Assembloids: Recreating the Brain with Sergiu Paşca

23:57Well, this sort of like a self-assessment 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 the, as you progress in development, the cells become less and less permissive. We don't have cells moving in our brain right now. 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 are already formed. So it's not that easy. I got you know, um, to the dumbass circuitry. The dumbass circuitry is fully formed and very, very strong.

24:31However, 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. 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. That's amazing. That's amazing. All right. So, Professor, you did some work and some research with cells, and you said you work with autism patients and the like, and there's something called Timothy syndrome, which is autism and epilepsy, which seems a terrible combination to... It's terrible for Timothy.

25:12Damn. But you then afflicted cells with this Timothy syndrome. Is that correct? Yeah. And then reverse-engineered how you could find a way to work with and do basically what you said, take that away. Is that, I mean, I am explaining that at all well, but you probably could do it better than I am. Yeah. If you would. I mean, this goes back to like, you know, the previous point when we were talking about how the 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?

25:53I mean, psychiatric disorders are mysterious disorder. We still don't know how like this, you know, thoughts 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. So there's this rare, rare syndrome. I mean, literally they're about, we found about 30, 40 patients in the English speaking world today, They're very few. But they have a mutation, this patient, in a protein that is actually a channel for calcium in the cells.

26:29Every 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 these patients 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. 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.

27:06And 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 a disease process that is relevant. So 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? Well, sadly, you would have to change it everywhere in the brain. There you go. And that is not doable today. Okay. And this patient are very severely affected.

27:40I 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 where we sort of like started with cells from these patients. And then with these models that I've told you now over the past 15 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 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.

28:23Either just like look at it and they would say, oh, this makes sense. This is what we need to do. And so I don't want to go into the details of how we then 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 15 years damn just like within you know a couple of days this is insane i know what you're talking about these are sherlock holmes this is real detective work i mean to work out that that is exactly what's necessary i mean you said it was obvious but obviously it wasn't otherwise someone would have seen it a long time so if you were around in Frankenstein's day, Frankenstein could have just been a regular Joe on the street.

29:11Yeah, he would have walked out instead of like, he'd have been like, hey, what's going on? How you guys feeling?

29:20Are 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? 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 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. And so of course the question is like, how do you actually know that it would work?

29:57Generally 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 the aspects of disease. It doesn't work that well. So now what do you do? You can't also just go straight into a patient. You want to make sure that sort of like 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 organates and the assembloids that we've been building are rather complex, they still don't receive sensory input.

30:31They 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 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.

31:11But 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.

31:43So 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. You tell me they have feelings? Is this what you're telling me? No. Let the professor explain. No, you know, I mean, it turns out that 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.

32:25Think 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. So we decided to reconstruct the corticospinal pathway.

33:02So that means, and 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 to like text to biology. So we thought, could we actually reconstruct this? You may think that it's easy, but here it is.

33:36We don't know how the cells find each other in development, by the way. We have no ideas about the rules. 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.

34:13Wow. That was a three-part assembloid. All right. And that told us that even, you know, against the odds, because the probabilities 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, so like, preparation. You can add this poliovirus and you can cause a paralysis of that circuit in a dish.

34:50This work is not yet published, but it tells you just how useful a preparation like this can be. It's beyond useful. I mean, what I'm trying to figure, not figure out, envision is a time where we've mapped everything, right? So 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? Perhaps even an easier scenario for that. Okay, go ahead.

35:40have a mutation, you know that the 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 want to screen quickly for drugs. And then you use that in a patient. 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.

36:17Now just boom, boom, boom. Every single person with that mutation gets that drug delivered. And that's how you – wow. That's amazing. But to get there, we do need to get a better understanding of how because you see we're quite – 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 new scientist? Scientist. That's right. Because he said, look at Neil. Neil's looking at me like, how dare you? He's a scientist. How dare you? We don't accept just what is. I understand. Go on, go on, go on. Please. 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.

36:57And you know, if you think a little bit about this, right? If we cannot recreate the circuits outside, it's going to 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. Because the tissue of interest was accessible. You get the blood of these patients 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.

37:35because 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 psychiatry and neurology as we've done in cardiology and other branches of medicine. That's sort of like how I see it, but I may be wrong. 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.

38:13Oh, okay. I thought you meant like they're going to have that little vial of assembloids just screaming in the middle of the night. Ah! No. Ah! Why did you give me pain? Not that one. No, you're right. One of the things that we're trying, and actually this just came out. I mean, we made the first assembloid in like 2017. it took us three years to 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 sends their information.

38:48So think about it. If you 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. 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.

39:22So, you know, the receptors for pain actually respond to capsaicin, you know, red hot chili pepper. That's why it's like, it's so hot. So they have these specialized receptors and you add capsaicin and they just beautifully respond, like electrically. But this had never been witnessed before, had it? No, I mean, to put the entire circuit together has never really been done before. Now, the biology of my - What was it like for you to witness this the first ever time? 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.

39:52And it takes about 100 days to make them, by the way. And then another 100 days for the cells to connect with each other. And then at one point, we started looking at them and seeing what's going on. And we've discovered something really remarkable. The cells in the circuit become synchronized with each other. So initially, they were all sparkling in a non-coordinated way. And then at one point, the activity just seems to be starting on one side, and it goes unidirectional. So the circuit is almost, and there's no stimulus, by the way. 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.

40:32It's almost like practicing. So it's practicing to add the stimulus. And then the relevance for pain is that there are this interesting, maybe you've heard about this, neurologists discovered them in the past 20 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, and genetically modified the cells in a dish to half the mutations that are present in patients.

41:13Then 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. 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, the brain is more than the sum of its parts, obviously.

41:46And so clearly in order to understand some of these disorders, we're going to need to have some of these parts put together to get this emergent new properties. So you're not feeling pain. Well, that's the Novocaine movie, isn't it? Yeah, but, you know, I mean, we see this in certain people that, okay, I remember we did on the TV show, and Neil has this crazy thing. He can stick his hand in water, ice water. And I'm not saying it right. Take a bunch of ice, add water to it, and it actually becomes colder than freezing, okay? Yes. All right? Then you put your hand in it, and it burns your hand.

42:23So 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 was not cool. And 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 talked it up to, he got a lot more fat on his hands. But seriously, it's a matter of sensitivity to pain.

43:05No. Absolutely. No, it's not? No. What is it? I didn't say I didn't feel the pain. It's just that I could deal with it. Yeah. Oh. Well, that just changes everything. Oh, no, no. Okay, so explain to me the mind over matter aspect here. 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.

43:47It 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, you know, I 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.

44:22So 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, right? So I think it's sort of like mitigating this risk moving forward that I think is very important. How do you now, having had this experience with the sensory aspect of it, reverse engineer again the way to get a drug to alleviate the hypersensitivity to pain?

45:04Sure. I mean, there are many ways that you can do this. Yes, it's called scotch. Well, no, everybody's got a thing with opioids. There must be a mechanism there where opioids use that you can sort of tag onto but not get that addictive part. Exactly. And think about it. It's sad that the best treatment that we have for pain comes out of poppy seeds and was 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. Don't you make opium from poppy seeds? Yes. Okay, I just want to clarify that. So I think the idea now is that we have the circuit in a dish.

45:44You 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. Right. One that is sort of like, you know, driven by the biology behind it. And I think that's the beauty of it. 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 in the pain-free opiate that is non-addictive because that is, I mean, that's the end of the game right there. And just to be clear, Chuck.

46:21What? Because when my hand was, I just want to get back to my hand in the ice bucket. In the bucket, yeah. Okay. Long ago, when I began wrestling in high school. And I was going to bring this up. I think it's because you were an athlete, and athletes have to deal with pain all the time. 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? But who cares? I'm not going to get frostbite from it. So you and Gary have that, I'm sure.

46:54Because Gary's had a ton of surgeries. Oh, yeah, we'd have ice buckets. He's played in pain. He sat in ice after games. Right? See, and I have not played any reals. You have done none of that. I've done none of that. That's why you wimped out in the time of need. 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! Oh, that's what... Okay. 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 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 you know the way i look at it is you know 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?

48:10You 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 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? 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.

48:44Suddenly we could actually see what word does what. And you know the cool thing about the Rosetta Stone? It's like a shopping list or something. It's like, it's not any deep. Just like bread and eggs. I don't know if it's exactly a shopping list, but it's something completely mundane. 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 this mental processes that are so complex into what we can deal with, which is really molecular biology. That's what we can control.

49:15Molecular 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 phenomena 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. We don't know that, you know, that has not yet been done. And, you know, we'll have to see whether clinical trial will actually be successful.

49:47I mean, we're preparing for a clinical trial for Timothy syndrome right now. We're still like in the last stages of preparation. We found most of the patients in the world, we're 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, and I look at Timothy syndrome as really being the first first, but we have half a dozen of other conditions that we've been studying from various angles. Really, I mean, I see this is going to be the golden age for human neuroscience.

50:16And 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, at least the people have the benefit of your attention given to it rather than someone just making the cost-benefit analysis. And saying, we're not doing anything. We're not going there. We're not going down that road. Right, right. Not making any money. So 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 syndrome, but take on other horrific diseases?

50:55Oh, we're already working on others. 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, you know, I lead a center here. And in the beginning, it was, you know, 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 want to do it too.

51:24And 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? 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.

51:56Because 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. It's a huge burden. Are we going to come across a situation where you are going to be faced with building an assembloid or creating an assembloid that would just be too complex? Is there a limit to what you can assemble? There are absolutely limits to what we can assemble.

52:31And, you know, while like many of the features of this assemblage 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. Think about if you have a kitten where you cover one eye, if 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.

53:12So, you know, again, while our models are relatively complex already, they lack a lot of the complexity. And, you know, 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 over a circuit that will give us the breakthrough therapeutically. I wouldn't be so harsh with the term model there. I would say all models are almost by construct incomplete. Right. But that wouldn't make them wrong necessarily. They're just not the whole story.

53:48That's why they're a model. That's why they're a model. 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. It would be the thing itself. Right, okay, yeah. I just love that Assembloids sounds like a Cartoon Network show, like Assembloids Weekdays at 3 right after Transformers. It actually depends on how 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 Assemblet. Cool. Where do we hit the ethical wall and hit the regulatory and all the other things?

54:22Did you say regulatory? I did. This is America, Jack. It's regulatory. Regulatory. Not even regulatory. Regulatory. I didn't come here for a lecture on geography. I know it's America. It was America, Jack. Anyway, he was saying. 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.

54:58You 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? That's very much like, who is the woman who? Lacks. What's her name? Lacks. Lacks, yes. Whose cancer 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. And that's why it's critical. Every time we collect the skins. Henrietta Lacks, yes.

55:34You know, the patients or, you know, the parents in the case, if they're minors, will actually be clearly informed about what will happen with the cells, 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 philosophical in a way, is like, are there any new emergent properties?

56:08Like, are there features, complex features that are arising from this that would make one thing that we need to regulate this field? Currently, I think the models that we have in vitro are not sufficiently complex to justify the presence of any complex features. That's why we don't use the term generally, 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 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.

56:49And that's why last year we had an Assyllamar meeting, 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 70s when cloning, gene cloning was 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, with journalists. So that's what we're also doing now. We're getting together a larger group and thinking what are some of the implications, sociologically, religiously, philosophically, while at the same time thinking that psychiatric disorders are a huge burden.

57:28And if you have a technology that has the potential to change that, to provide cures, is it unethical not to use it? I mean, there's even that argument. How far do we go in that? So those are ongoing discussions. I mean, it's been really interesting. I spend more and more of my time as part of this conversation. 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. Yes. And 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?

58:21Sure. Your counterparts not long ago would have labeled homosexuality as a mental disorder in need of repair. And only recently, been historical times recently, was that removed from the list of human 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. 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.

59:03And 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? They are unable to make any eye contact. They need a caregiver for the rest of their life. 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.

59:48And 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. Because I once asked Oliver Sacks, who is a friend of our show, we have some archival content with him. Oh, that's amazing. 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. He has sort of certain neuro issues.

1:00:31he has, correct me on the word here, prognopragnesia. Yes, he did, yeah, he couldn't really identify. He had face blindness, okay? And some other elements to it. I sometimes wish I had that. So I asked him, if you could take a pill that would just cure that back when you were 17, would you, looking back at that time? And he said no, because it was that, those differences in the way his mind works, that got him interested in neuroscience to begin with. In the first place, right. That was his destiny. But you see, that's exactly the point where we started. The beauty of building a nervous system is that while there is a basic plan that makes our brains the same, we pretty much can do the same things, it also creates a lot of diversity.

1:01:19Even monozygotic twins, right? They have the same genetic material. They share the same womb. And then they can have different sexual orientation. You know, they like, they have different hobbies. They have different fingerprints, if I remember correctly. Don't they? They do. They do. Yes. Because again, there is a lot of stochastic forces in development. And those are the ones that make us different. And that's how evolution actually works too. You know, by selecting these differences that, I mean, to a large extent, probably that's what made us as a species so successful. The fact there is always an individual who has a vision, who wants to go and, you know, discover a new continent.

1:01:58So I think that's the power of our species. And I think I know very few, honestly, psychiatrists or neurologists who would want to cure that or change that. Right, right. I think what we're dealing really on the field is really these devastating conditions that make essentially most of these children unable to really function as adults or as children. So this is a very human-centric view. So if you were 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. They are the true owners of this planet. That's right.

1:02:37Let's be honest. The viruses. The viruses. They're true owners of this planet. You said it at microbes. We're just an Uber. Yeah, that's all. We're just an Uber ride. Uber ride. Right. 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. They are right here behind me. Yeah. And really, they're the ones that are doing all the work.

1:03:10I 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 takes a long time. 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. Well, thank you again. I'd like to reflect on this with a brief cosmic perspective, if I may. Please. This moving neuroscience frontier has got me thinking. You look at the progress of civilization.

1:03:47It 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. 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.

1:04:45But 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.