TED|我们能重写DNA来治疗基因疾病吗?

Can we cure genetic diseases by rewriting DNA?

温馨提示

看视频之前，小编想给大家安利一下视频“享用”方法：
1.盲听视频内容，听出内容大意。
2.一边看可滑动的【中英对照文本】，一边听视频内容。

3.在【原文及翻译】中进行精读。
4.各位学友在精读时总结到的表达方式可以放在评论区哦，欢迎大家共享学习～

The most important gift your mother and father ever gave you was the two sets of three billion letters of DNA that make up your genome. But like anything with three billion components, that gift is fragile. Sunlight, smoking, unhealthy eating, even spontaneous mistakes made by your cells, all cause changes to your genome. The most common kind of change in DNA is the simple swap of one letter, or base, such as C, with a different letter, such as T, G or A. In any day, the cells in your body will collectively accumulate billions of these single-letter swaps, which are also called "point mutations." 

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，它们构成了你的基因组。但就像任何包含太多零件的东西一样，这个礼物非常脆弱。太阳光、吸烟、不健康的饮食，甚至是细胞自身出现的错误，都能改变你的基因组。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），换成了别的碱基，如T(胸腺嘧啶)、G(鸟嘌呤)或者A(腺嘌呤)。每一天，你身体里的细胞会累计发生数亿次单碱基的改变，这也被称作“点突变”。

Now, most of these point mutations are harmless. But every now and then, a point mutation disrupts an important capability in a cell or causes a cell to misbehave in harmful ways. If that mutation were inherited from your parents or occurred early enough in your development, then the result would be that many or all of your cells contain this harmful mutation. And then you would be one of hundreds of millions of people with a genetic disease, such as sickle cell anemia or progeria or muscular dystrophy or Tay-Sachs disease. 

大部分点突变是无害的。但时不时，点突变会干扰细胞的某项重要功能，或者引起细胞出现异常行为。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，那么结果很可能是你的大部分甚至全部细胞都带有这种有害变异。你可能就会像其他成千上万人一样患上基因疾病，像镰刀型红血球病，或者早衰症，或者肌肉萎缩症，或者家族黑蒙性痴呆症。

Grievous genetic diseases caused by point mutations are especially frustrating, because we often know the exact single-letter change that causes the disease and, in theory, could cure the disease. Millions suffer from sickle cell anemia because they have a single A to T point mutations in both copies of their hemoglobin gene. And children with progeria are born with a T at a single position in their genome where you have a C, with the devastating consequence that these wonderful, bright kids age very rapidly and pass away by about age 14. Throughout the history of medicine, we have not had a way to efficiently correct point mutations in living systems, to change that disease-causing T back into a C. Perhaps until now. Because my laboratory recently succeeded in developing such a capability, which we call "base editing." 

由点基因突变引起的这些不幸的遗传疾病让我们尤其沮丧，因为我们往往已经知道哪个具体字母（碱基）发生了突变，从而导致了疾病。因此理论上，我们可以治愈它。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都含有从A到T的点突变。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，而正常的基因应该是C，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。纵观整个医药史，我们还没有找到有效的方法可以在生命系统中纠正点突变，将引起疾病的T改回正常的C。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，叫做“碱基编辑”。

The story of how we developed base editing actually begins three billion years ago. We think of bacteria as sources of infection, but bacteria themselves are also prone to being infected, in particular, by viruses. So about three billion years ago, bacteria evolved a defense mechanism to fight viral infection. That defense mechanism is now better known as CRISPR. And the warhead in CRISPR is this purple protein that acts like molecular scissors to cut DNA, breaking the double helix into two pieces. If CRISPR couldn't distinguish between bacterial and viral DNA, it wouldn't be a very useful defense system. 

关于我们如何发明“碱基编辑”的故事可以追溯到30亿年前。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，特别是被病毒。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。这种防御机制如今被称为CRISPR。CRISPR里最强的武器是这种紫色的蛋白质，它就像分子剪刀一样，可以剪断DNA链，将双螺旋结构剪成2条单螺旋链。如果CRISPR分不清细菌和病毒的DNA，这就不能算是一个好的防御系统。

But the most amazing feature of CRISPR is that the scissors can be programmed to search for, bind to and cut only a specific DNA sequence. So when a bacterium encounters a virus for the first time, it can store a small snippet of that virus's DNA for use as a program to direct the CRISPR scissors to cut that viral DNA sequence during a future infection. Cutting a virus's DNA messes up the function of the cut viral gene, and therefore disrupts the virus's life cycle. 

但CRISPR最神奇之处在于剪刀可以被编辑，专门寻找、锁定和剪断特定的DNA片段。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以此来引导CRISPR的剪刀，如果将来发生感染，就剪断病毒的DNA链。剪断病毒的DNA会扰乱该病毒基因的表达功能，从而中断病毒的生命。

Remarkable researchers including Emmanuelle Charpentier, George Church, Jennifer Doudna and Feng Zhang showed six years ago how CRISPR scissors could be programmed to cut DNA sequences of our choosing, including sequences in your genome, instead of the viral DNA sequences chosen by bacteria. But the outcomes are actually similar. Cutting a DNA sequence in your genome also disrupts the function of the cut gene, typically, by causing the insertion and deletion of random mixtures of DNA letters at the cut site. 

许多优秀的研究者，比如埃马纽埃尔·卡彭蒂耶、乔治·丘奇，詹妮佛·杜德纳和张锋，在6年前展示了CRISPR的剪刀可以被编辑，用来剪断我们选择的DNA片段，人类的基因片段，而不是细菌选的病毒的DNA片段。效果是相似的。通过剪断基因中的DNA片段同样会影响被剪基因的功能，方法就是在被剪的位置上增加或删除随机的DNA碱基组合。

Now, disrupting genes can be very useful for some applications. But for most point mutations that cause genetic diseases, simply cutting the already-mutated gene won't benefit patients, because the function of the mutated gene needs to be restored, not further disrupted. So cutting this already-mutated hemoglobin gene that causes sickle cell anemia won't restore the ability of patients to make healthy red blood cells. And while we can sometimes introduce new DNA sequences into cells to replace the DNA sequences surrounding a cut site, that process, unfortunately, doesn't work in most types of cells, and the disrupted gene outcomes still predominate. 

在某些情况下，扰乱基因非常有用。但对于大部分引起遗传疾病的点突变而言，仅仅剪断已经发生变异的基因，对病人而言并没有意义，因为这些变异基因的功能需要重置，而不是进一步打乱。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，并不能恢复病人的造血功能。有时候我们可以加入一些新的DNA片段到细胞中，替代被剪断区域周围的DNA链，但可惜的是这一过程对大部分细胞不起作用，被影响的基因仍占主导地位。

Like many scientists, I've dreamed of a future in which we might be able to treat or maybe even cure human genetic diseases. But I saw the lack of a way to fix point mutations, which cause most human genetic diseases, as a major problem standing in the way. 

像许多科学家一样，我梦想着未来有一天，我们可以治疗甚至治愈人类遗传疾病。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，是我们需要解决的主要问题。

Being a chemist, I began working with my students to develop ways on performing chemistry directly on an individual DNA base, to truly fix, rather than disrupt, the mutations that cause genetic diseases. The results of our efforts are molecular machines called "base editors." Base editors use the programmable searching mechanism of CRISPR scissors, but instead of cutting the DNA, they directly convert one base to another base without disrupting the rest of the gene. So if you think of naturally occurring CRISPR proteins as molecular scissors, you can think of base editors as pencils, capable of directly rewriting one DNA letter into another by actually rearranging the atoms of one DNA base to instead become a different base. 

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，从而真正修复，而不仅仅是终止引起基因疾病的变异。我们的成果就是分子机器，叫做“碱基编辑器”。碱基编辑器使用的是类似CRISPR剪刀的可编程搜索机制，但与剪断DNA不同的是，它们直接将一个碱基变成另一个，而不会破坏基因的其他部分。如果将CRISPR蛋白质比作分子剪刀的话，碱基编辑器就像铅笔，它能直接改写DNA碱基，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。

Now, base editors don't exist in nature. In fact, we engineered the first base editor, shown here, from three separate proteins that don't even come from the same organism. We started by taking CRISPR scissors and disabling the ability to cut DNA while retaining its ability to search for and bind a target DNA sequence in a programmed manner. To those disabled CRISPR scissors, shown in blue, we attached a second protein in red, which performs a chemical reaction on the DNA base C, converting it into a base that behaves like T. Third, we had to attach to the first two proteins the protein shown in purple, which protects the edited base from being removed by the cell. The net result is an engineered three-part protein that for the first time allows us to convert Cs into Ts at specified locations in the genome. 

But even at this point, our work was only half done. Because in order to be stable in cells, the two strands of a DNA double helix have to form base pairs. And because C only pairs with G, and T only pairs with A, simply changing a C to a T on one DNA strand creates a mismatch, a disagreement between the two DNA strands that the cell has to resolve by deciding which strand to replace. We realized that we could further engineer this three-part protein to flag the nonedited strand as the one to be replaced by nicking that strand. This little nick tricks the cell into replacing the nonedited G with an A as it remakes the nicked strand, thereby completing the conversion of what used to be a C-G base pair into a stable T-A base pair. 

但做到这一步，我们的工作也仅仅完成了一半。因为为了保持细胞的稳定，DNA双螺旋结构中的两条链必须形成碱基对。因为C只能跟G配对，T只能跟A配对，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，要解决这个问题，细胞需要决定替换哪一条链。我们认识到可以改进这个由3部分组成的蛋白质，将未编辑的那条链标记为要被切割掉。这个小缺口诱骗细胞用A取代未编辑的G，因为它重新生成了完整的单链，这样就完成了C-G碱基对到稳定的T-A碱基对的转变。

After several years of hard work led by a former post doc in the lab, Alexis Komor, we succeeded in developing this first class of base editor, which converts Cs into Ts and Gs into As at targeted positions of our choosing. Among the more than 35,000 known disease-associated point mutations, the two kinds of mutations that this first base editor can reverse collectively account for about 14 percent or 5,000 or so pathogenic point mutations. But correcting the largest fraction of disease-causing point mutations would require developing a second class of base editor, one that could convert As into Gs or Ts into Cs. Led by Nicole Gaudelli, a former post doc in the lab, we set out to develop this second class of base editor, which, in theory, could correct up to almost half of pathogenic point mutations, including that mutation that causes the rapid-aging disease progeria. 

在实验室前博士后AlexisKomor领导的几年努力工作之后，我们成功地开发了第一代碱基编辑器，将指定位置的C都转变为T，G都转变为A。在3.5万多个已知的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总共占致病点突变的14%或5000种左右。但是，纠正大部分致病点突变需要开发第二代碱基编辑器，一个可以将A都转变为G或T都转变为C的工具。在实验室前博士后NicoleGaudelli的领导下，我们着手开发了这个第二代碱基编辑器，从理论上讲，这样可以纠正近一半的致病点基因突变，包括导致早衰症的突变。

We realized that we could borrow, once again, the targeting mechanism of CRISPR scissors to bring the new base editor to the right site in a genome. But we quickly encountered an incredible problem; namely, there is no protein that's known to convert A into G or T into C in DNA. Faced with such a serious stumbling block, most students would probably look for another project, if not another research advisor. (Laughter) But Nicole agreed to proceed with a plan that seemed wildly ambitious at the time. Given the absence of a naturally occurring protein that performs the necessary chemistry, we decided we would evolve our own protein in the laboratory to convert A into a base that behaves like G, starting from a protein that performs related chemistry on RNA. We set up a Darwinian survival-of-the-fittest selection system that explored tens of millions of protein variants and only allowed those rare variants that could perform the necessary chemistry to survive. We ended up with a protein shown here, the first that can convert A in DNA into a base that resembles G. And when we attached that protein to the disabled CRISPR scissors, shown in blue, we produced the second base editor, which converts As into Gs, and then uses the same strand-nicking strategy that we used in the first base editor to trick the cell into replacing the nonedited T with a C as it remakes that nicked strand, thereby completing the conversion of an A-T base pair to a G-C base pair. 

Thank you. 

谢谢。

As an academic scientist in the US, I'm not used to being interrupted by applause. 

作为一个美国学术科学家，我还不是很习惯被掌声打断。

We developed these first two classes of base editors only three years ago and one and a half years ago. But even in that short time, base editing has become widely used by the biomedical research community. Base editors have been sent more than 6,000 times at the request of more than 1,000 researchers around the globe. A hundred scientific research papers have been published already, using base editors in organisms ranging from bacteria to plants to mice to primates. 

我们开发的这两代碱基编辑器分别诞生于3年前和1年半前而已。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。碱基编辑器应全球超过1000位研究者的请求已经被发送到全球各地多达6千次。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使用的碱基编辑器。

While base editors are too new to have already entered human clinical trials, scientists have succeeded in achieving a critical milestone towards that goal by using base editors in animals to correct point mutations that cause human genetic diseases. For example, a collaborative team of scientists led by Luke Koblan and Jon Levy, two additional students in my lab, recently used a virus to deliver that second base editor into a mouse with progeria, changing that disease-causing T back into a C and reversing its consequences at the DNA, RNA and protein levels. 

碱基编辑器还太新，尚未进入人体临床试验，科学家们已经在为之努力了，他们成功使用动物的碱基编辑器来纠正导致人类遗传疾病的点突变。比如，由LukeKoblan和JonLevy领导的一个科学家合作小组，外加我们实验室的两个学生，最近使用了一种病毒将第二代碱基编辑器植入患有早衰症的老鼠体内，把致病的T变回C，并在DNA、RNA和蛋白质层面上逆转了其导致的后果。

Base editors have also been used in animals to reverse the consequence of tyrosinemia, beta thalassemia, muscular dystrophy, phenylketonuria, a congenital deafness and a type of cardiovascular disease -- in each case, by directly correcting a point mutation that causes or contributes to the disease. In plants, base editors have been used to introduce individual single DNA letter changes that could lead to better crops. 

碱基编辑器也被用于动物身上来逆转酪氨酸血症，地中海贫血，肌营养不良，苯丙酮尿症，某种先天性耳聋和某种类型的心血管疾病——在这些案例中，通过直接纠正导致或者参与致病的点突变就可以逆转病症。在植物中，碱基编辑器已被用于引入单个DNA字符的改变以带来更好的收成。

And biologists have used base editors to probe the role of individual letters in genes associated with diseases such as cancer. Two companies I cofounded, Beam Therapeutics and Pairwise Plants, are using base editing to treat human genetic diseases and to improve agriculture. All of these applications of base editing have taken place in less than the past three years: on the historical timescale of science, the blink of an eye. 

生物学家也使用了碱基编辑器来探索单个碱基在与癌症等疾病相关的基因中的作用。我联合创办的两家公司，BeamTherapeutics和PairwisePlants，正使用碱基编辑器治疗人类基因疾病和改善农业。所有这些对碱基编辑的应用都发生在不到三年的时间里：在科学的历史尺度上，这只是一眨眼的功夫。

Additional work lies ahead before base editing can realize its full potential to improve the lives of patients with genetic diseases. While many of these diseases are thought to be treatable by correcting the underlying mutation in even a modest fraction of cells in an organ, delivering molecular machines like base editors into cells in a human being can be challenging. Co-opting nature's viruses to deliver base editors instead of the molecules that give you a cold is one of several promising delivery strategies that's been successfully used. Continuing to develop new molecular machines that can make all of the remaining ways to convert one base pair to another base pair and that minimize unwanted editing at off-target locations in cells is very important. And engaging with other scientists, doctors, ethicists and governments to maximize the likelihood that base editing is applied thoughtfully, safely and ethically, remains a critical obligation. 

在碱基编辑器提升基因疾病病人的生命质量前，我们仍有很多额外的工作要做。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的潜在突变就能治疗的，将分子机器(如碱基编辑器)送入人体细胞仍然富有挑战。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，是几种已经成功实践的有前景的传递策略之一。继续研究开发新的分子机器，找到其他的方法将一个碱基对转变成另一个碱基对，并尽量减少细胞非目标位置上不必要的编辑是非常重要的。与其他科学家、医生、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、安全和合乎道德的可能性，仍然是一项重要义务。

These challenges notwithstanding, if you had told me even just five years ago that researchers around the globe would be using laboratory-evolved molecular machines to directly convert an individual base pair to another base pair at a specified location in the human genome efficiently and with a minimum of other outcomes, I would have asked you, "What science-fiction novel are you reading?" Thanks to a relentlessly dedicated group of students who were creative enough to engineer what we could design ourselves and brave enough to evolve what we couldn't, base editing has begun to transform that science-fiction-like aspiration into an exciting new reality, one in which the most important gift we give our children may not only be three billion letters of DNA, but also the means to protect and repair them. 

尽管有这些挑战，如果你在五年前告诉我全球的研究人员将使用实验室发明的分子机器来直接有效地把单个碱基对转变成另一个碱基对，放在特定的基因组位置，而且不会产生其他结果，我会反问你，“你是不是在读哪本科幻小说？”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，并勇敢地去进化原本无法进化出的特征，碱基编辑已经开始将科幻小说般的渴望转变成令人兴奋的现实，我们给孩子们最重要的礼物可能不再只是30亿DNA个碱基，同时还有保护和修复它们的方法。

Thank you. 

谢谢。