. But if it does, then what's left behind are the protons. And if it's an acidic environment, well, that's thermodynamically not favoured. You're putting, you're putting protons into an acidic environment, which is defined as lots of protons. Whereas if if what you do is you put, you're in an alkaline environment, you offload your electrons, the protons are now going to react immediately

• 39:07Speaker 04

  with hydroxide ions. So that's an acid-base titration. It's strongly favoured. When I was at school, we used to do that in our own mouths to, and you'd feel the fizz as they, as they reacted together. And so that is now thermodynamically favoured to the tune of 60 millivolts per pH unit. So it's just physical chemistry, and you're going from two gases that don't want to react with each other to a structure, to the chemistry which says hydrogen now really wants to push its electrons on. And CO2, if it picks up those electrons, if it's in an acidic environment, it balances the charges by picking up a proton, picks up another electron, another negative charge, picks up a proton, positive charge to balance it.

• 39:50Speaker 04

  So it wants to be in an acidic environment, and it will then pick up those electrons from hydrogen. So it's just pure physical chemistry, and it requires structured environment, and that's what these vents give you.

• 40:01Brian Keating?

  So, the very famous Miller-Yori experiment is briefly mentioned in the book. And you may know that Harold Yori was a professor here at UC San Diego at the end of his life with Miller, Stanley Miller was here as well. I wonder if you could kind of recapitulate in simple terms for a simple cosmologist like me, the, you know, kind of proposition of the Miller-Yori experiment and some of the lacunae in it that, as you just mentioned, the importance of reducing environment. As I understand it, they assumed, you know, they require an extremely strongly reducing environment, which the early Earth didn't have because of the paucity of these, you know, cyanobacteria in the early Earth. So, can you explain for the audience exactly what they were kind of conjecturing, what they came up with, and what are some of the flaws?

• 40:46Brian Keating?

  And maybe what are some of the modern updates to the Miller-Yori experiment?

• 40:50Speaker 04

  Yeah, yeah, yeah. I mean, the Miller-Yori experiment, 1953, it was really Stanley Miller himself, Yori kind of encouraged him to do it, but wasn't really part of it as such. And it was based on the atmosphere of Jupiter, and the assumption was maybe the early Earth's atmosphere was a little bit like that. And I think most cosmologists wouldn't agree with that anymore. So hydrogen, ammonia, methane, those kind of gases. And then in a glass flask with electrical discharges to simulate lightning, the thinking being there would be lots of lightning strikes, and a kind of an ocean, so water in there

• 41:35Speaker 04

  as well. And so, these gases, hydrogen, methane, and ammonia, reacted with the electrical discharges to form amino acids, the building blocks of proteins. And this was a big deal. It was the first time anybody had really done an experiment on the origin of life and shown that, you know, here's a set of conditions that we think the early Earth might have looked like, here's a simple experiment, and we get the building blocks of biochemistry straight out of it. So, it was an astonishingly brilliant experiment and a beautiful demonstration that you can do experiments on the origin of life. From there, there was an assumption which actually predates that. It goes back to J.B.S. Haldane, who was at UCL where I am.

• 42:18Speaker 04

  Who coined the term primordial soup? So the idea was you have this chemistry going on. There's nothing to eat it, so it accumulates in the oceans and you end up with a kind of a broth of organic molecules. And then the first life forms would be viruses or RNA and you end up with what we would now call an RNA world. So that was, that really set the scene for all experimental work on the origin of life. It was criticised because probably the early Earth's atmosphere didn't have lots of methane and ammonia and hydrogen in it, probably mostly CO2. Other people these days have kind of moved towards, okay, it's cyanide and it's UV radiation.

• 43:02Speaker 04

  It's questionable whether they were there or not, but it's very good chemistry. I don't agree with it, but it's good chemistry. I can't knock it. The problems that I have with that whole view is that there's no continuous flow, there's no continuous disequilibrium, there's nothing that really, once you've got these molecules, why would they then form a cell and why would that cell now divide in two? You know, there aren't driving forces, whereas if what you've got is a continuous flow in a vent, then you've got a continuous reactivity, a continuous transformation from gases into organic molecules and a continuous growth. So this impetus to reproduce goes right back to hydrothermal flow.

• 43:46Speaker 04

  And ironically, within the hydrothermal, within these vents, we have hydrogen, we also have methane and probably some ammonia. So actually, the chemistry is not so far removed from that Milliore experiment. And the charges on some of these minerals, if you get down to, you know, a few atoms away, so Angstrom scale, we are talking charges equivalent to lightning strikes that they were simulating. So there are arguments to say you've gone around in a complete circle and we've simply changed the environment, but we're still doing a kind of Milliore-type chemistry.

• 44:19Brian Keating?

  So another type of cycle to Calvin and Cribbs. So that maybe that doesn't solve origin of life itself, but maybe origin of life on Earth, which is still be a huge accomplishment. So I'm thinking of the late, great Fred Hoyle, who of course is well-known to cosmologists, but was a proponent of what's called panspermia. And that life perhaps arrived on little meteorites like this one's yours, Nick. I'm going to bring it when I see you in London someday. But if you're like Nick or like me, but you're unlike Nick, but like me, and you live in the United States and you have a .edu email account, you can get one of these babies mailed to you. Just go to briankeating.com/edu. I'll send one to you. Otherwise, I give them out to people in the US at briankeating.com/yt.

• 45:04Brian Keating?

  So make sure if you want to, you know, and it will have biological material on it because I, you know, licked the stamp and put them in. I don't lick the stamp. But Nick, tell me, what are thoughts about that? That perhaps, okay, so Earth didn't have, you know, a strongly reducing environment, but maybe somewhere else did. And then that got blasted off by a meteorite on some other planet and came to Earth. What's, what's sort of your thinking on panspermia?

• 45:29Speaker 04

  I mean, we know that organic molecules get carted around the universe. We can measure them in space. We can see them on meteorites. It definitely happens. Cells almost certainly could survive in space. Bacteria will be able to survive in space. So in that sense, it's perfectly reasonable. I think it's questionable as to whether it's actually science. Because what we're really doing is just pushing the problem away to somewhere else, somewhere less knowable than the Earth. So the idea that life started on Earth is an assumption. It may have come from space. But, but actually, science is based on assumptions. Science is based on an assumption of naturalism, that is, we don't explain things by miracles.

• 46:13Speaker 04

  We explain things by laws, which are, you know, last long enough to, that we can assume. We assume that the laws of physics hold just as well at the other side of the universe that we can see as they do here. They're assumptions, and as far as we can see, they're largely true. And I would say the assumption that life started on Earth is largely borne out by what we know about the kind of conditions on the early Earth and the kind of chemistry that that will facilitate. So, you know, I said the... The vents are doing a kind of a form of milliory chemistry almost. They are reducing conditions, it's just not on a planetary scale.

• 46:55Speaker 04

  But if you had reducing conditions on a planetary scale, what you get is a soup and that soup, then the question is what's it going to do? And I think the answer is nothing much, because you don't have this flow. So the point about vents is you've got a continuous flow.

• 47:09Speaker 00

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• 47:34Speaker 04

  Oh, so then, I think, coming back to your question, can I, let's pretend that I can explain the origin of life on Earth. Is that meaningful to life anywhere else? I think the answer is yes. And the reason I think so is that, there are good arguments to say that carbon is pretty special. I mean, apart from being ubiquitous, it's, you know, it's one of the more abundant elements in the universe. It's also incredibly good at the kind of chemistry that it does. And it comes as a handy Lego brick, it comes as CO2, and then again, that's very common. We know that from, from looking at exoplanets and things. We know that the CO2, we can just look around our own solar system, the CO2 is very common in planetary atmospheres. And water is very common.

• 48:19Speaker 04

  Again, we're dealing, it's ubiquitous in interstellar space. So this idea of a wet rocky planet with a CO2-rich atmosphere, we're going to find them, we already are finding them again and again and again and again, probably billions of them in the Milky Way alone. So the same conditions that we had on the early Earth are going to be repeated throughout. And what does that mean? Well, we've got, you know, another, the mineral olivine is again ubiquitous in interstellar dust. The mantle of the Earth is basically made of olivine. It's iron and magnesium and low in silicates and, you know, not much else. Again, pretty abundant. So, so you have a wet rocky planet with a CO2 atmosphere, and you're going to get the same chemistry I'm talking about every time. And if this chemistry is basically...

• 49:05Speaker 04

  Thermodynamically favoured network of chemical reactions, starting with CO2. You're going to get something that looks like metabolism every time. And there'll be variations depending on conditions, but, but, but, you know, I, I, I think we can generalize somewhat. I'm not saying life is always going to be like that, but it would be unsurprising if we found that life often is like that.

• 49:28Brian Keating?

  Would you wager to bet, you know, that life in the universe, if, if it is common, is microbial, you know, by, by and large?

• 49:36Speaker 04

  I would wager that bet, yeah, yeah. I'm not sure I bet my house on it.

• 49:41Brian Keating?

  Always bet your neighbor's dog, that, that's what Martin Rees, that's what Martin Rees told me. So, uh, why don't we see ginormous bacteria, you know, micro, I mean, they're so productive, they're such, you know, so, so basic, so primitive. And yet they seem to have not evolved much, you know, it's like my, my, my wife tells me, you know, I haven't changed much. You know, since we got married, these things haven't changed much in billions of years, but other animals have. Why, why don't we see ginormous bacteria?

• 50:10Speaker 04

  They are limited. I, I mean, we mentioned eukaryotes earlier on and the, the, this endosymbiosis that gave rise to mitochondria. That basically restructured metabolism, restructured energy transduction. So these membranes, these highly charged membranes in relation to where genes are. So mitochondria have their own genes. We have basically internalized power packs with their own control units. That's what mitochondria are, genetic control unit for, for a power pack. We have as many of these as we want, the overhead costs are trivial. So if we want to scale up, we just have, you know, we just increase the number of mitochondria. If a bacteria wants to scale up, it's doing this over its plasma membrane. It can invaginate the plasma membrane.

• 50:52Speaker 04

  I mean, there's things it could do, but generally for bacteria, the ones that get larger or more complex also lose power and get outcompeted. They're slower replicating, they, they.

• 51:05Speaker 04

  The observation is they're not favoured. And we have explanations for why they may not be favoured. Are they correct observations, correct explanations, as may be? But it seems to me that bacteria are unable to become, because of this, they haven't internalised their their energy supply with this genome, which is the control unit.

• 51:33Speaker 04

  They've been unable to do that, and therefore they don't have the power packs that allow them to swell up their nuclear genome. And then, you know, any any large plant or animal has got is made of large, complex cells, and those large, complex cells have got a big nuclear genome. And that allows us to differentiate, which is to say, every cell is basically genetically the same, and you just express a different proportion of those genes in different, you know, in the brain cell. It's got the same genome as my kidney cell, but the proteins that are made from it are quite a different subset of proteins. And because all my cells are genetically very similar to each other, they don't fight that much. That's kind of standard evolutionary biology. Whereas if you had a if you had an organism made from a load of different types of bacteria,

• 52:15Speaker 04

  the one thing you could bet your house on is that they would squabble, they would fight, and the whole thing would get taken down.

• 52:20Brian Keating?

  On the other hand, we do know, at least there's evidence, perhaps, that during the Great Oxidation Event, there were ginormous insects and simpler animals. Talk about, were there giant fruit flies flying around back then?

• 52:36Speaker 04

  First thing, just one quick correction. The Great Oxidation Event was 2.3 billion years ago, and there were no animals then. That was when oxygen first appeared in the atmosphere in kind of measurable quantities. You're talking about the Carboniferous Period, which was about 300 million years ago, when there was probably a spike in oxygen in the atmosphere. How big it was is uncertain. There was a wonderful man, Robert Berner, who I wrote about in a book that I wrote on oxygen 20 something years ago, who had claimed that oxygen levels got up to about 35%.

• 53:15Speaker 04

  And he kind of climbed down from that high point to maybe 28%, he died a few years ago, but still very substantially higher than modern levels at 21%. And at that same time, there were giant dragonflies around.

• 53:30Brian Keating?

  Yes.

• 53:31Speaker 04

  With a one metre wingspan. And giant millipedes and, you know, huge trees and things. So the thinking was, is that with more oxygen, you can become larger. It's probably not quite as simple as that, but it does seem to, I mean, people have done experiments on, can you, if you, if you, if you raise dragonflies in a, in a, let's say, 30% oxygen, generation after generation, do they get bigger? And the answer is, well, they can, not by, they don't become a metre wingspan, but they become 30, 40% larger. And it seems that part of the reason for that is that your, your, your spiral calls,

• 54:11Speaker 04

  these kind of tubes down which the atmosphere, the air flows, they can be thinner if you have more oxygen in the air. And if they can be thinner, then you can have effectively more strength surrounding them. So you can have greater mechanical support and that allows you to become bigger. So it's not just about the oxygen, it's really about the ratio, what, what, what are your investments in these different things? So mechanical support really matters. And the reason dragonflies could become so big is, is in part that they have a relatively, despite their astonishing skill at flying, they don't really ventilate their, their respiratory system in the way that most other insects do.

• 54:53Speaker 04

  They, other insects can kind of compress their abdomen and effectively force oxygen down the trachea. And dragonflies don't do that, they can do that by beating their wings faster. And so they, they've got a little bit of a catch 22 situation there. And having more oxygen seems to allow dragonflies in particular to, to become larger.

• 55:14Brian Keating?

  Well, let's move from dragonflies to the dew-loving blackbellies, which you know. As fruit flies, I never knew that that's what Drosophila mega melagon master.

• 55:27Speaker 04

  Drosophila melanagaster, I would have said, but yes.

• 55:30Brian Keating?

  That's right. Do loving black bellies. You've done some phenomenal groundbreaking work with these little critters. What's the most surprising or fascinating thing you've found about them? And what can they tell us about our lifespan, our fertility, stress resistance, aging and so forth?

• 55:48Speaker 04

  Yeah, I mean, the reason we've been looking at them initially at least is is that they've been a lab animal for a century. And so there's all kinds of genetic techniques that you can use with them. But that means you're able to produce a population of effectively genetically identical flies. They're as close to that as you can get. And you know, there's a certain amount of inbreeding going on with that. So there's always questions if you've got an inbred population and they don't live as long and all kinds of things like that as compared to wild flies. But the place where they become really useful is that you can take mitochondria from other populations

• 56:32Speaker 04

  and effectively transplant them in. That's not exactly what we're doing, but that's roughly the outcome. What you can do then is quantify the effects that against a genetically identical kind of nuclear background. What are the effects of different mitochondrial DNAs? What we see is that it can be very trivial, it can be very small, but sometimes it can be really important. And it's quite unpredictable. And when I say important, it can prevent flies from developing at all. It can kill you in embryo in effect. It can probably double your lifespan or half your lifespan. It can double or half your fertility, that kind of scale of effect.

• 57:19Speaker 04

  You may say, okay, so as it says in Fruit Flies, what's it got to do with us? We have the same system, we have the same mitochondria with the same mitochondrial DNA against complex nuclear backgrounds. So what it allows us to do is effectively say, well, this is the scale of effect we'd expect to see in ourselves as well. So it's not trivial and we all have a different nuclear background. So it's very difficult to do a direct comparison. But with the fruit flies, you're able to say, right, this effect is actually pretty big. Do you want to live to 50 or are you going to live to 100? Well, a lot depends on how your mitochondria work.

• 57:54Brian Keating?

  So we started off the conversation with, you know, some vague speculation about artificial intelligence and these transformers that we have come to know and fear called generative pre-trained transformers, GPTs. And at the end of the book, you kind of go into some speculation on electricity and consciousness and you speak about metabolic flux and electrical fields. But, you know, in my work in physics, I've always found it much easier to manipulate magnetic fields and yet they play almost no role in life. There are some creatures that have magnetic susceptibility and the origin of magnetism is very poorly understood as well, cosmologically speaking.

• 58:37Brian Keating?

  But what would some of the physical links between electrical fields, which as I said are, you know, hard to manipulate in the lab, harder than magnetic fields? What is sort of the relevance there? I mean, you mentioned Pascal Michael Levin as well. Where is it, you know, kind of the link between the evidence for the preponderance of the importance, at least of electrical fields and life or consciousness? I mean, I could see life certainly, but how does consciousness, maybe perhaps sharpening my question, has consciousness rely on electricity?

• 59:08Speaker 04

  Yeah. I mean, in some trivial sense, you know, all neurons are electrical. So we already know that the brain is generating a lot of voltage and we're measuring it with an EEG and we know that anesthetics will take that away and you can measure that with an EEG as well. So we know. The voltage matters. But the assumption has always been that the relevant unit that we should be looking at is the neuron, whether a neuron is firing or not. And what we're measuring with an EEG is patterns of neural firing. And actually, we don't know that. We don't know exactly what is generating the EEG. And there's quite an abstruse literature on this kind of thing, but the bottom line is we're not absolutely sure.

• 59:49Speaker 04

  And it could be that mitochondria are a major contributor to that. The reason I became interested in it was that it turns out that anesthetics target mitochondria. And we don't know for sure if that's the only thing they do. I mean, there's plenty of other things anesthetics are supposed to target, but the evidence for it all is pretty weak. And we know for sure, from my own experience in fruit flies, we know for sure that anesthetics affect specifically complex I in the mitochondria. And that leads to all kinds of interesting questions. Why? Why would that take away consciousness?

• 1:00:30Speaker 04

  And there's a few other things about complex I which is odd. You're transferring electrons over a surprisingly long distance through a whole bunch of iron-sulfur clusters. There's nine of them in there, and nobody really knows why there's so many. And there's a branch of physics which has risen up over the last 15 years called chiral-induced spin selectivity. And the interesting thing there is that as you transfer electrons through a chiral medium, and that includes chiral amino acids in the protein, you will polarize the spin of the electrons, and that will generate a magnetic field. So an anesthetic seemed to disrupt that. So there's all kinds of interesting things going on there, which we're just looking into because it's fun.

• 1:01:14Speaker 04

  And we're trying to do standard molecular biology to see, can we demonstrate that the effect is specifically on complex I? Potentially linking to magnetic fields, or is it downstream, which is the simplest answer, it's actually about ATP and energy. If that's true, then it's interesting, but it's hardly very earth shattering. If we're able to show it's not about ATP, it has to be about fields, then that's really a big shift in where we should put emphasis in biology. I would love it if it turned out that what mitochondria are really doing is, at least in some neurons, is generating magnetic fields which are influencing the way that neurons fire. I'd love it if that were true.

• 1:01:58Speaker 04

  I think we're a long way from demonstrating that that's true, and it's notoriously difficult to measure these things and manipulate these things and, you know, use a Faraday cage, whatever it may be. They're difficult measurements to make. And you don't want to go there unless you're fairly sure you're there for a good reason.

• 1:02:15Brian Keating?

  Maybe we'll get a GPT to help us with it. All right, Nick, so we've reached the end of the generous time that you've allotted, but I wonder if you would indulge with a bit of your characteristic British forbearance with a few more rapid fire questions, just a few.

• 1:02:31Speaker 04

  Sure. You want rapid fire answers, I presume?

• 1:02:33Brian Keating?

  Yeah, that would be great. Yeah, I want to keep you up any later than I've already kept you up. Okay. First one. Most overrated idea in the origin of life research?

• 1:02:43Speaker 04

  Haha. Most overrated, the RNA world, I would say.

• 1:02:47Brian Keating?

  Mm-hmm.

• 1:02:48Speaker 04

  I can expand on that indefinitely, but I think it's, I mean, there is truth in it, it's not as if it's completely wrong. But the RNA world says RNA as a kind of primitive gene invented everything, and there's no evidence for that.

• 1:03:04Brian Keating?

  Okay. What's the most underrated experiment or the most, you know, sort of exciting experiment that maybe inspired you to do the work that you do?

• 1:03:14Speaker 04

  I tend to be inspired by ideas and probably if I go back about the most inspirational ideas were coming from Bill Martin and Mike Russell about 25 years ago, 30 years ago, about the origin of life and hydrothermal vents and how a kind of geological system could drive biology as we know it into existence. So it wasn't really experiments, but it was a beautiful set of ideas and it was grounded in experimental research and probably more than anything else, that's what's inspired me.

• 1:03:47Brian Keating?

  Well, as your late, great countryman, Sir Arthur C Clarke, who gave me the inspiration for the name of this podcast with one of his many quips, you know, he's very quotable, Nick. He said things like, for every expert, there's an equal and opposite expert. He said, he said, the only way of determining the limits of the possible is to go beyond them into the impossible. That's where I got the name of the podcast. But he also said that when a distinguished but older scientist, I'm not calling you old, you're about the same age as me, but a distinguished but

• 1:04:17Speaker 04

  I've got a few years on you, I think.

• 1:04:19Brian Keating?

  Oh, you can't tell. A distinguished but older scientist says something is possible, he is very, or she is very much likely to be right. But when he says something is impossible, he or she is very much likely to be wrong. I want to use that as a question. What, what idea have you been wrong about, if anything?

• 1:04:36Speaker 04

  I'm wrong every day. As one of the great things about doing lab work is I make predictions about every experiment that we do and mostly I'm wrong. And it's very humbling and it's very good for the soul. And, you know, we failed to repeat our own experiments sometimes and you wonder why and you can spend years trying to figure out why. So I'm, I'm wrong about a tremendous amount. I'd like to think I'm broadly right about the big ideas.

• 1:05:06Speaker 04

  I haven't, I can't say I'm wrong yet. What I would like to be able to say, so let's say you start with CO2 and you get metabolism, that's a big idea. There's a fair chance that's wrong. You, you, I would like pH gradients to drive CO2 fixation into all the metabolism. There's a fair chance that's wrong too. I can't say that I'm wrong yet, but in 20 years' time, when I failed dismally every day for 20 years, I hope that at that point I will have the humility to stand up and say, "Well, it was good, well, it lasted, but I'm afraid it was wrong." I think one of the great things about science is you can be wrong about anything. And actually, I think most people get out of bed in the morning because they think everybody else is wrong about everything. So what you're really trying

• 1:05:51Speaker 04

  to do is find something new and exciting and overturn the apple cart. And that's what, that's what makes me excited about science. But, but again, you've got to be very aware that if you're going to try and overturn an apple cart, you're probably going to be wrong about most of it.

• 1:06:08Brian Keating?

  Yeah, that's, I never thought of it that way. That, yeah, we get out of bed thinking we're right about everything and everyone else is wrong. We also think that, you know, everybody's thinking about us and really we're only thinking about ourselves. And so we don't have the theory of mind, I guess, to apply to other scientists, that they also think that they're right and that we're wrong about them. That's a really fun way to put it. Okay. So, speaking of being wrong, you know, as Lord Martin Rees says, you know, it's, it's easy to make predictions about the future as long as you're not too precise, right? There'll be unrest in the Middle East, there'll be fluctuations in the price of Bitcoin, as he's, he's a big hobler of, no, I don't know if he has any Bitcoin. But if we discover alien life, as we seem to do every couple of years, or some signature,

• 1:06:49Brian Keating?

  what metabolic signature would convince you that this time it's real?

• 1:06:56Speaker 04

  Um, you asked me right at the beginning, what is life? And I said, it's a continuum. And it's, you know, you start with geology and you end up with life. And there is no point, of course, which you can, so it's a problem in terms of you find a signature and that signature can be generated by geology, or it can be generated by biology. Probably the one signal which is... Not going to be generated in a serious way by geology is chirality. That if you have got chiral amino acids, chiral sugars, whatever it may be, that almost certainly is a sign of biology.

• 1:07:37Brian Keating?

  Because normally, just for people that aren't

• 1:07:39Speaker 04

  Normally you'd have a what's called a recemic mixture. You have the both handed forms of it. Biology has one handed amino acids and one handed sugars and so on. And that's generated by enzymes, really. And it's an interesting question of the origin of life. How did it get going? And there's a lovely line of work that suggests that's actually also about magnetic fields, mineral surfaces.

• 1:08:01Brian Keating?

  Yeah.

• 1:08:02Speaker 04

  So, so, but it, you know, a magnetic field on a mineral surface is not going to give you 100% chirality. You'd need selectivity going on all of the time to, to kind of generate that. But, but I, I think that's what would persuade me that this really was alive. You know, I'm constantly being asked questions about, oh, we've found high concentrations of this improbable molecule on Venus or something. Do you think it's a proof of life? And I think it's, chemistry is capable of wondrous, wondrous things. And I think we need more than, you know, an improbable molecule to, to make me believe it's going to be alive.

• 1:08:43Brian Keating?

  Okay, last couple of questions. I'm going to ask you about my, my supplement routine, NAD supplementation, worth doing or not?

• 1:08:53Speaker 04

  I don't do it, but I am on the scientific advisory board of a company that makes NMN. I actually joined it in part to demonstrate that it didn't work on fruit flies and it turns out it does. So, so I was wrong about that.

• 1:09:09Brian Keating?

  There you go.

• 1:09:10Speaker 04

  So, so if I were to take any, that's probably the one that I would, I would take. I don't really take any because I don't really know.

• 1:09:20Speaker 04

  The way in which they can distort metabolism as we know it. I remember reading years ago one experiment that was giving beta carotin to rabbits and they went blind. And the reason they went blind was because in the in the back of the eye, the red spot, the macular lutea,

• 1:09:40Speaker 04

  those are carotenoids that are in there, lutein and zeaxanthin. And if you overtake beta carotin, then it seemed that it was to retrain that to kind of regain that balance that was taking lutein and zeaxanthin out of the macular. And that's why the rabbits went blind. I don't know if that study is true. It just rings true. There are balances to things. So if you ask me, eat well, don't eat too much and get some exercise. And funnily enough, I was talking to Linda Partridge, who's at UCL and one of the kind of pioneers of research on aging. And she said more or less the same thing.

• 1:10:17Brian Keating?

  Well, that's good to know. And last one is citric acid. I think Linus Pauling was obsessed with citric acid, if I'm if I'm not mistaken.

• 1:10:24Speaker 04

  Well, that was vitamin C, really. It's a scorbic acid. Yeah.

• 1:10:30Brian Keating?

  What about taking citric acid? Since it's so central to the Krebs cycle, it's the other name for it, right? Citric acid cycle.

• 1:10:36Speaker 04

  I mean, that'd be like eating lemons all the time. Do you think that would be good for you?

• 1:10:41Brian Keating?

  I like, you know, orange juice with my bangers.

• 1:10:43Speaker 04

  Yeah. Yeah. I mean, I used to drink quite a lot of orange juice. And then I realized how much sugar there was in it and decided I was going to stop. But yeah, I think it's a bad idea to take too many supplements. I mean, you could say Linus Pauling lived to a ripe old age of 93 or something. But, you know, lots of folk do who also smoke and eat sausages all their lives. So it's a little bit unpredictable as to why someone lived to 93.

• 1:11:12Speaker 04

  I think the trouble with supplements is you're somewhat distorting the natural balance.

• 1:11:17Brian Keating?

  Yes, the homeostatic balance. Okay, last question, Nick. What's your next book going to be about? I can't wait to read it.

• 1:11:23Speaker 04

  The title, the working title, I imagine the publishers will change it, but it's Six Steps to the Origin of Life is the main title. And it's going to be an attempt to explain the whole lot, starting with prebiotic chemistry and ending up with cells with an agenda.

• 1:11:38Brian Keating?

  Please, please let me know as soon as it's ready. I would, I would read the phone book if you wrote it. And I hope that you will write a book about fruit flies. I mean, you can make anything interesting, Nick. So you owe it to, to the intellectual diversity of the planet to share your gifts with the world. This has been extraordinary. Nick Lane, UCL. Thank you for joining us, staying up late. And hopefully, hopefully, we can, we can meet in person someday.

• 1:12:07Speaker 04

  That will be a pleasure. Thanks very much. Great talking.

• 1:12:48Speaker 05

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