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

翻译人员: Shuhui Huang 校对人员: Yip Yan Yeung

How does the human brain build itself?

大脑是如何形成的？

How do circuits in the human brain

人类大脑里的回路

wire together?

是如何互相连接的？

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

举个例子，一个微小的神经元 是如何从大脑外层

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

把一个细细的轴突 一路送到脊髓，

find the right neuron

找到对应的神经元

and then control muscle contraction

来控制肌肉的伸缩，

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

从而使我们能够 伸手拿到一瓶水的？

I'm here to tell you

今天我站在这里告诉你

that we can finally grow parts of the human brain

我们终于可以从任何人身上 培育出部分人类大脑了，

from any individual

and then build functioning human circuits

而且可以在实验室细胞培养皿中

in a laboratory cell culture dish.

以此建立功能正常的人体回路。

These clumps of neural tissue are known as brain organoids.

这一团团的神经组织， 就是所谓的大脑类器官。

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

而当它们被放到一起形成回路， 就形成了“类组装体”。

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

类组装体可能是 认识人脑组成的关键。

Today, most of what we know about the human brain

如今大部分我们知道的 有关人脑的知识都

comes from studies in animals, typically mice.

来自于对动物的研究， 尤其是老鼠。

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

虽然动物大脑让我们知道了很多，

the characteristics that make the human brain unique,

但那些让人脑独特

and uniquely susceptible to disease,

且易患疾病的特征，

remain mysterious.

仍是个谜。

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

我是一名受过培训的医生， 也是斯坦福大学的教授。

where my laboratory has been taking unconventional approaches

我的实验室一直在采用 非常规的方法，

to study how the human brain develops,

来研究人类大脑的发育过程、

how disorders in the human brain arise

人脑疾病的形成，

and find new ways of treatment.

并寻找新的治疗方法。

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

不过我觉得， 解释我们的做法的最好办法

is through the eyes of one of my patients.

是透过我的一位患者的眼睛来看。

When I opened my lab at Stanford,

当我在斯坦福开设实验室时，

Eduard, who's on the autism spectrum,

爱德华（Eduard）， 一位自闭症患者，

sent me this drawing

给我看了这副画，

depicting how he thought we were studying brain disorders.

画的是他以为的 我们研究大脑疾病的方式。

Now to paraphrase him, he said,

他当时的意思就是说，

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

“我以为你们是爬上了一个梯子，

poking holes in people's brains

然后在人们脑子里钻洞，

and then use tiny telescopes to watch neural cells."

再用迷你显微镜 去观察神经细胞。”

Of course, that's not what we do.

那我们当然不是这么干的。

So I called him up, explained the process,

所以我给他打了个电话， 并解释了整个过程。

and then the next morning he sent me another drawing,

所以第二天早上 他给我发了另一幅画，

which I think ended up being a quite accurate representation

这副画我觉得 就相当精确地描述了

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

我们与业界其他人在做的事情。

Again, to paraphrase him, he said,

复述一下他说的就是，

"You're taking skin cells

“从患有特定脑部疾病的患者身上，

from patients that have specific brain disorders,

你们提取了皮肤细胞，

then doing some mumbo jumbo to the cells

然后搞一些高深莫测的魔法，

to push them back in time

让这些细胞的时间倒退

and turn them into stem cells."

而成为干细胞。”

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

他知道干细胞可以被诱导成 任何类型的细胞。

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

“最后你们就把这些干细胞 变成了脑细胞，

that form brain circuits.”

再把脑细胞组成脑回路。”

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

没错，我们可以在一个小碟子里 建造人类的脑回路。

How is that possible?

这怎么可能的？

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

多亏了生物学家们 在过去十五年里的努力研究，

we can today take any cell type from any individual

如今我们可以提取任何人的 任何类型的细胞，

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

逆转这些细胞的时间， 把它们倒推回干细胞，

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

最后引导这些干细胞成为 任何其他类型的细胞。

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

患者先会提供一个 小的皮肤样本，

We then take those skin cells,

我们从中提取出皮肤细胞，

reprogram them by putting a series of genetic factors

向其注入一系列遗传因子 从而重新编码，

and push them back in time

逆转时间，

so that those skin cells become stem cells.

这些皮肤细胞就成为干细胞了。

It's like cellular alchemy.

就像是细胞炼金术一样。

These stem cells have almost magical abilities

这些干细胞有着神奇的能力，

to turn into any other cell type.

可以变成任何细胞类型。

So what do we do?

所以我们是怎么做的呢？

We take the stem cells, we dissociate them,

我们把这个干细胞

we then aggregate them

分离再聚合，

so that they form spheres or tiny balls of cells.

让它们变成球形， 或是像小球一样的细胞。

We then take those, move them into a special plate

再放入一个 盛有化学汤剂的特质的盘中。

where there is a kind of chemical soup.

And that chemical soup will allow them to grow

这种化学汤剂可以让干细胞

and transform and turn into a brain organoid.

生长成为大脑类器官。

By providing different cues, we can turn this brain organoid

通过不同的刺激信号， 我们可以让这个大脑类器官

to resemble specific regions of the central nervous system.

变得类似于 中枢神经系统的特定区域。

For instance, we have a recipe

举个例子，我们有一个配方

that allows them to become a cerebral cortex,

可以让它们成为大脑皮层组织，

the outer layer of the brain.

就是大脑的外层。

By using a slightly different combination of factors,

稍微换一换配方，

we can turn them into a spinal cord.

我们可以把它们变成脊髓。

The secret to this process is careful guidance.

最重要的因素， 就是严谨仔细的引导。

In the end, they look like this.

最后，它们看起来就是这样。

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

在碟子底部 一簇簇的微小脑细胞。

And let me be clear.

话说在前头，

This are not brains in a jar.

这可不是缸中之脑。

(Laughter)

（观众笑）

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

这些是在一个实验室培养皿里的 神经系统的一部分。

Each of them contains millions of cells,

每一个都含有数百万个细胞。

and we can even listen as they fire electrical signals.

我们甚至能听到它们发射电信号。

(Electrical signals firing)

（电信号发射声）

Or we can watch them

我们也可以看着它们

as they sparkle with electrical activity.

迸射出电信号的火花。

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

我们还可以看到 细胞互相交流的图像。

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

光是想象一下就不可思议： 在几个月之前，

these cells were skin cells in a patient,

这些只是一位患者的皮肤细胞，

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

现在就成为了培养皿中 供人研究的神经细胞。

that we can study at ease.

(Applause)

（鼓掌）

Thank you.

谢谢。

So with these models of brain growth,

有了这些大脑生长的模型，

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

我们就开始畅想， 也许我们可以用它们来了解疾病？

So for instance, we wanted to know,

举个例子，我们想要知道

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

低氧量是如何影响早产儿的大脑的？

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

为此，我们将大脑类器官 放入一个特殊的培养箱中。

We then lowered the concentration of oxygen and watched them.

然后在降低氧气浓度的同时 进行观察。

We discovered something quite interesting.

我们观察到了 一个很有趣的现象。

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

只有一种特定的细胞类型 被低氧浓度影响了。

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

这种细胞负责的是 人类大脑皮层的扩张。

We found exactly how that happens

我们不仅知道了它是如何发生的，

and even found the drug that could prevent that process.

甚至找到了 可以阻止这个过程发生的药品。

These clumps of three-dimensional tissue

这一团团三维的细胞组织

can be grown in a dish for years.

可以在培养皿里生长数年。

In fact, we've maintained the longest cultures

事实上，我们保持着迄今为止 最长培养时间的纪录，

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

超过 800 天。

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

在九到十个月的时候， 差不多是胎儿孕育的时长，

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

这些脑细胞慢慢开始变化， 开始变得像胎儿出生后的大脑。

We have discovered a brain clock

我们发现了一个大脑时钟，

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

这个时钟在培养皿或子宫之外， 都记录着时间。

Understanding the molecular mechanisms that underlie this brain clock

了解构成这种脑时钟的分子机制

could be key to finding new strategies

可能是找到加速、减慢或复原

to either accelerate or decelerate or rejuvenate human brain cells.

人类脑细胞的新策略的关键。

The work that I've shown you so far

目前为止我刚刚展示的成果

is pioneering not just because of what it teaches us

是非常开创性的， 不仅是因为我们能以此研究大脑，

about the human brain,

but also because of the frontiers of ethics.

也是因为它代表了伦理学的前沿。

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

类器官和类组装体 并不是人类大脑的完整复制品。

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

它们不是缸中之脑， 也不是迷你脑。

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

它们不是制造科学怪人的垫脚石。

They have no blood flow,

它们没有血液，

they receive no meaningful inputs and outputs.

并不接受或释放有意义的信号。

But at one point, they may become more complex.

但它们可能会在某一个时间点 变得更复杂。

At one point, they may receive sensory input.

在某个时刻，它们可能会收到感官信号。

So as the science advances,

所以在科学发展的同时，

we in the scientific community have been very careful

我们科学界也在非常认真地讨论着

about discussing what are some of the ethical questions,

一些伦理问题、社会影响 和潜在法规。

the societal implications and potential regulations.

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

我已经向你们展示的这些成果

has been in one specific brain region.

目前只是在某一个大脑区域。

But to really understand circuits,

但为了真正理解脑回路，

we actually need to build more complicated brain circuits.

我们确实需要建造更复杂的脑回路。

And so to do this, six years ago,

为此，六年前，

we came up with a new approach to build human circuits

我们想到了一个 建造人类脑回路的新办法，

called an assembloid.

叫做类组装体。

Assembloids are essentially blocks of tissue

类组装体本质上就是

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

我们在培养皿中 用多个类器官构建的组织块。

When we put two brain organoids together,

当我们把两个大脑类器官放在一起，

we discovered something really fascinating.

我们发现了非常特别的事。

First, they fused to each other.

首先，它们彼此融合了起来。

But then they started to communicate,

然后它们开始了互相交流，

and brain cells from one side

一边的大脑细胞开始 慢慢地向另一边移动，

started to slowly migrate onto the other side

and form circuits,

并形成了脑回路，

much like they would in the actual brain.

就像它们在真正的大脑里那样。

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

事实上，我们甚至可以实时看着 它们从一边移动到另一边。

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

我还记得当时 我们是怎样带着无比的敬畏，

when we saw for the first time

第一次看着人类的细胞 进行这种奇特的跳跃行为。

how human cells undergo this peculiar jumping behavior.

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

这一切都看起来非常有趣。 但它实际上有什么用呢？

Dysfunction in the human brain causes brain disorders,

人脑功能障碍会导致脑部疾病，

such as autism and schizophrenia and Alzheimer's disease,

例如自闭症、精神分裂症 和阿尔茨海默病，

devastating conditions that are poorly understood.

我们对这些可怕的疾病知之甚少。

Nearly one in five individuals suffers from a psychiatric disease.

每五个人里， 就有一个患有某种精神疾病。

What is even more striking

而更惊人的是，

is that the lowest success rate for finding new drugs

在所有医药分支中，

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

寻找精神病新药的成功率是最低的。

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

很有可能是因为直到现在， 我们都无法真正接触到人类大脑。

Using brain organoids and assembloids,

通过大脑类器官和类组装体，

we can create avatars for a patient's brain development

我们可以为患者的大脑发育过程 创建许多副本，

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

然后使用这些副本 来剖析疾病的分子机制。

Let me give you one example.

让我来举个例子。

As you have seen,

你们已经看到了，

assembloids can be used

类组装体可以被用来

to model this healthy jumping behavior of neurons.

模拟神经元的 这种正常的跳跃行为。

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

而我们创建了长QT综合症患者的 大脑类组装体。

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

这是一种少见的遗传疾病， 经常伴随有自闭症和癫痫发作。

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

当我们仔细观察这些类组装体， 我们发现了很了不起的事。

The cells were moving much faster,

细胞的移动速度 要比正常的快很多，

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

但它们每一次跳跃的距离， 都要短很多。

So in the end, they would be left behind.

所以最后，它们就会落在后面。

Over the past six years in extensive studies,

在过去六年的全面研究中，

we've actually dissected the molecular mechanism of this defect

我们剖析了 造成这种缺陷的分子机制，

and even found ways of restoring it.

甚至找到了修复它的方法。

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

我们很高兴能在未来一年左右

in the next year or so.

找到潜在的治疗方法。

(Applause)

（观众鼓掌）

The premise of organoids and assembloids

类器官和类组装体的前景在于

is that they will slowly allow us to gain new insights

它们将让我们慢慢地 对隐藏在人类大脑内部的生物学

into the hidden biology of the human brain.

获得新的见解。

And by doing so,

而这就有可能

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

颠覆我们对人类大脑的了解， 包括其发展、进化、功能和疾病。

function and disease.

So what's next?

那下一步是什么呢？

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

那就是， 为了了解更复杂的大脑疾病，

we need to build more complex circuits.

我们需要构建更复杂的回路。

So in the last minute, let me show you

那么在这最后一分钟， 让我来向你们展示，

the most complicated circuit we have built to date.

至今为止我们构建的 最复杂的大脑回路。

The circuit that controls voluntary movement.

一个控制自主运动的回路。

To do this, we've created three organoids.

为此我们创造了三个类器官。

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

一个在此处用紫色表示， 类似大脑皮质。

One, in yellow, that resembles the spinal cord,

一个用黄色表示， 类似于脊髓。

and one, in red, that resembles human muscle.

还有一个用红色表示， 类似于人类的肌肉。

We then put them together and watched them fuse

我们把它们三个放在一起， 并看着它们融合起来，

and noticed something really spectacular.

并注意到了一些 非常惊人的现象。

Neurons on the cortical side started extending axons,

皮质部分的神经元 开始伸长轴突，

find spinal motor neurons in the spinal side,

在脊髓部分找到了 脊髓运动神经元，

connect with them,

与它们连接，

and then those farther project and connect to muscle.

然后向更远处投射 并连接到了肌肉部分。

When we put a light stimulus on the cortical site,

当我们用灯光 对皮质部位施加刺激时，

we noticed the muscle on the opposite side contract.

我们注意到 另一边的肌肉进行了收缩。

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

我们模拟了历史上的首次 人类皮质运动通路。

(Applause)

（鼓掌）

And let me be clear.

让我先澄清一下。

These cells find each other.

这些细胞是自己找到彼此的。

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

与建造工程不同， 我们没有一个大致规划，

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

不提供规划是因为， 人类大脑会建造它自己。

And then in itself, it's a remarkable opportunity

然后就其本身而言， 这是一个绝佳的机会，

to try to reverse engineer

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

用逆向工程来发现 人类大脑发育的过程。

I know that this all sounds science fiction,

我知道 这一切都听起来像是科幻小说，

but we now do this routinely in the lab.

但我们现在在实验室里 经常这样做。

We have derived thousands and thousands of organoids and assembloids

我们从患有各种 神经精神疾病的患者身上

from patients with various neuropsychiatric diseases,

提取了成千上万的 类器官和类组装体，

including, for instance,

再加上，比如，

infecting them with viruses such as polio virus

用类似脊髓灰质炎病毒的病毒 感染这些（类器官和组装体），

to understand how diseases arise.

以了解疾病是如何产生的。

The statistician George Box famously said,

统计学家乔治·博克斯（George Box） 有句名言，

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

“所有模型都是错误的， 但有些模型是有用的。”

(Laughter)

（笑）

I do the work that I do

我做我所做的工作是因为

because the promise and hope of brain assembloids and organoids

大脑类组装体和类器官 给予了我们希望，

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

让我们可以通过重建人脑回路

we will gain new insights into human biology.

来获得对于人类生物学的新见解。

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

而这本身将开启 治疗脑部疾病的新纪元。

Thank you.

谢谢。

(Applause)

（鼓掌）