What are the biggest questions in science today: Can we cure cancer, solve the climate crisis, make it to Mars? For Nobel laureate Jack Szostak, the biggest question is still much more fundamental: What is the origin of life?
A professor of genetics at Harvard University, Szostak has dedicated his lab to piecing together the complex puzzle of life’s origins on Earth. The story takes us back billions of years and may provide answers to some of our most mysterious questions: Where did we come from—and are we alone in the universe?
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Paul Rand: If you had to think of the three biggest questions in science today, what would they be? Maybe you’re thinking, ‘‘Can we cure cancer? Can we solve the climate crisis?’’ Or maybe even, ‘‘Can we make it to Mars?’’ For Jack Szostak, the biggest questions are much more fundamental.
Jack Szostak: Yeah. To me, they’re the origin of the universe, the origin of life, and the origin of the mind or consciousness.
Paul Rand: Szostak is a Nobel Laureate and professor of genetics at Harvard.
Jack Szostak: They’re the big questions, I think, everyone would like to have some understanding of.
Paul Rand: The origins of the universe, life, and mind are, needless to say, all quite complicated, so Szostak decided to answer
Jack Szostak: The first and third just seemed too hard. The origin of life is much easier.
Paul Rand: Szostak has dedicated the last two decades of his prolific career to figuring out how life on earth began.
Jack Szostak: We all want to know one way or another how we came to be here. If you just look around at life and the world, it’s so amazing and varied and beautiful and it’s so different from everything that’s inanimate. It just raises the question of: How did this difference arise and how did it lead to us?
Paul Rand: Szostak’s career has positioned him to be uniquely prepared to find that out. He’s been at Harvard for more than 40 years, won a Nobel Prize in Medicine for his work and telomeres, or the structures at the end of chromosomes, and he holds a distinguished position at Mass General Hospital and the Howard Hughes Medical Institute. Recently, he gave a lecture as part of the University of Chicago’s Origins of Life speaker series.
Jack Szostak: Yeah, I’ve always more or less worked on some aspect of nucleic acid chemistry and that's fundamental for the origin of life because what you need to have a living system is something that can carry information from generation to generation.
Paul Rand: From the University of Chicago, this is Big Brains, a podcast about the pioneering research and pivotal breakthroughs that are reshaping our world. This episode: How Life Began. I’m your host, Paul Rand. What does that actually mean in your mind when you talk about the origin of life?
Jack Szostak: Yeah, so we can’t go back to the early Earth. We don’t have time machines, so what I’d like to have is a picture of the whole process, going all the way from planet formation and understanding early environments, understanding the chemistry that gave rise to the building blocks of life, and then how those molecules assembled together to make very simple cells that could start to evolve, and then through the process of evolution, eventually lead to us.
Paul Rand: When we think about it early on and at least historically with philosophers and theologians and others, this whole concept of a creator or a life-giver comes into this. Maybe get this out of the way right up at the start: How do you think about that?
Jack Szostak: The problem just seemed so hard, so incomprehensible that people had to come out with these kinds of supernatural explanations. If you think of the origin of life or the nature of life as a scientific question, then you can break it down into simpler questions and try to understand how life actually didn’t get started. I think everything that we’re learning says that this is a natural process that follows the laws of physics and chemistry and there's nothing magical about it.
Paul Rand: Rather than despair in the idea that there’s nothing magical about life, Szostak delights in it. It seems to free him to appreciate the world in all of its natural wonder.
Jack Szostak: Yeah, yeah, exactly.
Paul Rand: Szostak started to fixate on the origins of life back in the 1990s.
Jack Szostak: My lab was working on what we call ‘‘directed evolution.’’
Paul Rand: ‘‘Directed evolution’’ means introducing mutations to molecules, looking for variants that could be useful and then allowing those novel molecules to reproduce. Think of it like GMOd foods, but for molecules like RNA.
Jack Szostak: We’re doing this molecular evolution in the lab and it’s very successful and it gives you lots of interesting new kinds of molecules that you can evolve things to do what you want. But it’s one thing to do this in a lab, right, where you have all the resources of modern science at your disposal and you have all kinds of brilliant students helping out and doing the experiments, and yet, somehow, evolution got started all by itself when the planet was young, and so I started to wonder more and more about how that could possibly have happened.
Paul Rand: Life has, of course, evolved over billions of years, but what did it evolve from? How did molecules first get together and start acting like a living system? Well, let’s start with what we know. First, Earth formed a little over four-and-a-half billion years ago.
Jack Szostak: After the moon-forming impact, it was certainly a very violent, hot, unfriendly place to be. But it didn’t take that long, considering the entire history of the planet, to cool down; maybe a hundred million years or so. You have liquid water on the surface, you have some areas of dry land, and then you can start to have local environments where different kinds of chemistry can start to happen.
Paul Rand: But this is where things get fuzzy. About 4.3 billion years ago, Earth may have had a habitat suitable for life, but we don't have solid evidence for life until the earliest fossils dated to about 3.7 billion years ago.
Jack Szostak: That’s a big stretch of time, right?
Paul Rand: It is.
Jack Szostak: Somewhere in that 700 or 800 million years, life got started and that could have been early on. Life could have popped up and been wiped out by impacts and then started to come up again. Well, what we’re trying to figure out are what were the necessary environments and the right kinds of chemistry and roughly where in that timeline and under what environments could life have got started.
Paul Rand: To explore what those environments may have been like, Szostak actually looks to Earth as it is right now. He and his students have gone out in the field to explore extreme habitats.
Jack Szostak: Places in Norway and in Iceland and most recently to Yellowstone, so they tend to be volcanically-active regions and they’re in many ways closely related to impact environments.
Paul Rand: Does that mean meteorites when you say an ‘‘impact environment’’?
Jack Szostak: Yeah, yeah, yeah. When you have like a large meteorite or a comet strike the planet, one of the key things is that you have fractured rock and it’s hot and water circulates through it and it extracts compounds from the rocks and brings them up to the surface, so you can see that kind of thing happening, for example, in Yellowstone.
Paul Rand: Szostak is focused on volcanic areas in part because those kinds of environments would have created the extreme temperature fluctuations that are useful for chemical reactions.
Jack Szostak: Exactly. Yes, yes. The whole point is to get evolution going out of a chemical system.
Paul Rand: Those chemicals might have collected in pools or ponds and then you need energy.
Jack Szostak: The best source of energy is the sun. The ultraviolet radiation on the early Earth was stronger than what we experience now, and so that’s a great source of energy and it can drive chemical reactions in the atmosphere. This can bring down to the surface compounds like cyanide. That’s one of our favorites, a really great starting material for making all the building blocks of biology. It’s kind of ironic, something as deadly as cyanide is maybe the best starting material to make the molecules of life, but that’s how it looks.
Jack Szostak: Then what you need is surface environments where these chemical feedstocks can be concentrated, they can come together, and start to react with each other. Then there’s a whole series of pathways where you build up gradually more complicated molecules and there’s been a huge amount of work from other labs, gradually unraveling how you actually can make not just a random collection of thousands of millions of different compounds, but just the subset that you want to build life. To me, the most interesting questions are once you’ve got those correct chemicals in the right environment, how do they get together and what are the processes that give rise to the first cells?
Paul Rand: All right, so let’s assume that we’ve got the environment, we’ve got the chemicals.
Jack Szostak: Then we have to put it in a cellular context, right? It has to be in some kind of membrane vesicle, it’s something that looks like the compartment that you see in a modern cell. We know how to make those membrane vesicles. We know how to make them grow and divide.
Paul Rand: By combining fatty acids with water, but what about genetic material?
Jack Szostak: Here’s where the fundamental puzzle of the origin of life is, that in modern cells, you have this really complicated biochemistry where you start with information stored in DNA.
Tape: Oh, Mr. DNA. Where did you come from?
Tape: From your blood. Just one drop of your blood contains billions of strands of DNA, the building blocks of life.
Jack Szostak: Transfer it to RNA, and then you translate it to proteins, and every part of that system depends on every other part. It was always a puzzle as to how such a self-referential system could get started.
Tape: A DNA strand like me is a blueprint for building a living thing.
Jack Szostak: But in the beginning, what you need is something simple, just good enough to get by and something that you can get to from the chemistry. The breakthrough came from the realization that RNA, this molecule in the middle between DNA and proteins, RNA can actually do what DNA does because it carries information and its sequence of letters and the big surprise was that RNA can also act like an enzyme, so it can catalyze chemical reactions, you can build structures with it, so RNA is probably not as good at doing either job, but it can do them both.
Paul Rand: Okay. Help translate that and help me understand the meaning of what the RNA world hypothesis is.
Jack Szostak: I mean, it’s almost in some sense, silly to call it a hypothesis. It’s pretty firmly-
Paul Rand: Established?
Jack Szostak: ... established, yeah.
Paul Rand: It gives it a bit of gravitas though, by calling it that.
Jack Szostak: Yeah, yeah. It’s very simple, it‘s just the idea that the most primitive cells, the primordial cells were based on RNA, which played the role of the genetic material and they used RNA to carry out biochemical functions to catalyze reactions. The smoking gun is the cellular machine, the ribosome, right, which it turns out it’s built partly out of RNA and partly out of proteins, but it’s the RNA part that actually makes new proteins, so RNA makes all the proteins in our bodies and every cell, so it makes sense that RNA came first. All we have to do is figure out how something as complicated as RNA came to exist on the early Earth.
Paul Rand: This is what Szostak’s lab focuses almost entirely on: How RNA came into existence.
Jack Szostak: Especially the hardest problem, the thing we’ve really been struggling with for the last 10 years or so, is how you could replicate RNA without enzymes, just using chemistry and physics. In modern cells, when cells make a new RNA molecule, they use building blocks. I don’t want to get too technical, but they‘re nucleoside triphosphates. They’re molecules that are quite stable. You have enzymes that string them together in the right way and it’s great, but at the origin of life, there were no enzymes. You could only rely on chemistry and the right environment. One of the breakthroughs was to figure out a new, what we call ‘‘activation chemistry,’’ a way of making these building blocks more reactive. Well, the way the story develops actually quite interesting. The postdoc in the lab figured out a little bit of the chemistry that could make this work much better and then a couple of other people in the lab figured out that actually, this is a way of doing it that totally makes sense for early Earth prebiotic chemistry.
Paul Rand: Without enzymes?
Jack Szostak: Yeah, yeah. It makes the whole thing work much better without enzymes.
Paul Rand: Is there a point where you say, ‘‘For this series of experiments, we’ve discovered what we wanted to get to?‘‘ What is the finale here?
Jack Szostak: What we’re aiming for is being able to start with, say, one molecule of RNA or some collection of RNAs, and then set up the right chemical environment and have it spontaneously replicate and make more of itself. We’re not there yet. We have ideas about how to do it and I think we might solve that within the next couple of years if things work out and we need to put it all together, so we’re going to have replicating RNA inside replicating compartments. Once we have that, that kind of system should start to evolve spontaneously.
Paul Rand: And that would be a pathway to life. There are other scientists who are looking for alternatives to RNA as the start to life and that’s because, as Szostak puts it, ‘‘RNA is a big, complicated molecule,’’ so some people think that maybe life started with something simpler.
Jack Szostak: Ultimately, we may end up with several paths to life and we may never know which was the one that actually happened on the early Earth, but that would be great, too, because right now, we don’t have any paths, right? We’d just like to have at least one and maybe more.
Paul Rand: Coming up: Was life on Earth inevitable? Everyone likes to feel special. We like to think of life on Earth as a one in a billion trillion quintillion chance, and everything had to go just so for us to get here, right?
Jack Szostak: That is one of the big questions. I think when I started to get into this seriously, there were so many gaps in our knowledge. It did seem like maybe it was a very, very hard process, something very unlikely for all the pieces to come together. The more I‘ve worked in this area, more and more of those gaps are getting filled in a way that makes it look like maybe all the steps are not that hard.
Paul Rand: Life requires the right environments, the right chemistry, but ...?
Jack Szostak: It’s possible that given a planetary environment, it might be almost inevitable.
Paul Rand: Wow.
Jack Szostak: I wouldn’t say that confidently yet, but it could be.
Paul Rand: What does that mean?
Jack Szostak: Well, then the implication is that there should be life everywhere in the universe, right?
Paul Rand: If life is inevitable, given the right conditions, maybe we are not alone.
Jack Szostak: Yeah. I mean, our field is very closely tied in with all these advances in astronomy, the whole amazing story of exoplanets, and the fact that we now know that Earth is not unique, there are hundreds of millions of rocky planets in our galaxy. One way of looking at this question of whether it’s easy or hard for life to get started is it’s basically the same question as, is life common, present on lots of these exoplanets, or is it only here on our planet? And so we’re all asking the same question and the astronomers are trying to get a clue by looking at the chemistry of the atmospheres of some of these distant planets and we‘re trying to get clues by doing experiments in the lab.
Jack Szostak: If the astronomers get evidence for life on another planet, that would say, ‘‘Okay, it's not this incredibly improbable event that maybe only happened once in the whole history of the universe,’’ right? It can’t be that hard, and so that would mean for us, yeah, there’s an answer. We just have to go and find it. On the other hand, if we’re able to build living cells in the lab in a series of relatively simple steps, then I think that would inspire the exoplanet community to look even harder for examples of life elsewhere.
Paul Rand: I had to ask, of course, does Szostak believe in alien life?
Jack Szostak: Well, you know what? I used to say that I can’t answer that because we‘re trying to get the answer to that question by trying to understand, is it easy or hard to get from chemistry to life? But I will say, over the last 10 years, I’m edging closer to the idea that it might not be that hard to go from chemistry to life, and so I’d say there's a higher profitability now than what I used to think that life is common on other planets.
Paul Rand: Whereas your thinking may have been it was really quite a distinct and unique process is you keep saying, which is sort of hard to fathom, ‘‘It’s not that hard to create life under the right circumstances.’’ Seeing that happen elsewhere starts giving a different level of confidence.
Jack Szostak: Yeah, yeah. I mean, we were just filling in a lot of the gaps in our knowledge and every time there’s something that just seemed like, ‘‘How on Earth could this possibly happen?’’ then we figure it out and it’s, ‘‘Oh, yeah, it's actually quite trivial.’’ When that starts to happen enough times, then you think, ‘‘Well, maybe the whole pathway is easy.’’
Paul Rand: Well, I go back to the point where we start our conversation about the three fundamental questions of science. I wonder if you can tell me, as you have these thoughts, do you find it hard to shut off your brain and to not be obsessing about this on a moment-by-moment basis? Or is this something you’re always turning over inside your head?
Jack Szostak: I do think about it a lot, but I love it. It’s fun. It's exciting. One of my favorite things is just to take a blank pad of paper and start scribbling down ideas and sometimes something interesting comes up and then we can go in the lab and try things out.
Paul Rand: The thing about Szostak is that he believes the question of how life began is one that he and his team will be able to answer, and soon, and as excited as he is about finding that answer, he remains the utmost pragmatic scientist. I asked him what he thinks it will be like when he figures it all out.
Jack Szostak: I don’t think that there‘s likely to be a aha moment where, ‘‘Wow, now we see it,’’ it'll be a gradual shift where we can do little bits of coffee in chemistry now. We need to make it a little bit better, a little bit better. At some point, we’ll start to see replication, but maybe it‘ll be too error-prone, and then we’ll get it to work a little more accurately, and there‘s still a lot more to do, but step-by-step.
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