Manolis Kellis is a professor at MIT and head of the MIT Computational Biology Group. Please check out our sponsors to get a discount and to support this podcast:
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EPISODE LINKS:
Manolis Website: http://web.mit.edu/manoli/
Manolis Twitter: https://twitter.com/manoliskellis
Manolis Wikipedia: https://en.wikipedia.org/wiki/Manolis_Kellis

PODCAST INFO:
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Full episodes playlist: https://www.youtube.com/playlist?list=PLrAXtmErZgOdP_8GztsuKi9nrraNbKKp4
Clips playlist: https://www.youtube.com/playlist?list=PLrAXtmErZgOeciFP3CBCIEElOJeitOr41

OUTLINE:
0:00 - Introduction
6:20 - Epigenome
10:28 - Evolution
15:26 - Neanderthals
27:15 - Origin of life on Earth
43:44 - Life is a fight against physics
49:56 - Life as a set of transformations
51:35 - Time scales
1:00:31 - Transformations of ideas in human civilization
1:05:19 - Life is more than a rat race
1:13:18 - Life sucks sometimes and that's okay
1:30:16 - Getting older
1:36:21 - The best of MIT
1:49:01 - Poem 1: The Snow
2:01:52 - Love
2:06:16 - Poem 2: The Tide Waters

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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 1 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 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 the 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.

1 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.

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.

For Joe, that involved talking to his friends, comedians, especially ones that brought out the best in him.

Duncan Trussell and the 5 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 5 Stars on Apple Podcast, follow on Spotify, support on Patreon, or connect with me on Twitter at Lex Friedman.

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.

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Personally, I'm kind of a long-time big fan of this planet.

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This episode is also supported by Magic Spoon, low carb, keto friendly cereal.

You might've 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 the cereal and he now 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.

He hasn't bought the 8 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.

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They gave me a suggested opening line of, using the internet without ExpressVPN is like going to the bathroom and not closing the door.

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And now here's my conversation with Manolis Kalis.

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 1 of your cells contains 2 meters worth of DNA, and this is compacted in a radius which is 1 thousandth of a millimeter.

To give you a sense of scale, it's as if a string as tall as the Burj al-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 2 meters worth of DNA in every 1 of your trillion cells, you would basically reach all the way to Jupiter a hundred times.

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 1 human body, into just the nuclei of 1 human body, and the vast majority of the human body is not even needed these nuclei.

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 1 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.

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

So the genome is the DNA and the epigenome is anything on top of the DNA.

And there's 3 types of things on top of the DNA.

The first is chemical modifications on the DNA itself.

So we like to think of 4 bases of the DNA, ACGT.

C has a methyl form, which is sometimes referred to as the fifth base.

So in the same way that you have annotations in an orchestra score that basically say whether you should play something softly or loudly or space it out or, you know, interpret basically the score.

The human epigenome allows you to modify that primary score.

So a modified C basically says, play this 1 softly.

It's basically a sign of repression in a gene regulatory region.

I love how you're talking about the function that emerges from the epigenome as a musical score.

And 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 chapters 7 from chromosome 23 and chapters 4 from chromosome 2 and so on and so forth.

And each of those pieces are all encoding 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 to play.

1 thing that kind of blows my mind, maybe you can tell me your thoughts about it, is the way evolution works with natural selection is based on the final, sort of, the entirety of the orchestra musical performance, right?

But there's these incredibly rich structural things, like each 1 of them doing their own little job that somehow work together.

The evolution selects based on the final result and yet all the individual pieces are doing like infinitely minuscule specific things.

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 you basically have at the very bottom every single nucleotide being selected.

But then that nucleotide function is selected at the level of each gene and every, 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 1 cell.

And many cells are converging onto the function of 1 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?

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 symbiosis of, there's plants, for example, that love CO2 and there's humans that love O2.

And we're sort of trading different types of gases to each other.

If you look at ecosystems where 1 organism was just really nasty, that organism actually died because everyone they were being nasty to was killed off.

And then that kind of universe of life is gone.

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

Yeah, I wonder if it's possible to break it down into levels that's selection even beyond humans.

Like you said environment, but there's environments that are all different levels too, right?

At the minuscule, at the organ level, at the tissue level, like you said, maybe at the microscopic level.

It'd be fascinating if there's a kind of selection going on at both the quantum level and the galaxy level.

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.

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, in the out of Africa event and you know, all of this sort of human history of evolution.

So basically, if you look at Neanderthal genes, for example, which again happened long after that 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, you know, that cellular environment constitutes the genetics of that gene, but also, of course, all of the epigenomics of that gene.

It's fascinating that the gene has a history.

I mean, we talked about this a little bit last time, and then some of your research goes into that, but the genes as they are today have a story from the beginning of time.

And then Sometimes their story was, like their path was useful for survival for the particular organisms and sometimes not.

Let me ask as a tangent, we kind of started talking offline about Neanderthals.

Do you have something interesting genetically, biologically, in terms of difference between Neanderthal and like the different branches of human evolution that you find fascinating?

are only 1 of about 5 branches that we are pretty confident about.

So basically there's Neanderthals, there's Denisovans.

1 tiny little fragment of 1 pinky from 1 cave in Siberia.

Recently, relatively recently discovered, right?

Yeah, and those are like little folks, right?

No, no, no, no, no, that's yet another 1 though.

Homo florensis, it had the little folks in sort of Indonesia.

But then the Nisovans are basically another branch that we only know about genetically from that 1 bone.

And eventually we realized that it's 1 of the 3 major branches along with Neanderthal, modern human and the Nisovan.

And then that 1 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 precursors that were wiped out by Zeus or by all kinds of wars and so on and so forth, like the Titans and the, you know, 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 archaeological evidence has been there and has probably entered the folk imagination migrating into those stories, but it's not that far, you know, removed from what actually happened of massive wars of wiping out Neanderthals as humans are, modern humans are populating Europe.

Do you think what killed the Neanderthals and all those other branches is human conflict or is it genetic conflict?

So Is it us humans being the opposite of altruistic towards each other?

Or is it some other competition at some other level like as we're discussing?

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, oh, I can't believe we're from the same region, my friend, come here, my family.

And like 2 neighboring countries fighting.

And as soon as they're off in another country, you're like, oh, I can't believe that.

So, it's kind of funny, like this tribalism is nonsensical in many ways.

It's like cognitive incongruent, that basically we like kin, and selection for sort of liking kin is hugely advantageous genetically.

Probably across all kinds of organs, across all kinds of life.

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 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 a 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 between,

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

Even before the out of Africa, there's, you know, within Africa selection, which was probably massive battles of larger and larger tribes selecting for our social networking and savviness and, you know, probably all our conspiracy theory genes are, you know, dating back from then.

And, you know, so there's a lot of this mischievousness in the history of human evolution that unfortunately is still present in many ugly forms today, but probably contributed to our success as a species in wiping out other species.

It just sucks that we don't have neighboring species that are intelligent like us, but yet very different than us.

So we have like, you know, dogs or wolves, I guess, co-evolved, they figured out how to neighbor up with humans in a friendly way and collaborate and develop in time.

You're describing this as if the wolves made a choice.

It's possible that the wolves never had a say, that basically humans were just so overpowering that they had captive wolves and then at every generation killed off 8 of the 9 pups and only kept the 1 that was milder.

And it only takes a few generations to then sort of have pups that are really mild.

And so the Neanderthals weren't useful in the same way that wolves were.

I don't know if it's a question of useful.

My thinking is that they were scary, that basically something that almost resembles you is something that you try to eliminate first.

And speaking of, you know, species that are intelligent and sort of what's left of evolution, it is a shame exactly like you say that so many different amazing life forms were extinct and the kind of boring ones remained.

So if you look at dinosaurs, I mean, the diversity that they had, if you look at sub, you know, like there's just so many different lineages of life that were just abruptly killed.

And yet, out of that death emerged, you know, many new kinds of really awesome lineages.

Do you think there was in the history of life on earth species that may be still alive today that are more intelligent than humans?

So there's a case that we made for dolphins.

Like if you look at their brains, if you look at the way that they play, if you look at the way that they learn, You know, I mean, they don't have opposable thumbs, and we do, so, you

know, that probably made a big difference.

It's terrifying to think that, like, not terrifying, I don't know how

to feel about it, that they're more intelligent than us.

I know, but how do you define intelligence?

Basically, like I was saying last time, you know, stupid is as stupid does, and smart is as smart does.

So if the dolphins are basically super smart, figured out the meaning of life, and just go around playing with water all day, which is probably the meaning of life, then we wouldn't know, because all they're doing is kicking water, just like sharks are, and sharks are probably pretty stupid.

So basically, it's very difficult to sort of judge a species' intelligence unless they kind of go out of

Yeah, and that's instructive for our understanding of any kind of life form.

You know, I recently talked to Sarah Seager looking for life out there on other planets.

It'd be fascinating to think if we discover a habitable planet you know, outside of Earth in 1 day, maybe many centuries away, or be able to travel with like a robot there, how would we actually know that this species would probably be able to detect that it's a living being, but how would we know if it's an intelligent being?

I mean, it's both exciting and terrifying to sort of come face to face with a life form that's of another world.

Like something that clearly is moving in a, how would you say, like a deliberate way?

And to then like ask, well how do I ask that thing whether it's intelligent?

No, but the question that you're asking is applicable to every species on the Earth now.

So basically, you know, dolphins are a great example.

We know that they're clearly capable hardware-wise and behavior-wise of intelligence.

So basically, if your question is about crossing species boundaries of communication, the way that I want to put it is that humans have achieved a level of sophistication in our behaviors, in our communication, in our language, in our ways of expressing ourselves, that I have no doubt that if we encountered a human-like form of intelligence, we'd figure out their language in a few weeks.

As long as, you know, of course, they're both trusting each other, not annihilating each other, and not sort of fearing each other and attacking each other.

What about, let me ask, just out of curiosity and into science fiction land a little bit.

So clearly you're 1 of the top scientists in the world, so if we were to discover an alien life form, you would be brought in to study its genetics.

Do you think the epigenome that we talked about, the genome, the code, the digital code that underlies that alien life form would be similar to ours?

Like in fundamental ways, maybe not exactly, but in fundamental ways of how it's structured?

Yeah, so you're getting to the very definition of life.

You're getting to the very definition of what makes life life and how do we decode that life.

And it's so easy to think that every life form would basically have to like oxygen, have to like heat from the sun, and rely on sort of being in the habitable zone of its solar system, and so on and so forth.

But I think we have to sort of go beyond this sort of, oh, life on another planet must be exactly like life is on Earth.

Because of course, life on Earth happens to rely on the proximity to the sun and benefit from that amount of energy.

But we're talking at timescales of human life, where we kind of live, I don't know, between, and I'm gonna be super wide here, we're gonna live between 6 Earth months and

So basically, if you look at the time scale that we inhabit on Earth, it is very much dictated by the amount of energy that we receive from the sun.

If you look at, I don't know, Europa, you know, the smallest, the fourth smallest moon of Jupiter, the smallest of the Galilean moons and also the smallest in its distance from Jupiter.

It has an iron core, it has a rock exterior, it has ice all around it and it has probably massive liquid oceans underneath.

And the gravitational pull of Jupiter is probably creating all kinds of movement under that ice.

Yes, sure, life now, most of life that we above the surface look at has to do with exploiting the solar energy for 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, you know, ducts that basically emanate a massive amount of energy from the core of our planet.

Does it need energy from, you know, the earth itself?

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