TED演講者：Sergiu P. Pasca / 塞爾吉·帕斯卡

演講標(biāo)題：How we're reverse engineering the human brain in the lab / 我們?nèi)绾卧趯?shí)驗(yàn)室中對(duì)人腦進(jìn)行逆向工程

內(nèi)容概要：Neuroscientist Sergiu P. Pasca has made it his life's work to understand how the human brain builds itself -- and what makes it susceptible to disease. In a mind-blowing talk laden with breakthrough science, he shows how his team figured out how to grow "organoids" and what they call brain "assembloids" -- self-organizing clumps of neural tissue derived from stem cells that have shown the ability to form circuits -- and explains how these miniature parts of the nervous system are...

神經(jīng)科學(xué)家塞爾吉·帕斯卡（Sergiu P. Pasca）畢生致力于了解人類大腦是如何自我構(gòu)建的以及是什么讓它容易患病。 在充滿突破性科學(xué)的令人興奮的演講中，他展示了他的團(tuán)隊(duì)如何找到了培養(yǎng)“類器官”以及他們所謂的大腦“類組裝體”——來自干細(xì)胞的可以自我組織并形成回路的神經(jīng)組織塊——并解釋神經(jīng)系統(tǒng)的迷你版本如何使我們更接近于揭開大腦的神秘面紗。

*******************************************

【1】How does the human brain build itself?

大腦是如何形成的？

【2】How do circuits in the human brain wire together?

人類大腦里的回路 是如何互相連接的？

【3】For instance, how does one tiny neuron in the outer layer of the brain send a thin axon all the way to the spinal cord, find the right neuron and then control muscle contraction as we extend a hand and grasp a glass of water?

舉個(gè)例子,一個(gè)微小的神經(jīng)元 是如何從大腦外層 把一個(gè)細(xì)細(xì)的軸突 一路送到脊髓, 找到對(duì)應(yīng)的神經(jīng)元 來控制肌肉的伸縮, 從而使我們能夠 伸手拿到一瓶水的？

【4】I'm here to tell you that we can finally grow parts of the human brain from any individual and then build functioning human circuits in a laboratory cell culture dish.

今天我站在這里告訴你 我們終于可以從任何人身上 培育出部分人類大腦了, 而且可以在實(shí)驗(yàn)室細(xì)胞培養(yǎng)皿中 以此建立功能正常的人體回路。

【5】These clumps of neural tissue are known as brain organoids.

這一團(tuán)團(tuán)的神經(jīng)組織, 就是所謂的大腦類器官。

【6】And when we put them together to form circuits, they become “assembloids.” Assembloids could be key to understanding how the human brain is built.

而當(dāng)它們被放到一起形成回路, 就形成了“類組裝體”。 類組裝體可能是 認(rèn)識(shí)人腦組成的關(guān)鍵。

【7】Today, most of what we know about the human brain comes from studies in animals, typically mice.

如今大部分我們知道的 有關(guān)人腦的知識(shí)都 來自于對(duì)動(dòng)物的研究, 尤其是老鼠。

【8】And while we've learned a lot from these animal brains, the characteristics that make the human brain unique, and uniquely susceptible to disease, remain mysterious.

雖然動(dòng)物大腦讓我們知道了很多, 但那些讓人腦獨(dú)特 且易患疾病的特征, 仍是個(gè)謎。

【9】I’m a physician by training and a professor at Stanford, where my laboratory has been taking unconventional approaches to study how the human brain develops, how disorders in the human brain arise and find new ways of treatment.

我是一名受過培訓(xùn)的醫(yī)生, 也是斯坦福大學(xué)的教授。 我的實(shí)驗(yàn)室一直在采用 非常規(guī)的方法, 來研究人類大腦的發(fā)育過程、 人腦疾病的形成, 并尋找新的治療方法。

【10】I think the best way to explain, though, how we do this is through the eyes of one of my patients.

不過我覺得, 解釋我們的做法的最好辦法 是透過我的一位患者的眼睛來看。

【11】When I opened my lab at Stanford, Eduard, who's on the autism spectrum, sent me this drawing depicting how he thought we were studying brain disorders.

當(dāng)我在斯坦福開設(shè)實(shí)驗(yàn)室時(shí), 愛德華（Eduard）, 一位自閉癥患者, 給我看了這副畫, 畫的是他以為的 我們研究大腦疾病的方式。

【12】Now to paraphrase him, he said, "What I think you're doing is you're climbing up a ladder, poking holes in people's brains and then use tiny telescopes to watch neural cells."

他當(dāng)時(shí)的意思就是說, “我以為你們是爬上了一個(gè)梯子, 然后在人們腦子里鉆洞, 再用迷你顯微鏡 去觀察神經(jīng)細(xì)胞。”

【13】Of course, that's not what we do.

那我們當(dāng)然不是這么干的。

【14】So I called him up, explained the process, and then the next morning he sent me another drawing, which I think ended up being a quite accurate representation of the work that we and many others now are doing.

所以我給他打了個(gè)電話, 并解釋了整個(gè)過程。 所以第二天早上 他給我發(fā)了另一幅畫, 這副畫我覺得 就相當(dāng)精確地描述了 我們與業(yè)界其他人在做的事情。

【15】Again, to paraphrase him, he said, "You're taking skin cells from patients that have specific brain disorders, then doing some mumbo jumbo to the cells to push them back in time and turn them into stem cells."

復(fù)述一下他說的就是, “從患有特定腦部疾病的患者身上, 你們提取了皮膚細(xì)胞, 然后搞一些高深莫測(cè)的魔法, 讓這些細(xì)胞的時(shí)間倒退 而成為干細(xì)胞?！?/p>

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

他知道干細(xì)胞可以被誘導(dǎo)成 任何類型的細(xì)胞。

【17】“So then you’re taking them and turning them into brain cells that form brain circuits.” That's right. We can build human brain circuits in a dish.

“最后你們就把這些干細(xì)胞 變成了腦細(xì)胞, 再把腦細(xì)胞組成腦回路。” 沒錯(cuò),我們可以在一個(gè)小碟子里 建造人類的腦回路。

【18】How is that possible?

這怎么可能的？

【19】Building on the hard work of biologists over the past 15 years or so, we can today take any cell type from any individual and then push it back in time to turn them into stem cells and then guide those stem cells to become any other cell type.

多虧了生物學(xué)家們 在過去十五年里的努力研究, 如今我們可以提取任何人的 任何類型的細(xì)胞, 逆轉(zhuǎn)這些細(xì)胞的時(shí)間, 把它們倒推回干細(xì)胞, 最后引導(dǎo)這些干細(xì)胞成為 任何其他類型的細(xì)胞。

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

患者先會(huì)提供一個(gè) 小的皮膚樣本,

【21】We then take those skin cells, reprogram them by putting a series of genetic factors and push them back in time so that those skin cells become stem cells.

我們從中提取出皮膚細(xì)胞, 向其注入一系列遺傳因子 從而重新編碼, 逆轉(zhuǎn)時(shí)間, 這些皮膚細(xì)胞就成為干細(xì)胞了。

【22】It's like cellular alchemy.

就像是細(xì)胞煉金術(shù)一樣。

【23】These stem cells have almost magical abilities to turn into any other cell type.

這些干細(xì)胞有著神奇的能力, 可以變成任何細(xì)胞類型。

【24】So what do we do?

所以我們是怎么做的呢？

【25】We take the stem cells, we dissociate them, we then aggregate them so that they form spheres or tiny balls of cells.

我們把這個(gè)干細(xì)胞 分離再聚合, 讓它們變成球形, 或是像小球一樣的細(xì)胞。

【26】We then take those, move them into a special plate where there is a kind of chemical soup.

再放入一個(gè) 盛有化學(xué)湯劑的特質(zhì)的盤中。

【27】And that chemical soup will allow them to grow and transform and turn into a brain organoid.

這種化學(xué)湯劑可以讓干細(xì)胞 生長(zhǎng)成為大腦類器官。

【28】By providing different cues, we can turn this brain organoid to resemble specific regions of the central nervous system.

通過不同的刺激信號(hào), 我們可以讓這個(gè)大腦類器官 變得類似于 中樞神經(jīng)系統(tǒng)的特定區(qū)域。

【29】For instance, we have a recipe that allows them to become a cerebral cortex, the outer layer of the brain.

舉個(gè)例子,我們有一個(gè)配方 可以讓它們成為大腦皮層組織, 就是大腦的外層。

【30】By using a slightly different combination of factors, we can turn them into a spinal cord.

稍微換一換配方, 我們可以把它們變成脊髓。

【31】The secret to this process is careful guidance.

最重要的因素, 就是嚴(yán)謹(jǐn)仔細(xì)的引導(dǎo)。

【32】In the end, they look like this.

最后,它們看起來就是這樣。

【33】Tiny clusters of brain cells at the bottom of a dish.

在碟子底部 一簇簇的微小腦細(xì)胞。

【34】And let me be clear.

話說在前頭,

【35】This are not brains in a jar.

這可不是缸中之腦。

【36】(Laughter) These are parts of the nervous system in a laboratory dish.

（觀眾笑） 這些是在一個(gè)實(shí)驗(yàn)室培養(yǎng)皿里的 神經(jīng)系統(tǒng)的一部分。

【37】Each of them contains millions of cells, and we can even listen as they fire electrical signals.

每一個(gè)都含有數(shù)百萬個(gè)細(xì)胞。 我們甚至能聽到它們發(fā)射電信號(hào)。

【38】(Electrical signals firing) Or we can watch them as they sparkle with electrical activity.

（電信號(hào)發(fā)射聲） 我們也可以看著它們 迸射出電信號(hào)的火花。

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

我們還可以看到 細(xì)胞互相交流的圖像。

【40】Isn't it remarkable to think that just a few months ago these cells were skin cells in a patient, and now they are neural cells at the bottom of a dish that we can study at ease.

光是想象一下就不可思議: 在幾個(gè)月之前, 這些只是一位患者的皮膚細(xì)胞, 現(xiàn)在就成為了培養(yǎng)皿中 供人研究的神經(jīng)細(xì)胞。

【41】(Applause) Thank you.

（鼓掌） 謝謝。

【42】So with these models of brain growth, we started wondering: Could we use them to start to understand disease?

有了這些大腦生長(zhǎng)的模型, 我們就開始暢想, 也許我們可以用它們來了解疾??？

【43】So for instance, we wanted to know, could we understand how low oxygen impacts the brains of premature babies?

舉個(gè)例子,我們想要知道 低氧量是如何影響早產(chǎn)兒的大腦的？

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

為此,我們將大腦類器官 放入一個(gè)特殊的培養(yǎng)箱中。

【45】We then lowered the concentration of oxygen and watched them.

然后在降低氧氣濃度的同時(shí) 進(jìn)行觀察。

【46】We discovered something quite interesting.

我們觀察到了 一個(gè)很有趣的現(xiàn)象。

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

只有一種特定的細(xì)胞類型 被低氧濃度影響了。

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

這種細(xì)胞負(fù)責(zé)的是 人類大腦皮層的擴(kuò)張。

【49】We found exactly how that happens and even found the drug that could prevent that process.

我們不僅知道了它是如何發(fā)生的, 甚至找到了 可以阻止這個(gè)過程發(fā)生的藥品。

【50】These clumps of three-dimensional tissue can be grown in a dish for years.

這一團(tuán)團(tuán)三維的細(xì)胞組織 可以在培養(yǎng)皿里生長(zhǎng)數(shù)年。

【51】In fact, we've maintained the longest cultures that have been reported to date, going beyond 800 days.

事實(shí)上,我們保持著迄今為止 最長(zhǎng)培養(yǎng)時(shí)間的紀(jì)錄, 超過 800 天。

【52】At nine to 10 months, which is the equivalent of birth, they slowly transitioned, and they started to resemble the postnatal brain.

在九到十個(gè)月的時(shí)候, 差不多是胎兒孕育的時(shí)長(zhǎng), 這些腦細(xì)胞慢慢開始變化, 開始變得像胎兒出生后的大腦。

【53】We have discovered a brain clock which keeps track of time in a dish and outside of the uterus.

我們發(fā)現(xiàn)了一個(gè)大腦時(shí)鐘, 這個(gè)時(shí)鐘在培養(yǎng)皿或子宮之外, 都記錄著時(shí)間。

【54】Understanding the molecular mechanisms that underlie this brain clock could be key to finding new strategies to either accelerate or decelerate or rejuvenate human brain cells.

了解構(gòu)成這種腦時(shí)鐘的分子機(jī)制 可能是找到加速、減慢或復(fù)原 人類腦細(xì)胞的新策略的關(guān)鍵。

【55】The work that I've shown you so far is pioneering not just because of what it teaches us about the human brain, but also because of the frontiers of ethics.

目前為止我剛剛展示的成果 是非常開創(chuàng)性的, 不僅是因?yàn)槲覀兡芤源搜芯看竽X, 也是因?yàn)樗砹藗惱韺W(xué)的前沿。

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

類器官和類組裝體 并不是人類大腦的完整復(fù)制品。

【57】They're not brains in a jar. They're not minibrain.

它們不是缸中之腦, 也不是迷你腦。

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

它們不是制造科學(xué)怪人的墊腳石。

【59】They have no blood flow, they receive no meaningful inputs and outputs.

它們沒有血液, 并不接受或釋放有意義的信號(hào)。

【60】But at one point, they may become more complex.

但它們可能會(huì)在某一個(gè)時(shí)間點(diǎn) 變得更復(fù)雜。

【61】At one point, they may receive sensory input.

在某個(gè)時(shí)刻,它們可能會(huì)收到感官信號(hào)。

【62】So as the science advances, we in the scientific community have been very careful about discussing what are some of the ethical questions, the societal implications and potential regulations.

所以在科學(xué)發(fā)展的同時(shí), 我們科學(xué)界也在非常認(rèn)真地討論著 一些倫理問題、社會(huì)影響 和潛在法規(guī)。

【63】Most of the work that I’ve shown you so far has been in one specific brain region.

我已經(jīng)向你們展示的這些成果 目前只是在某一個(gè)大腦區(qū)域。

【64】But to really understand circuits, we actually need to build more complicated brain circuits.

但為了真正理解腦回路, 我們確實(shí)需要建造更復(fù)雜的腦回路。

【65】And so to do this, six years ago, we came up with a new approach to build human circuits called an assembloid.

為此,六年前, 我們想到了一個(gè) 建造人類腦回路的新辦法, 叫做類組裝體。

【66】Assembloids are essentially blocks of tissue that we build in a dish from multiple organoids put together.

類組裝體本質(zhì)上就是 我們?cè)谂囵B(yǎng)皿中 用多個(gè)類器官構(gòu)建的組織塊。

【67】When we put two brain organoids together, we discovered something really fascinating.

當(dāng)我們把兩個(gè)大腦類器官放在一起, 我們發(fā)現(xiàn)了非常特別的事。

【68】First, they fused to each other.

首先,它們彼此融合了起來。

【69】But then they started to communicate, and brain cells from one side started to slowly migrate onto the other side and form circuits, much like they would in the actual brain.

然后它們開始了互相交流, 一邊的大腦細(xì)胞開始 慢慢地向另一邊移動(dòng), 并形成了腦回路, 就像它們?cè)谡嬲拇竽X里那樣。

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

事實(shí)上,我們甚至可以實(shí)時(shí)看著 它們從一邊移動(dòng)到另一邊。

【71】I still remember how we were in the lab in absolute awe when we saw for the first time how human cells undergo this peculiar jumping behavior.

我還記得當(dāng)時(shí) 我們是怎樣帶著無比的敬畏, 第一次看著人類的細(xì)胞 進(jìn)行這種奇特的跳躍行為。

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

這一切都看起來非常有趣。 但它實(shí)際上有什么用呢？

【73】Dysfunction in the human brain causes brain disorders, such as autism and schizophrenia and Alzheimer's disease, devastating conditions that are poorly understood.

人腦功能障礙會(huì)導(dǎo)致腦部疾病, 例如自閉癥、精神分裂癥 和阿爾茨海默病, 我們對(duì)這些可怕的疾病知之甚少。

【74】Nearly one in five individuals suffers from a psychiatric disease.

每五個(gè)人里, 就有一個(gè)患有某種精神疾病。

【75】What is even more striking is that the lowest success rate for finding new drugs is in psychiatry, out of all the branches of medicine, likely because until now we couldn't really access the human brain.

而更驚人的是, 在所有醫(yī)藥分支中, 尋找精神病新藥的成功率是最低的。 很有可能是因?yàn)橹钡浆F(xiàn)在, 我們都無法真正接觸到人類大腦。

【76】Using brain organoids and assembloids, we can create avatars for a patient's brain development and then use those to dissect the molecular mechanism of disease.

通過大腦類器官和類組裝體, 我們可以為患者的大腦發(fā)育過程 創(chuàng)建許多副本, 然后使用這些副本 來剖析疾病的分子機(jī)制。

【77】Let me give you one example.

讓我來舉個(gè)例子。

【78】As you have seen, assembloids can be used to model this healthy jumping behavior of neurons.

你們已經(jīng)看到了, 類組裝體可以被用來 模擬神經(jīng)元的 這種正常的跳躍行為。

【79】So what we did is we created assembloids from patients with Timothy syndrome, which is a rare genetic disease associated with autism and epilepsy.

而我們創(chuàng)建了長(zhǎng)QT綜合癥患者的 大腦類組裝體。 這是一種少見的遺傳疾病, 經(jīng)常伴隨有自閉癥和癲癇發(fā)作。

【80】When we looked inside the assembloids, we noticed something remarkable.

當(dāng)我們仔細(xì)觀察這些類組裝體, 我們發(fā)現(xiàn)了很了不起的事。

【81】The cells were moving much faster, but every time they would jump, they would jump a shorter distance.

細(xì)胞的移動(dòng)速度 要比正常的快很多, 但它們每一次跳躍的距離, 都要短很多。

【82】So in the end, they would be left behind.

所以最后,它們就會(huì)落在后面。

【83】Over the past six years in extensive studies, we've actually dissected the molecular mechanism of this defect and even found ways of restoring it.

在過去六年的全面研究中, 我們剖析了 造成這種缺陷的分子機(jī)制, 甚至找到了修復(fù)它的方法。

【84】And we're excited to be moving towards a potential therapeutic avenue in the next year or so.

我們很高興能在未來一年左右 找到潛在的治療方法。

【85】(Applause) The promise of organoids and assembloids is that they will slowly allow us to gain new insights into the hidden biology of the human brain.

（觀眾鼓掌） 類器官和類組裝體的前景在于 它們將讓我們慢慢地 對(duì)隱藏在人類大腦內(nèi)部的生物學(xué)

【86】And by doing so, they could revolutionize the way we think about human brain development, evolution, function and disease.

而這就有可能 顛覆我們對(duì)人類大腦的了解, 包括其發(fā)展、進(jìn)化、功能和疾病。

【87】So what's next?

那下一步是什么呢？

【88】Well, to really be able to gain insight into more complex brain disorders, we need to build more complex circuits.

那就是, 為了了解更復(fù)雜的大腦疾病, 我們需要構(gòu)建更復(fù)雜的回路。

【89】So in the last minute, let me show you the most complicated circuit we have built to date.

那么在這最后一分鐘, 讓我來向你們展示, 至今為止我們構(gòu)建的 最復(fù)雜的大腦回路。

【90】The circuit that controls voluntary movement.

一個(gè)控制自主運(yùn)動(dòng)的回路。

【91】To do this, we've created three organoids.

為此我們創(chuàng)造了三個(gè)類器官。

【92】One, shown here in purple, that resembles the cortex.

一個(gè)在此處用紫色表示, 類似大腦皮質(zhì)。

【93】One, in yellow, that resembles the spinal cord, and one, in red, that resembles human muscle.

一個(gè)用黃色表示, 類似于脊髓。 還有一個(gè)用紅色表示, 類似于人類的肌肉。

【94】We then put them together and watched them fuse and noticed something really spectacular.

我們把它們?nèi)齻€(gè)放在一起, 并看著它們?nèi)诤掀饋? 并注意到了一些 非常驚人的現(xiàn)象。

【95】Neurons on the cortical side started extending axons, find spinal motor neurons in the spinal side, connect with them, and then those farther project and connect to muscle.

皮質(zhì)部分的神經(jīng)元 開始伸長(zhǎng)軸突, 在脊髓部分找到了 脊髓運(yùn)動(dòng)神經(jīng)元, 與它們連接, 然后向更遠(yuǎn)處投射 并連接到了肌肉部分。

【96】When we put a light stimulus on the cortical site, we noticed the muscle on the opposite side contract.

當(dāng)我們用燈光 對(duì)皮質(zhì)部位施加刺激時(shí), 我們注意到 另一邊的肌肉進(jìn)行了收縮。

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

我們模擬了歷史上的首次 人類皮質(zhì)運(yùn)動(dòng)通路。

【98】(Applause) And let me be clear.

（鼓掌） 讓我先澄清一下。

【99】These cells find each other.

這些細(xì)胞是自己找到彼此的。

【100】Unlike in engineering, we don't have a master plan, we don't provide a plan because the human brain builds itself.

與建造工程不同, 我們沒有一個(gè)大致規(guī)劃, 不提供規(guī)劃是因?yàn)? 人類大腦會(huì)建造它自己。

【101】And then in itself, it's a remarkable opportunity to try to reverse engineer what are some of the steps that underlie human brain development?

然后就其本身而言, 這是一個(gè)絕佳的機(jī)會(huì), 用逆向工程來發(fā)現(xiàn) 人類大腦發(fā)育的過程。

【102】I know that this all sounds science fiction, but we now do this routinely in the lab.

我知道 這一切都聽起來像是科幻小說, 但我們現(xiàn)在在實(shí)驗(yàn)室里 經(jīng)常這樣做。

【103】We have derived thousands and thousands of organoids and assembloids from patients with various neuropsychiatric diseases, including, for instance, infecting them with viruses such as polio virus to understand how diseases arise.

我們從患有各種 神經(jīng)精神疾病的患者身上 提取了成千上萬的 類器官和類組裝體, 再加上,比如, 用類似脊髓灰質(zhì)炎病毒的病毒 感染這些（類器官和組裝體）, 以了解疾病是如何產(chǎn)生的。

【104】The statistician George Box famously said, "All models are wrong, but some are useful."

統(tǒng)計(jì)學(xué)家喬治·博克斯（George Box） 有句名言, “所有模型都是錯(cuò)誤的, 但有些模型是有用的?！?/p>

【105】(Laughter) I do the work that I do because the promise and hope of brain assembloids and organoids is that by allowing us to recreate circuits of the human brain, we will gain new insights into human biology.

（笑） 我做我所做的工作是因?yàn)?大腦類組裝體和類器官 給予了我們希望, 讓我們可以通過重建人腦回路 來獲得對(duì)于人類生物學(xué)的新見解。

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

而這本身將開啟 治療腦部疾病的新紀(jì)元。

【107】Thank you.

謝謝。

【108】(Applause)