How We're Reverse Engineering the Human Brain in the Lab | Sergiu P. Pasca | TED

Translator: Javier Varela Reviewer: Servizo de Normalización Lingüística

How does the human brain build itself?

Como se constrúe o cerebro humano?

How do circuits in the human brain

Como se conectan os circuítos no cerebro?

wire together?

For instance, how does one tiny neuron in the outer layer of the brain

Por exemplo, como unha pequena neurona na capa externa do cerebro

send a thin axon all the way to the spinal cord,

envía un delgado axón ata a medula espiñal,

find the right neuron

atopa a neurona adecuada

and then control muscle contraction

e controla a contracción muscular

as we extend a hand and grasp a glass of water?

mentres estendemos a man e collemos un vaso de auga?

I'm here to tell you

Estou aquí para dicirvos

that we can finally grow parts of the human brain

que por fin podemos cultivar partes do cerebro humano

from any individual

de calquera individuo

and then build functioning human circuits

e construír circuítos humanos funcionais

in a laboratory cell culture dish.

nunha placa de cultivo do laboratorio.

These clumps of neural tissue are known as brain organoids.

Estes grupos de tecido neural coñécense como organoides cerebrais

And when we put them together to form circuits, they become “assembloids.”

e, ao xuntalos para formar circuítos, convértense en “asembloides”.

Assembloids could be key to understanding how the human brain is built.

Os asembloides serían clave para entender a construción do cerebro humano.

Today, most of what we know about the human brain

Actualmente, a maioría do que sabemos sobre o cerebro

comes from studies in animals, typically mice.

vén de estudos en animais, xeralmente ratos.

And while we've learned a lot from these animal brains,

E aínda que aprendemos moito dos cerebros destes animais,

the characteristics that make the human brain unique,

as características que fan único o cerebro humano

and uniquely susceptible to disease,

e máis susceptible ás enfermidades,

remain mysterious.

seguen sendo descoñecidas.

I’m a physician by training and a professor at Stanford,

Son médico de profesión e profesor en Stanford,

where my laboratory has been taking unconventional approaches

onde o meu laboratorio adoptou enfoques pouco convencionais

to study how the human brain develops,

para estudar o desenvolvemento do cerebro,

how disorders in the human brain arise

como xorden os trastornos mentais

and find new ways of treatment.

e atopar novos tratamentos.

I think the best way to explain, though, how we do this

Creo que a mellor maneira de explicar como facemos isto

is through the eyes of one of my patients.

é por medio dun dos meus pacientes.

When I opened my lab at Stanford,

Cando abrín o meu laboratorio en Stanford,

Eduard, who's on the autism spectrum,

Eduard, que ten autismo,

sent me this drawing

envioume este debuxo

depicting how he thought we were studying brain disorders.

no que describe como pensaba que estudabamos os trastornos cerebrais.

Now to paraphrase him, he said,

Nas súas propias palabras, dixo:

"What I think you're doing is you're climbing up a ladder,

“O que creo que fas é que sobes unha escaleira,

poking holes in people's brains

furando o cerebro da xente

and then use tiny telescopes to watch neural cells."

e logo usades telescopios diminutos para observar as células neuronais”.

Of course, that's not what we do.

Loxicamente, non é o que facemos.

So I called him up, explained the process,

Chameino e expliqueille o proceso,

and then the next morning he sent me another drawing,

e á mañá seguinte envioume outro debuxo,

which I think ended up being a quite accurate representation

que terminou sendo unha representación próxima

of the work that we and many others now are doing.

do traballo que nós e moitos outros facemos agora.

Again, to paraphrase him, he said,

De novo, nas súas palabras, dixo:

"You're taking skin cells

“Estás a extraer células da pel

from patients that have specific brain disorders,

de pacientes con trastornos cerebrais específicos

then doing some mumbo jumbo to the cells

e facendo cousas raras ás células

to push them back in time

para facelas retroceder no tempo

and turn them into stem cells."

e convertelas en células nai”.

And then he knew that stem cells can be coaxed to become any cell type.

E entón decatouse de que as células nai poden converterse en calquera célula.

“So then you’re taking them and turning them into brain cells

“Así que as colles e convértelas en células cerebrais

that form brain circuits.”

que forman circuítos cerebrais”.

That's right. We can build human brain circuits in a dish.

Exacto. Construímos circuítos cerebrais nun recipiente.

How is that possible?

Como é posible?

Building on the hard work of biologists over the past 15 years or so,

Partindo do duro traballo dos biólogos dos últimos 15 anos,

we can today take any cell type from any individual

hoxe podemos tomar células dun individuo,

and then push it back in time to turn them into stem cells

facelas retroceder no tempo e convertelas en células nai

and then guide those stem cells to become any other cell type.

e guialas para transformalas noutro tipo de célula.

We start by asking a patient to provide a small skin sample.

Comezamos pedindo ao paciente unha pequena mostra de pel.

We then take those skin cells,

Logo tomamos esas células cutáneas,

reprogram them by putting a series of genetic factors

reprogramámolas introducindo factores xenéticos

and push them back in time

e facémolas volver atrás

so that those skin cells become stem cells.

para que esas células da pel se convertan en células nai.

It's like cellular alchemy.

É como alquimia celular.

These stem cells have almost magical abilities

Estas células nai teñen capacidades case máxicas

to turn into any other cell type.

para converterse noutro tipo de célula.

So what do we do?

Entón, que facemos?

We take the stem cells, we dissociate them,

Tomamos as células nai, disociámolas

we then aggregate them

e acumulámolas

so that they form spheres or tiny balls of cells.

de modo que formen esferas ou pequenas bólas de células.

We then take those, move them into a special plate

Entón collémolas e movémolas a unha placa especial

where there is a kind of chemical soup.

onde hai unha especie de sopa química.

And that chemical soup will allow them to grow

E esa sopa química permitiralles crecer

and transform and turn into a brain organoid.

e transformarse nun organoide cerebral.

By providing different cues, we can turn this brain organoid

Proporcionando diferentes estímulos, podemos converter este organoide cerebral

to resemble specific regions of the central nervous system.

para que se pareza a certas rexións do sistema nervioso central.

For instance, we have a recipe

Por exemplo, temos unha fórmula

that allows them to become a cerebral cortex,

que lles permite converterse en cortiza cerebral,

the outer layer of the brain.

a capa externa do cerebro.

By using a slightly different combination of factors,

Empregando unha combinación de factores,

we can turn them into a spinal cord.

podemos convertelas en medula espiñal.

The secret to this process is careful guidance.

O segredo deste proceso é unha minuciosa supervisión.

In the end, they look like this.

Ao final, quedan así.

Tiny clusters of brain cells at the bottom of a dish.

Pequenos grupos de células cerebrais no fondo dunha placa.

And let me be clear.

E permitídeme ser claro:

This are not brains in a jar.

non son cerebros nun tarro.

(Laughter)

(Risas)

These are parts of the nervous system in a laboratory dish.

Estas son partes do sistema nervioso nunha placa de laboratorio.

Each of them contains millions of cells,

Cada unha delas contén millóns de células,

and we can even listen as they fire electrical signals.

e mesmo podemos escoitar mentres emiten impulsos eléctricos.

(Electrical signals firing)

(Son dos impulsos eléctricos)

Or we can watch them

Ou podemos velas

as they sparkle with electrical activity.

mentres chispean coa actividade eléctrica.

Or we can image inside and watch the cells as they communicate with each other.

Ou visualizar o interior e ver as células mentres se comunican entre si.

Isn't it remarkable to think that just a few months ago

Non é sorprendente que hai só uns meses

these cells were skin cells in a patient,

fosen células da pel dun paciente

and now they are neural cells at the bottom of a dish

e agora sexan células neuronais no fondo dunha placa

that we can study at ease.

que podemos estudar tranquilamente?

(Applause)

(Aplausos)

Thank you.

Grazas.

So with these models of brain growth,

Cos modelos do desenvolvemento cerebral,

we started wondering: Could we use them to start to understand disease?

preguntámonos: poderiamos usalos para entender as enfermidades?

So for instance, we wanted to know,

Por exemplo, queriamos saber

could we understand how low oxygen impacts the brains of premature babies?

como afecta a falta de osíxeno ao cerebro dos bebés prematuros,

So to do this, we took brain organoids and put them in a special incubator.

polo que collemos organoides cerebrais e puxémolos nunha incubadora especial.

We then lowered the concentration of oxygen and watched them.

Logo baixamos a concentración de osíxeno e observámolos.

We discovered something quite interesting.

Descubrimos algo moi interesante.

Only one specific cell type was affected by the low oxygen.

Só un tipo específico de célula se viu afectada pola falta de osíxeno.

That cell type is responsible for the expansion of the human cortex.

Ese tipo de célula é responsable da expansión do córtex humano.

We found exactly how that happens

Descubrimos exactamente como sucede

and even found the drug that could prevent that process.

e mesmo atopamos o fármaco que podería previr ese proceso.

These clumps of three-dimensional tissue

Estes grupos de tecido tridimensional

can be grown in a dish for years.

poden cultivarse nunha placa durante anos.

In fact, we've maintained the longest cultures

De feito, mantivemos os cultivos máis lonxevos

that have been reported to date, going beyond 800 days.

que se coñecían ata a data, indo máis aló dos 800 días.

At nine to 10 months, which is the equivalent of birth,

Aos nove ou dez meses, que é o equivalente ao nacemento,

they slowly transitioned, and they started to resemble the postnatal brain.

cambiaron lentamente e empezaron a parecerse ao cerebro posnatal.

We have discovered a brain clock

Atopamos un mecanismo cerebral

which keeps track of time in a dish and outside of the uterus.

que rexistra o paso do tempo nunha placa e fóra do útero.

Understanding the molecular mechanisms that underlie this brain clock

Entender os mecanismos moleculares que subxacen a este reloxo cerebral

could be key to finding new strategies

podería revelar novas estratexias

to either accelerate or decelerate or rejuvenate human brain cells.

para acelerar ou frear ou rexuvenecer células cerebrais humanas.

The work that I've shown you so far

O traballo que vos mostrei ata agora

is pioneering not just because of what it teaches us

é pioneiro non só polo que nos ensina

about the human brain,

do cerebro humano,

but also because of the frontiers of ethics.

senón tamén polas fronteiras éticas.

Organoids and assembloids are not full replicas of the human brain.

Os organoides e asembloides non son réplicas do cerebro humano.

They're not brains in a jar. They're not minibrain.

Non son cerebros nun tarro. Non son minicerebros.

They're not some stepping stone to a Frankenstein monster.

Non son un chanzo cara a un monstro de Frankenstein.

They have no blood flow,

Non teñen rega sanguínea,

they receive no meaningful inputs and outputs.

non reciben información significativa ningunha.

But at one point, they may become more complex.

Chegará un momento en que poidan ser máis complexos.

At one point, they may receive sensory input.

Nun momento dado, pode que reciban información sensorial.

So as the science advances,

A medida que avanza a ciencia,

we in the scientific community have been very careful

na comunidade científica fomos moi coidadosos

about discussing what are some of the ethical questions,

ao debater sobre algunhas das cuestións éticas,

the societal implications and potential regulations.

as implicacións sociais e as posibles normativas.

Most of the work that I’ve shown you so far

A maior parte do traballo mostrado ata agora

has been in one specific brain region.

foi nunha rexión específica do cerebro.

But to really understand circuits,

Pero para comprender os circuítos,

we actually need to build more complicated brain circuits.

en realidade necesitamos construír circuítos cerebrais máis complicados.

And so to do this, six years ago,

E para iso, hai seis anos,

we came up with a new approach to build human circuits

ocorréusenos unha nova forma para crear circuítos humanos

called an assembloid.

chamada asembloide.

Assembloids are essentially blocks of tissue

Os asembloides son esencialmente bloques de tecido

that we build in a dish from multiple organoids put together.

que construímos nunha placa a partir de múltiples organoides xuntos.

When we put two brain organoids together,

Ao xuntar dous organoides cerebrais,

we discovered something really fascinating.

descubrimos algo apaixonante.

First, they fused to each other.

Primeiro, fusionáronse entre si.

But then they started to communicate,

Pero logo empezaron a comunicarse,

and brain cells from one side

e as células cerebrais dun lado

started to slowly migrate onto the other side

comezaron a migrar lentamente cara ao outro lado

and form circuits,

e a formar circuítos,

much like they would in the actual brain.

como farían nun cerebro real.

In fact, we can even watch them live as they move from one side to the other.

De feito, ata podemos velas en directo mentres se desprazan dun lado a outro.

I still remember how we were in the lab in absolute awe

Recordo como estabamos no laboratorio de asombrados

when we saw for the first time

cando vimos por primeira vez

how human cells undergo this peculiar jumping behavior.

como as células humanas experimentaban este curioso comportamento

This is all fascinating, but what is it actually good for?

É fascinante, pero para que serve realmente?

Dysfunction in the human brain causes brain disorders,

A disfunción do cerebro humano provoca trastornos cerebrais,

such as autism and schizophrenia and Alzheimer's disease,

como o autismo, esquizofrenia e a enfermidade do alzhéimer,

devastating conditions that are poorly understood.

enfermidades devastadoras que non se coñecen ben.

Nearly one in five individuals suffers from a psychiatric disease.

Case un de cada cinco individuos padece unha enfermidade psiquiátrica.

What is even more striking

E o que é máis sorprendente

is that the lowest success rate for finding new drugs

é que a taxa de éxito máis baixa para descubrir fármacos

is in psychiatry, out of all the branches of medicine,

de entre todas as ramas da medicina é en psiquiatría,

likely because until now we couldn't really access the human brain.

probablemente porque non podiamos acceder ao cerebro humano.

Using brain organoids and assembloids,

Usando organoides e asembloides cerebrais,

we can create avatars for a patient's brain development

podemos crear avatares do desenvolvemento cerebral dun paciente

and then use those to dissect the molecular mechanism of disease.

e utilizalos para estudar o mecanismo molecular da enfermidade.

Let me give you one example.

Dareivos un exemplo.

As you have seen,

Como vistes,

assembloids can be used

os asembloides poden empregarse

to model this healthy jumping behavior of neurons.

para modelar este san comportamento de salto das neuronas.

So what we did is we created assembloids from patients with Timothy syndrome,

O que fixemos foi crear asembloides de pacientes con síndrome de Timothy,

which is a rare genetic disease associated with autism and epilepsy.

unha enfermidade xenética rara, asociada ao autismo e á epilepsia.

When we looked inside the assembloids, we noticed something remarkable.

Cando miramos dentro dos asembloides, démonos conta de algo.

The cells were moving much faster,

As células movíanse moito máis rápido,

but every time they would jump, they would jump a shorter distance.

pero cada vez saltaban unha distancia máis curta.

Ao final, quedarían atrás.

So in the end, they would be left behind.

Over the past six years in extensive studies,

Nos últimos seis anos de amplos estudos,

we've actually dissected the molecular mechanism of this defect

analizamos o mecanismo molecular deste defecto

and even found ways of restoring it.

e mesmo atopamos formas de restauralo.

And we're excited to be moving towards a potential therapeutic avenue

Emociónanos avanzar cara a unha posible vía terapéutica

in the next year or so.

o próximo ano.

(Applause)

(Aplausos)

The premise of organoids and assembloids

A aposta polos organoides e os asembloides

is that they will slowly allow us to gain new insights

é que pouco a pouco permitiranos adquirir coñecementos

into the hidden biology of the human brain.

da bioloxía oculta do cerebro humano

And by doing so,

e, ao facelo,

they could revolutionize the way we think about human brain development, evolution,

revolucionar o modo de pensar sobre o cerebro humano e a súa evolución,

function and disease.

funcionamento e enfermidades.

So what's next?

Que é o seguinte?

Well, to really be able to gain insight into more complex brain disorders,

Para ser capaz de gañar unha visión en desordes cerebrais máis complexos,

we need to build more complex circuits.

debemos construír circuítos complexos.

So in the last minute, let me show you

Así que, deixádeme que vos mostre

the most complicated circuit we have built to date.

o circuíto máis complicado que construímos ata a data,

The circuit that controls voluntary movement.

o circuíto que controla o movemento voluntario.

To do this, we've created three organoids.

Para iso, creamos tres organoides.

One, shown here in purple, that resembles the cortex.

Un, aquí en púrpura, aseméllase ao córtex;

One, in yellow, that resembles the spinal cord,

outro, en amarelo, parécese á medula espiñal,

and one, in red, that resembles human muscle.

e outro, en vermello, que se asemella ao tecido muscular.

We then put them together and watched them fuse

Logo xuntámolos, vimos como se unían

and noticed something really spectacular.

e observamos algo espectacular.

Neurons on the cortical side started extending axons,

As neuronas do lado cortical comezaron a espallar axóns,

find spinal motor neurons in the spinal side,

a atopar neuronas motoras espiñais na columna vertebral,

connect with them,

a conectar con elas,

e as máis afastadas estendéronse e conéctáronse ao músculo.

and then those farther project and connect to muscle.

When we put a light stimulus on the cortical site,

Cando aplicamos un lixeiro estímulo na área cortical,

we noticed the muscle on the opposite side contract.

notamos que o músculo do lado oposto se contraía.

We have modeled for the first time a human cortical motor pathway.

Fixemos por primeira vez unha vía motora cortical humana.

(Applause)

(Aplausos)

And let me be clear.

Serei claro:

These cells find each other.

estas células atópanse entre si.

Unlike in engineering, we don't have a master plan,

A diferenza da enxeñería, non temos ningún plano,

we don't provide a plan because the human brain builds itself.

non proporcionamos un plano porque o cerebro humano créase a si mesmo.

And then in itself, it's a remarkable opportunity

Por si soa, é unha oportunidade extraordinaria

to try to reverse engineer

para facer enxeñería inversa

what are some of the steps that underlie human brain development?

dos pasos que constitúen a base do cerebro humano.

I know that this all sounds science fiction,

Sei que todo isto soa a ciencia ficción,

but we now do this routinely in the lab.

pero xa o facemos no laboratorio.

We have derived thousands and thousands of organoids and assembloids

Creamos miles de organoides e asembloides

from patients with various neuropsychiatric diseases,

de pacientes con enfermidades neuropsiquiátricas

including, for instance,

como, por exemplo,

infecting them with viruses such as polio virus

infectándoos con virus como o da polio para entender a orixe das enfermidades.

to understand how diseases arise.

The statistician George Box famously said,

O famoso estadista George Box dixo:

"All models are wrong, but some are useful."

“Todos os modelos son erróneos, pero algúns son útiles”.

(Laughter)

(Risas)

Fago o traballo que fago

I do the work that I do

because the promise and hope of brain assembloids and organoids

pola promesa e a esperanza de que os asembloides e organoides,

is that by allowing us to recreate circuits of the human brain,

ao permitirnos recrear circuítos do cerebro humano,

we will gain new insights into human biology.

nos permitan obter información da bioloxía humana.

And this in itself will open a new era in the treatment of brain disorders.

Isto abrirá unha nova era no tratamento dos trastornos cerebrais.

Thank you.

Moitas grazas.

(Applause)

(Aplausos)