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How does the human brain build itself?
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How do circuits in the human brain
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wire together?
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For instance, how does one tiny neuron
in the outer layer of the brain
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send a thin axon
all the way to the spinal cord,
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find the right neuron
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and then control muscle contraction
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as we extend a hand
and grasp a glass of water?
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I'm here to tell you
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that we can finally grow
parts of the human brain
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from any individual
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and then build functioning human circuits
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in a laboratory cell culture dish.
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These clumps of neural tissue
are known as brain organoids.
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And when we put them together to form
circuits, they become “assembloids.”
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Assembloids could be key to understanding
how the human brain is built.
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Today, most of what we know
about the human brain
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comes from studies in animals,
typically mice.
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And while we've learned a lot
from these animal brains,
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the characteristics
that make the human brain unique,
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and uniquely susceptible to disease,
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remain mysterious.
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I’m a physician by training
and a professor at Stanford,
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where my laboratory has been taking
unconventional approaches
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to study how the human brain develops,
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how disorders in the human brain arise
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and find new ways of treatment.
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I think the best way to explain,
though, how we do this
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is through the eyes of one of my patients.
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When I opened my lab at Stanford,
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Eduard, who's on the autism spectrum,
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sent me this drawing
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depicting how he thought
we were studying brain disorders.
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Now to paraphrase him, he said,
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"What I think you're doing
is you're climbing up a ladder,
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poking holes in people's brains
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and then use tiny telescopes
to watch neural cells."
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Of course, that's not what we do.
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So I called him up, explained the process,
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and then the next morning
he sent me another drawing,
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which I think ended up
being a quite accurate representation
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of the work that we
and many others now are doing.
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Again, to paraphrase him, he said,
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"You're taking skin cells
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from patients that have
specific brain disorders,
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then doing some mumbo jumbo to the cells
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to push them back in time
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and turn them into stem cells."
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And then he knew that stem cells
can be coaxed to become any cell type.
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“So then you’re taking them
and turning them into brain cells
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that form brain circuits.”
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That's right. We can build
human brain circuits in a dish.
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How is that possible?
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Building on the hard work of biologists
over the past 15 years or so,
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we can today take any cell type
from any individual
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and then push it back in time
to turn them into stem cells
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and then guide those stem cells
to become any other cell type.
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We start by asking a patient
to provide a small skin sample.
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We then take those skin cells,
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reprogram them
by putting a series of genetic factors
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and push them back in time
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so that those skin cells
become stem cells.
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It's like cellular alchemy.
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These stem cells
have almost magical abilities
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to turn into any other cell type.
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So what do we do?
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We take the stem cells,
we dissociate them,
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we then aggregate them
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so that they form spheres
or tiny balls of cells.
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We then take those,
move them into a special plate
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where there is a kind of chemical soup.
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And that chemical soup
will allow them to grow
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and transform
and turn into a brain organoid.
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By providing different cues,
we can turn this brain organoid
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to resemble specific regions
of the central nervous system.
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For instance, we have a recipe
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that allows them
to become a cerebral cortex,
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the outer layer of the brain.
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By using a slightly different
combination of factors,
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we can turn them into a spinal cord.
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The secret to this process
is careful guidance.
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In the end, they look like this.
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Tiny clusters of brain cells
at the bottom of a dish.
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And let me be clear.
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This are not brains in a jar.
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(Laughter)
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These are parts of the nervous system
in a laboratory dish.
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Each of them contains millions of cells,
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and we can even listen
as they fire electrical signals.
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(Electrical signals firing)
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Or we can watch them
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as they sparkle with electrical activity.
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Or we can image inside and watch the cells
as they communicate with each other.
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Isn't it remarkable to think
that just a few months ago
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these cells were skin cells in a patient,
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and now they are neural cells
at the bottom of a dish
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that we can study at ease.
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(Applause)
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Thank you.
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So with these models of brain growth,
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we started wondering: Could we use them
to start to understand disease?
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So for instance, we wanted to know,
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could we understand how low oxygen
impacts the brains of premature babies?
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So to do this, we took brain organoids
and put them in a special incubator.
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We then lowered the concentration
of oxygen and watched them.
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We discovered something quite interesting.
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Only one specific cell type
was affected by the low oxygen.
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That cell type is responsible
for the expansion of the human cortex.
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We found exactly how that happens
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and even found the drug
that could prevent that process.
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These clumps of three-dimensional tissue
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can be grown in a dish for years.
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In fact, we've maintained
the longest cultures
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that have been reported to date,
going beyond 800 days.
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At nine to 10 months,
which is the equivalent of birth,
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they slowly transitioned, and they started
to resemble the postnatal brain.
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We have discovered a brain clock
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which keeps track of time
in a dish and outside of the uterus.
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Understanding the molecular mechanisms
that underlie this brain clock
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could be key to finding new strategies
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to either accelerate or decelerate
or rejuvenate human brain cells.
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The work that I've shown you so far
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is pioneering not just because
of what it teaches us
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about the human brain,
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but also because
of the frontiers of ethics.
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Organoids and assembloids
are not full replicas of the human brain.
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They're not brains in a jar.
They're not minibrain.
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They're not some stepping stone
to a Frankenstein monster.
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They have no blood flow,
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they receive no meaningful
inputs and outputs.
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But at one point,
they may become more complex.
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At one point, they may
receive sensory input.
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So as the science advances,
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we in the scientific community
have been very careful
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about discussing what are
some of the ethical questions,
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the societal implications
and potential regulations.
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Most of the work
that I’ve shown you so far
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has been in one specific brain region.
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But to really understand circuits,
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we actually need to build
more complicated brain circuits.
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And so to do this, six years ago,
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we came up with a new approach
to build human circuits
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called an assembloid.
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Assembloids are essentially
blocks of tissue
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that we build in a dish
from multiple organoids put together.
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When we put two brain organoids together,
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we discovered something
really fascinating.
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First, they fused to each other.
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But then they started to communicate,
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and brain cells from one side
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started to slowly migrate
onto the other side
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and form circuits,
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much like they would in the actual brain.
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In fact, we can even watch them live
as they move from one side to the other.
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I still remember how we were
in the lab in absolute awe
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when we saw for the first time
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how human cells undergo
this peculiar jumping behavior.
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This is all fascinating,
but what is it actually good for?
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Dysfunction in the human brain
causes brain disorders,
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such as autism and schizophrenia
and Alzheimer's disease,
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devastating conditions
that are poorly understood.
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Nearly one in five individuals
suffers from a psychiatric disease.
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What is even more striking
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is that the lowest success rate
for finding new drugs
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is in psychiatry,
out of all the branches of medicine,
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likely because until now
we couldn't really access the human brain.
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Using brain organoids and assembloids,
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we can create avatars
for a patient's brain development
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and then use those to dissect
the molecular mechanism of disease.
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Let me give you one example.
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As you have seen,
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assembloids can be used
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to model this healthy
jumping behavior of neurons.
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So what we did is we created assembloids
from patients with Timothy syndrome,
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which is a rare genetic disease
associated with autism and epilepsy.
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When we looked inside the assembloids,
we noticed something remarkable.
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The cells were moving much faster,
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but every time they would jump,
they would jump a shorter distance.
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So in the end, they would be left behind.
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Over the past six years
in extensive studies,
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we've actually dissected
the molecular mechanism of this defect
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and even found ways of restoring it.
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And we're excited to be moving towards
a potential therapeutic avenue
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in the next year or so.
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(Applause)
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The promise of organoids and assembloids
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is that they will slowly allow us
to gain new insights
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into the hidden biology
of the human brain.
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And by doing so,
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they could revolutionize the way we think
about human brain development, evolution,
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function and disease.
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So what's next?
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Well, to really be able to gain insight
into more complex brain disorders,
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we need to build more complex circuits.
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So in the last minute, let me show you
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the most complicated circuit
we have built to date.
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The circuit that controls
voluntary movement.
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To do this, we've created three organoids.
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One, shown here in purple,
that resembles the cortex.
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One, in yellow,
that resembles the spinal cord,
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and one, in red,
that resembles human muscle.
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We then put them together
and watched them fuse
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and noticed something really spectacular.
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Neurons on the cortical side
started extending axons,
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find spinal motor neurons
in the spinal side,
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connect with them,
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and then those farther project
and connect to muscle.
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When we put a light stimulus
on the cortical site,
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we noticed the muscle
on the opposite side contract.
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We have modeled for the first time
a human cortical motor pathway.
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(Applause)
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And let me be clear.
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These cells find each other.
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Unlike in engineering,
we don't have a master plan,
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we don't provide a plan
because the human brain builds itself.
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And then in itself,
it's a remarkable opportunity
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to try to reverse engineer
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what are some of the steps
that underlie human brain development?
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I know that this all sounds
science fiction,
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but we now do this routinely in the lab.
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We have derived thousands and thousands
of organoids and assembloids
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from patients with various
neuropsychiatric diseases,
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including, for instance,
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infecting them with viruses
such as polio virus
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to understand how diseases arise.
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The statistician George Box famously said,
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"All models are wrong,
but some are useful."
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(Laughter)
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I do the work that I do
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because the promise and hope
of brain assembloids and organoids
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is that by allowing us
to recreate circuits of the human brain,
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we will gain new insights
into human biology.
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And this in itself will open a new era
in the treatment of brain disorders.
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Thank you.
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(Applause)
