Paola Arlotta: Brain Development from Stem Cell to Organoid | Lex Fridman Podcast #32

1. 0:00 – 13:57

   Intro

   1. LFLex Fridman0:00

      The following is a conversation with Paola Arlotta. She's a professor of stem cell and regenerative biology at Harvard University and is interested in understanding the molecular laws that govern the birth, differentiation, and assembly of the human brain's cerebral cortex. She explores the complexity of the brain by studying and engineering elements of how the brain develops. This was a fascinating conversation to me. It's part of the Artificial Intelligence podcast. If you enjoy it, subscribe on YouTube, give it five stars on iTunes, support it on Patreon, or simply connect with me on Twitter at Lex Fridman, spelled F-R-I-D-M-A-N. And I'd like to give a special thank you to Amy Jefferies for her support of the podcast on Patreon. She's an artist and you should definitely check out her Instagram at lovetruthgood. Three beautiful words. Your support means a lot and inspires me to keep this series going. And now here's my conversation with Paola Arlotta. You studied the development of the human brain for many years, so let me ask you an out-of-the-box question first. How likely is it that there's intelligent life out there in the universe outside of Earth with something like the human brain? So I can put it another way, how unlikely is the human brain? How difficult is it to build a thing-

   2. PAPaola Arlotta1:28

      Yeah.

   3. LFLex Fridman1:28

      ... through the evolutionary process?

   4. PAPaola Arlotta1:30

      Well, it has happened here, right? On this planet.

   5. LFLex Fridman1:33

      Once, yes.

   6. PAPaola Arlotta1:34

      Once. (laughs) So that simply tells you that it could, of course, happen again other places. It's only a matter of probability. What the probability that you would get a brain like the ones that we have, like, like the human brain. So how difficult is it to make the human brain? It's pretty difficult, but most importantly, um, I guess we know very little about how this process really happens and there is a reason for that, actually multiple reasons for that. Most of what we know about how the mammalian brain, so the brain of mammals, develop comes from studying in labs other brains, not our own brain. The brain of mice, for example. But if I showed you a picture of a mouse brain and then you put it next to a picture of a human brain, they don't look at all (laughs) like each other. So they're very different and, and therefore there is a limit to what you can learn about how the human brain is made by studying the mouse brain. Um, the re- there is a huge value in studying the mouse brain, there are many things that we have learned, but it's not the same thing.

   7. LFLex Fridman2:46

      So in having studied the human brain or through the mouse and through-

   8. PAPaola Arlotta2:50

      Yeah.

   9. LFLex Fridman2:50

      ... other methodologies that we'll talk about, do you have a sense, I mean, you're one of the experts in the world, how much do you feel you know about the brain and how much, how often do you find yourself in awe of this mysterious thing?

   10. PAPaola Arlotta3:07

       Yeah. You pretty much find yourself in awe all the time. It's an amazing process. It's a process by which, by means that we don't fully understand, at the very beginning of embryogenesis, the structure called the neural tube literally self-assembles and it happens in an embryo and it can happen also from stem cells in a dish. Okay? And then from there, these stem cells that are present within the neural tube give rise to all of the thousands and thousands of different cell types that are present in the brain through time, right? With the interesting, very intriguing, interesting observation is that the time that it takes for the human brain to be made, it's human time. Meaning that for me and you, it took almost nine months of gestation to build a brain and then another 20 years of learning post-natally to get the brain we have today that allows us to do this conversation.

   11. LFLex Fridman4:11

       Yeah.

   12. PAPaola Arlotta4:12

       A mouse takes 20 days or so to-

   13. LFLex Fridman4:16

       So it's mouse time.

   14. PAPaola Arlotta4:17

       ... for an embryo to be born. Um, and so, and, and so the brain is built in a much shorter period of time and the beauty of it is that if you take mouse stem cells and you put them in a culture dish, the brain, the org- the brain organoid that you get from a mouse is formed faster than if you took human stem cells and put them in the dish and let them make a human brain organoid.

   15. LFLex Fridman4:42

       So the very developmental process is, uh...

   16. PAPaola Arlotta4:45

       Controlled by the speed of the species.

   17. LFLex Fridman4:49

       Which means it's, uh, by-

   18. PAPaola Arlotta4:51

       (laughs)

   19. LFLex Fridman4:51

       ... it's on purpose, it's not accidental or, uh, there's something in that temporal dynamic to that development.

   20. PAPaola Arlotta4:58

       It's very, exactly, that is very important for us to get the brain we have and we can speculate for why that is. You know, it takes us a long time as, as human beings after we're born to learn all the things that we have to learn to have the adult brain. It's actually 20 years. Think about it. From when a baby is born to when a teenager goes through puberty to adults-

   21. LFLex Fridman5:25

       Okay.

   22. PAPaola Arlotta5:25

       ... it's a long time.

   23. LFLex Fridman5:27

       Do you think you can maybe talk through the first few months and then on to the first 20 years and then for the rest of their lives, what does the development of the human brain look like? What are the different stages?

   24. PAPaola Arlotta5:42

       Yeah. At the beginning you have to build a brain, right? And the brain is made of cells.

   25. LFLex Fridman5:49

       What's the very begin- which beginning are we talking about? (laughs)

   26. PAPaola Arlotta5:52

       In the embryo.

   27. LFLex Fridman5:53

       In the embryo.

   28. PAPaola Arlotta5:53

       As the embryo is developing in the womb, in addition to making all of the other tissues of the embryo, the muscle, the heart, the blood, the embryo is also building the brain and it builds from a very simple structure.... called the neural tube, which is basically nothing but a tube of cells that spans the sort of the length of the embryo from the head all the way to the tail, let's say-

   29. LFLex Fridman6:19

       Right.

   30. PAPaola Arlotta6:19

       ... of the embryo. And then over, in human beings, over many months of gestation, from that neural tube, uh, which contains, uh, stem cell-like cells of the brain, you will make many, many other building blocks of the brain, so all of the other cell types, because there are many, many different types of cells in the brain that will form specific structures of the brain. So, you can think about embryonic development of the brain as just a time in which you are making the building blocks, the cells.
2. 13:57 – 54:08

   Brain development organization as a distributed vs centralized system

   1. LFLex Fridman13:57

      this is not, the building process is not a dictatorship. It seems like there's not a centralized, like, high-level mechanism that says, "Okay, this cell built itself the wrong way."

   2. PAPaola Arlotta14:10

      Yeah.

   3. LFLex Fridman14:10

      "I'm gonna kill it." It seems like it's, there's a really strong distributed mechanism. Is that (laughs) is that in your sense from what you know?

   4. PAPaola Arlotta14:17

      There are a lot of, there are a lot of possibilities, right?

   5. LFLex Fridman14:21

      Right.

   6. PAPaola Arlotta14:21

      And, uh, if you think about, for example, different species building their brain, uh, each brain is a little bit different. So the brain of a lizard is very different from that of a chicken, from that of a (laughs) , you know-

   7. LFLex Fridman14:34

      Right.

   8. PAPaola Arlotta14:34

      ... one of us, um, and so on and so forth. And still is a brain, but it was built, uh, differently f- starting from stem cells that pretty much had the same potential. But in the end, evolution builds different brains in different species because that serves, in a way, the purpose of that species and the well-being of that organism.

   9. LFLex Fridman14:56

      Right.

   10. PAPaola Arlotta14:56

       And, um, s- so there are many possibilities, but then, um, there is a way, and you were talking about a code.

   11. LFLex Fridman15:04

       Mm-hmm.

   12. PAPaola Arlotta15:04

       Nobody knows what the entire code of development is. Of course we don't. We know bits and, bits and pieces of very specific aspects of development of the brain, what genes are involved to make a certain cell types, how those two cells interact to make the next-level structure. That we might know, but the entirety of it, how it's so well-controlled, it's really mind-blowing.

   13. LFLex Fridman15:26

       So then the first two months in the embryo or whatever, the first few weeks-

   14. PAPaola Arlotta15:30

       Few months, yeah.

   15. LFLex Fridman15:31

       ... months, few months, uh, so yeah, the, the, the building blocks are constructed. Uh, the actual, uh, the different regions of the brain, I guess, and the, the nervous system?

   16. PAPaola Arlotta15:42

       Well, this continues way longer than just th- the first, uh, few months. So over the, the, the very first, uh, you know, few months, you build a lot of the cells, but then there is continuous building of new cell types, uh, all the way through birth, and then even postnatally, um, you know, I don't know if you've ever heard of myelin. Myelin is this sort of insulation that is built around the cables-

   17. LFLex Fridman16:09

       Mm-hmm.

   18. PAPaola Arlotta16:09

       ... of the neurons so that the electricity can go really fast from-

   19. LFLex Fridman16:12

       The axons, I guess they're called.

   20. PAPaola Arlotta16:13

       ... from the axons.

   21. LFLex Fridman16:14

       Yeah.

   22. PAPaola Arlotta16:14

       They're called axons, exactly. And, uh, um, and so as human beings, we myelinate ourselves-

   23. LFLex Fridman16:23

       Mm-hmm.

   24. PAPaola Arlotta16:23

       ... uh, postnatally. A kid at, you know, a six-year-old kid has barely started the process of making the mature oligodendrocytes, which are the cells that then eventually will wrap the axons into myelin. And this will continue, believe it or not, until we are about, you know, 25, 30 years old. So there is a continuous process of maturation and tweaking and additions and, and also in response to what we do.

   25. LFLex Fridman16:51

       I remember taking AP Biology in high school, and in the textbook, it said that, I'm going by memory here, that scientists disagree on the purpose of myelin, eh, in the, in the brain. Is that, is that totally wrong? (laughs)

   26. PAPaola Arlotta17:07

       (laughs)

   27. LFLex Fridman17:07

       So like, it, it, I guess-

   28. PAPaola Arlotta17:08

       Yeah.

   29. LFLex Fridman17:08

       ... it speeds up the, uh, uh, uh, b- okay, might be wrong here.

   30. PAPaola Arlotta17:13

       Yeah.
3. 54:08 – 57:48

   Merging with AI

   1. LFLex Fridman54:08

      uh, quick comment on that. Do you see, do you think, uh, there's a, there's a, a lot of fascination and hope for artificial intelligence, of creating artificial brains. You said the next brain. Do, when you imagine over a period of a thousand years the evolution-

   2. PAPaola Arlotta54:24

      Yeah.

   3. LFLex Fridman54:24

      ... of the human brain, do you sometimes, envisioning that future, see an artificial one? Artificial intelligence as it is hoped by many ... not hoped, thought by many people would be actually the next evolutionary step in the development of humans?

   4. PAPaola Arlotta54:40

      Yeah. Yeah. I think in a way...That will happen, right? It's almost like a part of the way we evolve.

   5. LFLex Fridman54:48

      Right.

   6. PAPaola Arlotta54:48

      We evolve in the world that we created, that we interact with, that, that shape us as we grow up and so on and so forth. Um, uh, sometime I think about something that may sound silly, but think about the use of, of cell phones. Part of me thinks that somehow in their brain there will be a region of the cortex, uh, that is, uh-

   7. LFLex Fridman55:10

      (laughs) The smart phone region.

   8. PAPaola Arlotta55:11

      ... attuned, attuned-

   9. LFLex Fridman55:12

      Yeah.

   10. PAPaola Arlotta55:12

       ... to that tool, and, and this comes from a lot of studies in, in, in, in modern organisms where really the, the cortex especially adapts-

   11. LFLex Fridman55:22

       Right.

   12. PAPaola Arlotta55:22

       ... to the kind of things you have to do. So if we need to move our fingers in a very specific way, we have a part of our cortex that allows us to do this kind of very precise movement. Um, a, an, an owl that has to see very, very far away with big eyes, the visual cortex very big. It's, the, the brain attunes to your environment, so the brain will attune to the, to the technologies that we will have and will be shaped by it.

   13. LFLex Fridman55:51

       So the cortex very well may be, uh-

   14. PAPaola Arlotta55:52

       Will be shaped by it.

   15. LFLex Fridman55:54

       In artificial intelligence. It may merge with it. It may get, uh, envelop it and adjust to it.

   16. PAPaola Arlotta56:01

       Yeah. Even if it's not, you know, a merge of the kind of, oh, let's have a, a synthetic element-

   17. LFLex Fridman56:06

       Right.

   18. PAPaola Arlotta56:06

       ... together with a biological one, the very space around us, the fact, for example, think about we put on some goggles of virtual reality and we physically are surfing the ocean, right? Like, I've done it and you have all these emotions that come to you. Your brain placed you in that reality and it was able to do it like (snaps fingers) that just by putting the goggles on. It didn't take thousands of years of adapting to this. The brain is plastic, so adapts to new technology. So you could do it from the outside by (laughs) simply hijacking some sensory capacities that we have. So clearly, uh, over, you know, recent evolution, the cerebral cortex has been a part of the brain that has known the most evolution. So we have put a lot of chips on evolving this specific part of the brain and the evolution of cortex is plasticity. It's this ability to change in response to things. So yes, they will integrate, that we want it or not.

   19. LFLex Fridman57:13

       (laughs) Well, there's no better way to end it, Paola. Thank you so much for talking today.

   20. PAPaola Arlotta57:19

       You're very welcome.

   21. LFLex Fridman57:20

       That was great. (laughs)

   22. PAPaola Arlotta57:20

       This was very exciting.

Episode duration: 57:41