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

1. 0:00 – 15:00

   The following is a…

   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. 15:00 – 30:00

   Mm-hmm. …

   1. PAPaola Arlotta15:00

      but then, um, there is a way, and you were talking about a code.

   2. LFLex Fridman15:04

      Mm-hmm.

   3. 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.

   4. LFLex Fridman15:26

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

   5. PAPaola Arlotta15:30

      Few months, yeah.

   6. 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?

   7. 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-

   8. LFLex Fridman16:09

      Mm-hmm.

   9. PAPaola Arlotta16:09

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

   10. LFLex Fridman16:12

       The axons, I guess they're called.

   11. PAPaola Arlotta16:13

       ... from the axons.

   12. LFLex Fridman16:14

       Yeah.

   13. PAPaola Arlotta16:14

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

   14. LFLex Fridman16:23

       Mm-hmm.

   15. 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.

   16. 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)

   17. PAPaola Arlotta17:07

       (laughs)

   18. LFLex Fridman17:07

       So like, it, it, I guess-

   19. PAPaola Arlotta17:08

       Yeah.

   20. LFLex Fridman17:08

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

   21. PAPaola Arlotta17:13

       Yeah.

   22. LFLex Fridman17:13

       But I guess it speeds up the electricity traveling down the axon or something?

   23. PAPaola Arlotta17:17

       Yeah.

   24. LFLex Fridman17:17

       But is it-

   25. PAPaola Arlotta17:17

       So that's the most sort of canonical, and, and definitely that's the case. So, uh, you have to imagine an axon, and you can think about it as a cable of some type with electricity going through. And what myelin does, by insulating the outside, um, I should say there are tracts of myelin and pieces of axons that are naked without myelin.

   26. LFLex Fridman17:39

       Mm-hmm.

   27. PAPaola Arlotta17:39

       And so by having the insulation, the electricity, instead of going straight through the cable, it would jump over a piece of myelin, right, uh, to the next naked little piece and jump again, and therefore you, you know, that's the idea, that you go faster. And it was always thought-... that in order to build a big brain, a big nervous system, in order to have a nervous system that can do very complex type of things, then you need a lot of myelin because you wanna go fast with this information from point A to point B. Uh, well, uh, a, a few years ago, maybe five years ago or so, we discovered that some of the most evolved, which means the, the newest type of neurons that we have as non-human primates, as, as human beings in the top of our cerebral cortex, which should be the neurons that do some of the most complex things that we do, well, those have axons that have very little myelin.

   28. LFLex Fridman18:37

       Wow.

   29. PAPaola Arlotta18:37

       (laughs) And they have very interesting ways in which they put this myelin on their axons, you know, a little piece here, then a long tract with no myelin, another chunk there, and some don't have myelin at all. So now, you have to explain- (laughs)

   30. LFLex Fridman18:54

       (Laughs)
3. 30:00 – 45:00

   Yeah, astrocytes? Yeah. …

   1. PAPaola Arlotta30:00

   2. LFLex Fridman30:00

      Yeah, astrocytes? Yeah.

   3. PAPaola Arlotta30:00

      The astrocytes are not neurons, so they're not nerve cells, but they, they play very important roles. One important role is to support the neuron.

   4. LFLex Fridman30:08

      Mm-hmm.

   5. PAPaola Arlotta30:09

      But of course, the- they have much more active type of roles that are very important. For example, to make the synapses, which are the point of contacts and communication between two neurons. They do a lot of things.

   6. LFLex Fridman30:21

      So all that chemistry fun happens betw- in the synapses, happens, uh, because of these cells? Are they the medium in which-

   7. PAPaola Arlotta30:29

      The- it happens because of the interactions, happens because you're making the cells, and they have certain properties, including the ability to make, um, you know, neurotransmitters, which are the chemicals that are secreted to the synapses, including the ability of making these axons grow with their growth cones and so on and so forth. And then you have other cells around there that release chemicals or touch the neurons or interact with them in different ways to really foster this perfect process, in this case, of synaptogenesis.

   8. LFLex Fridman31:02

      Yeah.

   9. PAPaola Arlotta31:02

      Um, and this does happen within, within organoids. So you-

   10. LFLex Fridman31:05

       Oh, with organoids.

   11. PAPaola Arlotta31:06

       They do-

   12. LFLex Fridman31:06

       So the mechanical and the chemis- chemical stuff happens...

   13. PAPaola Arlotta31:09

       Yeah. The connectivity between neurons-

   14. LFLex Fridman31:11

       Wow.

   15. PAPaola Arlotta31:11

       This, in a way, is not surprising because scientists have been culturing neurons forever. (laughs) And when you take a neuron, even a very young one, and you culture it, eventually, if it finds another cell or another neuron to talk to, it will form a synapse.

   16. LFLex Fridman31:27

       Are we talking about mice neurons? Are we talking about human neurons?

   17. PAPaola Arlotta31:29

       It doesn't matter. Both.

   18. LFLex Fridman31:30

       So you can culture a neuron, like a single neuron, and g- g- give it a little friend, and it starts interacting?

   19. PAPaola Arlotta31:38

       Yes. So neurons are able to... It sounds, i- it's more simple than what it may sound to you.

   20. LFLex Fridman31:43

       (laughs) Okay.

   21. PAPaola Arlotta31:43

       Um, it, uh, neurons have molecular properties and structural properties that allow them to really communicate with other cells. And so if you put not one neuron, but if you put several neurons together, chances are that they will form synapses with each other.

   22. LFLex Fridman32:00

       Okay, great. So an organoid is not a brain.

   23. PAPaola Arlotta32:03

       No.

   24. LFLex Fridman32:04

       But (laughs) -

   25. PAPaola Arlotta32:06

       (laughs)

   26. LFLex Fridman32:06

       But, uh, i- there's some, it's, it's able to, especially what you're talking about, mimic some properties of the cerebral cortex, for example.

   27. PAPaola Arlotta32:15

       Mm-hmm.

   28. LFLex Fridman32:15

       So what, what can you understand about the brain by studying an organoid of the ce- cerebral cortex?

   29. PAPaola Arlotta32:21

       I can literally study how all this incredible diversity of cell type, all these many, many different classes of cells, how are they made?

   30. LFLex Fridman32:30

       Hm.
4. 45:00 – 57:48

   Mm-hmm. …

   1. PAPaola Arlotta45:00

      his process of brain development-

   2. LFLex Fridman45:02

      Mm-hmm.

   3. PAPaola Arlotta45:02

      ... with his, with his or her genetics.

   4. LFLex Fridman45:04

      Mm-hmm.

   5. PAPaola Arlotta45:04

      And we could understand perhaps what is going wrong. Perhaps we could use as a platform, as a cellular platform to screen for drugs, to fix a process and so on and so forth, right? So, we could do it now, we couldn't do it five years ago. Should we not do it?

   6. LFLex Fridman45:20

      What is the downside of doing it? Of-

   7. PAPaola Arlotta45:24

      I don't see a downside at this very moment.

   8. LFLex Fridman45:26

      But if you were to put, if we invited a lot of people-

   9. PAPaola Arlotta45:29

      Yes.

   10. LFLex Fridman45:29

       ... if, I'm sure there would be somebody who would s- would argue against it. What would be, uh, the devil's advocate argument?

   11. PAPaola Arlotta45:38

       Yeah.

   12. LFLex Fridman45:38

       Uh, what's, yeah.

   13. PAPaola Arlotta45:39

       Yeah. So, uh, it's exactly perhaps what you alluded at with your question that you are making a, uh, e- enabling, you know, so- some, some process of, of formation of the brain that could be misused at some point. Or that could be, um, showing properties, uh, that, uh, ethically we don't wanna see in a tissue. Uh, so today, I repeat, today this is not an issue. And so you, uh, you just gain dramatically from the science without because the system is so simple and, and so different-

   14. LFLex Fridman46:15

       Yeah.

   15. PAPaola Arlotta46:15

       ... in a way from, from the actual brain. But, but because it is the brain, we have an obligation to really consider all of this.

   16. LFLex Fridman46:23

       Yeah.

   17. PAPaola Arlotta46:23

       Right? And again, it's, it's a balanced conversation where we should put disease and betterment of humanity also on that plate.

   18. LFLex Fridman46:32

       What do you think at least historically there was some politicization, politicization-

   19. PAPaola Arlotta46:39

       (laughs)

   20. LFLex Fridman46:40

       ... of, uh, embryonic-

   21. PAPaola Arlotta46:43

       Mm-hmm.

   22. LFLex Fridman46:44

       ... stem cells-

   23. PAPaola Arlotta46:44

       Yes.

   24. LFLex Fridman46:44

       ... of stem cell research. Do, do you still see that out there? Is, is there, is that still a force that we have to think about especially in this larger discourse that we're having about the role of science in at least American society?

   25. PAPaola Arlotta47:00

       Yeah. This is a very good question, it's very, very important. I see a very central role for scientists to inform decisions about what we should or should not do in society. And this is because the scientist have their firsthand look and understanding of really the work that they are doing. And again, this varies depending on what we're talking about here. So now we're talking about brain organoids, uh, I think that the scientist need to be part of that conversation about what is, will be allowed in the future or not allowed in the future to do with the system. And, um, I think it's, that is very, very important because they bring reality of data to the conversation, um, and, and, and so they should have a voice.

   26. LFLex Fridman47:51

       So data should have a voice. (laughs)

   27. PAPaola Arlotta47:53

       Data needs to have a voice because-

   28. LFLex Fridman47:56

       Okay.

   29. PAPaola Arlotta47:56

       And not only data, we should also be good at communicating with known scientists the data.

   30. LFLex Fridman48:04

       Right.

Episode duration: 57:41