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

134,496 views ・ 2022-08-29

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譯者: Lilian Chiu 審譯者: Helen Chang
00:03
How does the human brain build itself?
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人腦是如何把自己建造出來的?
00:08
How do circuits in the human brain
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人腦中的迴路是如何連接起來的?
00:10
wire together?
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00:12
For instance, how does one tiny neuron in the outer layer of the brain
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比如,
在大腦外層的一個小小神經元如何
00:16
send a thin axon all the way to the spinal cord,
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把極細的軸突一路送到脊髓,
00:19
find the right neuron
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找到對的神經元,
00:20
and then control muscle contraction
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接著控制肌肉收縮,讓我們能
00:22
as we extend a hand and grasp a glass of water?
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把手伸出去拿起一杯水?
00:27
I'm here to tell you
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我要來告訴各位,
00:28
that we can finally grow parts of the human brain
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我們終於能夠培育出 任何人的人腦的某些部分,
00:31
from any individual
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00:33
and then build functioning human circuits
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並在實驗室的細胞培養皿中 建造出能運作的人類迴路。
00:35
in a laboratory cell culture dish.
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00:39
These clumps of neural tissue are known as brain organoids.
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這些塊狀的神經組織
就是一般所知的類人腦。
00:44
And when we put them together to form circuits, they become “assembloids.”
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把它們組合成迴路, 就成了「類裝配體」。
00:49
Assembloids could be key to understanding how the human brain is built.
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要了解人腦是如何建造出來的, 類裝配體有可能是關鍵。
00:54
Today, most of what we know about the human brain
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現今,我們對人腦的了解 多半來自於動物研究,
00:56
comes from studies in animals, typically mice.
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通常是老鼠。
01:00
And while we've learned a lot from these animal brains,
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雖然我們從動物的大腦學到很多,
01:04
the characteristics that make the human brain unique,
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但人腦仍然有些獨一無二的特徵,
01:06
and uniquely susceptible to disease,
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其受疾病的影響也獨一無二,
01:09
remain mysterious.
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這些特徵仍然是謎。
01:11
I’m a physician by training and a professor at Stanford,
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我的背景是醫師, 也在史丹佛擔任教授。
01:14
where my laboratory has been taking unconventional approaches
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我在史丹佛的實驗室 採用非傳統的方法,
01:18
to study how the human brain develops,
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來研究人腦如何發展、
01:20
how disorders in the human brain arise
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人腦中的病症如何出現,
01:23
and find new ways of treatment.
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並找出新的治療方法。
01:26
I think the best way to explain, though, how we do this
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我認為,
要解釋我們怎麼做,最好的方式
01:30
is through the eyes of one of my patients.
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是透過我的病人之一的視角。
01:34
When I opened my lab at Stanford,
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我在史丹佛成立實驗室時,
01:36
Eduard, who's on the autism spectrum,
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有自閉症的艾德華
01:38
sent me this drawing
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送給我這張圖,說明在他看來
01:40
depicting how he thought we were studying brain disorders.
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我們是這樣研究大腦疾病的。
01:44
Now to paraphrase him, he said,
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引用他的話,他說:
01:46
"What I think you're doing is you're climbing up a ladder,
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「我認為你們的做法 就像是爬上梯子,
01:49
poking holes in people's brains
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在別人的大腦上戳洞,
01:51
and then use tiny telescopes to watch neural cells."
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然後用迷你望遠鏡來看神經細胞。」
01:55
Of course, that's not what we do.
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當然我們沒有這樣做, 於是我打電話給他,
01:56
So I called him up, explained the process,
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解釋我們的流程,
02:00
and then the next morning he sent me another drawing,
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隔天早上,
他又給了我另一張圖, 我認為非常精確地呈現了
02:02
which I think ended up being a quite accurate representation
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02:05
of the work that we and many others now are doing.
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我們和許多其他人在做的研究。
02:08
Again, to paraphrase him, he said,
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再次引述他的話:
02:10
"You're taking skin cells
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「你從患有特定大腦疾病的 病人身上取得皮膚細胞,
02:12
from patients that have specific brain disorders,
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然後對它們做些怪力亂神的事, 把它們送回到過去,
02:15
then doing some mumbo jumbo to the cells
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02:17
to push them back in time
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02:18
and turn them into stem cells."
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再把它們轉變成幹細胞。」
02:21
And then he knew that stem cells can be coaxed to become any cell type.
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接著,他知道幹細胞可以 被處理成為任何細胞型。
「接著,你把它們
02:25
“So then you’re taking them and turning them into brain cells
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變成形成大腦迴路的腦細胞。」
02:28
that form brain circuits.”
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02:30
That's right. We can build human brain circuits in a dish.
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沒錯,
我們可以在一個培養皿中 建造出人腦迴路。
02:36
How is that possible?
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怎麼可能?
02:38
Building on the hard work of biologists over the past 15 years or so,
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以過去十五年左右的生物學家 所做的努力為基礎,
02:43
we can today take any cell type from any individual
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現今,我們可以從任何人 身上取得任何細胞型,
02:47
and then push it back in time to turn them into stem cells
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接著,讓它回到過去,轉為幹細胞,
02:50
and then guide those stem cells to become any other cell type.
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接著,引導那些幹細胞 變成任何其他細胞型。
02:53
We start by asking a patient to provide a small skin sample.
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一開始,我們先請病人 提供一點皮膚樣本。
02:58
We then take those skin cells,
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接著,我們取得皮膚細胞,
03:01
reprogram them by putting a series of genetic factors
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用一連串的遺傳因素 將它們重新編程,
03:05
and push them back in time
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再讓那些皮膚細胞 回到過去,變成幹細胞。
03:06
so that those skin cells become stem cells.
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03:10
It's like cellular alchemy.
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就像細胞鍊金術。
03:12
These stem cells have almost magical abilities
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這些幹細胞幾乎可以說有魔法能力,
03:15
to turn into any other cell type.
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能變身為任何細胞型。
03:18
So what do we do?
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我們怎麼做?
03:19
We take the stem cells, we dissociate them,
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我們將幹細胞分離出來,
03:23
we then aggregate them
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接著,我們將它們聚合起來, 形成球體或者小細胞球。
03:24
so that they form spheres or tiny balls of cells.
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03:28
We then take those, move them into a special plate
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接著我們再把這些球體 移到特殊的盤子裡,
03:31
where there is a kind of chemical soup.
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盤子裡有一種化學湯。
03:34
And that chemical soup will allow them to grow
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那種化學湯能讓它們成長、轉型,
03:37
and transform and turn into a brain organoid.
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變成類大腦。
03:42
By providing different cues, we can turn this brain organoid
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透過提供不同的提示線索,
我們就能指示這個類大腦 模仿中樞神經系統的特定區域。
03:46
to resemble specific regions of the central nervous system.
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03:50
For instance, we have a recipe
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比如,我們有個秘方,
03:52
that allows them to become a cerebral cortex,
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能讓它們變成大腦皮質, 即大腦的外層。
03:54
the outer layer of the brain.
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03:56
By using a slightly different combination of factors,
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若略微改變因素的組合, 我們能將它們變成脊髓,
03:58
we can turn them into a spinal cord.
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04:01
The secret to this process is careful guidance.
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這個過程的秘訣, 就在於小心地引導。
04:05
In the end, they look like this.
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最後,它們看起來會像這樣。
04:08
Tiny clusters of brain cells at the bottom of a dish.
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在培養皿底部一小團 一小團的腦細胞。
04:12
And let me be clear.
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讓我說清楚。
04:14
This are not brains in a jar.
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這不是放在容器中的大腦。
04:16
(Laughter)
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(笑聲)
04:17
These are parts of the nervous system in a laboratory dish.
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是把部分的神經系統 放在實驗室培養皿中。
04:23
Each of them contains millions of cells,
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每個當中都有數百萬個細胞,
04:26
and we can even listen as they fire electrical signals.
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我們還可以聽見 它們所發出的電訊號。
04:30
(Electrical signals firing)
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(發送電訊號的聲音)
04:32
Or we can watch them
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或者,我們可以觀看它們,
04:35
as they sparkle with electrical activity.
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看它們隨著電活動發光閃耀。
04:38
Or we can image inside and watch the cells as they communicate with each other.
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或者,我們可以用內部成像 來觀看細胞和彼此溝通。
04:43
Isn't it remarkable to think that just a few months ago
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想想這有多麼不凡,
這些細胞原本是病人的皮膚細胞。
04:46
these cells were skin cells in a patient,
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04:48
and now they are neural cells at the bottom of a dish
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而現在,
它們成了培養皿底部的神經細胞, 讓我們可以輕易地研究。
04:51
that we can study at ease.
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04:53
(Applause)
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(掌聲)
04:54
Thank you.
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謝謝。
04:59
So with these models of brain growth,
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有了這些大腦成長模型,
05:01
we started wondering: Could we use them to start to understand disease?
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我們開始納悶:能不能 用它們來了解疾病?
05:05
So for instance, we wanted to know,
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比如,我們想知道,我們能不能了解
05:07
could we understand how low oxygen impacts the brains of premature babies?
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低氧對早產嬰兒的大腦有什麼影響?
05:14
So to do this, we took brain organoids and put them in a special incubator.
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為此,我們採用了類大腦,
把它們放入特殊的早產兒保溫箱。
05:21
We then lowered the concentration of oxygen and watched them.
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接著我們一邊降低氧濃度一邊觀察。
05:26
We discovered something quite interesting.
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我們的發現十分有意思。
05:28
Only one specific cell type was affected by the low oxygen.
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只有一種細胞型有受到低氧的影響,
05:32
That cell type is responsible for the expansion of the human cortex.
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那型細胞負責的是 人腦皮質的擴延。
05:36
We found exactly how that happens
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我們獲知確切的發生過程, 甚至找到能阻止該過程的藥物。
05:38
and even found the drug that could prevent that process.
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05:42
These clumps of three-dimensional tissue
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這些 3D 組織塊
05:46
can be grown in a dish for years.
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可以在培養皿中生長數年。
05:49
In fact, we've maintained the longest cultures
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事實上,我們是至今最長的 培養記錄保持者,超過八百天。
05:52
that have been reported to date, going beyond 800 days.
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05:55
At nine to 10 months, which is the equivalent of birth,
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在九到十個月時,等同於出生時,
05:59
they slowly transitioned, and they started to resemble the postnatal brain.
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它們漸漸地轉變,
開始變得很像產後的大腦。
06:05
We have discovered a brain clock
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我們發現的是大腦時鐘,
06:08
which keeps track of time in a dish and outside of the uterus.
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它在子宮外,在培養皿中 也能持續追蹤時間。
06:13
Understanding the molecular mechanisms that underlie this brain clock
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了解這種大腦時鐘背後的分子機制
06:17
could be key to finding new strategies
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可能十分關鍵,也許能 協助找出新策略以加速、
06:20
to either accelerate or decelerate or rejuvenate human brain cells.
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減慢人類大腦細胞, 或讓它們恢復活力。
06:26
The work that I've shown you so far
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目前我給各位看的研究成果
06:28
is pioneering not just because of what it teaches us
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很具開創性,不僅是因為 它能讓我們更了解人腦,
06:31
about the human brain,
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06:32
but also because of the frontiers of ethics.
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還有一個原因:倫理的新領域。
06:36
Organoids and assembloids are not full replicas of the human brain.
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類大腦和類裝配體 並非人腦的完整複製品。
06:40
They're not brains in a jar. They're not minibrain.
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它們不是裝在容器中的 大腦,不是迷你大腦。
06:43
They're not some stepping stone to a Frankenstein monster.
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它們不是創造出科學怪人的跳板。
06:47
They have no blood flow,
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它們沒有血流,接收不到 有意義的輸入和輸出。
06:48
they receive no meaningful inputs and outputs.
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06:51
But at one point, they may become more complex.
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但在某個時點, 它們可能會變得更複雜。
06:55
At one point, they may receive sensory input.
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在某個時點,它們可能 會接收到感官輸入。
06:58
So as the science advances,
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所以,隨著科學進步, 在科學圈裡的我們一直都
07:00
we in the scientific community have been very careful
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非常小心地討論
07:03
about discussing what are some of the ethical questions,
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一些倫理問題、
07:06
the societal implications and potential regulations.
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社會意涵,以及可能的規定。
07:11
Most of the work that I’ve shown you so far
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目前我給各位看的研究成果
07:13
has been in one specific brain region.
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都只屬於大腦的一個特定區域。
07:16
But to really understand circuits,
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但,若要真正了解迴路,
07:18
we actually need to build more complicated brain circuits.
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我們得要創造更複雜的大腦迴路。
07:22
And so to do this, six years ago,
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為此,六年前,
07:25
we came up with a new approach to build human circuits
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我們提出了一種新方法
來創造人類迴路,稱為類裝配體。
07:28
called an assembloid.
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07:30
Assembloids are essentially blocks of tissue
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基本上,類裝配體就是
我們在培養皿中創造的組織塊,
07:33
that we build in a dish from multiple organoids put together.
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做法是將多個類器官組合起來。
07:38
When we put two brain organoids together,
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當我們把兩個類大腦放在一起,
07:41
we discovered something really fascinating.
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我們的發現相當夢幻。
07:45
First, they fused to each other.
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首先,它們會融入彼此。
07:48
But then they started to communicate,
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但,接著,它們開始溝通。
07:51
and brain cells from one side
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一邊的腦細胞
07:54
started to slowly migrate onto the other side
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開始慢慢遷移到另一邊, 並且形成迴路。
07:57
and form circuits,
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07:58
much like they would in the actual brain.
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很像真實大腦中的狀況。
08:00
In fact, we can even watch them live as they move from one side to the other.
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事實上,我們甚至可以實況 觀察它們從一邊移到另一邊。
08:05
I still remember how we were in the lab in absolute awe
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我還記得在實驗室裡 我們全都感到相當敬畏,
08:08
when we saw for the first time
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那是我們第一次看到
08:10
how human cells undergo this peculiar jumping behavior.
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人類細胞如何進行 這種獨特的跳躍行為。
08:14
This is all fascinating, but what is it actually good for?
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這些都很炫,但到底有什麼好處?
08:18
Dysfunction in the human brain causes brain disorders,
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人腦中的功能異常
會造成大腦疾病,比如
08:22
such as autism and schizophrenia and Alzheimer's disease,
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自閉症、精神分裂症、阿茲海默症
08:25
devastating conditions that are poorly understood.
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這些我們不甚了解的棘手病症。
08:28
Nearly one in five individuals suffers from a psychiatric disease.
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有接近五分之一的人 為精神疾病所苦。
08:32
What is even more striking
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更讓人吃驚的是,
08:34
is that the lowest success rate for finding new drugs
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在所有的醫學領域中,最不容易
08:37
is in psychiatry, out of all the branches of medicine,
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成功找到新藥物的領域 就是精神病學,
08:40
likely because until now we couldn't really access the human brain.
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很可能是因為,在此之前
我們尚無法真正進入人腦。
08:46
Using brain organoids and assembloids,
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運用類大腦和類裝配體,我們能創造
08:50
we can create avatars for a patient's brain development
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病人腦部發展的化身,
08:54
and then use those to dissect the molecular mechanism of disease.
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接著,用它們來仔細研究 疾病的分子機制。
08:59
Let me give you one example.
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讓我舉個例子。
09:01
As you have seen,
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各位已經見識到,
09:03
assembloids can be used
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類裝配體可以用來
09:05
to model this healthy jumping behavior of neurons.
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建立模型,模擬神經元 這種健康的跳躍行為。
09:09
So what we did is we created assembloids from patients with Timothy syndrome,
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所以,我們的做法是
用提摩西症候群患者 來創造類裝配體,
09:14
which is a rare genetic disease associated with autism and epilepsy.
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它是種罕見遺傳疾病,
和自閉症及癲癇有關。
09:19
When we looked inside the assembloids, we noticed something remarkable.
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當我們研究類裝配體的 內部時,有了驚人的發現。
09:23
The cells were moving much faster,
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細胞的移動速度
更快很多,但它們每次 跳躍的疾病卻越來越短。
09:27
but every time they would jump, they would jump a shorter distance.
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所以,最後,它們會被拋在後頭。
09:30
So in the end, they would be left behind.
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09:32
Over the past six years in extensive studies,
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在過去六年間,
我們進行了大量研究來仔細探討 這種缺陷的分子機制,
09:35
we've actually dissected the molecular mechanism of this defect
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09:38
and even found ways of restoring it.
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甚至找到方法來把它修好。
09:41
And we're excited to be moving towards a potential therapeutic avenue
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我們很興奮,在明年左右 就有可能有治療的方法。
09:44
in the next year or so.
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09:46
(Applause)
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(掌聲)
09:50
The premise of organoids and assembloids
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類器官和類裝配體的前提
09:53
is that they will slowly allow us to gain new insights
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是它們能慢慢地讓我們
對人腦背後隱密的生物學 有更多的新洞見。
09:57
into the hidden biology of the human brain.
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10:00
And by doing so,
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藉此,
10:01
they could revolutionize the way we think about human brain development, evolution,
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可以徹底改變我們如何 看待人腦的發展、
演化、功能,以及疾病。
10:05
function and disease.
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10:08
So what's next?
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接下來呢?
10:09
Well, to really be able to gain insight into more complex brain disorders,
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要能真正深入了解 更複雜的大腦疾病,
10:14
we need to build more complex circuits.
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我們就得創造更複雜的迴路。
10:17
So in the last minute, let me show you
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在場演說的最後一分鐘,
讓我展示給各位看看,至今 我們打造過最複雜的迴路。
10:20
the most complicated circuit we have built to date.
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10:24
The circuit that controls voluntary movement.
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控制自主運動的迴路。
10:28
To do this, we've created three organoids.
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為了創造它,
我們先創造了三個類器官。
10:31
One, shown here in purple, that resembles the cortex.
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紫色的這一個類似皮質,
10:35
One, in yellow, that resembles the spinal cord,
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黃色的這一個類似脊髓,
10:37
and one, in red, that resembles human muscle.
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紅色的這一個類似人類肌肉。
10:40
We then put them together and watched them fuse
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接著,把它們擺在一起, 看著它們融合。
10:43
and noticed something really spectacular.
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注意看看,這個現象很壯觀。
10:46
Neurons on the cortical side started extending axons,
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在皮質端的神經元開始延伸出軸突,
10:50
find spinal motor neurons in the spinal side,
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在脊髓端找到脊運動神經元,
10:52
connect with them,
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和它們連結,
它們又再延伸出去,連結到肌肉。
10:54
and then those farther project and connect to muscle.
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10:58
When we put a light stimulus on the cortical site,
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當我們在皮質端加上光刺激時,
11:02
we noticed the muscle on the opposite side contract.
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我們注意到在另一端的肌肉收縮了。
11:07
We have modeled for the first time a human cortical motor pathway.
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我們建立出了第一個 人類皮質運動路徑的模型。
11:12
(Applause)
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(掌聲)
11:19
And let me be clear.
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讓我說清楚。
11:22
These cells find each other.
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這些細胞會找到彼此。
11:26
Unlike in engineering, we don't have a master plan,
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這和工程不一樣,
我們沒有總體設計, 我們不提供計畫圖,
11:29
we don't provide a plan because the human brain builds itself.
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因為人腦是自己建立起來的。
11:34
And then in itself, it's a remarkable opportunity
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而就其本身而言,也是個 做逆向工程的不凡機會,
11:36
to try to reverse engineer
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11:38
what are some of the steps that underlie human brain development?
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可試圖了解人腦發展 背後的一些步驟。
11:43
I know that this all sounds science fiction,
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我知道這一切聽起來像科幻小說, 但我們在實驗室中經常在做。
11:45
but we now do this routinely in the lab.
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11:48
We have derived thousands and thousands of organoids and assembloids
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我們已經靠著患有各種 神經精神疾病的病人,做出了
11:51
from patients with various neuropsychiatric diseases,
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數千個類器官和類裝配體,
包括,比如,
11:54
including, for instance,
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11:55
infecting them with viruses such as polio virus
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讓它們感染到小兒麻痺病毒 等病毒,以了解疾病如何產生。
11:57
to understand how diseases arise.
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11:59
The statistician George Box famously said,
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統計學家喬治‧巴克斯有句名言:
12:04
"All models are wrong, but some are useful."
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「所有的模型都是錯的, 但有些是有用的。」
12:08
(Laughter)
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(笑聲)
我投入我的工作,
12:11
I do the work that I do
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12:13
because the promise and hope of brain assembloids and organoids
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就是因為大腦類裝配體 及類大腦的前景和希望,
12:17
is that by allowing us to recreate circuits of the human brain,
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即:藉由讓我們能 重新創造出人腦的迴路,
12:20
we will gain new insights into human biology.
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我們將能夠得到 人類生物學的新洞見。
12:24
And this in itself will open a new era in the treatment of brain disorders.
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而這本身就能為大腦疾病 治療開創新的紀元。
12:29
Thank you.
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謝謝。
12:30
(Applause)
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(掌聲)
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