56 | Kate Adamala on Creating Synthetic Life

0:00:00 Sean Carroll: 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 the 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.

0:00:34 SC: So today we're going to be talking to Kate Adamala, who is 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 Venter 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 was he took a pre-existing bacterial cell, removed its genome, and replaced it with a 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.

0:01:26 SC: 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... We're at 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!

[music]

0:02:41 SC: Kate Adamala, welcome to the Mindscape podcast.

0:02:49 Kate Adamala: Thank you, it's great to be here.

0:02:50 SC: So you know, as someone who has done cosmology, in my life, I sometimes get accused of 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.

0:03:08 KA: We are trying, we are not as good as the original God must have been, but we're trying to get there.

0:03:14 SC: So is it fair to say that one of your goals in the lab is to create life from scratch?

0:03:19 KA: 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 bio-organic molecules and enzymes and trying to put them together into something that resembles a living system.

0:03:46 SC: Okay, so you are 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...

0:03:54 KA: I don't know if he did it right, but he definitely did it, we're trying to improve on it.

0:04:00 SC: And how did you get into this? Are you a biologist by training?

0:04:04 KA: No, I'm actually a chemist by training, and my approach to it is chemical, I think life is just 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 kinda cool. [laughter] I mean, growing up, when you watch all those science fiction movies they always have an astrobiologist on a spaceship, and one day I realized that this is actually a job one can do, so I went and started doing it, and it was great.

0:04:32 SC: So, let's back up a little bit, I mean, if you are 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 in my book, The Big Picture, I quoted the famous NASA definition of life, and I said I didn't like this definition.

0:04:49 KA: I don't like it either but...

0:04:50 SC: So tell us what it is, and then why you don't like it.

0:04:52 KA: So, the 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 is because it's not a functional, experimentally verifiable definition. So when we go out and drill under the ice of Europa, are we going to find some organic soup? The 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.

0:05:28 SC: 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 would still be alive, right?

0:05:43 KA: That's a very good point too. For example, I'm not alive myself because I cannot undergo Darwinian evolution myself.

0:05:49 SC: There you go. And I've chosen not to, so maybe I'm not alive either. [laughter]

0:05:52 KA: Exactly, the problem with definitions of life is that as soon as you come up with one, you will find an exception that doesn't fit it.

0:06:00 SC: Do we need to have a definition? Is that an important thing?

0:06:01 KA: 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.

0:06:11 SC: What do you mean when you say the word organics?

0:06:13 KA: 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 spectrophotometrically in interstellar clouds. We know there will be organics like that on pretty much any surface that can support liquid water in the universe.

0:06:39 SC: Yeah, I think that some non-scientists can get confused by this because they think that 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.

0:06:54 KA: Yup, pesticides are organic, believe it or not.

0:06:58 SC: Yeah. [chuckle]

0:07:00 KA: Yeah. By organic I mean not a biotic molecule, just an organic molecule in the organic chemistry since.

0:07:07 SC: But 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.

0:07:19 KA: Absolutely. There are amino acids out there, there are nucleobases out there. There are probably sugars out there.

0:07:26 SC: And this does not mean that there's living beings out there.

0:07:28 KA: That does not mean there are living beings out there. And that's the problem of lack of a functional definition of life 'cause 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.

0:07:40 SC: Okay.

0:07:41 KA: If I go out to Mars and find the right sterile chemistry terrestrial amino acid, that just means we've contaminated Mars, which we probably did anyway by now.

0:07:47 SC: Do you think we did?

0:07:48 KA: Oh, totally.

0:07:49 SC: Haven't we tried... Doesn't NASA try very hard not to contaminate?

0:07:53 KA: They also try very hard not to crash on landing and we...

0:07:55 SC: Yeah, that's true.

0:07:56 KA: 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 the moon with all the crap we crashed there. But we have not yet had a chance to contaminate neither Europa nor Enceladus, and these are the very likely candidates for places where there could be life in... At least in our solar system.

0:08:28 SC: So this is jumping ahead, 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?

0:08:37 KA: 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.

0:09:01 KA: More likely on Mars really than on...

0:09:02 KA: Definitely.

0:09:04 SC: Yeah.

0:09:05 KA: Another problem, though, is that Earth is spreading crap as we speak. 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 a tardigrade spore on Mars, that doesn't mean tardigrades originated on Mars independently.

0:09:23 SC: No. It's amazing to me also. 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.

0:09:33 KA: Galaxies, planetary systems, even whole galaxies share material with each other. 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 at spreading everywhere, and...

0:10:09 SC: 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?

0:10:16 KA: 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.

0:10:29 SC: So what would you... What would be on your personal list of characteristics that you would call kind of lifey?

0:10:36 KA: I like homeostasis.

0:10:38 SC: Oh, homeostasis.

0:10:39 KA: It's 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 than an environment but actually work for it. And that's homeostasis to me and...

0:11:00 SC: 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.

0:11:12 KA: Yes.

0:11:12 SC: Okay.

0:11:12 KA: To me that's the biggest hallmark of a living system. Replication is important. I'm actually a big fan of Darwinian 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. And every individual organism does not and does not have to undergo Darwinian evolution.

0:11:33 SC: 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. The fact that you and I do not have children is not going to stop us from being alive.

0:11:43 KA: Exactly.

0:11:44 SC: Members of our species do.

[chuckle]

0:11:45 KA: Exactly. And 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 in 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 to 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...

0:12:43 SC: It's a little vague, but...

0:12:44 KA: It's very vague and not experimentally trackable at this point.

0:12:48 SC: 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.

0:13:01 KA: Yes.

0:13:02 SC: So that's actually a dividing line, if only we could sort of formalize what we meant.

0:13:06 KA: Yeah, exactly.

0:13:07 SC: 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 little bit more general than that. So we have... Often people say compartmentalization, but is that tied up with your idea of homeostasis?

0:13:24 KA: To me personally, yes. I'm a lipid bilayer person, so I wrote 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.

0:13:47 SC: Well, good, this is one of the questions that I had coming in. And 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?

0:14:00 KA: Yes.

0:14:00 SC: There's some... Like, a virus is maybe always a sticking point?

0:14:05 KA: 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 impact the cell to replicate.

0:14:14 SC: Okay. And so it's obvious why that would be helpful 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 on the outside. But let's just... Because there's many examples in the history of science where scientists guessed one way and it turned out to be wrong. Are we really sure you couldn't have something like life without membranes at all?

0:14:38 KA: Oh, we totally could. We need a compartment, but the compartment doesn't have to be a membrane at 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.

0:15:00 SC: And some people even proposed things like that as the origin of life.

0:15:03 KA: Yes.

0:15:03 SC: Right, yeah. But I guess when I meant membrane I was thinking as a non-biologist, like any compartment. But could we even have non-compartmentalized life? Just life sort of in a network that had different parts spread over some environment?

0:15:15 KA: 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.

[chuckle]

0:15:25 KA: And that's stupid because as scientists 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.

0:15:52 SC: When we say we have one example. We have many organisms but they all came from a...

0:15:56 KA: Yeah, they're all...

0:15:57 SC: Same original organism.

0:15:58 KA: On the biochemical level, life is... Terrestrial life is kind of boring because there's not much variety. Everyone has 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.

[chuckle]

0:16:29 KA: There's not that much variety.

0:16:31 SC: Not a lot of cleverness in the engineering.

0:16:33 KA: There's cleverness for sure, but there's not enough variety.

0:16:36 SC: Not of variety I should say, yeah, okay.

0:16:37 KA: So we can't 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.

0:16:49 SC: And let's... I really got into the whole idea of the bi-lipid membranes, is that...

0:16:57 KA: Lipid bilayers.

0:16:58 SC: Lipid bilayers.

0:16:58 KA: They're bilayers because they have two leaflets.

0:17:00 SC: So tell me what a lipid is, talk about the hydrophilia and the hydrophobia and all that stuff because it's amazing to me.

0:17:07 KA: So yeah, lipids are really cool. So a lipid has a tail and a head.

0:17:11 SC: Lipid is a molecule.

0:17:12 KA: Yes, lipid is a molecule, and it has to be... To be classified as a lipid it has to have a tail and a head. And the head is polar, which makes it hydrophilic, and the tail is non-polar, which makes it hydrophobic.

0:17:26 SC: So liking water or hating water.

0:17:27 KA: 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 trucks backing up into each other. The backs of the trucks are facing each other, and the fronts of the trucks 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 hydrophilicity 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.

0:18:33 SC: Yeah, the other nice thing is is they're pretty easy to make then, right, because they just happen.

0:18:36 KA: They just happen, exactly. And that's why I'm a big fan of lipids because we know lipids can be synthesized abiotically, so there were lipids around even before there was life around. And once you have lipids you are going to have bilayer membranes, and once you have bilayer membranes they like to be spherical. It's not...

0:18:53 SC: That's another amazing thing, right?

0:18:55 KA: Yeah. It's not healthy for a membrane to be flat, it wants to be spherical. It's basically like a soap bubble; 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 bilayers do, they end up being spheres. And then once you have that sphere you can put stuff inside and start living.

0:19:17 SC: Yeah. So these lipids very naturally give us a way to compartmentalize.

0:19:21 KA: Yes.

0:19:22 SC: Are there other ways besides lipids?

0:19:24 KA: 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, face change transition, depending on external environment. And we actually have them; we have those membraneless organelles in our cytoplasm that create just kind of islands of different chemical composition just because they want to, like 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.

0:20:13 SC: Okay, but most life as we know it, cells are... The membranes of the cells are made of these bilayers...

0:20:20 KA: All life as we know it uses lipids in their bilayers.

0:20:23 SC: So on the one hand, it's... They're easy to make, but on the other hand, they're not completely watertight, right? Some things can come in and out, which is important to being a living organism.

0:20:33 KA: Yes, yes. And the really good ones, they're 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 memory channels, and that's actually really good because then you have control over what goes across your membrane, 'cause you control your channels.

0:20:51 SC: So in some sense, the cell is like a little island, and there are these bridges across the membrane...

0:20:55 KA: Yes. And they have control over those bridges.

0:20:57 SC: Yeah, there's border patrols, letting some things in and out.

0:21:01 KA: Yes, yup.

0:21:02 SC: So you can see how things are beginning to get a bit more complicated, yeah.

0:21:05 KA: 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.

0:21:20 SC: 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?

0:21:34 KA: Yes. It's the one that we made a lot of progress on.

0:21:37 SC: Yeah.

0:21:38 KA: 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 pain in the lower back. That's 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 the great scheme of things, there are... A lot of other experiments are easier, but the origins field made great progress in making those compartments.

0:22:13 SC: Good. And then the other things we mentioned were, the need to be able to replicate, and you need some sort of engine inside you, right? You need some metabolism?

0:22:22 KA: Yes.

0:22:22 SC: So that's how I think of what life is. It has those three aspects of compartmentalization, metabolism and replication. Is that fair? Am I over-simplifying?

0:22:31 KA: No, that's definitely fair, it's definitely over-simplified, but it's also fair.

0:22:34 SC: Yeah. And what qualifies exactly as metabolism? And this is where I get into physics, right? Life uses fuel, it uses the low entropy energy from its environment one way or another.

0:22:47 KA: 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 homeostasis, 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 you're... 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.

0:23:45 SC: 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."

[chuckle]

0:23:52 KA: Oh, absolutely.

0:23:53 SC: Metabolism and then we're still searching for the precise definitions.

0:23:57 KA: Absolutely, and we're kinda again, hampered by the fact that we don't have anything to compare with. We only have one... We only know one way of doing metabolism, because we only know one life form. If we had a few other to look at, we could try to generalize more.

0:24:14 SC: 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.

0:24:23 KA: Yup, and they're all made by one company, everybody uses ATP. So that's...

0:24:26 SC: Yeah. [chuckle]

0:24:27 KA: Kinda hard to generalize and...

0:24:29 SC: There's a monopoly.

0:24:30 KA: Yeah, there's totally is monopoly.

0:24:32 SC: And is it... 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?

0:24:50 KA: 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.

0:25:08 SC: Okay, that's good. So the other special thing then is the... On the replication side, we use DNA, right?

0:25:13 KA: Mm-hmm.

0:25:13 SC: DNA and RNA are both involved. And then, like you said, the ribosome tells the RNA, or actually takes the RNA in and make proteins.

0:25:22 KA: Yes.

0:25:22 SC: 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 a 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, forget about living beings, DNA is a really good information storage mechanism.

0:25:46 KA: 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 back bone, which is what 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 starting nucleobases, those forward DNA nucleobases, and these I think are relatively random. 'Cause you can imagine different kinds of nucleobases that could easily do the same thing.

0:26:29 SC: Right. And there's this weird thing that there are four different nucleobases, and they appear in groups of three. So 4 x 4 x 4 is 64, right? So 64 different possibilities. And we use all of them but in kind of a redundant coding scheme. There's only sort of 20 of the categories that we actually make use of. Is that right?

0:26:51 KA: 21, yeah.

0:26:52 SC: 21. Okay.

0:26:53 KA: Stop.

0:26:53 SC: Oh, yeah, there's one, the period at the end of the sentence.

0:26:55 KA: Yes.

0:26:55 SC: You need that, right? Okay. And so you're not sure or you're suspecting that this choice for nucleobases could've been very, very different.

0:27:07 KA: 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 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.

0:27:29 SC: Is that something that synthetic life researchers are looking into? Could they improve on DNA?

[chuckle]

0:27:35 KA: It wouldn't necessarily be improving you. I think most of the other choices wouldn't actually improve. DNA is great because it's just stable enough. Its base pair is stable enough to be solid when 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 nucleobases and it works.

0:27:58 SC: Okay, that's good to know. A slightly more radical question is, DNA is, or 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 to generalize that would be what about a two-dimensional sheet? Could we imagine 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?

0:28:29 KA: This would probably work, but then your cells would have to be ginormous.

[chuckle]

0:28:33 SC: You're a synthetic biologist, you can make that happen.

[chuckle]

0:28:36 KA: There are actual physical chemical limitations on the size of a cell. If you have too much surface you're spending too much time working on that surface and that's your problem.

0:28:46 SC: So there are basic laws of physics, chemistry, etcetera in the environment we have.

0:28:50 KA: Yes.

0:28:50 SC: But it may be in very different environments the conditions look very different.

0:28:54 KA: Yes.

0:28:54 SC: Okay, good to know. Well, mark it down that we talked about that here if we discover it on Europa or something like that.

0:29:01 KA: 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.

0:29:08 SC: Okay, alright. And so that...

0:29:09 KA: Pancake life.

0:29:10 SC: Pancake life, yes. Mmm, pancakes. So we have those basic ingredients. I think that it behooves us as scientists to try to think beyond these obvious things, 'cause 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?

0:29:47 KA: That depends who you ask.

0:29:50 SC: 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 an artificial life. 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?

0:30:04 KA: We've made the biggest progress on compartmentalization. We can recreate artificially compartments that look 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 has not been solved. We are unable to recreate a autonomous spontaneous replication system. We can replicate those compartments by hand, 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 homeostasis. We can make those little synthetic cell compartments that actively maintain their composition that is different than the composition of the outside.

0:31:05 SC: That's pretty good.

0:31:06 KA: They're not as robust, but they're nowhere nearly as robust as living systems, but again, they're kind of lame attempts at recreating living systems, so they won't be as robust.

0:31:16 SC: 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 get yet have an example of synthetic single molecules that reproduce themselves, right?

0:31:28 KA: No, not yet.

0:31:30 SC: We should've mentioned this earlier, but of course when we say reproduction, things like fire reproduce themselves or crystals reproduce themselves, but now we're talking about reproduction with information storage is the crucial thing. That's why RNA is so good.

0:31:44 KA: Yeah. RNA and DNA and all the other NAs.

0:31:48 SC: Yeah, okay, okay. We did... Explain to us what we've heard in the news. There was several years ago we heard the Craig Venter made artificial life, but it all depends on what you mean. So forget about whether he made artificial life or not, what did he do?

0:32:03 KA: 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.

0:32:49 SC: Yeah.

0:32:49 KA: 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, it might not divide as 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.

0:33:29 KA: Now, then next thing is they actually synthesized 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 they did it. Then, how do you make it to be actually alive is you take that synthetic genome, that DNA was synthesized on a machine and had 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 and just slightly more complex and they developed this procedure called genome transplantation. Where they take the 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.

0:34:27 SC: So, you didn't remove the original DNA.

0:34:29 KA: No, they did not.

0:34:30 SC: You just superseded it.

0:34:31 KA: 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 a live 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, yeah, so... So they took the artificial genome, put it inside another cell, and that cell started expressing proteins of that... From the 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 syn cells were born. Syn as of synthetic cells.

0:35:20 SC: So, it's certainly pretty good what they did?

0:35:21 KA: Oh, they're amazing. It was the technological advancements that we get out of those products are incredible. The most 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 then there are several iterations of that syn cell. They made it smaller and then yet smaller and then yet smaller and then they made it slightly bigger because it started too slow for anyone to be able to put up with it. But there is many of those organisms right now where we know every single gene and we can control basically what every one of those genes do.

0:36:05 SC: It might be worth just thinking about the actual process of this. 'Cause I think people have in mind going in there with tweezers and a scalpel and cutting and repasting DNA.

0:36:17 KA: Very tiny tweezers.

0:36:18 SC: Very tiny tweezers. But that's not what we actually do?

0:36:20 KA: No.

0:36:21 SC: What do we do?

0:36:22 KA: 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.

0:36:39 SC: Which really just means, let the chemistry happen that brings it back together.

0:36:42 KA: Yes.

0:36:43 SC: We are never picking up one strand and another strand and with our hands putting them together.

0:36:47 KA: Not quite, nobody has hands that small.

0:36:49 SC: 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, 'cause I myself am not completely clear on this, is it like we literally have the complete list GCTTA and we could type in any list we want and make a DNA molecule like that?

0:37:10 KA: Yes, yes.

0:37:10 SC: That's pretty good.

0:37:11 KA: That's how we're making DNA these days is 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 order.

0:37:24 SC: And it doesn't take forever to do that? I mean, these are long, right? These are millions of nucleobases?

0:37:28 KA: 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 few hundred to a couple thousand nucleobases long and that doesn't take very long.

0:37:43 SC: But that wouldn't be enough to power whole bacteria.

0:37:46 KA: Absolutely not. The smallest known genome is 474 genes and that's quite a bit of DNA.

0:37:53 SC: Yeah, so how many bases in a gene? I know there's wildly different numbers, but...

0:37:58 KA: It's very wildly different. It's from a few hundred to a few thousand.

0:38:02 SC: Okay, right. So if the state of the art then at that time, a few years ago, was sort of redesigning the DNA and then plugging it back into an existing bacterium, how far have we come since then?

0:38:19 KA: 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 to get life out of it.

0:38:32 SC: Yeah, okay.

0:38:33 KA: That's what my lab is trying to do with collo...

0:38:35 SC: That's what you're trying to do.

0:38:36 KA: With collaboration with the Craig Venter 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 right itself up, can start making all the proteins that will organize a proper way in which we expect life to organize.

0:39:16 SC: And that would really be... Well, I don't know, I already said we shouldn't argue about the definitions, but it sounds like that would really be a synthetic life form.

0:39:26 KA: That would be a life form that was created from non-living components.

0:39:30 SC: Yeah.

0:39:33 KA: 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.

0:39:56 SC: Sure.

0:39:57 KA: If you want to talk about artificial, 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 on what's the current...

0:40:09 SC: Okay. This is why I don't care about the definitions 'cause 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 Venter 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.

0:40:34 KA: Absolutely. They're called essential genes of unknown 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 kinda frustrating.

0:40:48 SC: So even when we're typing in our keyboard GTTAC, 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?

0:41:01 KA: That's so frustrating about life in general, it's a black box.

0:41:04 SC: Yeah. Is that an ongoing research thing we're trying to figure that out?

0:41:08 KA: Yes.

0:41:09 SC: 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?

0:41:16 KA: 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.

0:41:25 SC: And is it just these things are too complicated? Is that the obstacle?

0:41:27 KA: Yes, yeah.

0:41:28 SC: Okay. So one of the things you're trying to do is not only make a synthetic living, breathing, not breathing, but living cell but also things that are cell-like that might not quite rise to the level of being alive.

0:41:42 KA: Yes.

0:41:43 SC: And so what comes afterward?

0:41:44 KA: We're quite good at that actually. We can make things that are not alive but are quite complex.

0:41:50 SC: So for instance, what? What do they do? What stops them from being alive?

0:41:56 KA: 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.

0:42:06 SC: So it looks like a cell...

0:42:07 KA: Looks like a cell...

0:42:08 SC: Has DNA in it.

0:42:08 KA: Quacks like a cell but is not a cell.

0:42:10 SC: Okay, but it does have DNA.

0:42:11 KA: It does have DNA. It does have RNA. It does have ribosomes.

0:42:15 SC: It makes proteins.

0:42:15 KA: Makes proteins.

0:42:16 SC: It won't duplicate itself, it won't replicate.

0:42:18 KA: It won't duplicate itself.

0:42:19 SC: You can go in there, you can clone it.

0:42:21 KA: Yes.

0:42:22 SC: Okay. And what is the usefulness of these things?

0:42:24 KA: We can study processes that we cannot study in a complex live cell because the natural live 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, from the every single building block can be manipulated. So if we want to, for example, reconstitute a signaling pathway or reconstitute a 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.

0:43:17 SC: And is this potentially useful just for down-to-earth crass commerce kind of reasons for engineering and medicine and things like that beyond the fundamental questions of life and time?

0:43:28 KA: 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, maybe a little bit of 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.

0:44:07 KA: 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 chemical factories we can think of that will always be sustainable, which is biomanufacturing 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 no part of it. They say, "I'm not going to do it because it's toxic to me."

0:44:45 KA: And that's the biggest problem in biomanufacturing right now is how do you make all those complex toxic molecules. Now, a nice being 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.

0:45:50 SC: Yeah, there's no such thing as off-topic, so don't worry about that. We should talk about this 'cause I like that you brought up the petrochemical thing, 'cause that always struck me when people worried about 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 are literally burning it.

0:46:17 KA: Absolutely.

0:46:18 SC: So what 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.

0:46:29 KA: I mean, we have to find a way of doing it because, 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.

0:46:56 SC: Well, and it opens up a whole set of vistas that I've heard people sort of mention in passing about, for example, combating climate change or something like that, by designing little microorganisms to go chew up the CO2 and the other things in the atmosphere that we don't want, the greenhouse gases. Is that at all feasible in your mind?

0:47:20 KA: 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 an environment that doesn't...

0:47:33 SC: What could go wrong? [chuckle]

0:47:34 KA: 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.

0:47:50 SC: 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 you healthy all the time.

0:48:09 KA: I hope so, I bet my money on it. I actually have a little startup that's betting money on it.

0:48:13 SC: Oh, okay.

0:48:14 KA: So we're hoping to get, to make it a reality.

0:48:16 SC: Skin in the game, yes.

0:48:17 KA: I also feel, 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, without all the problems that the natural immune cells have as in self-replication ability to turn on your own cells.

0:48:43 SC: And fighting allergies and things like that, maybe even combating cancer, I don't know what we're...

0:48:48 KA: 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 variable, as in cancer 'cause there's no such disease as cancer.

0:49:09 SC: No.

0:49:10 KA: Every single cancer is slightly different and we make those cancer drugs that just go in and kill everything and this, then... No, this is probably not the best or most efficient way of targeting, at least some of those.

0:49:25 SC: 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.

0:49:32 KA: 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 a specific medicine, once you're half way through your five-year mission to Mars, you're not going to know what you will need a few years in advance. Like, so 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 the 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.

0:50:14 KA: 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 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 crew mate develops another kind of cancer, you make yet another drug, and so on.

0:50:53 SC: 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?

0:51:03 KA: Yes.

0:51:03 SC: Okay. Because clearly we don't understand a lot about the interplay between our own microbiomes and our cells, right? So introducing new cells into people might be risky, I don't know.

0:51:13 KA: 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 the 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 one, some of the most deadly cancers with experimental therapies, because we don't have all that much to lose. I mean, a patient who has six months left to live, if you extend that life span by another six months, you, I don't want to say you won, but you have...

0:51:53 SC: You've done something good.

0:51:54 KA: You've done something good.

0:51:55 SC: But I've heard that you're allergic to cats so that's...

0:51:57 KA: I am.

0:51:57 SC: So that's a pretty big disaster, here at Mindscape, we're pretty, we're very pro-cat.

0:52:01 KA: But, I'm pro-dog personally, and I'm not allergic to dogs, so.

0:52:05 SC: [chuckle] Alright, 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. Robots, computers, engineering, this is all kinds of things you can do with your synthetic cells.

0:52:34 KA: We're working on bio-computing right now too, we're trying to make genetic circuits that perform computation and store memory. And again, that's where synthetic cells are kinda handy, because people have done a lot of good biocomputing with light 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.

0:52:56 SC: Darwin, man.

0:52:57 KA: I know. Synthetic cells are dumb enough that they don't think they can get away with anything.

[chuckle]

0:53:02 KA: 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.

0:53:10 SC: Yeah, that's part of the fact that they're not alive.

0:53:13 KA: Exactly.

0:53:14 SC: So, they have some of the good benefits of living creatures, for our engineering purposes, without the drawbacks.

0:53:20 KA: Yes.

0:53:21 SC: And are there particular kinds of computations that it might be useful to do this way?

0:53:26 KA: Right now, we're still baby-stepping it. We're doing Boolean logic gates, so the very simple logic gates that people know from playing with doing informatics "on paper," so like AND GATE or OR GATE.

0:53:41 SC: Yeah, start somewhere.

0:53:42 KA: Have to start somewhere.

0:53:44 SC: Builds an abacus next. Yeah, next. [chuckle] And is there... And I'm just making this up, 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 skeletons and bones, which have the ability to be rigid, but you can break them and they will fix themselves, to robotic, metallic things, which once they break, that's it. Is there a hope of making materials that are stiff and sturdy, but self-repairing?

0:54:18 KA: Absolutely, that's one of the probably most exciting promises of this field, is that you can imagine, programming semi-living or sort-of-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.

0:54:40 SC: I think we need a word for this semi-living state, [chuckle] where it doesn't replicate, it's not on its own, it needs some help, but...

0:54:46 KA: What's wrong with semi-living?

0:54:48 SC: Semi-living... Well, yeah, it's a little creepy, but that's okay. I think...

0:54:51 KA: Sort-of-living?

0:54:52 SC: Sort-of... If you have a new word, go back to the Greek roots or something like that. You can definitely coin a term there. Yeah, it's a brave new world. How do you see where we'll be 50 or 100 years from now and what we're doing with synthetic cells?

0:55:08 KA: 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 on living systems and people that do the classical bioengineering with live 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.

0:55:48 SC: 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 from my iPhone and I could build a cell, but we're not quite there yet.

0:55:56 KA: There actually is a game where you can put together a live organism. We're not related to that, but...

[chuckle]

0:56:03 KA: It's the first hit when you Google our collaboration.

0:56:06 SC: So, what is Build-a-Cell aiming at?

0:56:08 KA: 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 there as... 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 the Build-a-Cell community. We're basically people that can come together and talk about making life from scratch and nobody makes fun of us.

[chuckle]

0:56:56 SC: It reminded me a little bit of large-scale particle physics experiments. When you build a detector at the Large Hadron Collider, there's 1,000 people in the collaboration and one of them builds a little calorimeter and the other solders wires together and... So, you have sub-groups that are interested in lipid bio-layers, others are interested in ribosomes and so forth, and you're all working together?

0:57:18 KA: 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.

0:57:27 SC: Are you going to reach the particle physics scale, where there are thousands of authors on every paper?

0:57:30 KA: I would love that.

[chuckle]

0:57:33 SC: But you're not there yet.

0:57:34 KA: We're not there yet, we're not quite there yet.

0:57:37 SC: Okay, so let's... I think the final topic... Let's go back to outer space, 'cause 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, 'cause part of 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.

0:58:09 KA: If not better.

0:58:11 SC: Why would they be better?

0:58:12 KA: 'Cause they're smaller and they can hold onto water, they're not as hot, they actually have a surface. We like surface.

0:58:19 SC: Why does Europa... Why, historically, was Europa better at holding onto water better than Mars?

0:58:26 KA: That, I actually don't know. I know why Mars lost water.

0:58:29 SC: Why did Mars lose water?

0:58:30 KA: Because it never developed plate tectonics. If you develop plate tectonics, you can re-circulate your water. You can have water vapor in the atmosphere that gets spit out of the volcanoes, and it comes back at 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 onto it.

0:59:16 SC: It's frozen at the surface with the ice, but then beneath that there's huge amounts of liquid water on Europa.

0:59:20 KA: 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 its water stuff. It's clearly warm enough to be liquid. So it's doing stuff and that's why we have hopes for it.

0:59:34 SC: There's chemistry going on in a aqueous solution, yeah.

0:59:38 KA: If you have aqueous solution, you will have organic chemistry going on in there.

0:59:42 SC: And so, one of your things is studying synthetic life, because we want to be better at knowing alien life when we see it. What should we be looking for when we do go visit and contaminate Europa?

[chuckle]

1:00:00 KA: 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 homochiral. So chirality is this orientation of 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 there.

1:00:33 SC: This is left-handedness versus right-handedness in the molecules. Yeah.

1:00:36 KA: Exactly. Yep. And that is not natural, natural as in abiotic. You cannot get such conserved homochirality, at least we don't know non-living catalysts that would give you that much specific system-wide homochirality. 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.

1:01:15 SC: 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, 'cause the light reflects the same from left-handed and right-handed molecules.

1:01:25 KA: You need to go scoop it up, analyze it.

1:01:27 SC: And we're hoping to do that.

1:01:28 KA: 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 vapor is probably lousy with organics. So we can just do a fly-over, and... I'm saying just, it's going to...

1:01:49 SC: Yeah, just fly to Saturn.

1:01:51 KA: Fly over to pick up a sample sounds easier to me than land the drill, pick up a sample.

1:01:57 SC: Sure. Have we ever done that? Have we ever done flybys to kind of scoop up chemicals and test them?

1:02:02 KA: Not that I know of.

1:02:03 SC: Okay. The slowing down is always hard, it's much easier to zoom by a planet than to slow down.

1:02:09 KA: Yep. Slow down, get into orbit, go low enough.

1:02:11 SC: Bringing fuel with you is hard. Right.

1:02:13 KA: Yeah. It doesn't even have to be sample return. You don't actually have to bring enough fuel to get off the planet or moon. But even get there and get close enough is hard enough.

1:02:25 SC: 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, a lot of really long complicated molecules, the only way we know how to make them is via life or biotic processes.

1:02:41 KA: 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 a biotic way, with no life.

1:02:53 SC: Okay. So this is a controversial point, different people have different feelings about this?

1:02:56 KA: Different people have different opinions.

1:02:57 SC: Yeah, okay. That's why it's hard.

[laughter]

1:03:00 SC: And what about far away? If we look at exoplanets, we've discovered bushels full of exoplanets now. We can't go do the 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?"

1:03:17 KA: So we're not as good at looking at exoplanets as people seem to think. The way we discover most of our exoplanets is we're looking at the star, and that star's 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.

1:03:39 SC: Right. We see the star wobble, or get eclipsed, or something like that.

1:03:43 KA: And then that's how we actually... We have seen some exoplanets as in we've seen some of either light reflected from that exoplanet, which is incredibly hard, or we've seen the planet's 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.

1:04:10 SC: Okay, but let's say that astronomers get good at it, is there something to look for?

1:04:14 KA: I think the easiest way to do it is to look for physical chemical conditions on those planets, 'cause 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 the planet lies within that orbit. If we get better at defining what physical chemical conditions we need for life, so building different kind 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."

1:05:09 KA: 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 sites that equals one but from that sample, we can tell that life is almost inevitable under certain physical and chemical conditions of a planet.

1:05:29 SC: 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.

1:05:36 KA: Nobody knows the answer.

1:05:38 SC: No one actually knows the answer, right. But people have convictions, nevertheless.

1:05:41 KA: Yeah.

1:05:43 SC: 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. 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 was no life then. But as soon as it cool 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?

1:06:18 KA: 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 a somewhat different life form.

1:06:45 SC: Very different, I would think.

1:06:46 KA: It's 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.

1:07:08 SC: Fair enough.

1:07:10 KA: 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.

1:07:32 SC: But we just don't know, right?

1:07:32 KA: We have no idea.

1:07:34 SC: And so, since it's the end of the podcast now, we can let our hair down and speculate a little bit. Everyone... 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 road blocks to life becoming big and complex?

1:07:57 KA: It's very unlikely for that to happen, because 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 and...

1:08:23 SC: It has its drawbacks.

1:08:24 KA: It has its... The intelligence has its 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 sapiency of any sort is rather low.

1:08:38 SC: Okay. So there's getting nuclei, a cellular nucleus to go to eukaryotes and then becoming multicellular.

1:08:45 KA: That's just what we know from the terrestrial Earth life.

1:08:49 SC: Right, but...

1:08:49 KA: We think multicellular organisms have to be eukaryotic, as in have a nucleus, but that we don't know that.

1:08:55 SC: But do you think that getting a cellular nucleus was a hard step or an easy one?

1:09:00 KA: I think that was actually an easy one.

1:09:01 SC: That's an easy one. Okay.

1:09:02 KA: 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 prokaryotes that don't have nucleus.

1:09:16 SC: All of these steps... It's always a competition 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.

1:09:33 KA: Absolutely.

1:09:34 SC: And so your guess is that that leap to multicellularity might be hard in the leap to smartness, intelligence. 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.

1:09:51 KA: It might be just a matter of time if you think about developing a smartness of a dog or a dolphin.

1:10:00 SC: So you don't think that once you're a smart as a dolphin, you'll be building spaceships eventually?

1:10:03 KA: Dolphins haven't built many yet.

1:10:05 SC: They don't have opposable thumbs, yeah, so...

1:10:07 KA: 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 test some kind of a way of processing raw materials. You have to have opposable thumbs more likely, like I think dogs would rule the world if they had opposable thumbs. Fortunately for us, they don't.

1:10:26 SC: Yes.

1:10:27 KA: And that life span of a civilization at least, given all we know right now is probably not that long in the grand scheme of things. So even if there was ever another intelligent civilization, the likelihood of them running into us is rather low.

1:10:43 SC: My personal guess is that thousands of years from now when we're visiting all these different solar systems in the galaxy, that we'll 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.

1:11:03 KA: Yeah, probably not.

1:11:03 SC: But we'll see. I don't know.

1:11:05 KA: No.

1:11:05 SC: 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 principled scientific way.

1:11:15 KA: Yeah, and we will have no way of knowing it until we actually go out there and look.

1:11:19 SC: 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.

1:11:26 KA: You would think so. That would be kinda boring, I think.

1:11:29 SC: By forever, I mean just a few thousand years. We don't need to go crazy.

1:11:31 KA: Okay, okay. I'll take that.

1:11:33 SC: All right. So I'll let you get back to work on that. Kate Adamala, thank you so much for being on the podcast.

1:11:38 KA: Thank you so much. Thanks for having me.

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