TED2019
David R. Liu: Can we cure genetic diseases by rewriting DNA?
刘如谦: 我们能重写DNA来治疗基因疾病吗？
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在一个科学发现的故事中，化学生物学家刘如谦（David R. Liu）分享了一个突破：他的实验室开发出了可以重写DNA的碱基编辑器。基因组编辑的这一关键步骤将CRISPR的前景提升到了一个新的水平：如果CRISPR蛋白质是分子剪刀，经过编程可以剪切特定的DNA片段，那么碱基编辑器就是铅笔，能够直接将一个DNA字母改写成另一个。通过该演讲了解更多关于这些分子机器的工作原理，以及它们治疗甚至治愈遗传疾病的潜力。
David R. Liu - Chemical biologist
David R. Liu leads a research group that combines chemistry and evolutionary techniques to create revolutionary new medicines. Full bio
David R. Liu leads a research group that combines chemistry and evolutionary techniques to create revolutionary new medicines. Full bio
Double-click the English transcript below to play the video.
00:13
The most important gift
your mother and father ever gave you
your mother and father ever gave you
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你父母给你的最重要的礼物
就是2组包含30亿个碱基的DNA，
00:17
was the two sets
of three billion letters of DNA
of three billion letters of DNA
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它们构成了你的基因组。
00:20
that make up your genome.
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00:22
But like anything
with three billion components,
with three billion components,
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但就像任何包含太多零件的东西一样，
这个礼物非常脆弱。
00:24
that gift is fragile.
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00:26
Sunlight, smoking, unhealthy eating,
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太阳光、吸烟、不健康的饮食，
甚至是细胞自身出现的错误，
00:30
even spontaneous mistakes
made by your cells,
made by your cells,
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都能改变你的基因组。
00:33
all cause changes to your genome.
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00:36
The most common kind of change in DNA
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最常见的DNA改变
就是一个字母，也叫一个碱基，
比如C（胞嘧啶），
比如C（胞嘧啶），
00:40
is the simple swap of one letter,
or base, such as C,
or base, such as C,
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换成了别的碱基，如T(胸腺嘧啶)、
G(鸟嘌呤)或者A(腺嘌呤)。
G(鸟嘌呤)或者A(腺嘌呤)。
00:44
with a different letter,
such as T, G or A.
such as T, G or A.
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00:48
In any day, the cells in your body
will collectively accumulate
will collectively accumulate
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每一天，你身体里的细胞
会累计发生数亿次
会累计发生数亿次
单碱基的改变，
这也被称作“点突变”。
这也被称作“点突变”。
00:52
billions of these single-letter swaps,
which are also called "point mutations."
which are also called "point mutations."
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00:58
Now, most of these
point mutations are harmless.
point mutations are harmless.
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大部分点突变是无害的。
但时不时，
01:00
But every now and then,
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点突变会干扰细胞的某项重要功能，
01:01
a point mutation disrupts
an important capability in a cell
an important capability in a cell
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或者引起细胞出现异常行为。
01:05
or causes a cell to misbehave
in harmful ways.
in harmful ways.
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01:10
If that mutation were inherited
from your parents
from your parents
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如果这种变异是从父母遗传而来的，
或者发生于你生命早期，
01:13
or occurred early enough
in your development,
in your development,
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那么结果很可能是
你的大部分甚至全部细胞
你的大部分甚至全部细胞
01:15
then the result would be
that many or all of your cells
that many or all of your cells
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都带有这种有害变异。
01:18
contain this harmful mutation.
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01:21
And then you would be one
of hundreds of millions of people
of hundreds of millions of people
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你可能就会像其他成千上万人一样
患上基因疾病，
01:24
with a genetic disease,
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像镰刀型红血球病，或者早衰症，
01:26
such as sickle cell anemia or progeria
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或者肌肉萎缩症，
或者家族黑蒙性痴呆症。
或者家族黑蒙性痴呆症。
01:29
or muscular dystrophy
or Tay-Sachs disease.
or Tay-Sachs disease.
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01:34
Grievous genetic diseases
caused by point mutations
caused by point mutations
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由点基因突变引起的
这些不幸的遗传疾病
这些不幸的遗传疾病
让我们尤其沮丧，
01:37
are especially frustrating,
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因为我们往往已经知道
哪个具体字母（碱基）发生了突变，
哪个具体字母（碱基）发生了突变，
01:39
because we often know
the exact single-letter change
the exact single-letter change
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从而导致了疾病。
因此理论上，我们可以治愈它。
因此理论上，我们可以治愈它。
01:42
that causes the disease
and, in theory, could cure the disease.
and, in theory, could cure the disease.
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01:47
Millions suffer from sickle cell anemia
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数百万人被镰刀型红血球病折磨，
因为他们的血红蛋白基因中
01:50
because they have
a single A to T point mutations
a single A to T point mutations
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都含有从A到T的点突变。
01:53
in both copies of their hemoglobin gene.
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01:57
And children with progeria
are born with a T
are born with a T
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而患有早衰症的孩子
只不过生来就在基因组中的
某个位置有一个T，
某个位置有一个T，
02:00
at a single position in their genome
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而正常的基因应该是C，
02:02
where you have a C,
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02:05
with the devastating consequence
that these wonderful, bright kids
that these wonderful, bright kids
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令人悲伤的是，这些聪明美好的孩子
衰老得非常快，通常活不过14岁。
02:08
age very rapidly and pass away
by about age 14.
by about age 14.
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02:14
Throughout the history of medicine,
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纵观整个医药史，
我们还没有找到有效的方法
02:16
we have not had a way
to efficiently correct point mutations
to efficiently correct point mutations
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可以在生命系统中纠正点突变，
02:19
in living systems,
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将引起疾病的T改回正常的C。
02:20
to change that disease-causing
T back into a C.
T back into a C.
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02:25
Perhaps until now.
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但现在我们有办法了。
因为我的实验室
最近成功发明了一种技术，
最近成功发明了一种技术，
02:27
Because my laboratory recently succeeded
in developing such a capability,
in developing such a capability,
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叫做“碱基编辑”。
02:31
which we call "base editing."
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02:35
The story of how we developed base editing
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关于我们如何发明“碱基编辑”的故事
可以追溯到30亿年前。
02:37
actually begins three billion years ago.
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02:41
We think of bacteria
as sources of infection,
as sources of infection,
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我们通常认为细菌是感染源，
但其实细菌本身也容易被感染，
02:43
but bacteria themselves are also
prone to being infected,
prone to being infected,
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特别是被病毒。
02:47
in particular, by viruses.
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02:49
So about three billion years ago,
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因此大约30亿年前，
细菌进化出一种防御机制，
来抵抗病毒感染。
来抵抗病毒感染。
02:52
bacteria evolved a defense mechanism
to fight viral infection.
to fight viral infection.
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02:57
That defense mechanism
is now better known as CRISPR.
is now better known as CRISPR.
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这种防御机制如今被称为CRISPR。
03:01
And the warhead in CRISPR
is this purple protein
is this purple protein
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CRISPR里最强的武器
是这种紫色的蛋白质，
是这种紫色的蛋白质，
它就像分子剪刀一样，
可以剪断DNA链，
可以剪断DNA链，
03:03
that acts like molecular
scissors to cut DNA,
scissors to cut DNA,
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将双螺旋结构剪成2条单螺旋链。
03:07
breaking the double helix into two pieces.
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03:11
If CRISPR couldn't distinguish
between bacterial and viral DNA,
between bacterial and viral DNA,
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如果CRISPR分不清
细菌和病毒的DNA，
细菌和病毒的DNA，
这就不能算是一个好的防御系统。
03:15
it wouldn't be a very useful
defense system.
defense system.
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03:18
But the most amazing feature of CRISPR
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但CRISPR最神奇之处在于
剪刀可以被编辑，
03:21
is that the scissors can be
programmed to search for,
programmed to search for,
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专门寻找、锁定和剪断
03:26
bind to and cut
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特定的DNA片段。
03:28
only a specific DNA sequence.
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03:32
So when a bacterium encounters
a virus for the first time,
a virus for the first time,
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所以当细菌首次遇到某个病毒时，
它会存储一小段病毒的DNA
03:36
it can store a small snippet
of that virus's DNA
of that virus's DNA
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以此来引导CRISPR的剪刀，
03:39
for use as a program
to direct the CRISPR scissors
to direct the CRISPR scissors
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如果将来发生感染，
就剪断病毒的DNA链。
就剪断病毒的DNA链。
03:43
to cut that viral DNA sequence
during a future infection.
during a future infection.
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03:47
Cutting a virus's DNA messes up
the function of the cut viral gene,
the function of the cut viral gene,
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剪断病毒的DNA
会扰乱该病毒基因的表达功能，
会扰乱该病毒基因的表达功能，
从而中断病毒的生命。
03:52
and therefore disrupts
the virus's life cycle.
the virus's life cycle.
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03:58
Remarkable researchers including
Emmanuelle Charpentier, George Church,
Emmanuelle Charpentier, George Church,
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许多优秀的研究者，比如
埃马纽埃尔·卡彭蒂耶、乔治·丘奇，
埃马纽埃尔·卡彭蒂耶、乔治·丘奇，
詹妮佛·杜德纳和张锋，
04:02
Jennifer Doudna and Feng Zhang
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在6年前展示了
CRISPR的剪刀可以被编辑，
CRISPR的剪刀可以被编辑，
04:05
showed six years ago how CRISPR scissors
could be programmed
could be programmed
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用来剪断我们选择的DNA片段，
04:09
to cut DNA sequences of our choosing,
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人类的基因片段，
04:12
including sequences in your genome,
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而不是细菌选的病毒的DNA片段。
04:14
instead of the viral DNA sequences
chosen by bacteria.
chosen by bacteria.
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04:18
But the outcomes are actually similar.
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效果是相似的。
04:21
Cutting a DNA sequence in your genome
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通过剪断基因中的DNA片段
同样会影响被剪基因的功能，
04:24
also disrupts the function
of the cut gene, typically,
of the cut gene, typically,
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04:28
by causing the insertion and deletion
of random mixtures of DNA letters
of random mixtures of DNA letters
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方法就是在被剪的位置上增加或删除
随机的DNA碱基组合。
04:33
at the cut site.
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04:36
Now, disrupting genes can be very
useful for some applications.
useful for some applications.
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在某些情况下，扰乱基因非常有用。
04:42
But for most point mutations
that cause genetic diseases,
that cause genetic diseases,
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但对于大部分引起遗传疾病的
点突变而言，
点突变而言，
仅仅剪断已经发生变异的基因，
对病人而言并没有意义，
对病人而言并没有意义，
04:46
simply cutting the already-mutated gene
won't benefit patients,
won't benefit patients,
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因为这些变异基因的功能需要重置，
04:50
because the function of the mutated gene
needs to be restored,
needs to be restored,
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而不是进一步打乱。
04:54
not further disrupted.
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04:57
So cutting this
already-mutated hemoglobin gene
already-mutated hemoglobin gene
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因此，把那些引起镰刀型贫血的，
已经变异的血红蛋白基因剪断，
05:00
that causes sickle cell anemia
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并不能恢复病人的造血功能。
05:02
won't restore the ability of patients
to make healthy red blood cells.
to make healthy red blood cells.
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05:07
And while we can sometimes introduce
new DNA sequences into cells
new DNA sequences into cells
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有时候我们可以加入
一些新的DNA片段到细胞中，
一些新的DNA片段到细胞中，
替代被剪断区域周围的DNA链，
05:11
to replace the DNA sequences
surrounding a cut site,
surrounding a cut site,
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但可惜的是这一过程
对大部分细胞不起作用，
对大部分细胞不起作用，
05:15
that process, unfortunately, doesn't work
in most types of cells,
in most types of cells,
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被影响的基因仍占主导地位。
05:19
and the disrupted gene outcomes
still predominate.
still predominate.
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05:24
Like many scientists,
I've dreamed of a future
I've dreamed of a future
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像许多科学家一样，
我梦想着未来有一天，
我梦想着未来有一天，
我们可以治疗甚至治愈
05:26
in which we might be able to treat
or maybe even cure
or maybe even cure
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人类遗传疾病。
05:29
human genetic diseases.
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05:31
But I saw the lack of a way
to fix point mutations,
to fix point mutations,
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但我们缺乏修复点突变的方法，
而点突变是大部分
人类基因疾病的主因，
人类基因疾病的主因，
05:34
which cause most human genetic diseases,
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是我们需要解决的主要问题。
05:38
as a major problem standing in the way.
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05:41
Being a chemist, I began
working with my students
working with my students
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我是一名化学家，我跟我的学生们
一起研究将化学反应
应用于单个DNA碱基上的方法，
应用于单个DNA碱基上的方法，
05:44
to develop ways on performing chemistry
directly on an individual DNA base,
directly on an individual DNA base,
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从而真正修复，而不仅仅是
终止引起基因疾病的变异。
终止引起基因疾病的变异。
05:49
to truly fix, rather than disrupt,
the mutations that cause genetic diseases.
the mutations that cause genetic diseases.
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05:56
The results of our efforts
are molecular machines
are molecular machines
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我们的成果就是分子机器，
叫做“碱基编辑器”。
05:59
called "base editors."
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06:01
Base editors use the programmable
searching mechanism of CRISPR scissors,
searching mechanism of CRISPR scissors,
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碱基编辑器使用的是
类似CRISPR剪刀的可编程搜索机制，
类似CRISPR剪刀的可编程搜索机制，
但与剪断DNA不同的是，
06:07
but instead of cutting the DNA,
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它们直接将一个碱基变成另一个，
06:10
they directly convert
one base to another base
one base to another base
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而不会破坏基因的其他部分。
06:13
without disrupting the rest of the gene.
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06:16
So if you think of naturally occurring
CRISPR proteins as molecular scissors,
CRISPR proteins as molecular scissors,
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如果将CRISPR蛋白质
比作分子剪刀的话，
比作分子剪刀的话，
碱基编辑器就像铅笔，
06:20
you can think of base editors as pencils,
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它能直接改写DNA碱基，
06:23
capable of directly rewriting
one DNA letter into another
one DNA letter into another
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06:28
by actually rearranging
the atoms of one DNA base
the atoms of one DNA base
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通过重新排列DNA碱基上的原子，
而不是将它变成一个不同的碱基。
06:31
to instead become a different base.
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06:35
Now, base editors don't exist in nature.
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碱基编辑器在大自然中并不存在。
06:38
In fact, we engineered
the first base editor, shown here,
the first base editor, shown here,
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实际上，我们制造的
第一个碱基编辑器，如图所示，
第一个碱基编辑器，如图所示，
是由3种独立的蛋白质组成，
06:41
from three separate proteins
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它们甚至都不是来自同一个生物体。
06:43
that don't even come
from the same organism.
from the same organism.
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06:46
We started by taking CRISPR scissors
and disabling the ability to cut DNA
and disabling the ability to cut DNA
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我们首先抑制CRISPR剪刀
剪断DNA的功能，
剪断DNA的功能，
并通过编程的方法，保持其搜索和锁定
06:51
while retaining its ability to search for
and bind a target DNA sequence
and bind a target DNA sequence
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目标DNA片段的能力。
06:55
in a programmed manner.
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06:58
To those disabled CRISPR
scissors, shown in blue,
scissors, shown in blue,
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在功能被抑制的CRISPR剪刀上，
图中蓝色的部分，
图中蓝色的部分，
我们加上了第2种蛋白质，
在这里用红色标出，
在这里用红色标出，
07:01
we attached a second protein in red,
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它会与DNA碱基C发生化学反应，
07:03
which performs a chemical reaction
on the DNA base C,
on the DNA base C,
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将其转换成与T行为相似的碱基。
07:08
converting it into a base
that behaves like T.
that behaves like T.
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07:12
Third, we had to attach
to the first two proteins
to the first two proteins
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第3步，我们将图片中
用紫色标出的蛋白质
用紫色标出的蛋白质
加在前2种蛋白质上，
07:16
the protein shown in purple,
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来保护被编辑过的碱基不被细胞移除。
07:17
which protects the edited base
from being removed by the cell.
from being removed by the cell.
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07:22
The net result is an engineered
three-part protein
three-part protein
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最终结果就是制造出一个
由3部分组成的蛋白质，
由3部分组成的蛋白质，
这也是我们在史上首次
将基因组特定位置的
将基因组特定位置的
07:25
that for the first time
allows us to convert Cs into Ts
allows us to convert Cs into Ts
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07:29
at specified locations in the genome.
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碱基C转换为T。
07:33
But even at this point,
our work was only half done.
our work was only half done.
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但做到这一步，
我们的工作也仅仅完成了一半。
我们的工作也仅仅完成了一半。
因为为了保持细胞的稳定，
07:36
Because in order to be stable in cells,
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DNA双螺旋结构中的两条链
必须形成碱基对。
必须形成碱基对。
07:39
the two strands of a DNA double helix
have to form base pairs.
have to form base pairs.
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07:44
And because C only pairs with G,
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因为C只能跟G配对，
T只能跟A配对，
07:47
and T only pairs with A,
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07:51
simply changing a C to a T
on one DNA strand creates a mismatch,
on one DNA strand creates a mismatch,
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如果只是将一链上的碱基C变成T，
会造成DNA双螺旋的不匹配，
07:56
a disagreement between the two DNA strands
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要解决这个问题，
细胞需要决定替换哪一条链。
细胞需要决定替换哪一条链。
07:59
that the cell has to resolve
by deciding which strand to replace.
by deciding which strand to replace.
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08:05
We realized that we could further engineer
this three-part protein
this three-part protein
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我们认识到可以改进
这个由3部分组成的蛋白质，
这个由3部分组成的蛋白质，
08:10
to flag the nonedited strand
as the one to be replaced
as the one to be replaced
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将未编辑的那条链标记为
要被切割掉。
08:14
by nicking that strand.
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08:17
This little nick tricks the cell
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这个小缺口诱骗细胞
用A取代未编辑的G，
08:19
into replacing the nonedited G with an A
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因为它重新生成了完整的单链，
08:24
as it remakes the nicked strand,
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这样就完成了C-G碱基对
08:27
thereby completing the conversion
of what used to be a C-G base pair
of what used to be a C-G base pair
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到稳定的T-A碱基对的转变。
08:31
into a stable T-A base pair.
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08:36
After several years of hard work
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在实验室前博士后Alexis Komor
领导的几年努力工作之后，
08:38
led by a former post doc
in the lab, Alexis Komor,
in the lab, Alexis Komor,
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我们成功地开发了第一代碱基编辑器，
08:42
we succeeded in developing
this first class of base editor,
this first class of base editor,
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将指定位置的C都转变为T，
08:45
which converts Cs into Ts and Gs into As
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G都转变为A。
08:49
at targeted positions of our choosing.
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08:52
Among the more than 35,000 known
disease-associated point mutations,
disease-associated point mutations,
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在3.5万多个已知的
与点突变有关的疾病中，
与点突变有关的疾病中，
第一代碱基编辑器可以逆转的两种突变
08:57
the two kinds of mutations
that this first base editor can reverse
that this first base editor can reverse
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总共占致病点突变的
14%或5000种左右。
14%或5000种左右。
09:01
collectively account for about 14 percent
or 5,000 or so pathogenic point mutations.
or 5,000 or so pathogenic point mutations.
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09:08
But correcting the largest fraction
of disease-causing point mutations
of disease-causing point mutations
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但是，纠正大部分致病点突变
需要开发第二代碱基编辑器，
09:13
would require developing
a second class of base editor,
a second class of base editor,
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一个可以将A都转变为G
或T都转变为C的工具。
或T都转变为C的工具。
09:17
one that could convert
As into Gs or Ts into Cs.
As into Gs or Ts into Cs.
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09:22
Led by Nicole Gaudelli,
a former post doc in the lab,
a former post doc in the lab,
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在实验室前博士后
Nicole Gaudelli的领导下，
Nicole Gaudelli的领导下，
我们着手开发了这个第二代碱基编辑器，
09:26
we set out to develop
this second class of base editor,
this second class of base editor,
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从理论上讲，这样可以
纠正近一半的致病点基因突变，
纠正近一半的致病点基因突变，
09:29
which, in theory, could correct up to
almost half of pathogenic point mutations,
almost half of pathogenic point mutations,
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包括导致早衰症的突变。
09:35
including that mutation that causes
the rapid-aging disease progeria.
the rapid-aging disease progeria.
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09:42
We realized that we could
borrow, once again,
borrow, once again,
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我们意识到我们可以再次借助，
CRISPR剪刀的靶向机制，
09:45
the targeting mechanism of CRISPR scissors
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将新的碱基编辑器
带到基因组的正确位置。
带到基因组的正确位置。
09:49
to bring the new base editor
to the right site in a genome.
to the right site in a genome.
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09:55
But we quickly encountered
an incredible problem;
an incredible problem;
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但我们很快遇到了
一个棘手的难题；
一个棘手的难题；
09:59
namely, there is no protein
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具体来说，在DNA中没有
已知的蛋白质
可以将A转化成G
可以将A转化成G
10:02
that's known to convert
A into G or T into C
A into G or T into C
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或者T转化成C。
10:06
in DNA.
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10:08
Faced with such a serious stumbling block,
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面对如此严重的困难险阻，
很多学生可能会寻找其他方案，
10:10
most students would probably
look for another project,
look for another project,
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而不是咨询其他研究顾问。
10:13
if not another research advisor.
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（笑声）
10:15
(Laughter)
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但Nicole同意继续实施一项
10:16
But Nicole agreed to proceed with a plan
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当时看来雄心勃勃的计划。
10:18
that seemed wildly ambitious at the time.
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10:21
Given the absence
of a naturally occurring protein
of a naturally occurring protein
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鉴于缺乏一种自然产生的蛋白质
来进行必要的化学反应，
10:24
that performs the necessary chemistry,
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我们决定在实验室里
进化我们自己的蛋白质
进化我们自己的蛋白质
10:26
we decided we would evolve
our own protein in the laboratory
our own protein in the laboratory
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来把A转化成一个像G一样的碱基，
10:29
to convert A into a base
that behaves like G,
that behaves like G,
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从一种对RNA进行相关
化学反应的蛋白质开始。
化学反应的蛋白质开始。
10:33
starting from a protein
that performs related chemistry on RNA.
that performs related chemistry on RNA.
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10:39
We set up a Darwinian
survival-of-the-fittest selection system
survival-of-the-fittest selection system
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我们建立了达尔文适者生存选择体系，
探索了数千万种蛋白质变异，
10:43
that explored tens of millions
of protein variants
of protein variants
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只允许那些能够进行
10:47
and only allowed those rare variants
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必要化学反应的罕见变异存活下来。
10:49
that could perform the necessary
chemistry to survive.
chemistry to survive.
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10:53
We ended up with a protein shown here,
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我们最终得到了这里显示的蛋白质，
第一个能把DNA中的A
10:56
the first that can convert A in DNA
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转化成类似G的碱基。
10:59
into a base that resembles G.
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当我们把这个蛋白质连接到
11:01
And when we attached that protein
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受到抑制的CRISPR剪刀上，
这里用蓝色标示，
这里用蓝色标示，
11:02
to the disabled CRISPR
scissors, shown in blue,
scissors, shown in blue,
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第二代碱基编辑器就诞生了，
11:05
we produced the second base editor,
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可以把A转变为G，
11:07
which converts As into Gs,
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然后使用第一代碱基编辑器中
11:10
and then uses the same
strand-nicking strategy
strand-nicking strategy
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同样的链切割策略
11:14
that we used in the first base editor
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11:16
to trick the cell into replacing
the nonedited T with a C
the nonedited T with a C
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诱骗细胞用C取代未编辑的T，
当它重新生成单链后，
11:21
as it remakes that nicked strand,
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就完成了A-T碱基对
到G-C碱基对的转变。
到G-C碱基对的转变。
11:23
thereby completing the conversion
of an A-T base pair to a G-C base pair.
of an A-T base pair to a G-C base pair.
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11:28
(Applause)
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（鼓掌）
谢谢。
11:30
Thank you.
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（鼓掌）
11:32
(Applause)
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作为一个美国学术科学家，
11:35
As an academic scientist in the US,
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11:37
I'm not used to being
interrupted by applause.
interrupted by applause.
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我还不是很习惯被掌声打断。
（笑声）
11:40
(Laughter)
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我们开发的这两代碱基编辑器
11:43
We developed these
first two classes of base editors
first two classes of base editors
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分别诞生于3年前和1年半前而已。
11:47
only three years ago
and one and a half years ago.
and one and a half years ago.
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11:51
But even in that short time,
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但在这短短的时间里，
碱基编辑器已经被
生物医学团队广泛使用。
生物医学团队广泛使用。
11:52
base editing has become widely used
by the biomedical research community.
by the biomedical research community.
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11:57
Base editors have been sent
more than 6,000 times
more than 6,000 times
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碱基编辑器应全球超过
1000位研究者的请求
1000位研究者的请求
已经被发送到全球各地多达6千次。
12:02
at the request of more than
1,000 researchers around the globe.
1,000 researchers around the globe.
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12:07
A hundred scientific research papers
have been published already,
have been published already,
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目前发表的相关科研论文多达百篇，
包括了从细菌到植物，
从老鼠到灵长类动物的生物体中
从老鼠到灵长类动物的生物体中
12:11
using base editors in organisms
ranging from bacteria
ranging from bacteria
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使用的碱基编辑器。
12:14
to plants to mice to primates.
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12:19
While base editors are too new
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碱基编辑器还太新，
尚未进入人体临床试验，
12:21
to have already entered
human clinical trials,
human clinical trials,
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科学家们已经在为之努力了，
12:24
scientists have succeeded in achieving
a critical milestone towards that goal
a critical milestone towards that goal
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他们成功使用动物的碱基编辑器
12:29
by using base editors in animals
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来纠正导致人类遗传疾病的点突变。
12:32
to correct point mutations
that cause human genetic diseases.
that cause human genetic diseases.
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12:37
For example,
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比如，
由Luke Koblan和Jon Levy领导
的一个科学家合作小组，
的一个科学家合作小组，
12:38
a collaborative team of scientists
led by Luke Koblan and Jon Levy,
led by Luke Koblan and Jon Levy,
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外加我们实验室的两个学生，
12:42
two additional students in my lab,
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最近使用了一种病毒
将第二代碱基编辑器
将第二代碱基编辑器
12:45
recently used a virus to deliver
that second base editor
that second base editor
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植入患有早衰症的老鼠体内，
12:49
into a mouse with progeria,
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把致病的T变回C，
12:51
changing that disease-causing
T back into a C
T back into a C
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并在DNA、RNA和蛋白质层面上
逆转了其导致的后果。
逆转了其导致的后果。
12:55
and reversing its consequences
at the DNA, RNA and protein levels.
at the DNA, RNA and protein levels.
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13:00
Base editors have also
been used in animals
been used in animals
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碱基编辑器也被用于动物身上
来逆转酪氨酸血症，
13:03
to reverse the consequence of tyrosinemia,
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13:07
beta thalassemia, muscular dystrophy,
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地中海贫血，肌营养不良，
苯丙酮尿症，某种先天性耳聋
13:11
phenylketonuria, a congenital deafness
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和某种类型的心血管疾病——
13:14
and a type of cardiovascular disease --
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在这些案例中，通过直接纠正
13:16
in each case, by directly
correcting a point mutation
correcting a point mutation
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导致或者参与致病的点突变
就可以逆转病症。
就可以逆转病症。
13:21
that causes or contributes to the disease.
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13:25
In plants, base editors have been used
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在植物中，碱基编辑器已被用于
引入单个DNA字符的改变
13:27
to introduce individual
single DNA letter changes
single DNA letter changes
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以带来更好的收成。
13:31
that could lead to better crops.
228
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1968
13:34
And biologists have used base editors
to probe the role of individual letters
to probe the role of individual letters
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生物学家也使用了碱基编辑器
来探索单个碱基
来探索单个碱基
在与癌症等疾病相关的基因中的作用。
13:38
in genes associated
with diseases such as cancer.
with diseases such as cancer.
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13:43
Two companies I cofounded,
Beam Therapeutics and Pairwise Plants,
Beam Therapeutics and Pairwise Plants,
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我联合创办的两家公司，
Beam Therapeutics和Pairwise Plants，
Beam Therapeutics和Pairwise Plants，
正使用碱基编辑器治疗人类基因疾病
13:47
are using base editing
to treat human genetic diseases
to treat human genetic diseases
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3825
和改善农业。
13:51
and to improve agriculture.
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13:53
All of these applications of base editing
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821953
1966
所有这些对碱基编辑的应用
都发生在不到三年的时间里：
13:55
have taken place in less
than the past three years:
than the past three years:
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3094
在科学的历史尺度上，
13:59
on the historical timescale of science,
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2364
这只是一眨眼的功夫。
14:01
the blink of an eye.
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14:04
Additional work lies ahead
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1253
在碱基编辑器
提升基因疾病病人的生命质量前，
14:05
before base editing can realize
its full potential
its full potential
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3032
我们仍有很多额外的工作要做。
14:08
to improve the lives of patients
with genetic diseases.
with genetic diseases.
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3614
14:13
While many of these diseases
are thought to be treatable
are thought to be treatable
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尽管许多这些疾病被认为是
只需要纠正器官中
很小一部分细胞
很小一部分细胞
14:16
by correcting the underlying mutation
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的潜在突变就能治疗的，
14:17
in even a modest fraction
of cells in an organ,
of cells in an organ,
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3516
将分子机器(如碱基编辑器)
14:21
delivering molecular machines
like base editors
like base editors
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送入人体细胞
14:24
into cells in a human being
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仍然富有挑战。
14:26
can be challenging.
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14:28
Co-opting nature's viruses
to deliver base editors
to deliver base editors
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3373
利用自然界的病毒来传递碱基编辑器，
而不是让你感冒的分子来做这个，
14:32
instead of the molecules
that give you a cold
that give you a cold
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是几种已经成功实践的
14:34
is one of several promising
delivery strategies
delivery strategies
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有前景的传递策略之一。
14:37
that's been successfully used.
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14:40
Continuing to develop
new molecular machines
new molecular machines
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2365
继续研究开发新的分子机器，
找到其他的方法
14:42
that can make all of the remaining ways
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将一个碱基对转变成
另一个碱基对，
另一个碱基对，
14:44
to convert one base pair
to another base pair
to another base pair
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并尽量减少细胞非目标位置上
不必要的编辑
不必要的编辑
14:47
and that minimize unwanted editing
at off-target locations in cells
at off-target locations in cells
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是非常重要的。
14:51
is very important.
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1200
14:53
And engaging with other scientists,
doctors, ethicists and governments
doctors, ethicists and governments
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4706
与其他科学家、医生、
伦理学家和政府合作，
伦理学家和政府合作，
最大限度地提高
碱基编辑用于深思熟虑、
碱基编辑用于深思熟虑、
14:58
to maximize the likelihood
that base editing is applied thoughtfully,
that base editing is applied thoughtfully,
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4791
安全和合乎道德的可能性，
15:03
safely and ethically,
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仍然是一项重要义务。
15:05
remains a critical obligation.
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15:09
These challenges notwithstanding,
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1611
尽管有这些挑战，
如果你在五年前告诉我
15:11
if you had told me
even just five years ago
even just five years ago
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全球的研究人员
15:14
that researchers around the globe
262
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1651
将使用实验室发明的分子机器
15:16
would be using laboratory-evolved
molecular machines
molecular machines
263
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3539
来直接有效地把单个碱基对
15:20
to directly convert
an individual base pair
an individual base pair
264
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2997
转变成另一个碱基对，
15:23
to another base pair
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1182
15:24
at a specified location
in the human genome
in the human genome
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2619
放在特定的基因组位置，
而且不会产生其他结果，
15:26
efficiently and with a minimum
of other outcomes,
of other outcomes,
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3825
我会反问你，
15:30
I would have asked you,
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1168
“你是不是在读哪本科幻小说？”
15:31
"What science-fiction novel
are you reading?"
are you reading?"
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2474
15:35
Thanks to a relentlessly dedicated
group of students
group of students
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3460
感谢我们孜孜不倦的学生，
他们有惊人的创造力来设计工具，
使得我们可以改造自身，
使得我们可以改造自身，
15:39
who were creative enough to engineer
what we could design ourselves
what we could design ourselves
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4460
并勇敢地去进化
原本无法进化出的特征，
原本无法进化出的特征，
15:43
and brave enough
to evolve what we couldn't,
to evolve what we couldn't,
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碱基编辑已经开始将
科幻小说般的渴望
科幻小说般的渴望
15:46
base editing has begun to transform
that science-fiction-like aspiration
that science-fiction-like aspiration
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转变成令人兴奋的现实，
15:51
into an exciting new reality,
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15:54
one in which the most important gift
we give our children
we give our children
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我们给孩子们最重要的礼物
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may not only be
three billion letters of DNA,
three billion letters of DNA,
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可能不再只是30亿DNA个碱基，
同时还有保护和修复它们的方法。
16:00
but also the means to protect
and repair them.
and repair them.
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16:04
Thank you.
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谢谢。
（鼓掌）
16:05
(Applause)
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谢谢。
16:10
Thank you.
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ABOUT THE SPEAKER
David R. Liu - Chemical biologistDavid R. Liu leads a research group that combines chemistry and evolutionary techniques to create revolutionary new medicines.
Why you should listen
During his PhD research at Berkeley, David R. Liu initiated the first general effort to expand the genetic code in living cells. As a professor at Harvard and the Broad Institute, Liu integrates chemistry and evolution to illuminate biology and develop next-generation therapeutics. He has published more than 170 papers and is an inventor on more than 65 issued US patents.
Liu's major research interests include development and use of genome editing technologies to study and treat genetic diseases; the evolution of proteins with novel therapeutic potential; and the discovery of bioactive synthetic molecules using DNA-encoded libraries. Base editing, phage-assisted continuous evolution (PACE) and DNA-encoded libraries are three technologies pioneered in his laboratory that are now widely used in the biomedical sciences. Liu has also cofounded six biotechnology and therapeutics companies, including Editas Medicine, Beam Therapeutics, Pairwise Plants and Exo Therapeutics.
Liu grew up in Riverside, California, where playing with insects in his backyard crystallized his interest in science. He also is passionate about photography and has been banned from playing blackjack at virtually every major casino in Las Vegas after developing a creative and highly advantageous card-counting system.
David R. Liu | Speaker | TED.com