Assembloids: Recreating the Brain with Sergiu Paşca

How do you recreate a brain circuit in a dish, and what can it unlock about our minds? Neil deGrasse Tyson, Chuck Nice, and Gary O’Reilly explore the frontier of neuroscience with Sergiu Pașca, to break down stem cells, how the brain forms itself, and assembloids: self-organizing brain circuits.

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

• 0:00Neil deGrasse Tyson?

  So Gary, you keep digging up these neuroscience topics.

• 0:03Gary O'Reilly?

  Yeah.

• 0:03Neil deGrasse Tyson?

  They seem endless.

• 0:04Gary O'Reilly?

  Because we do not know yet all that we need to know.

• 0:08Neil deGrasse Tyson?

  This is good.

• 0:09Chuck Nice?

  I thought you were doing it because you were trying to give me a message.

• 0:12Neil deGrasse Tyson?

  Which was?

• 0:12Chuck Nice?

  Something's wrong with my brain.

• 0:15Neil deGrasse Tyson?

  That too, coming up on StarTalk.

• 0:20Neil deGrasse Tyson?

  Welcome to StarTalk, your place in the universe where science and pop culture collide. StarTalk begins right now.

• 0:32Neil deGrasse Tyson?

  This is StarTalk. Neil deGrasse Tyson, your personal astrophysicist, and today it's going to be special edition, which means we've got Gary O'Reilly. Gary?

• 0:41Gary O'Reilly?

  Hey Neil.

• 0:42Neil deGrasse Tyson?

  All right, man.

• 0:42Gary O'Reilly?

  Yeah.

• 0:43Neil deGrasse Tyson?

  Always good to have you.

• 0:44Gary O'Reilly?

  Pleasure mine.

• 0:45Neil deGrasse Tyson?

  Very good. And Chucky, baby?

• 0:47Chuck Nice?

  Hey man, what's happening?

• 0:48Neil deGrasse Tyson?

  All right.

• 0:49Chuck Nice?

  Not good to have me, I guess. Okay.

• 0:51Neil deGrasse Tyson?

  Okay, good to have you.

• 0:54Chuck Nice?

  Gary, always good to have you and?

• 0:55Neil deGrasse Tyson?

  And Chuck.

• 0:59Neil deGrasse Tyson?

  So you've got a word here, assembloids.

• 1:03Gary O'Reilly?

  Yes.

• 1:03Neil deGrasse Tyson?

  That sounds like somebody just made that up.

• 1:05Gary O'Reilly?

  Just assembled it. Yeah.

• 1:08Neil deGrasse Tyson?

  Assembloids. Well, this is a show on assembloids. What can you tell us about it?

• 1:12Gary O'Reilly?

  All right. Not that long ago, we did a show on synthetic biological intelligence, or if you prefer, organoid intelligence.

• 1:19Chuck Nice?

  Organoid, yes, I remember.

• 1:21Gary O'Reilly?

  Right, now.

• 1:22Chuck Nice?

  And those are, if I remember, like 3D cultures to build brain-like structures for bio-computing.

• 1:30Gary O'Reilly?

  Right, so that's what that was being used for.

• 1:33Neil deGrasse Tyson?

  For our future overlords.

• 1:36Gary O'Reilly?

  So this was putting biology onto technology. This is something different, however, it's based around the organoid. But this now becomes organized assembling together.

• 1:47Chuck Nice?

  Oh.

• 1:48Gary O'Reilly?

  Now that then?

• 1:49Neil deGrasse Tyson?

  Self-organizing organoids.

• 1:50Gary O'Reilly?

  So our guest today?

• 1:52Chuck Nice?

  All right. Oh, we just, okay, we're getting into it, baby.

• 1:57Neil deGrasse Tyson?

  What could go wrong?

• 2:00Gary O'Reilly?

  Let's not do that question just yet.

• 2:02Neil deGrasse Tyson?

  I'll say that for the end.

• 2:03Gary O'Reilly?

  Thank you.

• 2:03Neil deGrasse Tyson?

  Okay, go.

• 2:04Gary O'Reilly?

  So our guest today had the great idea of trying to get these organoids to work together and coined the phrase assembloids. So assembloids is down to our guest's work. Now, these assembloids can help us uncover the biological mysteries of our own minds.

• 2:20Gary O'Reilly?

  So are we just clumps of cells in the big Petri dish we can call life?

• 2:25Neil deGrasse Tyson?

  Yes.

• 2:26Gary O'Reilly?

  I think sometimes.

• 2:27Neil deGrasse Tyson?

  Speak for yourself.

• 2:27Gary O'Reilly?

  Sometimes it can feel like that. So um let's find our guest.

• 2:31Neil deGrasse Tyson?

  Did you say in the Petri dish of life?

• 2:33Gary O'Reilly?

  Yes.

• 2:33Neil deGrasse Tyson?

  That was beautiful.

• 2:34Gary O'Reilly?

  Was. You're welcome. I'm just reading it. And um.

• 2:39Gary O'Reilly?

  So let's let's see what mysteries have been sold, what mysteries are still out there. And our guest now. So drop in on our guest.

• 2:46Neil deGrasse Tyson?

  Yes, please. So we have Sergio Pasca. Sergio, welcome to StarTalk.

• 2:52Speaker 03

  It's great to be here. Thank you so much for having me.

• 2:54Neil deGrasse Tyson?

  Yeah. So you're a neuroscientist on StarTalk special edition. We love neuroscientists. Because that there's a serious future opening up right before our eyes.

• 3:03Speaker 03

  Yes, it is.

• 3:03Neil deGrasse Tyson?

  In plain in plain sight.

• 3:04Speaker 03

  A fresh frontier.

• 3:06Neil deGrasse Tyson?

  Fresh frontier. A stem cell biologist. Stem cells have been pretty much in the news on and off.

• 3:13Speaker 03

  Yeah.

• 3:13Neil deGrasse Tyson?

  The past couple of decades.

• 3:14Speaker 03

  Yeah.

• 3:15Neil deGrasse Tyson?

  A professor of psychiatry and behavioral sciences at Stanford. When I think about this, however, I think of a psychiatrist or behavioral scientist. They're just putting someone in a couch or observing their behavior. This sounds way more invasive than what it is you're doing.

• 3:33Speaker 03

  It sounds very puppeteerish.

• 3:34Neil deGrasse Tyson?

  Exactly. And you've also been Ted'ing. That's good. So we can dig you up in the TED archives, correct?

• 3:43Speaker 03

  Yeah.

• 3:44Neil deGrasse Tyson?

  Excellent. And at here in 2023, you've made a knight of the Order of Merit of Romania.

• 3:51Speaker 03

  Ooh.

• 3:52Neil deGrasse Tyson?

  All right. So let's get back to basics here and put us all on the same page with what an organoid is.

• 4:00Speaker 03

  So an organoid is a clump of cells that is cultured in a dish, in a three dimensional structure. And the name actually organoid, which is organ like, is supposed to suggest that it resembles an organ. So it's similar in some function. Of course, it's not a replica of an organ, but is supposed to model features of an organ.

• 4:26Neil deGrasse Tyson?

  So it's a scaffold, a scaffold of an organ.

• 4:30Speaker 03

  Well, I guess like parts of an organ or like parts of the function of an organ. So for instance, for the brain, it's not really a brain in miniature. It's not the entire organ in miniature, but it would be like parts or aspects of the brain uh that are being modeled.

• 4:44Neil deGrasse Tyson?

  And by the way, asteroids, they show up as stars on a on a in a photo because they're so tiny. Right. But they're not stars, so that's asteroids. Asteroid, little star. Yeah, yeah.

• 4:54Speaker 03

  Exactly. So it's organ-like, I guess, the same way you like star-like.

• 4:58Neil deGrasse Tyson?

  Mm-hmm. Oh, wait. Oh, so those are organoids?

• 5:01Speaker 03

  Yes.

• 5:02Neil deGrasse Tyson?

  All right. And so now, so now you organize them in some way? Or do they self-organize? You give them instructions that they follow?

• 5:10Speaker 03

  Well, I guess all of this work, to be honest, like started with the ability to actually even grow stem cells in a dish. If you were to kind of like step back and think like how this all came together. You know, stem cells, as you know, generally are derived, you know, from an embryo.

• 5:26Neil deGrasse Tyson?

  Right.

• 5:26Speaker 03

  Uh, and that has been certainly like very difficult uh to do studies, but then about.

• 5:31Neil deGrasse Tyson?

  It's certainly politically fraught with issues related to the ethics of using human human embryos. And and that was a big issue until you guys figured out, or your people figured out how to create stem cells without. Out of regular cells? Out of regular cells. So this is.

• 5:48Speaker 03

  Well, that happened twenty years ago, almost twenty years ago, nineteen years ago. Uh, when a Japanese scientist, Shinia Yamanaka, made this like breakthrough discovery. Where he actually showed that you could actually turn any cell that we have in our body that is already differentiated. So like back in time to look like those embryonic stem cells. And so almost like a, you know, so like cellular alchemy, so to speak, right? Because it was like, we always thought that it's a one-way street. Uh, development is a one-way street. You never sort of like go back.

• 6:20Neil deGrasse Tyson?

  Just to run the same page, stem cells, while it's always in the news, just as a reminder to the non-biologist. It is a kind of cell that you, under the right conditions, can turn into any other cell of the human body. Is that correct?

• 6:34Speaker 03

  Exact. Yeah.

• 6:35Neil deGrasse Tyson?

  Nerve cells. Muscle cells.

• 6:38Speaker 03

  Yeah.

• 6:38Neil deGrasse Tyson?

  And that's why they're prevalent in the embryo, because the embryo is manufacturing.

• 6:43Speaker 03

  All the cells.

• 6:44Neil deGrasse Tyson?

  All the cells.

• 6:44Speaker 03

  Right.

• 6:45Neil deGrasse Tyson?

  Okay. Gotcha.

• 6:46Speaker 03

  Stem cells have have two properties. They can turn into any other cells. And they can renew themselves. So they can stay as stem cells for a very long time. And of course, there are multiple levels of stem cells. The first ones are the ones that are the most powerful. They can turn to everything. And then as you progress in development, they become more and more restricted in what they can do. But the ones that are really in the beginning. Uh, are, you know, the ones that you would like to have so that you can ultimately guide them to become different other cells and tissues in in the body.

• 7:16Neil deGrasse Tyson?

  Wait, so you put them in a time machine. Is that that box that's sitting behind you?

• 7:21Gary O'Reilly?

  You say that, but how how is that possible? How how are you able to take a brain cell that you've cultured and dial it back to a stem cell and then bring it into whichever area you need to bring it to?

• 7:35Speaker 03

  So it was it's really a brilliant idea, uh, the build on work that was done before. And uh, essentially, the experiment was like very simply done. He just looked at the main genes that are expressed in the stem cells. And then he said, let's see which ones are really important. So he took them and he put them in a, actually in the skin cell. Took a skin cell and starting putting various combinations of those genes that are very strongly present in those stem cells. And through this combinatorial, you know, experiment, he found out four that if you put at the same time, you know, pretty much, you know, confuse the cell, so to speak,

• 8:17Speaker 03

  and the cell becomes reprogrammed. That's why we call it cell reprogramming. Because the cell is really reprogrammed to that state. And it turns out that they have all the properties of those embryonic stem cells. But you can make them from anybody in a non-invasive way. And of course, you can store them, you can ship them to others. And so that was. Really a breakthrough for the field because that opened up the possibility for the first time that you could get stem cells from anybody, from any patient, and then start to study it. In addition, I was finishing my clinical training around that time and really to a large extent like dropped everything because my expertise, I'm a physician by training, my expertise is actually autism spectrum disorders and neurodevelopmental conditions.

• 8:58Speaker 03

  And I was like incredibly frustrated by the lack of models to study this disease. We, you know, there are animal models, but you know, what is an animal model of autism? Right? I mean, that has been like a challenging aspect. We can't really access the human brain, right? I mean, that is sort of like the, you know, this curse, this unbearable inaccessibility of the human brain. I mean, it's behind the skull and unlike any other organ, you can't just like go there, get a biopsy and study it. So we were sort of like blocked, so to speak, locked into this state where we couldn't really make progress. And yeah, so about, you know, 16, 17 years ago, I came to Stanford mesmerized by the like potential of this stem cells that we can make, which we called induced pluripotent

• 9:43Speaker 03

  stem cells. And then started thinking, could we actually turn them into neurons from patients? And then study whatever defects are characteristic of that disease, but outside of the human body. And that's really what enabled, you know, all of this. And initially- So that blew open the whole field at that point. Yeah, exactly. They opened the whole field. And you know, in the beginning, just to make it clear, it was, you know, I mean, I got all the grants and all the fellowships rejected all the time as this being absolutely insane. You know, like, how can you actually like make neurons in a dish? And then even expect to find something from a disease that is so mysterious, right? Think about, I mean, autism is a complex disease of social behavior. What are you going to see actually in a dish? So I mean, we'll get back probably to this conversation, but it was actually key for

• 10:26Speaker 03

  us to focus on a disease where we actually like knew what to expect, sort of like to calibrate. And that's sort of like started that, you know, this entire journey. And in the beginning, most of these experiments were very simple. You know, you would take the stem cells from patients that would derive in a dish and then kind of like spike in various molecules in a dish. So like guide them to try to become neurons. And those differentiation experiments were like easy. But then about 10 years ago, it became clear that we're going to need more of the three dimensional aspect of development to really capture even more complex features of the brain. And that's how some of these 3D cultures, which are now known as organoids, appear first.

• 11:04Chuck Nice?

  So if the neurons are self-organizing, A, how do they know that they're self-organizing? And how do they know where to go and be organized?

• 11:15Speaker 03

  That's a very good question. And, you know, I mean, self-organization is a remarkable force of nature and biology, right? And very often, when we do these experiments in a dish, to be honest, for a very long time, I was still like thinking like an engineer. And that says that, oh, if you want to build something in a dish, let's say a circuit, you know, you better so like know the blueprint. You better know like the instructions and provide them at the right time. And so you don't start building a new house until you really have a very clear plan and the tools. But what we realize with time is that in biology, actually, you know, cells come with the instructions. You know, so once you make a specific cell, cell actually comes with the instruction. And then by connecting, let's say, to another cell, it reveals another set of instructions.

• 11:59Chuck Nice?

  Right.

• 11:59Speaker 03

  And another one, and another one. And that's why we call this process self-organization. So which really is the formation of order structured from, you know, relatively homogeneous elements, which, which, by the way, like talking of physics and chemistry, this was known from the 19th century. I mean, there are classic experiments that show, you know, that molecules organize quite beautifully. You know, the Riedel-Bernhard convection, I guess, is the classic example. But biology just brings it to the next level and now organize the cells pretty much on their own.

• 12:29Chuck Nice?

  So what you're doing is you're bringing these together in this culture, this 3D culture where the message and directions are already resident inside of the cell. So when you put them together or group them, they basically do what they were going to do anyway.

• 12:48Speaker 03

  Exactly.

• 12:49Chuck Nice?

  Okay.

• 12:50Speaker 03

  With, with, with one detail, which is we have to make the parts right. If you don't have the right parts, then of course they won't know what to do.

• 12:59Chuck Nice?

  What to do.

• 12:59Speaker 03

  Actually, what we spend a lot of time generally is making the parts. Let's think about the human brain. I mean, the reason why the human brain is remarkable is because it has all these parts, which are very different. You know, unlike, let's say, the liver. The liver is relatively homogeneous, right? A few cell types, kind of like any part is like any other.

• 13:17Chuck Nice?

  Mm-hmm.

• 13:18Speaker 03

  You look at the brain, and now you have thousands of cell types. I mean, the recent estimates, you know, say that there are probably 2,000 cell types just in the human brain. Right? Scattered through all these nuclei and regions. And the remarkable abilities of the brain really result from the cells interacting with each other. So in the early days, like, you know, 15 years ago, we were making just a few cells, like a few spinal cord neuron cells, or maybe a few cortical neurons. But then we've never really leveraged the ability of the cells to connect with each other. And so that's where essentially assembloids came, where once we figure out how to make some of the cell types, some of these brain regions, putting them together essentially, you know, was unleashing like new forces of self-organization,

• 14:00Speaker 03

  which is really what the brain does. I mean, the brain builds itself at the end of the day, you know, if you think about it, right?

• 14:05Chuck Nice?

  And it reorganizes itself. Like if you damage a part of your brain, it will reorganize itself so that that function might be taken up someplace else.

• 14:16Speaker 03

  At least early in development, yes. Early in development, it will do so. And then the more you progress, the, you know, the less you can do that.

• 14:23Chuck Nice?

  The less that happens, right.

• 14:24Gary O'Reilly?

  What if you leave your cultured brain cells in the dish for nine months, a year? What happens to them then? Do they just take care of business on their own, or do they just fade away?

• 14:35Chuck Nice?

  Something crawls out of the Petri dish.

• 14:36Gary O'Reilly?

  There you go.

• 14:37Chuck Nice?

  You have the smartest dish in the world. It'll chase you down the corridor. Get that fork away from me.

• 14:44Speaker 03

  But that was something actually, you know, really fascinating that we discovered, like, you know, almost 10 years ago. So at one point, we were, you know, my lab was still like in the early days. And at one point, you know, we realized that, well, I mean, it's a very expensive experiment. You have to keep feeding the cells and I was running out of money in the lab. And so I told everybody in the lab, I said, you better go in your incubators and like make sure that you're not maintaining cultures that we don't need. We need to focus, we need to save money. And then somebody in the lab comes and says, oh, should I also like remove the ones that are like 300 days old? I was like, what do you mean like 300 days old? It's like, yeah, I mean, you know, you know, I knew that we were keeping them for very long periods of time, but I had no idea that we could keep them for such a long period of time.

• 15:29Speaker 03

  And it turns out that once you make this cluster of cells and, you know, it's sort of like, I wish I could show you, I wish you were here in the lab and I could show you, or maybe I can try, but they look something like this.

• 15:38Gary O'Reilly?

  All right.

• 15:39Chuck Nice?

  I see it.

• 15:39Speaker 03

  They're a lot, they're still like fixed, you see. So they're like relatively large clumps of cells, they're floating in the media in the incubators, you keep going and change media. And then at one point, we realized we can keep them for very long periods of time. In fact, we maintain now the longest cultures that have ever been reported. Like, you can keep them for years. And so now the question was, are they stuck in development? Are they progressing in development? And through a series of papers, we discovered something really fascinating. It's like, they actually keep track of time really well. So well, that once they actually arrive at about nine months of keeping them in a dish, they actually transition in terms of their gene expression and some of the properties of the cells to a postnatal brain.

• 16:23Speaker 03

  So it's almost like they know that birth should happen. Wow. It's almost like, we think that there is some sort of internal clock that keeps track of time.

• 16:31Gary O'Reilly?

  Is this the brain clock that I've read about?

• 16:33Speaker 03

  Yeah, this is the brain clock, exactly.

• 16:44Speaker 04

  I'm Ali Khan Hemraj, and I support StarTalk on Patreon. This is StarTalk with Neil deGrasse Tyson.

• 16:59Gary O'Reilly?

  I'm fascinated now that these cells have the ability to understand, basically, a calendar. I mean, because they're not observing the sun going across the sky a day and a night.

• 17:13Chuck Nice?

  Yeah, so what's doing the ticking?

• 17:14Speaker 03

  Exactly. So, I mean, you may think that this is, you know, surprising, but if you think about it, it's not that surprising. I mean, every time you make a human, you always make it in like 280 days. And here's the interesting thing. If you take mouse stem cells, okay? Or we have like chimp stem cells, and you differentiate them the same way in a dish, they'll finish development in their own time.

• 17:38Chuck Nice?

  And the same, but in that same time period reflects the gestation period of a chimp or a mouse?

• 17:44Speaker 03

  Like, it will be three weeks for the rat, and it will be like, you know, whatever is for... So this is, I mean, evolution has actually selected, you know, very well, like, these periods of development. And so they're intrinsic to the cells. I think what was surprising for us was... Is that this happens also outside of the of the body, right, outside of the uterus. Of course, this is not to say that all aspects of development are recapitulated. I mean, there are all kinds of things that are coming, right, all kinds of informations that are coming, that are shaping development, and we know that the more you invest in human brain development, the more the environment is important. Like sensory information, right, like cognitive development, think about motor behavior afterwards. But especially at early stages of development, everything is quite well regimented and goes according to a calendar.

• 18:30Speaker 03

  Nobody knows what the clock is. So nobody knows what the molecular mechanism of it is. But it is somewhere in the cells, it's something that is counting somehow time and that's why it's such a great time to do neuroscience. Like more people should like come and do that.

• 18:45Gary O'Reilly?

  So where do these cells derive their energy from? Because you talk about a clock, there's not a battery in the back. What is powering this? Because they're outside of the body, they've not got the whole human system to back it up.

• 18:58Speaker 03

  So we feed them, so like, you know, a soup of chemicals that is made sort of like in the lab. So we like, we provide them glucose, right, I mean, they need glucose. And some of the amino acids, and we give them lipids, right, and so they need fats. And so we just like have, we call them cell culture media.

• 19:15Chuck Nice?

  And how do you measure if and when they are expressing their prescribed function? Because a neuron has a very specific function.

• 19:28Speaker 03

  Absolutely.

• 19:29Chuck Nice?

  How do you know that they are actually expressing that function?

• 19:33Speaker 03

  So we do all kinds of things, like, first of all, we just look to see, very often, you know, cells, I mean, not very often, all the time, cells have a signature. You know, they express a certain combination of genes. And so generally, the first question is, if you think you've made a cortical neuron, let's say a neuron from the outer layer of the brain, how do you know that it's a cortical neuron? Well, first of all, you kind of like look at what genes it expresses and you compare it with what we know from a neuron in the actual brain. Then you can look at how it looks. There are often neurons in the cortex have sort of like a pyramidal shape. We call them pyramidal neurons. So you look, do they look pyramidal?

• 20:09Neil deGrasse Tyson?

  Pyramid, that means like a pyramid?

• 20:11Speaker 03

  Yeah, exactly.

• 20:12Neil deGrasse Tyson?

  Pyramid, that, don't know, okay. For me.

• 20:15Speaker 03

  Pyramid, yeah, I guess. They really look like a tiny pyramid.

• 20:19Neil deGrasse Tyson?

  Okay.

• 20:19Speaker 03

  Yeah, an inverted pyramid, like that's how they sit in the cortex. So you look at this like the shape of the, of the cell body. Or the other thing is sometimes they move in very specific ways. And that's actually how the first assembloids were actually looking at how cells are moving. So here, here's this interesting fact. You know, you may think that, you know, you have all the cell types in the brain, right? But they're all made, you know, when you build the brain, they're all made sort of like in their place and then they sit there. Actually, it's more an, you know, a rule rather than an exception that cells do not reside in the place in which they're born in the brain. So there is a lot of movement. So think about the cortex, okay, like the outer layer of the brain. It has neurons that are exciting other neurons and it has neurons that are inhibiting other neurons.

• 21:04Speaker 03

  And there is a very good balance between the two of them. Too much excitation, you get epilepsy, right? So, you know, think about that. Now, here's the interesting thing. All the excitatory neurons are born there in the cortex. But all the neurons that are inhibitory are built in a deep part of the brain. And literally during brain development, they start moving, crawling for inches and for many, many months until they arrive into the cortex. And then they kind of like establish that balance. So in order for you to build that cortex, it's not enough just to make the excitatory cells, you have to make the inhibitory cells. But then the question is, how do they come together? How do they assemble? Cause that's where the name assembloid came.

• 21:49Speaker 03

  And essentially the vision was like almost, you know, 12 years ago was let's make these two parts of the brain. The one that makes the excitatory neurons and the one that makes the inhibitory neurons. And then just put them close to each other. And hopefully the cells will know what to do because we certainly don't know how to guide them to move. And it turns out that exactly what they do, you put them together and these gastric cells immediately start like they have this processes, the cellular processes, they start sort of like smelling where the cortex is and they literally start jumping. You know, you see the cells, they literally spend three hours, they look in that direction and then they make a jump 40 microns, then they wait for another three hours, kind of like smell where the cortex is, make another jump. And this process has never really been seen in humans.

• 22:34Speaker 03

  This happens in the third trimester of life.

• 22:36Chuck Nice?

  But this is, this is what's going on in every developing human being, what you're describing. So Professor, what you're saying is basically we have a bunch of cells that are in a field and they, they're looking and they recognize one another and then they just start running to each other in slow motion.

• 22:50Speaker 03

  Pretty much, pretty much because they really come with instructions of how to do this. And I think that's what happens in development and that's why you build a brain. I mean, our brains may be a little bit different from each other, but in the grand scheme of things, they're quite the same, right? I mean, we have the same structures. It's not like, you know, you have a thalamus in the spinal cord, right? We all have pretty much in the same position. So in order for, you know, the brain to build itself that way, there are these remarkable forces that bring all the cells together over and over again, every time you build a human brain.

• 23:26Chuck Nice?

  Wow. Okay, this is the last thing, I'm sorry. I know we gotta move on to the next subject, but here's what is like percolating in my brain right now. Is this, once you kind of perfect this technology, would you be able to then introduce these cells and have them go in and let's say for instance, repair a part of my brain that kind of makes me so stupid, I don't believe in climate change or something?

• 23:57Speaker 03

  Well, this sort of like a self-assembly actually works really well early in development in the sense that all the cells are open to like connecting with the others. But then it turns out that as you progress in development, the cells become less and less permissive. We don't have cells moving in our brain right now.

• 24:16Chuck Nice?

  Okay.

• 24:17Speaker 03

  You know, it's just not very adaptive. So the challenge is that if you start to add the cells into an adult, like those circuits already form, so it's not that easy.

• 24:25Chuck Nice?

  I got you.

• 24:26Neil deGrasse Tyson?

  To the dumbass circuitry.

• 24:27Chuck Nice?

  The dumbass circuitry is fully formed and very, very strong. However, if you're able prenatal to identify brain disorders or any disorder in a child, you might be able during the gestation process to go in and make changes.

• 24:46Speaker 03

  Exactly, and that's exactly what we're doing, actually even early after birth. Because the human brain develops for like years, even after we're born.

• 24:52Chuck Nice?

  That's amazing.

• 24:53Gary O'Reilly?

  So Professor.

• 24:54Chuck Nice?

  That's amazing.

• 24:56Gary O'Reilly?

  All right, so Professor, you did some work and some research with cells and you said you worked with autism patients and the like. And there's something called Timothy Syndrome, which is autism and epilepsy, which seems a terrible combination to.

• 25:10Chuck Nice?

  It's terrible for Timothy, damn.

• 25:12Gary O'Reilly?

  But you then afflicted cells with this Timothy Syndrome, is that correct?

• 25:19Speaker 03

  Yeah.

• 25:20Gary O'Reilly?

  And then reverse engineered how you could find a way to work with and do basically what you said, take that away.

• 25:29Chuck Nice?

  Right.

• 25:29Gary O'Reilly?

  Is that, I mean, I am explaining that at all well, but you probably could do it better than I.

• 25:34Speaker 03

  Yeah.

• 25:34Gary O'Reilly?

  If you would.

• 25:35Speaker 03

  I mean, this goes back to like, you know, the previous point when we were talking about how these stem cells were so like discovered and what their potential was. So the question was, if you really want to model a disease, you know, you want to model a complex disease such as autism and epilepsy, you know, where do you actually start? I mean psychiatric disorders are mysterious disorder. We still don't know how like this, you know, starts and this complex social behavior arises in the brain. So actually, we thought we would start with genetics. Because one thing that we do know about many of these neurodevelopmental disorders is that they're caused by mutations. They're caused by very severe mutations.

• 26:12Chuck Nice?

  Alright.

• 26:13Speaker 03

  So there's this rare, rare syndrome. I mean, literally, there are about, we found about thirty, forty patients in the English-speaking world today, very few. But they have a mutation, this patient, in a protein that is actually a channel for calcium in the cells. Every time a neuron communicates with another neuron, it opens up these channels, lets calcium in, and it essentially translates electrical information into chemical information inside the cell. So it turns out that this patient have one single letter mutation in their entire genome, one single letter, that makes this channel open for a little bit longer. That's it. It's not all the time open, it's not, you know, just slightly longer.

• 26:57Speaker 03

  So the idea was that if you were to model this disease, you could make neurons from these patients, then look at them and actually monitor calcium inside the cells. And if we were to see more calcium, it means that we started modeling the disease. And that's exactly what we did, because we wanted to really ascertain that we were really studying the disease process that is relevant.

• 27:17Chuck Nice?

  So if, if you know the actual letter, and when you're talking about that, you're talking about the DNA sequencing, so if you know the actual letter, why not do something like CRISPR, where you just go in and snip out the letter?

• 27:30Speaker 03

  Well, sadly, you would have to change it everywhere in the brain.

• 27:33Chuck Nice?

  Ah, there you go.

• 27:34Speaker 03

  And that, and that is not, you know, doable today.

• 27:37Chuck Nice?

  Okay.

• 27:38Speaker 03

  And these patients are very severely affected. I mean, they'll have epilepsy, they'll have autism spectrum disorder, they have a heart problem, so many of them would die because of a heart problem. And so that's, that's where we sort of like started, with, with cells from these patients. And then with these models that I've told you now for the past fifteen years, we kept building the models to be more complex and try to understand this disease. And first we understood how calcium gets into the cells, then we saw that the cells are not moving right, they're not connecting properly. And about three years ago, which was, you know, one of the most interesting, you know, times in, in sort of like my academic life, was at one point, we just accumulated enough information about the disease that essentially the therapeutic just became self-evident, so to speak.

• 28:23Speaker 03

  You know, just like, look at it, and they would say, oh, oh, this makes sense, this is what we need to do. And so I don't want to go into the details of how within does, but it has to do with how this gene is processed inside the cells. We've done a screen and essentially identify a tiny piece of a nucleic acid. That if you add to cells, goes right into them. Changes the channel and essentially restores almost every single defect that we've discovered over the past fifteen years.

• 28:49Neil deGrasse Tyson?

  Damn.

• 28:50Speaker 03

  Just like within, you know, a couple of days.

• 28:52Neil deGrasse Tyson?

  This is insane.

• 28:53Gary O'Reilly?

  I know, but this.

• 28:54Neil deGrasse Tyson?

  What you're talking about.

• 28:55Gary O'Reilly?

  He's a Sherlock Holmes. This is real detective work.

• 28:58Neil deGrasse Tyson?

  I mean.

• 28:58Gary O'Reilly?

  To work out that that is exactly what's necessary. I mean, you said it was obvious, but obviously it wasn't, but otherwise someone would have seen it a long time ago.

• 29:07Neil deGrasse Tyson?

  So if you were around in Frankenstein's day, Frankenstein would have just been a regular Joe.

• 29:10Chuck Nice?

  Yeah.

• 29:11Neil deGrasse Tyson?

  On the street.

• 29:11Chuck Nice?

  Yeah, he would have walked out instead of like, ah, he would have been like, hey, what's going on? How you guys feeling?

• 29:20Gary O'Reilly?

  Are you mapping this with sort of an AI technology? I mean, CRISPR's one tool, but there are others out there. Is that what it is? Or is this just the empirical evidence from experiment?

• 29:31Speaker 03

  It's largely empirical. I mean, we've just, you know, just accumulated enough information about the biology that at one point it became clear. And it's quite interesting if you think about it, because this is could be the first psychiatric disease. That has been exclusively understood with this human stem cell models, meaning by studying it, by studying human brain cells outside of the body of those patients. Right? And so of course the question is like, how do you actually, you know, know that it would work? You know, generally what we do is we use an animal model for the disease, right? You have an animal model, you have a mouse that has the same mutation. Well, it turns out that if you do this mutation in a mouse, it doesn't really recapitulate aspects of disease. It doesn't work that well. So now what do you do? You can also just go straight into a patient. You want to make sure that sort of like.

• 30:15Speaker 03

  It it it works sort of like in an in vivo setting. And so that's why one of the things that we've done over the past years is actually also develop transplantation methods. Meaning that while the organisms and the assemblies that we've been building are rather complex. They still don't receive sensory input. They don't mature to the same level. So what we started doing is actually transplanting them. Meaning we essentially take the organ that we've made in a dish. But now we put it into the brain of a rat. And then if you do it early in development, then the rat can actually grow to have about a third of a hemisphere to be made out of human cells. You can literally see it on an MRI. And you may think, oh, this is, you know, why would you even do that experiment? Well, the reason is because now we actually have

• 30:58Speaker 03

  human tissue from patients in a living organism, and you can test the drug. So what we did is we took the drug that we tested in vitro in a dish, but then injected it into the rat the way you would do into a patient. But then we looked at the effect on human cells, making sure that it doesn't kill human cells or it doesn't do something else. So that is like one way that allows us actually to test therapeutics in a way that is like safe, essentially.

• 31:43Gary O'Reilly?

  So the thing is, if you want to solve the issues of complex brain disorders, you're going to need more complex assembloids. Now, you've taken this assembloid up a notch, have you not? And daisy chained four organoids together, but then gone down the path of sensory? If you could sort of expand on that for us, because I think this is absolutely fascinating.

• 32:12Neil deGrasse Tyson?

  You're telling me they have feelings? Is this what you're telling them?

• 32:14Gary O'Reilly?

  No. Let the professor explain.

• 32:16Speaker 03

  No, you know, I mean, it turns out that if you, if you think about like brain disorders, you know, some of them are sort of like hardware defects, right? I mean, parts are just missing. Think about in a stroke, right? You like, you know, you lose like parts of the cortex. But most disorders that we consider today psychiatric, autism, schizophrenia, we think of them more as like disorders of software, of communication between the cells. So it becomes really clear that if you really want to capture those processes outside of the human body, we still like need to reconstruct those circuits outside. And so this started like, you know, maybe five, six years ago when we thought, could we actually build a circuit that is actually has an output, you know, really easy to measure.

• 32:58Speaker 03

  So we decided to reconstruct the cortical spinal pathway. So that means, and you, you know this really well. Everybody knows this. This is like biology textbook information. You have a neuron in the cortex that generally goes all the way to the spinal cord, makes a connection or a synapse with the spinal cord neuron. And that spinal cord neuron goes to muscle. You have essentially three neurons, two connections. You stimulate the cortical neuron. Information goes down to the spinal cord, to the muscle, the muscle contracts. Right? You know, it's as easy as like textbook biology. So we thought, could we actually reconstruct this? You may think that it's easy, but here is, we don't know how the cells find each other in development. By the way, we have no ideas about the rules.

• 33:41Speaker 03

  So what we did is we made an organoid that resembles the cortex, one that resembles the spinal cord. And then we made a ball of human muscle from a biopsy. You can get a biopsy of muscle, build it as a ball. And then we put them all three together. And it turns out that once you do this, those specialized neurons in the cortex, not every cortical neuron, but the ones that really go to the spinal cord, start to leave the cortex, find the motor neurons. Then the motor neurons leave and find the muscle. And then the three preparation starts to contract.

• 34:13Chuck Nice?

  Wow.

• 34:14Speaker 03

  Now, that was, that was a three-part assembloid.

• 34:16Chuck Nice?

  All right.

• 34:17Speaker 03

  And that, that told us that even, you know, against the odds, because the probability is for the cells to find each other is very, very low. And yet this works beautifully. And you can actually stimulate the cortex and you get beautiful muscle contractions. And we've been using this, you know, really in the last years to identify, for instance, how polio virus and other non-polio enteroviruses actually affect the spinal cord and cause paralysis, which is very difficult to study otherwise. So it is a very important sort of like preparation. You can add this polio virus and you can cause a paralysis of that circuit in a dish. This work is not yet published, but it tells you like just how useful a preparation like this can be.

• 34:57Chuck Nice?

  It's beyond useful. I mean, I'm, what I'm trying to figure, not figure out, envision is a time where we've mapped like,

• 35:07Chuck Nice?

  Everything, right? So you have, you have the layout. Now, would there be a time because of what you're saying that we'll be able to go in, identify in a child that is developing in the womb, and then identify mutations? And then, take the assembloids, put them into the child, and have those mutations corrected before the child is born? Is that the deal?

• 35:37Speaker 03

  Perhaps even an easier scenario for that.

• 35:39Chuck Nice?

  Okay, go ahead.

• 35:40Speaker 03

  Have a mutation. You know that a patient will have a serious mutation. You build an assembloid that models the disease of that patient without using the patient brain. So like, an avatar, if you want, right? I mean, that's what an assembloid is, if you think about it, right? It's an avatar for that circuit. Simplified in a dish. You test the drug, or you screen for drugs. Maybe you wanna screen quickly for drugs.

• 36:04Chuck Nice?

  Right.

• 36:05Speaker 03

  And then you use that in a patient.

• 36:06Chuck Nice?

  So now you can do that for every single patient? You don't have to actually do the process in any particular patient? Because now you developed a drug for the mutation itself. Now, just boom, boom, boom. Every single person with that mutation gets that drug delivered. And that's how, wow, that's amazing.

• 36:24Speaker 03

  But to get there, we do need to get a better understanding of how. Because you see, we're quite...

• 36:28Chuck Nice?

  Why do, wait, why do you have to understand why the cells do what they do? They're doing it. You already know, why do you have to? Are you just that newsy?

• 36:36Neil deGrasse Tyson?

  He's a scientist.

• 36:38Chuck Nice?

  That's right, because he's looking, look at Neil. Neil's looking at me like, how dare you?

• 36:42Neil deGrasse Tyson?

  He's a scientist.

• 36:43Chuck Nice?

  How dare you?

• 36:44Neil deGrasse Tyson?

  We don't accept just what is.

• 36:46Chuck Nice?

  I understand.

• 36:47Neil deGrasse Tyson?

  Go on, go on, please.

• 36:48Speaker 03

  If you actually think about, like, Richard Feynman. He famously said, and I'm sure you know this, that what I cannot create, I do not understand. And you know, if you think a little bit about this, right? If we cannot recreate the circuits outside, it's gonna be difficult for us to understand. And if we don't understand the biology, all the breakthroughs in medicine that came over the last decades. Think about cancer in children, right? In the 60s, 90% lethal. Today, less than 10% lethal. Why this entire revolution? Molecular biology.

• 37:21Chuck Nice?

  Right.

• 37:22Speaker 03

  Because the tissue of interest was accessible. You get the blood of this patient in leukemia or the tumor, you bring it to the lab and you deploy the power of molecular biology. We in psychiatry and neurology are really the last ones because we cannot access the brain. So my belief is that as we gain access to the brain through these methods and others, non-invasively, we're going to be able to deploy the power of molecular biology and make breakthroughs in molecular, you know, psychiatry and neurology as we've done in, you know, uh, cardiology and other branches of medicine. That's, that's sort of like how I see it, but I may be wrong.

• 37:56Gary O'Reilly?

  But haven't you got an assembloid now that's, like I said, a four-stage assembloid, but you've worked it so as it's sensory and you can feel the understanding of pain? And then how that becomes hypersensitivity or to the point where people do not feel pain at all?

• 38:13Chuck Nice?

  Oh, okay. I thought you meant like they're gonna have that little vial of assembloids just screaming in the middle of the night.

• 38:22Chuck Nice?

  Why did you give me pain?

• 38:24Gary O'Reilly?

  Not that one.

• 38:25Speaker 03

  No, you're, you're right. That one of the things that we're trying, and actually this, this just came out. I mean, we made the first assembloid in like 2017. It took us three years to make fro- go from two-part assembloids to three-part assembloids, the one with the motor that I was explaining. And then it took us another five years to get to four-part assembloids. Just because it's technically more and more complicated. And this is the pathway that senses, you know, sensory information. So think about it, if you, you know, want to sense anything, even a painful stimulus on a finger, you have nerve terminals that are coming from neurons that sit close to the spinal cord. They have receptors that sense that. Then they send that information to the spinal cord. The spinal cord shoots that information up to the thalamus in the middle of the brain, and the thalamus sends it to the cortex.

• 39:10Speaker 03

  And then you sense that something happened. You know, that's how it works. So what we did is essentially we tried to reconstruct that from part. So we made neurons that have some of these receptors, including receptors for pain. So you know, the receptors for pain actually respond to capsaicin, you know, red hot chili pepper. That's why it's like so hot. So they have this specialized receptors and you add capsaicin and they just beautifully respond, like electrically.

• 39:34Gary O'Reilly?

  But this had never been witnessed before, had it?

• 39:37Speaker 03

  No, I mean, to put the entire circuit together has never really been done before.

• 39:40Gary O'Reilly?

  Now, what was that like for you to witness this the first ever time?

• 39:45Speaker 03

  Well, the most beautiful part of it was, to be honest, once we made the parts, which took us years, you know, the four parts of the circuit and then put them together. And it takes about a hundred days to make them, by the way. And then another hundred days for the cells to connect with each other. And then at one point, we started like looking at them and seeing like what's going on. And we've discovered something, you know, really remarkable. The cells in the circuit become synchronized with each other. So initially they were all sparkling, you know, in a non-coordinated way. And then at one point, the activity just seems to be starting on one side and it goes, you know, one unidirectional. So the circuit is almost, you know, and there's no stimulus, by the way.

• 40:25Speaker 03

  You know, it's almost like, which we know also from brain development, that the brain prepares itself before it even receives sensory inputs for what is about to come. It's almost like practicing. So it's practicing to add, you know, the stimulus. And then the relevance for pain is that there are this interesting, maybe you've heard about this, neurologists discovered them, you know, in the past twenty years. There are these patients that have mutations that make them either completely insensitive to pain. So they literally feel no pain. And it's really caused by a mutation in a channel, in a sodium channel. Or they have the opposite. They have this channel hypersensitive, so they're hypersensitive to pain. Both of them are obviously very bad. So now what we did, we used CRISPR, because we were talking about CRISPR before,

• 41:08Speaker 03

  and genetically modified the cells in addition to half the mutations that are present in patients. Then put them together, all four, and started watching to see what happens. And in the patients that have that hypersensitivity to pain, they're very sensitive to pain, you just see the information going really, really fast. The cells are super active and they sense it. But in the ones that have no pain, it's not like there's no activity at all. Actually, what we found is there's a lack of coordination.

• 41:34Chuck Nice?

  Right.

• 41:35Speaker 03

  The cells are essentially like lost that coordination. So that's why it's so important to have the parts, because really, at the end of the day, you know, the brain is more than the sum of its parts, obviously. And so clearly, in order to understand some of these disorders, we're gonna need to have some of these parts put together to get this emergent new properties.

• 41:54Gary O'Reilly?

  See, not feeling pain, well, that's the new, that's the Novocain movie, isn't it?

• 41:57Chuck Nice?

  Yeah, but you know, that, I mean, we see this in certain people that, okay, I remember we did on, on the TV show, and Neil has this crazy thing, he could stick his hand in water, ice water. I'm not, and I'm not saying it right. Take a bunch of ice, add water to it, and it actually becomes colder than freezing, okay?

• 42:18Speaker 03

  Yes.

• 42:19Chuck Nice?

  All right. Then you put your hand in it, and it burns your hand. So we did an experiment, and I stuck my hand in, and he stuck his hand in, and literally my hand started burning in what a normal person would have their hand burn. And then, he was able to leave his hand in there for a god-awful amount of time, to the point where- This is while you were squealing at the time. Well, yes, I was, because it burned. It, it was not cool, so- Not literally burned, because it's cold, not hot. Right. It not literally burned, but it felt like it was burning. Okay. But for you, for some reason, and you know, I just chalked it up to, he got a lot more fat on his hands to get-

• 43:01Chuck Nice?

  But seriously, it's a matter of sensitivity to pain. No.

• 43:06Speaker 03

  Absolutely.

• 43:06Chuck Nice?

  No, it's not? No. What is it?

• 43:09Neil deGrasse Tyson?

  I didn't say I didn't feel the pain. It's just that I could deal with it.

• 43:13Gary O'Reilly?

  Yeah.

• 43:14Neil deGrasse Tyson?

  Oh. Well, that just changes everything.

• 43:17Gary O'Reilly?

  Okay, so explain to me the mind over matter aspect here.

• 43:20Speaker 03

  Yeah, and that's a great point, actually, because you see, this is not the only pathway for pain. It turns out that we have at least two pathways in the brain. One of them allows you to tell there is a painful stimulus. You know, I sense it, it's on my finger, or my hand is in the water, not my feet. Right? That's the one that tells you that. And then there is a second pathway that actually leverage other brain regions, the amygdala, the cingulate cortex, that tell you that that is really bad. It gives you the unpleasant feeling, the emotional component of pain. And you know, they're interesting. There are patients who dissociate between the two. So there are patients who, let's say, have a stroke or a tumor in the insula or in the cingulate cortex. And you'll have these patients and they'll tell you,

• 44:03Speaker 03

  you know, I know you're, you know, you're hurting like my finger and I can tell you that it is my finger, but it doesn't feel unpleasant at all. So these pathways are dissociated in the brain. Now, in the work that we've done, we've reconstructed the basic pathway that just processes pain stimuli, not the emotional component. So we wouldn't say that they're feeling pain in any way, right? Just to make it clear, because as you can imagine, there are all kinds of other ethical issues that are arising from like most of the work that we do, obviously, because, you know, we want our models to be closer to the human brain because we think that many of the psychiatric disorders are uniquely human. And yet, the more, the closer they are to the human brain, the more uncomfortable we feel.

• 44:45Speaker 03

  Right? So I think it's sort of like mitigating this risk moving forward that I think is very important.

• 44:49Gary O'Reilly?

  How do you now, having had this experience with, with the sense, sensory aspect of it, reverse engineer again the way to get a drug to alleviate the hypersensitivity to pain?

• 45:04Gary O'Reilly?

  Sure.

• 45:05Speaker 03

  I mean, there are many ways that you can do this. So like, now think about it.

• 45:07Chuck Nice?

  It's called scotch.

• 45:09Gary O'Reilly?

  Well, no, everybody, everybody, everybody's got a thing with opioids. But there must, there must be a mechanism there where opioids used that you can sort of

• 45:17Speaker 03

  Exactly.

• 45:17Gary O'Reilly?

  tag on to, but not get that addictive part.

• 45:20Speaker 03

  Exactly. And think about it, like, it's, it's sad that the best, the best treatment that we have for like pain comes out of like poppy seeds and what's discovered thousands of years ago by chance, right? I mean, essentially, piggybacks on the circuit does not come from a deep understanding of the circuit itself.

• 45:35Chuck Nice?

  The circuit.

• 45:36Neil deGrasse Tyson?

  Don't you make opium from poppy seeds?

• 45:37Chuck Nice?

  Yes.

• 45:38Neil deGrasse Tyson?

  Okay, I just want to clarify that.

• 45:39Speaker 03

  Yeah. So I think the, the idea now is that we have the circuit in a dish. You can add opioids, by the way, and see how they modulate this and see, okay, this is what opioids do to the circuit. But let's now try to do the same thing in a different way.

• 45:53Chuck Nice?

  Right.

• 45:53Speaker 03

  Right? One that is sort of like, you know, driven by the biology behind it. And I think that, that's the beauty of it.

• 45:59Chuck Nice?

  That is a beauty. And by the way, Professor, if you ever get to that place, please email me right before you make that public, because I would like to be the first investor

• 46:11Chuck Nice?

  in the pain-free opiate that is non-addictive, because that is, I mean, that's the, that's the end of the game right there.

• 46:19Neil deGrasse Tyson?

  And just to be clear, Chuck.

• 46:21Chuck Nice?

  What?

• 46:21Neil deGrasse Tyson?

  Because when my hand was, I just wanted to like, get back to my hand in the ice bucket.

• 46:25Chuck Nice?

  Yeah.

• 46:25Neil deGrasse Tyson?

  Okay. Long ago.

• 46:27Chuck Nice?

  Right.

• 46:27Neil deGrasse Tyson?

  When I began wrestling in high school.

• 46:29Chuck Nice?

  And I was gonna bring this up. I think it's because you were an athlete and athletes have to deal with pain all the time.

• 46:33Neil deGrasse Tyson?

  Exactly. And I judge by looking at the situation, is this pain something that will cause irreparable damage? Or is it just simply pain? Okay? And I'm looking at it, my hand is in a bucket of ice. Yeah, it hurts, but who cares?

• 46:48Chuck Nice?

  But who cares?

• 46:49Neil deGrasse Tyson?

  Yes. I'm not gonna get frostbite from it. Okay?

• 46:52Chuck Nice?

  So. See, you and Gary have that, I'm sure, because Gary's had a ton of surgeries.

• 46:55Gary O'Reilly?

  Oh, yeah, we'd have ice buckets.

• 46:56Chuck Nice?

  He's played in, in pain. He sat in ice after games. Right? See, and I have not played any real.

• 47:02Neil deGrasse Tyson?

  You have not done none of that.

• 47:03Chuck Nice?

  I've done none of that. And this is.

• 47:05Neil deGrasse Tyson?

  That's why you wimped out in the time of need.

• 47:08Chuck Nice?

  Because this is how pain works for me. Okay? The way pain works for me is I experience it and then my brain, my body, and everything in my soul goes, "Jesus, no! Please, Lord, no!" So.

• 47:22Neil deGrasse Tyson?

  Oh, that's what.

• 47:26Neil deGrasse Tyson?

  Okay.

• 47:29Gary O'Reilly?

  So when you're saying you're building these avatars and the detective work that comes, are you finding more clues and more answers? Or are you just finding clues and then we've got to sit there, scratch our heads and hopefully come up with an answer? Or is this really empowering the sort of psychiatric research that you're interested in?

• 47:51Speaker 03

  You know, the way I look at it is psychiatric disorders have been a mystery, like no doubt. I mean, how does complex behavior or hallucination arises from the brain? In mesmerizing us for such a long time? And it's almost like, if you were to think about it, it's almost as like seeing, you know, Egyptians writing for the first time, right? You look at them, you know, where do you even start? I mean, they're beautiful drawings, you know? You could classify them based on like the animals, but then you can't make sense of what the meaning is. And you see, that's why, you know, if you think about it, like historically, the discovery of the Rosetta Stone, right? Like this tiny piece tablet that for the first time had hieroglyphs on one side and Greek writing on the other one, right?

• 48:34Speaker 03

  And then, you know, this French scientist who came with Napoleon finds this, starts looking at it. And that becomes essentially the, you know, enabling tool. Suddenly we could actually see what word does what.

• 48:46Neil deGrasse Tyson?

  And you know, cool thing about the Rosetta Stone? It's like a shopping list or something. It's not any deep. Just like brown eggs. I don't know if it's exactly a shopping list, but it's something completely mundane.

• 48:57Speaker 03

  Very, yeah. Well, something really trivial, absolutely. And yet, like, it was the only writing that we know that had both on both sides. So I think the question is, we need to somehow translate at one point. So like these mental processes that are so complex into what we can deal with, which is really molecular biology. That's what we can control. Molecular biology, we can control. So I think, you know, to a large extent, I've seen this, like the mission, you know, for my lab and in general, like I think for the community more broadly, is really to try to translate some of this complex phenomenon of the brain in very simple processes. Calcium in a neuron, you know, two neurons connecting with each other. And then hopefully by doing that and finding ways of reversing it, those will. Also reverse or at least improve. Well, we don't know that.

• 49:41Speaker 03

  You know, we, you know, that has not yet been done. And, uh, you know, we'll have to see whether clinical trial will actually be successful. I mean, we're preparing for a clinical trial for Timothy's syndrome right now. We're still like in the last stages of preparation. We found most of the patients uh in the world were building a special unit here at Stanford where we're gonna be hopefully bringing them in the next year or so and doing the clinical trial. So we'll see. And then, you know, this is the first disease. I mean, uh, and I, I look at Timothy's syndrome as so like really being the first first. But we have half a dozen of other conditions that we've been studying from various angles. Really, I, I mean, I see this, this is gonna be the golden uh age for human neuroscience.

• 50:16Neil deGrasse Tyson?

  And I'm delighted to learn that you're putting in this much effort for a disease that is so rare. Yeah. I mean, think about that. So the rarity, the, at least the people have the benefit of your attention given to it. Yeah. Rather than someone just making the cost benefit analysis. And saying we're not, we're not doing anything. We're not going there. We're not going down that road. Right, right. Not making any money.

• 50:38Gary O'Reilly?

  Are we saying here that your assembloid research and work is going to be the key to understanding what has been hidden brain biology? How soon do you think maybe you really will be able to not just tick off the Timothy's syndrome, but take on other horrific diseases?

• 50:56Speaker 03

  Oh, we're already working on others. Uh, I mean, you know, at least half a dozen we've been studying. Like some are associated with epilepsy, some with intellectual disability. We have a few forms of schizophrenia. So we've been deploying this like systematically. And another thing that we've done, to be honest, and this is sort of like being in the spirit of what we do at Stanford is, uh, you know, I lead a, a center here. And in the beginning it was, you know, there were, when we published some of the first methods, everybody was like, oh, you know, can we come to the lab and learn how to do it? Like, we wanna do it too. And we brought people here initially, but then at one point, you know, we couldn't train enough people. So we actually started doing literally courses where we bring students from all over the world, from various labs. And for about a week, almost like in a cooking show, if you want to think about it, right?

• 51:40Speaker 03

  Because you know, the experiments are done before. We just show them, these are the critical steps that you need to do. And so we've been helping more than 300 labs around the world to, you know, implement these methods. And if the breakthrough is not going to come from my lab, therapeutically speaking, that's fine, because it will probably come from somebody else, somewhere like, you know, in a corner of Europe, or who knows, of South America, doing experiments on a rare form of disease and finding a therapeutic, that would be fine, I think. Because there's so much to do for, you know, one in four individuals suffers from a psychiatric disease today.

• 52:13Gary O'Reilly?

  Right.

• 52:14Speaker 03

  It's a huge burden.

• 52:15Gary O'Reilly?

  Are we going to come across a situation where you are going to have, you'd be faced with building an assembloid or creating an assembloid that would just be too complex? Or is there a limit to what you can assemble?

• 52:28Speaker 03

  There are absolutely limits to what we can assemble. And, you know, while, like, many of the features of this assembler is are really fascinating and surprising, you know, they still have a lot of limitations, you know? I mean, they're not vascularized, they don't receive blood supply. We may be able to stimulate them with like capsaicin or something else, but they're not receiving the rich sensory information that is important. You know, think about the, you know, if, if you have a kitten where you, you know, you cover one eye, you cover that eye for a week, that cat will never see with that eye. You do it in an adult cat, for a week, no problem whatsoever. So, early in development, if some of the circuits do not receive the right input, they won't develop properly.

• 53:11Speaker 03

  So, you know, again, while our models are relatively complex already, they lack a lot of the complexity. And you know, is as, as George Box famously said, that all models are wrong, or some are useful. You know, and the models that we make are not, our goal is not to make a perfect model of the brain. It's like to make a good enough model of a part of a brain or of a circuit that will give us the breakthrough therapeutically.

• 53:37Neil deGrasse Tyson?

  I wouldn't be so harsh with the term model there. I would say all models are almost by construct incomplete.

• 53:43Chuck Nice?

  Right.

• 53:44Neil deGrasse Tyson?

  But that wouldn't make them wrong necessarily. They're just, they're not the whole story. That's why they're a model.

• 53:50Chuck Nice?

  Otherwise it would be the exact thing. You wouldn't need it. You wouldn't need a model if you could replicate the exact thing.

• 53:55Neil deGrasse Tyson?

  It would be the thing itself.

• 53:56Chuck Nice?

  Right, okay, yeah. I just love that Assembloids sounds like a Cartoon Network show. Like Assembloids weekdays at three, right after Transformers, you know?

• 54:06Speaker 03

  Actually, there is a game. There is a video game for it, which I didn't know when I put out the term. But there is a very popular video game that is literally called Assemblant.

• 54:14Chuck Nice?

  Cool.

• 54:16Gary O'Reilly?

  Where do we hit the ethical wall and hit the regulatory and all the other things and?

• 54:22Neil deGrasse Tyson?

  Did you say regulatory?

• 54:24Gary O'Reilly?

  I did.

• 54:25Neil deGrasse Tyson?

  This is America, Jack. It's regulatory.

• 54:27Chuck Nice?

  Regulatory. Not even regula- regulatory.

• 54:31Gary O'Reilly?

  I didn't come here for a lecture on geography. I know it's America.

• 54:37Neil deGrasse Tyson?

  It's America, Jack.

• 54:38Gary O'Reilly?

  Anyway, you were saying?

• 54:40Speaker 03

  You know, we think about this like all the time. Honestly, in the beginning, obviously there are like not that many ethical issues. But as we've progressed, it becomes clear that we have to think carefully. So they're like, you know, the way I think of it is like in multiple levels. Like on one hand, there are like issues about the cells. These are human cells that we're using. You know, who owns the cells? You have to give consent for this experiment to be done, and we do that all the time. And so we always have to put that into the context of like, what are we doing with the cells? What the cells were consented for?

• 55:09Chuck Nice?

  That's very much like, uh, who is the woman who?

• 55:12Neil deGrasse Tyson?

  Lax.

• 55:12Chuck Nice?

  What's her name?

• 55:13Neil deGrasse Tyson?

  Lax.

• 55:14Chuck Nice?

  Lax, yes. Whose cancer cells were, whose cells were used for decades and saved and created many breakthroughs in cancer. And the family got nothing and she never gave permission. So it's good to know you're doing that.

• 55:30Speaker 03

  And that's why it's critical every time we collect the skins.

• 55:33Chuck Nice?

  Henrietta Lax, yes.

• 55:35Speaker 03

  Patients or you know who you know the parents in the case if they're minors will actually be clearly informed about what will happen with the cells. Uh, how the cells will be shared with others, for instance, under what conditions and so on and so forth. So on one hand, there are like these issues about the cells. Then sometimes, as you know, we're using animals. So sometimes we transplant this into the animal. So we also have to think about the welfare of an animal. I mean, you transplant more, is the animal suffering in any way? And then the third problem, which is perhaps the more kind of like philosophical in a way. Is like, are there any new emerging properties? Like, are there? Um, you know, features, complex features that are rising from this that would make one thing that we need to regulate this field.

• 56:15Speaker 03

  Currently, I think the models that we have in vitro are not sufficiently complex to justify, you know, the presence of any complex features. Like, that's why we don't use the term generally, you know, the term intelligence for this, because intelligence is really a property of an organism. It involves like goal directed behavior and involves learning. None of our cultures do that. And using, you know, anthropomorphizing, it's not generally a very useful thing to do in this case. But as the models become more complex, we have to start having these conversations. And that's why, you know, last year we had an Estelima meeting.

• 56:53Speaker 03

  Uh, which is like this historic place here in California, you may have heard, where many of these ethical discussions have started in biology in the seventies when cloning, gene cloning was so like discovered, then everybody was like, what is going to happen? We're now modifying these genes and we're going to create new organisms. So scientists got together there with philosophers, uh, you know, with journalists. So that's what we've, we're also doing now. We're getting together a larger group and thinking, what are some of the implications? You know, sociologically, religiously, philosophically, while at the same time, thinking that psychiatric disorders are a huge burden. And if you have a technology that has the potential to change that, to provide cures, is it?

• 57:37Speaker 03

  You know, unethical not to use it, right? I mean, there's even that argument, you know, where, you know, how far do we go uh in that? So that those are like ongoing discussions. I mean, it's been really interesting. I spend more and more of my time uh as part of these conversations.

• 57:50Neil deGrasse Tyson?

  Let me take just one other place before we land the plane here. You came into this as an expert in the autism spectrum patients and.

• 58:01Neil deGrasse Tyson?

  A new term that's been bandied about for the last certainly 10 years is the concept of neurodiversity. When you look at it that way, who is anyone to say that someone needs repair if they're simply manifesting on a spectrum of neurodiversity?

• 58:20Speaker 03

  Sure.

• 58:21Neil deGrasse Tyson?

  Your counterparts, not long ago, would have labeled homosexuality as a mental disorder in need of repair.

• 58:30Speaker 03

  Yeah.

• 58:31Neil deGrasse Tyson?

  And only recently, been historical times recently, was that removed from the list of human

• 58:38Speaker 03

  Maladies.

• 58:39Neil deGrasse Tyson?

  Maladies and disorders. So, there's an ethical, another ethical frontier about what it is you judge needs repair versus is just another kind of person.

• 58:50Speaker 03

  And that's absolutely one of the discussions that we've been having, one of the ethical discussions that we've been having. And you know, all psychiatric disorders are on a spectrum with the population. And some of them are more severe and some of them are less severe. And that's also the case for autism. You know, autism is certainly a spectrum, but what we're focusing on is actually what we now call profound autism. This is the autism that is really debilitating. So patients with Timothy syndrome, or like some of the other patients that were like with other disorders, can have 60 seizures a day. Oh my, really? That's just awful. They are unable to make any eye contact. They need a caregiver for the rest of their life.

• 59:33Speaker 03

  You know, the biggest fear that a parent has when they have, you know, a child is like, what if I die? So, I am seeing it through the eyes of some of these parents that are dealing with like really the devastating forms of autism, what we call profound autism. And then of course, there is like what you mentioned, which are neurotypical or, you know, aspects of how we interact with each other that do not require any, nobody wants to cure or to provide treatments for anybody, but these patients are severely affected. Most patients with psychiatric disorders are severely affected.

• 1:00:09Neil deGrasse Tyson?

  Because I once asked Oliver Sacks, who is a friend of our show, we have some archival content with him.

• 1:00:16Speaker 03

  Oh, that's amazing.

• 1:00:17Neil deGrasse Tyson?

  Yeah, yeah. I asked him after a public talk that he gave. If you could go back in time and carry with you a pill that would cure your own ailments. Uh, he had sort of certain neuro issues. Uh, he has, correct me on the word here, prognoplasia?

• 1:00:35Speaker 03

  Uh, yes, he did. Yeah, he couldn't really identify.

• 1:00:38Neil deGrasse Tyson?

  He had face blindness, okay? Oh, wow. And, and some other elements to it. I sometimes wish I had that. So, so I asked him, if you could take a pill that would just cure that back when you were seventeen, would you, looking back at that time? And he said, no, because it was that, those differences in the way his mind worked, that got him interested in neuroscience to begin with. In the first place, right. That is, that was his destiny.

• 1:01:03Speaker 03

  Uh huh. But, but you see, that's exactly, you know, the point where we started, like, the beauty of like, building a nervous system is that while there is a basic plan that makes our brains the same, we pretty much, you know, can do the same things, it also creates a lot of diversity. Even monozygotic twins, right? They have the same genetic, uh, uh, you know, material. They share the same womb.

• 1:01:26Neil deGrasse Tyson?

  Yeah.

• 1:01:26Speaker 03

  And then they can have different sexual orientations, you know, they like, they have different hobbies.

• 1:01:31Neil deGrasse Tyson?

  They have different fingerprints, if I remember correctly, don't they?

• 1:01:33Speaker 03

  They do, they do, yes.

• 1:01:35Neil deGrasse Tyson?

  Wow.

• 1:01:35Speaker 03

  Because again, there is a lot of stochastic forces in development. And those are the, those are the ones that make us different. And that's how evolution actually works too. You know, by selecting these differences that, yeah, I mean, to a large extent, probably that's what made us as a species so successful.

• 1:01:51Neil deGrasse Tyson?

  Yeah.

• 1:01:51Speaker 03

  Uh, the fact there is always an individual who has a vision, who wants to go and, you know, discover a new continent.

• 1:01:58Neil deGrasse Tyson?

  Yeah.

• 1:01:59Speaker 03

  So I, I think that's the power of our species. And I, I think, I, I know very few, honestly, psychiatrists or neurologists who would wanna cure that or, or change that.

• 1:02:08Neil deGrasse Tyson?

  Right, right.

• 1:02:09Speaker 03

  I think what we're dealing really on the field is really these devastated conditions that make essentially most of these children unable to really function as, as adults or as children.

• 1:02:20Neil deGrasse Tyson?

  So this is a very human, human-centric view. So if you were the, the COVID virus, you would say, let's invent humans who then have airplanes so that we can cross continents and affect other people. Absolutely.

• 1:02:33Chuck Nice?

  They are the true owners of this planet.

• 1:02:36Neil deGrasse Tyson?

  That's right.

• 1:02:37Chuck Nice?

  Let's be honest.

• 1:02:37Neil deGrasse Tyson?

  The viruses.

• 1:02:38Chuck Nice?

  The viruses. They're true owners of this planet.

• 1:02:40Gary O'Reilly?

  You said it, we're microbes, we're just an Uber.

• 1:02:41Chuck Nice?

  Yeah, that's all.

• 1:02:42Neil deGrasse Tyson?

  We're just an Uber ride.

• 1:02:44Chuck Nice?

  Uber ride.

• 1:02:45Neil deGrasse Tyson?

  Well, Sergio, it's been a delight to have you on StarTalk, sharing your expertise with us and taking time out of what we know is your busy research schedule to give us a little glimpse into what you're doing in your lab. Just congratulations to you and all the people who work in your lab, who are surely working there right now while you're talking to us.

• 1:03:05Speaker 03

  Oh, they are, right here, I mean, yeah.

• 1:03:08Speaker 03

  Yeah, and really, they're the ones that are doing all the work. I mean, you know, this work, I mean, hopefully, it came through from the discussions, but these experiments are long. I mean, they last hundreds of days. Because human development, it takes a long time.

• 1:03:19Neil deGrasse Tyson?

  Yeah.

• 1:03:20Speaker 03

  So it requires a lot of dedication, but I think the promise of what this could yield ultimately, you know, understanding the human brain is, you know, is addictive. So, you know, you really want to figure this out.

• 1:03:32Neil deGrasse Tyson?

  Well, thank you again. I'd like to reflect on this with a brief cosmic perspective, if I may.

• 1:03:38Chuck Nice?

  Please.

• 1:03:39Neil deGrasse Tyson?

  This moving neuroscience frontier has got me thinking.

• 1:03:44Neil deGrasse Tyson?

  You look at the progress of civilization. It always comes about when we have the proper match between a tool and a goal. And when they come together, we build things that didn't exist before.

• 1:04:04Neil deGrasse Tyson?

  Or we disassemble things that had never been taken apart before. But in all cases, it has to do with the precision of the tools you bring to the task. And to learn what's going on on the frontier of neuroscience, it feels to me that it's finally catching up with the methods and tools that have shaped engineering throughout the history of civilization. Engineers built dams and buildings and aqueducts and everything that we value and care about in our modern lives.

• 1:04:46Neil deGrasse Tyson?

  But the time has come to care about what's going on inside our brains, within our minds. And I'm delighted to learn that that is a frontier that finally has tools befitting the task. Welcome to the club. Neuroscience. And that is a cosmic perspective. Keep looking up.