Today I’m chatting with Nick  Lane, who is an evolutionary  

biochemist at University College London. He has many books and papers which help  

us reconceptualize life’s 4 billion years  in terms of energy flow and helps explain  

everything from how life came to be in the  first place, to the origin of eukaryotes, to  

many contingencies we see today in how life works. Nick, maybe a good place to start would be here. 

Why are eukaryotes so significant in your  worldview of why life is the way it is? 

First, thanks for having me here. This is  fun. I love talking about this kind of thing.  

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. Everything that’s large and complex that  

you can see is composed of this one  cell type called the eukaryotic cell. 

We have a nucleus where all the DNA is,  where all the genes are, and then all this  

machinery, cell membranes and things. There’s a lot of kit in these cells. 

The weirdness is, if you look inside a plant cell  or a fungal cell, it looks exactly the same under  

an electron microscope to one of our cells. But they have a completely different lifestyle. 

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. 

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. 

We’ve got this singularity which happened about  2 billion years ago, about 2 billion years into  

the history of life on Earth. This thing happens once that  

gives rise to all complex life on Earth. The one thing you could conclude from that  

is bacteria and archaea, in terms of their genetic  repertoire, they’ve actually 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 cells that overall  they’ve explored genetic sequence space. 

They had 4 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. 

That something is the acquisition of these  power packs in our cells called mitochondria. 

Now let’s go to the origins of life. You have this really compelling story  

where you imagine that the first life forms  were continuous with Earth’s geochemistry. 

Can you recapitulate the story a little bit? I’ll tell you how I got there first. 

I started out working on mitochondria. That took me into the evolution of eukaryotes. 

Eukaryotes acquire these endosymbionts  that become mitochondria and they  

change the potential of evolution. It doesn’t change everything immediately,  

but it changes where the endpoints can be. It allows the evolution of these large, complex  

cells and eventually multicellular organisms and  us. What are mitochondria actually doing? 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. 

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. 

That charge is small, but  the membrane’s really thin. 

The charge is about 150 to 200 millivolts, but  the membrane is five nanometers in thickness,  

so that’s five millionths of a millimeter. If you shrank yourself down to the size of a  

molecule and stood next to that membrane, you  would experience 30 million volts per meter,  

which is equivalent to a bolt of lightning. That’s the strength of the force of the  

voltage across the membrane, which is colossal. It’s generated by really sophisticated proteins  

that pump protons across the membrane. Then it’s ATP synthase, which is 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 factory. 

It’s pretty much everywhere across life. You wonder, how on earth  

did life come to be that way? If it’s conserved universally across life,  

it looks like it goes right back to the common  ancestors of all cells. So there’s the question.  

How did it arise in the first place? That was, for me, tremendously  

thrilling because it’s a way in, as  a researcher, to the origin of life. 

How did these energy-generating  systems arise in the first place? 

My way in was, the gates were opened  by Bill Martin and Mike Russell who,  

around the early 2000s, were publishing  some amazing papers together. 

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. 

You’ve got an acidic early ocean. You’ve got alkaline fluids coming out of these. 

You’ve got mixing going on in this whole system. 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. 

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. 

It’s very much like a cell is structured. The other thing is, what are these minerals? 

You’ve got these mineralized pores with minerals. The minerals, we think, on early Earth would have  

been a lot of metals in there, things like iron  sulfide or nickel sulfides and things like that. 

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 make all the building blocks of life. 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 that they have  got hydrogen bubbling out of a hydrothermal vent. 

They just take the hydrogen straight  as gas, and they react it with CO2  

and they make all the building blocks of life. What are the enzymes that they use to do that? 

They’re very often using these same metals that  you would have found in the early oceans—nickel  

and iron and so on. How are they powering  

the reaction between hydrogen and CO2? They’re using this membrane potential,  

the electrical potential—the difference  in protons between the outside and the  

inside—to drive that work, effectively,  to power the reaction between hydrogen  

and CO2 to make organics and drive growth. This was all in place before I came along. 

This was coming from Mike Russell and Bill  Martin. The details are very uncertain.  

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. If it did emerge that way, then it would say,  

"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. 

That’s why, in the end, an  endosymbiosis that gives rise to  

eukaryotes would free you from the constraints  of generating a charge on the membrane. 

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

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. What are the forces that are going to give  

rise to life, 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? It becomes astrobiology, really. It’s  a thrilling change of perspective to come from my  

own background, which was to do with mitochondrial  biology, an organ transplantation once upon a  

time, and spinning on a pinhead, you end up  working on the origin of life. It’s fantastic. 

It’s so fascinating. Just to recapitulate,  for my own understanding and the audience’s,  

let’s just break down what we have here. You have the analog of a cell in these pores. 

You have something which concentrates the buildup  of these organics so that they don’t just all  

diffuse in some big primordial soup. This is why you think some primordial  

lake is not where this happened. It had to be concentrated in some entity. 

Then you’ve got a chemiosmotic gradient,  a proton gradient, which drives work. 

Specifically, it favors the fixation  of carbon dioxide to drive the reaction  

with hydrogen gas to make organics. Then you’ve got, along this membrane,  

catalysts, which are basically early enzymes. You’ve got enzymes, you’ve got the cell,  

you’ve got the proton gradient. The story is that you make very simple  

organics with CO2 and H2, and then those simple  organics are then recatalyzed to make more and  

more complex organics, and TL;DR, metabolism,  fatty acids, and nucleotides, everything else. 

That’s basically it. What do you  get if you react hydrogen and CO2? 

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 2, 3, 4, 5 carbon units in the chain. 

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. There are lots of steps along here,  

but this is the basic starting point  for all of biosynthesis in biochemistry. 

Then if you make fatty acids, they will  spontaneously, because of the hydrophilic  

nature of their different sides, they  will spontaneously form a membrane. 

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

A fatty acid is a long chain, 10, 12, 15  carbons in the chain instead of four or five. 

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. 

You can make these things at 70-90° centigrade,  across a range of pH from around pH 7 up to  

about pH 12, and in the presence of ions like  calcium and magnesium and other salts and so on. 

You make a vesicle with a bilayer membrane around  it, which is the same as a cell membrane. They’re  

amazingly dynamic things. They’re always  fusing with each other and breaking apart,  

fissioning, separating into two or three. They’re very dynamic things under a microscope. 

You could have imagined that life is this  Frankenstein-like moment where things zap  

alive, and now you’ve got life. I hate that as an idea, but go on. 

Yeah, but that’s the alternative, where the bolt  of lightning makes these organics, et cetera. 

Here you have this story where every life  form you see is continuous with something  

which is continuous with something which  is eventually just continuous with entirely  

spontaneous chemical reactions. That’s just a very interesting  

way to think about the evolution of life. A cell is effectively reduced inside, which  

is to say it’s got electrons inside. Outside it’s  relatively oxidized. You pump all these protons  

out, so it’s acidic outside, it’s alkaline inside,  and it’s reduced inside. That’s like the Earth.  

All the electrons are in the iron in the core and  the mantle of the Earth. It’s relatively alkaline  

inside. That’s why there’s alkaline fluids in  these vents. The outside is relatively oxidized.  

You’ve got all the CO2 in the oceans. The cells are a little battery with  

the same structure as the Earth. If you look in a hydrothermal system,  

the cell membranes around 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. 

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

You keep having on multiple scales this same  kind of… The idea that the Earth is a giant  

battery that produces little living, cell-like,  mini batteries, it’s a rather beautiful idea. 

You can’t allow yourself to get too hung up  on a metaphor, but it’s a beautiful image. 

Yeah, 100%. Basically you’ve got Earth as this  giant cell, and then from the hydrothermal vent,  

this little bubble pops off. Bubbling off many copies of the Earth. 

It’s such a fascinating theory. The thing  I want to understand is what part of  

life the way it works now is contingent,  and which would you expect to be shared  

even if you found life on another planet? It sounds like you’re saying that carbon,  

the chemical profile, is just the obvious  candidate to build life on top of. Proton  

gradients? Is there another way you could  build these chemiosmotic gradients that  

drive work? We have other chemistry. In principle, yes, you could use sodium  

ions instead of protons, but it’s very different. If you’re starting with carbon dioxide, the first  

thing to realize about that is that 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. I think of CO2 as 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. 

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

You can’t do that with silicon. 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 life would start  on a planet where there isn’t an intelligent  

designer who’s putting it all together, you  need molecules that can do that chemistry,  

and CO2 is the outstanding example. Water is  everywhere. Hydrogen, oxygen, these are all  

elements that are very common in the universe. So you’re going to keep on getting this same  

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. What fraction of them would  

you say have a non-eukaryotic life? I’ll take a punt here. I would expect  

that if you’ve got these same conditions  on a wet, rocky planet, you’re going to  

be producing these same vents because it’s  the same chemistry that’s going to happen. 

So even the vents are not contingent in your view? No. The vents are produced by a mineral called  

olivine, which is really  common in interstellar dust. 

The mantle of the Earth is made of this  mineral called olivine. It will react  

with water. When it reacts with water, it’s  slow, if you were to put a lump of olivine in  

a bucket of water, you’ll not see very much. But if you’re dealing with the pressures down  

at the bottom of the ocean and warmer  temperatures, you’re producing bucket  

loads of hydrogen gas in alkaline fluids. That’s what these hydrothermal vents are. 

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. This is going on in  

our own solar system right now. If there are 20–30 billion Earth-like  

planets and presumably some big fraction of  them have these vents if they all have these  

rock formations, is your view that a notable  fraction of them have life that also operates… 

My view would be yes. Any wet,  rocky planet would have a decent… 

With the same metabolism? Yes. 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 with  

another CO2 molecule, the parts of the molecules  that are going to react are quite predictable. 

This is a naive question, but what is the reason  to think that there are no alternative chemistries  

which lead to alternative metabolisms? Perhaps under very different conditions,  

you could end up with… But if you’ve got essentially  

similar conditions… The other thing is that we  know that even with very different chemistries,  

you end up with a similar subset of molecules. The kind of organics you see on meteorites,  

it’s 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. 

These are molecules which are basically  stable and tend to be formed under a  

wide range of conditions. So 20 billion Earth-like  

planets with water and these rocks. Not necessarily Earth-like, but wet and rocky. 

If you just had to pull a number out of  nowhere and just say, "This fraction has  

nucleotides," what fraction would you say? I would say a substantial fraction. 

Like over 1%? Yes. I would imagine 50% or something. 

Really? You say pull a number out of a hat. 

I’m doing exactly what you’re saying. I’m pulling a number out of a hat. 

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

Again, I know we’re just chatting here. But according to this story, pretty  

sophisticated organics are extremely  abundant throughout the universe. 

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 throughflow. 

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 not necessarily in the oceans or in  

the atmosphere or anywhere else. I guess you could have prokaryotes  

then who just take over. We did have this,  

they proliferated through the oceans and  changed the composition of the atmosphere. 

Not just the atmosphere, but  also the whole of geology. 

Hundreds of minerals are  basically the product of life. 

So your view is that if eukaryotes are the  fundamental bottleneck, you can go from  

geochemistry to early life, that’s easy. Going from early life to changing the  

entire composition of the Earth  through early prokaryotes is easy. 

If those two things are easy and then you’ve got  10 billion planets in the Milky Way that have gone  

to the middle step, does that imply that  there’s on the order of 10 billion planets that… 

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

So there’s a long gap there as well. So just having nucleotides,  

that’s a requirement to get any further. I see. Again, if you had to pull a number out  

of the air, what fraction have done that? Well, a lower fraction, obviously. 

Over a billion? I would like to be 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. 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 work. Because if you’re dealing with CO2 and hydrogen,  

you’ve got this same fundamental problem. How do you make them react? 

So there are hundreds of millions of planets  in the Milky Way which presumably have  

something like ribosomes and DNA and RNA? Yes, that’s my own thinking. 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. Now, the further from CO2  

fixation towards genetics you get, the  less similarity there’s going to be. 

This is not my inclination, but  if I were a God-fearing person,  

I would hear this and I’d be like, "Wow,  this is a vindication of intelligent design." 

The laws of the universe just favor this chemistry  which leads to life, at least according to the  

story, so strongly that it’s hard to resist this  formation. I’m curious about your interpretation. 

I agree with you. I find it  almost a little disturbing. 

I have to say that I’m not a religious person  either, but I don’t object to religion. 

I’m not a militant atheist at all. I like the fact that religions have  

searched for meaning and searched for origins. I have some fellow feeling with that search  

and 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. This is Einstein’s  

God. In terms of what most people understand  by God, most people look for comfort in God and  

are looking for something which is meaningful  to them and who’s been involved in humanity. 

This is a very cold kind of "God as  thermodynamics" who sets the laws  

of the universe in motion, reproducibly  gives rise to the same kinds of things. 

Yes, you could interpret it in a  natural theistic way, but I don’t  

think many people would get that much comfort  or meaning from that way of seeing the world. 

A very basic question, but if life is not  only abundant but almost inevitable in all  

these rocky planets, then the bottleneck to  not seeing aliens everywhere, presumably,  

is eukaryotes which leads to complexity. There’s more than one bottleneck,  

but eukaryotes is in my own mind the big one. It would have to be the case that out of  

billions of potential planets that  could give rise to eukaryotes, only on  

Earth does this chance occurrence happen. I wouldn’t argue that. Only on Earth? No,  

I don’t think so. What I would  dig my heels in about a little  

bit is there’s a Carl Sagan cosmological view. We’re talking about almost the inevitability  

of life arising according to these laws of  chemistry and thermodynamics, and you get life. 

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. 

If you roll back the clock 2  million years, there aren’t any  

humans around either. We’re just the icing. Why is it supposedly this hard to have this  

successful endosymbiotic event? There are multiple reasons. One  

of them is that prokaryotes, we should say  archaea and bacteria, are pretty small things. 

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. 

Once you’ve got these cells inside you, that  may have happened on scores of occasions. 

There’s some tentative evidence that  suggests it happened with archaea. 

There’s one nice example where the  haloarchaea 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. The question is, how often would it go  

wrong and you lose your endosymbiont? I guess that would be the more likely outcome,  

that you pick up a bunch of genes and you  lose your endosymbiont. It simply doesn’t  

work out. It’s hard to know exactly  what all the bottlenecks are here. 

But there has been some modeling work  done to see if 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? 

Under most conditions that these people have  looked at there in Santa Fe, the answer is you  

do better if you’re not part of the symbiosis. Only under certain conditions will you do better. 

So predictably, the endpoint  is that it doesn’t work. 

Given how many bacteria and archaea there are,  throughout Earth’s history there are trillions,  

trillions, and trillions of these running around,  there are many situations in which there was an  

endosymbiosis, and in only one case it succeeded. The odds would have to be remarkable. 

It would have to be extremely, extremely tough. It is a vivid way of seeing it. 

We know what bacteria and archaea  look like and people have been  

studying these things and finding new examples. 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. 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 a standard prokaryotic genome size. 

You’re talking four or five thousand genes. So these are not eukaryotic by any  

stretch of the imagination. Then you look at a eukaryotic cell. 

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 weird. 

Why would a single-celled alga living  in the ocean have all the same kit  

that one of my kidney cells has? The easiest way to understand that  

is to say 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 battle between  the host cell and the endosymbiont for finding  

a way of living together, you can argue for the  nucleus arising that there is all kinds of genetic  

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

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

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. 

The broader thing we’re trying to understand here  is if this story is true, there’s life everywhere. 

But eukaryotes giving rise to intelligent life,  which is about to go explore the cosmos, is as  

far as we can tell, happening only in one place  in our light cone. So why is that? You could say,  

"Well, the bottleneck is the eukaryote and it  is very hard to get a successful endosymbiosis  

which then continues over time. But what is the fundamental  

problem this is solving? Large genomes. To have a multicellular  

organism where effectively you’re deriving  from a single cell, that restricts the chances  

of effectively all the cells having a fight. There are plenty of examples of multicellular  

slime molds, for example,  where the cells come together. 

They can form structures like a stalk,  for example, which loosens spores into  

the environment, but they 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. You express this lot in the  

liver and that lot in the brain. So you must have a large genome. 

The only way you can have a large genome is by  having mitochondria and having a eukaryotic cell. 

There are no examples of this level of  sophistication of a multicellular bacterium. 

That’s quite interesting. The reason you need a  large genome is just to put all your eggs in one  

basket so that every cell in the body feels  incentivized to make the germline continue. 

You’re restricting the amount of fighting. The thing I was getting at is,  

the eukaryote is solving for a large genome. It’s allowing the cell to get much bigger. 

Why are we so confident that this is the  only way this problem could have been solved? 

It just seems like if there are billions of  planets which have gotten to the precursor  

stage here, none of them can find an  alternative solution to mitochondria  

for just letting themselves get bigger? Beggars belief. I know where you’re coming from. 

It kind of makes me wonder whether we’re,  because we’ve only observed one way to solve  

this solution, we’re assuming that there  must be only one way to solve the problem. 

The problem itself doesn’t seem… You just want  a smaller copy of the genome sitting next to  

the site of respiration. That’s the basic  problem. There’s no other way to solve that? 

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

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. 

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, we’re  talking a three-megabase genome,  

so around 3,000 genes in it. And you’ve got tens of thousands of copies. 

Sometimes the very largest ones have 700,000  to 800,000 copies of their complete genome. 

The energy requirements for copying all of that  and expressing all of those genomes are colossal. 

What we have with endosymbiosis,  we still have extreme polyploidy,  

but we’ve whittled away all  the genes that you don’t need. 

A symbiosis is based on  effectively complementarity. 

You’ve got a symbiont that’s doing  something for the host cell and  

the host cell that’s taking something or  giving something back to the endosymbiont. 

So it’s 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 of 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. But just to make sure I understood the  

feature request correctly, it’s basically:  you want a smaller copy of the genome that  

is only relevant to respiration sitting  across the entire membrane, and many copies  

of it sitting across the entire membrane. I guess I’m just, it seems hard for me to… 

You’re incredulous that this same  thing would be repeated. Yes. 

There’s no other way to solve  this on the billions of planets? 

Because if there were another way to solve it,  then what you would expect is that as soon as  

you get to the stage of prokaryotes that have  other niches that they could colonize if only  

they could drive towards complexity, this would  somehow be solved and then you’d have eukaryote,  

and then intelligence… 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. Of course, I cannot say that there’s no other  

way that it could possibly happen. But it’s also hand-waving to say, "Oh,  

evolution’s so clever, the universe is so big,  there’s got to be another way that it can happen." 

You know, engage your brain and  tell me how it’s going to work. 

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

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. Ok,  

I’m limited. But if you think there are some, then  you tell me what they might be and you test them. 

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…  I grew up watching Star Wars and Star Trek and  

reading Hitchhiker’s Guide to the Galaxy. I love the idea that the universe is full  

of all kinds of stuff as much as anybody. So I don’t like my position of saying,  

"Actually it’s quite limited and you’re going  to see the same kinds of things elsewhere." 

It’s not a position that I dreamt of having. 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 if you simply say  

you’re limited by your imagination, you’re wrong  because you 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 them, 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 probabilistic thing that carbon is  so common, water is so common, you are going to  

keep seeing the same constraints again and again. If it’s the case that a significant fraction of  

rocky planets should have at least  organics and cells and so forth,  

it feels like we should be able to learn pretty  soon whether this story is correct, right? 

If that part ends up being true, and we  also don’t see eukaryotes elsewhere, then  

the whole picture is lent a lot more credence. But are we about to go to a couple of moons  

and see if we can find some  organics there and so forth? 

That may take us a while but yeah, we  already know that there are organics. 

On Enceladus, for example, one of the moons of  Saturn, when Cassini flew by some years ago,  

there were plumes coming through cracks in the  ice of water, but with organics dissolved in  

the water, and hydrogen and organic molecules. The pH is around eight or nine, so it implies  

that underneath that frozen surface,  which people say is about 5km thick,  

underneath that there’s a liquid ocean. Underneath that there are hydrothermal  

systems producing alkaline fluids  which have made the oceans alkaline. 

It’s the same 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 we shouldn’t  introduce bacteria from our own system into there. 

Bacteria from the Earth would probably survive  extremely well in a place like Enceladus. 

It would be lovely to know, and  I’m all in favor of exploration. 

Help me understand how  replicators arise in this world. 

If you’ve got these independent pores and  they’re each individually accumulating their  

own organics through the spontaneous processes,  initially at least there’s no shared inheritance. 

It’s not like if there’s a very  successful pore, it then causes  

there to be more pores exactly like it. Think what I would call protocells inside  

these pores. The organics  

that you’re making are self-organizing. A fatty acid bilayer membrane will form. 

What you really need for positive feedbacks  is to be making the organics inside this  

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. 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. 

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. 

So the rise of replicators  happens relatively early. 

I would hesitate to use the word  replicator here. These are growing.  

I would say they are 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. At what point do we get to the gene’s-eye  

point of view, where the gene is  the coherent unit of replication? 

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 evolve into something more complex. 

To some extent you can, but you’re  always going to get the same thing. 

The same environment will  always give you the same thing. 

As 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  vents in the end and do other things. 

So as soon as you’ve got genes, you’ve  got the potential to do almost anything. 

If you’ve got naked bits of  RNA, what tends to happen is  

they’re selected for their replication speed. They just go on making copies of themselves. 

They don’t become more complex, they  don’t start encoding metabolism, they  

just go on copying themselves and it’s a dead end. If you’re trapping them inside growing protocells,  

then effectively they’re sharing the same fate. 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’s growing faster, it makes  

a copy of itself and it’s still associated. So you’ve got selection as we know it in cells  

today, where the replicators are the genes, but  the system which is being reproduced is the cell. 

Your sort of mitochondria-first viewpoint  that helps explain why there’s two sexes. 

Maybe you can recapitulate that argument. But I’m just curious if there were a world  

where prokaryotes had evolved sex, do you think  they would have likely evolved just one sex? 

I’m going to unpack that a little bit because  what have mitochondria got to do with sex? 

So what they have to do with sex is that  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. 

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. 

That’s an approximation, it’s not always true. There are exceptions to that rule, but it’s  

a rule of thumb in biology that the females  pass on the mitochondrial DNA. 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. 

Everything which is worse than it would  have been gets eliminated by selection. 

So 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. 

There’s a very small genome, but  there are multiple copies of it. 

The question is, how do you keep that clean? How do you prevent that from degrading  

and degenerating over time? Because let’s say 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. Now you acquire another couple  of mutations and you can degenerate over time,  

a process called Muller’s ratchet. It’s basically, these mutations  

are somewhat screened from selection by being  compensated for by other clean copies you have. 

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 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. You can do that by multiple  

rounds of cell division. But it helps if you’ve  

got two sexes where effectively only  one sex passes on the mitochondria. 

You’re already sampling, you’re  already increasing the variance  

and you’re increasing visibility to selection. It’s about the quality of mitochondrial genes. 

Can you help me understand why it’s  the case that uniparental inheritance  

of mitochondria helps increase variance? We’re talking about variance between cells. 

If you imagine that you have 100 cells and  they all come from the same parent, let’s say. 

If you give all the mitochondria that you have  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  

take a small subsection of those and 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 and this cell is  going to happen to have got all the bad copies. 

Now you subject these 100 cells to  selection and say, "How are you doing?" 

The one that got all the good  copies does well, that gets on. 

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

The ones that got all the mutants, they get hit. 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? It’s about sampling, basically. And  uniparental inheritance is a form of sampling. 

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

You’re not mixing up mutations that both parents  had. You’re taking a subset. So you’re always  

increasing variance between the daughter cells. Uniparental inheritance is giving you a subset. 

Then there’s the question  of why there’s two sexes. 

We explained why there’s this evolutionary niche  for only one parent to pass on the mitochondria. 

So there’s at least two niches. One is to pass on the mitochondria,  

one is don’t pass on the mitochondria. Once you’ve established those two,  

then you can ask the question, "Why  aren’t there more than two sexes?" 

Then you could just say, "Well, there would  just be a repetition of one of these two. 

These are the two fundamental ones." I mean, it’s more complex, but the  

thing about two sexes is you could say  it’s the worst of all possible worlds. 

Let’s take it away from humans so  we can be dispassionate about it. 

You’ve got these single-celled critters swimming  around and they’re all producing gametes. 

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 do exactly the same thing  

that we do on a single-cell scale. But having two sexes means that you  

can only mate with 50% of the population. The other 50% is the same sex as you and  

it’s not going to accept your gametes. If you had three sexes or four sexes,  

then you would be able to mate with a  larger proportion of the population. 

With some fungi, they still have two  sexes, but they have mating types as well. 

You can have 27,000 mating types in some  fungi, which is all about outbreeding. 

So you can mate with just about anything. If you’ve been to some college campuses today,  

they’re replicating some portion of that. Becoming fungal, yes. Two sexes then, in that  

sense, is the worst of all possible worlds. If you had only one sex, if everyone was a  

hermaphrodite, you could mate with everybody. If you had three sexes, you could mate with  

two-thirds of the population  and so on. So why two? Well,  

there’s the 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 that passes on the  

mitochondria and the other one doesn’t. So in these fungi that have all of these  

mating types, there’s 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 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 a minimization of error. You have this really interesting discussion  

about how this not only explains why there’s  two sexes, but the particular differences in  

why eggs and sperm developed the way they do,  why there’s different amounts of replications  

before they are mature, et cetera. I wonder if we can recapitulate that. 

So as soon as you’ve got this fundamental  difference, even in single-celled critters,  

that one of the sexes passes on the  mitochondria and the other one doesn’t…  

Males do not pass on their mitochondria. This is beginning to explain differences  

in multicellular organisms between the  sexes, between the nature of the germline. 

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

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. There’s a lovely phrase from James Crow, who’s  

a geneticist: "there’s no greater genetic health  hazard in the population than fertile old men." 

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

Part of it is you don’t have to pass  on the mitochondria, so you’re freeing  

yourself up to mass-produce sperm. 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 the oocytes, in the case of the  egg cells, you’re passing on those mitochondria. 

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

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

Very much the differences between how  the sexes end up becoming different  

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

Let’s talk about the Y chromosome,  which is also not recombined. 

Just the same way that female egg cells try to  minimize the amount of duplications in order to  

preserve the quality of the mitochondrial  DNA and prevent errors, why isn’t the  

same thing happening with the Y chromosome? Shouldn’t all this sperm duplication be resulting  

in all kinds of errors in the Y chromosome? Well, it does. The Y chromosome is degenerate. 

I’m going to make that the title. But there are some things that have  

lost their Y chromosome altogether. And they still have sexes because  

it’s not strictly dependent on the Y chromosome. If you look at what determines sexes across the  

whole canvas of evolution, it’s weird. Because amphibians, for example,  

have temperature-dependent sex determination. So males would develop at a higher temperature  

than females, or sometimes  it’s the other way around. 

Birds have different sex  chromosomes to mammals, for example. 

So sex chromosomes have evolved on  multiple different occasions. What’s  

the Y chromosome doing? Well, the Y chromosome  is encoding a growth factor, and that growth  

factor switches on other growth factors. The earliest difference that you could tell  

between the two sexes in embryonic development  is not the activation of the Y chromosome,  

the SRY gene. It’s the growth rate.  There was a woman at UCL, where I am,  

called Ursula Mittwoch, who spent her career…  She had about 15 Nature papers in the 1960s. 

She worked on these kinds of questions. She saw the growth rate as the common  

denominator that the Y chromosome is saying,  "Grow fast." Why would you 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.  

This might 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. 

Until you’ve done that, you don’t  want to trash your mitochondria. 

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

Interesting. Is this why women live longer? Ursula Mittwoch 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 usually do. Suppose that evolution on humans just continued  

naturally for the next billion years. We didn’t have AGI and  

human gene editing, et cetera. Is the equilibrium that you’d anticipate that the  

Y chromosome would then just fade away altogether  and there’d be some other way of determining sex  

and sex-dependent characteristics? There are, and it has disappeared  

altogether in some species. Usually what you retain is one gene which causes  

a different rate of growth. The Y chromosome  is degenerate. It’s lost most of its genes. 

The thing about Muller’s ratchet—which is  the degradation of things when you don’t  

have sex or you don’t have any recombination—is  that there are two factors that influence it. 

One of them is the population size. 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 get towards an infinitely large  

population, they’re not all going  to accumulate the same mutations. 

So the population as a whole is going to be fine. This goes back decades in population genetics. 

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

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. With the Y chromosome, yes it shrunk. 

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

It’s really how many genes can  you maintain in a good state? 

With the Y chromosome, you only  need a couple of genes in there. 

It’s the SRY gene saying grow faster, and  you only need that to remain functional. 

Selection at the level of fertile or infertile  men will weed out the ones that have got a  

non-functional SRY gene. It’s not as if you’ve  

got a patchwork of mutations. You can afford to degenerate your  

Y chromosome down to almost nothing  and you’ll still be functional. 

It’s quite interesting because you were  saying that the same thing happened to  

the mitochondrial DNA, which is a tiny  genome, and has shrunk over time, starting  

from the original bacteria that was engulfed. It’s gone down from, say, 3,000 or 4,000 genes to,  

in our own case, 37 genes. You cannot sustain a  

large genome if you’re inside. As 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. 

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-sized genome. 

It might be worth explaining why it is the  case that sex is preferable to lateral gene  

transfer in the sense of systematic pooling  and parallel search across gene space. 

If there is this advantage of sex and  bacteria have some antecedent to it,  

why didn’t they just get the whole thing? 

Is it just that it’s not  compatible with their size? 

I think they had no need for it. What they do is lateral gene transfer. 

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. It’s usually small pieces,  

usually one gene’s worth or something. 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. For most critters, most of the time it’s not  

going to work, but for one of them  it does, and they will take over. 

It speeds up adaptation to a changing environment. 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 kind of a disadvantage to have a big,  

unwieldy genome. Eukaryotes have  that. It’s an interesting question.  

Why would you have such a big, unwieldy genome  that takes longer to copy? 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  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. Bacterial genome sizes are small.  They’ve got what you’d say is a small genome,  

but then a large pan-genome, which is  all of the genes they have access to. 

So an E. coli cell might have 3,000  to 4,000 genes in a single cell,  

but access to 30,000 to 40,000 genes. What is keeping the metagenome around? 

Why doesn’t everybody just  converge to this streamlined  

thing that is needed for the current context? What keeps the metagenome around is the fact that  

different strains of E. coli, or whatever bacteria  they may be, are living in different environments. 

You could have commensal  bacteria living in your gut. 

You could have bacteria E. coli living on  your skin, a 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. You’ve got all of these things going on  

side by side and they can all  borrow genes from each other. 

This is within the same species,  whatever species exactly means with  

bacteria, it doesn’t quite have a meaning. This is the dynamic of bacterial evolution. 

They retain small genomes with  access to large pan-genomes,  

and they’re forever borrowing, matching and so on. They effectively remain competitive by keeping  

their own genome pretty small. Eukaryotes threw all of  

that out and got larger genomes. Then the question is, if you try to 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. 

It just becomes less and less  efficient the bigger your genome is. 

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  

endosymbiont, 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. 

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. Bacteria never had the need to do that. 

As I was reading your book,  just to ease my own ignorance,  

I was trying to come up with an analogy. Please let me know in which ways it’s naive. 

Also thanks for tolerating all  my other naive questions today. 

Here in Silicon Valley, maybe an analogy that will  work for us is to think about a GitHub repository. 

I’m already out of my depth now. Basically you have this code base,  

and you have ways in which you do version control. The usual way this is done, and this may be  

analogous to sexual recombination, is that  somebody makes what is called a new branch. 

In that branch, they might make  changes which are organized next  

to the function that they’re trying to change. When the maintainer is looking at the code, they  

can see what the original code was at this point. Here’s the modification to that point of code,  

and you see the diff, and then you can  merge it back if it seems sensible. 

The analogy here might be sexual recombination  that’s organized along the relevant gene. 

You see this allele, you see that allele. Evolution here is a maintainer which is  

then driving one of them to fixation. The analogy for asexual reproduction,  

cloning with mutation, would be one where you fork  the repository, then you make a random change. 

You just change some random variable,  you change a word, you change a bit. 

Almost every single time this will be deleterious. 

And even when it’s not deleterious,  there’s no merge functionality. 

You’ve got millions of repositories that are  then spawning millions of other repositories. 

Even if some improvement has been made on one  of them, there’s no systematic way in which the  

improvements can be merged together. It sounds quite similar, yes. 

Finally lateral gene transfer. Here  the analogy might be, you’ve got one  

repository for editing web pages and another  repository for controlling airline software. 

What you just do is you take a  random 500-line sequence in this  

web page editing software and you just put it in a  random point in the airplane management software. 

There’s no systematic organization of,  "Here’s where the relevant functionality is." 

There is a bit, which is to say with lateral  gene transfer, you would normally match the  

ends to something you’ve got already. I don’t know enough about coding to  

give a comparable example, but effectively  you would be picking up a module which had  

some resemblance in terms of, "Okay,  it fits into this part of the code." 

So you’d only put that in. 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  you don’t know what you put in. 

So then I don’t really have a good intuition  for why lateral gene transfer does not produce  

similar benefits to recombination. It’s really just a scaling thing. 

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

how fast can you pick up DNA from the environment? You’d have to pick up 10 times as much to do that. 

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

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 it, the more you  will degenerate yourself as well. 

There are costs and benefits to doing it. Maybe to close this off,  what is the  

experiment or method of interrogation,  which would give us the most amount  

of information about the this story? There are so many aspects of this story,  

so many possible answers I could give there. In terms of eukaryotes, giant bacteria, the  

likelihood of life, a lot depends on observation. We simply don’t know enough about what’s out  

there. So it’s not necessarily experimentation.  If I assert that giant bacteria are always going  

to have extreme polyploidy with multiple copies  of their genome, and you find an example that’s  

not like that, my ideas are already breaking up.  So that’s 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. 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 calcium carbonate and magnesium  hydroxides and things like that. 

So the chemistry it can do is very different,  and there’s lots of bacteria living there. 

I would gain, beyond just the  sheer amazement of seeing it,  

there’s not a lot it would be able to tell me. 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  reacting hydrogen and CO2. 

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

It’s slow and laborious, and you get small  amounts and sometimes you get contaminations. 

Sometimes you have to start all over again. It’s slow work, but it’s moving forward. It’s  

not just us, either. There are  other groups around the world. 

Joseph Moran’s group, for example, has done a lot  of really nice biochemistry along these lines. 

That’s moving forward, but 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 are  12 steps in this synthetic pathway, and all the  

intermediates are unstable and break down easily. It has been done in things like methanol,  

so not in water. In water, stuff breaks down.  We’re trying to do it. It’s difficult. I believe  

we’ll get there, which is why we’re trying  to do it, but maybe we won’t, in which case,  

again, the hypothesis is wrong. You’ve got to wake up every morning  

and think the hypothesis could be wrong. It’s beautiful, it makes sense, but there are  

so many beautiful ideas killed by ugly facts. There’s no good believing that you’re right. 

You’ve got to believe you’re  probably wrong and keep going anyway. 

The other thing which I’m excited about at the  moment is work on anesthetics and mitochondria,  

it turns out - I heard this from a guy called  Luca Turin a few years ago now—who pointed out  

to me that anesthetics affect mitochondria. I had no idea that anesthetics affect  

mitochondria. They do. We’ve been doing  experiments on it, and it seems not fully  

established yet, but it does seem as  if their main effect is mitochondria. 

Anesthetics work on all kinds of  things, including things like amoeba. 

It doesn’t prove anything but it’s beginning  to say, if you can make an amoeba unconscious,  

then was it conscious before? Not as we  understand consciousness. The way we would  

understand consciousness is really  about neural nets, a nervous system,  

and all the complexity of human consciousness. That’s what we primarily think about. 

But there’s a deep problem which goes back. It’s the mind-body problem, but it was framed  

by David Chalmers as the hard problem of  consciousness, which boils down, as my  

understanding of this is, to more or less that we  don’t know what a feeling is in physical terms. 

You can understand the information  processing of a neural network. 

But if you feel miserable or you feel pain  or you feel love or whatever it may be, what  

actually is that in the chemistry of the system? The problem is that you have all of these neural  

nets firing and some of them are conscious. We’re aware of what we’re thinking about. 

Others, which seem to have all the same properties  in terms of the neurons—they have synapses,  

they have neurotransmitters, they depolarize,  they pass on an action potential—but we’re  

not conscious of it. It’s non-conscious  information processing. So there’s this  

question. If anesthetics affect things that don’t  have neural nets, and feelings are something that  

we can’t define in terms of a neural net, could  it be that feelings are somehow linked more  

broadly to life? So why would they be? The way I  think about this is as an evolutionary biologist. 

The first question is, would we think that  the feelings are real? I would say yes. Do  

we think that they evolved? I would say  yes. I think any evolutionary biologist  

would say yes to those questions. If it’s real and it evolved,  

then natural selection must be able  to see it and act on it in some way. 

In other words, there’s something physical  about it that can be selected for. 

I don’t think there’s anything  controversial about that statement. 

But if it’s physical and real and has  been selected on, the implication is we  

should be able to measure it. It has to offer an advantage  

for selection to act on, and if it’s a  physical process, it should be measurable. 

But we don’t really know what  we’re trying to measure here. 

I then revert back to thinking, what would  a bacterial cell need to do? This is just  

back-of-the-envelope thinking. I immediately  think about metabolism. What’s the difference  

between the inside of a bacterial cell and  the outside world? The inside is metabolically  

alive. It’s doing stuff with its chemistry  all the time, and it’s at a colossal rate. 

A bacterial cell will have about a billion  reactions every second in this metabolism. 

I’m immediately left wondering,  how is it all controlled? 

How do you get this cell to have  a coherent behavior so it decides,  

"I’m going to crawl over there"? How do you even know what state you’re in? 

How do you synchronize all of this biochemistry? Probably most people’s answer to that would be  

metabolic regulation of one sort or another. But that’s not really the driver. 

The driver in the end is  the thermodynamic drivers. 

How many electrons do you have? That’s in the form of food  

or NADH or whatever it may be. How much energy do you have in the form of ATP? 

These are the things that are going to  synchronize reactions in the same phase. 

The problem there is when you’re dealing with  molecules, you’re dealing with tens of thousands  

of them, so you’ve got a large statistical  sampling which is time-consuming to figure out. 

But there is a better way of doing it, which is  to say, if you’re taking electrons from food in  

NADH and you’re passing them to oxygen, but  you’re generating a membrane potential and  

that’s driving ATP synthesis, you can measure  the rate of change and the membrane potential  

and the fields that would be generated,  electrostatic and electromagnetic fields. 

That’s going to give you a handle on your  state, on your metabolic state in relation  

to the outside world. Is there enough food  there? Is there enough oxygen there? Is it  

too hot? Is there a virus? Do I have enough  iron to be able to do all these reactions? 

You’ve got all these potentially conflicting  feedback loops, and you’ve got to make a decision. 

Just thinking loosely about how a bacterial cell  is going to behave, you find that you’re already  

framing it in terms of, as an entity, as a cell,  it’s got to make some decision about what to do. 

It’s got to integrate all this information  and make a coherent decision as a self,  

as an entity. Is that free will? Probably  not in any way that we recognize it,  

but it makes a decision in relation to its  environment, and the outcome is survival or not. 

What I think a feeling is then is effectively  the electromagnetic fields generated by membrane  

potential, which is telling you what your  physical metabolic state is in relation  

to the environment you’re in. That leads me to a question. 

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 deficit so the brain closes down? 

That would be dull if it were true, but it  would be useful to know if it were true. 

Much more exciting would be, do mitochondria  generate the kind of fields that I was talking  

about in bacteria that are giving some indication  of your status in certain mitochondria, certain  

neurons, and the anesthetics interfere with that? That would be magical if that were true. 

That would be a whole new direction  of research, which would be fantastic. 

It’s very difficult to measure fields. It’s very easy to measure artifacts  

that you don’t know what you’re really doing. We need more physicists working in this area to  

do the hard calculations, and we need more data. Is it really just in one of these respiratory  

complexes, complex I? So there’s lots of  

standard molecular biology that we can do. It’s beginning to point to this idea that yes,  

there’s something going on about the  way that complex I works which may  

link to generating fields that may link to how  anesthetics work. That’s just fun. The thing  

that’s great about science is it’s really fun. It’s one thing I’m always trying to get across  

to the people in my lab. You can’t forget the fun.  If it becomes drudgery, then you best go because  

you’ll make much more money somewhere else. You’ll have a better life somewhere else. 

But if what you really care about is the  science and the experiments, it’s got to be fun. 

You’ve got to really enjoy  wanting to go and do that. 

I have to say, one of the great  things for me is it’s always been fun. 

It’s been great to vicariously get a sense  of that feeling from reading your books. 

Thank you. For the audience, this conversation has been  

most coupled with Nick’s book, The Vital Question. I would recommend getting that if you want to  

better follow the argument here. There’s way more detail there  

that would be helpful. One, this is a thing I was  

telling you earlier, it fills a niche of books  which, unfortunately, there are just very few of. 

There are textbooks where you can spend  2,000 pages learning about molecular biology. 

But a layperson who’s curious is just  practically not going to get a chance to do that. 

On the other end, there are what are  basically just anecdotes about scientists  

or anecdotes about the history of science. This one discoverer was really mercurial,  

and here’s how he ran his lab, and  here’s how his parents were like. 

But it never really talks about  the actual relevant science. 

A book like this actually does  fill the explanatory middle. 

Thank you. Physicists are very good at writing  books about the big questions of the universe. 

There’s a large readership for having  your mind blown by a book that you’re  

not going to understand everything  because you know it’s difficult. 

How do we know anything at all about  the Big Bang or how black holes work  

or background radiation or whatever it may be? With life, the origin of life or the trajectory  

of life on a planet, and whether we  get complex life inevitably or whether  

we’re going to get stuck with bacteria in most  places, these are big universe-sized questions. 

There’s not many people writing about them and  trying to take you to the edge of what we know  

in the way that the physicists very often do  and just saying, "Well, here’s how I see it. 

Here are the questions through my eyes." You’ve got to try and be honest and say, "Okay, I  

see it this way, other people see it differently." By the way, the fact that LLMs exist has made the  

process of reading a book like this  much more feasible and productive. 

I had a book club with a couple of my friends.  We’re not biologists. We’re laypeople to this  

audience. I do encourage people for a book  like this to see if you can form a book club  

or something and just talk to LLMs a bunch  because there’s just a bunch of extremely  

basic remedial chemistry and biology that we were  able to recapitulate with the help of the LLMs. 

This whole thing of, "Why is the CO2 and H2  reaction incentivized when one side is alkaline  

and one side is acidic in this early environment?" You just go through the  

remedial chemistry with the LLM. Yes, I did my best to explain it in the book,  

and it seems that I didn’t do a great job of it. There’s so much detail, and you can’t avoid that  

because it’s there in the questions. This is a problem with biology,  

it’s incredibly complex. Physicists look at biology  

and they think it’s just too hard to explain, and  biologists have got all of this terminology and  

often get lost in the terminology. I find myself, by nature,  

trying to find simple common denominators. That lends itself then to writing about them. 

I probably oversimplify all the time, or  maybe I fail and don’t simplify it enough. 

But you wrestle with it and  you try and make it work. 

It’s genuinely interesting for me to talk  to you and the other guys in the book club  

to see where you were struggling with it. I will build this into the next time I’m writing  

a book and try to figure out how I do that better. Nick, this has been great. Thank you for the guide  

through both the remedial biology and chemistry,  but also through many of the most interesting  

questions that you could ask about life. Been great fun. Thanks a lot.