Manolis Kellis: Origin of Life, Humans, Ideas, Suffering, and Happiness | Lex Fridman Podcast #123

1. 0:00 – 6:20

   Introduction

   1. LFLex Fridman0:00

      The following is a conversation with Manolis Kellis, his second time on the podcast. He's a professor at MIT and head of the MIT Computational Biology Group. He's one of the most brilliant, productive, and kind people I've had the fortune of talking to. A lot of my colleagues at MIT and former MIT faculty and students wrote to me after our first conversation with some version of, "Manolis is awesome, isn't he? I'm glad you guys are now friends." I am too, and I'm happy that he makes time in his insanely busy schedule to sit down and have a chat with me. Quick summary of the sponsors: Public Goods, Magic Spoon, and ExpressVPN. Please check out these sponsors in the description to get a discount and to support this podcast. As a side note, let me say that I just got back from talking to Joe Rogan on his podcast, my fifth time on there. I also got a chance to record a separate conversation with Joe on this podcast. We talked on both quite a bit about his journey and his advice for mine. One of the things that I think made his show special is that he just had fun and made choices that didn't get in the way of him having fun and loving life. I'm learning to do just that. It's tough since I'm naturally full of self-doubt and anxiety, but I'm learning to let go and have fun, even if my monotone, robotic voice sometimes sounds otherwise. (laughs) For Joe, that involved talking to his friends, comedians, especially ones that brought out the best in him. Duncan Trussell and the five-hour first episode on Spotify comes to mind as an example of that. Duncan has been a guest probably close to if not more than 50 times on Joe's podcast. My hope with amazing people like Manolis is to find my Duncan Trussell, my Joey Diaz, and yes, even my Eddie Bravo. Obviously, Joe and I are very different people, but ultimately both love life when we can interact often with people we love and who inspire us, make us smile, make us think, and make us have fun when we get behind the mic of a podcast, whether anyone is listening or not. If you enjoy this thing, subscribe on YouTube, review it with five stars on Apple Podcast, follow on Spotify, support on Patreon, or connect with me on Twitter @lexfridman. I also this time put a link in the description to a survey for this podcast on how I can improve and also an option if you like, I don't know why you would like to, but if you like to join an inner circle of people that help guide the direction of this podcast via email or occasional video chats. If you have a few minutes, please fill it out. As usual, I'll do a few minutes of ads now and no ads in the middle. I try to make these interesting, but I give you timestamps so you can skip. But still, please do check out the sponsors by clicking the links in the description. It's the best way, honestly, to support this podcast. This show is sponsored by Public Goods, an online store for basic health and household stuff. Their products have a minimalist black and white design that I find to be just clean, elegant, and beautiful. It goes nicely, at least I think so, with the design of Crew Dragon and the recent SpaceX NASA mission that sent two humans into space. To me, very few things are as inspiring as us humans reaching out into the unknown, the harsh challenges of space. Colonizing Mars may not have obvious near-term benefits, but I believe it will challenge our scientists and our engineers to create technologies whose impact will be immeasurable for us humans here on Earth, or those of us who, uh, choose to stay here on Earth. Personally, I'm kind of a longtime big fan of this planet. (laughs) Anyway, visit, uh, publicgoods.com/lex and use code LEX at checkout to get 15 bucks off your first order. This episode is also supported by Magic Spoon, low-carb, keto-friendly cereal. You might have heard on other videos that I eat keto mostly these days, so Magic Spoon is a delicious healthy treat on a hard workout day that fits into that crazy diet. Also, they're a sponsor of Episode 100 with my dad and got my dad to buy this cereal, and he now loves it, honestly just loves it. It's kind of funny actually. The deep heartfelt nature of that conversation and the silliness of the cereal captures my dad perfectly. Much of the hardship in his life he dealt with using wit and humor. His favorite flavor happens to be cocoa. Mine is too. He hasn't bought the Eight Sleep mattress yet, though my mom wants to, but he's all about this Magic Spoon cereal. I think it's his actually favorite sponsor of this podcast, probably because they chose to sponsor the episode he's on. Anyway, click the magic spoon.com/lex link in the description and use code LEX at checkout for free shipping, to let them know I sent you, and also indirectly to make my dad happy. This show is also sponsored by ExpressVPN. Get it at expressvpn.com/lexpod. They gave me a suggested opening line of, "Using the internet without ExpressVPN is like going to the bathroom and not closing the door." This is like GPT-3 suggesting to me how to be more human-like, and I'll honestly take all the help I can get. By way of life advice, let me tell you that you need a VPN to protect you from Russians like me. In fact, this podcast is a kind of hack of your biological network where I use my monotone, low-energy voice to convince you to buy a kind of expensive cereal as a way to influence the stability of the US economy. I use ExpressVPN on both Windows and Linux to protect myself if I ever do shady things on the internet, which of course I never do and never will.So, secure your online activity by going to expressvpn.com/lexpod to get a extra three months free, and to support this podcast. And now, here's my conversation with Manolis Kellis.

2. 6:20 – 10:28

   Epigenome

   1. LFLex Fridman6:20

      What is beautiful about the human epigenome?

   2. MKManolis Kellis6:24

      Don't get me started. So, first of all, as an engineering feat, the human epigenome manages the most compact, the most incredible compaction you could imagine. So, every single one of your cells contains two meters worth of DNA, and this is compacted in a radius which is one-thousandth of a millimeter. That's six orders of magnitude. To give you a sense of scale, it's as if a string as tall as the Burj Khalifa, which is about a kilometer tall, was compacted into a tiny little ball the size of a millimeter. And if you put it all together, if you stretch the trillions of cells that we have, we have about 30 trillion cells in your body, if you stretch the DNA, the two meters worth of DNA in every one of your trillion cells, you would basically reach all the way to Jupiter...

   3. LFLex Fridman7:24

      (laughs)

   4. MKManolis Kellis7:24

      ... a hundred times.

   5. LFLex Fridman7:26

      Yeah. It's all curled up in there.

   6. MKManolis Kellis7:28

      It's all-

   7. LFLex Fridman7:28

      You said 30 trillion cells...

   8. MKManolis Kellis7:31

      30 trillion cells.

   9. LFLex Fridman7:31

      ... in the human body.

   10. MKManolis Kellis7:32

       Every one of them, two meters worth of DNA. So, all of that is compacted through the epigenome. The epigenome basically has the ability to compact this massive amount of DNA, from here to Jupiter 10 times, into one human body, into just the nuclei of one human body, and the vast majority of the human body's not even nee- these nuclei. And that's sort of the structural part. So, so, so that's the boring part, that's the structural part. The functional part is way more interesting. So, functionally, what the human epigenome allows you to do is basically control the activity patterns of thousands of genes. So, 20,000 genes in your human body, every one of your cells only needs a few thousand of those, but a different few thousand of those. And the way that your cells remember what their identity is, is basically driven by the epigenome. So, the epigenome is both structural, in sort of making this dramatic compaction, and it's also functional, in being able to actually control the activity patterns of all your cells.

   11. LFLex Fridman8:37

       Now, can we draw a loo- a definition distinction between the genome and the epigenome?

   12. MKManolis Kellis8:43

       Again, being Greek, epi means on top of.

   13. LFLex Fridman8:46

       Mm-hmm.

   14. MKManolis Kellis8:47

       So, the genome is the DNA, and the epigenome is anything on top of the DNA. And there's, you know, three types of things on top of the DNA. The first is chemical modifications on the DNA itself. So, we like to think of four bases of the DNA, A, C, G, T. C has a methyl form, which is sometimes referred to as the fifth base. So, methyl-C takes a different meaning. So, in the same way that, uh, you have annotations in a orchestra score that basically say whether you should play something softly, or loudly, or space it out, or you know, uh, interpret basically the score, the human epigenome allows you to modify that primary score. So, a modified C basically says, "Play this one softly." It's basically a-

   15. LFLex Fridman9:36

       Yeah.

   16. MKManolis Kellis9:36

       ... sign of repression in a gene regulatory region.

   17. LFLex Fridman9:39

       (laughs) I, I love how you're talking about the, the function that, uh, emerges from the epigenome as a, as a musical score.

   18. MKManolis Kellis9:48

       (laughs)

   19. LFLex Fridman9:48

       It's a-

   20. MKManolis Kellis9:48

       It is in many ways. And, uh, every single cell plays a different part of that score. It's like having all of human knowledge in 23 volumes, like 23 giant books, which are your chromosomes, and every single cell has a different profession, a different role. Some cells play the piano, and they're looking at chapter 7 from chromosome 23, and chapter 4 from chromosome 2, and so on and so forth. And each of those, uh, pieces are all encoded in the same DNA, but what the epigenome allows you to do is effectively conduct the orchestra, and sort of coordinate the pieces so that every instrument plays only the things that it needs

3. 10:28 – 15:26

   Evolution

   1. MKManolis Kellis10:28

      to play.

   2. LFLex Fridman10:29

      One thing that kind of blows my mind, maybe you can tell me your thoughts about it, is the, the way evolution works with natural selection is, uh, based on the final sort of, the entirety of the orchestra musical performance, right? And then, but there's these incredibly rich structural things, like each one of them doing their own little job, that somehow work to get, like the evolution selects based on the final result, and yet the, all the individual pieces are doing like infinitely minuscule, specific things. How the heck-

   3. MKManolis Kellis11:06

      It's a very-

   4. LFLex Fridman11:06

      ... does that work? Like-

   5. MKManolis Kellis11:07

      It's a very good insight. And you can even go beyond that and basically say evolution doesn't select at the level of an organism, it actually selects at the level of whole environments, whole ecosystems. So, let me break this down. So, you basically have, at the very bottom, every single nucleotide being selected. But then that nucleotide's function is selected at the level of, you know, each gene, and every, uh, not even each gene, each gene regulatory control element, and then those control elements are basically converging onto the function of the gene. And many genes are converging onto the function of one cell, and many cells are converging onto the function of one tissue or organ, and all of these organs are converging onto the level of an organism. But now that organism is not in isolation. So, if you basically think about why is altruism, for example, a thing? Why are people being nice to each other? It was probably selected. And it was probably selected because those species that were just nasty to each other didn't survive as a species.And now if you think about, um, symbiosis of, you know, uh, there's plants, for example, that love CO2, and there's humans that love O2, and we're sort of, you know, trading, um, different types of, uh, gases to each other. If you look at, um, ecosystems where one organism which is really nasty, that organism actually died, because everyone they were being nasty to was killed off. And then that kind of, you know, universe of life is gone.

   6. LFLex Fridman12:53

      Mm-hmm.

   7. MKManolis Kellis12:53

      So basically what emerges is selection at so many different layers of benefit, including, you know, all of these nucleotides within a body interacting for the emergent functions at the body level.

   8. LFLex Fridman13:10

      Yeah, I wonder, I wonder if it's possible to break it down into levels, that selection even beyond humans. Like, you said environment, but there's environments at all different levels too, right? Uh, at the minuscule, at the organ level, at the tissue level, like you said, maybe at the microscopic level. It'd be fascinating if, like, there's a kind of selection going on at, like, both the quantum level and, like, the, the galaxy level.

   9. MKManolis Kellis13:35

      Yeah, yeah, yeah.

   10. LFLex Fridman13:36

       Right?

   11. MKManolis Kellis13:36

       So, so, um-

   12. LFLex Fridman13:37

       Of all different forms.

   13. MKManolis Kellis13:38

       Yeah. Let's again sort of break down these different layers. So basically if you think about the environment in which a gene operates, that gene, of course, the first definition of environment that we think of is pollution or sunlight or heat or cold and so on and so forth. That's the external environment. But every gene also operates at the level of the internal cellular environment that it's in. If I take a gene from, say, an African individual and I put it in a European context, will it perform the same way? Probably not, because there's a cellular context of thousands of other genes that that gene has co-evolved with, you know, in the out of Africa event and, you know, all of this, uh, sort of human history of evolution. So basically if you look at neanderthal genes, for example, which again happened long after that, uh, out of Africa event, there's incompatibilities between neanderthal genes and modern human genes that can lead to diseases. So in the context of the neanderthal genome, that gene version, that allele was fine, but in the context of the modern human genome, that neanderthal gene version is actually detrimental. So it's, it's, you know, that cellular environment constitutes the genetics of that gene, but also, of course, all of the epigenomics of that gene.

   14. LFLex Fridman14:57

       Yeah, it's fascinating that the, the gene has a history. I mean, we talked about this a little bit last time, but to th- and, and then s- some of your research goes into that, but the, the genes as they are today have, have a story from the beginning o- of time, and then somet- sometimes their story was, like, their path was useful for survival for the particular organisms and sometimes not. That's fascinating. Let me ask, as a tangent,

4. 15:26 – 27:15

   Neanderthals

   1. LFLex Fridman15:26

      we kind of started talking offline about neanderthals. Uh, do you have something interesting genetically, biologically, in terms of difference between, uh, neanderthal and, like, the different branches of human evolution that, uh, you find fascinating?

   2. MKManolis Kellis15:42

      Neanderthals are only one of about five branches that we are pretty confident about. One branch-

   3. LFLex Fridman15:49

      Branches of?

   4. MKManolis Kellis15:50

      Of out of Africa events. So basically there's neanderthals, there's denisovans. What is the evidence for denisovans? One tiny little fragment of one pinky from one cave in Siberia.

   5. LFLex Fridman16:05

      (laughs) Recent, so relatively recently discovered, right?

   6. MKManolis Kellis16:08

      Less than 10 years ago.

   7. LFLex Fridman16:09

      Yeah.

   8. MKManolis Kellis16:09

      So-

   9. LFLex Fridman16:09

      And those are, like, little folks, right? I- Were they-

   10. MKManolis Kellis16:11

       No, no, no, no, no. That's yet another one.

   11. LFLex Fridman16:13

       (laughs)

   12. MKManolis Kellis16:13

       Homo floresiensis. Yeah, the little folks-

   13. LFLex Fridman16:16

       Yeah.

   14. MKManolis Kellis16:16

       ... in sort of Indonesia. But then, uh, denisovans are basically another branch that we only know about genetically from that one bone and eventually we realized that it's one of the three major branches along with neanderthal, modern human, and denisovan. And then that one branch has now resurfaced in many different areas and we kind of know about the gene flow that happened in between them. So when I was reading my Greek mythology, it was talking about the age of the heroes, these eras of human-like, you know, precursors that were wiped out by Zeus or by all kinds of wars and so on and so forth, like the Titans and the, the, you know. It's, it's ridiculous to sort of read these stories as a kid because you're like, "Oh, yeah, whatever." And then you're growing up and you're like, "Whoa. Layers and layers of human-like ancestors." And who knows if those stories were inspired by bones that they found that kind of looked human-like, but were not quite human-like? Who knows if stories of dragons were inspired by bones of dinosaurs? And basically this archeological evidence has been there and has probably entered the folk imagination, migrated into those stories, but it's not that far re- you know, removed from what actually happened, of massive wars, of wiping out neanderthals as humans are, modern humans were populating, um, you know, Europe.

   15. LFLex Fridman17:37

       Do you think, do you think what killed the neanderthals and all those other branches is human conflict or is it genetic conflict? So is it, uh, us humans being the opposite of altruistic towards each other? Or is it, uh, some other, uh, uh, competition at some other level, like as we're discussing?

   16. MKManolis Kellis17:58

       Yeah. So if you look at a lot of human traits today, they're probably not that far removed from the human traits that got us where we are now. So, you know, this whole tribalism, you know, "You're my sports team." Or, "You're my, you know, political party." Or, "You're my, you know, tiny little village," and therefore, you know, if you're from that other village, "I hate you." But as soon as we're both...... in the major city, "I can't believe we're from the same region, my friend! Come here!"

   17. LFLex Fridman18:26

       (laughs) Yeah.

   18. MKManolis Kellis18:26

       "My family!" And, like, two neighboring countries fighting, and as soon as they're off in another country, we're like, "Oh, I can't believe that."

   19. LFLex Fridman18:32

       Right.

   20. MKManolis Kellis18:32

       So, it's, it's kind of funny, like, the, this tribalism is nonsensical in many ways. It's like, con- cognitive incongruent, that basically we like kin, and selection for, for sort of liking kin is hugely advantageous genetically.

   21. LFLex Fridman18:49

       Probably across all kinds of organ-

   22. MKManolis Kellis18:50

       Of course.

   23. LFLex Fridman18:50

       All, all, across all kinds of life.

   24. MKManolis Kellis18:52

       Of course, yeah. So, so basically if you now transport that to the sort of humans arriving in Europe and Neanderthals are everywhere, what are you gonna do? You're gonna kill them off. Uh, you know, there's this battle for territory, and this battle for, "They're not like us, we have to get rid of them." So basically, there's, um, you know, very interesting mix there, but, and yet, and yet, when you look at the genetics, there's tons of gene flow between them. So basically, you know, love, romance-

   25. LFLex Fridman19:23

       (laughs)

   26. MKManolis Kellis19:23

       ... between, you know-

   27. LFLex Fridman19:24

       Yeah, it's funny.

   28. MKManolis Kellis19:24

       ... new species.

   29. LFLex Fridman19:24

       We have tribes but love, uh, uh, spans, uh, uh, the gap between the different tribes.

   30. MKManolis Kellis19:30

       It's-
5. 27:15 – 43:44

   Origin of life on Earth

   1. MKManolis Kellis27:15

      How did life evolve on Earth? Yes, sure, life now, most of life that we above the surface look at, has to do with ex- exploiting the solar energy for, you know, our daily behavior. But that's not the case everywhere on the planet. If you look at the bottom of the ocean, there are hydrothermal vents. There's both black smokers and white smokers, and they are near these volcanic, uh, you know, ducts that basically emanate a massive amount of energy from the core of our planet. What does life need? It needs energy. Does it need energy from the sun? It couldn't care less. Does it need energy from, you know, the Earth itself? Yeah, possibly. It could use that. And if you look at how did life evolve on, you know, on Earth, there are many theories. I mean, uh, a kind of silly theory is that it came from outer space, that basically there's a meteorite out there that sort of landed on Earth and brought with it DNA material. I think it's a little silly because it kind of pushes the buck down the road. Basically, the next-

   2. LFLex Fridman28:23

      (laughs)

   3. MKManolis Kellis28:23

      ... question is, how did it evolve over there?

   4. LFLex Fridman28:24

      Yeah, exactly.

   5. MKManolis Kellis28:25

      Uh, whereas our planet has basically all of the right ingredients. Why would it evolve here? So basically, let's kind of ignore that one. And now the- the two other competing hypotheses are from the outside in or from the inside out.

   6. LFLex Fridman28:36

      What's that mean?

   7. MKManolis Kellis28:36

      From the outside in means from the surface to the bottom of the ocean.

   8. LFLex Fridman28:40

      Ah.

   9. MKManolis Kellis28:41

      From the inside out means from the bottom of the ocean to the surface.

   10. LFLex Fridman28:44

       (laughs)

   11. MKManolis Kellis28:46

       So life on the surface is pretty brutal. Life obviously evolved in the water, and then there was an out-of-water event. But basically, before it exited, it was clearly in the water, which is a much nicer and shielded environment.

   12. LFLex Fridman29:05

       So just to be clear, on the surface, are- are you referring to the ...

   13. MKManolis Kellis29:10

       The surface of the sea or the bottom of the sea.

   14. LFLex Fridman29:12

       Uh, versus the bottom, uh, of the sea.

   15. MKManolis Kellis29:15

       Of the ocean.

   16. LFLex Fridman29:15

       And you're saying life on the surface is, uh, is harsh chemically.

   17. MKManolis Kellis29:19

       Life outside the ... Li- life outside the water is horrible. It takes huge amounts of evolutionary innovations to sustain living outside the water.

   18. LFLex Fridman29:30

       Why? Yeah, that's so interesting.

   19. MKManolis Kellis29:32

       (laughs)

   20. LFLex Fridman29:32

       Why- why is that? So it's easier to ... Life is easier in- in the water. Maybe ... See? I'm telling you dolphins are-

   21. MKManolis Kellis29:37

       We are- we are 70% water.

   22. LFLex Fridman29:39

       ... onto something.

   23. MKManolis Kellis29:39

       No, dolphins went back into the water.

   24. LFLex Fridman29:42

       Really? Oh-

   25. MKManolis Kellis29:42

       Of course.

   26. LFLex Fridman29:42

       ... 'cause dolphins are mammals.

   27. MKManolis Kellis29:44

       Of course. Yeah.

   28. LFLex Fridman29:45

       Interesting. Well, again, they might be smarter. They went back.

   29. MKManolis Kellis29:48

       (laughs)

   30. LFLex Fridman29:48

       They're like, "Screw this."
6. 43:44 – 49:56

   Life is a fight against physics

   1. LFLex Fridman43:44

      uh, now I was talking about you being a scientist on Earth, but say you were a scientist, uh, that were shipped over to Europa to investigate if there's life. What would you look for in terms of signs of life?

   2. MKManolis Kellis43:57

      Life is unmistakable, I would say. The way that life transforms a planet surrounding it is not the kind of thing that you would expect from the physical laws alone. So it's, uh, uh, I would say that as soon as life arises, it creates this compartmentalization. It starts pushing things away. It starts sort of keeping things inside that are self. And there's a whole signature that you can see from that. So when I was organizing my Meaning Of Life Symposium, my, uh, my- my friend who's an astrophysicist, um, basically, uh, we were- we were deciding on what would be the themes for the- for the symposium, and then, uh, I said, "Well, we're gonna have biology. We're gonna have physics." And she's like, "Ah, psh, come on. Biology's just a small part of physics." (laughs)

   3. LFLex Fridman44:47

      (laughs) Everything's a small part of physics, right? (laughs)

   4. MKManolis Kellis44:50

      And, uh, I mean, in- in- in many ways it is.

   5. LFLex Fridman44:53

      (laughs)

   6. MKManolis Kellis44:53

      But my immediate answer was, "No, no, no, no. Wait. Life challenges physics. It supersedes physics. It- it sort of f- fights against physics." And that's what I would look for in Europa. I would basically look for this fight against physics, for anything that's sort of signatures of not just entropy at work, not just things diffusing away, not just gravitational pulls. But clear signatures of... You remember when I was talking earlier about this whole selection for environment, selection for biospheres, for ecosystems, for these multi-organism form of life? And I think that's sort of the- the first thing that you can look for. You know, chemical signatures that are not simply predicted from the reactions you would get randomly.

   7. LFLex Fridman45:38

      That's such a beautiful way to look at life. So you're basically leveraging some energy source to enable you to resist the physics of the universe? (laughs)

   8. MKManolis Kellis45:48

      Fighting against physics.

   9. LFLex Fridman45:49

      (laughs)

   10. MKManolis Kellis45:50

       But that's- that's the first transformation. If you look at humans, we're way past that.

   11. LFLex Fridman45:54

       What do you mean by transformation?

   12. MKManolis Kellis45:55

       So- so basically there's- there's layers. I sort of see life, you know... When- when we talk about the meaning of life, life can be construed at many levels. We talked about life in the simplest form of sort of the ignition of evolution, and that's sort of the basic definition that you can check off. Yes, it's alive. But when Alexander the Great was asked, (laughs) "To whom do you owe your life, to your teachers or to your parents?" And Alexander the Great, uh, answered, "I owe to my parents the zene, the life itself, and I owe to my teachers the euphzene." Like euphony, euph means good, the opposite of cacophony, which means, you know, bad. So, euphzene, in his, uh, words, was basically living a human life, a proper life. So basically we can go from the zene (laughs) to the euphzene. And that transformation has taken several additional leaps. So basically, you know, life on Europa, I'm pretty sure has gotten to the stage of A makes B makes C makes A again. But getting to the euphzene is a whole other, um, level. And that level requires cooperation. That level requires altruism. That level requires specialization. Remember how we were talking about the RNA specializing into DNA for storage, proteins, and then compartmentalizations? And if you look at prokaryotic life, there's no nucleus. It's all one soup of things intermingling. If you look at eukaryotic life, again eu- for true, good, you know? So a eukaryote basically has a nucleus, and that's where you compartmentalize further the organization of the information storage from all of the daily activities. If you look at a, you know, human body plan, or any animal, you have a compartmentalization of the germ line. You basically have one lineage that will basically be saved for the future generations, and everything outside that lineage is almost superfluous. If you think about it, the rest of your body, all it does is ensure that that lineage will make it to the next generation, that these germ lines will make it to the next generation. The rest is packaging. (laughs) I'm- I'm sorry to be so blunt.

   13. LFLex Fridman48:27

       Yeah.

   14. MKManolis Kellis48:27

       And if you look at nutrition, you know, we're deuterostomes. What does deuterostome mean? Deutero means second. We're the- this is the second mouth. The first mouth is actually down here. It's the esophagus.

   15. LFLex Fridman48:39

       Mm-hmm.

   16. MKManolis Kellis48:39

       So deuterostomes have evolved a second layer of eating, kinda like alien with the two mouths. (laughs)

   17. LFLex Fridman48:45

       Yeah. (laughs)

   18. MKManolis Kellis48:46

       (laughs) So you can think of us as alien, where the first mouth is up here and then the second mouth is down there. And of course-

   19. LFLex Fridman48:52

       Is- is- is the first mouth just the- the physical manipulation of the food to make it more consumable?

   20. MKManolis Kellis48:56

       Correct. Correct. Correct. And basically, again, you know, if you look at-

   21. LFLex Fridman48:59

       So weird.

   22. MKManolis Kellis48:59

       ... if you look at a worm-

   23. LFLex Fridman49:01

       Yeah. (laughs)

   24. MKManolis Kellis49:01

       ... it's an extremely simple life form.

   25. LFLex Fridman49:02

       Yeah.

   26. MKManolis Kellis49:02

       Basically has a mouth, it has an anus-

   27. LFLex Fridman49:05

       Yeah.

   28. MKManolis Kellis49:05

       ... and it has, you know, just some organs in between that consume the food and just spit- spit out poop.

   29. LFLex Fridman49:09

       Yeah.

   30. MKManolis Kellis49:10

       Um, humans are basically a fancy form of that. So you basically have the mouth, you have the digestive tract, and then you have limbs to get better at getting food...... you have eyesight, hearing, et cetera, to get better at getting foo- food.
7. 49:56 – 51:35

   Life as a set of transformations

   1. MKManolis Kellis49:56

   2. LFLex Fridman49:56

      So, okay, uh, th- that's such a fascinating way to look at life as a set of transformations.

   3. MKManolis Kellis50:01

      Exactly.

   4. LFLex Fridman50:02

      So, like, is there some interesting transformations through our history here on Earth-

   5. MKManolis Kellis50:07

      Of course.

   6. LFLex Fridman50:07

      ... that, like-

   7. MKManolis Kellis50:07

      Of course.

   8. LFLex Fridman50:07

      ... appeal to you?

   9. MKManolis Kellis50:08

      Of course. So-

   10. LFLex Fridman50:09

       I mean, what are the most brilliant innovations and transformations you can say?

   11. MKManolis Kellis50:12

       Yeah. Yeah, yeah. I mean, this is such a fascinating question. Of course, like, you know, we're talking about basic, basic life forms, and we're talking about eukaryotic life forms, and then the next big transformation is multicellular life forms, where the specialization separates the germ line from everything else that accompanies it and- and sort of carries it. And then that specialization then sort of has this massive new innovation, like above the second mouth, which is this massive brain, and this massive brain is basically something that arises much, much later on. Basically, you know, notochords, like having the first spinal cord, this whole concept that along with the- these very simple layers, you basically now have a coordinating agent, and this coordinating agent is starting to make decisions. And remember when we were talking about, uh, free will?

   12. LFLex Fridman51:04

       Mm-hmm.

   13. MKManolis Kellis51:04

       I mean, you know, as a worm is hunting for food, oh, it has plenty of free will. It can choose to, you know, follow chemotaxis to the left or chemotaxis to the right.

   14. LFLex Fridman51:13

       Yeah.

   15. MKManolis Kellis51:13

       And maybe that's free will because it's unpredictable beyond a certain level. So, um, you basically now have more and more decision-making and coordination of all of these different body parts and organs by a central operating system, a central machine that basically will control the rest of the body. And

8. 51:35 – 1:00:31

   Time scales

   1. MKManolis Kellis51:35

      the other thing that I love talking about is the different timescales at which things happen. You know, we were talking about the human epigenome before. The human epigenome is basically able to find what genes should be expressed in response to environmental stimuli in the order of minutes, and basically receive a stimulus, transfer all that data through this humongously long string of searching, and then sort of find what genes to turn on, and then create all that. All of that is happening in the timescale of minutes, basically, you know, three minutes to an h- to half an hour. That's the expression response. But our daily life doesn't happen on the order of three minutes to an h- to half an hour. It happens on the order of milliseconds. Like, I throw a ball at you, you catch it right away. No gene expression changes there. You just don't have time to do that. So, you basically have a layer of control built on a hardware that supports it, but that hardware itself lives in a different timescale than the controlling machine on top of that.

   2. LFLex Fridman52:37

      Is that an accident, by the way? Is that, like, a feature? Is it- was it possible for life to have evolved where the- our d- the daily life of the organism as it interacts with its environment was on a timescale similar to, uh, the- the way our internals work?

   3. MKManolis Kellis52:54

      If you look at trees, they look kind of boring and stupid. You're, like, looking at a tree, you're like, "Stupid." If you speed up the movie of a tree-

   4. LFLex Fridman53:02

      Yeah.

   5. MKManolis Kellis53:02

      ... from spring until October, you'll be like, "Oh my God, it's intelligent." And the reason for that is that at that timescale, the tree is basically saying, "Oh, I'm looking for a- a, you know, a thing to catch onto. Ooh, I just caught onto that. I'm gonna grow more here, I'm gonna spawn out there," et cetera. Like, I can see the trees in my garden just growing and sort of, you know, looping around, and, um, it's all a matter of timescale. And if you look at the human timescale, remember we were talking about neoteny the last time around, the whole fact that our young are pretty useless until, you know, maybe, you know, a few months of age, if not a few years of age, if not, I don't know, getting out of college. Um, and then we- we basically hold them, enabling their brain to continue being malleable and infusing it with knowledge and, you know, thoughts as, you know, that period of neoteny increases and expands. If you fast-forward, I don't know, another million years. So, humans have only been around, you know, different from apes for about that long. Jump another unit of that, another human-chimp divergence. What could happen? From an evolutionary gain- timescale, a lot. One of the things that's happening already is expansion of human lifespan. We have longer and longer periods before we mature, and we have longer and longer periods because before we have babies. So, intergenerational dif- distance is s- you know, grown from, I don't know, 16 years to 40 years.

   6. LFLex Fridman54:36

      You're saying that's in the genetics, like-

   7. MKManolis Kellis54:38

      No, no, not necessarily, but- but it's- it's sort of an environmental tendency that's happening. But as we medically expand human lifespan, the generations might actually be pushed instead of 40 years to 60 years to 100 years.

   8. LFLex Fridman54:57

      Like, if we look at the long arc of the-

   9. MKManolis Kellis54:59

      The- exactly.

   10. LFLex Fridman54:59

       ... evolutionary history.

   11. MKManolis Kellis55:00

       Exactly. So, as we start thinking-

   12. LFLex Fridman55:03

       Yeah.

   13. MKManolis Kellis55:03

       ... about intergalactic travel now ...

   14. LFLex Fridman55:05

       (laughs) Sorry. That- (laughs) that's- that's a heck of a transition. Uh, yeah, so let's talk about intergalactic travel.

   15. MKManolis Kellis55:12

       No, no, no, no, no, no.

   16. LFLex Fridman55:13

       Yeah.

   17. MKManolis Kellis55:13

       As- as we as a species start thinking about... I b- I'm- I'm talking about these transitions that are happening, right?

   18. LFLex Fridman55:18

       Oh, that's- that's- that's awesome.

   19. MKManolis Kellis55:19

       So, continuing along these transitions, what does the future hold in the next million years? So, the concept of us going to another planet and that taking three human lifetimes...... might be a joke if the human lifetime starts being 400 years, or 800 years. So, imagine-

   20. LFLex Fridman55:37

       It's all timescale.

   21. MKManolis Kellis55:38

       It's all timescale, just different timescales.

   22. LFLex Fridman55:40

       Yeah.

   23. MKManolis Kellis55:41

       Y- you asked me offline whether I would like to live forever. I mean, my answer is absolutely. And there's many different types of forevers. One forever is, do I want to live today forever? Kind of like Groundhog Day. And the answer is absolutely. The stuff that I wanna learn today will probably take a lifetime just to learn, you know, (laughs) basically to clear my to-do list for the day.

   24. LFLex Fridman56:06

       You mean, like, relive the day-

   25. MKManolis Kellis56:07

       Relive the day.

   26. LFLex Fridman56:08

       ... and then, and then pick up different things from the richness of the experiences-

   27. MKManolis Kellis56:11

       Exactly.

   28. LFLex Fridman56:11

       ... they're all in today?

   29. MKManolis Kellis56:12

       Uh, there's just so much happening in the world every single day, so much knowledge that has happened already, that just to catch up on that will probably take me around forever.

   30. LFLex Fridman56:20

       (laughs) O- on that, on that point, um, just, I would just love to see you in a groundhog movie just (laughs) because you're so naturally as a scientist, but just the way your mind works beautifully, just all the richness of the experiences that you will pick up from that. Uh, uh, uh, it's a beautiful visual. But you say-
9. 1:00:31 – 1:05:19

   Transformations of ideas in human civilization

   1. MKManolis Kellis1:00:31

   2. LFLex Fridman1:00:31

      Yeah.

   3. MKManolis Kellis1:00:32

      And, you know, that takes us back to the, the question you, you asked about sort of the transformations that have happened in humanity.

   4. LFLex Fridman1:00:37

      Yeah.

   5. MKManolis Kellis1:00:37

      The Minoan civilization is one of them. You know, there's this paper that was published just a couple of years ago by one of my friends, um, that basically looked at the, uh, genetic makeup of the Minoans and the Mycenaeans in ancient Greek, in ancient Greece and how they, they're, they relate to modern Greeks. And they found that indeed there was very little gene flow from, you know, the outside. And, you know, it's, it's fantastic to sort of think about these amazing civilizations that transformed the way that human thought happens, that basically looked for rules in nature, that looked for principles, that looked for the standards of beauty, not human beauty, but beauty in the natural world. This whole concept that the world must be elegant and there must be deeper ways of understanding that world, to me, that's a massive transformation of our species.... similar to, you know, the earlier transformation that we were talking about, of even evolving a brain. (laughs) Of, you know, learning how to communicate, language, or the evolution of eyesight. If you look at sort of, you know, we were talking about these worms crawling around and then sensing which direction are the chemicals more abundant, you know, chemotaxis. So eventually, they grow a nose, eventually they grow a... Yeah, I mean, when I say nose, I mean ways of sensing chemicals. That's probably one of the earliest senses. You- you know, we always talk about how deep-rooted it is in our brain. That's one of the earliest senses. If you look at hearing, that's a much later sense. If you look at eyesight, that's an intermediate sense, where you're basically sensing where the light direction comes from. That's probably something that life didn't need until it got o- you know, into the surface, and so on and so forth. So, there's a lot of, you know, milestones, and I was talking about the latest milestone, which is LIGO, uh, last time, of being able to detect gravitational waves, and sort of being able to sort of have a sense that humans haven't had before.

   6. LFLex Fridman1:02:39

      (laughs) So, you see that as a j- yet another transformation-

   7. MKManolis Kellis1:02:41

      Of course.

   8. LFLex Fridman1:02:41

      ... that gives us an extra little sense?

   9. MKManolis Kellis1:02:43

      Of course. And now if you go back to this history of ancient Greece, I mean, this- this transformation that happened, I mean, of course, the Egyptians had this incredible, you know, civilization for thousands of years. But what happened in Greece was this whole concept of, "Let's break things down and understand the natural world. Let's break things down and understand physics. Let's basically build rules around architecture, about, around elegance, around, you know, statues and tragedy." I mean, a- a- an- another question that you asked me in passing was this whole concept of embracing the good and the bad, embracing your, the full range of human emotions. And if you look at Greek tragedy, it's the definition of that. It's, I mean, drama, I mean, again, it's a Greek word. (laughs) But- but the whole concept of some problems that are just so vast and large that dying is the easy way out.

   10. LFLex Fridman1:03:40

       (laughs)

   11. MKManolis Kellis1:03:42

       (laughs) That death-

   12. LFLex Fridman1:03:42

       Yeah.

   13. MKManolis Kellis1:03:42

       ... "Oh, that's the easy solution." You know, so- so I wanna touch a little bit on that point, and- and, um, sort of talk about this concept that life supersedes physics, and that the brain supersedes life, that basically, we have a brain that can decide to not follow evolution's path. We can decide to not have children. We can decide to not eat. We can decide to suicide. We can decide to sort of abolish communication with the outside world. I mean, all the things that make us human, we can basically decide not to do that. And that- that is basically when-

   14. LFLex Fridman1:04:27

       Yeah. (laughs)

   15. MKManolis Kellis1:04:27

       ... the brain itself-

   16. LFLex Fridman1:04:28

       So brilliant.

   17. MKManolis Kellis1:04:28

       ... is basically superseding what evolution programmed us for. Pow. (laughs)

   18. LFLex Fridman1:04:34

       So, uh, so I, okay, j- so one of the, it's, okay, I will, my mind was already blown at the beautiful formulation of the idea that life is, uh, is a system that resists physics.

   19. MKManolis Kellis1:04:49

       Yeah.

   20. LFLex Fridman1:04:50

       And our brain, or perhaps the content of it, or however it may be functionally our brain is a thing that resists life.

   21. MKManolis Kellis1:05:00

       Yes. Yes.

   22. LFLex Fridman1:05:03

       You're- you're so f-

   23. MKManolis Kellis1:05:05

       (laughs)

   24. LFLex Fridman1:05:05

       You're so brilliant. (laughs)

   25. MKManolis Kellis1:05:07

       But- but- but- but- but, uh, I want you to see all of that as a continuum. Basically, you're sort of talking about the sort of individual transformations, but it's a path...

   26. LFLex Fridman1:05:16

       Yeah.

   27. MKManolis Kellis1:05:16

       ... that- that humanity has been taking.

   28. LFLex Fridman1:05:17

       It's a transformation.

   29. MKManolis Kellis1:05:18

       It's a path

10. 1:05:19 – 1:13:18

    Life is more than a rat race

    1. MKManolis Kellis1:05:19

       of transformation. And then I want us to think about what it truly means to become human, like the F-zine. And you asked me about what motivated my Meaning of Life Symposium.

    2. LFLex Fridman1:05:30

       Mm-hmm.

    3. MKManolis Kellis1:05:30

       What motivated it, in part, I mean, of course, it was an inside joke of turning 42-

    4. LFLex Fridman1:05:35

       (laughs) Yeah.

    5. MKManolis Kellis1:05:36

       ... but what motivated it in part was actually a midlife crisis. So, the joke that I always like to say is Christos Papadimitriou, a famous Greek professor who was previously at MIT, at Harvard, at Stanford, Berkeley, everywhere, uh, brilliant, brilliant person, as, actually Costis' advisor.

    6. LFLex Fridman1:05:53

       Advisor, yeah, yeah.

    7. MKManolis Kellis1:05:54

       Uh, so- so Christos Papadimitriou likes to say that when you're an undergrad, you work like a rat to get into grad school, and when you're a grad student, you work like a rat to get your PhD, and when you're a post-doc, you work like a rat to get your assistant professorship.

    8. LFLex Fridman1:06:08

       Yeah.

    9. MKManolis Kellis1:06:09

       And when you're an assistant professor, you work like a rat to become a full professor. And then when you're a full professor, well, by then, you're basically a rat. (laughs)

    10. LFLex Fridman1:06:18

        (laughs) Ah, that's brilliant.

    11. MKManolis Kellis1:06:19

        So- so basically, what happened to me is that I arrived at the end of the rat race.

    12. LFLex Fridman1:06:24

        Yeah.

    13. MKManolis Kellis1:06:25

        You know, life is a rat race. You constantly have hurdles to jump over. You constantly have tunnels and secret pathways, and I figured it all out, and eventually, as I was turning 42, I looked back and I was like, "Wow, that was an awesome rat race, but I'm not a rat." I basically got out of the labyrinth and I was like, "I'm not- I'm not a rat, it turns out." (laughs)

    14. LFLex Fridman1:06:47

        Is that the first moment where you saw that it's, that you weren't in a rat race?

    15. MKManolis Kellis1:06:53

        It- it, no, no, no. I've known that I'm in a rat race for a long time, and it's so easy to be in a rat race. It's so easy to be an undergrad-

    16. LFLex Fridman1:06:58

        Day-to-day?

    17. MKManolis Kellis1:06:58

        ... 'cause you have problem sets. And-

    18. LFLex Fridman1:07:00

        (laughs) Problem sets.

    19. MKManolis Kellis1:07:00

        ... you- you know, we're all smart people. You know, problem set, it has a solution. Somebody made it for you, you can just solve it.

    20. LFLex Fridman1:07:06

        Yeah.

    21. MKManolis Kellis1:07:06

        Everything was made as a test, and you keep passing those tests and tests and tests and tests, and you have tasks that are well-defined. The PhD is a little different, because it's more open-ended, but again, you have an advisor who's guiding you. And then you become a professor, and tenure is a well set, defined set of tasks, and you do all that. And at 42, I basically had bought a house, three kids, beautiful wife, tenure-

    22. LFLex Fridman1:07:34

        Yeah.

    23. MKManolis Kellis1:07:36

        ... awesome students, tons of grants.Life was basically laid out for me.

    24. LFLex Fridman1:07:40

        Yeah.

    25. MKManolis Kellis1:07:41

        And that's when I had my ... midlife crisis. That's when people usually buy a Harley-Davidson. (laughs)

    26. LFLex Fridman1:07:46

        (laughs)

    27. MKManolis Kellis1:07:47

        And they basically say, "Oh, I need something new, I need something different, I need to be young myself," etc. But basically, that was my realization, that it's not a rat race, that there's no rat race. It's over, that I have to basically think, "How do I fully instantiate myself? How do I complete my transformation into an actual human being?" 'Cause it's very easy to sort of forget all the intangibles of life. It's very hard to just sort of think about the next task, then the next task, and it's all metrics, and, you know, what is the number of viewers I have? What is the number of, you know, publications I have? What is the number of citations, the number of talks, the number of grants? It's very easy to quantify everything. And then at some point, you're like, "This is real life. It's not a test anymore." And that's something that I told my wife early on, w- I was like, "No, no, no, our life is not gonna be let's put the kids through college." And that, you know, maybe that's when I escaped the rat race. Maybe it continued being a rat race. Maybe the next step would have been, "All right, how do I make sure that my kid is first in class?"

    28. LFLex Fridman1:08:45

        Right.

    29. MKManolis Kellis1:08:46

        How do I make sure that they're-

    30. LFLex Fridman1:08:47

        Exactly.
11. 1:13:18 – 1:30:16

    Life sucks sometimes and that's okay

    1. MKManolis Kellis1:13:18

    2. LFLex Fridman1:13:18

       So, we ... You mentioned kind of the ups and downs of life, and the midlife crisis, and right now, you said focusing kind of on the journey.

    3. MKManolis Kellis1:13:28

       Mm-hmm.

    4. LFLex Fridman1:13:29

       But what the journey involves is ups and downs.

    5. MKManolis Kellis1:13:33

       Mm-hmm.

    6. LFLex Fridman1:13:34

       Is there, uh, advice or any kind of thoughts that you can elucidate about the downs in your life-

    7. MKManolis Kellis1:13:44

       Yeah.

    8. LFLex Fridman1:13:44

       ... the hard ...... parts of your life and how you got out, or maybe not, or is there... Yeah, how do you see the dark parts-

    9. MKManolis Kellis1:13:54

       Yeah.

    10. LFLex Fridman1:13:54

        ... of life?

    11. MKManolis Kellis1:13:55

        So, I, I'm so glad you're asking this question because it's something that our society does a terrible job at preparing us for. Every Hollywood movie has to have a happy ending. It is ridiculous. You can count on your 10 fingers the number of bad-ending movies that you've ever watched. And you probably wouldn't need all 10 fingers.

    12. LFLex Fridman1:14:15

        (laughs) Yeah.

    13. MKManolis Kellis1:14:16

        We strive to tell everyone, "Yes, you can succeed. Yes, you're a millionaire, just temporarily disabled. And yes," you know, uh, "the prince will f- eventually figure out his princess and they will have a l- happily-ever-after ending. And yes, the hero will be beaten and beaten and beaten, but you know that at the end of the movie, the good guys will win." We need more movies where the bad guys win. We need more movies where just everybody dies.

    14. LFLex Fridman1:14:46

        (laughs)

    15. MKManolis Kellis1:14:47

        (laughs) Where, where just, you know, MacGyver doesn't figure out how to disable the bomb and it just explodes. (laughs) You just, you just need more movies that are more realistic about the fact that life kind of sucks sometimes and it's okay. So, again, growing up in Greece, I, I, uh, have been exposed to songs that are not just sad, but they're miserable.

    16. LFLex Fridman1:15:11

        (laughs)

    17. MKManolis Kellis1:15:11

        Miserable. So-

    18. LFLex Fridman1:15:14

        So they-

    19. MKManolis Kellis1:15:14

        ... so one of them, one of them comes to mind.

    20. LFLex Fridman1:15:17

        (laughs)

    21. MKManolis Kellis1:15:17

        And, and it's, it's basically talking about this woman who's lamenting in the early morning about losing the joyful kid, the joyful young man, who basically died in the civil war in the arms of our own fellow citizens. And she's like, "If only he had died fighting the foreign forces. If only he had died at the, you know, sides of the, you know, uh, general. If only he had died with honor-

    22. LFLex Fridman1:15:52

        Yeah.

    23. MKManolis Kellis1:15:52

        ... I would be proud to have lost the joyful kid." I mean, it's devastating, right?

    24. LFLex Fridman1:15:58

        (laughs)

    25. MKManolis Kellis1:15:59

        It's like, he didn't just die-

    26. LFLex Fridman1:16:01

        (laughs)

    27. MKManolis Kellis1:16:02

        ... he died without honor.

    28. LFLex Fridman1:16:03

        Yeah.

    29. MKManolis Kellis1:16:04

        And, and, uh, uh, my friend who was with me was listening to this song and she's like, "This is depressing." I'm like, "Whoa, whoa, whoa. You have to listen to another one. It's not as sad."

    30. LFLex Fridman1:16:12

        (laughs)

Episode duration: 2:10:52