有人听说过 CRISPR 吗
So, has everybody heard of CRISPR?
大家不可能没听过吧
I would be shocked if you hadn’t.
这是一种人为改变染色体的技术
This is a technology — it’s for genome editing —
这种技术如此全能却又十分引人争议
and it’s so versatile and so controversial
以至于各种有趣的争论应运而生
that it’s sparking all sorts of really interesting conversations.
我们应该复活猛犸象吗
Should we bring back the woolly mammoth?
我们应该改造人类胚胎吗
Should we edit a human embryo?
我最喜欢的一个问题是
And my personal favorite:
我们能够接受
How can we justify wiping out an entire species
用这种技术
that we consider harmful to humans
将一个人类认为有害的物种
off the face of the Earth,
从地球上完全消灭吗？
using this technology?
这种科技比控制它本身的常规技术
This type of science is moving much faster
发展的还要快
than the regulatory mechanisms that govern it.
在过去六年里
And so, for the past six years,
我致力于
I’ve made it my personal mission
让更多人了解这种技术
to make sure that as many people as possible understand
以及它的意义何在
these types of technologies and their implications.
现在 CRISPR已经成了媒体炒作的焦点
Now, CRISPR has been the subject of a huge media hype,
最普遍的用于描述它的词是“容易” 和“廉价”
and the words that are used most often are “easy” and “cheap.”
我想将这个话题深入下去
So what I want to do is drill down a little bit deeper
并探讨与之有关的谜团以及现实状况
and look into some of the myths and the realities around CRISPR.
如果 你想在一条染色体上做CRISPR
If you’re trying to CRISPR a genome,
你得首先破环DNA分子
the first thing that you have to do is damage the DNA.
这种破坏需要从双螺旋结构上
The damage comes in the form of a double-strand break
斩断双链结构
through the double helix.
随后细胞的修复机制开始插手
And then the cellular repair processes kick in,
这时我们就可以让这些修复系统
and then we convince those repair processes
来改造我们想要的基因了
to make the edit that we want,
这不是自然的改造
and not a natural edit.
这就是这种技术的原理
That’s how it works.
这是一个两步走的技术
It’s a two-part system.
首先要有一个Cas9蛋白质 还有一种向导RNA
You’ve got a Cas9 protein and something called a guide RNA.
可以将其比作定向引导导弹
I like to think of it as a guided missile.
于是Cas9蛋白质 我喜欢将其拟人化
So the Cas9 — I love to anthropomorphize —
Cas9 就像是吃豆人中的小圆脸
so the Cas9 is kind of this Pac-Man thing
迫不及待地想要吃掉 DNA
that wants to chew DNA,
向导RNA相当于拉住它 使它远离染色体的牵引绳(类似遛狗)
and the guide RNA is the leash that’s keeping it out of the genome
直到它找到特定的位点
until it finds the exact spot where it matches.
这两种分子的结合体就叫做 CRISPR
And the combination of those two is called CRISPR.
这是一种我们从
It’s a system that we stole
古老的细菌结构中发现的方法
from an ancient, ancient bacterial immune system.
最令人惊奇的部分是 RNA
The part that’s amazing about it is that the guide RNA,
虽只有20个有效信息
only 20 letters of it,
但却是整个结构的定位部分
are what target the system.
CRISPR 设计起来非常容易
This is really easy to design,
并且价格低廉
and it’s really cheap to buy.
这种手法已经被模块化
So that’s the part that is modular in the system;
并且一成不变
everything else stays the same.
因此这种技术用起来十分便捷 并且有效
This makes it a remarkably easy and powerful system to use.
向导 RNA 和 Cas9 蛋白质组成一个整体
The guide RNA and the Cas9 protein complex together
在染色体上来回穿梭
go bouncing along the genome,
当它们发现一个与向导 RNA 吻合的部位时
and when they find a spot where the guide RNA matches,
就会嵌入双螺旋结构
then it inserts between the two strands of the double helix,
将其撕裂
it rips them apart,
导致 Cas9 蛋白质开始切割工作
that triggers the Cas9 protein to cut,
于是突然之间
and all of a sudden,
你就让一个细胞处在了极大的恐慌之中
you’ve got a cell that’s in total panic
因为它的一条 DNA 被破坏
because now it’s got a piece of DNA that’s broken.
这时它该怎么办呢
What does it do?
呼叫现场急救员
It calls its first responders.
细胞有着两种主要的修复机制
There are two major repair pathways.
第一种是直接将断掉的 DNA 接上
The first just takes the DNA and shoves the two pieces back together.
这种方法不是最有效的
This isn’t a very efficient system,
由于有时会多一个链环
because what happens is sometimes a base drops out
有时又会少一个
or a base is added.
这种方法只能… 算撞出一个基因来
It’s an OK way to maybe, like, knock out a gene,
但不是我们通常想要的基因改造方式
but it’s not the way that we really want to do genome editing.
第二种修复机制更为有趣
The second repair pathway is a lot more interesting.
在这种机制中
In this repair pathway,
细胞会寻找一条相同的 DNA
it takes a homologous piece of DNA.
在有着双染色体的生物 比如说人类
And now mind you, in a diploid organism like people,
我们得到了我们父母 各自的一组染色体
we’ve got one copy of our genome from our mom and one from our dad,
如果一条 DNA 受损
so if one gets damaged,
细胞可以用另外一条来修复它
it can use the other chromosome to repair it.
这就是这种技术的原理
So that’s where this comes from.
修复成功之后
The repair is made,
染色体又重获安全
and now the genome is safe again.
我们将其调包的方法
The way that we can hijack this
是用一条新的DNA替换中间段
is we can feed it a false piece of DNA,
两端与原来相同
a piece that has homology on both ends
的新DNA来修复它
but is different in the middle.
于是你可以随心所欲地将你想要的中间部分安装上去
So now, you can put whatever you want in the center
细胞本身却毫无察觉
and the cell gets fooled.
你可以改变基因中的一条信息
So you can change a letter,
也可以删除它
you can take letters out,
但最为重要的是你可以像特洛伊木马一样
but most importantly, you can stuff new DNA in,
将一条全新的 DNA 嵌入
kind of like a Trojan horse.
CRISPR 的作用出人预料
CRISPR is going to be amazing,
它能推动许多
in terms of the number of different scientific advances
不同领域的科技发展
that it’s going to catalyze.
它的特殊之处在于这个攻击系统模块
The thing that’s special about it is this modular targeting system.
我们多年来一直尝试着将 DNA 嵌入生物体中
I mean, we’ve been shoving DNA into organisms for years, right?
但由于这种模块攻击系统
But because of the modular targeting system,
我们能将它放在我们想要的地方
we can actually put it exactly where we want it.
问题是现在有很多关于 它的廉价性
The thing is that there’s a lot of talk about it being cheap
和便捷性的话题
and it being easy.
我有一所社区实验室
And I run a community lab.
并且开始收到人们的来信
I’m starting to get emails from people that say stuff like,
我能在开放夜来你那吗？
“Hey, can I come to your open night
我能用 CRISPR 编辑一下自己的基因吗？
and, like, maybe use CRISPR and engineer my genome?”
（笑声）
(Laugher)
讲真的
Like, seriously.
我说 不能
I’m, “No, you can’t.”
（笑声）
(Laughter)
但我听说那很便宜 很简单啊
“But I’ve heard it’s cheap. I’ve heard it’s easy.”
我们谈谈这个吧
We’re going to explore that a little bit.
究竟有多便宜
So, how cheap is it?
相对来说确实便宜
Yeah, it is cheap in comparison.
实验所需材料
It’s going to take the cost of the average materials for an experiment
花费从几千美元降至几百美元
from thousands of dollars to hundreds of dollars,
还能节约时间
and it cuts the time a lot, too.
几周的工作几天就能完成
It can cut it from weeks to days.
这很好
That’s great.
但你仍需要专业的实验室来做
You still need a professional lab to do the work in;
没有实验室是不可能完成这项技术的
you’re not going to do anything meaningful outside of a professional lab.
别相信那些说
I mean, don’t listen to anyone who says
你可以在自家厨房里做实验的人
you can do this sort of stuff on your kitchen table.
这项技术真的不简单
It’s really not easy to do this kind of work.
更别说有一场如火如荼的专利战打的正酣
Not to mention, there’s a patent battle going on,
即使发明者创造出了这样的奇思妙想
so even if you do invent something,
布罗德研究所和 UC 伯克利也在为专利权而争斗不休
the Broad Institute and UC Berkeley are in this incredible patent battle.
隔岸观火很有趣
It’s really fascinating to watch it happen,
因为他们都在不断控诉对方 称其发布诬告性言论
because they’re accusing each other of fraudulent claims
他们中的有人常常说
and then they’ve got people saying,
我在我的笔记本上到处都记了笔记
“Oh, well, I signed my notebook here or there.”
这件事好几年都没完
This isn’t going to be settled for years.
即使真的解决了
And when it is,
到那时你就得为使用这项技术
you can bet you’re going to pay someone a really hefty licensing fee
支付高昂的费用
in order to use this stuff.
所以它真的便宜吗
So, is it really cheap?
如果你有自己的实验室 并且在做基础学科实验的话 确实很便宜
Well, it’s cheap if you’re doing basic research and you’ve got a lab.
容易吗 现在我们来谈谈这个
How about easy? Let’s look at that claim.
魔鬼总藏在深处
The devil is always in the details.
我们仍然不十分了解细胞
We don’t really know that much about cells.
他们就像是一个黑匣子
They’re still kind of black boxes.
比如说 我们不知道为什么有一些RNA十分好用
For example, we don’t know why some guide RNAs work really well
有一些却不好使
and some guide RNAs don’t.
我们也不知道为什么 一些细胞采用一种修复机制
We don’t know why some cells want to do one repair pathway
另一些采用另外一种
and some cells would rather do the other.
除了这些以外
And besides that,
在一开始 将这个系统植入细胞时
there’s the whole problem of getting the system into the cell
同样面临着问题
in the first place.
在培养皿中 这不是很难
In a petri dish, that’s not that hard,
可是如果是整个生物体
but if you’re trying to do it on a whole organism,
那就很麻烦了
it gets really tricky.
采用血液或是骨髓是可行的
It’s OK if you use something like blood or bone marrow —
它们也是现在的研究重点
those are the targets of a lot of research now.
有个关于一位女孩的奇迹
There was a great story of some little girl
她患了白血病
who they saved from leukemia
最后通过将血取出 人为将其改造后放回人体
by taking the blood out, editing it, and putting it back
最终痊愈——用的是CRISPR的前期技术
with a precursor of CRISPR.
这是一种人们希望从事的研究
And this is a line of research that people are going to do.
但是如果你想针对整个人体
But right now, if you want to get into the whole body,
可能就要用到病毒了
you’re probably going to have to use a virus.
采集病毒以后 将 CRISPR 放进去
So you take the virus, you put the CRISPR into it,
你需要让病毒感染细胞
you let the virus infect the cell.
但只要你将病毒注入细胞内部
But now you’ve got this virus in there,
就可能出现长期的副作用
and we don’t know what the long-term effects of that are.
而且 CRISPR 还有一些伤及无辜的攻击行为
Plus, CRISPR has some off-target effects,
只占很小一部分—— 但总是存在的
a very small percentage, but they’re still there.
一段时间过后又会发生什么呢
What’s going to happen over time with that?
这不是小事
These are not trivial questions,
有科学家一直想要解决这些问题
and there are scientists that are trying to solve them,
而且它们最终会被解决 很有这种可能
and they will eventually, hopefully, be solved.
但研究需要时间
But it ain’t plug-and-play, not by a long shot.
这种方法真的容易吗
So: Is it really easy?
在经过几年的深入研究之后
Well, if you spend a few years working it out in your particular system,
它才真正变得容易
yes, it is.
还有一个问题是
Now the other thing is,
我们不知道怎样通过改变染色体中的某个部位
we don’t really know that much about how to make a particular thing happen
来达到我们想要的目的
by changing particular spots in the genome.
我们现在还无法获知
We’re a long way away from figuring out
怎样使一只猪长出翅膀
how to give a pig wings, for example.
或是多长一条腿 就拿这个举例
Or even an extra leg — I’d settle for an extra leg.
那会十分有趣 不是吗
That would be kind of cool, right?
但现状是
But what is happening
CRISPR 正被成千上万的科学家
is that CRISPR is being used by thousands and thousands of scientists
用来完成十分重要的工作
to do really, really important work,
例如 构建更好的动物疾病模型
like making better models of diseases in animals, for example,
或是找到可用的化学物质生产方法
or for taking pathways that produce valuable chemicals
用它们进行工业生产和发酵
and getting them into industrial production in fermentation vats,
甚至是有关基因功能的基本研究
or even doing really basic research on what genes do.
这就是 CRISPR 的故事
This is the story of CRISPR we should be telling,
我不喜欢它浮华的那一面
and I don’t like it that the flashier aspects of it
将它真正的光芒掩盖了
are drowning all of this out.
是不计其数的科学家呕心沥血地造就了 CRISPR
Lots of scientists did a lot of work to make CRISPR happen,
让我感到欣慰的是
and what’s interesting to me
这些科学家得到了社会的广泛支持
is that these scientists are being supported by our society.
想一想
Think about it.
我们有着能够让一小部分人愿意倾其一生
We’ve got an infrastructure that allows a certain percentage of people
从事科学研究的机构
to spend all their time doing research.
这让我们所有人成为了 CRISPR 的创造者
That makes us all the inventors of CRISPR,
让我们成为 CRISPR 的掌控者
and I would say that makes us all the shepherds of CRISPR.
我们需要负起责任来
We all have a responsibility.
所以我们需要重视这方面的技术
So I would urge you to really learn about these types of technologies,
因为 只有这样
because, really, only in that way
我们才能掌控这些技术的发展
are we going to be able to guide the development of these technologies,
和它们的应用
the use of these technologies
然后确保到最后我们能得到正面的结果
and make sure that, in the end, it’s a positive outcome —
不管是对这颗星球还是我们自己
for both the planet and for us.
谢谢
Thanks.
(掌声)
(Applause)