一位女科學(xué)家的兩個戰(zhàn)場

Jennifer Doudna, a Pioneer Who Helped Simplify Genome Editing

一位女科學(xué)家的兩個戰(zhàn)場

BERKELEY, Calif. — As a child in Hilo, one of the less touristy parts of Hawaii, Jennifer A. Doudna felt out of place. She had blond hair and blue eyes, and she was taller than the other kids, who were mostly of Polynesian and Asian descent.

加利福尼亞州伯克利——在游客稀少的夏威夷城市希洛(Hilo)，孩提時的詹妮弗·A·杜德納(Jennifer A. Doudna)感覺自己和這個地方格格不入。她擁有一頭金發(fā)，藍色的眼睛，又比其他孩子高出一截，周圍的孩子大部分是波利尼西亞裔或亞裔。

“I think to them I looked like a freak,” she recently recalled. “And I felt like a freak.”

“我想在他們看來我像是一個怪胎，”不久前杜德納回憶道，“而且我感覺自己也像是個怪胎。”

Her isolation contributed to a kind of bookishness that propelled her toward science. Her upbringing “toughened her up,” said her husband, Jamie Cate. “She can handle a lot of pressure.”

與外界的隔閡帶給她的是促使她走向科學(xué)的一種書卷氣。這樣的生長環(huán)境“讓她在磨礪中成長”，她的丈夫杰米·凱特(Jamie Cate)說。“她能夠應(yīng)對巨大的壓力。”

These days, that talent is being put to the test.

近來，這位才女正面臨著考驗。

Three years ago, Dr. Doudna, a biochemist at the University of California, Berkeley, helped make one of the most monumental discoveries in biology: a relatively easy way to alter any organism’s DNA, just as a computer user can edit a word in a document.

杜德納博士是加州大學(xué)伯克利分校的生物化學(xué)家。3年前，她幫助完成了生物學(xué)界堪稱不朽的一項發(fā)現(xiàn)：用一種比較簡單的方法來改變?nèi)魏紊矬w的DNA，猶如電腦使用者可以在文檔中編輯一個單詞一樣。

The discovery has turned Dr. Doudna (the first syllable rhymes with loud) into a celebrity of sorts, the recipient of numerous accolades and prizes. The so-called Crispr-Cas9 genome editing technique is already widely used in laboratory studies, and scientists hope it may one day help rewrite flawed genes in people, opening tremendous new possibilities for treating, even curing, diseases.

這一發(fā)現(xiàn)讓杜德納成為名人，她獲得了無數(shù)的榮譽和獎項。這一被稱為Crispr-Cas9的基因組編輯技術(shù)已經(jīng)被廣泛應(yīng)用于實驗室研究，科學(xué)家們希望，未來它可以幫助重新編寫人類有缺陷的基因，為治療甚至是治愈疾病帶來新的、巨大的可能性。

But now Dr. Doudna, 51, is battling on two fronts to control what she helped create.

不過現(xiàn)在，51歲的杜德納正奮戰(zhàn)在兩個戰(zhàn)場，來控制她幫助發(fā)明的Crispr-Cas9技術(shù)。

While everyone welcomes Crispr-Cas9 as a strategy to treat disease, many scientists are worried that it could also be used to alter genes in human embryos, sperm or eggs in ways that can be passed from generation to generation. The prospect raises fears of a dystopian future in which scientists create an elite population of designer babies with enhanced intelligence, beauty or other traits.

就在每個人都樂見Crispr-Cas9成為治療疾病的一種策略時，許多科學(xué)家擔(dān)憂，它可能會被用于改變?nèi)祟惻咛?、精子或卵子中的基因，如此一來，這些基因改變可以被遺傳給一代又一代人。這樣的前景讓我們對未來充滿恐懼：在這個反烏托邦的未來，科學(xué)家制造出一個精英群體，經(jīng)過設(shè)計的嬰兒擁有增強的智力、美貌或其他特性。

Scientists in China reported last month that they had already used the technique in an attempt to change genes in human embryos, though on defective embryos and without real success.

上個月，中國科學(xué)家宣稱，他們已經(jīng)使用這項技術(shù)嘗試改變?nèi)祟惻咛サ幕?，這個實驗是在有缺陷的胚胎上進行，并沒有成功。

Dr. Doudna has been organizing the scientific community to prevent this ethical line from being crossed. “The idea that you would affect evolution is a very profound thing,” she said.

杜德納博士一直在組織科學(xué)界人士防止倫理底線遭到破壞。“影響進化的想法是一件非常嚴重的事。”她說。

She is also fighting for control of what could be hugely lucrative intellectual property rights to the genome editing technique. To the surprise of many, the first sweeping patents for the technology were granted not to her, but to Feng Zhang, a scientist at the Broad Institute and M.I.T.

杜德納同時也在爭取控制這項基因編輯技術(shù)的知識產(chǎn)權(quán)，它可能會帶來巨大的財富。令人驚訝的是，與這項技術(shù)相關(guān)的第一批專利并沒有授予她，而是授予麻省理工學(xué)院和布羅德研究所(Broad Institute)的科學(xué)家張鋒。

The University of California is challenging the decision, and the nasty skirmish has cast a bit of a pall over the field.

加州大學(xué)對這一決議提出了質(zhì)疑。因為巨大的爭議，基因編輯技術(shù)籠罩在陰云之中。

“I really want to see this technology used to help people,” Dr. Doudna said. “It would be a shame if the I.P. situation would block that.”

“我真的希望看到這項技術(shù)用于幫助人類。”杜德納博士說，“如果知識產(chǎn)權(quán)機構(gòu)阻止這么做，這將令人遺憾。”

The development of the Crispr-Cas9 technique is a story in which obscure basic biological research turned out to have huge practical implications. For Dr. Doudna, though, it is only one accomplishment in a stellar career.

Crispr-Cas9技術(shù)的發(fā)展，可以被認為是一個鮮為人知的基礎(chǔ)生物學(xué)研究發(fā)展為巨大應(yīng)用價值的故事。不過，對杜德納博士來說，Crispr-Cas9只是她輝煌職業(yè)生涯中的一項成就而已。

“She’s been a high-impact scientist from the time she was a graduate student,” said Thomas Cech, a Nobel laureate and professor of chemistry and biochemistry at the University of Colorado, for whom Dr. Doudna was a postdoctoral researcher. “New topics, new fields of science, but she just has a knack for discovery.”

“從研究生時代開始，她就一直是個具有高度影響力的科學(xué)家。”諾貝爾獎得主托馬斯·切赫(Thomas Cech)說，他是科羅拉多州大學(xué)化學(xué)和生物化學(xué)教授，杜德納曾跟隨他做博士后研究。“新的主題，新的科學(xué)領(lǐng)域，但是她就是有發(fā)現(xiàn)的技能。”

Dr. Doudna was 7 when she moved to Hilo, where her father taught literature at the University of Hawaii campus there, and her mother lectured on history at a community college. Their daughter loved exploring the rain forests and was fascinated by how things worked. She found her calling in high school after hearing a lecture by a scientist about her research into how normal cells became cancerous.

杜德納7歲時，全家搬到希洛。父親在夏威夷大學(xué)教文學(xué)，母親在一個社區(qū)大學(xué)講授歷史，他們的女兒喜歡探索熱帶雨林，對事物如何運行很著迷。在高中時期，她聽了一個科學(xué)家的講座，這位科學(xué)家講解了自己是怎樣研究正常的細胞如何變成癌細胞的。因為這次講座， 杜德納找到了自己的使命。

“I was just dumbstruck,” Dr. Doudna recalled. “I wanted to be her.”

“我當(dāng)時目瞪口呆。”杜德納回憶道，“我希望自己成為像她那樣的科學(xué)家。”

After studying biochemistry at Pomona College in California, she went to Harvard for graduate school. There her adviser, the future Nobel laureate Jack Szostak, was doing research on RNA. Some scientists believe that RNA, not DNA, was the basis of early life, since the molecule can both store genetic information and catalyze chemical reactions.

在加州的波莫納學(xué)院(Pomona College)學(xué)習(xí)生物化學(xué)后，她去了哈佛的研究生院。她的導(dǎo)師、2009年諾貝爾生理學(xué)或醫(yī)學(xué)獎獲得者杰克·紹斯塔克(Jack Szostak)當(dāng)時在做RNA的研究。一些科學(xué)家相信，RNA是早期生命的基礎(chǔ)，而不是DNA，因為RNA分子可以同時存儲遺傳信息，又能催化化學(xué)反應(yīng)。

Dr. Doudna earned her doctoral degree by engineering a catalytic RNA that could self-replicate, adding evidence to that theory. But her inability to visualize this catalytic RNA hindered her work.

杜德納憑借改造催化性RNA使之具有自我復(fù)制能力獲得博士學(xué)位，這也為RNA是早期生命基礎(chǔ)的理論增加了證據(jù)。但是，無法使這種催化性RNA可視化阻礙了她的研究。

So as a postdoctoral researcher in Colorado, she decided to try to determine the three-dimensional atomic structure of RNA using X-ray diffraction — and succeeded, though she had had no formal training in the technique. Structural and biochemical studies of RNA in action have been her forte ever since.

因此，在科羅拉多州從事博士后研究時，她決定嘗試使用X射線衍射確定RNA的三維原子結(jié)構(gòu)并且取得了成功，盡管她沒有經(jīng)過正規(guī)的技術(shù)訓(xùn)練。自那之后，RNA結(jié)構(gòu)和生物化學(xué)研究成為她的特長。

In 2000, while on the faculty at Yale, she won the Alan T. Waterman Award, given each year by the National Science Foundation to an exceptional young scientist. She moved to Berkeley in 2002.

2000年，還是耶魯教員的杜德納獲得艾倫·沃特曼獎(Alan T. Waterman Award)，這一獎項由美國國家科學(xué)基金每年授予一位杰出的青年科學(xué)家。2002年，她赴伯克利任職。

In 2005, Dr. Doudna was approached by Jillian Banfield, an environmental researcher at Berkeley who had been sequencing the DNA of unusual microbes that lived in a highly acidic abandoned mine. In the genomes of many of these microbes were unusual repeating sequences called “clustered regularly interspaced short palindromic repeats,” or Crispr.

2005年，伯克利大學(xué)的一位環(huán)境科學(xué)的研究者吉利安·班菲爾德(Jillian Banfield)找到杜德納，班菲爾德當(dāng)時正在對高度酸性的廢氣礦井中的罕見微生物進行DNA測序。許多這些微生物的基因組存在罕見的重復(fù)序列，被稱作 “規(guī)律成簇的間隔短回文重復(fù)”，即Crispr。

No one was quite sure what they did, though over the next few years scientists elsewhere established that these sequences were part of a bacterial immune system. Between the repeated sequences were stretches of DNA taken from viruses that had previously infected the bacteria — genetic most-wanted posters, so to speak.

即便在此后的幾年時間里，沒有人確定它們的功能，直到其他地方的科學(xué)家證實，這些序列是細菌免疫系統(tǒng)的一部分。這些重復(fù)序列之間的DNA片段源自于曾經(jīng)侵染細菌的病毒——可以這么說，這是細菌最想得到的遺傳標識。

If the same virus invaded again, these stretches of DNA would permit the bacteria to recognize it and destroy it by slicing up its genetic material. Dr. Doudna was trying to figure out exactly how this happened.

如果相同的病毒再次入侵，這些DNA片段將允許細菌識別這一病毒并通過切割它的遺傳物質(zhì)摧毀它。杜德納試圖弄清楚這到底是如何發(fā)生的。

“I remember thinking this is probably the most obscure thing I ever worked on,” she said.

“我記得，我當(dāng)時認為這可能是我研究過的最難懂的東西。”她說。

It would prove to have wide use. At a conference in early 2011, she met Emmanuelle Charpentier, a French microbiologist at Umea University in Sweden, who had already made some fundamental discoveries about the relatively simple Crispr system in one bacterial species.

日后它將被證明有著廣泛的用途。在2011年初的一個會議上，她遇到了瑞典于默奧大學(xué)(Umea University)的法國微生物學(xué)家埃馬紐埃爾·卡彭蒂耶(Emmanuelle Charpentier)，她已經(jīng)在一個細菌物種中發(fā)現(xiàn)了一個相對簡單的Crispr系統(tǒng)。

The bacterial expert and the structural biologist decided to work together.

細菌專家和結(jié)構(gòu)生物學(xué)家決定聯(lián)手研究。

“It was very enjoyable, because we were complementary,” said Dr. Charpentier, who recalled sitting in her office near the North Pole while Dr. Doudna regaled her with stories about Hawaii.

“合作很愉快，因為我們剛好互補。”卡彭蒂耶博士說。她坐在靠近北極的辦公室回憶起，杜德納講述的關(guān)于夏威夷的故事讓她樂不可支。

Along with postdoctoral researchers Martin Jinek and Krzysztof Chylinski, the two scientists eventually figured out how two pieces of RNA join up with a protein made by the bacteria called Cas9 to cut DNA at a specific spot. The researchers also found that the two RNA pieces could be combined into one and still function.

杜德納的兩個博士后馬丁·伊內(nèi)克(Martin Jinek)和克日什托夫·黑林斯基(Krzysztof Chylinski)，最終找到了兩段RNA以及由細菌產(chǎn)生的蛋白質(zhì)系統(tǒng)，又被稱為Cas9蛋白系統(tǒng)，它可以在DNA特定位置進行剪切。研究人員還發(fā)現(xiàn)，這兩個RNA片段可組合成一個片段，并仍能發(fā)揮作用。

In a eureka moment, the scientists realized that this cellular defense system might be used to edit genomes, not just kill viruses.

在這靈光閃現(xiàn)的時刻，科學(xué)家們意識到，這種細菌防御系統(tǒng)不僅可用來殺死病毒，也可用來編輯基因組。

A specific sequence of guide RNA could be made to attach to a spot virtually anywhere on the genome, and the Cas9 protein would cleave the DNA at that spot. Then pieces of the DNA could be deleted or added, just as a film editor might cut a film and splice in new frames.

Cas9蛋白系統(tǒng)中一個特定的向?qū)NA 序列可附著在基因組上幾乎任何一個位置， Cas9蛋白會切開DNA序列的特定位點，然后在這個位點添加或刪除特定的DNA片段，如同電影剪輯那樣，刪掉或拼接上一個新的電影片段。

The researchers demonstrated this using DNA in a test tube. While there were other genome editing techniques, they found that Crispr-Cas9 was much simpler.

研究人員在試管中演示了DNA編輯這一操作過程。雖然目前還有其他的基因組編輯技術(shù)，但是他們發(fā)現(xiàn)Crispr-Cas9技術(shù)要簡單得多。

The paper describing the technique, published by the journal Science in June 2012, set off a race to see if it would work in human, plant and animal cells.

對這項技術(shù)的最早研究發(fā)表在2012年6月的《科學(xué)》雜志上，隨后引發(fā)了一場對該技術(shù)是否可應(yīng)用于人類、植物和動物細胞的爭論。

Dr. Doudna, whose expertise was in working with molecules, not cells, reported such a demonstration in human cells in January 2013. But her report came four weeks after two papers were published simultaneously, one by George Church at Harvard and the other by the Broad Institute’s Dr. Zhang.

杜德納博士的專業(yè)知識是在分子生物學(xué)領(lǐng)域，而不是細胞生物學(xué)領(lǐng)域。2013年1月，她在開放期刊eLife上發(fā)表了這項技術(shù)在人類細胞中的應(yīng)用，就在4周之前，哈佛大學(xué)的喬治·切奇(George Church)以及布羅德研究所的張鋒博士分別發(fā)表了一篇論文。

Now the University of California and the Broad Institute are arguing before the federal patent office over whether Dr. Doudna or Dr. Zhang, who last year received the Waterman Award for young scientists that Dr. Doudna had won years earlier, was the first to invent the genome editing technique. So far, the patents have gone to Dr. Zhang.

Crispr-Cas9技術(shù)專利之戰(zhàn)悄然打響，現(xiàn)在，加州大學(xué)和布羅德研究所在美國聯(lián)邦專利局就Crispr-Cas9技術(shù)專利應(yīng)授予誰而爭論不休。張鋒博士去年也獲得了杜德納多年前獲得過的沃特曼獎。不過，到目前為止，張鋒博士仍是Crispr-Cas9技術(shù)專利的擁有者。

The Broad Institute claims that the paper by Dr. Doudna and Dr. Charpentier in 2012 did not demonstrate how to alter DNA in cells with nuclei, including human cells, something requiring the inventive steps that Dr. Zhang took. His patent application included pages from a lab notebook he said demonstrated that he was doing Crispr genome editing even before the 2012 paper was published.

布羅德研究所稱，杜德納博士和卡彭蒂耶博士2012年的那篇論文，并沒有說明這項技術(shù)在包括人類細胞在內(nèi)的有核細胞中如何改變DNA， 而張鋒的工作則闡明了這一點。在Crispr-Cas9技術(shù)的專利申請材料中，包含有張鋒的實驗記錄，顯示他在2012年杜德納的研究發(fā)表之前， 就在使用 Crispr編輯技術(shù)。

The University of California says it filed for a patent months before Dr. Zhang did, though the Broad Institute says that initial application lacked necessary details. The university’s request to the patent office says that once the 2012 paper laid out the recipe, it was obvious how to use it in cells. The university also says Dr. Zhang’s notebook does not prove he could edit genomes before the 2012 paper.

盡管布羅德研究所認為，最初的申請材料缺乏必要的細節(jié)，加州大學(xué)表示，他們提出專利申請的時間比張鋒早幾個月。加州大學(xué)還向美國專利局表示，杜德納博士2012年的這篇論文一經(jīng)發(fā)表，在細胞中如何使用它就變得顯而易見，還說，張鋒的實驗記錄材料并不能證明他在杜德納發(fā)表論文之前就能編輯基因組。

Patent disputes are often settled in time. In any event, Dr. Church of Harvard said, before Crispr-Cas9 could be used to treat disease, it would need important refinements from many other researchers.

解決專利糾紛通常需要時日。哈佛大學(xué)切奇教授稱，無論如何，在Crispr-Cas9技術(shù)可用來治療疾病之前，還需要許多研究者對其加以改進。

“It’s going to be hard to use Feng’s without Jennifer’s, and it would be hard to use either of them without further improvements,” he said.

“如果沒有杜德納的發(fā)現(xiàn)，張鋒的發(fā)明很難得到應(yīng)用，而(這項技術(shù))如果沒有進一步的改進，他們二人的方法都難以應(yīng)用。” 切奇教授說。

The scientists have formed competing companies with rights to their patents and pending patents. Dr. Doudna co-founded Caribou Biosciences to work on research uses of Crispr-Cas9, and more recently, Intellia Therapeutics to work on disease treatments.

此后，兩位科學(xué)家憑借已有的專利以及申請中的專利分別成立了自己的公司。杜德納博士與其他人共同創(chuàng)立Caribou Biosciences公司來繼續(xù)Crispr-Cas9技術(shù)的研究，最近則成立了另一家公司Intellia Therapeutics，專注于疾病治療。

Dr. Church and Dr. Zhang are co-founders of Editas Medicine, which Dr. Doudna also helped start but then withdrew from. Dr. Charpentier, who is now at the Helmholtz Center for Infection Research in Germany, helped start Crispr Therapeutics. She and Dr. Doudna remain friends, but no longer collaborate on research.

張鋒與切奇教授聯(lián)合創(chuàng)立了Editas Medicine公司，杜德納博士也參與了公司的創(chuàng)建，但是之后她退出了。在德國亥姆霍茲感染研究中心(Helmholtz Center for Infection Research)工作的卡彭蒂耶博士幫助創(chuàng)建了Crispr Therapeutics公司。盡管她和杜德納仍是朋友，但是她們兩人不再合作研究。

Even before the dust settles, researchers are moving ahead. While contending with the patents, Dr. Doudna began hearing reports that researchers were trying to use Crispr-Cas9 to make inheritable DNA changes in embryos. Genetically altered monkeys had already been created in China using the technique.

在專利歸屬塵埃落定之前，研究人員仍在繼續(xù)探索Crispr-Cas9技術(shù)。不過，最近杜德納博士開始注意到，有研究者開始利用這一技術(shù)修飾人類胚胎細胞DNA的報告。去年，中國研究者就利用這一技術(shù)讓基因編輯猴子成為現(xiàn)實。

“It’s very far afield from the kind of chemistry I think about and know about,” she said. Still, she felt it would be irresponsible to ignore the rumors.

“這和我所理解以及思考的化學(xué)領(lǐng)域相距甚遠。”杜德納說。但是她認為如果自己忽視這一傳言，將是不負責(zé)任的。

She organized a meeting of leading biologists in Napa, Calif., in January. In a subsequent commentary published in Science, the group called for a moratorium on attempts to create altered babies, though they said basic research on inheritable changes should still be done.

今年1月，杜德納在加利福尼亞納帕(Napa)地區(qū)組織了一場由頂尖生物學(xué)家參加的會議。隨后，這一群體有關(guān)呼吁暫停嘗試創(chuàng)造基因改造的嬰兒的評論發(fā)表在《科學(xué)》雜志上，盡管他們認為，關(guān)于人類遺傳物質(zhì)改變的基礎(chǔ)研究仍可以進行 。

Dr. Doudna said it was not practical to prohibit basic research. “You can’t really put a lid on it, even if you wanted to,” she said. She and others are trying to organize a bigger international meeting with participants from companies and governments as well as universities, possibly to set new guidelines.

杜德納博士稱，禁止這一領(lǐng)域的基礎(chǔ)研究工作并不現(xiàn)實。“即使你想要禁止，絕對的禁止顯然是不可能的。”她說。目前，她正與其他研究者組織一個更大的國際會議，其中包括企業(yè)、大學(xué)以及政府的代表，將共同制定新的指導(dǎo)方針。

She is also trying to cope with her newfound quasi-celebrity status. She has been invited to hobnob with entrepreneurs in Silicon Valley, to speak to science fiction writers, to advise Hollywood on science-themed movies. The garden, her hobby, has had to wait.

杜德納正在努力地適應(yīng)她的準名人生活。她經(jīng)常被企業(yè)家們邀請去硅谷演講，參與科幻小說作家的暢談，以及為好萊塢科學(xué)電影提供科學(xué)咨詢。而她卻無瑕顧及自己對花園種植的愛好 。

In November, Dr. Doudna and Dr. Charpentier were each awarded $3 million Breakthrough Prizes, endowed by leading Internet entrepreneurs. They accepted their awards at an Oscars-like black-tie affair attended by movie stars like Cameron Diaz and Benedict Cumberbatch. Recently Time magazine listed the two scientists among the 100 most influential people in the world.

2014年11月，杜德納博士和卡彭蒂耶博士共同獲得了生命科學(xué)突破獎(Breakthrough Prizes)，每人獲得300萬美元的獎金，該獎項由互聯(lián)網(wǎng)領(lǐng)域的巨頭企業(yè)家們創(chuàng)立。生命科學(xué)突破獎授獎儀式就如同奧斯卡獎一樣隆重，參加者身著盛裝，電影明星卡梅隆·迪亞茲(Cameron Diaz)和本尼迪克特·康伯巴奇(Benedict Cumberbatch)也受邀出席。同年，這兩位女科學(xué)家被美國《時代》雜志評選為世界上100位最有影響力的人物。

Dr. Doudna, who has a 12-year-old son, Andrew, also finds herself a role model for women in science. Her secret: “I have a great partner,” with whom she shares the chores.

杜德納有一個12歲的兒子，名叫安德魯(Andrew)。杜德納也深知自己成為女性科學(xué)家的榜樣，而她的秘訣是，“有一個偉大的伴侶”，幫她分擔(dān)家務(wù)活。