How did life begin on Earth? It’s one of the greatest and most ancient mysteries in all of science — and the clues to solving it are all around us. Biologists have sometimes imagined evolutionary history as a recorded “tape of life” that might turn out differently if it were replayed again and again. In this episode, Steven Strogatz speaks with two researchers inspecting different parts of the tape. First, hear from the Nobel Prize-winning biologist Jack Szostak, who explores how a boiling pool laced with cyanide could have given rise to essential life elements like RNA and DNA. Then hear from Betül Kaçar, a paleogeneticist and astrobiologist who resurrects ancient genes to learn how they helped evolve the processes essential to modern life.
Steven Strogatz (00:02): I’m Steve Strogatz, and this is The Joy of Why, a podcast from Quanta Magazine that takes you into some of the biggest unanswered questions in science and math today. In this episode, we’re going to be looking at our best current understanding of the origin of life. How did life begin on Earth?
(00:21) Did life begin, as Charles Darwin once speculated, in a warm little pond somewhere? The kind of nurturing, supportive place where it’s easy to picture delicate biology taking shape? Or more counterintuitively, as some scientists have proposed, did life get started deep down in the ocean, near hydrothermal vents, a seemingly inhospitable place where the pressures are enormous, and the temperatures are scalding? And, wherever life began, what were the earliest building blocks of life? Were they the molecules that we hear so much about today — RNA and DNA, amino acids, lipids — or were there something much simpler? In the past few years, some important clues have turned up. The payoff to answering these kinds of questions would be huge, not just for understanding how life began on Earth, but also to help us look for life on other planets, and maybe to figure out if we are alone in the universe.
(01:17) Joining me to discuss all this is Jack Szostak. Jack is a professor of chemistry and chemical biology at Harvard University, a professor of genetics at Harvard Medical School, and an investigator in the department of molecular biology at Mass General Hospital. He shared a Nobel Prize in 2009 for his work on the discovery of telomerase, an enzyme that protects chromosomes from degrading. Later, we’ll be joined by Betül Kaçar, an assistant professor of bacteriology at the University of Wisconsin, Madison. Jack Szostak, thank you so much for joining us today.
Jack Szostak (01:53): And thank you for having me here.
Strogatz (01:55): Let me start with a question about the origin of life. As I say, it’s one of the greatest mysteries in all of science and the attempt to solve it seems like one of the greatest detective stories of all time. What would be your best guess for how life began on Earth?
Szostak (02:09): Okay, so, so I think we have to think about some environment on the surface of the Earth, some kind of shallow lake or pond where the building blocks of RNA were made and accumulated, along with lipids and other molecules relevant to biology. And then they self-assembled into lipid vesicles encapsulating RNA, under conditions where the RNA could start to replicate driven by energy from the sun. And that would allow Darwinian evolution to get started. So that the, some RNA sequences that did something useful for the protocell that they’re in would confer an advantage, those protocells would start to take over the population. And then you’re off and running, and life can gradually get more complex and evolve to spread to different environments, until you end up with what we see around us today.
Strogatz (03:01): What are some of the scenarios, though? You know, just to give us something concrete to think about. Because I mean, I remember as a kid taking high school biology, we all heard about Stanley Miller and the Miller-Urey experiment. Why don’t you first remind — I mean, is that where, you would say, that the scientific investigation of some of these questions began? With that, or is there an earlier place we should look?
Szostak (03:22): Well, that was certainly a revolutionary landmark, I mean it created such a splash. You know, the idea that you could make amino acids, the building blocks of proteins, in such a seemingly simple way was — was a revelation to people, and it stimulated a huge amount of interest. Stanley was a graduate student at the University of Chicago in Harold Urey’s lab. Urey, of course, was a Nobel Prize-winning scientist who discovered the isotopes of hydrogen, like deuterium, and so on. The way I understand the story is that Stanley said that he would like to try mimicking what was then thought to be the atmosphere of the early Earth — so hydrogen, ammonia, methane, some water, stuff like that — blast it with some energy in the form of spark discharge and see what happened. And his advisor told him not to do it, that’ll never work, you know? And, of course, it did. It was, it was a huge success, and all kinds of interesting molecules were made.
Okay, but then, you know, when you start to look at it more carefully, and you know, with the benefit of what, 70 years of hindsight, what we see is that what actually got made was not just the molecules that you might want, but traces of amino acids mixed in with thousands or tens of thousands of other chemicals, some of — some few of which were relevant to biology, but most of which are not. And some of the key building blocks are not present at all. So, it is clearly a sign that that is not the right way to do the chemistry to get life started.
Strogatz (05:02): Okay. You know, you mentioned RNA world. Is that the next big conceptual thing in our story? Or, or maybe there’s something in between RNA world and Miller-Urey.
Szostak (05:12): For decades, thinking about the origin of life was confused, because everything in modern life depends on everything else. So it’s, so you have the DNA encoding the sequence of RNA and proteins, but you need the proteins to replicate the DNA. And to transcribe DNA into RNA, you need RNA to make protein. So you need — all parts of the system need all the other parts. So it was kind of a logical conundrum. And the answer, the solution to that, came with the so-called RNA world idea, which was originally postulated by some very smart people, like Francis Crick, and Leslie Orgel in the late ’60s, with the idea that RNA maybe had the ability to act as an enzyme.
Strogatz (05:58): So, the idea that RNA could, not just carry information, but be the enzyme needed to help, say, replicate. I didn’t realize — that was a hypothesis before it was discovered in the lab.
Szostak (06:09): That’s right, yeah. So that was put forward in the late ’60s, when the structure of tRNA came out, and people for the first time could see that RNA could fold up into these complicated three-dimensional shapes. Which is what you need, right, to build a catalytic center.
Strogatz (06:25): But so, you were saying that there was this prediction, that you say came about after the discovery of what tRNA looked — transfer RNA. So maybe you remind us a bit about that, for those who are a little hazy on their high school biology. What’s tRNA, what’s it doing for us?
Szostak (06:40): Okay, so tRNA is short for transfer RNA. It’s a relatively short set of RNA molecules, around 70 or 80 nucleotides long, and they carry amino acids to the ribosome. And then the catalytic machinery of the ribosome takes the amino acids from the tRNA, and assembles them into a growing peptide chain. So there’s a lot of roles for RNA in making proteins. There’s the tRNA that brings in the amino acids, there’s the RNA components of the ribosome, that it turns out actually orchestrate everything, do the catalysis. And of course, there’s the messenger RNA, which, you know, I think now everybody knows about messenger RNA these days, don’t they?
Strogatz (07:24): Right, because we have the mRNA vaccines, like the Moderna and Pfizer. Right. So we’ve got these three interesting roles, messenger RNA, transfer RNA, and the ribosome itself built of RNA. And so this is part of the clue, since we’re talking about clues, that suggests that RNA is very, very fundamental.
Szostak (07:43): Yes, exactly. When the crystal structure of the ribosome was solved, we could actually see the catalytic site. It’s clear that RNA is what makes proteins. So, logically, then, you get out of this kind of self-referential loop, and all you need is the idea that early forms of life used RNA as their genetic material, you know, just like we see in viruses today. And they also used RNA as their catalytic material. And so their enzymes were made out of RNA. And so now, the problem is much simpler, right? You just have to know, or figure out, how to go from chemistry to simple RNA-based cells.
Strogatz (08:26): This is great. So, Sherlock, you’ve brought us to this, this point where right now we’ve got a really important suspect, that RNA is somehow very pivotal in the story of early life on Earth.
Szostak (08:38): So, you have to figure out how to get RNA. And that is not so easy.
Strogatz (08:44): Aha. And that in particular is not something that appeared in Stanley Miller’s lightning sparks zapping. Right, they didn’t produce RNA at all in that experiment, as I recall.
Szostak (08:55): That’s right. But there may have been traces of some of the components, like adenine, because, actually, cyanide is made in those Miller-Urey type experiments, and cyanide fairly easily assembles into adenine. But a lot of the other building blocks are harder to make.
Strogatz (09:14): Well, maybe we should talk about cyanide, since you brought it up. I’m sure many people listening to this will be horrified, thinking that cyanide is how you kill people.
Szostak (09:22): I think it’s one of the lovely ironies of the whole field, that the best starting material to build all of the molecules of life, turns out to be cyanide.
Strogatz (09:31): This is amazing. Okay, so tell us more about this.
Szostak (09:34): So, it had actually been known, I think, again going back to the ’60s or maybe the ’70s, that cyanide has a very rich chemistry when it starts to react with itself. And there was a key experiment done by Joan Oró, showing that cyanide could assemble to make adenine fairly efficiently. And a lot of people worked on ways of starting from cyanide and related compounds to get to the other building blocks of RNA.
(10:06) One of the issues with cyanide is that you can make cyanide in the atmosphere, but it will rain out onto the surface as a very dilute solution. And that is not very helpful, you need a way to concentrate it and to store it. And that is something that has an actually very remarkable, simple and effective solution, which is that you can capture cyanide [with] iron, in solution to make a very safe non-toxic compound called ferrocyanide. So then, in certain kinds of lakes, ferrocyanide can accumulate over time.
(10:44) So, so the iron comes up from the groundwater. The cyanide comes from the atmosphere. They combine in these, perhaps, shallow lakes, ponds, whatever. Some salts of cyanide can precipitate out and build up as a kind of sediment. Anyway, that’s, that’s the idea. So you have a huge reservoir of concentrated cyanide.
Strogatz (11:06): Mm. So this is actually not so far from Darwin’s little pond, if I’m hearing you right.
Szostak (11:11): The idea is that now you have this solid reservoir of cyanide in the form of ferrocyanide. But now, how do you access that to do chemistry, right? So there are different scenarios, but basically, when you heat it up — so if there’s an impact from a meteorite, or if you have lava flowing over it, you can basically transform the ferrocyanide into a range of other compounds that are, again, more reactive. And now, you can start building up more complex molecules.
Strogatz (11:44): So it’s not just a matter of the sun shining on it, you’re saying you need something kind of violent. You’re talking about either meteors hitting or comets or something.
Szostak (11:53): Yeah, or, you know, volcanic — yeah, we think the environments were very volcanically active. So, having, you know, lava flows would be something very common. That can transform the ferrocyanide. Then, yeah, later on, things cool down, rain falls, dissolves these compounds, again into a shallow lake, a pond. Now we’re a little closer to Darwin’s warm little pond. And now, sunlight has a critical role, because the many, many photochemical reactions that are needed, at least in the Sutherland chemistry, to bring you up to the level of nucleotides, amino acids, lipids. [Editor’s note: Szostak is referring to theories about prebiotic chemistry championed by John Sutherland of the Medical Research Council Laboratory of Molecular Biology and others.] But, essentially, the idea is you make all of these compounds from cyanide.
Strogatz (11:54): Hm. Incredible. So, maybe we should return then to this theme of, you know, now that we’ve got cyanide world, we can somehow go up to RNA world, except that, apparently, that’s a big mystery, still, right?
Szostak (12:51): Well, I think the pathway to getting to two of the four building blocks of RNA is maybe 90% worked out? And I’d say one of the biggest steps — we have all this energy from sunlight, right? But the question is, how do you transform that energy into energy that’s in a useful form, a kind of chemical energy that can drive these building blocks to condense into long RNA chains? I think we would all agree that that has not been solved.
Strogatz (13:25): So, you’ve spoken to us a lot about the virtues of RNA as a sort of a triple threat, all these things it does in modern biology. But it’s a little surprising to not hear about its more famous cousin DNA. Is there something wrong with DNA compared to RNA for early life?
Szostak (13:41): So that’s actually a super interesting question. We used to think that life definitely started with just RNA, because we were thinking about ribozymes, RNA catalysts, RNA’s roles in modern cells. But there are some clues from the chemistry that have come out recently that suggest that the building blocks of RNA and DNA might have been made side by side, in the same environment at the same time, same place. And so, one possibility is that the early genetic material was actually some kind of mixed copolymer of RNA and DNA. Our experiments suggest that the RNA-copying chemistry is faster than the same reactions that would copy DNA, so I still kind of think that RNA would have outcompeted DNA early on, but this is a very active area of research. Lots of people are working on this, the synthetic pathways are still being worked out.
Strogatz (14:41): Earlier, you did mention one other important clue, which is that modern-day membranes are often, well, are maybe invariably made of lipids. So we should talk about that aspect of the problem, the compartmentalization that you mentioned in the early creation of cells or protocells or — I know you’ve worked on that yourself, why don’t you tell us some of those stories?
Szostak (15:03): If we look at modern biology, cells are bounded by membranes, and they tend to be pretty complicated structures. The molecules, the lipids that build modern membranes are relatively complex molecules — phospholipids and a whole range of related types of molecules. But it turns out that you can make very similar membranes from much simpler molecules. Things like fatty acids, basically soap. I think it’s very attractive, you know, that you can build the membranes you need to make primordial compartments out of such simple building blocks.
Strogatz (15:39): So, I guess I don’t understand how replication would, at the level of the whole cell, or this protocell, would happen at that point.
Szostak (15:47): Okay, I can tell you where we are. So, several years ago, we found ways of making these primitive membranes, fatty acid membranes, grow and divide. They’re easy to feed with more fatty acids. And it doesn’t take very much to make them divide. So, for example, gentle shaking will do it. On the other hand, getting RNA sequences to replicate is a much harder problem. And so, that’s why that’s — we’re really focusing on that in my lab at the moment. We’ve been getting better at copying RNA sequences. So that means if you have, say you have one strand of RNA, you can use it as a template to build up the complementary strand, and then you’ll get a double helix, sort of like the double helix of DNA, except an RNA double helix. But a big problem then is how do you get those strands apart and copy the copies, and then copy those copies. And we have ideas about how to do it, but we haven’t gotten there yet. That’s the big challenge for the next couple of years.
Strogatz (16:53): Well, thank you so much, Jack. This was really fascinating, and we really appreciate your making the time to be with us today.
Szostak (16:59): Thank you, Steve. It’s been my pleasure. Talking about the origin of life, it’s my favorite subject, so, glad to talk about it.
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Strogatz (17:36): Jack Szostak is trying to understand how life could have emerged from non-life, from chemistry and physics and geology. It’s like he’s starting at the beginning, before life existed, and trying to run the tape forward, to see how life began. But there are also scientists trying the opposite strategy. They start with what we know about life today, and try to run the tape backward, using evolution to try to see far back in time, billions of years ago, to reconstruct what life may have been like in its earliest days. Except they’re not using fossils to build their tree of life. They’re using molecules, like DNA, as their clues.
Joining me now is Betül Kaçar. She’s an assistant professor at the University of Wisconsin, Madison, in the department of bacteriology. She’s also the principal investigator of Project MUSE, a major NASA-funded astrobiology research initiative. Betül Kaçar, thanks very much for being here.
Betül Kaçar (18:33): Thanks for having me.
Strogatz (18:34): I’m so excited to be talking to you, I love your work. And I wonder if we could start with you telling us a little about your approach to looking for answers to, what was life like billions of years ago? What kind of clues are you looking for?
Kaçar (18:48): We are interested in understanding early life. If you think about it, life’s origins and early evolution created the blueprints for everything complex around us. We are interested in understanding that blueprint. We use modern biological information in order to trace the history of life on this planet, particularly by focusing on important metabolisms, essential reactions, and essential biological processes. We are trying to understand how they emerged, how did they flourish? How did they set the tone of life on this planet, in some ways, too.
Strogatz (19:29): It’s such a cool idea that the clues are lying all around us today, as you say, in the metabolisms of living things today, yet somehow you can use that information to go backward billions of years?
Kaçar (19:41): Yeah, so we try to understand what commonalities do current living organisms share amongst each other? You may even think of this as a Venn diagram of all the metabolisms that exist in all domains of life. And then we try to understand what is common amongst the living organisms today, and whether we can assign them as the shared processes that also existed early on, billions of years ago. So that’s sort of the starting assumption that we make. And I must say this really openly, in the very beginning, that studying early life relies on making a lot of assumptions. Nobody had a checkbox, nobody had a board to go back and record everything, and bring back to today. And we are very careful about what kind of assumptions we make in order to understand the past. This is very challenging, you know, we are trying to figure out something that, the clues of these processes, most of them have been erased. So, it’s quite a, sort of a Sherlock Holmes way of looking into the past, and I think the challenge itself makes it very exciting.
Strogatz (20:47): It’s fantastic. I love that analogy. It’s perfect. It is like Sherlock Holmes. I mean, because there’s some deductive reasoning. There’s clues but they’re imperfect, you have to make some assumptions, some good guesses.
Kaçar (20:58): Exactly. I actually always wanted to be an archaeologist. And I feel like I’ve fulfilled that dream.
Strogatz (21:04): Interesting. So you’re like a molecular or biological archaeologist or something.
Kaçar (21:09): There you go. A paleogeneticist. So, this is the closest I could get to my childhood dream.
Strogatz (21:14): You know, you mention Sherlock Holmes. I’ve heard you say, in another interview, that you feel like what you’re doing is waking Sleeping Beauty.
Kaçar (21:24): Yeah, some of them are beautiful and some of them are very ugly, actually.
Strogatz (21:27): Them who? What is them?
Kaçar (21:29): Proteins, and sometimes their networks, when we bring them to the present, they simply do not want to be here. By that I mean, experimentally, we are interested in studying them in the lab, and they can increase challenges in terms of our ability to purify them, our ability to synthesize them at first place, our ability to characterize them. These are difficult problems, even for today’s modern proteins. And dealing with an ancestral DNA that we generate using mathematical models, and evolutionary models and a lot of inferences, and that we then generate in the lab by synthesizing using modern organisms as their host, adds another layer of challenge into the problem of protein biochemistry overall. They are almost alien to us. So it’s safe to say that we are dealing with a form of an alien molecule, if you think about it. A fragment of the past that once existed on this planet.
Strogatz (22:25): Yeah, it occurs to me as we’re telling it now, that there are some steps missing that I should probably have you walk us through. So a few minutes ago, you said you think about the molecules today associated with metabolism, let’s say. Or I suppose they could be information molecules, RNA and DNA and things like that. And then you try to reconstruct, through a kind of tree of life or maybe a molecular tree of some… In a different field, in linguistics, linguists can look at languages today — French, Spanish, German, Turkish — and try to reconstruct what languages they may have evolved from. And I know that linguists believe there were some ancient languages that are no longer spoken on Earth. There’s one called Indo-European that’s thought to be sort of an ancestral language to a lot of the languages in, in Europe anyway, today. But it’s hypothetical, there are no speakers of Indo-European today. I wonder if you would say your process is somewhat like that except with molecules rather than languages.
Kaçar (23:25): It is very similar. We are focusing on life’s language, amino acids, DNAs, and how they express themselves in the form of proteins. And we then try to use life’s language — DNA and amino acids, really referring to the genes and their products, proteins — to reconstruct the past at first place. This is very similar to what linguists do. While linguists resurrect ancient languages, they also do this with the goal of trying to understand the culture that uses ancient language, how did they survive, what tools they relied on to get by day-to-day, and it’s very similar to what we are trying to do. We are trying to reconstruct the language of life to understand life’s early culture.
Strogatz (24:12): Let’s see here. You get information about these ancestral molecules analogous to ancestral languages. Walk us through that a little bit in detail, like what exactly do you do? Tell us about some of the molecules that you’ve, to use your wonderful word, resurrected.
Kaçar (24:27): We try to focus on molecules that we think extend their presence all the way back into the origin of life, or at least first life. So we tend to think that these are essential and really ancient molecules. If they are shared by all life as we know it today, we assume that they must have been present, or a version of those molecules must have been present billions of years ago as well. But now, with the improved computational and mathematical and evolutionary modeling that’s around us, as well as the improved sequence availability, we can attempt and we do this too, to resurrect the ancient DNA sequences. And I’m talking about billions of years, billion-year-old gene sequences.
So these are not ancient DNA sequences coming from a permafrost. These are inferred sequences that are as old as 3, 3.5 billion years old. And then we, once we make the prediction in the computer, we then synthesize these genes in the lab. So we sort of bring them back to the present. And we ask these molecules, okay, tell us about yourself, right? Tell us about where you lived. Tell us about what you prefer.
Strogatz (25:38): Well, you know, I mean, many people listening to this will be thinking of Jurassic Park. And maybe you have, people have asked you about that.
Kaçar (25:45): The major difference here is that we are not dealing with an ancient organism. But — so it’s kind of the opposite, because we are dealing with a fragment that we engineer inside the modern organism. So we don’t deal with the ancient organism or the relic in any way. Especially because we are dealing with molecules that have operated themselves over billions of years of time, we simply cannot extract DNA that is not well-conserved, from rocks anyway.
Strogatz (26:13): Let’s get a little more specific about the molecule. So I remember, years ago, learning about the work of Carl Woese, who was using back in, like, I think, the late 1960s, ribosomal RNA, which pretty much every living thing on Earth today — I mean, it’s correct, right? Everybody has to have ribosomes?
Kaçar (26:30): Yes. Isn’t that marvelous, by the way?
Strogatz (26:35): Right, we’ve all got them! Bacteria, people, elephants, mice.
Kaçar (26:38): Yeah, it’s absolutely fascinating that we are all, like, bunch of organic computers walking around with this processing center, that we think of as ribosome, that is processing the information that’s fed to it in the form of RNA, that is translating this information into most-of-the-time meaningful — meaningful meaning useful — products that will then be taken by the rest of the cell, and then does this continuously for billions of years. Some may even say that there may not be any forms of life in the universe that does not have a similar information processing center. Something like ribosome must be the foundation, a universal property of all life, wherever it might be.
Strogatz (27:23): I’m really struck by this word that you just used, a phrase of, you said an organic computer. But to hear it put so vividly, that the ribosomes are organic computers that translate — you know, that they take an input, some information molecule, like RNA, and then they produce an output, like the proteins that do everything our body needs. I love that metaphor, or that analogy.
Kaçar (27:46) It’s one of life’s major, and probably maybe the first invention, and it’s almost a revolution, probably, for it may even catalyze the transition between nonliving to living. And yet, we don’t know how this happened to be. So, you see why we study early life now? This is what I mean by the blueprint of life, that these inventions, revolutions at the molecular level, set the tone for what we see around us today, billions of years ago.
So every eon that we go through, and everything we rely on, our biological — as biological systems, depend on these revolutions that took place billions of years ago. Ribosome can be seen as the prime processing center at the core of life’s problem-solving skills. And it creates a nice bridge between RNA world and complex cellular systems because it combines RNA, it combines RNA dependent enzymes, it combines protein. So it has a bit of everything that we think existed early on at the dawn of life.
Strogatz (27:46): If we do find life elsewhere in the universe, you think there will be something akin to a ribosome, something like that, that, you think it’s sort of maybe a universal problem. It doesn’t have to be, necessarily, ours with the same chemistry. But you think there’s got to be something that plays the role that a ribosome plays here on Earth.
Kaçar (29:06): I would think so. Because I would think that a living system, or a system that is behaving like living, or lifelike, it should be able to sense and process its own environment. At the chemical level, I would think that something, like a translation — I like that we call it translation, it is really translating the language of the environment into language of life — must be one of the necessary components. So I would think that if we were to find life outside of our planet, somewhere else, I will argue that it will probably have something like ribosome.
Strogatz (29:39): I feel like we should still talk a little bit more specifically about your work, the resurrection issue. Like, do you, in your work, actually reconstruct ancestral ribosomal RNA? Or what — tell me what molecules, I just don’t even know what you mean when you speak about this.
Kaçar (29:56): My lab is interested — we start by understanding first, or trying to understand, how life learned how to elongate, and what the proteins functioning in this elongation step did, billions of years ago. So that was my first —
Strogatz (30:10): Hold on one second with that. So we’re talking about elongating a, what, a DNA polymer? Or an RNA, or what?
Kaçar (30:16): We are talking about how the amino acid chains are, now, elongated in leaving the ribosome.
Strogatz (30:22): Okay, okay, so elongation of the amino acid chain.
Kaçar (30:25): Elongation of the product. Exactly.
Strogatz (30:27): Are you checking, say, different strains of bacteria, or yeast? Or who are your — who are your organisms?
Kaçar (30:34): So my organisms are bacteria. We use microbes pretty much for everything in my lab. I was a postdoctoral fellow, working at NASA Astrobiology Institute at this time. So I was reading a lot of Stephen Jay Gould, watching a lot of — way too much — Star Trek, and reading way too many Daniel Dennett books, and I thought, okay, well, maybe, if we have this methodology that was developed, first as an idea, in the ’60s — the chemical paleogenetics proposed by [Linus] Pauling and [Emile] Zuckerkandl, that maybe we can use DNA and amino acids as a way to reconstruct early organisms — and then been realized by synthetic biologists in the ’90s, why can’t we use microbes as the host organisms where we now, not only reconstruct the ancient DNA molecules, but engineer them inside the organisms? And again, then resurrect them by using the modern organisms as a host?
Strogatz (31:29): Let me just underline that. I think I’m getting — I want to check that I’m with you, I think I am. That earlier researchers talked about the inference step, trying to imagine what these ancestral sequences might have been like, and then they could — assuming the genetic code was similar back then to what it is today — they could infer what the peptides would be that would result from those sequences after being translated. Your new thing is to actually make those. You know, again, assuming the conservation of the genetic code over a long period of time. That you can make those molecules, you don’t have to just think about what their sequences were, you could actually make them now.
Kaçar (32:04): Yes, make them and not only synthesize them, and analyze them outside of the cell, but also genetically modify the organisms with these ancient DNA molecules, to study the evolution of these genes in tandem with the organism over geologic time. The goal I had was perhaps we can combine synthetic biology, evolutionary biology, phylogenetic trees, and develop experimental systems to make an attempt to reconstruct these early steps.
Kaçar (32:36): Translation was screaming at us, really saying “study me!” because it’s so essential, so conserved. It’s the, sort of the M.O. [modus operandi] of every cell. And yet, we don’t understand how the early steps evolved. So instead of focusing on the ribosome, we started by focusing on the proteins around it that make this ribosome do its job. Because if you think about it, a ribosome is a little, like, diva, in a way, it’s sort of sitting on its throne. And all these other proteins, the shuttle proteins as we like to think of them, really enable its function. They’re obsessed with this core system. It’s almost like butterflies and moths flying into the light. They bring amino acids and just sort of serve this entire, you know, this macromolecule that we call a ribosome. And to me, understanding how that — as a behavior, emerges, it’s just such a challenging and important question. And that’s also what we will be pushing forward over the next decade. And I’m really excited about that.
Strogatz (33:38): So one of the things I find really intriguing about your work is that it seems like you’re not just watching how ancient genes and their products behave, but also some of the experiments that you’ve done have addressed the question of how they might have evolved over long periods of time. That is, I mean, it feels like it’s related to a thought experiment that Stephen Jay Gould once discussed, where he was imagining rewinding the tape of life and letting evolution play out again and again, and he sort of thought that the story of life would turn out different every time. How did you approach this question with actual experiments and what did you find?
Kaçar (34:15): The debate that Steve Jay Gould initiated in the literature with regards to replaying tape of life definitely fed a lot of the early experiments that I’ve done. Not only, we reconstructed early components of the translation machinery and engineered them inside bacteria, but I also set up an evolution experiment to then replay the evolution for this system that is presumably representing a fragment of billions of years into the past. And I thought that paleogenetics, resurrecting ancient DNA, inserting these ancient DNA inside modern systems, and then evolving these ancient DNA systems in the lab would perhaps be a way to realize this thought experiment of rewinding and replaying. That was the motivation.
And I also, of course, got inspired by the work of Rich Lenski, at Michigan State, that set in-laboratory evolution experiment decades ago, and is creating his own fossil record of microbes, by simply subjecting them to controlled reproduction and populating them every day for a really long time. It’s the same E. coli bacteria that I used to engineer ancient translation gene. And I followed this similar experimental evolution system to watch how bacteria that is now operating using an ancient translation protein, that it’s not happy, meaning it’s growing really slow, looks really sick, really unhealthy —
Strogatz (35:46): Really? So with the ancestral protein, it sort of looks inferior or sick. It’s messed up.
Kaçar (35:52): Oh, yeah, it messed up the organism that was — they needed each other, but they didn’t want each other. So, you know, it was like a very complicated relationship unfolding in front of me. What are you going to do? I mean, the organism needed the elongation factor, and the only one that it used is this one that we forced it to live with. And then to just watch how the two will communicate.
Strogatz (36:15): Wait, I want to hear more about this. So it’s like, it’s like you have some modern-day car, but you’re giving it an old, some junky old part from a long time ago or something?
Kaçar (36:24): Exactly. And essential, too. So we deleted any other copy that may be present in the genome — that’s the modern version way to present. And forced bacteria to survive only by using this particular ancient elongation protein. After this insertion — and the engineering was a little messed up — it grew almost twice as slow. And even the colonies were looking really messed up to me. But the amazing thing about experimental evolution, and what we saw, is that the organism was able to recover from the small function in a matter of just tens of generations. So the recovery was very rapid.
It made sense if you think about it because they need to, again, to get along. This is, this is not a game. This is a survival thing, and life needs to find a way, and life did. Then we spent really long years to understand how this solution came about and what mutations that bacteria accumulate to deal with this old problem.
Strogatz (37:30): Please tell us a little bit about where you’re heading next. I mean, it sounds like you’re starting to work on this multi-year project called MUSE. What is that all about?
Kaçar (37:38): We expand our studies now to understand how metals and elements play a role in early life. We obtained a pretty substantial grant from NASA. It’s a multimillion-dollar, multi-investigator, multi-year grant to explore particularly how molybdenum, iron, vanadium, and many other interesting metals factor in the emergence and evolution of metabolisms, and how such interactions impacted the rock record.
Strogatz (38:09): Fantastic. Congratulations on that. And thanks again for sharing all these interesting insights you have about origins of life and early life. It’s been a great pleasure talking to you. Thank you.
Kaçar (38:20): Thank you so much for having me.
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Strogatz (41:05): The Joy of Why is a podcast from Quanta Magazine, an editorially independent publication supported by the Simons Foundation. Funding decisions by the Simons Foundation have no influence on the selection of topics, guests, or other editorial decisions in this podcast or in Quanta Magazine. The Joy of Why is produced by Susan Valot and Polly Stryker. Our editors are John Rennie and Thomas Lin, with support by Matt Carlstrom, Annie Melchor, and Leila Sloman. Our theme music was composed by Richie Johnson. Our logo is by Jackie King, and artwork for the episodes is by Michael Driver and Samuel Velasco. I’m your host, Steve Strogatz. If you have any questions or comments for us, please email us at [email protected]. Thanks for listening.