Betül Kaçar: Origin of Life, Ancient DNA, Panspermia, and Aliens | Lex Fridman Podcast #350

1. 0:00 – 0:56

   Introduction

   1. BKBetül Kaçar0:00

      You can study chemistry, you can study physics, you can study geology anywhere in the universe, but this is the only place you can study biology. This is the only place to be a biologist.

   2. LFLex Fridman0:09

      Earth.

   3. BKBetül Kaçar0:09

      That's it.

   4. LFLex Fridman0:10

      Yeah.

   5. BKBetül Kaçar0:10

      So, so, definitely something very fundamental happened here, and you cannot take biology out of the equation. If you want to understand how that vast chemistry space, how that general sequence space got narrowed down to what was, what is available or what is used by life, you need to understand the rules of selection. And that's where evolution and biology comes into play.

   6. LFLex Fridman0:36

      The following is a conversation with Betul Kacar, an astrobiologist at University of Wisconsin, studying the essential biological attributes of life. This is the Lex Fridman Podcast. To support it, please check out our sponsors in the description, and now, dear friends, here's Betul Kacar.

2. 0:56 – 9:00

   History of life on Earth

   1. LFLex Fridman0:56

      What is the phylogenetic tree, or the evolutionary tree of life, and what can we learn by running it back and studying ancient gene sequences as you have?

   2. BKBetül Kaçar1:05

      I think phylogenetic trees could be one of the most, uh, romantic and, um, beautiful notions that can come out of biology. It shows us a way to depict the connectedness of life and all living beings with one another. It itself is an ever-evolving notion. Biologists like visualizations. They like these graphics, these diagrams, and tree of life is one of them.

   3. LFLex Fridman1:33

      So, the tree starts at a common ancestor.

   4. BKBetül Kaçar1:36

      It's actually the other way around. It starts (laughs) from-

   5. LFLex Fridman1:39

      At the end? (laughs)

   6. BKBetül Kaçar1:39

      It starts from the, um, from the branches. It starts from the tip of the branch, actually, and then, uh, you f- do further, d- depending on how, what you collected, uh, to build the tree. So, depending on the branches, depending on what's on the tip of the branch, and I will explain what I mean, the root will be determined by what is really sitting on the tip of the branch of the tree.

   7. LFLex Fridman2:01

      So, we could study the leaves of the tree by looking at what we have today and then start to, uh, reverse engineer it, start to move back in time to try to understand what the rest of the tree, what the roots of the tree look like?

   8. BKBetül Kaçar2:11

      Exactly. So, the tree itself, by just taking a few steps back and looking at the entire tree itself, can give you an idea about the connectedness, the relatedness of the organisms, or whatever, again, you use to create your tree. There are different ways. But, I mean, in this case, I'm imagining entire diversity of life today is sitting on the tips of the branches of this tree. And we, um, look at, biologists look at the, the tree itself. We like to think of it as the topology of the tree, to understand when certain organisms or their ancestry may have merged over time. Depending on, uh, the tools you use, you might use this tree to then reconstruct the ancestors as well.

   9. LFLex Fridman3:02

      And so, what are the different ways to do the reconstruction? So, you can do that at the gene level, uh, or you could do it at the higher complex biology level, right? So, what, what, i- i- in which way have you approached this, this fascinating problem?

   10. BKBetül Kaçar3:17

       We approached it in every way we can. So, it's the gene, could be protein, the product of the gene, or species, uh, or could be even groups of species. It will depend, it totally depends on what you want to do with your tree. If you wanna understand a certain past events, whether an organism exchanged a certain DNA with another one along the course of evolution, you can build your tree accordingly. If you, um, rather use the tree to reconstruct or resurrect ancient DNA, which is what we do, um, then, uh, i- in our case, for instance, we do both gene, protein, and species, because we want to compare the tree that we create using these different information.

   11. LFLex Fridman4:02

       Okay. Well, let me ask you the ridiculous question then. So, how realistic is Jurassic Park? (laughs) Can we study the genes of ancient organisms, and can we bring the, those ancient organisms back? So, the reason I ask that kind of ridiculous sounding question is, um, maybe gives us context of what we can and can't do-

   12. BKBetül Kaçar4:21

       Yeah.

   13. LFLex Fridman4:21

       ... by looking back in time.

   14. BKBetül Kaçar4:23

       Yeah. So, um, dinosaurs, or all these mammals, in, in, in at least for us-

   15. LFLex Fridman4:28

       Mm-hmm.

   16. BKBetül Kaçar4:28

       ... is the exciting thing already happened by the time we hit to, uh, larger organisms or to eukaryotes.

   17. LFLex Fridman4:36

       Oh, to you, the fun stuff is before we got to the mammals?

   18. BKBetül Kaçar4:39

       The fun stuff is what people think is boring, I think. The, the, the, the phase that's, uh, well, there's two different times in the geologic history. One is the first life, uh, past origin of life, how the first life looked like.

   19. LFLex Fridman4:52

       Mm-hmm.

   20. BKBetül Kaçar4:53

       And the second is, why do we think that over certain periods of geologic time, no significant innovation happened to the degree of leaving no record behind?

   21. LFLex Fridman5:05

       So, what do we not have a record of? Which pa- which part? So, you say, y- uh, the fun stuff to you is after the origin of life, which we'll talk about, after the origin of life, there's single-cell organisms, the, the whole thing with the photosynthesis, the whole thing with the eukaryotes, and, uh, multi-cell organisms, and, uh, what e- what else is the fun stuff? The whole oxygen thing, which mixes in with the origin of life. Uh, there's a bunch of different inventions, all they have to do with this primitive kind of looking organisms. That, we don't have a good record of?

   22. BKBetül Kaçar5:38

       So, I will tell you the more interesting things for us.

   23. LFLex Fridman5:41

       Sure.

   24. BKBetül Kaçar5:41

       One is the origin of life, or what happened, uh, right following the emergence of life. How did the first cells look like? And then, pretty much anything that we think shaped the environment and ver- was shaped by the environment in a way that it impacted the entire planet-

   25. LFLex Fridman6:01

       Mm-hmm.

   26. BKBetül Kaçar6:01

       ... that enabled you and I to have this conversation.We have very little understanding of the biological innovations that took place in the past, of this planet.

   27. LFLex Fridman6:11

       Mm-hmm.

   28. BKBetül Kaçar6:11

       We work with a very limited set of, um, I don't wanna even say data, because they are fossil records. So let's say imprints, either that comes from the rock and the rock record itself, um, or what I just described, these trees that we create and whatever we can infer about the past. So we have two distinct ways that comes from geology and biology, and they each have their limitations.

   29. LFLex Fridman6:40

       Okay, so... (laughs) All right. Right, so there's an interplay be- th- the geology gives you that little bit of data, and then the biology gives you that little bit of kind of constraints in the materials you get to work with to infer, "How does this result in the kind of data that we're seeing?" And now we can have this, through the fog, we can see, we can look back hundreds of millions of years, a couple of billion years, and try to infer.

   30. BKBetül Kaçar7:07

       Even further, and, and I like that you said fog. It is pretty foggy, what we are do- and it gets foggier and foggier the, the, the more you, the further you try to see into the past. Um, biology is you, you basically study the, study the survivors-
3. 9:00 – 31:47

   Origin of life

   1. LFLex Fridman9:00

      study bacteria. So which organisms gives you hints, that are alive today, they give you, um, hints about what ancient organisms were like? Is it bacterias or viruses? What do you study in the lab?

   2. BKBetül Kaçar9:12

      We study variety of different bacteria, depending on the questions that we ask. We engineer bacteria, uh, so ideally, we wanna work with bacteria that we can engineer, um, seldom we developed the tools to engineer them. And, um, it depends on the question that we are interested in. If we are interested in connecting the biology and geology, uh, to understand the early life and, and fundamental innovations across billions of years, there are really good candidates, like cyanobacteria. So we, we use cyanobacteria, uh, very frequently in the lab. Uh, we can engineer its genome. We can perturb its function by poking its own DNA with the foreign DNA that we engineer in the lab. We work with E. coli. Um, it's the most simple in, in terms of model systems go- goes, uh, organism that one can study, well-established, uh, sort of a pet, lab pet, uh, that we use it a lot for cloning and for understanding, uh, basic functions of the cell given that it's really well studied.

   3. LFLex Fridman10:20

      So, and then what you do with that E. coli, you said that you inject it with foreign DNA?

   4. BKBetül Kaçar10:25

      We inject pretty much all the bacteria that we work with with foreign DNA. We also work with diazotrophs. These are azotobacteria. Uh, they're one of the prime nitrogen fixers, uh, nitrogen-fixing bacteria, um-

   5. LFLex Fridman10:39

      Can you explain what that is, nitrogen fixing? Is that, is that the source of its energy?

   6. BKBetül Kaçar10:43

      So nitrogen is a triple bond gas that's pretty abundant in the atmosphere, but nitrogen itself cannot be directly utilized by cells given it is triple bound. Um, it needs to be converted to ammonia that is then used, uh, for the downstream cellular functions.

   7. LFLex Fridman11:04

      And that's what counts as nitrogen fixing-

   8. BKBetül Kaçar11:07

      Yes, so nitrogen needs to be fixed-

   9. LFLex Fridman11:09

      ... converts it to ammonia.

   10. BKBetül Kaçar11:09

       ... before our cells can make use of it, and, and it's, uh-

   11. LFLex Fridman11:13

       No offense to nitrogen either.

   12. BKBetül Kaçar11:14

       Well, uh, it's actually a very important element. It's one of the most, uh, abundant elements on, on, on our planet that is used by biology. It's in ATP. It's in chlorophyll, um, that, uh, uses, uh, that relies on nitrogen, uh, so it's a very important enzyme for a lot of cell functions.

   13. LFLex Fridman11:34

       And there's just one mechanism that evolution invented to convert it, to fix it?

   14. BKBetül Kaçar11:39

       It is... So far we know, there is, there is only one nitrogen fixation pathway, as opposed to, say, carbon, you can find up to seven or eight different carbon ways, uh, microbes invented to fix carbon. That's not the case for nitrogen. It's a, it's a singularity across geologic time. We think it evolved around 2.7 maybe, um, roughly three, probably less than three billion year old, bi- billion years ago.... and that's the only way that nature invented to fix the nitrogen in the atmosphere for the subsequent use.

   15. LFLex Fridman12:12

       Would we still have life as we know it today if we didn't invent that nitrogen-fixing step?

   16. BKBetül Kaçar12:17

       I cannot think of it, no. It's, it's, uh, it's essential to life as we know. You, you and I are having this conversation because life found a way to fix nitrogen.

   17. LFLex Fridman12:27

       Is that one of the tougher ones? If you put it, sort of, uh, oxygen, nitrogen, carbon, what, what are, in terms of being able to work with these, uh, elements, what is the hardest thing? What is the most essential for life?

   18. BKBetül Kaçar12:45

       Mm-hmm.

   19. LFLex Fridman12:45

       Just to give context-

   20. BKBetül Kaçar12:46

       Well, we, we think of this as the cocktail you may hear, schnapps.

   21. LFLex Fridman12:49

       What, what's in the cocktail?

   22. BKBetül Kaçar12:50

       It's the schnapps, right? Carbon, hydrogen, oxygen, nitrogen, sulfur. So there are five elements that life relies on. We don't quite know, uh, whether that's the only, out of many options, that, um, life necessarily needs to operate on, but that's just how it, how it happened on our own planet.

   23. LFLex Fridman13:10

       Mm-hmm.

   24. BKBetül Kaçar13:10

       And, um, there are many abiotic ways to fix nitrogen, uh, and, like, lightning, right? Lightning can, uh, accumulate, uh, ammonia. Uh, humans found a way about 100 years ago, uh, I think around, uh, World War I. Um, the Haber-Bosch process that we can abiotically convert nitrogen into ammonia. M- actually 50% of the nitrogen in our bodies comes from the human, um, conversion of nitrogen to ammonia. It's helped... Uh, it, it's the fertilizer that we use, urea, comes from that process. Uh, it's, it's in our food. So we helped, we found a way to, uh, fix our own nitrogen for ourselves.

   25. LFLex Fridman13:55

       Yeah. But that, you know, that's way after the original invention of how-

   26. BKBetül Kaçar13:59

       Oh, absolutely.

   27. LFLex Fridman14:00

       ... to fix nitrogen.

   28. BKBetül Kaçar14:01

       Absolutely.

   29. LFLex Fridman14:01

       And without that, we wouldn't have, we wouldn't have all the steps of evolution along the way.

   30. BKBetül Kaçar14:06

       Oh, absolutely. It's very... We tried to replicate in the most simplest way what nature has come up with, right? We do this by taking nitrogen, using a lot of pressure, and then generating ammonia. Life does this in a more sophisticated way, relying on one single enzyme called nitrogenase. It's the nitrogen that is used together with eight electron donor and ATP, together with, uh, a lot of hydrogen. Life pushes this metabolism down to create fixed nitrogen. It's quite remarkable.
4. 31:47 – 44:43

   Genetic language of life

   1. BKBetül Kaçar31:47

      So you're looking at, um, like, this is life's alphabet, right? And so I, I also wanna make a very quick link now to your first question, the tree of life. Um, when, when we link, when we try to understand ancient languages, right, or the cultures of the, the... or the cultures, uh, that use these extinct languages, we start with the modern languages, right? So we look at, um, Indo-European languages and, and try to understand certain words and make trees, um, to understand, you know, this, this is what, uh, Slavic, uh, word is for snow, something like snig.

   2. LFLex Fridman32:25

      Now, we jumped to languages that humans spoke.

   3. BKBetül Kaçar32:27

      Humans spoke.

   4. LFLex Fridman32:28

      Human history.

   5. BKBetül Kaçar32:28

      Exactly. So we make trees to understand what is the original ancestor, what did they use to say snow? And if you have a lot of cultures who use the word snow, you can imagine that, uh, it was snowy, that's why they needed that word. It's the same thing for biology, right?

   6. LFLex Fridman32:46

      Yeah.

   7. BKBetül Kaçar32:46

      If, if they have some... if we understand some function about that enzyme, we can understand the environment that they lived in. It's, it's the similar... it's similar in that sense. So now you're looking at the alphabet for, of life. In this case, it's not 20 or 25 letters. It's... you have four letters. So what is really interesting that stands out to me when I look at this, on the outer shell, you're looking at the 20 amino acids that compose life, right? The one, the methionine that you see, that's the start. So the start is always the same.

   8. LFLex Fridman33:21

      Got it.

   9. BKBetül Kaçar33:21

      To me, that is fascinating, that all life starts with the same start. There's no other start code. So you send the, uh, AG, you know, AUG to the cell that when that information arrives, the translation knows, "Right, I gotta start. Function is coming." (laughs)

   10. LFLex Fridman33:37

       (laughs)

   11. BKBetül Kaçar33:37

       The... Following this is a chain of information, until the stop code arrives, which are highlighted in black squares.

   12. LFLex Fridman33:46

       So for people just listening, we're looking at a standard RNA-colored table organized in a wheel. There's an outer shell and there's an inner shell, all using the four letters that we're talking about. And with that, we can compose all of the amino acids. Then there's a start and there's a stop. And presumably, you put together the, the... with these letters, you walk around the wheel to put together the words, the sentences that make-

   13. BKBetül Kaçar34:10

       Yeah, the words, the sentences. And, um, you, uh, again, you get one start, you get three st- there are three different ways to stop this, one way to start it. And for each letter, you have multiple options. So you, say, have a code A, the second code can be another A, and even if you mess that up, you still can rescue yourself. So you can get a... for instance, I'm looking at the lysine K, you get an A, and you get an A, and then you get an A, that gives you the lysine.

   14. LFLex Fridman34:39

       Mm-hmm.

   15. BKBetül Kaçar34:40

       Right? But if you get an A, and if you get an A and get a G, you still get the lysine.

   16. LFLex Fridman34:44

       (laughs)

   17. BKBetül Kaçar34:44

       So th- there are, uh, different combinations. So even if there's an error, we don't know if these are selected because they were e- err- erroneous and somehow they got locked down. We don't know if there's a mechanism behind this to... or we, we certainly don't know this definitively. But this is informatic, uh, part of this, and notice that the, the colors, and in some tables too, the colors will be coded in a way that, um, the, the type of the nucleotides can be similar chemically. Uh, but the, the point is that you will still end up with the same amino acids or something similar to it, even if you mess up the code.

   18. LFLex Fridman35:20

       Do we understand the mechanism, how natural selection interplays with this resilience to error?

   19. BKBetül Kaçar35:28

       So-

   20. LFLex Fridman35:28

       Which errors result in the same, uh, output, like, the same function and which don't, uh, which actually results in a dysfunction or which are...

   21. BKBetül Kaçar35:40

       We understand, to some degree, the... how translation and the rest of the cell work together-

   22. LFLex Fridman35:46

       Yeah.

   23. BKBetül Kaçar35:47

       ... how an error at the translation level, this is a really core level, can impact entire cell. But we understand very little about the evolutionary mechanisms behind the selection of the system. It's thought to be as... one of the hardest problems in biology. And it is still the dark side of biology. We... even though it is so essential. So th- this is, uh, yeah, you're looking at the language of life, so to speak, and h- how it's can... found ways rather to tolerate its own mistakes.

   24. LFLex Fridman36:24

       So the entire phylogenetic tree...... can be like, uh, deconstructed with this wheel of l- language.

   25. BKBetül Kaçar36:33

       Because all the final letters, those are, that's the 20 amino acids. That's our alphabet.

   26. LFLex Fridman36:38

       Yeah.

   27. BKBetül Kaçar36:38

       They are all brought together with these bits of information, right? So you, when you look at the genes, you're looking at those four letters. When you look at the proteins, you're looking at the 20 amino acids. Uh, which may be a little easier way to track the information when we create, uh, the tree.

   28. LFLex Fridman36:56

       So using this language, we can describe all life that's lived on Earth?

   29. BKBetül Kaçar37:01

       Uh, I wish.

   30. LFLex Fridman37:02

       It's one- one perspective.
5. 44:43 – 55:26

   Life and energy

   1. BKBetül Kaçar44:43

      going- going back to the biological component, um, all of these attributes that we think about life or that we associate with biology stems from translation and as well as metabolism. But I see metabolism as a way to keep translation going, and translation keeps metabolism going, but translation is arguably a bit more sophisticated process for the reasons that, um, I just described.

   2. LFLex Fridman45:14

      So metabolism is a source of energy for this translation process?

   3. BKBetül Kaçar45:17

      It's a, it's a pr- it's a way to process materials, uh, and it is inherently dynamic, and it is, um, flexible, but it is not focused on repet- repetition as translation does. So that's the main difference. Translation is the kind of in a way just repeats, right? So you have the metabolism that can synthesize materials, i- it creates or benefits from available energy, and again, it's a dynamic system, um, and then you have computation that it, that is inherently, uh, repetitive, right? Needs to carry out repetitive processes, uh, it, and it does the tasks, and it's, it implements an algorithm, but it is not dynamic. So you see both of those attributes in translation combined. It is repetitive, and it is dynamic, uh, and it also processes this information, so they are fundamentally different. I don't know if you can get, um, life if- if you don't find a way to process the information around you.

   4. LFLex Fridman46:19

      In a repetitive, dynamic way.

   5. BKBetül Kaçar46:21

      Yeah, and somehow that- that's what's, uh, got, um, selected. Ma- maybe not selected. I don't know if it was, um, accidental, but that- that's what seems to be conserved for four billion years, that that's what life established among.

   6. LFLex Fridman46:35

      What- what's the connection between translation and the self-replication, which seems to be a- another weird thing that life just started doing, wanting to just replicate itself?

   7. BKBetül Kaçar46:45

      I think when we truly understand the answer to that question, we may have just made ourselves life, right? We, I don't think we know quite how translation machinery as a whole, uh, fits into equation, 'cause so f- we- we try to understand, um, ribosomes, RNA, how the linear information is processed, um, or the genetic code, why this co- codons, not others, why 20, not more, not less, uh, and we are sort of moving towards translation. That's- that's what we are working on anyway, uh, to finally look at the patterns in which this, uh, system operates itself, and y- and if you understand that, you're really unlocking a very emergent behavior.

   8. LFLex Fridman47:31

      Uh, one of the things you didn't mention is physical. Is there something to mention about that component that's interesting?

   9. BKBetül Kaçar47:37

      There's actually a paper, uh, published in 2013. I wanna say the first author was Zhirnov. Um, so they, uh, surveyed a computational, um, engineered systems level computation energy consumption, okay? And they tried to understand whether the universe is using its own, uh, or life is using its full capacity of energy consumption and whether, um, i- if different planets in the universe had life, would the c- uh, capacity would increase or decrease. Is- does life operate at its energy maximum? And, uh, and they think that it does, that it actually operates at an efficiency that is far more above and beyond any computational system.

   10. LFLex Fridman48:27

       How is that possible to determine at all?

   11. BKBetül Kaçar48:29

       That you tell me. That's why I dropped the citation.

   12. LFLex Fridman48:32

       Yeah.

   13. BKBetül Kaçar48:32

       I- I found the citation. It's quite an interesting paper. It's a bit, you know, it's a, um...... uh, and it's, uh, obviously you can only calculate and infer these things. Uh, but, uh...

   14. LFLex Fridman48:43

       That's a good question to ask. Is the life that we see here on earth and life elsewhere in the universe, is it using the energy most efficiently?

   15. BKBetül Kaçar48:54

       Yeah. Yeah. I- I...

   16. LFLex Fridman48:55

       It seems to be very efficient. A- again, if we compare it to computers, it seems to be incredibly efficient at using energy.

   17. BKBetül Kaçar49:01

       Yeah. I think they, they look at the, like, the theoretical optimum for electronic devices.

   18. LFLex Fridman49:05

       Got it.

   19. BKBetül Kaçar49:06

       And then try to understand, uh, where life falls on, on this. And life is certainly more efficient.

   20. LFLex Fridman49:12

       And that's ultimately the physical side, how well are you using for this entire mechanism the energy available to you. And, um, so given, given all the resilience to errors and all that kind of stuff, it seems that it's close to its maximum.

   21. BKBetül Kaçar49:25

       Yep.

   22. LFLex Fridman49:26

       And this, this paper aside, it does seem that life, obviously, that's the constraint we have on earth, right, is the amount of energy.

   23. BKBetül Kaçar49:35

       Yeah.

   24. LFLex Fridman49:36

       So that's one way to define life. Well, the input is energy, and the output is what? I don't know. Self-replicating... Wait, how, okay, let's go there. How do you, how do you personally define life? Do you have a, do you have a favorite definition that you try to sneak up on?

   25. BKBetül Kaçar49:58

       Um...

   26. LFLex Fridman49:59

       Is it possible-

   27. BKBetül Kaçar50:00

       I-

   28. LFLex Fridman50:00

       ... to define life on Earth?

   29. BKBetül Kaçar50:02

       I don't know. It depends on what you are defining it for. If you're defining it for finding different life forms, then i- it probably needs to have some quantification in it, so that you can, um, use it in, in whatever the mission that you're operating to more like-

   30. LFLex Fridman50:19

       So you mean, like, it's not binary, it's, uh, it's, like, a seven out of ten? U- uh, and, uh, l- l-
6. 55:26 – 1:14:24

   Ancient DNA

   1. BKBetül Kaçar55:26

   2. LFLex Fridman55:26

      Well, actually, let me ask you about selection. You have a paper, uh, on evolutionary stalling, where you describe that evolution is not good at multitasking. Or like, uh, in, uh populations that have evolved quickly. I mean, it's a very specific thing, but there could be a generalizable fundamental thing to this, that evolution is not able to improve multiple modules simi- simultaneously. Uh, I guess the question is, um, what part of the organism does evolution, quote unquote, focus on to improve?

   3. BKBetül Kaçar55:58

      Hmm. Yeah, that was the driving question. We, um, meddled with the part we shouldn't be messing up, the translation. This is the...

   4. LFLex Fridman56:07

      Should or should not?

   5. BKBetül Kaçar56:08

      You shouldn't. Uh, as I said, there are many ways to break it and, uh, all life needs it, so-

   6. LFLex Fridman56:13

      That's one of the thi- your favorite things to do is to break life to see what happens.

   7. BKBetül Kaçar56:19

      It's the, uh, yeah, because that's how kids learn, right? So you have to break something-

   8. LFLex Fridman56:23

      Yeah.

   9. BKBetül Kaçar56:23

      ... and see how it will... Then you do it over and over again to see if it will fix itself in the same ways.

   10. LFLex Fridman56:29

       Yeah.

   11. BKBetül Kaçar56:29

       So that's, it's our, I don't know, it's the most fundamental properties of our- ourselves as human beings. So if we shouldn't break translation, then we should try to break it-

   12. LFLex Fridman56:38

       Yes.

   13. BKBetül Kaçar56:38

       ... to see how it will repair.

   14. LFLex Fridman56:39

       So which part did you break?

   15. BKBetül Kaçar56:41

       I broke elongation. So, uh-

   16. LFLex Fridman56:43

       What, what, what's the role of elongation in this process?

   17. BKBetül Kaçar56:46

       So, the, we, we have, uh, four steps of the, of the transitions, initiate, elongate, so it elongate the chain of the, the information chain that you're now creating, the peptide chain, uh, uh, or let's say broadly, polymer chain. Um, and there's the termination step and there's the recycling. So all of these com- steps are carried out by proteins that are also named after these steps. Initiation is the initiation factor protein. Elongation is the elong- elongator protein. Um, we, um, broke elongation. So the cell, the starting codon could still arrive to where it's supposed to go. But the following information couldn't get carried out because we replaced elongation with, uh, its own ancestral version. So we inserted roughly 700 million year old elongation factor protein after removing the modern gene. So we made this ancient modern hybrid organism.

   18. LFLex Fridman57:57

       And that essentially creates, in some way, the ancient version of that organism.

   19. BKBetül Kaçar58:02

       I wouldn't say so. It's the, it's a, it's a hybrid organism. It's not nece- because you, the rest of this cell, the rest of the, uh, genome is still modern.

   20. LFLex Fridman58:14

       Mm-hmm.

   21. BKBetül Kaçar58:14

       And that goes back to the difference between Jurassic Park. There are many differences, obviously, given that this is not fiction, we are doing it. But also, um, we are not necessarily, I think in Jurassic Park, they are taking an ancient org- they find an ancient organism and then put a modern gene inside the ancient organism.

   22. LFLex Fridman58:32

       Mm-hmm.

   23. BKBetül Kaçar58:32

       In our case, we are still working with what we got. But putting an ancestral DNA inside the modern organism.

   24. LFLex Fridman58:38

       So you're like taking a new car and putting a old engine into it?

   25. BKBetül Kaçar58:42

       In a way, yeah. Yes.

   26. LFLex Fridman58:43

       (laughs) And seeing what happens?

   27. BKBetül Kaçar58:45

       Yes. In, but in our case, the, it's more like Transformer than just a regular car. It is doing things.

   28. LFLex Fridman58:51

       (laughs) It's, yeah, so it's a more complicated organism than just a car.

   29. BKBetül Kaçar58:55

       Yeah.

   30. LFLex Fridman58:56

       Uh, I got it. So what does that, what does that teach you?
7. 1:14:24 – 1:25:55

   Evolution

   1. LFLex Fridman1:14:24

      let me ask the, the romantic question: Uh, how did evolution create so much beautiful complex variety on Earth? Like, from that, you're saying, like... We're talking about improving different modules, but if we step back and look at the entirety of the tree, of the different organisms that created all throughout history, the, the stuff that's fun to you with the, the, the first few billion, and the, the stuff that's fun to me when I watch on YouTube, which is like the, the lion versus gorilla fights and so on. Uh, but the whole thing is fun. So, all that beautiful variety, from the predator and the prey, uh, from the self-replicating bacteria and all that kind of stuff. How did it do it?

   2. BKBetül Kaçar1:15:04

      How is a very difficult question, especially when we don't understand, um, the past with clarity at all. I can tell you that there seems to be very critical innovations that happened throughout the history of life, uh, that are each themselves very sophisticated singularities that emerged once and then they set the tone. One of which is e- emergence of translation. It's... Seems like it happened once, it had to happen once. Seems like that's all it took. 3.8 billion year, maybe older. Clearly, um, subjected to a lot of chemical evolution even prior to last universal common ancestor. And then you jump and you see, um, e- emergence of cyanobacteria, that's undeniably changed the course of this planet and the subsequent aerobic, um, photosynthesis. That's life learned, uh, how to utilize what's available in its environment in the most profound way. And then you move forward, you see the emergence of eukaryotes, which is endosymbiosis. Also, another singular event. And then you move forward and in comes the plants. So, these are... I counted, I think, six different things that seems to have happened just once. And-

   3. LFLex Fridman1:16:33

      The singularity events in the history of evolution of life on Earth.

   4. BKBetül Kaçar1:16:37

      So, what's really fascinating here is that there seems to be two different courses. The time course. Evolution, or at the mo- is operating at the molecular level, right? We're talking about seconds. We're talking about mutations that happen every second. We're talking about selection that's also happening under a minute, right? So, that is very fast process. The fact that I can evolve bacteria in a lab and I say, uh, almost complainingly, "Oh my goodness, it took me 150 days." I mean, that's pretty rapid to, for, for a change to be seen. But then the big changes, and the ones that I'm talking, the really big innovations that increased, that caused an increase of oxygen on this planet, or even its own mere presence are due to these molecular innovations. Seems to only happen a handful of times over billions of years of time scale.

   5. LFLex Fridman1:17:29

      Let me ask you this question, having to do with my half-asleep Tweet. So, saying that we all originated from one common ancestor, um, that's just one of the miraculous things about life on Earth. Of course, you could say there's multiple common ancestors in the beginning, multiple organisms and so on. But the other stuff that you're talking about is this, these singular events, these leaps of invention throughout evolutionary history. Now, there's a bunch of people who were commenting, a bit surprising to me, who were basically skeptical of this idea.

   6. BKBetül Kaçar1:18:06

      The idea of?

   7. LFLex Fridman1:18:07

      Well, I would say evolution, honestly. The process of evolution. But when you just actually focus in on like, holy crap, uh, e- eukaryotes were invented. Holy crap, photosynthesis was invented. Like, those are incredible inventions. And also, we can even go to homo sapiens, like intelligence. Like, where did that come from? It's, it... There's these mysteries. I think where that skeptical comments were coming from were also just the general skepticism of science. I think, from the pandemic, people, maybe a failure of institutions and so on. Like, they, um... There's been a growing distrust of science. And it's not so, so much that it's anti-evolution. It's, it's more of a stepping back and saying, "Wait a minute. Maybe scientists don't have it all figured out." And I think, uh...... to steel man that case is almost a step back into realize there's so much mystery to each of these leaps, I- so it makes you wonder, "Is there something that in 100, 200 years we'll figure out that we totally don't understand yet?" Like some, uh, you know there's ... I, I talked to a bunch of people about another mystery which is consciousness, right? And there's people called panpsychists who believe consciousness is one of the fundamental laws of the universe. So there could be, um, you know, like we have laws of physics, there could be something that's like a consciousness field or something that permeates all matter. And so like there mi- might be, uh ... it's kind of like Newtonian physics versus general relativity. Like, we have a good understanding of how things happen, but we need another layer of understanding to fill in the gaps of the mysteries of it all. And that sort of is a sobering reality, that maybe there's something we really deeply don't understand. Do you have a sense of where the biggest mysteries here are? Is it the origin of life itself? Is it the leaps that we're talking about? So you, you see the beauty ... you're fascinated about the translational mechanism. Wh- what are the deep mysteries there to you?

   8. BKBetül Kaçar1:20:30

      We are n- nothing but chemical systems capable of, um, formulating or answering questions about our own existence.

   9. LFLex Fridman1:20:39

      We humans, or all of life, you think? Or no, no-

   10. BKBetül Kaçar1:20:43

       Humans. Humans are, uh ... I mean, the fact that we can, we even have this conversation about, uh, our, um, place in the universe is, is, at least to our knowledge, is quite specific to our own chemical species. But-

   11. LFLex Fridman1:21:00

       Yeah, it's kind of wild. We're, we're, we're, uh, introspecting on our evolutionary history, and we're just a couple of organisms.

   12. BKBetül Kaçar1:21:08

       Yes, and we're-

   13. LFLex Fridman1:21:08

       With like, another organism listening to this.

   14. BKBetül Kaçar1:21:11

       (laughs) .

   15. LFLex Fridman1:21:11

       And like, their mind blown. There's like three organisms, two of them talking and the third one's like, "Holy shit." (laughs) .

   16. BKBetül Kaçar1:21:20

       I, I think that understanding the ... what I really find interesting about understanding origin of life, or, or even contemplating about our own place in the universe, if at the end of this would come down to appreciating, uh, or even before appreciating, really truly comprehending what it is that we got here. Um, that to me is a huge gain. 'Cause there's no single question in biology, I think, that will give that ... th- that will deliver th- that magnitude of that message and understanding but understanding how life here started at first place. If, if we truly comprehend that. We ... this is not a concept that is well taught in schools. We ask students to memorize these concepts. May ... if, if they are lucky, they learned RNA world, chicken and egg problem, et cetera. That's the extent to which that go ... and maybe their biology teacher was personally interested in the subject matter. If they're lucky. You know the saying that the, the, uh, brain, brains are evenly distributed, uh, across any metric you can imagine, but opportunities are not. So if pe- people aren't understanding the importance of this is because that's a lack of opportunity right there. That's ... was skipped through proper education and training in the delivery of why science matters, or how science actually works.

   17. LFLex Fridman1:22:51

       Yeah, but how do you even begin to, uh, seriously think about the origin of life? I mean, uh, every problem of existence, of life, has its time. So I don't know if it's time to understand consciousness yet. We might be 100 years away from that. The origin of life, I don't know if it's time for us to understand that yet. Maybe we need to solve so many more problems along the way. And so ...

   18. BKBetül Kaçar1:23:22

       It's not a competition of problems, right? So there, there are all kinds of problems, and it takes a lot of people to make the world. So you will always have some interesting brain in- going after an interesting problem to

   19. NANarrator1:23:33

       (laughs) .

   20. BKBetül Kaçar1:23:35

       ... their own. The issue here is that we, we need to first of all understand that we ... what we have going on on this planet is pretty good. Good planets are hard to find. If we are ...

   21. LFLex Fridman1:23:47

       Yeah.

   22. BKBetül Kaçar1:23:47

       ... alone in the universe, that's, that's huge. We need to take care of what we got here. And y- we are incredibly vulnerable to the changes that our own species also helped create on, at the biosphere, at the ecosystem level. We take it for granted. We, we take what we created for granted because of the fact that we think we are some sort of ultimate end point, the most sophisticated amazing thing that nature could generate.

   23. LFLex Fridman1:24:17

       Yeah.

   24. BKBetül Kaçar1:24:17

       I think understanding th- and not even us understanding but asking these questions of where did this even come from, how did this even begin, and attempting to understand that using chemistry and physics and biology d- and because we can, that's the ultimate gift we can give back to the entire species on this planet.

   25. LFLex Fridman1:24:42

       Yeah. I mean, it's humbling. It's humbling to realize the c- the complexity of this whole mechanism. It certainly puts humans in their proper perspective, that we're not, um ... just 'cause we have brains and brains are intelligent doesn't mean we're the most intelligent thing, because ultimately, the, the whole mechanism of nature seems to be orders of magnitude more intelligent. All, all of it. Like, we're, we're a bunch ... we're like a hierarchy of organisms that have a history of several billion years and that all somehow came together to make a human. And there'll be life after us just as was life before us. And something that comes after will be perhaps even more fascinating.

   26. BKBetül Kaçar1:25:23

       ... yeah. I think when you understand the magnitude of what happened here, there is, there is no room for arrogance. It should overwhelm you and humiliate. It's pretty humiliating.

   27. LFLex Fridman1:25:32

       Yeah. (laughs)

   28. BKBetül Kaçar1:25:33

       That, you know, it's, it's, it's quite amazing what, what, what was, what happened here. And there is no other discipline that will deliver that, but exploring our own origins and looking at life as a more planetary system phenomena rather than one single species at a time. A collective look.

8. 1:25:55 – 1:53:55

   Alien life

   1. BKBetül Kaçar1:25:55

   2. LFLex Fridman1:25:55

      Uh, y- you mention this question in your TED Talk, is... the two possibilities of the universe being full of life and the universe being empty, and we're the only life in the universe. Um, how do you feel about both options? Just actually, you as a single chemical organism introspecting about its existence in this w- world.

   3. BKBetül Kaçar1:26:21

      It's... having a planet full of life is interesting because there are... we talked about life being all about chemistry exploring solutions.

   4. LFLex Fridman1:26:30

      Mm-hmm.

   5. BKBetül Kaçar1:26:30

      And having solutions in front of you is, is, is great. It's beneficial, right?

   6. LFLex Fridman1:26:35

      S- solutions being different organisms, like other humans, you see them as a solution to a chemistry problem.

   7. BKBetül Kaçar1:26:39

      D- different, different... yeah, if I don't-

   8. LFLex Fridman1:26:41

      Oh, that's an interesting solution. That's not... next time (laughs) we're in Austin so there's a bunch of weirdos. Every time I see a weirdo, I'll be like, "Oh, that's an interesting solution to this chemistry problem." (laughs) I'm gonna... (laughs)

   9. BKBetül Kaçar1:26:52

      Now you think like an origin of life scientist.

   10. LFLex Fridman1:26:53

       (laughs)

   11. BKBetül Kaçar1:26:54

       But it's-

   12. LFLex Fridman1:26:55

       Funny that that one worked out.

   13. BKBetül Kaçar1:26:57

       (laughs) But-

   14. LFLex Fridman1:26:57

       Let's see where else it goes.

   15. BKBetül Kaçar1:26:58

       But having this emptiness and unpredictability, uh, of uncovering a novel solution can also have its own benefits. And, and we should, uh, be open to what other solutions might be out there and, and exploring those solutions.

   16. LFLex Fridman1:27:16

       Or to different chemistry problems.

   17. BKBetül Kaçar1:27:17

       Different chemistry problems.

   18. LFLex Fridman1:27:17

       So, that's where you see, you see the other planets out there as different chemistry problems.

   19. BKBetül Kaçar1:27:21

       To their own local environment, yes.

   20. LFLex Fridman1:27:23

       So, how many chemistry problems have solutions that are life-like to you out there in the universe?

   21. BKBetül Kaçar1:27:33

       It's a wide open pallette, if you think about it. I don't quite know. It's the... we know the, the chemistry is chemistry. I don't think the chemistry will be different elsewhere. But, again, what is selected by chemistry will be determined by the environment, most likely.

   22. LFLex Fridman1:27:46

       See, I think there's life everywhere out there. So, there's a guy named Nick Lane whose gut... and it's interesting to me, uh, I wonder what you think about it... his gut is there's life everywhere out there, but it stops at like the bacteria stage. So he says the eu- eukaryotes is like the biggest invention and the hardest one.

   23. BKBetül Kaçar1:28:13

       I wonder if he thinks that's an accidental outcome. If he thinks that's inevitable. I wonder what that means. But it's, it's very... it's a likely possibility that the, uh, bacterial or microbial life is definitely more attainable. Um-

   24. LFLex Fridman1:28:28

       So that's, that's a weird world where our entire galaxy just has-

   25. BKBetül Kaçar1:28:33

       But our-

   26. LFLex Fridman1:28:33

       ... bacteria everywhere.

   27. BKBetül Kaçar1:28:34

       ... so, you know, if you don't like microbes, you are on, on the wrong planet.

   28. LFLex Fridman1:28:39

       I know. Yeah.

   29. BKBetül Kaçar1:28:40

       (laughs)

   30. LFLex Fridman1:28:41

       And viruses. I don't know which one there's more of, but they're b- they're both... and most of them are, like, productive.

Episode duration: 2:40:17