Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas - 166 | Betül Kaçar on Paleogenomics and Ancient Life

Episode Date: September 27, 2021

In the question to understand the biology of life, we are (so far) limited to what happened here on Earth. That includes the diversity of biological organisms today, but also its entire past history. Using modern genomic techniques, we can extrapolate backward to reconstruct the genomes of primitive organisms, both to learn about life's early stages and to guide our ideas about life elsewhere. I talk with astrobiologist Betül Kaçar about paleogenomics and our prospects for finding (or creating!) life in the universe. Support Mindscape on Patreon. Betül Kaçar received her PhD in biomolecular chemistry from Emory University. She is currently an assistant professor in the Department of Bacteriology at the University of Wisconsin-Madison. She is also principal investigator of Project MUSE, a NASA-funded astrobiology research initiative and an associate professor (adjunct) at Earth-Life Science Institute of Tokyo Institute of Technology. Among her awards are a NASA Early Career Faculty Fellow in 2019, and a Scialog Fellow for the search for life in the universe. Web site Google Scholar publications Wikipedia Twitter "Do We Send the Goo?"

Aging is real. And so are the benefits of adding vital proteins collagen peptides to your daily routine. New vital proteins collagen sparkling water. Your daily glow-up now in three fresh flavors. Strawberry blossom, lemon, lime, and blood orange. Improved skin health in as little as 30 days thanks to collagen peptides? Cheers to that. Or go with our classic collagen peptides. So you can stay vital, stay you. Visit vital proteins.com to learn more and where to buy. These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease. When I competed in track and field at the collegiate level, there were times I second guessed myself. That's why it's important for female athletes to have a space to build confidence

and self-esteem. Colgate supports female athletes of all levels through the Colgate women's games, the nation's longest running indoor track and field series for girls and women. By supporting female athletes, Colgate hopes to put more smiles out into the world. Colgate, your smile is your strength. Hello everyone and welcome to the Mindscape podcast. I'm your host, Sean Carroll. N equals one. That's fighting words in scientific circles, where N means the number of data points you have,

and one is the smallest number of data points you can have that is more than zero. When you're looking for trends or features of scientific systems and you only have one data point, it's tempting to say things of sweeping generality, but it's very hard to know that you're on the right track. Sadly, there's a famous case where we're stuck in the science, sense with n equals one, which is the origin of life here on earth. Not only do we only have one example of life in the universe, namely life here on earth, but as far as we know, life only began

once, or if it began multiple times, the evidence has been wiped out of everything else. So what can we do about this if we want to understand things like what is the likelihood of life elsewhere? And if it is out there, how do we go looking for it? So today's guest, Betuel Kachar, is an astrobiologist and synthetic biologist who studies paleogenomics. So I think that's how you pronounce it. I never know how many syllables are in these biology words. But the idea is to learn about early life, not just by looking at fossils, because many fossils that we would like to have just don't exist,

or all the interesting information has been wiped out, but to look at current life to compare the genomes and the proteins and other things going on in different contemporary organisms, and learn about their commonalities, look in detail at their family trees, right? That's the phylo in phylogenomics, and try to reconstruct what it was like in the past. What are the structures that we all share?

And the great news is that this kind of approach moves us from n-equals 1 to n-equals quite a few, because after all, there are a lot of organisms on Earth today, and there were a lot of evolutionary events that they went through. So amazingly, the folks in this field are able, able to push our knowledge back more than three billion years to think about our last universal common ancestor, maybe even about the origin of life itself. And you learn a lot of things along the way, as you'll hear in the podcast. For example, one obvious moral of the story is that

there's a relationship between biological transitions and physical transitions. You know, here on Earth, we have geology, we have chemistry, we have atmospheric science, there's even astrophysics with changes in the sun, the temperature of the atmosphere, and there are biological changes in what biology can do. And even though the total mass of stuff in biology is much less than the total mass of the Earth, it still has an outsized role in what happens in both geology and atmospheric science. So you're going to learn a lot about biology. I learn a lot, since I know almost nothing about it. And the fascinating complex history of how things have been going since life began to now with important implications for what we should be looking at for life elsewhere.

So let's go. Michelle Katjar, welcome to the Mindscape Podcast. Hi, thanks for having me. So it's interesting to think about a comparison between what you do for a living and what some of my friends do for a living, the observational astronomers. You know, they look out into the sky and they look at things that are very far away. and because of a finite speed of light, the things they're looking at they're seeing from the past, right?

So we get automatic access to the past just because the speed of light is slow in cosmology. Now, you're looking at the past, but it's much more complicated for you because you're trying to figure out what was going on with life, and as far as I can tell, you're mostly looking at things that are currently alive and trying to infer the past.

Is that more or less accurate? It is fairly accurate. I am sort of in a way in Sherlock Holmes of the past. If I may say so myself, we are trying to understand what happened billions of years ago by relying on very limited and mostly raised information that exists today. And so we want to go into the details a little bit. I always tell people that the Minescape audience are not experts,

They're not biologists or physicists or whatever, but they're willing to get into the details a little bit. So what do we do? Like, what do we actually look at? I guess maybe the first thing to try to do is to say, what are we trying to figure out? Are you mostly interested in what, like, the DNA, the genome was of the early organisms, or is it more to it than that? It is, broadly speaking, I am interested in the way they expressed themselves, their behavior, and how did they lay? they provide the foundation of life we see around us today. If you think about it, so life is a minimum or approximately, let's say, 3.5 billion-year-old.

And every minute and second and day that we spent on this planet today, we rely on the innovations that life figured out over this time. I think this is incredibly profound. yet we know very little about these past steps that most likely enabled what we see around us today. So I am trying to understand the first steps. And is it a matter of looking at very different organisms and comparing their genomes and seeing what probably stuck around for a long time? Yeah, so there are different ways to do this, although not a lot of different ways.

So we can either read the rock record, which is a prime way of inferring the past, and try to understand from the remnants of past organisms, what sort of story they tell us to understand the environment that they lived in or what sort of maybe catastrophes they had to bear through. Alternatively, we could use the DNA that exists today and make inferences firstly to understand the relationship between today's organisms. which we do fail well. Genomic sequence right now is more resolved than ever before. This is not to say that we have a complete picture in hand, but it's probably better than it has ever been.

And we try to infer the relationships between the organisms anyway, but on top of that, a relatively new application of this is to read these phylogenetic trees, the tree view of life to infer the ancestral states of these organisms. And if you want to drill a little deeper to understand the relationship between these organisms and their ancestors at the molecular level. So that's what I'm trying to do. And actually, tell me a little bit more about the rocks or the fossils because, you know, I know if we look at dinosaurs, we care about fossils, but are there really fossils that are telling us that are capturing an organism from three billion years ago? So this is why it's challenging and why also I think it's incredibly exciting. We have very little information.

We maybe have the tops handful of rocks that relatively harbor, I'm sorry, we have a few rocks that have relatively well-conserved fossil information. Because we are dealing with really, really, really early in life, right? We're looking at life that existed, say, over 3 billion years into the past. So what do you do with that? You try to look at the morphology or some sort of certain chemistry maybe that you will be able to extract from these rocks that will tell you something about the organism that may have been the responsible party that left the signature on the rock.

So we have really a handful of these things to make sense of. So it is fair to say that when it comes to understanding the past, we make a lot of assumptions. The picture is far from complete. And you're trying to connect the dots using a few data points. and then try to write a story about what early life looked like. But just to be very, very clear, those little rocks, those little fossils, you're not getting DNA from them, are you? No, so these are way too old to extract DNA from. Maybe if you deal with a permafrost or some conserved organism in some ice location,

you may be able to extract the DNA for maybe a few thousand. 10,000 a year old or something. But when it comes to billion years old, you don't have much. Right. Good. Actually, you have nothing, really. Okay. So then let's go back to then the phylogenetic trees. These seem to be more the way to get at the DNA.

So we get DNA from a whole bunch of organisms. I don't know. I mean, how many organisms do we understand the complete genome for? So we don't quite know, right? It's very difficult to understand. what we don't understand or that to know that we are not understanding what we're thinking we're understanding. So the more we explore the oceans, the more we explore all this, you know, maybe previously

difficult to access locations, the more we are finding amazing the microbial diversity today. That's good for people in my field, because we rely on today's diversity to infer the past. So the more data we gather from today's biodiversity, the better it is for us, or easier it is for us to understand the past. That doesn't mean it's easy, but it makes our job a little easier. So it totally depends on what you are trying to access, what question that you're interested in, what system you want to explore, and how well refined and understood that system is today. Yeah, but forgetting about like the fraction, I know there's, we keep discovering more and more organisms, which is, I mean, good for you, right? Full employment. You're never

going to run out of things to do. But when we study these, I'm very much ignorant about this. So do you just, do we collectively just discover a new microbe and then sequence its DNA and put it in a database somewhere? Yeah. So that's exactly what we do and why we, I don't mean me. That's what they used to very well. And find the, you know, the more, you know, the more. organisms are discovered or they are sequenced, the more we develop these technologies that enable us to sequence them properly, the more database we have in terms of understanding today's biodiversity. But my approach is similar to perhaps a linguist that is trying to resurrect an ancient language. It's very similar. If you were to reconstruct the ancestor of modern

Egyptian, what would you do, right? You would try to understand whatever ancient civilizations left in a similar way, maybe in some cases on the rocks. You know, like what did they write behind? What is the written record that they left behind? And you also would independently, but also in a complimentary fashion, would try to understand the culture of these old civilizations and try to understand what sort of, I don't know, cups that they use, where did they live?

Did they have windows? Okay, what does that mean that they constantly protected themselves from the sun? Okay, they were living in a hot environment. So it's very similar to what we do in a way, that we are trying to extract the ancient language of today's biology. And there are a lot of gaps, perhaps similar to enlinguists that is trying to extract a really old language, that there will be gaps or maybe mistranslated stories. But we've got to start from somewhere. Yeah, so is it as simple?

you look at all sorts of different microbes or even, you know, more complex organisms and you say, what are the common sequences of DNA and those probably are old? Is that basically the idea? So that's where we start. We first take a picture of the entire story and try to understand what does the ancestry tells us. But my lab, we've developed this system where we took this a little step further and used synthetic biology and created these ancient DNA sequences in the lab. So if the listeners are thinking, ding, ding, ding, d Jurassic Park, come down. It's not that bad.

It's much older. And it's actually the opposite of Jurassic Park. Anyway, so we are trying to, we actually developed this system where we aimed to engineer modern organisms by basically treating them like a shuttle in a world. way and by directly modifying their genome with these ancient DNA sequences. So we wanted to animate the ancient life components in the lab. So that's sort of where the fun started for me, because looking at the tree or the relationship is really like looking at the picture.

It tells you only so much. It's more static. I wanted to bring them back to life and see what they do and what they impose on the organism. ultimately to compare that behavior with what we extract from the rock record. Right. But I guess I'm still missing something pretty simple here. How do we know what sequences of DNA are ancient? And how do we know which ones are recent?

Okay. That's a very good question. So we rely on a lot of mathematical models, a lot of evolutionary algorithms to make these predictions. And it is safe to say that we are making a lot of predictions and a lot of assumptions. So it is, we need to sort of live with our own limitations and our own statistical significances or lack thereof sometimes. And know to a degree how confident we are that we are dealing with a true ancestor. So if this, we have 60% certainty, then we have 60% certainty. And because of using these evolutionary algorithms, we have some idea about, for example,

when two organisms that live today, when did their ancestor survive on this planet? Was it a billion year ago? Was it two billion years ago? If you track everything, we are all connected. That's the major, in a way, the most poetic and beautiful assumptions of biology, that the entire biological taxa is connected through ancestry, right? So if you go further and further, you go back to the last universal common ancestor, and that's going to take you to 3.5 billion-year-old. So you need to then ask yourself, what do I think that existed back then? Did life function exactly the same as we see today, or where you're there are components that were even more older than the rest. And if I were to assume that a last universal common ancestor existed with components similar to what I see today, what were those? And so if I look in the DNA of a bacterium or a fungus, can I literally identify sequences of base pairs that also appear in human DNA or palm tree DNA? Yeah, of course, there are segments that in all modern life today that is shared, right?

So there are components that are shared. We all rely on translation machinery, for example. It is almost imagining that we all have the same computational processor inside of us. You do, I do, a plant does. We all rely on the same system. Life needs to translate the language of DNA into hopefully meaningful, sometimes meaningless, protein sequences and then use them for whatever there's required. So if you abstract life, if you abstract the

complexity that you see today, like it or not, you are reaching to some components that are shared. So you may assume that whatever is shared across all life today may be the common component and was the common component or shared component in the past as well. And maybe this is just worth rehearsing because I'm sure that most of our listeners have heard this in high school biology or whatever, but this machinery that you're talking about is what takes the genetic info from DNA, converts it to RNA, and then to proteins. You're saying that that basic setup

is common to literally all the life we've seen ever on Earth. Yes, I would say universal, but because we didn't find life outside of Earth, I will just say Terran. But so far, all life we know relies on this machinery. And maybe a human system would be a little bit more complex, of course, anarchy. Anarchy may be more complex than bacteria, but in some form, the same, the computational system, so to speak, exists in all life. It's quite remarkable.

You may imagine that some computer from the 60s, and you can look at the computers today, and you may find similar components in each, even though they look absolutely different. Maybe they look bigger and smaller. By the way, bigger computer doesn't mean more complex, right? Like a very small eye watch is actually arguably more complicated than a giant processor, you know, from 60s 70s. I keep saying 60s 70s.

I don't know the computers back to be honest. I wasn't alive. I'm too young, yeah. I've seen photos. So it's the, it's very similar in biology in a very simplified way, if I may put it that way. And is there, again, a naive question? Is there anything that we can learn from studying the protein side of this story in its own right? Or are the proteins basically determined by the DNA, so we can just study the DNA?

So we use both information to access early life components. We use DNA and we also use their products, proteins. So in general, if we can track the past using both. information source sources, but hopefully they will agree with each other, whatever we infer. And if they don't, we report that as well. So it is, but we try to rely on anything we can. It's, you know, we will do what we can, whatever we have around us. We will try to extract the juice out of it and try to understand the past life in any way we can.

And what about the, again, my ignorance showing. There's DNA that codes for proteins and there's non-coding DNA, right? Right, junk DNA. Like, is that, is the junk DNA also useful to you in these investigations? I know there's a lot of debate on the way when we call these components junk, because we don't quite know. Yes, truly what they do. But because I work with microbial systems in general, we don't deal with a lot of nonsensical, so to speak, or mysterious DNA. That also makes my life a bit more complicated given, I've got to limit my amount of, you know,

in a way, the battles that I have. Take your battles, yes. So I rely on the components that we know for sure are essential for life. And then we try to extract the past using those. What's the secret to your best night's sleep? First, toss out the memory foam. Upgrade to Awara, organic luxury hybrid mattress with natural foam and New Zealand wool fiber. Awara features premium Sri Lankan latex and wrapped coil spring.

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we trace Luca, the last universal common ancestor, to about 3.5 billion years ago. But that's not the origin of life, right? I mean, how far away is it from the origin of life? Is that even something we can say? It's not easy to put a very clear mark in terms of the timeline and say this is when the threshold from chemistry to biology happened. We don't quite know.

But we have some reason to think that around 4.1, years into the past, something happened. So we're looking 400 million years following planet formation. And it's very quick, if you think about it. And it's quite magnificent that that's sort of the time that set the stage in terms of the planetary context that enabled the chemistry crossing this threshold to biology, a participant, some sort of agency, something with an agency that's enabled everything we see today. And it's not probably directly related to your research in paleogenetics, but I ask

everyone, every early life, origin of life biologist who comes on the show. Do you think life began more than once? And do you think that starting life out is pretty easy and pretty robust, or did it require some really, really unlikely fluctuations and we just got lucky? Well, that's a very interesting question. We actually do some work. At the one level, we rely on today's biology and rewind the tape and try to understand ancient systems and track them as far as we can in terms and we need biology for that, given that we are tracking life. But at the same time, we are trying to start from chemicals and then see experimentally whether we can generate some behaviors in or some organizational attributes that may look like life. So we are.

are trying to access that time point in using both ants from backwards from today and forward from past. And so to answer your question, if it was very easy, we would probably have done it by now ourselves in the lab, right? So either nature is a better chemist than us, that is for sure. It's not a competition. But I also think that within our lifetimes, it's very likely that we will be solving this particular problem of life's origin now we'll be able to replicate exactly what happened into the past.

No one can know. Nobody has a time machine. I mean, I'm looking at you. I don't have one. But we don't. So we will probably never know if what we created alone is exactly what happened. But we will start constraining what we generate the moment we get there. And I really think that within our lifetime, that's possible.

So it does, I'm totally on board. Most everyone I asked that question to gives that kind of answer. Like, we don't know. It must be pretty hard to start life, but we really don't know. But let's be more specific about it. You mentioned this whole mechanism by which DNA becomes RNA, and then there's the ribosome, which converts that RNA into proteins. And that's common to all life, but it seems awfully complex.

Like, what are the thoughts that we have about how undirected chemistry could have come up with something quite so structured and intricate? I think there are laboratories right now that are trying to piece together this information from different ends. We can create systems that are able to process some level of information albeit limited or however much we directed and we feed. that information. We see that happening. However, we can't make that system evolveable yet, which we need that component for, to pin it as life. And, but, yeah. So we can do that, so we can get self-replicating molecules, but like the separate idea of a machine, the ribosome, right? I mean, there's something more, I think, grandeere that is bigger than translation machinery or a common shared component.

I think maybe there are, I don't want to divide these problems into different disciplines because nature does not know it yet, right? Okay. Yeah. I know who said we divide things, physics, biology, chemistry, but nature does not know that. Right.

So, you know, so I'm not sure, you know, how likely this is, but everything that that we study may be founded by some, you know, a grand dear chemical information system that we are yet to find out. You know, we may be slicing the pie way too much here. Because whether life chooses a translation missionary as a universal system and then runs with it, that's one problem. And we don't know why life does that either. You can say, okay, life is lazy.

And it is lazy. You know, we see this more, you know, over and over again. You see this when organisms chew different isotopes in the atmosphere. They always pick the lighter one because you just don't want to deal with the heavy one, right? So physics imposes itself a lot. in the way biology operates itself. But there may be, we don't know exactly what enables life as a chemical system for it to explore solutions,

what enables life as a chemical system that evolves and figures out solutions to the problems and then maintains a memory of these problems over billions of years of time. We don't know what enables lives in life to do that. That's, I think, sort of the bigger, grand-year problem here that we have yet to solve. Okay, maybe the origin of life is, of course, fascinating for philosophical as well as scientific reasons,

but I mostly want to talk about things that you and your collaborators are actually able to learn about, not the hard problems that everyone would like to learn about. So I get the impression from reading your papers, et cetera, that the great oxygenation event is something that you can actually say something about using your technique. So maybe tell the audience what that event is and what we're able to learn about it. Okay, so that's actually a very good point because you now took us from 3.5 billion years into the past.

We are traveling forward in time and to almost be a billion year. And what we see is significant change in the atmosphere in terms of the levels of oxygen. And it's not quite, I think, there is a lot of debate as to why this may have happened coming. from, there's a lot of geological reasons, there's a biological reasons, and maybe it depends on whom you ask and what they know. They will tell you different, maybe they will point you to different directions as the major drivers of this rise of oxygen. That being said, in our system, we were able to see the signatures of this atmospheric change embedded on the proteins themselves. I still remember the day we just sort of found this. I got chills.

because you would think that proteins are just sort of this, I love proteins. I always think, oh, they're not getting the respect that they deserve. And most of the time people ask me, hey, are you saying that the change in the protein enabled, it triggered a big change in the atmosphere? How is that possible? Because we're looking at layers and layers of hierarchical steps in between. How with such a molecule can make such an impact? And I tell them, with all due respect, I mean, if you remove,

I don't know, lizards today. With all the respect to lizards, we would probably not feel that much. But if you remove, like, molybdenum, we are all doomed. Okay? We're doomed. Like, we won't last, period. So we do rely on these elements and molecules and proteins to enable everything.

And that is, to me, one of the main reasons why we should study proteins, but also their evolution in deep time. So coming back to the rise of oxygen, we were able to see one of the prime drivers of this metabolism today. We were able to access its ancestry, access and resurrect it as three billion-year-old ancestors, engineer them inside microbes, and then find out how the microbe responds to its own past and choose oxygen and carbon dioxide differently. And we were able to see that some parts of the protein responsible from greeting oxygen today

were in fact different 2.5 billions of years ago. So it's almost like oxygen tickled to this protein, and we can see these signatures on it. It's just so amazing. That is pretty amazing, but as you mentioned, I did skip a billion years. So maybe give us some context for what the world was like 2.5 billion years ago.

So before this great oxygenation event, did we have, you can, Caryotes? Did we have cells with nuclei? Did we have multicellular life at that time? What was the world like? So we didn't have eukaryotes. It was pretty, in a way, maybe boring. It was not, it was a pretty solid life if you were a microbe. So the rise of oxygen is a very, you know, it's a horrible catastrophe for microbes. But it's great news if you are eukaryotes or multi-sale organism because the stage, the stage is being set for eukaryotes to rise. but they don't show up for another few million years, 500 million years after the rise of oxygen, they do. So although, again, there are microbes and there's no oxygen.

So that's very important because when we also look for life elsewhere, we look for oxygen as a sort of a, or we think oxygen will be a smoking gum, but no, the first, you know, over a billion year of life didn't have any oxygen. And microbes were just fine, they were just hanging out. They weren't probably as big in terms of. size. But you're looking into, as far as we know, a really hot planet, probably acidic, and a relatively stable atmosphere, because that happened fairly fast on this planet and microbial diversity as far as we can tell. But you carry out sort of all the complicated and maybe more

exciting for some organisms didn't show up for another billion years. Okay, so we have microbial life, the atmosphere is mostly nitrogen and carbon dioxide, I guess. Exactly, and there's almost rich sulfur chemistry going on. And we have different levels of metals in the oceans compared to following the rise of oxygen that we definitely see a shift in different elemental abundances over time. And the microbes are they mostly in the ocean, or are they on land, or do we even get to say that? I am probably not quite sure about that, actually. I probably shouldn't say either way.

But because we are able to infer the ancient oceans, most of the things we infer about them also comes from that locality. Okay. So the oxygenation event, I think you already said this, but it skipped by me. Do we think that it was chemistry first and then the biology made use of it? Or did biology actually cause the oxygenation? So it depends. In fact, there were just recent papers that said it was primarily geological trigger.

But for a biologist, of course, the invention of photosynthesis and the sort of cyanobacterial, the origination of cyanobacteria, the emergence of cyanobacteria, rather, all triggered the rise of oxygen and what we see. Of course, we have the invention of organisms, microbes were able to do unoxygenic photosynthesis back then. But the oxygenic photosynthesis, of course, didn't take place until the rise of oxygen. Now, you may argue that life invented an oxygenic photosynthesis in response to the oxygen. But then how did the environment affect the organisms and vice versa? It's quite a big unknown. Because, again, nobody had a clipboard. It may it comes to the past, we make a lot of assumptions.

So just to restate it so I understand. So it's possible that there was just a little bit of. geology that spewed some oxygen into the atmosphere. And if that's true, then the existing microbes were not adapted to that, and they had to quickly adapt. But it's also possible that some clever microbes learned how to do photosynthesis and started creating oxygen, and it's their fault. Yeah, so cyanobacteria can do both of these things. It can do anaerobic photosynthesis and anaerobic. But, you know, early organism lifestyle, I guess there was a lot of stromatolites, right and there's there's definitely more than oxygen than the rise of oxygen on this planet

methanogens are quite a you know sort of they were running the show and a lot of ammonia amonoxylizing right later on these bacteria showed up so so it is definitely just it is definitely more than oxygen okay when it comes to the rise of oxygen but we know that the photosynthesis definitely played a significant role in the composition of the atmosphere. Okay, that's fair. And in particular, I keep reading about Rubisco in your research. So that's a protein, right?

That's a protein that does something important. That's a relatively large protein. It's one of the highest expressed, the most abundant proteins that exist today. And one of the big questions, of course, is that we know that this behavior of this protein impacts the biomass that is available today. Yet we really know almost nothing about when it comes to the ancient planet's biomass. So this is why, again, understanding, we go back to understanding the contemporary organisms and their behavior and the proteins in which they enable what we see that they do anyway. So understanding the ancestral versions of these proteins makes it more exciting the ability to perhaps one day calculate the biomass of early Earth.

But Rubisco is involved in carbon fixation. It's quite an important enzyme that functions in the production of biomass. At the same time, it's a pretty slow catalyst considering the important job it does. So a lot of synthetic biology applications has been towards improving the function of Rubisco in one way or another. So we wanted to know where the hell did Rubisco come from. and how did it behave billions of years ago? Because one thing that makes Rubisco exciting from a geology point of view is that when we look at even strometalites

and maybe look at this early life, we have a way of knowing that life extends itself all the way to 3.5 billion years old. When we say this is how old life is, how do we know that? We know that because this remnants of these bugs that once lived in these environments tell us that, hey, I did something that is similar to what an organism that around you today does.

And that is that I chewed the amount of carbon dioxide in the atmosphere, the isotopes in the atmosphere, similarly that a micro in the future in your time today does. So we basically compare that past information to today's data set and see if what we find is biological or if it is abiotic. So, of course, discerning the two records is just so hard, right? It's tricky. It's very fun. I highly recommend attending geology meetings about these timings.

Just really heated conversations. I love it. So it's the – and when it comes – so when I remember when I first saw this, I was actually at Harvard at that time, and Indy Knoll drew the sort of timeline on the board and said, okay, this is how old life is in this. There is a carbon record, a biological. carbon record that dates all the way to 3.5 billion years into the past. And I thought, okay, wait, wait, wait, what's the protein that did that, right? So there must be, when you talk

about metabolism and early life, all I hear is molecules. What is the molecule that caused this? And then comes Rubisco. So it blew my mind. I thought, okay, wait a second. So are you telling me that a protein that exists today existed three point something billion years ago and we are able to read its record, we are able to read its signature, and we are assuming it is similar to what we see around us today. Whoa, especially when we know that atmosphere wasn't the same, right? We know all the significant changes, as you said, right, nitrogen amount or oxygen, you know, the different chemistries.

How is that possible? So, and then I realized we don't know. Again, it's an assumption. We sort of assume that because we don't quite know because we think we can't, right? So how can we access a billion-year-old evolution of an enzyme? So that's where we came in. That's where, you know, what I will be doing actually is a part of this new Nassau Center that we will be investigating these problems.

I'm so excited. It's good. We could tell. So this is actually, and it's especially good. You don't even know how good it is because I just recently did a podcast. with Nigel Goldenfeld, who is a physicist who works on life also. And we mentioned we were both fans of Michael Russell's work on The Origin of Life. And the quote that I always use from Michael is that the purpose of life is to hydrogenate carbon dioxide. And so what you're telling me

is that when you hear a statement like that, you're like, that's all molecules. What's the protein that does it? And the answer is Rubisco. Rubisco is the protein responsible for hydrogenate carbon dioxide? It is one of many. There are many enzymes, but I guess what I was trying to highlight is that we know very little, right, about the past. So we try to understand the significant players of our time now and then pin these essential roles on their ancestry as well, which makes total sense.

That's, you know, we have to start from somewhere. But, I mean, of course, you know, we are, it's not to say that a molecule alone can, can do what life, it's, it's an entire system that is interacting with itself. And that's, that's the hard problem, right? It's similar, life detection in a way, it's similar to trying to understand ancient life. You are trying to translate what molecules are enabling that planet to do. And as I said, there are a lot of different steps in between. So this is not necessarily to say that, okay, molecules and that's it. But there are a lot of complex interactions involved in this. And we need to, of course, tie them in together. But, you know, we also need to understand each of them in the most deep way we possibly can. So the problem we picked were the ancestry of the molecules themselves.

And is this what you were actually able to do? I mean, with Rubisco, you're saying that it's all around here today. It's in us today. We still use it, that particular. You're saying enzyme and protein, but enzymes are in this sense a kind of protein, right? A kind of protein that helps. Yeah, we can just say that there are proteins that can have a catalytic activity. They can do, you know, cool and fast kinetics in general.

But the enzymes are proteins. So we can just call them proteins with large. Okay. So, yeah, today's life, of course, not us, but microbes use Rubisco and plants, of course. And we, by we, I mean, living organisms rely on such metabolisms. So this is not to say that this is one most important enzyme out there, but that's one of the main or thought to be one of the main enzymes moving forward. So our approach has been using the DNA sequences today, sort of predict this ancient version, just like, as I was saying early on, like a linguist, and then reconstruct this ancient DNA sequence,

use synthetic biology and actually synthesize them in the lab. That's when we say resurrection. So now we made them, we didn't just reconstruct them, and then engineer them inside the organisms by swapping what is currently in the organism with this ancestral. version and then watch what the organism will do in response to this ancient component. If in fact this protein is the prime dominator of this metabolism, will it also impose itself in a way that it replicates or maybe contradicts what we see in the rock record. So we were able to engineer the billion-year-old version.

We are now working on the older variants. So we want to go further away from the geo-grade oxidation event and access the variance that we think existed when there was no oxygen on this planet. What makes Rubisco interesting is that it's an old enzyme, it is slow, it's also very confused. It cannot differentiate oxygen from carbon dioxide very well. And that was really the main start point here, that we are trying to increase the specificity of this enzyme. towards carbon dioxide. And perhaps maybe we are not better engineers or chemists than nature. We cannot do this.

It's been many, many graduate thesis. Many graduate students started this endeavor and just couldn't really make some, definitely some advances, but not to the degree that satisfied, I think, any application. So that's also an interesting angle here, that we are trying to, in a way, revert this enzyme to what it was before. So why not access the version that already existed when there was no oxygen and see what it does and what's its specificity towards CO2 was? So, yeah, I mean, this is extremely cool. So I'm going to try to say exactly what you just said to see that it's in my brain. So we can't directly say what the ancient protein looked like, the ancient enzyme protein.

But clearly it's playing an important role today. And like you say, it's kind of clunky and inefficient. So maybe that's a sign that it's old and was very, very important back in the day. What you can do using the phylogenetic trees that we already talked about is figure out what the DNA used to look like. And in principle, you should be able to go from the DNA to assemble the protein. And that's the kind of thing you do in your lab? Yeah, exactly. So we infer, this is all statistics and mathematics and evolutionary models.

at that point, all computational. We then send the sequence to a company. They synthesized this to us. They charge us some 10 cents per nucleic acid. How long is it? How long is the sequence? It depends. So sometimes it's 1,500 base pair.

But when I first started, they used to charge us a dollar per base. So now it's 10 cents. So it's pretty amazing. And then they send us a standard. back to us. Sometimes they can't make it. Sometimes they say your sequence is, you know, your sequence sucks. And then we have to either choose another target or understand what's the, of course, as a, you know, protein scientists, I love those moments when something doesn't work. That's why it's exciting. Okay, why is it so bad? Wow, like so horrible that it can't even be synthesized. That's

very interesting. And then, but for the sake of the project, we usually pick a variance that can be made. and then we make these proteins in the lab, we express them. Most of the time, things don't work as plant, right? Because we have to find the optimal condition for these genes that are not supposed to be here. But it's also important to notice and I think about the fact that past is not necessarily less optimal. I think when we think about ancient life or things in the past, we tend to think that, somehow today is better. And it's a very human-centric view,

even I think, that we impose on biology as well. The past conditions weren't necessarily bad solutions. They were optimal and they were innovative at their time. And they need to be treated and such. So we are not looking at a less optimal system. We are looking at a system that was optimal at its given time. For something else, yeah. So you and your graduate students invent basically a code,

use your science to figure out what the DNA sequence was. You send it off to a company that will literally make strands of DNA. And presumably sometimes it doesn't work just because that was not a physical, I don't know, is it not possible to strand together arbitrary collections of ACGT? Do some hold together in some not? Sometimes I think they are either super coiled, so they cannot be linearized in some case.

Some case, they are not soluble. So they fail. we need to add sometimes rationally add some sequences to make them more stable for the downstream application. And in some cases, we just, you know, say, it didn't work. It didn't work out. This is very part ways. And I learned it's important to let go. Because sometimes you can get obsessed with them and say, no, it's going to work out.

And no, I now reached a certain wisdom. That I learned to let go of the proteins that just are not. you know, it's difficult to synthesize them for whatever reason. Most of the time they work. And then, of course, it's another challenge to bring them back to the lab and purify them and synthesize them ourselves. And we either engineer them inside the microbe and let the microbe created for us. In some cases, we do more in silico applications.

So we just do classic biochemistry experiments. It depends also what we are trying to understand. We did this with Rubisco, we did this with nitrogen fixation enzymes, nitrogenases. We did this with translation proteins. So I'm really excited. I really think that there is a lot of potential here combining evolutionary mathematics, models, and experiments in synthetic biology, and then applying all these things to understand paleobiology, early life. It's just so profound.

We are missing, you know, this is Lynn Margul is saying that the story of life on earth is so magnificent that you cannot miss the beginning. You need to understand the early steps of this. It's just so mysterious and exciting. So you get in the mail from Amazon some DNA strands. and what you want. I love that you liked that part. I like that part.

I just like, you know, you're waiting by the mailbox for your DNA to come in. Because we wait a lot sometimes. But you want not the DNA. The DNA is great, but you want the protein. And so I guess you partially answered this, but I was going to ask, do we human beings have the technology to take a DNA strand and make protein from it? Or do you have to put it inside a cell and let biology do the work? We can do this.

We have technology to do this without. a cell, we can do these cell-free translation expressions, expressions relying on cell-free translation systems, and make them, if they are easy. We tend to pick hard problems, and we don't realize how difficult they are until we hit the wall. And so Rubisco is not an easy enzyme to just dance around with it. You need to sort of every different enzyme or every different process. that you study, you need to speak their language and you need to let them show you what they are

and what they prefer without imposing your own agenda on them. That's very, I think, beauty of studying biology in general because you're dealing with living systems. So every experiment is a different endeavor in its own right, which can be hard. And of course one challenges, I teach history of life course and students are always shocked at the level of unknowns we deal with. They're almost feeling disappointed

that you don't know anything because they want us to, I think they assume that we figured this all out. As you said, oh, DNA and then comes RNA and then comes protein and then bam, it's translation and then Selk shows up and then before you know it's dinosaurs. Like they may be assuming that it's not. And it's, yeah,

so they get disappointed. when they hear that we hardly know anything. Well, and I like the point you made that, you know, we've all seen science fiction movies of the frozen Neanderthal who awakes in the present day and cannot adapt to current conditions. And in some sense, your proteins are like that, right? I mean, you're saying you're putting DNA sequences in microbes, but they're modern microbes in modern conditions.

And even if they worked well back in the day, two billion years ago, right now maybe it's not so obvious that they will succeed. Yeah, yes, and your careful listeners already were, I think, asking these things to themselves. Wait a second. She's putting these things in modern systems. So everything else is modern. Yeah. You know, there's only one thing that's ancestral, and that's exactly right.

So we are not able to, we're not there yet, and not my group anyway. We are not the ones trying to generate an entire ancestral organism. That we are our, we're just simply, you know, we're modern. way trying to resurrect three billion year old life. It's very, very difficult. But not the entire organism. So we want to fill in the gaps. Early on in our conversation,

we talked about how maybe we have a handful of evidence of life in the past. So we have a lot of gaps in between. And the gaps between data sets and evidences get more, they become narrower as we reach towards the presence, right, especially after the rise of oxygen, once the eukaryotes throws up, and then we see plants, and the rest is easier and easier. We have more and more evidence for life and maybe more diverse, too. But such, perhaps using the synthetic systems may enable us to fill in that gap in however artificial it is.

We need to just, again, make our assumptions and then learn to live with them, and be very honest with our shortcomings and what we are capturing and what we are missing. and hope that as technology and this mindset really settles in, we are able to fill in this gap evermore. And just to close the book on the Rubisco here, you seem to say that you've been successful so far at pushing back more than a billion years. So, you know, there's some applause that is required there,

but still not yet all the way back to the oxygenation event, and that's the goal? That's the goal. We are working on it. We are also, as you know, moving our lab. So it's a, we looked at, we froze everything, we put them in the freezers and just sort of looking at how significant it is that we might be storing a tiny piece of Earth's history in our freezers.

That's important. Well, so let me just give you the opportunity to say, I really enjoyed the Rubisco story that I read about on your website, but what other kinds of things are you trying to learn from these techniques. I mean, are there other proteins you're trying to make, other events you're focusing in on? Yeah. So another question we are interested in, aside from sort of what the rise of oxygen embedded on proteins like Rubisco is understanding how proteins respondent elemental changes in ancient

oceans and how we can use enzymes to sense the paleo environments. So that's a bit more focused on nitrogen fixation and molybdenum amounts in the different iron levels and how they may have impacted enzyme change. So I think this is sort of a concept. When you think about it, it's no-brainer that we can use enzymes as a proxy to understand early earth. But again, it's a concept that doesn't yet really exist. So that's really where we are going with this. Owning a home is full of surprises.

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That's homeserv.com. Not available everywhere. Most plans range between $499 to $11.99 a month your first year. Terms apply on covered repairs. Yeah, you mentioned molybdenum earlier, and biologists love molybdenum, and apparently it's very, very necessary. So maybe this is a slight tangent, but should we be surprised that as bizarre an element as malibdinum is that important to life? Is it that life is opportunistic and noticed that there was some molybdenum around that was really useful? Or is this another aspect in which we're really lucky?

that malibdenum exists because otherwise life would not be possible. So this is a very good point. And you're almost quoting my first sentence in the new proposal that was funded by NASA. That we don't know. And we called it what does life wants, right? So we don't know how life ended up selecting these certain elements. Is it because they were, as you said, available in the environment and there was abundant amount of these elements around?

and that's hence life picked them because of convenience versus whether there were different evolutionary forces in charge that may have not been directed by the environmental abundance that we have yet to explore. So I always say this, that we need to not judge biology by the cover. And it's a similar thing when we look at the environment. It's easy to say that there was a lot of molybdenum, Therefore, we see molybdenum in early life.

But that's not true, actually. Mollibdum wasn't high. And yet we see these enzymes that we desperately need to fix the nitrogen in the atmosphere need these metals. So how did this happen? And that's one of our latest findings that we reconstructed molybdenum-depending enzyme nitrogenase. And we think we traced all the way back to its origins, which is about 2.5 billion years. It's not quite clear when that this enzyme emerge.

But we find that the enzyme actually preferred molybdenum early on as well, even though geologists tell us that early oceans did not have high, weren't high in the molybdenum amounts. So that already tells you that it's not a simple just-so story that this wasn't the environment, therefore life picked it. But we tend to go there. And again, maybe we needed to start from somewhere.

But the story is very complicated when evolution gets involved. Yeah, no, the story is very complicated, which reminds me of another thing I wanted to emphasize. Again, it has been implicit in a lot that you've already said, that what you're doing is much more rich in context-dependent than just tracing DNA through time. Like you keep mentioning these physical and geological events that played a big role, right? And so to do what you do, you need to constantly be going back and forth between phylogenetic trees and fossils and all these things.

And all of these stories need to be told together, right? Exactly. I mean, so this is why our news center, and we named it muse, it's metal utilization and selection across eons, is going to be bringing together bio. a handful of biologists, but mostly geologists and environmental microbiologists and physicists and astronomers. Because clearly, and if geologists, if it was listening to me, maybe thinking, oh, my gosh, you missed a complete picture in geology. And it's true. I did. And, you know, it's so this is a very complicated, intertwined problem, understanding. You're trying to understand an entire planet that

existed billions of years ago. So it does require all hands of. on deck and all kinds of expertise that will correct when maybe a poor little biologist makes all these assumptions or a chemist misses the entire picture of the power of natural selection. So it's funny because tomorrow actually we are having our first meeting as a group and we will have about 20 professors from all of these fields only talking about metals and how they see what they see. And we specifically ask them to keep it very top level so that we all communicate with each other.

You know, especially for non-scientists, and I was like this before I became a scientist that I thought there's a sort of universal science language. I guess there is one. Sadly. But other than that, it's really divided. And for problems like this, the challenge is to break down those walls

and enable communication. across these different disciplines. It is harder than you think. No, oh, no, it's not harder than I think. It might be harder than one thing, but I've also tried, and it's very, very hard. Which reminds me of an example of this, because you use the word metals, and I bet that for a lot of people, they think of like a chunk of metal, right? Like a chunk of iron or a wire or something like that.

So what's so special about metals that we should devote a new center to their use in biological history. Well, you know, they are supply, they supply almost all the metabolic functions. They are the intermediaries that enable almost all life components to do their job, right? They, they do all kinds of cool chemistry. They convert reactives to some other product. So they enable all this catalysis. And so if you remove them from the picture, most, uh, for, functions just they will collapse, right? So it is, this is why life is a chemical system and elements are the building blocks of this. And we also think that understanding the elemental composition of a planet is so important that it may even tell us clues about the habitability of that planet.

So we know life relies on about 30 different elements here and common and shared. We know these six of them, this Schnapps cocktail that astrobiologists like to call carbon, hydrogen, nitrogen, oxygen, sulfurous. So this cocktail is important for life. We see it as an essential. And then there's all these ancillary elements. But we don't yet know how important it was that life distilled out of all the available metals and elements this selection, whether it was essential and necessary. or it's just chemically made sense, which may make it more universal, we don't know.

So that's an interesting problem. And also why we will see more and more characterization of different planets at their metal and elemental level. So I'm thinking like a cosmologist now, or even a multiverse cosmologist. You know, if we lived in a universe where the laws of physics allowed for a periodic table with 20 or 30 elements.

You could certainly make most, by mass, you know, most organic compounds, right? Carbon and hydrogen with little bits of oxygen and nitrogen, et cetera, in there, sulfur. But what you're saying is that real life here on Earth has also all these heavier things, iron and molybdenum and potassium or whatever. Potassium's not so heavy, but you know what I mean. And it really seems to rely on that. Like maybe it couldn't have worked in any interesting way if it weren't for all of those different abilities to choose a different atom here or a different atom there to make some fun kind of enzyme.

Yeah, it's all about life's battery, right? And how you push energy from one level to the other and how you need that difference between two different states of maybe two elements or whatever molecular system that you're looking. And that's, the battery is everything, right? So, and how you feed that is when it comes to, it all comes down to coordination chemistry and physical chemistry. And even when you look at enzymes like Rubisco or photo enzymes or all kinds of other early systems that Mike Russell's favorite, you know, or do we look at the methanogens, whatever the enzyme is important for a certain chemistry or sulfur chemistry, it always comes down to physical coordination, physical chemistry and physics.

It's really true because life prefers lighter isotopes because of biophysics. So it is definitely really cool if you drill it down. And there are some people who look at the quantum states of this, quantum chemistry of early life and try to understand whether this sort of chemical coordination had anything to do, what sort of physical constraints were active. on what enzymes speak. So that's definitely a big field right now, but some people are trying to apply that to early life as well. And we welcome them. No, no, yeah, everyone is welcome. I mean, does learning, does what we've learned from your sort of paleo genomics help us think about

life on other planets in our one universe, both whether it exists and how to look for it? So we want to be ready when enough data arrives to our, in our, to our hands. So I wouldn't say that we are there yet in terms of connecting ancient planets to different planets out there. So we can start with our solar system. Definitely learning about, say, Mars will enable us to understand our own planet's ancient past, for sure. Right? Because Mars is not as rich. Our planet has a rich chemistry than Mars. That is not to say that Martian conditions won't allow us to understand our early history.

So we have a nice control system in our neighborhood. But when it comes to exoplanets, we will be able to understand the chemical composition of these planets, especially the atmospheric composition over the next decade. The technology is going towards there. So even though there is not going to be a smoking gun that, okay, give me nitrogen and give me molyptanum, And I think you will have this, the chance of this planet harboring life or the habitability chances are 40%. We are not there yet. We don't have an equation like that.

But every decade, we will get there, I think, for every decade of research, each decade will get us there. And we want to be ready, right? Because we tend to treat, we think, okay, there's an equals one problem, there's one life, there's one sample, this is a problem. But that's actually not quite true. Our past is itself an alien planet. As you also ask me, right, the early planet we are looking at a place that is completely different than us. It's not, I look at outside the window now I see, well, I'm in desert. So it's a, you know, I see quite actually maybe similar.

But there's no trees. You're not looking at mountains. You know, you're not looking at this. The landscape is completely different than what you see. atmosphere is different. The chemical composition is different. So who is to say that? That is an equals one. Yet we miss a big opportunity if we don't truly understand this extra sample that our planet processed through once in the past. So to wind things up, I have to ask you a philosophy question. And it's not entirely my fault. It's your fault because you wrote a provocative article

in Eon about exactly this philosophy question. Of course, we're looking for life elsewhere. and whether or not we find it will probably go there ourselves. But you made an interesting suggestion that we could just seed the possibility of life elsewhere on other planets. Forget about sending actual living things or even people. We could like send the chemistry to other planets and let life evolve there. And if we could do that, should we do it, I guess is the question. Yeah. So this is a thought experiments.

I just boldly went there. So it is very likely that we will have a particular solution to life's origins in our hand. I think it may be a general solution that could lead to a general solution to understanding or rather assessing how far along any planet that we are looking at is to reaching that threshold of chemistry transitioning into biology. So this may mean that we may reach a general solution that will allow us to connect the dots between non-living and living anywhere in the universe. So we are talking about perhaps knowing what a planet that we are studying is missing in order to make that transition. I think this is not to say that we should do it, but I wanted to pose that we will have this ability, perhaps, once we understand,

of storage because this is what it will mean. And this is not about spreading our life out there. This is not about colonizing different planets. This is actually empowering them and giving them that maybe nudge that they might be missing themselves towards that threshold. And maybe a nudge that will turn into reality over millions of years of time. And should we do it was the question just because we can. And that's really the, I guess, cracks of that article.

Yeah. And what is the answer? So I think here's an important thing. What we have is very special. And this is beyond our presence here, that there is a very interesting chemistry. There's a very interesting chemistry that's going on on this planet that so far we know did not happen anywhere. and it may be important to think that we may want to protect this chemistry and save it. And this is, again, not to say that we should go plant a tree on Mars or build a skyscraper.

I'm talking about something more bigger than that, actually. It's more about backing up life's chemistry. And, yeah, I think it's just, again, the capability of unlocking life. under a broader area of circumstances, and that's the knowledge that we're getting to. I know I'm dancing around your question. No, I think actually you're secretly convincing me the answer is yes. I think we should do it.

You know, if you came across the planet where you really didn't have any, you're very, very, very sure that there wasn't already life there, right? Yes, we need to be very sure that there's not a quality life there. And we need to understand them well, right? So instead of imposing our own life over there, this is more about, an important thought exercise, given that what we did to, you know, in a way on this planet,

to different cultures, without completely understanding them. So this is really appreciating what we are studying and understanding it before even thinking about meddling. And this is, again, not about seeding these planets with Earth's life. This is not terraforming. It is not panspermia. I called it proto-spermia. that again, so it's this sort of empowering the capacity of these planets to express their own unique forms of life that are not genetically related to or look nothing like us.

And so it's almost like a kickstart project for thousands or millions of years into the future that is spreading a biotic potential, not the actual architecture. And I think when we talk about we're going to say what we have, such exercise may allow us to think about how unique it is what we have here. I think perhaps understanding origin of life or studying that alone gives you that humility as well. It's overwhelming what we are not able to do and overwhelming to see what life achieved and continue to do so here if we don't destroy it ourselves, as Hagen said, that's, you know, and maybe studying these problems and really thinking about these exercises may give us that sense of protecting what we have a little better. No, that's very important.

But in a much more frivolous vein, it does not, it's not possible to then resist wondering whether this happened to us, whether life on Earth was, you know, poked along by a Prometheus kind of way. That's true. And that's also, you may remember the episode from Star Trek, of course. But it's also, yeah, you may want to ask yourself, we are live and that does life, we are a chemical system capable of formulating and maybe sometimes answering questions about its own existence, right? Or itself, do we have a responsibility or should we have a prohibition against spreading more of this? Yeah. And this is important to ask ourselves. And of course, is there an ethical difference between spreading a particular form of life or spreading a capacity? And where is that difference?

I'm not the person to answer these things. I don't study space ethics. But I think it's a useful exercise. You can ask them, yeah. And sorry, I'm just, you know, my imagination is running now. I mean, forgetting about starting life, maybe ancient astronauts, as it were, came along and said, you know, life on this planet is going, but it's kind of stuck. It needs a little help.

So let's oxygenate the atmosphere because otherwise it'll never really be able to do good metabolism. Well, that would certainly make it interesting X-Files episode. And with that, I think that we've reached about as far as we could take this. So Beto Kachar, thanks so much for being on the Mindscape podcast. This was wonderful. Thank you so much for having me.