Paola Arlotta: Brain Development from Stem Cell to Organoid

Paola Arlotta is a professor of stem cell and regenerative biology at Harvard University. She 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 conversation is part of the Artificial Intelligence podcast. If you would like to get more information about this podcast go to https://lexfridman.com/ai or connect with @lexfridman on Twitter https://twitter.com/lexfridman, LinkedIn https://www.linkedin.com/in/lexfridman/, Facebook https://www.facebook.com/lexfridman, Medium https://medium.com/@lexfridman, or YouTube https://www.youtube.com/lexfridman where you can watch the video versions of these conversations. If you enjoy the podcast, please rate it 5 stars on iTunes or support it on Patreon https://www.patreon.com/lexfridman.

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Lex 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 LexFriedman, spelled F-R-I-D-M-A-N. And I'd like to give a special thank you to Amy Jeffers for her support of the podcast on Patreon.

• 0:45Lex Fridman?

  She's an artist, and you should definitely check out her Instagram at @love-truth-good. Three beautiful words. Your support means a lot and inspires me to keep the series going. And now, here's my conversation with Paola Arlotta.

• 1:19Lex Fridman?

  You've 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 could put it another way, how unlikely is the human brain? How difficult is it to build a thing through the evolutionary process?

• 1:46Speaker 01

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

• 1:49Lex Fridman?

  Once, yes.

• 1:50Speaker 01

  Once. 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 the human brain. So how difficult is it to make the human brain is pretty difficult. But most importantly,

• 2:15Speaker 01

  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 brains or 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 like each other. So they're very different. And therefore, there is a limit to what you can learn about how the human brain is made by studying the mouse brain.

• 2:56Speaker 01

  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.

• 3:02Lex Fridman?

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

• 3:23Speaker 01

  Yeah. You pretty much find yourself, you know, 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

• 4:07Speaker 01

  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 postnatal to get the brain that we have today that allows us to this conversation. A mouse takes 20 days or so to

• 4:33Lex Fridman?

  So it's mouse time?

• 4:34Speaker 01

  For an embryo to be born. 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 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.

• 4:58Lex Fridman?

  So the very developmental process is...

• 5:01Speaker 01

  Controlled by the speed of the species.

• 5:05Lex Fridman?

  Which means it's by, it's on purpose, it's not accidental? Or there is something in that temporal dynamic to that development?

• 5:16Speaker 01

  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, it's a long time.

• 5:43Lex 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?

• 5:58Speaker 01

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

• 6:05Lex Fridman?

  What's the very beginning? Which beginning are we talking about?

• 6:08Speaker 01

  In the embryo.

• 6:09Lex Fridman?

  In the embryo.

• 6:09Speaker 01

  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 sort of the length of the embryo from the head all the way to the tail, let's say, of the embryo. And then, over in human beings, over many months of gestation, from that neural tube, which contains stem cell-like cells of the brain, you will make many, many other building blocks of the brain.

• 6:53Speaker 01

  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 the time in which you are making the building blocks, the cells.

• 7:10Lex Fridman?

  Are the stem cells relatively homogeneous, like uniform? Or are they all different?

• 7:15Speaker 01

  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.

• 7:25Lex Fridman?

  What's multipotent?

• 7:26Speaker 01

  Multipotent, it means that it can, it has the potential to make many, many different types of other cells. And then with time, these progenitors become more heterogeneous, which means more diverse. There are going to be many different types of these stem cells. And also, they will give rise to progeny, to other cells that are not stem cells, that are specific cells of the brain, that are very different from the mother's 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.

• 8:11Speaker 01

  So you can think about the embryonic development of the brain as the time where you're building the bricks. You're putting a bricks together 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 transmit action potentials and electricity.

• 8:35Lex Fridman?

  I've heard you also say somewhere, I think, correct me if I'm wrong, that the order of the way this builds matters.

• 8:41Speaker 01

  Oh, yes. If you are an engineer and you think about development, you can think of it as, well, I could also take all the cells and print 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 subserve the final product that you need to get. And so, for example, all of the nerve cells, the neurons, are made first. 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,

• 9:25Speaker 01

  they influence their own development. So it's a different thing for a glia to be made alone in a dish than a glia be made, in a glia cell be made in a developing embryo with all these other cells around it that produce all these other signals.

• 9:39Lex Fridman?

  First of all, that's mind blowing, that this development process. From my perspective in artificial intelligence, you often think of how incredible the final product is.

• 9:49Speaker 01

  Yeah.

• 9:49Lex Fridman?

  The final product, the brain. But you're making me realize that the final product is just, is the beautiful thing is the actual development process. Do we know the code that drives that development?

• 10:07Speaker 01

  Yeah.

• 10:07Lex Fridman?

  Do we have any sense?

• 10:09Speaker 01

  First of all, thank you for saying that it's really the formation of the brain. It's really its development, this incredibly choreographed dance that happens the same way every time each one of us builds the brain, right? And that builds an organ that allows us to do what we're doing today, right?

• 10:30Lex Fridman?

  Yeah.

• 10:31Speaker 01

  That is mind blowing, and this is why developmental neurobiologists never get tired. 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. But also mechanical forces of pressure bending. This embryo is not just, will not stay a tube. 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?

• 11:14Speaker 01

  Now, the, the forces that control that the cells feel, and this is another beautiful thing, the very force that they feel, which is different from a week before, a week ago, will tell the cell, oh, you're being squished in a certain way. Begin to produce these new genes. Because now you are at the 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.

• 11:45Lex Fridman?

  So.

• 11:46Speaker 01

  It's not only chemical, it's also mechanical.

• 11:48Lex Fridman?

  Mechanical. So from my perspective, biology is this incredibly complex mess, gooey mess. So you're saying mechanical forces.

• 11:59Speaker 01

  Yes.

• 12:00Lex Fridman?

  How different is a, like a, a computer or any kind of mechanical machine that we humans build and the biological systems?

• 12:10Speaker 01

  Yeah.

• 12:10Lex Fridman?

  Have you been, because you've worked a lot with biological systems.

• 12:12Speaker 01

  Yes.

• 12:13Lex Fridman?

  Are they as much of a mess as it seems from a perspective of an engineer, a mechanical engineer?

• 12:19Speaker 01

  Yeah. They are much more prone to taking alternative routes, right? So if you.

• 12:30Speaker 01

  We go back to printing a brain versus developing a brain. Of course, if you print a brain, given that you start with the same building blocks, the same cells, you could potentially print it the same way every time. But that final brain may not work the same way as a brain built during development does, because the very same building blocks that you're using developed in a completely different environment, right? That was not the environment of the brain. Therefore, they're going to be different, just by definition. So if you instead use development to build, let's say, a brain organoid, which maybe we will be talking about in a few minutes.

• 13:11Lex Fridman?

  For sure. Those things are fascinating.

• 13:13Speaker 01

  Yes. So if you use processes of development, then when you watch it, you can see that sometimes things can go wrong in some organoids. And by wrong, I mean different one organoid from the next. While if you think about that embryo, it always goes right. So this development, for as complex as it is, every time a baby is born has, you know, with very few exceptions, the brain is like the next baby. But it's not the same if you develop it in a dish. And first of all, we don't even develop a brain. You develop something much simpler in the dish. But there are more options for building things differently, which really tells you

• 13:57Speaker 01

  that evolution has played a really tight game here for how, in the end, the brain is built in vivo.

• 14:09Lex Fridman?

  So just a quick, maybe dumb question, but it seems like this is not, the building process is not a dictatorship. It seems like there's not a centralized...

• 14:21Lex Fridman?

  Like high level mechanism that says, okay, this cell built itself the wrong way. I'm gonna kill it. It seems like it's there's a really strong distributed mechanism. Is that is that in your sense?

• 14:33Speaker 01

  There are a lot of there are a lot of possibilities, right? And if you think about, for example, different species building their brain. 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, you know, one of us, and so on and so forth, and still is a brain, but it was built differently. 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. And so there are many possibilities.

• 15:16Speaker 01

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

• 15:42Lex Fridman?

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

• 15:47Speaker 01

  Few months, yeah.

• 15:47Lex Fridman?

  Few months. So yeah, the building blocks are constructed. The actual, the different regions of the brain, I guess, and the nervous system.

• 15:58Speaker 01

  Well, this continues way longer than just the first few months. So over the very first, you know, few months, you build a lot of the cells. But then there is continuous building of new cell types all the way through birth. And then even post natali, 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 of the neurons so that the electricity can go really fast from.

• 16:28Lex Fridman?

  The axons, I guess they're called.

• 16:29Speaker 01

  The axons, they're called axons, exactly. And so as human beings, we myelinate our cells postnatally. A kid, 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 also in response to what we do.

• 17:07Lex 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 in the brain. Is that totally wrong? So like, I guess it speeds up the...

• 17:28Lex Fridman?

  Okay, I might be wrong here, but I guess it speeds up the electricity traveling down the axon or something.

• 17:33Speaker 01

  Yeah, so that's the most sort of canonical, and definitely that's the case. So 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, I should say there are tracts of myelin and pieces of axons that are naked without myelin. And so by having the insulation, the electricity, instead of going straight through the cable, it will jump over a piece of myelin, right, to the next naked little piece and jump again. And therefore, you know, that's the idea that you go faster.

• 18:10Speaker 01

  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 want to go fast with this information from point A to point B. Well, a few years ago, maybe five years ago or so, we discovered that some of the most evolved, which means the newest type of neurons that we have as non-human primates, 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.

• 18:53Lex Fridman?

  Wow.

• 18:54Speaker 01

  And they have very interesting ways in which they put this myelin on their axons, you know, a little piece here, then a long track with no myelin, another chunk there, and some don't have myelin at all. So now, you have to explain where we're going with evolution. And if you think about it, perhaps as an electrical engineer, when I looked at it, I initially thought, and I'm a developmental neurobiologist, I thought maybe 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

• 19:36Speaker 01

  brain. Less myelin may 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.

• 19:50Lex Fridman?

  Well, so it seems like it's controlling the timing of the signal. So there, in the timing, you can encode a lot of information. And so the brain-

• 20:00Speaker 01

  The timing, the chemistry of that little piece of axon, perhaps it's a dynamic process where the myelin can move. Now you see how many layers of variability you can add, and that's actually really good if you're trying to to come up with a new function or a new capability or something unpredictable in a way.

• 20:22Lex Fridman?

  So we're gonna jump around a little bit, but the old question of how much is nature and how much is nurture? In terms of this incredible thing after the development is over, we seem to be kind of somewhat smart, intelligent, cognition, consciousness, all these things are just incredible ability of reason and so on emerge. In your sense, how much is in the hardware? In the nature and how much is in the nurture is learned through with our parents through interacting with the environment and so on.

• 20:58Speaker 01

  It's really both, right? If you think about it. 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, then we have this 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 genetic cues will then be used to incorporate the environment in its further maturation and development. And so your experiences do shape your, your brain.

• 21:43Speaker 01

  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. So perhaps some of the most illuminating studies that were done were studies in which the sensory organs were not working, right? Like if you are born with eyes that don't work, then your very brain, that piece of

• 22:28Speaker 01

  the brain that normally would process vision, the visual cortex, develops postnatally differently and it might be used to do something different, right? So that's the most extreme.

• 22:41Lex Fridman?

  The, the plasticity of the brain, I guess, is the magic hardware that it, and then it's, it's flexibility in all forms is what enables the learning postnatally. Can you talk about organoids? What are they?

• 22:56Speaker 01

  Yes.

• 22:57Lex Fridman?

  And how can you use them to help us understand the brain and the development of the brain?

• 23:02Speaker 01

  This is very, very important. So the first thing I'd like to say, please keep this in the video. The first thing I'd like to say is that an organoid, a brain organoid is not the same as a brain. Okay, it's a fundamental distinction. It's a system, a cellular system, that one can 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.

• 23:44Speaker 01

  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 of our own brain by studying a mouse? Well, we can 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.

• 24:27Speaker 01

  Remember that tube that is made by the embryo 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. But you can also think about diseases where development of the brain does not proceed normally, right? Properly. Think about neurodevelopmental diseases. There are many, many different types. 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,

• 25:10Speaker 01

  watch a process of formation of a brain organoid of that person.

• 25:14Lex Fridman?

  Of that person.

• 25:15Speaker 01

  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.

• 25:31Lex 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.

• 25:42Speaker 01

  Yeah.

• 25:42Lex Fridman?

  How often will it look similar? What's the um?

• 25:46Speaker 01

  Yeah.

• 25:47Lex Fridman?

  Uh, yeah, so.

• 25:47Speaker 01

  Reproducibility?

• 25:49Lex Fridman?

  Yes, or how much variability is the flip side of that?

• 25:52Speaker 01

  Yeah, so there is much more variability in building organoids than there than there is in building brain. It's really true that the majority of us, when we are born as babies, our brains look a lot like each other. This is the magic that the embryo does, where it builds a brain in the context of a body. And um, and there is very little variability there. There is disease, of course, but in general, a 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 somewhat builds itself because there are some structures of the brain that the cells know how to make.

• 26:34Speaker 01

  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.

• 26:46Lex Fridman?

  Right.

• 26:46Speaker 01

  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. Um, which happens instead in in in vivo. And also, uh, the variability that you see, one organo to the next, uh, tends to be higher than when you compare an embryo to the next.

• 27:21Lex Fridman?

  So, okay, then the next question is,

• 27:23Speaker 01

  Yes.

• 27:23Lex Fridman?

  How hard and maybe another flip side of that, expensive is it to go from one stem cell to an organoid?

• 27:30Speaker 01

  Yeah.

• 27:31Lex Fridman?

  How many can you build in life? Because it sounds very complicated.

• 27:34Speaker 01

  It's work, definitely, and it's money, definitely. But you can really grow a very high number of these organoids. You know, can go perhaps, I told you the maximum they become about five millimeters in diameter.

• 27:50Lex Fridman?

  Which is how many cells?

• 27:51Speaker 01

  So this is about the size of a tiny, tiny, you know, raisin.

• 27:56Lex Fridman?

  Yeah.

• 27:56Speaker 01

  Or perhaps the seed of an apple.

• 27:58Lex Fridman?

  Yeah.

• 27:59Speaker 01

  And so you can grow 50 to 100 of those inside one big bioreactors, which are these flasks where the media provides nutrients for the organoids. So the problem is not to grow more or less of them. It's really to figure out how to grow them in a way that they are more and more reproducible. For example, organoid to organoid, so they can be used to study a biological process. Because if you have too much variability, then you never know if what you see is just an exception or really the rule.

• 28:35Lex Fridman?

  So what does an organoid look like? Are there different neurons already emerging? Is there, you know, well, first, can you tell me what kind of neurons are there?

• 28:46Speaker 01

  Yes.

• 28:47Lex Fridman?

  Are they sort of all the same? Are they not all the same? Is, how much do we understand? And how much of that variance, if any, can exist in organoids?

• 29:02Speaker 01

  Yes. So you could grow, I told you that the brain has different parts.

• 29:08Lex Fridman?

  Right.

• 29:08Speaker 01

  So the cerebral cortex is on 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. And so we are very interested in the cerebral cortex.

• 29:32Lex Fridman?

  That's the coolest part, right?

• 29:33Speaker 01

  Very cool. I agree with you. We wouldn't be here talking if we didn't have a cerebral cortex. 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 many different types of neurons of the cortex appear. And at some point, also the astrocytes, so the glia cells of the cerebral cortex also appear.

• 30:13Lex Fridman?

  What are these?

• 30:15Speaker 01

  Astrocytes.

• 30:16Lex Fridman?

  Astrocytes.

• 30:16Speaker 01

  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. But of course, they have much more active type of roles. They're very important, for example, to make the synapses, which are the point of contact and communication between two neurons. They.

• 30:37Lex Fridman?

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

• 30:45Speaker 01

  It happens because of the interactions. It happens because you're making the cells, and they have certain properties, including the ability to make, 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. And this does happen within within organisms.

• 31:21Lex Fridman?

  With organisms, so the mechanical and the chemical stuff happens?

• 31:26Speaker 01

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

• 31:43Lex Fridman?

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

• 31:45Speaker 01

  It doesn't matter, both.

• 31:46Lex Fridman?

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

• 31:54Speaker 01

  Yes, so neurons are able to, it sounds, it's more simple than what it may sound to you. 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.

• 32:16Lex Fridman?

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

• 32:19Speaker 01

  No.

• 32:20Lex Fridman?

  But, but there's some, it's able to, especially what you're talking about, mimic some properties of the cerebral cortex, for example. So what, what can you understand about the brain by studying an organoid of the cerebral cortex?

• 32:37Speaker 01

  I can literally study how all this incredible diversity of cell type, all these many, many different classes of cells, how are they made? How do they look like? What do they need to be made properly? And what goes wrong? If now the genetics of that stem cell that I used to make the organoid came from a patient with a neurodevelopmental disease, can I actually watch for the very first time what may have gone wrong years before in this kid when its own brain was being made? Think about that loop. In a way, it's a little tiny rudimentary window into the past,

• 33:17Speaker 01

  into the time when that brain in a kid that had this neurodevelopmental disease was being made. And I think that's unbelievably powerful because today we have no idea of what cell types. We barely know what brain regions are affected in these diseases. Now we have an experimental system that we can study in the lab. And we can ask, what are the cells affected? When during development, things went wrong? What are the molecules, among the many, many different molecules that control brain development? Which ones are the ones that really messed up here? And we want perhaps to fix? And what is really the final product?

• 34:00Speaker 01

  Is it a less strong kind of circuit and brain? Is it a brain that lacks a cell type? Is it, what is it? Because then we can think about treatment and, and care for these patients that is informed, rather than just based on current diagnostics.

• 34:18Lex Fridman?

  So how hard is it to detect through the developmental process? It's a super exciting tool to, to see how different conditions develop.

• 34:31Lex Fridman?

  How hard is it to detect that, wait a minute, this is abnormal development?

• 34:37Speaker 01

  Yeah.

• 34:38Lex Fridman?

  That's how hard it, how much signal is there? How much of it is it a mess?

• 34:42Speaker 01

  Because things can go wrong at multiple levels, right? You could have 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 cells differently, and so on and so forth. So today, we have technology that we did not have even five years ago 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 that they produce, between a control individual and an individual with a neurodevelopmental disease,

• 35:26Speaker 01

  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 levels here. And we can study the cells at the molecular level, but also, we can use the organoids to ask questions about the properties of the neurons, the functional properties, how they communicate with each other, how they respond to stimulus, and so on and so forth. And we may get abnormalities there, right?

• 36:02Lex Fridman?

  Detect those. So how early is this work in the, maybe in the history of science?

• 36:11Speaker 01

  What a basic question.

• 36:13Lex Fridman?

  I mean, like, so if you were to, if you and I time travel a thousand years into the future, organoids seem to be, maybe I'm romanticizing the notion, but you're building, not a brain, but something that has properties of a brain. So it feels like you might be getting close to, in the building process, to build this to understand. So how, how far are we in this understanding process of development?

• 36:47Speaker 01

  A thousand years from now, it's a long time from now. So if this planet is still gonna be here a thousand years from now.

• 36:54Lex Fridman?

  So I mean, if, you know, like, they write a book, obviously, there'll be a chapter about you.

• 37:00Speaker 01

  That's right, that's science fiction book, today.

• 37:03Lex Fridman?

  Yeah, today, but, I mean, I guess where, we really understood very little about the brain a century ago. I was a big fan in high school of reading Freud and so on, still am of psychiatry. I would say we still understand very little about the functional aspect of just...

• 37:19Speaker 01

  Yeah.

• 37:20Lex Fridman?

  But, how, in the history of understanding the biology of the brain, the development, how far are we along?

• 37:27Speaker 01

  It's a very good question, and so this is just, of course, my opinion. I think that we did not have technology, even 10 years ago, or 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 of many other organisms. Now, we have some technologies which will spell out that allow us to actually look at the real thing, and look at the brain, at the human brain. So what are these technologies? There has been huge progress in stem cell biology.

• 38:06Speaker 01

  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, for example, make a brain, there was a huge, 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 build over the many, many, many years to say, how do we make these stem cells? Now make more and more complex aspects of development of the human brain. 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

• 38:51Speaker 01

  framework and really building on, you know, solid science for what reality is and what is not. And but it will go faster and it will be more and more powerful. We also have technology that allows us to basically study the properties of single cells 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 with very, very high resolution, the 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.

• 39:36Speaker 01

  So it's not going to be a thousand years. It's going to be a shorter amount of time. And I see this as sort of an exponential growth of this field enabled by these technologies that we didn't have before. And so we're going to see something transformative that we didn't see at all in the prior thousand years.

• 39:57Lex Fridman?

  So I apologize for the crazy sci fi questions, but the developmental process is fascinating to watch and study. But how far are we away from and maybe how difficult is it to build not just an organoid, but a human brain?

• 40:16Speaker 01

  Okay.

• 40:17Lex Fridman?

  From a stem cell?

• 40:18Speaker 01

  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.

• 40:38Lex Fridman?

  So let me just comment on that. It's fascinating. It shows to me the difference between you and I is you're actually trying to understand the beauty of the human brain and to use it to really help thousands or millions of people with disease and so on, right? From an artificial intelligence perspective, we're trying to build systems that we can put in robots and try to create systems that have echoes of the intelligence about reasoning about the world, navigating the world. It's different objectives, I think.

• 41:12Speaker 01

  Yeah, that's very much science fiction.

• 41:13Lex Fridman?

  Science fiction, but we operate in science fiction a little bit. So on that point of building a brain, even though that is not the focus or interest perhaps of the community, how difficult is it? Is it truly science fiction at this point?

• 41:27Speaker 01

  I think the field will progress, like I said, and that the system will be more and more complex in a way, right? But there are properties that emerge from the human brain that have to do with the mind, that may have to do with consciousness, that may have to do with intelligence or whatever, that we really don't understand even how they can emerge from an actual real brain and therefore we cannot measure or study in an organoid. So I think that this field many, many years from now may lead to the building of better neural circuits of, you know, that really are built out of understanding of how this process really works.

• 42:08Speaker 01

  And it's hard to predict how complex this really will be. I really don't think we're so far from, it makes me laugh really, it's really that far from building the human brain. But you're gonna be building something that is, you know, always a bad version of it, but that may have really powerful properties and might be able to, you know, respond to stimuli or be used in certain contexts. And this is why I really think that there is no other way to do this science but within the right ethical framework. Because where you're going with this is also, you know, we can talk about science fiction

• 42:49Speaker 01

  and write that book, and we could today, but this work happens in a specific ethical framework that we don't decide just as scientists, but also as a society.

• 43:01Lex Fridman?

  So the ethical framework here is a fascinating one, is a complicated one.

• 43:05Speaker 01

  Yes.

• 43:07Lex Fridman?

  Do you have a sense, a grasp of how we think about ethically of 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 by understanding it. But is there more, is there gray areas that are ethi- that we have to think about ethically?

• 43:38Speaker 01

  Absolutely. We must think about that. Every discussion about the ethics of this needs to be based on actual 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. They clearly can help you in many ways without much, 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, lawyers, philosophers, psychiatrists, psychologists, and so on and so forth,

• 44:22Speaker 01

  to decide as a, as a society, really, what we should and what we should not do. So that's the way to think about the ethics. Now, I also think, though, that as a scientist, I have a moral responsibility. So if you, if you think about how transformative it could be for understanding and curing a neuropsychiatric disease, to be able to actually watch and study and treat with drugs the very brain of the patient that you are trying to study. How transformative, at this moment in time, this could be. We couldn't do it five years ago. We could do it now, right?

• 45:07Lex Fridman?

  Taking a stem cell of a particular patient.

• 45:09Speaker 01

  Patient and make an organoid for a simple and, you know, different from the, from the human brain. It still is his process of brain development with his, with his or her genetics. 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?

• 45:36Lex Fridman?

  What is the downside of doing it?

• 45:40Speaker 01

  I don't see a downside.

• 45:42Lex Fridman?

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

• 45:45Speaker 01

  Yes.

• 45:45Lex Fridman?

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

• 45:55Speaker 01

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

• 46:40Speaker 01

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

• 46:48Lex Fridman?

  What do you think, at least historically, there was some politicization? Politicization of embryonic stem cells, of stem cell research? Do, do you still see that out there? 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?

• 47:16Speaker 01

  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 scientists have. The first-hand 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. I think that the scientists 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.

• 47:56Speaker 01

  And I think that is very, very important because they bring reality of data to the conversation. And so they should have a voice.

• 48:07Lex Fridman?

  So data should have a voice.

• 48:09Speaker 01

  Data needs to have a voice. Because, and not only data, we should also be good at communicating with non-scientists the data. So there has been, oftentimes, there is a lot of discussion and, you know, excitement and fights about certain topics just because of the way they are described. I'll give you an example. If I called the same cellular system we just talked about, a brain organoid, or if I called it a human mini-brain, your reaction is gonna be very different to this. And so the way the systems are described,

• 48:53Speaker 01

  I mean, we and journalists alike need to be a bit careful that this debate is a real debate and informed by real data. That's all I'm asking.

• 49:04Lex Fridman?

  And yeah, the language matters here. So I work on autonomous vehicles and there, the use of language could drastically change the interpretation and the way people feel about what is the right way to proceed forward. You are, as I've seen from a presentation, you're a parent. I saw you show a couple of pictures of your son. Is it just the one?

• 49:27Speaker 01

  Two.

• 49:28Lex Fridman?

  Two.

• 49:28Speaker 01

  Son and a daughter.

• 49:29Lex Fridman?

  Son and a daughter. So what have you learned from the human brain by raising two of them?

• 49:36Speaker 01

  More than I could ever learn in a lab.

• 49:40Speaker 01

  What have I learned? I've learned that children really have these amazing plastic minds, right? That we have a responsibility to, you know, foster their growth in good, healthy ways. That keep them curious, that keep some adventures, that doesn't raise them in fear of things. But also respecting who they are, which is in part, you know, coming from their genetics we talked about. My children are very different from each other despite the fact that they're the product of the same two parents. I also learned that what you do for them comes back to you. Like, you know, if you're a good parent, you're gonna

• 50:23Speaker 01

  most of the time have, you know, perhaps decent kids at the end.

• 50:28Lex Fridman?

  So what do you think, just a quick comment? What do you think is the source of that difference? That's often the surprising thing for parents.

• 50:36Speaker 01

  Yeah.

• 50:37Lex Fridman?

  Is that they can't believe that our kids are they're so different, yet they came from the same parents.

• 50:44Speaker 01

  Well, they are genetically different. Even they came from the same two parents because the mixing of gametes, you know, we know this genetics creates every time a genetically different individual, which will have a specific mix of genes that is a different mix every time from the two parents. And so, um, so they're not twins, they are genetically different.

• 51:08Lex Fridman?

  Even just that little bit of variation. As you said, really, from a biological perspective, the brains look pretty similar.

• 51:16Speaker 01

  Well, so let me clarify that. So the genetics you have, the genes that you have, that play that beautiful orchestrated symphony of development, different genes will play it slightly differently. It's like playing the same piece of music, but with a different orchestra and a different director, 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.

• 51:48Speaker 01

  In Stradale Scala in Milan.

• 51:49Lex Fridman?

  Yeah.

• 51:50Speaker 01

  And so you are born superficially with the same brain. It has the same cell types, similar patterns of connectivity. But the properties of the cells and how the cells would then react to the environment as you experience your world will be also shaped by who genetically you are. Speaking just as a parent, this is not something that comes from my work. I think you can tell at birth that these kids are different, that they have a different personality in a way, right? So both is needed, the genetics as well as the nurturing afterwards.

• 52:28Lex Fridman?

  So you are one human with a brain, sort of living through the whole mess of it, the human condition, full of love, maybe fear, ultimately mortal. How has studying the brain changed the way you see yourself? When you look in the mirror, when you think about your life, the fears, the love, when you see your own life, your own mortality?

• 52:50Speaker 01

  Yeah, that's a very good question. It's almost impossible to dissociate sometime for me. Some of the things we do or some of the things that other people do from, oh, that's because that part of the brain is working in a certain way. Or thinking about a teenager, you know, going through teenage years and being at times funny in the way they think. And impossible for me not to think it's because they're going through this period of time called critical periods of plasticity, where their synapses are being eliminated here and there, and they're just confused.

• 53:34Speaker 01

  And so from that comes perhaps a different take on that behavior or maybe I can justify scientifically in some sort of way. I also look at humanity in general and I am amazed by what we can do and the kind of ideas that we can come up with. And I cannot stop thinking about how the brain is continuing to evolve. I don't know if you do this, but I think about the next brain sometimes. Where are we going with this? Like, what are the features of this brain that, you know, evolution is really?

• 54:13Speaker 01

  Playing with to get us, you know, in the future, the new brain. It's not over, right? It's a work in progress.

• 54:23Lex Fridman?

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

• 54:56Speaker 01

  Yeah, I think in a way, that will happen, right? It's almost like a part of the way we evolve. We evolve in the world that we created, that we interact with, that shape us as we grow up and so on and so forth. Sometime I think about something that may sound silly, but think about the use of cell phones. Part of me thinks that somehow in their brain, there will be a region of the cortex that is attuned to that tool. And this comes from a lot of studies in model organisms where really the cortex especially adapts to the kind of things you have to do.

• 55:40Speaker 01

  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. An owl that has to see very, very far away with big eyes, the visual cortex, very big. The brain attunes to your environment. So the brain will attune to the technologies that we will have and will be shaped by it.

• 56:07Lex Fridman?

  So the cortex very well may be

• 56:09Speaker 01

  Will be shaped by it.

• 56:10Lex Fridman?

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

• 56:17Speaker 01

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

• 56:55Speaker 01

  So you could do it from the outside by simply hijacking some sensory capacities that we have. So clearly, 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.

• 57:31Lex Fridman?

  Well, there's no better way to end it, Paula. Thank you so much for talking today.

• 57:35Speaker 01

  You're very welcome. This is very exciting.