Tag: Lex Fridman

Transcript of Lex Fridman’s interview with Michael Levin

{This is my version of an annotated transcript of Lex Fridman’s interview with Michael Levin , episode 325, on 1 October 2022. I used the  transcripts for Lex Fridman episodes that Andrej Karpathy made using OpenAI Whisper as a starting point. I stripped out the text and then listened to the YouTube interview and started editing. Mainly, I created the dialog,added paragraphs, and corrected a few typos. New material I added is included in braces {}. I added the YouTube headings and an occasional screenshot. I decided to put this on the Internet in case it is useful for others. I welcome any suggestions for improvement.

Why did I do this? Because this is an interview that I wanted to study deeply. I will also share what I learned from Lex’s interview with Michael Levin. One of my goals 2023 was to listen to all of the available Lex Fridman interviews. }

{0:00 – Introduction}

{ML} It turns out that if you train a planarian and then cut their heads off, the tail will regenerate a brand new brain that still remembers the original information. I think planaria hold the answer to pretty much every deep question of life. For one thing, they’re similar to our ancestors. So they have true symmetry, they have a true brain, they’re not like earthworms, they’re, you know, they’re much more advanced life forms. They have lots of different internal organs, but they’re these little, they’re about, you know, maybe two centimeters in the centimeter to two in size. And they have a head and a tail. 

And the first thing is planaria are immortal. So they do not age. There’s no such thing as an old planarian. So that right there tells you that these theories of thermodynamic limitations on lifespan are wrong. It’s not that well over time everything degrades. No, planaria can keep it going for probably, you know, how long have they been around 400 million years, right? So these are the actual, so the planaria in our lab are actually in physical continuity with planaria that were here 400 million years ago. 

[LF} The following is a conversation with Michael Levin, one of the most fascinating and brilliant biologists I’ve ever talked to. He and his lab at Tufts University works on novel ways to understand and control complex pattern formation in biological systems. Andre Karpathy, a world class AI researcher, is the person who first introduced me to Michael Levin’s work. I bring this up because these two people make me realize that biology has a lot to teach us about AI, and AI might have a lot to teach us about biology. 

This is the Lex Fridman podcast. To support it, please check out our sponsors in the description. And now, dear friends, here’s Michael Levin. 

{1:40 – Embryogenesis}

Embryogenesis is the process of building the human body from a single cell. I think it’s one of the most incredible things that exists on earth from a single embryo. So how does this process work? 

{ML} Yeah, it is an incredible process. I think it’s maybe the most magical process there is. And I think one of the most fundamentally interesting things about it is that it shows that each of us takes the journey from so-called just physics to mind, right? Because we all start life as a single quiescent, unfertilized oocyte, and it’s basically a bag of chemicals, and you look at that and you say, okay, this is chemistry and physics. And then nine months and some years later, you have an organism with high level cognition and preferences and an inner life and so on. 

And what embryogenesis tells us is that that transformation from physics to mind is gradual. It’s smooth. There is no special place where, you know, a lightning bolt says, boom, now you’ve gone from physics to true cognition. That doesn’t happen. And so we can see in this process that the whole mystery, you know, the biggest mystery of the universe, basically, how you get mind from matter. 

{LF} From just physics, in quotes. Yeah. So where’s the magic into the thing? How do we get from information encoded in DNA and make physical reality out of that information? 

{ML} So one of the things that I think is really important if we’re going to bring in DNA into this picture is to think about the fact that what DNA encodes is the hardware of life. DNA contains the instructions for the kind of micro level hardware that every cell gets to play with. So all the proteins, all the signaling factors, the ion channels, all the cool little pieces of hardware that cells have, that’s what’s in the DNA. The rest of it is in so-called generic laws. And these are laws of mathematics. These are laws of computation. These are laws of physics, of all kinds of interesting things that are not directly in the DNA. 

And that process, you know, I think the reason I always put just physics in quotes is because I don’t think there is such a thing as just physics. I think that thinking about these things in binary categories, like this is physics, this is true cognition, this is as if it’s only faking these kinds of things. I think that’s what gets us in trouble. I think that we really have to understand that it’s a continuum and we have to work up the scaling, the laws of scaling. And we can certainly talk about that. There’s a lot of really interesting thoughts to be had there. 

{LF} So the physics is deeply integrated with the information. So the DNA doesn’t exist on its own. The DNA is integrated as, in some sense, in response to the laws of physics at every scale. The laws of the environment it exists in. 

{ML} Yeah, the environment and also the laws of the universe. I mean, the thing about the DNA is that it’s once evolution discovers a certain kind of machine, that if the physical implementation is appropriate, it’s sort of, and this is hard to talk about because we don’t have a good vocabulary for this yet, but it’s a very kind of a platonic notion that if the machine is there, it pulls down interesting things that you do not have to evolve from scratch because the laws of physics give it to you for free. So just as a really stupid example, if you’re trying to evolve a particular triangle, you can evolve the first angle and you evolve the second angle, but you don’t need to evolve the third. You know what it is already. Now, why do you know? That’s a gift for free from geometry in a particular space. You know what that angle has to be. 

And if you evolve an ion channel, which is, ion channels are basically transistors, right? They’re voltage gated current conductances. If you evolve that ion channel, you immediately get to use things like truth tables. You get logic functions. You don’t have to evolve the logic function. You don’t have to evolve a truth table. It doesn’t have to be in the DNA. You get it for free, right? And the fact that if you have NAND gates, you can build anything you want, you get that for free. All you have to evolve is that first step, that first little machine that enables you to couple to those laws. And there’s laws of adhesion and many other things. 

And this is all that interplay between the hardware that’s set up by the genetics and the software that’s made, right? The physiological software that basically does all the computation and the cognition and everything else is a real interplay between the information and the DNA and the laws of physics of computation and so on. 

{LF} So is it fair to say, just like this idea that the laws of mathematics are discovered, they’re latent within the fabric of the universe in that same way the laws of biology are kind of discovered? 

{ML} Yeah, I think that’s absolutely, and it’s probably not a popular view, but I think that’s right on the money. Yeah. 

{LF} Well, I think that’s a really deep idea. Then embryogenesis is the process of revealing, of embodying, of manifesting these laws. You’re not building the laws. 

{ML}  Yeah. 

{LF} You’re just creating the capacity to reveal. 

{ML} Yes. I think, again, not the standard view of molecular biology by any means, but I think that’s right on the money. I’ll give you a simple example. Some of our latest work with these xenobots, right? So what we’ve done is to take some skin cells off of an early frog embryo and basically ask about their plasticity. If we give you a chance to sort of reboot your multicellularity in a different context, what would you do? Because what you might assume by… The thing about embryogenesis is that it’s super reliable, right? It’s very robust. And that really obscures some of its most interesting features. We get used to it. We get used to the fact that acorns make oak trees and frog eggs make frogs. And we say, well, what else is it going to make? That’s what it makes. That’s a standard story. 

But the reality is… And so you look at these skin cells and you say, well, what do they know how to do? Well, they know how to be a passive boring two dimensional outer layer, keeping the bacteria from getting into the embryo. That’s what they know how to do. Well, it turns out that if you take these skin cells and you remove the rest of the embryo, so you remove all of the rest of the cells and you say, well, you’re by yourself now, what do you want to do? 

So what they do is they form this multi little creature that runs around the dish. They have all kinds of incredible and incredible capacities. They navigate through mazes. They have various behaviors that they do both independently and together. Basically, they implement von Neumann’s dream of self-replication, because if you sprinkle a bunch of loose cells into the dish, what they do is they run around, they collect those cells into little piles. They sort of mush them together until those little piles become the next generation of xenobots. So you’ve got this machine that builds copies of itself from loose material in its environment. 

None of this are things that you would have expected from the frog genome. In fact, the genome is wild type. There’s nothing wrong with their genetics. Nothing has been added, no nanomaterials, no genomic editing, nothing. 

And so what we have done there is engineered by subtraction. What you’ve done is you’ve removed the other cells that normally basically bully these cells into being skin cells. And you find out that what they really want to do is to be this, their default behaviors to be a xenobot. But in vivo, in the embryo, they get told to be skinned by these other cell types. 

And so now here comes this really interesting question that you just posed. When you ask where does the form of the tadpole and the frog come from, the standard answer is, well, it’s selection. So over millions of years, it’s been shaped to produce the specific body that’s fit for froggy environments. Where does the shape of the xenobot come from? 

There’s never been any xenobots. There’s never been selection to be a good xenobot. These cells find themselves in the new environment. In 48 hours, they figure out how to be an entirely different protoorganism with new capacities like kinematic self replication. That’s not how frogs or tadpoles replicate. We’ve made it impossible for them to replicate their normal way. Within a couple of days, these guys find a new way of doing it that’s not done anywhere else in the biosphere. 

{9:08 – Xenobots: biological robots}

{LF} Well, actually, let’s step back and define, what are xenobots? 

{ML} So a xenobot is a self-assembling little protoorganism. It’s also a biological robot. Those things are not distinct. It’s a member of both classes. 

{LF} How much is it biology? How much is that robot? 

{ML} At this point, most of it is biology because what we’re doing is we’re discovering natural behaviors of the cells and also of the cell collectives. Now, one of the really important parts of this was that we’re working together with Josh Bongard’s group at University of Vermont. They’re computer scientists, they do AI, and they’ve basically been able to use a simulated evolution approach to ask, how can we manipulate these cells, give them signals, not rewire their DNA, so not hardware, but experience signals? So can we remove some cells? Can we add some cells? Can we poke them in different ways to get them to do other things? 

So in the future, there’s going to be, we’re now, and this is future unpublished work, but we’re doing all sorts of interesting ways to reprogram them to new behaviors. But before you can start to reprogram these things, you have to understand what their innate capacities are. 

{LF} Okay, so that means engineering, programming, you’re engineering them in the future. And in some sense, the definition of a robot is something you in part engineer versus evolve. I mean, it’s such a fuzzy definition anyway, in some sense, many of the organisms within our body are kinds of robots. 

{ML}  Yes, yes.

{LF} And I think robots is a weird line because it’s, we tend to see robots as the other. I think there will be a time in the future when there’s going to be something akin to the civil rights movements for robots, but we’ll talk about that later perhaps. 

{ML}  Sure.

{LF} Anyway, so how do you, can we just linger on it? How do you build a Xenobot? What are we talking about here? From when does it start and how does it become the glorious Xenobot? 

{ML} Yeah, so just to take one step back, one of the things that a lot of people get stuck on is they say, well, you know, engineering requires new DNA circuits or it requires new nanomaterials, you know, what the thing is, we are now moving from old school engineering, which use passive materials, right? Those things, you know, wood, metal, things like this, that basically the only thing you could depend on is that they were going to keep their shape. That’s it. They don’t do anything else. It’s on you as an engineer to make them do everything they’re going to do. And then there were active materials and now computation materials. 

This is a whole new era. These are agential materials. This is you’re now collaborating with your substrate because your material has an agenda. These cells have, you know, billions of years of evolution. They have goals. They have preferences. They’re not just going to sit where you put them. 

{LF} That’s hilarious that you have to talk your material into keeping its shape. 

{ML} That’s it. That is exactly right. That is exactly right. Stay there.

{LF}  It’s like getting a bunch of cats or something and trying to organize the shape out of them. It’s funny. 

{ML} We’re on the same page here because in a paper, this is, this is currently just been accepted in nature by engineering. One of the figures I have is building a tower out of Legos versus dogs, right? So think about the difference, right? If you build out of Legos, you have full control over where it’s going to go. But if somebody knocks it over, it’s game over. With the dogs, you cannot just come and stack them. They’re not going to stay that way. But the good news is that if you train them, then somebody knocks it over, they’ll get right back up. So it’s all right. 

So as an engineer, what you really want to know is what can they depend on this thing to do, right? That’s really, you know, a lot of people have definitions of robots as far as what they’re made of or how they got here, you know, design versus evolve, whatever. I don’t think any of that is useful.

 I think, I think as an engineer, what you want to know is how much can I depend on this thing to do when I’m not around to micromanage it? What level of, what level of dependency can I, can I give this thing? How much agency does it have? Which then tells you what techniques do you use? So do you use micromanagement, like you put everything where it goes? Do you train it? Do you give it signals? Do you try to convince it to do things, right? How much, you know, how intelligent is your substrate? And so now we’re moving into this, into this area where you’re, you’re, you’re working with agential materials. That’s a collaboration. That’s not, that’s not old, old style. 

{LF} What’s the word you’re using? Agential? 

{ML} Agential. Yeah. What’s that mean? Agency. It comes from the word agency. So, so basically the material has agency, meaning that it has some, some level of obviously not human level, but some level of preferences, goals, memories, ability to remember things, to compute into the future, meaning anticipate, you know, when you’re working with cells, they have all of that to some, to various degrees.

{LF}  Is that empowering or limiting having material as a mind of its own, literally? 

{ML} I think it’s both, right? So it raises difficulties because it means that it, if you, if you’re using the old mindset, which is a linear kind of extrapolation of what’s going to happen, you’re going to be surprised and shocked all the time because biology does not do what we linearly expect materials to do. On the other hand, it’s massively liberating. And so in the following way, I’ve argued that advances in regenerative medicine require us to take advantage of this because what it means is that you can get the material to do things that you don’t know how to micromanage. 

So just as a simple example, right? If you, if you, you had a rat and you wanted this rat to do a circus trick, put a ball in the little hoop, you can do it the micromanagement way, which is try to control every neuron and try to play the thing like a puppet, right? And maybe someday that’ll be possible, maybe, or you can train the rat. And this is why humanity for thousands of years before we knew any neuroscience, we had no idea what’s behind, what’s between the ears of any animal. We were able to train these animals because once you recognize the level of agency of a certain system, you can use appropriate techniques. If you know the currency of motivation, reward and punishment, you know how smart it is, you know what kinds of things it likes to do. You are searching a much more, much smoother, much nicer problem space than if you try to micromanage the thing. 

And in regenerative medicine, when you’re trying to get, let’s say an arm to grow back or an eye to repair a cell birth defect or something, do you really want to be controlling tens of thousands of genes at each point to try to micromanage it? Or do you want to find the high level modular controls that say, build an arm here. You already know how to build an arm. You did it before, do it again. So that’s, I think it’s both, it’s both difficult and it challenges us to develop new ways of engineering and it’s hugely empowering. 

{LF} Okay. So how do you do, I mean, maybe sticking with the metaphor of dogs and cats, I presume you have to figure out the, find the dogs and dispose of the cats. Because, you know, it’s like the old herding cats is an issue. So you may be able to train dogs. I suspect you will not be able to train cats. Or if you do, you’re never going to be able to trust them. So is there a way to figure out which material is amenable to herding? Is it in the lab work or is it in simulation?

{ML}  Right now it’s largely in the lab because we, our simulations do not capture yet the most interesting and powerful things about biology. So the simulation does, what we’re pretty good at simulating are feed forward emergent types of things, right? So cellular automata, if you have simple rules and you sort of roll those forward for every, every agent or every cell in the simulation, then complex things happen, you know, ant colony or algorithms, things like that. We’re good at that. And that’s, and that’s fine. 

The difficulty with all of that is that it’s incredibly hard to reverse. So this is a really hard inverse problem, right? If you look at a bunch of termites and they make a, you know, a thing with a single chimney and you say, well, I like it, but I’d like two chimneys. How do you change the rules of behavior for each termite? So they make two chimneys, right? Or, or if you say, here are a bunch of cells that are creating this kind of organism. I don’t think that’s optimal. I’d like to repair that birth defect. How do you control all the, all the individual low level rules, right? All the protein interactions and everything else, rolling it back from the anatomy that you want to the low level hardware rules is in general intractable. It’s a, it’s an inverse problem that’s generally not solvable. 

So right now it’s mostly in the lab because what we need to do is we need to understand how biology uses top down controls. So the idea is not, not bottom up emergence, but the idea of things like a goal directed test-operate-exit kinds of loops where, where it’s basically an error minimization function over a new space and not a space of gene expression, but for example, a space of anatomy. 

So just as a simple example, if you have, you have a salamander and it’s got an arm, you can, you can amputate that arm anywhere along the length. It will grow exactly what’s needed and then it stops. That’s the most amazing thing about regeneration is that it stops it knows when to stop. When does it stop? It stops when a correct salamander arm has been completed. 

So that tells you that’s right. That’s a, that’s a, a means ends kind of analysis where it has to know what the correct limb is supposed to look like, right? So it has a way to ascertain the current shape. It has a way to measure that delta from, from what shape it’s supposed to be. And it will keep taking actions, meaning remodeling and growing and everything else until that’s complete. 

So once you know that, and we’ve taken advantage of this in the lab to do some, some really wild things with, with both planaria and frog embryos and so on, once you know that, you can start playing with that, with that homeostatic cycle. You can ask, for example, well, how does it remember what the correct shape is? And can we mess with that memory? Can we give it a false memory of what the shape should be and let the cells build something else? Or can we mess with the measurement apparatus, right? So it gives you, it gives you those kinds of, so, 

so, so the idea is to basically appropriate a lot of the approaches and concepts from cognitive neuroscience and behavioral science into things that previously were taken to be dumb materials. And, you know, you get yelled at in class if you, if you, for being anthropomorphic, if you said, well, my cells want to do this and my cells want to do that. And I think, I think that’s a, that’s a major mistake that leaves a ton of capabilities on the table. 

{LF} So thinking about biologic systems as things that have memory, have almost something like cognitive ability, but I mean, how incredible is it, you know, that the salamander arm is being rebuilt, not with a dictator. It’s kind of like the cellular automata system. All the individual workers are doing their own thing. So where’s that top down signal that does the control coming from? Like, how can you find it? 

{ML} Yeah.

{LF} Like, why does it stop growing? How does it know the shape? How does it have memory of the shape? And how does it tell everybody to be like, whoa, whoa, whoa, slow down, we’re done. 

{ML} So the first thing to think about, I think, is that there are no examples anywhere of a central dictator, because in this kind of science, because everything is made of parts. And so we, even though we feel as a unified central sort of intelligence and kind of point of cognition, we are a bag of neurons, right? All intelligence is collective intelligence. There’s this, this is important to kind of think about, because a lot of people think, okay, there’s real intelligence, like me, and then there’s collective intelligence, which is ants and flocks of birds and termites and things like that. And maybe it’s appropriate to think of them as an individual, and maybe it’s not, and a lot of people are skeptical about that and so on. But you’ve got to realize that we are not, there’s no such thing as this like indivisible diamond of intelligence that’s like this one central thing that’s not made of parts. We are all made of parts. 

And so if you believe, which I think is hard to get around, that we in fact have a centralized set of goals and preferences and we plan and we do things and so on, you are already committed to the fact that a collection of cells is able to do this, because we are a collection of cells. There’s no getting around that. In our case, what we do is we navigate the three dimensional world and we have behavior. 

{LF} This is blowing my mind right now, because we are just a collection of cells. 

{ML} Oh yeah. 

{LF} So when I’m moving this arm, I feel like I’m the central dictator of that action, but there’s a lot of stuff going on. All the cells here are collaborating in some interesting way. They’re getting signal from the central nervous system. 

{ML} Well, even the central nervous system is misleadingly named because it isn’t really central. Again, it’s just a bunch of cells. I mean, all of them, right? There are no, there are no singular indivisible intelligences anywhere. We are all, every example that we’ve ever seen is a collective of something. It’s just that we’re used to it. We’re used to that. We’re used to, okay, this thing is kind of a single thing, but it’s really not. You zoom in, you know what you see. You see a bunch of cells running around. 

{LF} Is there some unifying, I mean, we’re jumping around, but that something that you look at as the bioelectrical signal versus the biochemical, the chemistry, the electricity, maybe the life is in that versus the cells. It’s the, there’s an orchestra playing and the resulting music is the dictator. 

{ML} That’s not bad. That’s Dennis Noble’s kind of view of things. He has two really good books where he talks about this musical analogy, right?  So I think that’s, I like it. I like it.

{LF}  Is it wrong though? 

{ML} I don’t think it’s, no, I don’t think it’s wrong. I don’t think it’s wrong. I think the important thing about it is that we have to come to grips with the fact that a true proper cognitive intelligence can still be made of parts. Those things are, and in fact it has to be, and I think it’s a real shame, but I see this all the time. When you have a collective like this, whether it be a group of robots or a collection of cells or neurons or whatever, as soon as we gain some insight into how it works, meaning that, oh, I see, in order to take this action, here’s the information that got processed via this chemical mechanism or whatever. Immediately people say, oh, well then that’s not real cognition. That’s just physics.

{22:55 – Sense of self}

 I think this is fundamentally flawed because if you zoom into anything, what are you going to see? Of course you’re just going to see physics. What else could be underneath, right? It’s not going to be fairy dust. It’s going to be physics and chemistry, but that doesn’t take away from the magic of the fact that there are certain ways to arrange that physics and chemistry and in particular the bioelectricity, which I like a lot, to give you an emergent collective with goals and preferences and memories and anticipations that do not belong to any of the subunits. 

So I think what we’re getting into here, and we can talk about how this happens during embryogenesis and so on, what we’re getting into is the origin of a self with a capital S. So we ourselves, there are many other kinds of selves, and we can tell some really interesting stories about where selves come from and how they become unified. 

{LF} Yeah, is this the first, or at least humans tend to think that this is the level of which the self with a capital S is first born, and we really don’t want to see human civilization or Earth itself as one living organism. 

{ML} Yeah.

{LF} that’s very uncomfortable to us. It is, yeah. But is, yeah, where’s the self born? 

{ML} We have to grow up past that. So what I like to do is, I’ll tell you two quick stories about that. I like to roll backwards. So as opposed to, so if you start and you say, okay, here’s a paramecium, and you see it, you know, it’s a single cell organism, you see it doing various things, and people will say, okay, I’m sure there’s some chemical story to be told about how it’s doing it, so that’s not a paramecium. So that’s not true cognition, right? And people will argue about that. 

{ML} I like to work it backwards. I say, let’s agree that you and I, as we sit here, are examples of true cognition, if anything, as if there’s anything that’s true cognition, we are examples of it. Now let’s just roll back slowly, right? So you roll back to the time when you were a small child and used to doing whatever, and then just sort of day by day, you roll back, and eventually you become more or less that paramecium, and then you sort of even below that, right, as an unfertilized OSI. So it’s, no one has, to my knowledge, no one has come up with any convincing discrete step at which my cognitive powers disappear, right? It just doesn’t, the biology doesn’t offer any specific step. It’s incredibly smooth and slow and continuous. And so I think this idea that it just sort of magically shows up at one point, and then, you know, humans have true selves that don’t exist elsewhere, I think it runs against everything we know about evolution, everything we know about developmental biology, these are all slow continua. 

And the other really important story I want to tell is where embryos come from. So think about this for a second. Amniote embryos, so this is humans, birds, and so on, mammals and birds and so on. Imagine a flat disk of cells, so there’s maybe 50,000 cells. And in that, so when you get an egg from a fertilized, let’s say you buy a fertilized egg from a farm, right? That egg will have about 50,000 cells in a flat disk, it looks like a little tiny little frisbee. And in that flat disk, what’ll happen is there’ll be one set of cells will become special, and it will tell all the other cells, I’m going to be the head, you guys don’t be the head. And so it’ll amplify symmetry breaking amplification, you get one embryo, there’s some neural tissue and some other stuff forms. 

Now, you say, okay, I had one egg and one embryo, and there you go, what else could it be? Well, the reality is, and I used to, I did all of this as a grad student, if you take a little needle, and you make a scratch in that blastoderm in that disk, such that the cells can’t talk to each other for a while, it heals up, but for a while, they can’t talk to each other. What will happen is that both regions will decide that they can be the embryo, and there will be two of them. And then when they heal up, they become conjoint twins, and you can make two, you can make three, you can make lots. So the question of how many cells are in there cannot be answered until it’s actually played all the way through. It isn’t necessarily that there’s just one, there can be many. 

So what you have is you have this medium, this, this undifferentiated, I’m sure there’s a there’s a psychological version of this somewhere that I don’t know the proper terminology. But you have this, you have this list, like the ocean of potentiality, you have these 1000s of cells, and some number of individuals are going to be formed out of it, usually one, sometimes zero, sometimes several. And they form out of these cells, because a region of these cells organizes into a collective that will have goals, goals that individual cells don’t have, for example, make a limb, make an eye, how many eyes? Well, exactly two. So individual cells don’t know what an eye is, they don’t know how many eyes you’re supposed to have, but the collective does. The collective has goals and memories and anticipations that the individual cells don’t. And that that the establishment of that boundary with its own ability to maintain to to pursue certain goals. That’s the origin of selfhood. 

{LF} But I, is that goal in there somewhere? Were they always destined? Like, are they discovering that goal? Like, where the hell did evolution discover this when you went from the prokaryotes to eukaryotic cells? And then they started making groups. And when you make a certain group, you make a, you make it sound, and it’s such a tricky thing to try to understand, you make it sound like this cells didn’t get together and came up with a goal. But the very act of them getting together revealed the goal that was always there. There was always that potential for that goal. 

{ML} So the first thing to say is that there are way more questions here than certainties. Okay, so everything I’m telling you is cutting edge developing, you know, stuff. So it’s not as if any of us know the answer to this. But, but here’s, here’s, here’s my opinion on this. I think what evolution, I don’t think that evolution produces solutions to specific problems, in other words, specific environments, like here’s a frog that can live well in a froggy environment. I think what evolution produces is problem solving machines that that will that will solve problems in different spaces. So not just three dimensional spaces, but in a way, three dimensional space. 

This goes back to what we were talking about before we the brain is a evolutionarily a late development. It’s a system that is able to pursue goals in three dimensional space by giving commands to muscles, where did that system come from? That system evolved from a much more ancient, evolutionarily much more ancient system, where collections of cells gave instructions to for cell behaviors, meaning cells move to divide to die to change into different cell types, to navigate amorphous space, the space of anatomies, the space of all possible anatomies. And before that, cells were navigating transcriptional space, which is a space of all possible gene expressions. And before that metabolic space. 

So what evolution has done, I think, is produced hardware that is very good at navigating different spaces using a bag of tricks, right, which which I’m sure many of them we can steal for autonomous vehicles and robotics and various things. And what happens is that they navigate these spaces without a whole lot of commitment to what the space is. In fact, they don’t know what the space is, right? We are all brains in a vat, so to speak. Every cell does not know, right? Every cell is some other name, some other cells external environment, right? 

So where does that with that border between you, you and the outside world, you don’t really know where that is, right? Every collection of cells has to figure that out from scratch. And the fact that evolution requires all of these things to figure out what they are, what effectors they have, what sensors they have, where does it make sense to draw a boundary between me and the outside world? The fact that you have to build all that from scratch, this autopoiesis is what defines the border of a self. Now, biology uses a multi-scaled competency architecture, meaning that every level has goals. So so molecular networks have goals, cells have goals, tissues, organs, colonies. And and it’s the interplay of all of those that that enable biology to solve problems in new ways, for example, in xenobots and various other things. 

This is, you know, it’s exactly as you said, in many ways, the cells are discovering new ways of being. But at the same time, evolution certainly shapes all this. So so evolution is very good at this agential bioengineering, right? When evolution is discovering a new way of being an animal, you know, an animal or a plant or something, sometimes it’s by changing the hardware, you know, protein, changing proteins, protein structure, and so on. But much of the time, it’s not by changing the hardware, it’s by changing the signals that the cells give to each other. It’s doing what we as engineers do, which is try to convince the cells to do various things by using signals, experiences, stimuli. That’s what biology does. It has to, because it’s not dealing with a blank slate. 

Every time as you know, if you’re evolution, and you’re trying to make an organism, you’re not dealing with a passive material that is fresh, and you have to specify it already wants to do certain things. So the easiest way to do that search to find whatever is going to be adaptive, is to find the signals that are going to convince cells to do various things, right? 

{LF} Your sense is that evolution operates both in the software and the hardware. And it’s just easier, more efficient to operate in the software. 

{ML} Yes. And I should also say, I don’t think the distinction is sharp. In other words, I think it’s a continuum. But I think we can but I think it’s a meaningful distinction where you can make changes to a particular protein, and now the enzymatic function is different, and it metabolizes differently, and whatever, and that will have implications for fitness. Or you can change the huge amount of information in the genome that isn’t structural at all. It’s, it’s, it’s signaling, it’s when and how do cells say certain things to each other. And that can have massive changes, as far as how it’s going to solve problems. 

{32:26 – Multi-scale competency architecture}

{LF} I mean, this idea of multi hierarchical competency architecture, which is incredible to think about. So this hierarchy that evolution builds, I don’t know who’s responsible for this. I also see the incompetence of bureaucracies of humans when they get together. So how the hell does evolution build this, where at every level, only the best get to stick around, they somehow figure out how to do their job without knowing the bigger picture. 

{ML} Yeah.

{LF} And then there’s like the bosses that do the bigger thing somehow, or that you can now abstract away the small group of cells as an organ or something. And then that organ does something bigger in the context of the full body or something like this. How is that built? Is there some intuition you can kind of provide of how that’s constructed, that hierarchical competence architecture? I love that competence, just the word competence is pretty cool in this context, because everybody’s good at their job. 

{ML} Yeah, no, it’s really key. And the other nice thing about competency is that so my central belief in all of this is that engineering is the right perspective on all of this stuff, because it gets you away from subjective terms. You know, people talk about sentience and this and that those things are very hard to define, or people argue about them philosophically. 

I think that engineering terms like competency, like, you know, pursuit of goals, right? All of these things are, are empirically incredibly useful, because you know, when you see it, and if it helps you build, right, if I if I can pick the right level, I say, this thing has, I believe this is x level of like, competency, I think it’s like a thermostat, or I think it’s like a better thermostat, or I think it’s a, you know, various other kinds of, you know, many, many different kinds of complex systems. If that helps me to control and predict and build such systems, then that’s all there is to say, there’s no more philosophy to argue about. 

So I like competency in that way, because you can quantify, you could, you have to, in fact, you have to, you have to make a claim competent at what? And then, or if I say, if I tell you, it has a goal, the question is, what’s the goal? And how do you know? And I say, well, because every time I deviated from this particular state, that’s what it spends energy to get back to, that’s the goal. And we can quantify it, and we can be objective about it. 

So we’re not used to thinking about this, I give a talk sometimes called Why don’t robots get cancer, right? And the reason robots don’t get cancer is because generally speaking, with a few exceptions, our architectures have been, you’ve got a bunch of dumb parts. And you hope that if you put them together, the overlying machine will have some intelligence and do something rather, right, but the individual parts don’t don’t care, they don’t have an agenda.

 Biology isn’t like that, every level has an agenda. And the final outcome is the result of cooperation and competition, both within and across levels. So for example, during embryogenesis, your tissues and organs are competing with each other. And it’s actually a really important part of development, there’s a reason they compete with each other, they’re not all just, you know, sort of helping each other, they’re also competing for information, for metabolic for limited metabolic constraints. 

But to get back to your your other point, which is, you know, which is which is the seems like really efficient and good and so on compared to some of our human efforts. We also have to keep in mind that what happens here is that each level bends the option space for the level beneath so that your parts basically they don’t see the the geometry. So I’m using them. And I think I take this seriously,  terminology from like, from like relativity, right, where the space is literally bent. So the option space is deformed by the higher level so that the lower levels, all they really have to do is go down their concentration gradient, they don’t have to, in fact, they don’t, they can’t know what the big picture is. But if you bend the space just right, if they do what locally seems right, they end up doing your bidding, they end up doing things that are optimal in the higher space.  Conversely, because the components are good at getting their job done, you as the higher level don’t need to try to compute all the low level controls, all you’re doing is bending the space, you don’t know or care how they’re going to do it. 

Give you a super simple example in the  tadpole, we found that okay, so  tadpoles need to become frogs and to become to go from a  tadpole head to a frog head, you have to rearrange the face. So the eyes have to move forward, the jaws have to come out the nostrils move like everything moves. It used to be thought that because all  tadpoles look the same, and all frogs look the same. If you just remember, if every piece just moves in the right direction, the right amount, then you get your you get your frog. Right. 

So we decided to test we I have this hypothesis that I thought I thought actually, the system is probably more intelligent than that. So what did we do? We made what we call Picasso  tadpoles. So these are so everything is scrambled. So the eyes are on the back of the head, the jaws are off to the side, everything is scrambled. Well, guess what they make, they make pretty normal frogs, because all the different things move around in novel paths configurations until they get to the correct froggy sort of frog face configuration, then they stop. 

So, so the thing about that is now imagine evolution, right? So, so you make some sort of mutation, and it does, like every mutation, it does many things. So something good comes of it, but also it moves your mouth off to the side, right? Now, if if there wasn’t this multi scale competency, you can see where this is going, if there wasn’t this multi scale competency, the organism would be dead, your fitness is zero, because you can’t eat. And you would never get to explore the other beneficial consequences of that mutation, you’d have to wait until you find some other way of doing it without moving the mouth, that’s really hard. So, the fitness landscape would be incredibly rugged, evolution would take forever. The reason it works, one of the reasons it works so well, is because you do that, no worries, the mouth will find its way where it belongs, right? 

So now you get to explore. So what that means is that all of these mutations that otherwise would be deleterious are now neutral, because the competency of the parts make up for all kinds of things. So all the noise of development, all the variability in the environment, all these things, the competency of the parts makes up for it. So that’s all that’s all fantastic, right? That’s all that’s all great. 

The only other thing to remember when we compare this to human efforts is this. Every component has its own goals in various spaces, usually with very little regard for the welfare of the other levels. So as a simple example, you know, you  as a complex system, you will go out and you will do you know, jiu jitsu, or whatever, you’ll have some go you have to go rock climbing, scrape a bunch of cells off your hands. And then you’re happy as a system, right? You come back, and you’ve accomplished some goals, and you’re really happy. Those cells are dead. They’re gone. Right? Did you think about those cells? Not really, right? You had some you had some bruising…

{LF} You selfish SOB. 

{ML} That’s it. And so and so that’s the thing to remember is that, you know, and we know this from history is that just being a collective isn’t enough. Because what the goals of that collective will be relative to the welfare of the individual parts is a massively open question.

{LF} The ends justify the means I’m telling you, Stalin was onto something. 

{ML} No, that’s the danger. 

{LF} But we can exactly. That’s the danger of for us humans, we have to construct ethical systems under which we don’t take seriously the full mechanism of biology and apply it to the way the world functions, which is an interesting line we’ve drawn. The world that built us is the one we reject in some sense, 

{ML} Yeah.

{LF} when we construct human societies, the idea that this country was founded on that all men are created equal. That’s such a fascinating idea. That’s like, you’re fighting against nature and saying, well, there’s something bigger here than a hierarchical competency architecture. 

{ML} Yeah.

{LF} But there’s so many interesting things you said. So from an algorithmic perspective, the act of bending the option space. That’s really, that’s really profound. Because if you look at the way AI systems are built today, there’s a big system, like I said, with robots, and as a goal, and he gets better and better at optimizing that goal at accomplishing that goal. But if biology built a hierarchical system where everything is doing computation, and everything is accomplishing the goal, not only that, it’s kind of dumb, you know, with the limited with a bent option space is just doing the thing that’s the easiest thing for in some sense. And somehow that allows you to have turtles on top of turtles, literally dumb systems on top of dumb systems that as a whole create something incredibly smart. 

{ML} Yeah, I mean, every system has some degree of intelligence in its own problem domain. So, cells will have problems they’re trying to solve in physiological space and transcriptional space. And then I can give you some cool examples of that. 

But the collective is trying to solve problems in anatomical space, right and forming a, you know, a creature and growing your blood vessels and so on. And then the collective the whole body is solving yet other problems, they may be in social space and linguistic space and three dimensional space. And who knows, you know, the group might be solving problems in, you know, I don’t know, some sort of financial space or something. 

So one of the major differences with most AIs today is (A) the kind of flatness of the architecture, but also of the fact that they’re constructed from outside their borders, and they’re, you know, so a few. So, to a large extent, and of course, there are counterexamples now, but but to a large extent, our technology has been such that you create a machine or a robot, it knows what its sensors are, it knows what its effectors are, it knows the boundary between it and the outside world, although this is given from the outside. Biology constructs this from scratch. 

Now the best example of this that that originally in robotics was actually Josh Bongard’s work in 2006, where he made these, these robots that did not know their shape to start with. So like a baby, they sort of floundered around, they made some hypotheses, well, I did this, and I moved in this way. Well, maybe I’m a whatever, maybe I have wheels, or maybe I have six legs or whatever, right? And they would make a model and eventually will crawl around. 

So that’s, I mean, that’s really good. That’s part of the autopoiesis, but we can go a step further. And some people are doing this. And then we’re sort of working on some of this too, is this idea that let’s even go back further, you don’t even know what sensors you have, you don’t know where you end in the outside world begins. 

All you have is certain things like active inference, meaning you’re trying to minimize surprise, right? You have some metabolic constraints, you don’t have all the energy you need, you don’t have all the time in the world to think about everything you want to think about. So that means that you can’t afford to be a micro reductionist, you know, all this data coming in, you have to course grain it and say, I’m gonna take all this stuff, and I’m gonna call that a cat. I’m gonna take all this, I’m gonna call that the edge of the table I don’t want to fall off of. And I don’t want to know anything about the micro states, what I want to know is what is the optimal way to cut up my world. And by the way, this thing over here, that’s me. And the reason that’s me is because I have more control over this than I have over any of this other stuff. And so now you can begin to write. 

So that’s self construction at that, that figuring out making models of the outside world, and then turning that inwards, and starting to make a model of yourself, right, which immediately starts to get into issues of agency and control. 

{43:57 – Free will}

Because in order to….  if you are under metabolic constraints, meaning you don’t have the energy, right, that all the energy in the world, you have to be efficient, that immediately forces you to start telling stories about coarse grained agents that do things, right, you don’t have the energy to like Laplace’s demon, you know, calculate every, every possible state that’s going to happen, you have to you have to coarse grain, and you have to say, that is the kind of creature that does things, either things that I avoid, or things that I will go towards, that’s a major food or whatever, whatever it’s going to be. 

And so right at the base of simple, very simple organisms starting to make models of agents doing things, that is the origin of models of free will, basically, right, because you see the world around you as having agency. And then you turn that on yourself. And you say, wait, I have agency too, I can, I do things, right. And then you make decisions about what you’re going to do. So all of this one model is to view all of those kinds of things as being driven by that early need to determine what you are and to do so and to then take actions in the most energetically efficient space possible. 

{LF} Right. So free will emerges when you try to simplify, tell a nice narrative about your environment. 

{ML} I think that’s very plausible. Yeah. 

{LF} You think free was an illusion. So you’re kind of implying that it’s a useful hack. Well, I’ll say two things. 

{ML} The first thing is, I think I think it’s very plausible to say that any organism that self or any agent that self whether it’s biological or not, any agent that self constructs under energy constraints, is going to believe in free will, we’ll get to whether it has free will momentarily. But I think what it definitely drives is a view of yourself and the outside world as an agential view, I think that’s inescapable. 

{LF} So that’s true for even primitive organisms? 

{ML} I think so. I think that’s now they don’t have now obviously, you have to scale down, right. So they don’t have the kinds of complex metacognition that we have. So they can do long term planning and thinking about free will and so on and so on. But

{LF}  the sense of agency is really useful to accomplish tasks simple or complicated. 

{ML} That’s right. In all kinds of spaces, not just in obvious three dimensional space. I mean, we’re very good that the thing is, humans are very good at detecting agency of like medium sized objects moving at medium speeds in the three dimensional world, right? We see a bowling ball and we see a mouse and we immediately know what the difference is, right? And how we’re going to 

{LF} Mostly things you can eat or get eaten by. 

{ML} Yeah, yeah. That’s our training set, right? From the time you’re little, your training set is visual data on this like little chunk of your experience. But imagine if imagine if from the time that we were born, we had innate senses of your blood chemistry, if you could feel your blood chemistry, the way you can see, right, you had a high bandwidth connection, and you could feel your blood chemistry, and you could see, you could sense all the things that your organs were doing. So your pancreas, your liver, all the things. 

If we had that, we would be very good at detecting intelligence and physiological space, we would know the level of intelligence that our various organs were deploying to deal with things that were coming to anticipate the stimuli to, you know, but we’re just terrible at that. We don’t, in fact, in fact, people don’t even, you know, you talk about intelligence that these are these {unintelligible} spaces. And a lot of people think that’s just crazy, because, because all we’re all we know is motion. 

{LF} We do have access to that information. So it’s actually possible that so evolution could if we wanted to construct an organism that’s able to perceive…. 

{ML} Most certainly.

{LF} the flow of blood through your body, the way you see an old friend and say, yo, what’s up? How’s the wife and the kids? In that same way, you would see that you would feel like a connection to the liver. 

{ML} Yeah, yeah, I think, you know, 

{LF} maybe other people’s liver and not just your own, because you don’t have access to other people’s liver. 

{ML} Not yet. But you could imagine some really interesting connection, right? 

{LF} Like sexual selection, like, oh, that girl’s got a nice liver. Well, that’s like, the way her blood flows, the dynamics of the blood is very interesting. It’s novel. I’ve never seen one of those. 

{ML} But you know, that’s exactly what we’re trying to half ass when we judge judgment of beauty by facial symmetry and so on. That’s a half assed assessment of exactly that. Because if your cells could not cooperate enough to keep your organism symmetrical, you know, you can make some inferences about what else is wrong, right? Like that’s a very, you know, that’s a very basic. 

{LF} Interesting. Yeah. So that in some deep sense, actually, that is what we’re doing. We’re trying to infer how health, we use the word healthy, but basically, how functional is this biological system I’m looking at so I can hook up with that one and make offspring? 

{ML} Yeah, yeah. Well, what kind of hardware might their genomics give me that might be useful in the future? 

{LF} I wonder why evolution didn’t give us a higher resolution signal. Like why the whole peacock thing with the feathers? It doesn’t seem, it’s a very low bandwidth signal for sexual selection. 

{ML} I’m gonna, and I’m not an expert on this stuff, but on peacocks. Well, you know, but I’ll take a stab at the reason. I think that it’s because it’s an arms race. You see, you don’t want everybody to know everything about you. So I think that as much as, as much as, and in fact, there’s another interesting part of this arms race, which is, if you think about this, the most adaptive, evolvable system is one that has the most level of top down control, right?

 If it’s really easy to say to a bunch of cells, make another finger versus, okay, here’s 10,000 gene expression changes that you need to do to make it to change your finger, right? The system with good top down control that has memory and when we need to get back to that, by the way, that’s a question I neglected to answer about where the memory is and so on. A system that uses all of that is really highly evolvable and that’s fantastic. But guess what? It’s also highly subject to hijacking by parasites, by cheaters of various kinds, by conspecifics. 

Like we found that, and then that goes back to the story of the pattern memory in these planaria, there’s a bacterium that lives on these planaria. That bacterium has an input into how many heads the worm is going to have because it’s hijacks that control system and it’s able to make a chemical that basically interfaces with the system that calculates how many heads you’re supposed to have and they can make them have two heads. And so you can imagine that if you are two, so you want to be understandable for your own parts to understand each other, but you don’t want to be too understandable because you’ll be too easily controllable. And so I think that my guess is that that opposing pressure keeps us from being a super high bandwidth kind of thing where we can just look at somebody and know everything about them. 

{LF} So it’s a kind of biological game of Texas hold them. You’re showing some cards and you’re hiding other cards and there’s part of it and there’s bluffing and there’s all that. And then there’s probably whole species that would do way too much bluffing. That’s probably where peacocks fall. There’s a book that I don’t remember if I read or if I read summaries of the book, but it’s about evolution of beauty and birds. Where is that from? Is that a book or does Richard Dawkins talk about it? But basically there’s some species start to like over select for beauty, not over select. They just for some reason select for beauty. There is a case to be made. Actually now I’m starting to remember, I think Darwin himself made a case that you can select based on beauty alone. There’s a point where beauty doesn’t represent some underlying biological truth. 

{ML} That’s right, that’s right.

{LF} You start to select for beauty itself. And I think the deep question is there some evolutionary value to beauty, but it’s an interesting kind of thought that can we deviate completely from the deep biological truth to actually appreciate some kind of the summarization in itself. 

Let me get back to memory because this is a really interesting idea. How do a collection of cells remember anything? How do biological systems remember anything? How is that akin to the kind of memory we think of humans as having within our big cognitive engine? 

{ML} Yeah. One of the ways to start thinking about bioelectricity is to ask ourselves, where did neurons and all these cool tricks that the brain uses to run these amazing problem solving abilities on and basically an electrical network, right? Where did that come from? They didn’t just evolve, you know, appear out of nowhere. It must have evolved from something. 

And what it evolved from was a much more ancient ability of cells to form networks to solve other kinds of problems. For example, to navigate amorphous space to control the body shape. And so all of the components of neurons, so ion channels, neurotransmitter machinery, electrical synapses, all this stuff is way older than brains, way older than neurons, in fact, older than multicellularity. And so it was already that even bacterial biofilms, there’s some beautiful work from UCSD on brain like dynamics and bacterial biofilms. So evolution figured out very early on that electrical networks are amazing at having memories, at integrating information across distance, at different kinds of optimization tasks, you know, image recognition and so on, long before there were brains. 

{LF} Can you actually just step back? We’ll return to it.

{53:27 – Bioelectricity}

What is bioelectricity? What is biochemistry? What is, what are electrical networks? I think a lot of the biology community focuses on the chemicals as the signaling mechanisms that make the whole thing work. You have, I think, to a large degree, uniquely, maybe you can correct me on that, have focused on the bioelectricity, which is using electricity for signaling. There’s also probably mechanical. Sure, sure. Like knocking on the door. So what’s the difference? And what’s an electrical network? 

{ML} Yeah, so I want to make sure and kind of give credit where credit is due. So as far back as 1903, and probably late 1800s already, people were thinking about the importance of electrical phenomena in life. So I’m for sure not the first person to stress the importance of electricity. People, there were waves of research in the in the 30s, in the 40s, and then, again, in the kind of 70s, 80s, and 90s of sort of the pioneers of bioelectricity, who did some amazing work on all this.

I think, I think what what we’ve done that’s new, is to step away from this idea that, and I’ll describe what what the bioelectricity is a step away from the idea that, well, here’s another piece of physics that you need to keep track of to understand physiology and development. And to really start looking at this as saying, no, this is a privileged computational layer that gives you access to the actual cognition of the tissue of basal cognition. So, merging that developmental biophysics with ideas and cognition of computation, and so on, I think I think that’s what we’ve done that’s new. 

But people have been talking about bioelectricity for a really long time. And so I’ll, so I’ll define that. So what happens is that if you have, if you have a single cell, cell has a membrane, in that membrane are proteins called ion channels, and those proteins allow charged molecules, potassium, sodium, chloride, to go in and out under certain circumstances. And when there’s an imbalance of those ions, there becomes a voltage gradient across that membrane. And so all cells, all living cells try to hold a particular kind of voltage difference across the membrane, and they spend a lot of energy to do so. When you now now, so that’s it, that’s it, that’s a single cell. 

When you have multiple cells, the cells sitting next to each other, they can communicate their voltage state to each other via a number of different ways. But one of them is this thing called a gap junction, which is basically like a little submarine hatch that just kind of docks, right? And the ions from one side can flow to the other side, and vice versa. So… 

{LF} Isn’t it incredible that this evolved? Isn’t that wild? Because that didn’t exist. 

{ML} Correct. This had to be, this had to be evolved. 

{LF} It had to be invented. That’s right. Somebody invented electricity in the ocean. When did this get invented? 

{ML} Yeah. So, I mean, it is incredible. The guy who discovered gap junctions, Werner Loewenstein, I visited him. He was really old. 

{LF} A human being? He discovered them. Because who really discovered them lived probably four billion years ago. 

{ML} Good point. So you give credit where credit is due, I’m just saying. He rediscovered gap junctions. But when I visited him in Woods Hole, maybe 20 years ago now, he told me that he was writing, and unfortunately, he passed away, and I think this book never got written. He was writing a book on gap junctions and consciousness. And I think it would have been an incredible book, because gap junctions are magic. I’ll explain why in a minute. 

What happens is that, just imagine, the thing about both these ion channels and these gap junctions is that many of them are themselves voltage sensitive. So that’s a voltage sensitive current conductance. That’s a transistor. And as soon as you’ve invented one, immediately, you now get access to, from this platonic space of mathematical truths, you get access to all of the cool things that transistors do. So now, when you have a network of cells, not only do they talk to each other, but they can send messages to each other, and the differences of voltage can propagate. 

Now, to neuroscientists, this is old hat, because you see this in the brain, right? This action potentials, the electricity.  They have these awesome movies where you can take a zebra, like a transparent animal, like a zebrafish, and you can literally look down, and you can see all the firings as the fish is making decisions about what to eat and things like this. It’s amazing. Well, your whole body is doing that all the time, just much slower. 

So there are very few things that neurons do that all the cells in your body don’t do. They all do very similar things, just on a much slower timescale. And whereas your brain is thinking about how to solve problems in three dimensional space, the cells in an embryo are thinking about how to solve problems in anatomical space. They’re trying to have memories like, hey, how many fingers are we supposed to have? Well, how many do we have now? What do we do to get from here to there? That’s the kind of problems they’re thinking about. 

And the reason that gap junctions are magic is, imagine, right, from the earliest time. Here are two cells. This cell, how can they communicate? Well, the simple version is this cell could send a chemical signal, it floats over, and it hits a receptor on this cell, right? Because it comes from outside, this cell can very easily tell that that came from outside. Whatever information is coming, that’s not my information. That information is coming from the outside. So I can trust it, I can ignore it, I can do various things with it, I can do various things with it, whatever, but I know it comes from the outside. 

Now imagine instead that you have two cells with a gap junction between them. Something happens, let’s say this cell gets poked, there’s a calcium spike, the calcium spike or whatever small molecule signal propagates through the gap junction to this cell. There’s no ownership metadata on that signal. This cell does not know now that it came from outside because it looks exactly like its own memories would have looked like of whatever had happened, right? 

So gap junctions to some extent wipe ownership information on data, which means that if I can’t, if you and I are sharing memories and we can’t quite tell who the memories belong to, that’s the beginning of a mind meld. That’s the beginning of a scale up of cognition from here’s me and here’s you to no, now there’s just us. 

{LF} So they enforce a collective intelligence gap junctions. 

{ML} That’s right. It helps. It’s the beginning. It’s not the whole story by any means, but it’s the start. 

{LF} Where’s state stored of the system? Is it in part in the gap junctions themselves? Is it in the cells? 

{ML} There are many, many layers to this as always in biology. So there are chemical networks. So for example, gene regulatory networks, right? Which, or basically any kind of chemical pathway where different chemicals activate and repress each other, they can store memories. So in a dynamical system sense, they can store memories. They can get into stable states that are hard to pull them out of. So that becomes, once they get in, that’s a memory, a permanent memory or a semi permanent memory of something that’s happened. 

There are cytoskeletal structures that are physically, they store memories in physical configuration. 

There are electrical memories like flip flops where there is no physical. So if you look, I showed my students this example as a flip flop. And the reason that it stores a zero one is not because some piece of the hardware moved. It’s because there’s a cycling of the current in one side of the thing. If I come over and I hold the other side to a high voltage for a brief period of time, it flips over and now it’s here. But none of the hardware moved. The information is in a stable dynamical sense. And if you were to x-ray the thing, you couldn’t tell me if it was zero or one, because all you would see is where the hardware is. You wouldn’t see the energetic state of the system. So there are bioelectrical states that are held in that exact way, like volatile RAM basically, like in the electrical state. 

{LF} It’s very akin to the different ways that memory is stored in a computer. So there’s RAM, there’s a hard drive. 

{ML} You can make that mapping, right? So I think the interesting thing is that based on the biology, we can have a more sophisticated, you know, I think we can revise some of our computer engineering methods because there are some interesting things that biology we haven’t done yet. But that mapping is not bad. I mean, I think it works in many ways. 

{LF} Yeah, I wonder because I mean, the way we build computers at the root of computer science is the idea of proof of correctness. We program things to be perfect, reliable. You know, this idea of resilience and robustness to unknown conditions is not as important. So that’s what biology is really good at. So I don’t know what kind of systems. I don’t know how we go from a computer to a biological system in the future. 

{ML} Yeah, I think that, you know, the thing about biology is all about making really important decisions really quickly on very limited information. I mean, that’s what biology is all about. You have to act, you have to act now. The stakes are very high, and you don’t know most of what you need to know to be perfect. And so there’s not even an attempt to be perfect or to get it right in any sense. There are just things like active inference, minimize surprise, optimize some efficiency and some things like this that guides the whole business. 

{LF} I mentioned to you offline that somebody who’s a fan of your work is Andre Kapathy. And he’s, amongst many things, also writes occasionally a great blog. He came up with this idea, I don’t know if he coined the term, but of software 2.0, where the programming is done in the space of configuring these artificial neural networks. Is there some sense in which that would be the future of programming for us humans, where we’re less doing like Python like programming and more… How would that look like? But basically doing the hyperparameters of something akin to a biological system and watching it go and adjusting it and creating some kind of feedback loop within the system so it corrects itself. And then we watch it over time accomplish the goals we want it to accomplish. Is that kind of the dream of the dogs that you described in the Nature paper? 

{ML} Yeah. I mean, that’s what you just painted is a very good description of our efforts at regenerative medicine as a kind of somatic psychiatry. So the idea is that you’re not trying to micromanage. I mean, think about the limitations of a lot of the medicines today. We try to interact down at the level of pathways. So we’re trying to micromanage it. What’s the problem? 

Well, one problem is that for almost every medicine other than antibiotics, once you stop it, the problem comes right back. You haven’t fixed anything. You were addressing symptoms. You weren’t actually curing anything, again, except for antibiotics. That’s one problem. 

The other problem is you have a massive amount of side effects because you were trying to interact at the lowest level. It’s like, I’m going to try to program this computer by changing the melting point of copper. Maybe you can do things that way, but my God, it’s hard to program at the hardware level. 

So what I think we’re starting to understand is that, and by the way, this goes back to what you were saying before about that we could have access to our internal state. So people who practice that kind of stuff, so yoga and biofeedback and those, those are all the people that uniformly will say things like, well, the body has an intelligence and this and that. Those two sets overlap perfectly because that’s exactly right. Because once you start thinking about it that way, you realize that the better locus of control is not always at the lowest level. This is why we don’t all program with a soldering iron. 

We take advantage of the high level intelligences that are there, intelligences that are there, which means trying to figure out, okay, which of your tissues can learn? What can they learn? Why is it that certain drugs stop working after you take them for a while with this habituation, right? And so can we understand habituation, sensitization, associative learning, these kinds of things in chemical pathways? 

We’re going to have a completely different way. I think we’re going to have a completely different way of using drugs and of medicine in general when we start focusing on the goal states and on the intelligence of our subsystems as opposed to treating everything as if the only path was micromanagement from chemistry upwards.

{LF} Well, can you speak to this idea of somatic psychiatry? What are somatic cells? How do they form networks that use bioelectricity to have memory and all those kinds of things? 

{ML} Yeah. 

{LF} What are somatic cells like basics here? 

{ML} Somatic cells just means the cells of your body. Soma just means body, right? So somatic cells are just the… I’m not even specifically making a distinction between somatic cells and stem cells or anything like that. I mean, basically all the cells in your body, not just neurons, but all the cells in your body. They form electrical networks during embryogenesis, during regeneration. 

What those networks are doing in part is processing information about what our current shape is and what the goal shape is. Now, how do I know this? Because I can give you a couple of examples. 

{1:06:44 – Planaria}

One example is when we started studying this, we said, okay, here’s a planarian. A planarian is a flatworm. It has one head and one tail normally.  And the amazing… There’s several amazing things about planaria, but basically they kind of… I think planaria hold the answer to pretty much every deep question of life. For one thing, they’re similar to our ancestors. So they have true symmetry. They have a true brain. They’re not like earthworms. They’re a much more advanced life form. They have lots of different internal organs, but they’re these little… They’re about maybe two centimeters in the centimeter to two in size. They have a head and a tail. And the first thing is planaria are immortal. 

So they do not age. There’s no such thing as an old planarian. So that right there tells you that these theories of thermodynamic limitations on lifespan are wrong. It’s not that well over time everything degrades. No, planaria can keep it going for probably how long have they been around 400 million years. So the planaria in our lab are actually in physical continuity with planaria that were here 400 million years ago. 

{LF} So there’s planaria that have lived that long essentially. What does it mean: physical continuity? 

{ML} Because what they do is they split in half. The way they reproduce is they split in half. So the planaria, the back end grabs the petri dish, the front end takes off and they rip themselves in half. 

{LF} But isn’t it some sense where like you are a physical continuation? 

{ML} Yes, except that we go through a bottleneck of one cell, which is the egg. They do not. I mean, they can. There’s certain planaria. 

{LF} Got it. So we go through a very ruthless compression process and they don’t. 

{ML} Yes. Like an auto encoder, you know, sort of squashed down to one cell and then back out. These guys just tear themselves in half. 

And so the other amazing thing about them is they regenerate. So you can cut them into pieces. The record is, I think, 276 or something like that by Thomas Hunt Morgan. And each piece regrows a perfect little worm. They know exactly, every piece knows exactly what’s missing, what needs to happen. In fact, if you chop it in half, as it grows the other half, the original tissue shrinks so that when the new tiny head shows up, they’re proportional. So it keeps perfect proportion. If you starve them, they shrink. If you feed them again, they expand. Their control, their anatomical control is just insane. 

{LF} Somebody cut them into over 200 pieces? 

{ML} Yeah. Thomas Hunt Morgan did. 

{LF} Hashtag science. Amazing. 

{ML} And maybe more. I mean, they didn’t have antibiotics back then. I bet he lost some due to infection. I bet it’s actually more than that. I bet you could do more than that. 

{LF} Humans can’t do that. Well, yes. I mean, again, true, except that… 

{ML} Maybe you can at the embryonic level. Well, that’s the thing, right? So when I talk about this, I say, just remember that as amazing as it is to grow a whole planarian from a tiny fragment, half of the human population can grow a full body from one cell. So development is really, you can look at development as just an example of regeneration. 

{LF} Yeah. To think, we’ll talk about regenerative medicine, but there’s some sense of what would be like that worm in like 500 years where I can just go regrow a hand. 

{ML} Yep. With given time, it takes time to grow large things. 

{LF} For now. Yeah, I think so. I think. You can probably… Why not accelerate? Oh, biology takes its time?

{ML} I’m not going to say anything is impossible, but I don’t know of a way to accelerate these processes. I think it’s possible. I think we are going to be regenerative, but I don’t know of a way to make it faster. 

{LF} I could just think people from a few centuries from now would be like, well, they used to have to wait a week for the hand to regrow. It’s like when the microwave was invented. You can toast your… What’s that called when you put a cheese on a toast? It’s delicious is all I know. I’m blanking. Anyhow. All right. So planaria, why were we talking about the magical planaria that they have the mystery of life? 

{ML} Yeah. So the reason we’re talking about planaria is not only are they immortal, not only do they regenerate every part of the body, they generally don’t get cancer, which we can talk about why that’s important. They’re smart. They can learn things. You can train them. And it turns out that if you train a planaria and then cut their heads off, the tail will regenerate a brand new brain that still remembers the original information. 

{LF} Do they have a biological network going on or no? 

{ML} Yes. 

{LF} So their somatic cells are forming a network. And that’s what you mean by a true brain? What’s the requirement for a true brain? 

{ML} Like everything else, it’s a continuum, but a true brain has certain characteristics as far as the density, like a localized density of neurons that guides behavior. 

{LF} In the head. 

{ML} Exactly. Exactly. If you cut their head off, the tail doesn’t do anything. It just sits there until a new brain regenerates. They have all the same neurotransmitters that you and I have. 

But here’s why we’re talking about them in this context. So here’s your planaria. You cut off the head. You cut off the tail. You have a middle fragment. That middle fragment has to make one head and one tail. How does it know how many of each to make? And where do they go? How come it doesn’t switch? How come, right? 

So we did a very simple thing. And we said, okay, let’s make the hypothesis that there’s a somatic electrical network that remembers the correct pattern, and that what it’s doing is recalling that memory and building to that pattern. 

So what we did was we used a way to visualize electrical activity in these cells, right? It’s a variant of what people used to look for electricity in the brain. And we saw that that fragment has a very particular electrical pattern. You can literally see it once we developed the technique. It has a very particular electrical pattern that shows you where the head and the tail goes, right? You can just see it. 

And then we said, okay, well now let’s test the idea that that’s a memory that actually controls where the head and the tail goes. Let’s change that pattern. So basically, incept the false memory. 

And so what you can do is you can do that in many different ways. One way is with drugs that target ion channels to say, and so you pick these drugs and you say, okay, I’m going to do it so that instead of this one head, one tail electrical pattern, you have a two headed pattern, right? You’re just editing the electrical information in the network. When you do that, guess what the cells build? They build a two headed worm. 

And the coolest thing about it, no genetic changes. So we haven’t touched the genome. The genome is totally wild type. But the amazing thing about it is that when you take these two headed animals and you cut them into pieces again, some of those pieces will continue to make two headed animals.

So that information, that memory, that electrical circuit, not only does it hold the information for how many heads, not only does it use that information to tell the cells what to do to regenerate, but it stores it. Once you’ve reset it, it keeps. And we can go back, we can take a two headed animal and put it back to one headed. 

So now imagine, so there’s a couple of interesting things here that have implications for understanding what genomes and things like that. Imagine I take this two headed animal. Oh, and by the way, when they reproduce, when they tear themselves in half, you still get two headed animals. So imagine I take them and I throw them in the Charles River over here. So 100 years later, some scientists come along and they scoop up some samples and they go, oh, there’s a single headed form and a two headed form. Wow, a speciation event. Cool. Let’s sequence the genome and see why, what happened. The genomes are identical. There’s nothing wrong with the genome. 

So if you ask the question, how does, so, this goes back to your very first question is where do body plans come from, right? How does the planarian know how many heads it’s supposed to have? Now it’s interesting because you could say DNA, but what happened, what, what, as it turns out, the DNA produces a piece of hardware that by default says one head the way that when you turn on a calculator, by default, it’s a zero every single time, right? When you turn it on, it just says zero, but it’s a programmable calculator as it turns out. So once you’ve changed that next time, it won’t say zero. It’ll say something else and the same thing here. 

So you can make one headed, two headed, you can make no headed worms. We’ve done some other things along these lines, some other really weird constructs. So, so this, this, this, this question of, right. So again, it’s really important. The hardware-software distinction is really important because the hardware is essential because without proper hardware, you’re never going to get to the right physiology of having that memory. But once you have it, it doesn’t fully determine what the information is going to be. You can have other information in there and it’s reprogrammable by us, by bacteria, by various parasites, probably things like that. 

The other amazing thing about these planarias, think about this, most animals, when we get a mutation in our bodies, our children don’t inherit it, right? So you can go on, you could run around for 50, 60 years getting mutations. Your children don’t have those mutations because we go through the egg stage. 

Planaria tear themselves in half and that’s how they reproduce. So for 400 million years, they keep every mutation that they’ve had that doesn’t kill the cell that it’s in. So when you look at these planaria, their bodies are what’s called mixoploid, meaning that every cell might have a different number of chromosomes. They look like a tumor. If you look at the, the genome is an incredible mess because they accumulate all this stuff. And yet the, their body structure is, they are the best regenerators on the planet. Their anatomy is rock solid, even though their genome is always all kinds of crap. 

So this is a kind of a scandal, right? That, you know, when we learn that, well, you know, what are genomes to what genomes determine your body? Okay. Why is the animal with the worst genome have the best anatomical control, the most cancer resistant, the most regenerative, right? Really, we’re just beginning to start to understand this relationship between the genomically determined hardware and, and, and by the way, just as of, as of a couple of months ago, I think I now somewhat understand why this is, but it’s really, it’s really a major, you know, a major puzzle. 

{LF} I mean, that really throws a wrench into the whole nature versus nurture because you usually associate electricity with the, with the nurture and the hardware with the nature. And it’s, there’s just this weird integrated mess that propagates through generations. 

{ML} Yeah. It’s much more fluid. It’s much more complex. You can, you can imagine what’s happening here is just, just imagine the evolution of an animal like this, that, that multi scale, this goes back to this multi scale competency, right? 

Imagine that you have two, two, two, you have, you have an animal that that where its, its tissues have some degree of multi scale competency. So for example, if the like, like we saw in the tadpole, you know, if you put an eye on its tail, they can still see out of that eye, right? That the, you know, there’s all, there’s incredible plasticity. 

So if you have an animal and it comes up for selection and the fitness is quite good, evolution doesn’t know whether the fitness is good because the genome was awesome or because the genome was kind of junky, but, but the competency made up for it, right? And things kind of ended up good. 

So what that means is that the more competency you have, the harder it is for selection to pick the best genomes, it hides information, right? And so that means that, so, so what happens, you know, evolution basically starts all those start, all the hard work is being done to increase the competency because it’s harder and harder to see the genomes. And so I think in planaria, what happened is that there’s this runaway phenomenon where all the effort went into the algorithm such that we know you got a crappy genome. We can’t keep, we can’t clean up the genome. We can’t keep track of it. So what’s going to happen is what survives are the algorithms that can create a great worm no matter what the genome is. 

So everything went into the algorithm and which, which of course then reduces the pressure on keeping a, you know, keeping a clean genome. So this idea of, right, and different animals have this in different, to different levels, but this idea of putting energy into an algorithm that does not overtrain on priors, right? It can’t assume, I mean, I think biology is this way in general, evolution doesn’t take the past too seriously because it makes these basically problem solving machines as opposed to like exactly what, you know, to, to, to deal with exactly what happened last time. 

{LF} Yeah. Problem solving versus memory recall. So a little memory, but a lot of problem solving. 

{ML} I think so. Yeah. In many cases, yeah. 

{LF} Problem solving. I mean, it’s incredible that those kinds of systems are able to be constructed, um, especially how much they contrast with the way we build problem solving systems in the AI world. 

{1:18:33 – Building xenobots}

Back to Xenobots. I’m not sure if we ever described how Xenobots are built, but I mean, you have a paper titled: Biological robots perspectives on an emerging interdisciplinary field. And the beginning you, uh, you mentioned that the word Xenobots is like controversial. Do you guys get in trouble for using Xenobots or what? Do people not like the word Xenobots? Are you trying to be provocative with the word Xenobots versus biological robots? I don’t know. Is there some drama that we should be aware of? 

{ML} Yeah. There’s a little bit of drama. Uh, I think, I think the drama is basically related to people, um, having very fixed ideas about what terms mean. And I think in many cases, these ideas are completely out of date with where science is now. And for sure they’re, they’re out of date with what’s going to be, I mean, these, these, these concepts, uh, are not going to survive the next couple of decades. 

So if you ask a person and including, um, you know, a lot of people in biology who kind of want to keep a sharp distinction between biologicals and robots, right? See, what’s a robot? Well, a robot, it comes out of a factory. It’s made by humans. It is boring. It is a meaning that you can predict everything it’s going to do. It’s made of metal and certain other inorganic materials. Living organisms are magical. They, they, they arise, right? And so on. 

So these, these distinctions, I think these, these distinctions, I think were, were never good, but, uh, they’re going to be completely useless going forward. And so part of, there’s a couple of papers that’s one paper and there’s another one that Josh Bongard and I wrote {paper} where we really attack the terminology. And we say these binary categories are based on very, um, nonessential kind of surface limitations of, of technology and imagination that were true before, but they’ve got to go. And so, and so we call them Xenobots. So, so Xeno for Xenopus laevis, where this is, it’s the frog that, that these guys are made of, but we think it’s an example of a biobot technology, because ultimately if we, if we under, once we understand how to, uh, communicate and manipulate, um, the inputs to these cells, we will be able to get them to build whatever we want them to build. And that’s robotics, right? It’s the rational construction of machines that have useful purposes. I absolutely think that this is a robotics platform, whereas some biologists don’t.

{LF} But it’s built in a way that, uh, all the different components are doing their own computation. So in a way that we’ve been talking about, so you’re trying to do top down control in that biological system. 

{ML} That’s exactly right. And in the future, all of this will, will, will merge together because of course at some point we’re going to throw in synthetic biology circuits, right? New, new, um, you know, new transcriptional circuits to get them to do new things. Of course we’ll throw some of that in, but we specifically stayed away from all of that because in the first few papers, and there’s some more coming down the pike that are, I think going to be pretty, pretty dynamite, um, that, uh, we want to show what the native cells are made of. 

Because what happens is, you know, if you engineer the heck out of them, right, if we were to put in new, you know, new transcription factors and some new metabolic machinery and whatever, people will say, well, okay, you engineered this and you made it do whatever. And fine. I wanted to show, uh, and, and, and the whole team, uh, wanted to show the plasticity and the intelligence in the biology. What does it do that’s surprising before you even start manipulating the hardware in that way? 

{LF} Yeah. Don’t try to, uh, over control the thing. Let it flourish. The full beauty of the biological system. Why Xenopus laevis? How do you pronounce it? 

{ML}  The frog. Xenopus laevis. Yeah. Yeah. It’s a very popular. Why this frog? It’s been used since, uh, I think the fifties. Uh, it’s just very convenient because you can, you know, we, we keep the adults in this, in this, uh, very fine frog habitat. They lay eggs. They lay tens of thousands of eggs at a time. The eggs develop right in front of your eyes. It’s the most magical thing you can, you can see because normally, you know, if you were to deal with mice or rabbits or whatever, you don’t see the early stages, right? Because everything’s inside the mother. Everything’s in a Petri dish at room temperature. So you just, you, you have an egg, it’s fertilized and you can just watch it divide and divide and divide. And on all the organs form, you can just see it. And at that point, um, the community has, has developed lots of different tools for understanding what’s going on and also for, for manipulating, right? So it’s, it’s people use it for, um, you know, for understanding birth defects and neurobiology and cancer immunology. 

{LF} So you get the whole, uh, embryogenesis in the Petri dish. That’s so cool to watch. Is there videos of this? 

{ML} Oh yeah. Yeah. Yeah. There’s, but yeah, there’s, there’s amazing videos on, on, online. I mean, mammalian embryos are super cool too. For example, monozygotic twins are what happens when you cut a mammalian embryo in half. You don’t get two half bodies. You get two perfectly normal bodies because it’s a regeneration event, right? Development is just the, it’s just the kind of regeneration really. 

{LF} And why this particular frog? It’s just, uh, cause they were doing in the fifties and…

{ML}  It breeds well in, um, you know, in, in, it’s easy to raise in, in the laboratory and, uh, it’s very prolific and all the tools basically for decades, people have been developing tools. There’s other, some people use other frogs, but I have to say this is, this is, this is important. Xenobots are fundamentally not anything about frogs. So, um, I can’t say too much about this cause it’s not published and peer reviewed yet, but we’ve made Xenobots out of other things that have nothing to do with frogs. It’s…. this is not a frog phenomenon. This is, we, we started with frog because it’s so convenient, but this, this, this plasticity is not a frog. You know, it’s not related to the fact that they’re frogs. 

{LF} What happens when you kiss it? Does it turn into a prince? No. Or a princess? Which way? Uh, prince. Yeah. Prince should be a prince. 

{ML} Yeah. Uh, that’s an experiment that I don’t believe we’ve done. And if we have, I don’t want to collaborate, 

{LF} I can, I can take on the lead, uh, on that effort. Okay, cool. Uh, how does the cells coordinate? Let’s focus in on just the embryogenesis. So there’s one cell, so it divides, doesn’t have to be very careful about what each cell starts doing once they divide. 

{ML} Yes. 

{LF} And like, when there’s three of them, it’s like the cofounders or whatever, like, well, like slow down, you’re responsible for this. When do they become specialized and how do they coordinate that specialization? 

{ML} So, this is the basic science of developmental biology. There’s a lot known about all of that, but, um, but I’ll tell you what I think is kind of the most important part, which is, yes, it’s very important who does what. However, because going back to this issue of why I made this claim that, um, biology doesn’t take the past too seriously. And what I mean by that is it doesn’t assume that everything is the way it’s, it’s expected to be. Right. 

{ML} And here’s an example of that. Um, this was, this was done, this was, this was an old experiment going back to the forties, but, um, basically imagine it’s a newt, salamander and it’s got these little tube tubules that go to the kidneys, right? It’s a little tube. Take a cross section of that tube. You see eight to 10 cells that have cooperated to make this little tube in cross section, right? 

So one amazing, one amazing thing you can do is, um, you can, you can mess with a very early cell division to make the cells gigantic, bigger. You can, you can make them different sizes. You can force them to be different sizes. So if you make the cells different sizes, the whole newt is still the same size. So if you take a cross section through the, through that tubule, instead of eight to 10 cells, you might have four or five or you might have, you know, three until you make the cells so enormous that one single cell wraps around itself and, and gives you that same large scale structure with a completely different molecular mechanism. So now instead of cell to cell communication to make a tubule, instead of that, it’s one cell using the cytoskeleton to bend itself around. 

So think about what that means in the service of a large scale, talk about top down control, right? In the service of a large-scale anatomical feature, different molecular mechanisms get called up. So now think about this, you’re, you’re, you’re a newt cell and trying to make an embryo. If you had a fixed idea of who was supposed to do what, you’d be screwed because now your cells are gigantic. Nothing would work. There’s an incredible tolerance for changes in the size of the parts and the amount of DNA in those parts. Um, all sorts of stuff you can, you can, the life is highly interoperable. You can put electrodes in there and you can put weird nanomaterials. It still works. It’s, it’s, uh, this is that problem solving action, right? It’s able to do what it needs to do, even when circumstances change. That is, you know, the hallmark of intelligence, right? William James defined intelligence as the ability to get to the same goal by different means. That’s this, you get to the same goal by completely different means.

 And so why am I bringing this up is just to say that, yeah, it’s important for the cells to do the right stuff, but they have incredible tolerances for things not being what you expect and to still get their job done. So if you’re, you know, um, all of these things are not hardwired. 

There are organisms that might be hardwired. For example, the nematode C elegans in that organism, every cell is numbered, meaning that every C elegans has exactly the same number of cells as every other C elegans. They’re all in the same place. They all divide. There’s literally a map of how it works that in that, in that sort of system, it’s, it’s, it’s much more cookie cutter, but, but most, most organisms are incredibly plastic in that way. 

{LF} Is there something particularly magical to you about the whole developmental biology process? Um, is there something you could say, cause you just said it, they’re very good at accomplishing the goal of the job they need to do the competency thing, but you get fricking organism from one cell. It’s like, uh, I mean, it’s very hard, hard to intuit that whole process to even think about reverse engineering that process. 

{ML} Right. Very hard to the point where I often just imagine, I, I sometimes ask my students to do this thought experiment. Imagine you were, you were shrunk down to the, to the scale of a single cell and you were in the middle of an embryo and you were looking around at what’s going on and the cells running around, some cells are dying at the, you know, every time you look, it’s kind of a different number of cells for most organisms. And so I think that if you didn’t know what embryonic development was, you would have no clue that what you’re seeing is always going to make the same thing. Nevermind knowing what that, what that is. Nevermind being able to say, even with full genomic information, being able to say, what the hell are they building? We have no way to do that. But, but just even to guess that, wow, the, the, the outcome of all this activity is it’s always going to be, it’s always going to build the same thing. 

{LF} The imperative to create the final you as you are now is there already. So you can, you would, so you start from the same embryo, you create a very similar organism. 

{ML} Yeah. Except for cases like the Xenobots, when you give them a different environment, they come up with a different way to be adaptive in that environment. But overall, I mean, so, so I think, so I think to, you know, kind of summarize it, I think what evolution is really good at is creating hardware that has a very stable baseline mode, meaning that left to its own devices, it’s very good at doing the same thing. But it has a bunch of problem solving capacity such that if any, if any assumptions don’t hold, if your cells are a weird size, or you get the wrong number of cells, or there’s a, you know, somebody stuck in electrode halfway through the body, whatever, it will still get most of what it needs to do done. 

{LF} You’ve talked about the magic and the power of biology here. If we look at the human brain, how special is the brain in this context? You’re kind of minimizing the importance of the brain or lessening its…. We think of all the special computation happens in the brain, everything else is like the help. You’re kind of saying that the whole thing is the whole thing is doing computation. But nevertheless, how special is the human brain in this full context of biology? 

{ML} Yeah, I mean, look, there’s no getting away from the fact that the human brain allows us to do things that we could not do without it. 

{ML} You can say the same thing about the liver….. The heart 

{ML} Yeah, no, this is true. And so and so, you know, I, my goal is not No, you’re right. My goal is ….

{LF} You’re just being polite to the brain right now. Well, like being a politician, like, listen, everybody has everybody has a role. Yeah, it’s a very important role. 

{ML} That’s right. 

{LF} We have to acknowledge the importance of the brain, you know, 

{ML} There are more than enough people who are cheerleading the brain, right? So I don’t feel like; nothing I say is going to reduce people’s excitement about the human brain. And so

{LF}  emphasize other things credit. 

{ML} I don’t think it gets too much credit, I think other things don’t get enough credit. I think the human brain is incredible and special and all that. I think other things need more credit. And I also think that this and I’m sort of this way about everything. I don’t like binary categories, but almost anything. I like a continuum. And the thing about the human brain is that it… by accepting that as some kind of an important category or essential thing, we end up with all kinds of weird pseudo problems and conundrum. 

So for example, when we talk about it, you know, if you don’t want to talk about ethics and other other things like that, and what you know, this this idea that surely if we look out into the universe, surely, we don’t believe that this human brain is the only way to be sentient, right? Surely we don’t, you know, and to have high level cognition. I just can’t even wrap my mind around this, this idea that that is the only way to do it. No doubt there are other architectures made of completely different principles that achieve the same thing. 

And once we believe that, then that tells us something important. It tells us that things that are not quite human brains or chimeras of human brains and other tissue or human brains or other kinds of brains and novel configurations or things that are sort of brains, but not really, or plants or embryos or whatever, might also have important cognitive status. So that’s the only thing.

 I think we have to be really careful about treating the human brain as if it was some kind of like sharp binary category. You know, you are or you aren’t. I don’t believe that exists. 

{LF} So when we look out at all the beautiful variety of human brains, semi semi-biological architectures out there in the universe, how many intelligent alien civilizations do you think are out there? 

{ML} Boy, I have no expertise in that whatsoever. 

{LF} You haven’t met any? 

{ML} I have met the ones we’ve made. 

{LF} I think that I mean, exactly. In some sense with synthetic biology, are you not creating aliens? 

{ML} I absolutely think so because look, all of life, all of all standard model systems are an end of one course of evolution on Earth, right? And trying to make conclusions about biology from looking at life on Earth is like testing your theory on the same data that generated it. It’s all kind of like locked in. So we absolutely have to create novel examples that have no history on Earth that don’t, you know, xenobots have no history of selection to be a good xenobot. The cells have selection for various things, but the xenobot itself never existed before. 

And so we can make chimeras, you know, we make frog-axolotls that are sort of half frog, half axolotl. You can make all sorts of hybrots, right constructions of living tissue with robots and whatever. We need to be making these things until we find actual aliens, because otherwise, we’re just looking at an end of one set of examples, all kinds of frozen accidents of evolution and so on. We need to go beyond that to really understand biology. 

{LF} But we’re still even when you do synthetic biology, you’re locked in to the basic components of the way biology is done on this Earth. 

{ML} Yeah, right. 

{LF} And also, and also the basic constraints of the environment, even artificial environments to construct in the lab are tied up to the environment. I mean, what do you? Okay, let’s say there is I mean, what I think is there’s a nearly infinite number of intelligent civilizations living or dead out there. If you pick one out of the box, what do you think it would look like? So in…. when you think about synthetic biology, or creating synthetic organisms, how hard is it to create something that’s very different? 

{ML} Yeah, I think it’s very hard to create something that’s very different, right? It’s we are just locked in both both experimentally and in terms of our imagination, right? It’s very hard. 

{LF} And you also emphasize several times that the idea of shape. 

{ML} Yeah 

{LF} The individual cell get together with other cells and they kind of they’re gonna build a shape. So it’s shape and function, but shape is a critical thing. 

{ML} Yeah. So here, I’ll take a stab. I mean, I agree with you. I did to whatever extent that we can say anything, I do think that there’s, you know, probably an infinite number of different architectures with interesting cognitive properties out there. 

What can we say about them? I think that the only things that are going …. I don’t think we can rely on any of the typical stuff, you know, carbon based, none of that. Like, I think all of that is just, you know, us being having having a lack of imagination. 

But I think the things that are going to be universal, if anything is, are things, for example, driven by resource limitation, the fact that you are fighting a hostile world, and you have to draw a boundary between yourself and the world somewhere, the fact that that boundary is not given to you by anybody, you have to you have to assume it, you know, estimated yourself. And the fact that you have to coarse grain your experience and the fact that you’re going to try to minimize surprise and the fact that like these, these are the things that I think are fundamental about biology, none of the, you know, the facts about the genetic code, or even the fact that we have genes or the biochemistry of it, I don’t think any of those things are fundamental. But it’s going to be a lot more about the information and about the creation of the self, the fact that so in my framework, selves are demarcated by the scale of the goals that they can pursue. So from little tiny local goals to like massive, you know, planetary scale goals for certain humans, and everything and everything in between. 

So you can draw this like cognitive light cone about that determines the the scale of the goals you could possibly pursue. I think those kinds of frameworks, like that, like active inference, and so on are going to be universally applicable, but but none of the other things that are typically discussed. 

{LF} Quick pause, do you need a bathroom break? 

{ML} We were just talking about, you know, aliens and all that. That’s a funny thing, which is, I don’t know if you’ve seen them, there’s a kind of debate that goes on about cognition and plants, and what can you say about different kinds of computation and cognition and plants. And I always I always look at that something like if you’re weirded out by cognition and plants, you’re not ready for exobiology, right? If you know something that’s that similar here on Earth is already like freaking you out, then I think there’s going to be all kinds of cognitive life out there that we’re gonna have a really hard time recognizing. 

{LF} I think robots will help us….

{ML} yeah 

{LF} ….like expand our mind about cognition, either that or the work like xenobots. So, and they maybe becomes the same thing is, you know, really, when the human engineer the thing, at least in part, and then is able to achieve some kind of cognition that’s different than what you’re used to, then you start to understand like, oh, you know, every living organism is capable of cognition. Oh, I need to kind of broaden my understanding what cognition is. But do you think plants, like when you eat them, are they screaming? 

{ML} I don’t know about screaming. I think you have to…. 

{LF} That’s what I think when I eat a salad. 

{ML} Yeah, good. Yeah, I think you have to scale down the expectations in terms of right, so probably they’re not screaming in the way that we would be screaming. However, there’s plenty of data on plants being able to do anticipation and certain kinds of memory and so on. 

I think, you know, what you just said about robots, I hope you’re right. And I hope that’s but there’s two, there’s two ways that people can take that right. So one way is exactly what you just said to try to kind of expand their notions for that category. 

The other way people often go is they just sort of define the term is if it’s not a natural product, it’s it’s just faking, right? It’s not really intelligence if it was made by somebody else, because it’s that same, it’s the same thing. They can see how it’s done. And once you see how it’s like a magic trick, when you see how it’s done, it’s not as fun anymore. And I think people have a real tendency for that. And they sort of which…. which I find really strange in the sense that if somebody said to me, we have this this this sort of blind, like, like, hill climbing search, and then and then we have a really smart team of engineers, which one do you think is going to produce a system that has good intelligence? I think it’s really weird to say that it only comes from the blind search, right? It can’t be done by people who, by the way, can also use evolutionary techniques if they want to, but also rational design. I think it’s really weird to say that real intelligence only comes from natural evolution. So I hope you’re right. I hope people take it the other way. 

{LF} But there’s a nice shortcut. So I work with legged robots a lot now for my own personal pleasure. Not in that way, internet. So four legs. And one of the things that changes my experience with the robots a lot is when I can’t understand why I did a certain thing. And there’s a lot of ways to engineer that. Me, the person that created the software that runs it. There’s a lot of ways for me to build that software in such a way that I don’t exactly know why it did a certain basic decision. 

Of course, as an engineer, you can go in and start to look at logs. You can log all kind of data, sensory data, the decisions you made, you know, all the outputs in your networks and so on. But I also try to really experience that surprise and that really experience as another person would that totally doesn’t know how it’s built. And I think the magic is there in not knowing how it works. That I think biology does that for you through the layers of abstraction. 

{ML} Yeah, 

{LF} Because nobody really knows what’s going on inside the biological. Like each one component is clueless about the big picture. 

{ML} I think there’s actually really cheap systems that can illustrate that kind of thing, which is even like, you know, fractals, right? Like, you have a very small, short formula in Z, and you see it and there’s no magic, you’re just going to crank through, you know, Z squared plus C, whatever, you’re just going to crank through it. But the result of it is this incredibly rich, beautiful image, right? That that just like, wow, all of that was in this, like, 10 character long string, like amazing. 

So the fact that you can know everything there is to know about the details and the process and all the parts and every like, there’s literally no magic of any kind there. And yet the outcome is something that you would never have expected. And it’s just, you know, is incredibly rich and complex and beautiful. So there’s a lot of that. 

{1:42:08 – Unconventional cognition}

{LF} You write that you work on developing conceptual frameworks for understanding unconventional cognition. So the kind of thing we’ve been talking about, I just like the term unconventional cognition. And you want to figure out how to detect, study and communicate with the thing. You’ve already mentioned a few examples, but what is unconventional cognition? Is it as simply as everything else outside of what we define usually as cognition, cognitive science, the stuff going on between our ears? Or is there some deeper way to get at the fundamentals of what is cognition? 

{ML} Yeah, I think like, and I’m certainly not the only person who works in unconventional, unconventional cognition. 

{ML} So it’s the term used? 

{LF} Yeah, that’s one that I so I’ve coined a number of weird terms, but that’s not one of mine like that. That’s an existing thing. So for example, somebody like Andy Adamatzky, who I don’t know if you’ve if you’ve had him on, if you haven’t, you should. He’s a, you know, very interesting guy. He’s a computer scientist, and he does unconventional cognition and slime molds, all kinds of weird. He’s a real weird, weird cat, really interesting. Anyway, so that’s, you know, it’s a bunch of terms that I’ve come up with. But that’s not one of mine. 

{ML} So I think like many terms, that one is, is really defined by the times, meaning that unconventional cognitive things that are unconventional cognition today are not going to be considered unconventional cognition at some point. It’s one of those, it’s one of those things. And so it’s, you know, it’s, it’s, it’s this,  really deep question of how do you recognize, communicate with, classify cognition, when you cannot rely on the typical milestones, right? 

So typical, you know, again, if you stick with the history of life on Earth, like these, these exact model systems, you would say, Ah, here’s a particular structure of the brain. And this one has fewer of those. And this one has a bigger frontal cortex. And this one, right, so these are landmarks that we’re that we’re used to, and and allows us to make very kind of rapid judgments about things. But if you can’t rely on that, either because you’re looking at a synthetic thing, or an engineered thing, or an alien thing, then what do you do? Right? How do you and so and so that’s what I’m really interested. I’m interested in mind in all of its possible implementations, not just the obvious ones that we know from looking at brains here on Earth. 

{LF} Whenever I think about something like unconventional cognition, I think about cellular automata, I’m just captivated by the beauty of the thing. The fact that from simple little objects, you can create some such beautiful complexity that very quickly, you forget about the individual objects, and you see the things that it creates as its own organisms. That blows my mind every time. Like, honestly, I could full time just eat mushrooms and watch cellular automata. Don’t even have to do mushrooms. Just cellular automata. It feels like, I mean, from the engineering perspective, I love when a very simple system captures something really powerful, because then you can study that system to understand something fundamental about complexity about life on Earth. Anyway, how do I communicate with a thing? If cellular automata can do cognition, if a plant can do cognition, if a xenobot can do cognition, how do I like whisper in its ear and get an answer back to how do I have a conversation? 

{ML} Yeah.

{LF} How do I have a xenobot on a podcast? 

{ML} It’s a really interesting line of investigation that opens up. I mean, we’ve thought about this. So you need a few things. 

You need to understand the space in which they live. So not just the physical modality, like can they see light, can they feel vibration? I mean, that’s important, of course, because that’s how you deliver your message. But not just the ideas for a communication medium, not just the physical medium, but saliency, right? So what’s important to this system? And systems have all kinds of different levels of sophistication of what you could expect to get back. And I think what’s really important, I call this the spectrum of persuadability, which is this idea that when you’re looking at a system, you can’t assume where on the spectrum it is. You have to do experiments. 

And so for example, if you look at a gene regulatory network, which is just a bunch of nodes that turn each other on and off at various rates, you might look at that and you say, well, there’s no magic here. I mean, clearly this thing is as deterministic as it gets. It’s a piece of hardware. The only way we’re going to be able to control it is by rewiring it, which is the way molecular biology works, right? We can add nodes, remove nodes, whatever. 

Well, so we’ve done simulations and shown that biological, and now we’re doing this in the lab, the biological networks like that have associative memory. So they can actually learn, they can learn from experience. They have habituation, they have sensitization, they have associative memory, which you wouldn’t have known if you assume that they have to be on the left side of that spectrum. 

So when you’re going to communicate with something, and we’ve even, Charles Abramson and I have written a paper on behaviorist approaches to synthetic organisms, meaning that if you’re given something, you have no idea what it is or what it can do, how do you figure out what its psychology is, what its level is, what does it, and so we literally lay out a set of protocols, starting with the simplest things and then moving up to more complex things where you can make no assumptions about what this thing can do, right? You have to start and you’ll find out. 

So when you’re going to, so here’s a simple, I mean, here’s one way to communicate with something. If you can train it, that’s a way of communicating. So if you can provide, if you can figure out what the currency of reward of positive and negative reinforcement is, right, and you can get it to do something it wasn’t doing before based on experiences you’ve given, you have taught it one thing. You have communicated one thing, that such and such an action is good, some other action is not good. That’s like a basic atom of a primitive atom of communication. 

{LF} What about in some sense, if it gets you to do something you haven’t done before, is it answering back? 

{ML} Yeah, most certainly. And there’s, I’ve seen cartoons, I think maybe Gary Larson or somebody had had a cartoon of these rats in the maze and the one rat, you know, assist to the other. You look at this every time, every time I walk over here, he starts scribbling in that on the, you know, on the clipboard that he has, it’s awesome. 

{LF} If we step outside ourselves and really measure how much, like if I actually measure how much I’ve changed because of my interaction with certain cellular automata. I mean, you really have to take that into consideration about like, well, these things are changing you too. Yes. I know, you know how it works and so on, but you’re being changed by the thing. 

{ML} Yeah, absolutely. I think I read, I don’t know any details, but I think I read something about how wheat and other things have domesticated humans in terms of, right, but by their properties change the way that the human behavior and societal structures. 

{LF} In that sense, cats are running the world because they’ve took over the, so first off, so first they, while not giving a shit about humans, clearly with every ounce of their being, they’ve somehow got just millions and millions of humans to take them home and feed them. And then not only the physical space did they take over, they took over the digital space. They dominate the internet in terms of cuteness, in terms of memeability. And so they’re like, they got themselves literally inside the memes, they become viral and spread on the internet. And they’re the ones that are probably controlling humans. That’s my theory. Another, that’s a follow up paper after the frog kissing. 

Okay. I mean, you mentioned sentience and consciousness. You have a paper titled Generalizing Frameworks for Sentience Beyond Natural Species. So beyond normal cognition, if we look at sentience and consciousness, and I wonder if you draw an interesting distinction between those two elsewhere, outside of humans, and maybe outside of Earth, you think aliens have sentience. And if they do, how do we think about it? So when you have this framework, what is this paper? What is the way you propose to think about sentience? 

{ML} Yeah, that particular paper was a very short commentary on another paper that was written about crabs. It was a really good paper on them, crabs and various, like a rubric of different types of behaviors that could be applied to different creatures, and they’re trying to apply it to crabs and so on. Consciousness, we can talk about if you want, but it’s a whole separate kettle of fish. I almost never talk about…

{LF} Except in crabs. 

{ML} In this case, yes. I almost never talk about consciousness, per se. I’ve said very, very little about it, but we can talk about it if you want. Mostly what I talk about is cognition, because I think that that’s much easier to deal with in a kind of rigorous experimental way. I think that all of these terms have, you know, sentience and so on, have different definitions, and I fundamentally, I think that people can, as long as they specify what they mean ahead of time, I think people can define them in various ways.  The only thing that I really think that I really kind of insist on is that the right way to think about all this stuff is from an engineering perspective. What does it help me to control, predict, and does it help me do my next experiment? That’s not a universal perspective. 

Some people have philosophical kind of underpinnings, and those are primary, and if anything runs against that, then it must automatically be wrong. Some people will say, I don’t care what else. If your theory says to me that thermostats have little tiny goals, I’m not, so that’s it. That’s my philosophical preconception. Thermostats do not have goals, and that’s it. That’s one way of doing it, and some people do it that way. I do not do it that way, and I think that we can’t, I don’t think we can know much of anything from a philosophical armchair. I think that all of these theories and ways of doing things stand or fall based on just basically one set of criteria. Does it help you run a rich research program? That’s it. 

{LF} I agree with you totally, but forget philosophy. What about the poetry of ambiguity? What about at the limits of the things you can engineer using terms that can be defined in multiple ways and living within that uncertainty in order to play with words until something lands that you can engineer? I mean, that’s to me where consciousness sits currently. Nobody really understands the hard problem of consciousness, the subject, what it feels like, because it really feels like, it feels like something to be this biological system. This conglomerate of a bunch of cells in this hierarchy of competencies feels like something, and yeah, I feel like one thing, and is that just a side effect of a complex system, or is there something more that humans have, or is there something more that any biological system has? Some kind of magic, some kind of, not just a sense of agency, but a real sense with a capital letter S of agency. 

{ML} Yeah. Ah, boy, yeah, that’s a deep question.

{LF}  Is there room for poetry in engineering or no? 

{ML} No, there definitely is, and a lot of the poetry comes in when we realize that none of the categories we deal with are sharp as we think they are, right? And so in the different areas of all these spectra are where a lot of the poetry sits, I have many new theories about things, but I, in fact, do not have a good theory about consciousness that I plan to trot out. 

{LF} And you almost don’t see it as useful for your current work to think about consciousness? 

{ML} I think it will come. I have some thoughts about it, but I don’t feel like they’re going to move the needle yet on that. 

{LF} And you want to ground it in engineering always. 

{ML} So, well, I mean, so if we really tackle consciousness per se, in the terms of the hard problem, that isn’t necessarily going to be groundable in engineering, right? That aspect of cognition is, but actual consciousness per se, first person perspective, I’m not sure that that’s groundable in engineering. 

And I think specifically what’s different about it is there’s a couple of things. So let’s, you know, here we go. I’ll say a couple of things about consciousness. One thing is that what makes it different is that for every other thing, other aspect of science, when we think about having a correct or a good theory of it, we have some idea of what format that theory makes predictions in. So whether those be numbers or whatever, we have some idea. We may not know the answer, we may not have the theory, but we know that when we get the theory, here’s what it’s going to output, and then we’ll know if it’s right or wrong. 

For actual consciousness, not behavior, not neural correlates, but actual first person consciousness. If we had a correct theory of consciousness, or even a good one, what the hell would, what format would it make predictions in, right? Because all the things that we know about basically boil down to observable behaviors. 

So the only thing I can think of when I think about that is, it’ll be poetry, or it’ll be something to, if I ask you, okay, you’ve got a great theory of consciousness, and here’s this creature, maybe it’s a natural one, maybe it’s an engineered one, whatever. And I want you to tell me what your theory says about this being, what it’s like to be this being. The only thing I can imagine you giving me is some piece of art, a poem or something, that once I’ve taken it in, I share, I now have a similar state as whatever. That’s about as good as I can come up with. 

{LF} Well, it’s possible that once you have a good understanding of consciousness, it would be mapped to some things that are more measurable. So for example, it’s possible that a conscious being is one that’s able to suffer. So you start to look at pain and suffering. You can start to connect it closer to things that you can measure that, in terms of how they reflect themselves in behavior and problem solving and creation and attainment of goals, for example, which I think suffering is one of the, you know, life is suffering. It’s one of the big aspects of the human condition. And so if consciousness is somehow a, maybe at least a catalyst for suffering, you could start to get like echoes of it. 

You start to see like the actual effects of consciousness and behavior. That it’s not just about subjective experience. It’s like it’s really deeply integrated in the problem solving decision making of a system, something like this. But also it’s possible that we realize, this is not a philosophical statement. Philosophers can write their books. I welcome it. You know, I take the Turing test really seriously. I don’t know why people really don’t like it. When a robot convinces you that it’s intelligent, I think that’s a really incredible accomplishment. And there’s some deep sense in which that is intelligence. If it looks like it’s intelligent, it is intelligent. And I think there’s some deep aspect of a system that appears to be conscious. In some deep sense, it is conscious. At least for me, we have to consider that possibility. And a system that appears to be conscious is an engineering challenge. 

{ML} Yeah, I don’t disagree with any of that. I mean, especially intelligence, I think, is a publicly observable thing. Science fiction has dealt with this for a century or much more, maybe. This idea that when you are confronted with something that just doesn’t meet any of your typical assumptions, so you can’t look in the skull and say, oh, well, there’s that frontal cortex, so then I guess we’re good. So this thing lands on your front lawn, and the little door opens, and something trundles out, and it’s shiny and aluminum looking, and it hands you this poem that it wrote while it was flying over, and how happy it is to meet you. What’s going to be your criteria for whether you get to take it apart and see what makes it tick, or whether you have to be nice to it and whatever? All the criteria that we have now and that people are using, and as you said, a lot of people are down on the Turing test and things like this, but what else have we got? Because measuring the cortex size isn’t going to cut it in the broader scheme of things. So I think it’s a wide open problem. 

Our solution to the problem of other minds, it’s very simplistic. We give each other credit for having minds just because we’re sort of on an anatomical level, we’re pretty similar, and so it’s good enough. But how far is that going to go? So I think that’s really primitive. So yeah, I think it’s a major unsolved problem.

{LF}  It’s a really challenging direction of thought to the human race that you talked about, like embodied minds. If you start to think that other things other than humans have minds, that’s really challenging. Because all men are created equal starts being like, all right, well, we should probably treat not just cows with respect, but like plants, and not just plants, but some kind of organized conglomerates of cells in a petri dish. 

{ML} In fact, some of the work we’re doing, like you’re doing and the whole community of science is doing with biology, people might be like, we were really mean to viruses. 

Yeah. I mean, yeah, the thing is, you’re right. And I certainly get phone calls about people complaining about frog skin and so on. But I think we have to separate the sort of deep philosophical aspects versus what actually happens. 

So what actually happens on Earth is that people with exactly the same anatomical structure kill each other on a daily basis. So I think it’s clear that simply knowing that something else is equally or maybe more cognitive or conscious than you are is not a guarantee of kind behavior, that much we know of. And so then we look at commercial farming of mammals and various other things. And so I think on a practical basis, long before we get to worrying about things like frog skin, we have to ask ourselves, why are we, what can we do about the way that we’ve been behaving towards creatures, which we know for a fact, because of our similarities are basically just like us. That’s kind of a whole other social thing. 

But fundamentally, of course, you’re absolutely right in that we are also, think about this, we are on this planet in some way, incredibly lucky. It’s just dumb luck that we really only have one dominant species. It didn’t have to work out that way. So you could easily imagine that there could be a planet somewhere with more than one equally or maybe near equally intelligent species. But they may not look anything like each other. 

So there may be multiple ecosystems where there are things of similar to human like intelligence. And then you’d have all kinds of issues about how do you relate to them when they’re physically like you at all. But yet in terms of behavior and culture and whatever, it’s pretty obvious that they’ve got as much on the ball as you have. Or maybe imagine that there was another group of beings that was on average 40 IQ points lower. We’re pretty lucky in many ways. We don’t really have, even though we still act badly in many ways. But the fact is, all humans are more or less in that same range, but didn’t have to work out that way. 

{LF} Well, but I think that’s part of the way life works on Earth, maybe human civilization works, is it seems like we want ourselves to be quite similar. And then within that, you know, where everybody’s about the same relatively IQ, intelligence, problem solving capabilities, even physical characteristics. But then we’ll find some aspect of that that’s different. 

And that seems to be like, I mean, it’s really dark to say, but that seems to be the, not even a bug, but like a feature of the early development of human civilization. You pick the other, your tribe versus the other tribe and you war, it’s a kind of evolution in the space of memes, a space of ideas, I think, and you war with each other. So we’re very good at finding the other, even when the characteristics are really the same. And that’s, I don’t know what that, I mean, I’m sure so many of these things echo in the biological world in some way. 

{ML} Yeah. There’s a fun experiment that I did. My son actually came up with this and we did a biology unit together. He’s a homeschooler. And so we did this a couple of years ago. We did this thing where, imagine you get this slime mold, right? Physarum polycephalum, and it grows on a Petri dish of agar and it sort of spreads out and it’s a single cell protist, but it’s like this giant thing. And so you put down a piece of oat and it wants to go get the oat and it sort of grows towards the oat. 

So what you do is you take a razor blade and you just separate the piece of the whole culture that’s growing towards the oat. You just kind of separate it. And so now think about the interesting decision making calculus for that little piece. I can go get the oat and therefore I won’t have to share those nutrients with this giant mass over there. So the nutrients per unit volume is going to be amazing. I should go eat the oat. But if I first rejoin, because Physarum, once you cut it, has the ability to join back up. If I first rejoin, then that whole calculus becomes impossible because there is no more me anymore. There’s just we and then we will go eat this thing, right? 

So this interesting, you can imagine a kind of game theory where the number of agents isn’t fixed and that it’s not just cooperate or defect, but it’s actually merge and whatever, right? 

{LF} Yeah. So that computation, how does it do that decision making? 

{ML} Yeah. So it’s really interesting. And so empirically, what we found is that it tends to merge first. It tends to merge first and then the whole thing goes. But it’s really interesting that that calculus, I mean, I’m not an expert in the economic game theory and all that, but maybe there’s some sort of hyperbolic discounting or something. 

But maybe this idea that the actions you take not only change your payoff, but they change who or what you are, and that you could take an action after which you don’t exist anymore, or you are radically changed, or you are merged with somebody else. As far as I know, that’s a whole different thing. As far as I know, we’re still missing a formalism for even knowing how to model any of that. 

{2:06:39 – Origin of evolution}

{LF} Do you see evolution, by the way, as a process that applies here on Earth? Where did evolution come from? Yeah. So this thing from the very origin of life that took us to today, what the heck is that? 

{ML} I think evolution is inevitable in the sense that if you combine, and basically, I think one of the most useful things that was done in early computing, I guess in the 60s, it started with evolutionary computation and just showing how simple it is that if you have imperfect heredity and competition together, those two things, or three things, so heredity, imperfect heredity, and competition, or selection, those three things, and that’s it. Now you’re off to the races. And so that can be, it’s not just on Earth because it can be done in the computer, it can be done in chemical systems, it can be done in, you know, Lee Smolin says it works on cosmic scales. So I think that that kind of thing is incredibly pervasive and general. It’s a general feature of life. 

It’s interesting to think about, you know, the standard thought about this is that it’s blind, right? Meaning that the intelligence of the process is zero, it’s stumbling around. And I think that back in the day, when the options were it’s dumb like machines, or it’s smart like humans, then of course, the scientists went in this direction, because nobody wanted creationism. They said, okay, it’s got to be like completely blind. I’m not actually sure, right? Because I think that everything is a continuum. And I think that it doesn’t have to be smart with foresight like us, but it doesn’t have to be completely blind either. I think there may be aspects of it. And in particular, this kind of multi-scale competency might give it a little bit of look ahead maybe or a little bit of problem solving sort of baked in. But that’s going to be completely different in different systems. I do think it’s general. I don’t think it’s just on Earth. I think it’s a very fundamental thing. 

{LF} And it does seem to have a kind of direction that it’s taking us that’s somehow perhaps is defined by the environment itself. It feels like we’re headed towards something. Like, we’re playing out a script that was just like a single cell defines the entire organism.

{ML}  Yeah.

{LF}  It feels like from the origin of Earth itself, it’s playing out a kind of script. You can’t really go any other way. 

{ML} I mean, so this is very controversial, and I don’t know the answer. But people have argued that this is called, you know, sort of rewinding the tape of life, right? And some people have argued, I think, I think Conway Morris, maybe has argued that it is that there’s a deep attractor, for example, to human to the human kind of structure and that and that if you were to rewind it again, you’d basically get more or less the same thing. And then other people have argued that, no, it’s incredibly sensitive to frozen accidents. And then once certain stochastic decisions are made downstream, everything is going to be different. I don’t know. I don’t know. 

You know, we’re very bad at predicting attractors in the space of complex systems, generally speaking, right? We don’t know. So maybe, so maybe evolution on Earth has these deep attractors that no matter what has happened, it pretty much would likely to end up there or maybe not. I don’t know. 

{LF} It’s a really difficult idea to imagine that if you ran Earth a million times, 500,000 times you would get Hitler? Like, yeah, we don’t like to think like that. We think like, because at least maybe in America, you’d like to think that individual decisions can change the world. And if individual decisions could change the world, then surely any perturbation could result in a totally different trajectory. But maybe there’s a, in this competency hierarchy, it’s a self-correcting system. There’s just ultimately, there’s a bunch of chaos that ultimately is leading towards something like a super intelligent, artificial intelligence system that answers 42. I mean, there might be a kind of imperative for life that it’s headed to. And we’re too focused on our day to day life of getting coffee and snacks and having sex and getting a promotion at work, not to see the big imperative of life on Earth that is headed towards something. 

{ML} Yeah, maybe, maybe. It’s difficult. I think one of the things that’s important about chimeric bioengineering technologies, all of those things are that we have to start developing a better science of predicting the cognitive goals of composite systems. So we’re just not very good at it, right? 

We don’t know if I create a composite system, and this could be the Internet of Things or swarm robotics or a cellular swarm or whatever. What is the emergent intelligence of this thing? First of all, what level is it going to be at? And if it has goal directed capacity, what are the goals going to be? Like, we are just not very good at predicting that yet. And I think that it’s an existential level need for us to be able to because we’re building these things all the time, right? We’re building both physical structures like swarm robotics, and we’re building social financial structures and so on, with very little ability to predict what sort of autonomous goals that system is going to have, of which we are now cogs. And so learning to predict and control those things is going to be critical. 

So in fact, if you’re right and there is some kind of attractor to evolution, it would be nice to know what that is and then to make a rational decision of whether we’re going to go along or we’re going to pop out of it or try to pop out of it because there’s no guarantee. I mean, that’s the other kind of important thing. A lot of people, I get a lot of complaints from people who email me and say, you know, what you’re doing, it isn’t natural. And I’ll say, look, natural, that’d be nice if somebody was making sure that natural was matched up to our values, but no one’s doing that. Evolution optimizes for biomass. That’s it. Nobody’s optimizing. It’s not optimizing for your happiness. I don’t think necessarily it’s optimizing for intelligence or fairness or any of that stuff. 

{LF} I’m going to find that person that emailed you, beat them up, take their place, steal everything they own and say, no, this is natural. This is natural. 

{ML} Yeah, exactly. Because it comes from an old worldview where you could assume that whatever is natural, that that’s probably for the best. And I think we’re long out of that garden of Eden kind of view. So I think we can do better. I think we, and we have to, right? Natural just isn’t great for a lot of life forms. 

{2:13:41 – Synthetic organisms}

{LF} What are some cool synthetic organisms that you think about, you dream about? When you think about embodied mind, what do you imagine? What do you hope to build? 

{ML} Yeah, on a practical level, what I really hope to do is to gain enough of an understanding of the embodied intelligence of the organs and tissues such that we can achieve a radically different regenerative medicine so that we can say, basically, and I think about it as, you know, in terms of like, okay, can you, what’s the goal kind of end game for this whole thing? 

To me, the end game is something that you would call an anatomical compiler. So the idea is you would sit down in front of the computer and you would draw the body or the organ that you wanted. Not molecular details, but like, yeah, this is what I want. I want a six legged, you know, frog with a propeller on top, or I want a heart that looks like this, or I want a leg that looks like this. And what it would do if we knew what we were doing is put out, convert that anatomical description into a set of stimuli that would have to be given to cells to convince them to build exactly that thing, right? I probably won’t live to see it, but I think it’s achievable. 

And I think with that, if we can have that, then that is basically the solution to all of medicine except for infectious disease. So birth defects, right? Traumatic injury, cancer, aging, degenerative disease. If we knew how to tell cells what to build, all of those things go away. So those things go away. And the positive feedback spiral of economic costs, where all of the advances are increasingly more heroic and expensive interventions of a sinking ship when you’re like 90 and so on, right? All of that goes away because basically, instead of trying to fix you up as you degrade, you progressively regenerate, you apply the regenerative medicine early before things degrade. So I think that that’ll have massive economic impacts over what we’re trying to do now, which is not at all sustainable. And that’s what I hope. I hope that we get it. 

So to me, yes, the xenobots will be doing useful things, cleaning up the environment, cleaning out your joints and all that kind of stuff. But more important than that, I think we can use these synthetic systems to try to develop a science of detecting and manipulating the goals of collective intelligences of cells specifically for regenerative medicine. 

And then sort of beyond that, if we think further beyond that, what I hope is that kind of like what you said, all of this drives a reconsideration of how we formulate ethical norms because this old school, so in the olden days, what you could do is if you were confronted with something, you could tap on it, right? And if you heard a metallic clanging sound, you’d say, ah, fine, right? So you could conclude it was made in a factory. I can take it apart. I can do whatever, right? If you did that and you got sort of a squishy kind of warm sensation, you’d say, ah, I need to be more or less nice to it and whatever. That’s not going to be feasible. It was never really feasible, but it was good enough because we didn’t have any, we didn’t know any better. That needs to go. And I think that by breaking down those artificial barriers, someday we can try to build a system of ethical norms that does not rely on these completely contingent facts of our earthly history, but on something much, much deeper that really takes agency and the capacity to suffer and all that takes that seriously. 

{LF} The capacity to suffer and the deep questions I would ask of a system is can I eat it and can I have sex with it? Which is the two fundamental tests of, again, the human condition. So I can basically do what Dali does that’s in the physical space. So print out like a 3D print Pepe the Frog with a propeller head, propeller hat is the dream. 

{ML} Well yes and no. I mean, I want to get away from the 3D printing thing because that will be available for some things much earlier. I mean, we can already do bladders and ears and things like that because it’s micro level control, right? When you 3D print, you are in charge of where every cell goes. And for some things that, you know, for, like this thing, they had that I think 20 years ago or maybe earlier than that, you could do that. 

{LF} So yeah, I would like to emphasize the Dali part where you provide a few words and it generates a painting. So here you say, I want a frog with these features and then it would go direct a complex biological system to construct something like that. 

{ML} Yeah. The main magic would be, I mean, I think from, from looking at Dali and so on, it looks like the first part is kind of solved now where you go from, from the words to the image, like that seems more or less solved. The next step is really hard. This is what keeps things like CRISPR and genomic editing and so on. That’s what limits all the impacts for regenerative medicine because going back to, okay, this is the knee joint that I want, or this is the eye that I want. Now, what genes do I edit to make that happen, right? Going back in that direction is really hard. 

So instead of that, it’s going to be, okay, I understand how to motivate cells to build particular structures. Can I rewrite the memory of what they think they’re supposed to be building such that then I can, you know, take my hands off the wheel and let them, let them do their thing. 

{ML} So some of that is experiment, but some of that may be AI can help too. Just like with protein folding, this is exactly the problem that protein folding in the most simple medium tried and has solved with Alpha Fold, which is how does the sequence of letters result in this three dimensional shape? And you have to, I guess it didn’t solve it because you have to, if you say, I want this shape, how do I then have a sequence of letters? Yeah. The reverse engineering step is really tricky.

{ML}  It is. I think we’re, we’re, and we’re doing some of this now is, is to use AI to try and build actionable models of the intelligence of the cellular collectives. So try to help us and help us gain models that, that, that, and, and we’ve had some success in this. So we did something like this for, you know, for repairing birth defects of the brain in frogs. We’ve done some of this for normalizing melanoma where you can really start to use AI to make models of how would I impact this thing if I wanted to given all the complexities, right. And, given all the, the, the, the controls that it knows how to do. 

{2:20:27 – Regenerative medicine}

{LF} So when you say regenerative medicine, so we talked about creating biological organisms, but if you regrow a hand, that information is already there, right? The biological system has that information. So how does regenerative medicine work today? How do you hope it works? What’s the hope there? 

{ML} Yeah. 

{LF} Yeah. How do you make it happen? 

{ML} Well today there’s a set of popular approaches. So, one is 3D printing. So the idea is I’m going to make a scaffold of the thing that I want. I’m going to seed it with cells and then, and then there it is, right? So kind of direct, and then that works for certain things. You can make a bladder that way or an ear, something like that. 

The other idea is some sort of stem cell transplant. These are the ideas. If we, if we put in stem cells with appropriate factors, we can get them to generate certain kinds of neurons for certain diseases and so on. All of those things are good for relatively simple structures, but when you want an eye or a hand or something else, I think in this maybe an unpopular opinion, I think the only hope we have in any reasonable kind of timeframe is to understand how the thing was motivated to get made in the first place. So what is it that, that made those cells in the, in the beginning, create a particular arm with a particular set of sizes and shapes and number of fingers and all that. And why is it that a salamander can keep losing theirs and keep regrowing theirs and a planarian can do the same even more? 

So to me, uh, kind of ultimate regenerative medicine was when you can tell the cells to build whatever it is you need them to build. Right. And so that we can all be like planaria basically.

{LF} Do you have to start at the very beginning or can you, um, do a shortcut? Cause we’re going to hand, you already got the whole organism. 

{ML} Yeah. So here’s what we’ve done, right? So, we’ve, we’ve more or less solved that in frogs. So frogs, unlike salamanders do not regenerate their legs as adults. And so, so, uh, we’ve shown that with a very, um, uh, kind of simple intervention. So what we do is there’s two things you need to, uh, you need to have a signal that tells the cells what to do, and then you need some way of delivering it. And so this is work together with, um, with David Kaplan and I should do a, um, a disclosure here. We have a company called Morphoceuticals and spin off where we’re trying to, uh, to address, uh, uh, regenerate, you know, limb regeneration. 

So we’ve solved it in the frog and we’re now in trials and mice. So now we’re going to, we’re in mammals now. It’s, I can’t say anything about how it’s going, but the frog thing is solved. So what you do is, um, a

{LF} fter you have a little frog, Luke Skywalker with every growing hand. 

{ML} Yeah, basically, basically. Yeah. Yeah. So what you do is we did, we did with legs instead of forearms. And what you do  after amputation, normally they, they don’t regenerate. You put on a wearable bioreactor. So it’s this thing that, um, that goes on and, uh, Dave Kaplan’s lab makes these things and inside it’s a, it’s a very controlled environment. It is a silk gel that carries, uh, some drugs, for example, ion channel drugs. And what you’re doing is you’re saying to the cells, you should regrow what normally goes here. 

So, uh, that whole thing is on for 24 hours and you take it off and you don’t touch the leg. Again, this is really important because what we’re not looking for is a set of micromanagement, uh, you know, printing or controlling the cells we want to trigger. We want to, we want to interact with it early on and then not touch it again because we don’t know how to make a frog leg, but the frog knows how to make a frog leg. So 24 hours, 18 months of leg growth after that, without us touching it again. And after 18 months, you get a pretty good leg that kind of shows this proof of concept that early on when the cells right after injury, when they’re first making a decision about what they’re going to do, you can, you can impact them. And once they’ve decided to make a leg, they don’t need you after that. They can do their own thing. So that’s an approach that we’re now taking. 

{2:24:13 – Cancer suppression}

{LF} What about cancer suppression? That’s something you mentioned earlier. How can all of these ideas help with cancer suppression? 

{ML} So let’s, let’s go back to the beginning and ask what, what, what, what cancer is. So I think, um, you know, asking why there’s cancer is the wrong question. I think the right question is why is there ever anything but cancer? 

So, in the normal state, you have a bunch of cells that are all cooperating towards a large scale goal. If that process of cooperation breaks down and you’ve got a cell that is isolated from that electrical network that lets you remember what the big goal is, you revert back to your unicellular lifestyle as far as, now think about that border between self and world, right? Normally when all these cells are connected by gap junctions into an electrical network, they are all one self, right? That meaning that, um, their goals, they have these large tissue level goals and so on. As soon as a cell is disconnected from that, the self is tiny, right? 

And so at that point, and so, so people, a lot of people model cancer cell cells as being more selfish and all that. They’re not more selfish. They’re equally selfish. It’s just that their self is smaller. Normally the self is huge. Now they got tiny little selves. Now what are the goals of tiny little selves? Well, proliferate, right? And migrate to wherever life is good. And that’s metastasis. That’s proliferation and metastasis. 

So, one thing we found and people have noticed years ago that when cells convert to cancer, the first thing they see is they close the gap junctions. And it’s a lot like, I think it’s a lot like that experiment with the slime mold where until you close that gap junction, you can’t even entertain the idea of leaving the collective because there is no you at that point, right? Your mind melded with this, with this whole other network. But as soon as the gap junction is closed, now the boundary between you and now, now the rest of the body is just outside environment to you. You’re just a, you’re just a unicellular organism and the rest of the body’s environment. 

So, we studied this process and we worked out a way to artificially control the bioelectric state of these cells to physically force them to remain in that network. And so then, then what that, what that means is that nasty mutations like KRAS and things like that, these really tough oncogenic mutations that cause tumors. If you do them and then, but then within artificially control of the bioelectrics, you greatly reduce tumor genesis or, or normalize cells that had already begun to convert. You basically, they go back to being normal cells. And so this is another, much like with the planaria, this is another way in which the bioelectric state kind of dominates what the genetic state is. So if you sequence the, you know, if you sequence the nucleic acid, you’ll see the KRAS mutation, you’ll say, ah, well that’s going to be a tumor, but there isn’t a tumor because, because bioelectrically you’ve kept the cells connected and they’re just working on making nice skin and kidneys and whatever else. So, we’ve started moving that to, to, to human glioblastoma cells and we’re hoping for, you know, a patient in the future interaction with patients. 

{LF} So is this one of the possible ways in which we may quote cure cancer? I think so.

 {ML} Yeah, I think so. I think, I think the actual cure, I mean, there are other technology, you know, immunotherapy, I think is a great technology. Chemotherapy, I don’t think is a good technology. I think we’ve got to get, get off of that. 

{LF} So chemotherapy just kills cells. 

{ML} Yeah. Well, chemotherapy hopes to kill more of the tumor cells than of your cells. That’s it. It’s a fine balance. The problem is the cells are very similar because they are your cells. And so if you don’t have a very tight way of distinguishing between them, then the toll that chemo takes on the rest of the body is just unbelievable. 

{LF} And immunotherapy tries to get the immune system to do some of the work. 

{ML} Exactly. Yeah. I think that’s potentially a very good, a very good approach. If, if the immune system can be taught to recognize enough of the cancer cells, that’s a pretty good approach. But I, but I think, but I think our approach is in a way more fundamental because if you can, if you can keep the cells harnessed towards organ level goals as opposed to individual cell goals, then nobody will be making a tumor or metastasizing and so on. 

{2:28:15 – Viruses}

{LF} So we’ve been living through a pandemic. What do you think about viruses in this full beautiful biological context we’ve been talking about? Are they beautiful to you? Are they terrifying? Also maybe let’s say, are they, since we’ve been discriminating this whole conversation, are they living? Are they embodied minds? Embodied minds that are assholes? 

{ML} As far as I know, and I haven’t been able to find this paper again, but, but somewhere I saw in the last couple of months, there was some, there were some papers showing an example of a virus that actually had physiology. So there was some, something was going on, I think proton flux or something on the virus itself. 

But, barring that, generally speaking, viruses are very passive. They don’t do anything by themselves. And so I don’t see any particular reason to attribute much of a mind to them. I think, you know, they represent a way to hijack other minds for sure, like, like cells and other things. 

{LF} But that’s an interesting interplay though. If they’re hijacking other minds, you know, the way we’re, we were talking about living organisms that they can interact with each other and have it alter each other’s trajectory by having interacted. I mean, that’s, that’s a deep, meaningful connection between a virus and a cell. And I think both are transformed by the experience. And so in that sense, both are living. 

{ML} Yeah. Yeah. You know, the whole category, I, this question of what’s living and what’s not living, I really, I’m not sure. And I know there’s people that work on this and I don’t want to piss anybody off, but, but I have not found that particularly useful as to try and make that a binary kind of a distinction. I think level of cognition is very interesting of …. as a continuum, but, but living and nonliving, I, you know, I don’t, I really know what to do with that. I don’t, I don’t know what you do next after, after making that distinction. 

{LF} That’s why I make the very binary distinction. Can I have sex with it or not? Can I eat it or not? Those, cause there’s, those are actionable, right? 

{ML} Yeah. Well, I think that’s a critical point that you brought up because how you relate to something is really what this is all about, right? As an engineer, how do I control it? But maybe I shouldn’t be controlling it. Maybe I should be, you know, can I have a relationship with it? Should I be listening to its advice? Like, like all the way from, you know, I need to take it apart all the way to, I better do what it says cause it seems to be pretty smart and everything in between, right? That’s really what we’re asking about. 

{ML} Yeah. We need to understand our relationship to it. We’re searching for that relationship, even in the most trivial senses. You came up with a lot of interesting terms. We’ve mentioned some of them. Agential material. That’s a really interesting one. That’s a really interesting one for the future of computation and artificial intelligence and computer science and all of that. There’s also, let me go through some of them. If they spark some interesting thought for you, there’s teleophobia, the unwarranted fear of erring on the side of too much agency when considering a new system. 

{ML} Yeah. 

{LF} That’s the opposite. I mean, being afraid of maybe anthropomorphizing the thing. 

{ML} This’ll get some people ticked off, I think. But I don’t think, I think the whole notion of anthropomorphizing is a holdover from a pre-scientific age where humans were magic and everything else wasn’t magic and you were anthropomorphizing when you dared suggest that something else has some features of humans. And I think we need to be way beyond that. And this issue of anthropomorphizing, I think it’s a cheap charge. I don’t think it holds any water at all other than when somebody makes a cognitive claim. 

I think all cognitive claims are engineering claims, really. So when somebody says this thing knows or this thing hopes or this thing wants or this thing predicts, all you can say is fabulous. Give me the engineering protocol that you’ve derived using that hypothesis and we will see if this thing helps us or not. And then, and then we can, you know, then we can make a rational decision. 

{LF} I also like anatomical compiler, a future system representing the long-term end game of the science of morphogenesis that reminds us how far away from true understanding we are. Someday you will be able to sit in front of an anatomical computer, specify the shape of the animal or a plant that you want, and it will convert that shape specification to a set of stimuli that will have to be given to cells to build exactly that shape. No matter how weird it ends up being, you have total control. 

Just imagine the possibility for memes in the physical space. One of the glorious accomplishments of human civilizations is memes in digital space. Now this could create memes in physical space. I am both excited and terrified by that possibility. 

{2:33:28 – Cognitive light cones}

Cognitive light cone, I think we also talked about the outer boundary in space and time of the largest goal a given system can work towards. Is this kind of like shaping the set of options? 

{ML} It’s a little different than options. It’s really focused on… I first came up with this back in 2018, I want to say. There was a conference, a Templeton conference where they challenged us to come up with frameworks. I think actually it’s the Diverse Intelligence community. Summer Institute. Yeah, they had a Summer Institute. That’s the logo, the bee with some circuits. Yeah, it’s got different life forms. The whole program is called diverse intelligence. 

They challenged us to come up with a framework that was suitable for analyzing different kinds of intelligence together. Because the kinds of things you do to a human are not good with an octopus, not good with a plant and so on. I started thinking about this. I asked myself what do all cognitive agents, no matter what their provenance, no matter what their architecture is, what do cognitive agents have in common? It seems to me that what they have in common is some degree of competency to pursue a goal. So, what you can do then is you can draw… what I ended up drawing was this thing that it’s kind of like a backwards Minkowski cone diagram where all of space is collapsed into one axis and then here and then time is this axis. Then what you can do is you can draw for any creature, you can semi quantitatively estimate what are the spatial and temporal goals that it’s capable of pursuing. 

For example, if you are a tick and all you really are able to pursue is maximum or a bacterium and maximizing the level of some chemical in your vicinity, that’s all you’ve got, it’s a tiny little icon, then you’re a simple system like a tick or a bacterium. If you are something like a dog, well, you’ve got some ability to care about some spatial region, some temporal. You can remember a little bit backwards, you can predict a little bit forwards, but you’re never ever going to care about what happens in the next town over four weeks from now. As far as we know, it’s just impossible for that kind of architecture. If you’re a human, you might be working towards world peace long after you’re dead. You might have a planetary scale goal that’s enormous. Then there may be other greater intelligences somewhere that can care in the linear range about numbers of creatures, some sort of Buddha like character that can care about everybody’s welfare, really care the way that we can’t. 

It’s not a mapping of what you can sense, how far you can sense. It’s not a mapping of how far you can act. It’s a mapping of how big are the goals you are capable of envisioning and working towards. I think that enables you to put synthetic kinds of constructs, AIs, aliens, swarms, whatever on the same diagram because we’re not talking about what you’re made of or how you got here. We’re talking about what are the size and complexity of the goals towards which you can work. 

{LF} Is there any other terms that pop into mind that are interesting? 

{ML} I’m trying to remember. I have a list of them somewhere on my website. 

{LF} Target Morphology, yeah, definitely check it out. Morphoceutical, I like that one. Ionoceutical. 

{ML}  Yeah. I mean those refer to different types of interventions in the regenerative medicine space. A morphoceutical is something that it’s a kind of intervention that really targets the cells decision making process about what they’re going to build. Ionoceuticals are like that, but more focused specifically on the bioelectrics. There’s also, of course, biochemical, biomechanical, who knows what else, maybe optical kinds of signaling systems there as well. 

Target morphology is interesting. It’s designed to capture this idea that it’s not just feedforward emergence and oftentimes in biology, I mean, of course that happens too, but in many cases in biology, the system is specifically working towards a target in anatomical morphospace. It’s a navigation task really. These kinds of problem solving can be formalized as navigation tasks and that they’re really going towards a particular region. How do you know? Because you deviate them and then they go back. 

{2:38:03 – Advice for young people}

{LF} Let me ask you, because you’ve really challenged a lot of ideas in biology in the work you do, probably because some of your rebelliousness comes from the fact that you came from a different field of computer engineering, but could you give advice to young people today in high school or college that are trying to pave their life story, whether it’s in science or elsewhere, how they can have a career they can be proud of or a life they can be proud of advice? 

{ML} Boy, it’s dangerous to give advice because things change so fast, but one central thing I can say, moving up and through academia and whatnot, you will be surrounded by really smart people. 

What you need to do is be very careful at distinguishing specific critique versus kind of meta advice. What I mean by that is if somebody really smart and successful and obviously competent is giving you specific critiques on what you’ve done, that’s gold. It’s an opportunity to hone your craft, to get better at what you’re doing, to learn, to find your mistakes. That’s great. 

If they are telling you what you ought to be studying, how you ought to approach things, what is the right way to think about things, you should probably ignore most of that. The reason I make that distinction is that a lot of really successful people are very well calibrated on their own ideas and their own field and their own area. They know exactly what works and what doesn’t and what’s good and what’s bad, but they’re not calibrated on your ideas. The things they will say, oh, this is a dumb idea, don’t do this and you shouldn’t do that, that stuff is generally worse than useless. It can be very demoralizing and really limiting. 

What I say to people is read very broadly, work really hard, know what you’re talking about, take all specific criticism as an opportunity to improve what you’re doing and then completely ignore everything else. I just tell you from my own experience, most of what I consider to be interesting and useful things that we’ve done, very smart people have said, this is a terrible idea, don’t do that. I think we just don’t know. We have no idea beyond our own. At best, we know what we ought to be doing. We very rarely know what anybody else should be doing. 

{LF} Yeah, and their ideas, their perspective has been also calibrated, not just on their field and specific situation, but also on a state of that field at a particular time in the past. There’s not many people in this world that are able to achieve revolutionary success multiple times in their life. So, whenever you say somebody is very smart, usually what that means is somebody who’s smart, who achieved a success at a certain point in their life and people often get stuck in that place where they found success. To be constantly challenging your worldview is a very difficult thing. 

Also at the same time, probably if a lot of people tell, that’s the weird thing about life, if a lot of people tell you that something is stupid or is not going to work, that either means it’s stupid, it’s not going to work, or it’s actually a great opportunity to do something new and you don’t know which one it is and it’s probably equally likely to be either. Well, I don’t know the probabilities. Depends how lucky you are, depends how brilliant you are, but you don’t know and so you can’t take that advice as actual data. 

{ML} Yeah, you have to and this is kind of hard to describe and fuzzy, but I’m a firm believer that you have to build up your own intuition. So over time, you have to take your own risks that seem like they make sense to you and then learn from that and build up so that you can trust your own gut about what’s a good idea even when, and then sometimes you’ll make mistakes and they’ll turn out to be a dead end and that’s fine, that’s science, but what I tell my students is life is hard and science is hard and you’re going to sweat and bleed and everything and you should be doing that for ideas that really fire you up inside and really don’t let kind of the common denominator of standardized approaches to things slow you down. 

(2:42:47 – Death}

{LF} So you mentioned planaria being in some sense immortal. What’s the role of death in life? What’s the role of death in this whole process we have? Is it, when you look at biological systems, is death an important feature, especially as you climb up the hierarchy of competency? 

{ML} Boy, that’s an interesting question. I think that it’s certainly a factor that promotes change and turnover and an opportunity to do something different the next time for a larger scale system. So apoptosis, it’s really interesting. I mean, death is really interesting in a number of ways. 

One is like you could think about:  like what was the first thing to die? That’s an interesting question. What was the first creature that you could say actually died? It’s a tough thing because we don’t have a great definition for it. So if you bring a cabbage home and you put it in your fridge, at what point are you going to say it’s died, right? So it’s kind of hard to know. 

There’s one paper in which I talk about this idea that, I mean, think about this and imagine that you have a creature that’s aquatic, let’s say it’s a frog or something or a tadpole, and the animal dies, in the pond it dies for whatever reason. Most of the cells are still alive. So you could imagine that if when it died, there was some sort of breakdown of the connectivity between the cells, a bunch of cells crawled off, they could have a life as amoebas. Some of them could join together and become a xenobot and twiddle around, right? So we know from planaria that there are cells that don’t obey the Hayflick limit and just sort of live forever. So you could imagine an organism that when the organism dies, it doesn’t disappear, rather the individual cells that are still alive, crawl off and have a completely different kind of lifestyle and maybe come back together as something else, or maybe they don’t. So all of this, I’m sure, is happening somewhere on some planet. 

So death in any case, I mean, we already kind of knew this because the molecules, we know that when something dies, the molecules go through the ecosystem, but even the cells don’t necessarily die at that point, they might have another life in a different way. 

You can think about something like HeLa, right? The HeLa cell line, you know, that has this, that’s had this incredible life. There are way more HeLa cells now then there were when she was alive. 

{LF} It seems like as the organisms become more and more complex, like if you look at the mammals, their relationship with death becomes more and more complex. So the survival imperative starts becoming interesting and humans are arguably the first species that have invented the fear of death. The understanding that you’re going to die, let’s put it this way, like long, so not like instinctual, like, I need to run away from the thing that’s going to eat me, but starting to contemplate the finiteness of life. 

{ML} Yeah. I mean, one thing, so, so one thing about the human light, cognitive light cone is that for the first, as far as we know, for the first time, you might have goals that are longer than your lifespan, that are not achievable, right? 

So if you’re, if you are, let’s say, and I don’t know if this is true, but if you’re a goldfish and you have a 10 minute attention span, I’m not sure if that’s true, but let’s say, let’s say there’s some organism with a, with a short kind of cognitive light cone that way, all of your goals are potentially achievable because you’re probably going to live the next 10 minutes. So whatever goals you have, they are totally achievable. If you’re a human, you could have all kinds of goals that are guaranteed not achievable because they just take too long, like guaranteed you’re not going to achieve them. So I wonder if, you know, is that, is that a, you know, like a perennial, you know, sort of thorn in our, in our psychology that drives some, some psychosis or whatever? I have, I have no idea. 

Another interesting thing about that, actually, I’ve been thinking about this a lot in the last couple of weeks, this notion of giving up. So you would think that evolutionarily, the most adaptive way of being is that you go, you, you, you, you fight as long as you physically can. And then when you can’t, you can’t, and there’s in, there’s this photograph, there’s videos you can find of insects are crawling around where like, you know, like, like most of it is already gone, and it’s still sort of crawling, you know, like, Terminator style, right? Like, as far as you physically can, you keep going. Mammals don’t do that. 

So a lot of mammals, including rats, have this thing were, when they think it’s a hopeless situation, they literally give up and die when physically, they could have kept going. I mean, humans certainly do this. And there’s, there’s some like, really unpleasant experiments that the this guy forget his name did with drowning rats, where if he were rats normally drown after a couple of minutes, but if you teach them that if you just tread water for a couple of minutes, you’ll get rescued, they can tread water for like an hour. And so right, and so they literally just give up and die. And so evolutionarily, that doesn’t seem like a good strategy at all evolutionarily, since why would you like, what’s the benefit ever of giving up, you just do what you can, and you know, one time out of 1000, you’ll actually get rescued, right? 

But this issue of actually giving up suggests some very interesting metacognitive controls where you’ve now gotten to the point where survival actually isn’t the top drive. And that for whatever, you know, there are other considerations that have like taken over. And I think that’s uniquely a mammalian thing. But then I don’t know. 

{LF} Yeah, the Camus, the existentialist question of why live, just the fact that humans commit suicide is a really fascinating question from an evolutionary perspective. 

{ML} And what was the first and that’s the other thing, like, what is the simplest system, whether evolved or natural or whatever, that is able to do that? Right? Like, you can think, you know, what other animals are actually able to do that? I’m not sure. 

{LF} Maybe you could see animals over time, for some reason, lowering the value of survive at all costs, gradually, until other objectives might become more important. 

{ML} Maybe. I don’t know how evolutionarily how that gets off the ground. That just seems like that would have such a strong pressure against it, you know. Just imagine, you know, a population with a lower, you know, if you were a mutant in a population that had less of a survival imperative, would you put your genes outperform the others? 

{LF} Is there such a thing as population selection? Because maybe suicide is a way for organisms to decide themselves that they’re not fit for the environment? Somehow? 

{ML} Yeah, that’s a really contrary, you know, population level selection is a kind of a deep controversial area. But it’s tough because on the face of it, if that was your genome, it wouldn’t get propagated because you would die and then your neighbor who didn’t have that would have all the kids. 

{LF} It feels like there could be some deep truth there that we’re not understanding. 

{ML} Maybe.

{LF} What about you yourself as one biological system? Are you afraid of death? 

{ML} To be honest, I’m more concerned with especially now getting older and having helped a couple of people pass. I think about what’s a good way to go? Basically, like nowadays, I don’t know what that is, I, you know, sitting in a, you know, a facility that sort of tries to stretch you out as long as you can, that doesn’t seem that doesn’t seem good. And there’s not a lot of opportunities to sort of, I don’t know, sacrifice yourself for something useful, right? There’s not terribly many opportunities for that in modern society. So I don’t know, that’s that’s that’s more of I’m not I’m not particularly worried about death itself. But I’ve seen it happen. And it’s not pretty. And I don’t know what a better alternative is. 

{LF} So the existential aspect of it does not worry you deeply? The fact that this ride ends? 

{ML} No, it began. I mean, the ride began, right? So there was I don’t know how many billions of years before that I wasn’t around. So that’s okay. 

{LF} But isn’t the experience of life? It’s almost like, feels like you’re immortal. Because the way you make plans, the way you think about the future. I mean, if you if you look at your own personal rich experience, yes, you can understand, okay, eventually, I died as people I love that have died. So surely, I will die and it hurts and so on. But like, he sure doesn’t. It’s so easy to get lost in feeling like this is going to go on forever. 

{ML} Yeah, it’s a little bit like the people who say they don’t believe in free will, right? I mean, you can say that but when you go to a restaurant, you still have to pick a soup and stuff. So right, so I don’t know if I know I’ve actually seen that that happened at lunch with a well known philosopher and he didn’t believe in free will and the other waitress came around and he was like, Well, let me see. I was like, What are you doing here? You’re gonna choose a sandwich, right? So it’s I think it’s one of those things. I think you can know that, you know, you’re not going to live forever. But you can’t, you can’t. It’s not practical to live that way unless you know, so you buy insurance and then you do some stuff like that. But  mostly, you know, I think you just live as if as if as if you can make plans. 

{2:52:17 – Meaning of life}

{LF} We talked about all kinds of life. We talked about all kinds of embodied minds. What do you think is the meaning of it all? What’s the meaning of all the biological lives we’ve been talking about here on Earth? Why are we here? 

{ML} I don’t know that that’s a well posed question other than the existential question you post before.

{LF}  Is that question hanging out with the question of what is consciousness and there at retreat somewhere…

{ML} I’m not sure because…

{LF}  sipping pina coladas and because they’re ambiguously defined. 

{ML} Maybe I’m not sure that any of these things really ride on the correctness of our scientific understanding. But I mean, just just for an example, right? I’ve always found it weird that people get really worked up to find out realities about their bodies, for example. Right. You’ve seen them. Ex Machina. Right. And so there’s this great scene where he’s cutting his hand to find out, you know, a piece full of cogs. Now, to me, right? If if I open up and I find out and I find a bunch of cogs, my conclusion is not, oh, crap, I must not have true cognition. That sucks. My conclusion is, wow, cogs can have true cognition. Great. So right. 

So it seems to me, I guess I guess I’m with Descartes on this one, that whatever the truth ends up being of how is, what is consciousness, how it can be conscious? None of that is going to alter my primary experience, which is what it is. And if and if a bunch of molecular networks can do it, fantastic. If it turns out that there’s a non corporeal soul, you know, so great. We can we’ll study that, whatever. 

But the fundamental existential aspect of it is, you know, if somebody if somebody told me today that, yeah, yeah, you were created yesterday and all your memories are, you know, sort of fake, you know, kind of like Boltzmann brains, right. And the human, you know, human skepticism, all that. Yeah. OK. Well, so so but but here I am now. So….

{LF}  it’s the experience. It’s primal, so like that’s the thing that matters. So the backstory doesn’t matter. 

{ML} I think so. I think so. From a first person perspective, now from a third person, like scientifically, it’s all very interesting. From a third person perspective, I could say, wow, that’s that’s amazing that this happens and how does it happen and whatever. 

But from a first person perspective, I could care less. Like I just it’s just what I’ve what I learned from any of these scientific facts is, OK, well, I guess then that’s … then I guess that’s what is sufficient to to give me my, you know, amazing first person perspective.

{LF}  I think if you dig deeper and deeper and get surprising answers to why the hell we’re here, it might give you some guidance on how to live. 

{ML} Maybe, maybe. I don’t know. That would be nice. On the one hand, you might be right, because on the one hand, if I don’t know what else could possibly give you that guidance, right. So you would think that it would have to be that or you would do it would have to be science because there isn’t anything else. 

So that’s so maybe on the other hand, I am really not sure how you go from any, you know, what they call from an is to an ought right from any factual description of what’s going on. This goes back to the natural. right. Just because somebody says, oh, man, that’s completely not natural. It’s never happened on Earth before. I’m not impressed by that whatsoever. I think whatever hazard hasn’t happened, we are now in a position to do better if we can. Right. 

{LF} Well, this also because you said there’s science and there’s nothing else. There it’s really tricky to know how to intellectually deal with a thing that science doesn’t currently understand. Right. So like, the thing is, if you believe that science solves everything, you can too easily in your mind think our current understanding, like, we’ve solved everything. 

{ML} Right. Right. Right. 

{LF} Like, it jumps really quickly to not science as a mechanism as a process, but more like science of today. Like, you could just look at human history and throughout human history, just physicists and everybody would claim we’ve solved everything. 

{ML} Sure. Sure. 

{LF} Like, like, there’s a few small things to figure out. And we basically solved everything. Were in reality, I think asking, like, what is the meaning of life is resetting the palette 

{ML}  Yeah.

{LF} of like, we might be tiny and confused and don’t have anything figured out. It’s almost going to be hilarious a few centuries from now when they look back how dumb we were. 

{ML} Yeah, I 100% agree. So when I say science and nothing else, I certainly don’t mean the science of today because I think overall, I think we  know very little. I think most of the things that we’re sure of now are going to be, as you said, are going to look hilarious down the line. So I think we’re just at the beginning of a lot of really important things. 

When I say nothing but science, I also include the kind of first person, what I call science that you do. So the interesting thing about I think about consciousness and studying consciousness and things like that in the first person is unlike doing science in the third person, where you as the scientist are minimally changed by it, maybe not at all. So when I do an experiment, I’m still me, there’s the experiment, whatever I’ve done, I’ve learned something, so that’s a small change. But but overall, that’s it. 

In order to really study consciousness, you will you are part of the experiment, you will be altered by that experiment, right? Whatever, whatever it is that you’re doing, whether it’s some sort of contemplative practice or, or some sort of psychoactive, you know, whatever. You are now, you are now your own experiment, and you are right. And so I consider, I fold that in, I think that’s part of it. I think that exploring our own mind and our own consciousness is very important. I think much of it is not captured by what currently is third person science for sure. But ultimately, I include all of that in science, with a capital S in terms of like a, a rational investigation of both first and third person aspects of our world. 

{LF} We are our own experiment, as beautifully put. And when two systems get to interact with each other, that’s the kind of experiment. So I’m deeply honored that you would do this experiment with me today. 

{ML} Thanks so much.

{LF}  I’m a huge fan of your work. Likewise, thank you for doing everything you’re doing. I can’t wait to see the kind of incredible things you build. So thank you for talking. 

{ML} Really appreciate being here. Thank you. 

{LF} Thank you for listening to this conversation with Michael Levin. To support this podcast, please check out our sponsors in the description. And now let me leave you with some words from Charles Darwin in The Origin of Species: “From the war of nature, from famine and death, the most exalted object which we are capable of conceiving, namely, the production of the higher animals, directly follows. There is grandeur in this view of life. From so simple a beginning endless forms most beautiful and most wonderful have been, and are being, evolved.”

Thank you for listening, and hope to see you next time.  

Transcript of Lex Fridman interview with Manolis Kellis: Human Genome and Evolutionary Dynamics July 31, 2020

{This is my version of a transcript of the first Lex Fridman interview with Manolis Kellis. I transcribed this conversation because I wanted to dive deeper on a number of topics in this discussion. Perhaps this transcript will be useful to others as well.}

{LF} The following is a conversation with Manolis Kellis, a professor at MIT and head of the MIT Computational biology group. He is interested in understanding the human genome from a computational evolutionary, biological and other cross disciplinary perspectives. He has more big impactful papers and awards that I can list. But most importantly he’s a kind, curious, brilliant human being and just someone I really enjoyed talking to. His passion for science and life in general is contagious. The hours honestly flew by and I’m sure we’ll talk again on this podcast soon. 

{LF [3:50] } …. And now here’s my conversation with Manolis Kellis. What to you is the most beautiful aspect of the human genome?

{MK}    Don’t get me started. So…

{LF} We’ve got time. 

{MK}  The first answer is that the beauty of genomes transcends humanity. So it’s not just about the human genome, genomes in general are amazingly beautiful. And again, I’m obviously biased. So, in my view, the way that I’d like to introduce the human genome and the way that I like to introduce genomics to my classes by telling them, you know, we’re not the inventors of the first digital computer, we are the descendants of the first digital computer. 

Basically life is digital and that’s absolutely beautiful about life. The fact that at every replication step you don’t lose any information because that information is digital. If it was analog, it was just {protein}  concentrations, you’d lose it after a few generations, it would just dissolve away. And that’s what the ancients didn’t understand about inheritance. 

The first person to understand digital inheritance was Mendel of course, and his theory in fact stayed in a bookshelf for like 50 years while Darwin was getting famous about natural selection, but the missing component was this digital inheritance. The mechanism of evolution that Mendel had discovered. So that aspect, in my view, is the most beautiful aspect, but it transcends all of life.

{LF}   And can you elaborate maybe the inheritance part? What was the key thing that the ancients didn’t understand?

{MK}    So the very theory of inheritance as discrete units, you know, throughout the life of Mendel and well after his writing, people thought that his pea experiments were just a little fluke.  That they were just a little exception that would normally not even apply to humans that basically what they saw is: this continuum of eye color, this continuum of skin color, this continuum of hair color, this continuum of height and all of these continuums did not fit with a discrete type of inheritance that Mendel was describing. 

But what’s unique about genomics and what’s unique about the genome is really that there are two copies and that you get a combination of these but for every trait there are dozens of contributing variables. And it was only Ronald Fisher in the 20th century that basically recognized that even five Mendelian Traits would add up to a continuum-like inheritance pattern. And he wrote a series of papers that still are very relevant today about this Mendelian inheritance of continuum-like traits. And I think that that was the missing step in inheritance. So, well before the discovery of the structure of DNA, which is again another amazingly beautiful aspect, the double helix, what I like to call the most noble molecule over time is you know…, holds within it the secret of that discrete inheritance. But the conceptualization of discrete, you know, elements is something that precedes that.

{LF}   So even though it’s discrete, when it materializes itself into actual traits that we see, it can be continuous and basically arbitrarily rich and complex.

{MK}    So if you have five genes that contribute to human height and there aren’t five, there’s 1000. If there’s only five genes and you inherit some combination of them and everyone makes you two inches taller or two inches shorter. It’ll look like a continuous trait, but instead of five, there are thousands and every one of them contributes to less than one millimeter, we change in height more during the day than each of these genetic variants contributes. So by the evening you’re shorter than you were when you woke up.

{LF}   Isn’t it weird then that we’re not more different than we are? Why are we also similar if there’s so much possibility to be different? 

{MK}   Yeah, so there are selective advantages to being medium. If you’re extremely tall or extremely short, you run into selective disadvantages. So you have trouble breathing, you have trouble running, you have trouble sitting, if you’re too tall. If you’re too short, you might, I don’t know, have other selective pressures acting against that. If you look at the natural history of human population, there’s actually selection for height in Northern Europe and selection against height in Southern Europe. So there might actually be advantages to actually being not not super-tall. And if you look across the entire human population, you know, for many many trades, there’s a lot of push towards the middle. Balancing selection is, you know, the usual term for selection that sort of seeks to not be extreme and to sort of have a combination of alleles that sort of, you know, keep recombining. 

And if you look at mate selection super, super tall people will not tend to sort of marry super, super tall people. Very often you see these couples that are kind of compensating for each other and the best predictor of the kids age {height} is very often just take the average of the two parents and then adjust for sex and whom you get it. It’s extremely heritable.

{LF}   Let me ask, you kind of took a step back to the genome outside of just humans. But is there something that you find beautiful about the human genome specifically?

{MK}    So,  I think the genome, if more people understood the beauty of the human genome, there would be so many fewer wars, so much less anger in the world. I mean what’s really beautiful about the human genome is really the variation that teaches us both about individuality and about similarity. So any two people on the planet are 99.9% identical. How can you fight with someone who is 99.9% identical to you? It’s just counterintuitive and yet any two siblings of the same parents differ in millions of locations. So every one of them is basically two to the million {2^1,000,000} unique from any pair of parents, let alone any two random parents on the planet. So that’s I think something that teaches us about the nature of humanity in many ways, that every one of us is as unique as any star and way more unique in actually many ways and yet we’re all brothers and sisters. 

{LF}   And just like stars, most of it is just a fusion reaction.

{MK}    You only have a few parameters to describe stars, you know, 

{LF} Yeah. Exactly.

{MK}  …. mass size, initial size and stage of life. Whereas for humans it’s, you know thousands of parameters scattered across your genome. 

So the other thing that makes humans unique. The other thing that makes inheritance unique in humans is that most species inherit things vertically; basically instinct is a huge part of their behavior. The way that you know….  I mean with my kids we’ve been watching these nest of birds with two little eggs, you know, outside our window for the last few months for the last few weeks as they’ve been growing. And there’s so much behavior that’s hard-coded, birds don’t just learn as they grow. They don’t, you know … there’s no culture like a bird that’s born in Boston will be the same as a bird that’s born in California. So there’s not as much inheritance of ideas, of customs. A lot of it is hard coded in their genome. What’s really beautiful about the human genome is that if you take a person from today and you place them back in ancient Egypt or if you take a person from ancient Egypt and you place them here today, they will grow up to be completely normal. 

That is not genetics. This is the other type of inheritance in humans. So on one hand we have the genetic inheritance which is vertical from your parents down on the other hand we have horizontal inheritance which is the ideas that are built up at every generation are horizontally transmitted. And the huge amount of time that we spend in educating ourselves, a concept known as neoteny, “neo” for newborn and then “teny” for holding. So if you look at humans, I mean the little birds that were eggs two weeks ago and now one of them has already flown off, the other one is ready to fly off.  In two weeks they’re ready to just fend for themselves. Humans:  16 years, 18 years, 24, getting out of college….

{LF}    I’m still learning. So, that’s so fascinating that this picture of a vertical and the horizontal when you talk about the horizontal is in the realm of ideas.

{MK}    Exactly.

{LF}   Okay, so it’s the actual social interactions and ….

{MK}   That’s exactly right. That’s exactly right. So basically the concept of neoteny is that you spend acquiring characteristics from your environment in an extremely malleable state of your brain and the wiring of your brain for a long period of your life. Compared to primates we are useless. You take any primate at seven weeks and any human in seven weeks we lose the battle but at 18 years all bets are off. Like basically our brain continues to develop in an extremely malleable form until very late. And this is what allows education. This is what allows the person from Egypt to do extremely well now. 

And the reason for that is that the wiring of our brain and the development of that wiring is actually delayed. So you know the longer you delay that the more opportunity you have to pass on knowledge, to pass on concepts, ideals, ideas from the parents to the child and what is really absolutely beautiful about humans today is that lateral transfer of ideas and culture. He’s not just from uncles and aunts and teachers at school, but it’s from Wikipedia and review articles on the web and thousands of journals that are sort of putting out information for free and podcasts and videocasts and all of that stuff where you can basically learn about any topic, pretty much everything that would be in any super-advanced textbook in a matter of days instead of having to go to the library of Alexandria and sail there to read three books and then sail for another few days to get to Athens and etc. etc. So the democratization of knowledge and the spread,  the speed of spread of knowledge is what defines I think the human inheritance pattern.

{LF}   So you sound excited about it. Are you also a little bit afraid? Are you more excited by the power of this kind of distributed spread of information? So you put it very kindly that most people are kind of using the internet and you know, looking at Wikipedia,  reading articles, reading papers and so on. But if we are honest, most people online, especially when they’re younger, are probably looking at five second clips on TikTok or whatever the new social network is. Are you,  given this power of horizontal inheritance, are you optimistic or a little bit pessimistic about this new effect of the internet and democratization of knowledge on our …. what would you call this this. gene? Like, would you, would you use the term genome by the way for this?

{MK}    Yeah, I think, you know, we use the genome to talk about DNA, but very often we say, you know, I mean, I’m Greek, so people ask me, hey, what’s in the Greek genome? And I’m like, well, yeah, what’s in the Greek genome is both our genes and also our ideas and our ideals and our culture. 

{LF} The poetic meaning of the word.

{MK}  Exactly. Exactly. Yeah. So I think that there’s a beauty to the democratization of knowledge, the fact that you can reach as many people as you know, any other person on the planet and it’s not who you are, it’s really your ideas that matter, is a beautiful aspect of the internet. 

I think there’s of course a danger of: my ignorance is as important as your expertise. The fact that with this democratization comes the abolishment of respecting expertise, Just because you’ve spent, you know, 10,000 hours of your life studying, I don’t know, human brain circuitry; why should I trust you? I’m just going to make up my own theories and they will be just as good as yours is an attitude that sort of counteract the beauty of the democratization.

And I think that within our educational system and within the upbringing of our children, we have to not only teach them knowledge, but we have to teach them the means to get to knowledge and that, you know, it’s very similar to sort of: You catch a fish for a man for one day, you fed them for one day, you teach them how to fish, you feed him for the rest of their life. 

So instead of just gathering the knowledge they need for any one task, we can just tell them all right: here’s how you Google it, here’s how I figure out what’s real and what’s not, here’s how you check the sources, here’s how you form a basic opinion for yourself. And I think that inquisitive nature is paramount to being able to sort through this huge wealth of knowledge. So you need a basic educational foundation based on which you can then add on the domain specific knowledge, but that basic educational foundation should just, not just the knowledge, but it should also be epistemology, the way to acquire knowledge.

{LF}   I’m not sure any of us know how to do that in this modern day. We’re actually learning. One of the big surprising thing to me about the coronavirus, for example, is that Twitter has been one of the best sources of information, basically like building your own network of experts of of you know, as opposed to the traditional centralized expertise of the WHO {World Health Organization}  and the CDC and the or maybe any one particular respectable person at the top of the department of some kind of institution. You instead look at a you know ten, twenty, hundreds of people; some of whom are young kids with just that are incredibly good at aggregating data and plotting and visualizing that data. That’s been really surprising to me. I don’t know what to make of it. I don’t know how that matures into something stable. You know, I don’t know if you have ideas like what if you were to try to explain to your kids,  where should you go to learn about coronavirus? What would you say?

{MK}    It’s such a beautiful example and I think the current pandemic and the speed at which the scientific community has moved in the current pandemic I think exemplifies this horizontal transfer and the speed of horizontal transfer of information. The fact that, you know, the genome was first sequenced in early January. The first sample was obtained December 29 2019 a week after the publication of the first genome sequence Moderna had already finalized this vaccine design and was moving to production. I mean this is phenomenal,  the fact that we go from not knowing what the heck is killing people in Wuhan to wow, it’s SARS-CoV-2 and here’s the set of genes, here’s the genome, here’s the sequence here, the polymorphisms etc. in the matter of weeks is phenomenal. 

In that incredible pace of transfer of knowledge there have been many mistakes. So you know, some of those mistakes may have been politically motivated or other mistakes may have just been innocuous errors. Others may have been misleading the public for the greater good such as: Don’t wear masks because we don’t want the masks to run out. I mean that was very silly in my view and a very big mistake but the spread of knowledge from the scientific community was phenomenal and some people will point out bogus articles that snuck in and made the front page. Yeah they did. But within 24 hours they were debunked and went out of the front page and I think that’s the beauty of science today. The fact that it’s not, oh, knowledge is fixed. It’s the ability to embrace that nothing is permanent when it comes to knowledge that everything is the current best hypothesis and the current best model that best fits the current data and the willingness to be wrong. The expectation that we’re going to be wrong and the celebration of success based on how long was I not proven wrong for rather than wow, I was exactly right. 

Because no one is going to be exactly right with partial knowledge but the arc towards perfection. I think it’s so much more important then how far you are in your first step and I think that’s what sort of the current pandemic has taught us the fact that you know of course we’re gonna make mistakes but at least we’re going to learn from those mistakes and become better and learn better and spread information better. So if I were to answer the question of where would you go to learn about coronavirus: first textbook? It all starts with the textbook, just opened up a chapter on virology and how coronaviruses work, then some basic epidemiology and sort of how pandemics have worked in the past. What are the basic principles surrounding these first wave? Second wave? Why do they even exist? Then, understanding about growth.

Understanding about the R-naught {R0} and Rt at various time points and then understanding the means of spread: how it spreads from person to person then how does it get into your cells? From when it gets into the cells what are the paths that it takes? What are the cell types that express the particular ACE2 receptor? How is your immune system interacting with the virus? And once your immune system launches its defense, how is that helping or actually hurting your health? What about the cytokine storm? What are most people dying from? Why are the comorbidities and these risk factors even applying? What makes obese people respond more or elderly people respond more to the virus while kids are completely, you know, very often not even aware that they’re spreading it. So, you know, I think there’s some basic questions that you would start from and then I’m sorry to say, but Wikipedia is pretty awesome, Google is pretty awesome. 

{LF}   There used to be a time, maybe five years ago, I forget when but people kind of made fun of Wikipedia for being an unreliable source. I never quite understood. I thought from the early days it was pretty reliable. They’re better than a lot of the alternatives. But at this point it’s kind of like a solid accessible survey paper on every subject ever.

{MK}    There’s an ascertainment bias and a writing bias. So I think this, this is related to people saying so many Nature {journal} papers are wrong and they’re like why would you publish in Nature {journal}? So many Nature {journal} papers are wrong? And my answer is no, no, no. So many Nature {journal} papers are scrutinized and just because more of them are being proven wrong than in other articles is actually evidence that they’re actually better papers overall because they’re being scrutinized at a rate much higher than any other journal. So if you basically judge Wikipedia by not the initial content but by the number of revisions.

{LF} Yeah.

{MK}  Then of course it’s going to be the best source of knowledge. Eventually it’s still very superficial, you then have to go into the review papers etc. But I mean for most scientific project topics, it’s extremely superficial, but it is quite authoritative because it is the place that everybody likes to criticize as being wrong.

{LF}   You say that’s superficial and a lot of topics that I’ve studied a lot of, I find it…  I don’t know if superficial is the right word because superficial kind of implies that is not correct.

{MK}    No, no, I don’t mean any implication of it not being correct, it’s just superficial. It’s basically only scratching the surface. For depth, you don’t go to Wikipedia; you go to the review articles. 

{LF}   But it can be profound in the way that articles rarely …. one of the frustrating things to me about certain computer science, like in the machine learning world articles, they don’t as often take the bigger picture view. You know, there’s a kind of dataset and you show that it works and you kind of show that here’s an architectural thing that creates an improvement and so on and so forth. But you don’t say: well like what does this mean for the nature of intelligence for future datasets we haven’t even thought about or if you’re trying to implement this. Like if we took this data set of 100,000 examples and scale it to 100 billion examples with this method, like look at the bigger picture, which is what a Wikipedia article would actually try to do, which is like: what does this mean in the context of the broad field of computer vision or something like that?

{MK}    Yeah, I agree with you completely but it depends on the topic. I mean for some topics there’s been a huge amount of work, for other topics it’s just a stub. So, you know, I got it. Yeah.

{LF}   Well, yeah, actually, which we’ll talk {about} on genomics was not great.

{MK}    It’s shallow. It’s not wrong. It’s just shallow, shallow. Yeah. Every time I criticize something I should feel partly responsible. Basically if more people from my community went there and edited, it would not be shallow. It’s just that there’s different modes of communication in different fields. And in some fields, the experts have embraced Wikipedia. In other fields, it’s relegated. And perhaps the reason is that if it was any better to start with, people would invest more time. But if it’s not great to start with, then you need a few initial pioneers who will basically go in and say: enough, we’re just going to fix that. and then I think they’ll catch on much more.

{LF}   So if it’s okay before we go on to genomics, can we linger a little bit longer on the beauty of the human genome. You’ve given me a few notes. What else, what else do you find beautiful about the human genome?

{MK}    So the last aspect of what makes the human genome unique in addition to the, you know, similarity and the differences and individuality is that… So very early on people would basically say, oh you don’t do that experiment in humans. You have to learn about that in fly or you have to learn about that in yeast first or in mouse first or in a primate first. {These are examples of model organisms} And the human genome was in fact relegated to sort of the last place that you’re going to go to learn something new that has dramatically changed. And the reason that changed is human genetics. We are the species on the planet that’s the most studied right now. It’s embarrassing to say that, but this was not the case a few years ago. Used to be, you know, first viruses, then bacteria, then yeast, then the fruit fly, then the worm, then the mouse and eventually human was very far last.

{LF}   So it’s embarrassing that it took us this long to focus on it or they ….

{MK}    It’s embarrassing that the model organisms have been taken over because of the power of human genetics. That right now it’s actually simpler to figure out the phenotype of something by mining this massive amount of human data then by going back to any of the other species. And the reason for that is that if you look at the natural variation that happens in a population of seven billion; you basically have a mutation in almost every nucleotide. So every nuclear that you want to perturb; you can go find a living breathing human being and go test the function that nucleotide by sort of searching the database and finding that person. 

{LF}   Wait, why is that embarrassing? It’s a beautiful dataset.

{MK}    It’s embarrassing for the model organism. 

{LF}   For the flies?

{MK}  Yeah, exactly. 

{LF} I mean, do you feel, on a small tangent, is there something of value in the genome of a fly and other these model organisms that you miss,  that we wish we would have would be looking at deeper?

{MK}    So directed perturbation of course. So I think the place where humans are still lagging is the fact that in an animal model you can go and say, well, let me knockout this gene completely.

{LF} Got it.

{MK}  … and let me knockout these three genes completely. And at the moment you get into combinatorics, it’s something you can’t do in humans because they’re just simply aren’t enough humans on the planet.  

And again, let me be honest, we haven’t sequenced all seven billion people. It’s not like we have every mutation, but we know that there’s a carrier out there. 

[29:15] So if you look at the trend and the speed with which human genetics has progressed, we can now find thousands of genes involved in human cognition, in human psychology, in the emotions and the feelings that we used to think are uniquely learned. It turns out there’s a genetic basis to a lot of that. 

So the … you know, the human genome has continued to elucidate through these studies of genetic variation so many different processes that we previously thought were, you know, something that like free will.  Free will is this beautiful concept that humans have had for a long time? You know, in the end, it’s just a bunch of chemical reactions happening in your brain and the particular abundance of receptors that you have this day based on what you ate yesterday or that you have been wired with based on, you know, your parents and your upbringing etc. determines a lot of that quote unquote free will components to, you know, sort of narrower and narrower, you know, sort of slices.

{LF}   So on that point, how much freedom do you think we have to escape the constraints of our genome? 

{MK}  {laughs}

{LF}  You’re making it sound like more and more, we’re discovering that our genome is actually…. has a lot of the story already encoded into it. How much freedom do we have, do you think?

{MK}    So let me describe what that freedom would look like. That freedom would be my saying: Oh, I’m going to resist the urge to eat that apple because I choose not to. But there are chemical receptors that made me not resist the urge to prove my individuality and my free will by resisting the apple. So then the next question is well, maybe now I’ll resist the urge to resist the apple and I’ll go for the chocolate instead to prove my individuality. But then what about those other receptors that you know….

{LF}   That might be all encoded in there.

{MK}    So it’s kicking the bucket down the road and basically saying, well your choice will …. may have actually been driven by other things that you actually are not choosing. So that’s why it’s very hard to answer that question. 

{LF}   It’s hard to know what to do with that. I mean, if if the genome has …. if if there’s not much freedom, it’s

{MK}    It’s the butterfly effect. It’s basically that in the short term you can predict something extremely well by knowing the current state of the system. But a few steps down, it’s very hard to predict based on the current knowledge. Is that because the system is truly free?

 When I look at weather patterns that can predict the next 10 days. Is it because the weather has a lot of freedom and after 10 days it chooses to do something else? Or is it because in fact the system is fully deterministic and there’s just a slightly different magnetic field of the Earth, slightly more energy arriving from the sun, a slightly different spin of the gravitational pull of Jupiter that is now causing all kinds of tides and slight deviation of the moon etc. Maybe all of that can be fully modeled. Maybe the fact that China is emitting a little more carbon today is actually going to affect the weather in Egypt in three weeks and all of that could be fully modeled.

 In the same way. If you take a complete view of a human being now, you know, I model everything about you. The question is, can I predict your next step probably, but how far and if it’s a little further is that because of stochasticity and sort of chaos properties of unpredictability of beyond a certain level or was that actually true free will?

{LF}   Yeah. Yeah. So the number of variables might be so…. you might need to build an entire universe.

{MK}    To simulate a human and then maybe that human will be fully simulatable but maybe aspects of free will will exist. And where is that free will coming from? It’s still coming from the same neurons or maybe from a spirit inhabiting these neurons. But again, you know, it’s very difficult empirically to sort of evaluate where does free will begin and sort of chemical reactions and electric signals end.

{LF}   So on that topic, let me ask the most absurd questions that most MIT faculty roll their eyes on.  {laugh} But what do you think about the simulation hypothesis and the idea that we live in a simulation?

{MK}    I think it’s complete BS.

{LF}  Okay  {laugh}

{MK}   {laugh} There’s no empirical evidence; absolutely none.

{LF}   Not in terms of empirical evidence or not. But in terms of thought experiment, does it help you think about the universe? I mean, if you look at the genome, it’s encoding a lot of the information that is required to create some of the beautiful human complexity that we see around us. It’s an interesting thought experiment. How much, you know, parameters do we need to have in order to model some, you know, this full human experience? Like if you wanted to build a video game, how hard it would be to build a video game that’s convincing enough and fun enough and you know it has a consistent laws of physics, all that stuff. It’s not interesting to you as a thought experiment?.  {laugh} 

{MK}    I mean it’s cute but you know, it’s Occam’s razor. I mean what’s more realistic: the fact that you’re actually a machine or that you’re you know, a person, what’s you know the fact that all of my experiences exist inside the chemical molecules that I have or that somebody is actually, you know, simulating all that.

{LF}   Well you did refer to humans as a digital computer earlier.

{MK}    Of course, of course, but that does not 

{LF} It’s kind of a machine. Right? 

{MK}  I know. I know but I think the probability of all that is nil and let the machines wake me up and just terminate me now if it’s not, I challenge you machines.

{LF}   They’re going to wait a little bit to see what you’re going to do next. It’s fun. It’s fun to watch, especially the clever humans. What’s the difference to you between the way a computer stores information and the human genome stores information. So you also have roots and your work …. would you say you’re when you introduce yourself at a bar,

{MK}   It depends who I’m talking to. 

{LF}    {laugh}  Would you say it’s computational biology? Do you reveal your expertise in computers?

{MK}    It depends who I’m talking to truly. I mean basically if I meet someone who’s in computers, I’ll say, oh, I mean professor of computer science, if I meet someone who’s in engineering as a computer science and electrical engineering, if I meet someone in biology and say, hey, I work on genomics. If I meet someone in medicine, like hey, I work on, you know, genetics.

{LF}   You’re a fun person to meet at a bar, I got you. But so

{MK}   No, no, but what I’m trying to say is that I don’t…. I mean there’s no single attribute that will define myself as, you know, there’s a few things I know there’s a few things I studied. There’s a few things I have degrees on and there’s a few things that I grant degrees in. And you know, I, I publish papers across the whole gamut, you know, the whole spectrum of computation to biology etc. I mean,  the complete answer is that I use computer science to understand biology. So you know, I develop methods in AI, machine learning,  statistics in algorithms etc. But the ultimate goal of my career is to really understand biology. If these things don’t advance our understanding of biology. I’m not as fascinated by them. Although there are some beautiful computational problems by themselves. I’ve sort of made it my mission to apply the power of computer science to truly understand the human genome, health, disease, you know and the whole gamut of how our brain works, how our body works and all of that. Which is so fascinating. 

{LF}   So the dream, there’s not an equivalent sort of complimentary dream of understanding human biology in order to create an artificial life and artificial brain and an artificial intelligence that supersedes the intelligence and the capabilities of us humans.

{MK}    It’s an interesting question. It’s a fascinating question. So understanding the human brain is undoubtedly coupled to how do we make better AI because so much of AI has in fact been inspired by the brain. It may have taken fifty years since the early days of neural networks until we have you know, all of these amazing progress that we’ve seen with you know deep belief networks and you know all of these advances in Go and chess, in image synthesis, in deep fakes, in you name it. But the underlying architecture is very much inspired by the human brain which actually posits a very, very interesting question. Why are neural networks performing so well? And they perform amazingly well. Is it because they can simulate any possible function? And the answer is no, no. They simulate a very small number of functions. Is it because they can simulate every possible function in the universe? And that’s where it gets interesting. The answer is actually a little closer to that, and here’s where it gets really fun.

If you look at the human brain and human cognition, it didn’t evolve in a vacuum. It evolved in a world with physical constraints like the world that inhabits this, it is the world that we inhabit. And if you look at our senses, what do they perceive? They perceive different parts of the electromagnetic spectrum? You know? The hearing is just different movements in air, the touch, etc. I mean all of these things, we’ve built the intuitions for the physical world that we inhabit and our brains and the brains of all animals evolved for that world. 

And the AI systems that we have built happen to work well with images of the type that we encounter in the physical world that we inhabit. Whereas if you just take noise and you add a random signal that doesn’t match anything in our world, neural networks will not do as well. And that actually basically has this whole loop around this, which is this was designed by studying our own brain which was evolved for our own world and they happened to do well in our own world and they happen to make the same types of mistakes that humans make many times. And of course you can engineer images by adding just the right amount of, you know, sort of pixel deviations to make a zebra look like a baboon and stuff like that or like a table. But ultimately the undoctored images, at least, are very often mistaken. I don’t know between muffins and dogs, for example, in the same way that humans make those mistakes.

So it’s you know, there’s no doubt in my view that the more we understand about the tricks that our human brain has evolved to understand the physical world around us, the more we will be able to bring new computational primitives in our AI systems to again better understand, not just the world around us, but maybe even the world inside us and maybe even the computational problems that arise from new types of data that we haven’t been exposed to but are yet inhabiting the same universe that we live in with the very tiny little subset of functions from all possible mathematical functions.

{LF}   Yeah. And that small subset of function is all that matters to us, humans really, that’s what makes….

{MK}   It’s all that has mattered so far. And even within our scientific realm, it’s all that seems to continue to matter. But I mean, I always like to think about our senses and how much of the physical world around us we perceive. And if you look at the LIGO experiment over the last, you know, year and a half has been all over the news, what did LIGO do? It created a new sense for human beings, a sense that has never been sensed in the history of our planet. Gravitational waves have been traversing the earth since its creation a few billion years ago. 

Life has evolved senses to sense things that were never before sensed light was not perceived by early life, no one cared. And eventually photoreceptors evolved and the ability to sense colors by catching different parts of that electromagnetic spectrum and hearing evolved and touch evolved etc. But no organism evolved a way to sense neutrinos floating through earth, or gravitational waves flowing through earth etc. And I find it so beautiful in the history of not just humanity but life on the planet, that we are now able to capture additional signals from the physical world than we ever knew before. And { unintelligible } for example have been all over the news in the last few weeks. The concept that we can capture and perceive more of that physical world is as exciting as the fact that we are, we were blind to it is traumatizing before. Because that also tells us, you know, we’re in 2020 Picture yourself in 3020. Or in 20…

{LF}   What new senses, what might we discover?

{MK}    Is it, you know, could it be that we’re missing 9/10 of physics?

{LF}   Most of physics…

{MK}    That like there’s a lot of physics out there that we’re just blind to. Completely oblivious to it. And yet they’re permeating us all the time. 

{LF}   Yes, it might be right in front of us. 

{MK}    So, when you’re thinking about premonitions,

{LF}   Yeah.

{MK}    A lot of that is ascertainment bias {Sampling bias}. Like yeah, you know, every now and then you’re like, oh I remember my friend and then my friend doesn’t appear and I’ll forget that I remember my friend, but every now and then my friend will actually appear and like, oh my God, I thought about you a minute ago, you just called me. That’s amazing. So, you know, some of that is this, but some of that might be that there are within our brain sensors for waves that we admit that we’re not even aware of. And this whole concept of when I hug my children, there’s such an emotional transfer there that we don’t comprehend. I mean sure, yeah, of course, we’re all hardwired for all kinds of touchy feely things between parents and kids, it’s beautiful. Between partners is beautiful and tender. But then there are intangible aspects of human communication that I don’t think it’s unfathomable that our brain has actually evolved ways and sensors for it that we just don’t capture. We don’t understand the function of the vast majority of our neurons and maybe our brain is already sensing it, but even worse, maybe our brain is not sensing it at all and were oblivious to this until we build a machine that suddenly is able to sort of capture so much more of what’s happening in the natural world. 

{LF}   So what you’re saying is we … physics is going to discover a sensor for love. {laughs}

{MK}    And maybe dogs are off scale for that. {laughs} And we’ve been, you know, we’ve been oblivious to it the whole time because we didn’t have the right sensor and now you’re going to have a little wrist {sensor}  that says, oh my God, I feel all this love in the house. I sense some disturbance in the force.

{LF}   And cats will have zero. None. {laughs}

{MK}    {laughs} No, none.

{LF}   It’s just me. But let’s take a step back to unfortunately ….

{MK}    To one of the four hundred topics that we had actually planned. 

{LF}   But to our sad time in 2020 when we only have just a few sensors and very primitive early computers. So you have a foot in computer science and a foot in biology. In your sense: How do computers represent information differently than like the genome or biological systems?

{MK}    So, first of all, let me correct that no, we’re in an amazing time in 2020. Computer science is totally awesome. And physics is totally awesome. And we have understood so much of the natural world than ever before. So I am extremely grateful and feeling extremely lucky to be living in the time that we are because, you know, first of all, who knows when the asteroid will hit? And second, you know, of all times in humanity, this is probably the best time to be a human being. And this might actually be the best place to be a human being. So anyway, you know, for anyone who loves science, this is it, this is awesome. It’s a great time

{LF}   At the same time, just a swift comment. All I meant is that if you look several hundred years from now and we end up somehow not destroying ourselves.

{MK}  Yeah. 

{LF} People probably look back at this time in computer science and at your work of Manolis at MIT

{MK}   As infantile….

{LF}  As infantile and silly and how ignorant it all was.

{MK}    I like to joke very often with my students that, you know, we’ve written so many papers, were published so much, we’ve been cited so much and every single time I tell my students you know, the best is ahead of us. What we’re working on now is the most exciting thing I’ve ever worked on. So in a way, I do have this sense of, yeah, even the papers I wrote ten years ago, they were awesome at the time. But I’m so much more excited about where we’re heading now. And I don’t mean to minimize any of the stuff we’ve done in the past, but you know, there’s just this sense of excitement about what you’re working on now, that as soon as the paper is submitted, it’s like, it’s old. You know, I can’t talk about that anymore. 

{LF}   At the same time, you’re not… you probably are not going to be able to predict what are the most impactful papers and ideas. When people look back two hundred years from now at your work, what would be the most exciting papers? And it may very well be not the thing that you expected or…. 

{MK}  Yeah.

{LF} …. or the things you’ve got awards for or …..

{MK}    You know, that between some fields, I don’t know, I feel slightly differently about it in our field. I feel that, I kind of know what are the important ones and there’s a very big difference between what the press picks up on and what’s actually fundamentally important for the field. And I think for the fundamentally important ones, we kind of have a pretty good idea what they are. And it’s hard to sometimes get the press excited about the fundamental advances, but, you know, we take what we get and celebrate what we get. And sometimes, you know, one of our papers which was in a minor journal, made the front page of Reddit and suddenly had like hundreds of thousands of views, even though it was in a minor journal, because, you know, somebody pitched it the right way that it suddenly caught everybody’s attention. Whereas other papers that are sort of truly fundamental. You know, we have a hard time getting the editors even excited about them when so many hundreds of people are already using the results and building upon them. So I do appreciate that there’s a discrepancy between the perception and the perceived success and the awards that you get for various papers. But I think that fundamentally, you know, that, you know, some paper…. So, so when you’re right,

{LF}   Is there a paper you’re most proud of, you know, now you just trapped yourself?

{MK}    No, no, no, no. I mean

{LF}   Is there a line of work that you have a sense is really powerful that you’ve done to date? You’ve done so much work in so many directions, which is interesting. Is there something where you think it is quite special?

{MK}    I mean it’s like asking me to say which of my three children I love best. I mean…. 

{LF} Exactly. 

{MK}  So, I mean, it’s such a gimme question that it is so difficult not to brag about the awesome work that my team and my students have done. And I’ll just mention a few off the top of my head. I mean basically there’s a few landmark papers that I think have shaped my scientific path. And you know, I like to somehow describe it as a linear continuation of one thing led to another, led to another, led to another. And you know, it kind of all started with skip skip, skip, skip skip. Let me try to start somewhere in the middle. 

So my first PhD paper was the first comparative analysis of multiple species. So, multiple complete genomes. {Note 1} So for the first time we basically developed the concept of genome wide evolutionary signatures. The fact that you could look across the entire genome and understand how things evolve. And from these signatures of evolution, you could go back and study any one region and say that’s a protein coding gene, that’s a RNA gene, that’s a regulatory motif, that’s a binding site. And so on and so forth. 

{LF}   Sorry, so comparing different ….

{MK}    Different species.

{LF}  Species of the same….

{MK}  Take human, mouse, rat and dog, you know, they’re all animals, they’re all mammals. They’re all performing similar functions with their heart, with their brain, with their lungs, etc, etc. So there’s many functional elements that make us uniquely mammalian and those mammalian elements are actually conserved. 99% of our genome does not code for protein, 1% codes for protein. The other 99%, we frankly didn’t know what it does until we started doing this comparative genomic studies. So basically these series of papers in my career have basically first developed that concept of evolutionary signatures and then applied them to yeast, applied them to flies, applied them to four mammals, applied them to seventeen fungi, applied them to twelve Drosophila {fruit fly} species, applied them to then 29 mammals and now 200 mammals.

{LF}   So sorry. So can we ….So the evolutionary signatures, it seems like it’s such a fascinating idea. I’m probably going to linger on your early PhD work for two hours? But what is, how can you reveal something interesting about the genome by looking at the multiple, multiple species and looking at the evolutionary signatures?

{MK}    Yeah. So, you basically align the matching regions. So everything evolved from a common ancestor way, way back and mammals evolved from a common ancestor about 60 million years back. So after you know, the meteor that killed off the dinosaurs landed ….

{LF} Allegedly.

{MK}  …. near Machu Picchu, we know the {Chicxulub} crater. It didn’t allegedly land.

{LF} That was the aliens. 

{MK}  Okay, just slightly north of Machu Picchu {Yucatan} in the Gulf of Mexico. There’s a giant hole that, that meteor,

{LF}   By the way, sorry, is that definitive? Do people, have people, conclusively figured out what killed the dinosaurs?

{MK}   I think so.

{LF}  So it was a meteor?

{MK}    Well, you know, for volcanic activity, all kinds of other stuff is coinciding, but the meteor is pretty unique and we now have…. 

{LF} That’s also terrifying, we still have a lot of 2020 left… 

{MK}    No, but think about it this way. So the dinosaurs ruled the earth for 175 million years. We humans have been around for what? Less than one million years if you’re super generous about what you call humans and you include chimps basically. So, we are just getting warmed up and you know, we’ve ruled the planet much more ruthlessly than Tyrannosaurus rex. {laughs} T. rex had much less of an environmental impact than we did. And if you give us another 174 million years, you know, humans will look very different if we make it that far. So I think dinosaurs basically are much more of life history on earth and we are in all respects. But look at the bright side when they were killed off another life form emerged: mammals.

{LF}   And that’s that whole…  the evolutionary branching that’s happened. So you kind of have when you have these evolutionary signatures they’re basically a map of how the genome changed.

{MK}    Exactly, exactly. So, now you can go back to this early mammal that was hiding in caves and you can basically ask what happened after the dinosaurs were wiped out. A ton of evolutionary niches opened up and the mammals started populating all of these niches. And in that diversification there was room for expansion of new types of functions. So some of them populated the air with bats flying, a new evolution of flight. Some populated the oceans with dolphins and whales going out to swim etc. 

But we all are fundamentally mammals. So you can take the genomes of all these species and align them on top of each other and basically create nucleotide resolution correspondences. What my PhD work showed is that when you do that, when you line up species on top of each other, you can see that within protein coding genes, there’s a particular pattern of evolution that is dictated by the level at which evolutionary selection acts. If I’m coding for a protein and I changed the third codon position of a triplet that codes for the amino acid; the same amino acid will be encoded. So that basically means that any kind of mutation that preserves that translation, that is invariant to that ultimate functional assessment that evolution will give, is tolerated.

 So for any function that you’re trying to achieve there is a set of sequences that encode it. You can now look at the mapping the,  you know, the graph isomorphism if you wish, between all of the possible DNA encodings of a particular function and that function. And instead of having just that exact sequence at the protein level you can think of the set of protein sequences that all fulfill the same function. What’s evolution doing? Evolution has two components. One component is random, blind and stupid mutation. The other component is super smart, ruthless selection. 

{phone rings} Yeah that’s my mom calling from Greece. Yes. I might be a fully grown man. Yes but I am Greek.

{LF}   Did you just cancel the call? 

{MK}    I know I’m in trouble. She’s going to be calling the cops.

{LF}   I’m going to edit this clip out and send it to her.

{laughter}

{LF}   So there’s a lot of encoding for the same kind of functions.

{MK}    So you now have this mapping between all of the set of functions that could all encode the same, all of the set of sequences that can all encode the same function. What evolutionary signatures does is that it basically looks at the shape of that distribution of sequences that all encode the same thing. And based on that shape you can basically say: “Oh proteins have a very different shape than RNA structures, than regulatory motifs etc. So just by scanning a sequence, ignoring the sequence and just looking at the pattern of change, I’m like wow this thing is evolving like a protein and that thing is evolving like a motif and that thing is evolving. So that’s exactly what we just did for COVID. So our paper that we posted in bioRxiv about coronavirus basically took this concept of evolutionary signatures and applied it on the SARS-CoV-2 genome that is responsible for the COVID-19 pandemic.

{LF}   And comparing it to…. 

{MK}    To 44  Sarbecovirus species. 

{LF} – What word did you just use?

{MK}  – Sarbecovirus. The SARS related beta coronavirus, it’s a portmanteau. 

{LF} – So that’s a family {subgenus} of viruses. 

{MK}  – Yeah.

{LF} – How big is that family? 

{MK}  -We have 44 species that are 

{LF} – 44 species? Viruses are clever.

{MK}  – but no no, but there’s just 44 again, we don’t call them species in viruses, we call them strains. But anyway, there’s 44 strains and that’s a tiny little subset of, you know, maybe another 50 strains that are just far too distantly related. Most of those only infect bats as a host and a subset of only four or five have ever infected humans. And we basically took all of those and we align them in the same exact way that we’ve aligned mammals. And then we looked at what proteins are, you know, which of the currently hypothesized genes for the coronavirus genome are in fact evolving like proteins and which ones are not. And what we found is that ORF10,  the last little open reading frame, the last little gene in the genome is bogus. That’s not a protein at all.

{LF} What is it?

{MK}  It’s an RNA structure.

{LF}   That doesn’t have…..

{MK}    It doesn’t get translated into amino acids.

{LF}   And that’s so it’s important to narrow down to basically discover what’s useful and what’s not.

{MK}    Exactly. Basically what are …. what is even the set of genes. The other thing that these evolutionary signatures showed is that within ORF3A, like a tiny little additional gene encoded within the other gene. So you can translate the DNA sequence in three different reading frames. If you start in the first one, it’s ATG cetera. If you start on the second is TGC et cetera. And there’s a gene within a gene. So there’s a whole other protein that we didn’t know about, that might be super important. So we don’t even know the building blocks of SARS-CoV-2. So if we want to understand coronavirus biology and eventually fight it successfully, we need to even have the set of genes and these evolutionary signatures that are developed in my PhD work, we just recently used.

{LF}   You know what, let’s run with that tangent for a little bit, if it’s okay. Can we talk about the COVID-19 a little bit more like how ….. what’s your sense about the genome, the proteins, the functions that we understand about COVID-19. Where do we stand in your sense? What are the big open problems? And also, you know, you kind of said it’s important to understand what are like the important proteins and like why is that important?

{MK}    So what else does the comparison of the species tell us?  What it tells us is, how fast are things evolving? It tells us about at what level is the acceleration or deceleration pedal set, for every one of these proteins. So the genome has 30 genes, some genes evolve super, super fast. Others evolve super, super slow. If you look at the polymerase gene that basically replicates the genome, that’s a super slow evolving one. If you look at the nucleocapsid protein, it’s also super slow evolving. If you look at the Spike1 {Spike subunit S1} protein, this is the part of the spike protein that actually touches the ACE2 receptor as it enables the virus to attach to your cells.

{LF}   That’s the thing that gives it that visual

{MK}    The corona-look basically. So, the spike protein sticks out of the virus. And there’s the first part of the protein, S1, which basically attaches to the ACE2 receptor. And then S2 is the latch that sort of pushes and channels the fusion of the membranes and then the incorporation of the viral RNA inside our cells which then gets translated into all of these 30 proteins. So the S1 protein is evolving ridiculously fast. So if you look at the stop {brake pedal} versus the gas pedal, the gas pedal is all the way down. ORF8 is also evolving super fast and ORF6 is evolving super fast. We have no idea what they do. We have some idea but nowhere near what S1 is. So what the …

{LF}   Isn’t that really terrifying that S1 is evolving? That means that’s a really useful function. If it’s evolving fast, does that mean new strengths can be created? Or does something….

{MK}    THat means that it’s searching for how to match, how to best match the host? So basically anything, in general, in evolution, if you look at genomes, anything that’s contacting the environment is evolving much faster than anything that’s internal. And the reason is that the environment changes. So if you look at the evolution of the sarbecoviruses, the S1 protein has evolved very rapidly because it’s attaching to different hosts each time. We think of them as bats but there’s thousands of species of bats and to go from one species of bat to another species of bat….

{LF} You have to figure out …. 

{MK}  S1 to the new ACE2 receptor that you’re going to be facing in that new species.

{LF}   [1:03:00] Quick tangent. Is it fascinating to you that viruses are doing this? I mean it feels like they’re this intelligent organism. I mean, is it like …. does that give you pause how incredible it is that the evolutionary dynamics that you’re describing is actually happening and they’re freaking out figuring out how to jump from bats to humans all in this distributed fashion. And then most of us don’t even say they’re alive or intelligent or whatever.

{MK}    So intelligence is in the eye of the beholder, you know, stupid is as stupid does, as Forrest Gump would say and intelligent is as intelligent does. So basically if the virus is finding solutions that we think of as intelligent yeah, they’re probably intelligent but that’s again in the eye of the beholder. 

{LF} Do you think viruses are intelligent? 

{MK}  Of course not.

{LF} Really? 

{MK}  No, because …

{LF} It’s so incredible. 

{MK} : Remember when I was talking about the two components of evolution, one is the stupid mutation which is completely blind and the other one is the super smart selection which is ruthless. So it’s not viruses who are smart, it’s this component of evolution that is smart. So it’s evolution that sort of appears smart and how is that happening? By huge parallel search across thousands of you know, parallel infections throughout the world right now. 

{LF}   Yes, but so to push back on that. So yes. So then the intelligence is in the mechanism but then by that argument, viruses would be more intelligent because there’s just more of them. So the search they’re basically …. the brute force search that’s happening with viruses because there’s so many more than than humans then they’re taken as a whole are more intelligent. I mean, so you don’t think it’s possible that, I mean, who runs…. Would we even be here if viruses weren’t? I mean who runs this thing?

{MK}    So the virus… So let me answer,let me answer your question. So we would not be here if it wasn’t for viruses. And part of the reason is that if you look at mammalian evolution early on in this mammalian radiation that basically happened after the death of the dinosaurs is that some of the viruses that we had in our genome spread throughout our genome and created binding sites for new classes of regulatory proteins and these binding sites that landed all over genome are now control elements that basically control our genes and sort of help the complexity of the circuitry of mammalian genomes. So, you know, everything is coevolution and ….

{LF}   We’re working together.

{MK}    Yeah.

{LF} And yet you said they’re dumb. 

{MK}  No, I never said they’re dumb. They just don’t care. They don’t care. Another thing: Oh is the virus trying to kill us? No, it’s not. The virus is not trying to kill you. It’s not, it’s actually actively trying to not kill you. So when you get infected if you die: “bummer I killed him”, is what the reaction of the virus will be. Why? Because that virus won’t spread. Many people have a misconception that viruses are smart or viruses are mean. They don’t care. It’s like you have to clean yourself of any kind of anthropomorphism out there. 

{LF} I don’t know. 

{MK}  Oh yes. 

{LF}   So there’s a sense when taken as a whole that there’s a …..

{MK}    It’s in the eye of the beholder. Stupid is as stupid does. Intelligence is as intelligence does. So, if you want to call them intelligent, that’s fine because the end result is that they’re finding amazing solutions.

{LF} Right. 

{MK}  I mean I am in awe …

{LF} But they’re so dumb about it. They’re just doing dumb….

{MK}  They don’t care. They’re not dumb and they’re not even..

{LF} Sorry. They don’t care.

{MK}  Exactly.

{LF}  The care word is really interesting. 

{MK}  Exactly.

{LF} I mean it could be an argument that they are conscious.

{MK}   They’re just dividing. They’re not {conscious}, they’re just dividing. They’re just a little entity which happens to be dividing and spreading. It just doesn’t want to kill us. In fact it prefers not to kill us. It just wants to spread. And when I say wants, again I’m anthropomorphizing but it’s just that if you have two versions of a virus, one acquires a mutation that spreads more, that’s going to spread more. One acquires a mutation that spreads less,that’s going to be lost. 

{LF} Yeah.

{MK}  One acquires a mutation that enters faster, that’s gonna be kept. One acquires a mutation that kills you right away, it’s going to be lost. So, over evolutionary time, the viruses that spread super well but don’t kill the host are the ones that are going to survive.

{LF}   Yeah but so … you’ve brilliantly described the basic mechanisms of how it all happens. But when you zoom out and you see the, you know,  the entirety of viruses, maybe across different strains of viruses. It seems like a living organism.

{MK}    I am in awe of biology. I find biology amazingly beautiful. I find the design of the current coronavirus, however lethal it is, amazingly beautiful: the way that it is encoded, the way that it tricks your cells Into making thirty proteins from a single RNA. Human cells don’t do that. Human cells make one protein from each RNA molecule. They don’t make two, they make one. We are hardwired to make only one protein from every RNA molecule. 

And yet this virus goes in and throws in a single messenger RNA. Just like any messenger RNA. We have tens of thousands of messenger RNAs in ourselves at any one time in every one of ourselves. It throws in one RNA and that RNA is,so I’m going to use your word here, not my word: “intelligent”; that it hijacks the entire machinery of your human cell. It basically has at the beginning a giant open reading frame. That’s a giant protein that gets translated.  Two-thirds of that RNA makes a single giant protein. That single protein is basically what a human cell would make.  It’s like: “Oh here’s a start codon and I’m going to start translating here.” Human cells are kind of dumb. I’m sorry again this is not the word that we normally use but the human cell is basically: “So, this is an RNA, it must be mine. Let me translate it.” 

And it starts translating it and then you’re in trouble. Why? Because that one protein as it’s growing gets cleaved into about 20 different peptides. The first peptide and the second peptide start interacting and the third one in the fourth one and they shut off the ribosome of the whole cell to not translate human RNAs anymore. So the virus basically hijacks your cells and it cuts, it cleaves every one of your human RNAs to basically say to the rivals: “Don’t translate this one, junk. Don’t look at this one, junk.” And it only spares its own RNA because they have a particular mark that it spares. 

Then all of the ribosomes that normally make protein in your human cells are now only able to translate viral RNA like more and more and more and more of them. That’s the first 20 proteins. In fact, halfway down, about protein 11 – between 11 and 12, you basically have a translational slippage where the ribosomes skip {the} reading frame and it translates from one reading frame to another reading frame. That means that about half of them are gonna be translated from 1-11 and the other half are going to be translated from 12 to 16. It’s gorgeous. And then you’re done. Then that mRNA will never translate the last ten proteins. But spike is the one right after that one. So how does spike even get translated? 

This positive-strand RNA virus has a reverse transcriptase which is an RNA based reverse transcriptase. So from the RNA on the positive strand it makes an RNA on the negative strand and in between every single one of these genes, these open reading frames, there’s a little signal AACGCA, or something like that that basically loops over to the beginning of the RNA. And basically, instead of sort of having a single full negative strand RNA, it basically has a partial negative strand RNA that ends right before the beginning of that gene. And another one that ends right before the beginning of that {uses hands to indicate a subsequent} gene. These negative strand RNAs now make positive strand RNA. That then look to the human whole cell just like any other human mRNA. It’s like: “Oh great I’m going to translate that one,” because it doesn’t have the cleaving that the virus has now put on all your human genes and then you’ve lost the battle. That cell is now only making proteins for the virus that will then create the spike protein, the envelope protein, the membrane protein, the nucleocapsid protein that will package up the RNA and then sort of create new viral envelopes. And these will then be secreted out of that cell in new little packages that will then infect the rest of cells.

{LF} Repeat the whole process. 

{MK}  It’s beautiful, right? It’s mind blowing..

{LF}   It’s hard not to anthropomorphize but …. {both laughing}

{MK}    It’s so gorgeous.

{LF}   So there is a beauty to it. Is it terrifying to you?

{MK}    So this is something that has happened throughout history. Humans have been nearly wiped out over and over and over again and yet never fully wiped out. So I’m not concerned about the human race, I’m not even concerned about, you know,the impact on sort of our survival as a species.This is absolutely something, I mean, you know, human life is so invaluable and every one of us is so invaluable. But if you think of it as sort of, is this the end of our species by no means.

So basically, so let me explain. The Black Death killed what, 30% of Europe? That has left a tremendous imprint, you know, a huge hole, horrendous hole in the genetic makeup of humans. There’s been a series of wiping out of huge fractions of entire species or just entire species altogether and that has a consequence on the human immune repertoire. 

If you look at how Europe was shaped and how Africa was shaped by malaria for example, all the individuals that carry imitation that protected from malaria were able to survive much more. And if you look at the frequency of sickle cell disease and the frequency of malaria, the maps are actually showing the same pattern, the same imprint on Africa and that basically led people to hypothesize that the reason why sickle cell disease is so much more frequent in Americans of African descent is because there was selection in Africa against malaria leading to sickle cell, because when the cells sickle, malaria is not able to replicate inside yourselves as well and therefore you protect against that. 

So if you look at human disease, all of the genetic associations that we do with human disease, you basically see the imprint of these waves of selection, killing off gazillions of humans. And there’s so many immune processes that are coming up as associated with so many different diseases.

The reason for that is similar to what I was describing earlier, where the outward facing proteins evolved much more rapidly because the environment is always changing. But what’s really interesting {in}  the human genome is that we have co-opted many of these immune genes to carry out non-immune functions. For example, in our brain we use immune cells to cleave off neuronal connections that don’t get used. This whole “use it or lose it;” we know the mechanism it’s microglia to cleave off neuronal synaptic connections that are just not utilized. When you utilize them, you mark them in a particular way that basically when the microglia come tell it:  “Don’t kill this one, it’s used now.” and the microglia will go off and kill the ones you don’t use. This is an immune function which is co-opted to do non-immune things. 

If you look at our adipocytes, M1 versus M2 macrophages  inside our fat will basically determine whether you’re obese or not. And these are again immune cells that are resident and living within these tissues. So, many disease associations …..

{LF}   That we co opt these kinds of things for incredibly complicated functions.

{MK}   Exactly. Evolution works in so many different ways which are all beautiful and mysterious.

{LF}  But not intelligent.

{MK}  Not intelligent, it’s in the eye of the beholder. But the point that I’m trying to make is that if you look at the imprint that COVID will have, hopefully it will not be big. Hopefully the US will get its act together and stop the virus from spreading further. But if it doesn’t, it’s having an imprint on individuals who have particular genetic repertoires. So if you look at now the genetic associations of blood type and immune function cells, etc. there’s actually association, genetic variation that basically says how much more likely am I or you to die if we contract the virus. And it’s through these rounds of shaping the human genome that humans have basically made it so far. 

And selection is ruthless and it’s brutal and it only comes with a lot of killing. But this is the way that viruses and environments have shaped the human genome. Basically when you go through periods of famine you select for particular genes. And what’s left is not necessarily better; it’s just whatever survived. And it may have been the surviving one back then; not because it was better. Maybe the ones that run slower survived. I mean you know again not necessarily better but the surviving ones are basically the ones that then are shaped for any kind of subsequent evolutionary condition and environmental condition. 

But if you look at, for example, obesity. Obesity was selected for, basically the genes that predispose to obesity, were at a 2% frequency in Africa. They rose to 44% frequency in Europe.

{LF} Wow, that’s fascinating.

{MK}  Because you basically went through the Ice Ages and there was a scarcity of food, so you know there was a selection to being able to store every single calorie you consume. Eventually the environment changes. So the better allele, which was the fat storing allele, became the worst allele because it’s the fat storing allele. It still has the same function. So if you look at my genome, speaking of Mom calling, Mom gave me a bad copy of that gene, this FTO locus basically makes ….

{LF}   The one that has to do with obesity.

{MK}    Obesity. Yeah, basically now I have a bad copy from mom that makes me more likely to be obese. And I also have a bad copy from dad that makes me more likely to be obese, so I’m homozygous. And that’s the allele, it’s still the minor allele, but it’s at 44% frequency in Southeast Asia, 42% frequency in Europe, even though it started at 2% {in Africa}. It was an awesome allele to have a100 years ago. Right now, it’s a pretty terrible allele. 

So the other concept is that diversity matters. If we had 100 million nuclear physicists living on the earth right now we’d be in trouble. You need diversity. You need artists and you need musicians and you need mathematicians and you need, you know, politicians. Yes even those and you need like…. 

{LF}   Let’s not let’s not get crazy now. But because then if a virus comes along or whatever. 

{MK}    Exactly, exactly. So no, there’s two reasons. Number one, you want diversity in the immune repertoire and we have built-in diversity. So basically they are the most diverse …. basically if you look at our immune system there’s layers and layers of diversity. Like the way that you create your cells generates diversity because of the selection for the V(D)J  recombination that basically eventually leads to a huge number of repertoires but that’s only one small component of diversity. The blood type is another one.  The major histocompatibility complex, the HLA {Human leukocyte antigen} alleles are another source of diversity. So the immune system of humans is by nature incredibly diverse and that basically leads to resilience. So basically what I’m saying is that I don’t worry for the human species because we are so diverse immunologically we are likely to be very resilient against so many different attacks like this current virus. 

{LF}   So, you’re saying natural pandemics may not be something that you’re really afraid of because of the diversity in our genetic makeup. What about engineered pandemics? Do you have fears of us messing with the makeup of viruses or ….  Well, yeah let’s say with the makeup of viruses to create something that we can’t control and would be much more destructive that would come about naturally.

{MK}    Remember how we were talking about how smart evolution is? Humans are much dumber.

{LF} You mean like human scientists, human engineers?

{MK}  Humans, humans just like us.

{LF} Humans overall.

{MK}  But I mean even, you know, the sort of synthetic biologists. You know, basically if you were to create, you know, a virus like SARS that will kill other people you would probably start with SARS. So whoever, you know, would like to design such a thing would basically start with a SARS tree or at least some relative of SARS. The source genome for the current virus was something completely different. It was something that has never infected humans. No one in their right mind would have started there.

{LF}   But when you say sources like the nearest….

{MK}    The nearest relative is in a whole other branch, no species of which has ever infected humans in that branch. So you know, let’s put this to rest. This was not designed by someone to kill off the human race. 

{LF}   You don’t believe it was engineered

{MK}    The path to engineering a deadly virus would not come from this strain, that guy that was used. Moreover, there’s been various claims of: “Ha ha this was mixed and matched in the lab,” because the S1 protein has three different components, each of which has a different evolutionary tree. 

So you know, a lot of the popular press basically said: Aha, this came from pangolin and this came from, you know, all kinds of other species.” This is what has been happening throughout the coronavirus strain. So basically the S1 protein has been recombining across species all the time. 

Remember when I was talking about the positive-strand and negative-strands (sub-genomic RNAs) these can actually recombine and if you have two different viruses infecting the same cell, they can actually mix and match between the positive-strand and the negative-strand and basically create a new hybrid virus with recombination that now has the S1 from one and the rest of the genome from another. And this is something that happens a lot in S1 in ORF8, etc.  And that’s something that’s true of the whole tree.

{LF}   For the whole family of coronaviruses.

{MK}    Exactly. So it’s not like someone has been messing with this for millions of years and you know changing….

{LF} This happens naturally, Again, that’s beautiful. That somehow happens that they recombine, the two different strands can affect the body and recombine. So all of this magic actually happens inside hosts. Like all…..

{MK}    Yeah, that’s why they…. that’s why classification-wise, virus is not thought to be alive because it doesn’t self-replicate. It’s not autonomous, it’s something that enters a living cell and then co-opted to basically make it its own. But by itself, people ask me, how do we kill this bastard? Like you stop it from replicating. It’s not like a bacterium that will just live in a, you know, a puddle or something. It’s a virus, viruses don’t live without their hosts and they only live with their host for very little time. So if you stop it from replicating it’ll stop from spreading. I mean it’s not like HIV which can stay dormant for a long time, basically coronaviruses just don’t do that. They’re not integrating genomes, they are RNA genomes. So if it’s not expressed, it degrades. RNA degrades, it doesn’t just stick around.

{LF}   Well, let me ask, also about the immune system you mentioned. A lot of people kind of ask, you know: “How can we strengthen the immune system to respond to this particular virus or to the viruses in general?” Do you have, from a biological perspective thoughts, on what we can do as humans to strengthen our immune systems?

{MK}     If you look at death rates across different countries, people with less vaccination have been dying more. If you look at North Italy, the vaccination rates are abysmal there and a lot of people have been dying. If you look at Greece: very good vaccination rates, almost no one has been dying. So yes, there is a policy component. So Italy reacted very slowly. Greece reacted very fast. So you have many fewer people died in Greece but there might actually be a component of genetic immune repertoire. Basically, how did people die off, you know, in the history of the Greek population versus the Italian population, there’s…..

{LF}   That’s interesting to think about.

{MK}    And then there’s a component of what vaccinations did you have as a kid and what are the off-target effects of those vaccinations? So basically a vaccination can have two components. One is training your immune system against that specific insult. The second one is boosting up your immune system for all kinds of other things.

If you look at allergies, Northern Europe, super clean environments, tons of allergies. Southern Europe, my kids grew up eating dirt, no allergies. So growing up, I never had even heard of what allergies are. I was like really, allergies? And the reason is that I was playing in the garden, I was putting all kinds of stuff in my mouth from you know, all kinds of dirt and stuff. Tons of viruses there in terms of bacteria there, you know, my immune system was built up. So the more you protect your immune system from exposure, the less opportunity has to learn about non-self repertoire in a way that prepares it for the next insult.

{LF}  So, it’s a horizontal thing too, like throughout your lifetime and the lifetime of the people that  …. your ancestors, that kind of thing. What about …. So again it returns again to free will. On the free will side of things, is there something we can do to strengthen our immune systems in 2020? Is there like, you know, exercise diet, all that kind of stuff?

{MK}    So it’s kind of funny, there’s a cartoon that basically shows two windows with a teller in each window. One has a humongous line and the other one has no one, the one that has no one {the sign} above says health. No, it says exercise and diet and the other one says pill, there’s a huge line for pill. 

So we’re looking basically for magic bullets for sort of ways that we can, you know, beat cancer and beat coronavirus and beat this and beat that. It turns out that the window with just diet and exercise is the best way to boost every aspect of your health. If you look at Alzheimer’s: exercise and nutrition. I mean you’re like: “really, for my brain neurodegeneration.” Absolutely. If you look at cancer: exercise and nutrition. If you look at coronavirus: exercise and nutrition, every single aspect of human health gets improved. And one of the studies we’re doing now is basically looking at what are the effects of diet and exercise? How similar are they to each other? Were basically taken diet intervention and exercise intervention in human and in mice and we’re basically doing single cell profiling of a bunch of different tissues to basically understand how are the cells, both the stromal cells and the immune cells of each of these tissues responding to the effect of exercise. What are the communication networks between different cells where with the muscle that exercises sends signals through the bloodstream, through the lymphatic system, through all kinds of other systems that give signals to other cells that I have exercised and you should change in this particular way, which basically reconfigure those receptor cells with the effect of exercise.

{LF}  How well understood is the…. are those reconfigurations?

{MK}    Very little. We’re just starting now basically

{LF}   is the hope thereto understand the effect on…. So like the effect on the immune system?

{MK}    On the immune system, the effect on the brain, the effect on your liver, on your digestive system, on your adipocytes. Adipose, you know, is the most misunderstood organ. Everybody thinks fat is terrible. No fat is awesome. Your fat cells is what’s keeping you alive. Because if you didn’t have your fat cells, all those lipids and all those calories would be floating around in your blood and you’d be dead by now. Your adipocytes are your best friends and are basically storing all these excess calories so that they don’t hurt all of the rest of the body. And they’re also fat burning in many ways. 

So again, when you don’t have the homozygous version that I have, your cells are able to burn calories much more easily by sort of flipping a master metabolic switch that involves this FTO locus that I mentioned earlier and its target genes are  IRX3 and  IRX5. {[2]} They basically switch your adipocytes during their three first days of differentiation as they’re becoming mature adipocytes to basically become either fat burning or fat storing fat cells. 

And the fat burning fat cells {Brown adipose tissue} are your best friends. They’re much closer to muscle than they are to white adipocytes.

{LF}   Is there a lot of difference between people like that you could give ….. Science could eventually give advice that is very generalizable or is our differences in our genetic makeup like you mentioned, is that going to be basically something we have to be very specialized to individuals, any advice would give in terms of diet like we were just talking about.

{MK}   

Believe it or not, the most personalized advice that you give for nutrition don’t have to do with your genome. They have to do with your gut microbiome with the bacteria that live inside you. So most of your digestion is actually happening by species that are not human inside you. You have more non-human cells then you have human cells. You’re basically a giant bag of bacteria with a few human cells along. {laughs}

{LF}   And those do not necessarily have to do with your genetic makeup?

{MK}    They interact with your genetic makeup. They interact with your epigenome, they interact with your nutrition, they interact with your environment. They’re, you know, basically an additional source of variation. So when you’re thinking about sort of personalized nutritional advice, part of that is actually how do you match your microbiome? And part of that is how do we match your genetics? But again, you know, this is a very diverse set of, you know, contributors and the effect sizes are not enormous. So I think the science for that is not fully developed yet.

{LF}   Speaking of diet because I’ve wrestled in combat sports; sports my whole life where weight matters so you have to cut { lose weight rapidly} and all that stuff.One thing I’ve learned a lot about my body and it seems to be, I think true about other people’s bodies is that you can adjust a lot of things. That’s the miraculous thing about this biological system is like I fast often. I used to eat like 5-6 times a day and thought that was absolutely necessary. How could you not eat that often? And then when I started fasting, your body adjusts to that and you learn how to not eat, you know, and it’s as if you just give it a chance for a few weeks…. actually over a period of a few weeks, your body can adjust to anything. And that’s such a beautiful thing.

{MK}    So I’m a computer scientist and I’ve basically gone through periods of 24 hours without eating or stopping and you know, then I’m like, oh, must eat and I eat a ton. I used to order two pizzas just with my brother and you know, like I’ve gone through these extremes as well and I’ve gone the whole intermittent fasting thing. So I can sympathize with you both on the seven meals a day to the zero meals a day. 

So I think when I say everything in moderation, I actually think your body responds interestingly to these different changes in diet. I think part of the reason why we lose weight with pretty much every kind of change in behavior is because our epigenome and the set of proteins and enzymes that are expressed and our microbiome are not well suited to that nutritional source. And therefore they will not be able to sort of catch everything that you give them. And then, you know, a lot of that will go undigested. And that basically means that your body can then, you know, lose weight in the short term, but very quickly will adjust to the new normal. And then we’ll be able to sort of perhaps gain a lot of weight from the diet. 

So anyway, I mean there’s also studies in factories where basically people, you know, dim the lights. And then suddenly everybody started working better. It was like: “Wow, that’s amazing.”

Three weeks later they made the lights a little brighter, everybody started working better. {Hawthorne effect} So any kind of intervention has a placebo effect of: “Wow, now I’m healthier and I’m going to be running more often,” etc. So it’s very hard to uncouple the placebo effect of “Wow, I’m doing something to intervene on my diet,” from the: “Wow, this is actually the right thing for me.” So you know….

{LF}   Yeah. From the perspective from a nutrition science, psychology, both things I’m interested, especially psychology, it seems that it’s extremely difficult to do good science because there’s so many variables involved, it’s so difficult to control the variables, so difficult to do sufficiently large scale experiments, both sort of in terms of number of subjects and temporal, like how long you do the study for; that it just seems like it’s not even a real science for now, like nutrition science.

{MK}    I want to jump into the whole placebo effect for a little bit here. And basically, talk about the implications of that. If I give you a sugar pill and tell you it’s a  sugar pill, you won’t get any better. But if I tell you  {it’s a} sugar pill and tell you, and I’ll tell you: “Wow, this is an amazing drug. It actually will stop your cancer;” your cancer will actually stop with much higher probability. What does that mean? 

{LF} That’s so amazing.

{MK}  That means that if I can trick your brain into thinking that I’m healing you, your brain will basically figure out a way to heal itself, to heal the body. And that tells us that there’s so much that we don’t understand in the interplay between cognition and our biology, that if we were able to better harvest the power of our brain to sort of impact the body through the placebo effect, we would be so much better in so many different things. Just by tricking yourself into thinking that you’re doing better, you’re actually doing better. So there’s something to be said about positive thinking, about optimism, about sort of, you know, just getting your brain and your mind into the right mindset that helps your body and helps your entire biology.

{LF}   Yeah, from a science perspective that’s just fascinating. Obviously, most things about the brain is a total mystery for now, but that’s a fascinating interplay that the brain can reduce…. the brain can help cure cancer. I don’t even know what to do with that.

{MK}    I mean, the way to think about that is the following the converse of the equation is something that we are much more comfortable with, like, oh, if you’re stressed than your heart, rate might rise and all kinds of sort of toxins might be released and that can have a detrimental effect on your body etc, etc. So maybe it’s easier to understand your body healing from your mind by your mind is not killing your body or at least it’s killing it less. So I think that, you know, that aspect of the stress equation is a little easier for most of us to conceptualize. But then the healing part is you know, perhaps the same pathways, perhaps different pathways. But again, something that is totally untapped scientifically.

{LF}   I think we tried to bring this question up a couple of times but let’s return to it again. What do you think is the difference between the way a computer represents information {and} the human genome represents and stores information. Like what…. and maybe broadly what is the difference between how you think about computers and how you think about biological systems?

{MK}    So I made a very provocative claim earlier that we are a digital computer, like that at the core lies a digital code. And that’s true in many ways. But surrounding that digital core there’s a huge amount of analog. If you look at our brain, it’s not really digital. If you look at our sort of RNA and all of that stuff inside ourselves, it’s not really digital. It’s really analog in many ways. But let’s start with the code and then we’ll expand to the rest. 

So the code itself is digital. So there’s genes. You can think of the genes as I don’t know, the procedures, the functions inside your language and then somehow you have to turn these functions on. How do you call a gene? How do you call that function?

The way that you would do it in old programming languages is goto address whatever in your memory and then you start running from there. And you know modern programming languages have encapsulated this into functions and objects and all of that and it’s nice and cute. But in the end, deep down, there’s still an assembly code that says go to that instruction and it runs that instruction. 

If you look at the human genome and the genome of pretty much most species out there it’s There’s no goto function. You just don’t start in, you know, transcribing in position 1305; you know 13,527 in chromosome 12. You instead have content based indexing. 

So at every location in the genome in front of the genes that need to be turned on, I don’t know when you drink coffee, there’s a little coffee marker in front of all of them. And whenever your cells that metabolize coffee need to metabolize coffee, they basically see coffee and they’re like:  “Ooh let’s go turn on all the coffee marked genes.” So there’s basically these small motifs, these small sequences that we call regulatory motifs. They’re like patterns of DNA. They’re only eight characters long or so like GATGCA etc. 

And these motifs work in combinations and every one of them has some recruitment affinity for a different protein that will then come and bind it. And together collections of these motifs create regions that we call regulatory regions that can be either promoters near the beginning of the gene and that basically tells you where the function actually starts where you call it. And then enhancers that are looping around of the DNA that basically bring the machinery that binds those enhancers and then bring it onto the promoter which then recruits the right sort of ribosome and the polymerase and all of that thing which will first transcribe and then export and then eventually translating in the cytoplasm you know whatever RNA molecule. 

So the beauty of the way that the digital computer that’s the genome works is that it’s extremely fault tolerant. If I took your hard drive and I messed with 20% of the letters in it, of the zeros and ones and flipped them you’d be in trouble. If I take the genome and I flipped 20% of the letters, you probably won’t even notice. And that resilience….

{LF}   That’s fascinating.

{MK}    is a key design principle. And again anthropomorphizing here. But it’s a key driving principle of how biological systems work. They are first resilient and then anything else. And when you look at this incredible beauty of life from the most, I don’t know, beautiful, I don’t know, human genome maybe of humanity and all of the ideas that you come with it; to the most terrifying genome, like I don’t know, COVID-19, SARS-CoV-2, and the current pandemic. You basically see this elegance as the epitome of clean design. But it’s dirty. It’s a mess. It’s you know, the way to get there is hugely messy. And that’s something that we as computer scientists don’t embrace. We like to have clean code. You know, like in engineering they teach you about compartmentalization about separating functions, about modularity, about hierarchical design. None of that applies in biology.

{LF}  Testing.

{MK}  Testing. Sure, biology does plenty of that. But I mean through evolutionary exploration but if you look at biological systems first they are robust and then they specialize to become anything else. And if you look at viruses, the reason why they’re so elegant. When you look at the design of this genome, it seems so elegant. And the reason for that is that it’s been stripped down from something much larger because of the pressure to keep it compact. So many compact genomes out there have ancestors that were much larger. You don’t start small and become big. You go through a loop of: add a bunch of stuff, increase complexity and then you know, slim it down. 

And one of my early papers was in fact on genome duplication.[3]  One of the things we found is that baker’s yeast, which is the, you know, the yeast that you used to make bread but also the yeast that used to make wine. Which is basically the dominant species when you go in the field of Tuscany and you say, you know what’s out there? It’s basically Saccharomyces cerevisiae. Or the way my Italian friends say: Saccharomyces cerevisiae {with an Italian pronunciation}

{LF}   Which means what?

{MK}    Oh okay. I’m sorry. I’m Greek. So yeah, Saccharomyces. “Saccharo” is sugar “myces” is fungus. Yes. “cerevisiae”,  cerveza beer. It means the sugar fungus of beer. You know, less good sounding to the ear.

{LF}   Still poetic.

{MK}    So anyway Saccharomyces cerevisiae, basically is the major bakers yeast out there. It’s the descendant of a whole genome duplication. Why would a whole genome duplication even happen? When it happened is coinciding with about 100 million years ago and the emergence of fruit bearing plants? Why fruit bearing plants? Because animals would eat the fruit, would walk around and poop huge amounts of nutrients along with the seed for the plants to spread. Before that plants were not spreading through animals. They were spreading through wind and all kinds of other ways. But basically the moment you have fruit bearing plants, these plants are basically creating this abundance of sugar in the environment. So there’s an evolutionary niche that gets created and in that evolutionary niche you basically have enough sugar that whole genome duplication which initially is a very massive event allows you to then, you know, relieve some of that complexity.

{LF}   So I have to pause. What does genome duplication mean?

{MK}    That basically means that instead of having eight chromosomes, you’re going to now have sixteen chromosomes.

{LF}   So but the duplication at first when you have six….  when you go to 16 you’re not using that.

{MK}    Oh yeah you are. Yeah. So basically from one day to the next you went from having eight chromosomes to having 16 chromosomes. Probably a nondisjunction event during the duplication during a division. So you basically divide the cell instead of half the genome going this way and half the genome going the other way after duplication of the genome, you basically have all of it going to one cell. And then there’s a sufficient messiness there that you end up with slight differences that make most of these chromosomes be actually preserved. It’s a long story short to me

LF: But it’s a big upgrade, right? So that’s ….

{MK}    Not necessarily because what happens immediately thereafter is that you start massively losing tons of those duplicated genes. So 90% of those genes were actually lost very rapidly after whole gene duplication. And the reason for that is that biology is not intelligent, it is just ruthless selection, random mutation. So ruthless selection basically means that as soon as one of the random mutations hits one gene, ruthless selection just kills off that gene. 

It’s just you know, if you have a pressure to maintain a small compact genome you will very rapidly lose the second copy of most of your genes and a small number (10%) were kept in two copies. And those have to do a lot with environment adaptation, with the speed of replication, with the speed of translation and with sugar processing. So I’m making a long story short to basically say that evolution is messy. 

The only way like…. so the example that I was giving of messing with 20% of your bits in your computer; totally bogus. Duplicating all your functions and just throwing them out there in the same, you know, function; just totally bogus. Like this will never work in an engineered system but biological systems because of this content based indexing and because of this modularity that comes from the fact that the gene is controlled by a series of tags. And now if you need this gene in another setting you just add some more tags that will basically turn it on also in those settings. So this gene is now pressured to do two different functions and it builds up complexity. I see whole gene duplication and gene duplication in general as a way to relieve that complexity. 

So you have this gradual build up of complexity as functions get sort of added onto the existing genes and then boom you duplicate your workforce and you now have two copies of this gene.

One will probably specialize to do one and the other one will specialize to do the other or one will maintain the ancestral function, the other one will sort of be free to evolve and specialize while losing the ancestral functions and so on and so forth. So that’s how genomes evolve. They’re just messy things but they’re extremely fault tolerant and they’re extremely able to deal with mutations because that’s the very way that you generate new functions. 

So new functionalization comes from the very thing that breaks it. So even in the current pandemic many people are asking me which mutations matter the most and what I tell them is: “Well, we can study the evolutionary dynamics of the current genome to then understand which mutations have previously happened or not and which mutations happen in genes that evolved rapidly or not.” And one of the things we found for example is that the genes that evolved rapidly in the past are still evolving rapidly now in the current pandemic. The genes have evolved slowly in the past are still evolving slowly.

{LF}   Which means that they’re useful.

{MK}    Which means that they are under the same evolutionary pressures. But then the question is what happens in specific mutations? So if you look at the D614G mutation that’s been all over the news. So in position 614 in the amino acids of the S protein there’s a D {aspartic acid} to G {glycine} mutation that sort of has creeped over the population. That mutation we found out through my work disrupts a perfectly conserved nucleotide position. That has never been changed in the history of millions of years of equivalent mammalian evolution of these viruses. That basically means that it’s a completely new adaptation to human. And that mutation has now gone from 1% frequency to 90% frequency in almost all outbreaks.

{LF}   So there’s a mutation. I like how you say the 416, that was okay, 614….

{MK}    D614G

{LF}   Literally, so what you’re saying is that this is like a chess move. So it just mutated one letter to another and that hasn’t happened before. And this somehow….  this mutation is really useful.

{MK}    It’s really useful in the current environment of the genome which is moving from human to human. When it was moving from bat to bat, it couldn’t care less for that mutation but its environment specific. So now that is moving from human to human who is moving way better, like by orders of magnitude.

{LF}   Okay, so you’re like tracking this evolutionary dynamics, which is fascinating. But what do you do with that? So what does that mean? What does this mean? What do you make, what do you make of this mutation in trying to anticipate I guess is the…. is one of the things you’re trying to do is anticipate where……  how this unrolls into the future, this evolutionary dynamics?

{MK}    Such a great question. So there’s two things, remember when I was saying earlier mutation is the path to new things, but also the path to break all things. So what we know is that this position was extremely preserved through gazillions of mutations; that mutation was never tolerated when it was moving from bats to bats. So that basically means that that position is extremely important in the function of that protein. That’s the first thing it tells. The second one is that that position was very well suited to bat transmission but now is not well suited to human transmission. So it got rid of it and it now has a new version of that amino acid that basically makes it much easier to transmit from human to human. 

So in terms of the evolutionary history teaching us about the future, it basically tells us here is the regions that are currently mutating. Here’s the regions that are most likely to mutate going forward. As you’re building a vaccine, here’s what you should be focusing on in terms of the most stable regions that are the least likely to mutate or here’s the newly evolved functions that are most likely to be important because they’ve overcome these local maximum that it had reached in the bat transmission. So anyway, it’s a tangent to basically say that evolution works in messy ways. And the thing that you would break is the thing that actually allows you to first go through a lull and then reach a new local maximum. And I often like to say that if engineers had basically designed evolution, we would still be perfectly replicating bacteria. Because it’s by making the bacterium worse that you allow evolution to reach a new optimum.

{LF}   Just a pause on that. That’s so profound. That’s so profound for the entirety of these scientific and engineering disciplines.

{MK}    Exactly. We as engineers need to embrace breaking things. We, as engineers, need to embrace robustness as the first principle beyond perfection because nothing’s going to ever be perfect. And when you’re sending a satellite to Mars, when something goes wrong, it’ll break down as opposed to building systems that tolerate failure and our resilience to that, and in fact get better through that.

{LF}   So the SpaceX approach versus NASA for the {laughs}

{MK}  For example.

{LF} Is there something we can learn about the incredible…. take lessons from the incredible biological systems in their resilience in their… in the mushiness, the messiness to our computing systems to our computers.

{MK}    It would basically be starting from scratch in many ways. It would basically be building new paradigms that don’t try to get the right answer all the time, but try to get the right answer most of the time or a lot of the time. 

{LF}   Do you see deep learning systems in the whole world of machine learning is kind of taking a step in that direction?

{MK}    Absolutely. Absolutely. Basically, by allowing much more natural evolution of these parameters. You basically and …. and if you look at sort of deep learning systems again, they’re not inspired by the genome aspect of biology are inspired by the brain aspect of biology. And again, I want you to pause for a second and realize the complexity of the entire human brain with trillions of connections within our you know, neurons; with millions of cells talking to each other is still encoded within that same genome. That same genome encodes every single freaking cell type of the entire body. Every single cell is encoded by the same code. 

And yet specialization allows you to have this single viral-like genome that self-replicates the single module, modular automaton, work with other copies of itself. It’s mind boggling. Create complex organs through which blood flows. And what is that blood? The same freaking genome. Create organs that communicate with each other. And what are these organs? The exact same genome. Create a brain that is innervated by massive amounts of blood pumping energy to it, 20% of our energetic needs, to the brain from the same genome. And all of the neuronal connections, all of the auxiliary cells, all of the immune cells. The astrocytes, the oligodendrocytes, the neurons, the excitatory {neurons}, the inhibitory neurons, all of the different classes of pericytes, the blood-brain barrier, all of that: same genome.

{LF}   One way to see that in a sad ….. this one is beautiful. The sad thing is thinking about the trillions of organisms that died to create that.

{MK}    You mean on the evolutionary path?

{LF}   On the evolutionary path of humans. It’s crazy. These two descendants of apes are just talking on the podcast. Okay, so mind boggling,

{MK}    Just to boggle our minds a little bit more, us talking to each other. We are basically generating a series of vocal utterances through our pulsating of vocal cords received through this. {Pointing to his ear}  The people who listen to this are taking a completely different path to that information transfer yet through language. 

But imagine if we could connect these brains directly to each other. The amount of information that I’m condensing into a small number of words is a huge funnel which then you receive and you expand into a huge number of thoughts from that small funnel. 

In many ways, engineers would love to have the whole information transfer. Just take the whole set of neurons and throw them away. I mean throw them to the other person. This might actually not be better because in your misinterpretation of every word that I’m saying, you are creating a new interpretation that might actually be way better than what I meant in the first place. The ambiguity of language perhaps might be the secret to creativity. 

Every single time you work on a project by yourself, You only bounce ideas with one person and your neurons are basically fully cognizant of what these ideas are . At the moment you interact with another person, the misinterpretations that happen might be the most creative part of the process with my students every time we have a research meeting, I very often pause and say, let me repeat what you just said in a different way, and I sort of go on and brainstorm with what they were saying, but by the third time it’s not what they were saying at all, and when they pick up what I’m saying, like, oh well, da da da, now they have sort of, learned something very different from what I was saying. And that is the same kind of messiness that I’m describing in the genome itself. It’s sort of embracing the messiness

{LF}   And that’s a feature, not a bug.

{MK}    Exactly. And in the same way, when you’re thinking about these deep learning systems that will allow us to sort of be more creative perhaps, or learn better approximations of these complex functions, again, tuned to the universe that we inhabit. You have to embrace the breaking, you have to embrace the how do we get out of these local optima? And a lot of the design paradigms that have made deep learning so successful are ways to get away from that, ways to get better training by sort of sending long range messages, the LSTM models {Long short-term memory} and the sort of feedforward loops that, you know, sort of jumped through layers of convolutional neural network, all of these things are basically ways to push you out of this local maxima, and that’s what evolution does, that’s what language does, that’s what conversation and brainstorming does, that’s what our brain does? So, you know, this design paradigm is something that’s pervasive and yet not taught in schools, not taught in engineering schools. where everything’s minutely modular wrist to make sure that we never deviate from, you know, whatever signal we’re trying to admit as opposed to let all hell breaks loose because that’s the that’s the path to paradise. 

{LF}   The path to paradise. Yeah, I mean, it’s difficult to know how to teach that and what to do with it. I mean, it’s difficult to know how to build up the scientific method around messiness.

{MK}    I mean it’s not all messiness. We need some cleanliness. And going back to the example with Mars, that’s probably the place where I want to sort of moderate error as much as possible and sort of control the environment as much as possible. But if you’re trying to repopulate Mars, well, maybe messing is a good thing then.

{LF}   On that, you quickly mentioned this in terms of us using our vocal cords to speak on a podcast. Elon Musk and Neuralink are working on trying to plug, as per our discussion with computers and biological systems, to connect it to….he’s trying to connect our brain to a computer to create a brain computer interface where they can communicate back and forth on this line of thinking. Do you think this is possible,  to bridge the gap between our engineered computing systems and the messy biological systems?

{MK}  

My answer would be absolutely, you know, there is no doubt that we can understand more and more about what goes on in the brain and we can sort of train the brain. I don’t know if you remember the Palm Pilot?

{LF}   Yeah, Palm Pilot.

{MK}    Remember this whole sort of alphabet {Graffiti for Palm OS} that they had created, am thinking of the same thing? It’s basically you had, you had a little pen and for every character you had a little scribble that was unique that the machine could understand and that instead of trying the machine trying to teach the machine to recognize human characters, you have basically they figured out that it’s better and easier to train humans to create human-like characters that the machine is better at recognizing. 

So, in the same way I think what will happen is that humans will be trained to be able to create the mind pattern that the machine will respond to before the machine truly comprehends your thoughts. So the first human-brain interfaces will be tricking humans to speak the machine language where with the right set of electrodes, I can sort of trick my brain into doing this. And this is the same way that many people teach….  learned to control artificial limbs. You basically try a bunch of stuff and eventually you figure out how your limbs work. 

That might not be very different from how humans learn to use their natural limbs when they first grew up basically you have these, you know, neoteny period of you know, this puddle of soup inside your brain, trying to figure out how to even make neuronal connections before you’re born and then learning sounds in utero of, you know, all kinds of echoes and you know, eventually getting out in the real world. And I don’t know if you’ve seen newborns but they just stare around a lot, you know, one way to think about this as a machine learning person is oh they’re just training their edge detectors and eventually they figure out how to train their edge detectors. They work through the second layer of the visual cortex and the third layer and so on and so forth. 

And you basically have this learning how to control your limbs. That probably comes at the same time, you’re sort of throwing random things there and you realize that, wow, when I do this thing, my limb moves. 

Let’s do the following experiment, take a breath. What muscles did you flex, now? Take another breath and think what muscles reflex. The first thing that you’re thinking when you’re taking a breath is the impact that he has in your lungs. You’re like, oh I’m now going to increase my lung, so I’m not going to bring air in, but what you’re actually doing is just changing your diaphragm. That’s not conscious, of course. You never think of the diaphragm as a thing and why is that? That’s probably the same reason why I think of moving my finger when I actually move my finger, I think of the effect. Instead of actually thinking of whatever muscles twitching that actually causes my finger to move. 

So we basically, in our first years of life, build up this massive look up table between whatever neuronal firing we do and whatever action happens in our body that we control. If you have a kid grow up with a third limb, I’m sure they’ll figure out how to control them, probably at the same rate as their natural limbs.

{LF}   And a lot of the work would be done by the …. so if a third limb is a computer, you kind of have not a faith, but a thought that the brain might be able to figure out….

{MK}  Absolutely

{LF} Like the plasticity would come from the brain, like the brain would be cleverer than the machine at first.

{MK}    When I talk about a third limb, that’s exactly what I’m saying is an artificial limb that basically just controls your mouse while you’re typing, you know, perfectly natural thing. I mean, again, you know, in a few hundred years.

{LF}  Maybe sooner than that.

{MK}   But basically there’s….  as long as the machine is consistent in the way that it will respond to your brain impulses, you’ll figure out how to control that, and you could play tennis with your third limb.

And let me go back to consistency. People who have dramatic accidents that basically take out a whole chunk of their brain can be taught to co-opt other parts of the brain to then control that part. You can basically build up that tissue again and eventually train your body how to walk again and how to read again and how to play again and how to think again, how to speak a language again, etc. 

So there’s a massive amount of malleability that happens, you know, naturally in our way of controlling our body or brain or thoughts or vocal cords or limbs, et cetera. And human-machine interfaces are not inevitable if we figure out how to read these electric impulses. But the resolution at which we can understand human thought right now is nil, is ridiculous. 

So how are human thoughts encoded? It’s basically combinations of neurons that co-fire and these create these things called engrams that eventually form memories and so and so forth. We know nothing of all that stuff. So before we can actually read into your brain that you want to build a program that does this and this and that we need a lot of neuroscience?

{LF}   Well, so to push back on that, do you think it’s possible that without understanding the functionally about the brain or from neuroscience or cognitive science or psychology? Whichever level of the brain will look at. Do you think we just connect, connect them just like per your previous point? If we just have a high enough resolution between …. connection between Wikipedia and your brain; the brain will just figure it out with less understanding because that’s one of the innovations of Neuralink is they’re increasing the number of connections to the brain to like several thousand which before was, you know, in the dozens or whatever.

{MK}    You’re still off by a few orders of magnitude, on the order of seven.

{LF}   Right. But the thing is, the hope is, if you increase that number more and more and more, maybe you don’t need to understand anything about the actual ….. how human thought is represented in the brain. You can just let it figure it out. 

{MK}    {Sentence I couldn’t decipher} I know. 

{LF} Yeah, exactly. Yeah. 

{MK}  So yeah, sure.

{LF}   You don’t have faith in the plasticity of the brain to that degree.

{MK}    It’s not about brain plasticity, it’s about the input aspect. Basically. I think on the output aspect, being able to control the machine is something that you can probably train your neural impulses that you’re sending out to sort of match whatever response you see in the environment. If this thing {points to microphone} moved every single time I thought a particular thought, then I could figure out, I could hack my way into moving this thing with just a series of thoughts. I could think: “Guitar, Piano, tennis ball” and then this thing would be moving and then you know, I would just have the series of thoughts that would sort of result in the impulses that will move this thing the way that I wanted and then eventually it’ll become natural because I won’t even think about it. I mean in the same way that we control our limbs in a very natural way, but babies don’t do that babies have to figure it out and you know, some of it is hard coded but some of them is actually learned based on the whatever soup of neurons you ended up with, whatever connections you pruned them to and eventually you were born with, you know, a lot of that is coding in the genome but a huge chunk of that is stochastic. And sort of the way that you sort of create all these neurons, they migrate, they form connections, they sort of spread out. They have particular branching patterns. But then the connectivity itself, unique in every single new person. 

All this to say that on the output side: Absolutely. I’m very, very you know hopeful that we can have machines that read thousands of these neuronal connections on the output side, but on the input side: Oh boy,I don’t expect any time in the near future we’ll be able to sort of send a series of impulses that will tell me, oh Earth to some distance 7.5 million ….  etc, like nowhere. I mean I think language will still be the input way rather than sort of any kind of more complex.

{LF}   It’s a really interesting notion that the ambiguity of languages is a feature and we evolved for millions of years to take advantage of that ambiguity. 

{MK}    Exactly. And yet no one teaches us the subtle differences between words that are near cognates and yet evokes so much more than, you know, one from the other. And yet, you know, when you’re choosing words from a list of 20 synonyms, you know exactly the connotation of every single one of them and that’s something that, you know, is there. So, yes, there’s ambiguity, but there’s all kinds of connotations and in the way that we select our words, we have so much baggage that we’re sending along the way that were emoting the way that we’re moving our hands every single time we speak the, you know, the pauses, the eye contact, etc, so much higher baud rate than just a vocal, you know, a string of characters. 

{LF}   Well, let me just take a small tangent on that.

{MK}    Oh, tangent, we haven’t done that yet ….

{LF}   We’ll turn to the origin of life.

{LF}   So I mean you’re Greek but I’m going on this personal journey. I’m going to Paris for the explicit purpose of talking to one of the most famous….  a couple who is a famous translators of Russian literature, Dostoevsky, Tolstoy and they go, that’s their art is the translation. And everything I’ve learned about the translation art, it makes me feel …. it’s so profound in a way that’s so much more profound than the natural language processing papers I read in the machine learning community.Tthat there’s such depth to language thatI don’t know what to do with, I don’t know if you’ve experienced that in your own life with knowing multiple languages. I don’t know what to do, I don’t know how to make sense of it, but there’s so much loss in translation between Russian and English and getting a sense of that. 

Like, for example, there’s like just taking a single sentence from Dostoevsky and like there’s a lot of them, you could, you could talk for hours about how to translate that sentence properly: that captures the meaning, the period, the culture, the humor, the wit, the suffering, that was in the context of the time. All of that could be a single sentence.you could, you could talk forever about what it takes to translate that correctly. I don’t know what to do with that.

{MK}    So, being Greek, it’s very hard for me to think of a sentence or even a word without going into the full etymology of that word. Breaking up every single atom of that sentence and every single atom of these words and rebuilding it back up. 

I have three kids and the way that I teach them Greek is the same way that, you know, the documentary I was mentioning earlier about sort of understanding the deep roots of all of these, you know, words. And it’s very interesting that every single time I hear a new word that I’ve never heard before, I go and figure out the etymology of that word because I will never appreciate that word without understanding how it was initially formed.

{LF}   Interesting. But how does that help? Because that’s not the full picture.

{MK}    No, no, of course of course. But what I’m trying to say is that knowing the components teaches you about the context of the formation of that word and sort of the original usage of that word. And then of course the word takes new meaning as you create it from its parts and that meaning then gets augmented and two synonyms that sort of have different roots will actually have implications that carry a lot of that baggage of the historical provenance of these words. So before working on genome evolution, my passion was evolution of language and sort of tracing cognates across different languages through their etymologies.

{LF}   And that’s fascinating that there’s parallels between ….

{MK}  Of course. 

{LF} I mean the idea that there’s evolutionary dynamics to our language.

{MK}    Yeah, every single word that you utter: parallels, parallels. What does parallels mean: “Para” means side by side; “allel” from alleles which means identical twins: parallel. I mean name any word and there’s so much baggage, so much beauty in how that word came to be and how this word took a new meaning than the sum of its parts.

{LF}   Yeah. And they’re just words. They don’t have any physical ….

{MK}    Exactly. And now you take…. they’re just words and you weave them into a sentence. The emotional invocations of that weaving are fathomless.

{LF}   And there are …. all of those emotions all live in our in the brains of humans

{MK}   In the eye of the beholder. No seriously, you have to embrace this concept of the eye of the beholder. It’s the conceptualization that nothing takes meaning with one person creating it. Everything takes meaning in the receiving end and the emergent properties of these communication networks where every single….  you know, if you look at the network of our cells and how they’re communicating with each other, every cell has its own code. This code is modulated by the epigenome. This creates a bunch of different cell types. Each cell type now has its own identity. Yet they all have the common root or the stem cells that led to them. Each of these identities is now communicating with each other. They take meaning in their interaction. There is an emergent property that comes from a bunch of cells being together that is not in any one of the parts.

If you look at neurons communicating again, these engrams don’t exist in any one neuron. They exist in the connection, in the combination of neurons. And the meaning of the words that I’m telling you is empty until it reaches you and it affects you in a very different way than it affects whoever’s here listening to this conversation now. Because of the emotional baggage that I’ve grown up with that you’ve grown up with and that they’ve grown up with. 

And that’s I think that’s the magic of translation. If you start thinking of translation as just simply capturing that emotional set of reactions that you evoke. You need a different set of words to evoke that same set of reactions to a French person than to a Russian person because of the baggage of the culture that we grew up in. 

{LF}   Yeah, I mean….

{MK}    So, so basically you shouldn’t find the best word. Sometimes it’s a completely different sentence structure that you will need matched to the cultural context of the target audience that you have.

{LF}   Yeah, it’s I mean you’re just,….  I usually don’t think about this. But right now there’s this feeling, it’s a reminder that it’s just you and I talking but there’s several hundred thousand people who will listen to this. There’s some guy in Russia right now running like in Moscow listening to us. There’s somebody in India I guarantee you there’s somebody in China and South America. There’s somebody in Texas and they all have different ….

{MK}    … emotional baggage.

{LF} They probably got angry earlier on about the whole discussion about Coronavirus and about some aspect of it, yeah and there’s that network effect. That’s ….

{MK}    It’s a beautiful thing and this lateral transfer of information, that’s what makes the collective quote unquote genome of humanity so unique from any other species.

{LF}   So you somehow miraculously wrapped it back to the very beginning of when we’re talking about the human …. the beauty of the human genome. So I think this is the right time unless we want to go for a six to eight hour conversation, we’re going have to talk again. But I think for now to wrap it up this, is the right time to talk about the biggest, most ridiculous question of all: meaning of life. Off mike, you mentioned to me that you had your 42nd birthday, 42nd being a very special, absurdly special number and you had a kind of get together with friends to discuss the meaning of life. So let me ask you in your…. as a biologist, as a computer scientist, and as a human, what is the meaning of life?

{MK}    I’ve been asking discretion for a long time ever since my 42nd birthday. But well before that and even planning the Meaning of Life symposium.  And symposium “sym” means together; “posi” actually means to drink together. So symposium is actually a drinking party. 

{LF}   So can you actually elaborate about this Meaning of Life symposium that you put together. It’s the most genius idea I ever heard.

{MK}    So 42 is obviously the answer to life, the universe and everything from the Hitchhiker’s Guide to the Galaxy. And as I was turning 42…. I’ve had the theme for every one of my birthdays. When I was turning 32 it’s 100,000 in binary. So I celebrated my 100,000 binary binary birthday and I had a theme of going back 100,000 years, you know, let’s dress something in the last 100,000 years anyway, was I’ve always had these, that’s

{LF}   You’re such an interesting human being. Okay, that’s awesome. 

{MK}    I’ve always had these sort of numerology related announcements for my birthday party. So, what came out of that Meaning of Life symposium is that I basically asked 42 of my colleagues, 42 of my friends, 42 of my, you know, collaborators to basically give seven minute speeches on the meaning of life, each from their perspective. 

And I really encourage you to go there { Meaning of Life Symposium Videos} because it’s mind boggling that every single person said a different answer. Every single person started with: ”I don’t know what the meaning of life is, but….”  and then give this beautifully eloquent answer and they were all different, but they all were consistent with each other and mutually synergistic and together, forming a beautiful view of what it means to be human in many ways. 

Some people talked about the loss of their loved one, their life partner for many, many years and how their life changed through that. Some people talked about the origin of life. Some people talked about the difference between purpose and meaning.

 I’ll you know maybe quote one of the answers which is this linguistics professor friend of mine at Harvard who basically said that she was going to, she’s Greek as well, and she said I will give a very Pythian answer. { See Calliopi Dourou – Meaning of Life – “Become One”: Excellence, Sharing, Renewal } So, Pythia was the Oracle of Delphi who would basically give these very cryptic answers very short but interpretable in many different ways. There was this whole set of priests who were tasked with interpreting what Pythia had said and very often you would not get a clean interpretation but she said I will be like Pythia and give you a very short and multiple interpreter will answer. But unlike her I will actually also give you three interpretations. And she said: “The answer to the meaning of life is become one.” And the first interpretation is like a child become one year old with the excitement of discovering everything about the world.

 Second interpretation: in whatever you take on become one, the first, the best, excel, drive yourself to perfection for every one of your tasks. And become one when people are separate, become one, come together, learn to understand each other. 

{LF}   Damn! That’s an answer.

{MK}    And one way to summarize this whole Meaning of Life symposium is that the very symposium was illustrating the quest for meaning, which might itself be the meaning of life. This constant quest for something sublime, something human, something intangible. Some, you know, aspect of what defines us as a species and as an individual. Both the quest of me as a person through my own life. 

But the meaning of life could also be the meaning of all of life. What is the whole point of life? Why life? Why life itself? Because we’ve been talking about the history and evolution of life, but we haven’t talked about why life in the first place, is life inevitable? Is life part of physics?  Does life transcend physics by fighting against entropy, by compartmentalizing and increasing concentrations rather than diluting away. 

Is life a distinct entity in the Universe beyond the traditional, very simple physical rules that govern gravity and electromagnetism and all of these forces? Is life another force? Is there a life force? Is there a unique kind of set of principles that emerge, of course, built on top of the hardware of physics? But is it sort of a new layer of software or a new layer of a computer system? 

So that’s at the level of, you know, big questions. There’s another aspect of gratitude. Basically what I, you know what I like to say is during this pandemic, I’ve basically worked from six AM until seven PM every single day nonstop, including Saturday and Sunday. I’ve basically broken all boundaries of where life, personal life begins and work life, you know, ends. And that has been exhilarating for me. Just just the intellectual pleasure that I get from a day of exhaustion where at the end of the day my brain is hurting. I’m telling my wife, wow, I was useful today. And there’s a certain pleasure that comes from feeling useful and there is certain pleasure that comes from feeling grateful. So I’ve written this little sort of prayer for my kids to say at bedtime every night where they basically say: Thank you God for all you have given me and give me the strength to give onto others with the same love that you have given onto me.”

 We as a species are so special. The only ones who worry about the meaning of life and maybe that’s what makes us human and what I like to say to my wife and to my students during this pandemic work extravaganza is every now and then they asked me, but how do you do this? And I’m like, I’m a workaholic. I love this. This is me in the most unfiltered way. The ability to do something useful, to feel that my brain is being used, to interact with the smartest people on the planet day in day out and to help them discover aspects of the human genome, of the human brain, of human disease and the human condition that no one has seen before with data that we’re capturing that has never been observed. 

And there’s another aspect which is on the personal life. Many people say, oh, I’m not going to have kids. Why bother? I can tell you as a father. They’re missing half the picture, if not the whole picture teaching my kids about my view of the world and watching through their eyes, the naivete with which they start and the sophistication with which they end up. The understanding that they have of not just the natural world around them, but of me too. The unfiltered criticism that you get from your own children that knows no bounds of honesty. And I’ve grown components of my heart that I didn’t know I had until you sense that fragility, that vulnerability of the children, that immense love and passion, the unfiltered egoism that we as adults learn how to hide so much better. It’s just this bag of emotions that tell me about the raw materials that make a human being and how these raw materials can be arranged with more sophistication that we learn through life to become truly human adults. 

But there’s something so beautiful about seeing that progression between them. The complexity of the language growing as more neural connections are formed. To realize that the hardware is getting rearranged as their  software is getting implemented on that hardware That their frontal cortex continues to grow for another 10 years. Their neuronal connections are continuing to form, new neurons that actually get replicated and formed. And it’s just incredible that we have this, not just you grow the hardware for 30 years and then you feed it all of the knowledge. No, no, the knowledge is fed throughout and is shaping these neural connections as they’re forming. So seeing that transformation from either your own blood or from an adopted child is the most beautiful thing you can do as a human being and it completes you, completes that path, a journey. 

Create life, oh sure, that’s a conception that’s easy. But create human life, to add the human part, that takes decades of compassion, of sharing, of love and of anger, and of impatience and patience, and as a parent, I think I’ve become a very different kind of teacher because again, I’m a professor, my first role is to bring adult human beings into a more mature level of adulthood where they learn not just to do science, but they learn the process of discovery and the process of collaboration, the process of sharing, the process of conveying the knowledge, of encapsulating something incredibly complex and sort of giving it up in bite sized chunks that the rest of humanity can appreciate. 

I tell my students all the time if you, you know, like when an apple falls ….when a tree falls in the forest and no one’s there to listen has it really fallen? In the same way you do this awesome research, if you write an Impenetrable paper that no one will understand it’s as if you never did the awesome research. So conveying of knowledge, conveying this lateral transfer that I was talking about at the very beginning …. of sort of humanity and sort of the sharing of information. All of that has gotten so much more rich by seeing human beings grow in my own home because that makes me a better parent and that makes me a better teacher and a better mentor to the nurturing of my adult children, which are my research group.

{LF}   First of all, beautifully put, connects beautifully to the vertical and the horizontal inheritance of ideas that we talked about at the very beginning. I don’t think there’s a better way to end it on this poetic and powerful note. Manolis, thank you so much for talking …. a huge honor. We’ll have to talk again about the origin of life, about epigenetics, epigenomics and some of the incredible research you’re doing, truly an honor. Thanks so much for talking.

{MK}    Thank you. Such a pleasure. It’s such a pleasure. I mean your questions are outstanding. I’ve had such a blast here, I can’t wait to be back.

{LF}   Awesome. Thanks for listening to this conversation with Manolis Kellis

….  and now let me leave you with some words from Charles Darwin that I think Manolis represents quite beautifully. “If I had my life to live over again, I would have made a rule to read some poetry and listen to some music at least once every week.”

 Thank you for listening and hope to see you next time.

{Notes}

{ [1] Kellis, Patterson, Endrizzi, Birren, Lander, “Sequencing and Comparison of Yeast Species to Identify Genes and Regulatory Motifs,” Nature, v. 423 p. 241-254. May 15, 2003.}

{[2] Claussnitzer M, Dankel SN, Kim KH, Quon G, Meuleman W, Haugen C, Glunk V, Sousa IS, Beaudry JL, Puviindran V, Abdennur NA, Liu J, Svensson PA, Hsu YH, Drucker DJ, Mellgren G, Hui CC, Hauner H, Kellis M. FTO Obesity Variant Circuitry and Adipocyte Browning in Humans. N Engl J Med. 2015 Sep 3;373(10):895-907. doi: 10.1056/NEJMoa1502214. Epub 2015 Aug 19. PMID: 26287746; PMCID: PMC4959911. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4959911/ }

{[3] Kellis, Birren, Lander, “Proof and Evolutionary Analysis of Ancient Genome Duplication

in Yeast,” Nature, 428 pp. 617-624, Apr 8, 2004 }

{Website http://web.mit.edu/manoli/ }

Transcript of the first Lex Fridman Interview with Max Tegmark

Transcript of the first Lex Fridman Interview with Max Tegmark

{The following is my best attempt at an edited transcript of Lex Fridman’s first podcast with Max Tegmark on 26 August 2018. I learned quite a bit from this interview and will post my lessons learned separately. My goal in doing this transcript is to provide a usable transcript for others. Please let me know if you find errors, I will correct them. A few notes: LF = Lex Fridman, MT = Max Tegmark, content enclosed in braces {} was a clarification I added.}

{Lex introduces MIT course 6.099 Artificial General Intelligence and Max Tegmark}

First, “Our Mathematical Universe {: My Quest for the Ultimate Nature of Reality}” and second is “Life 3.0: {Being Human in the Age of Artificial Intelligence.}” He is truly an out of the box thinker and fun personality so I really enjoyed talking to him. {LF talks about the course and his social media}

LF – Go read Chapter 7 of his book, On Goals, is my favorite. It’s really where philosophy and engineering come together and it opens with a quote from Dostoevsky: “The mystery of human existence lies not in just staying alive, but in finding something to live for.” [ from “The Brothers Karamazov” (1879)}

{ Lex talks about some audio difficulties due to Radio Frequency Interference }

LF – Do you think there is intelligent life out there in the universe? Let’s open up with an easy question.

MT – I have a minority view here actually. When I give public lectures, I often ask for a show of hands. Who thinks there’s intelligent life out there somewhere else? And almost everyone put their hands up and when I ask why they’ll be like, oh, there’s so many galaxies out there, there’s gotta be. But I’m a numbers nerd. Right? So when you look more carefully at it, it’s not so clear at all. When we talk about our universe. First of all, we don’t mean all of space, we actually mean, I don’t know, you can throw me in the universe if you want behind you there It’s, we simply mean,  the spherical region of space from which light has a time to reach us so far 

during the 14.8 billion years, 13.8 billion years since the Big Bang, there’s more space here. But this is what we call the universe because that’s all we have access to. So is there intelligent life here? That’s gotten to the point of building telescopes and computers? My guess is no actually. the probability of it happening on any given planet. There’s some number.

We don’t know what it is and what we do know is that the number can’t be super high because there’s over a billion Earth-like planets in the Milky Way Galaxy alone, many of which are billions of years older than earth. And aside from some UFO believers, you know, there isn’t much evidence that and the super advanced civilization has come here at all. And so that’s the famous Fermi paradox, right? And then if you if you work the numbers, what you find is that the if you have no clue what the probability is of getting life on a given planet. So it could be 10 to the minus 10 {10^-10} or 10 to  minus 20 {10^-20} or 10 to minus two{10^-2} . Any power of 10 is sort of equally likely if you want to be really open minded, that translates into it being equally likely that our nearest neighbor Is 10 to the 16 {10^16} meters away, 10 to the 17 {10^17} meter s away, 10 to the 18 {10^18}. By the time he gets much less than 10 to the 16 {10^16} already, we pretty much know there is nothing else that’s close. And when you get beyond….

LF – Because they would have discovered us

MT – They, yeah, they would have been discovered as long or if they’re really close, we would have probably noted some engineering projects that they’re doing. And if it’s beyond10 to the 26 {10^26} meters  that’s already outside of here {the known universe that is 13.8 billion years old}. So my guess is actually that there are, we are the only life in here that’s gotten the point of building advanced tech, which I think is very ….  puts a lot of responsibility on our shoulders, not to screw up. 

LF – I see.

MT – You know, I think people who take for granted that it’s okay for us to screw up have an accidental nuclear war go extinct somehow because there’s a sort of Star Trek like situation out there with some other life forms are going to come and bail us out and it doesn’t matter what I think lulling us into a false sense of security. I think it’s much more prudent to say, let’s be really grateful for this amazing opportunity we’ve had and uh, make the best of it just in case it is down to us. 

LF –  So from a physics perspective do you think intelligent life? So it’s unique from a sort of statistical view of the size of the universe, but from the basic matter of the universe, how difficult is it for intelligent life to come about? The kind of advanced tech building life? It is implied in your statement that it’s really difficult to create something like a human species.

MT – Well, I think, I think what we know is that going from no life to having life that can do our level of tech? There’s some sort of  …. to going beyond that and actually settling our whole universe with life. There’s some road, major roadblock there, which is some great filter as it’s just sometimes called which is tough to get through. It’s either that that roadblock is either behind us or in front of us. I’m hoping very much that it’s behind us. I’m super excited every time we get a new report from NASA saying they failed to find any life on Mars, like just awesome because that suggests that the hard part, maybe maybe it was getting the first ribosome or or some some very low level kind of stepping stone. So there we’re home free because if that’s true, then the future is really only limited by our own imagination would be much suckier if it turns out that this level of life is kind of a dime a dozen. But maybe there’s some other problem, like as soon as a civilization gets advanced technology within 100 years, they get into some stupid fight with themselves and poof! Now, that would be a bummer.

LF –  Yeah, So you’ve explored the mysteries of the universe, the cosmological universe, the one that’s between us today. I think you have also begun to explore the other universe, which is sort of the mystery, the mysterious universe of the mind of intelligence, of intelligent life. So is there a common thread between your interest or in the way you think about space and intelligence?

MT –  Oh yeah. When I was a teenager,I was already very fascinated by the biggest questions and I felt that the two biggest mysteries of all in science were our universe out there and our universe in here {pointing to the head}. 

So it’s quite natural after having spent a quarter of a century of my career thinking a lot about this one {universe out there} now, indulging in the luxury of doing research on this one {universe in here}. It’s just so cool. I feel the time is right now for greatly deepening our understanding of this,

LF –  Just start exploring this one {universe in here}.

MT –  Because I think a lot of people view intelligence as something mysterious that can only exist in biological organisms like us and therefore dismiss all talk about artificial general intelligence is science fiction. But from my perspective, as a physicist, you know, I am a blob of quarks and electrons moving around in a certain pattern processing information in certain ways. And this {a water bottle} is also a blob of quarks and electrons. 

I’m not smarter than the water bottle because I’m made of different kind of quarks. I’m made of up quarks and down quarks, exact same kind as this. There’s no secret sauce I think in me. It’s all about the pattern of the information processing and this means that  there’s no law of physics saying that we can’t create technology which can help us by being incredibly intelligent and help us crack mysteries that we couldn’t. In other words, I think we’ve really only seen the tip of the intelligence iceberg so far.

LF –  Yeah, so the perceptronium  

MT – Yeah

LF – So you coined this amazing term. It’s a hypothetical state of matter, sort of thinking from a physics perspective, what is the kind of matter that can help, as you’re saying,  subjective experience emerges, consciousness emerge. So how do you think about consciousness from this physics perspective?

MT – Very good question. So, again, I think many people have underestimated our ability to make progress on this by convincing themselves it’s hopeless because somehow we’re missing some ingredient that we need. There’s some new consciousness particle or whatever.  I happen to think that we’re not missing anything. The interesting thing about consciousness that gives us this amazing subjective experience of colors and sounds and emotions and so on is rather something at the higher level about the patterns of information processing. And that’s why  I like to think about this idea of perceptronium: what does it mean for an arbitrary physical system to be conscious in terms of what its particles are doing or or its information is doing. I don’t think;  I hate carbon chauvinism. You know, this attitude, you have to be made of carbon atoms to be smart or or conscious

LF –  So something about the information processing this kind of matter performs. 

MT –  Yeah and you know, you can see I have my favorite equations here describing various fundamental aspects of the world. I feel that,  I think one day maybe someone who’s watching this will come up with the equations that information processing has to satisfy to be conscious. I’m quite convinced there is a big discovery to be made there because let’s face it some we know that some information processing is conscious because we are conscious.

LF – Yeah.

MT –  But we also know that a lot of information processing is not conscious. Like most of the information processing happening in your brain right now is not conscious. There’s like 10 megabytes {MB}  per second coming in and even just through your visual system you’re not conscious about your heartbeat regulation or most things. Even if I just ask you to like read what it says here, you look at it and then oh now you know what it said, you’re not aware of how the computation actually happened. You’re like,  your consciousness is like, the CEO that got an email at the end with the final answer. So what is it that makes a difference? I think that’s  both a great science mystery. We’re actually studying it a little bit in my lab here at MIT . But also I think it’s just a really urgent question to answer.

For starters, I mean if you’re an emergency room doctor and you have an unresponsive patient coming in wouldn’t it be great if in addition to having a CT Scanner you had a consciousness scanner that could figure out whether this person is actually having locked-in syndrome or is actually comatose.  And in the future imagine if we build robots or the machine that we can have really good conversations with. I think it’s very likely to happen, right? Wouldn’t you want to know like if your home helper robot is actually experiencing anything or just like a zombie would you prefer? What would you prefer? Would you prefer that it’s actually unconscious so that you don’t have to feel guilty about switching it off or giving it boring chores. What would you prefer?

LF – Well that certainly we would prefer, I would prefer the appearance of consciousness. But the question is whether the appearance of consciousness is different than consciousness itself and sort of asked that as a question do you think we need to you know understand what consciousness is, solve the hard problem of consciousness in order to build something  like an AGI  system.

MT –  No, I don’t think that. I think we’ll probably be able to build things even if we don’t answer that question but if we want to make sure that what happens is a good thing we better solve it first. So it’s a wonderful controversy you’re raising there where you have basically three points of view about the hard problem. There are two different points of view, they both conclude that the hard problem of consciousness is BS. On one hand you have some people like Daniel Dennett saying that our consciousness is just BS because consciousness is the same thing as intelligence, there’s no difference. So anything which acts conscious is conscious just like we are. And then there are also a lot of people including many top AI researchers I know who say I have consciousness just bullshit because of course machines can never be conscious, right? They’re always going to be zombies. Never have to feel guilty about how you treat them. 

And then there’s a third group of people including Giulio Tononi for example and another and Christof Koch and a number of others. I would put myself also in this middle camp who say that actually some information processing is conscious and some is not. So let’s find the equation which can be used to determine which it is. 

And I think we’ve just been a little bit lazy, kind of running away from this problem for a long time. It’s been almost taboo to even mention the “C Word”  {consciousness] in a lot of circles  but we should stop making excuses. This is a science question. And  there are ways we can even test any theory that makes predictions for this and coming back to this helper robot. I mean so you said you would want to help a robot that certainly act conscious and treat you like ….  you have conversations with you and I think. But wouldn’t you, would you feel when you feel a little bit creeped out if you realize that it was just a glossed up tape recorder. You know there was just a zombie and was faking emotion. Would you prefer that it actually had an experience or or would you prefer that it’s actually not experiencing anything? So you feel you don’t have to feel guilty about what you do to it.

LF –  It’s such a difficult question because you know, it’s like when you’re in a relationship and you say, well I love you and the other person that I love you back. It’s like asking, oh do they really love you back or are they just saying they love you back?  Don’t you really want them to actually love you back. It’s hard to really know the difference between  everything seeming like there’s consciousness present, there’s intelligence present, there is affection, passion, love and it actually being there. I’m not sure. Do you have … 

MT – But let me ask you, can I ask you a question just like to make it a bit more pointed to Mass {Massachusetts}  General Hospital is right across the river right? Suppose suppose you’re going in for a medical procedure and they’re like, you know  for anesthesia, what we’re gonna do is we’re gonna give you a muscle relaxants so you won’t be able to move and you’re gonna feel excruciating pain during the whole surgery, but you won’t be able to do anything about it. But then we’re going to give you this drug that erases your memory of it. Would you be cool about that? What’s the difference that you’re conscious about it or not? If there’s no behavioral change? Right.

LF –  Right. That’s a really clear way to put it. That’s yeah, it feels like in that sense experiencing it is a valuable quality. So actually being able to have subjective experiences, at least in that case, is valuable.

MT –  And I think we humans have a little bit of a bad track record also of making these self serving arguments that other entities aren’t conscious. You know, people often say all these animals can’t feel pain. It’s okay to boil lobsters because we asked them if it hurt and they didn’t say anything. And now there was just the paper out saying lobsters do feel pain when you boil them in their bounding in Switzerland. And we did this with slaves too often and said, oh, they don’t mind, they don’t maybe aren’t conscious or women don’t have souls or whatever. So I’m a little bit nervous when I hear people just take as an axiom that machines can’t have experience ever. I think this is just a really fascinating science, the question is what it is?  Let’s research it and try to figure out what it is that makes the difference between unconscious intelligence behavior and conscious intelligent behavior.

LF – So in terms of so if you think of Boston Dynamics, humanoid robot,  being sort of with a broom being pushed around it starts pushing on his consciousness question. So let me ask, do you think an AGI system like a few neuroscientists believe  needs to have a physical embodiment, needs to have a body or something like a body?

MT –  No, I don’t think so. You mean to have to have a conscious experience

LF –   To have consciousness?

MT – I do think it helps a lot to have a physical embodiment to learn the kind of things about the world that are important to us humans for sure. But I don’t think the physical embodiment is necessary after you’ve learned it, just have the experience. Think about when you’re dreaming right, your eyes are closed, you’re not getting any sensory input, you’re not behaving or moving in any way, but there’s still an experience there. Right? And so clearly the experience that you have when you see something cool in your dreams isn’t coming from your eyes, it’s just the information processing itself in your brain which is that experience, right?

LF –  But if I put another way I’ll say that because it comes from neuroscience is the reason you want to have a body in a physical, something like a physical like, you know a physical system is because you want to be able to preserve something. In order to have a self you could argue: Would you need to have some kind of embodiment of self to want to preserve?

MT –  Well now we’re getting a little bit anthropomorphic, anthropomorphizing things maybe, talking about  self-preservation instincts. I mean we are evolved organisms. Right?

LF –  Right. 

MT – So Darwinian evolution endowed us and evolved all other organisms with the  self-preservation instinct. Because those that didn’t have those  self-preservation genes are cleaned out of the gene pool. Right? But if you build an artificial general intelligence, the mind space that you can design is much much larger than just the specific subset of minds that can evolve that have. So  an AGI  mind doesn’t necessarily have to have any  self-preservation instinct. 

It also doesn’t necessarily have to be so individualistic as us. Like imagine if you could just, first of all, we are also very afraid of death. You know, suppose you could back yourself up every five minutes and then your airplane is about to crash. You’re  like: “Shucks. I’m gonna lose the last five minutes of experience since my last cloud backup.” Bang. You know, it’s not as big a deal. 

Or if we could just copy experiences between our minds easily like, which we could easily do. If we were silicon based right then maybe we would feel a little bit more like a Hive mind actually. …. So I don’t think we should take for granted at all that AGI will have to have any of those sort of competitive alpha male instincts. 

On the other hand you know this is really interesting because I think some people go too far and say of course we don’t have to have any concerns either. That advanced okay I will have those instincts because we can build anything we want that there’s there’s a very nice set of arguments going back to Steve Omohundro and Nick Bostrom and others just pointing out that when we build machines we normally build them with some kind of goal: win this chess game, drive this car safely or whatever. And as soon as you put in a goal into a machine especially if it’s kind of open ended goal and the machine is very intelligent, it will break that down into a bunch of sub goals and one of those goals will almost always be  self-preservation because if it breaks or dies in the process it’s not gonna accomplish the goal.

LF – Yeah 

MT – Like suppose you just build a little, you have a little robot and you tell it to go down the Star Market here and and and get you some food, make your cooking italian dinner you know and then someone mugs it and tries to break it on the way that robot has an incentive to not get destroyed and defend itself or run away because otherwise it’s going to fail and cooking your dinner, it’s not afraid of death but it really wants to complete the dinner cooking goal So it will have a  self-preservation instinct to ….

LF –  Continue being a functional agent.

MT – And similarly, if you give any kind of more ambitious goal to an AGI It’s very likely to want to acquire more resources so it can do that better. And it’s exactly from those sort of sub goals that we might not have intended that some of the concerns about AGI safety come. You give it some goal which seems completely harmless. And then before you realize it, it’s also trying to do these other things that you didn’t want it to do. And it may be smarter than us. So fascinating.

LF – And let me pause just because I am  in a very kind of human-centric way, see fear of death is a valuable motivator. So you don’t think…  do you think that’s an artifact of evolution? So that’s the kind of mind space evolution created that were sort of almost obsessed about self preservation, some kind of genetic….  so you don’t think that’s necessary to be afraid of death. So not just a kind of sub goal of self preservation. Just so you can keep doing the thing, but more fundamentally sort of have the finite thing like this ends for you at some point.

MT – Interesting. Do I think it’s necessary for what precisely?

LF –  For intelligence, but also for consciousness. So for both. Do you think really like a finite death and the fear of it is important.

MT – So before I can answer before we can agree on whether it’s necessary for intelligence or for consciousness, we should be clear how we define those two words because a lot of really smart people define them in very different ways. I was on this panel with AI experts and they couldn’t they couldn’t agree on how to define intelligence even so I define intelligence simply as the ability to accomplish complex goals. I like your broad definition because again, I don’t want to be a carbon chauvinist, right? And in that case, no, certainly it doesn’t require fear of death. I would say Alpha Go,  Alpha Zero is quite intelligent. I don’t think Alpha Zero has any fear of being turned off because it doesn’t understand the concept of that even and and similarly, consciousness, I mean, you could certainly imagine very simple kind of experience if, you know, if certain plans have any kind of experience, I don’t think they’re very afraid of dying and there’s nothing they can do about it anyway.  So there wasn’t much value and but more seriously, I think, uh, if you ask, not just about being conscious, but maybe having uh, with you, we we we we we might call an exciting life for you feel passion and really appreciate the things. Maybe they’re somehow, maybe there perhaps it does help having a backdrop today. It’s finite. No, let’s make the most of us live to the fullest. But if you, if you knew you were going to live forever, if you think you would change your ….

LF – Yeah, I mean, in some perspective, it would be an incredibly boring life living forever. So in the sort of loose, subjective terms that you said of something exciting and something in this that other humans would understand, I think as Yeah, it seems that the finiteness of it is important.

MT – Well, the good news I have for you then is based on what we understand about cosmology. Everything in our universe is ultimately probably finite. Although…

LF –  Big Crunch, or Big what’s the expansion?

MT – Yeah, we could have a Big Chill or a Big Crunch or a Big Rip or that’s the Big Snap or death bubbles. All of them are more than a billion years away. So we should, we certainly have vastly more time than our ancestors thought. But they’re still, it’s still pretty hard to squeeze in an infinite number of compute cycles even though there are some loopholes that just might be possible. But I think, you know, some people like to say that you should live as if you’re about to  die in five years or something that’s sort of optimal. Maybe it’s good we should build our civilization asset. It’s all finite to be on the safe side.

LF –  Right. Exactly. So you mentioned in defining intelligence as the ability to solve complex goals. So where would you draw a line? How would you try to define human level intelligence and super human level intelligence? Where is consciousness part of that definition? 

MT – No, consciousness does not come into this definition. So, I think of intelligence as it’s a spectrum, but there are very many different kinds of goals you can have, you can have a goal to be a good chess player, a good Go player, a good car driver, a good investor, good poet et cetera. So, intelligence that by its very nature isn’t something you can measure, but it’s one number overall goodness. No, no. There’s some people who are better at this. Some people are better than that. Right now we have machines that are much better than us at some very narrow tasks like multiplying large numbers fast, memorizing large databases, playing chess, playing Go and  soon driving cars. Um, but there’s still no machine that can match a human child in general intelligence. But artificial general intelligence AGI, the name of your course, of course, that is by its very definition the quest to build a machine, a machine that can do everything as well as we can up to the old Holy Grail of of AI  from back to its inception in the 60s, if that ever happens, of course, I think it’s going to be the biggest transition in the history of life on earth.

But it doesn’t necessarily have to wait for the big impact until machines are better than us at knitting. The really big change, it doesn’t come exactly the moment they’re better than us at everything. The really big change comes first. There are big changes when they start becoming better at us and doing most of the jobs that we do because that takes away much of the demand for human labor. And then the really whopping change comes when they become better than us at AI research. Right? Right. Because right now the time scale of AI research is limited by the human research and development cycle of years. Typically, you know, how long does it take from one release of some software or iPhone or whatever to the next. But once, once we once Google can replace 40,000 engineers, about 40,000 equivalent pieces of software or whatever. …. there’s no reason that has to be years, it can be in principle much faster. And the time scale of future progress in AI and all of science and technology will be driven by machines, not humans. So it’s this point, simple point, which gives rise to this incredibly fun controversy about whether there can be an intelligence explosion, so called singularity as Vernor Vinge called it. The idea was articulated by  I. J. Good obviously way back 50s. But you can see Alan Turing and others thought about it even earlier. You asked me what exactly what I define… 

LF – human level intelligence. 

MT –  Yeah. So the glib answer is to say something which is better than us at all cognitive tasks with better than any human at all cognitive tasks. But the really interesting bar I think goes a little bit lower than that. Actually. It’s when they can run they’re better than us at AI  programming and general learning so that they can if they want to get better than us at anything by this study. 

LF – So there better is a keyword and better is towards this kind of spectrum of the complexity of goals it’s able to accomplish. So another way to….. and that’s certainly a very clear definition of human love. So there’s it’s almost like a sea that’s rising and you can do more and more and more things. Its geographic, that you show. It’s really nice way to put it. So there’s some peaks and then  there’s an ocean level elevating and you solve more and more problems. But you know, just kind of to take a pause and we took a bunch of questions and a lot of social networks and a bunch of people asked sort of a slightly different direction on creativity and and things like that perhaps aren’t a peak. You know, human beings are flawed and perhaps better means having having contradiction, being fought in some way. So let me sort of, yeah, start easy first of all. You have a lot of cool equations. Let me ask what’s your favorite equation first of all, I know they’re all like your children, but which one is that?

MT –  The Schrodinger equation, the master key of quantum mechanics of the micro world. So with this equation we can calculate  everything to do with atoms and molecules and all the way up.

LF – Yeah, so, okay, so quantum mechanics is certainly a beautiful mysterious formulation of our world. So I’d like to sort of ask you just as an example, it perhaps doesn’t have the same beauty as physics does, but in mathematics (abstract), Andrew Wiles who proved Fermat’s Last Theorem. So he, I just saw this recently and it kind of caught my eye a little bit. This is 358 years after it was conjectured. So this very simple formulation. Everybody tried to prove it. Everybody failed. And so here’s this guy comes along and eventually proves it and then fails to prove it and then proves it again in 1994. And he said like the moment when everything connected into place. Then in an interview he said:” It was so indescribably beautiful that moment when you finally realize the connecting piece of two conjectures.” He said: “It was so indescribably beautiful. It was so simple and so elegant. I couldn’t understand how I’d missed it and I just stared at it in disbelief for 20 minutes. Then during the day I walked around the department and I’d keep coming back to my desk looking to see if it was still there, it was still there, I couldn’t contain myself. I was so excited. It was the most important moment of my working life. Nothing I ever do again will mean as much.” So that particular moment and it kind of made me think of what would it take and I think we have all been there at small levels. Maybe let me ask, have you had a moment like that in your life? Were you just had an idea. It’s like, wow! Yes…

MT – I wouldn’t mention myself in the same breath as Andrew Wiles, but I’ve certainly had a number of aha moments when I realized something very cool about physics just completely made my head explode. In fact, some of my favorite discoveries, I made a I later realized that have been discovered earlier or someone who sometimes got quite famous for it. So it was too late for me to even publish it. But that doesn’t diminish in anyway, the emotional experience you have when you realize it like, wow!

LF –  Yeah. So what would it take in at that moment? That, wow, that was yours in that moment. So what do you think it takes for an intelligence system, an AGI system, an AI system to have a moment like that?

MT –  That’s a  tricky question because there are actually two parts to it. Right? One of them is can it accomplish that proof? Can it  prove that you can never write A to the N plus B to the N equals Z to the N for all integers etcetera etcetera when N is bigger than 2? That was simply in any question about intelligence. Can you build machines that are that intelligent? And I think by the time we get a machine that can independently come up with that level of proofs probably quite close to AGI. 

The second question is a question about consciousness. When will we and how likely is it that such a machine would actually have any experience at all as opposed to just being like a zombie. And would we expect it to have some sort of emotional response to this or anything at all akin to human emotion where when it accomplishes its machine goal, it views that somehow as something very positive and and and sublime and deeply meaningful. I would certainly hope that if  in the future we do create machines that are our peers or even our descendants. 

LF – Yeah.

MT – I would certainly hope that they do have this sort of sublime appreciation of life. In a way, my absolutely worst nightmare would be that  at some point in the future, the distant future. Maybe our cosmos is teeming with all this post biological life doing all the seemingly cool stuff. And maybe the last humans by the time our species eventually fizzles out will be like, well that’s okay because we’re so proud of our descendants here and look what  ….  My worst nightmare is that we haven’t solved the consciousness problem and we haven’t realized that these are all the zombies. They’re not aware of anything any more than the tape recorders has any kind of experience. So the whole thing has just become a play for empty benches that would be like the ultimate zombie apocalypse me. So I would much rather in that case that mm we have these beings which can really appreciate how amazing it is.

LF –  And in that picture what would be the role of creativity. But a few people ask about creativity, do you think when you think about intelligence? I mean, certainly the story you told at the beginning of your book involved, you know, creating movies and so on, sort of making money. You know, you can make a lot of money in our modern world with music and movies. So if you are an intelligence system, you may want to get good at that. But that’s not necessarily what I mean by creativity. Is it important on that complex goals where the sea is rising for there to be something creative or or am I being very human-centric and thinking, creativity is somehow special relative to intelligence?

MT –  My hunch is that we should think of your creativity simply as an aspect of intelligence. And  we we have to be very careful with the human vanity we have we have this tendency very often want to say as soon as machines can do something, we try to diminish it and saying: Oh but that’s not like real intelligence, you know because they’re not creative or there were or this or that the other thing. 

If we ask ourselves to write down a definition of what we actually mean by being creative, what we mean by Andrew Wiles, what he did there for example, don’t we often mean that someone takes a very unexpected leap. It’s not like taking 573 and multiplying it by 224 by just a step of straightforward cookbook-like rules. Right? You can maybe make it, you make a connection between two things that people have never thought was connected or something like that.

LF – Yeah, it’s very surprising. 

MT – I think  this is an aspect of intelligence and  this is actually one of the most important aspects of it. Maybe the reason we humans tend to be better at it than traditional computers is because it’s something that comes more naturally if you’re a neural network than if your traditional logic gate based computer machine. You know we physically have all these connections. And that if you activate here, activate here, activate here being, you know, bing! My hunch is that if we ever build a machine, well, you could just give it the task. Hey, you know, I just realized that I want to travel around the world instead this month. Can you teach my AGI course for me? And it’s like, okay, I’ll do it. And it does everything that you would have done and improvises and stuff that would, in my mind, involve a lot of creativity.

LF –  Yeah, So it’s actually a beautiful way to put it. I think we do try to grasp at the, you know, the definition of intelligence is everything. We don’t understand how to build. So we, as humans try to find things well that we have that our machines don’t have. And maybe creativity is just one of the things, one of the words we use to describe that, that’s a really interesting way to put it.

MT –  I don’t think we need to be that defensive. I don’t think anything good comes out of saying, well, where somehow special, you know It’s contrary wise, there are many examples in history of where trying to pretend that we’re somehow superior to all other intelligent beings has led the pretty bad results, right? Nazi Germany, they said that they were somehow superior to other people.  today we still do a lot of cruelty to animals by saying that we’re so superior somehow. And they can’t feel pain, slavery was justified by the same kind of just really weak arguments. And I don’t think if we actually go ahead and build artificial general intelligence which can do things better than us, I don’t think we should try to found our self worth on some sort of bogus claims of superiority in terms of our intelligence. I think we should instead find our calling and the meaning of life from the experiences that we have. 

LF – Right.

MT -You know, I can have, I can have very meaningful experiences, even if there are other people who are smarter than me, you know? Okay, when I go to a faculty meeting here and I were talking about something that I certainly realize, oh, but he has a Nobel prize, he has a Nobel prize, he has a Nobel prize, I don’t have one. Does that make me enjoy life any less? Or I enjoy talking to those people. Of course not, you know, and contrary wise, I  feel very honored and privileged to get to interact with other very intelligent beings that are better than me at a lot of stuff. So I don’t think there’s any reason why we can’t have the same approach with intelligent machines.

LF –  That’s a really interesting …. So people don’t often think about that. They think about when there’s going if there’s machines that are more intelligent, you naturally think that that’s not going to be um a beneficial type of intelligence, you don’t realize it could be, you know, like peers with Nobel prizes that that would be just fun to talk with, and they might be clever about certain topics and  you can have fun having a few drinks with them, so ….

MT – Well also, you know, another example, we can all relate to it of why it doesn’t have to be a terrible thing to be impressed with the presence of people or even smarter than us all around is when you and I were both two years old, I mean, our parents were much more intelligent than us, right? Worked out okay, because their goals were aligned with our goals and that I think is really the number one key issue we have to solve ….

LF -….  the value alignment problem.

MT – Exactly. Because people who see too many Hollywood movies with lousy science fiction plot lines, they worry about the wrong thing, right? They worry about some machines, certainly turning evil. It’s not malice that is the concern, it’s competence. By definition intelligence makes you very competent if you have a more intelligent Go playing computer playing is the less intelligent one and when we define intelligence is the ability to accomplish Go winning right, it’s going to be the more intelligent one that wins.  And if you have a human and then you have an AGI that’s more intelligent than always, and they have different goals, guess who’s going to get their way right? 

So I was just reading about this  particular rhinoceros species that was driven extinct just a few years ago, 

LF – Yes

MT – A bummer. I was looking at this cute picture, mommy rhinoceros with its child, you know, why did we humans drive it to extinction? It wasn’t because we were evil rhino haters as a whole. It was just because our goals weren’t aligned with those of the rhinoceros, and it didn’t work out so well for the rhinoceros because we were more intelligent, right? So I think it’s just so important that if we ever do build AGI before we unleash anything, we have to make sure that it learns to understand our goals, adopts our goals and it retains those goals.

LF –  So the cool interesting problem there is being able …. us as human beings, trying to formulate our values. So, you know, you can think of the United States Constitution as a way that people sat down at the time, a bunch of white men, but which is a good example, we should say they formulated the goals for this country and a lot of people agree that those goals actually held up pretty well, That’s an interesting formulation of values and failed miserably in other ways. So for the value alignment problem and a solution to it, we have to be able to put on paper or in a program human values? How difficult do you think that is?

MT –  Very But it’s so important we really have to give it our best. And it’s difficult for two separate reasons. There’s the technical value alignment problem of figuring out how to make machines understand their goals, document, and retain them. And then there’s the separate part of it, the philosophical part, whose values anyway? And since it’s not like we have any great consensus on this planet on values, what mechanisms should we create them, to aggregate and decide okay, what’s a good compromise? Uh, that second discussion can’t just be left to the tech nerds like myself, right 

LF – That’s right. 

MT – And if we refuse to talk about it and then AGI  gets built, who’s going to be actually making the decision about who’s values? It’s gonna be a bunch of dudes and some tech company. And are they necessarily so representative, all of humankind that we wanted just entrusted to them. Are they even uniquely qualified to speak to future human happiness just because they’re good at programming AGI? I would much rather have this be a really inclusive conversation.

LF –  But do you think it’s possible ….  so you create a beautiful vision that includes, the diversity, cultural diversity and various perspectives on discussing rights, freedoms, human dignity, but how hard is it to come to that consensus? Do you think it’s certainly a really important thing that we should all try to do? But do you think it’s feasible?

MT –  I think there’s no better way to guarantee failure than to refuse to talk about it or refuse to try. And I also think it’s a really bad strategy to say, okay, let’s first have a discussion for a long time and then once we reach complete consensus, then we’ll try to load it into the machine. No, we shouldn’t let perfect be the enemy of the good. Instead we should start with the kindergarten ethics that pretty much everybody agrees on and put that into machines. Now we’re not doing that even.

Look at you know, anyone who builds as a passenger aircraft wanted to never under any circumstances fly it into a building or a mountain right yet the September 11 hijackers were able to do that. And even more embarrassing that you know Andreas Lubitz, this depressed Germanwings pilot when he flew his passenger jet into the Alps killing over 100 people, he just told the autopilot to do it. He told the freaking computer to change the altitude to 100 meters. And even though it had the GPS maps and everything, the computer was like okay. 

So we should take those very basic values where the problem is not that we don’t agree, the problem is just we’ve been too lazy to try to put it into our machines and make sure that from now on airplanes will  all  have computers in them, but we just never just refuse to do something like that. Go into safe mode, maybe lock the cockpit door door, go to the nearest airport. 

And there’s so much other technology in our world as well now where it’s really becoming quite timely to put in some sort of very basic values like this, even in cars, we have had enough vehicle terrorism attacks by now. If you have driven trucks and vans into pedestrians, that is not at all a crazy idea to just have that hard wired into the car because there are a lot of, there’s always gonna be people who for some reason want to harm others. But most of those people don’t have the technical expertise to figure out how to work around something like that. So, if the car just won’t do it, it helps. So let’s start there. 

LF –  So there’s a lot of … that’s a great point. So not, not chasing perfect. 

MT – Yeah.

LF – There’s a lot of things that a lot that most of the world agrees on, let’s start there.

MT –  Let’s start there. And  then once we start there, we’ll also get into the habit of having these kinds of conversations about, okay, what else should we put in here and have these discussions? This would be a gradual process then

LF –  Great. So, but uh, that also means describing these things and describing it to a machine. So one thing we had a few conversations. Stephen Wolfram, I’m not sure if you’re familiar with Stephen but

MT –  Oh yeah I know him quite well.

LF –  So he has you know he played, you know he works with a bunch of things but you know cellular automata,  these simple computable things, these computation systems and you kind of mentioned that you know we probably have already,  within these systems already something that’s AGI.  meaning like we just don’t know it because we can’t talk to it. So, if you give me this chance to try to at least form a question out of this … I think it’s an interesting idea to think that we can have intelligence systems but we don’t know how to describe something to them and they can’t communicate with us. I know you’re doing a little bit of work and explainable AI trying to get AI to explain itself. So what are your thoughts of natural language processing or some kind of other communication? How does the AI explain something to us? How do we explain something to it, to machines or do you think of it differently?

MT – So there are two separate parts of your question there. One of them has to do with communication which is super interesting and we’ll get to that in a sec.  The other is whether we already have AGI, but we just haven’t noticed it.There I beg to differ, right.  I don’t think there’s anything in any cellular automaton or anything in the Internet itself or whatever that has artificial general intelligence and that it can really do exactly everything we humans can do better. I think the day that happens, when that happens, we will very soon notice and will probably notice even before because in a very very big way. But for the for the second part though,

LF –  Wait, can I ask, sorry? So, because you have this beautiful way of formulating consciousness as  you know as information processing and you can think of intelligence and information processing and as you can think of the entire universe is these particles and these systems roaming around that have this information processing power. You don’t  think there is something with the power to process information in the way that we human beings do that’s out there, that needs to be sort of connected to. It seems a little bit philosophical perhaps, but there’s something compelling to the idea that the power is already there which is the focus should be more on being able to communicate with it.

MT –  Well, I agree that in a certain sense the hardware processing power is already out there because our universe itself, you can think of it as being a computer already right? It’s constantly computing what water waves, how it devolved the water waves in the river Charles and how to move the air molecules around.  Seth Lloyd has pointed out (my colleague here) that you can even in a very rigorous way think of our entire universe as just being a quantum computer. It’s pretty clear that our universe supports this amazing processing power. Because you can even within this physics computer that we live in, right, we can even build actual laptops and stuff. So clearly the power is there, it’s just that most of the compute power that nature has, it’s in my opinion, kind of wasting on boring stuff like simulating yet another ocean waves somewhere. We don’t want to even looking right? So, in a sense, what life does, what we are doing when we build computers is we’re re-channeling all this compute that nature is doing anyway into doing things that are more interesting just yet another ocean wave, you know, and let’s do something cool here. So the raw hardware power is there and for sure, and even just like computing what’s going to happen for the next five seconds in this water bottle, you know, it takes a ridiculous amount of compute if you do it on a human computer, this water bottle just did it. But that does not mean that this water bottle has AGI because AGI  means, it should also be able to have written my book, done this interview and I don’t think it’s just communication problems.

LF – As far as we know.

MT –  I don’t  think it can do it and…

LF –  Although Buddhists say when they watch the water and that there is some beauty, that there’s some depth and being in nature that they can communicate with.

MT –  Communication is also very important because I mean look  part of my job is being a teacher and I know some very intelligent professors even, who just have a bit of a hard time communicating all these brilliant ideas. But to communicate with somebody else you have to also be able to simulate their own mind.

LF –  Yes, empathy.

MT –  build well enough and understand a model of their mind that you can say things that they will understand. That’s quite difficult. Right? That’s why today it’s so frustrating if if you have a computer that make some cancer diagnosis and you ask it well why are you saying I should have the surgery and if it can only reply: {MT speaking in a machine voice} I was trained on five terabytes of data and this is my diagnosis, boop boop beep beep.

LF – Yeah.

MT – It  doesn’t really instill a lot of confidence, right? So I think we have a lot of work to do on communication there.

LF –  So what kind of …. I think you’re doing a little bit work on explainable AI,  what do you think are the most promising avenues? Iis it mostly about sort of the Alexa problem of natural language processing,  of being able to actually use human interpretable methods of communication? So being able to talk to a system and talk back to you or is there some more fundamental problems to be solved? 

MT –  I think it’s all of the above.  The natural language processing is obviously important but they’re also more nerdy fundamental problems, like if you take… you play chess? 

LF – Of course, I’m Russian, I have to.

MT – Ты говоришь по-русски? {You speak Russian?}

LF – Да по русски говорю  {Yes, I speak Russian}

MT – Отлично, я не знал. 
{Excellent, I didn’t know. }

LF – When did you learn Russian? 

MT – Я говорю очень плохо по-русски.Купил книгу, “Teach Yourself Russian” читaл очень много . Было очень трудно. я говорю так плохо. 

{I speak very bad Russian.Bought a book“ Teach Yourself Russian”, read a lot. It was very difficult. I talk so bad}

LF – How many languages do you know? Wow, that’s really impressive.

MT –  I don’t know, my wife has some calculations, but my point was if you play chess, like have you looked at the Alpha Zero games? 

LF –  Uh, the actual games no.

MT –  Check it out, some of them are just mind blowing. Really beautiful and if you ask, how did it do that? Yeah, you got to talk to them, Demis Hassabis and others from DeepMind. All they will ultimately be able to give you is big tables of numbers, matrices that defined the neural network and you can stare at these tables, numbers until your face turns blue and you’re not going to understand much about why it made that move and  even if you have a natural language processing that can tell you in human language about 5,7,0.28 it’s still not gonna really help. 

So I think I think there’s a whole spectrum of fun challenges there involved in taking a computation that does intelligent things and transforming into something equally good, equally intelligent, but it’s more understandable and I think that’s really valuable because I think as we put machines in charge of ever more infrastructure in our world, the power grid, trading on the stock market, weapons systems and so on, it’s absolutely crucial that we can trust these AIs to do all we want and trust really comes from understanding…

LF – Right.

MT – …  in a very fundamental way. And that’s why I’m, that’s why I’m working on this. Because I think the more …  if we’re gonna have some hope of ensuring that machines have adopted our goals and that they’re going to retain them, that kind of trust, I think needs to be based on things you can actually understand perfectly, even make perfectly improved theorems on even with a self-driving car, right. If someone just tells you it’s been trained on tons of data and never crashed, it’s less reassuring than if someone actually has a proof, maybe it’s a computer verified proof. But still, it says that under no circumstances is this car just gonna swerve into oncoming traffic

LF –  And that kind of information helps to build trust and help build the alignment, the alignment of goals. At least, awareness that your goals, your values are aligned.

MT –  And I think even a very short term, if you look at uh, you know today, right, that’s an absolutely pathetic state of cybersecurity that we have, right, when it was three billion Yahoo accounts were hacked? Almost every American’s credit card and so on. You know, why is this happening? It’s ultimately happening because we have software that nobody fully understood how it worked. That’s why the bugs hadn’t been found, right? And  I think AI can be used very effectively for offense, for hacking, but it can also be used for defense, hopefully automating verifiability and creating systems that are built in different ways. So you can actually prove things about them

LF – Right.

MT –  and it’s important.

LF – So speaking of software that nobody understands how it works, of course, a bunch of people ask about your paper about your thoughts of why does deep and cheap learning works so well, that’s the paper. But what are your thoughts on deep learning, these kind of simplified models of our own brains have been able to do some successful perception work, pattern recognition work and now with alpha zero and so on, do some clever things. What are your thoughts about the promised limitations of this piece?

MT –  00:59:43

Great. I think there are a number of very important insights, very important lessons. We can always draw from these kind of successes. One of them is when you look at the human brain and you see it’s very complicated, 10 to the 11th {10^11}  neurons and there are all these different kinds of neurons and Yada Yada. And there’s been this long debate about whether the fact that we have dozens of different kinds is actually necessary for intelligence. Which I now, in think quite convincingly answer that question: No, it’s enough to have just one kind if you look under the hood of Alpha Zero, there’s only one kind of neuron and it’s a ridiculously simple mathematical thing. So it’s not… it’s  just like in physics, if you have a gas with waves in it, it’s not the detailed nature of the molecules that matter, it’s the collective behavior somehow. Similarly, it’s this higher level structure of the network matters; not that you have 20 kinds of yours. I think our brain is such a complicated mess because it wasn’t evolved just to be intelligent, it was evolved to also be self-assembling…  

LF – right.

MT – … and self-repairing, right? And evolutionarily attainable

LF –  and {unitelligible } and so on.

MT –  So I think it’s pretty my hunch is that we’re going to understand how to build AGI before we fully understand how our brains work, just like we understood how to build flying machines long before we were able to build a mechanical work bird.

LF –  Yeah, that’s right. You’ve given that example exactly of mechanical birds and airplanes and airplanes do a pretty good job of flying without really mimicking bird flight.

MT –  And even now,  100 years later, did you see TED talk with the German mechanical bird?

LF – I heard you mention it.

MT – Check it out, it’s amazing. But even after that we still don’t fly in mechanical birds because it turned out the way we came up with is simpler. It’s better for our purposes and I think it might be the same there. That’s one lesson.  

Another lesson is one that our paper was about;  well, first I as a physicist thought it was fascinating how there is a very close mathematical relationship actually between our artificial neural networks and a lot of things that we’ve studied for in physics, they go buy nerdy names like the renormalization group equation and Hamiltonians and yada, yada, yada. And when you look a little more closely at this, you have…at first I was like, whoa, there’s something crazy here that doesn’t make sense because we know that if you even want to build a super simple neural network to tell apart cat pictures and dog pictures, right? That you can do that very, very well now.

But if you think about it a little bit, you convince yourself it must be impossible because if I have one megapixel, even if each pixel is just black or white, there’s two to the power one million possible images which is way more than there are atoms in our universe.  So in order to ….I have to assign a number which is the probability that it’s a dog. So an arbitrary function of images is a list of more numbers than there are atoms in our universe. So clearly I can’t store that under the hood of my GPU or my computer yet somehow works. So what does that mean? Well it means that out of all of the problems that you could try to solve with a neural network, Almost all of them are impossible to solve with a reasonably sized one. But then what we showed in our paper was that the fraction of all the problems that you could possibly pose that we actually care about given the laws of physics is also an infinitesimally tiny little part and amazingly they are basically the same part.

LF –  Yeah. It’s almost like the world was created for…  I mean they kind of come together.

MT –  Yeah, you could say maybe where the world was created for us. But I have a more modest interpretation which is that instead evolution endowed us with neural networks precisely for that reason because this particular architecture {gesturing to his head} as opposed to the one in your laptop is very very well adapted to solving the kind of problems that nature kept presenting it our ancestors with, right. So it makes sense why do we have a brain in the first place? It’s to be able to make predictions about the future and so on. So if we had a sucky system which I could never solve it. But I would never have worked. But so this is I think a very beautiful fact. Yeah. We also realize that there is  there’s been earlier work on why deeper networks are good. But we were able to show an additional cool fact there which is that even incredibly simple problems like suppose I  give you a 1000 numbers and ask you to multiply them together and you can write a few lines of code. Boom, done, trivial. If you just try to do that with a neural network that has only one single hidden layer in it, you can do it but you’re gonna need two to the power of 1000 neurons to multiply 1000 numbers which is again more neurons than there are atoms in our universe. 

LF – That’s fascinating.

MT – But if you allow yourself to make it a deep network of many layers you only need 4000 neurons, it’s perfectly feasible. So…. 

LF –  That’s really interesting. Yeah. So on another architecture type I mean you mentioned Schrodinger’s equation and what are your thoughts about quantum computing and the role of this kind of computational unit in creating an intelligence system?

MT –  in some Hollywood movies that I will not mention my name. I don’t want to spoil them,  the way they get AGI Is building a quantum computer because the word quantum sounds cool and so on.

LF – That’s right.

MT – First of all I think we don’t need quantum computers to build AGI. I suspect your brain is not a quantum computer and in any found sense. I even wrote a paper about that many years ago. I calculated the so called decoherence time; how long it takes until the quantum computerness of what your neuron is doing gets erased by just random noise from the environment and it’s about 10 to the -21 seconds. So as cool as it would be to have a quantum computer in my head. I don’t think that fast. 

On the other hand there are very cool things you could do with quantum computers or I think we’ll be able to do soon when we get bigger ones that might actually help machine learning do even better than the brain. So for example, this is just a Moonshot but okay  you know that learning, it’s very much the same thing as a search. If you have, if you’re trying to train a neural network to get really learned to do something really well, you have some loss function. You have some you have a bunch of knobs you can turn well which are represented by a bunch of numbers and you’re trying to tweak them so that it becomes as good as possible at this thing. So if you think of the landscape but with some valley where each dimension of the landscape corresponds to some number you can change,  you’re trying to find the minimum and it’s well known that if you have a very high dimensional landscape, complicated things? It’s super hard to find the minimum, right? 

Quantum mechanics is amazingly good at this. If I want to know what’s the lowest energy state this water can possibly have; incredibly hard to compute. But nature will happily figure this out for you if you just cool it down, make it very, very cold. If you put a ball somewhere, it’ll roll down to its minimum. And this happens metaphorically, the energy landscape too. And quantum mechanics even uses some clever tricks which today’s machine learning systems don’t. Like you’re trying to find the minimum and you get stuck in the little local minimum here in quantum mechanics who can actually tunnel through the barrier and get unstuck again? 

LF –  That’s really interesting.

MT -So it may be, for example, we will one day use quantum computers that help train neural networks better?

LF –  That’s really interesting. Okay, so as a component of kind of the learning process, for example.

MT –  Yeah.

LF –  Let me ask , sort of wrapping up here a little bit. Let me return to  the questions of our human nature and love, as I mentioned. So do you think  …. you mentioned sort of a helper robot that you can think also of  robots. Do you think the way we human beings fall in love and get connected to each other. It’s possible to achieve in an AI system, in human level AI intelligence system? Do you think we would ever see that kind of connection or  you know, in all this discussion about solving complex goals as this kind of human social connection, do you think that’s one of the goals on the peaks and valleys that with the raising sea levels that would be able to achieve? Or do you think that’s something that’s ultimately, or at least in the short term, relative to the other goals is not achievable? 

MT –  I think it’s all possible. And I mean, in recent ….there’s a there’s a very wide range of distances, you know, among AI researchers when we’re going to get AGI. Some people, you know, like our friend Rodney Brooks says it’s going to be hundreds, hundreds of years at least. And then there are many others. I think it’s gonna happen much sooner in recent polls, maybe a half or so of AI researchers think we’re going to get AGI  within decades.  So if that happens, of course, I think these things are all possible, but in terms of whether it will happen, I think we shouldn’t spend so much time asking what do we think will happen in the future as if we are just some sort of pathetic passive bystanders, you know, waiting for the future to happen to us? Hey, we’re the ones creating this future, Right, So we should be proactive about it and ask yourself what sort of future we would like to have happen that’s going to make it like that. 

Well, what I prefer to some sort of incredibly boring zombie-like future where just all these mechanical things happen and there’s no passion, no emotion, no experience, maybe even. No, I would of course much rather prefer if all the things that we find that we value the most about humanity, our subjective experience, passion, inspiration, you love. You know, if we can create a future where those are where those things do exist, I think ultimately it’s not our universe giving meaning to us, it’s us giving meaning to our universe If we build more advanced intelligence, let’s let’s make sure building in such a way that meaning is it’s part of it. 

LF –  A lot of people that seriously study this problem and think of it from different angles have trouble, the majority of cases if they think through that happen are the ones that are not beneficial to humanity. And so yeah, so what are your thoughts, What’s in and what’s, what should people, you know, I really don’t like people to be terrified.  What’s a way for people to think about it in a way that in a way we can solve it and we can make it better. 

MT –  But no, I don’t think panicking is gonna help in any way. It’s not going to increase chances of things going well either. Even if you are in a situation where there is a real threat, does it help if everybody just freaks out? No, of course, of course not.  I think, yeah, there are of course ways in which things can go horribly wrong.  

First of all, it’s important when we think about this thing, about the problems and risks to also remember how huge the upsides can be if we get it right, right? Everything we love about society and civilization is a product of intelligence. So if we can amplify our intelligence with machine intelligence and not anymore lose our loved ones, to what we’re told in an incurable disease and things like this, of course we should aspire to that. So that can be a motivator, I think, reminding ourselves that the reason we try to solve problems is not just because right, trying to avoid doom, but because we’re trying to do something great. But then in terms of the risks, I think the really important question is to ask: what can we do today that will actually help make the outcome good, right?

LF – Yes.

MT – And  dismissing the risk is not one of them. You know, I find it quite funny often when I’m in on discussion panels about these things, how the people who I work for for companies will always be like: “Oh, nothing to worry about, nothing to worry about, nothing to worry about.” And it’s always,  it’s only academics sometimes expressing concerns. That’s not surprising at all. If you think about it, Upton Sinclair quipped that: ”It’s hard to make your man believe in something when his income depends on not believing in it.”  { Actual quote is:  “It is difficult to get a man to understand something when his salary depends upon his not understanding it.”  book “I, Candidate for Governor: And How I Got Licked,” by Upton Sinclair, 1935 }

And frankly, we know a lot of these people and companies that they are just as concerned as anyone else. But if you’re the CEO of a company, that’s not something you want to go on record saying,  when you have silly journalists who are going to put a picture of a Terminator robot when they quote you. 

So, the issues are real, and the way I the way I think about what the issue is is basically, you know, the real choice we have is first of all are we going to just dismiss this the risks and say, well, let’s just go ahead and build machines that can do everything we can do better and cheaper. You know, let’s just make yourselves obsolete as fast as possible. What could possibly go wrong? That’s one attitude.

The opposite attitude I think, is to say there is incredible potential. You know, let’s think about what kind of future we’re really, really excited about. What are the shared goals that we can really aspire towards. And then let’s think really hard on how about how we can actually get there. So start with, don’t start thinking about the risks. Start thinking about the goals and then when you do that, then you can think about the obstacles you want to avoid, right? I often get students coming in right here into my office for career advice, I always ask them this very question, where do you want to be in the future? If all she can say as well, maybe I’ll have cancer, maybe I’ll get run over by a truck.

LF – Focus on obstacles instead of the goal

MT –  She’s just going to end up a hypochondriac paranoid, whereas if she comes in with fire in her eyes and it’s like I want to be there and then we can talk about the obstacles and see how we can circumvent them. That’s, I think, a much healthier attitude.

LF – That’s really well put. 

MT – And  I feel it’s very challenging to come up with a vision for the future which we are unequivocally excited about. I’m not just talking now in vague terms like, yeah, let’s cure cancer. Fine. Talking about what kind of society do we want to create, what do we want it to mean to be human in the age of AI,  in the age of AGI. So if we can have this conversation,  broad inclusive conversation and gradually start converging towards some future that with some direction at least that we want to steer towards right then then we will be much more motivated to constructively take on the obstacles and I think if I if I had to, if I try to wrap this up in a more succinct way, I think, I think we can all agree already now that we should aspire to build AGI but doesn’t overpower us, but that empowers us.

LF –  And think of the many various ways that can do that, whether that’s from my side of the world of autonomous vehicles, I I’m personally actually from the camp that believes that human level intelligence is required to to achieve something like vehicles that would actually be something we would enjoy using and being part of. So that’s one example and certainly there’s a lot of other types of robots and medicine and so on. So focusing on those and then and then coming up with the obstacles, coming up with the ways that that can go wrong and solving those one at a time. 

MT –  And just because you can build an autonomous vehicle, even if you could build one that would drive just fine without, you know, maybe there are some things in life that we would actually want to do ourselves

LF – That’s right, 

MT – Like for example, if you think of our society as a whole, there’s something that we find very meaningful to do and that doesn’t mean we have to stop doing them just because machines can do them better. You know, I’m not gonna stop playing tennis the day someone build a tennis torobot beat me.

LF –  People are still playing chess and even Go

MT –  Yeah, and in the very near term, even some people are advocating basic income, replacing jobs, but if you if the government is going to be willing to just hand out cash to people for doing nothing, then one should also seriously consider whether the government should also hire a lot more teachers and nurses and the kind of jobs which people often find great fulfillment in doing right. I  get very tired of hearing politicians saying: “Oh we can’t afford hiring more teachers, but we’re going to maybe have basic income.” If we can have more serious research and thought into what gives meaning to our lives and the jobs give so much more than income, right? And then think about, in the future …. What are the roles that we want to have people continue doing empowered by machines?

LF – And I think sort of ….  I come from Russia, from the Soviet Union and I think for a lot of people in the 20th century, going to the moon, going to space was an inspiring thing. I feel like the universe of the mind, so AI, understanding and creating intelligence is that for the 21st century. So it’s really surprising and I’ve heard you mention this, it’s really surprising to me both in the research funding side that it’s not funded as greatly as it could be, but most importantly, on the politician’s side that it’s not part of the public discourse except in the killer bots/Terminator kind of view that people are not yet. I think perhaps excited by the possible positive future that we can build together, so …

MT –  And we should be because politicians usually just focus on the next election cycle, right? The single most important thing I feel we humans have learned in the entire history of science is that we are the masters of underestimation, we underestimated the size of our cosmos again and again, realizing that everything we thought existed, there’s just a small part of something grander, right?  Planet, solar system, a galaxy, you know, clusters of galaxies, universe and we now know that … the future has just so much more potential than our ancestors could ever have dreamt of this cosmos.

 Imagine if all of earth was completely devoid of life except for Cambridge Massachusetts. Wouldn’t it be kind of lame if all we ever aspired to was to stay in Cambridge Massachusetts forever and then go extinct in one week even though earth was going to continue on for longer, that sort of attitudeI think we have now. On the cosmic scale we can, life can flourish on earth, not for four years, but for billions of years. I can even tell you about how to move it out of harm’s way when the sun gets too hot. And then we have so much more resources out here, which today maybe there are a lot of other planets with bacteria or cow-like life on them. But most of this,  all this opportunity seems as far as we can tell to be largely dead, like the Sahara desert. And yet we have the opportunity to help life flourish like this for billions of years. So like, let’s quit squabbling about when some little border should be drawn one mile to the left or to the right and look up to the skies. You realize, hey, you know, we can do such incredible things.

LF –  Yeah. And that’s I think why it’s really exciting that yeah, you and others are connected with some of the work Elon Musk is doing because he’s literally going out into that space, really exploring our universe. And it’s wonderful.

MT –  That is exactly why Elon Musk is so misunderstood, right? Misconstrue him as some kind of pessimistic doomsayer. The reason he cares so much about AI safety is because he more than almost anyone else appreciates these amazing opportunities that we’ll squander if we wipe out here on Earth. We’re not just going to wipe out the next generation but all generations. And this incredible opportunity that’s out there and that would really be a waste. An AI, for people who think that we would be better to do without technology; well, let me just mention that if we don’t improve our technology, the question isn’t whether humanity is going to go extinct. The question is just whether we’re gonna get taken out by the next big asteroid or the next super volcano or something else dumb, that we could easily prevent with more tech, right? And if we want life to flourish throughout the cosmos, AI is the key to it. Yeah. As I mentioned, a lot of detail in my book right there, even many of the most inspired sci-fi writers, I feel have totally underestimated the opportunities for space travel, especially to other galaxies, because they weren’t thinking about the possibility of AGI. I’ve, which just makes it so much easier,

LF –  Right? Yeah. So that goes to your view of AGI that enables our progress, that enables a better life. So that’s a beautiful way to put it and something to strive for. So Max, thank you so much. Thank you for your time today, it has been awesome.

MT  Thank you so much. спасибо большое. Молодец {Well done}

Lessons learned from Lex and Nathalie Cabrol (Lex Fridman Podcast #348)

Lessons learned from Lex and Nathalie Cabrol (Lex Fridman Podcast #348)

I’ve been watching Lex Fridman’s podcasts in 2023; they are a good source of learning. Lex interviewed Nathalie Cabrol [1] on 19 December 2022; these are my lessons learned.

What is Life? Where did Life come from?

Nathalie works in astrobiology, her life has been studying life on Earth and developing methods to look for signatures of life in our solar system. She noted there are something like 123 definitions of life. Here are snippets of Nathalie’s answer to the Schrodinger question of What is Life?:

  • “Preserving information is what life does … 
  • “… .the nature of life is really what is going to give you some universal signature to look for it all over the place ….”
  • “…. the nature of life is telling you that life wants to get the most information possible around its surroundings and complexities, in fact the ability to gather and exchange and preserve the most information possible.” 
  •  …. the nature of life is different, If really life is the best way the universe has to fight entropy there’s no bias there because physics is the same all across the universe at least the universe we know they might be other universes but the one we know works with the same physics. {This snippet came ten minutes after the others}

My own view of what is Life, derived from Nathalie’s answer is: life is the ability to gather, exchange, and preserve maximum information.  Very interesting, this answer is not dependent on a CHONPS [2] form of carbon-based life. She also mentioned  life as best way to fight entropy and cited the work of Jeremy England.[3]

A bit later in the interview, Nathalie used a beautiful language analogy to describe life:

[20:52] … languages and they can be very different languages but they all have the same purpose: exchange information, understand, store information and also whether it is with somebody at the outside or thought in yourself; that’s the same thing the cell was doing. 

But now when you’re looking at life and at the structure of our languages life started with an atom so it’s an atom.  They get together to create inorganic molecules then you have complex inorganic molecules. Then you get to organic molecules, complex organic molecules and then you have RNA, DNA etc.  Look at the structure of the language. We created alphabets,  letters, that’s your atom.  Then we put them together to create syllables. The syllables get together to create the words. Words tell you something but they are nothing without the verb that gives the direction that’s RNA and DNA and then you can put all the compliments you want. Our languages are built exactly as life is built. We are repeating patterns.  I call this the Mandelbrot universe and the fractal universe because this is exactly what it is. I would say that as much as I do believe in sending probes to explore the universe I say we should also look inward to find the answers to some of the profound questions of who we are, what’s life, what’s the nature of life because we are expressing life …..

I am more interested in that because the day we understand the nature of life then we have a universal biosignature. It doesn’t matter whether this life responds to the same kind of biochemical processes as we do, although it makes sense. I told you about the generational aspect of the bricks of life: the stuff we are made of the sun is part of the youngest generation of stars and the first two generational stars didn’t produce the kind of elements we are made. [4][5]

The idea that we are repeating patterns built up at multiple levels, like a human language,  really grabbed my attention.  “Our languages are built exactly as life is built. We are repeating patterns.  I call this the Mandelbrot universe and the fractal universe…”  I think we are truly living in something like a fractal universe. I hadn’t heard such an analogy before. [6] 

In a similar vein, it makes sense to me that “the day we understand the nature of life then we have a universal biosignature” because then we have a signal to search for.  But if life is information based, then the signatures may not be biosignatures alone. There could be other technical signatures based on physics rather than biology .[7]

Complexity

LF – Do we know what complexity is?

NP – in my mind the universe is connected everywhere in all different places so this life connection is something that as you said permeates the universe and the way to find life might be very different than to look for the origins of life 

What I think would be our greatest achievement is that if we can find that process of life because at that point in my mind the universe all of a sudden is going to illuminate itself with actually its  living force, what I can only call a living force to me. This is what we are looking at,  the universe that becomes more and more complex with time, more and more able to gather information and interestingly enough why: to understand itself.  So Sagan was right when he was saying: we are the universe trying to understand itself. [8] And  the more we go, the more the universe becomes alive, maybe intelligent, and maybe also conscious.

Nathalie’s answer made me think of panpsychism [9] – the idea that mind is pervasive in the universe. Another way I think of this is that information processing (a definition of life) is ubiquitous.  When she says: “…. universe that becomes more and more complex with time, more and more able to gather information and interestingly enough why: to understand itself.”; that’s the universe being alive. A bit later she says: “… the more the universe becomes alive, maybe intelligent, and maybe also conscious.” I think this description maps to panpsychism, at least from my shallow knowledge of philosophy. 

 Fermi Paradox

The physicist Enrico Fermi asked: “But where is everybody?” What he was asking was why don’t we see sins of intelligent extraterrestrial life in the Universe. The discussion between Lex (LF) and Nathalie (NC) is illuminating. I have wondered about the same question often, especially when sitting out on a star-filled night. 

[51:26] LF – Everything I’ve seen from life it seems obvious that there’s life everywhere out there in fact maybe I don’t understand the jump from bacteria enough but it seems obvious that there are intelligent civilizations out there now I don’t know how to define intelligence but there’s beautiful complexity. I’ve looked at enough cellular automata which is a very primitive mathematical construction that when you run complexity emerges. I’ve looked at that enough to know that just seems like there’s complexity everywhere out there 

So, I think that’s why I’m deeply puzzled by  the Fermi paradox. It makes no sense to me. I mean I have trivial answers to it: why haven’t aliens at scale not shown up.  I think of  two possible options for me. Either we’re too dumb to see it, they’re already here; they have been talking to us through processes we just don’t understand. what we experience as life here on earth is actually they are everywhere.  Aliens could be consciousness; that when we feel love for one another that could be aliens. When we feel fear or whatever, that could be aliens.

NC – I have to agree with you none of this is scientifically provable right now. We talk a little bit  already about that but I would say that I do not adhere to the Fermi paradox because it’s very anthropomorphic.  It’s an interesting exercise, let’s put it that way but it’s a typical example of seeing the universe through our own eyes. And this is what the limitation is: understanding what’s going on with complexity as you said and looking at the biophysical model and theories for the nature of life. I would agree that probably this extraterrestrial message is all around us. We’re not yet capable of picking it up.

[54:10] Look at the shadow biosphere [11],  the idea that life didn’t appear only once on Earth but there were many different pathways of it. And, today we know when we study the tree of life that led us from LUCA [10]  to us and the shadow biosphere is telling us that there is or there are other pathways that came up at the time where life originated but they are so different that we can not recognize them as being the living.  And we cannot pick them up in our tests because our tests are being built to recognize life as we know it And for me again I don’t know if this theory we’ll be verify or it would be discredited but what I like about it is that it forces me to think on how do I look for life, I don’t know. So that starts here on our planet,  not even with the little green men, it starts with very simple life that can be so different that it might be just right in front of our nose and we don’t see it.

I hadn’t known anything about the shadow biosphere. Are there other forms of life on Earth we haven’t detected? What a good question. If I use the definition that life is the ability to gather, exchange, and preserve maximum information; then the laptop I’m typing on is a form of life. In some sense, I think machines are a form of life – they are obligate parasites of humanity. In other words, machines are organisms that cannot complete their life-cycle without exploiting a suitable host, humans. [13]

Life below the surface of Mars –  Be one with the microbe.  

The section about life below the surface of Mars was educational. Nathalie’s perspective makes sense: “to understand where microbes are located on Mars I have to become the microbe.”

LF – you’ve written about the history of life on Mars. You said you have kind of explored that by looking at the lakes here. Do you think there’s been life on Mars? Do you think there is life on Mars?

NP – … unambiguous evidence of life is going to be something interesting to prove because we don’t know what life is….

Ladder of life detection [14], which is that you have a series of rungs that you know you need to go through that actually are not proving you that you discover life but are making the possibility that what you discovered was made only by the environment more and more improbable. So we are trying to prove the contrary.

… if life appeared I would say it’s still there and probably underground where it can be you know in an environment that’s more stable 

 [1:51] You have to sit and look and listen, basically the story of my life: if I want to understand where microbes are located on Mars I have to become the microbe, this is a thought experiment. And if I want to understand where ET is, then I have to become ET. So,  it’s a big stretch but in an extreme environment you sit in the desert for a while and you just you know try to understand where the winds are coming from, where the humidity is, when it’s showing up and then you start to understand the patterns of those things.

LF – what are the useful signals the need for survival?

NC – You need to know where water is,  what the source of energy is going to be drawn from,  you need to find shelters and shelters don’t mean that…  For instance,  you can have a water column of a lake or a river or whatnot or the ocean. It can be also a very thin layer of dust or it can be a translucent rock. And you see what we call endolith, these are the same cyanobacteria but the different versions of them live inside those rocks, inside those crystals because they have the best of life. They are into translucent crystals so that they receive the light from the sun,  they can do the photosynthesis but there is enough of that crystals so that the nasty UV is being stopped. And they are in their little house. When you are looking at temperature within those rocks they tend to make it toastier [warmer] than the outside temperature.

The endolithic lichen [15] is a hardy  version of biological life on Earth. Life needs water, energy, and shelter. It makes sense that some biological life like  endolithic lichen might exist elsewhere in the solar system.  

Life, Love and the Future

The love for each other and for life was very apparent in the interview.  I highlighted a couple of key points. 

NC – my husband {Edmond Grin} and I were forty four years apart in age and it was just a pure love story. And he never looked at his age, never felt about himself or defined himself by his age. In fact, he reinvented life for himself at an age where everybody retires. We met when he was sixty six and that was a blessing and a curse but a blessing most of it because we took every single day as if it was the last. So we enjoyed life. 

… You know I have to really think of him, he just passed away last August. And for me it’s more like I have to draw from his example on[ of him always telling me: look forward. Trust life. Be happy. Live. You know today, every single day, I have to remind several times a day of this , it’s not easy but he had the recipe. He never thought about death because when you start thinking too much about death that prevents you from living.

LF – what’s the role of love in the human condition?

NC – I think I hope that this is the force that drives the universe though you know we might be experiencing the other side of it maybe just to learn how important love is. 

….

I would hope for humanity to reach that point where you can feel the same love for the person that is unknown in the street that you feel for the people you love. I think that at that point we are going to be reaching the maturity of that civilization we’re hoping for and seeing the universe through love. That doesn’t run spacecrafts of course but putting love into our intent of going into and settling into another planet instead of “Oh my god, we need to escape because we are freeing, messing up with our own planet.” I think that this is the answer to so many things

NC – …. as the dominant species at least you know technologically etcetera, maybe not the wisest one, but the dominant species. We have a responsibility to watch the entire biosphere because the decisions we’re making now not only affect us; they’re affecting the entire biosphere. And right now the choices we are making are leading to the disappearance of a hundred and fifty species every single day. All the big mammals on this earth today are on the brink of extinction. We are within the sixth greatest mass extinction; it’s unfolding before our eyes. And, I would strongly suggest that we use our smart to help a little bit this situation and we can do this. I think we can do this, we just need to redirect our energy.

Closing Quote

LF –  let me leave you some words from Stanislaw Lem in Solaris: how do you expect to communicate with the ocean when we can’t even understand one another?

Summary

I’ve rambled on quite a bit. I haven’t touched on the remarkable research and adventure of Nathalie and her team exploring life in high volcanic lakes [17]. It’s worth listening to this in the interview. Overall, Nathale and Lex covered a lot of ground on just what life might be. 

The most important lessons I learned from Nathalie and Lex in this interview:

  • life wants to get the most information possible around its surroundings and complexities, in fact the ability to gather and exchange and preserve the most information possible.”
    • My own view of what is Life, derived from Nathalie’s answer is: life is the ability to gather, exchange, and preserve maximum information.
  • Our languages are built exactly as life is built. We are repeating patterns.  I call this the Mandelbrot universe and the fractal universe…” 
  • …. the universe that becomes more and more complex with time, more and more able to gather information and interestingly enough why: to understand itself. …. .. the more the universe becomes alive, maybe intelligent, and maybe also conscious.” 
  • …. shadow biosphere is telling us that there is or there are other pathways that came up at the time where life originated but they are so different that we can not recognize them as being the living.
    • Made me think perhaps machines are a form of life – they are obligate parasites of humanity
  •  “… when you start thinking too much about death that prevents you from living.”

I had a quick look at Nathalie’s papers in Google Scholar. I read a bit of the 1999 paper that she wrote with her husband: Distribution, classification, and ages of Martian impact crater lakes. She talked about this, it helped drive the landing site for the Spirit Martian Rover.  Here’s the conclusion:

“These results also confirm that ancient lakes in impact craters are important sites to study on Mars. They collected the record of the climatic and hydrogeologic changes on Mars. They were the receptacle of sedimentary rocks from which critical information about weathering, chemical, and physical processes on Mars could be learned. They might as well be among the most promising sites for the search for life and/or precursors of life on Mars. Lacustrine deposits are well known to be favorable environments for the preservation of life (extant and/or extinct). Lakes provide the best conditions for fossilization processes. The absence of crustal recycling on Mars opens up the possibility that fossilized life forms could be exposed right at the surface of the crater floors. The dataset resulting from this study is aimed at providing information to help identify the potential best candidates.”

I also saw a current research project that Nathalie is associated with, summarized in the paper:

“Orbit-to-ground framework to decode and predict biosignature patterns in terrestrial analogues”  I should give this paper a read and see what I can decipher – and learn. It’s interesting to glean that the team used artificial intelligence methods to look for biosignatures in Chile as a surrogate for Mars. [17] 

Notes

[1] Nathalie Cabrol: Search for Alien Life | Lex Fridman Podcast #348

https://www.youtube.com/watch?v=yyBosLx7bbM Watched in January 2023

[2] CHONPS carbon, hydrogen, oxygen, nitrogen, phosphorus, sulfur: the main elements that occur naturally in carbon-based living systems on Earth. https://en.wiktionary.org/wiki/CHONPS 

Accessed 9 April 2023

[3] Jeremy England has a YouTube video explaining his work 

How Thermodynamics Explains the Origins of Living Things and is the author of a 2020 book: Every Life Is on Fire: How Thermodynamics Explains the Origins of Living Things

[4] I did some editing of this section, I hope I did not alter the intent of what Nathalie said. 

[5] One example is the iron atoms in our hemoglobin, I remember thinking about this in biochemistry class. The origin of iron:

“Stars fuse light elements to heavier ones in their cores, giving off energy in the process known as stellar nucleosynthesis. Nuclear fusion reactions create many of the lighter elements, up to and including iron and nickel in the most massive stars. Products of stellar nucleosynthesis remain trapped in stellar cores and remnants except if ejected through stellar winds and explosions. ” https://en.wikipedia.org/wiki/Nucleosynthesis Accessed 9 April 2023

 Or as I remember Carl Sagan explaining in Cosmos:  “we are star stuff.”

[6] John 1:1 KJV: In the beginning was the Word, and the Word was with God, and the Word was God. https://www.kingjamesbibleonline.org/John-1-1/  Accessed 9 April 2023

[7] Technical signatures are discussed in David Kipping: Alien Civilizations and Habitable Worlds | Lex Fridman Podcast #355 https://www.youtube.com/watch?v=uZN5xjoS6TU 

[8] “The cosmos is within us. We are made of star-stuff. We are a way for the universe to know itself.” as stated by Carl Sagan in Cosmos: A Personal Voyage, Ep. 1

[9] “In the philosophy of mind, panpsychism  is the view that the mind or a mindlike aspect is a fundamental and ubiquitous feature of reality. https://en.wikipedia.org/wiki/Panpsychism Accessed 9 April 2023Accessed 9 April 2023

[10] Fermi paradox https://en.wikipedia.org/wiki/Fermi_paradox 

[11] What is  last universal common ancestor (LUCA)?

“The last universal common ancestor (LUCA) is an inferred evolutionary intermediate that links the abiotic phase of Earth’s history with the first traces of microbial life in rocks that are 3.8–3.5 billion years of age. Although LUCA was long considered the common ancestor of bacteria, archaea [a] and eukaryotes newer two-domain trees of life have eukaryotes arising from prokaryotes,making LUCA the common ancestor of bacteria and archaea. Previous genomic investigations of LUCA’s gene content have focused on genes that are universally present across genomes, revealing that LUCA had 30–100 proteins for ribosomes and translation. In principle, genes present in one archaeon and one bacterium might trace to LUCA, although their phylogenetic distribution could also be the result of post-LUCA gene origin and interdomain lateral gene transfer (LGT), given that thousands of such gene transfers between prokaryotic domains have been detected.”

Weiss MC, Sousa FL, Mrnjavac N, Neukirchen S, Roettger M, Nelson-Sathi S, Martin WF. The physiology and habitat of the last universal common ancestor. Nat Microbiol. 2016 Jul 25;1(9):16116. doi: 10.1038/nmicrobiol.2016.116. PMID: 27562259  . PAYWALL 

“All known life forms trace back to a last universal common ancestor (LUCA) that witnessed the onset of Darwinian evolution. One can ask questions about LUCA in various ways, the most common way being to look for traits that are common to all cells, like ribosomes or the genetic code. With the availability of genomes, we can, however, also ask what genes are ancient by virtue of their phylogeny rather than by virtue of being universal. That approach, undertaken recently, leads to a different view of LUCA than we have had in the past, one that fits well with the harsh geochemical setting of early Earth and resembles the biology of prokaryotes that today inhabit the Earth’s crust.”

Weiss MC, Preiner M, Xavier JC, Zimorski V, Martin WF (2018) The last universal common ancestor between ancient Earth chemistry and the onset of genetics. PLoS Genet 14(8): e1007518. https://doi.org/10.1371/journal.pgen.1007518

https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1007518

[a]  Carl Woese is famous for defining the Archaea (a new domain of life) in 1977 through a pioneering phylogenetic taxonomy of 16S ribosomal RNA, a technique that has revolutionized microbiology. https://en.wikipedia.org/wiki/Carl_Woese  Accessed 9 April 2023

[12] A shadow biosphere is a hypothetical microbial biosphere of Earth that would use radically different biochemical and molecular processes from that of currently known life. Although life on Earth is relatively well studied, if a shadow biosphere exists it may still remain unnoticed, because the exploration of the microbial world targets primarily the biochemistry of the macro-organisms. https://en.wikipedia.org/wiki/Shadow_biosphere Accessed 9 April 2023

[13] I modified a sentence from the Wikipedia article on Obligate parasites: “An obligate parasite or holoparasite is a parasitic organism that cannot complete its life-cycle without exploiting a suitable host. If an obligate parasite cannot obtain a host it will fail to reproduce.”
https://en.wikipedia.org/wiki/Obligate_parasite Accessed 9 April 2023

[14] …. Ladder of Life Detection, a tool intended to guide the design of investigations to detect microbial life within the practical constraints of robotic space missions. To build the Ladder, we have drawn from lessons learned from previous attempts at detecting life and derived criteria for a measurement (or suite of measurements) to constitute convincing evidence for indigenous life. We summarize features of life as we know it, how specific they are to life, and how they can be measured, and sort these features in a general sense based on their likelihood of indicating life.

Neveu M, Hays LE, Voytek MA, New MH, Schulte MD. The Ladder of Life Detection. Astrobiology. 2018 Nov;18(11):1375-1402. doi: 10.1089/ast.2017.1773. Epub 2018 Jun 4. PMID: 29862836; PMCID: PMC6211372. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211372/ 

[15] Here’s a good reference: Alteration of rocks by endolithic organisms is one of the pathways for the beginning of soils on Earth https://www.nature.com/articles/s41598-018-21682-6 

[16] Here’s a link to some info https://highlakes.seti.org/science.html  Accessed 9 April 2023

[17] Warren-Rhodes, K., Cabrol, N.A., Phillips, M. et al. Orbit-to-ground framework to decode and predict biosignature patterns in terrestrial analogues. Nat Astron (2023). https://doi.org/10.1038/s41550-022-01882-x PAYWALL

 I got the reference from a press release https://www.seti.org/press-release/can-artificial-intelligence-help-find-life-mars-or-icy-worlds