Dwarkesh (host)

Today, I'm chatting with Nick Lane, who is an evolutionary biochemist at University College London.

And he has many books and papers which help us reconceptualize life's four billion years in terms of energy flow and helps explain everything from how life came to be in the first place to the

origin of eukaryotes to many contingencies we see today in how life works.

So, Nick, maybe a good place to start would be, why are eukaryotes so significant in your worldview of why life is the way it is?

Well, first, thanks for the

Now let's go to the origins of life.

And you have this really compelling story where you imagine that the first life forms were continuous with Earth's geochemistry.

And if you can recapitulate the story a little bit at the end.

Yeah.

I mean, it's so fascinating.

So just to recapitulate for my own understanding and the audience's,

Let's just break down what we have here.

So you have the analog of a cell in these pores.

You have something which concentrates the buildup of these organics so that they don't just all diffuse in some big primordial soup.

And so this is why you think like some primordial lake is not where this happened.

It had to be concentrated in some entity.

Then you've got...

a chemiosmotic gradient, a proton gradient, which drives work and specifically it favors the fixation of carbon dioxide and to drive the reaction with hydrogen gas to make organics.

And then you've got along this membrane, you've got catalysts, which are basically early enzymes.

So you've got enzymes, you've got the cell, you've got the proton gradient.

And then the story is basically that

You make very simple organics with CO2 and H2, and then those simple organics are then recatalyzed to make more and more complex organics, and basically TLDR metabolism, and fatty acids and nucleotides and everything else.

Then if you make fatty acids, they will sort of spontaneously, because of the hydrophilic nature of their different sides, they will spontaneously form the membrane if they're created.

You could have had, imagine that life is this like, there's like Frankenstein-like moment where things zaps alive and then now you've got life.

Yeah, so that's the alternative where like the bolt of lightning makes these organics, et cetera.

And here you have this story where...

every life form you see is continuous with something which is continuous with something.

Yes.

Which is eventually just continuous with entirely spontaneous chemical reactions.

And so that's just a very interesting way to think about the evolution of life.

Yeah, 100%.

So just basically you've got Earth as this sort of like giant cell and then this like from the hydrothermal vent, this little bubble pops up.

Yeah, it's such a fascinating theory.

So the thing I want to understand is what part of life the way it works now

is contingent and which would you expect to be shared even if you found life on another planet?

So it sounds like you're saying, look, carbon, the chemical profile, this is just the obvious candidate to build life on top of.

Proton gradients, is there another way you could build this sort of chemiosmotic gradients that drive work, right?

Like, we have other chemistries for batteries.

What fraction of them would you expect to have a non-eukaryotic life?

Even the vents are not contingent.

Right.

So if there's 20, 30 billion Earth-like planets, which have presumably some big fraction of them have these vents, if they all have these rock formations.

So like, is there a view that a notable fraction of them have life that also operates?

Sorry, this is a naive question, but what is the reason to think that there's no alternative chemistries which lead to alternative metabolisms?

So 20 billion Earth-like planets with water and these rocks in- Not necessarily Earth-like, but wet and rocky.

If you just had to pull a number out of nowhere and just say, this fraction have nucleotides, what fraction would you say?

Again, I know we're just chatting here, but according to this story, pretty sophisticated organics are extremely abundant through the universe, right?

Yeah, I guess you could have prokaryotes then who did just take over.

I mean, we did have this, right?

We kind of proliferated through the oceans and changed the composition of the atmosphere.

So your view is that the fundamental bottleneck to that, if eukaryotes are the fundamental bottleneck,

You can go from geochemistry to early life is easy, early life to just changing the entire composition of the Earth through early prokaryotes is easy.

And if those two things are easy, and then you've got 10 billion planets in the Milky Way that have gone to the middle step, does it imply that there's on the order of 10 billion planets?

I see.

And what fraction would you, again, you had to pull a number out of the air.

So this happens to be the 101st episode of the Thorkesh podcast.

And obviously that doesn't include, you know, clips and shorts and the other content that we put out on the channel.

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All right, back to Nick.

This is not my inclination, but if I was a sort of God-fearing person, I would hear this and I'd be like, wow, this is a sort of vindication of intelligent design, where the laws of the universe just favor this chemistry which leads to life, at least according to this story, so strongly that it's hard to resist this formation.

Okay, so very basic question, but if life is not only abundant but almost inevitable in all these rocky planets, then the bottleneck to not seeing aliens everywhere presumably is eukaryotes, which lead to complexity.

So it would have to be the case that out of billions of potential planets that could give rise to Eukaryotes, only on Earth does this chance occurrence happen.

I wouldn't argue that.

Okay.

Why is it supposedly this hard to...

have this successful endosymbiotic event?

I guess given how many bacteria in our care there are,

you know, through Earth's history, there's like trillion, trillion, trillion of these running around.

And there's many situations in which there was an endosymbiosis.

And in only one case it succeeded.

So the odds would have to just be like remarkable.

It would have to be like extremely, extremely tough.

So I guess the broader thing we're trying to figure out here is, if this story is true, there's life everywhere.

But eukaryotes giving rise to intelligent life, which is about to go explore the cosmos, is, as far as we can tell, happening only in one place in our light cone.

So why is that?

And now you could say, well, look, 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?

What's solving the problem of that?

Large genomes.

Exactly.

That's quite interesting.

The reason you need a large genome is actually just to put all your eggs in one basket so that every cell in the body feels incentivized to make the- You just restrict the amount of fighting.

Yeah, yeah.

They're all inside to make the germline continue.

But the thing I was getting at is like, okay, the eukaryote is solving large genome and it's allowing the cell to get much bigger.

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

It just seems like if there's billions of planets which have like gotten to the precursor stage here, none of them can find an alternative solution to mitochondria for just letting themselves get bigger.

Beggar's belief.

It kind of makes me wonder whether we're like, because we've only observed one way to solve the solution, we're sort of assuming that there must be only one way to solve the problem.

Whereas the problem itself doesn't seem like, OK, you just want a smaller copy of your genome sitting next to the site of respiration, right?

That's the basic problem.

But just to make sure I understood the feature request correctly, it's basically like you want...

a smaller copy of the genome that is only relevant to respiration sitting across the entire membrane and many copies of it sitting across the entire membrane.

I guess I'm just, it seems hard for me to... You're incredulous that this same thing will be repeated.

On like the billions of planets.

Because if there was another way to solve it, then what you would expect is that as soon as you get to the stage of

prokaryotes that have other niches that they could colonize, if only they could drive towards complexity, this would somehow be solved.

And then you'd have eukaryotes, dot, dot, dot, intelligence.

If it's the case that a significant fraction of rocky planets should have at least organics and cells and so forth,

Feels like we should be able to learn pretty soon whether this story is kind of correct, right?

Because obviously...

If that part ends up being true, and also we don't see eukaryotes elsewhere, then the whole picture is lent a lot more credence.

But like, I don't know, are we about to go to a couple moons and see if we can find some organics there and so forth?

LabelBox has this massive network of subject matter experts, who they call aligners, to help them generate data for training and evaluating frontier models.

In order to help prep for this episode, I asked LabelBox to connect me with one of their chemistry experts for a quick tutoring session.

I got to chat with Neil, who's a researcher that's currently working on chemistry ML models.

So how did the first cell division happen?

I remember him saying that the first version of division might have been membranes naturally will split the same way a bubble will split if it gets too big.

Yes.

Neil quizzed me on my understanding of redox chemistry, the same way that he interrogates models to make sure that they are developing a non-superficial understanding of all the scientific topics.

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Help me understand how replicators arise in this world.

Because if you've got these independent pores, and they're each individually accumulating their own organics through these spontaneous processes.

But initially, at least, there's no shared inheritance.

It's not like if there's a very successful pore, it then causes there to be more pores that are exactly like it.

And sorry, what's happening is that, so the thing buds off and then like settles into another pore?

Yes.

I see.

Okay, got it.

And this happens like relatively early in this process?

Yes.

And so the rise of replicators happens relatively early.

And so at what point do we get to the gene's point of view where the gene is the coherent unit of replication?

So your sort of mitochondria first viewpoint helps explain why there's two sexes.

Maybe you can recapitulate that argument, but I'm curious if there was a world where prokaryotes had evolved sex, do you think that they would have likely evolved just one sex?

Can you help me understand why it's the case that uniparental inheritance of mitochondria helps increase variance?

So then the question of why there's two sexes.

Well, you explained why there's this evolutionary need for only one parent to pass on the mitochondria.

Yeah.

So there's at least two niches.

One is pass on the mitochondria.

One is don't pass on the mitochondria.

So once you've established those two, then you can ask the question, why aren't there more than two sexes?

Yeah.

And then you can just say, well, there would just be a repetitive one of these two.

We've been to some college campuses today, you know.

We're probably getting some portion of that.

You have this really interesting discussion about how this not only explains why there's two sexes, but the particular differences in why eggs and sperm develop the way they do, why there's different amounts of replications before they are mature, etc.

I wonder if we can recapitulate that.

Okay, so let's talk about the Y chromosome, which is also not recombined.

Now, just the same way that female egg cells

try to minimize the amount of duplications in order to preserve the quality of the mitochondrial DNA and prevent errors.

Why doesn't the same thing happen with the Y chromosome?

Shouldn't all this sperm duplication be resulting in all kinds of errors in the Y chromosome?

I'm going to read the title.

Is this a woman live longer?

Suppose that evolution on humans just continued naturally for the next billion years, and we didn't have AGI and human gene editing, etc.,

Is the equilibrium that you'd anticipate, that the Y chromosome would then just fade away altogether and there'd be some other way of determining sex and sex-dependent characteristics?

I mean, it's quite interesting because you were saying that the same thing happened to the mitochondrial DNA.

Which is a tiny genome.

And has shrunk over time, starting from the original bacteria that was engulfed.

so so you will accumulate mutations and you can't resist them so you'll lose genes so your genome shrinks that's what happened to the mitochondria you just can't maintain a bacterial size genome so maybe worth explaining why it's the case that sex is preferable to lateral gene transfer in the sense of being the systematic pooling and parallel search across gene space so if um

If there is this advantage of sex and then bacteria have some antecedent to it, why didn't they just get the whole thing?

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

What is keeping the metagenome around?

Right.

As I was reading your book, just to ease my own ignorance, I was trying to come up with an analogy.

And so please let me know in which ways it's naive.

And also, thanks for tolerating all my other naive questions today.

But here in Silicon Valley, maybe an analogy that will work for us is to think about, let's say, a GitHub repository.

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

Basically, you just have this code base, and then you have ways in which you do version control.

So the usual way this is done, and this may be analogous to sexual recombination, is that somebody makes what is called, they make a new branch.

In that branch, they might make changes which are organized next to the function that they're trying to change.

And then so when the maintainer is looking at the code, they can see, here was what the original code was at this point.

Here's the modification to that point of code.

And you see the diff.

And then you can merge it back if it seems sensible.

And so the analogy here might be sexual recombination that's organized along the relevant gene.

And you see this allele.

You see that allele.

And then I guess evolution here is a maintainer, which is then driving one of them to fixation.

The analogy for asexual reproduction, just cloning with mutation, would be, okay, you fork the repository.

Then you make a random change.

You just change some random variable.

You change a word.

You change a bit.

And almost every single time, this will be deleterious.

Yeah.

And even when it's not deleterious...

there's no merge functionality.

So these different, you've got millions of repositories that are then spawning millions of other repositories.

And even if some improvement has been made on one of them, there's no systematic way in which the improvements can be merged together.

Yeah, and then finally, lateral gene transfer.

So here's the analogy it might be.

Okay, so you've got one repository for, let's say, editing web pages and another repository for controlling airline software.

And what you just do is you take a random 500-line sequence in this web page editing software, and you just put it in a random point in the airplane management software.

And there's no...

So then I guess, honestly, I don't really have good intuition for why lateral gene transfer does not produce similar benefits to recombination.

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Okay, so maybe to close this off, what is the experiment or method of interrogation which would give us the most amount of information about this story?

And 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.

And so I would recommend getting that if you want to better follow the...

argument here.

And there's way more detail there that would be helpful.

And I think, one, this is the thing I was telling you earlier, that it fills a niche of books, which unfortunately, there's just very few of.

So there's textbooks, which, yeah, you can spend 2,000 pages learning about molecular biology, but a layperson just as practically, who's curious, is just practically not going to get a chance to do that.

On the other end, there's what are basically just anecdotes about scientists or anecdotes about the history of science.

And this one discoverer was really mercurial, and here's how he ran his lab, and here's what his parents were like.

But it never really talks about the actual relevant science.

And a book like this actually does fill the explanatory middle.

Yeah.

By the way, the fact that LLMs exist has made the process of reading a book like this much more feasible and productive.

So I had a book club with a

you know, we're just, we're not biologists.

We're sort of lay people to this audience.

And so it was, I do encourage people for a book like this to see if you can like form a book club or something because, and just like 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.

And so, you know, 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.

Well, Nick, this has been great.

And yeah, 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.

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