back to indexPaola Arlotta: Brain Development from Stem Cell to Organoid | Lex Fridman Podcast #32
link |
The following is a conversation with Paola Arlotta.
link |
She's a professor of stem cell and regenerative biology
link |
at Harvard University and is interested in understanding
link |
the molecular laws that govern the birth, differentiation,
link |
and assembly of the human brain's cerebral cortex.
link |
She explores the complexity of the brain
link |
by studying and engineering elements
link |
of how the brain develops.
link |
This was a fascinating conversation to me.
link |
It's part of the Artificial Intelligence podcast.
link |
If you enjoy it, subscribe on YouTube,
link |
give it five stars on iTunes, support it on Patreon,
link |
or simply connect with me on Twitter
link |
at Lex Friedman, spelled F R I D M A N.
link |
And I'd like to give a special thank you to Amy Jeffress
link |
for her support of the podcast on Patreon.
link |
She's an artist and you should definitely check out
link |
her Instagram at lovetruthgood, three beautiful words.
link |
Your support means a lot and inspires me
link |
to keep the series going.
link |
And now here's my conversation with Paola Arlotta.
link |
You studied the development of the human brain
link |
So let me ask you an out of the box question first.
link |
How likely is it that there's intelligent life out there
link |
in the universe outside of earth
link |
with something like the human brain?
link |
So I can put it another way.
link |
How unlikely is the human brain?
link |
How difficult is it to build a thing
link |
through the evolutionary process?
link |
Well, it has happened here, right?
link |
So that simply tells you that it could, of course,
link |
happen again other places.
link |
It's only a matter of probability.
link |
What the probability that you would get a brain
link |
like the ones that we have, like the human brain.
link |
So how difficult is it to make the human brain?
link |
It's pretty difficult, but most importantly,
link |
I guess we know very little
link |
about how this process really happens.
link |
And there is a reason for that,
link |
actually multiple reasons for that.
link |
Most of what we know about how the mammalian brain,
link |
so the brain of mammals develop comes from studying
link |
in labs other brains, not our own brain,
link |
the brain of mice, for example.
link |
But if I showed you a picture of a mouse brain,
link |
and then you put it next to a picture of a human brain,
link |
they don't look at all like each other.
link |
So they're very different.
link |
And therefore there is a limit to what you can learn
link |
about how the human brain is made
link |
by studying the mouse brain.
link |
There is a huge value in studying the mouse brain.
link |
There are many things that we have learned,
link |
but it's not the same thing.
link |
So in having studied the human brain,
link |
or through the mouse and through other methodologies
link |
that we'll talk about, do you have a sense?
link |
I mean, you're one of the experts in the world.
link |
How much do you feel you know about the brain
link |
and how often do you find yourself
link |
in awe of this mysterious thing?
link |
Yeah, you pretty much find yourself in awe all the time.
link |
It's an amazing process.
link |
It's a process by which,
link |
by means that we don't fully understand,
link |
at the very beginning of embryogenesis,
link |
the structure called the neural tube,
link |
literally self assembles.
link |
And it happens in an embryo
link |
and it can happen also from stem cells in a dish.
link |
And then from there,
link |
these stem cells that are present within the neural tube
link |
give rise to all of the thousands and thousands
link |
of different cell types that are present in the brain
link |
through time, right?
link |
With the interesting, very intriguing, interesting
link |
observation is that the time that it takes
link |
for the human brain to be made, it's human time.
link |
Meaning that for me and you,
link |
it took almost nine months of gestation to build the brain
link |
and then another 20 years of learning postnatally
link |
to get the brain that we have today
link |
that allows us to this conversation.
link |
A mouse takes 20 days or so for an embryo to be born.
link |
And so the brain is built in a much shorter period of time.
link |
And the beauty of it is that if you take mouse stem cells
link |
and you put them in a culture dish,
link |
the brain organoid that you get from a mouse
link |
is formed faster than if you took human stem cells
link |
and put them in the dish
link |
and let them make a human brain organoid.
link |
So the very developmental process is...
link |
Controlled by the speed of the species.
link |
Which means it's on purpose, it's not accidental
link |
or there is something in that temporal...
link |
It's very, exactly, that is very important
link |
for us to get the brain we have.
link |
And we can speculate for why that is.
link |
You know, it takes us a long time as human beings
link |
after we're born to learn all the things
link |
that we have to learn to have the adult brain.
link |
It's actually 20 years, think about it.
link |
From when a baby is born to when a teenager
link |
goes through puberty to adults, it's a long time.
link |
Do you think you can maybe talk through
link |
the first few months and then on to the first 20 years
link |
and then for the rest of their lives?
link |
What is the development of the human brain look like?
link |
What are the different stages?
link |
Yeah, at the beginning, you have to build a brain, right?
link |
And the brain is made of cells.
link |
What's the very beginning?
link |
Which beginning are we talking about?
link |
In the embryo, as the embryo is developing in the womb,
link |
in addition to making all of the other tissues
link |
of the embryo, the muscle, the heart, the blood,
link |
the embryo is also building the brain.
link |
And it builds from a very simple structure
link |
called the neural tube, which is basically nothing
link |
but a tube of cells that spans sort of the length
link |
of the embryo from the head all the way to the tail,
link |
let's say, of the embryo.
link |
And then over in human beings, over many months of gestation
link |
from that neural tube, which contains stem cell
link |
like cells of the brain, you will make many, many
link |
other building blocks of the brain.
link |
So all of the other cell types, because there are many,
link |
many different types of cells in the brain
link |
that will form specific structures of the brain.
link |
So you can think about embryonic development of the brain
link |
as just the time in which you are making
link |
the building blocks, the cells.
link |
Are the stem cells relatively homogeneous, like uniform,
link |
or are they all different types?
link |
It's a very good question.
link |
It's exactly how it works.
link |
You start with a more homogeneous,
link |
perhaps more multipotent type of stem cell.
link |
With multipotent it means that it has the potential
link |
to make many, many different types of other cells.
link |
And then with time, these progenitors become
link |
more heterogeneous, which means more diverse.
link |
There are gonna be many different types of the stem cells.
link |
And also they will give rise to progeny to other cells
link |
that are not stem cells, that are specific cells
link |
of the brain that are very different
link |
from the mother stem cell.
link |
And now you think about this process of making cells
link |
from the stem cells over many, many months
link |
of development for humans.
link |
And what you're doing, you're building the cells
link |
that physically make the brain,
link |
and then you arrange them in specific structures
link |
that are present in the final brain.
link |
So you can think about the embryonic development
link |
of the brain as the time where you're building the bricks,
link |
you're putting the bricks together to form buildings,
link |
structures, regions of the brain.
link |
And where you make the connections
link |
between these many different type of cells,
link |
especially nerve cells, neurons, right?
link |
That transmit action potentials and electricity.
link |
I've heard you also say somewhere, I think,
link |
correct me if I'm wrong,
link |
that the order of the way this builds matters.
link |
If you are an engineer and you think about development,
link |
you can think of it as, well, I could also take all the cells
link |
and bring them all together into a brain in the end.
link |
But development is much more than that.
link |
So the cells are made in a very specific order
link |
that subserve the final product that you need to get.
link |
And so, for example, all of the nerve cells,
link |
the neurons are made first,
link |
and all of the supportive cells of the neurons,
link |
like the glia, is made later.
link |
And there is a reason for that
link |
because they have to assemble together in specific ways.
link |
But you also may say, well,
link |
why don't we just put them all together in the end?
link |
It's because as they develop next to each other,
link |
they influence their own development.
link |
So it's a different thing for a glia
link |
to be made alone in a dish,
link |
than a glia cell be made in a developing embryo
link |
with all these other cells around it
link |
that produce all these other signals.
link |
First of all, that's mind blowing,
link |
this development process.
link |
From my perspective in artificial intelligence,
link |
you often think of how incredible the final product is,
link |
the final product, the brain.
link |
But you're making me realize that the final product
link |
is just, the beautiful thing
link |
is the actual development process.
link |
Do we know the code that drives that development?
link |
Do we have any sense?
link |
First of all, thank you for saying
link |
that it's really the formation of the brain.
link |
It's really its development.
link |
It is this incredibly choreographed dance
link |
that happens the same way every time
link |
each one of us builds the brain, right?
link |
And that builds an organ that allows us
link |
to do what we're doing today, right?
link |
That is mind blowing.
link |
And this is why developmental neurobiologists
link |
never get tired of studying that.
link |
Now you're asking about the code.
link |
Well, it's millions of years of evolution
link |
of really fine tuning gene expression programs
link |
that allow certain cells to be made at a certain time
link |
and to become a certain cell type,
link |
but also mechanical forces of pressure bending.
link |
This embryo is not just, it will not stay a tube,
link |
this brain for very long.
link |
At some point, this tube in the front of the embryo
link |
will expand to make the primordium of the brain, right?
link |
Now the forces that control that the cells feel,
link |
and this is another beautiful thing,
link |
the very force that they feel,
link |
which is different from a week before, a week ago,
link |
will tell the cell, oh, you're being squished
link |
in a certain way, begin to produce these new genes
link |
because now you are at the corner
link |
or you are in a stretch of cells
link |
or whatever it is, and that,
link |
so that mechanical physical force
link |
shapes the fate of the cell as well.
link |
So it's not only chemical, it's also mechanical.
link |
So from my perspective,
link |
biology is this incredibly complex mess, gooey mess.
link |
So you're saying mechanical forces.
link |
How different is like a computer
link |
or any kind of mechanical machine that we humans build
link |
and the biological systems?
link |
because you've worked a lot with biological systems.
link |
Are they as much of a mess as it seems
link |
from a perspective of an engineer, a mechanical engineer?
link |
Yeah, they are much more prone
link |
to taking alternative routes, right?
link |
So if you, we go back to printing a brain
link |
versus developing a brain,
link |
of course, if you print a brain,
link |
given that you start with the same building blocks,
link |
you could potentially print it the same way every time,
link |
but that final brain may not work the same way
link |
as a brain built during development does
link |
because the very same building blocks that you're using
link |
developed in a completely different environment, right?
link |
It was not the environment of the brain.
link |
Therefore, they're gonna be different just by definition.
link |
So if you instead use development to build,
link |
let's say a brain organoid,
link |
which maybe we will be talking about in a few minutes.
link |
Those things are fascinating.
link |
Yes, so if you use processes of development,
link |
then when you watch it,
link |
you can see that sometimes things can go wrong
link |
in some organoids and by wrong,
link |
I mean different one organoid from the next.
link |
While if you think about that embryo, it always goes right.
link |
So this development, it's for as complex as it is.
link |
Every time a baby is born has, with very few exceptions,
link |
so the brain is like the next baby,
link |
but it's not the same if you develop it in a dish.
link |
And first of all, we don't even develop a brain,
link |
you develop something much simpler in the dish,
link |
but there are more options for building things differently,
link |
which really tells you that evolution
link |
has played a really tight game here
link |
for how in the end the brain is built in vivo.
link |
So just a quick, maybe dumb question,
link |
but it seems like this is not,
link |
the building process is not a dictatorship.
link |
It seems like there's not a centralized,
link |
like high level mechanism that says,
link |
okay, this cell built itself the wrong way,
link |
I'm gonna kill it.
link |
It seems like there's a really strong distributed mechanism.
link |
Is that in your sense for what you mean?
link |
There are a lot of possibilities, right?
link |
And if you think about, for example,
link |
different species building their brain,
link |
each brain is a little bit different.
link |
So the brain of a lizard is very different
link |
from that of a chicken, from that of one of us
link |
and so on and so forth and still is a brain,
link |
but it was built differently starting from stem cells
link |
that pretty much had the same potential,
link |
but in the end, evolution builds different brains
link |
in different species because that serves in a way
link |
the purpose of that species
link |
and the wellbeing of that organism.
link |
And so there are many possibilities,
link |
but then there is a way and you were talking about a code.
link |
Nobody knows what the entire code of development is.
link |
Of course we don't.
link |
We know bits and pieces of very specific aspects
link |
of development of the brain,
link |
what genes are involved to make a certain cell types,
link |
how those two cells interact to make the next level structure
link |
that we might know, but the entirety of it,
link |
how it's so well controlled, it's really mind blowing.
link |
So in the first two months in the embryo or whatever,
link |
the first few weeks, months,
link |
so yeah, the building blocks are constructed.
link |
The actual, the different regions of the brain,
link |
I guess in the nervous system.
link |
Well, this continues way longer
link |
than just the first few months.
link |
So over the very first few months,
link |
you build a lot of the cells,
link |
but then there is continuous building of new cell types
link |
all the way through birth.
link |
And then even postnatally,
link |
I don't know if you've ever heard of myelin.
link |
Myelin is this sort of insulation
link |
that is built around the cables of the neurons
link |
so that the electricity can go really fast from.
link |
The axons, I guess they're called.
link |
The axons, they're called axons, exactly.
link |
And so as human beings,
link |
we myelinate our cells postnatally.
link |
A kid, a six year old kid has barely started
link |
the process of making the mature oligodendrocytes,
link |
which are the cells that then eventually
link |
will wrap the axons into myelin.
link |
And this will continue, believe it or not,
link |
until we are about 25, 30 years old.
link |
So there is a continuous process of maturation
link |
and tweaking and additions,
link |
and also in response to what we do.
link |
I remember taking AP Biology in high school,
link |
and in the textbook, it said that,
link |
I'm going by memory here,
link |
that scientists disagree on the purpose
link |
of myelin in the brain.
link |
Is that totally wrong?
link |
So like, I guess it speeds up the,
link |
okay, I might be wrong here,
link |
but I guess it speeds up the electricity
link |
traveling down the axon or something.
link |
Yeah, so that's the most sort of canonical,
link |
and definitely that's the case.
link |
So you have to imagine an axon,
link |
and you can think about it as a cable of some type
link |
with electricity going through.
link |
And what myelin does, by insulating the outside,
link |
I should say there are tracts of myelin
link |
and pieces of axons that are naked without myelin.
link |
And so by having the insulation,
link |
the electricity, instead of going straight
link |
through the cable, it will jump
link |
over a piece of myelin, right,
link |
to the next naked little piece and jump again.
link |
And therefore, that's the idea that you go faster.
link |
And it was always thought that in order to build
link |
a big brain, a big nervous system,
link |
in order to have a nervous system
link |
that can do very complex type of things,
link |
then you need a lot of myelin
link |
because you wanna go fast with this information
link |
from point A to point B.
link |
Well, a few years ago, maybe five years ago or so,
link |
we discovered that some of the most evolved,
link |
which means the newest type of neurons that we have
link |
as nonhuman primates, as human beings
link |
in the top of our cerebral cortex,
link |
which should be the neurons that do some
link |
of the most complex things that we do,
link |
well, those have axons that have very little myelin.
link |
And they have very interesting ways
link |
in which they put this myelin on their axons.
link |
You know, a little piece here,
link |
then a long track with no myelin, another chunk there.
link |
And some don't have myelin at all.
link |
So now, you have to explain
link |
where we're going with evolution.
link |
And if you think about it,
link |
perhaps as an electrical engineer,
link |
when I looked at it, I initially thought,
link |
and I'm a developmental neurobiologist,
link |
I thought maybe this is what we see now,
link |
but if we give evolution another few million years,
link |
we'll see a lot of myelin on these neurons too.
link |
But I actually think now that that's instead the future
link |
Less myelin might allow for more flexibility
link |
on what you do with your axons,
link |
and therefore more complicated
link |
and unpredictable type of functions,
link |
which is also a bit mind blowing.
link |
So it seems like it's controlling the timing of the signal.
link |
So they're in the timing, you can encode a lot of information.
link |
The timing, the chemistry of that little piece of axon,
link |
perhaps it's a dynamic process where the myelin can move.
link |
Now you see how many layers of variability you can add,
link |
and that's actually really good
link |
if you're trying to come up with a new function
link |
or a new capability or something unpredictable in a way.
link |
So we're gonna jump around a little bit,
link |
but the old question of how much is nature
link |
and how much is nurture?
link |
In terms of this incredible thing
link |
after the development is over,
link |
we seem to be kind of somewhat smart, intelligent,
link |
cognition, consciousness,
link |
all of these things are just incredible,
link |
ability to reason and so on emerge.
link |
In your sense, how much is in the hardware,
link |
in the nature and how much is in the nurture
link |
is learned through with our parents
link |
through interacting with the environment and so on.
link |
It's really both, right?
link |
If you think about it.
link |
So we are born with a brain as babies
link |
that has most of its cells and most of its structures.
link |
And that will take a few years to grow,
link |
to add more, to be better.
link |
But really then we have this 20 years
link |
of interacting with the environment around us.
link |
And so what that brain that was so perfectly built
link |
or imperfectly built due to our genetic cues
link |
will then be used to incorporate the environment
link |
in its further maturation and development.
link |
And so your experiences do shape your brain.
link |
I mean, we know that like if you and I
link |
may have had a different childhood or a different,
link |
we have been going to different schools,
link |
we have been learning different things
link |
and our brain is a little bit different because of that.
link |
We behave differently because of that.
link |
And so especially postnatally
link |
experience is extremely important.
link |
We are born with a plastic brain.
link |
What that means is a brain that is able to change
link |
in response to stimuli that can be sensory.
link |
So perhaps some of the most illuminating studies
link |
that were done were studies in which
link |
the sensory organs were not working, right?
link |
Like if you are born with eyes that don't work,
link |
then your very brain, that piece of the brain
link |
that normally would process vision, the visual cortex,
link |
develops postnatally differently
link |
and it might be used to do something different, right?
link |
So that's the most extreme.
link |
The plasticity of the brain, I guess,
link |
is the magic hardware that it,
link |
and then it's flexibility in all forms
link |
is what enables the learning postnatally.
link |
Can you talk about organoids?
link |
And how can you use them to help us understand the brain
link |
and the development of the brain?
link |
This is very, very important.
link |
So the first thing I'd like to say,
link |
please skip this in the video.
link |
The first thing I'd like to say is that an organoid,
link |
a brain organoid is not the same as a brain.
link |
It's a fundamental distinction.
link |
It's a system, a cellular system
link |
that one can develop in the culture dish,
link |
starting from stem cells that will mimic some aspects
link |
of the development of the brain, but not all of it.
link |
They are very small, maximum,
link |
they become about four to five millimeters in diameters.
link |
They are much simpler than our brain, of course,
link |
but yet they are the only system
link |
where we can literally watch a process
link |
of human brain development unfold.
link |
And by watch, I mean, study it.
link |
Remember when I told you that we can't understand
link |
everything about development in our own brain
link |
by studying a mouse?
link |
Well, we can't study the actual process
link |
of development of the human brain
link |
because it all happens in utero.
link |
So we will never have access to that process ever.
link |
And therefore, this is our next best thing.
link |
Like a bunch of stem cells that can be coaxed
link |
into starting a process of neural tube formation.
link |
Remember that tube that is made by the embryo early on.
link |
And from there, a lot of the cell types
link |
that are present within the brain,
link |
and you can simply watch it and study,
link |
but you can also think about diseases
link |
where development of the brain
link |
does not proceed normally, right, properly.
link |
Think about neurodevelopmental diseases.
link |
There are many, many different types.
link |
Think about autism spectrum disorders.
link |
There are also many different types of autism.
link |
So there you could take a stem cell,
link |
which really means either a sample of blood
link |
or a sample of skin from the patient,
link |
make a stem cell, and then with that stem cell,
link |
watch a process of formation of a brain organ
link |
or a brain organoid of that person with that genetics,
link |
with that genetic code in it.
link |
And you can ask, what is this genetic code doing
link |
to some aspects of development of the brain?
link |
And for the first time, you may come to solutions
link |
like what cells are involved in autism, right?
link |
So many questions around this.
link |
So if you take this human stem cell
link |
for that particular person with that genetic code,
link |
how, and you try to build an organoid,
link |
how often will it look similar?
link |
What's the, yeah, so.
link |
The reproducibility?
link |
Yes, or how much variability is the flip side of that?
link |
Yeah, so there is much more variability
link |
in building organoids than there is in building brain.
link |
It's really true that the majority of us,
link |
when we are born as babies,
link |
our brains look a lot like each other.
link |
This is the magic that the embryo does,
link |
where it builds a brain in the context of a body
link |
and there is very little variability there.
link |
There is disease, of course,
link |
but in general, a little variability.
link |
When you build an organoid,
link |
we don't have the full code for how this is done.
link |
And so in part, the organoid somewhat builds itself
link |
because there are some structures of the brain
link |
that the cells know how to make.
link |
And another part comes from the investigator,
link |
the scientist adding to the media factors
link |
that we know in the mouse, for example,
link |
would foster a certain step of development,
link |
but it's very limited.
link |
And so as a result,
link |
the kind of product you get in the end
link |
is much more reductionist,
link |
is much more simple than what you get in vivo.
link |
It mimics early events of development as of today,
link |
and it doesn't build very complex type of anatomy
link |
and structure does not as of today,
link |
which happens instead in vivo.
link |
And also the variability that you see,
link |
one organ to the next tends to be higher
link |
than when you compare an embryo to the next.
link |
So, okay, then the next question is,
link |
how hard and maybe another flip side of that expensive
link |
is it to go from one stem cell to an organoid?
link |
How many can you build in like,
link |
because it sounds very complicated.
link |
It's work definitely, and it's money definitely,
link |
but you can really grow a very high number
link |
of these organoids, can go perhaps,
link |
I told you the maximum,
link |
they become about five millimeters in diameter.
link |
So this is about the size of a tiny, tiny raisin,
link |
or perhaps the seed of an apple.
link |
And so you can grow 50 to 100 of those
link |
inside one big bioreactors, which are these flasks
link |
where the media provides nutrients for the organoids.
link |
So the problem is not to grow more or less of them.
link |
It's really to figure out how to grow them in a way
link |
that they are more and more reproducible,
link |
for example, organoid to organoid,
link |
so they can be used to study a biological process.
link |
Because if you have too much variability,
link |
then you never know if what you see
link |
is just an exception or really the rule.
link |
So what does an organoid look like?
link |
Are there different neurons already emerging?
link |
Is there, well, first, can you tell me
link |
what kind of neurons are there?
link |
Are they sort of all the same?
link |
Are they not all the same?
link |
How much do we understand?
link |
And how much of that variance, if any,
link |
can exist in organoids?
link |
So you could grow,
link |
I told you that the brain has different parts.
link |
So the cerebral cortex is on the top part of the brain,
link |
but there is another region called the striatum
link |
that is below the cortex and so on and so forth.
link |
All of these regions have different types of cells
link |
in the actual brain, okay?
link |
And so scientists have been able to grow organoids
link |
that may mimic some aspects of development
link |
of these different regions of the brain.
link |
And so we are very interested in the cerebral cortex.
link |
That's the coolest part, right?
link |
We wouldn't be here talking
link |
if we didn't have a cerebral cortex.
link |
It's also, I like to think, the part of the brain
link |
that really truly makes us human,
link |
the most evolved in recent evolution.
link |
And so in the attempt to make the cerebral cortex
link |
and by figuring out a way to have these organoids
link |
continue to grow and develop for extended periods of times,
link |
much like it happens in the real embryo,
link |
months and months in culture,
link |
then you can see that many different types of neurons
link |
of the cortex appear.
link |
And at some point, also the astrocytes,
link |
so the glia cells of the cerebral cortex also appear.
link |
What are these astrocytes?
link |
The astrocytes are not neurons, so they're not nerve cells,
link |
but they play very important roles.
link |
One important role is to support the neuron.
link |
But of course, they have much more active type of roles.
link |
They're very important, for example, to make the synapses,
link |
which are the point of contact and communication
link |
between two neurons.
link |
So all that chemistry fun happens in the synapses,
link |
happens because of these cells?
link |
Are they the medium in which?
link |
It happens because of the interactions,
link |
happens because you are making the cells
link |
and they have certain properties,
link |
including the ability to make neurotransmitters,
link |
which are the chemicals that are secreted to the synapses,
link |
including the ability of making these axons grow
link |
with their growth cones and so on and so forth.
link |
And then you have other cells around it
link |
that release chemicals or touch the neurons
link |
or interact with them in different ways
link |
to really foster this perfect process,
link |
in this case of synaptogenesis.
link |
And this does happen within organoids.
link |
So the mechanical and the chemical stuff happens.
link |
The connectivity between neurons,
link |
this in a way is not surprising
link |
because scientists have been culturing neurons forever.
link |
And when you take a neuron, even a very young one,
link |
and you culture it, eventually finds another cell
link |
or another neuron to talk to, it will form a synapse.
link |
Are we talking about mice neurons?
link |
Are we talking about human neurons?
link |
It doesn't matter, both.
link |
So you can culture a neuron, like a single neuron
link |
and give it a little friend and it starts interacting?
link |
Yes, so neurons are able to, it sounds,
link |
it's more simple than what it may sound to you.
link |
Neurons have molecular properties and structural properties
link |
that allow them to really communicate with other cells.
link |
And so if you put not one neuron,
link |
but if you put several neurons together,
link |
chances are that they will form synapses with each other.
link |
So an organoid is not a brain.
link |
But there's some, it's able to,
link |
especially what you're talking about,
link |
mimics some properties of the cerebral cortex, for example.
link |
So what can you understand about the brain
link |
by studying an organoid of a cerebral cortex?
link |
I can literally study all this incredible diversity
link |
of cell type, all these many, many different classes
link |
of cells, how are they made?
link |
How do they look like?
link |
What do they need to be made properly?
link |
And what goes wrong if now the genetics of that stem cell
link |
that I used to make the organoid came from a patient
link |
with a neurodevelopmental disease?
link |
Can I actually watch for the very first time
link |
what may have gone wrong years before in this kid
link |
when its own brain was being made?
link |
Think about that loop.
link |
In a way, it's a little tiny rudimentary window
link |
into the past, into the time when that brain
link |
in a kid that had this neurodevelopmental disease
link |
And I think that's unbelievably powerful
link |
because today we have no idea of what cell types,
link |
we barely know what brain regions
link |
are affected in these diseases.
link |
Now we have an experimental system
link |
that we can study in the lab.
link |
And we can ask, what are the cells affected?
link |
When during development things went wrong?
link |
What are the molecules among the many, many
link |
different molecules that control brain development?
link |
Which ones are the ones that really messed up here
link |
and we want perhaps to fix?
link |
And what is really the final product?
link |
Is it a less strong kind of circuit and brain?
link |
Is it a brain that lacks a cell type?
link |
Because then we can think about treatment
link |
and care for these patients that is informed
link |
rather than just based on current diagnostics.
link |
So how hard is it to detect
link |
through the developmental process?
link |
It's a super exciting tool
link |
to see how different conditions develop.
link |
How hard is it to detect that, wait a minute,
link |
this is abnormal development.
link |
How much signal is there?
link |
How much of it is it a mess?
link |
Because things can go wrong at multiple levels, right?
link |
You could have a cell that is born and built
link |
but then doesn't work properly
link |
or a cell that is not even born
link |
or a cell that doesn't interact with other cells differently
link |
and so on and so forth.
link |
So today we have technology
link |
that we did not have even five years ago
link |
that allows us to look for example
link |
at the molecular picture of a cell,
link |
of a single cell in a sea of cells with high precision.
link |
And so that molecular information
link |
where you compare many, many single cells
link |
for the genes that they produce
link |
between a control individual
link |
and an individual with a neurodevelopmental disease,
link |
that may tell you what is different molecularly.
link |
Or you could see that some cells are not even made,
link |
for example, or that the process of maturation
link |
of the cells may be wrong.
link |
There are many different levels here
link |
and we can study the cells at the molecular level
link |
but also we can use the organoids to ask questions
link |
about the properties of the neurons,
link |
the functional properties,
link |
how they communicate with each other,
link |
how they respond to a stimulus and so on and so forth.
link |
And we may get an abnormalities there, right?
link |
So how early is this work in the,
link |
maybe in the history of science?
link |
So, I mean like, so if you were to,
link |
if you and I time travel a thousand years into the future,
link |
organoids seem to be, maybe I'm romanticizing the notion
link |
but you're building not a brain
link |
but something that has properties of a brain.
link |
So it feels like you might be getting close to,
link |
in the building process, to build this to understand.
link |
So how far are we in this understanding
link |
process of development?
link |
A thousand years from now, it's a long time from now.
link |
So if this planet is still gonna be here
link |
a thousand years from now.
link |
So, I mean, if, you know, like they write a book,
link |
obviously there'll be a chapter about you.
link |
That's right, that science fiction book, today.
link |
Yeah, today, about, I mean, I guess where
link |
we really understood very little about the brain
link |
a century ago, I was a big fan in high school
link |
of reading Freud and so on, still am of psychiatry.
link |
I would say we still understand very little
link |
about the functional aspect of just,
link |
but how in the history of understanding
link |
the biology of the brain, the development,
link |
how far are we along?
link |
It's a very good question.
link |
And so this is just, of course, my opinion.
link |
I think that we did not have technology
link |
even 10 years ago or certainly not 20 years ago
link |
to even think about experimentally investigating
link |
the development of the human brain.
link |
So we've done a lot of work in science
link |
to study the brain or many other organisms.
link |
Now we have some technologies which I'll spell out
link |
that allow us to actually look at the real thing
link |
and look at the brain, at the human brain.
link |
So what are these technologies?
link |
There has been huge progress in stem cell biology.
link |
The moment someone figured out how to turn a skin cell
link |
into an embryonic stem cell, basically,
link |
and that how that embryonic stem cell
link |
could begin a process of development again
link |
to, for example, make a brain,
link |
there was a huge advance,
link |
and in fact, there was a Nobel Prize for that.
link |
That started the field, really,
link |
of using stem cells to build organs.
link |
Now we can build on all the knowledge of development
link |
that we build over the many, many, many years
link |
to say, how do we make the stem cells
link |
now make more and more complex aspects
link |
of development of the human brain?
link |
So this field is young, the field of brain organoids,
link |
but it's moving faster.
link |
And it's moving fast in a very serious way
link |
that is rooted in labs with the right ethical framework
link |
and really building on solid science
link |
for what reality is and what is not.
link |
But it will go faster and it will be more and more powerful.
link |
We also have technology that allows us
link |
to basically study the properties of single cells
link |
across many, many millions of single cells,
link |
which we didn't have perhaps five years ago.
link |
So now with that, even an organoid
link |
that has millions of cells can be profiled in a way,
link |
looked at with very, very high resolution,
link |
the single cell level to really understand
link |
And you could do it in multiple stages of development
link |
and you can build your hypothesis and so on and so forth.
link |
So it's not gonna be a thousand years.
link |
It's gonna be a shorter amount of time.
link |
And I see this as sort of an exponential growth
link |
of this field enabled by these technologies
link |
that we didn't have before.
link |
And so we're gonna see something transformative
link |
that we didn't see at all in the prior thousand years.
link |
So I apologize for the crazy sci fi questions,
link |
but the developmental process is fascinating
link |
to watch and study, but how far are we away from
link |
and maybe how difficult is it to build
link |
not just an organoid, but a human brain from a stem cell?
link |
Yeah, first of all, that's not the goal
link |
for the majority of the serious scientists
link |
that work on this because you don't have to build
link |
the whole human brain to make this model useful
link |
for understanding how the brain develops
link |
or understanding disease.
link |
You don't have to build the whole thing.
link |
So let me just comment on this, fascinating.
link |
It shows to me the difference between you and I
link |
as you're actually trying to understand
link |
the beauty of the human brain and to use it
link |
to really help thousands or millions of people
link |
with disease and so on, right?
link |
From an artificial intelligence perspective,
link |
we're trying to build systems that we can put in robots
link |
and try to create systems that have echoes
link |
of the intelligence about reasoning about the world,
link |
navigating the world.
link |
It's different objectives, I think.
link |
Yeah, that's very much science fiction.
link |
Science fiction, but we operate in science fiction a little bit.
link |
So on that point of building a brain,
link |
even though that is not the focus or interest, perhaps,
link |
of the community, how difficult is it?
link |
Is it truly science fiction at this point?
link |
I think the field will progress, like I said,
link |
and that the system will be more and more complex
link |
But there are properties that emerge from the human brain
link |
that have to do with the mind,
link |
that may have to do with consciousness,
link |
that may have to do with intelligence or whatever
link |
that we really don't understand
link |
even how they can emerge from an actual, real brain.
link |
And therefore, we can now measure or study in an organoid.
link |
So I think that this field, many, many years from now,
link |
may lead to the building of better neural circuits
link |
that really are built out of understanding
link |
of how this process really works.
link |
And it's hard to predict how complex this really will be.
link |
I really don't think we're so far from,
link |
it makes me laugh, really.
link |
It's really that far from building the human brain.
link |
But you're gonna be building something
link |
that is always a bad version of it,
link |
but that may have really powerful properties
link |
and might be able to respond to stimuli
link |
or be used in certain context.
link |
And this is why I really think
link |
that there is no other way to do this science,
link |
but within the right ethical framework,
link |
because where you're going with this is also,
link |
we can talk about science fiction and write that book,
link |
and we could today,
link |
but this work happens in a specific ethical framework
link |
that we don't decide just as scientists,
link |
but also as a society.
link |
So the ethical framework here is a fascinating one,
link |
is a complicated one.
link |
Do you have a sense, a grasp
link |
of how we think about ethically of building organoids
link |
from human stem cells to understand the brain?
link |
It seems like a tool
link |
for helping potentially millions of people cure diseases
link |
or at least start the cure by understanding it.
link |
But is there more, is there gray areas
link |
that we have to think about ethically?
link |
We must think about that.
link |
Every discussion about the ethics of this
link |
needs to be based on actual data
link |
from the models that we have today
link |
and from the ones that we will have tomorrow.
link |
So it's a continuous conversation.
link |
It's not something that you decide now.
link |
Today, there is no issue really.
link |
Very simple models that clearly can help you in many ways
link |
without much think about,
link |
but tomorrow we need to have another conversation
link |
and so on and so forth.
link |
And so the way we do this
link |
is to actually really bring together constantly
link |
a group of people that are not only scientists,
link |
but also bioethicists, the lawyers, philosophers,
link |
psychiatrists and so on,
link |
psychologists and so on and so forth
link |
to decide as a society really what we should
link |
and what we should not do.
link |
So that's the way to think about the ethics.
link |
Now, I also think though, that as a scientist,
link |
I have a moral responsibility.
link |
So if you think about how transformative it could be
link |
for understanding and curing a neuropsychiatric disease,
link |
to be able to actually watch and study
link |
and treat with drugs the very brain
link |
of the patient that you are trying to study.
link |
How transformative at this moment in time this could be.
link |
We couldn't do it five years ago,
link |
we could do it now, right?
link |
If we didn't do it.
link |
Taking a stem cell of a particular patient.
link |
Patient and make an organoid for a simple
link |
and different from the human brain,
link |
it still is his process of brain development
link |
with his or her genetics.
link |
And we could understand perhaps what is going wrong.
link |
Perhaps we could use as a platform,
link |
as a cellular platform to screen for drugs,
link |
to fix a process and so on and so forth, right?
link |
So we could do it now, we couldn't do it five years ago.
link |
Should we not do it?
link |
What is the downside of doing it?
link |
I don't see a downside at this very moment.
link |
If we invited a lot of people,
link |
I'm sure there would be somebody who would argue against it.
link |
What would be the devil's advocate argument?
link |
So it's exactly perhaps what you alluded at
link |
with your question,
link |
that you are enabling some process of formation of the brain
link |
that could be misused at some point,
link |
or that could be showing properties
link |
that ethically we don't wanna see in a tissue.
link |
So today, I repeat, today, this is not an issue.
link |
And so you just gain dramatically from the science without,
link |
because the system is so simple and so different
link |
in a way from the actual brain.
link |
But because it is the brain,
link |
we have an obligation to really consider all of this, right?
link |
And again, it's a balanced conversation
link |
where we should put disease and betterment of humanity
link |
also on that plate.
link |
What do you think, at least historically,
link |
there was some politicization,
link |
politicization of embryonic stem cells,
link |
a stem cell research.
link |
Do you still see that out there?
link |
Is that still a force that we have to think about,
link |
especially in this larger discourse
link |
that we're having about the role of science
link |
in at least American society?
link |
Yeah, this is a very good question.
link |
It's very, very important.
link |
I see a very central role for scientists
link |
to inform decisions about what we should
link |
or should not do in society.
link |
And this is because the scientists
link |
have the firsthand look and understanding
link |
of really the work that they are doing.
link |
And again, this varies depending on
link |
what we're talking about here.
link |
So now we're talking about brain organoids.
link |
I think that the scientists need to be part
link |
of that conversation about what is,
link |
will be allowed in the future
link |
or not allowed in the future to do with the system.
link |
And I think that is very, very important
link |
because they bring the reality of data to the conversation.
link |
And so they should have a voice.
link |
So data should have a voice.
link |
Data needs to have a voice.
link |
Because in not only data,
link |
we should also be good at communicating
link |
with non scientists, the data.
link |
So there has been often time,
link |
there is a lot of discussion and, you know,
link |
excitement and fights about certain topics
link |
just because of the way they are described.
link |
I'll give you an example.
link |
If I called the same cellular system
link |
we just talked about a brain organoid,
link |
or if I called it a human mini brain,
link |
your reaction is gonna be very different to this.
link |
And so the way the systems are described,
link |
I mean, we and journalists alike need to be a bit careful
link |
that this debate is a real debate and informed by real data.
link |
That's all I'm asking.
link |
And yeah, the language matters here.
link |
So I work on autonomous vehicles
link |
and there the use of language
link |
could drastically change the interpretation
link |
and the way people feel about
link |
what is the right way to proceed forward.
link |
You are, as I've seen from a presentation, you're a parent.
link |
I saw you show a couple of pictures of your son.
link |
Is it just the one?
link |
Son and a daughter.
link |
Son and a daughter.
link |
So what have you learned from the human brain
link |
by raising two of them?
link |
More than I could ever learn in the lab.
link |
What have I learned?
link |
I've learned that children really have
link |
these amazing plastic minds, right?
link |
That we have a responsibility to, you know,
link |
foster their growth in good, healthy ways.
link |
That keep them curious, that keeps them adventurous,
link |
that doesn't raise them in fear of things.
link |
But also respecting who they are,
link |
which is in part, you know,
link |
coming from the genetics we talked about.
link |
My children are very different from each other
link |
despite the fact that they're the product of
link |
the same two parents.
link |
I also learned that what you do for them comes back to you.
link |
Like, you know, if you're a good parent,
link |
you're gonna, most of the time,
link |
have, you know, perhaps a decent kids at the end.
link |
So what do you think, just a quick comment,
link |
what do you think is the source of that difference?
link |
That's often the surprising thing for parents.
link |
Is that they can't believe that our kids,
link |
oh, they're so different,
link |
yet they came from the same parents.
link |
Well, they are genetically different.
link |
Even they came from the same two parents
link |
because the mixing of gametes,
link |
you know, we know this genetics,
link |
creates every time a genetically different individual,
link |
which will have a specific mix of genes
link |
that is a different mix every time from the two parents.
link |
And so they're not twins.
link |
They are genetically different.
link |
Even just that little bit of variation,
link |
because you said really from a biological perspective,
link |
the brains look pretty similar.
link |
Well, so let me clarify that.
link |
So the genetics you have, the genes that you have,
link |
that play that beautiful orchestrated symphony
link |
of development, different genes
link |
will play it slightly differently.
link |
It's like playing the same piece of music,
link |
but with a different orchestra and a different director.
link |
The music will not come out.
link |
It will be still a piece by the same author,
link |
but it will come out differently
link |
if it's played by the high school orchestra
link |
instead of the Scala in Milan.
link |
And so you are born superficially with the same brain.
link |
It has the same cell types,
link |
similar patterns of connectivity,
link |
but the properties of the cells
link |
and how the cells will then react to the environment
link |
as you experience your world will be also shaped
link |
by who genetically you are.
link |
Speaking just as a parent,
link |
this is not something that comes from my work.
link |
I think you can tell at birth that these kids are different,
link |
that they have a different personality in a way, right?
link |
So both is needed, the genetics,
link |
as well as the nurturing afterwards.
link |
So you are one human with a brain,
link |
sort of living through the whole mess of it,
link |
the human condition, full of love, maybe fear,
link |
ultimately mortal.
link |
How has studying the brain changed the way you see yourself?
link |
When you look in the mirror, when you think about your life,
link |
the fears, the love, when you see your own life,
link |
your own mortality.
link |
Yeah, that's a very good question.
link |
It's almost impossible to dissociate some time for me.
link |
Some of the things we do or some of the things
link |
that other people do from,
link |
oh, that's because that part of the brain
link |
is working in a certain way.
link |
Or thinking about a teenager,
link |
going through teenage years and being at time funny
link |
in the way they think.
link |
And impossible for me not to think it's because
link |
they're going through this period of time
link |
called critical periods of plasticity
link |
where their synapses are being eliminated here and there,
link |
and they're just confused.
link |
And so from that comes perhaps a different take
link |
on that behavior, or maybe I can justify it scientifically
link |
in some sort of way.
link |
I also look at humanity in general,
link |
and I am amazed by what we can do
link |
and the kind of ideas that we can come up with.
link |
And I cannot stop thinking about how the brain
link |
is continuing to evolve.
link |
I don't know if you do this,
link |
but I think about the next brain sometimes.
link |
Where are we going with this?
link |
Like, what are the features of this brain
link |
that evolution is really playing with
link |
to get us in the future, the new brain?
link |
It's not over, right?
link |
It's a work in progress.
link |
So let me just a quick comment on that.
link |
Do you think there's a lot of fascination
link |
and hope for artificial intelligence
link |
of creating artificial brains?
link |
You said the next brain.
link |
When you imagine over a period of a thousand years,
link |
the evolution of the human brain,
link |
do you sometimes envisioning that future
link |
see an artificial one, artificial intelligence,
link |
as it is hoped by many, not hoped,
link |
thought by many people would be actually
link |
the next evolutionary step in the development of humans?
link |
Yeah, I think in a way that will happen, right?
link |
It's almost like a part of the way we evolve.
link |
We evolve in the world that we created,
link |
that we interact with, that shape us as we grow up
link |
and so on and so forth.
link |
Sometime I think about something that may sound silly,
link |
but think about the use of cell phones.
link |
Part of me thinks that somehow in their brain,
link |
there will be a region of the cortex
link |
that is attuned to that tool.
link |
And this comes from a lot of studies
link |
in modern organisms where really the cortex,
link |
especially adapts to the kind of things you have to do.
link |
So if we need to move our fingers in a very specific way,
link |
we have a part of our cortex that allows us
link |
to do this kind of very precise movement.
link |
An owl that has to see very, very far away
link |
with big eyes, the visual cortex, very big.
link |
The brain attunes to your environment.
link |
So the brain will attune to the technologies
link |
that we will have and will be shaped by it.
link |
So the cortex very well may be.
link |
Will be shaped by it.
link |
In artificial intelligence, it may merge with it,
link |
it may get, envelop it and adjust.
link |
Even if it's not a merge of the kind of,
link |
oh, let's have a synthetic element together
link |
with a biological one.
link |
The very space around us, the fact, for example,
link |
think about we put on some goggles of virtual reality
link |
and we physically are surfing the ocean, right?
link |
Like I've done it.
link |
And you have all these emotions that come to you.
link |
Your brain placed you in that reality.
link |
And it was able to do it like that
link |
just by putting the goggles on.
link |
It didn't take thousands of years of adapting to this.
link |
The brain is plastic.
link |
So adapts to new technology.
link |
So you could do it from the outside
link |
by simply hijacking some sensory capacities that we have.
link |
So clearly over recent evolution,
link |
the cerebral cortex has been a part of the brain
link |
that has known the most evolution.
link |
So we have put a lot of chips
link |
on evolving this specific part of the brain.
link |
And the evolution of cortex is plasticity.
link |
It's this ability to change in response to things.
link |
So yes, they will integrate.
link |
That we want it or not.
link |
Well, there's no better way to end it, Paola.
link |
Thank you so much for talking today.
link |
You're very welcome.
link |
This is very exciting.