Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas - 56 | Kate Adamala on Creating Synthetic Life

Episode Date: July 22, 2019

Scientists can't quite agree on how to define "life," but that hasn't stopped them from studying it, looking for it elsewhere, or even trying to create it. Kate Adamala is one of a number of scientists engaged in the ambitious project of trying to create living cells, or something approximating them, starting from entirely non-living ingredients. Impressive progress has already been made. Designing cells from scratch will have obvious uses is biology and medicine, but also allow us to build biological robots and computers, as well as helping us understand how life could have arisen in the first place, and what it might look like on other planets. Support Mindscape on Patreon or Paypal. Katarzyna (Kate) Adamala received her Ph.D. working with Pier Luigi Luisi at the University of Rome and Jack Szostak at Harvard. She is currently an assistant professor of Genetics, Cell Biology, and Development at the University of Minnesota. She is a member of the Build-A-Cell international collaboration, which brings together multiple groups to work on constructing artificial life. University of Minnesota web page Lab web site Google scholar publications Talk on synthetic life Twitter Build-A-Cell

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Life with CIDP can be tough, but the Thrive team, a specialized squad of experts, helps people living with CIDP, make more room in their lives for joy. Watch Rare Well Done. An all-new reality series, Rare Well Done offers help and hope to people across the country who live with the rare disease, CIDP. Watch the latest episode now, exclusively on rare well done.com. Hello everyone and welcome to the Mindscape podcast. I'm your host, Sean Carroll. And as might be becoming clear through the various topics of the podcast, one of the things I'm fascinated by is the boundary between living and not quite living,

by which I mean artificial life, artificial synthetic intelligence, robots, all the different ways in which we can build things that have some lifelike qualities but yet aren't really alive. and on the other side, how living things are manifestations of underlying physical processes. So today we're going to be talking to Kate Ottomala, who's an assistant professor of genetics, cell biology, and development at the University of Minnesota. And Kate is involved in building synthetic life, building individual cells from scratch. This is something, this is a field, artificial life, synthetic biology, that has a bunch of successes and controversies to its name.

There's different things you can do. So famously, Craig Ventner got in the news years ago, roughly 10 years ago now, for building the first artificial organism, which was a tremendous accomplishment, but what really happened is he took a pre-existing bacterial cell, removed its genome, and replaced it with the genome that he had synthesized. He and his team, of course, had synthesized. They had written a new DNA strand, and that booted up inside the cell and got it going. but it clearly wasn't starting from scratch.

So Kate and her collaborators are among a group of people who are trying to literally build cells from scratch, the cell wall, all the internal workings, and so forth. We don't yet have a working artificial cell that is truly alive in the sense that it reproduces, it goes its own way. But in some sense, that's better. As we learn in this conversation,

we can tune proto cells to do things that are useful to us without worrying about them, reproducing too much and going crazy and taking over the world. So Kate is a member of a large collaboration called Build a Cell, where we are working toward this goal of actually creating a self-sustaining cell all by itself from purely synthetic ingredients. And what we will be able to do with that, the prospects, the frontiers for the future here,

are truly amazing to me. It's really where at the very beginning of a revolution in this kind of thing. And Kate's an extremely articulate spokesperson for this kind of. work. So this is definitely a fun, mind-bending, and, you know, slightly provocative kind of podcast. So let's go. Kate Adamala, welcome to the Mindscape Podcast. Thank you. It's great to be here. So, you know, as someone who's done cosmology in my life, I sometimes get accused of, you know, playing God, thinking about the universe all at once. And so I'm very happy to be here with someone who creates life in their laboratory. You're way closer to playing God than I ever will be.

trying. We're not as good as the original God must have been, but we're trying to get there. So is it fair to say that one of your goals in the lab is to create life from scratch? From non-living components. The definition of scratch is flexible. Some people say to really start from scratch, you have to start from inorganic molecules and guide the chemical evolution all the way to a living system. This is not what we're doing. We're cheating big time. We're taking existing very complex bioorganic molecules and enzymes and trying to put them together into something that resembles a living system. Okay, so you're using the fact that life already exists and that's helpful and so you're going to take guidance. Why not? Like you said, God did it right the first time. So you can, you can,

I don't know if he did it right. He definitely did it. We're trying to improve on it. And how did you get into this? So you, you, a biology. just by training? No, I'm actually a chemist by training. Okay. And my approach to it is chemical. I think life's just a complex chemistry and I would like to be able to reconstitute it using principles of chemical engineering. And I got into it because I always thought it's kind of cool. I mean, growing up, when you watch all those science fiction movies, they always have like an astrobiologist on a spaceship and one day I realized this is actually a job one can do. Yeah. So I went and started doing it and it was great. So let's, let's back.

up a little bit. I mean, if you're making life from scratch, then it really makes you need to think about the question of what life is. What's the definition, right? And, you know, in my book the big picture, I quoted the famous NASA definition of life. And I said, I didn't like this definition. I don't, I don't like it either. So tell us what it is. And then why do you don't like it? So NASA definition of life is a chemical system capable of Darwinian evolution. And I don't like that definition, but it's the best one we have. The main reason why I don't like it, it's because it's not a functional, experimentally verifiable definition. So when we go out and drill under the ice on Europe, we're going to find some organic soup. NASA definition of life

is not going to help us to define whether there is life on Europa or not. Same for Mars, same for Enceladus. It's a great definition for philosophers, but it's not a practical definition that we can use when we get our hands on a sample. Well, yeah, the part I didn't like was the Darwinian evolution part. I mean, that's something that life, as we know it, clearly involves. But if I made a molecule by molecule replica of a living being, except didn't include its reproductive capacities, it's to be alive, right? That's a very good point, too. Like, for example, I'm not alive myself because I cannot undergo the ringian evolution myself.

There you go. And I've chosen not to, so maybe I'm not alive either. Exactly. So the problem with definitions of life, though, is as soon as you come up with one, you will find an exception that doesn't fit it. Do we need to have a definition? Is that an important thing? We need to have a working definition

because we will have samples from other planets and they will contain organics. We know that the universe is lousy with organics. Organic matter just gets formed abiotically. What do you mean

when you say the word organics? Anything that's carbon-based, anything that resembles organic molecules known on Earth. We know we can find amino acids, nucleotides, lipids. We are finding them spectrophotometically

in interstellar clouds. We know there will be organics like that on, and pretty much any surface that can support liquid water in the universe. Yeah, I think that some non-scientists can get to be confused by this because they think the word organic is like organic food, like it's been made naturally and stuff like that, or at the very least, has something to do with life. But chemists think that organic is just anything that has a carbon atom in it. Yep. Yeah, pesticides are organic, believe it or not. So, yeah, by organic, I mean, not a biotic molecule, just an organic molecule in the organic chemistry sense. But what amazingly, it was certainly amazing to me when I learned that you can find not just organic molecules, but several of the molecules that are very relevant to life are literally out there in interstellar space.

Absolutely. There are, I mean, acids out there. Yeah. There are nucleobases out there. There are probably sugars out there. And this does not mean that there's living beings out there. That does not mean there are living beings hung there, and that's the problem with lack of a functional definition of life. Because we're finding building blocks of life. So you cannot say that if I go out to Mars and find amino acids, that means there's life on Mars. Okay.

I mean, if I go out to Mars and find the right stereochemistry, terrestrial amino acids, that just means we contaminated Mars, which we probably did anyway by now. Do you think we did? Oh, totally. I mean, haven't we tried? Doesn't NASA try very hard to not contaminate? They also try very hard not to crash on landing. Yeah, that's true.

The track record is not in their favor. So I think we contaminated Mars. The question is whether anything we dragged out there would survive or not. And also there are probably still environments on Mars that we managed to not contaminate, and it would be nice to keep it that way, but I don't have high hopes. We probably also contaminated Moon with all the crap we crashed there. But we have not yet had a chance to contaminate neither Europa or nor Enceladus, and these are the very likely candidates for places where there could be life in,

at least in our solar system. So this is jumping ahead of it, but that's perfectly okay. So you think that the moons of Jupiter and Saturn are better places right now to look for life than Mars? I think we still should look because Mars is the only other planet that had conditions that closely resembled Earth before Mars lost its water and atmosphere. It was habitable by our definition of habitable, like human definition of habitable. So if there was a probiotic evolution that could lead to the origin of, terrestrial-like living beings that could have happened on Mars.

More likely on Mars, really, than on... More, definitely. Another problem, though, is that Earth is spreading crap as we speak. Like, we're always shedding atmosphere, and that atmosphere contains spores, and we know that those can travel. So if we find a tardigrade on Mars, or more likely tardigrade spore on Mars, that doesn't mean tardigrates originated on Mars independently. No.

I mean, it's amazing to be also... Like, space is amazing to me. You can find meteorites here on Earth that came from volcanoes on Mars, right? And the planets share material with each other. Galaxies, planetary systems, even whole galaxies share material with each other. Yeah. So I guess that's another reason why we need a functional definition of life, because if we find a system that resembles something we would expect life to look like,

we can't right now we don't have a good definition to say if it actually is alive or not but we know we'll find stuff because stuff is being shed all over and i guess life is just very promiscuous that spreading everywhere and but is it possible that the definition is less important than a list of characteristics and we can find things with some characteristics but not others and i think that's where the field is going right now people are starting to agree that we can make a experimentally trackable list of characteristics And if we find something that fits some of those, then we'll be really happy. So what would be on your personal list of characteristics that you would call kind of lifey? I like homeostasis because... Oh, homeostasis. Let's again, maintaining internal environment that is different, significantly different in composition of molecules, ions, pH and whatnot, to the external environment. And ability to maintain it actively.

so not just be different in an environment, but actually work for it. And that's homostasis to me. Good. So you're separate from your environment and you're somehow, it's not just because you're a locked room and there's things inside you, but you're interacting with the environment in some way and yet maintaining your difference. Okay. To me, that's the biggest hallmark of a living system. Replication is important.

I'm actually a big fan of the Iranian evolution for the living system. I mean, for a living system as a whole, I don't know of any better way to evolve than a Darwinian evolution. But every individual organism does not and does not have to undergo derision evolution. Sure. But I think, yeah, the people who want that to be the definition say, well, okay, but the species has to do it or something like that. Right. The fact that you and I do not have children is not going to stop us from being alive. Exactly. Members of our species do. Exactly. And that's, to me, that's another very important property.

And then another property that I have a hard time defining, and I don't quite understand it myself, but I really like it, is the complexity. So basically there is a certain threshold of complexity of molecules and the ways molecules interact with each other that we're only finding living systems on Earth and not in non-living. And that complexity is very hard to measure. But once you measure it and you plot it, complexity versus whatever other function of, aliveness you want the name, it's a very clear boundary between life and non-life is how complex you are. We're just, we as life are just insanely complex and we don't understand what properties of what we are come as those emergent properties of complex molecules interacting with each other. And to me, that is a hallmark of life, but it's a really terrible definition

because it's not very... It's all vague, but... It's very vague and not experimentally trackable at this point. And it's obviously, I mean, it's not obviously, but I will certainly buy the idea that every example we know of life is extremely complex, but you're making another interesting point that there's no examples of non-life that are that complex. Yes. So that's actually a dividing line. If only we could sort of formalize what we meant. Yeah, exactly. And okay, but there's sort of features of life as we know it like DNA and so forth, but I like that we're being a little bit more general than that. So we have, often people say compartmentalization, but is that tied up with your idea of homeostasis? To me personally, yes. I'm a lipid bilayer person, so I root for bilayers all over

the universe. I would like to find them, but there are other ways of maintaining compartmentalization without a cell membrane. So I think compartmentalization is necessary because you need to separate yourself from the environment. But it doesn't necessarily. have to be a cell membrane. Well, good. This is one of the questions that I had coming in. We're familiar with Life as We Know it, of course. Is it safe to say that all life as we know it is in the form of cells or multicellular organisms? Yes.

There's some, like, a virus is maybe always a sticking point? I would not consider viruses alive. And even if you do consider them alive, they still need crap inside a membrane to live because they have to infect the cell to replicate. Okay. And so it's obvious why that would be helpful, right, if you want to maintain this complexity and so forth. Let's seal yourself off. So there's a cell membrane around your inner workings and it's from the outside. But, you know, let's just, because there's many examples in the history of science where scientists guessed one way and turned out to be wrong, are we really sure you couldn't have something like life without membranes at all? Oh, we totally could. We need a compartment, but the compartment doesn't have to be a membrane. all. The compartment could be peptide. It could be any other polymer. The compartment could even be a physical containment. For example, a piece of rock with little cavities all over, and each of those cavities could have its own distinct environment. And some people even propose things like

that as the origin of life. Right. Yeah. No, but I guess when I meant membrane, I was thinking as a non-biologist, like any compartmental. But could we even have non-compartmentalized life? Just life sort of in a network that had different parts spread over some environment? It's not impossible, but everything we know about, that's another problem. Everything we know about properties of life is derived from this sample size that equals one. And that's stupid because a scientist, we like at least a triplicate, give me two more life forms and I can tell you more about properties of life. Right now, we only have one life form. So looking at everything that life form does, we absolutely need a compartment. and that's the current going knowledge based on all the data we have.

I would say it's not impossible to imagine a non-compartmentalized life, but it would have a lot of problems that would have to be solved one way or another. When you say we have one example, we have many organisms, but they all came from a same original. I mean, on the biochemical level, terrestrial life is kind of a boring because there's not much variety. Everyone does the same kind of metabolism. Everyone uses the same few hundred molecules to do life, to do the basic process of life. So, yes, we have incredible diversity in anatomy and physiology. But if you look at the biochemical level, everyone does DNA RNA proteins.

Everyone uses this crappy catalyst called the ribosome to make proteins. There's not that much variety. Not a lot of cleverness in the engineering. There's cleverness for sure, but there's not enough variety. Not a variety, I should say, yeah. Okay. So we can generalize. We cannot say life as a general biochemical phenomenon does this or that because we just simply don't know it because we only have one life right now to study.

And let's, I really got into the whole idea of the lipid, bilipid membranes. Is that right here? Lipid bilithes. Lipid bilayer. They're bilir because they have two leaflets. So tell me what a lipid is. Talk about the hydrophilia and hydrophobia and all that stuff. because it's amazing to me.

So yeah, lipids are really cool. So lipid has a tail and a head. Lipid is a molecule. Yes, lipid is a molecule. And it has to be classified as a lipid, it has to have a tail and a head. And a head is polar, which makes it hydrophilic. And a tail is non-polar, which makes it hydrophobic. So liking water or hating water.

Liking water and hating water. So head loves water. Tail hates water. So now drop it in water. What happens is heads get all happy because there's water around, so they stick their heads into the water. Tails hate water. So what are they going to do? They're going to snuggle other tails, and that's how a membrane is formed.

The tails do not like to be around water, so the tails face each other, and the heads stick out. The problem is if you have tails facing each other, they still have the problem of the fact that there is water at the end of them. So they solve that problem by inviting other tails to back them up. So imagine two tracks backing up into each other. The backs of the tracks are facing each other and the fronts of the tracks are facing outside. So the front likes water, two fronts like water and stare into the water. And that makes the membrane, the inside of the membrane, can hide all this hydrophobesity inside it. And it's an incredibly stable conformation.

They really hate to not do that. That's why membranes form spontaneously when you drop lipids into water. Yeah, the other nice thing is they're pretty easy to make them, right? They just happen. They just happen, exactly. And that's why I'm a big fan of lipids, because we know lipids can be synthesized bi biotically. So there were lipids around, even before there was life around. And once you have lipids, you're going to have bilayer membranes.

And once you have bilayer membranes, they like to be spherical. It's not... That's another amazing thing, right? Yeah, it's not healthy for a membrane to be flat. It wants to be spherical. It's basically like a soap bubble. I mean, membranes are essentially soap bubbles. So if you make a soap bubble, you cannot make a flat open soap bubble.

When you make a soap bubble, it ends up being a sphere, whether you want it or not. And that's what lipid by layers, do they end up being spheres. And then once you have that sphere, you can put stuff inside and start living. Yeah, so these lipids very naturally give us a way to compartmentalize. Are there other ways besides lipids? You can make protein compartments, and we do, we as life do. You can make compartments that are amorphous. There are those awesome proteins that are called intrinsically disordered proteins

that can undergo face change, phase transition, depending on external environment. And we actually have them. We have those membranless organelles in our cytoplasm that create just kind of islands of different chemical composition just because they want to. It's property of those molecules. So that's a way to compartmentalize things. you can also use completely different kind of molecules. You could imagine sugars making some sort of a compartment.

You could imagine other polymers making some sort of a compartment. Or you can imagine just rocks making a compartment. Okay. But most life as we know it, cells are the membranes of the cells are made of these bilayers. All life, as we know, it uses lipids in their bilayers. So on the one hand, they're easy to make. on the other hand, they're not completely watertight, right? Like some things can come in and out, which is important to being a living organism.

Yes. And the really good ones, the highly evolved, I mean, by highly, I mean bacteria and above evolved life, has pretty watertight membranes to get anything across the membrane, you need membrane channels. And that's actually really good because then you have control over what goes across your membrane because you control your channels. So in some sense, the cells like a little island and there's these bridges across the membrane. And they have control over those bridges. And there's border patrols letting some things in and out.

So you can see how things are beginning to get a bit more complicated. That's one of the problems when you think about the origin of life is a good membrane will not be very permeable. So life had to pretty early figure out how to get stuff across the membrane using membrane channels, membrane transporters. Right. Okay. So we have compartmentalization. My impression is in the origin of life community, among the aspects of life, compartmentalization is sort of the easiest one to understand how it could have gotten going. Is that right? It's the one that we made a lot of progress on.

Experimentally, it sounds easy, but experimentally, these are one of the toughest projects to run, because lipids, they do form those liposomes, if you want them to, but actually working with them, handling them is kind of a problem. pain in the lower back. So it's, I, that's all, all I've been doing through grad school. So to me, it's not that incredibly hard because I was just trained to do it. But in a great scheme of things, there are a lot of other experiments are easier. But the origins field made great progress in making those compartments. Good. And then the other things we mentioned were, you know, they need to be able to replicate and you need some sort of engine inside you, right? You need some metabolism. So that's how I think of what life is. It has those three aspects of compartmentalization, metabolism, and replication. Is that fair? Is that fair? Am I oversimplifying? No, that's definitely

fair. It's definitely oversimplified, but it's also fair. Yeah. And what qualifies exactly as metabolism? I mean, and this is where I get into physics, right? Like life uses fuel. It uses the low entropy energy from its environment one way or another. I'm the worst person to ask about it because I think of it from the practical, functional point of view. To me, metabolism is taking simple building blocks and making something different and more complex out of it. And that ties very strongly

to maintaining homostasis. Basically, taking, your environment has a certain chemical composition. Your guts have different chemical composition. If you want to do life, you have to take stuff from your environment and process it so it makes the inside of you.

So basically, your environment has something that doesn't look like you. And the reason you have metabolism is because that basically means you have machinery to take something that is not you and make it into you. And that's the easiest definition of metabolism to me, at least, is that processing, building blocks that don't look like end result and making it end result, the end result being you in this case. It's fascinating to me because this is definitely a field

where there's a lot of things that have the character of, We know it when we see it, metabolism, and then we're still searching for the precise definitions. Absolutely. And we're kind of, again, hampered by the fact that we don't have anything to compare with. We only know one way of doing metabolism because we only know one life form. If we had few other to look at, we could try to generalize more. And that one way we have is the story of ATP and things like that. We have little batteries, basically, little fuel.

storage services inside ourselves. Yep, and they're all made by one company. Everybody uses ATP, so that's kind of hard to generalize it. There's a monopoly. Yeah, there's totally as monopoly. And is it, I mean, as a cosmologist, I want to ask, or as someone who has been involved in debates on the fine tuning of the universe, is it, or would it ever be clear that this is simply the best way to do it rather than just some accident of history that chemistry

happened to make use of? It would be clear once we find completely independent life forms. If we find, let's say, 27 different life forms all over the universe and they all use ATP, then there's definitely something about ATP. But I don't think there is anything special about ATP. I think it just happened to be around and we started using it. Okay, that's good. So the other special thing then is on the replication side, we use DNA, right?

DNA and RNA are both involved. And then, like you said, the ribosome tells the RNA. or actually takes the RNA in and makes proteins, is that a fair way to say it, right? And this also seems very specific. I know friends of mine who, what they do for living is they build little computers and robots out of DNA. And my first guess was that that was because DNA is all over the place. We know about it from being living beings. But it was explained to me that, you know, forget about living beings.

DNA is a really good information storage mechanism. It is. It's a great information storage mechanism. but it's definitely not the only one you can imagine. And there are two parts to DNA. One is the backbone, which gives it stability and flexibility. And that, I think, might be one of the more common ways of doing it. If I were to bet how those 27 random life forms all over the universe would look like,

I would not be surprised for them to have something that resembles the backbone of our DNA. But then the information is actually stored in nucleobases, those four DNA nucleobases. And these, I think, are relatively random. Because you can imagine different kinds of nuclear bases that could easily do the same thing. Right. And there's this weird thing that there are four different nucleobases,

and they appear in groups of three. So four times four times four is 64, right? So 64 different possibilities. And we use all of them, but in kind of a redundant coding scheme, right? There's only sort of 20 of the categories that we actually make use of. Is that right? 21, yeah. 21, okay.

Stop. Oh, yeah, there's one at the period of the end of the sentence. You need that, right. Okay. And so you're not sure or you're suspecting that these, this choice of four nucleobases could have been very, very different. If you run, if you tell me you can run a probiotic evolution on Earth over and over again 10 times, I would say all of those 10 times.

times we would end up with an information storage polymer that would have slightly different nucleobases. There's many different types of nucleobases that could work chemically to do. Is that something that synthetic life researchers are looking into? Could they improve on DNA? It wouldn't necessarily be improving. I think most of the other choices wouldn't actually improve DNA is great because it's just stable enough.

It basperstably enough to be solid when you're not. you need it, but then when you need to unwind it, it doesn't hold on for dear life. It actually is willing to let go. And people have built experimental systems that use different nuclear bases, and it works. Okay, that's good to know. My slightly more radical question is something DNA like, the idea of a chain of bases or molecules that store information in a one-dimensional chain, it sounds pretty robust. The only way I could think could generalize that would be what about like a two-dimensional sheet? Could we imagine a genetic information being stored in some sort of two-dimensional pattern? And could that be more complicated or efficient,

but just hard to get off the ground in early life? This would probably work, but then your cells would have to be ginormous. You're a synthetic biologist. You can make that happen. There are actual physical chemical limitations on the size of a cell. Like if you have too much surface, you're spending too much time walking on that surface and that's your problem. So there are basic laws of physics, chemistry, etc., in the environment we have. But it may be in very different environments. Yes. The conditions might be very different.

Okay. Good to know. Well, mark it down that we talked about that here. If we discover it on Europa or something like that. You know, for example, if it's a rock-based life, you could imagine two-dimensional system. You could imagine most of the chemistry happening in a two-dimensional. Okay.

All right. Pancake life. Pancake life, yes. Hmm, pancakes. So we have those basic ingredients. I mean, I think that it behooves us as scientist to try to think beyond these obvious things. Because like you say, our imaginations are poisoned by the fact that we have this one example. But it does also seem pretty sensible that compartmentalization, metabolism, and replication will be essentially universal in life.

So how close have we come to making that ourselves, to being engineers as well as chemists and biologists? That depends who you ask. What have we done? Let me put it that way the other way around. I think there's a lot of sort of waste of time arguing over who made it artificial life. Like we've heard news reports and things like that. But let's put it this way. What have we done?

What steps have we made along the way? We've made the biggest progress on compartmentalization. We can recreate artificially compartments that looked like living compartments. We can make pretty good metabolism inside them. So we can put together molecules that make proteins, that uptake nutrients from the environment. We suck at replication still that problem have not been solved. We are unable to recreate a autonomous, spontaneous replication system. them. We can replicate those compartments by hand, like we can force them to replicate,

but we cannot design them in a way that they will be willing to replicate out of their own desire, as a result of the biochemical processes happening inside them. We made okay progress on homostasis. We can make those little synthetic cell compartments that actively maintain their composition that is different than the composition of the outside. That's pretty good. They're not as robust. And they're nowhere nearly as robust as living systems, but again, they're kind of a blame attempts at recreating living systems, so they won't be as robust. And I do have this recollection that there have been experiments where you tried to make either RNA or the equivalent of RNA that would reproduce itself.

We don't yet have an example of synthetic single molecules that reproduce themselves, right? No, not yet. And this is always, we should have mentioned this earlier, but of course, when we say reproduction, things like fire reproduce them. or crystals reproduce themselves, but now we're talking about reproduction with information storage, which is the crucial thing. That's why RNA is so good, right? RNA and DNA and all the other NAs. Yeah, okay. Okay, we did explain to us what we've heard in the news.

I mean, there was several years ago we heard that Craig Vettner made artificial life, but, you know, it all depends on what you mean. So forget about whether he made artificial life or not. What did he do? He took a bacteria called mycoplasma, which is the smallest known independently living cell. They're parasites, but they live outside of cells. So they took that cell, they took the genome of that cell, and they bombarded it with pieces of DNA that randomly insert random DNA sequences all over the genome.

That's called transposon insertion. So basically you force cells to uptake DNA and put it wherever in their genome. Now what happens is if you put this random piece of DNA anywhere in your genome, you can be lucky and put it somewhere where it's not going to kill you. Or you can put it inside a gene that you absolutely have to have to live and then you just end up dead. So that's what they did. And then they grew a whole bunch of those mutant bacteria. They sequenced it all.

And they found that there is a lot of genes that you can shut off. that you can insert those random pieces of DNA into, and the cell survives. It might not be as healthy, it might not be as happy, might not divide us quickly, but it will be alive. And so that way they figured out which genes are absolutely essential for survival and which are not. And they removed all of those genes that were not essential for survival, and they came up with this minimal genome. So that was the first step. They actually minimized an already smallest living organism. Now then the next thing, thing is they actually synthesize that whole genome chemically. That sounds easy right now in the age

of twist G9 and other high throughput DNA synthesis, but back then when they were doing it 10 years ago, that was a huge deal to actually synthesize the entire genome of a living organism. And I did it. Then how do you make it to be actually alive? Is you take that synthetic genome, that DNA that was synthesized on a machine and have never been alive, and you put it inside a cytoplasm, of another living cell. They picked a cell that was very closely related to what they started with. They picked another species of a mycoplasma, a slightly bigger, just slightly more complex.

And they developed this procedure called genome transplantation, where they take this synthetic DNA, put it inside a living cell, and that synthetic DNA takes over the natural DNA that came with that living cell to begin with. So you didn't remove the original DNA? No, you did not. You just superseded it. Yes, and that's why I think, I mean, this was probably one of the biggest achievements of synthetic biology and biotechnology to date, but it is not making life. Because you always had life cell.

That genome transplantation was replacing genome of one organism with a genome of another. So there was always life there. It was never dead and then not dead. But, yes, so they took the artificial gene. genome put it inside another cell and that cell started expressing proteins of that from that artificial genome and started slowly changing, morphing into that new organism and that's how the new organism was born. And that's how the sin cells were born, sin as of synthetic cells.

So it's certainly pretty good what they did. Oh, they're amazing. It was the technological advancements that we get out of those projects are incredible. common way everyone uses these days to do molecular cloning is a technique that was born during this project because they needed it and there was nothing available so they made it and also the genome transplantation technique didn't exist before they started working on it and there are several iterations of that sin cell they made it smaller and then yet smaller and then yet smaller and then they made it slightly bigger because it started growing too slow for anyone to be able to put up with it but there

many of those organisms right now where we know every single gene and we can control basically what every one of those genes do. It might be worth just thinking about the actual process of this because I think people have in mind going in there with tweezers and a scalpel and cutting and repasting DNA. Very tiny tweezers, but that's not what we actually do. No. What do we do? What we do is we cut the DNA to leave ends that have specific sequence, and then we bring in new DNA with ends that have a sequence that matches those cut points, and then we ligate it, we glue it back together. Which really just means let the chemistry happen that brings it back together. Yes.

We are never picking up one strand and another strand and with our hands putting it. Not quite. Nobody has hands that small. Yeah. They're molecules. I mean, there's nothing that we can make that is that small. And also when we say synthesizing a genome, because I myself am not completely clear on this, is it like we literally have the complete list, G-C-T-T-A, and we could type in any list we want and make a DNA molecule like that? That's how we're making DNA these days. There are those machines that take, so there are four nucleobases, and you can program a machine to couple to connect those nucleobases in a very specific oboe basis. order. And it doesn't take forever to do that? I mean, these are long, right? These are millions of nucleotism? So for the synthetic genome, they actually had to develop several techniques to

do it, to stitch it together. Most of the time what we do, like on a daily basis is we're making genes that are a few hundred to a couple thousand nucleobases long, and that doesn't take very long. But that wouldn't be enough to power a whole bacteria? Absolutely not. I mean, the smallest known genome is 474 genes, and that's quite a bit of DNA. Yeah, so how many bases in a gene? I know that's wildly different numbers, but... It's very wildly different. It's from a few hundred to few thousand.

Right. So if the state of the art then, at that time, you know, a few years ago was sort of redesigning the DNA and then plugging it back into an existing bacterium, how far we come since then? Not very. I mean, we've come really far in understanding how this organism works, but we're still unable to take a genome, plug it into a non-living system, and get life out of it. Yeah, okay.

That's what my lab is trying to do with collaboration with the Craig Venture Institute people. We're trying to basically do what they did, except our chassis is not alive. So when they took that artificial DNA, put it in a living, cell and that living cell changed into the new cell. What we're trying to do so far unsuccessfully, but we're hopefully getting there, is we're trying to take the non-living piece of DNA and mix it with non-living components that make proteins, that make membranes, and see if the system can write itself up, can start making all the proteins that will organize in a proper way in which we expect life to organize. And that would really be, uh, well,

I already said we shouldn't argue about the definitions, but it sounds like that would really be a synthetic life form. That would be a life form that was created from non-living components. The reason I'm hesitant to say synthetic, to me personally it would be synthetic, but there are many people that would consider a synthetic life form only something that is completely different from an existing architecture. So what we're making is still DNA RNA, 21 amino acids, perfect same. We're trying to make a copy of a living cell, basically, from non-living components.

If you want to talk about artificially in the proper sense of the word, it would be something that's designed to be different than what you're using as a template. Okay. This is why I don't care about the definitions because both of those are interesting, but they are different. So we'll count them as both interesting. One of the, is it true? One of the obstacles here is that even in the tiniest genomes for these little bacteria, we don't know exactly what all those genes do, right?

Like Vettner was able to knock out some and not kill it, but there's others that if you knock them out, the bacteria won't bacteriarize anymore, but we don't know why. Absolutely. They're called essential genes of a known function, and they're the biggest headache that we as a field have right now. We know those genes are absolutely necessary, but we've got no idea what they do and that's kind of frustrating.

So even when we're typing in our keyboard, G, T, T, T, A, C, whatever, we know that certain sequences are necessary, but it's not as if we can say, I'm typing this because this is going to do the following thing in the bacterium, right? That's so frustrating about life in general. It's a black box. Yeah. Is that an ongoing research thing?

We're trying to figure that out? Yes. Is there some dream at some point of being able to type in a genome sequence and just simulate on the computer what it will do? It would be amazing, and people are working towards it, but it's impossible right now because we don't know what all the proteins are actually doing. And is it just because things are too complicated? Is that the obstacle?

Yeah. Okay. So one of the things you're trying to do is not only make a synthetic living, not breathing, but living cell, but also, you know, things that are cell-like that might not quite rise to the level of being alive. Yes. And so what does that work? We're quite good at that, actually.

We can make things that are not alive, but are quite complex. So for instance, what? I mean, what do they do? What stops them from being alive? Complexity mostly. None of our systems self-replicate right now. So we can replicate it, but it doesn't self-replicate. It's a crucial distinction.

So it looks like a cell. Looks like a cell. Has DNA in it. It quacks like a cell, but it does have DNA. It does have DNA. It does have RNA. It does have ribosomes. So it makes proteins? It makes proteins.

It won't duplicate itself. It won't replicate itself. You can go in there. You can clone it. Yes. Okay. And what is the usefulness of these things? We can study processes that we cannot study in a complex life cell. Because the natural life cells are still black boxes, no matter how much we simplify it, we just have no idea what's going on in there.

We can study single pathway and hope we caught everything that interacts with that pathway. but we most likely didn't. In our system, it's engineerable from the first principles, like from every single building block can be manipulated. So if we want to, for example, reconstitute a signaling pathway or reconstitute an oncogenic pathway or make a gene circuit that produces a certain molecule, we can design it from scratch, we can build it and we know it's exactly what we were hoping it will be

because there is no endogenous metabolism that will mess with our experiments. And is this potentially useful just for, you know, down-to-earth, crass commerce kind of reasons, you know, for engineering and medicine and things like that, beyond the fundamental questions of life and time? Very much so. That's a lot of what is paying the bills right now is when you think about biomanufacturing, a lot of progress has been made in making pathways that can make anything you want. And we need those pathways because it may be a little bit off topic, but we need to ramp up our bioengineering, biomanufacturing capabilities

because we're running out of crude sources of chemicals. Like when people freak out about running out of oil, they freak out for energy reasons. But we have different ways of getting energy. We can have solar, we can have wind, we can have atomic. We do not have right now a good replacement for all the petrochemicals. So all the crap we get from oil that builds everything around us, we don't have a replacement source for that. So we need to learn how to do it with

the only good, renewable biochemical chemical factories we can think of that will always be sustainable, which is biomodufacturing processes. So we can have biological processes that make all the molecules we need. The problem is that cells kind of don't like doing it because a lot of those molecules are toxic to begin with. So we can build pathways that make the molecules we want, But then we introduce them to cells, to natural cells. They look at it and know out of it. They say, I'm not going to do it because it's toxic to me. And that's the biggest problem in biomanufacturing right now

is how do you make all those complex toxic molecules? Now, a nice thing about synthetic cells is that they're not alive, so they don't care. So you can build a synthetic cell that makes something incredibly toxic or hard to make and it will not kill it because you can't kill something that's already dead. Another thing is we're kind of slowly entering this area of so-called personalized medicine, where we want to make drugs in small quantities tailored to the needs of every particular patient. And if you think about chemical processes for making complex biomolecules that can be drugs, setting up a process for each molecule takes forever and it's really hard.

If you could have a platform that's very versatile, easily programmable to make small amounts, of biomolecules that can be used as medicine or nutrients on demand when you need it, where you need it, and not more and no less, that would be really useful. And that's another area where artificially engineered organisms could be really useful. Yeah, there's no such thing as off topics. So don't worry about that. We should talk about this. Because I like that you brought up the petrochemical thing because that always struck me when people worried about, you know, fossil fuels and stuff like that, running out of oil for gasoline. basically. And I always thought, like, we do a lot of things with oil other than gasoline. And these are, this is a finite resource and we are literally setting it on fire. Right? We're literally burning it. But so you're saying is that maybe your little semi-living synthetic cells can help

us reconstitute the sort of chemistry that we might get out of the ground for free. I mean, we have to find a way of doing it because I'm, maybe I'm a little too optimistic, but I think by the time we run out of oil, we will have enough renewable energy sources that we can drive our cars and run our AC or heat. But we still don't have a good path to replacing all of the chemicals. And that's something I feel like doesn't get enough attention because everyone just freaks out about energy and not about everything else we get from oil. Well, and it opens up a whole set of vistas that I've heard people sort of mentioned in passing about, for example, combating climate change or something like that, by designing little microorganisms to go chew up the CO2 and other things in the atmosphere that we don't want, the greenhouse gases.

Is that at all feasible in your mind? This is not the area that I'm an expert in. I would love to see that happen. I'm a little afraid of thinking about that because we've seen how well it goes when we try to release an organism into environment. What could go wrong? Exactly. So doing that on a planetary scale kind of gives me creeps, but that doesn't mean it's not doable. I also think there are a lot of problems with climate change that could be solved without those giant planetary scale interventions. It's by no means the replacement for doing more sensible things about fixing climate change.

But the medicine stuff, I think, is also extremely promising. I just get the impression that 100 years from now, everyone's body will be, filled with these little designed organisms that are keeping them healthy all the time. I hope so I bet my money on it. I actually have a little startup that's betting money on it. So we're hoping to get to make that reality. I absolutely do. So that's a disclaimer.

I'm very optimistic, but it's a self-serving optimism. We are basically trying to program those little cells to go in and act as natural kind of analogs to the immune system. them without all the problems that the natural immune cells have as in self-replication, ability to turn on your own cells. And fighting allergies and things like that? I mean, maybe even combating cancer. I don't know.

Yeah, we're looking more at cancer than allergies at this point. I would love to fight allergies as well, especially living in Minnesota in the summer. It would be awesome. But we're mostly looking at things that are very deadly and very, very, very. as in cancer. There's no such disease as cancer. Every single cancer is slightly different. And we make those cancer drugs that just go in and kill everything.

And this is probably not the best or most efficient way of targeting, at least some of those. But it's what we have. So it's a perfect target for personalized medicine in that way. And so being able to design things. Another kind of a medically related problem is we hopefully are going to start sending people back in space for longer periods of time again. And FedEx doesn't deliver to Mars yet. So if you need specific medicine once you're halfway through your five-year mission to Mars, you're not going to know what you will need a few years in advance.

Like you're going to send those astronauts. They're going to be as healthy as possible, but everybody can get sick at any time. with anything and if you're in a middle of your mission to Mars and you suddenly get sick you need a way to get a drug that is targeted to your needs without knowing in advance what your needs will be and that's one area where kind of a designable engineerable cells like synthetic cells might be really useful because they can be made to order they can be made from scratch from a set list of building blocks so you can imagine a building blocks that are defined in advance, but the way you combine them decides what the outcome is going to be.

And so when halfway through your mission to Mars, you become deadly allergic to Mars dust. You make one kind of drug. If you develop a cancer in the middle of that mission, you develop another kind of drug. If your crumate develops another kind of cancer, you make yet another drug and so on. So in this vision, are you not actually implanting the synthetic cells into the patient? you're just using the synthetic cells to make some medicine. Yes. Okay.

Because clearly we don't understand a lot about the interplay between our own microbiomes and ourselves, right? So introducing new cells into people might be risky. I don't know. Very much so. That's one of the reasons why all the commercial applications right now are focusing on things like cancer, because the risk to benefit ratio is, there is more risk acceptable when a disease is almost certain to kill you. That's why we probably won't be treating allergies with experimental therapies, but we will be treating some of the most deadly cancers with experimental therapies

because we don't have all that much to lose. I mean, the patient who has six months left to live, if you extend that lifespan by another six months, I don't want to say you won, but you've done something good. You've done something good. But I've heard that you're allergic to cats, so that's a pretty big disaster. Here at Mindscape, we're very pro-cat. But I'm pro-dog personally, and I'm not allergic to dogs. All right.

It's not really the same thing, but that's okay. We'll let you struggle through your life with that handicap. But the other thing that strikes me, as I read about this stuff, is the blurry line between medicine and biological things and just nanoscience, just all the things you might want to do at a very small scale. So robots, computers, engineering, this is all kinds of things you can do with your synthetic cells. We're working on biocomputing right now, too. We're trying to make genetic circuits that perform computation and store memory.

And again, that's where synthetic cells are kind of handy because people have done a lot of good biocomputing experiments in life cells. But as soon as you take your eyes off those cells, they will start going on their own and expressing genes they want, not the genes you want them to express. Darwin, man. I know. Synetic cells are dumb enough that they don't think they can get away with anything. Once you program them to do something, they will be doing that until they run out of energy, and at which point they will just sit and stare at the wall and not do anything else. Yeah, so that's part of the fact that they are not alive, right? So they have some of the good benefits of living creatures for our engineering purposes without the drawbacks.

And are there particular kinds of computations that it might be useful to do this way? Right now we're still baby stepping it. We're doing Bollyan logic gates. So the very simple logic gates that people know from playing with doing informatics, quote, unquote, on paper. So like end gate or or gate. Yeah. Start somewhere. Build an advocate next, you know, next.

And is there, and I'm just making this out, it's not something I've read, but is there some future hope of making more large-scale macroscopic materials, constituted from synthetic cells? I always, in my mind, compare and contrast, you know, skeletons and bones, which have the ability to be rigid, but you can break them and they will fix themselves to, you know, robotic, metallic things, which once they break, that's it. Is there a hope of making materials that are, you know,

stiff and sturdy but self-reparing? Absolutely. That's one of the probably most exciting promises of this field is that you can imagine programming semi-living or sort-living organisms so that they exhibit certain properties, but also keep some of those biggest hallmarks of biology, like ability to self-repair and grow. I think we need a word for this semi-living state,

where it doesn't replicate. It's not sort of on its own. It needs some help. What's wrong with semi-living? Semi-living? Well, you know, it's a little creepy, but that's okay. Sort of living? If you have a new word, you know, go back to the Greek roots or something,

like that. You can definitely coin a term there. Yeah, it's a brave new world. I mean, it's, how do you see where we'll be 50 or 100 years from now and what we're doing with synthetic cells? Hopefully in 100 years the boundary, because right now there is a pretty clear boundary between people like me who do this molecular biological engineering and working non-living systems and people that do the classical bioengineering with life cells. Hopefully once we get better at it, that boundary will disappear and we will be able to program living organisms like we program machines right now to do the things we want. And my goal is to erase that distinction between synthetic cells and natural cells. My goal is to build synthetic cells that are programmable,

understandable, definable, but behave like natural cells and are as robust as natural cells. Yeah, you're part of this build a cell collaboration. When I first heard build a cell, I was hoping it was an app I could download for my iPhone and I could build a cell, but we're not quite very good. There's actually is a game where you can put together a life organism. We're not related to that. But it's the first hit when you Google our collaboration. So what is build a cell aiming at?

It's an international collaboration that's supposed to bring together people that work on building cells. And since we have no definition of synthetic cell, we have no definition of life, and everyone is motivated by slightly different goals, we would like to unify the community. around this idea that biology is engineerable. And biology fundamentally should be engineerable. So anyone who's trying to engineer living systems from non-living components or engineer living systems so we have the ability to manipulate them,

that's as good as ability to manipulate electronic or non-living machines, all of those people are welcome in a build-de-cell community. We're basically people that can come together and talk about making life from scratch and nobody makes fun of us. It reminded me a little bit of large-scale particle physics experiments. Like when you build a detector at the Large Hadron Collider, there's a thousand people in the collaboration, and one of them builds a little calerimeter and the other solder's wires together.

And so you have subgroups that are interested in the lipid bi-layers, others are interested in ribosomes and so forth, and you're all working together. Yes. It's too big of a project for any single lab or even a single country to tackle it. So that's why we started self-organizing into this international community. Are you going to reach the particle physics scale where there are thousands of authors on every paper? I would love that. But you're not there yet. We're not there yet. We're not quite there yet. Okay. So let's, I think the final topic, let's go back to outer space, because we,

you know, we had outer space in mind at the beginning. We're looking for life elsewhere. I think that maybe some of the listeners don't necessarily know about the different environments where we can look for life. Because part of your your goal is to understand what to look for when we're looking for life. And part of that is where we should look. So even right here in the solar system, we've had this somewhat recent change of mind that moons of big planets are just as good a place to look for life as planets. If not better. So why would they be better? Because they're smaller and they can hold onto water. They're not as hot. They actually have a surface. We like surface. Why historically was Europa better at holding onto water than Mars? That I actually don't know.

I know why Mars lost water. Why did Mars lose water? Because it never developed plate tectonics. If you develop plate tectonics, you can recirculate your water. You can have water vapor in the atmosphere that gets spit out of the volcanoes and it comes back as rain and gets spit out again. Mars never developed plate tectonics. So my understanding, I'm not a planetary geologist, but my understanding is the reason Mars lost water and atmosphere is because it was passive. The planet was passive. It never developed plate tectonics.

Europa is frozen, and it was always frozen as far as we know. So that might help because if all your water is encrusted in this frozen layer of ice, it's much easier to hold on to it. It's frozen at the surface with the ice, but then beneath that, there's huge amounts of liquid. Water on Europa. Yes, and that's why it's promising because it's water that kind of stays there. It's encapsulated in that crust of ice. And it's doing it water stuff.

It's clearly warm enough to be liquid. So it's doing stuff. And that's why we have hope. There's chemistry going on in an aqua solution. Yeah. There's, yeah. I mean, if you have aquaous solution, you will have organic chemistry going on in there. And so one of your things is studying synthetic life because we want to be better at knowing

alien life when we see it, right? I mean, what should we be looking for when we do go visit and contaminate Europa? I think we, I can tell you very easily what should we not be looking for. I'm still not sure what should we be looking for. I would definitely look for organic molecules that are very complex and comochiral. So chirality is this orientation of which, in which direction, molecules point, basically. And on Earth, we're extremely particular about our chirality.

All peptides have certain chirality. All nucleic acids have certain chirality with no exceptions. This is left-handedness versus right-handiness in the molecules, yeah. Yep. And that is not natural, as in a biotic. You cannot get such conserved comocirality. At least we don't know non-living. catalyst that would give you that much specific system-wide comochyrality.

So that's one thing I would look for personally, is if you find a biochemistry and a set of molecules that are very complex and all have conserved the same chirality, then that might be one of the good clues that the process that gave rise to them is somewhat biological. But the only way to do that is to go and scoop up the molecules. You can't do it spectroscopically by looking at light reflected because the light reflects the same from left-handed and right-handed molecules. You need to go scoop it up, analyze it. And we're hoping to do that.

We're hoping. I think within our lifetimes we'll get to do that. It would be easier on Enceladus because Enceladus is nice enough to spit it out into the space for us. They have those giant plumes that spit out water vapors. And that water vapors probably loves you with organics, so we can just do a flyover. and I'm saying just. It's just, yeah, just fly.

Saturn. Fly over to pick up a sample sounds easier to me than land drill pick up a sample. Sure. Have we ever done that? Have we ever done flybys that kind of scoop up chemicals and test them? What I know of. Okay. Because slowing down is always hard.

It's much easier to zoom by a planet than to slow down. Slow down, get into orbit. Bringing fuel with you is hard. Right. Yeah. Okay. It doesn't even have to be sample return. You know, you don't actually have to be.

have to bring enough fuel to get off the planet or moon. But even get there and get close enough is hard enough. Is there some feeling? I've heard it mentioned the idea that if you just find chemistry where there's a lot of really heavy molecules, right? A lot of really long, complicated molecules. The only way we know how to make them is via life or biotic processes. I would not subscribe to that because there are many ways to polymerize

to make longer molecules from shorter molecules. And there are many ways of doing that in an abiotic way with no life. Okay. So this is a controversial point. Different people have different feelings about this. Yeah, okay. That's why it's hard. And what about far away?

You know, if we look at exoplanets, we discovered bushels full of exoplanets now. We can't go do chemical analysis of them on any short time scale. Are the ways just looking at the light we're getting from these other planets to say, oh, it looks like there might be life there? So we're not as good as looking at exoplanets as people seem to think. Most of the way, the way we discover most of our exoplanets is we're looking at the star and that stars doing something funky.

So we start doing the math and the only way that makes sense is that, okay, there's a planet in the orbit. We don't actually see many. We haven't seen many exoplanets yet. Right. We see the star wobble or get eclipsed or something like that. And then that's how we actually, here. we have seen some exoplanets as in we've seen some of either the light reflected from that exoplanet,

which is incredibly hard, or we've seen the star eclipsed by the planet that passes right in front of it. But it's not like we can actually look directly at the planet and take a spectra of it. So it will be very hard to do remote life sensing like that. Okay, but let's say that astronomers get good at it. Is there something to look for? I think the easiest way to do it is to look for physical chemical conditions on those planets. Because right now when we discover planets, we have estimated orbits that are so large in the radius

that it can go anywhere from no liquid water at all because it's too hot to completely dead frozen on the other end. And we're still not sure even where that planet lies within that orbit. If we get better at defining what physical chemical conditions, we need for life. So building different kinds of artificial life under different conditions in the lab to decide, okay, this is absolutely needed for life or this is not absolutely necessary for life.

Then we have those boundary conditions. And then we can look at the exoplanets and see, okay, this planet probably is likely to have the conditions that we know can support life. And then judging by the history of Earth, life happens quickly. as soon as Earth was habitable, life came to Earth. So again, it's sample size that equals one,

but from that sample, we can tell that life is almost inevitable under certain physical and chemical conditions of a planet. Well, I was going to ask you about this, because I think that there is some disagreement, or at least not everyone thinks that they know the answer. Nobody knows the answer. No one actually knows the answer, right, but people have convictions, nevertheless.

is making life easy or hard? So like you say, we have one data point. And in some sense, the data point says it was easy here on Earth. It happened relatively quickly. I mean, it might have taken almost a billion years, but like you say, as soon as it became habitable, the very, very early Earth was just inhabitable. And so there's no life then. But as soon as it cooled down enough, boom, there was life.

And so maybe that means that once you get complex chemistry and it cools down, you get life. But on the other hand, we have the other planets that don't obviously have life on them. So aren't those more data points in some sense? So right now we don't have any other planet that's currently habitable to terrestrial life, to Earth-type life, not even the very particular kind, but any life that would look like a terrestrial life. So that goes back to some of the problems we discussed before. It's possible that some of the planets in the solar system were habitable in the past like Mars, it's possible that Venus could be habitable right now to somewhat different life form.

Very different, I would think. Different-ish, like those, some, there are people that have very good arguments for the fact that those clouds we see on Venus could actually be made of living organisms. Except we're not going to know that unless we actually go there and test it. So we cannot say right now, if we have any other life in the solar system or not, we cannot say either way because we haven't been there and tested that. Fair enough. There is no other planet that would resemble Earth in physical chemically, in the solar system,

that would have liquid water within the correct range of temperatures and with the magnetosphere to block the radiation. So if there was a planet like that and it was sterile, then that would be a very good argument for the fact that Earth was in some way unique and we got lucky. But we just don't know, right? We have no idea. And so since it's the end of the podcast now, we can let her hair down and speculate a little. little bit. Everyone, you know, once we get this far, we have to ask about intelligent life out there in the universe. Life happened very quickly on Earth, but took a long time for it to become multicellular. Do you think, so what do you think are, if any, the roadblocks to life becoming

big and complex? It's very unlikely for that to happen because it's the cost of becoming complex is very high. And life on Earth only became complex when it had no other way. when there were those giant evolutionary bottlenecks, and life just had to find a way to survive. And intelligence isn't necessarily that good of a thing. Like we could sterilize Earth right now if we get into some big atomic conflicts. It has its drawbacks. The intelligence has a drawbacks.

So I think it's possible to imagine there would be complex multicellular life somewhere in the universe, but the probability of it developing a sapiency of any sort is rather low. Okay, so I mean, there's getting nuclei, right, a cellul nucleus that go to eukaryotes and then becoming multicellular. That's just what we know from the terrestrial life. Right. We think multicellular organisms have to be eukaryotic as in heaven nucleus, but we don't know that. But do you think that getting a cellular nucleus was a hard step or an easy one? I think that's what was actually an easy one.

That's an easy one, okay. Kind of pointless until you build up on it and you do more. but I could easily imagine a multicellular organism that's made of cells that look like procreotes that don't have nucleus. All of these steps, it's always a competition, right? Because when you become more complex, you need more resources, you need more specific conditions, but there's some benefit for it. And so it's always very unclear, other than the fact that it happened in our evolutionary history, which one of these was always going to happen and which one of these really got lucky.

Absolutely. And so you're getting... is that the leap to multicellularity might be hard in the leap to smartness, intelligence. I mean, once you're multicellular, part of me thinks that some of those cells are going to differentiate into neurons and then it's just a matter of time. I don't know. It might be just a matter of time if you think about developing a smartness of a dog or a dolphin. So you don't think that once you're as smart as a dolphin, you'll be building spaceships eventually?

Dolphins haven't built many yet. They don't have opposable thumbs. Exactly. So there are just so many things that have to come together for a civilization. You have to be able to make fire or have some kind of a way of processing raw materials. You have opposable thumbs more likely. I think dogs would rule the world if they had opposable thumbs. Fortunately for us, they don't.

And the lifespan of a civilization, at least given all we know right now, is probably not that long. the grand scheme of things. So even if there was ever another intelligent civilization, the likelihood of them running into us is rather low. My personal guess is that thousands of years from now, when we're visiting all these different solar systems in the galaxy, that will probably find cellular life all over the place. But I'm more skeptical about biospheres ruled by dolphins and dogs

that are smart and sociable but don't have technological capabilities. But we'll see. I don't know. This is a field where there's so little data that it's a good reminder of how much we're just beginning to ask some of these questions in a principal scientific way. Yeah, and we will have no way of knowing until we actually go out there and look. Well, hopefully your synthetic cells will help us live forever, so that will increase the chances that we'll be here to find out the answer. You'd think so. It would be kind of boring, I think. By forever, I mean just a few thousand years.

We don't need to go crazy. A few thousand years will be fine. like that. All right. So I'll let you get back to work on that. Kate Amadala. Thanks so much for being on the podcast. Thank you so much. Thanks for having me.