- My big question for you is, will animals that have brain organoids from humans put into their brains ever develop human-like consciousness?

Human-like thinking?

I'm Insoo Hyun, a philosopher and bioethicist.

I asked my friend and world renowned neuroscientist, Sergiu Pasca, to join me for a conversation about his groundbreaking research on human brain organoids, which he uses to unravel the mysteries of mental illness.

Sergiu Pasca.

- Perfect.

- That's a Romanian name.

- It is.

- You're from Transylvania in Romania.

- I am, yeah.

With so much misinformation around that, I mean, it's a beautiful part of the world, historically, extremely important, and everybody just leaps to conclusions about Dracula mythology.

- Right.

- So I wanna talk about mythology, I want to talk about misconceptions.

Maybe to unpack some of that, tell me, why is your work important for psychiatry?

- Well psychiatric disorders pose a huge burden to society.

I mean, one in five individuals or so suffer from a neuropsychiatric disease worldwide.

And in fact, psychiatric conditions are the biggest, you know, source of disability worldwide, first of all, because they're, you know, they're chronic conditions and also because they're like very prevalent.

And the reality is that, you know, we're still diagnosing most psychiatric disorders behaviorally, and just watching the behavior of, you know, of these patients in, of course, in a clinical setting, or in their social environment.

And the issue with that is that, you know, we still don't have much of a sense of the biology of these conditions.

And in the last 10 years or so, we've seen, you know, huge advances in understanding the genetics of these conditions.

So we now have long list of genes that are associated with psychiatric disorders.

And you see this in the news all the time.

You know, scientists identified gene X associated with autism or with schizophrenia and so on.

But you know, you end up with this kinda disconnect where on one hand we've been cataloging behavior of this conditions, the clinical phenotype of this conditions for centuries now.

And on the other hand, we finally have some of the genes that are presumably causing these conditions.

But in between, there are still a lot of unknowns.

We don't understand what cell types do those genes affect, and in what circuits do those cells sit.

And so what are the causes for those behavioral changes?

And the, you know, what we've learned from other branches of medicine, in particular from oncology, is that therapeutic advances come when you leverage the power of molecular biology, when you actually put it at work in cells of interest.

And so that became essentially one of my main goals as I was like finishing medical school.

- So this is the mental health exhibit, and it's all about psychiatry in the brain.

- So we can kind of talk a little bit about psychiatry here?

- So Sergiu, I brought you to our mental health exhibit at the museum, just because I think there's a really interesting connection between the history of psychiatry and the work you do.

We're actually, in fact, in the middle of a mock up of a psychiatrist's office as part of the exhibit.

So hopefully your approach in the future could help inform what goes on in a place like this.

- Absolutely, absolutely.

I mean, we still today talk about like schizophrenia, or like autism spectrum disorders, which are large groups of conditions that are behaviorally defined, have some common behavioral characteristics.

But we do know that they're like, very heterogeneous.

So the question is, will we in the future have, you know, 10 forms of autism, or 20, or 30?

Will they be based on, for instance, on whether they affect like immune cells of the brain, or whether they affect glial cells or neurons?

Will we have different types of treatments for this condition?

So just describing the biology of this condition systematically, and that will take years, will be strictly necessary towards developing treatments that are rationally designed.

- I wanna talk about your latest work, because there's such an amazing progression in this story you're telling about how we're studying the brain using organoids.

So as I understand it, an organoid is a three-dimensional model of an organ of interest.

So it could be like heart organoid, it can be gut organoid, in your case, cerebral cortex, or brain organoid.

These are three-dimensional models that are made from human stem cells that kind of go through the very early stages of development of that organ, and then tell us a little bit of something of how those organs might work, is that correct?

- Right.

Yes, it is correct.

And one other feature is that they're recapitulating aspects of that organ function.

Like, obviously not all the organs function, not necessarily all the features, but some aspect of it.

- Yeah.

And they're really small.

- They're very tiny.

- And except for maybe the gut organoids that I've seen, they don't even look like the organ in question, right?

- They're miniaturized versions.

- Yeah, yeah.

And I think the brain organoids, they're white, because they don't have like vasculature.

- Right.

- They're kind of pale.

They're not pink and squishy.

- Most of them are kind of like white-ish.

- And then an assembloid, is something that you've done, that's where you take organoids and you put 'em together and you sum them together to make something a little bit more complicated.

Is that, right?

- Yeah.

An assembloid can be formed by either putting at least two organoids together, or putting an organoid and combining it with cell types that are perhaps not present in that organoid.

So generally, organoids don't have immune cells.

But if you wanna model neuroimmune interactions, you can take immune cells from the same patients, and then insert them inside the organoids.

And just in general, assembloid would assume that there are some interactions between either the two parts, or the organoid and the cells that are giving rise to novel properties, emergent properties of the system.

Tamarins?

- Yeah, little primates, little guys, look at them.

Sergiu, these are actually real brain specimens of human, monkey, cat, turkey.

And I'm wondering though, why wouldn't you just do the kind of research you're doing just with other animal brains?

Why do you have to study the human brain?

- Most of what we know today about the brain actually comes from studies in animals, primarily rodents.

And what we've learned a lot about, you know, the mouse brain or the rodent brain, the characteristics that make the human brain unique are still to a large extent, mysterious.

And in fact, it is possible that the reasons why psychiatric disorders arise in humans, has something to do with those unique characteristics.

So, you know, many of the animal models for disease have been quite useful, but there's 70 millions years of evolution that separate us.

So it becomes more and more obvious that we also actually have to study human cells.

And in fact, if we think about human genetics and the susceptibility to disease, it becomes even more important to think in that genetic context.

- So your latest work is taking this to another level where you've transplanted human brain organoids into rodents, into their brains, and that gives a much more complex environment.

Tell me why you did that, and what are you hoping to learn with that move?

- So there are at least two motivations for this latest platform that we've developed.

One is that no matter how long we've kept the cells in a dish, either as organoids or assembloids, there are features of neurons that are not recapitulated in a dish.

So the cells are still not incredibly complex in their morphology.

Their electrical properties are not very mature.

And the other one had to do with, you know, what is the relevance of some of the defects that we can identify in a dish?

I mean, if a cell has blunted dendrites, let's say, or blunted processes, does it mean that it will cause changes at the behavioral level?

Or does, you know, the brain have a way of like compensating for that?

And the reality is that we have no behavioral, no circuit relevant behavioral readouts for the cells that were, you know, we've developed in a dish.

And so for those two reasons, trying to make more mature cells and then try to obtain behavioral readouts, we decided, you know, almost like seven years ago now to start this transplantation platform, which is just being published now, but this has been actually in the making for quite a long time.

And the idea behind this transplant is that you would develop an organ in a dish, but rather than let it develop in a dish, you can take it and gently position it in the brain of a rat that is immunosuppressed, so that, you know, it doesn't reject the graft.

And then what we do is actually we place them in the somatosensory cortex of the rat, the part of the rat's cortex that receives sensory input from whiskers.

And you know, essentially place them, and then we close and we just wait.

And it's interesting, we discovered very early on, almost by chance, that you can actually use MRI to identify the graft.

The graft has a different kind of composition and appearance on an MRI.

And that made a huge difference, because we could noninvasively monitor the transplant over long periods of time.

And we discovered that, you know, the transplant can grow very large.

In line to nine to 10 times growth in volume over like three to four months.

And so in the end, it actually becomes a unit of human cortex that sits on one hemisphere and covers perhaps, you know, one third of a rat's hemisphere.

And it goes all the way from the ventricle to the pia.

Again, it's important because it's reproducible in the same position.

So it's in the somatosensory cortex of the rat.

That made a huge difference, because we could just go and later on probe those human cells at specific time points.

- What did you learn from that experiment?

How is that important for a medical advance?

- So we've, you know, started looking very carefully at how neurons developed in vitro versus in vivo.

- So in a dish versus in a body.

- Exactly.

So we took like, you know, organoids derived from the same individual in the same differentiation experiments, and some of them we kept in a dish, and others we have transplanted.

And then we looked 250 days later to see how do they compare.

First of all, we just looked at cell composition and kinda like their properties and discovered very interestingly, actually, that cell types are much better refined.

So, you know, we note that cells in a dish, like in an organoid, will express markers of upper layers or deep layer cortical neurons, but they're often, they're kind of like mixed together so it's not that clear.

Surprisingly, in vivo, this cluster are much better separated.

And this is actually in line with recent work that shows that sensory input is quite important for the cells to fully mature.

And in fact, that seemed to be the case as well, because we found that the thalamus, which brings, relays information from the whiskers to the cerebral cortex, is directly connected to human cortical neurons.

And then in fact, you can even go and move the whiskers of the rat on the opposite side of the graft, and trigger responses in human neurons that are following that stimulation.

Showing that you can actually use sensory stimulation in a rat to trigger activity in human neurons.

(soft guitar music) - Isn't it amazing how nature has this built-in body plan that just runs on a program again and again, look at the consistency here across these specimens.

It is amazing.

You couldn't have human beings make this on an assembly line and get that kind of consistency, that's just fascinating.

And you see that also with the brain.

- Yeah, absolutely.

And in fact, that's something that we're trying to leverage in a dish as well.

This very robust programs, developmental programs that build organs.

And it is remarkable, right?

At the end of the day, we all have a quite similar brain.

A brain has kinda like the same parts, of course it's different for each of us, but some of this forces that put together parts of the human brain, the cells, are incredibly powerful.

And once you provide the minimal conditions necessary, they will take over and organize cells in a dish as well.

- That's remarkable.

Will animals that have brain organoids from humans put into their brains ever develop human-like consciousness, human-like thinking?

- Well, I think probably not at this point.

And there are number of reasons for that to believe that that is the case.

The human graft still represents a small portion of the rat brain at this point.

So it's one third of a hemisphere, but in, you know, there may two or 3 million cells, but the rat cortex with both hemisphere has maybe 31 million cells.

So there's still a small fraction, there's still cells that are missing in the human graft.

So for instance, we only put excitatory cells, we don't put inhibitory cells.

And perhaps the most important point is that timing of development is still conserved.

Meaning that you transplant the cells into a rat, but they still develop in their own pace.

And it takes, you know, a week or so to make a rat cortex, but it takes 20 weeks or more to make a human cortex.

So we may transplant them early in development, and that facilitates the integration of human cells very early on.

But there's very quickly, that disconnect between the timing of the two species.

And so as you can imagine, you know, as the human cells kinda like wake up and start to connect, the rat brain is already wrapping up human brain development, they're starting to alienate, and so they're limiting to some extent, you know, how far human neurons will go and connect.

And despite that, there's still quite some surprising levels of connectivity that we've discovered.

But there are some natural barriers, so to speak, just in the timing between the two species that at this point, preclude, you know, seeming less integration.

Of course, that would not be the case for a transplantation in a primate, I think.

- Yeah.

Well what's fascinating is that I think people need to understand that you're interested in circuitry.

And it's like the following analogy, like if you took wires from a Ferrari, if you took brain cells from a human, and you put 'em into a radio, and you got the radio to work like a radio, it doesn't make the radio a Ferrari when you do that, it's still a radio.

So this is still a rat.

- Right, it's still a rat.

- It's still a rat.

And what's interesting about the behavioral test you did, was the behavior that you're looking at was licking a water bottle, right?

- Oh, yes.

- So.

tell me more about like what did this... What that was all about?

Why the water bottle?

- Well, we had two type of behavioral experiments that we have done: one to test whether there was like input into the human graft, into the transplanting human neurons, and another one to see whether the human graft can actually participate to the rat circuit, integrate and perhaps participate to behavior.

- So it's not like the human brain organoid is giving human-like thoughts, it's just that it's participating in the way that it's like filling in that gap in the circuitry.

- Exactly.

- And it's still the rat behaving like a rat.

- Right.

But the first behavior, which is like sensory input, the sensory input comes from whiskers.

We obviously don't have whiskers, you know, kinda like to build on your analogy.

Yeah.

- So in this case, human cells are just capable of receiving inputs from whiskers.

- We're sending it along.

- And sending them along presumably.

But, you know, obviously they're integrating in a circuit that we don't necessarily have.

And the output, on the other hand, was to see whether, you know, the human cells could participate in a, you know, very clearly defined behavioral task.

So we decided to focus on a reward task.

- So this is like rat behavior in a rat context.

You're not seeing anything like human-like behavior?

- No, we have not.

- Not that we even understand what human-like behavior actually is, but it looks like the rats were behaving like normal rats.

- Right, yeah.

And actually we've tested that extensively.

I mean, one of our main concerns was the welfare of the animals.

In fact, you would be more concerned about the rats not doing very well.

- Right.

- Like their behavior deteriorating because of the transplant, than actually expect that they would like improve in some miraculous way.

And we've tested them in various cognitive and emotional task, and they were like not different than other rats.

They didn't, for instance, experience seizures, which was the main concern, because we're putting a lot of excitatory cells into the rat cortex.

But we wanted to see if manipulating human neurons could, for instance, change the behavior of a rat.

So what we essentially did is we transplanted the human organoid into the rat, but the cells were carrying this light-sensitive protein, that is sensitive to blue light only.

- So it's like the on and off switch.

- Exactly.

The on and on switch.

And so there's an optic fiber that goes to the rat skull, and it's able to deliver light.

- And this is not uncomfortable for the rat, because it's just a little optic fiber.

- No, it's a tiny optic fiber, they can move around.

This type of experiments are done in neuroscience.

- The real interesting thing about what you just said, is that actually your experiment succeeded in making them feel and behave like other normal rats.

- Yeah.

- 'Cause the one risk was that they could have actually taken a nose dive.

- Oh, absolutely.

- But they didn't.

- Absolutely.

- They were kind of like, you kind of rescued them back up to what typically they do.

- Right, yes.

- That's amazing.

- And so the rats can just like move around, and they receive water, and then we initially kinda like randomly stimulate with either blue light or red light.

Red light of course, is not expected to trigger a behavioral change.

And then we slowly kinda like teach the rats to associate blue light stimulation, so therefore stimulation of human neurons, with delivery of water.

And so we do training for about a couple of weeks or so.

And so in the end, what you can actually do, is you can just stimulate with blue light and rats will start seeking water.

So there's a water-seeking behavior that can be triggered by stimulating human neurons.

We still don't know exactly how this happens.

I mean, it could be that human neurons are somehow modulating reward centers in the rat, but it could also just be that they're like changing the, you know, the activity of surrounding rat cortical cells in the somatosensory cortex.

So we don't fully understand yet the mechanism.

Suffices to say, is that we have evidence now that by transplanting human neurons early in the developing rat, in the somatosensory cortex, you can actually change or manipulate aspects of the rat behavior.

And that, of course, is very exciting, because you can now do this with patient cells.

And so just imagine, these experiments that we have done, where you can transplant patient cells on one side, on one hemisphere, and then control cells onto the opposite side.

- Human on both sides.

- Humans, exactly.

And then be able to compare side by side the properties of the cells.

And we've actually used... We've used cells from patients with a specific form of autism and epilepsy, and found that only by transplantation, can we actually identify defects.

Like the cells, you would look at the cells in a dish, and you wouldn't find any differences.

But then you put them in, and suddenly we see differences in how complex the cells really are.

And that process is actually, as we've shown a number of years ago, is activity dependent, depends on the, you know, amount of electrical signal that the cells receive.

So this is to say that transplanting human cells will may most likely reveal disease phenotypes that we would not be able to see in a dish.

- Yeah, yeah.

So you're getting key information there about these diseases that have a genetic component.

They start early in development, you get a chance to witness the playbook of the disease, like how it actually unfolds in the brain as you compare with healthy cells in the rat.

You know, just to be clear then, you're not putting the brain organoids into the rat, and then trying to observe human-like behavior, you wanna see it will continue to display rat-like behavior.

- Absolutely.

- Human beings don't have whiskers.

- No.

- And it's not like when you blow air on your whisker, a human being will wanna lick a water bottle, right?

That's not exactly human behavior.

I don't know what typical human behavior is, but that's not typical human behavior.

That's rat behavior.

- Right.

- So you wanna, the readout, the behavioral readout you're getting is rat behavior.

It's not human.

- Right.

Yeah.

We wanna essentially see if patient cells versus, you know, cells derived from healthy controls would alter some of the, you know, behaviors of the rat in a way, in some of this tasks.

So that we can tell, are they important?

Are some of the changes that we see in cells from patients, are they relevant at the circuit, at the behavioral level?

Because you can find a lot of differences in a dish.

People have been describing numerous, numerous changes, but it's very difficult to tell, are they important?

Do they play a role in the pathophysiology of the disease?

- It was unexpected to me that that graph and your experiment would've worked in rats.

Because many people would assume, "Oh, to get that kind of result, you have to put it into a non-human primate."

And that is really, really controversial.

But you show that you can actually do, answer all these scientific questions, by using what in researchers considered to be kind of like the... And the tier of animal complexity.

- Yeah.

- You have rodents, and then you kind of get up to much more complex, much more controversial animals.

You are able to show that you can answer these questions in a basic animal model, in the rat.

Obviously, people are very concerned, many people are very concerned about research that uses animals.

And there's some who think that no animal research at all is ever justified.

Other people have a different view where they might get less and less comfortable as you get more and more complex with the animal.

So I think for those people, it's important to understand that so much of the work you're talking about could be done in rodent and you don't have to go to something much more complex.

- Right.

- That has much more complex emotions and experiences.

But this is research that you and I know is extremely tightly regulated.

- Right.

- So Stanford, I'm sure, took an extremely close look at what you are proposing and it was monitored very closely.

Can you tell me a little bit about that process?

- Yeah.

And you know, just to build on your point, because you know, certainly like one application of the work is just to try to get like cells more complex and capture disease features.

But there's another very important application of this platform and that is drug testing.

Because as you can imagine, as we're identifying potential drug targets and drugs that could be used in these patients, there is a limited, you know, there are a limited number of ways in which you can actually test them.

Right?

So there may be just simply animal models that don't recapitulate features of disease.

And so how do you go from like something- - And you use more animals than you need to- - Of course.

- Because the models are terrible.

- Of course.

- You're burning through so many animals unnecessarily, so if we can get much more efficient and targeted in the approach you're taking, you actually might use overall fewer animals.

- Of course.

Because, you know, the alternative to that is actually to use primate models.

Like genetically modified primate models, which obviously come with a lot of ethical and social like implications.

And it's just a question of scale.

There are hundreds of genes associated just with autism.

I mean, can we build that many models?

Is that ethically acceptable... - In the primate?

- In the primate.

And so as you can imagine here, if you have rats that have a fraction of their cerebral cortex to be human, you can deliver some of these drugs in their rats.

And understand just for gene therapy, or for just drugs, and see how are they affecting human cells in an in vivo context, which is like very important, especially for, let's say, gene therapy.

So another very important application of the system beyond just like modeling disease, is also try to reverse it by testing drugs in an in vivo environment where you have... You know, you inject them into the rat, but you hope to test in on human cells.

(soft guitar music) - So, Sergiu, I brought you up to the sixth floor of the museum because I just love the view here, you can see the entire city of Boston and Cambridge.

We have the water here.

In fact, you can actually see the duck boats that leave the museum and get into the water.

And the duck boats are so funny, right?

Because they're part boat and they're part bus.

They drive on the city and then they get into the water, and it's what I would call a chimeric vehicle.

I know you, and I don't really like the term chimera, but basically in biology, a chimera is an entity that has cells that come from other sources.

So for example, in medicine, as you know, someone who gets a hard transplant from a donor, technically they are a chimera, they are an individual that has an organ or cells that came from another individual.

Does a human-human chimera.

But I think what people are really concerned about are interspecies chimeras, where the cells come from a different species, right?

So in the kind of work you do, you put human cells, human brain organoids into a rat.

And in that case, I guess biologically speaking, that would be a chimera.

You know, we don't really love that term, but it has a long history.

The original chimera was a Greek monster from Greek mythology.

And it was a fire-breathing monster that had a lion's head, it was a goat in the middle, and it had a serpent's tail.

So it's actually a three-part chimera, not just a two-part.

And many people pointed that origin of that word, and they say chimera is in the lab that you create by putting human cells into an animal.

By the way, for things like cancer research, putting cancer cells into a laboratory animal and studying cancer cells.

Anyway, these chimeras, they say, are freaks of nature, they shouldn't exist, you shouldn't make them in the lab.

And they'll point to that chimera legend and say, "That original chimera was a freak of nature and it had to be destroyed."

And I looked at a little bit more into this chimera legend and I thought that can't be the simple lesson to learn from the chimera legend.

And so what I found was the chimera was actually defeated by a mortal human being.

This man was Bellerophon.

Bellerophon fell asleep one day, and Athena, the goddess of wisdom and philosophy, came down from Mount Olympus, and she gave him a golden bridal, a bridal made out of gold, which when he woke up, he used to tame Pegasus, the winged horse, which, by the way, is also a chimera.

- That's true.

- And so using ancient Greek technology of the day, the golden bridal, he tamed Pegasus and rode Pegasus and was able to defeat the chimera from up high.

He was able to shoot darts or arrows at the chimera, avoiding her fire breath and killed her.

And that was a great success story.

Modern, or at that time, modern technology saved the day.

And he went on, though, the story goes on.

It doesn't end with the death of the chimera.

He goes on and defeats many, many other Greek enemies.

And becomes a huge hero and is celebrated, until one day he decides he too is a God, and should ride Pegasus up to Mount Olympus to take his side next to Zeus and all the other gods.

So Pegasus realizes what's happening, and Pegasus objects and bucks Bellerophon off his back.

Bellerophon follows down to Earth, and he becomes crippled and blind for the rest of his life.

So when I look at the chimera legend from beginning to end, not just the introduction of the character of the chimera, my lesson that I get from that is just about hubris, right?

It's a lesson against using something to aggrandize yourself and to become bigger than who you actually are.

So my lesson from the chimera legend is not that mixed animals are bad, and they have to be destroyed.

Like the Pegasus, Pegasus was a widely admired, beautiful creature that went on to have many other adventures.

It's not that the mixture is bad, it's how they're used.

What they do for society.

Is it bad for society or does it help society?

Is it the chimera?

Is it the Pegasus?

So context matters a great deal, right?

- Naming matters a lot as well.

Because by using certain names, we make assumptions.

Using the term "mini brain" may sound like a, you know, a way of simplifying the science, but in fact, you're making an assumption that there's a tiny brain that has been miniaturized, which is not exactly what we do.

Same thing unfortunately, with chimera, is that because they're charged with the myths, they already, you know, bring a series of assumptions.

- Yeah, yeah.

- Into how the experiments are actually done.

- Somebody hears the word chimera, they'll look it up in the dictionary online, and the first thing that pops up is this monster with a lion's head.

- And that's not what we do, nor is the purpose of the research that we do.

- Right.

So many people, if they don't understand the details of an experiment or a scientific area, will backfill their lack of understanding with mythology.

It's a very common human trait to backfill in things you don't understand with things that are easy to grasp, like mythologies, science fiction, because you want to complete the story.

- Yeah.

And you know, as you mentioned, terms do matter.

And so for instance, one could also pick, instead of using the term chimera, you could say grafting, which is also, you know, an ancient, quite ancient... - In horticulture.

- In horticulture, where you would graft parts of a tree onto another.

With like purposes of, you know, getting new plants and better plant, and so on and so forth.

And in fact, one of the goals of the transplantation or the grafting work that we and many others are doing, is for therapeutic purposes.

You could also transplant cells into patients, for instance, in Parkinson's disease patients to actually restore some of the cells that have been, you know, have disappeared because of disease.

- You know?

And I think what's challenging about the kind of work you're doing is it runs up against a very, very big tide of like mythological thinking and kind of like quick and easy conclusions and assumptions.

People that have all kinds of funny assumptions about even animals, like people think the animals have a particular kind of nature.

Snakes are sneaky, right?

Foxes are cunning.

Pigs are greedy, glutinous.

And so the idea is if you move from one species to another, you somehow, when you're transferring cells, you're transferring that, somehow like essential energy, or that essential characteristic.

I'm sure there are people who think, "Oh, if I get a pig heart transplant you can make- People will make fun of me because I'll say, you know, you're gonna suddenly change your behavior."

I think that's also going on when you say you put human cells into the animal, then people assume, "Oh, well then it's gonna take on something that's essential about humans, like our own consciousness and self-awareness."

That leap, right?

To say, "Because you transfer the cells, you're transferring over something about the essence of what that being is."

So working in the kinda lab that you do that is not an easy job, because you and your lab folks have to be working 24/7.

The cells need care, the organoids need round-the-clock care, they don't take a day off.

The animals that are part of your work, they need monitoring, they need care 24/7.

So it's so much work going into the lab on the weekends, evenings, people are always there monitoring everything.

Do you ever- Does it help to stop and think, "Who am I doing all this for?

I have tenure at Stanford.

Like, why am I working so hard?"

Like, how do you get that inspiration to keep going on?

- No, as a physician by training, I wanted ultimately to find the treatment for some of this devastating conditions of development.

And in fact, I even still keep in contact with many of my patients.

Even back home in Romania that I've seen like many, many years ago.

- Wow.

You know, when I was starting.

And it's funny in a way because when I started doing research in autism, and autism was still considered at that time to be a rare disease, it was like unclear how common it actually is, and now we do know that it's actually quite common.

And so all I was able to do in Romania, I was actually measure in the blood of these patients various metabolites.

And, you know, the frustrating thing was, of course, that it was unclear like, well what does that tell us about the brain?

It's like so far away, like from the brain.

But in that journey, I got to meet many families, some of them who were just surprised at that time that anybody's interested in studying this disease.

- Interesting.

- Others who were like incredibly emotional about like somebody wanted to study this disease that also comes with a lot of stigma, especially at that time, came with a lot of stigma in society.

And so it was actually quite interesting.

So I kept in contact with many of my patients and one in particular, Edward, who's now actually an accomplished like musician and composer, but who very early on tried to depict in drawings like what he thought we were doing.

And so initially he sent me this drawing where he was showing a human brain and then, you know, showing somebody walking up stairs to poke holes in people's brains and look at cells inside.

Then he knew that they were like both like glial cells and neural cells, and he thought we were looking at both.

And of course I had to like have a conversation with him and explain one more time that that's not what we do, we don't poke holes in people brain to look at those cells and explain the process.

And you know, next day he essentially sent me another, you know, drawing, which I think is actually a pretty accurate representation of the work that we do.

- Oh, great.

- Again, showing like, taking skin cells from patients, turning back in time into stem cells, and then he knew that we can turn them into any other cell types, and then show that we can make like neural cells from patients.

And so that's actually quite interesting to see.

And you know, over the years I had the chance of actually working very closely with a number of foundations for some of these rare conditions, where parents are very actively involved in trying to encourage researchers to do some of the work.

And some of these families have are actually visited the lab quite often, met with the people in the lab, which is very often quite emotional.

And I think it puts the work that we do , as you said, in a broader context of, you know, we have a mission here, we try to understand this, the biology of this devastating disorders and try to find the cure.

And I think that's quite empowering for the team.

- Well, it's quite the journey you've been on from Romania to now Stanford.

We're so glad that you're here doing the amazing work you're doing.

- Thank you.

- Thank you for joining us.

- Thank you.

(soft guitar music)