Nick Lane – Life as we know it is chemically inevitable

in your worldview of why life is the way it is? Well, first, thanks for having me here. This is this is fun.

I love talking about this kind of thing. So 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 all those kind of machinery, cell membranes, and things. So it's just basically a lot of kit in in 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 algae 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, and this thing happens once that gives rise to all complex life on Earth. Mhmm. And the the one thing which I I I guess you could conclude from that is bacteria and archaea, in terms of their genetic repertoire, they're actually they've 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. Right. They had four billion years to have a go at that, and they never came up with a trick.

They said it's not in the genes. It's not about information. There's something else which is which is controlling it.

And that's something I think is the acquisition of these power packs in our cells called mitochondria.

Mhmm. And that took me into the evolution of eukaryotes. And eukaryotes acquire these endosymbionts that that that become mitochondria, and they change the potential of evolution.

It doesn't change everything immediately, but it changes where the endpoints can be. Yeah. And it allows the evolution of these large complex cells and eventually multicellular organisms and us.

So what a modern mitochondria are actually doing well, what they're actually doing is is respiration. They're generating energy for themselves. Doing They're plenty of other things as well.

But the the the 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 is really thin. So the charge is about a 150 to 200 millivolts. But the membrane is five nanometers in thickness, so that's five millionths of a millimeter.

So if you shrank yourself down to the size of a molecule or stood next to that membrane, you would experience 30,000,000 volts per meter, which is equivalent to a bolt of lightning. So that's the that's the the strength of the force of of the 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 colossally complex, interesting machinery, and it's universally conserved. It's as conserved as, say, a ribosome, the protein building factors.

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 cells.

And so there's the the question, how did it arise in the first place? Yeah. And that that was actually for me tremendously thrilling because it it 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 and and my way in was really the the gates were opened by by Bill Martin and Mike Russell, who around the early two thousands were publishing some amazing papers together where they were saying that in 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 a mineralized 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 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 these hydrothermal fluids.

So you 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 got these these mineralized sponge that pours with minerals. Well, the minerals we think on the early Earth would have been a lot 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 c o two and they take hydrogen and they react them together to basically make all the building blocks of life. Now plants do the plants get the hydrogen from water.

H two o, they take the h two out of water and throw away the oxygen and that collects in the atmosphere. But what what bacteria very often do is they've got hydrogen bubbling out of a hydrothermal vent. They just take the hydrogen straight as gas, and they react it with c o two, and they make all the building blocks of life.

So what 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 and iron and so on. And how are they powering the the the reaction between hydrogen and c o two?

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 c o two to make organics and drive growth. So so this is all this was all kind of in place before 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 but, you know, it's a thrilling idea because you've got a you've got a continuity between a geological environment and cells as we know them. And that if if 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 give would allow the it's kind of free you from the constraints of generating a charge on a membrane. Now you internalize that in eukaryotes, and now you're you're free to become large and more complex. So so so you've gone from, you know, 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 gonna 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 what are the fundamental reasons that it works this way? So it becomes astrobiology, really, and and and it's a it's a thrilling change of perspective to come from my my own background was to do with mitochondrial biology, actually an organ transplantation once upon a time.

That's basically it. Yeah. So so so so what do you get if you react hydrogen and c o two?

What you get are what are called Krebs cycle intermediates. So carboxylic acids, 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 you add on ammonia to this, and you you get an amino acid. You add more hydrogen on, and you're gonna get a sugar. You react amino acids with sugars, and you're gonna get nucleotides.

their different sides, they will spontaneously form the membrane if they're they're created. That's what I say. You know, Krebs cycle intermediates are short chain carboxylic acids.

The fatty acids is a long chain. Yeah. You know, you're ten, twelve, 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. 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 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 fissioning, separating into two or three. And, you know, they're they're very, very dynamic things under a microscope.

is effectively it's reduced inside, which is to say the it's got electrons inside. And and outside is relatively oxidized. And outside, it's rather you pump all these protons out.

It's acidic outside. It's alkaline inside. It's it's it's it's reduced inside.

That's like the Earth. The Earth is all the electrons are in the iron, in the core, in the mantle of the Earth, relatively alkaline inside. That's the alkaline fluids in these vents.

The outside is relatively oxidized. You've got all the c o two in the ocean. So the cells are a kind of little little battery with the same structure as the earth.

Right. And if you look in a hydrothermal system, the cell membranes around you know, the the the earth, the crust of the earth is like the membrane, where you have traffic going between the inside and the outside is the hydrothermal systems. That's exactly And the pores in these hydrothermal systems are little cell like entities as well.

So you keep having on multiple scales the same kind of so the idea that the earth is a giant battery that produces little living cell mini batteries, it's a rather beautiful idea.

ions instead of protons, but the but but but it's very different. Because what you'd if you're starting with with with carbon dioxide, and and the first thing to realize about that is carbon is extremely good at the chemistry that it does. It's forming, you know, very strong bonds with all kinds of molecules so you can form complex interesting molecules.

And you're effectively I think of c o two 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. 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 where 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 c o two is the is the outstanding example.

And water is everywhere. Well, you know, hydrogen, oxygen, these are all elements that are very, very common in the universe. So you're gonna keep on getting this same kind of chemistry everywhere.

We know that there are from from 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 in, say, the Milky Way is probably in the order of twenty, thirty, 40,000,000,000 of them. What fraction of them would you expect to have a non eukaryotic life? I mean, I'll go I'll 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 gonna be dealing with hydrogen vents are not contingent in your No. The 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. Ah. And it will react with water.

And when it reacts with water, it's it's it's slow if you were to put a lump of olivine in a bucket of water. You're not you'll not see very much. But if you're dealing with the pressures down at the bottom of the ocean and warmer temperatures and so on, you're producing, you know, bucket loads of of of hydrogen gas in alkaline fluids.

So that's what these hydrothermal vents are. Yeah. So any wet rocky planet will produce these vents.

We there's evidence for them on Mars from the early days of Mars when there were oceans on Mars. There's evidence now on moons, wet the icy moons, Enceladus and and and Europa.

favored chemistry. This same chemistry will just go on happening because if you react hydrogen with c o two and then with another c o two molecule, the parts of the molecules that are going to react are quite predictable.

Perhaps under very different conditions, you could end up with a but if you've got essentially similar conditions, you're and the other the other thing is we know that even with very different chemistries, you end up with basically a similar subset of molecules. From 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. A kind of these are molecules which are basically stable and tend to be formed under a wide range of conditions.

what fraction would you say? I would say a substantial fraction. Like over 1%?

Yes. Mean, I I I would imagine 50% or something. Really?

I I mean, I'm pulling you say pull a number out of a hat. I'm doing exactly what you're saying. Pulling number out of a hat.

I think this kind of chemistry is going to give you the same nucleotides repeatedly.

extremely abundant through the universe. Right? That's not to say they're collecting in an ocean at a high concentration.

What you have in a hydrothermal vent is a continuous through flow and and within pockets within this vent, within the pores within this vent, bound to the walls pretty much within cells. So within a vent system, you could have very high concentrations of things ultimately, but but not necessarily in the oceans or in the atmosphere or anywhere else. Yeah.

I mean, not just the atmosphere, but also the whole the whole of geology. Hundreds of minerals are basically the product of life.

from nucleotides, you've then got to get to RNA and DNA and and ribosomes and, you know, molecular machines. So there's a long gap there as well. So just having nucleotides, that's a that's a kind of it's a requirement to get any further.

I see. And then 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 I mean, I I would like to be, let's say, optimistic.

I would like to think that that that these processes are going to drive life into existence on on on a substantial proportion of these planets Yeah. Or moons. And and I would expect that there would be similarities in the genetic code.

I would expect there's 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 you know, if you're dealing with c o two and hydrogen, you've got this same fundamental problem. How do you make them react?

Yeah. Yeah.

yes. I I I that that's my that's my own thinking. I I don't I don't I I 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 feedbacks.

They're going to push things into similar directions.

almost disturbing. And I I have to say, I'm not I'm not a religious person either, but I'm I'm neither am I I don't object to religion. I'm not a I'm not a militant atheist at all.

I I rather I I I like the fact that religions have searched for meaning, search for origins, and I've I have some kind of fellow feeling with that search. And I I suppose truth in some sense in this with a small t in my own case. But insofar as this is is is 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 Right.

And they they're left to play out. Now, you know, this is kind of Einstein's god, really. In terms of what most people understand by gods, I think most people look for comfort in 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 Yeah. 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 Okay.

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.

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.

Sure. Sure. But is is there I suppose what I would dig my heels in a little bit is is is there's a a kind of Carl Sagan cosmological view that that once you've got you know, we're talking about the inevitability almost of life arising according to these laws of chemistry and thermodynamics and so on, and you you get life.

And and then is it gonna roll on and inevitably give rise to complex life and to humans and to to to intelligence? It's a it's a beautiful thought. It would be lovely if that was how the universe worked, but what we what we know on Earth is that you have two billion years of stasis where you'd and and then and then this apparent 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. That's right.

event? Well, there's there's multiple reasons. I mean, one of them is that the the prokaryotes, let me just say, archaea and bacterial, 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 engulf other cells, but that that's pretty uncommon. And once you got these cells inside you, you know, it may have that may have happened scores of occasions.

There's some tentative evidence that suggests that 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 endosymbiote that they then lost later on. So the question is, how often would it go wrong and and you lose your endosymbiote? And I I guess that would be the more likely outcome is that you pick up a bunch of genes and you lose your endosymbiote.

It it simply doesn't work out. So so it's it's hard to know exactly what are all the bottlenecks here, but there there have been some modeling work done to to see, okay, you get an endosymbiont. Are you gonna grow faster if you don't have the endosymbiont or you do have the endosynbound?

And if you're the endosynbound, are you gonna grow faster if you're outside or if you're inside? And under most conditions that that these people have looked at there at Santa Fe, the answer is, well, you you do better if you're not part of the symbiosis. Only under certain conditions will you do better.

So predictably, the endpoint is it doesn't work. Right.

We know what bacteria and archaea look like. And we we you know, people have been studying these things and finding new examples, and there's a there's a group discovered ten years ago called the Asgard Archaea. And they're they're relatively eukaryotic like, which is to say they've got proteins in there and genes that that are pretty similar to eukaryotic ones.

And they're they're interesting cells. They've got long processes, and they can possibly, can move vesicles around inside them. So they 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 the the these are these are 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 you you look at a plant cell or an animal cell or a fungal cell or an alga or amoeba under a microscope, and they've all got the same stuff, and it's kinda weird. Why would a single celled algae 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 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 between the host cell and the endosymbiote for for 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 there you can construct a lot of this history of eukaryogenesis, it would it's called.

So that you start with simple cells with a cell inside and you end up with with the same cell structure everywhere, all these endomembrane systems and everything else. Okay.

Exactly. So to to to have a to have a multicellular organism where effectively you're deriving from a single cell Right. And and that restricts the 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 which loosens Yeah. 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 you develop so there's less genetic fighting going on between the cells than there would be if they come together.

But that means then if you wanna have complex functions, if you wanna have a liver doing one thing and and kidneys doing something else and the brain doing something else, All of the cells have to have the same genes, but you you 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.

of certain things happening. So if you wanna have a giant bacterium, there are a bunch of giant bacteria around on earth. There's at least six or seven different quite, you know, unrelated species that have 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. So it may be a small genome, but we're talking a three megabase genome, so kind of 3,000 genes in it, and you've got tens of thousands of copies. Sometimes, you know, the very largest one have, you know, seven or 800,000 copies of their of their complete genome.

The the energy requirements for copying all of and 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.

Yeah. That you've got a symbiote that's doing something for the host cell, and the host cell is taking something or giving something back to the endosymbiote. So it's a kind of a relationship which is based on mutual needs.

Right. One of them becomes much smaller, 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. All of these examples of a a very large bacteria and they all have extreme polyploidy. None of them have come up with a complex trafficking network where you you effectively take things in and you ship it over there.

Yeah. There's just not enough genetic space to do to the feature request correctly.

I guess I'm just Yeah. It seems hard for me to You're incredulous that this Yeah.

I mean, a couple of things I'd say. Number one, there's a there's a thing called Orgel's second rule, which is that evolution is cleverer than you are. Yeah.

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, you know, evolution's so clever. The universe is so big.

There's gotta be another way that it can happen. Okay. You know, engage your brain and tell me here's how it's gonna work.

Because I I'm you know, I'm I cannot say it's the only way it could possibly happen. Right. But what I've said is that there's a the you know, wet rocky planets are common.

They're everywhere. You're going to have these same things. You're going to have c o two.

You're going to have a similar biochemistry. 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 there's a there's a constraint that probably probabilistically happens every time. Yeah. That 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 gotta 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. Right.

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 but but, you know, if you think there are some, then you tell me what they might be, and you test them. So it's you know, there's there's a there's a level and I get this a lot, and it's fair enough because if I just if I assert to you that life's going to be this way somewhere else in the universe and, you know, I grew up watching, you know, Star Wars and Star Trek, and I and and 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 gonna see the same kind of things elsewhere. Yeah. I I it's not a position that I I, you know, 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 but I suppose if you if if you simply say, ah, you're 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, you know, just imagination and hand waving, but it's not science. Yeah. So so I I'm giving reasons why probabilistically it's going to be this way.

I would what I would say is if you've got, you know, a thousand planets with life on, maybe life is gonna be the same way 999 out of a thousand times because it's gonna be carbon based. It's gonna be water. It's gonna be cells.

It's gonna be charges. It's gonna be hydrogen and c o two, and you're gonna face the same constraints. But maybe one other occasion is something completely different that I never thought of and under very different conditions.

But there's a kind of a probabilistic thing that, you know, carbon is so common. Water is so common. Are going to keep seeing the same constraints again and again.

for example, one of the moons of Saturn, when Cassini flew by some years ago, there are kind of plumes coming through cracks in the ice of water, but with organics dissolved in in in the water. And hydrogen and, you know, 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 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, you know, 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.

it then causes there to be more pores that are exactly like it. Think what I would call protocells inside these pores. So you think think that you're the organics that you're making are self organizing.

Right. A fatty acid bilayer membrane will form. Yeah.

And what you really need for positive feedbacks is to be making the organics inside this protocell and for that protocell 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 gonna make twice as many molecules, and they're gonna divide in two, now you've got two protocells.

So there's a form of heredity to that, which is they they get the same molecules because that's effectively all you're allowed to do. And sorry, what's happening is that so the thing buds off and then settles into another pore? Yes.

I see. Okay. Got it.

And this happens relatively early in this process? Yes. And so the rise replicators happens relatively early.

I would hesitate to use the word replicator here. These are growing, I would say growing, protocells that are effectively making more of themselves.

which is to say, you if you've got this deterministic chemistry, which is going to drive growth and make 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 you can't kind of evolve into something more complex. You you to some extent, you can, but basically, you're always gonna get the same and 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 events in the end and do other things. So as soon as you've got genes, you've got the potential to to do almost anything.

Yeah. If you've got naked bits of RNA, what tends to happen is they they they're selected for their replication speed. They they they just go on making copies of themselves.

They don't become more complex. They don't encoding metabolism. They just go on copying themselves, and and and it's a dead end.

Yeah. 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 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 so you've got actually selection as we know it in cells today, whereas where the replicator of the genes, but the system which is being reproduced is the cell.

I I'm gonna unpack that a little bit because see so so so so what have mitochondria got to do with sexes? 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, you know, obvious differences between gametes, which is to say they don't have oocytes and sperm or anything like that. They produce little motile gametes that look more like sperm than anything else.

Both sexes would do that. Mhmm. But by definition, the female sex passes on the mitochondria Mhmm.

And the male does not. And that's a kind of that's a that's an approximation. It's not always true.

There's there's exceptions to that rule, but it's a kind of a rule of thumb in biology that the females pass on the mitochondrial DNA. So why would that happen? With sex, what you're doing is you're increasing the variance in the in the nuclear genome, and you're subjecting that to selection, and the the winners are coming through that, and and and everything which is worse than it would have been gets eliminated by selection.

So you're effectively you're increasing variants on nuclear genes, the genomes, and and then and then and then selecting for what works. Mhmm. With the mitochondria, they're not doing they're not they're they're passing on asexually down the generations.

There is 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 a 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.

Yeah. So so so now you acquire another couple of mutations, and you you can degenerate over time. It's a process called Muller's ratchet, but it's basically it's it these mutations are kind of somewhat screened from selection by being compensated for by clean copies that you have of other 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 variance 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.

Yeah. So you can do that by by multiple rounds of cell division, but it helps if you've got two that effectively only one sex passes on the mitochondria. You're already sampling.

So you're already increasing the variance, and and you're increasing visibility to selection.

Because of so so so we're talking about variants between cells. So if you imagine that you have a 100 a 100 cells and you they all come from the same parent, let's say, and you randomly give each cell you know, if you give all the all the mitochondria that you have kind of straight into a single cell without without changing any of the ratios there, then then it's exactly the same as you are. It's 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% to 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 Yep. And this cell is going to happen to have got all the bad copies. And now you subject these 100 cells to selection and say, how are you doing?

And the one that got all the good copies, that does well, that that that gets on. So so what you're doing is increasing the variance between this kinda next generation of cells. So the ones that got all the mutants, they they get hit.

Yeah. And the ones that got all the clean copies, they do alright. The the parent had got both the mutations and the clean copies, but how do you, you know, how do you distinguish between them?

Well so 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 repair both parents had. You're kind of taking a subset. Yeah.

So you're you're you're always increasing variance between the daughter cells, and and and uniparental inheritance is basically giving you a subset. So then the question of why there's two sexes.

let's take it away from humans so we can be dispassionate about it. You you got you got these, you know, single celled critters swimming around, and they're all producing gametes. And the gametes look the same as each other, and and they'll fuse in the same way as sex, and they'll line up the chromosomes.

You know, they basically do exactly the same thing that we do, but on a single cell scale. But but having two sexes means that you you can only mate with 50% of the population. The other 50% is the same sex as you and and is not gonna accept Yeah.

Your your gametes. If you have three sexes or four sexes, then you'll be able to mate with a larger proportion of the population. Right.

Yes. So so two sexes then, in that sense, is the worst of all possible worlds you can only make with if you had only one sex, if everyone was a hermaphrodite, you can make with everybody. Right.

And if you had three sexes, you could make with two thirds of the population and so on. So why two? Well, this 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 you know, 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.

as soon as you've got this fundamental difference, even in single celled critters that one of the sex es passes on the mitochondria and the other one doesn't. Yeah. So males do not pass on their mitochondria.

And and and then this is beginning to explain, you know, differences in multicellular organisms between the sex between the nature of the germline. So Yeah. In some sense, male men do not really have a germline in the sense that that women have a germline.

So in the in the in the in the female germline, you you make these oocytes, and you put them on ice effectively. You you you look after them. You you you you switch them off as much as you can.

You try and protect them from mutations. You you molycoddle them effectively, whereas whereas men just mass produce sperm full of mutations. I mean, there's there's a lovely phrase from James Crow, who's a geneticist, who said there's no greater genetic health hazard in the population than fertile old men.

So 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. Mhmm.

So you're freeing yourself up to mass produce sperm, and then you've got the same things out. Some of them are full of mutations, but a lot of them aren't. You mass produce them, and and and, you know, the chances are it's gonna work out okay.

Because the ones that can swim best, for example, are the ones that are more likely to. That's not strictly true, but you can imagine it along those lines. But in the case of oocytes, in case of the egg cells, you're passing on those mitochondria, you don't wanna be accumulating mutations in that mitochondrial DNA, you wanna switch them off as much as possible, keep them on ice as much as possible.

That very much the differences between how the sexes end up kind of becoming different to each other Right. Boils down to what are what are the constraints on on on on on your reproductive system. Yeah.

Okay.

And the Y chromosome is degenerate.

Yeah. But I mean, there are, know, there are some things that have lost their y chromosome altogether, and and they still have sexes because it's not strictly dependent on the y chromosome. I mean, again, if you look at what determines sexes across the whole canvas of evolution, it's kinda 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. And, you know, birds have different sex chromosomes to to mammals, for example. So sex chromosomes have evolved on multiple different occasions.

And what 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 the the earliest difference that you could tell between the two sexes in in in embryonic development is is not the activation of the y chromosome and the SRY gene.

It's actually the growth rate. And and there's there was a there was a woman at at UCL where I am called Ursula Mitvak who spent her career she she had about 15 nature papers in the nineteen sixties. She worked on this this these kind of questions.

And she saw the growth rate as a common denominator, the the y chromosome is basically saying grow fast. Why would he grow fast? Well, in part, you can grow you don't have any constraints on trashing your own mitochondria because you're not passing them on.

So you can grow fast, and there'll be an advantage to growing fast if you're male. You're gonna get the resources you grow faster. If you're a female, you don't wanna grow so fast because you need to effectively cordon off germline to preserve the oocytes for the next generation.

Until you've done that, you don't wanna trash your mitochondria. So you you've got a, you know, a delay phase before you you can start growing fast. Interesting.

Is this how women live longer? Ursula Mittvak argued that that was exactly the case. Mhmm.

We don't know for a fact that that's true, but it is it's it's quite common that females live longer than males, not just in humans, but but in, you know, in Drosophila as well, they do usually.

sex and sex dependent characteristics? Well, there are, and it has disappeared altogether in in some species. Mhmm.

And usually, what you retain is one gene, which which which causes a different rate of growth. I see. So so really, the the y chromosome, yes, it's degenerate.

It's lost most of its genes. The thing about Muller's ratchet, which is the degradation of of things when when you don't have sex or you don't have any recombination, there's there's two factors that influence it. One of them is the population size.

So in bacteria, if you've a small population and they're not sexual, then you you accumulate mutations in that population. But if you've 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 gonna be fine.

And this this kinda goes back decades in population genetics. But the other thing which is less less explored in population genetics is the size of the genome. So so if you with bacteria, if you increase their genome size up to eukaryotic sized genomes, you can't maintain a larger genome.

You'll accumulate mutations in that genome, and it'll shrink again. And with the with the y chromosome, yes, it shrunk. It's a tiny it's a tiny chromosome in comparison with all of the rest.

So so it's really is 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. There basically is is the SRY gene is saying grow faster.

I see. And you only need that to remain functional, And then selection at the level of fertile or infertile men will kinda weed out the ones that have got a nonfunctional SRY gene. So it's not as if you've got a patchwork of mutate you can afford to degenerate your Y chromosome down to almost nothing, and you'll still be functional.

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 it's you know, you cannot sustain a large genome if you're inside you know, I say I said, but population size matters. If you're a mighty con if you were 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 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 what they do is lateral gene transfer is basically you 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 if if things aren't going well for you, you you you will then pick up bits of DNA, bind it into your genome, and hope for the best. And I guess for most critters, most of the time, it's not going to work. But for one of them, it does, and then they will they will take over.

And so it it kind of speeds up adaptation to a to a changing environment. Mhmm. So why are why are they only using one gene?

There's two ways of seeing this. You you you've got a a bacterial sized genome. It's pretty small.

Yeah. You're gonna replicate faster if you keep that genome small. It's a kind of a disadvantage to have a big unwieldy genome.

Eukaryotes 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 you know, bacteria are really streamlined. They get rid of genes they don't need, and then they can grow faster.

But now the conditions change, and now you need these genes. So what do you do? 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 so bacterial genome sizes are small.

They've got what you'd say is a it's a small genome, but then a large pangenome, which is a kind of the all of the genes they have access to. Mhmm. 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 is it why why doesn't everybody just converge to this streamlined thing that is needed for the the current I mean, I think what keeps the the metagenome around is 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's E.

Coli living on your skin, very different environment. You can then have noncommensal pathogenic E. Coli, which are, you know, behaving differently.

Again, they can differ in 50% of their genome. Yeah. So you 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. Mhmm.

So so so this is the 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 and so on. And and they they they effectively remain competitive by keeping their own genome pretty small. Yeah.

And then eukaryotes kinda 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. I see.

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 acquired this endosympathetic 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 so now, lateral gene transfer is just not good enough to maintain this larger genome. You're gonna 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 you can maintain the quality of genes in a much larger genome. So bacteria never had the need to do that. Right.

And then I'm already out of my depth now.

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. Mhmm. So I I don't know enough about coding to to to to give a to to give a comparable example.

But effectively, you would be picking up a module which had had some resemblance in terms of, okay. It fits into this part of the code. Yeah.

So you'd only put that in, and it may or may not be useful there. Mhmm. But it's not just completely random.

It is kind of it's 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 it's not it's not just random, but at the same time, it's you you don't know what you put in.

It's really just a scaling thing. If you if you pick up a random piece of DNA Yeah. You've got a you've got a genome which is 10 times larger.

I see. Okay. Then, you know, how fast can you pick up DNA from the invite?

You know, you'd have to pick up 10 times as much to to to do that. Do you do you have the capacity to pick up 10 times as much? And and 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 in that cassette?

You don't really know. So the more you do of it, the more you will degenerate yourself as well. I see.

So there's there's kind of costs and benefits to to to doing it. If you're running a frontier technology company, you know how essential it is to recruit the world's best talent.

Yeah. I mean, there's so many aspects to 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. Yeah.

And so it's not necessarily experimentation simply. If I assert that giant bacteria are always going to have, you know, extreme polyploidy with multiple copies of their genome, you find an example that's not like that. And already my ideas are breaking up, so useful to know.

Yeah. For the origin of life, you know, I 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 But the trouble is that the the ocean chemistry is completely different now to what it was four billion years ago.

It's now full of oxygen. It's full of bacteria and things as well, but the ocean chemistry is is different because there's oxygen. There's no iron.

There's no nickel in the oceans. So you can go to event like Lost City, and the walls are not made of catalytic minerals anymore. They're made of aragonite and and brucite, so kind of calcium carbonate and and magnesium hydroxide 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 so so what we're actually doing is experiments in a lab in a in an anaerobic glove box where you exclude the oxygen so you can do these experiments from reacting hydrogen and c o two. How how many of the molecules in in biochemistry can we produce that way? And it's slow and laborious, and you get small amounts.

And and sometimes you get contaminations, and sometimes you have to start all over again. And, you know, it's it's it's slow work. But it it's it's moving forward.

It's not just us either. I mean, there's other groups around the world. So so Joseph Morin's group, for example, has done a lot of really nice biochemistry along along these lines.

So so that's kinda moving forward, but I I think we're talking decades before we're we're getting to the level where we can say, right. We can drive flux through all of metabolism. Mhmm.

And here's the set of conditions that will 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 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 we'll I I 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.

We you've gotta wake up every morning and think, you know, the hypothesis could be wrong. It's it's it's beautiful. It might it makes 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 gotta believe you're probably wrong and keep going anyway.

And then the other the other thing which I'm excited about at the moment is is is work on anesthetics and mitochondria. It turns out I heard this from from a guy called Luca Turin a a few years ago now who pointed out to me that anesthetics affect mitochondria. I had no idea that anesthetics affect mitochondria.

Well, they do. We've been doing experiments on it, and and and it seems not fully established as this yet, but it does seem as if their main effect is mitochondria. And and anesthetics 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 con was it conscious before? Well, not as we understand consciousness. But the way we would understand consciousness is really about neural nets.

Yeah. And nervous system and and all the complexity of human consciousness. That's what we primarily think about.

But there's a deep problem which which goes back I mean, it's it's the mind body problem, but but it was 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 that of 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 it's it's nonconscious information processing. So so there's this question. Okay.

So if if anesthetics affect things that don't have neural nets and and 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 to life? So why would they be?

What would've so so so, again, the way I think about this is as an evolutionary biologist. So the first question is, would we think that that that 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 those questions.

If it's 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.

So but then if it's physical and real and has been selected on, you know, the implication is we should be able to measure it. There should be it it has to offer an advantage for selection to act on. And 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 kinda revert back to thinking, okay. What what would a bacterial cell need to do? And this is just 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 is 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 in this metabolism.

So I'm immediately left wondering, how is it all controlled? How do you have how do you how do you get this cell to have a coherent behavior so it decides I'm gonna crawl over there? Yeah.

How do you even know what states 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 is 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 food in the form of ATP? These are the things that are gonna synchronize reactions in the same kind of phase.

And the problem there is when you're dealing with molecules, you're dealing with with tens of thousands of them. So you 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 and 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 the the membrane potential and and and the the the fields that will be generated, electrostatic and electromagnetic fields.

That's gonna give you a handle on your state, on your metabolic state in relation to the outside world? And, you know, is there enough food there? Is there enough oxygen there?

Is 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 you're just just thinking loosely about how a bacterial cell is gonna behave. You find that you're you're you're already framing it in terms of as an entity, as a cell.

It's got to make some kind of decision about what to do. It's gotta 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 and and and the outcome is survival or not. So what I think a feeling is then is effectively it's the it's the it's the electromagnetic fields generated by membrane potential, is telling you what your physical metabolic state is in relation to the environment you're in. But but that leaves me to a question.

So if if if 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 will be useful to know if it were true.

But much more excitingly would be do do mitochondria generate kind of fields that I was talking about in in bacteria that are giving 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.

And we you know, it's very difficult measuring fields. It's it's very easy to to measure artifacts that you don't know what you're really doing. We need more physicists working in this area to, you know, do do the hard calculations.

And we need more data on, you know, what what actually is is it really just in one of these respiratory complexes, complex one? So there's lots of standard molecular biology that we can do. And he'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.

And 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 you'll you'll have a better life somewhere else.

But if what you really care about is is the is the science and the experiments, it's gotta be fun. You gotta really enjoy wanting to go and do that. And and and I have to say one of the great things for me is is it's always been fun.

Yeah. And it's been great to vicariously get a sense of that feeling from reading your books. Thank you.

there's a there's a large readership for for having your mind blown by a book that you're not gonna understand everything because you know it's difficult. Right. And and how do we know anything at all about the Big Bang or how black holes work or background radiation or whatever it may be.

And with life, you know, the origin of life or the the the trajectory of life on a planet and whether we get complex life inevitably or whether we're gonna get stuck with bacteria in most places, These are big questions, you know, universe sized questions. And there's not many people writing about them and trying to take you to the edge of what we know Right. In the way that the physicists very often do and and just say, well, you know, here's how I see it.

Here's the questions through my eyes. And you gotta try and be honest and say, okay, not I see it this way or the people see it differently. Yeah.

Yes. I mean, I did my best to explain it in the book, and it seems that I didn't do a great job of it. No.

No. No. You just It's it's very there's so much detail, and and and, you know, you can't avoid that because it's there in the questions, and this is a problem with biology is it's incredibly complex.

And, you know, physicists look at biology and they think, well, it's too hard to explain. And biologists who've got all of these terminology and often get lost in the terminology. And and I I I find myself by nature trying to find simple common denominators, and that lends itself into writing about them.

But, of course, I probably oversimplify all the time, or maybe I fail and don't simplify it enough. But you wrestle with it, and you try to And make it and it's actually it's genuinely interesting for me to to talk to you and the other guys in the book club to see where you were struggling with it and where you were. You know, I I will I will build this into next time I'm writing a book.

I'll try and figure out, okay. How how do I do that better? Nick, this has been great.