TED2019
David R. Liu: Can we cure genetic diseases by rewriting DNA?
劉如謙博士: 我們可以透過重寫 DNA 治癒遺傳性疾病嗎？
Filmed:
Readability: 6.4
1,976,595 views
患有遺傳性疾病、基因突變型疾病、鐮刀型紅血球疾病、酪胺酸血症、乙型地中海貧血症、苯丙酮尿症、先天性耳聾、早衰症、肌肉萎縮症、精神性痴呆症的病患們有希望了！
台裔美籍生化學家劉如謙博士在這場科學發現的演說中，與我們分享他的突破技術：他與實驗室成員開發的「鹼基編輯器」可以重新編寫 DNA ，把 CRISPR 技術再次邁前一大步：如果 CRISPR 蛋白質是分子剪刀，可以透過編碼方式剪斷特定 DNA 的序列，那麼鹼基編輯器就是鉛筆，可以直接把一個 DNA 字母重寫成另一個字母。讓我們來認識這些分子機制的工藝，以及它們將如何治療或治癒基因型疾病的潛力。
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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父母親給你的最貴重的禮物，
00:17
was the two sets
of three billion letters of DNA
of three billion letters of DNA
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就是兩組三十億個字母的 DNA，
00:20
that make up your genome.
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它們組成了你的基因組。
00:22
But like anything
with three billion components,
with three billion components,
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但，跟所有三十億個元件
組成的東西一樣，
組成的東西一樣，
00:24
that gift is fragile.
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這個禮物也很脆弱。
00:26
Sunlight, smoking, unhealthy eating,
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日曬、抽菸、不健康的飲食，
00:30
even spontaneous mistakes
made by your cells,
made by your cells,
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甚至你細胞自發產生的錯誤
00:33
all cause changes to your genome.
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都有可能會改變你的基因組。
00:36
The most common kind of change in DNA
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最常見的 DNA 改變
00:40
is the simple swap of one letter,
or base, such as C,
or base, such as C,
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就是換掉一個字母，也就是鹼基，
比如把 C 換成一個不同的字母，
00:44
with a different letter,
such as T, G or A.
such as T, G or A.
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比如 T、G，或 A。
00:48
In any day, the cells in your body
will collectively accumulate
will collectively accumulate
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每天，你身體中的細胞
全部加起來累積有
全部加起來累積有
00:52
billions of these single-letter swaps,
which are also called "point mutations."
which are also called "point mutations."
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數十億次這種單一字母替換，
亦稱為「點突變」。
亦稱為「點突變」。
00:58
Now, most of these
point mutations are harmless.
point mutations are harmless.
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大部分的點突變無害。
01:00
But every now and then,
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但有時候
01:01
a point mutation disrupts
an important capability in a cell
an important capability in a cell
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點突變會干擾細胞裡的
某個重要功能，
某個重要功能，
01:05
or causes a cell to misbehave
in harmful ways.
in harmful ways.
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或是導致傷害性的細胞失常行為。
01:10
If that mutation were inherited
from your parents
from your parents
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如果那個突變遺傳自你的父母親，
01:13
or occurred early enough
in your development,
in your development,
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或是在你年幼時就發生了，
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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那麼，造成的結果就是
你很多或所有的細胞
你很多或所有的細胞
01:18
contain this harmful mutation.
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都含有這種有害的突變。
01:21
And then you would be one
of hundreds of millions of people
of hundreds of millions of people
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那麼你就得到機率只有數億分之一的
01:24
with a genetic disease,
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基因（突變）型疾病，
01:26
such as sickle cell anemia or progeria
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比如鐮刀型紅血球疾病或是早衰症，
01:29
or muscular dystrophy
or Tay-Sachs disease.
or Tay-Sachs disease.
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或是肌肉萎縮症，
或精神性痴呆症。
或精神性痴呆症。
01:34
Grievous genetic diseases
caused by point mutations
caused by point mutations
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由點突變所造成的
令人痛苦的基因型疾病
令人痛苦的基因型疾病
01:37
are especially frustrating,
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特別令人挫折，
01:39
because we often know
the exact single-letter change
the exact single-letter change
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因為我們通常確知
是哪一個字母的改變
是哪一個字母的改變
01:42
that causes the disease
and, in theory, could cure the disease.
and, in theory, could cure the disease.
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造成這種理論上可以治癒疾病。
01:47
Millions suffer from sickle cell anemia
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數百萬人飽受
鐮刀型紅血球疾病之苦，
鐮刀型紅血球疾病之苦，
01:50
because they have
a single A to T point mutations
a single A to T point mutations
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因為他們血紅素基因的兩個複本
01:53
in both copies of their hemoglobin gene.
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都有一個 A 換成 T 的突變。
01:57
And children with progeria
are born with a T
are born with a T
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早衰症的兒童則是在出生時
基因組中的某個單一位置有個 T，
02:00
at a single position in their genome
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02:02
where you have a C,
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但那裡本來應該是 C，
02:05
with the devastating consequence
that these wonderful, bright kids
that these wonderful, bright kids
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產生的結果會有很大的影響，
這些美好、聰明的孩子，
這些美好、聰明的孩子，
02:08
age very rapidly and pass away
by about age 14.
by about age 14.
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會以非常快的速度老化，
大約在十四歲時就會過世。
大約在十四歲時就會過世。
02:14
Throughout the history of medicine,
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在醫學史上，
02:16
we have not had a way
to efficiently correct point mutations
to efficiently correct point mutations
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我們還沒有方法
可以在活體上有效地校正點突變，
02:19
in living systems,
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02:20
to change that disease-causing
T back into a C.
T back into a C.
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將造成疾病的 T 改回原本的 C。
02:25
Perhaps until now.
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也許現在有辦法了。
02:27
Because my laboratory recently succeeded
in developing such a capability,
in developing such a capability,
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因為我的實驗室最近
成功開發了這種能力，
成功開發了這種能力，
02:31
which we call "base editing."
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我們稱之為「鹼基編輯」。
02:35
The story of how we developed base editing
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關於我們如何開發出
鹼基編輯的故事，
鹼基編輯的故事，
02:37
actually begins three billion years ago.
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其實始於三十億年前。
02:41
We think of bacteria
as sources of infection,
as sources of infection,
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我們認為細菌是感染的源頭，
02:43
but bacteria themselves are also
prone to being infected,
prone to being infected,
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但細菌本身也有可能會受到感染，
02:47
in particular, by viruses.
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特別是會被病毒感染。
02:49
So about three billion years ago,
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所以，大約三十億年前，
02:52
bacteria evolved a defense mechanism
to fight viral infection.
to fight viral infection.
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細菌演化出一種防禦機制
來對抗病毒感染。
來對抗病毒感染。
02:57
That defense mechanism
is now better known as CRISPR.
is now better known as CRISPR.
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這就是如今較為熟知的
CRISPR 防禦機制。
CRISPR 防禦機制。
03:01
And the warhead in CRISPR
is this purple protein
is this purple protein
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CRISPR 中的導彈頭，
就是這個紫色的蛋白質，
就是這個紫色的蛋白質，
03:03
that acts like molecular
scissors to cut DNA,
scissors to cut DNA,
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它就像是分子剪刀，
可以剪斷 DNA，
可以剪斷 DNA，
03:07
breaking the double helix into two pieces.
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把雙股螺旋斷成兩半。
03:11
If CRISPR couldn't distinguish
between bacterial and viral DNA,
between bacterial and viral DNA,
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如果 CRISPR 無法區別出
細菌和病毒 DNA 的不同，
細菌和病毒 DNA 的不同，
03:15
it wouldn't be a very useful
defense system.
defense system.
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它就不會是個很有用的防禦系統。
03:18
But the most amazing feature of CRISPR
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但 CRISPR 最驚人的特色是
03:21
is that the scissors can be
programmed to search for,
programmed to search for,
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它的剪刀可以透過編程只去搜尋、
03:26
bind to and cut
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結合和剪斷
03:28
only a specific DNA sequence.
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特定的 DNA 序列。
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，當細菌初次遇到病毒時，
03:36
it can store a small snippet
of that virus's DNA
of that virus's DNA
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它能夠儲存病毒的一小段 DNA，
03:39
for use as a program
to direct the CRISPR scissors
to direct the CRISPR scissors
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當成引導 CRISPR 剪刀的程式，
03:43
to cut that viral DNA sequence
during a future infection.
during a future infection.
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在將來被感染時，能夠剪斷
該病毒的 DNA 序列。
該病毒的 DNA 序列。
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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剪斷病毒的 DNA，
會打亂它的基因功能，
會打亂它的基因功能，
03:52
and therefore disrupts
the virus's life cycle.
the virus's life cycle.
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進而干擾該病毒的生命週期。
03:58
Remarkable researchers including
Emmanuelle Charpentier, George Church,
Emmanuelle Charpentier, George Church,
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出色的研究者，包括埃馬紐埃爾
卡彭蒂耶、喬治丘奇、
卡彭蒂耶、喬治丘奇、
04:02
Jennifer Doudna and Feng Zhang
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詹妮弗杜德納，及張鋒，
04:05
showed six years ago how CRISPR scissors
could be programmed
could be programmed
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六年前就示範過如何
透過編程讓 CRISPR 剪刀
透過編程讓 CRISPR 剪刀
剪斷我們選定的 DNA 序列，
04:09
to cut DNA sequences of our choosing,
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04:12
including sequences in your genome,
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包括在你的基因組中的序列，
04:14
instead of the viral DNA sequences
chosen by bacteria.
chosen by bacteria.
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將細菌所選擇的
病毒 DNA 序列取代掉。
病毒 DNA 序列取代掉。
04:18
But the outcomes are actually similar.
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但，後果其實蠻相似的。
04:21
Cutting a DNA sequence in your genome
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剪斷你基因組中的 DNA 序列
04:24
also disrupts the function
of the cut gene, typically,
of the cut gene, typically,
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通常也會干擾被剪斷的基因的功能，
04:28
by causing the insertion and deletion
of random mixtures of DNA letters
of random mixtures of DNA letters
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就在我們剪斷點上插入和刪除
隨機混合的 DNA 字母時發生。
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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干擾基因在某些應用上非常有用。
04:42
But for most point mutations
that cause genetic diseases,
that cause genetic diseases,
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但，對於大部分會造成
基因型疾病的點突變，
基因型疾病的點突變，
04:46
simply cutting the already-mutated gene
won't benefit patients,
won't benefit patients,
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單單只剪斷已經突變的基因，
對病人並沒有益處，
對病人並沒有益處，
04:50
because the function of the mutated gene
needs to be restored,
needs to be restored,
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因為突變基因的功能
必須要被恢復，
必須要被恢復，
04:54
not further disrupted.
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而不是被進一步干擾。
04:57
So cutting this
already-mutated hemoglobin gene
already-mutated hemoglobin gene
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所以，剪斷這個已經突變
且造成鐮刀型
紅血球疾病的血紅素基因，
紅血球疾病的血紅素基因，
05:00
that causes sickle cell anemia
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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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並不能夠恢復病人
製造健康紅血球的能力。
製造健康紅血球的能力。
05:07
And while we can sometimes introduce
new DNA sequences into cells
new DNA sequences into cells
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雖然我們可以將新的
DNA 序列放入細胞中，
DNA 序列放入細胞中，
05:11
to replace the DNA sequences
surrounding a cut site,
surrounding a cut site,
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取代剪斷點周圍的 DNA 序列，
05:15
that process, unfortunately, doesn't work
in most types of cells,
in most types of cells,
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但不幸的是，這個過程
在大部分類型的細胞中行不通，
在大部分類型的細胞中行不通，
05:19
and the disrupted gene outcomes
still predominate.
still predominate.
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被干擾的基因仍主宰病患。
05:24
Like many scientists,
I've dreamed of a future
I've dreamed of a future
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和許多科學家一樣，
我也夢想在未來
我也夢想在未來
05:26
in which we might be able to treat
or maybe even cure
or maybe even cure
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我們可以治療或甚至治癒
05:29
human genetic diseases.
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人類的基因型疾病。
05:31
But I saw the lack of a way
to fix point mutations,
to fix point mutations,
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但我沒發現解決點突變問題的方法，
05:34
which cause most human genetic diseases,
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點突變正是大部分
人類基因型疾病的成因，
人類基因型疾病的成因，
05:38
as a major problem standing in the way.
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是檔在我們前面的大問題。
05:41
Being a chemist, I began
working with my students
working with my students
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身為化學家，我開始
和我的學生合作，
和我的學生合作，
05:44
to develop ways on performing chemistry
directly on an individual DNA base,
directly on an individual DNA base,
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開發新方法，直接對
個別 DNA 鹼基進行化學反應，
個別 DNA 鹼基進行化學反應，
05:49
to truly fix, rather than disrupt,
the mutations that cause genetic diseases.
the mutations that cause genetic diseases.
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不是干擾，而是真正修復
導致遺傳疾病的突變。
導致遺傳疾病的突變。
05:56
The results of our efforts
are molecular machines
are molecular machines
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經過努力，我們開發出了分子機器，
05:59
called "base editors."
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叫做「鹼基編輯器」。
06:01
Base editors use the programmable
searching mechanism of CRISPR scissors,
searching mechanism of CRISPR scissors,
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鹼基編輯器用 CRISPR 剪刀的
可編程搜尋機制，
可編程搜尋機制，
06:07
but instead of cutting the DNA,
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但不是用來剪斷 DNA，
06:10
they directly convert
one base to another base
one base to another base
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而是直接將一個鹼基
轉換成另一個鹼基，
轉換成另一個鹼基，
06:13
without disrupting the rest of the gene.
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不干擾到基因的其它部位。
06:16
So if you think of naturally occurring
CRISPR proteins as molecular scissors,
CRISPR proteins as molecular scissors,
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所以，如果你把渾然天成的
CRISPR 蛋白質視為分子剪刀，
CRISPR 蛋白質視為分子剪刀，
06:20
you can think of base editors as pencils,
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那麼你可以把鹼基編輯器視為鉛筆，
06:23
capable of directly rewriting
one DNA letter into another
one DNA letter into another
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能夠直接改寫 DNA 字母，
06:28
by actually rearranging
the atoms of one DNA base
the atoms of one DNA base
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做法是重新安排一個
DNA 鹼基的原子，
DNA 鹼基的原子，
06:31
to instead become a different base.
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讓它成為另一個不同的鹼基。
06:35
Now, base editors don't exist in nature.
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大自然中沒有鹼基編輯器。
06:38
In fact, we engineered
the first base editor, shown here,
the first base editor, shown here,
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事實上，我們設計了人類第一個
鹼基編輯器，在這裡可以看到，
鹼基編輯器，在這裡可以看到，
06:41
from three separate proteins
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我們用了三個不同的蛋白質，
06:43
that don't even come
from the same organism.
from the same organism.
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它們甚至可以不用是
來自同一個有機體。
來自同一個有機體。
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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我們先從 CRISPR 剪刀著手，
讓它失去剪斷 DNA 的能力，
讓它失去剪斷 DNA 的能力，
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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保持其以編程方式
搜尋和結合目標 DNA 序列的能力。
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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藍色標示的是失去
能力的 CRISPR 剪刀，
能力的 CRISPR 剪刀，
07:01
we attached a second protein in red,
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我們黏上第二種
蛋白質，用紅色標示，
蛋白質，用紅色標示，
07:03
which performs a chemical reaction
on the DNA base C,
on the DNA base C,
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它會在 DNA 鹼基 C 上面
發生化學反應，
發生化學反應，
07:08
converting it into a base
that behaves like T.
that behaves like T.
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將它轉換成一個
行為類似 T 的鹼基。
行為類似 T 的鹼基。
07:12
Third, we had to attach
to the first two proteins
to the first two proteins
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第三，在之前的兩個蛋白質上，
我們還要再加上
我們還要再加上
07:16
the protein shown in purple,
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用紫色標示的蛋白質，
07:17
which protects the edited base
from being removed by the cell.
from being removed by the cell.
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它能夠保護被編輯過的鹼基
不會被細胞給移除。
不會被細胞給移除。
07:22
The net result is an engineered
three-part protein
three-part protein
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最後就會產生一個
人造的三部件融合蛋白質，
人造的三部件融合蛋白質，
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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這是人類第一次製作出
可以在基因組中的特定位置
將 C 轉換成 T 的蛋白質。
將 C 轉換成 T 的蛋白質。
07:29
at specified locations in the genome.
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07:33
But even at this point,
our work was only half done.
our work was only half done.
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但，即使做到這樣，
我們的工作也才完成一半。
我們的工作也才完成一半。
07:36
Because in order to be stable in cells,
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為要在細胞中達到穩定，
07:39
the two strands of a DNA double helix
have to form base pairs.
have to form base pairs.
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DNA 雙股螺旋的兩股
必須要形成鹼基對。
必須要形成鹼基對。
07:44
And because C only pairs with G,
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因為 C 只能和 G 配對，
07:47
and T only pairs with A,
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且 T 只能和 A 配對，
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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若只把 DNA 上的 C 改成 T，
會造成無法配對的狀況，
會造成無法配對的狀況，
07:56
a disagreement between the two DNA strands
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當 DNA 的兩股之間產生衝突，
07:59
that the cell has to resolve
by deciding which strand to replace.
by deciding which strand to replace.
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細胞為了解決問題
必須選擇一股來替換。
必須選擇一股來替換。
08:05
We realized that we could further engineer
this three-part protein
this three-part protein
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我們發現可以進一步
將這個三部件融合蛋白質再改造，
將這個三部件融合蛋白質再改造，
08:10
to flag the nonedited strand
as the one to be replaced
as the one to be replaced
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將未被編輯的那一股
標記為要被取代的目標，
標記為要被取代的目標，
08:14
by nicking that strand.
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只要在那一股上刻記即可。
08:17
This little nick tricks the cell
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這個小小刻記便能騙過細胞，
08:19
into replacing the nonedited G with an A
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細胞便會在重製被刻記的那一股時，
08:24
as it remakes the nicked strand,
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用 A 來取代未被編輯的 G，
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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這樣就能完成轉換，
將原本的 C-G 配對
將原本的 C-G 配對
08:31
into a stable T-A base pair.
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轉換為穩定的 T-A 配對。
08:36
After several years of hard work
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由博士後研究員
艾莉西斯•柯摩爾領軍，
艾莉西斯•柯摩爾領軍，
08:38
led by a former post doc
in the lab, Alexis Komor,
in the lab, Alexis Komor,
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在實驗室努力多年後，
08:42
we succeeded in developing
this first class of base editor,
this first class of base editor,
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我們成功開發出了
第一類鹼基編輯器，
第一類鹼基編輯器，
08:45
which converts Cs into Ts and Gs into As
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它能在我們標靶的位置上，
將 C 轉換為 T，
將 G 轉換為 A。
將 G 轉換為 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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在已知的三萬五千種
和疾病相關的點突變中，
和疾病相關的點突變中，
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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第一鹼基編輯器可以
逆轉其中兩類突變，
逆轉其中兩類突變，
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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這兩類加總起來就佔了五千種
（14%）點突變疾病。
（14%）點突變疾病。
09:08
But correcting the largest fraction
of disease-causing point mutations
of disease-causing point mutations
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但若要校正最大部分
造成疾病的點突變，
造成疾病的點突變，
09:13
would require developing
a second class of base editor,
a second class of base editor,
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需要開發第二類鹼基編輯器，
09:17
one that could convert
As into Gs or Ts into Cs.
As into Gs or Ts into Cs.
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它能將 A 轉換為 G，
將 T 轉換為 C。
將 T 轉換為 C。
09:22
Led by Nicole Gaudelli,
a former post doc in the lab,
a former post doc in the lab,
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由博士後研究員妮可•嘉德利領軍，
09:26
we set out to develop
this second class of base editor,
this second class of base editor,
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我們在實驗室裡
準備開發第二類鹼基編輯器，
準備開發第二類鹼基編輯器，
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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理論上，幾乎可以校正
一半以上的點突變疾病。
一半以上的點突變疾病。
09:35
including that mutation that causes
the rapid-aging disease progeria.
the rapid-aging disease progeria.
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包括會造成快速老化的早衰症突變。
09:42
We realized that we could
borrow, once again,
borrow, once again,
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我們知道可以再次藉助
09:45
the targeting mechanism of CRISPR scissors
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CRISPR 剪刀的定位機制，
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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把新的鹼基編輯器
定位到基因組的特定位置。
定位到基因組的特定位置。
09:55
But we quickly encountered
an incredible problem;
an incredible problem;
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但我們很快就會遇到一個大問題；
09:59
namely, there is no protein
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換句話說，在 DNA 裡
沒有已知的蛋白質可以把 A 轉變成 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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10:06
in DNA.
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或 T 轉變成 C 。
10:08
Faced with such a serious stumbling block,
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面對這麼大的障礙，
10:10
most students would probably
look for another project,
look for another project,
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大部分學生不是另找專題
10:13
if not another research advisor.
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就是另找指導教授。
10:15
(Laughter)
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（笑聲）
10:16
But Nicole agreed to proceed with a plan
169
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但妮可同意繼續這個
10:18
that seemed wildly ambitious at the time.
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當時看起來相當瘋狂的研究計畫。
10:21
Given the absence
of a naturally occurring protein
of a naturally occurring protein
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由於沒有這個渾然天成的蛋白質
10:24
that performs the necessary chemistry,
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來完成必要的化學反應，
10:26
we decided we would evolve
our own protein in the laboratory
our own protein in the laboratory
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我們決定在實驗室自己設計出
10:29
to convert A into a base
that behaves like G,
that behaves like G,
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能把 A 轉換成
有 G 行為表現的蛋白質 ，
有 G 行為表現的蛋白質 ，
10:33
starting from a protein
that performs related chemistry on RNA.
that performs related chemistry on RNA.
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我們從 RNA 上尋找有相關
類似化學表現的蛋白質著手。
類似化學表現的蛋白質著手。
10:39
We set up a Darwinian
survival-of-the-fittest selection system
survival-of-the-fittest selection system
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我們建立了一個
達爾文適者生存的選擇系統，
達爾文適者生存的選擇系統，
10:43
that explored tens of millions
of protein variants
of protein variants
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它可以從好幾千萬個變體蛋白質中
篩選出稀有的變體，
10:47
and only allowed those rare variants
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只讓呈現必要化學反應的
蛋白質存活下來。
蛋白質存活下來。
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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我們最後找到了這個蛋白質，
10:56
the first that can convert A in DNA
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第一個在 DNA 裡可以把
10:59
into a base that resembles G.
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A 轉變成 G 的蛋白質。
11:01
And when we attached that protein
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當我們把蛋白質黏到
11:02
to the disabled CRISPR
scissors, shown in blue,
scissors, shown in blue,
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失去剪刀效力的 CRISPR 上，
用藍色顯示，
用藍色顯示，
11:05
we produced the second base editor,
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就可以做出第二鹼基編輯器，
11:07
which converts As into Gs,
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它可以把 A 轉變成 G。
11:10
and then uses the same
strand-nicking strategy
strand-nicking strategy
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然後利用相同的「股刻記」策略，
11:14
that we used in the first base editor
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也就是我們在第一鹼基編輯器上
運用的策略，
運用的策略，
11:16
to trick the cell into replacing
the nonedited T with a C
the nonedited T with a C
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可以在重製刻記股時騙過細胞，
讓還沒編輯過的 T 變成 C。
11:21
as it remakes that nicked strand,
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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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如此就完成了 AT 鹼基
轉換成 GC 鹼基的過程。
轉換成 GC 鹼基的過程。
11:28
(Applause)
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（掌聲）
11:30
Thank you.
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謝謝。
11:32
(Applause)
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（掌聲）
11:35
As an academic scientist in the US,
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身為一位美國的學術科學家，
11:37
I'm not used to being
interrupted by applause.
interrupted by applause.
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我還真不習慣講到一半
被掌聲中斷。
被掌聲中斷。
11:40
(Laughter)
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（笑聲）
11:43
We developed these
first two classes of base editors
first two classes of base editors
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我們開發出這兩個類型的
鹼基編輯器，
鹼基編輯器，
11:47
only three years ago
and one and a half years ago.
and one and a half years ago.
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一個是在三年前，
另一個在一年半之前。
另一個在一年半之前。
11:51
But even in that short time,
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雖然問世的時間不長，
11:52
base editing has become widely used
by the biomedical research community.
by the biomedical research community.
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鹼基編輯已經在生化研究領域
被廣泛運用了。
被廣泛運用了。
11:57
Base editors have been sent
more than 6,000 times
more than 6,000 times
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我們的鹼基編輯器
應全球一千多位研究人員的索取，
應全球一千多位研究人員的索取，
12:02
at the request of more than
1,000 researchers around the globe.
1,000 researchers around the globe.
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已經送出了六千多組。
12:07
A hundred scientific research papers
have been published already,
have been published already,
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有好幾百篇在有機體裡
運用鹼基編輯器的
運用鹼基編輯器的
相關科學研究論文
已經陸陸續續發佈了，
已經陸陸續續發佈了，
12:11
using base editors in organisms
ranging from bacteria
ranging from bacteria
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範圍從細菌到植物，
老鼠到靈長類動物都有。
老鼠到靈長類動物都有。
12:14
to plants to mice to primates.
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12:19
While base editors are too new
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因為鹼基編輯器的技術還很新，
12:21
to have already entered
human clinical trials,
human clinical trials,
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目前無法運用在人類的臨床實驗，
12:24
scientists have succeeded in achieving
a critical milestone towards that goal
a critical milestone towards that goal
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但科學家已經在動物身上，
成功地完成了相當重要的目標，
12:29
by using base editors in animals
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12:32
to correct point mutations
that cause human genetic diseases.
that cause human genetic diseases.
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已經把人類基因型疾病的
點突變校正回來。
點突變校正回來。
12:37
For example,
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例如，
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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由盧克•寇蘭及瓊•拉維領軍，
12:42
two additional students in my lab,
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與我實驗室的兩位學生
組成科研團隊，共同參與合作，
組成科研團隊，共同參與合作，
12:45
recently used a virus to deliver
that second base editor
that second base editor
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最近利用一個病毒
將第二鹼基編輯器
將第二鹼基編輯器
12:49
into a mouse with progeria,
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送進患有早衰症的老鼠身上，
12:51
changing that disease-causing
T back into a C
T back into a C
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成功地將肇病的 T 轉換回 C，
12:55
and reversing its consequences
at the DNA, RNA and protein levels.
at the DNA, RNA and protein levels.
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並把牠的序列逆轉回
DNA、RNA和蛋白質狀態。
DNA、RNA和蛋白質狀態。
13:00
Base editors have also
been used in animals
been used in animals
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鹼基編輯器也已被用在動物身上，
13:03
to reverse the consequence of tyrosinemia,
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它可以逆轉酪胺酸血症、
13:07
beta thalassemia, muscular dystrophy,
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3618
乙型地中海貧血症、肌肉萎縮症、
13:11
phenylketonuria, a congenital deafness
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苯丙酮尿症、先天性耳聾、
13:14
and a type of cardiovascular disease --
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還有心血管疾病的序列。
13:16
in each case, by directly
correcting a point mutation
correcting a point mutation
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每一個案例，都能直接校正
肇病的點突變。
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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鹼基編輯器也被運用在植物上，
13:27
to introduce individual
single DNA letter changes
single DNA letter changes
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藉由改變個別的 DNA 字母
13:31
that could lead to better crops.
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可以生產出更好的農產品。
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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生物學家也已經利用鹼基編輯器
探測出基因裡個別字母所扮演的角色，
例如癌症疾病基因。
例如癌症疾病基因。
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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兩家我共同創立的公司：
Beam Therapeutics 和 Pairwise Plants,
Beam Therapeutics 和 Pairwise Plants,
13:47
are using base editing
to treat human genetic diseases
to treat human genetic diseases
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正在運用鹼基編輯技術
治療人類的基因型疾病
治療人類的基因型疾病
13:51
and to improve agriculture.
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及改善農業。
13:53
All of these applications of base editing
234
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這些鹼基編輯的應用
發生在過去不到三年的時間裡：
發生在過去不到三年的時間裡：
13:55
have taken place in less
than the past three years:
than the past three years:
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在科學歷史的時間尺度上
僅僅是眨眼之間。
僅僅是眨眼之間。
13:59
on the historical timescale of science,
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14:01
the blink of an eye.
237
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14:04
Additional work lies ahead
238
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在全盤了解鹼基編輯器的潛力前，
14:05
before base editing can realize
its full potential
its full potential
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眼前還要再努力的工作就是
14:08
to improve the lives of patients
with genetic diseases.
with genetic diseases.
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改善基因型疾病病人的生活。
14:13
While many of these diseases
are thought to be treatable
are thought to be treatable
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雖然這些疾病被認為
可由校正潛在的突變來治療，
14:16
by correcting the underlying mutation
242
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14:17
in even a modest fraction
of cells in an organ,
of cells in an organ,
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但即使只是在器官裡一小部分細胞，
14:21
delivering molecular machines
like base editors
like base editors
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傳送鹼基編輯器這類的分子機器
14:24
into cells in a human being
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到人類的細胞裡面，
14:26
can be challenging.
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仍充滿著挑戰。
14:28
Co-opting nature's viruses
to deliver base editors
to deliver base editors
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利用會讓你感冒的自然界病毒，
14:32
instead of the molecules
that give you a cold
that give you a cold
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把鹼基編輯器傳送到細胞的方式，
14:34
is one of several promising
delivery strategies
delivery strategies
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是其中一個還不錯的傳送策略，
14:37
that's been successfully used.
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這個策略已經被成功運用。
14:40
Continuing to develop
new molecular machines
new molecular machines
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持續開發新的分子機器，
14:42
that can make all of the remaining ways
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找出剩餘還沒辦法轉換的鹼基，
14:44
to convert one base pair
to another base pair
to another base pair
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14:47
and that minimize unwanted editing
at off-target locations in cells
at off-target locations in cells
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盡可能不去編輯不在靶區的細胞
14:51
is very important.
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至關重要。
14:53
And engaging with other scientists,
doctors, ethicists and governments
doctors, ethicists and governments
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而其他科學家、醫生、
倫理學家、政府的參與也很重要，
倫理學家、政府的參與也很重要，
14:58
to maximize the likelihood
that base editing is applied thoughtfully,
that base editing is applied thoughtfully,
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大家一起深思熟慮看看要如何
最大化、安全地、符合倫理地
應用鹼基編輯技術，
應用鹼基編輯技術，
15:03
safely and ethically,
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15:05
remains a critical obligation.
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是我們的重責大任。
15:09
These challenges notwithstanding,
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雖然這些挑戰仍在，
15:11
if you had told me
even just five years ago
even just five years ago
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但如果你在五年前問我，
15:14
that researchers around the globe
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全球的研究人員，
15:16
would be using laboratory-evolved
molecular machines
molecular machines
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正在利用實驗室
設計出來的分子機器，
設計出來的分子機器，
15:20
to directly convert
an individual base pair
an individual base pair
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直接把單一鹼基對還原成
15:23
to another base pair
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另一鹼基對，
15:24
at a specified location
in the human genome
in the human genome
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而且是在人類基因組裡的特定位置上
15:26
efficiently and with a minimum
of other outcomes,
of other outcomes,
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有效地且最小化發生其它結果地
執行還原。
執行還原。
15:30
I would have asked you,
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我可能會問：
15:31
"What science-fiction novel
are you reading?"
are you reading?"
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「你在看哪一本科幻小說？」
15:35
Thanks to a relentlessly dedicated
group of students
group of students
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感謝這群全力付出、
勤奮努力的學生們，
勤奮努力的學生們，
15:39
who were creative enough to engineer
what we could design ourselves
what we could design ourselves
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他們的創意讓我們可以
透過基因工程設計我們自己。
透過基因工程設計我們自己。
15:43
and brave enough
to evolve what we couldn't,
to evolve what we couldn't,
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並勇敢地設計出
我們所辦不到的事，
我們所辦不到的事，
15:46
base editing has begun to transform
that science-fiction-like aspiration
that science-fiction-like aspiration
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鹼基編輯已經開始從
科幻小說裡渴望的夢想
科幻小說裡渴望的夢想
轉變成振奮人心的真實技術，
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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或許我們給後代的最重要禮物，
15:57
may not only be
three billion letters of DNA,
three billion letters of DNA,
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除了三十億個字母 DNA，
16:00
but also the means to protect
and repair them.
and repair them.
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還有保護及修護它們的方法。
16:04
Thank you.
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謝謝。
16:05
(Applause)
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（掌聲）
16:10
Thank you.
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謝謝。
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