Nick Lane – Life as we know it is chemically inevitable

Today I'm chatting with Nick Lane, who is an evolutionary biochemist at University College London. And he has many books and papers which help us reconsensualize life's four billion years in terms of energy flow and helps explain everything from how life came to be in the first place to the origin of eukaryotes to many contingencies we see today in how life works. So, Nick, maybe a good place to start would be, why are eukaryotes so significant in your overall view of why life is the way it is? Well, first, thanks for having me here. This is fun. I love talking about this kind of thing. So eukaryotes, what's a eukaryote? It's basically the cells that make us up, but also make up plants and make up things like amoeba or fungi, algae. So basically everything that's large and complex that you can see is composed of this one cell type called the eukaryotic cell. And we have a nucleus where all the DNA is, where all the genes are. And then all those kind of machinery cell membranes and things. So there's just basically a lot of kit in these cells. And the weirdness is, if you look inside a plant cell or a fungal cell, it looks exactly the same under an electron microscope as one of our cells, but they have a completely different lifestyle. So why would they have all the same kit if they evolved to be a single celled alga living in an ocean doing photosynthesis? It's still got the same kit that our cells have. So we know that because they share all of these things, they arose once in the whole history of life on earth, there could have been multiple origins, but there's no evidence for that. If there was, it disappeared without trace. So we've got this kind of singularity, which happened about two billion years ago, about two billion years into the history of life on earth. Then this thing happens once that gives rise to all complex life on earth. And the one thing which I guess you could conclude from that is bacteria and archaea, in terms of their genetic repertoire, they've got a lot more genes, a lot more... versatility than eukaryotes do. It's just that a single bacterial cell has much less in it, but there's so many different types of bacterial cell that overall they've kind of explored genetic sequence space. They had four billion years to have a go at that and they never came up with a trick, which says it's not in the genes. It's not about information. There's something else which is controlling it. And that's something I think is the acquisition of these power packs in our cells called mitochondria. Now let's go to the origins of life. And you have this really compelling story where you imagine that the first life forms were continuous with earth's geochemistry. If you can recapitulate the story a little bit and then... Yeah. I mean, I'll tell you how I got there first because I started out working on mitochondria. And that took me into the evolution of eukaryotes. Eukaryotes acquire these endosymbionts that become mitochondria and they change the potential of evolution. It doesn't change everything immediately, but it changes where the endpoints can be. And it allows the evolution of these large complex cells and eventually multicellular organisms and us. So what are mitochondria actually doing? Well, what they're actually doing is respiration. They're generating energy for cells. They're doing plenty of other things as well. But the main thing we can think about is they're the energy producers. And they're derived from bacteria and bacteria produce their energy in exactly the same way. They're generating energy by generating an electrical charge on the membrane. And that charge, it's small, but the membrane's really thin. So the charge is about 150 to 200 millivolts. But the membrane is 5 nanometers in thickness. So that's 5 millionths of a millimeter. So if you shrank yourself down to the size of a molecule and stood next to that membrane, you would experience 30 million volts per meter, which is equivalent to a bolt of lightning. So that's the strength of the force of the voltage across the membrane, which is colossal. And it's generated by really sophisticated proteins that pump protons across the membrane. And then it's ATP synthase, which is again pretty much universal. And it's a rotating nanomotor that sits in the membrane. This is a colossally complex, interesting machinery. And it's universally conserved. It's as conserved as say a ribosome, the protein building factories. It's pretty much everywhere across life. So you wonder, how on earth did life come to be that way? And if it's conserved universally across life, it looks like it goes right back to the common ancestors of all the cells. And so there's the question, how did it arise in the first place? And that was actually for me tremendously thrilling because it's a way in as a researcher to the origin of life. It says, how did these energy generating systems arise in the first place? And my way in was really, the gates were opened by Bill Martin and Mike Russell, who around the early 2000s were publishing some amazing papers together, where they were saying that in this deep sea hydrothermal vent, rather than it being like a black smoker with a chimney with smoke belching out of the top, it's like a mineralised sponge with lots of pores that are cell-like in their structure. And you've got an acidic early ocean and you've got alkaline fluids coming out of these. And you've got mixing going on in this whole system. And so you could at least imagine that you've got a pore in here, which is a bit like a cell in terms of its size and its shape. And on the outside, you've got acid ocean waters percolating in. And on the inside, you've got these hydrothermal fluids. So you've got a barrier, you've got an inside and an outside, and you've got more protons outside coming in, potentially driving work. So it's very much like a cell is structured. And the other thing is, what are these minerals? You've got these mineralised sponge with pores with minerals. Well, the minerals we think on the early earth would have been a lot of metals in there. So things like iron sulfide or nickel sulfides and things like that. Now, the reason that's important is that what plant cells do, but also what autotrophic bacteria do, is they take CO2 and they take hydrogen and they react them together to basically make all the building blocks of life. Now, plants do, they plants get the hydrogen from water, H2O. They take the H2 out of water and throw away the oxygen and that collects in the atmosphere. But what bacteria very often do is they've got hydrogen bubbling out of a hydrothermal vent. They just take the hydrogen gas and they react it with CO2 and they make all the building blocks of life. So what are the enzymes that they use to do that? Well, they're very often using these same metals that you would have found in the early oceans, nickel and iron and so on. And how are they powering the reaction between hydrogen and CO2? Well, they're using this membrane potential, the electrical potential, the difference in protons between the outside and the inside to drive that work. So effectively to power the reaction between hydrogen and CO2 is to make organics and drive growth. So this was all kind of in place before I came along. This was coming from Mike Russell and Bill Martin. And the details are very uncertain and whether or not you can really drive any biochemistry that way is very uncertain. But it's a thrilling idea because you've got a continuity between a geological environment and cells as we know them. And if it did emerge that way, then it would say, well, here's why bacteria have got this charge on their membrane because it was there in a hydrothermal vent from the beginning. It always powered work from the very beginning. And that's why in the end, an endosymbiosis that gives rise to eukaryotes would allow this kind of free you from the constraints of generating a charge on a membrane. Now you internalize that in eukaryotes and now you're free to become larger and more complex. So you've gone from thinking about a puzzle about why eukaryotes are special to thinking about planetary systems and thinking about the origin of life and what are the forces that are going to give rise to life and how would that constrain life and would we see the same things on other planets or something different? What are the fundamental reasons that it works this way? So it becomes astrobiology really. And it's a thrilling change of perspective to come from my own background was to do with mitochondrial biology, actually an organ transplantation once upon a time. And spinning on a pinhead, you end up working on the origin of life. It's fantastic. Yeah, I mean, it's so fascinating. So just to recapitulate for my own understanding of the audiences, let's just break down what we have here. So you have the analog of a cell in these pores. You have something which concentrates the buildup of these organics so that they don't just all diffuse in some big primordial soup. And so this is why you think like some primordial lake is not where this happened. It had to be concentrated in some entity. Then you've got a chemoosmotic gradient, a proton gradient, which drives work. And specifically, it favors the fixation of carbon dioxide to drive the reaction with hydrogen gas to make organics. And then you've got along this membrane, you've got catalysts, which are basically early enzymes. So you've got enzymes, you've got the cell, you've got the proton gradient. And then the story is basically that you make very simple organics with CO2 and H2. And then those simple organics are then recatalyzed to make more and more complex organics and basically TLDR metabolism. And fatty acids and cleotides, everything else. Yeah, that's basically it. Yeah. So what do you get if you react hydrogen and CO2? What you get are what are called Krebs cycle intermediates, a carboxylic acid, small molecules made only of carbon, hydrogen and oxygen with this organic acid group at the end, which can be two, three, four, five carbon units in the chain. And this is your basic building blocks. You add on ammonia to this and you get an amino acid. You add more hydrogen on and you're going to get a sugar. You react amino acids with sugars and you're going to get nucleotides. You know, there's lots of steps along here, but this is the basic kind of starting point for all of biosynthesis in biochemistry today. Then if you make fatty acids, they will sort of spontaneously because of the hydrophilic nature of their different sides. They will spontaneously form the membrane if they're created. So I say, you know, Krebs cycle intermediates are short chain carboxylic acids. The fatty acids is long chain, you know, you're 10, 12, 15 carbons in the chain instead of four or five. And they will spontaneously, not just alone usually, but if you've got other long chain hydrocarbons mixed up with them, then you will form a bilayer membrane spontaneously and we've done this in the lab. And it's pretty robust to, you know, you can you can make these things at 70 degrees, 90 degrees, centigrade across a range of pH from around about pH seven up to about pH 12. And in the presence of ions like calcium and magnesium and other salts and so on. So you can and you make a vesicle with a bilayer membrane around it, which is basically the same as a cell membrane. Yeah. They're amazingly dynamic things. They're always fusing with each other and breaking apart, kind of fishing, separating into two or three. And, you know, they're very, very dynamic things under a microscope. You could have had imagined that life is this like there's like Frankenstein like moment where things zaps alive. And then now you've got life. I hate that. Just an idea. But go on. Yeah. So that's the alternative where like the bulk of lightning makes these organics, etc. And here you have this story where every life form you see is continuous with something, which is continuous with something. Yes. Which is eventually just continuous with entirely spontaneous chemical reactions. And so that's just a very interesting way to think about the evolution of life. One thing, you know, a cell is effectively it's reduced inside, which is to say it's got electrons inside. And outside it's relatively oxidized. And outside it's rather pump all these protons out. It's acidic outside. It's alkaline inside. It's reduced inside. That's like the earth. The earth is all the electrons are in the iron in the core and the mantle of the earth. Relatively alkaline inside. That's why the alkaline fluid is in these vents. The outside is relatively oxidized. You've got all the CO2 in the oceans. So the cells are a kind of little battery with the same structure as the earth. And if you look in a hydrothermal system, the cell membranes around the earth, the crust of the earth is like the membrane and where you have traffic going between the inside and the outside is the hydrothermal systems. And the pores in these hydrothermal systems are little cell-like entities as well. So you keep having on multiple scales this same kind of... So the idea that the earth is a giant battery that produces little living cells, mini batteries. It's a rather beautiful idea. I mean, you can't allow yourself to get too hung up on a metaphor, but it's a beautiful image. Yeah, 100%. So just basically you've got earth as this sort of like giant cell and then this like from the hydrothermal vent, this little bubble pops out. Bubbling off mini copies of the earth. Yeah, that's such a fascinating theory. So the thing I want to understand is what part of life the way it works now is contingent and which would you expect to be shared even if you found life on another planet? So it sounds like you're saying, look, carbon, the chemical profile, this is just the obvious candidate to build life on top of. Proton gradients, is there another way you could build this sort of chemo's amount of gradients that drive work? Right? Like we have other chemistry for batteries. Principle, yes, you could use sodium ions instead of protons, but it's very different. Because if you're starting with carbon dioxide, and the first thing to realise about that is carbon is extremely good at the chemistry that it does. It's forming very strong bonds with all kinds of molecules. So you can form complex, interesting molecules and you're effectively, I think of CO2 as a kind of a Lego brick that you pluck out of the air and you bind it onto something. You can build things one brick at a time that way. And then you can build really interesting, complex molecules like DNA and RNA from doing that. You can't do that with silicon. So you can, you know, with intelligent design, you can make really complex AI robots, whatever it may be. But the whole thing requires humans to do it. But if you're thinking about how would life start on a planet where there aren't, you know, there isn't an intelligent designer who's putting it all together, you need molecules that can do that kind of chemistry and CO2 is an outstanding example. And water is everywhere. You know, hydrogen, oxygen, these are all elements that are very, very common in the universe. So you're going to keep on getting this same kind of chemistry everywhere. We know that there are from discoveries of exoplanets in recent years. If you extrapolate how many we've not seen yet, the number of wet, rocky planets or moons in, say, the Milky Way, is probably in the order of 20, 30, 40 billion of them. Where for action of them would you expect to have a non-Eukaryotic life? I mean, I'll take a punt here. I would expect that if you've got these same kind of conditions on a wet, rocky planet, you're going to be producing these same kind of vents because it's the same chemistry that's going to happen. You're going to be dealing with hydrogen. Even the vents are not contingent in your view. No, the vents are produced by a mineral called olivine, which again is really common in interstellar dust. And the mantle of the earth is made of this mineral called olivine. And it will react with water. When it reacts with water, it's slow if you were to put a lump of olivine in a bucket of water. You're not on your lot C very much, but you're dealing with the pressures down at the bottom of the ocean and warmer temperatures and so on. You're producing bucket loads of hydrogen gas in alkaline fluids. So that's what these hydrothermal vents are. So any wet, rocky planet will produce these vents. There's evidence for them on Mars from the early days of Mars when there were oceans on Mars. There's evidence now on the icy moons Enceladus and Europa. This is going on in our own solar system right now. Right. So if there's 20, 30 billion earth-like planets, which have presumably some big fraction of them have these vents, if they all have these rock formations, is there a view that a notable fraction of them have life that also operates with their... I mean, my view would be yes. Any wet, rocky planet would have a decent... Yes. And if you're starting with CO2 and hydrogen, what I'm saying is that metabolism is thermodynamically favored chemistry. This same chemistry will just go on happening because if you react hydrogen with CO2 and with another CO2 molecule, the parts of the molecules that are going to react are quite predictable. Sorry, this is a naive question, but what is the reason to think that there's no alternative chemistry which leads to alternative metabolisms? Perhaps under very different conditions you could end up with it, but if you've got essentially similar conditions, and the other thing is we know that even with very different chemistries, you end up with basically a similar subset of molecules. So from the kind of organics you see on meteorites, utterly different chemistry going on. You're dealing with helium radicals, but you're still seeing amino acids and you're still seeing nuclear bases and so on. So there's a tendency, these are molecules which are basically stable and tend to be formed under a wide range of conditions. So 20 billion earth-like planets with water and these rocks in... Not necessarily earth-like, but wet and rocky. If you just had to pull a number out of nowhere and just say, this fraction have nucleotides, what fraction would you say? I would say a substantial fraction. Like over 1%? Yes. I would imagine 50% or something. Really? I mean, you say pull a number out of a hat, I'm doing exactly what you're saying. I'm pulling a number out of a hat. I think this kind of chemistry is going to give you the same nucleotides repeatedly. Again, I know you're just... We're just chatting here, but according to this story, pretty sophisticated organics are extremely abundant through the universe, right? That's not to say they're collecting in a notion at a high concentration. What you have in a hydrothermal vent is a continuous through-flow and within pockets within this vent, within the pores within this vent, bound to the walls pretty much, within cells. Within a vent system, you could have very high concentrations of things ultimately, but not necessarily in the oceans or in the atmosphere or anywhere else. Yeah. I guess you could have prokaryotes then who did just take over... I mean, we did have this, right? We kind of proliferated through the oceans and changed the composition of the atmosphere. So, I mean, not just the atmosphere, but also the whole of geology. Hundreds of minerals are basically the product of life. So, your view is that the fundamental bottleneck to that, if you carry out sort of the fundamental bottleneck, you can go from geochemistry to early life is easy, early life to just changing the entire composition of the earth through early prokaryotes is easy. And if those two things are easy, and then you've got 10 billion planets in the Milky Way that are going to the middle step, does that imply that there's like on the order of 10 billion planets? I mean, I think to get to nucleotides, from nucleotides, you've then got to get to RNA and DNA and ribosomes and molecular machines. So, there's a long gap there as well. So, just having nucleotides, that's a kind of... It's a requirement to get any further. I see. And what fraction would you... Again, you had to pull a number out of the air. Well, a lower fraction, obviously. Right. Over a billion? I mean, I would like to be, let's say, optimistic. I would like to think that these processes are going to drive life into existence on a substantial proportion of these planets, or moons. And I would expect that there would be similarities in the genetic code. I would expect that a lot of metabolism would look similar. I would expect that they would have a membrane potential driving the kind of work, because it's fun. If you're dealing with CO2 and hydrogen, you've got this same fundamental problem. How do you make them react? Yeah. But so, basically, there's hundreds of millions of planets in the Milky Way, which presumably have something like ribosomes and DNA and... To get to RNA, yes. That's my own thinking. I think we're talking about serious planetary driving forces, driving fairly deterministic chemistry that's going to give you the same kind of intermediates, which are going to have the same kind of chemistry, the same kind of feedback. So they're going to push things into similar directions. Now, the further from CO2 fixation towards genetics, you get the less similarity that it's going to be. So this happens to be the 101st episode of the Thorecache podcast. And obviously, that doesn't include clips and shorts and the other content that we put out on the channel. So at this point, it's gotten a bit tough to keep track of all of this data. But since Google Sheets has Gemini built in, I was able to just throw our channel data into a sheet and ask Gemini whatever questions that I wanted answered. For example, it's hard to evaluate patterns for our full episodes, given that some of the clips were in the same channel. So I just asked Gemini to make a new column called content type. Anything that came up with a formula to do this, to distinguish between the two different types of content. Another example, I was curious to see how many episodes we had done about different topics. And I didn't have any historical tags that I made for this, but I was just able to ask Gemini to use each episode's description to assign topics and then sum everything together to get a breakdown by category. Gemini lets you turn these big chunks of unstructured text into the type of data that you can actually sum and count and then use as the basis of different formulas. Gemini in Sheets is now available for Google Workspace users. I found it helpful for my podcast and you might find it helpful as well. All right, back to Nick. This is not my inclination, but if I was a sort of God fearing person, I would hear this and I'd be like, wow, this is a sort of vindication of intelligent design where the laws of the universe just favor this chemistry, which leads to life, at least according to this story, so strongly that it's a heart of resistance formation. Here's what you mean by that interpretation. Yes, I mean, I agree with you. I find it a little almost disturbing. And I have to say, I'm not a religious person either, but I'm neither am I... I don't object to religion. I'm not a militant atheist at all. I like the fact that religions have searched for meaning, searched for origins, and I have some kind of fellow feeling with that search. And I suppose truth in some sense, with a small team in my own case. But insofar as this is consistent with the idea of a God, the God would be a deist God that effectively set the laws of the universe in motion and they're left to play out. Now, this is kind of Einstein's God, really. In terms of what most people understand by God, I think most people look for comforting God and are looking for something which is meaningful to them and who's been involved in humanity. And so this is a very cold kind of goddess thermodynamics, sets the laws of the universe in motion, reproducibly gives rise to the same kinds of things. Yes, you could interpret it in a kind of theistic, natural theistic way, but I don't think many people would get that much comfort or meaning from that way of seeing it. Okay, so very basic question, but if life is not only abundant, but almost inevitable in all these rocky planets, then the bottleneck to not seeing aliens everywhere, presumably, is eukaryotes, which lead to complexity. Yeah, well, there's probably more than one bottleneck, but eukaryotes is in my own mind, the big one, yes. So it would have to be the case that out of billions of potential planets that could give rise to eukaryotes, only on earth does this chance occurrence happen. I wouldn't argue that. Okay. I mean, only on earth, no, I don't think so. But is there, I suppose what I would dig my heels in a little bit is there's a kind of Carl Sagan cosmological view that once you've got, we're talking about the inevitability almost of life arising according to these laws of chemistry and thermodynamics and so on, and you get life. And then is it going to roll on and inevitably give rise to complex life and to humans and to intelligence? It's a beautiful thought. It would be lovely if that was how the universe worked. But what we know on earth is that you have two billion years of stasis where you, and then this apparently singular event where eukaryotes arose, and then another long gap before you get to animals. And then if you roll back the clock two million years, there aren't any humans around either. So we're just icing. Why is supposedly this hard to have this success windows and view attic event? Well, there's multiple reasons. I mean, one of them is that prokaryotes, let me say archaea and bacteria, well, they're pretty small things. So just having another cell inside you is already a difficult thing to do. It's not. And there are no, there are occasional phagocytes in bacteria that can angle for the cells, but it's pretty uncommon. And once you've got these cells inside you, that may have happened scores of occasions. There's some tentative evidence that suggests that archaea, I mean, there's one nice example where the halo archaea seemed to have acquired more than a thousand bacterial genes from the same source, implying perhaps they had got an endosymbion that they then lost later on. So the question is, how often would it go wrong? And you lose your endosymbion? And I guess that would be the more likely outcome is that you pick up a bunch of genes and you lose your endosymbion. It simply doesn't work out. So it's hard to know exactly what are all the bottlenecks here, but there's been some modeling work done to see, okay, you get an endosymbion. Are you going to grow faster if you don't have the endosymbion or you do have the endosymbion? And if you're the endosymbion, are you going to grow faster if you're outside or if you're inside? And under most conditions that these people have looked out there at a Santa Fe, the answer is, well, you do better if you're not part of the symbiosis, only under certain conditions will you do better. So predictably, the end point is it doesn't work. I guess given how many bacteria in archaea there are, you know, through Earth history, there's like trillion, trillion, trillion of these running around. And there's many situations in which there was an endosymbiosis. And in only one case it succeeded. So the odds would have to just be like remark, which had to be like extremely much in the top. There is a vivid way of seeing it. We know what bacteria in archaea look like. And you know, people have been studying these things and finding new examples. And there's a group discovered 10 years ago called the Asgard archaea. And they're relatively eukaryotic like, which is to say, they've got proteins in there and genes that are pretty similar to eukaryotic ones. And they're interesting cells. They've got long processes and they can possibly, they can move vesicles around inside them. So they're doing a few eukaryotic things. But if you look at their internal structure, it's not very complex. It's nothing like a eukaryotic cell. And if you look at their genome size, it's basically a standard prokaryotic genome size, you're talking four, five thousand genes. So these are not eukaryotic by any stretch of the imagination. And then you look at a eukaryotic cell, and I said this at the beginning, you look at a plant cell or an animal cell or a fungal cell or an alga or a meber under a microscope, and they've all got the same stuff. And it's kind of weird. Why would a single celled alga living in the ocean have all the same kit that one of my kidney cells has? Well, the easiest way to understand that is to say, well, it wasn't adaptation to an external environment to a way of life. It was adaptation to an internal selection pressure. If you think about it in terms of a kind of a battle between the host cell and the endosymbion for finding a way of living together, you can argue for the nucleus arising that there's all kinds of genetic parasites coming out of the mitochondria, forcing you to do something to protect your own genome. So you can construct a lot of this history of eukaryogenesis, it's called. So you start with simple cells with a cell inside, and you end up with the same cell structure everywhere, all these endomembrane systems and everything else. Okay, so I guess the broader thing we're trying to figure out here is if this story is true, there's life everywhere, but eukaryotes giving rise to intelligent life, which is about to go to explore the cosmos, is as far as we can tell happening only in one place in our life cone. So why is that? And now you could say, well, look, the bottleneck is the eukaryote, and it just like very hard to get a successful endosymbiosis, which then continues over time. But what is the fundamental problem this is solving? What's solving the problem that you know, large genomes. Exactly. So to have a multicellular organism where effectively you're deriving from a single cell, and that restricts the chances of effectively all the cells having a fight. There's plenty of examples of multicellular slime molds, for example, where the cells come together, and they can form structures like a stalk, for example, which loosens spores into the environment, but they basically fight because they're genetically different to each other. So you start with a single cell and you develop, so there's less genetic fighting going on between the cells and there would be a thing to come together. But that means then if you want to have complex functions, if you want to have a liver doing one thing and kidney is doing something else and the brain doing something else, all of the cells have to have the same genes, but you express this lot in the liver and that lot in the brain. So you must have a large genome. The only way you can have a large genome is by having mitochondria and having a eukaryotic cell. There are no examples of this level of sophistication of a multicellular bacterium. That's quite interesting that the reason you need a large genome is actually just to put all your eggs in one basket so that every cell in the body feels incentivized to make the sort of restrict the amount of fighting. Yeah, yeah. They're all inside best make the sort of life continue. But the thing I was getting at is like, okay, the eukaryotic cell is having large genome and it's allowing the cell to get much bigger. Why are we so confident that this is the only way this problem could have been solved? It just seems like if there's billions of planets which have gotten to the precursor stage here, none of them can find an alternative solution to mitochondria for just letting themselves get bigger. That is belief. Yeah, no way you're coming from. It kind of makes me wonder why there were like, because we've only observed one rate is solved the solution. We're sort of assuming that there must be only one way to solve the problem, whereas the problem itself doesn't seem like, okay, you just want like a smaller copy of a genome sitting next to the site of respiration, right? That's like the basic problem. Like there's no other way to solve that. Yeah, well, maybe there is, but I think we have to look at the probability of certain things happening. So if you want to have a giant bacterium, there are a bunch of giant bacteria around on earth. There's at least six or seven different quite unrelated species that have evolved giant size. And the thing that they all have in common is they have what's called extreme polyploidy, which is to say they have literally tens of thousands of copies of their complete genome. Right. So maybe a small genome, but we're talking a three megabase genome, so kind of 3000 genes in it. And you've got tens of thousands of copies. Sometimes, you know, the very largest one have, you know, 700 or 800,000 copies of their complete genome. The energy requirements for copying or expressing all of those genomes are colossal. What we have with an endosymbiosis, we still have extreme polyploidy, but we've whittled away all the genes that you don't need. So a symbiosis is based on effectively complementarity. That you've got a symbion that's doing something for the host cell and the host cell is taking something or giving something back to the endosymbiosis. So it's a kind of a relationship which is based on mutual needs. One of them becomes much smaller, and that allows the other one to become much larger. So a symbiosis will do it. Now, there could be multiple ways of having a symbiosis, but there's no examples on it. There's all of these examples of very large bacteria, and they all have extreme polyploidy. None of them have come up with a complex trafficking network where you effectively take things in and you ship it over there. There's just not enough genetic space to do that. But just to make sure I understood the feature request correctly, it's basically like you want a smaller copy of the genome that is only relevant to respiration sitting across the entire membrane and many copies of it sitting across the entire membrane. I guess it seems hard for me to- You're incredulous that this same thing will be repeated on the billions of planets. Because if there was another way to solve it, then what you would expect is that as soon as you get to the stage of prokaryotes that have other niches that they could colonize, if only they could drive towards complexity, this would somehow be solved. And then you'd have e-karyotes, dot, dot, dot, intelligence. I mean, a couple of things I'd say. Number one, there's a thing called Orgel's second rule, which is that evolution is cleverer than you are. So, yeah, of course, I cannot say that there's no other way that it could possibly happen. But it's also hand-waving to say, oh, evolution's so clever, the universe is so big, there's got to be another way that it can happen. Okay, engage your brain and tell me is how it's going to work. Because I cannot say it's the only way it could possibly happen. But what I've said is that wet rocky planets are common there everywhere. You're going to have these same sub-pentanizing things. You're going to have CO2. You're going to have a similar biochemist. You're going to give rise to bacterial cells that have got a charge on their membrane. That constrains them. And every example that we know on Earth where they seem to have got bigger, there's a constraint that probably, probabilistically happens every time. They always end up with extreme polyploidy and they don't end up with sophisticated transport networks. So, that's not to say it's got to happen that way every time. Maybe there's a way around it, but it's not an easy way around it because they haven't done it regularly on Earth. They haven't done it at all on Earth. The only occasion where it worked on Earth was where they came up with Eukaryotes. That's not to say it's the only possible way of doing it. But if you try and dissect what are the alternatives, I can't think of any alternatives. Okay, I'm limited. I can't think of any. But if you think there are some, then you tell me what they might be and you test them. So, there's a level and I get this a lot and it's fair enough because if I assert to you that life's going to be this way somewhere else in the universe and I grew up watching Star Wars and Star Trek and reading Hitchhiker's Guide to the Galaxy, I love the idea that the universe is full of all kinds of stuff as much as anybody. So, I don't like my position of saying, actually, it's quite limited and you're going to see the same kind of things elsewhere. It's not a position that I dreamt of having or anything. It's just a position that I've been forced into by everything that I've learned about life on Earth. Now, maybe I'm just wrong, but I suppose if you simply say, you're limited by your imagination, you're wrong because you just can't think of it. Well, that's not science anymore. Now, we're talking about just imagination and hand waving, but it's not science. So, I'm giving reasons why, probabilistically, it's going to be this way. What I would say is if you've got a thousand planets with life on, maybe life is going to be the same way 999 out of a thousand times because it's going to be carbon-based, it's going to be water, it's going to be cells, it's going to be charges, it's going to be hydrogen and CO2, and you're going to face the same constraints. But maybe one other occasion, it's something completely different than I never thought of under very different conditions. But there's a kind of a probabilistic thing that carbon is so common, water is so common, you are going to keep seeing the same constraints again and again. If it's the case that a significant fraction of rocky planets should have at least organics and cells and so forth, it feels like we should be able to learn pretty soon whether this story is kind of correct, right? Because obviously, if that part ends up being true and also we don't see eukaryotes elsewhere, then the whole picture is lent a lot more credence. But like, I don't know, are we about to go to a couple moons and see if we can find some organics there and so forth? It may take us a while, but yeah, we already know that there are organics in, so on Enceladus, for example, one of the moons of Saturn when Cassini flew by two years ago, there are kind of plumes coming through cracks in the ice of water, but with organics dissolved in the water. And hydrogen and organic molecules, pH is around about eight or nine or something, so it implies that underneath that frozen surface, which people say is about five kilometers thick, underneath that there's a liquid ocean, underneath that there are hydrothermal systems producing alkaline fluids, which have made the oceans alkaline and it's the same kind of chemistry going on. So we know there's organics in these plumes, we don't know what's under the ice. I do think that the incentives to go to these places and drill into the ice and have a look will get the better of us. There will always be people saying, oh, we shouldn't introduce bacteria from our own system into there. I would have said bacteria from the earth would probably survive extremely well in a place like Enceladus, so it would be lovely to know. Yes, and I'm all in favor really of exploration. Labelbox has this massive network of subject matter experts who they call aligners to help them generate data for training and evaluating frontier models. In order to help her for this episode, I asked Labelbox to connect me with one of their chemistry experts for a quick tutoring session. I got to chat with Neil, who's a researcher that's currently working on chemistry ML models. So how did the first cell division happen? I suppose, and this is just me speculating here, but in these hydrothermal ventures, you've got water flowing down, you've got hydrogen bubbling up, and this water's not just going to be flowing in a completely linear fashion, there's going to be some shear, there's going to be some side to side movement. So I suppose perhaps you could begin to consider shearing some of these cells splitting them. I remember him saying that the first version of division might have been like membranes naturally will split the same way like a bubble will split if it gets too big. Yes. Neil quizzed me on my understanding of redox chemistry, the same way that he interrogates models to make sure that they are developing a non-superficial understanding of all the scientific topics. Labelbox has experts like Neil in a bunch of different domains from chemistry, obviously, to math, coding, even creative fields. Learn more at labelbox.com slash dworkesh. Help me understand how replicators arise in this world because if you've got these independent pores and they're each individually accumulating their own organics through these spontaneous processes, but initially at least there's no shared inheritance. It's not like if there's a very successful pore, it then causes their own pores to exactly like it. I think what I would call proto cells inside these pores. So you think that the organics that you're making are self-organizing. A fatty acid bilayer membrane will form. What you really need for positive feedbacks is to be making the organics inside this proto cell and for that proto cell to grow and to make a copy of itself. Now, it will make a copy of itself because the chemistry, if the chemistry is deterministic, it says this is the chemistry you're going to get. If you drive that chemistry through by the pressure of hydrogen in the system, you're just going to make twice as many molecules and they're going to divide into and now you've got two proto cells. So there's a form of heredity to that, which is they get the same molecules because that's effectively all you're allowed to do. And sorry, what's happening is that so that the thing buds off and then like settles into another pore? Yes. I see. Okay, got it. And this happens like relatively early in this process. Yes. And so the rise of replicators happens relatively early. I would hesitate to use the word replicator here. These are growing, I would say growing proto cells that are effectively making more of themselves. You could call it a replicator, but I would prefer to use the word replicator for something more like RNA, which would be the conventional term for a replicator, where you are literally replicating the exact sequence of this RNA. And so at what point do we get to the gene's eye point of view where the gene is the coherent unit of replication? Yeah, as soon as the better, which is to say, if you've got this deterministic chemistry, which is going to drive growth and make more cells, it's also a dead end. You can't do anything else. You're entirely dependent on the environment. You can't kind of evolve into something more complex. To some extent, you can, but basically you're always going to get the same in the same environment will always give you the same thing. Soon as you start introducing random bits of RNA into this, then you've got what you call evolvability, which is to say you can begin to resist the environment. You can begin to do things which are not just dictated by the environment. You can evolve and change and leave the vents in the end and do other things. So as soon as you've got genes, you've got the potential to do almost anything. If you've got naked bits of RNA, what tends to happen is they're selected for their replication speed. They just go on making copies of themselves. They don't become more complex. They don't start encoding metabolism. They just go on copying themselves and it's a dead end. If you're trapping them inside growing protocells, then effectively they're sharing the same fate. And if some of them are capable of making that protocell grow faster, then they will get more copies of themselves because they're inside this protocell. The protocell is growing faster. It makes a copy of itself and it's still associated. So you've got actually selection as we know it in cells today where the replicator of the genes, but the system which is being reproduced is the cell. So your mitochondria first viewpoint helps explain why there's two sexes. Maybe you can recapitulate that argument, but I'm curious if there was a world of prokaryotes had evolved sex, do you think that they would have likely evolved with just one sex? I'm going to unpack that a little bit because so what have mitochondria got to do with sex? So what they have to do with sexes is effectively the female sex and this goes even for single cells things that don't have any obvious differences between gametes, which is to say they don't have oocytes and sperm or anything that they produce little motile gametes that look more like sperm than anything else. Both sexes would do that. But by definition, the female sex passes on the mitochondria and the male does not. And that's an approximation. It's not always true. There's exceptions to that rule, but it's a kind of a rule of thumb in biology that the females pass on at the mitochondrial DNA. So why would that happen? With sex, what you're doing is you're increasing the variance in the nuclear genome and you're subjecting that to selection and the winners are coming through that and everything which is worse than it would have been gets eliminated by selection. So you're effectively, you're increasing variance on nuclear genes, the genomes and then selecting for what works. With the mitochondria, they're not doing, they're not, they're passing on asexually down the generations. There's a very small genome, but there's multiple copies of it. And so the question is, well, how do you keep that clean? How do you prevent that from degrading and degenerating over time? Because if you've got, let's say if you've got 100 copies of mitochondrial DNA and two of them acquire mutations, but you've still got 98 which are doing their job fine, what's the penalty for those two mutations? It's not very much. You'll hardly notice them. So now you acquire another couple of mutations and you can degenerate over time. It's a process called Muller's Ratchet, but it's basically, these mutations are kind of somewhat screened from selection by being compensated for by clean copies that you have other copies. So how do you get rid of those mutations that are building up over time? Well, the answer is you, what you need to do is increase variants of mitochondrial genes. What you need to do is effectively segregate into these cells all the mutants and into those ones all the wild type ones. So you can do that by multiple rounds of cell division, but it helps if you've got two sexes that effectively only one sex passes on the mitochondria. So you're already sampling. So you're already increasing the variants and you're increasing visibility to selection. So you're basically, it's about, it's about the quality of mitochondrial genes. Can you help me understand why it's a case that uniparent or inheritance of mitochondria helps increase variants? Because so, we're talking about variants between cells. So if you imagine that you have a hundred cells and you, they all come from the same parent, let's say, and you randomly give each cell, if you give all the mitochondria that you have kind of straight into a single cell without changing any of the ratios there, then it's exactly the same as you are. It's fully clonal. But if you give, if you take a small subsection of those and you say you take a random 10%, you give 10% of this one, a random 10% to that one, a random 10% to this one, randomly, this cell is going to happen to have got all the good copies. And this cell is going to happen to have got all the bad copies. And now you subject these hundred cells to selection and say, how are you doing? And the one that got all the good copies, that does well, that gets on. So what you're doing is increasing the variants between this kind of next generation of cells. So the ones that got all the mutants, they get hit. And the ones that got all the clean copies, they do all right. The parent had got both the mutations and the clean copies, but how do you distinguish between them? Well, so it's about sampling, basically. And uniparental inheritance, which is to say, it's a form of sampling, you're taking the mitochondria only for one of the two parents. So you're not mixing up mutations that both parents had, you're kind of taking a subset. So you're always increasing variants between the daughter cells and uniparental inheritance is basically giving you a subset. So then the question of why there's two sexes, well, we explain why there's this evolutionary need for only one parent to pass on the mitochondria. So there's at least two niches, one is passed on to mitochondria, one is don't pass on to mitochondria. So once you've established those two, then you can ask the question, why aren't there more than two sexes? And then you can just say, well, there would just be a repetitive one of these two. These are the two fundamental. I mean, it's more complex. But I mean, the thing about two sexes is, you could say it's the worst of all possible worlds. So again, if you kind of, let's take it away from humans so we can be dispassionate about it. You've got these single cells critters swimming around, and they're all producing gametes. And the gametes look the same as each other. And they'll fuse in the same way as sex and they'll line up the chromosomes. They basically do exactly the same thing that we do, but on a single cell scale. But having two sexes means that you can only mate with 50% of the population. The other 50% is the same sex as you and it's not going to accept your gametes. If you had three sexes or four sexes, then you'd be able to mate with a larger proportion of the population. And some fungi, they don't really have, they still have two sexes, but they have mating types as well. And you can have 27,000 mating types in some fungi, which is all about outbreeding. So you can mate with just about anything, but you still... You've been in some college campuses today, you know, we're probably getting some portion of that. It's becoming fungal. Yes. So two sexes then in that sense is the worst of all possible worlds you can only mate with. If you had only one sex, if everyone was at hermaphrodite, you could make with everybody. And if you had three sexes, you could mate with two thirds of the population and so on. So why two? Well, this fundamental difference that one is passing on the mitochondria and the other is not. Beyond that, if you've got multiple mating types, you still have one passes on the mitochondria and the other one doesn't. So in these fungi that have all of these mating types, there's a kind of a pecking order that the dominant one will pass on the mitochondria and the less dominant one doesn't pass on the mitochondria. So you end up with really complex systems that you can imagine that it's pretty hard to enforce this. It's pretty... Stuff can go wrong. The more complex the system is, the more it will go wrong. So I guess in that sense, why do you end up with two sexes? It's partly minimization of error. You have this really interesting discussion about how this not only explains why there's two sexes, but the particular differences in why eggs and sperm develop the way they do, why there's different amounts of replications before they are mature, et cetera. I wonder if we can recapitulate that. So as soon as you've got this fundamental difference, even in single-celled critters, that one of the sexes passes on the mitochondria and the other one doesn't. So males do not pass on their mitochondria. And then this is beginning to explain differences in multicellular organisms between the sexes, between the nature of the germline. So in some sense, male men do not really have a germline in the sense that the women have a germline. So in the female germline, you make these oocytes and you put them on ice, effectively. You look after them. You switch them off as much as you can. You try and protect them from mutations. You mollycoddle them, effectively. Whereas men just mass produce sperm full of mutations. I mean, there's a lovely phrase from James Crowe, who's a geneticist who said there's no greater genetic health hazard in the population than fertile old men. So why would you go on mass producing sperm all the time? Well, part of it is you don't have to pass on the mitochondria. So you're freeing yourself up to mass-produced sperm and then you've got the same thing as that. Some of them are full of mutations, but a lot of them aren't. You mass produce them and the chances are it's going to work out okay. Because the ones that can swim best, for example, are the ones that are more likely to. I think that's not strictly true, but you can imagine it along those lines. But in the case of the oocytes, in the case of the egg cells, you're passing on those mitochondria. You don't want to be accumulating mutations in that mitochondria DNA. You want to switch them off as much as possible, keep them on ice as much as possible. So very much the differences between how the sexes end up kind of becoming different to each other boils down to what are the constraints on your reproductive system. Okay, so let's talk about the Y chromosome, which is also not recombined. Now, just the same way that female egg cells try to minimize the amount of duplications in order to preserve the quality of the mitochondrial DNA and prevent errors. Why isn't the same thing happened with the Y chromosome? Why shouldn't all this sperm duplication be the result thing and all kinds of errors in the Y chromosome? Well, it does. And the Y chromosome is degenerate. I'm going to read that the title. Yeah, but there are some things that have lost their Y chromosome altogether. And they still have sexes because it's not strictly dependent on the Y chromosome. Again, if you look at what determines sexes across the whole canvas of evolution, it's kind of weird because amphibians, for example, have temperature-dependent sex determination. So males would develop at a higher temperature than females or sometimes it's the other way around. Birds have different sex chromosomes to mammals, for example. So sex chromosomes have evolved on multiple different occasions. What's the Y chromosome doing? Well, the Y chromosome is basically encoding a growth factor and that growth factor switches on other growth factors. And the earliest difference that you could tell between the two sexes in embryonic development is not the activation of the Y chromosome and the SRY gene. It's actually the growth rate. And there was a woman at UCL where I am called Ursula Mitfork who spent her career, she had about 15 nature papers in the 1960s. She worked on these kind of questions. And she saw the growth rate as a common denominator that the Y chromosome is basically saying grow fast. Why would he grow fast? Well, in part, you don't have any constraints on trashing your own mitochondria because you're not passing them on. So you can grow fast and be an advantage to growing fast. If you're a male, you're going to get the resources you grow faster. If you're a female, you don't want to grow so fast because you need to effectively cordon off your germline to preserve the oasites for the next generation until you've done that. You don't want to trash your mitochondria. So you've got a delay phase before you can start growing fast. Interesting. Is this a woman a little longer? Ursula Mitfork argued that that was exactly the case. We don't know for a fact that's true, but it's quite common that females live longer than males, not just in humans, but in you know, in Drosophila as well, they do usually. Suppose that evolution on humans just continued naturally for the next billion years and you know, we didn't have AGI and the human gene editing, etc. Is the equilibrium that you'd anticipate that the Y chromosome would then just fade away altogether and there'd be some other way of determining sex and sex dependent characteristics? Well, there are and it has disappeared altogether in some species. And usually what you retain is one gene which causes a different rate of growth. So really the Y chromosome, yes, it's degenerate. It's lost most of its genes. The thing about Mullah's ratchet, which is the degradation of things when you don't have sex or you don't have any recombination, there's two factors that influence it. One of them is the population size. So in bacteria, if you've got a small population and they're not sexual, then you accumulate mutations in that population. But if you've got a much larger population, the closer you kind of get towards an infinitely large population, they're not all going to accumulate the same mutations. And so the population as a whole is going to be fine. And this kind of goes back decades in population genetics. But the other thing which is less explored in population genetics is the size of the genome. So if you, with bacteria, if you increase their genome size up to your periodic size genomes, you can't maintain a larger genome, you'll accumulate mutations in that genome and it'll shrink again. And with the Y chromosome, yes, it shrunk. It's a tiny, it's a tiny chromosome in comparison with all of the rest. So it's really, how many genes can you maintain in a good state? And with the Y chromosome, basically you only need a couple of genes in there. Basically, it's the S-R-Y gene is saying grow faster. And you only need that to remain functional. And then selection at the level of fertile or infertile men will kind of weed out the ones that have got a non-functional S-R-Y gene. So it's not as if you've got a patchwork in your tail. You can afford to degenerate your Y chromosome down to almost nothing. And you'll still be functional. I mean, it's quite interesting because you were saying that the same thing happened to the mitochondrial DNA. Which is a tiny genome. And has shrunk over time, starting from the original bacteria that was engulfed. It's gone down from say three or 4,000 genes to, in our own case, 37 genes. So you cannot sustain a large genome if you're inside, I said population size matters. If you're a mitochondr... If you were a free living bacterium living out there in the wild with a population of a million and now you shelter inside another cell and it's a small cell, now you've got a population of five. So you will accumulate mutations and you can't resist them. So you'll lose genes. So your genome shrinks. That's what happened to the mitochondria. You just can't maintain a bacterial size genome. So maybe worth explaining why it's the case that sex is preferable to lateral gene transfer in the sense of being the systematic pooling and parallel search across gene space. So if there is this advantage of sex and then bacteria have some antecedent to it, why didn't they just get the whole thing? Is it just that it's not compatible with their size? I think they had no need for it. So what they do, is lateral gene transfer is basically you pick up random bits of DNA from the environment. It can be a bit more sinister than that. You can kill a cell next to you and take its DNA and load that in. That does happen. But for the most part, you pick up bits of DNA from the environment. Usually small pieces, usually kind of one gene's worth or something. And you'd only do that if you're a bit stressed. If things aren't going well for you, you will then pick up bits of DNA, bind it into your genome and hope for the best. I guess for most critters, most of the time is not going to work. But for one of them it does and then they will take over. And so it kind of speeds up adaptation to a changing environment. So why are they only using one gene? There's two ways of seeing this. You've got a bacterial size genome. It's pretty small. You're going to replicate faster if you keep that genome small. It's a kind of a disadvantage to have a big unwieldy genome. You carry its have that. And it's kind of an interesting question. Why would you have such a big unwieldy genome that takes longer to copy and longer bacteria are really streamlined. They get rid of genes they don't need and then they can grow faster. But now the conditions change. But now you need this gene. You pick it up. You just pick up random genes and hope for the best. Pick up the right one and off you go again. So bacterial genome sizes are small. They've got what you'd say is a small genome but then a large pan genome, which is kind of all of the genes they have access to. So an E. coli cell might have three or 4,000 genes in a single cell, but access to 30 or 40,000 genes. What is keeping the metagenome around? Why does everybody just converge to this streamlined thing that is needed for the current based... I mean, I think what keeps them the metagenome around is the fact that different strains of E. coli, whatever bacteria they may be, are living in different environments. So you could have a commensal bacteria living in your gut. You could have bacteria E. coli living on your skin, very different environment. You can then have non-comensal pathogenic E. coli, which are behaving differently again. They can differ in 50% of their genome. So you've got all of these things going on side by side and they can all borrow genes from each other. And this is basically within the same species, whatever species exactly means with bacteria. It doesn't quite have a meaning. So this is the kind of dynamic of bacterial evolution, is they retain small genomes with access to large pan genomes and they're forever borrowing, matching and so on. And they effectively remain competitive by keeping their own genome pretty small. And then E. coli is kind of threw all of that out and got larger genomes. And then the question is, well, if you try and do that with a large genome, a eukaryotic sized genome, and then you go on picking up little bits of DNA from the environment, the chances of you replacing the right gene gets lower. So it just becomes less and less efficient, the bigger your genome is. So by the time you get to eukaryotes, they have a large genome. Why do they have a large genome? I would say it's because you acquire this endosymbiotic and they become the mitochondria. Now you have a lot more energy available. There's all kinds of reasons why eukaryotes will tolerate a larger genome. But the bottom line is you've got the energy to do something with it, which bacteria never really had. And so now lateral gene transfer is just not good enough to maintain this larger genome. You're going to have to do something more systematic. So you pull on an entire genome, you line everything up, you cross over between them. Now it's systematic, it's reciprocal, and you can maintain the quality of genes in a much larger genome. So bacteria never had the need to do that. Right. As I was reading your book, just to ease my own ignorance, I was like, trying to come up with an analogy. And so please let me know in which ways it's naive. And also, thanks for tolerating all my other naive questions today. But here in Silicon Valley, maybe an analogy that will work for us is to think about, let's say, a GitHub repository. I'm already out of my depth now. Basically, you just have this code base and then you have ways in which you do version control. So the usual way this is done, and this may be analogous to sexual recombination is that somebody makes what is called the make a new branch. In that branch, they might make changes which are organized next to the function that they're trying to change. And then so when the maintainer is looking at the code, they can see, here was what the original code was at this point. Here's the modification to that point of code. And you see the diff, and then you can merge it back if it seems sensible. And so the analogy here might be, sexual recombination that's organized along the relevant gene. And you see this allele, you see that allele. And then I guess evolution here is the maintainer, which is then driving one of them to fixation. The analogy for asexual reproduction, just cloning with mutation, would be, okay, you fork the repository, then you make a random change, you just change some random variable, you change a word, you change a bit. And almost every single time this will be deleterious. And even when it's not deleterious, there's no merge functionality. So these different, you've got millions of repositories that they're spot, then spawning millions of other repositories. And even if some improvement has been made on one of them, there's no systematic way in which the improvements can be merged together. I mean, it sounds quite similar, I guess. Yeah. And then finally, lateral gene transfer. So here's the analogy might be, okay, so you've got one repository for, let's say, editing webpages and another repository for controlling airline software. And what you just do is you take a random 500 line sequence in this web page editing software, and you just put it in a random point in the airplane management software. And there's no systematic organization of like, here's where the relevant functionality is and here's like, well, there is a bit, which is to say, with lateral gene transfer, you would normally match the ends to something you've got already. So I don't know enough about coding to give a comparable example, but effectively, you would be picking up a module which had some resemblance in terms of, okay, it fits into this part of the code. So you'd only put that in. And it may or may not be useful there, but it's not just completely random. It's kind of, it's plugged into a place where you know you have something like that that used to be there or could be there. So it's not just random, but at the same time, it's, you don't know what you put in. So then I guess honestly, I don't really have good intuition for why lateral gene transfer does not produce similar benefits to recombination. It's really just a scaling thing. If you pick up a random piece of DNA, you've got a genome which is 10 times larger, then how fast can you pick up DNA from the environment? You'd have to pick up 10 times as much to do that. Do you have the capacity to pick up 10 times as much? And there's also a penalty for doing it, which is to say, like a mutation, you've got no idea what you're plugging in. It could be almost anything. You know where you're plugging it. You're plugging it in the right place, but what's in that cassette? You don't really know. So the more you do of it, the more you will degenerate yourself as well. So there's kind of costs and benefits to doing it. If you're running a frontier technology company, you know how essential it is to recruit the world's best talent. But this requires navigating the Byzantine US immigration system. 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Okay, so maybe to close this off, what is the experiment or method of interrogation which would give us the most amount of information about this story? Yeah, I mean, there's so many aspects of this story. There's so many possible answers I could give there. I mean, in terms of eukaryotes, giant bacteria, the likelihood of life, I think there's a lot depends on observation. We simply don't know enough about what's out there. And so it's not necessarily experimentation. Simply, if I assert that giant bacteria are always going to have extreme polyploidy with multiple copters of their genome, you find an example that's not like that. And already my ideas are breaking up. So useful to know. For the origin of life, I really wish I could come up with a convincing reason why I should go down in a submersible to a deep sea hydrothermal system like Lost City. I would love to go to Lost City. But the trouble is that the ocean chemistry is completely different now to what it was four billion years ago. It's now full of oxygen, full of bacteria and things as well. But the ocean chemistry is different because there's oxygen, there's no iron, there's no nickel in the oceans. So you can go to a vent like Lost City and the walls are not made of catalytic minerals anymore. They're made of araganite and brucite, so kind of calcium carbonate and magnesium hydroxides and things like that. And so the chemistry it can do is very different and there's lots of bacteria living there. So I would gain beyond just the sheer amazement of seeing it. There's not a lot it would be able to tell me. So what we're actually doing is experiments in a lab in an anaerobic love box where you exclude the oxygen so you can do these experiments in reacting hydrogen and CO2. How many of the molecules in biochemistry can we produce that way? And it's slow and laborious and you get small amounts and sometimes you get contaminations and sometimes you have to start all over again. And it's slow work. But it's moving for, it's not just us either. I mean, there's other groups around the world. So Joseph Moran's group, for example, has done a lot of really nice biochemistry along these lines. So that's kind of moving forward, but I think we're talking decades before we're getting to the level where we can say, right, we can drive flux through all of metabolism and here's the set of conditions that we'll do it. Certainly some years, there are big crux points like making purine nucleotides where there's 12 steps in this synthetic pathway and all the intermediates are unstable and break down easily. It's being done in things like methanol, so not in water. In water, stuff breaks down. So we're trying to do it. It's difficult. So I believe, I think we'll get there, which is why we're trying to do it. But maybe we won't, in which case again, the hypothesis is wrong. You've got to wake up every morning and think, you know, the hypothesis could be wrong. It's beautiful. It might make sense. But, you know, there's so many beautiful ideas killed by ugly facts. So there's no good believing that you're right. You've got to believe you're probably wrong and keep going anyway. And then the other thing which I'm excited about at the moment is work on anaesthetics and mitochondria. It turns out, I heard this from a guy called Luca Turin a few years ago now, who pointed out to me that anaesthetics affect mitochondria. I had no idea that anaesthetics affect mitochondria. Well, they do. We've been doing experiments on it and it seems not fully established as this yet, but it does seem as if their main effect is mitochondria. And anaesthetics work on all kinds of things, including things like amoeba. So it's already saying, it doesn't prove anything, but it's beginning to say, well, if you can make an amoeba unconscious, then is it conscious? Was it conscious before? Well, not as we understand consciousness. But the way we would understand consciousness is really about neural nets, another system and all the complexity of human consciousness. That's what we primarily think about. But there's a deep problem which goes back, I mean, it's the mind-body problem, but it was framed by David Chalmers as the hard problem of consciousness, which boils down as my understanding of this is more or less, we don't know what a feeling is in physical terms. So you can understand the information processing of a neural network, but what actually, if you feel miserable, you feel pain, or you feel love or whatever it may be, what actually is that in the chemistry of a system? And I suppose the problem is that you have all of these neural nets firing and some of them are conscious. We're aware of what we're thinking about. And others, which seem to have all the same properties in terms of the neurons, they have synapses, they have neurotransmitters, they depolarize, they pass on an action potential, but we're not conscious of it. It's non-conscious information processing. So there's this question, okay, so if anesthetics affect things that don't have neural nets, and feelings are something that we can't define in terms of a neural net, could it be that feelings are somehow linked more broadly to life? So why would they be? So again, the way I think about this is as an evolutionary biologist. So the first question is, would we think that feelings are real? I would say yes. Do we think that they evolved? I would say yes. I think any evolutionary biologist would say yes to those questions. If it's real and it evolved, then natural selection must be able to see it and act on it in some way. In other words, there's something physical about it that can be selected for. Again, I don't think there's anything controversial about that statement. But then if it's physical and real and has been selected on, the implication is we should be able to measure it. There should be, it has to offer an advantage for selection to act on. And if it's a physical process, it should be measurable, but we don't really know what we're trying to measure here. So I then kind of revert back to thinking, okay, what would a bacterial cell need to do? And this is just kind of back of the envelope thinking. And I immediately think about metabolism. What's the difference between the inside of a bacterial cell and the outside world? It's basically, you know, the inside is metabolically alive. It's doing stuff with its chemistry all the time. And it's at a colossal rate. A bacterial cell will have about a billion reactions every second in this metabolism. So I'm immediately left wondering, how is it all controlled? How do you get this cell to have a coherent behavior so it decides, I'm going to crawl over there? How do you even know what state you're in? How do you kind of synchronize all of this biochemistry? And probably most people's answer to that would be metabolic regulation of one sort or another. But that's not really the driver. The driver in the end is the thermodynamic drivers. How many electrons do you have? That's in the form of food or NADH or whatever it may be. How much energy do you have in the form of ATP? These are the things that are going to synchronize reactions in the same kind of phase. And the problem there is when you're dealing with molecules, you're dealing with tens of thousands of them. So you've got a kind of large statistical sampling, which is time consuming to figure out. But there is a better way of doing it, which is to say if you're taking electrons from food in NADH and you're passing them to oxygen, but you're generating a membrane potential and that's driving ATP synthesis, you can actually measure the rate of change and the membrane potential and the fields that will be generated, electrostatic and electromagnetic fields. That's going to give you a handle on your state, on your metabolic state in relation to the outside world. Is there enough food there? Is there enough oxygen there? Is it too hot? Is there a virus? Do I have enough iron to be able to do all these reactions? So you've got all these potentially conflicting feedback loops and you've got to make a decision. So you're just thinking loosely about how a bacterial cell is going to behave. You find that you're already framing it in terms of, well, as an entity, as a cell, it's got to make some kind of decision about what to do. It's got to integrate all this information and make a coherent decision as a self, as an entity. Is that free will? Probably not in any way that we recognize it, but it makes a decision in relation to its environment and the outcome is survival or not. So what I think a feeling is then is effectively it's the electromagnetic fields generated by membrane potential, which is telling you what your physical metabolic state is in relation to the environment you're in. But that leaves me to a question. So if consciousness is somehow about mitochondria, are the mitochondria in that sense just really simply an ATP generating engine and you interfere with the way they make ATP and so anesthetics work by effectively giving you an energy deficits, the brain closes down. That would be dull if it were true, but it would be useful to know if it were true. But much more excitingly would be do mitochondria generate the kind of fields that I was talking about in bacteria that are giving some kind of indication of your status in certain mitochondria, certain neurons, and the anesthetics interfere with that. That would be magical if that were true. That would be a whole new direction of research, which would be fantastic. It's very difficult measuring fields. It's very easy to measure artifacts that you don't know what you're really doing. We need more physicists working in this area to do the hard calculations. We need more data on what actually is it really just in one of these respiratory complexes, complex one, so there's lots of standard molecular biology that we can do. It's beginning to point to this idea that yes, there's something going on about the way that complex one works, which may link to generating fields, that may link to how anesthetics work. That's just fun. The thing that's great about science is it's really fun. It's one thing I'm always trying to get across to the people in my lab. You can't forget the fun. If it becomes drudgery, then you best go because you'll make much more money somewhere else. You'll have a better life somewhere else. But if what you really care about is the science and the experiments, it's got to be fun. You've got to really enjoy wanting to go and do that. I have to say one of the great things for me is it's always been fun. It's been great to make curiously get a sense of that feeling from reading your books. Thank you. For the audience, this conversation has been most coupled with next book, The Vital Question. I would recommend getting that if you want to better follow the argument here. There's a way more detail there that would be helpful. I think one, this is the thing I was telling you earlier, that it feels a niche of books, which unfortunately there's just very few of. There's textbooks, which you can spend 2,000 pages learning about molecular biology, but a layperson just is practically curious, is just practically not going to get a chance to do that. On the other end, there's what are basically just anecdotes about scientists or anecdotes about the history of science. This one discoverer was really mercurial, and here's how he ran his lab, and here's how his parents were like, but it never really talks about the actual relevant science. A book like this actually does fill the explanatory middle. Yeah, thank you. I think the physicists are very good at writing books about the big questions of the universe. There's a large readership for having your mind blown by a book that you're not going to understand everything because you know it's difficult. How do we know anything at all about the Big Bang or how black holes work or background radiation or whatever it may be? With life, the origin of life or the trajectory of life on a planet and whether we get complex life inevitably or whether we're going to get stuck with bacteria in most places, these are big questions, universe-sized questions, and there's not many people writing about them and trying to take you to the edge of what we know in the way that the physicists very often do and just say, well, here's how I see it. Here's the questions through my eyes, and you've got to try and be honest and say, okay, I see it this way, other people see it differently. By the way, the fact that LLMs exist has made the process of reading a book like this much more feasible and productive. I had a book club with a couple of my friends and we're not biologists. We're sort of lay people to this audience. I do encourage people for a book like this to see if you can form a book club or something and just talk to LLMs a bunch because there's just a bunch of extremely basic remedial chemistry and biology that we were able to recapitulate with the help of the LLMs. This whole thing of why is the CO2 and H2 reaction incentivized when one side is alkaline and one side is acidic in this early environment, you just go through the remedial chemistry with the LLM. Yes, I did my best to explain it in the book and it seems that I didn't do a great job of it. There's so much detail and you can't avoid that because it's there in the questions and this is a problem with biology. It's incredibly complex and physicists look at biology and they think, well, it's just too hard to explain and biologists have got all of these terminology and often get lost in the terminology and I find myself by nature trying to find simple common denominators and that lends itself then to writing about them. But of course, I probably over simplify all the time or maybe I fail and don't simplify it enough. But you wrestle with it and you try to make it work. And it's actually genuinely interesting for me to talk to you and the other guys in the book club to see where you are struggling with it and where you are. I will build this into next time in writing a book, I'll try and figure out, okay, how do I do that better? Well, I think this has been great. And thank you for the guide through both the remedial biology and chemistry, but also through many of the most interesting questions that you could ask about life. I think it's great fun. Thanks a lot. Hey, everybody. I hope you enjoyed that episode. If you did, the most helpful thing you can do is just share it with other people who you think might enjoy it. It's also helpful if you leave a rating or a comment on whatever platform you're listening on. 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