Nick Lane has some pretty wild ideas about the evolution of life.
He thinks early life was continuous with the spontaneous chemistry of undersea hydrothermal vents.
Nick’s story may be wrong, but I find it remarkable that with just that starting point, you can explain so much about why life is the way that it is — the things you’re supposed to just take as givens in biology class:
Why are there two sexes? Why sex at all?
Why are bacteria so simple despite being around for 4 billion years? Why is there so much shared structure between all eukaryotic cells despite the enormous morphological variety between animals, plants, fungi, and protists?
Why did the endosymbiosis event that led to eukaryotes happen only once, and in the particular way that it did?
Why is all life powered by proton gradients? Why does all life on Earth share not only the Krebs Cycle, but even the intermediate molecules like Acetyl-CoA?
His theory implies that early life is almost chemically inevitable (potentially blooming on hundreds of millions of planets in the Milky Way alone), and that the real bottleneck is the complex eukaryotic cell.
Watch on YouTube; listen on Apple Podcasts or Spotify.
Sponsors
Gemini in Sheets lets you turn messy text into structured data. We used it to classify all our episodes by type and topic, no manual tagging required. If you’re a Google Workspace user, you can get started today at docs.google.com/spreadsheets/
Labelbox has a massive network of domain experts (called Alignerrs) who help train AI models in a way that ensures they understand the world deeply, not superficially. These Alignerrs are true experts — one even tutored me in chemistry as I prepped for this episode. Learn more at labelbox.com/dwarkesh
Lighthouse helps frontier technology companies like Cursor and Physical Intelligence navigate the U.S. immigration system and hire top talent from around the world. Lighthouse handles everything, maximizing the probability of visa approval while minimizing the work you have to do. Learn more at lighthousehq.com/employers
To sponsor a future episode, visit dwarkesh.com/advertise.
Timestamps
(00:00:00) – The singularity that unlocked complex life
(00:08:26) – Early life continuous with Earth’s geochemistry
(00:23:36) – Eukaryotes are the great filter for intelligent life
(00:42:16) – Mitochondria are the reason we have sex
(01:08:12) – Are bioelectric fields linked to consciousness?
Transcript
00:00:00 – The singularity that unlocked complex life
Dwarkesh Patel 00:00:00
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?
Nick Lane 00:00:31
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.
Dwarkesh Patel 00:02:18
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?
Nick Lane 00:02:37
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.
00:08:26 – Early life continuous with Earth’s geochemistry
Dwarkesh Patel 00:08:26
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.
Nick Lane 00:09:38
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.
Dwarkesh Patel 00:10:16
Then if you make fatty acids, they will spontaneously, because of the hydrophilic nature of their different sides, they will spontaneously form a membrane.
Nick Lane 00:10:26
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.
Dwarkesh Patel 00:11:20
You could have imagined that life is this Frankenstein-like moment where things zap alive, and now you’ve got life.
Nick Lane 00:11:28
I hate that as an idea, but go on.
Dwarkesh Patel 00:11:30
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.
Nick Lane 00:11:54
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.
Dwarkesh Patel 00:13:02
Yeah, 100%. Basically you’ve got Earth as this giant cell, and then from the hydrothermal vent, this little bubble pops off.
Nick Lane 00:13:10
Bubbling off many copies of the Earth.
Dwarkesh Patel 00:13:13
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.
Nick Lane 00:13:39
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.
Dwarkesh Patel 00:15:03
What fraction of them would you say have a non-eukaryotic life?
Nick Lane 00:15:07
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.
Dwarkesh Patel 00:15:19
So even the vents are not contingent in your view?
Nick Lane 00:15:21
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.
Dwarkesh Patel 00:16:09
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…
Nick Lane 00:16:24
My view would be yes. Any wet, rocky planet would have a decent…
Dwarkesh Patel 00:16:26
With the same metabolism?
Nick Lane 00:16:28
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.
Dwarkesh Patel 00:16:44
This is a naive question, but what is the reason to think that there are no alternative chemistries which lead to alternative metabolisms?
Nick Lane 00:16:50
Perhaps under very different conditions, you could end. 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.
Dwarkesh Patel 00:17:23
So 20 billion Earth-like planets with water and these rocks.
Nick Lane 00:17:27
Not necessarily Earth-like, but wet and rocky.
Dwarkesh Patel 00:17:29
If you just had to pull a number out of nowhere and just say, “This fraction has nucleotides,” what fraction would you say?
Nick Lane 00:17:37
I would say a substantial fraction.
Dwarkesh Patel 00:17:39
Like over 1%?
Nick Lane 00:17:40
Yes. I would imagine 50% or something.
Dwarkesh Patel 00:17:45
Really?
Nick Lane 00:17:46
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.
Dwarkesh Patel 00:17:55
Again, I know we’re just chatting here. But according to this story, pretty sophisticated organics are extremely abundant throughout the universe.
Nick Lane 00:18:06
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.
Dwarkesh Patel 00:18:28
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.
Nick Lane 00:18:39
Not just the atmosphere, but also the whole of geology. Hundreds of minerals are basically the product of life.
Dwarkesh Patel 00:18:46
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…
Nick Lane 00:19:10
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.
Dwarkesh Patel 00:19:27
I see. Again, if you had to pull a number out of the air, what fraction have done that?
Nick Lane 00:19:31
Well, a lower fraction, obviously.
Dwarkesh Patel 00:19:34
Over a billion?
Nick Lane 00:19:35
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?
Dwarkesh Patel 00:20:04
So there are hundreds of millions of planets in the Milky Way which presumably have something like ribosomes and DNA and RNA?
Nick Lane 00:20:10
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.
Dwarkesh Patel 00:21:50
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.
Nick Lane 00:22:12
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.
00:23:36 – Eukaryotes are the great filter for intelligent life
Dwarkesh Patel 00:23:36
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.
Nick Lane 00:23:53
There’s more than one bottleneck, but eukaryotes is in my own mind the big one.
Dwarkesh Patel 00:23:59
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.
Nick Lane 00:24:10
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.
Dwarkesh Patel 00:25:07
Why is it supposedly this hard to have this successful endosymbiotic event?
Nick Lane 00:25:14
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.
Dwarkesh Patel 00:26:39
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.
Nick Lane 00:27:01
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.
Dwarkesh Patel 00:28:44
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?
Nick Lane 00:29:18
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.
Dwarkesh Patel 00:30:18
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.
Nick Lane 00:30:28
You’re restricting the amount of fighting.
Dwarkesh Patel 00:30:31
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?
Nick Lane 00:30:56
Beggars belief. I know where you’re coming from.
Dwarkesh Patel 00:30:58
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?
Nick Lane 00:31:13
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.
Dwarkesh Patel 00:32:49
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…
Nick Lane 00:33:05
You’re incredulous that this same thing would be repeated. Yes.
Dwarkesh Patel 00:33:10
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…
Nick Lane 00:33:28
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.
Dwarkesh Patel 00:36:20
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?
Nick Lane 00:36:50
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.
Dwarkesh Patel 00:39:09
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.
Nick Lane 00:39:31
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.
Dwarkesh Patel 00:40:09
So the thing buds off and then settles into another pore?
Nick Lane 00:40:14
Yes.
Dwarkesh Patel 00:40:15
I see. Okay got it. And this happens relatively early in this process?
Nick Lane 00:40:18
Yes.
Dwarkesh Patel 00:40:18
So the rise of replicators happens relatively early.
Nick Lane 00:40:21
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.
Dwarkesh Patel 00:40:42
At what point do we get to the gene’s-eye point of view, where the gene is the coherent unit of replication?
Nick Lane 00:40:50
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.
00:42:16 – Mitochondria are the reason we have sex
Dwarkesh Patel 00:42:16
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?
Nick Lane 00:42:32
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.
Dwarkesh Patel 00:44:57
Can you help me understand why it’s the case that uniparental inheritance of mitochondria helps increase variance?
Nick Lane 00:45:02
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.
Dwarkesh Patel 00:46:35
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.”
Nick Lane 00:46:57
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.
Dwarkesh Patel 00:47:52
If you’ve been to some college campuses today, they’re replicating some portion of that.
Nick Lane 00:47:57
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.
Dwarkesh Patel 00:48:48
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.
Nick Lane 00:49:04
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.
Dwarkesh Patel 00:50:52
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?
Nick Lane 00:51:18
Well, it does. The Y chromosome is degenerate.
Dwarkesh Patel 00:51:22
I’m going to make that the title.
Nick Lane00:51:25
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.
Dwarkesh Patel 00:53:08
Interesting. Is this why women live longer?
Nick Lane 00:53:11
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.
Dwarkesh Patel 00:53:22
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?
Nick Lane 00:53:44
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.
Dwarkesh Patel 00:55:26
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.
Nick Lane 00:55:36
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.
Dwarkesh Patel 00:56:07
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?
Nick Lane 00:56:29
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.
Dwarkesh Patel 00:58:02
What is keeping the metagenome around? Why doesn’t everybody just converge to this streamlined thing that is needed for the current context?
Nick Lane 00:58:10
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.
Dwarkesh Patel 00:59:57
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.
Nick Lane 01:00:15
I’m already out of my depth now.
Dwarkesh Patel 01:00:19
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.
Nick Lane 01:01:44
It sounds quite similar, yes.
Dwarkesh Patel 01:01:45
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.”
Nick Lane 01:02:18
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.
Dwarkesh Patel 01:02:55
So then I don’t really have a good intuition for why lateral gene transfer does not produce similar benefits to recombination.
Nick Lane 01:03:05
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.
Dwarkesh Patel 01:04:53
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?
Nick Lane 01:05:08
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.
01:08:12 – Are bioelectric fields linked to consciousness?
Nick Lane 01:08:12
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.
Dwarkesh Patel 01:15:49
It’s been great to vicariously get a sense of that feeling from reading your books.
Nick Lane 01:15:55
Thank you.
Dwarkesh Patel 01:15:56
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.
Nick Lane 01:16:54
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.”
Dwarkesh Patel 01:17:51
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.
Nick Lane 01:18:37
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.
Dwarkesh Patel 01:19:32
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.
Nick Lane 01:19:43
Been great fun. Thanks a lot.
