Speaker 1: 0:15

we're back season two. Thanks so much for all your support and positive feedback last year. We're excited about our deck of guests for the season.

Speaker 2: 0:25

So far we've recorded with Sam Harris, Laura Clark, nick Lane, susanna Sullivan, anil Seth, and there's going to be many more.

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If you don't want to miss any of these episodes, follow us on your podcast app of choice and if you enjoy listening, please do feel free to share with a friend.

Speaker 2: 0:48

Thank you, hi. This is Amita Starik and Natasha McElhone. Our guest today is Nick Lane, who offers fresh insights on the theories of the origins of life. He is a professor of evolutionary biochemistry in the Department of Genetics, evolution and Environment at University College London. Nick's research is on the way that energy flow has shaped evolution over 4 billion years, using a mixture of theoretical and experimental work to address the origin of life, the evolution of complex cells and downright peculiar behavior such as sex.

Speaker 1: 1:19

He has received many awards for his work, among the 2015 Biochemical Society Award for his outstanding contributions to molecular life sciences and the 2016 Royal Society Michael Faraday Prize and Lecture, the UK's premier award for excellence in communicating science. Nick is the author of five acclaimed books on evolutionary biochemistry, which have sold more than 150,000 copies worldwide and been translated into 25 languages.

Speaker 2: 1:47

We talk about how it all began in the deep blue sea the similarity between a cell and the planet. Is the earth just a giant battery?

Speaker 1: 2:01

How. There are no clear definitions of what life is.

Speaker 2: 2:04

How cloning is boring and sex creates difference.

Speaker 1: 2:08

The innovation of multi over single cell life.

Speaker 2: 2:12

How genes shouldn't be in the limelight while chemistry is doing all the work?

Speaker 1: 2:17

The three domains of life.

Speaker 2: 2:19

Let's go back to the beginning. Hi, this is Omid Ashtari and Natasha McElhone, and with us today we have I'm Nick Lane.

Speaker 1: 2:31

Thanks for taking the time. We will talk to you today about life, in particular, the origins of it. Sounds good and we wanted to maybe start off by going to the very beginning. The planet is 4.5 billion years old. At some point, something interesting happens. When does it happen, and what happens? And how does this all look like at the very beginning?

Speaker 3: 2:54

Well, I mean, I can give you some pat answers to that. Life starts at 4 billion years ago. It's a more interesting question how the hell do we know that? Yes, and the answer is well, we don't really. We see things that look like fossil bacteria from around about three and a half billion years ago, and we're pretty certain those are. We see things that look like fossil bacteria 3.8 billion years ago, but then there's debate about them and we see kind of chemical signatures in the rocks that suggest life might go back to 4 billion years ago.

Speaker 3: 3:27

But there's uncertainty about all of these things, and so I can spin you a story. But how true is it? The moon forming impact even there there's questions about whether it really was an impact, but that's about 4.5 billion years ago, just a little bit less, and we think there were oceans from not so long after that. So the idea that the world was a kind of boiling lava or something straight out of Star Wars, it was true very early on and perhaps for a period after this moon-forming impact, but we had oceans and a reasonably stable, tranquil tranquil is probably not the right word but something that looked like the Earth from certainly 4 billion years ago, maybe earlier than that.

Speaker 3: 4:16

And life started sometime around then we can't agree among ourselves. Where Was it on land? There wasn't much land, but was it in something like Yellowstone kind of geysers on land? Or was it in a deep sea hydrothermal vent? Or was it delivered from impacts of meteors? There's no agreement on these things, but there are people devoting their lives to working on it and asking questions.

Speaker 1: 4:41

And you have devoted yourself to one of these theories.

Speaker 2: 4:44

I have. Yes, Will you take us to the deep thermal vents?

Speaker 3: 4:50

Yeah. So my favorite idea is not actually that I have a. I don't have a commitment to a place. What I have a commitment to is using life as a guide to its own origin, because the origin of life is really a question about chemistry and the field has been dominated for decades.

Speaker 3: 5:13

Everyone's probably there's one thing that most people have heard of. It's the Miller-Urey experiment and the idea of a primordial soup. There were lightning flashes in an atmosphere that contained gases like methane and ammonia and things and amino acids are formed by those lightning flashes and you get a thin soup that gets thicker over time and then somehow it congeals together and makes viruses and makes cells and off you go. And there's a lot that's not only unsaid in there but probably completely impossible in that storyline. And the alternative well, we can look at life itself. So we're not thinking about the chemistry, the kind of almost Frankenstein chemistry of lightning flashes and somehow some congealed mass coming to life. Instead we can say, okay, well, life is cellular, it's powered in a really weird way. It's powered by electrical charge on membranes, so not like a bolt of lightning, but kind of a continuous buzz on the membranes which surround the cell. And all cells share the same metabolism broadly at the center of it. So the way in which they're keeping on living, all the chemical reactions that keep cells alive, that's basically the same in plant cells and animal cells and bacterial cells and so on.

Speaker 3: 6:36

And then DNA, the genetic code is called the universal genetic code. So these are things that all life has in common and you can kind of try and understand where did they come from? Why would life be that way rather than some other way? And when you think about those things it tends to point towards environments that share some similarity. So life now starts with gases, not the gases in the Miliori experiment, but things like carbon dioxide and hydrogen, which you find in deep-sea hydrothermal vents down at the bottom of the ocean, and it turns out the kind of work that we're doing in the lab. It turns out, if you react carbon dioxide and hydrogen, you kind of get the molecules of metabolism just forming spontaneously that way. So there's just enough of a clue there to say here's an environment, here's the place you could go. We can't go there now because it's changed, but you can try and simulate it in the lab.

Speaker 2: 7:30

But was that a discovery that was made relatively recently? The idea that perhaps life started under the seabed rather than as we've thought?

Speaker 3: 7:41

So the idea of deep sea hydrothermal vents goes back, actually, to the 1980s. Well, they were discovered in the late 70s, yeah, and the idea that maybe life started in those vents goes back almost to the time of their discovery. But there's all kinds of different types of vent. Some of them are really harsh it can be 400 degrees because it's so high pressure that the water doesn't really boil even several hundred degrees.

Speaker 1: 8:08

That's the black smokers. Right, those are black smokers. Yes.

Speaker 3: 8:11

So they're kind of a bit different in their chemistry, they don't kind of line up with life very well. But there's a guy called Mike Russell who had put forward this alternative set of ideas, a different kind of vent, which he was arguing 10 years before they were discovered, and he was calling attention to the electrical charges on barriers so not membranes but inorganic kind of rocky barriers and cell-like pores inside these vents and the reaction of gases like hydrogen and CO2. So he mapped out this vision and that was in the late 1980s, into the 90s and for 10 years I don't think anybody listened at all. And then the vents were discovered.

Speaker 3: 8:57

These kind of vents he was talking about were discovered in the year 2000 by Deb Kelly who at the University of Washington she was the captain of the Alvin submersible which had discovered the first vents. And they discovered this other kind of vent which is not a smoker at all, it's a kind of white non-smoker, I suppose you might say. But this is where the chemistry that Mike Russell had been talking about is happening. And that led to an explosion of interest from microbiologists, geologists, biochemists, the kind of people who are not from that background of let's look at the chemistry, but more of a background. Let's look at the context.

Speaker 2: 9:35

So and tell us about that chemistry. I think in your book you'd said something about this was geology and chemistry speaking to one another for the first time, rather than us just looking at it as either the beginning of life is all biological or it's all chemical. There was this sort of lovely meeting of different disciplines.

Speaker 3: 9:56

I mean, one of the problems with the origin of life is it sounds like a really particular. It's a moment. I think in people's imagination there's some kind of switch, like that bolt of lightning. There was no life and now there is life.

Speaker 2: 10:10

Maybe it's also a religious thing, yeah, yeah, you kind of think of God as doing it.

Speaker 3: 10:13

But the reality, to go from the simple chemistry that you would have in any of these systems to the complexity of living cells, it's a tremendously long distance of these systems to the complexity of living cells, it's a tremendously long distance. I mean, if you were to try and break it down, it's probably greater than the distance between, say, a bacterial cell and a dinosaur. You know, it's a tremendous evolutionary distance to go from really simple chemistry to things like ribosomes, which are the protein building factories in cells and cell division and DNA and all the rest of it.

Speaker 3: 10:44

It's a long, long way. So there's not one moment. There's got to be some process over time and what the chemists have been doing was actually genuinely beautiful chemistry. But they start in an odd place. They start with cyanide and you know it's not a bad place to start. There's questions about was there any cyanide there? And we hear cyanide and we think's not. It's not a bad place to start. There's questions about was there any cyanide there? And we kind of we hear cyanide. I mean, oh god, I'm gonna die.

Speaker 3: 11:09

Um, but you know it does good chemistry, but it follows, it starts in the wrong place and it follows a pathway to make things like dna, which is completely different to what biochemistry does. So when you've, when you've managed to make these molecules the molecules of life, you're then left with the problem of okay, and then what happens? Which apparently was Daniel Dennett's favorite question. He would always say at the end of anything he would always say and then what happens? So this is the problem. And then what happens with you've made the nucleotide building blocks of RNA and DNA, then they have to invent metabolism, then they have to invent cell. They have to do all of this stuff and there's a huge gap there. Nobody's ever done anything like that, nobody's even tried to do the experiments really.

Speaker 3: 11:59

So there's this kind of a big hole where there ought to be some evidence, and what happens the other way around is, instead of having this different path towards the origins of life that then has to somehow reinvent life in its own image, we have a pathway which looks much more like life as we know it.

Speaker 3: 12:21

So you start with gases that cells use hydrogen and carbon dioxide and you follow the pathways that the cells use and the genes come relatively late.

Speaker 3: 12:33

So it's a completely different set of predictions, but it says this kind of environment, geology, the kind of hydrothermal they're real, we know that they're here today, we think they were there four billion years ago and biology we can look at the cells that live in these modern vents and we can see how they live and we can see the chemistry that they're using and we can see that this same chemistry happens, some of it spontaneously, in those vents.

Speaker 3: 12:58

And so you've got this, as you said, geology and biology and chemistry, all kind of converging. And then you realize, when you're thinking about that as well, that this is a clash of disciplines that each have, you know, hundreds of years of intellectual history physics and chemistry, and biology and geology and so on. They've all got a noble history of thought, but they're also kind of stuck within the bounds of their thinking and somehow at the origin of life. You've got to break open those bounds and try and find what they all have in common, because they all point to the same place and somehow you have to become. I've had to make myself a worse biochemist so I can be a better scientist.

Speaker 2: 13:44

That's really interesting, yeah okay.

Speaker 1: 13:46

So there's a threshold moment where we go from complex chemistry to what we would call biological life. What is the threshold here?

Speaker 3: 13:56

oh, there is no threshold. Yeah, exactly, everyone wants there to be a threshold but there isn't one.

Speaker 1: 14:00

So how can we approach this, uh and and can think, think about it as laymen here.

Speaker 3: 14:05

So I mean, the first thing is we want there to be a definition of life. Right, this is the first question you're ever going to get from anybody who thinks about the origin of life. They say, okay, the origin of life. So what is life? Define life for me, and the expectation is I'm going to be able to say, oh, this is what life is. And the reality is we can't do it. There are probably literally scores, if not hundreds, of attempted definitions of life and all of them have got problems of one sort or another. Either you could include fire, or you could include minerals, or you could include viruses. There's all kinds of things you could, yes.

Speaker 3: 14:41

So to try and find a hard, fast dividing line between what life is and what some other property might be is practically impossible.

Speaker 2: 14:49

Something you do talk about a lot, though, is energy exchange.

Speaker 1: 14:55

And metabolism.

Speaker 2: 14:55

yes, yeah as being the defining.

Speaker 3: 14:59

I wouldn't want to use the word defining. What I try to do instead is say okay, so what is what is life actually doing and what's the simplest imaginable way of doing that? Um, so, what life is doing with energy is not just doing chemistry in a bucket. It's, it's, it's, it's got. I mentioned, it's got these membranes which are electrically charged, and and all inside our own cells we have these things called mitochondria, which are usually called the powerhouses of cells. But this is where respiration is happening, this is where we're producing all our energy to go on living.

Speaker 3: 15:35

And it's not just chemistry that's happening when we're burning food in oxygen. We've got a current of electrons going to oxygen from food inside the membrane, which you can then think of as kind of insulated. It's made of fats and things. So you've got this kind of insulated current of electrons and that powers the extrusion of protons. So we're really talking about the components of hydrogen atoms, electrons and protons. That's it. Physicists love these ideas because these are fundamental particles, and so we end up with protons. On one side of the membrane they have a positive charge, it's just H+, that's all it is, and the difference in charge across that membrane, which is very thin is about 150 to 200 millivolts, which doesn't sound like much, but the membrane is five millionths of a millimetre thick. These numbers are incomprehensible.

Speaker 2: 16:37

I can tell you the numbers, but you picture it in your head.

Speaker 1: 16:40

It's impossible, it's a really thin membrane.

Speaker 3: 16:42

If you were the size of a molecule and shrank yourself down and stood next to that membrane. What you'd experience is a is is what's called a field strength, but basically a voltage of 30 million volts per meter, which is like a bolt of lightning. I keep coming back around to bolts of lightning. It's an incredible strength of force field over a very short distance. So it's that kind of force field which is keeping us alive. That's what living is. If that charge goes, we die, and that's true of all of life.

Speaker 1: 17:14

So membranes seem to be very crucial here, right?

Speaker 3: 17:17

Membranes are really crucial. Long lipids, kind of chains that at some point become membranes, and it's not just kind of the plastic bag and the membrane is the bag. This is where everything happens's. It's a, it's it's a charged bag.

Speaker 1: 17:29

You say and then the sustained. This equilibrium between the inside and the outside here in terms of charge is another component.

Speaker 3: 17:36

It seems like yes I mean it's as if the inside of the bag and the outside of the bag is very different environments and, and because it's different chemistry, you end up with a charge across them and that charge is actually powering everything that life is doing.

Speaker 3: 17:49

And this is what you have. This is why I like deep sea hydrothermal vents, because you've got the oceans, which have their chemistry, you've got the hydrothermal fluids which are going to bubbling up into these vents, they've got their chemistry. Then you've got this almost a labyrinth of pores which are kind of almost like cells, all kind of clustered together with rocky walls around them very thin, and on one side you've got a lot more protons than the other side. So you've got the same setup. You've got basically the same structure and your continuous flow and the kind of reactivity and the same electrical charges that you have in cells, and so you've got a geological environment that's kind of giving you everything that life has in a really simple way as a starting point. And you feel, if you put your membranes inside this pore, which is a cell-shaped pore, and you just kind of put a cell inside it, then it's almost it's really there already.

Speaker 3: 18:41

Yeah, you feel as if okay, it's snug, it sits there, it's quite happy, it's really there already. Yeah, you feel as if okay, it's snug, it sits there, it's quite happy, it's got the same kind of flow of things going across the surface you get the same charges and so on.

Speaker 1: 18:51

And at some point it breaks out it's no longer contained in that vent but kind of lives on by itself somehow.

Speaker 3: 18:58

I mean there's a lot of steps before you get there. But yes, I mean you can see. Can see, though, from what I'm saying, there's some kind of, there's a seed of what's to come it's convenient a lot of steps to get there.

Speaker 1: 19:10

It's convenient that that environment exists because it makes a lot of sense that it could have started there right yeah, and then it's science, so you better do the experiments, yeah, but but you know you, you've got.

Speaker 3: 19:20

you've got this continuity. That's what I find really pleasing about it. You're going from a purely geological environment and a lifeless planet, just rocks and water and gases, but with structure. It's not as if there's nothing there. You've got storms, you've got ocean, you've got hydrothermal systems. All of these things have structures, and those structures come astonishingly close to cell-like structures sometimes. And so the starting point and you know where the end point is. So the question is well, can you fill in the gaps? And if this is what you think the steps are, can you then test those steps in the lab and come up with a story that makes sense?

Speaker 2: 19:59

That's something that helped me follow some a really small part of what was in your brilliant book transformer. Um, you talked about flow and then you talked about flux and you said that really flux is a sort of form of flow, but where things change along the way or get changed along the way. Maybe that could be a way in for Joe blogs like me.

Speaker 3: 20:27

I mean flux is one of those words that does people's head in.

Speaker 2: 20:31

So I found it really helpful. Oh, did you Well?

Speaker 3: 20:35

I don't think many people have a very clear idea. If I say flux, what exactly do I mean by that word? It's because we can think about. You know, what I was talking about in in the book is a biochemical pathway which already sounds a bit intimidating but where, effectively, what you've got you're you're starting with one molecule and it keeps getting transformed into a different molecule. Some chemistry happens to it now it's a slightly different molecule, then something else happens to it now it's a slightly different molecule, then something else happens to it now it's a slightly different molecule. And you can go, say, 10, even 15 steps down this pathway. So what goes in at one end and what comes out at the other end are completely different things. So it's not like a river where you've got flow. You've got continuous flow down this pathway. But in a river, water goes in and water comes out.

Speaker 2: 21:25

Flow down this pathway, but in a river, water goes in and water comes out and in a biochemical pathway, what goes in is not the same as what comes out.

Speaker 3: 21:30

your car analogy, that was great. So so I I I was trying to think of it is is there any way that I can bring this to life and just make it clear for people? And I I had a go at saying imagine a car going down a street and let's say it's a, you know it's a mini or something like that, and then there's suddenly a kind of a bang, a street, and let's say it's a, you know it's a mini or something like that, and then there's suddenly a kind of a bang, a flash and it transforms itself into, let's say, a Porsche, and then there's another bang and a flash and it becomes a Range Rover. And there's another bang and a flash and it becomes a tractor. Oh dear, we're going backwards. But, um, you know, you've got these constant transformations going down a pathway and what comes out at the end is always going to be a tractor and what goes in at the beginning is always going to be a mini, and you always have the same transformations.

Speaker 3: 22:12

But and you've got flow down down this pathway. That's flux. So the flux is is this kind of constant flow, but changing as it goes through. And that's what biochemistry is and the thing that I find hardest to get my head around with biochemistry is the sheer scale of it, the quantity of it there's about in a single bacterial cell, which is too small to see by a long way. There's about 1 billion reactions every second. So these transformations down the metabolic pathway, the biochemical pathways, a billion reactions a second, and now another billion, now another billion. It is incomprehensible. Yeah, I mean, our own cells are something in the order of maybe 20,000 times larger than the bacterial cell.

Speaker 3: 22:57

Yeah wow, and our mitochondria that I mentioned, where these transformations are taking place, for providing our energy. They were bacteria once themselves. I mean, there's an extraordinary history of life. It's all built into us. We can look at our own cells, our own way of working and understand something about where it all came from.

Speaker 1: 23:17

Let's actually rewind here quickly. So we're talking about membranes and then we understand that these of these processes, these transforming processes, occur. Um, at some point. Dna comes into the picture here, um when do we think this happened? Or rna, rather well so.

Speaker 3: 23:34

So rna is like dna, um, but it's dna. Everybody will have heard of the double helix. Rna is a kind of a single um stranded thing and and, and it can be a direct copy from DNA, but usually of a single gene rather than the whole thing, and it can. You can think of it as a bit of ticker tape that you can make a protein from, because it's the code for the protein, or it can fold itself into a knot of some sort and then it looks a bit like a protein. It's got a shape, it's got a structure. You'll always, with that sequence, you'll always get the same knot, and so you have.

Speaker 3: 24:14

You mentioned ribosomes. These are the protein building factors, but they're made mostly of RNA, and so the idea was RNA has got this versatility In principle, it's got the code, and so it can copy itself exactly. In principle it can be copied anyway, and it also can form a shape. And then it can well, we know it can do catalysis. It can catalyze reactions, it can catalyse reactions, it can catalyse some chemistry. So it seems like a beautiful halfway house between not having any complex molecules and having DNA with a stunning double helix. You've got this kind of knot-like molecule that can do chemistry, and it can also do replication and copying.

Speaker 2: 25:00

Just and do not answer this if it's going to take us way off piste, because I love where you've put us and the journey that we're on. How does it?

Speaker 3: 25:10

know to replicate itself. Oh, nothing knows anything. But it's a very good question. I think the answer that I've come to and this is not something which everybody would necessarily agree with, but I think what really matters is the environment.

Speaker 3: 25:32

So if you're in a hydrothermal vent, you've got a continuous venting of stuff coming out and it's reactive. So you've got hydrogen in there and in the ocean waters that are percolating in you've got carbon dioxide. Imagine that just a tiny bit reacted, so let's say, 1% reacted the hydrogen and the carbon dioxide to make an organic molecule, to make one of the building blocks of life. And the next second the same thing happens again. You've got a continuous flow. So now you've still got just as much hydrogen as you did before, just as much CO2.

Speaker 3: 26:04

It reacts a bit again. Then the next second it reacts a little bit again and so you're converting what's called an environmental disequilibrium Suddenly. It's unpleasant terms, but effectively it's a reactive environment and because it's continually flowing, it can never just everything react and it stops. Constant flow is meaning that it's a continuously reactive environment, which means you're continuously turning the gases in the environment into the structures of cells, and because you're doing it continuously and they don't necessarily leave. They may just get stuck there on the surface or something they are going to grow.

Speaker 3: 26:43

Yeah, and if what you're making is let's call them protocells or some really simple cells not much more than the membrane that will grow and just really, for almost geometric reasons, surface area to volume constraints. If you're growing a membrane, it will divide in two at some point. So you end up with two cells where you had one before, and then four cells and eight and so on. So you have growth and you have some form of simple replication and and within those cells, if they are continually doing chemistry as well, that's where the urge for replication is coming from. It's the chemistry of this environment which is forcing everything to double all the time but so it was an external lesson rather than something that was innate.

Speaker 3: 27:31

This is why there's a problem in defining life, because life depends on the environment completely. If you put a plastic bag on your head, you're going to be dead within a minute or two. And we have why. Because we've got a cardiovascular system that's taking oxygen to all of our cells. And we're got a cardiovascular system that's taking oxygen to all of our cells and we're burning food continuously in that oxygen there. And so if you kind of take a step back and think what's happening here, what we've got in our mitochondria, where we're burning food, is an environment which is continuously out of equilibrium. Oxygen level is never going down there. We're supplying oxygen all the time, continuously. The amount of food there is never going down there. We're supplying oxygen all the time, continuously. The amount of food there is never going down. We're supplying food in the bloodstream continuously.

Speaker 3: 28:14

So it's the same as in a hydrothermal vent. What we have is two things that want to react with each other in an environment that facilitates their reaction. So we have the mitochondria with all of the charge and all the rest of it in there that makes them react. And that's where we have the mitochondria with all of the charge and all the rest of it in there. That makes them react and that's where we get the energy from. Now, if you think about how a soup would work, well, stuff in a soup just sits there. What's it going to do next? There's no reason why it would do anything next really. You can zap it a little bit with some lightning or some UV, but then it sits there again. What we have in a hydrothermal vent is a little bit like a cardiovascular system from the environment. It's a continuous flow, it's continuous reactivity. So again, this is you. You don't. The complexity is coming from the environment. The driving force is coming from the environment. Life is almost the passive recipient of these things.

Speaker 1: 29:04

What follows from what you're saying is we, we cut um and and I know this maybe comes across a little bit weird, but we cut RNA and DNA. Maybe too much slack, because, yes, of course there are really important breakthroughs here, but it is actually in the context in which they have emerged that most of this intelligence somehow lies, or the factors that have gotten it to the level of complexity lies right, that have gotten it to the level of complexity lies right.

Speaker 3: 29:27

I mean, the amazing thing to me is that the chemistry I've been talking about is older than the genes we tend to. We just we have a kind of top-down managerial view of life that everything's organized by DNA. That's where the information is. It sits in the nucleus, which is the control center of the cell, and it tells everything what to do. And actually it seems to me the other way up that we have this chemistry. It's spontaneous chemistry which will just happen in the absence of genes or enzymes or any complexity at all, most of them I mean this is a bit of an assertion still, but there's a lot of experiments backing it up it will just happen.

Speaker 3: 30:07

The kind of chemistry that's happening right now in your cells happens spontaneously in a deep sea hydrothermal vent, and there's again some suggestion that the genes emerge from that kind of an environment. The suggestion is patterns in the genetic code itself that effectively says there are straight interactions between amino acids and the code, the bases in RNA or DNA, that code for those amino acids that make a protein. So I'm getting too technical here, but it's effectively what the patterns in the universal genetic code say. This is not a frozen accident. This is not something that just happened this way. This is something that happened because there were straight interactions between things, so between what?

Speaker 3: 30:56

Well, between a chemistry that was older than the genes, and what the genes ended up doing is just making that chemistry possible in a different environment. It just kind of recapitulates the same thing. So the chemistry happening in your mitochondria is the same chemistry that was happening in a deep sea hydrothermal vent four billion years ago, with some modifications. So we can do this chemistry in the presence of oxygen. Now, actually, we've become addicted to oxygen, we need it, but it's the same chemistry underlying it. We just need to be more clever and that's where the genes are coming in to be able to make that chemistry happen yeah, so there is no separation.

Speaker 2: 31:33

No, everything is made. There's a kind of a continuity.

Speaker 3: 31:38

Yeah, and I find that a really rather beautiful that there's this continuity from a, from an inanimate but but but but kind of vigorously active Earth. I mean, this is another thing. I think I mentioned in the book that there's a topological similarity between a cell and the planet. So the Earth you could see it as a giant battery. A lot of the electrons are down inside. We've got iron at the core of the Earth and in a lot of the mantle. You're really into iron? You do talk about that a lot. I talk. A lot of the electrons are down inside. We've got iron at the core of the earth and in a lot of the mantle.

Speaker 2: 32:10

You're really into iron. You do talk about that a lot. I talk a lot about iron, but it's kind of really important to these processes.

Speaker 3: 32:17

And then in the atmosphere and in the oceans we've effectively got carbon dioxide and that wants the electrons from the iron, and then so you could think of the crust of the earth as the cell membrane, and inside cells we've got the electrons. Basically the organic matter is rich in electrons. On the outside we've got carbon dioxide and the oxygen, things that are relatively poor in electrons, and so a cell is a kind of a battery where it's positively charged outside, negatively charged inside, and the earth is kind of a giant battery. And the hydrothermal vents are like the pores in the cell membrane. They're the bits where there's a communication between the inside of the Earth and the outside, and that's where all the chemistry is happening.

Speaker 2: 33:02

That's where it's all being funded. That's a great analogy, if what you say is true.

Speaker 3: 33:06

Well, I mean, it's slightly metaphorical, but it's broadly true. Yes, no, I mean if your thesis, if what you're trying to say, well, even regardless of everything I say about the origin of life turns out to be wrong nonetheless, cells and the planet do have those things in common.

Speaker 1: 33:21

Yes, right. So your book, the Ascent of Life, goes through these quantum leaps and the evolution of life. One of the next chapters would be multicellular life. We talked a little bit about the vents and, you know, inorganic things becoming organic. We talked about membranes. We talked about rna, a dna. Now we're getting to a place where there is you, there are eukaryotic cells versus prokaryotic cells, and that's a breakthrough in many ways. Let let's talk a little bit about that.

Speaker 3: 33:50

So this is another amazing thing. Again, if you look at the history of life again, we tend to think genes are. You know, genes are obviously incredibly important. It's not that I'm trying to do down genes or something, but we have three, they're called domains of life. Have um three, they're called domains of life, um. So if I were to say what you know, what are the, what are the, what are the kingdoms would be the old-fashioned words and you would say plants and animals and, um, fungi, and then single-celled critters, things like amoeba, um, so those are all eukaryotes.

Speaker 3: 34:26

And then there's bacteria, and then there's another group of cells that look essentially the same as bacteria, but it turned out about 30, 40 years ago that in their genetics they're really quite different to bacteria and a lot of the genes code for proteins, and the proteins are the enzymes that are supposed to be catalyzing these biochemical pathways. Well, I say, the chemistry is older than the genes. The bacteria and the archaea are the two oldest of these kingdoms domains we could call them. They're much older than the plants and animals and the eukaryotes. And the bacteria and the archaea. They do the same chemistry, but the genes that are catalyzing it, well, they're quite different very often. So these are two groups that look similar but actually they're very different in their genetics and they've had 4 billion years and they've got huge populations. I mean, bacteria are so small that they have enormous populations compared to anything else. And the way that natural selection works, the larger the population effectively, the more you can explore the possible sequence space. You know you've got some genes. You double your genome, you try these genes in different environments. What works works. So bacteria become amazingly good at adapting to different environments. Just about any chemistry that you could imagine. They're out there doing it somewhere. They're incredible. And the archaea are maybe slightly less inventive, but similar kind of scale. So you take a step back from all of this and you think, okay, they've got practically infinite populations, they've had 4 billion years, they've explored all of this sequence space. So you could see that in terms of the genetic possibilities, they've explored all the genetic possibilities. So what have they come up with? Well, it reminds me of that line from the Third man with Orson Welles. What did theiss come up with after 500 years of peace and brotherly love? The cuckoo clock. Um, you know what did bacteria come up with? Well, you know there's still bacteria. It's kind of an interesting. It's an interesting phenomenon.

Speaker 3: 36:40

Plants and animals, and basically everything that we can see, everything that biology has cared about for hundreds of years zoology and so on they are made up of this one group of eukaryotic cells which, in their structure, in their morphology, in the complexity of the cell structure, is enormously more complicated than bacteria. So if the evolution of life was just about find the right combination of genes to solve this problem of how do you get complex, well, bacteria should have done it, but they didn't, and neither did the archaea. They've had all the opportunity to do so and they never did. And eukaryotes this is another weirdness. Take a plant cell or a fungal cell or one of your cells and look at it down a microscope and you'd be really hard pressed to tell the difference. They both have a nucleus where the DNA is stored. They've got all these internal membrane systems which have got exactly the same structure. They've got motor proteins that power things around the cell. They all do sex. So by that I mean two cells fuse together like the sperm and the egg, and then they line up the chromosomes and they double everything, and then they crisscross between them and recombine and then go through two rounds of cell division to produce more gametes for the next generation. So plant cells do exactly that process. Amoeba does exactly that process. Our cells do. You know? It's amazing.

Speaker 3: 38:19

So you think, okay, how did this evolve? And the problem is well, you think, okay, well, let's look at the parts, let's look at the steps along the way. What are you going to compare them with? Because the plant cells and the animal cells and the amoeba and so on, well, they've all got the same parts. So you look at what are called the outgroups, you look at the bacteria and they don't have any of the parts.

Speaker 3: 38:38

So there's a kind of a black hole really at the heart of biology, which is we don't really know how complex life evolved. There's lots of ideas, there's always plenty of ideas, but a demonstration that here's what happens step-by-step and here's the experimental evidence that shows that that's what happens step-by-step. That's missing. There's just nothing there. So what did happen? It tells you a couple of things. It tells you it happened once. We share a common ancestor.

Speaker 3: 39:06

Now, maybe it could have happened thousands of times and, for whatever reasons, it went wrong 999 times out of 1,000. And there is not a jot of evidence for that in the fossil record. There's nothing that we've seen. We've searched the planet in all kinds of wacky environments deep, hot biosphere and hydrothermal vents and stagnant muds and up in the stratosphere, you name it. We've gone there, we've taken samples, we've sequenced it and we've found the same stuff.

Speaker 3: 39:35

So it seems to have been a singular origin and it doesn't seem to be findable by searching genetic sequence space. What seems to have happened is that there was a rare it's called an endosymbiosis, so some cells get inside other cells, and these kinds of things have been known about. It was introduced by Lynn Margulis back in the 60s and it was really controversial for well a couple of decades at least. A lot of people prefer to rely on the power of genes and conventional biology and see this as a kind of quirkiness that you've got some accidental combination of cells. Why would that matter? And Lynn Margulis, she kind of took it to her enemies. She didn't like the kind of the mainstream evolutionary biologists who talked actually in quite economic terms, like the economic, selfish man.

Speaker 2: 40:39

She was an amazing writer as well. Oh, yes, she's so articulate and such a good communicator, carl Sagan's partner for a while.

Speaker 3: 40:48

For a while, yeah, for a while.

Speaker 2: 40:49

I don't know we mustn't go there. No, let's not.

Speaker 3: 40:56

But she saw life in terms of cooperation rather than competition, and a lot of evolutionary biologists didn't like the way that she saw it and she certainly was not right about everything. She was wrong about quite a lot, but she was also right about some really big things, and this is now the generally accepted version for the origin of these complex cells and endosymbiosis probably not multiple ones, but maybe just one, one kind of main one, which was the acquisition of these bacteria that went on to become our mitochondria.

Speaker 1: 41:29

Mitochondria, yeah.

Speaker 3: 41:30

So if you're dealing with a bacterial cell or an archaeal cell, specifically, but effectively a simple cell that doesn't have a nucleus, that acquires an endosymbiont, that goes on to become the power packs and the mitochondria, you've got it all to do. At that point You're going from simple cells and it's not easy for a simple cell to acquire another cell inside it. It's not necessarily going to go around engulfing other cells Maybe it can, but there's no evidence for that either. And we kind of know the end point, which is something completely different to anything that we see in bacteria and archaea. But you now have an evolutionary driving force, which is to say you've got this really intimate relationship of cells living inside cells and they've got to get along. And you know, in the end they become so tightly integrated.

Speaker 3: 42:22

You think they're the same being, but at the beginning they were cells with their own agendas, in some kind of conflict but also some kind of marriage, and they got to make it work out or it goes wrong and you die. So suddenly this idea that maybe there was a thousand goes at making eukaryotes and it went wrong. 999, that kind of conflict between the different agendas of different types of cell, and you can try and then understand what the steps might have been, from this endosymbiosis through to complex eukaryotic cells, as we know. You can try and think about. Okay, why would they become sexual? Why would they not do what bacteria do, which is to say pass?

Speaker 3: 43:08

around little bits of DNA. They do do a kind of sex, but it's nothing like what we do. But again, it's interesting to me that some of the big figures in 20th century evolutionary biology you know names who I really look up to, like John Mayn smith and bill hamilton and so on spent the practical of their careers working on why sex exists at all. Um, and so what do you compare it against? Well, you compare it against cloning. So dandelions are clonal, um, and there's, there's plenty of some clonal animals and things around. So here are these clonal guys. They should be able to go twice as fast. You don't need to find a mate, you don't need to mess around.

Speaker 3: 43:56

Mess around in so many ways you just copy yourself, double yourself, and on you go, but somehow then they go extinct. And so the question was well, why would they go extinct?

Speaker 2: 44:04

And the answer is well you've just got is well, because it's less variations, less funny, yes you just just to shoot yourself in the head.

Speaker 1: 44:09

Yeah, you're lacking robustness in the way you.

Speaker 3: 44:14

I mean, you could think of it, they're all the same and so you can get taken out by the same virus or whatever it may be exactly. Um, so this has become the kind of the mainstream view that sex generates variation. And anyone who has kids and you look at your kids, you realize that they're not like either of the parents. They're their own beings in their own way, and and, and it's amazing, yeah, it's, uh, it's. It's a way of just generating differences all the time. It's fantastic, um, so, so.

Speaker 3: 44:44

So that's what 20th century evolutionary biology kind of came to an answer. It said here's why sex is better than not having sex. But what they missed was that bacteria do their own form of sex, which kind of does the same thing on a really small scale. And then the question is okay, so why would you kind of transform it from this passing around bits of DNA that bacteria do to fusing cells together and lining up the chromosomes and just kind of this megalithic procedure, why would you do that? Well, again, as soon as you think all right, these cells have got mitochondria, they've got these endosymbionts, they're forcing them into a corner on one thing or another.

Speaker 3: 45:25

I mean, one thing they're doing is throwing DNA every time. If you've got cells living inside a cell and one of them dies, it leaves its DNA inside you. What do you do with that DNA? You clean it up and stick it in your own genome. So your genome swells, it starts getting bigger and then you've got a problem that you start accumulating mutations and you're going to die of a kind of overweight of mutations.

Speaker 3: 45:49

So how you fix that?

Speaker 1: 45:50

well, that's where sex is coming in so you split it again and we combine it yes, yeah, yeah, got it.

Speaker 3: 45:58

And this is, this is where the kind of the richard dawkins selfish gene comes in, because as soon as you, as soon as you're lining up chromosomes and switching over between them, you you're presenting to the next generation a unique genome.

Speaker 1: 46:12

Right.

Speaker 3: 46:13

And that may be good or it may be bad.

Speaker 1: 46:14

And this is the driver of all the complexity of eukaryotic cells, and is that one of the main drivers?

Speaker 3: 46:20

then, when we see that eukaryotic cells have gotten to… If, you want to have a large genome, you need two things you need to have mitochondria that give you the energy to allow you to have such a large genome. You need two things you need to have mitochondria that give you the energy to allow you to have such a large genome, and you need to have sex to keep your genome cleaned up and not just accumulating mutations.

Speaker 3: 46:38

So if you've got a you know you asked about multicellular organisms, animals, whatever you start with a single cell and and from that single cell you develop the whole organism. We have a brain, kidneys and liver and whatever else. So it's all the same genome in all of those different tissues, different organs. But you need to switch off that set of genes in this organ and switch on that set of genes in this organ and so on. So the fertilized egg has all of those genes. So it needs a really big genome because you need to be able to switch off some genes in some organs and other genes in other organs. So you need all the genes in all the cells.

Speaker 3: 47:21

And if you don't have that, then if you bring cells together from different environments that are not genetically related to each other, they will have a fight. Effectively they're different to each other, they don't like each other and they end up having a fight and so it falls to pieces and there are organisms like slime molds that do that. So the only times it works out where you have complex multicellular organisms is where you start with a single cell and that's basically plants and animals. That's it, and they start with a single cell that has all the genes required to make this complex thing. And the only way you can have all those genes is to have mitochondria and to have sex.

Speaker 1: 48:00

Silly question that just occurred to me. Now I don't know if this makes sense, but I never actually thought of it this way, the way you just described it. All the information is in the DNA, but at some point there has to be a master plan that tells these cells okay, we've now finished the kidney. The cell right next to the kidney has to be expressed differently than the cell right. That is the wall of the kidney. How does it understand where to draw the line?

Speaker 2: 48:29

between organs and how to express itself. You describe this at some point in your book around why we have gaps, or how we get the gaps between our fingers rather than being joined or there being another finger there. It was skipping exactly to your point.

Speaker 3: 48:42

Yes, I mean in the case of fingers. It's because cells will die, they will kill themselves by what's called apoptosis and that's true in the brain as well that we massively overproduce neurons and then weed them out. They die if they're not being used. So that's part of the answer, but to be honest, I don't think we yet know a large part of the answer. This is some beautiful work in recent years from a guy called Mike Levin.

Speaker 1: 49:10

Yeah, we were talking. He would have come up in my questions to you. Okay, yeah.

Speaker 3: 49:15

So the traditional view and there's definitely truth in this view is it's all about the interactions between molecules. It is about the genes. This set of genes is switched on here, that set of genes is switched on there. Why the difference? Because this has got a it's called the French flag model. You've got some kind of gradient. You've got more of this kind of molecule in this cell, a bit more of a different kind of molecule in a different cell that switches on or off genes. So the whole thing is about the kind of distribution of molecules, and there's definitely truth in that.

Speaker 3: 49:47

But there seems to be something else going on which I find fascinating and fun. I mean, this is another thing to say about science it's best when it's fun and when you kind of suddenly realize that, wow, there's a whole world here that I knew nothing about and not only do I know nothing about it, but really nobody does then it gets really exciting. So the work that Mike Levin has been doing is what he calls voltage maps and effectively this is known in simple animals but it's much less well-known in more complex things. But he's worked with flatworms and some of them are amazingly regenerative. So immediately this is kind of speaking to regenerative medicine and so on you can cut them in half and both sides will regenerate it. You can cut them into 200 pieces and each piece will regenerate itself into the whole flatworm.

Speaker 3: 50:43

And you can also show that there's a difference in voltage between the head and the tail of these things and actually quite subtle voltage maps in effect, between different regions, different organs almost have slightly different voltages, uh, across hundreds of cells. This is not just inside the mitochondria or something, but across hundreds of cells. They're kind of unified by what are called gap junctions, which is to say the two cells have got a connection between them and so the charge across them is balanced by these gap junctions. And if you fiddle with that charge and you can do it using molecular biology and you cut the flatworm in half, now it'll grow a head at both ends. And you haven't changed the genome at all, all you've done is change the voltage. And if you cut the next one in half, it will get ahead at both ends as well, and so on. So it's been stably inherited, but not by changing the genes. Now, this kind of thing, you can recognize cancer cells from their voltage as well.

Speaker 3: 51:48

A lot of developmental processes. You're asking about fingers. Well, an axolotl will kind of also amazingly regenerative, it's got beautiful fingers it will grow them back, and then it knows when to stop. And the question is how do you, how do you know where to start, when to stop? And this is, I think, the edge of developmental biology now, and it's not something I'm working on myself, but this idea that it's controlled by the voltage, not only the genome. There's a kind of a to and fro between the genome and the voltage maps.

Speaker 1: 52:19

So the point, just to kind of summarize, is that there may be an additional dimension in the expression of cells that is not only driven by DNA but, in this example, by the electrical map of the body right and this one. I won't have mike on the podcast as well at some point.

Speaker 3: 52:37

Yeah, well, he talks extremely interestingly about these things exactly if I take a step back. Yeah, we're talking about multicellular organisms and kind of voltage maps saying how you're going to develop right?

Speaker 2: 52:50

but can I just, yeah, and we can cut this if it doesn't end up being useful or helpful. But what you both just mentioned, there is there a spatial element. Then how does it? Because you said, when does it know how to stop?

Speaker 3: 53:06

I don't know how it knows when to stop. I think there is a spatial element and you retune the voltage by, say, 5 millivolts or something, and you get a different outcome. So the assumption is that there's some kind of electrical code, bioelectric code, which is specifying that if you've got this voltage, you become a finger. And if your voltage now you've got some feedback on that voltage which is specifying that, if you've got this voltage, you become a finger, and if your voltage now you've got some feedback on that voltage which is pushing it somewhere else, that's going to say stop, now you've done enough.

Speaker 3: 53:39

It touches on all kinds of other areas of biology as well. So it's not just about regeneration, it's also about resource allocation. So, coming back around to sex, there's all kinds of sex differences. So you can think of the peacock with its tail. There's a big cost to having a tail like that. You're going to make yourself much more vulnerable to predators. So it's considered to be what's called the handicap principle, this idea that if you can survive with this enormous kind of cumbersome yes then, then you must have got good genes um, so so.

Speaker 3: 54:22

So how, how do your gene? How do your genes know whether they're good enough to support that appendage or not? There's, there's some way in which somehow I can, they know, to say all right, now, stop. So there's got to be a feedback.

Speaker 2: 54:38

There's, there's I guess that's what I was trying to. Yes, where's? Where's the perception? Yeah, I think it's a balance.

Speaker 3: 54:46

It seems to be a balance, and that balance is between the electrical charges and the metabolism. The electrical charges are effectively generated by metabolism, and metabolism goes right back to the origin of life.

Speaker 1: 54:58

It goes all the way back.

Speaker 3: 55:00

So we've got the yin and the yang of the metabolism and the genes. It's not as if one is dominant over the other one, but they talk to each other and they balance each other but you did suggest um in your book that metabolism, that that it's the inverse of what we've always thought it was I think the metabolism comes first and the genes emerge from that. Can you take us through that? In in a shortcut way or not, um well, that would be going back to the hydrothermal events where we've got this spontaneous chemistry happening and the genes emerge from that spontaneous chemistry.

Speaker 3: 55:37

But whenever we have a cell and we have cell division or we have a formation of a new organism, a new embryo, the genes are never in isolation, they're always inside a cell. And so we have a cell from a cell. And that takes you right back to the origin of life. The question where did the first cells come from? But separately, the metabolism in that cell is always there as well. The electrical charges across the membranes are always there. They're there in the oocyte, they're there in the zygote. The genes are never in a vacuum. They're there in the oocyte, they're there in the zygote. The genes are never in a vacuum. They're never acting for themselves. They're always in an environment and that environment is always pushing back on what those genes can do.

Speaker 2: 56:20

So another thing that you talk about is the metabolism, whether there's an inbuilt, whether aging is because there's an inbuilt slowing down of that metabolic rate. That's pre-programmed, to use layman's terms.

Speaker 3: 56:38

I don't see it as being pre-programmed, so much as almost inevitable. I say almost inevitable because life itself doesn't age, organisms age, but you know, every time a new baby is born, it's young it's effectively being rebooted in some way, that the oocyte that gave rise to it has got all the properties of youthfulness.

Speaker 3: 57:06

It's being cleaned up. Um, and then there's an evolutionary question about okay, well, how much investment do you want to put into maintaining your body, your soma, and how long are you likely to live anyway? And how much investment do you want to put into reproduction? And these are kind of big evolutionary questions. That effectively says, okay, well, if statistically you can expect to live 30 years and you need to reproduce in that time, then I would better make sure that we get the reproduction sorted out within that first 30 years, or you're not going to leave a copy, you're not going to have a child. Do you have kids?

Speaker 2: 57:40

I do have kids, yeah, Actually having kids and being distracted by all of the responsibility. That actually slows down for those brains that are out there that are capable of understanding the sorts of things that you do, that maybe their time is best spent passing that on to a bunch of PhD students rather than changing nappies.

Speaker 1: 58:02

PhD students to be in your podcast.

Speaker 3: 58:04

I mean it's amazing. Kids are very time-consuming but you become very protective of the time you do have and you use it much better. I don't know if either of you have kids, but you use your time when you have your free time more effectively than I ever did before I had kids. And so there's also something about a bigger picture. I think I've got better at seeing what matters, what the lie of the landscape is, where the truth might lie. I mean, writing books helps with that as well. But I think there's a drift in life as we get older that we get maybe less good at nailing all the details but better at seeing where the details fit into the bigger picture, and I think having kids sometimes helps that process, that you see where the details fit into the bigger picture. So I don't know that it's a disadvantage, but it's certainly time consuming.

Speaker 1: 59:02

Yeah, I'd love to ask you to maybe off topic, actually pretty much on topic, if we talk about kids and the next generation is how you feel about your own mortality having to think so much about life and death? That's part of it. How do you feel about it?

Speaker 3: 59:20

Well, it's something I think about now, because I'm in my mid to late 50s and you become aware that you're pretty mortal and people start dying around you and you realize that, well, I've got high blood pressure and if I go for a run, perhaps I'm going to have a cerebral hemorrhage and I'll be a cabbage tomorrow. So you know, your sense of the time remaining is sharpened and your pleasure in what you do have is sharpened, and it's kind of interesting things. I'm not sure that's what you were getting is sharpened. They're kind of interesting things. I'm not sure that's what you were getting at when you were asking about mortality, but I'm glad for it. I wouldn't like to live indefinitely. I don't know that it would be good for humanity to live indefinitely.

Speaker 3: 1:00:07

There's a huge amount of interest now in trying to prolong lifespan, into investing in healthy aging, and I think there's some optimism that we can solve these questions. I'm rather more pessimistic. Actually. I think there's an incredible kind of circularity in a lot of biology Somehow evolution makes it look easy, but everything that has been done in the lab over 30 or 40 years makes it look surprisingly hard. So I'm not, and I think there's also interesting subcurrents in science here, which is to say, what AI is particularly good at doing is seeing patterns in the data.

Speaker 3: 1:00:52

And there's some places where we don't have any data. We can't see it. So, for example, with the mitochondria, they have their own genome. That's usually ignored in large genome studies, but they are actually tuning our overall fitness. They're playing into every aspect of life and if our mitochondria go wrong, we are going to be dead. They're implicated in diabetes and cancer you name it every disease you can think of. Mitochondria are playing a role and yet we tend to just bin their genome. We don't worry about that.

Speaker 3: 1:01:25

So what is an AI program going to see? You need to dig out all of that data. An AI program going to see? You need to dig out all of that data. But you know I work on mitochondria and the data that we see. It's confounding. We see improvements in respiration just when we see flies are dying in the lab and you think whoa, whoa, whoa, whoa, and this shouldn't be happening. You know why is respiration getting better when they're dying? And well, there are potentially structural reasons for that, which relate to the Christie in the mitochondria and their structure and the way that they work and the charges across those membranes and the power required to pump against charges. So there's all these kind of possible explanations for the data that we have, but we can't visualize it. If you want to take a very thin section of tissue and try and look at that tissue, try and look at the Christie in living tissue we can't see it. Superresolution microscopy is not quite good enough to see it.

Speaker 3: 1:02:30

Christie are the membranes right Christie are the membranes where respiration is happening. Sorry it Super resolution microscopy is not quite good enough to see it. We can kill the tissue Christie of the membranes where respiration is happening. Sorry, so there is no data there and if the answer is there, then AI is not going to find the answer there, unless AI is a lot more creative than we think it is at the moment. So I think there's still need for creative thinking about where the answer might lie. But I don't think many people working on aging are thinking that the answer lies where you can't see it.

Speaker 3: 1:03:00

Which is why I'm a little pessimistic about finding an answer to it anytime soon.

Speaker 1: 1:03:05

Okay, your books give me a good sense of the connection of my current being to those early hydrothermal vents the womb of life, it seems like, and makes me feel very connected to my surroundings when I read your writing, especially also the awareness of everything that's bubbling under the surface within me. So I thank you for that.

Speaker 3: 1:03:27

And.

Speaker 1: 1:03:28

I appreciate you taking the time to tell the story of life.

Speaker 3: 1:03:40

Thank you, yeah, it was so fascinating. Thank you that, and I appreciate you taking the time to tell the story of life. Thank you, yeah, it was so fascinating. Thank you so much. Thank you you.