Assembloids: Recreating the Brain with Sergiu Paşca

Summary

StarTalk Radio Summary: "Assembloids: Recreating the Brain with Sergiu Paşca"

Podcast Information:

• Title: StarTalk Radio
• Host: Neil deGrasse Tyson
• Episode: Assembloids: Recreating the Brain with Sergiu Paşca
• Release Date: May 2, 2025

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Introduction to Assembloids

At the outset (02:09), Neil deGrasse Tyson welcomes special edition guests Gary O'Reilly and Chuck Nice before introducing the episode's primary focus: assembloids. Assembloids are an advanced form of organoid intelligence, where multiple organoids self-organize to mimic more complex biological structures, particularly the human brain.

Understanding Stem Cells and Organoids

Sergiu Paşca (05:07) begins by explaining the foundation of his work:

“An organoid is a clump of cells that is cultured in a dish in a three-dimensional structure. It's supposed to model features of an organ, similar in function but not an exact replica” (05:07).

Neil interjects with a relatable analogy:

“Asteroids show up as stars in a photo because they're so tiny. But they're not stars. So that's organoids” (05:51).

This sets the stage for understanding how organoids serve as simplified models of human organs, particularly the brain.

The Evolution of Assembloids

Gary O'Reilly (02:10) highlights the transition from organoid intelligence to assembloids:

“Organizing them together unleashes new forces of self-organization, which is really what the brain does” (14:05).

Sergiu discusses the self-organizing nature of cells:

“Cells come with the instructions, so once you make a specific cell, it connects with others based on intrinsic instructions, forming ordered structures” (12:21).

Modeling Neurodevelopmental Disorders

The conversation pivots to the practical applications of assembloids in understanding and treating neurodevelopmental disorders. Sergiu recounts his journey into this field:

“I was incredibly frustrated by the lack of models to study diseases like autism. Induced pluripotent stem cells opened the possibility to study patient-derived neurons outside the human body” (07:40).

Case Study: Timothy Syndrome

Sergiu delves into a specific application involving Timothy syndrome, a rare condition combining autism and epilepsy. He explains how a single genetic mutation affects calcium channels in neurons:

“These patients have a single letter mutation that makes calcium channels open longer, disrupting neuronal communication” (28:03).

Chuck Nice (30:14) humorously suggests using CRISPR to fix the mutation:

“If you know the actual letter, why not do something like CRISPR, where you just go in and snip out the letter” (30:14).

Sergiu emphasizes the complexities of such interventions:

“Changing the mutation everywhere in the brain is not doable today” (30:18).

Advancements in Assembloid Complexity

Moving forward, Sergiu discusses the progression from simple organoids to complex assembloids capable of replicating functional neural circuits. An example is the corticospinal pathway reconstructed using assembloids:

“Once you put the cortical neurons, motor neurons, and muscle cells together, they form a functional circuit that can contract muscles in response to cortical stimulation” (36:38).

This breakthrough allows for realistic modeling of neurological diseases and testing potential treatments in vitro.

Ethical Considerations

As assembloid technology advances, ethical questions emerge. Sergiu addresses concerns about the use of human cells and the potential for emergent properties:

“As models become more complex, we have to consider whether new properties arise that require regulation. Currently, our in vitro models are not complex enough to justify concerns about intelligence or consciousness” (59:20).

He draws parallels to historical ethical debates in biology, such as cloning, highlighting the importance of ongoing interdisciplinary discussions.

The Future of Neuroscience and Therapeutics

Sergiu envisions a future where assembloids play a crucial role in understanding and treating a wide array of psychiatric and neurological disorders:

“We're preparing for a clinical trial for Timothy syndrome, and we're systematically studying other conditions like various forms of epilepsy and schizophrenia” (53:08).

Chuck Nice muses on the potential to correct developmental mutations pre-birth:

“Identify mutations in a child developing in the womb, model them with assembloids, and correct them before birth” (39:59).

Sergiu remains cautiously optimistic, acknowledging the challenges but emphasizing the transformative potential of assembloid research.

Neil's Cosmic Perspective

Wrapping up, Neil deGrasse Tyson offers a cosmic perspective on the significance of this scientific frontier:

“The progress of civilization comes about when we have the proper match between a tool and a goal. Neuroscience is finally catching up with the methods that have shaped engineering throughout history” (67:59).

He celebrates the advent of tools like assembloids that enable unprecedented exploration into the human brain, marking the beginning of a "golden age for human neuroscience."

Conclusion

Sergiu Paşca's work on assembloids represents a pioneering effort to bridge the gap between molecular biology and complex brain functions. By recreating and assembling human neural circuits in vitro, his research holds promise for unraveling the mysteries of neurodevelopmental disorders and paving the way for innovative treatments. As the field progresses, it will continue to navigate ethical landscapes while pushing the boundaries of our understanding of the human mind.

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Notable Quotes:

• Sergiu Paşca (05:07): “An organoid is a clump of cells that is cultured in a dish in a three-dimensional structure. It's supposed to model features of an organ, similar in function but not an exact replica.”

• Chuck Nice (30:14): “If you know the actual letter, why not do something like CRISPR, where you just go in and snip out the letter.”

• Sergiu Paşca (14:05): “Cells come with the instructions, so once you make a specific cell, it connects with others based on intrinsic instructions, forming ordered structures.”

• Neil deGrasse Tyson (67:59): “Neuroscience is finally catching up with the methods that have shaped engineering throughout history.”

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Timestamp Reference:

• (MM:SS) indicates the minute and second mark in the transcript where the quoted or discussed content appears.

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Note: Advertisements, introductory segments by Rob Lowe, and non-content sections were intentionally omitted to maintain focus on the episode's substantive discussions.

Transcript

[Rob Lowe]

Ever walk into a room and forget why you're there or misplace your keys? More than you'd like to admit. As we get older, our brain slows down. We need to protect it. That's why I use methylene blue, the nootropic everyone is talking about, to boost focus, memory, and mental clarity. Want to stay sharp, boost your focus, and protect your brain long term. Go to livegood.comsxm to shop all of Livegood's highest quality products at the lowest prices anywhere. Livegood.comsxm hey, everybody, it's Rob Lowe here.

If you haven't heard, I have a podcast that's called Literally with Rob Lowe. And basically it's conversations I've had that really make you feel like you're pulling up a chair at an intimate dinner between myself and people that I admire, like Aaron Sorkin or Tiffany Haddish, Demi Moore, Chris Pratt, Michael J. Fox. There are new episodes out every Thursday, so subscribe, please, and listen wherever you get your podcasts.

[Neil DeGrasse Tyson]

So, Gary, you keep digging up these neuroscience topics. Yeah, they seem endless.

[Gary O'Reilly]

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

[Neil DeGrasse Tyson]

This is good.

[Chuck Nice]

I thought you were doing it because you were trying to give me a message, which was, something's wrong with my brain.

[Neil DeGrasse Tyson]

That too. Coming up on StarTalk. Welcome to StarTalk, your place in the universe where science and pop culture collide. StarTalk begins right now. This is StarTalk, Neil DeGrasse Tyson, your personal astrophysicist. And today it's going to be special edition, which means we got Gary O'Reilly. Gary, Neil. All right, man.

[Sergio Pasca]

Yeah.

[Neil DeGrasse Tyson]

Always good to have you.

[Gary O'Reilly]

Pleasure's mine.

[Neil DeGrasse Tyson]

Very good. And Chucky, baby.

[Chuck Nice]

Hey, man.

[Neil DeGrasse Tyson]

All right.

[Chuck Nice]

Not good to have me, I guess. Okay.

[Neil DeGrasse Tyson]

Okay. Good to have Gary.

[Chuck Nice]

Always good to have you.

[Neil DeGrasse Tyson]

And Chuck. Chuck, so you got a word here? Assembloids.

[Gary O'Reilly]

Yes.

[Neil DeGrasse Tyson]

That sounds like somebody just made that up.

[Gary O'Reilly]

Just assembled it.

[Neil DeGrasse Tyson]

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

[Gary O'Reilly]

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

[Chuck Nice]

Organoid.

[Gary O'Reilly]

Yes, I remember right now.

[Chuck Nice]

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

[Gary O'Reilly]

Right? So that's what that was being used.

[Neil DeGrasse Tyson]

For, for our future overlords.

[Gary O'Reilly]

All right, so this was putting biology onto technology. This is something different. However, it's based around the organoid intelligence, but this now becomes organoids assembling together oh, now that.

[Neil DeGrasse Tyson]

Then self organizing. Organize.

[Chuck Nice]

Self organizing.

[Sergio Pasca]

Organizing.

[Gary O'Reilly]

So our guest today.

[Chuck Nice]

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

[Neil DeGrasse Tyson]

And what could go wrong?

[Gary O'Reilly]

Let's not do that question just yet.

[Neil DeGrasse Tyson]

I'll say that for the end. Thank you. Okay, go.

[Gary O'Reilly]

So our guest today had the great idea of trying to get these organoids to work together and coined the phrase assembloid. So assembloids is down to our guesswork now. These assembloids can help us uncover the biological mysteries of our own minds. So are we just clumps of cells in the big petri dish we can call life? Yes, I think.

[Neil DeGrasse Tyson]

Speak for yourself.

[Gary O'Reilly]

Sometimes it can feel like that. So let's find our guests, say, in.

[Neil DeGrasse Tyson]

The petri dish of life.

[Gary O'Reilly]

Yes.

[Neil DeGrasse Tyson]

That was beautiful.

[Gary O'Reilly]

What's. You're welcome. I'm just reading it. And so let's. Let's see what mysteries have been sold, what mysteries are still out there. And our guest, Neil. So drop in on our guest.

[Neil DeGrasse Tyson]

Yes, please. So we have Sergio Pasca. Sergio, welcome to Start Talk.

[Sergio Pasca]

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

[Neil 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. Yes, it is in plain sight.

[Chuck Nice]

A fresh frontier.

[Neil DeGrasse Tyson]

Fresh frontier. A stem cell biologist. Stem cells have been pretty much in the news on and off for the past couple of decades. 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.

[Chuck Nice]

It sounds very puppeteerish.

[Neil DeGrasse Tyson]

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

[Sergio Pasca]

Yeah.

[Neil DeGrasse Tyson]

Excellent. And here in 2023, you made a knight of the Order of Merit, Romania. Ooh. All right, so let's get back to basics here and put us all on the same page with what an organoid is.

[Sergio Pasca]

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 organization, but is supposed to model features of an organ.

[Neil DeGrasse Tyson]

So in the case, a scaffold of an organ.

[Sergio Pasca]

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 that are being modeled.

[Neil DeGrasse Tyson]

And by the way, asteroids, they show up as stars in a photo because they're so tiny. Right, but they're not stars. So that's asteroids little star.

[Chuck Nice]

Exactly.

[Sergio Pasca]

So it's organ like I guess the same. You like, star like.

[Neil DeGrasse Tyson]

Oh, wait. Oh, so those are organoids.

[Sergio Pasca]

Yes.

[Neil 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?

[Sergio Pasca]

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 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.

[Chuck Nice]

Right.

[Sergio Pasca]

And that has been certainly like very difficult to do studies. But then about.

[Neil DeGrasse Tyson]

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

[Sergio Pasca]

So that happened 20 years ago, almost 20 years ago, 19 years ago, when a Japanese scientist, Shinya 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, you know, sort of like cellular alchemy, so to speak. Right. Because it was like we always thought that it's a one way street. Development is a one way street. You never. So like go back just so we're.

[Neil DeGrasse Tyson]

On 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?

[Sergio Pasca]

Exactly, yeah.

[Neil DeGrasse Tyson]

Nerve cells, muscle cells.

[Sergio Pasca]

Yeah.

[Neil DeGrasse Tyson]

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

[Chuck Nice]

Right.

[Neil DeGrasse Tyson]

Okay, gotcha.

[Sergio Pasca]

Stem cells 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 are the ones that you would like to have so that you can ultimately guide them to become different other cells and tissues in the body.

[Neil DeGrasse Tyson]

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

[Gary O'Reilly]

See, you say that, but how is that possible? 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?

[Sergio Pasca]

So it was really a brilliant idea, the build on work that was done before and 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 experiment, he found out four that if you put at the same time, pretty much confuse the cell, so to speak, 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 dropped everything because my expertise, I'm a physician by training, my expertise is actually autism spectrum disorders and neurodevelopmental conditions. And I was like incredibly frustrated by the lack of models to study this disease. There are animal models, but what is an animal model of autism? That has been a challenging aspect. We can't really access the human brain that is sort of like 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 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 16, 17 years ago, I came to Stanford mesmerized by the potential of this stem cells that we can make, which we called induced pluripotent stem cells. And they 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 all of this.

[Neil DeGrasse Tyson]

And that blew open the whole field at that point.

[Sergio Pasca]

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 us to focus on a disease where we actually like knew what to expect, sort of like to calibrate. And that 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 we 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.

[Gary O'Reilly]

So if, 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?

[Sergio Pasca]

That's a very good question. And you know, I mean, self organization is, is a remarkable force of nature and biology, right? And very often when we do this experiment in a dish, to be honest, for, for very long time I was so like thinking like an engineer in the sense 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 and another one and another one. And that's why we call this process self Organization. So which really is the formation of order structures from relatively homogeneous elements. 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 Rylad Bernard convection, I guess, is the classic example. But biology just brings it to the next level and now organizes cells pretty much on their own.

[Chuck 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.

[Sergio Pasca]

Exactly. Okay, 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.

[Chuck Nice]

What to do.

[Sergio Pasca]

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. 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 was unleashing like new forces of self organization, which is really what the brain does. I mean, the brain builds itself at the end of the day, you know.

[Chuck Nice]

If you think about it, right, 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.

[Sergio Pasca]

Someplace else, at least early in development. Yes, early development, it will do so. And then the more you progress, the, you know, the less you can, less that happens, right?

[Gary 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?

[Neil DeGrasse Tyson]

Something crawls out of the petri dish.

[Sergio Pasca]

There you go.

[Chuck Nice]

You have the smartest dish in the world.

[Neil DeGrasse Tyson]

It'll chase you down the corridor.

[Chuck Nice]

Get that fork away from me.

[Sergio Pasca]

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 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. 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. And it turns out that once you make this cluster of cells and, you know, sort of like, I wish I could show you. I wish you were here in the lab and I could show you. Maybe I can try. They look something like this.

[Gary O'Reilly]

All right, I see it.

[Sergio Pasca]

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 discover something really fascinating is, 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. So it's almost like they know that birth should happen.

[Chuck Nice]

Wow.

[Sergio Pasca]

There's almost like. We think that there is some sort of internal clock that keeps track of time.

[Gary O'Reilly]

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

[Sergio Pasca]

Yeah, this is the brain clock. Exactly.

[Rob Lowe]

Ever walk into a room and forget why you're there or misplace Your keys. More than you'd like to admit. As we get older, our brain slows down. We need to protect it. That's why I use methylene Blue, the nootropic everyone is talking about, to boost focus, memory, and mental clarity. Want to stay sharp, boost your focus, and protect your brain long term. Go to livegood.comsxm to shop all of Livegood's highest quality products at the lowest prices anywhere. Livegood.comsxm hey, everybody, it's Rob Lowe here.

If you haven't heard. I have a podcast that's called Literally with Rob Lowe. And basically it's conversations I've had that really make you feel like you're pulling up a chair at an intimate dinner between myself and people that I admire, like Aaron Sorkin or Tiffany Haddish, Demi Moore, Chris Pratt, Michael J. Fox. There are new episodes out every Thursday, so subscribe, please, and listen wherever you get your podcasts.

[Kristen]

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[Neil DeGrasse Tyson]

What else?

[Kristen]

Oh, it's tracking, in fact. Value surge alert. Trucks up 2.5%, vans down 1.7, just as predicted.

[Sergio Pasca]

So we gonna, I don't know, could.

[Kristen]

Sell, could hold the power to always.

[Neil DeGrasse Tyson]

Know our car's worth.

[Kristen]

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[Sergio Pasca]

I'm Alikon Hemraj and I support StarTalk on Patreon. This is StarTalk with Neil DeGrasse Tyson.

[Gary O'Reilly]

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

[Neil DeGrasse Tyson]

Yeah. So what's doing the ticking inside the exact.

[Sergio Pasca]

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 in the same.

[Chuck Nice]

But. And that that same time period reflects the gestation period of a chimpanzee.

[Sergio Pasca]

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, the spirits of development. And so they're intrinsic to the cells. I think what we. What was surprising for us was 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? What kind 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. Nobody knows what the clock is, so nobody knows what the molecular mechanism of it is. But it is somewhere in the cell. 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.

[Gary 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. They're outside of the body. They've not got the whole human system to back it up.

[Sergio Pasca]

So we feed them so like 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 f. And so we just, like, have. We call them cell culture media.

[Chuck Nice]

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

[Sergio Pasca]

Absolutely.

[Chuck Nice]

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

[Sergio Pasca]

So we do all kind 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. Very often, neurons in the cortex have sort of like a pyramidal shape. We call them pyramidal neurons. So you look. Or do they look pyramidal?

[Neil DeGrasse Tyson]

Pyramidal. That means like a pyramid.

[Sergio Pasca]

Yeah, exactly.

[Neil DeGrasse Tyson]

Pyramidal. Okay.

[Sergio Pasca]

For me, pyramidal, yeah, they really look like a tiny pyramid.

[Neil DeGrasse Tyson]

Okay.

[Sergio Pasca]

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. 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? Because that's where the name assembloid came. 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. To. To move. And it turns out that exactly what they do, you put them together, and these GABAergic cells immediately start. Like, they have. This processes, the cellular processes, they start so, 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. This happens in the third trimester of life.

[Chuck Nice]

But this is. This is what's going on in Every developing human being, what you described. 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?

[Sergio Pasca]

Well, 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.

[Rob Lowe]

Wow.

[Chuck Nice]

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.

[Sergio Pasca]

So 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 the. As you progress in development, the cells become less and less permissive. We don't have cells moving in our brain right now.

[Chuck Nice]

Okay.

[Sergio Pasca]

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, you know.

[Neil DeGrasse Tyson]

Because the dumbass circuitry.

[Chuck Nice]

The dumbass circuitry is fully formed and very, very strong. Right. However, if you're able pro 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.

[Sergio Pasca]

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.

[Chuck Nice]

That's amazing.

[Gary O'Reilly]

So if.

[Chuck Nice]

Professor. That's amazing.

[Gary O'Reilly]

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 affect Timothy.

[Chuck Nice]

Damn.

[Gary O'Reilly]

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

[Rob Lowe]

Yeah.

[Gary O'Reilly]

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

[Chuck Nice]

Right.

[Gary O'Reilly]

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

[Sergio Pasca]

So I mean, this, 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? I mean, psychiatric disorders are mysterious disorder. We still don't know how like this, you know, thoughts and this complex social behavior rises 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.

[Neil DeGrasse Tyson]

All right, Right.

[Sergio Pasca]

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. 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 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 this patient, 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 ascertained that we were really studying a disease process that is relevant.

[Chuck 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.

[Sergio Pasca]

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

[Chuck Nice]

There you go.

[Sergio Pasca]

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

[Chuck Nice]

Okay.

[Sergio Pasca]

And this patient 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 this models that I've told you now for 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, 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. You, they just like look at it and they 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 we did this, 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.

[Chuck Nice]

Damn.

[Sergio Pasca]

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

[Chuck Nice]

This is insane. I know, but this is what you're talking about.

[Gary O'Reilly]

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. But otherwise someone would have seen it a long time ago.

[Neil DeGrasse Tyson]

So if you were around in Frankenstein's day, Frankenstein would. Could just be a regular Joe. Yeah, on the street. Yeah.

[Chuck Nice]

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

[Gary 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?

[Sergio Pasca]

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 know that it would work? 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, 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 organoids 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 organoid 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. 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.

[Rob Lowe]

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If you haven't heard, I have a podcast that's called Literally with Rob Lowe. And basically, it's conversations I've had that really make you feel like you're pulling up a chair at an intimate dinner between myself and people that I admire, like Aaron Sorkin or Tiffany Haddish, Demi Moore, Chris Pratt, Michael J. Fox. There are new episodes out every Thursday, so subscribe, please, and listen wherever you get your podcasts.

[Kristen]

Hey, Kristen, how's it tracking with Carvana Value Tracker?

[Neil DeGrasse Tyson]

What else?

[Kristen]

Oh, it's tracking, in fact. Value surge alert. Trucks up 2.5%, vans down 1.7, just as predicted.

[Sergio Pasca]

Mm. So we gonna.

[Kristen]

I don't know, could sell, could hold.

[Rob Lowe]

The power to own.

[Neil DeGrasse Tyson]

Always know our car's worth.

[Kristen]

Exhilarating, isn't it.

[Chuck Nice]

Tracking.

[Kristen]

Always know your car's worth with Carvana Value tracker.

[Gary 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.

[Neil DeGrasse Tyson]

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

[Gary O'Reilly]

No, let the professor explain.

[Sergio Pasca]

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 sort of, 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. 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. It's as easy as textbook biology. We thought, could we actually reconstruct this? You may think that it's easy, but here it is. We 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. Wow, that was a three part assembloid, all right. And that, 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 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 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 just how useful a preparation like this can be.

[Chuck Nice]

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

[Sergio Pasca]

Perhaps even an easier scenario for that.

[Chuck Nice]

Okay, good.

[Sergio Pasca]

Have 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 assembly 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.

[Chuck Nice]

Right.

[Sergio Pasca]

And then you use that in a patient.

[Chuck 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 you. Wow, that's amazing.

[Sergio Pasca]

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

[Chuck 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 a newsy scientist? That's right, because he said, look at, look at Neil. Neil's looking at me like, how dare.

[Neil DeGrasse Tyson]

He's a scientist. How dare you. We don't accept just what is.

[Chuck Nice]

I understand.

[Gary O'Reilly]

Please.

[Sergio Pasca]

No, 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 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 because we cannot access the brain. So my belief is that as we gain access to the brain through this 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, cardiology and other branches of medicine. That's, that's sort of like how I see it, but I may be wrong.

[Gary 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.

[Chuck Nice]

Oh, okay. I thought you meant like they're going to have that little vial of assembloids just screaming in the middle of the night. Why did you give me pain?

[Gary O'Reilly]

Not that one.

[Sergio Pasca]

No, you're right. That one of the things that we're trying. Actually this, this just came out. I mean we made the first assembloid in like 2017. It took us three years to make from go from two part assembloids to three parts assembly. The one with the motor that I was explaining. And then it took us another five years to get to Four parts assembly, 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. 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 these specialized receptors and you add capsaicin and they just beautifully respond, like electrically.

[Gary O'Reilly]

But this had never been witnessed before, had it?

[Sergio Pasca]

No. I mean, to put the entire circuit together has never really been done before. Now the biology of it for you.

[Gary O'Reilly]

To witness this the first ever time.

[Sergio Pasca]

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 100 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 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 one unidirectional. So the circuit is almost, you know, and there's no stimulus, by the way. 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 20 years. There are this patient 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, 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. 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.

[Gary O'Reilly]

Not feeling pain. Well, that's the new. That's the Novocaine movie, isn't it?

[Chuck 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. And I'm not saying it right. Take a bunch of ice, add water to it, and it actually becomes colder than freezing. Okay.

[Sergio Pasca]

Yes.

[Chuck 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.

[Neil DeGrasse Tyson]

Where this is all you were squealing at the time.

[Chuck Nice]

Well, yes, I was. Because it burned. It was not cool. So.

[Neil DeGrasse Tyson]

Not literally burned. Cause it's cold, not hot.

[Chuck Nice]

Right. It's 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 too, he got a lot more fat on his hands to get. But seriously, it's a matter of sensitivity to pain. No, absolutely it is not.

[Neil DeGrasse Tyson]

No.

[Chuck Nice]

What is it?

[Neil DeGrasse Tyson]

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

[Gary O'Reilly]

Yeah.

[Chuck Nice]

Oh, well, that just changes.

[Gary O'Reilly]

Oh, no, no. Okay, so explain to me the mind over matter aspect here.

[Sergio Pasca]

Yeah, 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. They're patients who dissociate between the two. So they're 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, 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. Right. So I think it's so like mitigating this risk moving forward that I think is very important.

[Gary O'Reilly]

How, 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.

[Sergio Pasca]

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

[Gary O'Reilly]

Well, not everybody. Everybody, everybody's got a thing with opioids. But there must, there must be a mechanism there where opioids use that you can sort of tag onto, but not get that addictive part.

[Sergio Pasca]

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 was discovered thousands of years ago by chance. Right. I mean, essentially, piggybacks on this circuit does not come from a deep understanding of the circuit itself.

[Chuck Nice]

Circuit?

[Neil DeGrasse Tyson]

Don't you make opium from poppy seeds?

[Chuck Nice]

Yes.

[Neil DeGrasse Tyson]

Okay. I just want to clarify that.

[Sergio Pasca]

So I think 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. One that is sort of like driven by the biology behind it. And I think that's the beauty of it.

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

[Neil DeGrasse Tyson]

And just to be clear, Chuck.

[Chuck Nice]

What?

[Neil DeGrasse Tyson]

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

[Sergio Pasca]

Yeah.

[Neil DeGrasse Tyson]

Okay. Long ago.

[Chuck Nice]

Right.

[Neil DeGrasse Tyson]

When I began wrestling in high school.

[Chuck Nice]

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.

[Neil 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. My hand is in a bucket of ice. Yeah, it hurts, but who cares?

[Chuck Nice]

But who cares?

[Neil DeGrasse Tyson]

I'm not gonna get frostbite from it.

[Chuck Nice]

Okay, so you and Gary have that, I'm sure. Cause Gary's had a ton of surgeries.

[Gary O'Reilly]

Oh, yeah, we'd have ice pops.

[Chuck Nice]

He'd played in pain. He sat in ice after games. Right, See? And I have not pulled.

[Neil DeGrasse Tyson]

You have not done none of that?

[Chuck Nice]

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

[Neil DeGrasse Tyson]

That's why you wimped out in the.

[Chuck Nice]

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. So.

[Neil DeGrasse Tyson]

Oh, that's what. Okay.

[Gary O'Reilly]

So when. 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?

[Sergio Pasca]

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? 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 make sense of what the meaning is. And you see, that's why 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. Suddenly we could actually see what word does what.

[Neil DeGrasse Tyson]

And, you know, cool thing about the Rosetta Stone, it's like a shopping list or something. It's like, it's not any deep, just.

[Chuck Nice]

Like bread and eggs.

[Neil DeGrasse Tyson]

I don't know if it's exactly a shopping list, but it's something completely mundane, something really trivial.

[Sergio Pasca]

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 to a large extent, I've seen this, the mission for my lab and in general, 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, 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 that has not yet been done. And, you know, we'll have to see whether a clinical trial will actually be successful. I mean, we're preparing for a clinical trial for T 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 going to 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. This is going to be the golden age for human neuroscience.

[Neil 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, 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.

[Chuck Nice]

We'Re not going down that road. Right, yeah, right.

[Gary 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 syndrome, but take on other horrific diseases?

[Sergio Pasca]

Oh, 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 us 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 want to 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. 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. Right, right. It's a huge burden.

[Gary O'Reilly]

Are we going to come across a situation where you are going to have. You'll be faced with building an assembloid or creating an assembloid that will just be too complex? Is there a limit to what you can assemble?

[Sergio Pasca]

There are absolutely limits to what we can assemble. And, you know, while like many of the features of disassemblers 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. 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, 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. So, you know, again, while our models are relatively complex already, they lack a lot of the complexity. And, you know, is as. As. As George Box famously said that all models are wrong, but 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 of a circuit that will give us the breakthrough therapeutically.

[Neil DeGrasse Tyson]

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

[Chuck Nice]

Right.

[Neil 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.

[Chuck Nice]

That's why they're a model.

[Neil DeGrasse Tyson]

Otherwise, it would be the exact thing.

[Chuck Nice]

You wouldn't need it. You wouldn't need a model. If you could replicate the exact thing.

[Neil DeGrasse Tyson]

It would be the thing itself.

[Chuck Nice]

Right, okay. Yeah. I just love that Assembloids sounds like a Cartoon Network show. Like assembloids weekdays at 3, right after transformers.

[Sergio Pasca]

You know, it actually turns out that there is a game there. 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 Assemblers. Cool.

[Gary O'Reilly]

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

[Neil DeGrasse Tyson]

Did you say regulatory?

[Sergio Pasca]

I did this.

[Neil DeGrasse Tyson]

America Jack. It's regulatory.

[Chuck Nice]

Regulatory. Not even regular regulatory.

[Gary O'Reilly]

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

[Neil DeGrasse Tyson]

It's American Jack.

[Sergio Pasca]

Anyway, he was, 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.

[Neil DeGrasse Tyson]

Yeah.

[Sergio Pasca]

You know, who owns the cells. You have to give consent for this experiments 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.

[Chuck Nice]

That's very much like, who is the woman who Lacks, what's her name?

[Neil DeGrasse Tyson]

Lax.

[Chuck Nice]

Lax, yes. Whose cancer cells were. Who 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.

[Sergio Pasca]

And that's why it's critical every time we go.

[Chuck Nice]

Henrietta Lacks. Yes.

[Sergio Pasca]

You know, the, the patients or you know, who, you know, the parents in the case, if they're minors, will actually be clear, 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 this issues about the cells. Then sometimes as, 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 emergent properties? Like are there, you know, 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, 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. It 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 Astilamar 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. And if you have a technology that has the potential to change that, to provide cures, is it, 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 in that? So that those are, like, ongoing discussions. I mean, it's been really interesting. I spend more and more of my time as part of this conversations.

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

[Sergio Pasca]

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.

[Chuck Nice]

Oh, my. Really, that's just.

[Sergio Pasca]

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 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 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.

[Neil DeGrasse Tyson]

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

[Sergio Pasca]

Oh, that's amazing.

[Neil 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. He had sort of certain neuro issues. He has, correct me on the word here, prognoplegnasia.

[Sergio Pasca]

Yes, he did. Yeah. He couldn't really identify.

[Neil DeGrasse Tyson]

He had face blindness and some other elements to it.

[Chuck Nice]

I sometimes wish I had that.

[Neil DeGrasse Tyson]

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 worked that got him interested in neuroscience in the first place.

[Chuck Nice]

Right.

[Neil DeGrasse Tyson]

That is. That was his destiny.

[Gary O'Reilly]

But.

[Sergio Pasca]

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. Have the same genetic, you know, material. They share the same womb.

[Chuck Nice]

Yeah.

[Sergio Pasca]

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

[Neil DeGrasse Tyson]

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

[Sergio Pasca]

They do. They do, yes.

[Chuck Nice]

Wow.

[Sergio Pasca]

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, I mean, to a large extent, probably that's what made us as a species, so successful.

[Chuck Nice]

Yeah.

[Sergio Pasca]

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

[Neil DeGrasse Tyson]

Right, right.

[Sergio Pasca]

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. As adults or as children.

[Neil 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.

[Chuck Nice]

Absolutely. They are the true owners of this planet.

[Neil DeGrasse Tyson]

That's right.

[Chuck Nice]

Let's be honest. Viruses, the virus, they're true owners of this planet.

[Gary O'Reilly]

Microbes, we're just an Uber.

[Chuck Nice]

Yeah, that's all micros. We're just an Uber.

[Neil 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.

[Sergio Pasca]

Oh, they are right here behind me. 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 this experiments are long. I mean, they last hundreds of days. Because human development, it takes a long time, so it requires a lot of dedication and. 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.

[Neil DeGrasse Tyson]

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

[Chuck Nice]

Please.

[Neil DeGrasse Tyson]

This moving neuroscience frontier has got me thinking. When 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, 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. 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.

[Rob Lowe]

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