The Joy of Why - What Is Life?

Episode Date: June 15, 2022

Without a good definition of life, how do we look for it on alien planets? Steven Strogatz speaks with Robert Hazen, a mineralogist and astrobiologist, and Sheref Mansy, a chemist, to learn more.

Daniel and Jorge Explain the Universe is a podcast about, well, everything in the universe. Do you want to understand what science knows about how the universe began and what mysteries remain? Are you curious about what lies inside a black hole? And if we'll ever know, Daniel is a physicist working at CERN who actually knows what he's talking about. And Jorge asks all the questions that pop up in your mind as you listen to make sure everything is crystal clear. Listen to Daniel and Jorge Explain the Universe on the iHeartRadio app, Apple Podcasts,

or wherever you get your podcasts. I'm Steve Strogatz, and this is The Joy of Why, a podcast from Quantum Magazine that takes you into some of the biggest unanswered questions in math and science today. In this episode, we're going to be talking about what it means to be alive. What is life? Can you define it? Scientists don't actually agree on a definition. It sounds weird, right? I mean, most of us would say with some confidence that a bird is alive and a chair is not. But going deeper, scientists ask questions like this. To be considered alive, does something have to be able to reproduce? Does it have to be a product of

evolution through natural selection? Does it need to have a metabolism and be able to process energy? Any definition along these lines is riddled with exceptions. For instance, is a virus alive? Well, viruses do evolve, but they don't replicate on their own. They use the host's cellular machinery to make more copies of themselves. The question of what life is also matters, because if we're going to be looking for life on other planets, don't we need to at least have some idea of what we're going to be looking for life on other planets, don't we need to at least

have some idea of what we're looking for? Later on in this episode, we'll hear from Sharif Mansi, professor of chemistry in the Department of Chemistry at the University of Alberta. But first, joining me now is Robert Hazen. He's a mineralogist, astrobiologist, and senior staff scientist at the Carnegie Institution's Earth and Planets Laboratory. Bob, thanks so much for joining us today. Oh, it's a pleasure. Thanks so much, Steve. Great. Well, let's jump right into this. Why is it so hard for scientists to agree on something that commonsensically most people would say they already understand? Like, we know that a plant is

alive and a rock is not. Why is it so hard to come to some agreement about the definition of life? Yeah, that seems strange, doesn't it? Because we all know things that are alive, and we all know things that aren't alive. And yet it's that gray area in between. So when we start saying, this is alive and this is dead, that's fine. But when you say everything either has to be alive or dead, you're setting up a false dichotomy. Because the taxonomy of what it means to be alive, I think, is much, much richer than just dead or alive. Hmm. How so? Well, think about it. You have an origin of life.

So that's a really good metric. There was a point in our Earth's history when there wasn't a single living thing. It was a blasted surface. It was covered with volcanoes and magma. And it was just basically inhospitable. There was no place that life could even get a tiny foothold. But gradually, as the Earth cooled, as oceans formed, as the atmosphere became more palatable for some kind of living thing, we think there was a process, a historical process, the origin of life, in which chemical systems became gradually more complex, became

more interesting. And at some point, yes, there was a first cell that probably had proteins and DNA, but there had to be something before that. And where do you draw the line? It's just difficult to say there's an absolute point in space and time when there was no life, and then the next point in space and time there was. Interesting, interesting. So the way you're phrasing it, it sounds like it's an issue of chemical complexity or something like that. It's a question of chemical complexity, but it's also a much more basic question of taxonomy. You know, it's so easy for humans to think in dichotomies. Good, bad, black, white, day, night. These are things that make life simple. It means we can categorize things very, very quickly. And early on in human history, this was the defense mechanism because you had to make decisions very, very quickly whether or not you were going to shake that person's hand or shoot an arrow at them. So we needed to make

these decisions. But we don't have to do that when we're thinking about the larger issues of the natural world. The natural world is amazingly intricate and complex. And how those chemical complex systems emerge, and at what point a complex chemical system is something that we truly will call alive is not at all obvious. So I get your point about the gray zone. I mean, it's black and white is usually too simple applied to practically anything, that there's always some ambiguity in between. Nevertheless, let's say in the case of space missions that NASA's running, maybe off in the future, we will be trying, or even with earlier missions when we sent probes to Mars and that kind of thing, there was a quest to see if we could detect life. And so you would think in order to address that question objectively, you have to have some

criteria for what you mean by have you found it or not. backbone or everywhere in the cosmos. Anywhere there's carbon, you get this thing called organic chemistry. Lots of different kinds of molecules. They're just sort of a jumble, a mush of these things form. But life is very, very particular. And one thing I think we can say is if something is alive, it's going to put its energy into making a few molecules that work really well and ignoring the vast number of molecules that don't do much of anything. So if you have a system that has the biological overprint, it's going to show very specific groups of molecules. Maybe molecules that are what are called chiral or left and right-handed. Maybe you'll have a predominance of just the left-handed

or just the right-handed molecule. Maybe you'll have just strings of carbon that have multiples of two, two, four, six, eight, rather than all the other odd numbers as well. Maybe you'll have some other characteristic that wouldn't form just by a random process, but forms by a selective process. So that's what NASA was looking for, and I think that's a smart thing to do. That's very interesting. The idea of chemical selectivity, you say, could be, or at least was proposed by NASA to be a possible, well, nowadays we speak of biosignatures. I don't know if that would be the language they would have used at that time.

Yeah, exactly right. That you're looking for biosignatures. So I think if you see those chemical idiosyncrasies, you can say, wow, something really interesting happened here. And it doesn't look like just the normal natural process. It looks like there was some real selection for function, molecules that did a job. They metabolized or they helped build strong cellular structures or something like that. So I think that's what they were looking for. But the fact of the matter is that doesn't define life, does it? It just says we're looking for something that we think is a characteristic of the kind of life that we're familiar with. How many other kinds of life might there be out there?

And that's something we just don't know. We don't have enough information to build a taxonomy to say these things are alive and these things are dead and these things have some other interesting chemical features that may be lifelike but don't quite get us there. What would be some others then besides functional? There's chemical systems that might be able to make exact copies of themselves, but they wouldn't undergo mutation and natural selection. There are chemical systems that might template themselves, so they grow laterally and they get larger and larger and they seem to grow, but they don't really have this characteristic of

encapsulating a separate entity that we think of as being lifelike. But they're all interesting systems and they're all part of a kind of continuum of chemical complexity. And to me, the much more interesting challenge is to develop this taxonomy. Now, think about the Linnaean classification system, where you have kingdoms, and below the kingdoms you have phyla, and you have orders, and so forth. Well, maybe in our taxonomy of chemical complexity, we'd have a kingdom of non-living things and a kingdom of living things, and we'd have a kingdom of ambiguous things. And then beneath that, we'd have a whole bunch of other subcategories and subtypes. And we began realizing that the universe is an amazing and wonderful place and that chemistry does just extraordinary things,

some of which we call life. So you've been emphasizing chemistry so far, which is interesting to me, given that I think of you as a person with a lot of expertise in mineralogy and geology. What about those fields? How do those overlap in this very expansive picture of the question of life and other interesting phenomena? It's a really good question. And it goes to a more fundamental aspect of human nature. Yeah, I'm trained in geology and mineralogy. So I see the origin of life in terms of geology and mineralogy or geochemistry. It's a process of chemical complexification, that the origin of life occurred on a non-living planet, which means what you had is geology and chemistry. You didn't have life. You're trying to jumpstart life in a sense. So that's my perception.

Other people, like Sharif, who you're going to be talking to, he has much more of a biochemical background. And so he thinks very deeply about DNA and RNA and information. That's another aspect of life as we know it, passing information from one generation to the next and storing it and copying it. Boy, that's a molecular challenge. And I can imagine some really interesting chemical systems, some of which might even have attributes that we think of as lifelike, but don't necessarily carry information. They're just chemical systems that, because of the nature of the molecules themselves, just sort of reorganize themselves in fascinating ways. So there's so many attributes to this, and to me, trying to pin down one very specific set of criteria and say this is life and everything else isn't,

it kind of defeats the whole purpose of exploring the wonder of nature, which itself is so infinitely varied and complex. Nature is what nature is, and we try to impose a taxonomy on it. But that doesn't mean that we have all those nuances. So then, getting back to NASA for a second, are there some kinds of things that you think they should be looking for when searching for life on other planets? Or should they just be kind of going for the most glorious, rich, bountiful taxonomy they can come up with? Why not both? Because you think about it,

one thing we do have a hunch about is habitability. There's sort of the range of temperature, pressure, composition, a water-rich world, a sunlit world. You have to have energy. You have to have various other criteria that allow chemical systems to do interesting things. If everything's molten or a vapor, it's much too hot. If everything's frozen and nothing moves, like on Pluto, then that seems much too cold. So we do think there's some sweet spots, and we do think there are things we can look for, like liquid water or some other fluid, but water is the only one that really seems to do the job. We need to look for carbon-based molecules, because it seems like carbon's the only element that forms the kind of richly varied backbones that you need for the structures of what we think of as life. And I really don't believe in cloud-based life or electronic life or life in a plasma or something like that. I mean, that just, you don't see the kinds of

structures that you need that spell what I think of as the complexity of a living system. So there are parameters, and that's what NASA is looking for. Let's look for water-rich worlds. Let's look for worlds that have the right kind of temperature and pressure and atmospheric composition. And rocks and minerals play a really interesting role. And they provide all sorts of chemical elements in addition to carbon that might be essential for a complex chemical system. If you'll allow me to get personal with you for a second, I'm sure you have some personal favorite things that you would love to see answered before you finish your career. Are there some you would share with us, things that puzzle you the most, or that are sort of dream questions you'd like to see us get more clues about? I would love to see microbes brought back from Mars. Microbes that had a different biochemistry,

a different genetic code, if that's part of the story. Because that would indicate there was something called a second genesis. Second genesis in the business of origin of life just means that life has arisen more than once. And, you know, in the universe, there's the old adage, it's zero, one, many. No life is sort of dull, but we know that's not true because we have one example. As soon as you find a second example, especially if it's in our solar system, then you know life is absolutely everywhere. Because it just arises. It's as natural as the forming of basalt on a terrestrial planet. Life is just another chemical process that happens inevitably. We don't know if that's true, and that's what I'd love to know. I'd love to know that life was an inevitable consequence.

And you know, the fact that I've spent a significant part of my career studying aspects of the origin of life means that I philosophically planted my flag in that field. If life never happened or happened only once in the entire history of the cosmos, then it would be futile to try to study its origin. If it's an incredibly rare chance event that only happens through the juxtaposition of just the right rocks and water and chemistry and so forth, and it only happens in one in every billion planets, then again, we're not going to be able to reproduce it in the laboratory. Even if it occurs commonly, but it takes 100 million years for it to get started,

it's going to be really, really hard to do it, you know, in the four years of a postdoctoral fellowship. So I would like to think that life, once we figure out the tricks, that it's something you can actually do in the laboratory. Yeah, that's such a fascinating question. I mean, everybody who's thought about this wonders. I can remember reading a book by Francis Crick on this life itself, where he's talking about directed panspermia. And I had never taken it seriously until I read his book that if the probability of spontaneous formation of life is small enough, we really could be alone. I mean, just sort of on Copernican grounds that were never anything special.

I was always led to believe, of course, there must be – as soon as we find planets in other solar systems. I mean, it just seems like hubris to think we're the only instance of life in the universe. But we don't know. Logically, as you say, the probability could be so, so tiny. We might be the only one. Steve, you're absolutely right. We might be the only one, or it might be that the only other living worlds, there may be thousands or millions of them in our Milky Way galaxy, but they're so far away and they're so non-communicative, we may never know.

But I do think that this is a problem that if the answer is we're not alone, that's something we can actually hope someday to learn. The negative is going to be really hard to prove, but all you need to do is find that one other living world, and then we have a very profound insight about the way the cosmos works. Wow. It's a cosmic thought. You know, I'm sort of encouraged by how quickly life started here. Speaking of geology, like, let's put it in a geological perspective. Give me the numbers, roughly, how old the Earth is and how soon it starts to team with life. Sure. So Earth began to form at 4.567 billion years ago. And it was not habitable for the first period of time. It may have had a window of habitability for a few tens of millions of years.

And then that huge impact, the Theia impact that formed the moon, and that just smushed everything. The whole planet was encircled by a magma ocean glowing red hot. That had to cool. So that may have been 4.45 billion years ago. I think something on that order, maybe as recently as 4.4. But that's the kind of extreme beginning date that we can think about. And we know that by 3.8, life was well-established. We have stromatolites. We have other

signs of life that were clearly there. So that's a block of, what, 600 million years, but I think life started much, much more quickly. But that's a hunch. I think probably we're looking at millions or tens of millions of years for a process to occur. If it's going to happen, you know, chemistry, you've got a vast surface area of Earth, you've got millions of years to play with, you've got all different kinds of chemical systems and fluxes. And so Earth is a great experimental laboratory for chemistry. And with hundreds of millions of years to play with over the entire surface of the planet, wow, that's a lot of combinations of chemicals you can try. And life pops out of it. It's really this wonderful vision you're giving us here where it's not just now geology and mineralogy and chemistry,

but you're bringing astronomy into it too too, with this story of the impact. Maybe just expand on that for a second. I'm not sure I've ever heard this idea of Theia. You're talking about the origin of the moon, where the moon came from. So the origin of the moon, when Earth was first forming, it was sort of a solar system dance. It was sort of a solar system dance. You had all these bodies that were gravitationally greedy, and they kept, like vacuum cleaners, sweeping up all the smaller worlds. And so in this game, the largest body always wins. Whatever has the most mass wins. And for a few tens of millions of years, Earth was competing with another smaller body, maybe about the size of Mars,

is what I've seen the calculations say. And so these two bodies were, they passed close to each other, they wouldn't quite kiss. But on one very dramatic day, one very dramatic moment, they collided. The smaller body, which has been called Theia, that's the mother of the moon in Greek mythology. Theia collides with earth. There's just this epic mixing and mashing and baking of all the ingredients, and part of what's left over becomes the moon, and part of what's left over becomes part of earth, and that clump of stuff that is blasted off the surface during the collision consolidates into the moon. And so we have this beautiful object in the sky, much, much closer back then, by the way, the moon was probably only a few tens of thousands of miles away, which means it looked

very, very large in the sky and the tidal effects were huge. But gradually, the moon has been receding, even as it does today. And that changes the whole surface condition of Earth. Earth was uninhabitable immediately after that collision. But then things settled down, oceans with big tides early on, and the moon shining in the sky and receding year by year. And somewhere in that period of tens or hundreds of millions of years, life caught on. Thank you, Bob. This has been so intriguing. I mean, really mind-blowing, actually, to think about the interplay of, well, I'm tempted to say names of subjects that we learn in school, astronomy, geology, mineralogy, chemistry, biology, but the way you tell it, it's really just one beautiful big story of, I don't know how to summarize it. Well, what would you say? What's the end of my sentence there? Steve, it's a one

unified web of knowledge. It's a way of knowing science is this most remarkable way for humans to look at our natural world. Not think about chemistry or geology or physics or astronomy or biology as separate things, but it's one interconnected web in which we see this amazing process of evolution, evolution of planets and moons, evolution of our solar system, and then the origin and evolution of life. Thank you, Bob. Thank you so much for joining us today. Thank you, Bob. Thank you so much for joining us today. Thank you, Steve. Want to know what's happening at the frontiers of math, physics,

computer science, and biology? Get entangled with Quantum Magazine, an editorially independent publication supported by the Simons Foundation. Our mission is to illuminate basic science and math research through public service journalism. Visit us at quantummagazine.org.

So, as we just heard, Bob Hazen questions the usefulness of a rigid definition of life, preferring instead to identify the characteristics of interesting chemical systems that display complex behavior. Our next guest has spent a lot of time thinking about cells that mimic life. When thinking about what life is, he agrees that evolution is a satisfying thing to look for. So is the ability to reproduce. But these criteria do not fully capture what we mean when we speak about life. For him, understanding what life is more broadly includes an organism's ability to persist over time and interact with other living things.

Sherif Mansi is a professor of chemistry in the Department of Chemistry, University of Alberta. He joins me now. Welcome. Thank you for having me. It's really a great pleasure. I'm very excited to hear about your work, which I found very captivating, I have to say. Okay, so let's start with this thorny issue of trying to define life. I've heard in other interviews that you've given that you say you have conflicting emotions about this issue of trying to define life. What do you mean by that? I mean, I understand the criticisms when people say that it's perhaps not even worth the time to try to articulate what it is that we mean by life. I've, you know, some of my colleagues in the field at times will say things a bit provocative, such as, you know, life is a term that's just for poets and scientists have no business using it. And these things can, of course, seem like a distraction.

But at the same time, I find it really bizarre that we have scientists all around the world that are trying to build something, but we can't even say what it is that we're trying to build. And how do you make progress in such a scenario? Well, what's so hard about it? I mean, maybe you could explain to us why. Because, you know, the average person thinks, I know, I recognize something. The desk in front of me as we talk, that's not alive. I think the big problem is that every time somebody proposes a definition of life, there's always somebody that can pop up and give an example of something that either we clearly perceive to be alive that doesn't fit the definition or even the other way around, you know, things that seem to fit the definition but are not alive. So, you know, you can think of some sort of classic examples like a mule, you know, so many people you'll ask, why isn't your desk alive? They'll say, well, it doesn't reproduce, you know, living things are

capable of reproduction, but we have examples of living things like a mule that clearly everybody thinks is alive, but is incapable of having offspring. And then you can play this sort of opposite game as well, you know. So salt crystals, you know, there's lots of crystallographers out there. And one of the tricks that crystallographers use to grow more crystals is they crush old ones and they use the little itty bitty pieces of their old crystals to seed the growth of new crystals. And you can do that even with just salt. You don't need to do that with proteins. And that's an example of replication. But, you know, nobody's deceived by that, right?

Nobody confuses replicating salt crystals as being alive. Right, right. So maybe not super useful to put a sharp boundary or to articulate necessary and sufficient conditions for life, because it seems like we could keep finding exceptions. But on the other hand, it feels like, as you say, it's hard to look for life elsewhere, like if we're trying to find life on other planets, if we have no concept what we're looking for. And so to that end, you've mentioned this criterion of persistence over time. I wonder if you could unpack that for us a little bit. You know, basically all things tend towards disorder, right? That's sort of the second law of thermodynamics.

And living things are out of equilibrium chemical systems. And so if they weren't alive, they would just sort of decay down back to their disordered component parts. That's basically what we would call death. You know, equilibrium essentially equals death. So what are these processes? What is the chemistry and physics behind life that essentially is always able to keep it out of equilibrium and persist

over time to maintain that state, that highly ordered sort of thermodynamically unfavorable state over time. Obviously, it's not forever. We do die, unfortunately, at one point. But that is an aspect that I guess you could just call it metabolism. But I think a lot of times, even there, when people use that word metabolism, they're not really thinking of this angle. They're more thinking in terms of, you know, molecule A gets converted to molecule B, then gets converted to molecule C. They don't seem to really be thinking about what is this sort of trick that biology uses to keep itself away from equilibrium and maintain this highly ordered state over time. So I'd really like to get into some work that you did over the past several years in your lab about what we could call a cellular Turing test.

What's your take on it? I mean, give us the background. What was the Turing test? What was it trying to do in its day? And then let's talk about, you know, your adaptation of it to the world of life. Sure. I mean, I should say that I wasn't the very first person to come up with this idea. There's a paper, you know, I just am highlighting all of my horrible memory. I think it was a nature biotechnology or nature where there was a lot of British scientists that sort of came together and said that this perhaps could be one way that we could address this lack of a definition of life to help us make progress. And they had proposed a cellular Turing test in this paper. And that was just one of those things that when I saw it, I thought, you know, I think I'm actually able to sort of put those pieces together in the lab and try to

pull off a model system there. So basically, the whole idea is, you know, these same sorts of problems existed in the artificial intelligence field, which I don't work in artificial intelligence, so probably you can speak much better about that than I can. But basically, it was the same sort, from my understanding, the same sort of problem. How can we tell if a machine or a computer program is displaying intelligence if we're incapable of even defining intelligence in the first place? They had the same stupid arguments that we have in my field, fighting back and forth as to what is the right definition and what exactly, you know, types of experiments we should be doing. And so what Turing essentially

proposed is let's forget about this stupid fight and come up with a functional test. And if you pass this test, then, you know, we haven't defined intelligence, but you're at least moving in the right direction. And so I always give a sort of very modern, I hope, modern take of it. You know, imagine that you're on your cell phone chatting with a friend or text messaging with a friend and your friend has been substituted with a computer program. Are you able to figure out or realize that you're no longer chatting with your friend? So if you're not capable of distinguishing between your friend and the computer program that's substituted for your friends, then they've passed, essentially. You've passed the turning test that the machine or the

program has passed. And so it has been, it successfully deceived you into thinking that you were chatting with your friends. So it was a manner in which you avoided coming up with a definition. And the opposite situation is also instructive, right? Because if it fails, and it doesn't matter why it fails, you know, the response time is a bit strange, the vocabulary is different than how your friend would speak, then you have to go back to the drawing board and develop a better program or better machine. And so basically, that was the inspiration for several of our projects was just seeing can we build artificial cells that can engage in the same types of chemical communication

that natural living cells engage in and do it so well that they can deceive the natural cells into thinking that they're speaking to a neighbor as opposed to the things that we built in the lab. It's really a fantastic, very elegant idea. But to make living cells be fooled by these artificial cells, it's really an interesting thought. And so, I mean, it sounds like you've done a series of experiments in this direction. What are some of them? So lots of bacteria. We started off with bacteria. We figured that would be the easiest thing to do,

and it's also closer to the types of stuff I had done in the past. And so bacteria, they engage in chemical communication. Many of them exploit these small molecules called acyl-homocerine lactones. And so we figured, you know, these pathways are pretty well known. People had engineered bacteria to talk to each other using these same known pathways. So we figured, you know, we should be able to reconstruct these same things in an artificial cell. So that was basically the goal. It turned out as, you know, always in science to be a bit more challenging than we had anticipated, the synthesis and release of chemical signals from our artificial cells to natural cells was not difficult. I think we never failed in that. Every time we tried to reconstitute a known system

in our artificial cells, that always worked. The part that was difficult was being able to sense the living cells through the molecules that they secrete. And I don't have a good answer as to why that's difficult. But you know, we're bad comedians, I suppose. But I guess, as many couples would say, it's, you know, it's much easier to talk than to listen or to hear your partner. And so I think that's the same thing with these artificial cells. It's easier to engineer these things to talk than it is to listen. But we essentially never failed in speaking, you know, making artificial cells speak by synthesizing or releasing molecules. Getting them to hear was a lot more difficult. And the best one that we were able to reconstitute was the system that was taken from Vibrio fishery. So it's just, you know, a marine organism that naturally bioluminesces. And that was the pathway

that we were able to fully reconstitute. But basically, in the end, we were able to put these pieces inside of lipid vesicles to mimic sort of morphologically somewhat a cell. And if you take something like Vibrio fissure, which naturally luminesces when it talks to each other, so when they reach a certain cell density, they know they've reached that density through communication with each other, they luminesce. So it's a very simple kind of qualitative test. And so if we take this bacteria and we grow them to half the density that they need to be to luminesce, and then we dump in our artificial cells to make up for the missing natural cells, they light up. We did do, you know, fancier experiments than that, but that was

probably the most satisfying experiment because at least visually we could see right away that we were on the right track. Okay. And the main point that you mentioned, I think, was that when there was a high enough density of them, they could act as surrogates for the bacteria that, I mean, they could fool the bacteria into thinking that the quorum had been achieved and therefore the living ones would light up. But these cells, these artificial cells, tell me more about them. They're lipid vesicles. Do they have anything inside them? Yeah. So they are lipid vesicles, fat molecules. They have an internal, let's say, lumen or internal aqueous space. And inside of there, we put the DNA constructs that we've engineered. I don't want to make it sound too fancy because these are not huge genomes, but we do put

engineered pieces of DNA inside that encodes for the function that we've set out to achieve, which in this case was sensing, synthesizing, and releasing chemical messages. Then we have to also put in the machinery that's necessary for transcription and translation. So to convert the information in DNA to RNA, and then that information, of course, into protein, which will have the enzymatic activity that we require for our cells. In these specific experiments

of the cellular turning test, we did use transcription translation machinery that came from extracts of E. coli. So these are somewhat ill-defined mixtures. And our system was incapable of growing and dividing. All it could do was essentially, you know, listen and speak. And that's all we programmed it to do. To give it more, you know, to endow it with more functionality would certainly take a lot more effort. But nevertheless, you know, I mean, I would say for this one specific task, which I think is a quite important aspect of life, by the way, something that doesn't often pop up in definitions of life, this ability to organize and communicate with your

neighbors. You know, my guess is this came really, really early. So I don't think that we hit upon some sort of trick here. I mean, I think we are looking at something that is important because we tend to look at life as really just these individual units. You know, can I build an actual, you know, one single cell or something along those lines? But I don't think that's how life works at all. You know, I mean, it is a community affair. Evolution, by definition, basically is a community type of process. If we find life on another planet, we're not going to find just like one organism or one cell. I mean, these things don't make sense, right? That's not how biology works.

Oh, yeah, that's beautiful. I really like what you were just saying there. And I think that that's a very deep point that doesn't get emphasized enough, that the communal aspect of early life, we have spoken with other guests about the possibility of the massive horizontal gene transfer in very early life. I don't know. Maybe I'm getting carried away. But I like your thought that communication is really early and deep in the story of life, maybe deeper even than what we think of as evolution today for the most part.

I mean I have to admit in my head I hadn't really thought of it in exactly that way. I tend – I mean I guess we all come at these things with our own biases. And mine typically is that I think that a lot of the stuff that we see as coming at different times, probably pieces of it were there from the beginning and emerged together because I tend to look at biology as being so incredibly complex. I don't say, I guess I just don't see biology modular the way I think a lot of people who try to engineer, you know, in the field of synthetic biology, they're always trying to sort of put together, you know, they love using the analogies of Lego pieces and things like that, which, of course, in some ways, we incorporate some of the stuff that they do. But I don't really see biology as being modular. I see it as a very messy,

intricate, you know, network of things that probably reflects its origins, you know, probably lots of these different processes that were necessary had to come up around the same time. Otherwise, it just wouldn't have survived. So on this early question that we were posing about what is life, it sounds like you already hinted at this in a remark you made a few minutes ago, that you would not have considered your artificial cells to be alive, but they had some of the functionality,

right? You say they had some of the important functions, but you pointed out they couldn't reproduce. What else could they not do? The thing that I find the most frustrating about these systems that we've built is they can basically listen once and then respond or speak once. They're not able to engage in a longer conversation, let's say. And that is something that frustrates me. That reflects, in large part, what I was talking about before, this concept of persistence over time. It lacks a supporting metabolism to sustain these activities, to have turnover, to degrade the molecules that were being used for talking and synthesize new ones. And just being able to sense once and respond once to me is not

sufficient. If you want to make something that better mimics life, it's got to persist for longer than that. And if you wanted to use this as a platform, you know, for some sort of technology, I think it would need to survive more than a couple of hours. So that gets us into something that I was hoping we could explore together about this idea that you mentioned a platform. Please tell us about some of these fascinating studies that you and your group did recently with artificial cells trying to interact with neurons. If you think about communication and chemical communication, I mean, I would imagine that lots of people, the first thing that pops to their mind, signal transduction through neurons. And of course,

that's true, right? And so for us, for a long time, even when we were working on a cellular Turing test, we really liked this idea. Could we build, I mean, I would not call it an artificial neuron because it's way too far from that, but something that can engage in communication with neurons. And that's not just fun intellectually, but I think that also has possibilities for technologies, right? I mean, there are lots of diseases, neurodegenerative diseases like Parkinson's disease, where essentially your neurotransmitters like dopamine are not being produced as you get older. And, you know, if you built artificial cells that can sense the concentrations of dopamine, for example, and then synthesize more dopamine whenever the levels get too low you know that sounds like a fantastic therapy you wouldn't have to sort of flood the patients with tons of drug molecules

that may or may not cross the blood-brain barrier and get to where you want to go you could have artificial cells that are targeted to different parts of the body again there's a lot of work to get there. And then very locally, you know, whenever the concentrations drop below what's needed, they can replenish the supplies. They sound really attractive. But again, I think this persistence problem that while I find it interesting from a more, let's say, intellectual perspective on what is life, has very practical implications as well. I mean, what's the point of taking an artificial cell into your body if it just, you know, falls apart almost immediately? As you say, if this artificial

cell could exist and thrive for a certain amount of time and do smart things like sense whether a cancer cell is present, and if so, what molecules, what chemotherapeutic agents to dump on that one. We're not there yet, it sounds like. But that's the vision, right? That's the dream, maybe. Yes, yes, yes, yes. I mean, to be able to encode multiple outputs, obviously, you know, and to increase the capacity for synthesis so that you can actually carry out whatever, you know, the synthesis for whatever drug molecules you need,

that I think would just be insanely satisfying. And an interesting example of how fundamental thinking about research, like you might be really driven by your curiosity about origin of life or thinking about this deep question of what does it mean to be alive or not alive. And then out of that pure curiosity-driven research comes these fantastic biomedical applications. It's not far-fetched, I think. For a long time, I mean, I would run into colleagues that did neurobiology and this kept popping up over and over again. So we built artificial cells because of the difficulty in sensing stuff. We had them sense the same sort of molecule that would have been secreted from bacteria. So in that sense, the listening component was,

from bacteria. So in that sense, the listening component was, you know, listening to bacteria talk. But in response, it could talk to neurons. And so what we actually did was they were neural stem cells. And this was done in collaboration with three different biology labs, because I have no experience with eukaryotic biology or doing any sort of tissue culture stuff. So this, you know, took a dedicated PhD student. His name is Duhan Topralak. Basically, these artificial cells could synthesize and release brain-derived neurotrophic factor, which is a neurotrophic factor, as the name suggests, that impacts the differentiation of neurons from immature to, let's say, mature neural cells.

So we took these neural stem cells. we incubated them with our artificial cells, we added the molecule that bacteria would secrete. We didn't actually mix bacteria with the neurons. So it was sensing this molecule in the environment and in response synthesized and released something that guided, in some sense, the differentiation of neural stem cells. So that's what we did. It's in some sense sounds like we did less in some ways than we did with the cellular turning test, but it took four or five years actually to get that to work. I see. So really what's going on in the experiments, there's artificial cells, there's

neural stem cells, and there's you dumping in the thing that's telling these artificial cells, there's neural stem cells, and there's you dumping in the thing that's telling these artificial cells, hey, say something. Say something helpful to make the neurons grow and differentiate. Exactly. And you did it. I mean, it sounds like this is a hard experiment from the way you're describing it. Yeah. Painful process, but in the end, we got it to work. Well, thank you, Sharif. This is super interesting, and I really appreciate your taking the time to talk to us today. It was a lot of fun.

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