- Welcome to "Healthy Minds."

I'm Dr. Jeff Borenstein.

Everyone is touched by psychiatric conditions, either themselves or a loved one.

Do not suffer in silence.

With help, there is hope.

Today on "Healthy Minds."

(gentle music) It sounds like science fiction, but it's actual science.

Taking skin cells, turning them into stem cells, and turning those into brain cells in order to better understand the brain, better understand various conditions, and potentially develop new treatments.

Today I speak with leading researcher, Dr. Sergiu Pasca, about these advancements.

That's today on "Healthy Minds."

This program is brought to you in part by the American Psychiatric Association Foundation, the John and Polly Sparks Foundation, and the WoodNext Foundation.

(gentle music fades) Sergiu, thank you so much for joining us today.

- Oh, thank you so much for having me.

- I wanna jump right in and talk about the work that you and your lab has been doing with stem cells turning them into brain cells and taking it from there.

So tell us, what exactly are you doing?

- Well, one of the biggest challenge that we've been having in psychiatry, and just in general, in studying neurological and psychiatric disorders, is that the human brain is the organ where all of these disorders arise is essentially inaccessible.

And it's inaccessible at the molecular and cellular level in a way that would allow us to sorta like probe and manipulate cells from patients and really understand what the biology behind it really is.

And one could argue that, to a large extent, you know, some of the high rates of failure of drugs for psychiatric disorders is due to the fact that we can't really access this organ of interest for psychiatric disorders.

So what we've been trying to do now for, you know, over 15 years has been to try to recreate some of these brain cells and some of the circuits outside of the human body in a non-invasive way, so no surgery involved, but try to recreate some of those cells and circuits from patients and then studying them in the lab in order to develop therapeutics.

And so the way we do this is essentially by taking a tiny skin biopsy from patients, let's say patients with autism, with specific forms of autism or schizophrenia, and then bring those cells to the lab.

And then in the lab, we use a series of genetic tricks to essentially push the cells back in time where they essentially become stem cell-like.

So they have all the properties of stem cells, meaning that they can self-renew so you can keep them indefinitely, but you can also turn them into other cell types.

And what we've been actually figuring out for now over a decade is to find recipes that would allow us to turn those stem cells into specialized type of cells in the nervous system.

And that really started, to a large extent, the journey of my lab, really an effort to try to recreate these key cell types in the brain from patients and then try to see what goes wrong to develop ultimately therapeutics.

- So basically, obviously we can't go around taking samples of brains from people because that's just too invasive, it's dangerous, we don't do that.

So what you are doing is sort of the next best thing, if not better, in terms of turning the skin cells into brain cells.

- Yeah, exactly.

And if you think about it, you know, unlike in any other branch of medicine where it's not that complicated to actually get a sample of the tissue of interest, right?

Think about cancer.

You wanna study a new, you know, patient that has just been diagnosed and really identify what goes wrong into that tumor, you take a cancer biopsy.

In fact you wanna remove the tumor as soon as possible, bringing it to the lab and then studying it directly.

You know, unfortunately for the brain, we can't just open the skulls of patients, take, you know, a biopsy of the brain and then study it separately.

So we've had to find some shortcuts, that's for sure.

- I'd like you to tell us, for our lay audience, some of the science.

'Cause in many ways it sounds like science fiction, what you're doing.

Tell us what exactly goes on.

- Yeah, well, it's been really a fascinating journey both in terms of understanding some of these disorders and we're sorta like on the verge of starting a clinical trial for a therapeutic that has been exclusively developed using the stem cell models, but also in terms of just learning new things about the brain.

I mean, you'll be surprised, but most of the things that we know about the human brain actually come from studies done in rodents and in other species.

And we keep extrapolating what is happening in the human brain based on studies that were done in rodents.

And don't get me wrong, that has been certainly like very useful in setting up, you know, the landmark, but we do need to understand human biology.

The human brain is unique.

And one could even argue that many of the psychiatric conditions arise because our human brain is unique.

So understanding that uniqueness is, in my opinion, gonna be key to understanding many of this disorders of the brain.

And so essentially the process has been trying to recapitulate in a dish what happens during development.

And essentially what we do is we take the stem cells that we derive from patients in a non-invasive way, and we found ways, now almost a dozen years ago, to essentially aggregate them in a tiny bowl of cells and then we grow them as such.

And then we spike in various molecules, like growth factors, essentially a cocktail of chemicals that are telling the cells what to become.

And of course we want them to become neurons.

So over the years we've essentially just discovered a lot of these recipes for making different parts of the nervous system in this miniature bowls of cells that are now collectively known as organoids, because they resemble an organ.

Of course they don't resemble the entire brain, but they resemble parts of the nervous system.

And we're now, you know, quite good at essentially making, out of those skin cells turned into stem cells, you know, a tiny piece of a human cortex or a tiny piece of the thalamus, this deep region in the brain that is responsible for relaying sensory information to the cortex, or a tiny piece of spinal cord.

And that has been quite remarkable if you think that we know so little about this and yet you can figure out some of this cocktails of molecules, add them and then really watch the cells becoming the cell types that are generally in the human brain.

- You've also taken it a next step and then begin to have these groups of cells interact with other groups of cells almost as if they were in the brain with what we refer to as circuits.

I'd like you to talk about that as well.

- Yeah, so I mean, most of our initial efforts were trying to make the cells like at the bottom of a dish, so what we would call like two-dimensional cultures.

So that was like work done, you know, 15 years ago.

Many of us were trying to do that.

Then, you know, about like 10 years ago we started realizing that there's so much more cell diversity and so many more properties of the brain can be, you know, captured once you started the cells in these three-dimensional cultures.

And then initially what we made is cultures that would resemble domains of the nervous system.

But really what makes the human brain unique, and the mammalian brain unique really, to a large extent, is that it has all these brain regions that are interacting with each other in rather complex way by forming circuits.

Neurons will project in the nervous system, you know, literally for many, many feet away to connect with another cell type, and let's say control muscle contraction.

So what we did is, almost a decade ago, was introduced a new approach that we called an assembloid, where essentially you make different brain regions separately and then you put them together at the right time.

The hope in that case would be that the cells would know what to do because very often we don't know how to guide them.

We know very little about these processes.

And then some of the circuits would essentially form on their own.

So one of the first examples for this was us trying to reconstruct the pathway that controls muscle contraction.

So when we reach out, for instance, for a glass of water, what happens is that neurons in deep layers of the cerebral cortex, the outer layer of the brain, will send signals all the way to the spinal cord, connect with the neuron that sits there in the spinal cord and that neuron will leave the spinal cord and control muscle contraction.

And really this essentially two synapsis, three cell types are controlling this really complicated process.

So what we did is essentially we made the three parts separately.

So we made, you know, an organoid that resembles the cerebral cortex, one that resembles the spinal cord, and we made a bowl of human muscle out of a biopsy, and then essentially we put them all three together.

And what we discovered was that, remarkably, cells knew what to do and tried to connect with each other in this meaningful way.

So after, you know, really weeks and weeks of putting them together and trying to connect, you could actually see muscle contraction.

So you can control, for instance, muscle contraction by stimulating some of the neurons in the circuit and triggering it afterwards.

And that really speaks to this remarkable ability of the circuits to assemble themselves and really become the circuits that, you know, we all have in the brain.

- In many ways you're sort of demonstrating the miracle of life, how our brains are put together and our bodies are put together, and you're sort of able to do that in a laboratory.

- Right, and isn't that amazing?

Because, you know, we think about human brain development as being such a complex process, and it is, and yet the human brain built itself every single time, you know, without really a blueprint.

Essentially the cells come with instructions.

And once, you know, they unveil a first set of instructions to assemble themselves, then the new cells are coming and providing a new set of instructions, and so on so forth, until we have the complex human brain.

And really what we're trying to do is, to a large extent, really leverage this early forces of self-organization.

Of course we don't have all the cues that you would have in the actual brain or in utero during development.

But sorta like in this minimalistic cultures, with the hope that, first of all, we will learn something about the rules that underlie the assembly of the human brain, but that more importantly, more importantly for me also as a physician, is really that ultimately we would learn how disorders of the human brain arise in these cultures and then develop therapeutics.

- I wanna ask you about a specific disorder that you've studied and are working on developing a new treatment, Timothy syndrome.

Could you tell us what that is and what you found with that syndrome?

- In early days of developing some of these human stem cell models, and I was finishing my clinical training when Shinya Yamanaka, this amazing researcher who discovered this reprogramming of cells, showed that you can derive the stem cells from essentially any cell, even in the adult.

And that really, in my mind, triggered the possibility that we would be able to actually make human neurons from patients one day.

And of course at that time, and, you know, it sounds kind of funny in retrospect, but, you know, most people did not believe that you'll be able to find any changes, right?

Because you take skin cells from a patient, you put them in the lab, you turn them into stem cells, then you take those stem cells, you turn them into neurons.

Months and months of processing.

And people thought whatever is abnormal about that disease is gonna be gone.

And so we thought, in those early days, that we should focus on a disorder, a genetic disorder, where there is some predictability about what we should observe, both to validate, but also to make the system much more deterministic in terms of like what we can do.

And so we focused on this rare form of autism and epilepsy called Timothy syndrome.

This is a very ultra-rare syndrome.

We only know of about 40 to 50 patients worldwide.

The patients are affected very early on when they're born.

They have first a heart problem, an arrhythmia that is life-threatening, but now it's very often addressable with the pacemaker.

But then what happens very soon after is that many of these patients develop symptoms of autism, epilepsy, intellectual disability, and is really a very severe disorder.

But it turns out that the mutation behind this is just one single letter.

So one single letter in the entire genome is changed in a gene that codes a calcium channel.

So these are protein that sit on excitable cells and allow ions, in this case calcium, to go inside the cells.

And of course calcium is really important for the function of brain cells and cardiac cells to that extent.

And it was predicted that this mutation would make the cells, you know, will allow the cells to actually let more calcium inside the cells.

So in these early days we recruited two of these patients here at Stanford and then harvested skin cells, made stem cells, derive human neurons, and then really watch under the microscope, as we were, you know, stimulating the neurons, to see whether calcium signals is abnormal.

You know, and to be honest, I still remember that day as if it was like yesterday.

And the excitement of actually seeing for the first time that patient cells had more calcium going inside the cells.

That was like an early proof or, you know, proof of concept that we could actually detect changes, even from complex disorders such as autism, in these early cultures.

And subsequently, as we've developed organoids and then assembloids, we discovered more and more of these defects in various cell types across the system, including how some of the circuits are not forming properly.

And then at one point, and this is really actually quite interesting, at one point after almost a decade of studying the mechanism of these disorders with the stem cell models, a therapeutic for the disease just became self-evident.

I mean, literally, we were looking at the data and at one point it just became clear this is exactly what we need to do to develop with therapeutic.

And that had to do with how the channel is processed and what we discovered in human cells.

Short story, you know, what we've done essentially is do a screen and identified a tiny piece of a nucleic acid that can go into the cells and correct how this channel is being processed in neurons.

And in doing so, we've been able to essentially restore most of the defects that we've discovered in this patient cells over the past 15 years.

- It's amazing, as you describe it, that being able to understand the very basic molecular basis for a condition can ultimately result in a treatment that can help people.

- And in a way it's not even surprising, you know, because that's what we've been doing in medicine for, you know, at least half a century, and more or so, since the revolution of molecular biology entered medicine, where we've systematically taken down barriers and figure out very complex disorders of the heart, of the liver.

Of course cancers now, you know, just, you know, thinking about like cancers and how in the '60s most leukemias in children were fatal, 90% of the cases.

And today's, you know, fatality is like down to 10%.

That is because those cells from those patients were brought to the lab and then we leveraged this remarkable power of molecular biology to reverse-engineer the mechanism of those disorders and then find therapeutics.

And it's of course sad that in psychiatry and in neurology we have not yet been able to do that.

And then going back to the point earlier, I think that has been primarily because we were not able to access the human brain.

And of course this is still the beginning, but I think the promise is that as these models are becoming more complex, and of course as they're becoming more democratized and we have helped literally hundreds of labs around the world to implement this technologies now in their own lab and apply them to the disorders that they're interested in studying, I think hopefully we will start seeing a deeper molecular stellar understanding of these disorders and, you know, I guess sorta like the beginning of a new era in psychiatry that is molecularly based.

- Do you see in the not too distant future a time that patient comes to your office or my office and a part of our diagnostic process and deciding what treatment would make most sense would be to take a skin cell or a blood cell, send it to a lab, and get some results back?

- Like today, all the disorders in psychiatry are defined on behavior, you know?

And while that has been certainly a very useful way of classifying these conditions, When it comes to therapeutics, it's not the most practical way to do it.

And we've seen this already with cancer, where initially, you know, most of the cancers were classified based on the morphology of the cells, the location of the cancer.

And then we've learned actually that the best predictors are actually molecular.

Once we were able to actually profile a cancer, whether it's a pancreatic cancer or a stomach cancer, we realized that the therapeutic were very often dictated by the molecular signature of that cancer.

So I think the promise here, certainly for the brain, is gonna be much more complex.

But I think the promise is that, as we're gonna understand many of these processes that underlie the assembly of the human brain and the formation of the circuits, we're gonna be able to point out to what process in human brain development some of these conditions are actually affecting.

And perhaps one day you can envision that we could even reclassify many of these brain disorders based on molecular/cellular features.

So perhaps we would know, well, this class of schizophrenias are actually caused by defecting microglia.

Well, for instance, these forms of autism are caused by really faulty synapse formation.

So synaptopathies.

And while, like let's say this other forms of epilepsies are caused by cells not migrating properly in the nervous system.

So then we could, you know, hopefully at one point, not in the too distant future, start to contemplate the possibility of actually targeting therapeutically these processes, these cellular/molecular processes rather than the behaviors themselves.

And really the entry point, you know, in this sorta like new ways of thinking has actually been genetics.

Because in the last two decades we've now identified, of course as a community, hundreds and hundreds of genes that when mutated cause severe psychiatric disorders.

And the psychiatric disorders of course have been mysterious for, you know, centuries.

And now yet we have specific genes that are impacting the human brain in such a way that they're changing the behavior dramatically and they're often irreversibly.

So I think the potential now will be to just figure out exactly how those genes are affecting cells, how those cells are affecting the circuits in the brain, and then reverse-engineer that in a way that would allow us to build therapeutics.

- In addition to what you just described, potentially it could help us avoid the person even getting to the point of illness as a method of prevention.

- Absolutely.

Or you can also envision that we will be able at one point to predict what is the best treatment.

As you know, very often, you know, even having a patient with schizophrenia, you very often have to try multiple antipsychotics not knowing exactly which one is the best fit.

And that's not very useful obviously for a disease that, you know, where there is deterioration with time, where of course the patient, if they don't respond, you know, will not be seen for a while.

So just, you know, imagine that, you know, at one point we'll be able, for specific patients, to have, certainly with a certain probability, be able to say, you know, these antipsychotics will be the first choice for this individual based on a molecular signature or based on a circuit.

You know, of course this is, you know, it's still early days.

But if the revolution in other branches of medicine are predictive of what could happen in psychiatry, then we can at least, you know, envision that at one point we'll be able to do something like this.

- You know, it is early days, but who would've envisioned that we could do what you and your lab and other labs are doing right now?

20, 25 years ago it really was science fiction, if that.

- No, absolutely.

And it's such an exciting time, you know, honestly for neuroscience.

I mean, you know, I see the enthusiasm of the students and the postdocs in my lab.

And really, you know, as people are coming from all over the world here at Stanford to learn some of the technologies that we're applying, there's so much enthusiasm.

Because for the first time we can really peek into this, you know, previously inaccessible stages of human brain development.

I mean, there is something mesmerizing about that.

And, you know, I hope more will, like, join this new adventure.

- I wanna shift gears a little bit and ask you about the ethics of this type of work, and here you're thinking about it, and where the scientific community and others are going in terms of ethical considerations.

- Well, we've been thinking very carefully about this from the very beginning.

Because, as you can imagine, as we work with, you know, not just recreating some of the circuits that are complex, but also just working with human cells, poses a number of ethical challenges.

Who owns those cells?

You know, how complex of a circuit can we actually build?

The problem, though, can maybe be, you know, summarized the following.

It's clear that psychiatric disorders arise in the human brain and that we need better models of the human brain.

Now the more human those models become, the more uncomfortable we are because of course the human brain is the source of, you know, what makes us human, is the source of sentients and consciousness.

And so I think the challenge has really been, if we move forward, and certainly that's not the case yet.

But as the circuits are becoming more and more complex, what sort of precautions do we really need to take?

And so we've been engaging from the very beginning, even here at Stanford, through my centers, you know, ethicists, legal scholars, sociologist of religion, really ethicists more broadly, and try to start thinking about what are the next steps.

And more broadly, actually the community has been meeting, not long time ago we had the first meeting at Sylmar, in this historical place here in California, where we met a few of us, a small group in the beginning, and started outlining what are really some of the ethical issues that are gonna arise as we move forward?

And then we're gonna have, very soon, another bigger meeting where we're gonna engage even more, people started to think about this, including patient advocates.

Because as you can imagine, the patients have to, you know, the patient advocates, the parents, the patients themselves have to sit at that table and really share essentially what the burden of the psychiatric disorders truly is, how important it is that we have new models.

Because as you can imagine, one can also make the argument that having a new tool that may allow us, you know, to develop therapeutic and not using that tool, that in itself may be unethical.

So really, you know, we're walking this uncharted territory thinking about all the implications both for patients as well as for society more broadly.

- Sergiu, I wanna thank you for joining us.

Thank you for that message of hope that's based on reality, real science, and thank you for all the work that you've been doing and continue to do in this important revolution of our understanding of the brain.

Thank you so much.

- Thank you.

(gentle music) - [Jeff] Do not suffer in silence.

With help, there is hope.

This program is brought to you in part by the American Psychiatric Association Foundation, the John and Polly Sparks Foundation, and the WoodNext Foundation.

(gentle music continues) (gentle music fades)