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The future of brain science

A neuroscientist is using stem cell approaches to create 3D, functional brain tissues in the lab to study neurological and psychiatric diseases as never before.
Vibrant, colorful illustration of a human brain.
Is it possible to grow living tissue that mimics parts of the brain? | shutterstock/ SpeedKingz​​

Guest Sergiu Pasca is a physician-scientist who turns skin cells into stem cells and then into brain tissues he calls “organoids” and “assembloids” in order to study psychiatric and neurological illness in a dish instead of in living human beings.

With this knowledge, Pasca hopes to develop new treatments for conditions ranging from schizophrenia and autism spectrum disorders to chronic pain, he tells host Russ Altman in this episode of Stanford Engineering’s The Future of Everything podcast.

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Transcript

[00:00:00] Sergiu Pasca: For Timothy Syndrome in particular, because this is, you know, the paper that is coming out next week. We got such a good understanding of the biology of this condition through these human cellular models, organoids, assembloids, 2D cultures, that at one point the therapeutic opportunity just became self-evident.

[00:00:18] It just became clear this is exactly what we need to do. And this came like three, four years ago. And then through a series of experiments that we've done, we've now developed a strategy that can essentially reverse almost all the phenotypes, all the defects that we've discovered in patient cells over the years, literally within some of them within hours, some of them within days, but they're essentially just like completely reversing them.

[00:00:47] Russ Altman: This is Stanford Engineering's The Future of Everything. And I'm your host Russ Altman. If you're enjoying the show or if it's helped you in any way, please consider rating and reviewing it to share your thoughts. Your input is extremely valuable and it'll help others learn about the show. 

[00:01:01] Today, Professor Sergiu Pasca from Stanford University will tell us how his group has figured out how to take skin cells, turn them into brain cells, and then study some of the most vexing psychiatric and neurological diseases in a dish with the idea of generating new therapies. It's The Future of Brain Science. 

[00:01:22] Before we get started, please remember to rate and review if the show has helped you in any way. That will help us immensely.

[00:01:35] Psychiatric and neurological diseases are some of the toughest diseases to study and to treat. And those are related. Because we don't have good ways to study the brain. Nobody wants to give up a piece of their brain for scientific research. It's really hard to understand what goes wrong at the molecular and cellular level, and how we can invent new ways to treat terrible diseases such as chronic pain, schizophrenia, bipolar disorder and depression.

[00:02:03] Well, Sergiu Pasca is a professor of Psychiatry and Behavioral Sciences at Stanford University. And his group has figured out how to take skin cells, make them go backwards in time to become stem cells, which have many potential future fates, and then get those stem cells to differentiate into little pieces of brain. His group has shown that they can do this reliably, and they can generate little circuits where the cells talk to one another and recapitulate some of the deficits that are seen in patients who have certain diseases. It's an amazing story, and you're about to hear about it. 

[00:02:43] Sergiu. You've developed this amazing ability to grow living tissue that mimics parts of the human brain. First of all, how does that work? Then we can talk about why you did it and what we can use it for. But tell me, how do we grow little pieces of brain? 

[00:02:57] Sergiu Pasca: Well, the process starts by generally taking a tiny skin biopsy, so just taking a few cells from the skin of any individual, say a patient with autism or with schizophrenia, bringing those cells into the lab and then essentially doing some mumbo jumbo to the cells, you know, playing cellular alchemy and pushing those cells back in time to essentially turn into stem cell like cells. Um, and the reason why we do this is because stem cells have this remarkable ability of turning into any other cell types. So once you have the stem cells from any individual, not only can you store them and share them with others, but now you can gently guide them in a dish to become brain cells.

[00:03:43] And we spent essentially the past fifteen years designing strategies to turn these stem cells from any individual, into various types of brain stems and ever, brain cells into various ever more complicated preparations. 

[00:03:59] Russ Altman: Fantastic. So a couple of questions to follow up. I think everybody knows that the part of what makes the brain is there's a very complicated architecture of the cells where they are and how they interact with one another.

[00:04:11] Are you able to get that to happen or are these just individual cells sitting in a dish, but not talking to each other and not creating the kinds of structures that we see when we do, you know, uh, studies of brain tissue?

[00:04:24] Sergiu Pasca: That's a very good question. So about fifteen years or so ago, we were doing exactly that, kind of like at the bottom of a dish, a flat layer of brain cells. Um, let's say cortical neurons, so neurons of the cerebral cortex. Of course, they're great. I mean, they look like neurons. They're human neurons, you know, their shape and their properties were those of human neurons. But they're not able to communicate with each other the way they do in the three-dimensional brain.

[00:04:49] And more importantly, as you pointed out, they're not able to communicate with neurons at a distance because what makes the human brain unique, or the brain really unique, is that unlike other organs that are more homogeneous, let's say the liver, it does matter which part you're actually probing or you're looking at.

[00:05:06] And so what we've actually slowly done is first of all, generate three dimensional preparations that are now known as organoids that resemble parts of the nervous system. Let's say parts of the spinal cord or parts of the cerebral cortex. And that we spend, you know, five, six, seven years, kept refining those methods.

[00:05:26] And at one point we really became interested in studying cell interactions. We thought that was important, that forming circuits from the cells will be, um, enabling for so many applications. So then we introduced what are now known as assembloids. 

[00:05:42] Russ Altman: Assembloids. 

[00:05:43] Sergiu Pasca: Assembloids, which are essentially assembled three dimensional cultures where, let's say, you, uh, make a three-dimensional culture that resembles a simple cortex. And one that resembles the spinal cord. And then you culture them separately. You provide different cues and small molecules so that they become those cells. And then at the right time, which, you know, depends a little bit on the brain region, you start putting them together. And by putting them together, literally you put them in physical proximity to each other.

[00:06:13] And initially we thought we're going to have to guide, and we're going to have to like tell the cells what to do, kind of like in engineering, right? Provide the blueprint. Of course, what we got wrong at that time was like in biology, the cells already know what to do. So once you actually put them together, there are this emergent properties.

[00:06:32] The cells will recognize where they actually have to go and they'll start project and find, for instance, motor neurons, connect with them. And then if you put a third part, let's say a piece of muscle that you get from a biopsy, then those neurons will connect to the muscle. And suddenly the muscle was just starts twitching in a dish under the control of cortical neurons.

[00:06:51] So I was like really exciting because suddenly you can witness the remarkable power of self-organization for a process that, to be honest, we don't even understand that well. It's not like we know how the rules of assembly of those, but once you provide, so like the minimal conditions necessary, you unleash these forces of self-organization.

[00:07:12] Russ Altman: So the cells really want to be a brain, they want to be a spinal cord, and you just have to let them do it almost. 

[00:07:19] Sergiu Pasca: Precisely. 

[00:07:20] Russ Altman: So one, one final preparatory question is when you're creating these individual organoids or that will become part, I guess, become part of an assembloid, does it always have to be just one type of cell?

[00:07:30] You talked about livers and even livers, as we know, are made out of multiple cell types. So how advanced is your ability to make a mix of cells, for example, the cells that are feeding the neurons or that are supporting the infrastructure of the brain? Or is that a future topic? 

[00:07:47] Sergiu Pasca: Well, I mean, one way to look at you know, brain developments is that, um, there are multiple niches. There are multiple places where cells are born. Um, and those niches will have cues for those stem cells to generate the diversity of cells. They're all kind of like coming from there. Let's take the example of the cerebral cortex, like the outer layer of the brain. The region of the brain where, you know, we think that all of our cognition and what makes us human comes from.

[00:08:13] Most of the cells in the cerebral cortex are born, uh, in a region close to the ventricle, a ventricular zone, where there are these progenitors called radial glia. This radial glia will essentially generate almost all the cells in the cerebral cortex in a sequential manner. For instance, they'll first make deep layers of the cortex and then upper layer of the cortex, and the cells will organize themselves in a sequential manner.

[00:08:38] So, as you can imagine, if you specify, um, the generation of this particular type of stem cells, you can expect to generate all of the cells. 

[00:08:48] Russ Altman: Fantastic. 

[00:08:49] Sergiu Pasca: Now that doesn't mean that you get all of them, because some of the cells do come from outside of the nervous system. So for instance, microglia, the resident immune cells of the brain are not even born in the brain. They're born far away. They're mesodermal in origin. So if you really want to put them in, you have to make them separately. And then insert them into this preparation. 

[00:09:07] Russ Altman: Okay. 

[00:09:08] Sergiu Pasca: And, uh, but it, so that becomes again, an assembloid to a large extent. 

[00:09:12] Russ Altman: Okay, great. Well, this is, I could go on forever, but that has set us up beautifully for the conversation, which is why did you do this? And what are you using these brain tissues to do? 

[00:09:24] Sergiu Pasca: Well, you know, deep in core, I think what I am is a frustrated physician. And that's what I think I've been, and I continue to be. And for me, as I was doing my medical training, I was, you know, in awe of what molecular biology can do for most branches of medicine, as you very well known.

[00:09:44] And, you know, I was training at a time where we started to see some of the first rationally designed drugs in oncology, where literally, you know, you weren't just like hitting all the cells, you know, so that they will all die, but you will have a pathway. Uh, and you'll have a targeted, uh, therapeutic that will just cure like the cancer.

[00:10:06] And then, you know, you go on the, you know, oncology and then you move and you go in psychiatry, uh, to see patients. And it's almost like a completely different world. Their disorders are not defined molecularly or cellularly in any way, they're defined behaviorally. And they're, um, you know, also most of the drugs that we already have, have not been designed rationally, have not been discovered because we understand the pathophysiology, but rather in reverse, you know, they're found by chance.

[00:10:36] And then we've kind of like tried to figure out how they work and what the disease is like based on that. And that was really frustrating for me, I must say. Um, and it became clear that the reason why psychiatry and neurology have been left behind versus all other branches of medicine is to a large extent because we cannot access the human brain.

[00:10:54] Russ Altman: Right. People don't usually want to give you a sample of their brain to study. 

[00:10:58] Sergiu Pasca: They don't. 

[00:11:00] Russ Altman: For understandable reasons. 

[00:11:01] Sergiu Pasca: For very understandable reasons and nor do they give you one to test a drug, you know, before you do it. And that was really, uh, frustrating for me at that time. And I was doing a lot of experiments in animals, uh, cat and rats and animals.

[00:11:16] And it was incredibly powerful to be able to like stick an electrode into the brain of an animal and listen to electrical activity. Right? As the animal was performing various tasks. And it becomes clear that if we really want to understand these neuropsychiatric diseases, ultimately we will need to listen very carefully, very closely to those neurons and understand the molecular basis for that.

[00:11:41] And at that time, as I was finishing my clinical training, there was this remarkable breakthrough that was published around that time. That certainly still sounded at science fiction. A lot of people didn't believe that it was true, which was this idea that you could take any cell, a skin cell, and turn it into a stem cell.

[00:12:03] And it was, as you can imagine, outrageous because everybody thought, and it was dogma at that time, that development is a one-way street, you can never go back. Once a cell has been formed, you just don't go back to become a stem cell. It would be a liability to like forming cancers. And yet, you know, Yamanaka showed convincingly that you could do that.

[00:12:24] And in my mind, that kind of like clicked. Uh, and realize that it would be a remarkable opportunity for us in psychiatry to form, uh, to build brain cells from individuals in a non-invasive way without really accessing their brains. 

[00:12:38] Russ Altman: Yep. 

[00:12:39] Sergiu Pasca: And that essentially derailed my career to a large extent. And I sort of like gave myself fifteen years of like trying to do basic science. Hoping that, uh, you know, we'll make some advances and I'm coming very close to those fifteen years, so we'll see how it goes. But for me, it really came out of this frustration that I felt we were making much biological progress in understanding this. 

[00:13:01] Russ Altman: Okay. So let's go right to it. So if you take the skin of somebody who has, let's say, bipolar disorder or schizophrenia, and if you make a little piece of brain, it's not the whole brain, it's a little piece. Can you tell that there are problems with that, with those cells that might relate to the fact that the patient has schizophrenia? Because that's, that would be remarkable, because then you could sprinkle drugs on top of it. I use that as a metaphor, of course. And see, does that fix whatever is wrong? So, does a schizophrenic patient, when they go through this process of giving them, giving you their skin cells, do you wind up with little pieces of brain that you that have relevance to schizophrenia?

[00:13:40] Sergiu Pasca: Well, the challenge with that approach generally is that we wouldn't even really know what to look for. 

[00:13:47] Russ Altman: Right, right. 

[00:13:48] Sergiu Pasca: You know, like for a patient with bipolar, how would we know that we found something? And then that was really the challenge in the beginning because a lot of people said like, well, sure you can make the cells, but how are we going to know?

[00:13:59] So actually choosing the disease that you study, uh, judiciously is actually crucial. So what we actually did is we anchored it in genetics, actually. We went back and we thought, well, there are genetic forms of psychiatric disease, highly penetrant disorders, where if you have this mutation, you will certainly be very sick.

[00:14:20] And some of those mutations are in genes that we kind of know what they do overall. So we could test the function of those cells and the classic example, the one that we focused on fifteen years ago. 

[00:14:31] Russ Altman: Yes. 

[00:14:32] Sergiu Pasca: Is this rare form of autism and epilepsy called Timothy Syndrome, which is caused by a mutation in a calcium channel. And calcium channel, as the name implies, they carry calcium inside the cells.

[00:14:43] Russ Altman: Yep. 

[00:14:44] Sergiu Pasca: So we thought if we're going to be able to make neurons from this patient, we could actually measure how calcium goes inside the cells. And if there's something abnormal, we'll know what to look for. 

[00:14:53] Russ Altman: Right. So you have the hook there that you know what you're expecting, where the abnormality might be.

[00:14:59] Sergiu Pasca: Precisely. At least we have some sort of, you know, benchmarking that we can do. Not that we would know what would come afterwards, but it would tell us at least that there is something valid about these models. And that's exactly what we did early on. And then of course, continued characterizing the cells.

[00:15:15] And you can find all kinds of like defects now we know, not just in how the cells handle calcium, but how the cells are moving, for instance, throughout the nervous system, how they're making connections with each other. And once you find some of these defects, whether they're like in organoids or in assembloids, then you can really start contemplating the idea, let's try to reverse them.

[00:15:33] Let's try to sprinkle specific drugs or, you know, find other therapeutics to reverse them. 

[00:15:39] Russ Altman: Yes. 

[00:15:39] Sergiu Pasca: With the idea that if you were to reverse those in a dish or in some of these models, they will have an effect in patients. Uh, and of course that step has not yet been done. Nobody has really, went all the way. We're getting close, but nobody has really gone all the way to saying, okay, we'll reverse this now in a dish. Let's move into a patient and show that this will work. 

[00:15:58] Russ Altman: Fantastic. Okay. So you have some big news coming out around now. Can you give us a little flavor as we close this first segment? What's the latest things that coming out of the lab that you're most excited about?

[00:16:12] Sergiu Pasca: Yeah, I mean, for the past ten, fifteen years, essentially what we did, I feel, has been building tools to a large extent. And then paradoxically, my lab is probably much more well known as a tool building lab than I wish. I don't consider myself a tool builder. I never really wanted to build tools, to be honest. I wanted to understand the pathophysiology of disease.

[00:16:35] All these years of actually using these novel tools or trying to understand the biology of these disorders are starting to pan out. In the sense that, for Timothy Syndrome in particular, because this is, uh, you know, the paper that is coming out next week, we got such a good understanding of the biology of this condition through this human cellular models, organoids, assembloids, 2D cultures, that at one point, the therapeutic, opportunity just became self-evident.

[00:17:04] Russ Altman: Wow. 

[00:17:04] Sergiu Pasca: It just became clear. This is exactly what we need to do. And this came like three, four years ago. And then through a series of experiments that we've done, we've now developed a strategy that can essentially reverse almost all the phenotypes, all the defects that we've discovered in patient cells, uh, over the years, literally within, some of them within hours, some of them within days. But they're essentially just like, uh, completely reversing them.

[00:17:28] And I think that's very powerful. Of course, it poses all kinds of questions of like, what do you do next? There's not a very good animal model for this disease. So how do you test before you go into patients? And that's where another tool that we were developing in parallel came uh, to help. Which is, uh, you know, most of the therapeutics really do need to be tested in a living organism, in vivo, rather than just in a dish.

[00:17:50] It's very important. We know that already. A lot of failures come from the fact that something works really well in the dish. You go in a living organism, it doesn't work, or it has like unanticipated side effects. So how do you do that? How do you test something, you know, while keeping the patient safe? How do you test it on human patient cells without harming the patient? 

[00:18:09] So, a few years ago, we devised a strategy where we actually can take some of these organoids, but then transplant them into animals. We put them into a rat early in development, so that you essentially build a unit of human cortex into that rat. So almost a third of a rat hemisphere will essentially have human tissue. 

[00:18:28] Russ Altman: Hemisphere of its brain. 

[00:18:31] Sergiu Pasca: Of a rat. Yes. So you can do an MRI and you can see that a third of a hemisphere now has human tissue that we transplanted there early on. And it's vascularized, it receives sensory input, you can move the whiskers of the rat.

[00:18:43] Russ Altman: I'm going to bookmark putting a human tissue, brain tissue, into a rat for later on in our discussion, but I just wanted to bookmark that. Keep going, keep going. 

[00:18:53] Sergiu Pasca: But essentially now the human cells, the human neurons, uh, are integrated into the rat circuitry. And the reason why that is important is because now you, if you have a therapeutic, uh, for that disease, you can come and inject it into the rat, so in an in vivo system, but then look at the effect on human cells. And you can envision that it could be exactly the patient that you plan on treating. 

[00:19:19] Russ Altman: Yep. Right. 

[00:19:20] Sergiu Pasca: And then a week later you can get out the tissue and say, has there been an effect? Is the drug working? Is it having unanticipated side effects, like an immune reaction or other? So I think that is a very powerful way, uh, to actually test these drugs before we move into the clinic. 

[00:19:38] Russ Altman: Yes. 

[00:19:39] Sergiu Pasca: And so that's one of the things that we've done for Timothy Syndrome in particular. As we've had all these in vitro studies at one point, we were like, what is next? Where are we going to do? How are we going to get into? 

[00:19:49] Russ Altman: And for just to finish up for this part of the conversation, do the rats that you generated have brain tissue from patient's skin who had Timothy Syndrome? 

[00:20:00] Sergiu Pasca: Exactly.

[00:20:02] Russ Altman: This is The Future of Everything with Russ Altman. More with Sergiu Pasca next.

[00:20:20] Welcome back to The Future of Everything. I'm Russ Altman, and I'm speaking with Professor Sergiu Pasca from Stanford University. In the last segment, Sergiu told us about his amazing ability to take skin cells and turn them into small pieces of human brain tissue that can be studied for disease and for new therapies.

[00:20:37] In this segment, he'll tell us how complex these brain circuits can get, and some new results showing that they're even able to model the complex circuits like the perception of pain. He's also going to address the ethical issues about manipulating what are peculiar to humans, brain cells. And also he'll talk about how his group is sharing their technologies so that brain scientists all over the world can benefit.

[00:21:03] Sergiu. There's a lot of things that go wrong in the brain, and it's not always as simple. It's sometimes a complex set of connections between cells. They call them, like, neural circuits. So, where is our ability to, uh, engineer these more complex communication pathways that are important to understand certain diseases?

[00:21:22] Sergiu Pasca: You're right on point, because most psychiatric disorders are likely gonna arise not from, you know, drastic changes to cell composition of the brain. It's not like parts of the nervous system are missing, but rather arise from faulty communication between neurons in specific circuits. So it's becoming really important that with our human cell models, we're building ever more complex circuitry in a dish that allows us to probe some of this mechanism.

[00:21:51] So, you know, initially the assemblers that we were building had just like two parts. You would just put them in close proximity. Cells will migrate from one part to the other or they'll project. Then of course we wanted to put like more parts because most of the circuits have more, um, uh, more components.

[00:22:05] So we put three parts, cortex, spinal cord, the muscle. But then of course, some of these pathways have more than three. And actually adding a fourth component was not trivial. It took several years. to create both the components and, you know, kind of like the technology that is necessary to grow some of these cultures for longer periods of time.

[00:22:24] And just to give you an example of something that we've, uh, put together quite recently has been to actually build a sensory pathway, a somatosensory pathway from four parts. And somatosensory, uh, or somatosensation, essentially sends information from the periphery to the nervous system. So for instance, tactile information or pain information or temperature is sent by terminals in our skin, uh, that send those signals to the spinal cord, the spinal cords project it all the way in the middle of the brain in a structure called the thalamus, and then the thalamus will send it to the cortex where that sensation ultimately arises. And so there are multiple components. So we spent several years making each of this component, components of the circuit, and then we put them together. And recently we've succeeded in assembling the entire pathway, uh, that actually, uh, can respond to pain stimuli, pain like stimuli.

[00:23:25] Um, so you can actually make a sensory organoid, a spinal cord organoid, a thalamus organoid, and a cortical organoid. You put them together and form a somatosensory assembly. 

[00:23:36] Russ Altman: So earlier in our conversation, you were telling us about this amazing capability for the cells. You just have to give them the chance to be successful and they figure out what to do.

[00:23:46] In this case of these four different cells, was that still the case that they knew what to do? Or do things get sufficiently complicated that you kind of have to nudge them a little bit more than you do in the previous cases? 

[00:23:57] Sergiu Pasca: Oh, actually, again, they know what to do. 

[00:23:59] Russ Altman: Wow. 

[00:24:00] Sergiu Pasca: I mean, they know what to do and we wouldn't know how to instruct them, to be honest. We're still like pretty ignorant about this. But the cell, some of the circuits are so ancestral and so well conserved, that probably their evolutionary mechanism in place to establish some of that basic connectivity, uh, almost intrinsically. 

[00:24:17] Russ Altman: And I find this so exciting because based on your story with the Timothy Syndrome, you now can create pain or create touch, and then you can try to manipulate with drugs to see if you can modify the experience in a dish, and then presumably, modify the experience in the rat and then the humans. Is that the kind of plan you imagine? 

[00:24:39] Sergiu Pasca: Absolutely. And you know, it's quite interesting because once you put all these four components together, you know, they connect with each other and the reason why we know they're connecting with each other is because if you look at the activity of the neurons across the four components, they become synchronized. Rather than each kind of like sparkling their own kind of like song, suddenly, they're all talking to each other, and you see this emergent property, uh, this emergent activity of the four-part component. And then, what you can do, is you can sprinkle in some of the stimuli that we know are mimicking uh, let's say pain. So, you know, one thing that people, 

[00:25:15] Russ Altman: We'll call it pepper. 

[00:25:17] Sergiu Pasca: Exactly. So you can take capsaicin from like hot pepper. And if you sprinkle that, which by the way, if you add it even to your skin, it's painful. But if you add it here, if you add it here, then you'll suddenly just see that the first component lights up the sensory one and it transmits activity throughout the entire pathway.

[00:25:35] So that gives us, you know, some indication that indeed it actually works. And then what you can do even more is you can now model diseases. And so there are mutations that cause either loss of pain, or exacerbation of pain. Both of which are bad, obviously. And you can induce those mutations that are generally in sodium channels.

[00:25:55] You can actually induce those mutations in this preparation and suddenly see that there's either, you know, this synchronization of activities, so the sensory systems are not, you know, processing the stimuli right, or there's over processing. So it gives us really, for the first time, the ability to watch this communication between the sensory neurons and the circuitry right in front of our eyes, but with human cells. 

[00:26:18] Russ Altman: And I can see how the adding of four, it's just the beginning because anybody who's a clinician knows that after patients are exposed to pain chronically, they start to get psychiatric responses to the pain.

[00:26:29] You know, part of the pain is their high-level processing of the experience of pain. I've even had guests on the show talking about these, and you can imagine that you're going to need to build level five, six, and seven so that we can start to understand how those raw stimulation of pain leads to changes in how you process information at a much higher level. I mean, I'm not, I don't mean to give you any homework, but I could imagine that this could be on the list. 

[00:26:54] Sergiu Pasca: Absolutely. And right now our system, and I think this is important to clarify also so to not create any confusion, is the valence of pain, the sensation of pain. It's usually processed in other brain regions.

[00:27:07] This is, this information is taken from the cortex and it's processed and it gives us the sensation of pain. We don't have that yet in the system.

[00:27:14] Russ Altman: Right. 

[00:27:15] Sergiu Pasca: That will have to be built exactly as you said, separately. And in fact, many of the circuits are loop circuits. They're going up in, in loop, which is really important.

[00:27:23] And so we've been working quite diligently in trying to build ever more complex circuits. Of course, they're all in vitro, so they're never going to have the full, you know, complexity of an in vivo circuit, but we also don't want the full complexity. We want the system to be sufficiently complex, yet simple for us to use to dissect the molecular components and move forward therapeutically. 

[00:27:46] Russ Altman: So as I promised a few minutes ago, I definitely want to go to the ethics of this because, you know, the headline here, well, the headline is really that you're addressing diseases that we didn't have an ability to address before. But another headline is that we're taking human, pieces of human brain cells and we're putting them in animals and basically you're manipulating a lot of things that some people may consider very sacrosanct, very human and very peculiar to humans. So tell me a little bit about how as a scientist and a physician, you have navigated some of the ethical issues about making sure that your work is accepted and that people understand what you are doing and where you, if you're drawing any lines, where you're drawing those, what's the situation there?

[00:28:27] Sergiu Pasca: Yeah, no, this is a very important component. To be honest, I never really kind of like thought or planned for it as we were like moving forward. But you know, the paradox is as follows. Psychiatric disorders are to a large extent uniquely human, or you know, most of them, if not all of them are uniquely human.

[00:28:45] And so, as you can imagine, if you want to understand this, the models that we have for those disorders need to be as human as possible. And yet, the more human they become, the more uncomfortable we feel about creating something that is really human like experience. And so, certainly we're not there with any of the preparations that we have.

[00:29:05] But as our preparations are getting ever more complex, there are all kinds of concerns that are being raised about this. Some of them, you know, very careful, uh, one, some of them anchored in misunderstanding of what it's actually done. But I think that is exactly the moment when you have to have conversations with, first of all, the broader scientific community, and then with the public itself.

[00:29:30] I think the public has a responsibility to be part of these conversations. You know, most of this work is paid by federal grants. And I think the general public has, uh, the right to be involved in this conversation. 

[00:29:41] Russ Altman: What kind of feedback have you gotten? Oh, I'm sure you've given popular talks like to, you know, to, to the lay public, how do they respond?

[00:29:49] Sergiu Pasca: So generally, I think like the public understands really well what the motivator, I think if the motivation comes through very clearly. Uh, I think it's, uh, you know, everybody will connect. Everybody knows somebody who's suffering from a psychiatric disease, right? I mean, this are affecting one in five individuals. And everybody knows just how devastating these conditions are and that we will need some solutions.

[00:30:11] So I think people will understand, but at the same time, this type of research needs to be done responsibly. Because we are crossing various boundaries, you know, you could say by building ever more complex circuitry. And I think in vitro, there are fewer concerns that I think are realistic, uh, in the sense that sure, the circuit can get very complex, but there's no sensory, uh, input that is like, there's no output that is meaningful, it's very difficult to do both.

[00:30:38] But you can envision that if you transplant into an animal, uh, there is another series of like controversies that are arising. So what I've done is, first of all, we've had a lot of conversations with others. I gave a series of public talks, including a TED talk, which was a really important component of engaging already the public. And, uh, just recently, uh, I co-organized a meeting at Asilomar in kind of like the historical, uh, side where some of this conversation actually started with like Berg doing, 

[00:31:09] Russ Altman: The 1970’s when genetic engineering became possible. Yes? 

[00:31:13] Sergiu Pasca: Yeah. So together with my colleague here at Stanford, Hank Greely, we co organized this meeting at, uh, at Asilomar where we brought together not just scientists from the field, but actually scientists from outside the field, people who are studying consciousness, philosophers, evolutionary biologists, uh, social scientists to really think, uh, you know, very openly about this.

[00:31:36] And we're putting together a series of, uh, guidelines, uh, that we're in the process of like writing up, that hopefully, uh, will catalyze farther discussions. And our hope is that in the future we'll have an even bigger meeting that will engage even more broadly, uh, you know, families of patients, but other scientists across the field and neuroscientists in particular as we think about these issues. 

[00:32:01] Russ Altman: Fantastic. Well, we're a little bit, we're almost out of time, but I wanted to give you thirty seconds to talk about the very exciting prospect that you are now sharing this technology so that others can use it. And just give me a fifteen, twenty seconds on what's the idea about sharing these technologies?

[00:32:16] Sergiu Pasca: Yeah, well, you know, as you know, I realized very quickly that, uh, as we were developing technologies, and again, as I mentioned, I never envisioned being a tool developer. I don't consider myself a tool developer, but at one point, once we've had, you know, half a dozen or a dozen of these techniques put out, there are a lot of people who wanted to implement them.

[00:32:34] There are a lot of like troubleshooting, and these experiments are not trivial, you know, unlike like CRISPR where, you know, you can do your experiments like very quickly in two or three days and maybe even try them in the kitchen at home. These experiments require hundreds of days. 

[00:32:46] Russ Altman: Not for the kitchen. 

[00:32:47] Sergiu Pasca: And there's a lot of troubleshooting, and not in the kitchen. And so they require a lot of effort. And initially we've helped individual labs one by one. I mean, literally more than a hundred labs. Helping them to implement step by step the technique. At one point it became overwhelming. 

[00:33:01] And so what we did is through the center that I lead here at Stanford, the Stanford Brain Organogenesis Center, we started putting together a course, an international course where we would bring, you know, twenty-five students at a time and teach them essentially all the tricks of the trade.

[00:33:17] And within one week, and we prepare of course for months before because it's kind of like a cooking show, you know, I mean, we have all the components ready. They do the critical steps. They would never be able to do a hundred days long experiments in a week. But they land their critical steps. And when they come here, they also make a pledge that they will go back home and they will teach others at their own institutions.

[00:33:36] And that has, you know, beautiful amplifying effects because now there are hundreds and hundreds of alumni. I mean, I travel around the world and people come and say, oh, we've learned at the course, or we've learned from somebody who learned at the course. So it's been really remarkable and there's so much to do in neurology and psychiatry for a lifetime.

[00:33:54] So, and I think here at Stanford, we've always had a culture of like broadly and openly sharing whatever we developed early. So it, it really just aligned beautifully, I think, with the philosophy that we have here. 

[00:34:05] Russ Altman: Thanks to Sergiu Pasca. That was The Future of Brain Science. Thanks for tuning into this episode with over 250 episodes back in our archive. You can have instant access to lots of good conversations with brilliant people passionate about their work. If you're enjoying the show, or if it helps you in any way, please write and review and give it a five. You can connect with me on X or Twitter @RBAltman, and you can follow Stanford engineering @StanfordENG.