The following is a conversation with Paola Arlada.

She is a professor of stem cell and regenerative biology

at Harvard University and is interested in understanding

the molecular laws that govern the birth, differentiation,

and assembly of the human brain's cerebral cortex.

She explores the complexity of the brain

by studying and engineering elements

of how the brain develops.

This was a fascinating conversation to me.

It's part of the Artificial Intelligence podcast.

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to keep the series going.

And now here's my conversation with Paola Arlada.

You studied the development of the human brain

for many years.

So let me ask you an out of the box question first.

How likely is it that there's intelligent life out there

in the universe outside of earth

with something like the human brain?

So I can put it another way.

How unlikely is the human brain?

How difficult is it to build a thing

through the evolutionary process?

Well, it has happened here, right?

On this planet.

Once, yes.

Once.

So that simply tells you that it could, of course,

happen again, other places is only a matter of probability.

What the probability that you would get a brain

like the ones that we have, like the human brain.

So how difficult is it to make the human brain?

It's pretty difficult.

But most importantly, I guess we know very little

about how this process really happens.

And there is a reason for that,

actually multiple reasons for that.

Most of what we know about how the mammalian brains

or the brain of mammals develop,

comes from studying in labs other brains,

not our own brain, the brain of mice, for example.

But if I showed you a picture of a mouse brain

and then you put it next to a picture of a human brain,

they don't look at all like each other.

So they're very different.

And therefore, there is a limit to what you can learn

about how the human brain is made by studying the mouse brain.

There is a huge value in studying the mouse brain.

There are many things that we have learned,

but it's not the same thing.

So in having studied the human brain

or through the mouse and through other methodologies

that we'll talk about, do you have a sense?

I mean, you're one of the experts in the world.

How much do you feel you know about the brain?

And how often do you find yourself in awe

of this mysterious thing?

Yeah, you pretty much find yourself in awe all the time.

It's an amazing process.

It's a process by which,

by means that we don't fully understand

at the very beginning of embryogenesis,

the structure called the neural tube literally self assembles.

And it happens in an embryo

and it can happen also from stem cells in a dish.

Okay.

And then from there, these stem cells that are present

within the neural tube give rise to all of the thousands

and thousands of different cell types

that are present in the brain through time, right?

With the interesting, very intriguing, interesting observation

is that the time that it takes for the human brain to be made,

it's human time, meaning that for me and you,

it took almost nine months of gestation to build the brain

and then another 20 years of learning postnatally

to get the brain that we have today

that allows us to this conversation.

A mouse takes 20 days or so

for an embryo to be born and so the brain is built

in a much shorter period of time and the beauty of it

is that if you take mouse stem cells

and you put them in a cultured dish,

the brain organoid that you get from a mouse is formed faster

that if you took human stem cells and put them in the dish

and let them make a human brain organoid.

So the very developmental process is...

Controlled by the speed of the species.

Which means it's by its own purpose, it's not accidental

or there is something in that temporal dynamic to that development.

Exactly, that is very important for us to get the brain we have

and we can speculate for why that is.

It takes us a long time as human beings after we're born

to learn all the things that we have to learn

to have the adult brain.

It's actually 20 years, think about it.

From when a baby is born to when a teenager

goes through puberty to adults, it's a long time.

Do you think you can maybe talk through the first few months

and then on to the first 20 years

and then for the rest of their lives?

What does the development of the human brain look like?

What are the different stages?

At the beginning you have to build a brain, right?

And the brain is made of cells.

What's the very beginning? Which beginning are we talking about?

In the embryo.

As the embryo is developing in the womb,

in addition to making all of the other tissues of the embryo,

the muscle, the heart, the blood,

the embryo is also building the brain.

And it builds from a very simple structure

called the neural tube,

which is basically nothing but a tube of cells

that spans sort of the length of the embryo

from the head all the way to the tail, let's say, of the embryo.

And then over in human beings,

over many months of gestation,

from that neural tube,

which contains a stem cell like cells of the brain,

you will make many, many other building blocks of the brain.

So all of the other cell types,

because there are many, many different types of cells in the brain,

that will form specific structures of the brain.

So you can think about embryonic development of the brain

as just the time in which you are making the building blocks, the cells.

Are the stem cells relatively homogeneous,

like uniform, or are they all different types?

It's a very good question. It's exactly how it works.

You start with a more homogeneous,

perhaps more multipotent type of stem cell.

That multipotent means that it has the potential

to make many, many different types of other cells.

And then with time, these progenitors become more heterogeneous,

which means more diverse.

There are going to be many different types of these stem cells.

And also they will give rise to progeny,

to other cells that are not stem cells,

that are specific cells of the brain,

that are very different from the mother stem cell.

And now you think about this process of making cells from the stem cells

over many, many months of development for humans.

And what you're doing here, building the cells that physically make the brain,

and then you arrange them in specific structures

that are present in the final brain.

So you can think about the embryonic development of the brain

as the time where you're building the bricks.

You're putting the bricks together to form buildings,

structures, regions of the brain,

and where you make the connections between these many different types of cells,

especially nerve cells, neurons, right,

that transmit action potentials and electricity.

I've heard you also say somewhere, I think, correct me if I'm wrong,

that the order of the way this builds matters.

Oh, yes.

If you are an engineer and you think about development,

you can think of it as, well, I could also take all the cells

and bring them all together into a brain in the end.

But development is much more than that.

So the cells are made in a very specific order

that subserve the final product that you need to get.

And so, for example, all of the nerve cells, the neurons, are made first.

And all of the supportive cells of the neurons, like the glia, is made later.

And there is a reason for that because they have to assemble together in specific ways.

But you also may say, well, why don't we just put them all together in the end?

It's because as they develop next to each other,

they influence their own development.

So it's a different thing for a glia to be made alone in a dish

than a glia cell be made in a developing embryo

with all these other cells around it that produce all these other signals.

First of all, that's mind blowing, that this development process.

From my perspective in artificial intelligence,

you often think of how incredible the final product is,

the final product, the brain.

But you just, you're making me realize that the final product is just,

is the beautiful thing is the actual development process.

Do we know the code that drives that development?

Do we have any sense?

First of all, thank you for saying that it's really the formation of the brain.

It's really its development, this incredibly choreographed dance

that happens the same way every time each one of us builds the brain, right?

And that builds an organ that allows us to do what we're doing today, right?

That is mind blowing.

And this is why developmental neurobiologists never get tired of studying that.

Now, you're asking about the code.

What drives this? How is this done?

Well, it's millions of years of evolution

of really fine tuning gene expression programs

that allow certain cells to be made at a certain time

and to become a certain cell type,

but also mechanical forces of pressure bending.

This embryo is not just, it will not stay a tube,

this brain for very long.

At some point, this tube in the front of the embryo will expand

to make the primordium of the brain, right?

Now, the forces that control the cells feel,

and this is another beautiful thing,

the very force that they feel, which is different from a week before,

a week ago, will tell the cell,

oh, you're being squished in a certain way,

begin to produce these new genes,

because now you are at the corner,

or you are in a stretch of cells or whatever it is.

And so that mechanical physical force

shapes the fate of the cell as well.

So it's not only chemical, it's also mechanical.

So from my perspective, biology is this incredibly complex mess,

gooey mess.

So you're seeing mechanical forces.

How different is a computer or any kind of mechanical machine

that humans build and the biological systems?

Have you been, because you've worked a lot with biological systems,

are they as much of a mess as it seems

from a perspective of an engineer, a mechanical engineer?

Yeah, they are much more prone to taking alternative routes, right?

So if you, we go back to printing a brain versus developing a brain,

of course, if you print a brain,

given that you start with the same building blocks, the same cells,

you could potentially print it the same way every time.

But that final brain may not work the same way

as a brain built during development does,

because the very same building blocks that you're using

developed in a completely different environment, right?

That was not the environment of the brain.

Therefore, they're going to be different just by definition.

So if you instead use development to build, let's say, a brain

organoid, which maybe we will be talking about in a few minutes.

Those things are fascinating.

Yes, so if you use processes of development,

then when you watch it, you can see that sometimes things can go wrong

in some organoids.

And by wrong, I mean different one organoid from the next.

While if you think about that embryo, it always goes right.

So it's this development, it's for as complex as it is.

Every time a baby is born has, you know, with very few exceptions,

the brain is like the next baby.

But it's not the same if you develop it in a dish.

And first of all, we don't even develop a brain.

You develop something much simpler in the dish.

But there are more options for building things differently,

which really tells you that evolution has played a really

tight game here for how in the end the brain is built in vivo.

So just a quick maybe dumb question,

but it seems like the building process is not a dictatorship.

It seems like there's not a centralized high level mechanism

that says, OK, this cell built itself the wrong way.

I'm going to kill it.

It seems like there's a really strong distributed mechanism.

Is that in your sense for what you have?

There are a lot of possibilities, right?

And if you think about, for example, different species,

building their brain, each brain is a little bit different.

So the brain of a lizard is very different from that

of a chicken, from that of one of us, and so on and so forth.

And still is a brain, but it was built differently.

Starting from stem cells, they pretty much

had the same potential.

But in the end, evolution builds different brains

in different species, because that

serves in a way the purpose of that species

and the well being of that organism.

And so there are many possibilities,

but then there is a way, and you were talking about a code.

Nobody knows what the entire code of development is.

Of course, we don't.

We know bits and pieces of very specific aspects

of development of the brain, what genes are involved

to make a certain cell types, how those two cells interact

to make the next level structure that we might know,

but the entirety of it, how it's so well controlled.

It's really mind blowing.

So in the first two months in the embryo,

or whatever, the first few weeks, few months.

So yeah, the building blocks are constructed,

the actual, the different regions of the brain,

I guess, in the nervous system.

Well, this continues way longer than just the first few months.

So over the very first few months,

you build a lot of these cells,

but then there is continuous building of new cell types

all the way through birth.

And then even postnatally,

I don't know if you've ever heard of myelin.

Myelin is this sort of insulation

that is built around the cables of the neurons

so that the electricity can go really fast from.

The axons, I guess they're called.

The axons are called axons, exactly.

And so as human beings, we myelinate ourselves

postnatally, a kid, a six year old kid,

as barely started the process of making

the mature oligodendrocytes,

which are the cells that then eventually

will wrap the axons into myelin.

And this will continue, believe it or not,

until we are about 25, 30 years old.

So there is a continuous process of maturation

and tweaking and additions,

and also in response to what we do.

I remember taking api biology in high school,

and in the textbook, it said that,

I'm going by memory here,

that scientists disagree on the purpose of myelin

in the brain.

Is that totally wrong?

So like, I guess it speeds up the,

okay, but I'd be wrong here,

but I guess it speeds up the electricity traveling

down the axon or something.

So that's the most sort of canonical,

and definitely that's the case.

So you have to imagine an axon,

and you can think about it as a cable or some type

with electricity going through.

And what myelin does by insulating the outside,

I should say there are tracts of myelin

and pieces of axons that are naked without myelin.

And so by having the insulation,

the electricity instead of going straight through the cable,

it will jump over a piece of myelin, right?

To the next naked little piece and jump again,

and therefore, that's the idea that you go faster.

And it was always thought that in order to build

a big brain, a big nervous system,

in order to have a nervous system

that can do very complex type of things,

then you need a lot of myelin because you wanna go fast

with this information from point A to point B.

Well, a few years ago, maybe five years ago or so,

we discovered that some of the most evolved,

which means the newest type of neurons that we have

as non human primates, as as human beings,

in the top of our cerebral cortex,

which should be the neurons that do some

of the most complex things that we do.

Well, those have axons that have very little myelin.

Wow. And they have very interesting ways

in which they put this myelin on their axons,

you know, a little piece here, then a long track

with no myelin, another chunk there,

and some don't have myelin at all.

So now you have to explain

where we're going with evolution.

And if you think about it, perhaps as an electrical engineer,

when I looked at it, I initially thought,

I'm a developmental neurobiology,

I thought maybe this is what we see now,

but if we give evolution another few million years,

we'll see a lot of myelin on these neurons too.

But I actually think now that that's instead

the future of the brain, less myelin,

and my allow for more flexibility

on what you do with your axons,

and therefore more complicated

and unpredictable type of functions,

which is also a bit mind blowing.

So it seems like it's controlling the timing of the signal.

So they're in the timing,

you can encode a lot of information.

And so the brain...

The timing, the chemistry of that little piece of axon,

perhaps it's a dynamic process where the myelin can move.

Now you see how many layers of variability you can add,

and that's actually really good.

If you're trying to come up with a new function

or a new capability or something unpredictable in a way.

So we're gonna jump right out a little bit,

but the old question of how much is nature

and how much is nurture,

in terms of this incredible thing

after the development is over,

we seem to be kind of somewhat smart, intelligent,

cognition, consciousness,

all these things are just incredible ability of reason

and so on emerge.

In your sense, how much is in the hardware,

in the nature and how much is in the nurtures

learned through with our parents

through interacting with the environment, so on.

It's really both, right?

If you think about it.

So we are born with a brain as babies

that has most of its cells and most of its structures

and that will take a few years to grow,

to add more, to be better.

But really then we have this 20 years

of interacting with the environment around us.

And so what that brain that was so perfectly built

or imperfectly built due to our genetic cues

will then be used to incorporate the environment

in its farther maturation and development.

And so your experiences do shape your brain.

I mean, we know that like if you and I

may have had a different childhood or a different,

we have been going to different schools,

we have been learning different things

and our brain is a little bit different

because of that we behave differently because of that.

And so especially postnatally,

experience is extremely important.

We are born with a plastic brain.

What that means is a brain that is able to change

in response to stimuli.

They can be sensory.

So perhaps some of the most illuminating studies

that were done were studies in which

the sensory organs were not working, right?

If you are born with eyes that don't work,

then your very brain, the piece of the brain

that normally would process vision, the visual cortex

develops postnatally differently

and it might be used to do something different, right?

So that's the most extreme.

The plasticity of the brain, I guess,

is the magic hardware that it,

and then its flexibility in all forms

is what enables the learning postnatally.

Can you talk about organoids?

What are they?

And how can you use them to help us understand

the brain and the development of the brain?

This is very, very important.

So the first thing I'd like to say,

please keep this in the video.

The first thing I'd like to say is that an organoid,

a brain organoid, is not the same as a brain, okay?

It's a fundamental distinction.

It's a system, a cellular system,

that one can develop in the culture dish

starting from stem cells that will mimic some aspects

of the development of the brain, but not all of it.

They are very small, maximum,

they become about four to five millimeters in diameters.

They are much simpler than our brain, of course,

but yet they are the only system

where we can literally watch a process

of human brain development unfold.

And by watch, I mean study it.

Remember when I told you that we can't understand

everything about development in our own brain

by studying a mouse?

Well, we can't study the actual process

of development of the human brain

because it all happens in utero.

So we will never have access to that process ever.

And therefore, this is our next best thing,

like a bunch of stem cells that can be coaxed

into starting a process of neural tube formation.

Remember that tube that is made by the embryo rion?

And from there, a lot of the cell types

that are present within the brain

and you can simply watch it and study,

but you can also think about diseases

where development of the brain

does not proceed normally, right, properly.

Think about neurodevelopmental diseases

that are many, many different types.

Think about autism spectrum disorders,

there are also many different types of autism.

So there you could take a stem cell

which really means either a sample of blood

or a sample of skin from the patient,

make a stem cell, and then with that stem cell,

watch a process of formation of a brain organoid

of that person, with that genetics,

with that genetic code in it.

And you can ask, what is this genetic code doing

to some aspects of development of the brain?

And for the first time, you may come to solutions

like, what cells are involved in autism?

So I have so many questions around this.

So if you take this human stem cell

for that particular person with that genetic code,

how, and you try to build an organoid,

how often will it look similar?

What's the, yeah, so.

Reproducibility.

Yes, or how much variability is the flip side of that, yeah.

So there is much more variability in building organoids

than there is in building brain.

It's really true that the majority of us,

when we are born as babies,

our brains look a lot like each other.

This is the magic that the embryo does,

where it builds a brain in the context of a body

and there is very little variability there.

There is disease, of course,

but in general, little variability.

When you build an organoid, we don't have the full code

for how this is done.

And so in part, the organoid somewhat builds itself

because there are some structures of the brain

that the cells know how to make.

And another part comes from the investigator,

the scientist, adding to the media factors

that we know in the mouse, for example,

would foster a certain step of development.

But it's very limited.

And so as a result,

the kind of product you get in the end

is much more reductionist.

It's much more simple than what you get in vivo.

It mimics early events of development as of today.

And it doesn't build very complex type of anatomy

and structure does not as of today,

which happens instead in vivo.

And also the variability that you see

one organoid to the next tends to be higher

than when you compare an embryo to the next.

So, okay, then the next question is how hard

and maybe another flip side of that expensive

is it to go from one stem cell to an organoid?

How many can you build in like,

because it sounds very complicated.

It's work, definitely, and it's money, definitely.

But you can really grow a very high number

of these organoids, you know, can go perhaps,

I told you the maximum they become

about five millimeters in diameter.

So this is about the size of a tiny, tiny, you know, raising

or perhaps the seed of an apple.

And so you can grow 50 to 100 of those

inside one big bioreactors, which are these flasks

where the media provides nutrients for the organoids.

So the problem is not to grow more or less of them.

It's really to figure out how to grow them in a way

that they are more and more reproducible.

For example, organoid to organoid,

so they can be used to study a biological process

because if you have too much of variability,

then you never know if what you see

is just an exception or really the rule.

So what does an organoid look like?

Are there different neurons already emerging?

Is there, you know, well, first,

can you tell me what kind of neurons are there?

Yes.

Are they sort of all the same?

Are they not all the same?

Is how much do we understand

and how much of that variance

if any can exist in organoids?

Yes, so you could grow,

I told you that the brain has different parts.

So the cerebral cortex is on the top part of the brain,

but there is another region called the striatum

that is below the cortex and so on and so forth.

All of these regions have different types of cells

in the actual brain.

Okay.

And so scientists have been able to grow organoids

that may mimic some aspects of development

of these different regions of the brain.

And so we are very interested in the cerebral cortex.

That's the coolest part, right?

Very cool.

I agree with you.

We wouldn't be here talking if we didn't have a cerebral cortex.

It's also, I like to think,

the part of the brain that really truly makes us human,

the most evolved in recent evolution.

And so in the attempt to make the cerebral cortex

and by figuring out a way to have these organoids

continue to grow and develop for extended periods of time,

much like it happens in the real embryo,

months and months in culture,

then you can see that many different types

of neurons of the cortex appear

and at some point also the astrocytes,

so the glia cells of the cerebral cortex also appear.

What are these?

Astrocytes.

Astrocytes.

The astrocytes are not neurons,

so they're not nerve cells,

but they play very important roles.

One important role is to support the neuron,

but of course they have much more active type of roles.

They're very important, for example,

to make the synapses,

which are the point of contact and communication

between two neurons, they...

So all that chemistry fun happens in the synapses

happens because of these cells?

Are they the medium in which?

Happens because of the interactions,

happens because you are making the cells

and they have certain properties,

including the ability to make neurotransmitters,

which are the chemicals that are secreted to the synapses,

including the ability of making these axons grow

with their growth cones and so on and so forth.

And then you have other cells around there

that release chemicals or touch the neurons

or interact with them in different ways

to really foster this perfect process,

in this case of synaptogenesis.

And this does happen within organoids.

Or with organoids.

So the mechanical and the chemical stuff happens.

The connectivity between neurons.

This, in a way, is not surprising

because scientists have been culturing neurons forever.

And when you take a neuron, even a very young one,

and you culture it, eventually finds another cell

or another neuron to talk to, it will form a synapse.

Are we talking about mice neurons?

Are we talking about human neurons?

It doesn't matter, both.

So you can culture a neuron like a single neuron

and give it a little friend and it starts interacting?

Yes. So neurons are able to...

It sounds... It's more simple than what it may sound to you.

Neurons have molecular properties and structural properties

that allow them to really communicate with other cells.

And so if you put not one neuron,

but if you put several neurons together,

chances are that they will form synapses with each other.

Okay, great.

So an organoid is not a brain.

No.

But there's some...

It's able to, especially what you're talking about,

mimic some properties of the cerebral cortex, for example.

So what can you understand about the brain

by studying an organoid of the cerebral cortex?

I can literally study all this incredible diversity of cell type,

all these many, many different classes of cells.

How are they made?

How do they look like?

What do they need to be made properly?

And what goes wrong?

If now the genetics of that stem cell

that I used to make the organoid came from a patient

with a neurodevelopmental disease,

can I actually watch for the very first time

what may have gone wrong years before in this kid

when its own brain was being made?

Think about that loop.

In a way, it's a little tiny rudimentary window

into the past, into the time when that brain,

in a kid that had this neurodevelopmental disease,

was being made.

And I think that's unbelievably powerful

because today we have no idea of what cell types,

we barely know what brain regions are affected in these diseases.

Now we have an experimental system

that we can study in the lab

and we can ask what are the cells affected?

When, during development, things went wrong.

What are the molecules among the many, many different molecules

that control brain development?

Which ones are the ones that really messed up here

and we want perhaps to fix?

And what is really the final product?

Is it a less strong kind of circuit and brain?

Is it a brain that lacks a cell type?

Is it a, what is it?

Because then we can think about treatment

and care for these patients that is informed

rather than just based on current diagnostics.

So how hard is it to detect through the developmental process?

It's a super exciting tool

to see how different conditions develop.

How hard is it to detect that, wait a minute,

this is abnormal development.

Yeah.

That's how hard it, how much signals there,

how much of it is it a mess?

Because things can go wrong at multiple levels, right?

You could have a cell that is born and built

but then doesn't work properly

or a cell that is not even born

or a cell that doesn't interact with other cells differently

and so on and so forth.

So today we have technology

that we did not have even five years ago

that allows us to look, for example,

at the molecular picture of a cell,

of a single cell in a sea of cells with high precision.

And so that molecular information

where you compare many, many single cells

for the genes that they produce

between a control individual

and an individual with a neurodevelopmental disease,

that may tell you what is different, molecularly.

Or you could see that some cells are not even made,

for example, or that the process of maturation

of the cells may be wrong.

There are many different levels here

and we can study the cells at the molecular level

but also we can use the organoids to ask questions

about the properties of the neurons,

the functional properties,

how they communicate with each other,

how they respond to a stimulus and so on and so forth

and we may get abnormalities there, right?

And detect those, so how early is this work in the,

maybe in the history of science?

So, so, I mean, like, so if you were to,

if you and I time travel a thousand years into the future,

organoids seem to be, maybe I'm romanticizing the notion

but you're building not a brain

but something that has properties of a brain.

So it feels like you might be getting close to,

in the building process, to build us to understand.

So how far are we in this understanding

process of development?

A thousand years from now, it's a long time from now.

So if this planet is still gonna be here,

a thousand years from now.

So I mean, if, you know, like they write a book,

obviously there'll be a chapter about you.

That's probably the science fiction book today.

Yeah, today.

But I mean, I guess where we really understood

very little about the brain a century ago,

where I was a big fan in high school,

reading Freud and so on, still am of psychiatry.

I would say we still understand very little

about the functional aspect of just,

but how in the history of understanding

the biology of the brain, the development,

how far are we along?

It's a very good question.

And so this is just, of course, my opinion.

I think that we did not have technology,

even 10 years ago or certainly not 20 years ago,

to even think about experimentally investigating

the development of the human brain.

So we've done a lot of work in science

to study the brain on many other organisms.

Now we have some technologies which I'll spell out

that allow us to actually look at the real thing

and look at the brain, at the human brain.

So what are these technologies?

There has been huge progress in stem cell biology.

The moment someone figured out how to turn a skin cell

into an embryonic stem cell, basically,

and that how that embryonic stem cell

could begin a process of development again

to, for example, make a brain,

there was a huge, you know, advance.

And in fact, there was a Nobel Prize for that.

That started the field, really,

of using stem cells to build organs.

Now we can build on all the knowledge of development

that we build over the many, many, many years

to say, how do we make these stem cells?

Now make more and more complex aspects

of development of the human brain.

So this field is young, the field of brain organoids,

but it's moving fast.

And it's moving fast in a very serious way

that is rooted in labs with the right ethical framework

and really building on, you know,

solid science for what reality is and what is not.

And, but it will go fast

and it will be more and more powerful.

We also have technology that allows us to basically study

the properties of single cells

across many, many millions of single cells,

which we didn't have perhaps five years ago.

So now with that, even an organoid

that has millions of cells can be profiled in a way,

looked at with very, very high resolution,

the single cell level to really understand what is going on.

And you could do it in multiple stages of development

and you can build your hypothesis and so on and so forth.

So it's not gonna be a thousand years.

It's gonna be a shorter amount of time.

And I see this as sort of an exponential growth

of this field enabled by these technologies

that we didn't have before.

And so we're gonna see something transformative

that we didn't see at all in the prior thousand years.

So I apologize for the crazy sci fi questions,

but the developmental process is fascinating to watch

and study, but how far are we away from

and maybe how difficult is it to build

not just an organoid, but a human brain from a stem cell?

Yeah, first of all, that's not the goal

for the majority of the serial scientists that work on this

because you don't have to build the whole human brain

to make this model useful for understanding

how the brain develops or understanding disease.

You don't have to build the whole thing.

So let me just comment on that, it's fascinating.

It shows to me the difference between you and I

is you're actually trying to understand the beauty

of the human brain and to use it to really help

thousands or millions of people with disease and so on, right?

From an artificial intelligence perspective,

we're trying to build systems that we can put in robots

and try to create systems that have echoes

of the intelligence about reasoning about the world,

navigating the world.

It's different objectives, I think.

Yeah, that's very much science fiction.

Science fiction, but we operate in science fiction a little bit.

But so on that point of building a brain,

even though that is not the focus or interest,

perhaps, of the community, how difficult is it?

Is it truly science fiction at this point?

I think the field will progress, like I said,

and that the system will be more and more complex in a way,

right?

But there are properties that emerge from the human brain

that have to do with the mind, that may have to do with consciousness,

that may have to do with intelligence or whatever.

We really don't understand even how they can emerge

from an actual real brain, and therefore, we cannot measure

or study in an organoid.

So I think that this field, many, many years from now,

may lead to the building of better neural circuits

that really are built out of understanding of how

this process really works.

And it's hard to predict how complex this really will be.

I really don't think we're so far from, it makes me laugh, really.

It's really that far from building the human brain.

But you're going to be building something that is always

a bad version of it, but that may have really powerful properties

and might be able to respond to stimuli

or be used in certain contexts.

And this is why I really think that there is no other way

to do this science, but within the right ethical framework.

Because where you're going with this is also,

we can talk about science fiction and write that book,

and we could today.

But this work happens in a specific ethical framework

that we don't decide just as scientists, but also as a society.

So the ethical framework here is a fascinating one,

is a complicated one.

Do you have a sense, a grasp of how we think about ethically,

of building organoids from human stem cells to understand the brain?

It seems like a tool for helping potentially millions of people

cure diseases, or at least start to cure by understanding it.

But is there more, is there gray areas that are ethical,

that we have to think about ethically?

Absolutely.

We must think about that.

Every discussion about the ethics of this

needs to be based on actual data from the models that we have today

and from the ones that we will have tomorrow.

So it's a continuous conversation.

It's not something that you decide now.

Today, there is no issue, really.

Very simple models that clearly can help you in many ways

without much to think about.

But tomorrow, we need to have another conversation,

and so on and so forth.

And so the way we do this is to actually really bring together

constantly a group of people that are not only scientists,

but also bioethicists, lawyers, philosophers, psychiatrists,

and psychologists, and so on and so forth,

to decide as a society, really, what we should

and what we should not do.

So that's the way to think about the ethics.

Now, I also think, though, that as a scientist,

I have a moral responsibility.

So if you think about how transformative

it could be for understanding and curing a neuropsychiatric

disease, to be able to actually watch and study

and treat with drugs the very brain of the patient

that you are trying to study, how transformative

at this moment in time this could be.

We couldn't do it.

Five years ago, we could do it now.

Taking a stem cell of a particular patient

and make an organoid for a simple and different

from the human brain, it still is his process

of brain development with his or her genetics.

And we could understand perhaps what is going wrong.

Perhaps we could use as a platform, as a cellular platform,

to screen for drugs, to fix a process,

and so on and so forth.

So we could do it now, we couldn't do it five years ago.

Should we not do it?

What is the downside of doing it?

I don't see a downside at this very moment.

If we invited a lot of people, I'm sure there would be

somebody who would argue against it,

what would be the devil's advocate argument?

So it's exactly perhaps what you alluded at

with your question, that you are making a,

enabling some process of formation of the brain

that could be misused at some point,

or that could be showing properties

that ethically we don't wanna see in a tissue.

So today, I repeat, today this is not an issue.

And so you just gain dramatically from the science

without, because the system is so simple

and so different in a way from the actual brain.

But because it is the brain,

we have an obligation to really consider all of this, right?

And again, it's a balanced conversation

where we should put disease and betterment of humanity

also on that plate.

What do you think, at least historically,

there was some politicization,

politicization of embryonic stem cells,

a stem cell research.

Do you still see that out there?

Is that still a force that we have to think about,

especially in this larger discourse

that we're having about the role of science

in at least American society?

Yeah, this is a very good question.

It's very, very important.

I see a very central role for scientists

to inform decisions about what we should

or should not do in society.

And this is because the scientists

have the firsthand look and understanding

of really the work that they are doing.

And again, this varies depending on

what we're talking about here.

So now we're talking about brain organoids.

I think that the scientists need to be part

of that conversation about what is,

will be allowed in the future

or not allowed in the future to do with the system.

And I think that is very, very important

because they bring reality of data to the conversation.

And so they should have a voice.

So data should have a voice.

Data needs to have a voice.

Because in not only data, we should also be good

at communicating with non scientists the data.

So there has been, often time,

there is a lot of discussion and excitement

and fights about certain topics

just because of the way they are described.

I'll give you an example.

If I called the same cellular system,

we just talked about a brain organoid.

Or if I called it a human mini brain,

your reaction is gonna be very different to this.

And so the way the systems are described,

I mean, we and journalists alike

need to be a bit careful that this debate

is a real debate and informed by real data.

That's all I'm asking.

And yeah, the language matters here.

So I work on autonomous vehicles

and there the use of language could drastically

change the interpretation and the way people feel

about what is the right way to proceed forward.

You are, as I've seen from a presentation,

you're a parent.

I saw you show a couple of pictures of your son.

Is it just the one?

Two.

Two.

Son and a daughter.

Son and a daughter.

So what have you learned from the human brain

by raising two of them?

More than I could ever learn in a lab.

What have I learned?

I've learned that children really have

these amazing plastic minds, right?

That we have a responsibility to, you know,

foster their growth in good, healthy ways

that keep them curious, that keep some adventures,

that doesn't raise them in fear of things.

But also respecting who they are,

which is in part, you know, coming from the genetics

we talked about, my children are very different

from each other despite the fact

that they're the product of the same two parents.

I also learned that what you do for them

comes back to you.

Like, you know, if you're a good parent,

you're gonna, most of the time have, you know,

perhaps decent kids at the end.

So what do you think, just a quick comment,

what do you think is the source of that difference?

It's often the surprising thing for parents.

I can't believe that our kids,

they're so different, yet they came from the same parents.

Well, they are genetically different.

Even they came from the same two parents

because the mixing of gametes,

so when we know these genetics,

creates every time a genetically different individual

which will have a specific mix of genes

that is a different mix every time from the two parents.

And so they're not twins.

They're genetically different.

Just that little bit of variation.

As you said, really from a biological perspective,

the brains look pretty similar.

Well, so let me clarify that.

So the genetics you have, the genes that you have,

that play that beautiful orchestrated symphony

of development, different genes

will play it slightly differently.

It's like playing the same piece of music

but with the different orchestra

and a different director, right?

The music will not come out.

It will be still a piece by the same author

but it will come out differently

if it's played by the high school orchestra

instead of the, instead of the Scala in Milan.

And so you are born superficially with the same brain.

It has the same cell types, similar patterns of connectivity

but the properties of the cells

and how the cells will then react to the environment

as you experience your world will be also shaped

by who genetically you are.

Speaking just as a parent,

this is not something that comes from my work.

I think you can tell at birth

that these kids are different

and that they have a different personality in a way, right?

So both is needed.

The genetics as well as the nurturing afterwards.

So you are one human with a brain

sort of living through the whole mess of it.

The human condition, full of love, maybe fear,

ultimately mortal.

How has studying the brain changed the way you see yourself?

When you look in the mirror, when you think about your life,

the fears, the love.

When you see your own life, your own mortality.

Yeah, that's a very good question.

It's almost impossible to dissociate some time for me.

Some of the things we do or some of the things

that other people do from,

oh, that's because that part of the brain

is working in a certain way.

Or thinking about a teenager,

going through teenage years and being a time funny

in the way they think.

And impossible for me not to think it's because

they're going through this period of time called

critical periods of plasticity.

Yeah.

Where their synapses are being eliminated here and there

and they're just confused.

And so from that comes perhaps a different take

on that behavior or maybe I can justify scientifically

in some sort of way.

I also look at humanity in general

and I am amazed by what we can do

and the kind of ideas that we can come up with.

And I cannot stop thinking about

how the brain is continuing to evolve.

I don't know if you do this,

but I think about the next brain sometimes.

Where are we going with this?

Like what are the features of this brain

that evolution is really playing with

to get us in the future, the new brain?

It's not over, right?

It's a work in progress.

So let me just a quick comment on that.

Do you see, do you think there's a lot of fascination

and hope for artificial intelligence

of creating artificial brains?

You said the next brain.

When you imagine over a period of a thousand years

the evolution of the human brain,

do you sometimes envisioning that future

see an artificial one?

Artificial intelligence as it is hoped by many,

not hoped, thought by many people

would be actually the next evolutionary step

in the development of humans.

Yeah, I think in a way that will happen, right?

It's almost like a part of the way we evolve.

We evolve in the world that we created,

that we interact with, that shape us as we grow up

and so on and so forth.

Sometime I think about something that may sound silly,

but think about the use of cell phones.

Part of me thinks that somehow in their brain

there will be a region of the cortex

that is attuned to that tool.

And this comes from a lot of studies

in model organisms where really the cortex

especially adapts to the kind of things you have to do.

So if we need to move our fingers in a very specific way,

we have a part of our cortex that allows us to do

this kind of very precise movement.

An owl that has to see very, very far away

with big eyes, the visual cortex, very big.

It's the brain attunes to your environment.

So the brain will attune to the technologies

that we will have and will be shaped by it.

So the cortex very well may be.

Will be shaped by it.

In artificial intelligence, it may merge with it,

it may get enveloped and adjusted.

Even if it's not a merge of the kind of,

oh, let's have a synthetic element together

with a biological one.

The very space around us, the fact, for example,

think about we put on some goggles of virtual reality

and we physically are surfing the ocean, right?

Like I've done it and you have all these emotions

that come to you, your brain placed you in that reality.

And it was able to do it like that

just by putting the goggles on.

I didn't take thousands of years of adapting to this.

The brain is plastic, so adapts to new technology.

So you could do it from the outside

by simply hijacking some sensory capacities that we have.

So clearly over recent evolution,

the cerebral cortex has been a part of the brain

that has known the most evolution.

So we have put a lot of chips on evolving

this specific part of the brain

and the evolution of cortex is plasticity.

It's this ability to change in response to things.

So yes, they will integrate that we want it or not.

Well, there's no better way to end it, Paola.

Thank you so much for talking to me.

You're very welcome.

That's great.

Thank you.