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

Lex Fridman and Paola Arlotta on harvard neuroscientist decodes human brain development using lab-grown organoids.

Lex FridmanhostPaola Arlottaguest

Aug 12, 201957mWatch on YouTube ↗

EVERY SPOKEN WORD

100 min read · 19,506 words

0:00 – 3:07
How unlikely is the human brain? Evolution, probability, and what we still don’t know
1. LFLex Fridman
  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 Arlotta
  Yeah.
3. LFLex Fridman
  ... through the evolutionary process?
4. PAPaola Arlotta
  Well, it has happened here, right? On this planet.
5. LFLex Fridman
  Once, yes.
6. PAPaola Arlotta
  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 Fridman
  So in having studied the human brain or through the mouse and through-
8. PAPaola Arlotta
  Yeah.
9. LFLex Fridman
  ... 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?
3:07 – 5:27
Species-specific developmental time: why humans take months and mice take days
1. PAPaola Arlotta
  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.
2. LFLex Fridman
  Yeah.
3. PAPaola Arlotta
  A mouse takes 20 days or so to-
4. LFLex Fridman
  So it's mouse time.
5. PAPaola Arlotta
  ... 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.
6. LFLex Fridman
  So the very developmental process is, uh...
7. PAPaola Arlotta
  Controlled by the speed of the species.
8. LFLex Fridman
  Which means it's, uh, by-
9. PAPaola Arlotta
  (laughs)
10. LFLex Fridman
  ... it's on purpose, it's not accidental or, uh, there's something in that temporal dynamic to that development.
11. PAPaola Arlotta
  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-
12. LFLex Fridman
  Okay.
13. PAPaola Arlotta
  ... it's a long time.
5:27 – 9:46
From neural tube to cortex: building blocks, cell diversity, and ordered assembly
1. LFLex Fridman
  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?
2. PAPaola Arlotta
  Yeah. At the beginning you have to build a brain, right? And the brain is made of cells.
3. LFLex Fridman
  What's the very begin- which beginning are we talking about? (laughs)
4. PAPaola Arlotta
  In the embryo.
5. LFLex Fridman
  In the embryo.
6. PAPaola Arlotta
  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-
7. LFLex Fridman
  Right.
8. PAPaola Arlotta
  ... 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.
9. LFLex Fridman
  Are the stem cells relatively homogeneous, like uniform, or are they all different types?
10. PAPaola Arlotta
  That's a very good question. It's exactly how it works. You start with a more homogeneous, perhaps more multipotent type of stem cell that-
11. LFLex Fridman
  What's multipotent?
12. PAPaola Arlotta
  Multipotent means that it can, uh, it has the potential to make many, many different types of other cells.
13. LFLex Fridman
  Mm-hmm.
14. PAPaola Arlotta
  And then with time, these progenitors become more heterogeneous, which means more diverse. There are gonna be many different types of the stem cells, and also they will give rise to progeny to other cells that- that are not stem cells that are specific cells of the brain that are very different from the mother stem cell. And now you think about this process of making cells from the stem cells over many, many months of development for humans, and what you're doing, you're building the cells that physically make the brain and then you arrange them in specific structures that are present in the final brain. So, you can think about the embryonic development of the brain as the time where you're building the bricks, you're putting the bricks together-
15. LFLex Fridman
  Mm-hmm.
16. PAPaola Arlotta
  ... to form buildings, structures, regions of the brain, and where you make the connections between these many different type of cells, especially nerve cells, neurons, right, that-
17. LFLex Fridman
  Yeah.
18. PAPaola Arlotta
  ... transmit action potentials and electricity.
19. LFLex Fridman
  I've heard you also say s- somewhere, I think, correct me if I'm wrong, that the order of the way this builds matters.
20. PAPaola Arlotta
  Oh, yes. If you are an engineer and you thi- think about development, you can think of it as, "Well, I could also, uh, take all the cells and bring them all together into a brain in the end." But development is much more than that. So, the cells are made in a very specific order that serve the final product that you need to get.
21. LFLex Fridman
  Mm-hmm.
22. PAPaola Arlotta
  And so for example, all of the nerve cells, the neurons are made first.
23. LFLex Fridman
  Mm-hmm.
24. PAPaola Arlotta
  And all of the supportive cells of the neurons, like the glia, is made later. And there is a reason for that, because they have to assemble together in specific ways. But you also may say, "Well, why don't we just put them all together in the end?" It's because as they develop next to each other, they influence their own development. So, it's a different thing for a glial to be made alone in a dish than a glia be m- than a glial cell be made in a developing embryo with all these other cells around it that produce all these other signals.
25. LFLex Fridman
  First of all, that's, uh, mind-blowing that this development process, uh, from my perspective in artificial intelligence, you often think of how incredible the final product is.
26. PAPaola Arlotta
  Yeah.
27. LFLex Fridman
  The final product, the brain. But you just, you're making me realize that the final product is just, uh, is, uh, the- the beautiful thing is the actual devel- uh, development process. Do we know (laughs) -
9:46 – 15:26
What is the ‘code’ of development? Genes plus mechanics (forces shape fate)
1. PAPaola Arlotta
  (laughs)
2. LFLex Fridman
  ... the code that drives that development? D- uh-
3. PAPaola Arlotta
  Yeah.
4. LFLex Fridman
  ... do- do we have any sense?
5. PAPaola Arlotta
  F- first of all, thank you for saying that it's really the formation of the brain, it's really its development, this- this incredibly choreographed dance that happens the same way every time each one of us builds the brain, right?
6. LFLex Fridman
  Mm-hmm.
7. PAPaola Arlotta
  And that builds an organ that allows us to do what we're doing today, right?
8. LFLex Fridman
  Yeah.
9. PAPaola Arlotta
  That is mind-blowing, and this is why developmental neurobiologists never get tired (laughs) -
10. LFLex Fridman
  (laughs) Yes.
11. PAPaola Arlotta
  ... of studying that. Now, you're asking about the code. What drives this? How is this done? Well, it's, you know, millions of years of evolution, of really fine-tuning gene expression programs that allow certain cells to be made at a certain time and to be, and to become a certain, you know, cell type.
12. LFLex Fridman
  Mm-hmm.
13. PAPaola Arlotta
  But also, um, mechanical forces, uh, of pressure, bending. This embryo is not just, will not stay a tube-
14. LFLex Fridman
  Mm-hmm.
15. PAPaola Arlotta
  ... uh, this- this brain for very long. At some point, this tube in the front of the, of the embryo will expand to make the primordium of the brain, right? Now, the- the forces, the control, um, that the cells feel, uh, and this is another beautiful thing, uh, the very force that they feel, which is different from a week before or a week ago, will tell the cell, "Oh, you're being squished in a certain way. Begin to produce-"
16. LFLex Fridman
  (laughs)
17. PAPaola Arlotta
  "... these new genes, because now you are at a corner or you are, you know, in a stretch of cells," or whatever it is, and that, so that mechanical, physical force shapes the fate of the cell as well.
18. LFLex Fridman
  So, uh-
19. PAPaola Arlotta
  It's not only chemical, it's also mechanical.
20. LFLex Fridman
  Mechanical. So, from my perspective, biology is this incredibly complex mess, gooey mess. Uh, so-
21. PAPaola Arlotta
  (laughs)
22. LFLex Fridman
  ... you're saying mechanical forces.
23. PAPaola Arlotta
  Yes.
24. LFLex Fridman
  Uh, how different is, uh, like a- a computer or any kind of mechanical machine that we humans build and the biological systems?
25. PAPaola Arlotta
  Yeah.
26. LFLex Fridman
  Have you been... 'cause you've worked a lot with biological systems.
27. PAPaola Arlotta
  Yes.
28. LFLex Fridman
  Are they as much of a mess as it seems from a-
29. PAPaola Arlotta
  (laughs)
30. LFLex Fridman
  ... from a perspective of an eng- engineer, a mechanical engineer?
15:26 – 20:06
Postnatal maturation and myelin: insulation, speed, and an evolutionary surprise
1. LFLex Fridman
  So then the first two months in the embryo or whatever, the first few weeks-
2. PAPaola Arlotta
  Few months, yeah.
3. LFLex Fridman
  ... 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?
4. PAPaola Arlotta
  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-
5. LFLex Fridman
  Mm-hmm.
6. PAPaola Arlotta
  ... of the neurons so that the electricity can go really fast from-
7. LFLex Fridman
  The axons, I guess they're called.
8. PAPaola Arlotta
  ... from the axons.
9. LFLex Fridman
  Yeah.
10. PAPaola Arlotta
  They're called axons, exactly. And, uh, um, and so as human beings, we myelinate ourselves-
11. LFLex Fridman
  Mm-hmm.
12. PAPaola Arlotta
  ... 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.
13. LFLex Fridman
  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)
14. PAPaola Arlotta
  (laughs)
15. LFLex Fridman
  So like, it, it, I guess-
16. PAPaola Arlotta
  Yeah.
17. LFLex Fridman
  ... it speeds up the, uh, uh, uh, b- okay, might be wrong here.
18. PAPaola Arlotta
  Yeah.
19. LFLex Fridman
  But I guess it speeds up the electricity traveling down the axon or something?
20. PAPaola Arlotta
  Yeah.
21. LFLex Fridman
  But is it-
22. PAPaola Arlotta
  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.
23. LFLex Fridman
  Mm-hmm.
24. PAPaola Arlotta
  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.
25. LFLex Fridman
  Wow.
26. PAPaola Arlotta
  (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)
27. LFLex Fridman
  (Laughs)
28. PAPaola Arlotta
  ... where we're going, um, with evolution, and if you think about it, perhaps as an electrical engineer, uh, when I l- looked at it, I initially thought, uh, and I'm a developmental neurobiologist, I thought maybe, uh, this is what we see now, but if we give evolution another few million years, we'll see a lot of myelin on these neurons too, but I actually think now that that's instead the future of the brain.
29. LFLex Fridman
  The less myelin.
30. PAPaola Arlotta
  Less myelin might allow for more flexibility on what you do with your axons, and therefore, more complicated and unpredictable type of functions, which is also a bit mind-blowing.
20:06 – 22:36
Nature vs nurture: plasticity, experience, and sensory-driven rewiring
1. LFLex Fridman
  So we're gonna jump around a little bit, but the old question of, uh, how much is nature and how much is nurture, in terms of this incredible thing after the development is over-
2. PAPaola Arlotta
  Yes.
3. LFLex Fridman
  ... uh, we seem to be kind of somewhat smart-
4. PAPaola Arlotta
  Growth.
5. LFLex Fridman
  ... intelligent- (laughs)
6. PAPaola Arlotta
  (laughs)
7. LFLex Fridman
  ... uh, cognition, consciousness, all these things are just incredible, ability to reason and so on emerge. In your sense, how much is in the hardware, in the nature, and how much is in the nurture as learned-
8. PAPaola Arlotta
  Yeah.
9. LFLex Fridman
  ... through, with our parents through interacting with the environment and so on?
10. PAPaola Arlotta
  Yeah. It's really both, right? If you think about it.
11. LFLex Fridman
  Yeah.
12. PAPaola Arlotta
  So we are born with a brain as babies that has most of its cells and most of its structures and that will take a few years to, you know, to grow, to add more, to be better, but really, um, then we have these 20 years of interacting with the environment around us, and so what that brain that was so, you know, perfectly built or imperfectly built due to our, uh, genetic cues, uh, will then be used to incorporate the environment in its further maturation and development. And so your experiences do shape your, your brain. I mean, we know that. Like, if, you know, you and I may have had a different childhood or a different, we have been going to different schools, we have been learning different things, and our brain is a little bit different because of that. We behave differently because of that. And, and so especially postnatally, experience is extremely important. We are born with a plastic brain. What, what that means is a brain that is able to change in response to stimuli. They can be sensory.
13. LFLex Fridman
  Right.
14. PAPaola Arlotta
  So perhaps some of the most, um, illuminating studies that were done were studies in which the sensory organs were not working, right?
15. LFLex Fridman
  Mm-hmm.
16. PAPaola Arlotta
  Like, if you are born with eyes that don't work, then your very brain that, no- piece of the brain that normally would process vision, the visual cortex, uh, develops postnatally differently, and it might be used to do something different, right? So that's the most extreme. (laughs)
17. LFLex Fridman
  So the, the, the plasticity of the brain, I guess, is the magic hardware that it, and then-
18. PAPaola Arlotta
  Yeah.
19. LFLex Fridman
  ... its, its flexibility in all f- forms is what enables the learning postnatally.
20. PAPaola Arlotta
  Yes.
22:36 – 24:24
What brain organoids are (and are not): a practical window into human development
1. LFLex Fridman
  Can you talk about o- organoids? What are they?
2. PAPaola Arlotta
  Yes.
3. LFLex Fridman
  And how can you use them to help us understand the brain and the development of the brain?
4. PAPaola Arlotta
  This is very, very important. So the first thing I like to say, and please keep this in the video. (laughs)
5. LFLex Fridman
  (laughs)
6. PAPaola Arlotta
  The first thing I like to say is that an organoid, a brain organoid-
7. LFLex Fridman
  Yeah.
8. PAPaola Arlotta
  ... is not the same as a brain, okay? It's a fundamental distinction. It's a, a system, a cellular system, uh, that one can, uh, develop in the culture dish starting from stem cells that will mimic some aspects of the development of the, of the brain, but not all of it. They are very small. Maximum, they become about, you know, four to five millimeters in diameters. They are much simpler than, than our brain, of course, but yet they are the only system where we can literally watch a process of human brain development unfold, and by watch, I mean study it. Remember when I told you that we can't understand everything about development in our own brain by studying a mouse? Well, we can't study the actual process of development of the human brain because it all happens in utero, so we will never have access to that process, ever.And therefore, this is our next best thing, like a, a bunch of stem cells that can be coaxed into starting a process of neural tube formation, remember that tube-
9. LFLex Fridman
  Yeah.
10. PAPaola Arlotta
  ... that is made by the embryo early on? And from there, a lot of the cell types that are present within, within the brain and you can simply watch it and study.
11. LFLex Fridman
  Mm-hmm.
24:24 – 25:16
Modeling neurodevelopmental disease: patient-specific organoids and autism questions
1. PAPaola Arlotta
  But you can also think about diseases where development of the brain does not proceed normally, right, properly.
2. LFLex Fridman
  Mm-hmm.
3. PAPaola Arlotta
  Think about neurodevelopmental diseases, there are many, many different types. Uh, think about autism spectrum disorders, there are also many different types of autism. So there, you could take a stem cell, which really means either a sample of blood or a sample of skin from the patient, make a stem cell, and then with that stem cell, watch a process of formation-
4. LFLex Fridman
  Mm-hmm.
5. PAPaola Arlotta
  ... of a brain organoid of that person.
6. LFLex Fridman
  Of that person.
7. PAPaola Arlotta
  With that genetics, with that genetic code in it, and you can ask, "What is this genetic code doing to some aspects of development of the brain?" And for the first time, you may come to solutions like, what cells are involved in autism, right?
25:16 – 28:19
Variability and scalability: why organoids differ, and how labs work to standardize them
1. LFLex Fridman
  So I have so many questions around this. So if you take this human stem cell for that particular person with that genetic code, how ... and you try to build an organoid-
2. PAPaola Arlotta
  Yeah.
3. LFLex Fridman
  ... how often will it look similar? What's the, um-
4. PAPaola Arlotta
  Yeah.
5. LFLex Fridman
  Uh, yeah, so, so h-
6. PAPaola Arlotta
  The reproducibility?
7. LFLex Fridman
  Y- yes, or b- or how much variability i- is the-
8. PAPaola Arlotta
  Yes.
9. LFLex Fridman
  ... flip side of that, yeah.
10. PAPaola Arlotta
  Yeah. Yeah. So, there is much more variability in building organoids than there a- than there is in building brain. It's really true-
11. LFLex Fridman
  What do you say?
12. PAPaola Arlotta
  ... that the majority of us when we're born as babies, our brains look a lot like each other.
13. LFLex Fridman
  Mm.
14. PAPaola Arlotta
  This is the magic that the embryo does, where it builds a brain the context of a body and, um, and there is very little variability there. There is disease, of course, but in general, little variability. When you build an organoid, um, you know, we don't have the full code for how this is done, and so in part, the organoid, uh, somewhat builds itself-
15. LFLex Fridman
  Mm-hmm.
16. PAPaola Arlotta
  ... because there, there are some structures of the brain that the cells know how to make, and another part comes from the investigator, the scientist adding to the media factors that we know in the mouse, for example, would foster a certain step of development.
17. LFLex Fridman
  Right.
18. PAPaola Arlotta
  But it's very limited, and so as a result, uh, the kind of product you get in the end is much more reductionist, it's much more simple than what you get in vivo. It mimics early events of development as of today, and it doesn't build very complex type of anatomy and structure, does not, as of today-
19. LFLex Fridman
  Right.
20. PAPaola Arlotta
  ... um, which happens instead in, in, in vivo. And also, uh, the variability that you see one organoid to the next, uh, uh, tends to be higher than when you compare an embryo to the next.
21. LFLex Fridman
  Mm-hmm. So, okay, then the next question is-
22. PAPaola Arlotta
  Yes.
23. LFLex Fridman
  ... how hard, and maybe another flip side of that, expensive is it to-
24. PAPaola Arlotta
  (laughs) .
25. LFLex Fridman
  ... go from one stem cell to an organoid?
26. PAPaola Arlotta
  Yeah.
27. LFLex Fridman
  How many can you build and like ... 'cause it sounds very complicated.
28. PAPaola Arlotta
  It's work, definitely-
29. LFLex Fridman
  Mm-hmm. (laughs)
30. PAPaola Arlotta
  ... and it's money, definitely.
28:19 – 34:02
Inside an organoid: cortical neurons, astrocytes, and synapse formation
1. LFLex Fridman
  So what does an organoid look like? Uh, a- are there different neurons already emerging? Is there, you know, uh ... well, first, can you tell me (laughs) what kind of neurons are there?
2. PAPaola Arlotta
  Yes.
3. LFLex Fridman
  Uh, are they sort of, uh, all the same? Uh, are they not all the same? Is, do, how much do we understand and how much of that variance, if any, can exist in organoids?
4. PAPaola Arlotta
  Yes. So, you could grow, I told you that the brain has different parts.
5. LFLex Fridman
  Right.
6. PAPaola Arlotta
  Uh, so the cerebral cortex is on to- uh, the top part of the brain, but there is another region called the striatum that is below the cortex and so on and so forth. All of these regions have different types of cells in the actual brain, okay? And so scientists have been able to grow organoids that may mimic some aspects of development of these different regions of the brain.
7. LFLex Fridman
  Yeah.
8. PAPaola Arlotta
  And so we are very interested in the cerebral cortex, which is the-
9. LFLex Fridman
  That's the coolest part, right? (laughs)
10. PAPaola Arlotta
  Very cool. (laughs)
11. LFLex Fridman
  (laughs)
12. PAPaola Arlotta
  I agree with you. (laughs)
13. LFLex Fridman
  Yeah. Sorry.
14. PAPaola Arlotta
  We wouldn't be here talking if we didn't have a cerebral cortex.
15. LFLex Fridman
  Yeah.
16. PAPaola Arlotta
  It's also, I like to think, the part of the brain that really truly makes us human, the most evolved in recent evolution. And so in the attempt to make the cerebral cortex and by figuring out a way to have these organoids continue to grow and develop for extended periods of times, much like it happens in the real embryo, months and months in culture, then you can see that, uh, many different types of neurons of the cortex appear, and at some point, also the astrocytes or the glia cells of the cerebral cortex also-... up here.
17. LFLex Fridman
  What are these, uh-
18. PAPaola Arlotta
  Those astrocytes.
19. LFLex Fridman
  Yeah, astrocytes? Yeah.
20. PAPaola Arlotta
  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.
21. LFLex Fridman
  Mm-hmm.
22. PAPaola Arlotta
  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.
23. LFLex Fridman
  So all that chemistry fun happens betw- in the synapses, happens, uh, because of these cells? Are they the medium in which-
24. PAPaola Arlotta
  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.
25. LFLex Fridman
  Yeah.
26. PAPaola Arlotta
  Um, and this does happen within, within organoids. So you-
27. LFLex Fridman
  Oh, with organoids.
28. PAPaola Arlotta
  They do-
29. LFLex Fridman
  So the mechanical and the chemis- chemical stuff happens...
30. PAPaola Arlotta
  Yeah. The connectivity between neurons-
34:02 – 35:46
Detecting ‘abnormal’ development: single-cell profiling and functional readouts
1. LFLex Fridman
  So how hard is it to detect through the developmental process, it's a super exciting me-
2. PAPaola Arlotta
  Yeah.
3. LFLex Fridman
  ... uh, tool to s- to see how, uh, different conditions develop. How hard is it to detect that, wait a minute, this is abnormal development?
4. PAPaola Arlotta
  Yeah.
5. LFLex Fridman
  Uh, that, that's sign- uh, how hard i- wh- how much signal is there?
6. PAPaola Arlotta
  I know.
7. LFLex Fridman
  How much of it is it, is it a mess?
8. PAPaola Arlotta
  'Cause things can go wrong at multiple levels, right?
9. LFLex Fridman
  Yeah.
10. PAPaola Arlotta
  You could have, uh, a cell that is born and built, but then doesn't work properly, or a cell that is not even born, or a cell that doesn't interact with other cell differently, and so on and so forth. So today, we have technology that we did not have even five years ago (laughs) uh, that allows us to look, for example, at the molecular picture of a cell, of a single cell in a sea of cells with high precision. And so that molecular information, where you compare many, many single cells for the genes they produce between a control individual and an individual with a neurodevelopmental disease, uh, that may tell you what is different molecularly. Or, you could see that some cells are not even made, for example, or that the process of maturation of the cells may be wrong. There are many different-
11. LFLex Fridman
  Right.
12. PAPaola Arlotta
  ... levels here. And, and i- we can study these cells at the molecular level, but also, we can use the organoids to ask, uh, questions about the properties of the neurons, the functional properties. How they communicate with each other, how they respond to a stimulus, and so on and so forth. And we may get abnormalities there, right?
35:46 – 42:45
Where the field is headed: fast-moving tech, not 1000 years—plus the ‘build a brain’ question
1. LFLex Fridman
  D- detect those. Uh, so how early is this work in the, maybe in the history of science? (laughs)
2. PAPaola Arlotta
  (laughs)
3. LFLex Fridman
  So, so, uh-
4. PAPaola Arlotta
  That is a question. (laughs) Yeah.
5. LFLex Fridman
  I mean, like, uh, so if you were to, if, if, uh, you and I time travel 1,000 years into the future, uh, o- organoids seem to be...Uh, maybe I'm romanticizing the notion, but you're building, not a brain, but, uh, something that has properties of a brain, so you- it feels like you might be getting close to, uh, in the building process to u- to, to build this to, to understand, so how, um, how far are we in this understanding process of development?
6. PAPaola Arlotta
  1000 years from now is a long time from now.
7. LFLex Fridman
  (laughs)
8. PAPaola Arlotta
  So, if this planet is still gonna be here 1000 years from now. (laughs)
9. LFLex Fridman
  So, I mean if, if, uh-
10. PAPaola Arlotta
  Yeah.
11. LFLex Fridman
  ... you know, like, th- they write a book, um, obviously you- there'll be a chapter about you.
12. PAPaola Arlotta
  Yeah. Let's w- let's write that science fiction book today. (laughs)
13. LFLex Fridman
  Yeah, today about, I mean, I, I guess, we're... We really understood very little about the brain a century ago. When I f- I, I was a big fan in high school of reading Freud and so on.
14. PAPaola Arlotta
  Yes.
15. LFLex Fridman
  Still am with psychiatry. I would say we still understand very little about the functional aspect of just-
16. PAPaola Arlotta
  Yeah.
17. LFLex Fridman
  ... m- but how, in the history of understanding the biology of the brain, the development, how far are we along?
18. PAPaola Arlotta
  It, it's a very good question. And so this is just, of course, my opinion, um, I think that we did not have technology, um, even 10 years ago or twen- certainly not 20 years ago to even think about experimentally investigating the development of the human brain. So, we've done a lot of work in science to study the brain or many other organisms.
19. LFLex Fridman
  Mm-hmm.
20. PAPaola Arlotta
  Now, we have some technologies which I'll spell out, that allow us to actually look at the real thing-
21. LFLex Fridman
  Mm-hmm.
22. PAPaola Arlotta
  ... and look at the brain, at the human brain. So, what are these technologies? There has been huge progress in stem cell biology. The moment someone figured out how to turn a skin cell into an embryonic stem cell basically, and that how that embryonic stem cell could begin a process of development again to pro- for example, make a brain, that was a huge and, you know, advance, and in fact there was a Nobel Prize for that. That started the field really of using stem cells to build organs. Now, we can build on all the knowledge of development that we built over the many, many, many years to say, "How do we make the stem cells now make more and more complex aspects of development of the human brain?" Uh, so this field is young, the field of brain organoids, but it's moving fast, and it's moving fast in a very serious way that is rooted in labs with the right ethical framework, and, uh, um, and really building on, you know, solid science for what reality is and what is not. And, uh, um, but it will go faster and it will be more and more powerful. Uh, we also have technology that allows us to basically study the properties of single cells, uh, across many, many millions of single cells, which we didn't have perhaps five years ago. So, now with that, even an organoid that has millions of cells can be profiled in a way, looked at-
23. LFLex Fridman
  Mm-hmm.
24. PAPaola Arlotta
  ... with h- very, very high resolution on a single cell level, to really understand what is going on. And you could do it in multiple stages of development, and you can build your hypothesis and so on and so forth. So, it's not gonna be 1000 years. It's gonna be a shorter amount of time, and I f- I see this as sort of a, an exponential growth-
25. LFLex Fridman
  Mm-hmm.
26. PAPaola Arlotta
  ... of this field enabled by these technologies that we didn't have before, and so we're gonna see something transformative that we didn't s- see at all in the prior 1000 years.
27. LFLex Fridman
  (laughs) So, I apologize for the crazy sci-fi questions, but, uh, the development and process is fascinating to watch and study, but how far are w- are we away from and maybe how difficult is it to build not just an organoid, but a human brain-
28. PAPaola Arlotta
  Okay.
29. LFLex Fridman
  ... from a stem cell?
30. PAPaola Arlotta
  Yeah. First of all, that's not the goal for the majority of the serious scientists that work on this because you don't have to build the whole human brain to make this model useful for understanding how the brain develops or understanding disease. You don't have to build the whole thing.
42:45 – 48:56
Ethics and public discourse: continuous oversight, misuse concerns, and the power of language
1. LFLex Fridman
  So, the ethical framework here is a fascinating one, it's a complicated one.
2. PAPaola Arlotta
  Yes.
3. LFLex Fridman
  Do you have a s- sense, a grasp of how we think about ethically of, uh, building organoids from human stem cells to understand the brain? It seems like a tool for helping potentially millions of people cure diseases or at least start the cure-
4. PAPaola Arlotta
  Yeah.
5. LFLex Fridman
  ... by understanding it. But is there more, is there gray areas that, uh-
6. PAPaola Arlotta
  Yeah.
7. LFLex Fridman
  ... are ethic, that we have to think about ethically?
8. PAPaola Arlotta
  Absolutely. We must think about that. Every, uh, discussion about the ethics of this needs to be based on actual (laughs) data from the models that we have today and from the ones that we will have tomorrow. So, it's a continuous conversation, it's not something that you decide now. Today, there is no issue really. Very simple models, um, they, they clearly can help you many ways, uh, without much, uh, much to think about. But tomorrow we need to have another conversation and so on and so forth, and so the way we do this is to actually really bring together constantly a group of people that are not only scientists, but also bioethicists, the lawyers, philosophers, psychiatrists and so o- uh, psychologists and so on and so forth to, uh, decide as a, as a society really (laughs) , um, w- what we should and what we should not do.
9. LFLex Fridman
  Yeah.
10. PAPaola Arlotta
  So, that's the way to think about the ethics. Now, I also think though that as a scientist, uh, I have a moral responsibility. So, if you, if you think about how transformative it could be for understanding and curing a, a neuropsychiatric disease, um, to be able to actually watch and study and treat with drugs the very brain of the patient that you are trying to study.
11. LFLex Fridman
  Mm-hmm.
12. PAPaola Arlotta
  How transformative at this moment in time this could be. We couldn't do it five years ago, we could do it now.
13. LFLex Fridman
  Mm-hmm.
14. PAPaola Arlotta
  Right? If we can do it-
15. LFLex Fridman
  Taking a stem cell of a particular patient-
16. PAPaola Arlotta
  ... patient and make-
17. LFLex Fridman
  Yeah.
18. PAPaola Arlotta
  ... an organoid for as simple and, you know, different from the, from the human brain it still is his process of brain development-
19. LFLex Fridman
  Mm-hmm.
20. PAPaola Arlotta
  ... with his, with his or her genetics.
21. LFLex Fridman
  Mm-hmm.
22. PAPaola Arlotta
  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?
23. LFLex Fridman
  What is the downside of doing it? Of-
24. PAPaola Arlotta
  I don't see a downside at this very moment.
25. LFLex Fridman
  But if you were to put, if we invited a lot of people-
26. PAPaola Arlotta
  Yes.
27. LFLex Fridman
  ... if, I'm sure there would be somebody who would s- would argue against it. What would be, uh, the devil's advocate argument?
28. PAPaola Arlotta
  Yeah.
29. LFLex Fridman
  Uh, what's, yeah.
30. PAPaola Arlotta
  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-
48:56 – 57:48
Parenting, individuality, and the ‘next brain’: plasticity, evolution, and AI-shaped environments
1. PAPaola Arlotta
  Yes.
2. LFLex Fridman
  ... and the way people feel about what is the right way to proceed forward. You are, as I've seen from your presentation, you're a parent. I s- I saw you show-
3. PAPaola Arlotta
  (laughs)
4. LFLex Fridman
  ... uh, a couple of pictures of your son.
5. PAPaola Arlotta
  Yeah.
6. LFLex Fridman
  Is it, uh, just the one?
7. PAPaola Arlotta
  Two.
8. LFLex Fridman
  Two.
9. PAPaola Arlotta
  Son and a daughter.
10. LFLex Fridman
  Son and a daughter. So, what have you learned from the human brain by raising two of them?
11. PAPaola Arlotta
  More than I could ever learn- (laughs)
12. LFLex Fridman
  (laughs)
13. PAPaola Arlotta
  ... in a lab. (laughs) What have I learned? I've learned that children really have these amazing plastic minds, right? That we have an r- a, a, a responsibility to, you know, foster their growth in good, healthy ways, um, that keep them curious, uh, that keeps them adventurous, uh, that doesn't raise them in fear of things. But also respecting who they are, which is in part, you know, coming from the genetics we talked about. My children are very different from each other, despite the fact that they're the product of two, the same two parents. I also learned that, uh, what you do for them comes back to you. Like, you know, if you're a good parent, you're gonna, uh, m- most of the time have, you know, perhaps decent kids at the end.
14. LFLex Fridman
  (laughs)
15. PAPaola Arlotta
  Um-
16. LFLex Fridman
  So what do you think, just a quick comment, what, what do you think is the source of that difference? That's often the surprising thing for parents.
17. PAPaola Arlotta
  Yeah.
18. LFLex Fridman
  Is that they can't believe that our kids, uh, th- oh-
19. PAPaola Arlotta
  Yes.
20. LFLex Fridman
  ... they're so, they're so different and yet they came from the same parents.
21. PAPaola Arlotta
  Yeah. Well, they are genetically different even though they c- they came from the same two parents because of the mixing of gametes and when, you know, we know there's genetics, creates every time a, a genetically different individual which will have spec- a specific mix of genes, uh, that is a different mix every time from the two parents. And so, um, uh, so they are not twins. They are genetically different. Uh-
22. LFLex Fridman
  Even just that little bit of variation, 'cause you said, really-
23. PAPaola Arlotta
  Yes.
24. LFLex Fridman
  ... from a biological perspective, the brains look pretty similar.
25. PAPaola Arlotta
  Well, so let me clarify that. So, the genetics you have, the genes that you have that play that beautiful orchestrated symphony of development, um, uh, different genes will play it slightly differently.
26. LFLex Fridman
  Right.
27. PAPaola Arlotta
  It's like playing the same piece of music but with a different orchestra and a different director.
28. LFLex Fridman
  Yes.
29. PAPaola Arlotta
  Right? The music will not come out ... It will be still a piece by the same, you know, author, but it will come out differently if it's played by the high school orchestra instead of the (laughs)
30. LFLex Fridman
  (laughs)

Episode duration: 57:41

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How unlikely is the human brain? Evolution, probability, and what we still don’t know

Species-specific developmental time: why humans take months and mice take days

From neural tube to cortex: building blocks, cell diversity, and ordered assembly

What is the ‘code’ of development? Genes plus mechanics (forces shape fate)

Postnatal maturation and myelin: insulation, speed, and an evolutionary surprise

Nature vs nurture: plasticity, experience, and sensory-driven rewiring

What brain organoids are (and are not): a practical window into human development

Modeling neurodevelopmental disease: patient-specific organoids and autism questions

Variability and scalability: why organoids differ, and how labs work to standardize them

Inside an organoid: cortical neurons, astrocytes, and synapse formation

Detecting ‘abnormal’ development: single-cell profiling and functional readouts

Where the field is headed: fast-moving tech, not 1000 years—plus the ‘build a brain’ question

Ethics and public discourse: continuous oversight, misuse concerns, and the power of language

Parenting, individuality, and the ‘next brain’: plasticity, evolution, and AI-shaped environments

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