Nick Lane

having me here.

This is fun.

I love talking about this kind of thing.

So eukaryotes, what's a eukaryote?

It's basically the cells that make us up, but also make up plants and make up things like amoeba, fungi, algae.

So basically everything that's large and complex that you can see is composed of this one cell type called the eukaryotic cell.

And we have a nucleus where all the DNA is, where all the genes are, and then all those kind of

machinery cell membranes and things.

There's just basically a lot of kit in these cells.

And the weirdness is, if you look inside a plant cell or a fungal cell, it looks exactly the same under an electron microscope as one of our cells.

But they have a completely different lifestyle.

So why would they have all the same kit if they evolved to be a single-celled alga living in an ocean doing photosynthesis?

It's still got the same kit that our cells have.

So we know that because they share all of these things, they arose once.

in the whole history of life on Earth, there could have been multiple origins, but there's no evidence for that.

If there was, it disappeared without trace.

So we've got this kind of singularity, which happened about 2 billion years ago, about 2 billion years into the history of life on Earth.

Then this thing happens once that gives rise to all complex life on Earth.

And the one thing which I guess you could conclude from that is bacteria and archaea

In terms of their genetic repertoire, they're actually, they've got a lot more genes, a lot more versatility than eukaryotes do.

It's just that a single bacterial cell has much less in it, but there's so many different types of bacterial cell that overall, they've kind of explored genetic sequence space.

They had four billion years to have a go at that, and they never came up with a trick, which says it's not in the genes.

It's not about information.

There's something else which is controlling it.

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

Yeah.

I mean, I'll tell you how I got there first, because I started out working on mitochondria, and that took me into the evolution of eukaryotes.

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

It doesn't change everything immediately, but it changes where the endpoints can be.

Yeah.

And it allows the evolution of these large complex cells and eventually multicellular organisms and us.

So what are mitochondria actually doing?

Well, what they're actually doing is respiration.

They're generating energy for cells.

They're doing plenty of other things as well.

But the main thing we can think about is they're the energy producers.

And they're derived from bacteria and bacteria produce their energy in exactly the same way.

They're generating energy by generating an electrical charge on the membrane.

And that charge, it's small, but the membrane is really thin.

So the charge is about 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 million volts per meter, which is equivalent to a bolt of lightning.

So that's the strength of the force of the voltage across the membrane, which is colossal.

And it's generated by really sophisticated proteins that pump protons across the membrane.

And then it's ATP synthase, which is, again, pretty much universal.

And it's a rotating nanomotor that sits in the membrane.

This is colossally complex, interesting machinery.

And it's universally conserved.

It's as conserved as, say, a ribosome.

The protein-building factors are pretty much everywhere across life.

So you wonder, how on earth did life come to be that way?

And if it's conserved universally across life, it looks like it goes right back to the common ancestors of all the cells.

And so there's the question, how did it arise in the first place?

And that was actually for me tremendously thrilling because it's a way in as a researcher to the origin of life.

It says, how did these energy generating systems arise in the first place?

And my way in was really the gates were opened by Bill Martin and Mike Russell, who around the early 2000s were publishing some amazing papers together where they were saying that in this deep sea hydrothermal vent, rather than it being like a black smoker with a chimney with smoke belching out of the top, it's like a 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 pore in here which is a bit like a cell in terms of its size and its shape and on the outside you've got acid ocean waters percolating in and on the inside you've got these hydrothermal fluids so you've got a barrier

you've got an inside and an outside, and you've got more protons outside coming in, potentially driving work.

So it's very much like a cell is structured.

And the other thing is, what are these minerals?

You've got these mineralized sponges that pours with minerals.

Well, the minerals we think on the early Earth would have been a lot of metals in there.

So things like iron sulfide or nickel sulfide and things like that.

Now, the reason that's important is that

What plant cells do, but also what autotrophic bacteria do, is they take CO2 and they take hydrogen and they react them together to basically make all the building blocks of life.

Now, plants get the hydrogen from water.

H2O, they take the H2 out of water and throw away the oxygen and that collects in the atmosphere.

But what bacteria very often do is they've got hydrogen bubbling out of a hydrothermal vent.

They just take the hydrogen gas and they react it with CO2 and they make all the building blocks of life.

So what are the enzymes that they use to do that?

Well, they're very often using these same metals that you would have found in the early oceans, nickel and iron and so on.

And how are they powering the reaction between hydrogen and CO2?

Well, they're using this membrane potential, the electrical potential, the difference in protons between the outside and the inside to drive that work.

So effectively to power the reaction between hydrogen and CO2 to make organics and drive growth.

So this was all kind of in place before I came along.

This was coming from Mike Russell and Bill Martin.

And the details are very uncertain.

And whether or not you can really drive any biochemistry that way is very uncertain.

But it's a thrilling idea because you've got a continuity between a geological environment and cells as we know them.

And if it did emerge that way, then it would say, well, here's why bacteria have got this charge on their membrane, because it was there in a hydrothermal vent from the beginning.

It always powered work from the very beginning.

And that's why, in the end, an endosymbiosis that gives rise to eukaryotes would free you from the constraints of generating a charge on a membrane.

Now you internalize that in eukaryotes, and now you're free to become larger and more complex.

So you've gone from thinking about a puzzle about why eukaryotes are special to thinking about planetary systems and thinking about the origin of life and what are the forces that are going to give rise to life and how would that constrain life and would we see the same things on other planets or something different?

What are the fundamental reasons that it works this way?

So it becomes astrobiology, really, and it's a thrilling change of perspective

to come from my own background was to do with mitochondrial biology, actually an organ transplantation once upon a time.

And spinning on a pinhead, you end up working on the origin of life.

It's fantastic.

Yeah, that's basically it.

Yeah.

So what do you get if you react hydrogen and CO2?

What you get are what are called Krebs cycle intermediates.

So carboxylic acid, small molecules made only of carbon, hydrogen, and oxygen with this organic acid group at the end, which can be two, three, four, five carbon units in the chain.

And this is your basic building blocks.

You add on ammonia to this and you get an amino acid.

You add more hydrogen on and you're going to get a sugar.

You react amino acids with sugars and you're going to get nucleotides.

You know, there's lots of steps along here, but this is the basic kind of starting point for all of biosynthesis in biochemistry today.

As I say, you know, Krebs cycle intermediates are short chain carboxylic acids.

A fatty acid is a long chain.

Yeah.

you know, your 10, 12, 15 carbons in the chain instead of four or five.

And they will spontaneously, not just alone usually, but if you've got other long chain hydrocarbons mixed up with them, then you will form a bilayer membrane spontaneously.

And we've done this in the lab.

And it's pretty robust to, you know, you can make these things at 70 degrees, 90 degrees centigrade across a range of pH from around about pH 7 up to about pH 12.

And in the presence of ions like calcium and magnesium and other salts and so on.

And you make a vesicle with a bilayer membrane around it, which is basically the same as a cell membrane.

Yeah.

they're amazingly dynamic things.

They're always fusing with each other and breaking apart, kind of fissioning, separating into two or three.

And, you know, they're very, very dynamic things under a microscope.

I hate that as an idea, but go on.

Yes, I mean, one thing, you know, a cell...

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

That's like the Earth.

The Earth is, all the electrons are in the iron in the core and the mantle of the Earth, relatively alkaline inside, that's why there are alkaline fluids in these vents.

The outside is relatively oxidized.

You've got all the CO2 in the ocean.

So the cells are a kind of little battery with the same structure as the Earth.

And if you look in a hydrothermal system, the cell membranes around the Earth, the crust of the Earth is like the membrane.

And where you have traffic going between the inside and the outside is the hydrothermal systems.

And the pores in these hydrothermal systems are little cell-like entities as well.

So you keep having on multiple scales 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.

I mean, you can't allow yourself to get too hung up on a metaphor, but it's a beautiful image.

Bubbling off mini copies of the Earth.

I mean, in principle, yes, you could use sodium ions instead of protons, but it's very different.

Because if you're starting with carbon dioxide, and the first thing to realize about that is carbon is extremely good at the chemistry that it does.

It's forming very strong bonds with all kinds of molecules.

So you can form complex, interesting molecules.

And you're effectively, I think of CO2 as a kind of a Lego brick that you pluck out of the air and you bind it onto something.

You can build things one brick at a time that way.

And then you can build really interesting complex molecules like DNA and RNA from doing that.

You can't do that with silicon.

So with intelligent design, you can make really complex AI robots, whatever it may be, but the whole thing requires humans to do it.

But if you're thinking about how would life start on a planet where there isn't an intelligent designer who's putting it all together, you need molecules that can do that kind of chemistry, and CO2 is an outstanding example.

And water is everywhere.

Hydrogen, oxygen, these are all elements that are very, very common in the universe.

So you're going to keep on getting this same kind of chemistry everywhere.

We know that there are, from discoveries of exoplanets in recent years, if you extrapolate how many we've not seen yet, the number of wet rocky planets or moons in, say, the Milky Way, is probably in the order of 20, 30, 40 billion of them.

I mean, I'll take a punt here.

I would expect that if you've got these same kind of conditions on a wet, rocky planet, you're going to be producing these same kind of vents because it's the same chemistry that's going to happen.

You're going to be dealing with hydrogen.

No, the vents are produced by a mineral called olivine, which again is really common in interstellar dust.

And the mantle of the Earth is made of this mineral called olivine.

And it will react with water.

And when it reacts with water, it's slow.

If you were to put a lump of olivine in a bucket of water, 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 bucket loads of hydrogen gas in alkaline fluids.

So that's what these hydrothermal vents are.

So any wet rocky planet will produce these vents.

There's evidence for them on Mars from the early days of Mars when there were oceans on Mars.

There's evidence now on moons, the icy moons Enceladus and Europa.

You know, this is going on in our own solar system right now.

I mean, my view would be yes.

Any rocky planet would have a decent, yes.

And if you're starting with CO2 and hydrogen, what I'm saying is the metabolism is thermodynamically favored chemistry.

This same chemistry will just go on happening because if you react hydrogen with CO2 and then with another CO2 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 thing is we know that even with very different chemistries, you end up with basically a similar subset of molecules.

So from the kind of organics you see on meteorites...

utterly different chemistry going on.

You're dealing with helium radicals, but you're still seeing amino acids and you're still seeing nuclear bases and so on.

So there's a tendency.

These are molecules which are basically stable and tend to be formed under a wide range of conditions.

I would say a substantial fraction.

Like over 1%?

Yes.

I mean, I would imagine 50% or something.

Really?

I mean, you say pull a number out of a hat.

I'm doing exactly what you're saying.

I'm pulling a number out of a hat.

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

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 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.

Yeah.

but not necessarily in the oceans or in the atmosphere or anywhere else.

I mean, not just the atmosphere, but also the whole of geology.

Hundreds of minerals are basically the product of life.

I mean, I think to get to nucleotides...

From nucleotides, you've then got to get to RNA and DNA and ribosomes and molecular machines.

So there's a long gap there as well.

So just having nucleotides, it's a requirement to get any further.

Well, a lower fraction, obviously.

Right.

Over a billion?

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

I would like to think that these processes are going to drive life into existence on a substantial proportion of these planets or moons.

And I would expect that there would be similarities in the genetic code.

I would expect that a lot of metabolism would look similar.

I would expect that they would have a membrane potential driving the kind of

work because it's fun you know if you're dealing with co2 and hydrogen you've got this same fundamental problem how do you make them react yeah but so basically there's hundreds of millions of planets in the milky way which like presumably have something like ribosomes and uh dna to get to rna yes i i that's my that's my own thinking i i don't i don't 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 feedback.

So they're going to push things into similar directions.

Now, the further from CO2 fixation towards genetics you get, the less similarity there's going to be.

Yes, I mean, I agree with you.

I find it a little...

almost disturbing.

And I have to say, I'm not a religious person either, but neither am I... I don't object to religion.

I'm not a militant atheist at all.

I rather

I like the fact that religions have searched for meaning, searched for origins, and I have some kind of fellow feeling with that search.

And I suppose truth in some sense, with a small t in my own case.

But insofar as this is consistent with the idea of a god, the god would be a deist god that effectively set the laws of the universe in motion and they're left to play out.

Now, you know, this is kind of Einstein's God, really.

In terms of what most people understand by God, I think most people look for comforting God and are looking for something which is meaningful to them and who's been involved in humanity.

And so this is a very cold kind of situation.

God as thermodynamics sets the laws of the universe in motion, reproducibly gives rise to the same kinds of things.

Yes, you could interpret it in a kind of theistic, natural theistic way, but I don't think many people would get that much comfort or meaning from that way of seeing the world.

Yeah.

Well, there's probably more than one bottleneck, but Eukaryotes is, in my own mind, the big one, yes.

I mean, only on Earth.

No, I don't think so.

But is there... I suppose what I would dig my heels in a little bit is there's a...

the kind of Carl Sagan cosmological view 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 get life.

And then is it going to roll on and inevitably give rise to complex life and to humans and to intelligence?

It's a beautiful thought.

It would be lovely if that was how the universe worked.

But what we know on Earth is that you have 2 billion years of stasis, 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 2 million years, there aren't any humans around either.

That's right.

We're just the icing.

Well, there's multiple reasons.

I mean, one of them is that prokaryotes, we should say archaea and bacteria, well, they're pretty small things.

So just having another cell inside you is already a difficult thing to do.

There are occasional phagocytes in bacteria that can engulf other cells, but it's pretty uncommon.

And once you've got these cells inside you, that may have happened scores of occasions.

There's some tentative evidence that suggests that archaea, I mean, there's one nice example where the halo archaea seem to have acquired more than a thousand bacterial genes from the same source, implying perhaps they had got an endosymbiont that they then lost later on.

So the question is, how often would it go wrong?

And you lose your endosymbiont.

And I guess that would be the more likely outcome is that you pick up a bunch of genes and you lose your endosymbiont.

It simply doesn't work out.

So it's hard to know exactly what are all the bottlenecks here.

But there have been some modeling work done to see, okay, you get an endosymbiont.

Are you going to grow faster if you don't have the endosymbiont or you do have the endosymbiont?

And if you're the endosymbiont, are you going to grow faster if you're outside or if you're inside?

And under most conditions that these people have looked at, they're Santa Fe.

the answer is, well, you do better if you're not part of the symbiosis.

Only under certain conditions will you do better.

So predictably, the end point is it doesn't work.

Here's a vivid way of seeing it.

We know what bacteria and archaea look like.

People have been studying these things and finding new examples.

And there's a group discovered 10 years ago called the Asgard Archaea.

And they're relatively eukaryotic-like, which is to say they've got proteins in there and genes that are pretty similar to eukaryotic ones.

And they're interesting cells.

They've got long processes, and possibly they can move vesicles around inside them.

So they're doing a few eukaryotic things.

But if you look at their internal structure, it's not very complex.

It's nothing like a eukaryotic cell.

And if you look at their genome size, it's basically a standard prokaryotic genome size.

You're talking 4,000, 5,000 genes.

So these are not eukaryotic by any stretch of the imagination.

And then you look at a eukaryotic cell, and I said this at the beginning, you look at a plant cell or an animal cell or a fungal cell or an alga or amoeba under a microscope, and they've all got the same stuff.

And it's kind of weird.

Why would a single-celled alga living in the ocean have all the same kit that one of my kidney cells has?

Well, the easiest way to understand that is to say, well, it wasn't adaptation to an external environment, to a way of life.

It was adaptation to an internal selection pressure.

If you think about it in terms of a kind of a battle between the host cell and the endosymbiont for finding a way of living together, you can argue for the nucleus arising that there's all kinds of genetic problems.

parasites coming out of the mitochondria, forcing you to do something to protect your own genome.

So you can construct a lot of this history of eukaryogenesis, it's called.

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

So to have a multicellular organism where effectively you're deriving from a single cell, and that restricts the chances of effectively all the cells having a fight.

There's plenty of examples of multicellular slime molds, for example, where the cells come together

And they can form structures like a stalk, for example, which loosens spores into the environment.

But they basically fight because they're genetically different to each other.

So you start with a single cell and you develop... So there's less genetic fighting going on between the cells than there would be if they come together.

But that means then if you want to have...

complex functions if you want to have a liver doing one thing and kidneys doing something else and the brain doing something else all of the cells have to have the same genes but 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 is no examples of this level of sophistication of a multicellular bacterium

Yeah, I know where you're coming from.

There's no other way to solve that.

Well, maybe there is, but I think we have to look at the probability of certain things happening.

So if you want to have a giant bacterium, there are a bunch of giant bacteria around on Earth.

There's at least six or seven different quite unrelated species that have evolved giant size.

And the thing that they all have in common is they have what's called extreme polyploidy, which is to say they have literally tens of thousands of copies of their complete genome.

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 the very largest one have 700,000 or 800,000 copies of their complete genome.

The energy requirements for copying 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, that you've got a symbiont that's doing something for the host cell and the host cell is taking something or giving something back to the endosymbiosis.

So it's a kind of a relationship which is based on mutual needs.

One of them becomes much smaller and that allows the other one to become much larger.

So a symbiosis will do it.

Now, there could be multiple ways of having a symbiosis, but there's no examples on it.

All of these examples of very large bacteria, and they all have extreme polyploidy.

None of them have come up with a complex trafficking network where you effectively take things in and you ship it over there.

There's just not enough genetic space to do that.

I mean, a couple of things I'd say.

Number one, there's a thing called Orgel's second rule, which is that evolution is cleverer than you are.

So, yeah, of course, I cannot say that there's no other way that it could possibly happen.

But it's also hand-waving to say, oh, you know, evolution's so clever, the universe is so big, there's got to be another way that it can happen.

Okay, you know, engage your brain and tell me here's how it's going to work.

Because I cannot say it's the only way it could possibly happen.

Right.

But what I've said is that wet rocky planets are common.

They're everywhere.

You're going to have these same serpentinizing things.

You're going to have CO2.

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 constraint that probabilistically happens every time.

They always end up with extreme polyploidy and they don't end up with sophisticated transport networks.

So that's not to say it's got to happen that way every time.

Maybe there's a way around it, but it's not an easy way around it because they haven't done it regularly on Earth.

They haven't done it at all on Earth.

The only occasion where it worked on Earth was where they came up with eukaryotes.

That's not to say it's the only possible way of doing it, but if you try and dissect what are the alternatives, I can't think of any alternatives.

Okay, I'm limited.

I can't think of any.

But, you know, if you think there are some, then you tell me what they might be and you test them.

So, you know, there's a level, and I get this a lot, and it's fair enough, because if I assert to you that life's going to be this way somewhere else in the universe, and, you know, I grew up watching, you know, Star Wars and Star Trek and reading Hitchhiker's Guide to the Galaxy, I love the idea that the universe is full of all kinds of stuff as much as anybody.

my position of saying, actually, it's quite limited and you're going to see the same kind of things elsewhere.

It's not a position that I dreamt of having or anything.

It's just a position that I've been forced into by everything that I've learned about life on earth.

Now, maybe I'm just wrong, but I suppose if you simply say, ah, you're limited by your imagination, you're wrong because you just can't think of it.

Well, that's not science anymore.

Now we're talking about...

just imagination and hand-waving, but it's not science.

So I'm giving reasons why probabilistically it's going to be this way.

What I would say is if you've got a thousand planets with life on, maybe life is going to be the same way 999 out of a thousand times because it's going to be carbon-based, it's going to be water, it's going to be cells, it's going to be charges, it's going to be hydrogen and CO2, and you're going to face the same constraints.

But maybe one other occasion, it's something completely different 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.

You are going to keep seeing the same constraints again and again.

It may take us a while.

But yeah, we already know that there are organics.

So on Enceladus, for example, one of the moons of Saturn, when Cassini flew by years ago, there are kind of plumes there.

coming through cracks in the ice of water, but with organics dissolved in the water.

And hydrogen and organic molecules, pH is around about eight or nine or something.

So it implies that underneath that frozen surface, which people say is about five kilometers thick, underneath that, there's a liquid ocean.

Underneath that, there are hydrothermal systems producing alkaline fluids, which is

made the oceans alkaline, and it's the same kind of chemistry going on.

So we know there's organics in these plumes.

We don't know what's under the ice.

I do think that the incentives to go to these places and drill into the ice and have a look will get the better of us.

There will always be people saying, oh, we shouldn't introduce bacteria from our own system into there.

I would have said bacteria from the earth would probably survive extremely well in a place like Enceladus.

So it would be lovely to know, yes.

And I'm all in favor, really, of exploration.

Yeah.

what I would call protocells inside these pores.

So you think that the organics that you're making are self-organizing.

A fatty acid bilayer membrane will form.

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 going to make twice as many molecules and they're going to divide in two and now you've got two protocells.

So there's a form of heredity to that, which is they get the same molecules because that's effectively all you're allowed to do.

I would hesitate to use the word replicator here.

These are growing, I would say, growing protocells that are effectively...

making more of themselves.

You could call it a replicator, but I would prefer to use the word replicator for something more like RNA, which would be the conventional term for a replicator, where you are literally replicating the exact sequence of this RNA.

The sooner the better, which is to say, if you've got this deterministic chemistry, which is going to drive growth and make more cells,

it's also a dead end.

You can't do anything else.

You're entirely dependent on the environment.

You can't kind of evolve into something more complex.

To some extent, you can, but basically you're always going to get the same.

In the same environment, we'll always give you the same thing.

Soon as you start introducing random bits of RNA into this, then you've got what you'd 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 do almost anything.

If you've got naked bits of RNA, what tends to happen is they're selected for their replication speed.

They just go on making copies of themselves.

They don't become more complex.

They don't start encoding metabolism.

They just go on copying themselves and it's a dead end.

if you're trapping them inside growing protocells, then effectively they're sharing the same fate.

And if some of them are capable of making that protocell grow faster, then they will get more copies of themselves because they're inside this protocell.

The protocell is growing faster.

It makes a copy of itself and it's still associated.

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

I'm going to unpack that a little bit.

So what have mitochondria got to do with sex?

So what they have to do with sex is effectively the female sex.

And this goes even for single-cells things that don't have any obvious differences between gametes, which is to say they don't have oocytes and sperm or anything like that.

They produce little motile gametes that look more like sperm than anything else.

Both sexes would do that.

But...

By definition, the female sex passes on the mitochondria and the male does not.

And that's an approximation.

It's not always true.

There's exceptions to that rule, but it's a kind of a rule of thumb in biology that the females pass on the mitochondrial DNA.

So why would that happen?

With sex, what you're doing is you're increasing the variance in the nuclear genome.

and you're subjecting that to selection and the winners are coming through that and everything which is worse than it would have been gets eliminated by selection.

So you're effectively, you're increasing variance on nuclear genes, the genomes, and then selecting for what works.

With the mitochondria, they're passing on asexually down the generations.

It's a very small genome, but there's multiple copies of it.

And so the question is, well, how do you keep that clean?

How do you prevent that from degrading and degenerating over time?

Because if you've got, let's say, if you've got 100 copies of mitochondrial DNA and two of them acquire mutations, but you've still got 98 which are doing their job fine, what's the penalty for those two mutations?

It's not very much.

You'll hardly notice them.

So now you require another couple of mutations and you can degenerate over time.

It's a process called Muller's ratchet, but it's basically, these mutations are kind of somewhat screened from selection by being compensated for by clean copies that you have of other copies.

So how do you get rid of those mutations that are building up over time?

Well, the answer is what you need to do is increase variants of mitochondrial genes.

What you need to do is effectively segregate into these cells all the mutants and into those ones all the wild-type ones.

Yeah.

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

So you're already sampling.

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

So basically it's about the quality of mitochondrial genes.

So we're talking about variance between cells.

So if you imagine that you have 100 cells and they all come from the same parent, let's say, and you randomly give each cell, if you give all the mitochondria that you have kind of straight into a single cell without changing any of the ratios there,

then it's exactly the same as you are.

It's fully clonal.

But if you give, if you take a small subsection of those and you say you take a random 10%, you give 10% 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.

Yeah.

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 gets on.

So what you're doing is increasing the variance between this kind of next generation of cells.

So the ones that got all the mutants, they get hit.

And the ones that got all the clean copies, they do all right.

The parent had got both the mutations and the clean copies.

But how do you distinguish between them?

Well, so it's about sampling, basically.

And uniparental inheritance, which is to say, it's a form of sampling.

You're taking the mitochondria only from one of the two parents.

So you're not mixing up mutations that both parents had.

You're kind of taking a subset.

So you're always increasing variance between the daughter cells.

And uniparental inheritance is basically giving you a subset.

These are the two fundamental... I mean, it's more complex.

But I mean, the thing about two sexes is you could say it's the worst of all possible worlds.

So again, if you kind of...

let's take it away from humans so we can be dispassionate about it.

You've got these single cells critters swimming around and they're all producing gametes and the gametes look the same as each other and they'll fuse in the same way as sex and they'll line up the chromosomes.

They basically do exactly the same thing that we do but on a single cell scale.

But having two sexes means that you can only mate with 50% of the population.

The other 50% is the same sex as you and is not going to accept your gametes.

If you had three sexes or four sexes, then you would be able to mate with a larger proportion of the population.

And some fungi...

They don't really have – they still have two sexes, but they have mating types as well.

And you can have 27,000 mating types in some fungi, which is all about outbreeding so you can mate with just about anything.

Oh, yeah.

It's becoming fungal.

Yes.

So two sexes then in that sense is the worst of all possible worlds you can only mate with.

If you had only one sex, if everyone was a hermaphrodite, you could mate with everybody.

And if you had three sexes, you could mate with two-thirds of the population and so on.

So why two?

Well, this fundamental difference that one is passing on the mitochondria and the other is not.

Beyond that, if you've got multiple mating types, you still have one passes on the mitochondria and the other one doesn't.

So in these fungi that have all of these mating types, there's a kind of a pecking order

that the dominant one will pass on the mitochondria and the less dominant one doesn't pass on the mitochondria.

So you end up with really complex systems.

You can imagine that it's pretty hard to enforce this.

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.

Yeah, so as soon as you've got this fundamental difference, even in single-celled critters, that one of the sexes passes on the mitochondria and the other one doesn't.

Yeah.

So males do not pass on their mitochondria.

And then this is beginning to explain, you know, differences in multicellular organisms between the sexes, between the nature of the germline.

So in some sense, male men do not really have a germline in the sense that women have a germline.

So in the female germline, you make these oocytes and you put them on ice effectively.

You look after them.

You switch them off as much as you can.

You try and protect them from mutations.

You mollycoddle them effectively, whereas men just mass produce sperm full of mutations.

I mean, there's a lovely phrase from James Crow, who's a geneticist, who said there's no greater genetic health hazard in the population than fertile old men.

Yeah.

So why would you go on mass-producing sperm all the time?

Well, part of it is you don't have to pass on the mitochondria.

So you're freeing yourself up to mass-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 the chances are it's going to work out okay.

Because the ones that can swim best, for example, are the ones that are more likely to.

That's not strictly true, but you can imagine it along those lines.

But in the case of oocytes, in the case of the egg cells, you're passing on those mitochondria.

You don't want to be accumulating mutations in that mitochondrial DNA.

You want to switch them off as much as possible, keep them on ice as much as possible.

So very much the differences between how the sexes end up kind of becoming different to each other.

boils down to what are the constraints on your reproductive system.

Yeah.

Well, it does.

Okay.

And the Y chromosome is degenerate.

Yeah, but I mean, there are some things that have lost their Y chromosome altogether.

And they still have sexes because it's not strictly dependent on the Y chromosome.

I mean, again, if you look at what determines sexes across the whole canvas of evolution, it's kind of weird because...

Amphibians, for example, have temperature-dependent sex determination.

So males would develop at a higher temperature than females, or sometimes it's the other way around.

And birds have different sex chromosomes to mammals, for example.

So sex chromosomes have evolved on multiple different occasions.

And what's the Y chromosome doing?

Well, the Y chromosome is basically encoding a growth factor, and that growth factor switches on other growth factors.

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

It's actually the growth rate.

And there was a woman at UCL where I am called Ursula Mitfock who spent her career.

She had about 15 nature papers in the 1960s.

She worked on these kind of questions.

And she saw the growth rate as a common denominator.

The Y chromosome is basically saying grow fast.

Why would he grow fast?

Well, in part, you can grow fast.

You don't have any constraints on trashing your own mitochondria.

Because you're not passing them on.

So you can grow fast and be an advantage to growing fast.

If you're a male, you're going to get the resources.

You grow faster.

If you're a female, you don't want to grow so fast because you need to effectively cordon off your germline to preserve the oocytes for the next generation.

And until you've done that, you don't want to trash your mitochondria.

So you've got a delay phase before you can start growing fast.

Ursula Mitvoeck argued that that was exactly the case.

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

Well, there are, and it has disappeared altogether in some species.

And usually what you retain is one gene, which causes a different rate of growth.

So really, the Y chromosome, yes, it's degenerate.

It's lost most of its genes.

The thing about Mueller's ratchet, which is the degradation of things when you don't have sex or you don't have any recombination, there's two factors that influence it.

One of them is the population size.

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

But if you've got a much larger population, the closer you kind of get towards an infinitely large population, they're not all going to accumulate the same mutations.

And so the population as a whole is going to be fine.

And this kind of goes back decades in population genetics.

But the other thing which is less explored in population genetics is the size of the genome.

So if you, with bacteria, if you increase their genome size up to 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 Y chromosome, yes, it shrunk.

It's a tiny chromosome in comparison with all of the rest.

So it's really how many genes can you maintain in a good state?

And with the Y chromosome, basically, you only need a couple of genes in there.

Basically, it's the SRY gene is saying grow faster.

And you only need that to remain functional.

And then selection at the level of fertile or infertile men will kind of weed out the ones that have got a non-functional SRY gene.

So it's not as if you've got a patchwork.

You can afford to degenerate your Y chromosome down to almost nothing, and you'll still be functional.

It's gone down from, say, 3,000 or 4,000 genes to, in our own case, 37 genes.

So you cannot sustain a large genome if you're inside.

I said population size matters.

If you were a free-living bacterium living out there in the wild with a population of a million, and now you shelter inside another cell, and it's a small cell, now you've got a population of five.

Yeah.

I think they had no need for it.

So what they do is lateral gene transfer is basically you pick up random bits of DNA from the environment.

It can be a bit more sinister than that.

You can kill the cell next to you and take its DNA and load that in.

That does happen.

But for the most part, you pick up bits of DNA from the environment, usually small pieces, usually kind of one gene's worth or something.

And you'd only do that if you're a bit stressed.

If things aren't going well for you, you will then pick up bits of DNA, bind it into your genome and hope for the best.

I guess for most critters, most of the time is not going to work.

But for one of them, it does.

And then they will take over.

And so it kind of speeds up adaptation to a changing environment.

So why are they only using one gene?

There's two ways of seeing this.

You've got a bacterial-sized genome.

It's pretty small.

You're going to replicate faster if you keep that genome small.

It's a kind of a disadvantage to have a big, unwieldy genome.

Eukaryotes have that, and it's kind of an interesting question.

Why would you have such a big, unwieldy genome?

It takes longer to copy and bacteria are really streamlined.

They get rid of genes they don't need, and then they can grow faster.

But now the conditions change.

Now you need this gene.

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 bacterial genome sizes are small.

They've got what you'd say is a small genome, but then a large pan genome, which is kind of all of the genes they have access to.

So an E. coli cell might have 3,000 or 4,000 genes in a single cell, but access to 30,000 or 40,000 genes.

Why doesn't everybody just converge to this streamlined thing that is needed for the current- I mean, I think what keeps the metagenome around is the fact that different strains of E. coli, whatever bacteria they may be, are living in different environments.

So you could have a commensal bacteria living in your gut.

You could have bacteria's E. coli living on your skin, very different environment.

You can then have non-commensal pathogenic E. coli, which are behaving differently.

Again, they can differ in 50% of their genome.

So you've got all of these things going on side by side, and they can all borrow genes from each other.

And this is basically within the same species, whatever species exactly means with bacteria.

It doesn't quite have a meaning.

So this is the kind of dynamic of bacterial evolution, is they retain small genomes with access to large pangenomes, and they're forever borrowing, matching, and so on.

And they effectively remain competitive by keeping their own genome pretty small.

And then eukaryotes kind of threw all of that out and got larger genomes.

And then the question is, well, if you try and do that with a large genome, a eukaryotic-sized genome, and then you go on picking up little bits of DNA from the environment, the chances of you replacing the right gene gets lower.

Right.

So it just becomes less and less efficient the bigger your genome is.

So by the time you get to eukaryotes, they have a large genome.

Why do they have a large genome?

I would say it's because you acquire this endosymbiont and they become the mitochondria.

Now you have a lot more energy available.

There's all kinds of reasons why eukaryotes will tolerate a larger genome.

But the bottom line is you've got the energy to do something with it, which bacteria never really had.

And so now lateral gene transfer is just not good enough to maintain this larger genome.

You're going to have to do something more systematic.

So you pull on an entire genome.

You line everything up.

You cross over between them.

Now it's systematic.

It's reciprocal.

And you can maintain the quality of genes in a much larger genome.

So bacteria never had the need to do that.

I mean, it sounds quite similar, I guess.

systematic organization of like, here's where the relevant functionality is, and here's like... Well, there is a bit, which is to say, with lateral gene transfer, you would normally match the ends to something you've got already.

So I don't know enough about coding to give a comparable example, but effectively, you would be picking up a module which had some resemblance in terms of, okay, it fits into this part of the code.

Yeah.

So you'd only put that in.

And it may or may not be useful there, but it's not just completely random.

It's plugged into a place where you know you have something like that that used to be there or could be there.

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

It's really just a scaling thing.

If you pick up a random piece of DNA, you've got a genome which is 10 times larger.

Then, you know, how fast can you pick up DNA from the environment?

You know, you'd have to pick up 10 times as much to do that.

Do you have the capacity to pick up 10 times as much?

And there's also a penalty for doing it, which is to say...

Like a mutation, you've got no idea what you're plugging in.

It could be almost anything.

You know where you're plugging it.

You're plugging it in the right place.

But what's in that cassette, you don't really know.

So the more you do of it, the more you will degenerate yourself as well.

I see.

So there's kind of costs and benefits to doing it.

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.

And so it's not necessarily experimentation.

Simply, if I assert that giant bacteria are always going to have 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.

For the origin of life, I really wish I could come up with a convincing reason why I should go down in a submersible to a deep sea hydrothermal system like Lost City.

I would love to go to Lost City.

But the trouble is that the ocean chemistry is completely different now to what it was 4 billion years ago.

It's now full of oxygen.

It's full of bacteria and things as well.

But the ocean chemistry is different because there's oxygen, there's no iron, there's no nickel in the oceans.

So you can go to a vent like Lost City and the walls are not made of catalytic minerals anymore.

They're made of aragonite and brucite, so kind of calcium carbonate and magnesium hydroxides and things like that.

And so the chemistry it can do is very different and there's lots of bacteria living there.

So I would gain beyond just the sheer amazement of seeing it.

There's not a lot it would be able to tell me.

So what we're actually doing is experiments in a lab in an anaerobic glove box where you exclude the oxygen so you can do these experiments from reacting hydrogen and CO2.

How many of the molecules in biochemistry can we produce that way?

And it's slow and laborious and you get small amounts and sometimes you get contaminations and sometimes you have to start all over again.

And it's slow work.

But it's moving forward.

It's not just us either.

I mean, there's other groups around the world.

So Joseph Morin's group, for example, has done a lot of really nice biochemistry along these lines.

So that's kind of moving forward, but I think we're talking decades before we're getting to the level where we can say, right, we can drive flux through all of metabolism and here's the set of conditions that 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's been done.

in things like methanol, so not in water.

In water, stuff breaks down.

So we're trying to do it.

It's difficult.

So I believe, I think we'll get there, which is why we're trying to do it.