Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas - 198 | Nick Lane on Powering Biology

Episode Date: May 23, 2022

The origin of life here on Earth was an important and fascinating event, but it was also a long time ago and hasn't left many pieces of direct evidence concerning what actually happened. One set of clues we have comes from processes in current living organisms, especially those processes that seem extremely common. The Krebs cycle, the sequence of reactions that functions as a pathway for energy distribution in aerobic organisms, is such an example. I talk with biochemist about the importance of the Krebs cycle to contemporary biology, as well as its possible significance in understanding the origin of life. Support Mindscape on Patreon. Nick Lane received his PhD from the Royal Free Hospital Medical School. He is currently a professor of Evolutionary Biochemistry at University College London. He was a founding member of the UCL Consortium for Mitochondrial Research, and is Co-Director of the UCL Centre for Life's Origin and Evolution. He was awarded the 2009 UCL Provost's Venture Research Prize, the 2011 BMC Research Award for Genetics, Genomics, Bioinformatics and Evolution, the 2015 Biochemical Society Award, and the 2016 Royal Society Michael Faraday Prize and Lecture. His new book is Transformer: The Deep Chemistry of Life and Death. Web site UCL web page Google Scholar publications Amazon author page Wikipedia

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bad dirt. What makes bad dirt so bad? The answer? The ingredients. But fear not true crime enthusiasts. This story has a happy ending. Miracle Grow organic raised bed and garden soil. It's made with quality organic ingredients from upcycled green waste like compost and aged bark. Unlike the other guys who can't say the same, looks like bad dirt's murdering days are over. Thanks to Miracle Grow. Join us next time on Plant Killer. Hello, everyone. Welcome to the Mindscape Podcast. I'm your host, Sean Carroll. When I wrote the big picture, that book that I wrote a few years ago, one of the most fun parts of the process to me was tracing what happens to energy that we get from the sun through the atmosphere of the earth and then into life here on Earth. You know, I always ask people when I give talks, what good is the sun to us here on Earth with the idea that probably they're thinking we get energy from the sun, which is true. But what is most important about the energy is that it is in a low entropy form. It is useful energy.

So that low entropy energy we get from the sun is captured by plants or unicellular organisms. And then it is basically bottled up in certain molecules, which then go on to be eaten, roughly speaking, by other organisms, and used as fuel. So once that energy is in the right molecules and gets into animals and other aerobic organisms, It goes through what is called the Krebs cycle or the citric acid cycle. The Krebs cycle is kind of amazing. It's basically the way that we take the fuel stored in these molecules and turn them into useful energy in our bodies.

And amazingly, it is really, really ubiquitous for life on earth here, which maybe is a hint that there's something important about it. Not only is it, of course, important for metabolism and so forth, but it is perhaps uniquely important for metabolism. So today's guest is Nick Lane, a very well-known biochemist and writer, who is one of the world's experts on the origin of life. But we're talking mostly in this podcast, not about the origin of life, but about how life uses energy in this creb cycle, in this citric acid cycle. That's important for figuring out the origin of life, because it is possible, it is conceivable, we don't know yet, that the

Krebs cycle predates life itself, that it has a non-biological origin, and coming into existence in a purely chemical way might have been one of the crucial steps into the origin of life. So this is fun stuff. Nick is an actual expert when I was writing my book. I was not an expert, but I tried, I learned, I talked to people, et cetera. You'll learn a lot from his perspective on this stuff, and it's crucially important to tackling some of these big questions about why there is life at all. So Nick has a new book out called Transformer, the Deep Chemistry of Life and Death, which is about exactly this topic. And let me assure you, if you're not familiar, he's a brilliant writer as well as scientist. Okay, occasional reminder that here at Mindscape, we have a website,

preposterousuniverse.com slash podcast, where you can get show notes and full transcripts for all of the episodes. And you can also support Mindscape by going and becoming a Patreon supporter at patreon.com. slash Sean M. Carroll. That's where you go. If you're a Patreon supporter, you get to ask the questions that we answer for the Ask Me Anything episodes. And you get ad-free versions of the podcast for, you know, a dollar a podcast. What better deal are you going to find than that? That's pretty awesome. Okay, that's the occasional reminder of the commercial side of the venture. So with that, let's go. Nick Lane, welcome to the Mindscape podcast. Pleasure. Thank you for the invitation. You know, we've had a couple of episodes recently learning about either

life in general or human life in particular in the ancient world from modern DNA. And that's a very sensible thing to do. But what we're doing here is a little bit different. I mean, you're kind of like not talking about DNA and RNA as much as many other books on these subjects talk about. You want to talk about energy and processes and so forth. So I guess my first question is, should we even expect to be able to say anything about the origins of life just by studying the process?

today. I mean, clearly they've changed a lot in the interim. Yeah, and it depends who you ask that question, too, as to what kind of an answer you get. Yes, it's a good question. Can we use life as a guide to its own origin, or is there some kind of circularity to that? And I think for the last 50 or 60 years, people have avoided that question and use chemistry as a guide to life's origin. And if we use genes and we try and go back to the first cells that we can reconstruct from genes. It was already a complex cell with, well, with genes and with DNA and proteins, and, you know, there's got nothing to do with the origin of life. So it's a genuine question, but there's a really interesting thing about how do these

complex metabolic pathways arise in the first place? And if they, there's one way of seeing, you could say, well, they evolve step by step. And if that's the case, then you have to have a gene for each step and each intermediate has to do something useful for you. And it becomes enormously complicated very quickly. Whereas if what you assume is these pathways are more or less just spontaneous chemistry and should happen anyway in the right environment, then all the genes really need to do when they emerge is just speed up processes that are happening anyway, in any which way you want it to do that. And so basically thinking the basic metabolic pathways of life is just spontaneous chemistry in the right environment really solves a lot of problems.

No, that's actually a very interesting point, even though I've talked to you and other people about this stuff many times before, that never quite sunk in. So whenever you have a process that is governed by evolution, it works incrementally, right? It starts with something. And then so you ask a question like, what good is half of a wing? But the answer is, well, it evolved for something else, and then it made it there. Quarter of a wing. Yeah, yeah.

What good is that? But so for these metabolic pathways, what you're saying is we can sort of sidestep that problem entirely because maybe they just all happen spontaneously. It's not that you're building up the whole pathway piece by piece. If you start with chemistry, as the whole field has done for decades, and you're guided by the chemistry itself, what you end up with is a kind of a soup, the primordial soup, the famous primordial soup, and you've got amino acids and you've got nucleotides. and you've got nuclear tie, you've got the building blocks of life floating around in this soup. And then what happens next? Well, somehow it polymerizes and you end up with DNA or RNA or something. And then somehow information appears.

There's a problem with the origin of information if you see the origin of life this way. And then you have genes and they invent metabolism. And so there's a lot, to my mind, there's a lot of jarring problems there. Whereas if, and one of the biggest ones is that chemistry that actually has worked well over decades doesn't look anything like life's chemistry as we know it. And so it forces there to be this inventiveness of genes at an early stage because genes have to invent metabolism as we know it because the processes that gave rise to the building blocks were nothing like metabolism as we know it. Now the alternative way is, as I say, you have this spontaneous pathways that just happen in the right environment. which give rise in the end to the building blocks of genes, to the nucleotides, and eventually they polymerize in that environment.

Now, that's not been a popular view. And the reason it's not been a popular view is because the way that life does it is it starts with CO2 and hydrogen, and they're just not very reactive with each other. And so for decades, nobody really ever succeeded in doing the experiments that show that this is really possible. But in the last five years, a lot of people have started to take it much more. seriously, and these experiments are being done now. And what do we see? We see exactly the molecules of the central metabolic pathways.

We see the Krebs cycle intermediates. We see the amino acids. We see basically life's chemistry all just happening from CO2 and hydrogen. And it's just gobsmackingly beautiful to watch. So this is, since I'm not a chemistry person at all, the idea here is that you have these molecules, CO2 and hydrogen. And in some sense, they would like to come. bind or they would like to rearrange, you know, make, turn the hydrogen, put hydrogen onto the

carbons. But there's no simple way to get there. But what chemistry can do is allow you to sort of catalyze it, right, with the right conditions around. Yes, I mean, it's a physics problem, really. It's just thermodynamics and kinetics. So thermodynamics, yes, they want to react and they want to make these organic molecules. And they do in all kinds of different environments.

But there are kinetic barriers to the reactions. And really what life is doing is lowering the kinetic barriers to thermodynamically favored reactions. That's kind of all it does. Good. And this is part of, just to put it in the context for the people who are listening, there's a debate in origin of life circles, metabolism first versus replication first. Is that a fair way to define the camps? Yes. I mean, it's exactly how a lot of the field has seen it.

I think in recent years, people have been trying to get away from these slightly extreme camps and say, oh, co-evolution, they happened together. But yes, it's a kind of way of seeing the question, really. And I suppose I would be in the metabolism first camp on the grounds that I want all this spontaneous chemistry to happen. But it's not really that I'm saying that life is about metabolism. Obviously, it needs genes and information. and I'm not sure that I would describe these protometabolic pathways that give rise to the building blocks of life. I wouldn't describe that as life. I would just describe that as geochemistry in the right environment.

And the people who say they want to have genes first, well, they've still got to make the nucleotides. They're still doing this prebiotic chemistry first. So it's really where do you want to draw an arbitrary line across a continuum. Yeah. And where you draw that line depends on which count. that you're in, but I think really there aren't camps. There are different ways of coming up with the requirements that biology has, and information is obviously one of the requirements. Genes is obviously one of them. The question is, what's the easiest way to produce them so that

they can do something useful for you? And if you have some kind of proto-metabolism and genes are introduced into that, what do they do? They speed up the proto-metabolism. They make it better than it was before. And so they have a purpose, a use from the very beginning. Yeah, I think that, I mean, again, this might be unfair, so correct me if I'm wrong. But, you know, the big picture message that seems to be coming across in not just your most recent book, but your previous one as well, is about energy versus information. And information is something that is very exciting these days, lots of scientists. So my own, you know, colleagues love information theory and information is physical and things like that. And you're pushing back on that a little bit.

saying, okay, but let's not make it all bloodless and forget about the role of energy, because energy is kind of important here. I think there are some serious problems in biology if we only focus on the information. I think we're, you know, it's not that I want to belittle it or anything. It's obviously centrally important in biology, but it's not the only thing that's centrally important in biology. And I think if you think about the other things that make up life, which is basically turning gases into matter. That's what's going on very often. That's called growth. And it's a

really simple question, but it's about physical chemistry. It's not something that we can, I mean, you probably can define it in informational terms, but it's easier just to think about it as chemistry. And that chemistry does, again, things which we can think about in informational terms like self-organization, but it's much easier just to understand, you put oil on water and it's going to separate into two layers, the oily layer and the aqueous layer, and that's more or less how cell membranes work. And you're getting order out of nothing. It's not out of nothing. It's about the thermodynamics of separation of two phases, depending on the molecular tractions between molecules, hydrophobic interactions or ionic bonds, or whatever it may be. Is there an informational way

of seeing that? I'm sure there is, but it's less easy to understand. understand than just the physical chemistry. Yeah. No, and I think it's always good to have multiple perspectives on these things, and we'll see which actually leads us to, you know, the breakthroughs. But, okay, I think this is enough for like the big picture ground laying where we're coming from stuff. Let's get our hands dirty a little bit. You've written a book about the Krebs cycle, which I can just imagine the reaction of your publisher when you, when you pitch this idea.

Explain to us why the Krebs cycle. Well, what is it and why should we care right now? Okay, it was partly, well, there's two reasons. One of them is I am a biochemist and the Krebs cycle is probably the single most iconic pathway in all of biochemistry, and it's hated by almost all biochemists and basically, especially medical students who have to do some biochemistry. It's kind of the perfect circle right at the heart of all of metabolism. And nobody really understands it, and people are forced to memorize it. And this is one of the things that puts people off biology for life or biochemistry. It's just incredibly dull.

And it's basically rearrangements of bonds in molecules composed only of carbon and hydrogen and oxygen. And half of these rearrangements seem pointless. It really is a very, very difficult challenge. I could see why my publishers were bothered by it. Now, why then would I even write a book about it? There's two reasons, really. They're both ends of the book. One of them is, and I have two laps.

One of the labs is working on the Origin of Life, and the other lab is working on fruit flies and mitochondria. Now, so the Krebs cycle is basically what's happening in our mitochondria. It's where we are stripping, down food to generate energy. We're stripping the electrons out of food. We're passing them into respiration. We're passing them onto oxygen to produce water as a waste product. And so we're basically burning hydrogen in oxygen and that's what's powering us. And it's the Krebs cycle, which is doing that. But it goes through this strange cycle of lots of peculiar intermediate steps,

which seem to be just a waste of time to try and understand. And lots of people did. It was, you know, discovered in the 1930s by Hans Krebs, it became dusty, textbook biochemistry. People have to learn it and don't want to know and forget it as soon as they can. But in the 60s, there was a really funky discovery at Berkeley that some bacteria living in deep sea hydrothermal vents do the Krebs cycle backwards. So what we're really doing in the Krebs cycle is we are. we're taking these carbon skeletons, which are composed of carbon, hydrogen, and oxygen. And we're stripping out the carbon and the oxygen

and putting it out of CO2. And we're pulling out the hydrogen. And we're burning the hydrogen with oxygen. That's generating our energy. And we're releasing water as a waste product. Now, what these bacteria are doing in the deep sea hydrothermal vents, is they're taking hydrogen that's bubbling out of the ground, and they're taking CO2 dissolved in the oceans.

And they're running the Krebs cycle backwards, putting in a bit of energy. and they're making these carbon skeletons. So this is the reverse Krebs cycle. And it's basically turning gases into the core molecules of life. And it took 20 years before these ideas were really accepted, in part because people were looking for the genes for it, and it was not so obvious exactly how it worked and so on.

So now move forward another 20 or 30 years from when it was final, accepted. The chemistry at the origin of life, we start with hydrogen and CO2, and what do we get? We get these Krebs cycle intermediates, and we get almost all of them forming under a fairly simple set of conditions. And when you look at the mechanisms of the chemistry, basically if you've got a carbon skeleton and you want to stick CO2 onto it, you get a Krebs cycle intermediate, and you get another one and another one, and you're building longer and longer chains of these core molecules. You want to make an amino acid? You, you effectively just stick it straight onto that,

the nitrogen straight on to where one of the oxygens used to be. And again, it happens spontaneously. And so the more we look at it, the more we realize that at this end, at the origin of life, you're starting with these gases that are definitely present in any hydrothermal system on the early earth, and you're making the core molecules of biochemistry very directly. And then the other end of this whole thing is to do with aging and cancer.

And it turns out, and it's turned out over the last 10 years, that often in cancer, the Krebs cycle runs backwards. It doesn't do the normal thing. Really? It basically, cancer cells and sometimes our own bodies are basically fixing CO2, taking it out of the atmosphere and converting it into these carbon skeletons and using them for growth and powering growth that way. We're almost photosynthetic in that sense.

No light involved, but we're taking CO2 from the atmosphere, from our own bodies and converting it into the, the intermediates of metabolism. So this has been a big step change in what's going wrong with cancer. And my own group working on mitochondria are looking at that. And so I've got two groups who are both trying in the lab to analyze these Krebs cycle intermediates, both with completely different questions in their mind. And just for my own sanity, I have to try and put it all together and say, well, hang on a

minute, they've got to be related. But labs, unlike chemical pathways, do not grow up spontaneously. you must have had some inkling that there were similar things involved in these two projects. Yes, I have and it's been building for a while, but it's really, the similar things is really to do with energy flow, in my own mind at least. So this is why it is that cells generate energy by electrical charges on membranes, and that's what's happening in mitochondria. And actually, that's what's happening in some of these deep sea hydrothermal vents, is you have barrary. with a natural electrical charge on them. And you ask the question, so what is this charge doing?

And the answer is in vents, well, it's powering the reaction between hydrogen and CO2 to make CREB cycle into media. And so the CREB cycle has come into it gradually through the back door, you might say. Yeah. My primary questions were to do with energy generation. But then you ask, well, what's the energy doing? And you end up thinking about the CREB cycle. And it's very strange, the way that it's kind of infiltrated into its way into my thinking.

And not just me, there's plenty of people thinking along these lines around the world now as well. So it's quite exciting. This June, the world comes to Los Angeles. Kick off FIFA World Cup 2026 at the FIFA Fan Festival at the iconic Los Angeles Memorial Coliseum. Watch matches live on Giant Scream. Feel every goal with thousands of fans. And celebrate with music, culture, and flavors from around the world. Join us June 11th through 14th opening weekend as the tournament kicks off in Los Angeles.

tickets are just $10 and kids under 12 or free. Get yours now at Los Angeles FWC26.com. Postpartum, depression, or PPD, consistently sad, loss of interest, numb, alone, irritable, empty, hopeless, anxious, exhausted. These aren't even

all the symptoms. And it's different for every woman. PPD is a real medical condition and there is treatment available. Trust what you're feeling. Talk to a doctor and visit treatpPD.com to learn more. Sponsored by Sopernus and Biogen. So let me think about this as a physicist because I'm trying to figure out, you know, why things are like this.

I mean, when we talk about energy and how we use it, the most basic thing to do is have some fuel source and burn it, right? Like in our car, we put in gasoline. And what's really happening there is that there's energy locked up in the fuel source and we're releasing it by some chemistry. That makes sense to me, but there's no cycles involved in that. So in a cycle, somehow you're taking various combinations of chemicals, as you said, carbon, hydrogen, oxygen. And by slightly changing, you know, the conditions, you're slightly raising and lowering the amount of energy that these guys have and sort of nudging the energy around a circle. So what's the point of that? Why are you doing something so complicated rather than just burning some fuel like my car does?

Yeah, I mean, there's two answers to that. One of them is surprisingly at the origin of life, everything's upside down. And we're not actually burning fuel. The fuel is being supplied by the planet. The fuel is the hydrogen gas bubbling straight out of the planet with a disequilibrium with CO2 in the oceans. Now, thermodynamically, they want to react together. And the question there is really more about the kinetic barriers that prevent them from reacting. But there is a physics question here as well that goes back to Harold Morowitz, who people have talked about the fourth law of thermodynamics.

And I think his snappy phrase for it was energy flows and matter cycles. Because nothing energy transfer is never perfect. You're always going to increase entropy. And that means you can never do a perfect reverse of any specific reaction. And so photosynthesis and respiration are kind of. opposite and equal processors, but not fully. Actually, matter is cycling through these two processes. I don't know if this is a profound insight or if it's kind of a statement of the obvious.

I really can't tell that it was beautifully put anyway by Morowitz. And he saw the Krebs cycle. This was back in the late 60s, I think. He saw the Krebs cycle as kind of necessary thermodynamically that matter is going to cycle. and that's why he pulled it out as something important. And there were lots of protests at the time, and I think by the early 2000s, the ideas were beginning to die,

mostly because nobody had succeeded in reproducing it in the lab. And now people have started reproducing it in the lab, and ironically, not as a cycle, but as kind of straight-line pathways of a handful of intermediates. So I'm not sure his ideas are fully, vindicated yet, but the kind of the thermodynamic drivers behind it, definitely. I mean, let's be a little bit more specific about that because I think this is crucial, because you've mentioned a couple times the hydrogen and the carbon dioxide. They want to

burn. And then the specific, maybe this is these, well, they want to make organic molecules. They want to make organic molecules. They want to become, you know, Kreps cycle intermediates, basically. That's thermodynamically the low energy state. I've gotten a lot of, of mileage out of our friend Michael Russell's line that the purpose of life is to hydrogenate carbon dioxide. And the way I interpret that is there's a barrier. I mean, explain, maybe you should do this rather than me. Explain what do you mean by a barrier. Why can't they just rearrange into a lower energy state? Well, I mean, you put them together in a test tube, hydrogen and CO2, and you warm up, let's say warm it up to 100 degrees centigrade and let's put a catalyst in there and shake it up and

let it get on with it and what happens well nothing happens and that's the problem they're stable molecules and they're just not easily going to react and this is why chemists a long time ago dropped this problem now it's coming back at least in part because we have serious problems with the climate emergency and CO2 and global warming and so on, and with energy security. So what happened if you were able to strip CO2 out of the atmosphere, split water to produce hydrogen, react to the hydrogen with the CO2 and make synthetic gasoline?

There's a nice solution, but that's basically what life is doing. And so there's been a big increase in the last few years in the chemistry of CO2 and hydrogen. And it's brought this problem, nothing to do with the origin of life, but it's made it more respectable again to think about, well, how can we make them react?

And then you think, well, okay, life makes them react all the time. What is life actually doing? How is it making them less stable, more reactive? And the answer is, in my view at least, well, life is not chemistry in a bucket. It's in a cell. And what's happening in the cell?

Well, it's the difference between the inside and the outside of the cell is the difference between the living thing in the outside world. But if you're dealing with a single cell, what is the difference? You've got a membrane. It's five nanometers thick, five millionths of a millimeter in thickness. And on one side of it, you've got one set of conditions, which is inside the cell. And the other side you've got the outside world. But really, all that membrane can tell is you've got some ions on this side and different ions. on that side and well what are they what are they doing well the answer is they're producing a charge

on that membrane an electrical charge and if you shrink yourself down to the size of a molecule it's equivalent to a bolt of lightning it's got the it's about 30 million volts per meter is the is the is the field strength that you would experience if you were in in that field um so what is that's doing well what is doing in modern cells is all kinds of funky things with molecular machinery made from proteins and so on, and none of it's relevant to the origin of life, but you think, well, actually some hydrothermal systems mimic this thing, where we've got a barrier, and we've got fluids with different compositions on opposite sides of the barrier, which generate a natural charge.

What could that charge do for us? And the answer is, it can make hydrogen more reactive, and it can make CO2 more reactive, so long as they're in separate phases. and if they can then be somehow brought together across the barrier, across the membrane, then you can make them react. And that's effectively what life is doing. And the question for me in a prebiotic chemistry point of view is if we don't have just bucket chemistry going on, but we've got some structure, can that structure

and the charges involved in the two separate phases, can that drive this reaction between hydrogen and CO2 to make the organic molecules and a, drive in effect growth. You're converting hydrogen CO2 in the environment into more of you. Good. I think that's a good thing. Not always a good thing, I suppose. There's too much of me already, but I wonder if you can campus our way out of that. So at a very, very basic level, are all cells, what is the arrangement of charges? Are they positively charged inside, and there's a negative charge on the cell wall, or is it not so simple? It's usually positive. It's usually positive outside. And the way that cells work now is by pumping protons. So protons

are the nucleus of hydrogen atoms and they have a positive charge. And what we're doing in our own mitochondria is we pump them out. And bacteria are doing exactly the same thing. They pump from the inside of the cell to the outside. And so you have a positive charge on the outside of the cell and a relatively negative charge on the inside of the cell. And what we have in these hydrothermal vents is acidic oceans full of protons and alkaline fluids bubbling into these vents, which is lacking protons. And so it's not that there's really an overall electrical charge. It's that there's a difference in the proton concentration between the outside and the inside, and they're going to flow in. And so it's really the pH gradient, which is potentially

driving things at the origin of life. I mean, just as a physicist, I want charge to be conserved. So you can't pump out protons forever. Somehow, either you have to pump out an electron or a proton has to come back. No, well, they flow back in again. Okay. Good. So in modern cells, you pump them out and then they come through a turbine, like the ATP synthase or something like that, and it powers work. So we're burning, we're burning foods in our own mitochondria, the energy release pumps protons across the barrier to charge up the barrier. And then that charged barrier is propelling their flux back through machinery in the membrane through these turbines like the ATP synthase.

Plenty of other proteins, though, that they work through. So it's powering work. And in the modern biology, the modern cell, contemporary cells, this will be very, very complicated and intricate. But from everything you're saying, it does make sense how, you know, focusing on the energy flow gives you a similarity between what's happening at the cell wall and what might happen in a completely inorganic thing in chemistry. underneath the ocean?

Yeah, I think I was, I misled myself for a long time because I was thinking, I think, much more strictly in terms of energy. And what you think about with mitochondria in terms of energy is ATP is the universal energy currency people talk about in cells. And the ATP synthase is this amazing rotating motor that sits in the membrane and is powered by the flux of protons and it kind of tranks its, it cranks around. and makes ATP. And it's, it's, it's, um, it's an astonishing protein, amazingly sophisticated. And you think, okay, so, so can I imagine you were saying, you were saying earlier on,

what's, what's half an ATP synthase useful for? And the answer is, well, I can't imagine half an ATP synthase. I can't imagine the prebiotic version of it. I, I, you know, it's plainly a product of genes. Right. And natural selection. Um, in which case, then you think, okay, well, what, what, What could a natural gradient have been useful for then if you already need genes before you can use it? So is there something simpler that it might power that a kind of continuous influx of protons might power something? And it took me a long time to put ATP out of my mind and realize, well, hang on a minute. What we're really dealing with in growth, in turning gases in the environment into more of me, we're really trying to make more of me.

We're trying to lower that kinetic barrier to the gases reacting to hydrogen and CO2 reacting with each other to make organic molecules. And in photosynthesis and in plenty of bacteria, the bacteria, for example, that are doing this reverse version of the Krebs cycle, while they're using the electrical charge and the proton gradient, the inflow of protons directly to drive this reaction between CO2 and hydrogen. So you think, well, could that happen prebiotically? And here we don't need a turbine and we don't need genes. We're dealing just with physical chemistry. And it's actually, it's to do with the merged equation, but I won't go into that. But in effect, if you've got hydrogen in an alkaline environment and you want it to react,

which means you want to pass its electrons onto something else, what's left behind? The protons are left behind and protons are acidic. and they're in an alkaline environment. They're going to react with the hydroxide ions to form water. And so this is going to be really favored in an alkaline environment. You're going to have a lot of people might remember doing neutralization reactions, acid-based neutralization, even in your mouth, and you get this fizzing reaction going on in your mouth.

It's spontaneous chemistry. It's unstoppable. And so you have hydrogen in this alkaline environment. It passes its electrons onto something else, onto the barrier, let's say. And now you've got protons reacting with hydrogen. hydroxide ions with this unstoppable reaction. If you put the hydrogen in an acidic environment and try and do the same thing, well, now you're making acid inside an acid environment. It's not much harder. Yeah. So hydrogen is reactive in alkaline solution. CO2, if you want to make it react,

well, first, it has to pick up an electron and now it's gotten a negative charge. How does it balance the charge? Well, if there's a proton handy right next to you in an acidic environment, pick that up. Now you balance the charge. And now you take another. electron, now you take another proton, it becomes much more reactive in an acidic environment. And so what you need is hydrogen in an alkaline phase and CO2 in an acidic phase. And there has to be, those two phases have to be juxtaposed right next to each other so that there can be a transfer of stuff. And the stuff that has to be transferred is electrons from one phase to the other phase.

And a semiconductor barrier will transfer those electrons from one phase to the other phase. And that's effectively what the cell membrane is today, and it's effectively what these barriers are in vents. They're semiconductors between two separate phases. By the time I hit my 50s, I'd learned a few things, like how family is precious. Work can always wait. And 99% of people over 50 already have the virus that causes shingles.

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But you just put them in a little bucket and they don't react. They're too stable. They're too happy all by themselves. But if we can segregate them a little bit and put one in an acidic environment and one in an alkaline environment, then they become much more ready to release their energy, to react in the right way, to do, to let that energy go. And so you need that kind of separation, a kind of barrier, a kind of membrane. You need acid and alkaline, and you need a proton gradient, as you said. And then the idea would be, I suppose, that these reactions that have been enabled by this simple setup keep going and maybe grow and become more sophisticated as they go from being some inorganic chemistry to being life? Yes. All I'm really trying to do is preserve the same topology as a cell.

So what you have in these vents is really a labyrinth of pores, cell-like pores, with a thin. inorganic barrier surrounding them. And at least in my imagination, a lot of these are down at the bottom of the ocean and not easy to get at. But we can do experiments in the lab using microfluidic chips and things like that and show that this kind of thing is at least possible.

That on the inside of the pore, you have your alkaline fluids. On the outside, you have your acidic fluids and the barrier between the two, let's say there's electrons or protons can cross that barrier and that's been shown to happen. which means you have separate phases. Mike Russell uses the phrase frustration.

The mixing is frustrated. It's slowed down. But it happens anyway. But the rate at which the fluids are replenished with hydrothermal flow or ocean waters percolating in is faster, if you like, than the rate of mixing is. And so you've constantly kept your two phases. So the planet is doing the work. It's really, it's gravity in the end that takes the iron down and puts the hydrogen coming from the Earth and the CO2 in the, So the planet is a giant battery.

It's like a giant cell where the inside is alkaline relative to the outside. And the way that the topology of cells is very similar to the topology of the planet. And the way that they function is very similar to, at a micro level, what you're seeing inside these vents. But it's a beautiful idea that really cells mimic the structure of the planet. And just to be, again, clear to the non-experts here, This is in contrast with what has been, I guess, the dominant view, or at least sort of the default view almost since Darwin, where he talked about like a little warm pond. And you would have just all these chemicals and they would be complicated enough and life would start.

And what you're emphasizing is you can't just put chemicals in a bucket. You need the separation of different phases across a membrane. And that kind of chemistry that we see in life can be mimicked in. in certain environments, but not a pond, maybe an underwater alkaline vent. To my mind, an underwater alkaline vent, there are some of these vents on the surface as well. So it's possible, but it's much harder to have, if you've got a, let's say, Yellowstone or something like that, or there are the cedars, for example, in northern California, that's a serpentinizing system, which is to say it's the same type of system as the deep sea vents, but it's on land.

but it provides some interesting problems because what you see then is this process of serpentinization produces alkaline fluids. So alkaline fluids come bubbling up through the ground and they form a pool at the surface. And the pool is alkaline. And

there are no proton gradients there because there's not going into an ocean which is acidic in the early on the early earth. Now there's a guy called Ken Nielsen who's done some beautiful work on the cedars and he was perplexed because there are these back that grow there.

And he thought, well, how are they doing it? They had a normal functional ATPAs, so they were able to jet. But normally it pumps protons. There aren't any protons in this environment because it's only alkaline. So how do they do it? He thought perhaps they pump sodium ions, but it's a freshwater environment. They don't pump sodium either. There's no sodium there.

So he thought maybe it's something funky. Maybe it's calcium ions that they're pumping or something really weird. No, it turns out they pump protons. Where do they get the protons from? They get them from the hydrogen gas that's bubbling straight out. So they're taking them from, and they pump them out of the cell, but they're growing, where do they get their CO2 from? CO2 doesn't dissolve in alkaline fluids.

So there's really starved of carbon, but if you squirt acid onto carbonates, then you dissolve the carbonate and you get your CO2 that way. So they take the protons from the hydrogen gas and they squirt them onto the carbonate's surrounding and dissolve the carbonate and get the CO2 that way. So they actually function as completely normal cells, but they're doing it in quite a complicated way. So the reason I'm telling you those complications is you think about life starting in a terrestrial geothermal system, and these gradients are not easy to come by.

The nice thing about having an ocean setting, even if it's a shallow ocean, is that we have gradients. We have alkaline water going into an acidic system. You don't really get that on land. And you can use the, sort of reasoning on the basis of chemistry and energetics to predict exactly what kind of environment you need. And we've even found the environments, right, in places like Lost City.

Yeah, the strong counter argument to it has been that it's all hypothetical that none of this chemistry actually works and that the chemistry starting with cyanide and UV radiation really works and we've done it in the lab. And that argument is getting weaker as time goes by because we and others, people like Joe Moran, Martina Priner and so on, have been doing this chemistry in the lab for the last five or six years. And it really works. You can start with hydrogen and CO2 and make the Krebs cycle intermediates. People are trying to make nucleotides that way now, the building blocks of DNA.

It's not so easy, but watch this spot within six months or a year. There will be papers showing nucleotide synthesis starting that way. Wow. Okay. That's very cool. I mean, good, I want to get there. Let's put a pin in that. But I want to build up a little bit because I get the analogy or the similarities between the

energetics inside cells and the energetic in these vents or similar things where there is some kind of membrane, some kind of gradient, some kind of acid, alkaline division. But how does that become a cell? How does it, how does that evolve into something we'd recognize as living? Where is the point at which you replace this inorganic barrier with something we would recognize as a cell membrane? Well, it's actually in a way surprisingly easy because what are we doing here where we're using the barrier and the gradients to drive the reaction between CO2 and hydrogen to make organic molecules. Some of the easiest organic molecules to make under those conditions are longish chain, meaning 10 to 15 carbons. fatty acids or fatty alcohols or simple hydrocarbons.

And what do they do? Well, they go through a standard phase transition. And they, if you have the, if you have the, especially the fatty acids, they have a charged head group. And that charged head group means that they will form a membrane very much like a bilayer membrane surrounding cells. And we've done some work that shows that you form what we kind of optimistically be called protocells because they're basically a bilare membrane surrounding an aqueous space.

That aqua space has got nothing in it. It's not a cell in any meaningful sense of the word, except that it's got a barrier around it, which is very much like a cell membrane, except that it's only made from fatty acids and fatty alcohol. So long chain, long chain meaning 10 to 15 carbons in a chain, the kind of things that have been made in those environments spontaneously form cells. Now, what happens to those cells? Well, they like to just stick to the barrier. and if they just sit there and stick to the barrier, then whatever's crossing that barrier is going to go into the cells as well. And so the question then is, well, can you use the same gradients across the barrier

and the cell to drive the growth of the cell? Can that cell now make two cells and so on? Right. We've not really shown that yet, but in principle it should happen. And if it does, then you've effectively got the natural gradients driving, the growth and replication of protocells just through converting gases into the fatty acids that you need. Good. So let me again try to summarize, and you can tell me where I'm wrong here, because I have, I've even written about this stuff in the big picture. So I have some vague recollection of what's going on.

If we think of life as requiring compartmentalization, right, the cell wall, metabolism, as we talked about, and also information, the DNA or RNA, whatever, my impression is that that compartmental mentalization, that cell wall part of it, that's the easy part, which is basically what you just said. It's a cell membrane I'm talking about rather than the cell wall. Oh, I don't even know that there's a difference between those two things. The cell membrane is really thin and it's made of these oily things. The fatty acids and so on. The cell wall is much more robust, but it's not really compartmentalizing things. It's providing a kind of rigid structure. Cell membrane, okay. Now, that's later to my mind.

To make a bilare membrane, it turns out to be a bit like mixing oil and water. It's not necessarily any more difficult than that. So it will form spontaneously. And the very interesting thing that you just added to that is this idea that because these membranes do form spontaneously, if they're right there in this environment where you have these disequilibria, these differences between alkali and acid, they can kind of inherit them. They can pick that up pretty quickly. and become places where that metabolism can happen.

Yeah. That's the hope. You've touched on the key point, I think, in how do you go from a purely inorganic system to a cell which is basically doing the same thing? And for that to happen, you need to have some kind of transition where instead of having a big mineral surface,

which is driving this reaction, instead it's happening over the membrane itself. So what would you need to have sitting in that membrane for the same thing to be going on? And the answer is, well, what does it today? And the answer is iron sulfur proteins. Okay. So what's an iron sulfur protein? And iron sulfur protein has got a little cluster of iron, ferric and ferrous ions, so iron two and iron three, and sulfide.

Maybe four of them, four ions, four solfers, or sometimes two or sometimes three. but they're very small clusters. And they're always, in proteins, they're always bound by an amino acid called cistering. We've shown relatively recently that if you just mix iron and sulfur and cysteine in water at alkaline pH, you spontaneously form these iron sulfur clusters. And they have a structure which is quite similar to the mineral grigite, which is part of the composition of these barriers that are doing.

So we've effectively, we've just sequestered a little bit of this mineral surface with a single amino acid. No polymers here at the moment. So this entire system, all the membrane itself is not made of polymers. It's just made of fatty acids. We have iron sulfur clusters bound by cysteine, which in principle could sit near the membrane and drive CO2 reduction. In practice, it's really hard to show that. We're kind of stuck trying to demonstrate. But in principle, you can imagine that maybe they kind of stick to the membrane and then they can drive CO2 fixation inside the protocell.

So now you've got an autotrophic protocell which is going to grow because it's going to make new organics inside itself rather than collecting them from the environment. So there's a lot of gaps there that we need to fill in. But in principle, if you've got autotrophic growing protocells, then you've got the perfect environment later on for introducing genes. And don't take this the wrong way, but you are absolutely reminding me of why I, do not want to be a chemist or a biologist. There's just too many things, too many chemicals, too many atoms. I just like a small number of electrons and protons and neutrons. Keep me happy.

It's a real problem with both biology and chemistry. And I think I kind of learn that the physicist's mindset is very opposed to chemistry and biology. And the other way around, most biologists really struggle with physics. And to my mind, you know, the answer is between physics, chemistry, and biology. And unless, you know, I attempt to wrestle with physics, I'm not a good physicist, but I love physics. And I, you know, I struggle with the physics. But unless I make the effort to do it, most of what I've been talking about is actually a problem in physics more than the problem in biology.

Yeah, yeah, yeah. Well, I mean, how do your structure matter? Exactly. that's what makes it fun because there are these general principles of energy flow and entropy increase and information, but in the context of these very, very specific properties of all the different atoms and molecules that we care about. I mean, that's why it's both intellectually challenging but rewarding when you figure it out. Yeah. And I think I do want to once again contrast slash compare to what is maybe the more common view in Origin of Life research, because we have this paradigm. We haven't even mentioned yet. of the RNA world, right? Where RNA is a wonderful molecule because it can hold information like DNA can, but it's not quite as stable, so it's easier to sort of make and break apart, and it can do functional things like proteins. So a lot of people really focus on creating RNA as the first step towards really understanding life. And you haven't even mentioned RNA yet.

So what? No, well, I mean, that's, RNA is clearly important. And it's central in how cells work today. I think some form of an RNA world certainly happened. It's a necessary intermediate step to get to DNA and to get to real informational systems. But there's different ways of imagining an RNA world. And it is imagination because nobody's really, you know, ever seen one. And you can create one by injecting a whole load of nucleotides into a bottle. But where did all those nucleotides come from? So the problem has been kind of compartmentalized, and we have the synthetic chemists

who say, right, you want to have an RNA world. Before you can make RNA, you need to make the building blocks, the nucleotides. And my job is to make you the nucleotides. And I'm a chemist. I make you nucleotides. Here's the way that works best. We start with cyanide in a terrestrial geothermal system. We have UV radiation.

I can make you bucket loads of nucleotides. And now you guys, you RNA world guys, you can come up with systems. auto-catalytic systems that are going to make copies of RNA. And once you've got a system which is capable of making copies of itself, then it's going to become more sophisticated and at some point it's going to say, hey, well, if I can use this ingredient from the environment to help me make a copy of myself, I'm going to build on some metabolism to the way the whole thing works. So that's the kind of the mainstream concept at the moment.

So you have prebiotic chemistry makes you nucleotides. The nucleotides polymerize in some favoured environment, wet dry cycles is the usual one that people talk about. Now you've got RNA. The RNA does its stuff and invents things and copies itself and we've got natural selection. And that invents all of metabolism. And to my mind, almost every step of that is backwards. So where would I introduce RNA? What does life do?

Well, life starts with CO2 and hydrogen to make Krebs cycle intermediates. From Krebs cycle intermediates, it makes amino acids and it makes sugars. And all of that has been done in the lab. To make nucleotides, you take the amino acids and you take sugar phosphates and you go through a bunch of steps, you know, 10 steps or something, to get the nucleotide building blocks for RNA. So this is quite hard. It's a lot of steps.

and to propose that this is going to happen spontaneously as prebiotic chemistry takes a lot of belief, I grant you. I've had a PhD student working on these questions for a few years. He's making progress, but we've not done all of it. But, you know, we're talking problems that last potentially for decades. Let's say it's successful. We're already in a kind of proto-cell world here because we've got, We're making the fatty acids. We're making the Krebs cycle intermediates.

They're kind of like fatty acids, really. So we have the spontaneous organization. We've got growing autotrophic protocells, as this term that I was using before, but cell-like things that are growing by converting CO2 and hydrogen into more of themselves. And this system over time. Can you define the word autotrophic? Sorry, yes. So it just means growing from.

instead of eating other things, you grow from gases in the environment. You grow from inorganic molecules in the environment. So like plants. Plants are autotrophic. They're growing from water and from CO2. Lots of bacteria are autotrophic and they can grow perhaps from hydrogen or hydrogen sulfide or something and carbon dioxide. It's very similar principles, but they're not growing from organic molecules.

They're not eating things. So heterotrophic is eating stuff. Okay. So what these early systems are doing then is of turning inorganic gases into organic molecules and they're growing. And let's say they get better at doing it. I won't go into how we think that they can get better at doing it, but we think there are basic physical mechanisms of heredity that can make them better at doing it. But basically positive feedback loops.

And we end up with nucleotides that polymerize. again, I'm hand-waving here. We now have nucleotides inside our protocells, and they're going to polymerize. So now we have RNA. We've introduced RNA quite late in these proceedings, and it's been introduced into something which is growing anyway. What's that RNA going to do? Well, it's going to improve protocell growth one way or another.

Its success depends on, you know, how could it possibly do that? Well, it can do that by effectively templating. peptides, proteins, nascent proteins. Why would it possibly do that? Well, there are patterns in the genetic code that suggest there are biophysical interactions between the codons or the anti-codons, the code itself, between the nucleotides,

and amino acids. And effectively, they'll bind to each other in one way or another. It depends on their hydrophobicity, how much they like or dislike water, their size. There's various principles. They're very difficult to show in the land,

lab. Again, I've got people working on that and it's a slow business. Some people claim they've succeeded. Other people don't believe them. I really don't know, but the patterns in the code suggest it's possible. So we get a small string of RNA and it templates a small peptide onto it. What does that peptide do? Well, it has properties, which are physical properties, either it's hydrophobic or it's hydrophilic. It wants to be in the solution or it wants to be in the membrane of a growing protocell. It's got those two phases right there. What's it going to do if it goes to the membrane? Well, it probably is going to improve the way that the protons come in and reduce CO2. So it's going to improve growth. What's it going to do if it sits there in the cytosol?

Chances are it's going to interact with ions like magnesium, in which case physical chemistry says it's going to come up with a structure which looks a bit like the active site of an enzyme, such as the RNA polymerase enzyme, which is what actually polymerizes RNA in modern cells. So we have functions right there, which depend only on physical chemistry. So all we need to do is copy the RNA and fix more CO2. Yeah. Okay. So this is where the RNA world is in my scheme. I like it. Yeah.

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Sponsored by Supernus and Biogen. By the time I hit my 50s, I'd learned a few things. Like how far. family is precious. Work can always wait. And 99% of people over 50 already have the virus that causes shingles. Not everyone at risk will develop it, but I did. The painful, blistering rash disrupted my life for weeks. Don't learn about your shingles risk the hard way. Talk to your doctor or pharmacist today. Sponsored by GSK. Okay, so you're blowing my mind here. So I'm going to try once again to repeat what you just said in words I understand and you can fix me. You know, biologists,

bless their hearts, they like to imagine that natural selection is the wonderful mechanism that improves things, right? Improves functions and so forth. But there are other mechanisms by which things improve. There's sort of optimization procedures just purely physically or chemically or, you know, energetically. So what we're, what we're saying here is that you can start with these primitive, uh, chemical reactions, protons flying across gradients, et cetera, et cetera. This can sort of, I mean, there's a step here that I'm missing, which is a very basic one, how this grows into something like the Krebs cycle. Um, but it becomes a little bit more dramatic and, you know, the Krebs cycle intermediaries as, as you've mentioned, uh, become involved.

And one thing I think maybe we glossed over is that in addition to shuffling energy around, the Krebs cycle is responsible for making amino acids? Is that a true statement? Yes, not exactly responsible for making them, but basically they are, it's a single step to go from a coboxylic acid, which is to say a Krebs cycle intermediate, to an amino acid. All you have to do is replace one oxygen with ammonia or something similar to ammonia. So, and it's, it's that oxygen that gets replaced is, is a pretty reactive oxygen. It's an alpha-kito oxygen.

We don't need to worry about the terms. But basically it's going to react with ammonia very quickly and does. And so you, the first thing you get if react to CO2 and hydrogen is a Krebs cycle intermediate. If you put ammonia into that mix, the next thing you get is an amino acid. If you, if you effectively steepen, if what you're doing is, is, you, you're doing, is, you, You're relying on hydrogen reacting with CO2. And a very small proportion is going to react, let's say. But a tiny proportion does.

And it's going to make a few things, including perhaps a couple of amino acids. What are those amino acids going to do? Well, they have physical properties of their own. They're going to interact with other things. I said already, they can interact with iron and sulfur to make iron sulfur clusters. Sistine will do that. What's that going to do? is going to sit in the membrane and it's going to convert more hydrogen and CO2 into organic molecules.

So we're effectively converting more of this environmental disequilibrium into more of me. Right, right. And because these pathways should happen spontaneously, stuff should happen right the way down the pathway. And the more you steepen that gradient, the more of central biochemistry you should get, right the way through to nucleotide building blocks of DNA. Right. So that's the basic idea. is it's really about steepening the driving force through all of proto-metabolism by lowering the barrier to the reaction between CO2 and hydrogen.

Right. So starting from this original CO2 and hydrogen desire to release their energies, we figured out chemistry that makes that happen. There's sort of a byproduct that is amino acids, which leads also to other organic molecules, and eventually even to RNA, RNA bases, which can then get. hang up. And then there's this fun step, which I'm not quite sure I understand, where just having RNA around lets you optimize the rest of the energetics in some sense, right? I mean, the RNA can kind of organize things and maybe... Well, what you have with, what you would have in we've got a population of protocells that are all growing and making copies of themselves, and we put RNA, we have RNA now inside it, and we've got a load of random sequences of RNA. So there's no information.

It's just random sequences. But those random sequences are capable of plating peptides non-randomly. So this random sequence is going to have a non-random peptide on it because the peptide that you form on that sequence depends on the sequence. Even though the sequence is random is going to define the amino acids in that peptide. So it's a non-random interaction there. And now we've got a population of these things, all producing random RNAs with non-remonic. random peptides that can do some form of work. What kind of work can they do in this environment? Well, the work which is going to be useful for a protocell is to make more protocell.

Convert more CO2 into more, and if all of this whole system is capable of regenerating itself, because all it is is just thermodynamics and the entire system is going to happen spontaneously so long as the catalysts are there, you will go right the way through. and you'll make more copies of yourself. Right. So we have natural, as soon as you have a random sequence of RNA in a growing protocell world, then we've got information and meaning because the meaning is coming from the context and the context is cell growth.

So genes are introduced into a world of growing cells from the very beginning, which is all they've ever done. Yeah. So the RNA was not, it's not like RNA came into existence and, and whipped up some cell membranes, etc. It's that RNA found itself in this environment with protocell membranes and started, I don't want to speak too teleologically here, but it started to optimize things. It started to fine-tune things in ways that we're trying to make more of itself,

trying to abet this reaction that is going on. But we've cut out all the problem about how is it going to invent information from nothing? The answer is it doesn't need to. All it needs to do is be a non-random template. for peptides which have function in the context of growing protocells. And as soon as you've got all of that lot together, then the whole information problem in biology just evaporates. Yeah, no, I'm very, very sympathetic to that. I've been thinking along similar lines myself. But, okay, we're a long way from modern day life. So, and, you know, we want to get to cancer and aging at some point. So,

let's accelerate ourselves because none of this stuff that we're talking about right now, in the proto cells or the very, very earliest cells, has anything that we would recognize as mitochondria, right? Mitochondria were swallowed up much later on. Two billion years later now. Yeah. So where do mitochondria come in? Because that's where the crept cycle happens these days, yeah?

Well, the crept cycle happens in our mitochondria, but mitochondria were bacteria once. And bacteria have their own crep cycle, and bacterial creb cycle in an oxygenated environment works exactly the same way that ours does. It's effectively burning hydrogen in oxygen to generate energy. But if you put this bacteria in a deep sea hydrothermal vent, then everything goes in the opposite direction. And the Krebs cycle is in reverse, and it's actually taking hydrogen and CO2 and making organic molecules. So we've got a long history of the planet, which started out four billion years ago with no oxygen in the atmosphere. And ends up sometime around the Cambrian explosion where animals first appear, where oxygen.

levels we're approaching modern levels, almost certainly. And we've got all of this spontaneous chemistry going on, which is going to depend really on the environment that it's in. And so the direction with the Krebs cycle either goes backwards or forwards, or it depends on the environment. So ours goes more or less forwards, from our own point. We're burning hydrogen in oxygen to generate energy. But if you have an anoxic environment or a hydrothermal system,

And it's doing exactly the opposite of that, is taking hydrogen and CO2 to make organic molecules. And so you have this very interesting question about the history of life on earth, about what happens to those cells where it suddenly flips? And the answer is, well, it probably doesn't suddenly flip. There are various, the idea that it's a perfect circle is almost certainly wrong. There's all kinds of different ways that it can operate, including a kind of two-pronged version of the Krebs cycle. So it's not a cycle.

in some sense, just calling it a cycle, is already misleading. There's something platonic in perfection about it and it's really not. It's just doing these two jobs that it always did. It's producing hydrogen to burn and it's on the one hand

or it's taking hydrogen and sticking it onto CO2 to make organic molecules. It can do either at any time. It just depends on the environment it's in. Let me just make a statement rather than asking a question then you can react to the statement because we've been talking about energy flow, right?

Part of me as a physicist, again, wants to say, but really it's not energy. It's entropy that is doing the work here because energy is just conserved. It's the same amount. But you have free energy. You have energy locked up in some low entropy form. In this case, the CO2 in the hydrogen. And you're increasing entropy by, you're finding a way to increase the entropy to lower the free energy. and I just want to make this statement because it is part of my campaign to convince people.

I use the term energy very loosely and I mean free energy most of the time when I'm talking about energy. And as far as entropy is concerned, I think this is one potential difference between the kind of physical chemistry that I've talked about and Shannon entropy, informational type entropy. If you mix oil and water, then you get the two phases, which form spontaneously. That's some form of order that you're getting from that. Why is it happening spontaneously? Well, it's happening spontaneously because the oil is hydrophobic and doesn't like water. And it is effectively releasing, it's a more stable state if it's separated. And the energy difference is heat, which is increasing the entropy in the surroundings.

So when oil and water separate, entropy increases. The overall entropy of the universe increases as a result of that separation. And if we think about cells, we see exactly the same things. A protein folds in on itself. So the hydrophobic bits that don't like water go on the inside and the hydrophilic bits that like water go on the outside. So it's actually a low energy state. It releases energy as it falls in that way.

And so it increases entropy. So everything's being driven by entropy increasing in the universe. But it's really being driven by the physical chemistry of hydrophobic and hydrophilic interactions of things. Now, I don't know that there is really an equivalent in Shannon entropy to that in purely informational terms. You tell me, I'm out of my depth with that. You know, I would say that there probably is. I would need to go through the details. But the point is that that...

I imagine there is. As long as you're generating heat, what's happening is you're not keeping track of all the degrees of freedom that you count as heat, right? You know, the motions of the molecules or even infrared photons that you're giving off. And you're sort of carrying away information in those. you're only paying attention to some subset of the whole system. So it looks like it's becoming more orderly. But as you already said, the universe is becoming less orderly. So the Shannon entropy is also going up, I think.

But the reason why I like to emphasize this is because I'm always hearing people lamenting the second law of thermodynamics. Everything's running down. Entropy is increasing. Isn't it sad? And I want to emphasize that we're only here because entropy is increasing. Like, we should be celebrating the second law of thermodynamics, not limit. Well, there would be no life without it. Exactly.

That's right. Okay, so the mitochondria, good. Our cells, I mean, maybe talk about, because this is always a crucial question for exobiology. It did take a while, right, for different cells to symbiotically absorb other kinds of cells, and now we call them mitochondria. And it did take some time, and we're not sure why, like roughly speaking. some proto-biotic chemistry happened pretty early, but this absorption took a lot longer. And then the eukaryotic transition also.

Yeah. So all the prebiotic chemistry we've been talking about so far is basically it's just chemistry, and it should happen spontaneously. It should happen in nanoseconds. You know, the timescale is not millions of years. The timescale is nanoseconds or picoseconds or something. And it doesn't, I mean, there's a lot of complexity there. but it doesn't strike me as necessarily that difficult.

I don't, you know, we've got as far as strands of RNA, and now as soon as that can copy itself, we have natural selection and the world's your oyster, really. So I don't think the origin of life is necessarily that serious a problem on a planetary scale. And I suppose nobody would be working on it if it was, because, you know, the idea is we can do it in the lab. We can solve this problem.

At least we can understand. how it might happen. But then, you know, from a biologists or a geologist's point of view, there was a long gap of more than two billion years before we see complex eukaryotic cells. So that's our own type of cell, which we've got mitochondria, and they've got a large nucleus with lots of DNA. And we are very closely related to plants and to mushrooms and other eukaryotic cells. So plainly, we share a common ancestor, and by definition, a common ancestor arises once. So you could say, well, maybe there were thousands of separate origins of complex things and

they all just disappeared. And that might be true. But it's also possible it only happened once. And the only evidence we have is that all the complex life we see around us is closely related and shares a common ancestor and by definition only happen once. So if it happened on thousands of occasions, then we ought to see something in the fossil record. We ought to see if we look in strange environments, maybe we'll find.

something. We never have. We've been looking for a long time. So you can turn the question on its head and say, okay, well, let's say it did happen once. Why would it only happen once? What are the, and the thing about, again, an informational context, you know, it's basically from the genes and the information that we know that it happened once. So, again, I'm not knocking genes, but if you think about the genetic variation in bacteria or in archaea, it dwarfs the amount of genetic variation in eukaryotes. They've explored genetic sequence space far more thoroughly than the eukaryotes ever did. And yet in their morphology, they remain small and simple and they've got amazing molecular machines, but they're always at the level of the molecular machines.

They don't have large bloated cells with lots of moving parts in them, lots of membranes, lots of structures inside. So why then would you have this step change? And I think the most beautiful answer, it may not be quite right, but the answer is, well, you had some cells, some bacterial cells getting inside an archaeal host cell, basically something very similar to bacteria. And that that changes the topology of what cells are. Instead of having a cell membrane, which is your interface with the outer world, which you're also using to power everything because that's where the charge is, now we've internalized the charge along with some genes, which are needed to control. that charge, and you can now use your outer membrane to do anything else. You no longer need it to be charged in the same way. You don't need to have genes next to it in the same way that bacteria do. So suddenly you've got a new structure, and over time, without asking anything other than normal

natural selection, the bacteria living inside are going to get smaller and simpler and throw away stuff they don't need. They're going to compete with each other, and they're going to end up That's basically little power stations, optimized power stations. And the host cell is going to pick up all this superfluous DNA that's floating around from these bacteria. And it's got more power than it knows what to deal, do with. It's got these pesky bacteria, parasitic bacteria living inside it that are probably going to eat it if they have half a chance. So it's got to try to make sure it's using them for something useful for itself but not being eaten. And so we've got a kind of a power struggle going on,

the conflicts of the interests between the host cell and the symbionts. And it's a very productive way of seeing selection to say, OK, well, number one, it's not that easy for one cell to get inside another cell if these cells are tiny bacterial things with a cell wall surrounding them. So that's rare, but we know of examples. And then once it's happened, we've got this power struggle going on where it's more likely to end in failure and extinction than it is. in a fancy eukaryotic amazing system.

So this gives you a reason why it only happened rarely. It doesn't say it had to happen once. It just says it's not going to happen all the time. We only have evidence for it happening once. Maybe it happened a few times and they disappeared. But it also says why bacteria do not become large and complex? Well, they don't become large and complex because they don't have end of symbion balance. They can't restructure their energy generation in the same way.

they're basically stunted by their cell structure. And so we have this step change where cells get inside cells and now we have a kind of Russian doll type setup where the whole relationship between genes and energy changes to a different format. And that changes everything that's possible. It effectively allows eukary cells to have a massive genome of nuclear genes, which allows you to become multicellular.

It allows you to, all the cells in your body have got exactly the same genome, but your brain cells only use some of those genes and your kidney cells use different genes. But if you made your brain cell from bacteria with one type of DNA and your kidney cells from another bacterial cell with a different type of DNA, they'd fight. Whereas if they're the same DNA, they're the same cell type, they don't fight in the same way. This is standard evolutionary biology now. But to be able to do that, you need to have a large genome. in the first place, these cells switch on these genes and off those genes and those ones

switch off these genes and on those genes and so on. You need a large genome, and to do that, you need a power supply and mitochondria are the power supply. So as soon as you've got a system which is effectively capable of building sophisticated bricks, you can build a sophisticated multicellular organism then which is capable of using those bricks to make organs and whatever. So if we buy the chemistry story that you laid out for the very origin of life, it's possible that that happened multiple times all over the place. I mean, you've said it's actually kind of easy and the time scale is short. But in contrast, you're saying that there probably was literally one cell that was the first eukaryotic cell and we were all descended from that. Not literally one cell, but one population of things snuggling up to each other.

probably some kind of trade going on in raw materials between cells that are snuggling up. And, you know, one of them gets inside another one. It happens here, but it also happens in the guys over there. You know, these are processes that are happening. We're dealing with populations. But it's, it's two populations of cells that are interacting with each other in a particular environment at a particular time. And it's that that gives rise to these complex cells. So we're not dealing with this kind of singularity of one cell gets inside one other cell. And, and there's an amazing explosion. We're dealing with processes and populations

and the probability of these relationships happening. So it is kind of normal probabilistic science. We're not talking miracles here, but we are talking about improbabilities. No, absolutely. And it wouldn't be surprising if we found life ubiquitous in the galaxy, but most of it was just simple, slimy, celled organisms. That would be my best get, which is a bit of a disappointing bet.

We'll find out. Like, I would like it to be like Hitchhiker's Guide to the Galaxy out there. Right. But my own science tells me it's not likely to be. Okay. So we're almost up to the present day. Like, that was a big leap to become eukaryotic and get mitochondria. But for better or for worse, there's a still, you know, family resemblance between the energetics of the Krebs cycle and ourselves today and this early chemistry that you're talking about.

But as biology does, biology is very opportunistic and it uses things for different things. And now the Krebs cycle is playing all these different roles. So we're winding down, but say a little bit about where we are in terms of aging or cancer or things like that. So there's basically this paradox then about the Krebs cycle. It does two things. It started out making the carbon skeletons for growth. So it was providing the precursors to make amino acids, to make nucleotides, whatever it is. It's basically biosynthetic.

It's making stuff. But today, we're using it, you know, if you read about it in textbooks, is going to say is used for burning things. It's used for respiration. We're stripping the hydrogen out of food and we're burning it with oxygen. When we're stripping it from food, we're stripping it from the Krebs cycle intermediates themselves. But actually, we're doing both. and that puts quite a pressure on how the mitochondria work. So if you've got good functional mitochondria,

you can do both at the same time. But as things run down over time, it gets harder and harder to do both. And then instead of having a kind of continuous flux going through the cycle, it begins to wear down a little bit, I suppose. You can get flux going in the opposite direction, like the bacteria, and this happens in cancer, It was discovered 10 years ago that where you're seeing reverse flux through parts of the crep cycle.

And the work that I've been doing on this is to do with fruit flies and how their mitochondria work. And what we found is that how well they grow and how fertile they are and things like that depends on how good their respiration is. If they respire well, then the crept cycle goes turning along and everything's hunky dory. and they're capable of providing enough energy that they need to power everything, to do their courtship dancers. They're great fun to watch these fruit flies. But they're also capable of growing, using the Krebs cycle intermediates, to make more cell membranes, to make more proteins, to make more DNA and RNA and so on.

So you need to do those two things. And what we know from cancer, is that the ATP is perhaps the less important of the two things that you need to grow. If you want to make two cells from one cell, you need some ATP, but actually you also need a lot of proteins. You need a lot of DNA. You need a lot of cell membranes. There's a lot of materials that you need to make two cells from one cell. You're doubling your materials.

And the Krebs cycle is providing a lot of that material. So you've got this tension there between making the energy you need not necessarily to double the content, but to live, to run around, to do stuff, to do a courtship dance in the case of these fruit flies and so on. At the same time, you need to make stuff. You need to make more cells. And it depends on how good your respiration is in the end. As we get older and respiration begins to run down a little bit. We get less good at doing the two things at the same time. And you end up doing one or the other. And the problem here then is, As we get older, the Krebs cycle begins to swing into reverse and begins to, we get less energy

and more growth, in effect. We slow down and we put on weight. And it's all about flux through the Krebs cycle. So the last chapters in the book are about, why is this happening? And again, it's thermodynamics in the end. It's really just about we are, we're doing a billion reactions a second in every cell, more than up to 20 billion reactions a second in every cell. If some of them go wrong and are not repaired, we do this second after second after second after second after second.

Over time, proteins get damaged. We know that. This is not a sexy theory for aging, but it's been around a long time. And what we've found is that as respiration becomes slightly damaged, the Krebs cycle starts to go the opposite into reverse. And that gives you a growth phenotype, which is a little bit like what cancer cells are doing, which is to say it's making more stuff. It's making more fats. It's making more membranes.

It's making more cells. We begin to put on weight. We begin to have less energy. We slow down. We don't want to go for the run, which might help our Krebs cycle, kind of go back into the forwards direction and so on. And this becomes an epigenetic state.

This flux state is reinforced in the activity of the genes then. Effectively, the Krebs cycle intermediates bleeding out of the mitochondria are saying to the genes. don't worry about making lots of energy, worry about making more fatty acids, worry about bulking up. And it's not a sustainable situation in the end. So we run down. Does this set of insights suggest any solutions?

Is there a crept cycle diet that will be your next self-help book that will help people run their crep cycles in the right way? It doesn't, obviously. I think the only solutions that come to my mind are things that people do anyway and things that I've started doing more as I'm finding myself in my mid-50s. And in my 40s, I was putting on weight and slowing down a bit and spent too much time at my desk. And I'm beginning to realize the only way to make my Kreve cycle go forward is eat less and run more. You're not going to make any money with this book.

Sorry, this is not going to. No, no, it's not a much of our self-help. All the people out there who are doing that anyway. way you're going to love it, but they're already doing it, so they're not going to learn anything. And the people who don't want to make their Krebs cycle work in the right way are going to be angry with me. All right. Here's the final question.

But most of them you've been talking about, perhaps because it's your interest, but it's certainly also mine, the origin of life question and how these things come in. Terribly unfair, but how close are we to figuring this out? I mean, is this a matter of like 100 years from now? we'll hope to have a complete picture, or do you think that progress is coming along sufficiently rapidly that people will come together? I mean, I've noticed anecdotally that folks in the origin of life community, especially senior people, tend to disagree with each other quite, quite energetically in various ways. We're not a consensus yet. We're a long, long way from a

consensus. And yeah, there's not much love lost in that field. It's, it's, it's, It's hard, actually, and not, I wish it wasn't like that. And I try not to be like that, but maybe some people will say, I am like that, but I don't want to be. But anyway, the point is, we'll never know how life started on Earth, which is to say, that's a historical question. And you can make a time machine and go back. And then what are you going to look for? Where are you going to go? Are you going to go to a terrestrial geothermal system or are you going to go to a deep sea hydrothermal vent?

And if you see some kind of slime on the walls of this thing, what are you going to analyze? Is it alive yet or is it not yet? Is this a failed experiment in the origin of life or is this one that worked? You know, as a historical question, it makes no sense at all. It's pointless. What we can do is understand intellectually how a sterile, wet rocky planet is capable of giving rise to living things. We can try and think through all of the steps and we can try and demonstrate each one that, really it can happen, that each step can happen. The idea that we can then put all of those

steps together and do a fine man and make life, I understand it because I can make it, I don't see that happening at all. Right. I certainly no time soon. You know, there's some people out there saying we'll be able to do it in five years time, but if you read the small print, really what they mean is, well, I can make some kind of prototype thing, which is capable of copying itself, but it's not really life as we know it. Um, what gave rise to life as a planet on a planetary scale? These vents that I talk about were probably across the entire sea floor of the early Earth. We're dealing with, I refer to the Earth as a battery.

It's a giant battery and the flow of energy and matter through this battery are what's animating cells today and we're dealing with planetary forces. The idea that in the lab with our poultry facilities we would be capable of producing cells that a planet, I don't know how many nanoseconds it took the planet to do this, but probably quite a lot, but maybe only a few million years. But the idea that we would be able to do it, I don't think it's realistic that we're ever going to create life. But I think that what we can do is understand and demonstrate the believability of the steps that it's possible that a planet gives rise to life in this way. And I think that's something to aspire to.

Yeah, it sounds like an appropriately humble goal in what is, after all, a pretty hubristic pursuit overall. Nick Lane, thanks so much for being on the Mindscape podcast. This is great. It's a great pleasure. Thank you.