How did life begin? It is one of the greatest and most ancient mysteries in all of science, and the clues to solve it are all around us. If evolutionary history were to be recorded again and again, it might turn out differently. Steven Strogatz spoke with two researchers about the tape. Jack Szostak is a Biologist who explores how a boiling pool could have given rise to essential life elements. Betül Kaçar is a paleogeneticist and Astrobiologist who resurrects ancient genes to learn how they helped evolve the processes essential to modern life.
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Steven Strogatz is the host of The Joy of Why, a show that takes you into some of the biggest unanswered questions in science and math. We are going to be looking at our best understanding of the origin of life in this episode. How did life begin?
Charles Darwin speculated that life began in a warm little pond. It's easy to picture delicate biology taking shape in a supportive place. Some scientists theorize that life may have started in the ocean near the hydrothermal vents, a seemingly inhospitable place where the pressures are enormous and the temperatures are hot. What were the earliest building blocks of life? Is there something simpler about the molecule that we hear so much about today? Some important clues have turned up in the past few years. 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.
Jack Szostak is with me to discuss this. Jack is a professor of chemistry and chemical biology at Harvard University, a professor of genetics at Harvard Medical School, and an investigator at Mass General Hospital. He received a prize for his work on telomerase, an enzyme that protects chromosomes from degrading. We will be joined by an assistant professor of bacteriology at the University of Wisconsin, Madison. Jack Szostak, thank you for joining us.
Jack Szostak thanks you for having him.
Strogatz asked about the origin of life. It is one of the greatest mysteries in all of science and the attempt to solve it is one of the greatest detective stories of all time. How life began on Earth would be your best guess?
I think we have to think about the environment on the surface of the Earth, a shallow lake or pond where the building blocks ofRNA were made and accumulated. Under the right conditions, the RNA could start to replicate under the power of the sun. That would allow Darwinian evolution to begin. The protocells would start to take over the population if there were someRNA sequences that did something useful for them. Life can gradually get more complex and evolve to different environments until you end up with what we see today.
What are some of the scenarios? We need something concrete to think about. Stanley Miller and the Miller-Urey experiment were something that we all heard about when I was a kid. Why don't you remind me that the scientific investigation of some of these questions began? Is there an earlier place we should look at?
That was a revolutionary landmark and it created a splash. It was a revelation to people that you could make the building blocks of proteins in a seemingly simple way. Stanley was a graduate student at the University of Chicago. Urey was a scientist who discovered the isotopes of hydrogen, like deuterium, and so on. Stanley wanted to try to mimic the atmosphere of the early Earth with hydrogen, ammonia, methane, some water, and some energy. His advisor told him not to do it. It did. It was a huge success and all kinds of interesting molecule were made.
When you start to look at it more carefully, you will see that what actually got made was more than just the molecule that you wanted. Some of the key building blocks are not present. It's a sign that chemistry isn't the right way to get life started.
Strogatz: Okay. You mentioned the RNA world. Is that the next big idea in our story? Maybe there is something in between Miller-Urey and the RNA world.
For a long time, thinking about the origin of life was confused because everything in modern life depends on everything else. You need the proteins to replicate the DNA, but you have the sequence ofRNA. You needRNA to make theProtein. All parts of the system need the other parts. It was a logical dilemma. The solution to that came with the idea of the so-calledRNA world idea, which was originally proposed by some very smart people, like Francis Crick and Leslie Orgel.
Strogatz says that the idea ofRNA carrying information, but being the enzyme needed to help replicate, is a new idea. I didn't know that was a hypothesis before it was discovered in the lab.
That's right, yeah. When the structure of tRNA came out, people for the first time were able to see that RNA could fold up into three-dimensional shapes. Which is what you need to build a center.
Strogatz: You said that there was a prediction after the discovery of transferRNA. You might remind us of that, for those who are a little hazy on their high school biology. What is it doing for us?
Szostak says that tRNA is short for transferRNA. It is a relatively short set ofRNAs, around 70 or 80 nucleotides long, and they carry the amino acids to the ribosome. The ribosome takes the tRNA and assembles it into a chain of peptides. There are a lot of roles for the RNA. It turns out that the ribosome's RNA components are actually orchestrating everything. I think now everybody knows about the messenger RNA, right?
We have the Moderna and Pfizer vaccines. Right. The ribosome itself is built of RNA and there are three interesting roles for it. This is part of the clue, since we are talking about clues, and it suggests that RNA is very fundamental.
Szostak is absolutely correct. When the ribosome's crystal structure was solved, we were able to see the catalytic site. It's clear that RNA is what makes the things we eat. You can get out of this kind of self-referential loop if you believe that early forms of life used the same genetic material as today's viruses. They used the material as a catalyst. They were made out of RNA. The problem is simpler now. You just have to figure out how to make simpleRNA-based cells.
This is great. This is the point where we have a really important suspect, that the story of early life on Earth is dependent on theRNA.
You have to figure out how to get it. That is not easy.
Aha. That is not something that appeared in Stanley Miller's lightning sparks. I recall that they didn't produce any RNA in that experiment.
That is correct. There may have been traces of adenine, because it is easy to make adenine in those Miller-Urey type experiments. A lot of the other building blocks are difficult to make.
Strogatz thinks we should talk about cyanide since you mentioned it. Many people will be horrified, thinking that cyanide is how you kill people.
One of the nice ironies of the whole field is that the best starting material to build all of the molecule of life is cyanide.
This is amazing. Tell us more about this.
It had been known for a long time that cyanide has a rich chemistry when it starts to react with itself. A key experiment done by Joan Or was showing that cyanide could be used to make adenine. A lot of people worked on ways to get to the other building blocks of RNA.
One of the issues with cyanide is that it will rain out onto the surface as a very dilute solution if you make it in the atmosphere. You need a way to store it and concentrate it. It is a very simple and effective solution, which is that you can make ferrocyanide, a non-toxic compound, by capturing cyanide with iron. ferrocyanide can accumulate over time in some lakes.
The iron comes up from the ground. The atmosphere is the source of the cyanide. They combine in shallow lakes. Some salts of cyanide can build up as a kind of sediment. That is the idea. You have a lot of concentrated cyanide.
Mm. Strogatz (11:06): Mm. If I'm correct, this is not so far from Darwin's little pond.
The idea is that you have a solid source of cyanide in the form of ferrocyanide. How do you get that to do chemistry? If there is an impact from a meteorite or lava flowing over it, you can transform ferrocyanide into a range of other compounds. You can begin to build more complex molecules now.
It's not just a matter of the sun shining on it, you need something violent. You are talking about either comets or meteors hitting.
We think the environments were very volcanically active. You know, lava flows would be very common. That can change ferrocyanide. After that, things cool down, rain falls, and the compounds are dissolved into a pond. We are close to Darwin's warm little pond. The many, many photochemical reactions that are needed to bring you up to the level of nucleotides, amino acids, and lipids is a critical role that sunlight plays. Szostak is referring to theories about prebiotic chemistry championed by John Sutherland of the Medical Research Council Laboratory of Molecular Biology and others. The idea is to make all of these compounds from cyanide.
Hm. Strogatz (11:54): Hm. Incredible. Maybe we should return to this theme now that we have a world of cyanide, but we can't go up to the world of RNA.
Szostak thinks the pathway to getting to two of the four building blocks of RNA is maybe 90 percent worked out. One of the biggest steps is having all the energy from sunlight. The question is, how do you transform that energy into energy that can be used to drive building blocks into long RNA chains? I think we all agree that that has not been solved.
Strogatz: So, you've spoken to us a lot about the virtues ofRNA as a sort of triple threat, all these things it does in modern biology. It's surprising to not hear about its cousin. Is there something wrong with the genes?
That is actually a really interesting question. We used to think that life started with just theRNA, because we were thinking about ribozymes and the roles they play in modern cells. There are some clues from the chemistry that suggest that the building blocks of the two substances could have been made in the same place. One possibility is that the early genetic material was a mixture of both genes. Our experiments show that the chemistry of the RNA-copying chemistry is faster than the chemistry of the DNA, so I still think that theRNA would have outcompeted the DNA early on, but this is a very active area of research. The synthetic pathways are still being worked on by lots of people.
One important clue is that modern-day membranes are often made of lipids. I know you've worked on that, why don't you tell us some of the stories about it?
Cells tend to be pretty complicated structures if we look at modern biology. The lipids that build modern membranes are not the only types of molecule that are complex. It turns out that you can make similar membranes from simpler molecules. It's basically soap with things like fat acids. It's very attractive, you know, that you can build the membranes you need to make primordial compartments out of simple building blocks.
I don't understand how replication would happen at the level of the whole cell.
Szostak can tell you where we are. Several years ago, we found ways of making these primitive membranes. They are easy to feed with more fat. It doesn't take much to divide them. Gentle shaking will do it. It's a much harder problem to get RNA sequences to replicate. That's why we're focusing on that in my lab at the moment. We have been getting better at copying. If you have a single strand ofRNA, you can use it as a template to build up a double helix, similar to the double helix of DNA. How do you separate the strands and then copy them? We have ideas about how to do it, but we haven't gotten there yet. The challenge for the next couple of years is that.
Thank you so much, Jack. We appreciate the time you spent with us today.
Szostak thanks Steve. It has been my pleasure. Talking about the origin of life is my favorite subject.
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Jack Szostak is trying to understand how life could have arisen from non-life. It is like he is starting at the beginning, before life existed, and trying to see how life began. Scientists are also trying different strategies. To reconstruct what life may have been like billions of years ago, they start with what we know about life today, and use evolution to look back in time. They are not using fossils to build their tree of life. They use molecule, like DNA, as their clues.
Bet FC;l Kaçar is with me now. She is an assistant professor at the University of Wisconsin, Madison. She is the principal investigator of Project MUSE, a major NASA-funded research initiative. Thank you very much for being here.
Thanks for having me.
Strogatz is excited to be talking to you. I wonder if you could tell us a little about your approach to looking for answers, what life was like billions of years ago? What kind of clues are you looking for?
We are interested in understanding early life. The blueprints for everything complex around us were created by life's beginnings and early evolution. We want to understand 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. How did they emerge and how did they flourish? They set the tone of life on this planet.
It's such a cool idea that the clues are all around us, yet you can use them to go back billions of years?
So we try to understand what similarities living organisms have? You may think of this as a diagram of metabolisms in all areas of life. We try to understand what is common amongst the living organisms today, and if we can assign them as the shared processes that existed billions of years ago. That's the starting assumption that we make. In the very beginning, I must say that studying early life requires a lot of assumptions. Nobody had a board to go back and record everything, and bring it back to today. We make assumptions in order to understand the past. We are trying to figure out something that the clues of these processes have been erased from. I think the challenge itself makes it very exciting, because it's a sort of way of looking into the past.
It's fantastic. I like the analogy. It's perfect. It is similar to a detective. I mean, because there is some logic to it. You have to make some assumptions, good guesses, because the clues are imperfect.
Exactly. I wanted to be an archaeologist. I feel like I have fulfilled that dream.
Interesting. You are like a biological archaeologist.
There you go. A paleogeneticist. This is the closest I could get to my childhood dream.
Strogatz: You mention the detective. I have heard you say that you feel like you are waking Sleeping Beauty.
Some of them are pretty and some of them are not.
Them who? Strogatz asked. What are they?
When we bring them to the present, they don't want to be here. 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 synthesise them, and our ability to conjugate them. These are not easy problems for the modern proteins. Adding to the challenge is dealing with 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. They are not familiar to us. If you think about it, we are dealing with a form of alien molecule. There was a fragment of the past on this planet.
It occurs to me that there are some steps missing that I should probably have you walk us through. You said a few minutes ago that you think about the molecule associated with metabolism. I suppose they could be something like information molecule or something. Linguists can look at languages today and try to reconstruct them through a kind of tree of life. Linguists believe there are some ancient languages that are no longer spoken. It is thought that the language is an ancestral one to a lot of the languages in Europe today. There aren't any speakers of Indo-European today. I wonder if your process is similar to that except with Molecules.
It is very similar. We are looking at how life expresses itself in the form of genes. We try to use the genes and their products to reconstruct the past first. This is similar to what linguists do. Linguists try to understand the culture that uses ancient language, how did they survive, what tools they relied on, and it's very similar to what we are trying to do. We are trying to understand the early culture of life.
Strogatz says let's see here. You can get information about these ancestral molecules. What do you do, walk us through it a little bit? To use your wonderful word, resurrected, tell us about some of the molecules that you have.
We try to focus on molecules that extend their presence all the way back into the origin of life, or at least first life. We think that these are essential and ancient. We assume that they must have been present billions of years ago if they are shared by all life as we know it today. With the improved computational and mathematical and evolutionary modeling around us, we can attempt to resurrect the ancient DNA sequence. Billions of years, billion-year-old genes are what I'm talking about.
These aren't ancient DNA from a permafrost. These are sequence that are as old as 3.5 billion years old. Once we make the prediction in the computer, we make the genes in the lab. We bring them back to the past. Tell us about yourself, right? Tell us where you lived. Tell us what you like.
Many people listening to this will be thinking of a movie. People have asked you about that.
The major difference is that we are not dealing with ancient organisms. We are dealing with a fragment that we engineer inside the modern organisms. We don't deal with the relic in any way. Because we are dealing with molecules that have operated themselves over billions of years of time, we can't extract DNA from rocks that isn't well-conserved.
Let's get a little more specific about the molecule. I remember learning about the work of Carl woese, who was using ribosomal RNA back in the 1960s, which is pretty much every living thing on Earth today. Everyone has to have ribosomes?
Yes, Kaçar. Isn't that wonderful?
Strogatz: We all have them! People, animals, and things.
It is fascinating that we are all walking around with a bunch of organic computers that are processing the information that is fed to them. Some may say that there are no forms of life in the universe that don't have the same information processing center. ribosome is a universal property of all life.
Strogatz is really struck by the word that you just used, an organic computer. The ribosomes are organic computers that translate information from one molecule to another, and then they produce an output, like the proteins that do everything our body needs. I like that analogy.
It's one of life's major inventions, and it may even be the first invention, for it may even change the way we live. We don't know how this happened. You can see why we study early life now. This is what I mean by the blueprints of life, that the revolutions at the molecular level set the tone for what we see today.
Our biological systems depend on revolutions that took place billions of years ago. Ribosome is seen as the center of life's problem-solving skills. It creates a nice bridge between the world ofRNA and the world of cellular systems. It has a lot of things that we think existed at the beginning of life.
If we find life elsewhere in the universe, you think there will be something similar to a ribosome, that's sort of a universal problem. It doesn't have to be ours with the same chemistry. You think that something plays a role that a ribosome plays here on Earth.
I would think so. I think that a living system should be able to sense and process its own environment. I would think that a translation is one of the necessary components to translate the language of the environment into the language of life. If we were to find life outside of our planet, I would argue that it would probably have ribosome.
Strogatz thinks we should talk more about the resurrection issue. Do you reconstruct ancestral ribosomal RNA in your work? I don't know what you mean when you talk about this.
My lab is interested in understanding how life learned how to elongate, and what the proteins that do that did billions of years ago. That was my first.
Hold on for one second. We're talking about elongating a DNA molecule. Or something else?
We are talking about how the ribosome's amino acid chains have been shortened.
Strogatz says that the elongation of the amino acid chain is important.
The product is long. Exactly.
Strogatz asks if you are checking different strains ofbacteria or yeast. Who are your organisms?
My organisms arebacteria. In my lab, we use a lot of microbes. At this time, I was working at the NASA Astrobiology Institute. I was reading a lot of Stephen Jay Gould, Star Trek, and Daniel Dennett books, and I thought maybe we could use this methodology. And then use the modern organisms as a host?
Let me just say that. I want to make sure that I'm with you, I think I am. The inference step is when researchers try to imagine what the ancestral sequence would have been like, assuming the genetic code was the same back then as it is today. It's your new thing to actually make those. You know, assuming the preservation of the genetic code over a long period of time. You don't have to think about what their sequence was when you make those molecules.
To study the evolution of these genes in tandem with the organisms over geologic time, make them and analyze them outside of the cell, but also genetically modify the organisms with these ancient DNA molecules. I wanted to combine synthetic biology, evolutionary biology, phylogenetic trees, and develop experimental systems to attempt to reconstruct these early steps.
It was screaming at us because it is so essential. It's the way the M.O. works in every cell. We don't know how the early steps evolved. Instead of focusing on the ribosome, we focused on the proteins that make it work. A ribosome is sort of sitting on its throne, in a way, if you think about it. The shuttle proteins are the ones that really enable its function. They are obsessed with the core system. It is almost like butterflies and moths. The ribosome is a macromolecule that we call a ribosome. Understanding how that behavior emerges is a challenging and important question. Over the next decade, we will push forward that. I'm really excited about that.
One of the things I find interesting about your work is that you are not just watching how ancient genes and their products behave, but also some of the experiments that you have done have addressed the question. It feels like it's related to a thought experiment that Stephen Jay Gould once had, where he was imagining that evolution would play out again and again, and he thought that the story of life would turn out. What did you find when you did the actual experiments?
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. We reconstructed early components of the translation machinery and engineered them insidebacteria, but I also set up an evolution experiment to replay the evolution for this system that is likely representing a fragment of billions of years into the past. I thought that paleogenetics, resurrecting ancient DNA, injecting these ancient DNA into modern systems, and then evolving these ancient DNA systems in the lab would be a way to realize this thought experiment. That was the motivating factor.
I was inspired by the work of Rich Lenski at Michigan State, who 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. I used to engineer ancient translation genes from the same E. colibacteria. I followed this experimental evolution system to see how the bacteria that is now using an ancient translation protein is growing and looking sick.
Strogatz is really? It looks like it's inferior or sick. It has messed up.
They needed each other, but they didn't want each other. It was like a very complicated relationship unfolding in front of me. What are you going to do? The only factor that the organisms used was this one, and we forced them to live with it. To watch how the two communicate.
Strogatz wants to hear more about this. It's like you have a modern-day car, but you're giving it an old part from a long time ago.
Exactly. Also essential. The modern version way to present the genome means that we deleted any other copy that may be present. Forcedbacteria to survive by using an ancient elongationProtein The engineering was a little messed up after this, and it grew almost twice as slow. The colonies looked really messed up to me. The organisms were able to recover from the small function in a matter of tens of generations. The recovery was very fast.
It made sense because they need to get along again. This is not a game. Life needs to find a way to survive, and life did. We spent a long time understanding how this solution came about and how thebacteria deal with this problem.
Please tell us a little bit about where you are going next. It sounds like you are starting to work on the MUSE project. What is that all about?
We are studying how metals and elements play a role in early life. We got a grant from NASA. It is a multimillion-dollar, multi-investigator, multi-year grant to explore how the emergence and evolution of metabolisms is influenced by the interaction of metals.
Fantastic, Strogatz. Thank you for that. Thanks again for sharing your insights about the origins of life and early life. It has been a pleasure talking to you. Thank you.
Thank you so much for having me.
Susan Valot is one of the producers of The Joy of Why and she hosts the Quanta Magazine SciencePodcast. Tell your friends about this and follow where you listen. It helps people find the show.
The Joy of Why is an editorially independent publication supported by the Simons Foundation. The selection of topics, guests, or other editorial decisions in this podcast or in Quanta Magazine are not influenced by the funding decisions of the Simons Foundation. Susan Valot and Polly Stryker are the producers of The Joy of Why. John Rennie and Thomas Lin are our editors. The theme music was composed by a man. The artwork for the episodes is by Michael Driver and Samuel Velasco. Steve Strogatz is your host. If you have a question, please email us at quanta@simonsfoundation.org. Thanks for listening.
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