How CRISPR lets us edit our DNA | Jennifer Doudna

譯者: 易帆 余 審譯者: Xiaoya Song

A few years ago,

幾年前，

with my colleague, Emmanuelle Charpentier,

我跟我同事Emmanuelle Charpentier

I invented a new technology for editing genomes.

發明了一個可以編輯基因組的新技術，

它叫做 "CRISPR-Cas9" 。

It's called CRISPR-Cas9.

The CRISPR technology allows scientists to make changes

CRISPR技術讓科學家

可以改變細胞裡的DNA。

to the DNA in cells

that could allow us to cure genetic disease.

這技術我們可以用來治療基因疾病。

你可能有興趣想知道，

You might be interested to know

that the CRISPR technology came about through a basic research project

CRISPR技術其實來自於 一個基礎的科學研究，

that was aimed at discovering how bacteria fight viral infections.

它的主要目的是了解細菌 如何與病毒感染做對抗。

Bacteria have to deal with viruses in their environment,

細菌必須在它們的環境裡對付病毒。

and we can think about a viral infection like a ticking time bomb --

我們可以這麼想， 病毒感染像是個定時炸彈，

a bacterium has only a few minutes to defuse the bomb

細菌在被消滅前，

只有一些時間可以解除炸彈。

before it gets destroyed.

So, many bacteria have in their cells an adaptive immune system called CRISPR,

很多細菌在它們的細胞裡有一種 適應力免疫系統叫做 "CRISPR" ，

that allows them to detect viral DNA and destroy it.

它可以使細菌偵測到病毒DNA並消滅它。

Part of the CRISPR system is a protein called Cas9,

CRISPR系統中，有一部分 是一種叫Cas9的蛋白質，

that's able to seek out, cut and eventually degrade viral DNA

它能夠以特殊的方式尋找出、剪斷

最後削弱病毒DNA。

in a specific way.

這就是我們大體上的研究：

And it was through our research

to understand the activity of this protein, Cas9,

了解Cas9蛋白質的活動，

that we realized that we could harness its function

這使我們懂得駕馭它的功能，

as a genetic engineering technology --

用一個基因工程技術來說明：

a way for scientists to delete or insert specific bits of DNA into cells

一種可以讓科學家用難以置信的精準度

來消除或插入特定DNA片段到細胞中，

with incredible precision --

這技術提供了一個前所未有的機會，

that would offer opportunities

to do things that really haven't been possible in the past.

讓我們可以做到 以前不可能達到的事。

CRISPR技術已經被應用在

The CRISPR technology has already been used

to change the DNA in the cells of mice and monkeys,

改變老鼠和猴子細胞裡的DNA，

other organisms as well.

包括其他有機體。

Chinese scientists showed recently

中國科學家最近發現，

that they could even use the CRISPR technology

他們甚至可以利用CRISPR技術

to change genes in human embryos.

改變人類胚胎裡的基因。

And scientists in Philadelphia showed they could use CRISPR

在費城的科學家證實， 他們可以利用CRISPR 技術

to remove the DNA of an integrated HIV virus

從一個感染的人類細胞中

移除HIV病毒( 人類免疫缺陷病毒 )。

from infected human cells.

這個充滿契機的基因組編輯技術，

The opportunity to do this kind of genome editing

also raises various ethical issues that we have to consider,

也引發了各種我們必須 認真思考的道德爭議。

because this technology can be employed not only in adult cells,

因為這種技術不僅可以運用在成人細胞上，

but also in the embryos of organisms,

也可以用在有機體的胚胎上，

including our own species.

包含我們人類。

And so, together with my colleagues,

所以，我跟我同事一起來呼籲，

I've called for a global conversation about the technology that I co-invented,

我們要針對這個技術召開一次全球對話，

so that we can consider all of the ethical and societal implications

讓我們可以思考這個技術

應賦予的道德與社會責任。

of a technology like this.

What I want to do now is tell you what the CRISPR technology is,

我現在已經告訴你們 CRISPER技術是甚麼、

它可以做甚麼、

what it can do,

where we are today

我們今天已走到甚麼程度、

and why I think we need to take a prudent path forward

及我為什麼認為我們需要一個縝密的思路

in the way that we employ this technology.

來運用這項技術。

當病毒感染一個細胞， 他們會插入他們的DNA

When viruses infect a cell, they inject their DNA.

在一個細菌中，

And in a bacterium,

the CRISPR system allows that DNA to be plucked out of the virus,

CRISPER系統可以把病毒的DNA拔掉，

and inserted in little bits into the chromosome --

並且插進一小片段DNA到染色體內，

the DNA of the bacterium.

也就是細菌的DNA，

And these integrated bits of viral DNA get inserted at a site called CRISPR.

而這些成簇的病毒DNA會被插入到 一個名為CRISPR位置點。

CRISPR也就是 "規律成簇的間隔短回文重複" 。

CRISPR stands for clustered regularly interspaced short palindromic repeats.

(Laughter)

(笑聲)

A big mouthful -- you can see why we use the acronym CRISPR.

很繞舌--你們可以了解為什麼 我們要使用CRISPER縮寫代替

It's a mechanism that allows cells to record, over time,

CRISPER是一種機制-- 它允許細胞隨時紀錄

the viruses they have been exposed to.

它們被感染到的病毒。

And importantly, those bits of DNA are passed on to the cells' progeny,

而且很重要的，這些片段DNA 會遺傳到細胞的後代

so cells are protected from viruses not only in one generation,

所以細胞不只一個世代會 一直被保護不受病毒感染，

but over many generations of cells.

而且是好幾世代的細胞。

This allows the cells to keep a record of infection,

這允許細胞持有受感染的紀錄，

and as my colleague, Blake Wiedenheft, likes to say,

就像我同事Blake Wiedenheft喜歡說的，

the CRISPR locus is effectively a genetic vaccination card in cells.

CRISPR的軌跡事實上就是 細胞的一張基因疫苗接踵卡。

Once those bits of DNA have been inserted into the bacterial chromosome,

一旦這些片段DNA被插入到細菌染色體，

the cell then makes a little copy of a molecule called RNA,

細胞就會複製出一小段叫RNA的分子，

which is orange in this picture,

就是照片上的橘色的部分，

that is an exact replicate of the viral DNA.

它就是病毒DNA的複製品。

RNA is a chemical cousin of DNA,

RNA是DNA的化學堂兄妹，

and it allows interaction with DNA molecules

RNA允許與DNA

相同序列的分子產生反應。

that have a matching sequence.

So those little bits of RNA from the CRISPR locus

所以這些從CRISPER區域轉錄的RNA片段，

associate -- they bind -- to protein called Cas9,

會協助他們結合出一種叫Cas9的蛋白質，

也就是照片上白色的部分，

which is white in the picture,

and form a complex that functions like a sentinel in the cell.

這個蛋白質綜合體像是細胞的衛兵，

It searches through all of the DNA in the cell,

它會搜尋細胞裡所有的的DNA，

to find sites that match the sequences in the bound RNAs.

在結合的RNA裡找到符合序列的位置，

And when those sites are found --

當這些位置找到後，

as you can see here, the blue molecule is DNA --

就如你所看到DNA上的藍色分子，

this complex associates with that DNA

這個綜合體協助DNA，

and allows the Cas9 cleaver to cut up the viral DNA.

並允許 Cas9蛋白質像刀一樣 切斷病毒DNA

It makes a very precise break.

這是一次非常精確的突破，

所以我們可以把Cas9 RNA

So we can think of the Cas9 RNA sentinel complex

like a pair of scissors that can cut DNA --

想像成像是一把DNA剪刀

it makes a double-stranded break in the DNA helix.

它在DNA螺旋結構中， 製造了一種"雙股螺旋斷裂"。

And importantly, this complex is programmable,

最重要的，這種綜合體是可以程式化的，

so it can be programmed to recognize particular DNA sequences,

所以它程式化後可以用來 辨認特定的DNA序列

並且在DNA的特定位置制造一個斷裂，

and make a break in the DNA at that site.

As I'm going to tell you now,

這也是我現在即將要告訴你們的，

we recognized that that activity could be harnessed for genome engineering,

我們已公認這個技術， 可以在基因工程上被駕馭，

to allow cells to make a very precise change to the DNA

它就在我今天介紹過的斷裂處

at the site where this break was introduced.

允許細胞裡的DNA有一個非常精準的變化。

這個方式有點類似於

That's sort of analogous

to the way that we use a word-processing program

我們使用的文書處理軟體

to fix a typo in a document.

好比在一個檔案夾裡修正一段錯字一樣

The reason we envisioned using the CRISPR system for genome engineering

我們在想使用CRISPR系統 用於基因組工程的原因是

is because cells have the ability to detect broken DNA

因為細胞具有檢測損壞的DNA的能力

and repair it.

並修復它。

So when a plant or an animal cell detects a double-stranded break in its DNA,

所以當一個植物或動物細胞在 它的DNA偵測到雙股螺旋斷裂時，

it can fix that break,

它可以修復它，

either by pasting together the ends of the broken DNA

或者把破裂的DNA尾端黏在一起，

with a little, tiny change in the sequence of that position,

以一個微小的變化 在那個位置的序列進行修復

or it can repair the break by integrating a new piece of DNA at the site of the cut.

或者它可以藉由在該位置處， 聚集新的DNA片段來修復斷裂

所以如果我們有一種方式

So if we have a way to introduce double-stranded breaks into DNA

可以引導 "雙股螺旋斷裂" 精準地進入DNA，

at precise places,

we can trigger cells to repair those breaks,

我們就可以啟動細胞來修復這些斷裂

by either the disruption or incorporation of new genetic information.

--無論藉由破壞或合併新的基因訊息。

So if we were able to program the CRISPR technology

所以如果我們可以程式化CRISPR技術

to make a break in DNA

在DNA裡製造斷裂

at the position at or near a mutation causing cystic fibrosis, for example,

例如，在囊性纖維化發生突變 的位置處或附近製造斷裂

we could trigger cells to repair that mutation.

我們可以啟動細胞去修復那個突變

Genome engineering is actually not new, it's been in development since the 1970s.

基因工程並不是新的工程 它在1970年代就開始發展

We've had technologies for sequencing DNA,

我們已經擁有DNA定序技術

複製DNA技術

for copying DNA,

and even for manipulating DNA.

甚至修改DNA技術

And these technologies were very promising,

這些技術非常有前途，

but the problem was that they were either inefficient,

問題是它們也不具有效率性，

or they were difficult enough to use

或者很難運用...

that most scientists had not adopted them for use in their own laboratories,

所以大部分的科學家們 在他們的實驗室並不採用它們，

or certainly for many clinical applications.

或是應用於臨床。

So, the opportunity to take a technology like CRISPR and utilize it has appeal,

因為CRISPER的技術相對簡單，

所以使用它的機會已展露曙光。

because of its relative simplicity.

We can think of older genome engineering technologies

我們可以想像一下 舊的基因工程技術

as similar to having to rewire your computer

就像每次你要跑新的軟體，

each time you want to run a new piece of software,

你的電腦就必須升級一樣。

whereas the CRISPR technology is like software for the genome,

而CRISPR技術就像基因組的軟體，

we can program it easily, using these little bits of RNA.

利用這些RNA小片段 我們可以簡單地編輯它

So once a double-stranded break is made in DNA,

所以一旦雙股螺旋斷裂發生在DNA裡，

we can induce repair,

我們就可以誘導修復，

and thereby potentially achieve astounding things,

因此有可能達到驚人的進展

like being able to correct mutations that cause sickle cell anemia

比如, 能夠修正引起貧血症的突變

or cause Huntington's Disease.

或引起亨廷頓氏病的突變。

I actually think that the first applications of the CRISPR technology

我真的在想, 第一個CRISPR技術的應用

are going to happen in the blood,

即將在血液裡發生。

where it's relatively easier to deliver this tool into cells,

它相對於堅硬組織而言,

更能相對簡單地能傳送應用這項技在細胞內。

compared to solid tissues.

Right now, a lot of the work that's going on

目前, 很多工作已經運用在

applies to animal models of human disease, such as mice.

人類疾病的動物模型中, 例如, 老鼠

The technology is being used to make very precise changes

這技術已經被使用做非常精準的改變。

that allow us to study the way that these changes in the cell's DNA

使我們可以用這個方式 研究細胞DNA裡的變化。

affect either a tissue or, in this case, an entire organism.

不論是一個組織或 像這個案例,整個有機體。

Now in this example,

在這案例中

the CRISPR technology was used to disrupt a gene

藉由在DNA裡的小改變

CRISPR技術被用來擾亂基因

by making a tiny change in the DNA

in a gene that is responsible for the black coat color of these mice.

這個基因是負責這些老鼠黑色皮膚的基因。

Imagine that these white mice differ from their pigmented litter-mates

想像一下, 這些白色的老鼠 與它們有色小同伴不同的原因

by just a tiny change at one gene in the entire genome,

僅是因為在整個基因組裡的一個小改變。

and they're otherwise completely normal.

除此之外, 他們幾乎一模一樣

And when we sequence the DNA from these animals,

當我對這些動物的基因做排序

we find that the change in the DNA

我們發現了在基因裡的變化

has occurred at exactly the place where we induced it,

就精準地發生在我們

using the CRISPR technology.

使用CRISPR技術的地方。

Additional experiments are going on in other animals

其他實驗也正在其它動物身上進行中，

that are useful for creating models for human disease,

用來製作人類疾病的的模型,

such as monkeys.

像是猴子。

And here we find that we can use these systems

我們在此發現, 我們可以使用這系統

to test the application of this technology in particular tissues,

在特定組織中進行這項技術的應用，

for example, figuring out how to deliver the CRISPR tool into cells.

例如, 找出如何傳送CRISPER工具到細胞中。

我們也想進一步了解

We also want to understand better

how to control the way that DNA is repaired after it's cut,

如何控制DNA在切斷後的修復方式，

and also to figure out how to control and limit any kind of off-target,

也更想知道如何控制並限制 任何一種偏離目標的狀況，

or unintended effects of using the technology.

或者使用這技術時的副作用。

I think that we will see clinical application of this technology,

我想我們即將看到, 它在臨床上的應用

certainly in adults,

特別是在成人身上,

within the next 10 years.

絕對會在10年內看到

I think that it's likely that we will see clinical trials

我想這就好像是我們即將看到的臨床試驗

and possibly even approved therapies within that time,

到時候，甚至也有可能 看到被認可的治療方式，

which is a very exciting thing to think about.

想想的確是件令人興奮的事。

And because of the excitement around this technology,

因為這項技術的興起

there's a lot of interest in start-up companies

已經有很多新的公司

that have been founded to commercialize the CRISPR technology,

已被挹注資金在研究 "將CRISPR技術商品化"，

and lots of venture capitalists

也有很多風險投資家

that have been investing in these companies.

已經投資在這些公司。

但我們也必須要思考一件事，

But we have to also consider

that the CRISPR technology can be used for things like enhancement.

就是CRISPR技術能被用在增進性能上。

Imagine that we could try to engineer humans

想像一下我們可以嘗試設計製造人類，

that have enhanced properties, such as stronger bones,

像是擁有強壯骨骼的性能

or less susceptibility to cardiovascular disease

或降低心血管疾病的誘發機率

甚至擁有我們認為

or even to have properties

that we would consider maybe to be desirable,

也許渴望很久的特徵

like a different eye color or to be taller, things like that.

像是不同的眼睛顏色, 或長的更高。

"Designer humans," if you will.

"訂製人" 如果你像這樣稱呼他們的話。

Right now, the genetic information

目前為止, 基因資訊在了解甚麼類型的基因

to understand what types of genes would give rise to these traits

會有這些特徵

is mostly not known.

目前為止大部分仍是未知的

But it's important to know

但了解CRISPR技術提供了我們一個工具

that the CRISPR technology gives us a tool to make such changes,

可以來做這些改變是很重要的

once that knowledge becomes available.

一旦那些知識變成能取得後。

This raises a number of ethical questions that we have to carefully consider,

這會引發一系列我們 必須仔細考量的道德問題，

and this is why I and my colleagues have called for a global pause

這也是為什麼我跟我同事 要呼籲全世界暫緩

in any clinical application of the CRISPR technology in human embryos,

任何臨床上有關人類胚胎 在CRISPER上的應用，

to give us time

給我們一些時間，

to really consider all of the various implications of doing so.

讓我們認真思考各種不同的CRISPER應用。

And actually, there is an important precedent for such a pause

實際上, 在1970年代，

已經有類似這樣暫緩的慣例，

from the 1970s,

when scientists got together

當時科學家們聚集在一起，

to call for a moratorium on the use of molecular cloning,

呼籲暫緩使用 "分子克隆"，

until the safety of that technology could be tested carefully and validated.

直到那個技術可以 安全地被小心測試並驗證。

So, genome-engineered humans are not with us yet,

雖然，人類基因組工程還沒到來

but this is no longer science fiction.

但這已經不是科幻小說。

動物及植物的基因組工程現在正在進行中。

Genome-engineered animals and plants are happening right now.

這也使我們每一個人眼前 面臨了一個重大責任，

And this puts in front of all of us a huge responsibility,

to consider carefully both the unintended consequences

來認真思考這個科技突破 可能會帶來的影響結果

as well as the intended impacts of a scientific breakthrough.

與不可預期的衝擊。

Thank you.

謝謝各位!

(Applause)

(掌聲)

(Applause ends)

(掌聲結束)

Bruno Giussani: Jennifer, this is a technology with huge consequences,

Bruno Giussani：Jennifer， 這是個具有很大影響力的技術，

就如你所提的

as you pointed out.

Your attitude about asking for a pause or a moratorium or a quarantine

關於你要求暫停、延期或隔離的態度

is incredibly responsible.

是非常負責任的。

There are, of course, the therapeutic results of this,

當然有一些會有療效，

but then there are the un-therapeutic ones

但也有一些無療效的，

and they seem to be the ones gaining traction,

而它們似乎

particularly in the media.

特別受媒體的關注。

This is one of the latest issues of The Economist -- "Editing humanity."

這是經濟學人雜誌最新的議題--"定製人類"

It's all about genetic enhancement, it's not about therapeutics.

大部分都關注在基因學上 能力的提升而非療效。

今天三月你跟你在科學世界裡的同事，

What kind of reactions did you get back in March

from your colleagues in the science world,

對此技術提出要求並建議

when you asked or suggested

" 我們必須立刻停止並思考 "後，

that we should actually pause this for a moment and think about it?

你們有得到什麼回應?

Jennifer Doudna: My colleagues were actually, I think, delighted

Jennifer Doudna:我想, 我同事們實際上很高興

to have the opportunity to discuss this openly.

有這機會可以公開討論這件事。

It's interesting that as I talk to people,

當我向人們訴說這件事情時的確很有趣，

my scientific colleagues as well as others,

我同事跟其他人也是，

there's a wide variety of viewpoints about this.

關於這件事大家都有不同的見解，

So clearly it's a topic that needs careful consideration and discussion.

所以很明顯地， 這件事需要深思熟慮及討論。

BG: There's a big meeting happening in December

BG：今年12月還有一次大型會議

that you and your colleagues are calling,

你跟你同事都有被邀請

together with the National Academy of Sciences and others,

與其他國際學術科學專家一起開會。

what do you hope will come out of the meeting, practically?

你希望會議中實際上能達到甚麼共識?

JD: Well, I hope that we can air the views

是的，我希望我們可以與很多 不同的私人機構及投資人

of many different individuals and stakeholders

針對如何負責任地使用此項技術

who want to think about how to use this technology responsibly.

做一次線上會議溝通。

It may not be possible to come up with a consensus point of view,

它也許不太可能會有一致的共識

but I think we should at least understand

但我認為我們至少要了解

what all the issues are as we go forward.

當我們往前走時會有那些後果

BG: Now, colleagues of yours,

BG：現在，舉你的同事George Church為例子

like George Church, for example, at Harvard,

在哈佛大學中，

they say, "Yeah, ethical issues basically are just a question of safety.

他們會說 "對啊，有關道德上的考量 ，基本上只是安全性問題，

We test and test and test again, in animals and in labs,

我們會不斷地在動物與實驗室裡測試

and then once we feel it's safe enough, we move on to humans."

一旦我們感覺它夠安全， 才會移到人體做測試啊!"

So that's kind of the other school of thought,

所以這有點像其他學校的想法，

that we should actually use this opportunity and really go for it.

我們應該利用此機會並大膽嘗試。

Is there a possible split happening in the science community about this?

這有沒有可能在科學界產生分歧呢?

I mean, are we going to see some people holding back

我的意思是，有些人忍住了，

because they have ethical concerns,

因為他們有道德方面的顧慮，

and some others just going forward

有些人則沒有，並繼續前進，

because some countries under-regulate or don't regulate at all?

因為有些國家有管制而有些則完全沒有。

JD: Well, I think with any new technology, especially something like this,

JD：我想很多新科技， 特別類似這種的，

there are going to be a variety of viewpoints,

大家都會有不同的觀點，

and I think that's perfectly understandable.

我想這完全都可以理解。

I think that in the end,

我想到最後，

this technology will be used for human genome engineering,

這個科技會被用在人類基因工程上，

but I think to do that without careful consideration and discussion

但我認為如果沒有深思熟慮並討論

of the risks and potential complications

其中的風險和可能的併發症，

would not be responsible.

那是不負責任的表現。

BG: There are a lot of technologies and other fields of science

BG：我想有很多技術和其他領域的科學

that are developing exponentially, pretty much like yours.

跟你的很像，正倍數的發展中

I'm thinking about artificial intelligence, autonomous robots and so on.

我有想到人工智慧、自主性機器人等等...

似乎沒有人 --

No one seems --

aside from autonomous warfare robots --

除了自主作戰機器人 --在這些領域中，

nobody seems to have launched a similar discussion in those fields,

似乎沒有人發表相同的言論。

要來呼籲暫緩之類的...

in calling for a moratorium.

Do you think that your discussion may serve as a blueprint for other fields?

你認不認為你的討論也許可以 成為其他領域的參考藍圖？

JD: Well, I think it's hard for scientists to get out of the laboratory.

JD：是的， 我認為，要讓科學家 離開實驗室是不太可能的。

Speaking for myself,

就我自己而言，

it's a little bit uncomfortable to do that.

這樣做有點不太舒服。

But I do think that being involved in the genesis of this

但我的確認為我們被捲入這件事的起源，

really puts me and my colleagues in a position of responsibility.

使我跟我同事必須站出來為這件事負責。

And I would say that I certainly hope that other technologies

而我也絕對希望其他的科學家

will be considered in the same way,

也能用同樣的方式來思考，

just as we would want to consider something that could have implications

正如我們考量到某些事也有可能會牽連到

in other fields besides biology.

生物或其他領域時一樣。

BG: Jennifer, thanks for coming to TED.

BG：Jennifer，感謝你來TED演講。

JD: Thank you.

JD：謝謝。

(Applause)

(掌聲)