探寻天外天

书名没敢写全，近期的政治局势似乎又到了转折点上，十月份召开二十大，不少人非常期盼，也有不少人感觉几乎没有意外。偶然被推荐这本书，读起来就上瘾了，几天时间集中读完的。理解共和国的这段历史对于理解当下、理解很多看起来矛盾的政治现象是非常有意义的。按惯例，简单做些摘要。

王洪文才四十二歲，是政治局裡最年輕的委員。他從原本是上海一家紡織工廠安全幹部，竄升到最高政治權力階層的速度之快，使得外界給他取了個「火箭式幹部」的綽號。沒有人知道毛為何喜歡這年輕人，並如此迅速的提拔他。王長得高大英俊，可他是個金箍馬桶，只有中學程度，不學無術，只會賣弄小聰明。他對中國的領導階層沒有任何貢獻。那年五月，毛的健康重大惡化時，王還建議我給毛服用珍珠粉，但我拒絕了。

升太快未必是好事，未必是能力，也未必是好运气，还可能成为历史的罪人。

毛死前兩個月，也就是七月時，汪東興曾跟我透露要逮捕江青的計劃。雖然汪對江表面上漠不關心，而華國鋒也一直是客客氣氣的，但我知道他兩人隨時會逮捕江青四人幫。

四人帮的倒台不只是外部压力，和内部打到了彼此你死我活的状态也是直接相关的。

《實踐論》主張真正的知識是從實踐中，而非讀死書而來，對我這想做外科醫生的人來說可真是一針見血。《矛盾論》使我瞭解解決任何問題的方式在於找出主要的矛盾所在──即尋求解決根本問題之道，而不是專注在外表徵兆上的小節。

经典。

“隨後他說：「我說過，中國對世界有三大貢獻，第一是中醫，第二是曹雪芹寫的《紅樓夢》，第三是打麻將牌。」他又問我會不會打麻將牌，我講不會。由於家庭教育，從少年時代我就將打麻將牌和吸鴉片看成是中國社會的兩個毒瘤，對之是十分厭惡。他說：「不要看輕了麻將，牌是一百八十四張，要按自己手上的牌，桌上打出來的牌，別家打出來的牌路，來判斷自己和每家的輸贏趨勢。你要是會打麻將，就可以更瞭解偶然性和必然性的關係。

M对中国文化的理解挺有意思，可以理解当下掼蛋的流行。

毛的政治觀點中，沒有道德的顧慮。我在知道毛不但認同中國的帝王，而且崇拜令人髮指的暴君後，非常震驚。毛不惜用最殘忍暴虐的方法來達到目標。毛認為在中國歷史上，紂王開闢了東南大片土地，使中國的疆土東抵大海，而且對中國的民族統一有不可磨滅的功勞。比干這些人反對紂王的開拓疆土政策，當然要殺掉。紂王搞了些女人是事實，但是哪個皇帝不搞？毛說：秦始皇是中國的廣闊版圖和統一的多民族國家的奠基人。至於焚書坑儒，焚的是宣傳分裂的書，坑的是主張分裂的儒，而且殺的儒生不過四百六十個，實在算不上什麼。有些人在這上面大作文章，真是「抓住一點，盡量擴大，不計其餘」，完全顛倒黑白。

换个角度来看历史，M是很有辩证思维的。

他大笑說：「陰陽五行是不好懂，可能是代表人體內的生理和病理狀態。我主張中西醫結合，首先要讓一些有根柢的西醫學中醫，老的中醫也應該學學解剖學、生理學、細菌學和病理學之類，要能用現代科學闡明中醫的理論，也應該將一些古典的中醫書翻譯成現代語言，或者加註解說明，經過一段時間，總可以形成中西醫結合起來的新醫學，對世界會有貢獻的。」停了一下，他又說：「我提倡中醫，可是我自己不信中醫，不吃中藥，你看怪不怪。」是很怪。

这也是当下中医的困境：挺好，别人用可以，我不用。

那晚是往後多次與毛徹夜長談的開端。毛很孤獨，很少見江青，也沒有什麼朋友。所謂「延安精神」不過是個神話罷了。劉少奇和周恩來有時會來，但毛與他們之間的交談只限於公文上的批閱往來，和不定期在「頤年堂」或毛所巡行的城市裡，舉行的會議討論。毛和其他領導同志之間很少相互來往。他最親近的人是那些年輕、知識水平很低的衛士。談話範圍自然有限。毛愛跟衛士們討論他們的女友，面授機宜，還代為寫情書。但毛無法跟衛士討論他最有興致的兩個話題──中國歷史和哲學。

这种高处不胜寒的孤独感，估计到今天也没有任何差异。高层之间能够敞开聊是件不容易的事情，公文往来更容易，却容易形成误会和隔阂，这也是为什么身边人那么重要。

到今天，我才懂文化大革命那場持續十年的政治大風暴，其實早在一九五六年便已播下了種子，赫魯雪夫於一九五六年二月蘇聯共產黨二十次黨代表大會中發表的那篇反史達林秘密報告是其導火線。赫魯雪夫突如其來的舉動使朱德措手不及。朱德向中央打電報請示時，表示要支持反史達林。毛十分震怒。毛說：「朱總司令這個人十分糊塗。可見朱德和赫魯雪夫都靠不住。

苏共的二十大，改变了苏联，也改变了中国。

到一九五六年，中國已深受蘇聯模式影響，此時已建立了一個深入鄉鎮，由共產黨直接控制的龐大國家官僚體系。農業合作化推展完成，城市中主要的工廠和商店收歸國營。規模較小的手工業工廠和商店不是合作社化，就是交由地方政府經營。就經濟和官僚制度而言，中國社會主義改革似乎已趨完善。　　但毛所極力追求的國民精神改造──也就是中國的浴火新生──仍遙遙無期。在龐大繁雜的官僚體制建立後，昔日的革命鬥士成為養尊處優的官僚，汲汲於追求顯赫地位，而將毛的革命理想拋諸腦後。毛深感不耐，他要快速地推動改革，繼續革命奮鬥。但黨官僚、領導幹部紛紛發出警訊，堅持遵循蘇聯的漸進改革模式。毛則認為他們對蘇聯的模仿缺乏創意，在不考慮中國的特殊國情之下，將蘇聯的組織體系全套抄襲過來。毛為此對當年並肩作戰的領導同志十分震怒。

毛為中國畫下的未來藍圖，規模宏大，大膽冒險；毛堅持中國必須迅速進入社會主義國家，此立場與其他中央領導的小心謹慎成為對立的狀態。毛說「不熟悉的事，不要一上來就反對」，便是在批評北京的那些保守派。

伟大的设想进行不下去，却归因为思想问题、意识形态问题，而不考虑人性、不考虑客观环境，这其实是唯心主义的表现，不是唯物主义。

一九五七年六月十九日，毛在二月二十七日擴大的最高國務院會議中所發表的講話，正式刊登在《人民日報》。許多民主人士看了正式出版的毛著都大吃一驚，說內容上同一九五六年最高國務會議上的講話完全不同了。　　毛在原本的開明講話中提倡大鳴大放，知無不言，「百花齊放，百家爭鳴」。但在六月十九日這篇修正的文章中，卻提到了原本沒有的「毒草」和「引蛇出洞」。

毛說：「我一向的辦法是後發制人。可以用三句話說明，一是老子不為天下先，老子指的是李耳，他的辦法就是不首先發難。第二是退避三舍，這是晉文公重耳的辦法，我們原來共事，對我有過幫助，現在打起來了，你打，我先不還手，不但不還手，還要退兵三十里，讓你以為得計，讓你暴露一下，讓大家看清你的面貌。三是來而不往非禮也，以其人之道還治其人之身。這是孔老夫子的話，既然你打來了，我讓了你，你還打，那麼我也就動手了，你怎麼打過來，我就如法炮製，照樣打回去。　　「原來大家還不知道什麼是右派，右派是什麼樣子，說不清楚。現在大家明白了。什麼右派啊，就是反革命派。我說不要叫反革命，不好聽，戴上反革命帽子也不好看，就叫右派吧。

后发制人、随意修改规则肯定是要失去信任。这也是过往政治中最黑暗的部分。

“毛原本希望「八大」將其激烈改革政策形成決議，並確立其為中國獨一無二的領導人。他便將細節交給劉少奇和鄧小平去處理。劉鄧兩人誤以為毛真的要交出權力。“毛說：「我提出辭去中華人民共和國主席，可是我仍然是黨的主席啊。召開八大為什麼事先不同我打招呼，八大的政治報告起草討論，我沒有參加，事先稿子也不給我看，說是來不及了。我又沒有離開中國，有什麼道理說來不及，不讓我看一看呢？」　　我不確知毛究竟批閱過劉的政治局報告沒有，但他顯然不喜歡其中強調經濟建設並避開階級鬥爭的論調。我想毛跟我發的牢騷，是他在氣頭上的話。八大路線（即堅持集體領導、發展經濟、反對個人崇拜、主張實事求是等）從未得到毛的支持。

最惨痛的误会。

“跟隨赫魯雪夫起舞，頌揚「集體領導制」的基調，特別令毛不安。如果中國共產黨員真的實施集體領導制，那表示領導人之間地位平等，所有重大決策將經集體裁決。毛的重要性便會銳減。但毛要做天下第一人，他想搞個人崇拜。　　毛說他想要退居二線時，他仍想由他決定所有重大事件。但問題就在劉、鄧兩人覺得重要的，毛覺得不重要，沒送來的文件，毛又覺得很要緊。這也就是毛後來所說的「大事不報告，小事天天送」。　　我在「八大」會議中首次發現，毛和他的指定接班人劉少奇之間，存在著如此重大的歧異。「八大」是毛與劉、鄧兩人關係的轉折點。毛覺得中央領導人是有意排擠他，並且想削減他的權力。”

今天的集体领导来之不易，虽然也有丧失的风险，但我还是相信有纠错能力。

“汪說：「吃飯當中，主席說，給你們講個故事。戰國時候張儀和蘇秦是同學好朋友。張儀在秦國當了承相，就是等於總理吧。可蘇秦還是個窮光蛋，也找不著工作。蘇秦想，既然張儀闊了，是個大官了，為什麼不去找張儀呢。蘇秦到了秦國，大約就是現在的陝西咸陽。打聽到了承相府。找門官，就等於現在的傳達室，一報。張承相說先住下吧。一送，送到了招待所，這等於北京飯店。蘇秦一住，住了兩個多月，張儀也不見他。蘇秦心裏的火大了。好啊，張儀你不講交情，不見就不見，不求你，老子回家。招待所長送蘇秦回家。到家裏一看，房也修了，家裏也有飯吃了。招待所長同蘇秦講，張承相的意思，怕你留在秦國沒有出息，所以不見你。他勸你，到六國去遊說，就是耍嘴皮子，讓六國聯合起來打秦國。“這樣，張承相在秦國穩當了，你蘇先生在六國也穩當了。蘇秦一聽，真有道理，就這樣做了。　　「主席說，講這個故事，不是說你們是蘇秦，我是張儀。這是說明，再好的朋友，也不能靠著過下去。要自己努力，打開出路，互相配合，才能成功。”

有趣的历史故事，好朋友也要靠自己努力、打开出路，才能成功。

“毛說：「在追求自己的目標的時候，如果不是不顧一切，殘酷無情去獲取的話，就不能達到目的。問題在於你確切要知道，你要什麼，你要做什麼，決定去做什麼，要無情地剷除妨礙實現你的計劃的那些無能，又阻礙你前進的一切事務。」由此也可以看到毛對農業公社化的信念。

残酷无情实现目标，不顾一切。

周主管中央日常工作，早在一九六四年，便跟汪抱怨過：「現在辦事情太困難了。黨的事只有彭真在管，軍隊全靠羅瑞卿，政府只有我。這麼大的國家，就這麼三個人管具體的事，別的人都只是說說，不做事。」現在彭和羅雙雙遭受批判，周自然寢食難安，辦事情更難了。所以周希望汪趕快回北京就任辦公廳主任。”

文革期间家更难当。

“毛與領導內部意見分歧其來有自，早在一九五六年，毛就發現黨內整風也起不了多大用處。他動員知識分子幫共產黨整風，反而倒戈相向。他號召「百花齊放，百家爭鳴」時，知識分子竟敢質疑起社會主義，還將批評的矛頭紛紛指向毛。這次文化大革命，他決定越過黨官僚的重重關卡，直接鼓勵這些崇拜他的年輕人起來造反。”

利用知识分子打击干部，再打击知识分子。螳螂捕蝉，黄雀在后。

“毛說：「日本的後面實際上是美國。可是東面的美國，離我們遠得很哪。我看，還是照我們老祖宗的辦法才好，叫做『遠交近攻』。」　　我說：「我們的報紙幾乎天天對美國口誅筆伐。越南又在同美國打仗。這怎麼能交往得起來呢？」　　毛說：「美國與蘇聯不同。美國沒有佔過中國一塊土地。美國新總統尼克森上台了。此人是個老右派，老反共分子。我是喜歡同右派打交道的，右派講實話。不像左派心口不一，說的和做的完全不一樣。”

远交近攻这个核心策略，要能坚持到现在就不一样了。

“毛接過來說：「這問題很好，我年輕的時候，就愛從不同角度看問題。至於我說過的話，今後肯定會有不同的解釋，必然如此。你看從孔老夫子到佛教、基督教，後來還不是分成許多派別，有著許多不同的解釋。任何事物沒有不同的解釋，就不會有新的發展、新的創造。否則就停滯，就死亡了。」　　

但毛這次會議的目的卻沒有達成。紅衛兵仍四分五裂，毛似乎決定不再信任年輕人。八月五日，毛為表示對工人的關懷，經汪東興給了他們一些巴基斯坦外交部長胡珊送的芒果。毛的這一行動顯示毛已對各成派系、相持不下的學生失去信心，轉而寄望於工人。不久後，數以百萬的中學和大學生相繼下放農村。毛認為學生該跟貧下中農好好學習，接受再教育。”

学生红卫兵们没让毛满意，就安排去上山下乡了。

“一時會議代表都以為這是毛的意旨，紛紛發言，主張設國家主席。早在一九七○年初，毛就向政治局常委表示，他決不再出任國家主席，也不要設國家主席。但大部份中全會的會議代表並不知道。一旦恢復設立國家主席而毛又不出任，在這種情況下，只有林彪為唯一可能人選。這便是林的如意算盤。林彪這下犯了和劉少奇一樣的政治錯誤──以為中國可以有兩個主席。在毛眼裏，想和他齊頭並立是犯上作亂。”

皇帝的权术就是不明说，可能还误导，看你能搞明白不。

“周恩來的癌症是促使鄧小平復出的原因之一。另一個原因則是，林彪死後，政治局勢日漸複雜。當時正是以江青、張春橋、王洪文、姚文元為一方，周恩來、葉劍英為另一方，正在明爭暗鬥得不可開交。他們雙方在林彪事件的看法上意見相左，涇渭分明。　　周恩來批林彪是極左，在工作上就要校正文化革命中的極左作法。江青、張春橋等一再宣稱林是極右。周則是「右傾回潮」。毛在此事上支持江青。在一九七二年十二月十七日，毛在一次談話中說：「林彪是極右，修正主義，分裂，陰謀詭計，叛黨叛國。”

“我同他們回到三○五醫院以後，他們都覺得毛的病很不好辦。在檢查以前，他們設想可能是帕金森氏症，或者是有過小的中風。但是檢查以後，他們共同認為是種罕見的運動神經元病（motor neuron disease），在西方稱之為肌肉萎縮症（amyotrophic lateral sclerosis）。也就是大腦延髓和脊髓內，主宰喉、咽、舌、右手、右腿運動的神經細胞逐漸變質死亡。”

ALS直到基因治疗药物出来才算有个办法。

“周那時的身體也不好，在等毛批准他動手術。據化驗員分析，周每天從尿中要排出不下一百毫升的血。周想做手術，醫生們也認為不能再拖下去了。可是原來毛已有話在前，不同意做手術切除。沒有毛的同意，周不敢開刀。這時尿血已經這樣明顯，沒有人向毛報告。最後是鄧穎超找化驗員小李，讓她向毛說明情況，爭取毛同意。小李也是醫療組的一員，因為不是醫生，沒有「醫生專嚇唬人」的嫌疑，而且尿血是她在檢驗，情況瞭解得比較清楚。李向毛說明以後，毛同意了。周在一九七四年六月一日住進三○五醫院動手術。”

总理不容易啊。

一本讲基因编辑技术发明人Doudna Jennifer和其竞争者张峰的故事。基因编辑的发现历史不过才十年的时间，下游的应用还尚未打开，但作为一项突破性的技术值得长期跟踪和关注，这样的书读起来对于理解技术和其局限是相当有帮助的。

It was fitting that a virus-fighting team would be led by a CRISPR pioneer. The gene-editing tool that Doudna and others developed in 2012 is based on a virus-fighting trick used by bacteria, which have been battling viruses for more than a billion years. In their DNA, bacteria develop clustered repeated sequences, known as CRISPRs, that can remember and then destroy viruses that attack them. In other words, it’s an immune system that can adapt itself to fight each new wave of viruses—just what we humans need in an era that has been plagued, as if we were still in the Middle Ages, by repeated viral epidemics.

基因编辑技术的发明源于对细菌防病毒攻击技术的发现，是细菌已经用了十亿年的技术了。和细菌的这个强大技术相比，人类一次次收到病毒的攻击，就像活在中世纪一样。

The invention of CRISPR and the plague of COVID will hasten our transition to the third great revolution of modern times. These revolutions arose from the discovery, beginning just over a century ago, of the three fundamental kernels of our existence: the atom, the bit, and the gene.

基因编辑和疫情将加速近期的第三次技术革命，基于原子/能量、比特/信息、基因/生物的三大发现。

“CRISPR evolved in bacteria because of their long-running war against viruses,” Doudna says. “We humans don’t have time to wait for our own cells to evolve natural resistance to this virus, so we have to use our ingenuity to do that. Isn’t it fitting that one of the tools is this ancient bacterial immune system called CRISPR? Nature is beautiful that way.”

Nature is beautiful. 人类对自然世界的认知还远远不够，某种意义上这也是靠山吃山。

Most of all, I want to convey the importance of basic science, meaning quests that are curiosity-driven rather than application-oriented. Curiosity-driven research into the wonders of nature plants the seeds, sometimes in unpredictable ways, for later innovations.Research about surface-state physics eventually led to the transistor and microchip. Likewise, studies of an astonishing method that bacteria use to fight off viruses eventually led to a gene-editing tool and techniques that humans can use in their own struggle against viruses.

基础科学应该是好奇心导向的研究，而不是应用导向的研究。

Many creative people—including most of those I have chronicled, such as Leonardo da Vinci, Albert Einstein, Henry Kissinger, and Steve Jobs—grew up feeling alienated from their surroundings. That was the case for Doudna as a young blond girl among the Polynesians in Hilo. “I was really, really alone and isolated at school,” she says. In the third grade, she felt so ostracized that she had trouble eating. “I had all sorts of digestive problems that I later realized were stress related. Kids would tease me every day.” She retreated into books and developed a defensive layer. “There’s an internal part of me they’ll never touch,” she told herself.Like many others who have felt like an outsider, she developed a wide-ranging curiosity about how we humans fit into creation.”

众多知名科学家童年时都很不合群。因为不合群转而会更有好奇心、更加关注自我和创造。

We all see nature’s wonders every day, whether it be a plant that moves or a sunset that reaches with pink fingers into a sky of deep blue. The key to true curiosity is pausing to ponder the causes. What makes a sky blue or a sunset pink or a leaf of sleeping grass curl?

Darwin and Wallace realized this could be applied to all species and thus lead to a theory of evolution driven by the survival of the fittest. “I happened to read for amusement Malthus on population, and… it at once struck me that under these circumstances favorable variations would tend to be preserved and unfavorable ones to be destroyed,” Darwin recalled.

造物主奇迹其实就在眼前，大多数人只是缺少好奇心。达尔文当年的适者生存理论也不仅是出自观察。

Watson and Crick finished their paper on the last weekend of March 1953. It was a mere 975 words, typed by Watson’s sister, who was persuaded to do so by his argument that “she was participating in perhaps the most famous event in biology since Darwin’s book.” Crick wanted to include an expanded section on the implications for heredity, but Watson convinced him that a shorter ending would actually carry more punch. Thus was produced one of the most significant sentences in science: “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.

复杂基因的复制机制很难说不是出自上帝之手，这个发现也就70年的时间。

Two revolutions coincided in the 1950s. Mathematicians, including Claude Shannon and Alan Turing, showed that all information could be encoded by binary digits, known as bits. This led to a digital revolution powered by circuits with on-off switches that processed information. Simultaneously, Watson and Crick discovered how instructions for building every cell in every form of life were encoded by the four-letter sequences of DNA. Thus was born an information age based on digital coding (0100110111001…) and genetic coding (ACTGGTAGATTACA…). The flow of history is accelerated when two rivers converge.

50年代信息和DNA两个二进制几乎同时发现，信息的二进制带来了全面的科技革命、信息革命，生物的这个二进制也将带来一场革命。

It sparked the realization that it was possible to peel back the layers of nature’s beauty and discover, as she says, “how and why things worked at the most fundamental and inner level.” Life was made up of molecules. The chemical components and structure of these molecules governed what they would do.

生命是分子构成的。

The key aspect of his intellect, she realized, was his ability to make unexpected connections between different fields. More than four thousand disease-causing DNA mutations were found. But no cure sprang forth for even the most simple of single-gene disorders, such as Tay-Sachs, sickle cell, or Huntington’s.

科学发现的核心能力是不同领域之间建立看似不存在的链接。DNA突变已经带来了4000种疾病。

As a young PhD student, Doudna mastered the special combination of skills that distinguished Szostak and other great scientists: she was good at doing hands-on experiments and also at asking the big questions. She knew that God was in the details but also in the big picture. Jennifer was fantastically good at the bench, because she was fast and sharp and could seemingly get anything to work,” Szostak says. “But we talked quite a bit about why the really big questions are the important questions.

上帝在细节中，也在大的图景中。

Many viruses are composed of DNA, but SARS was a coronavirus that instead contained RNA. By the time it died out after eighteen months, it had killed close to eight hundred people around the world. It was officially known as SARS-CoV. In 2020, it had to be renamed SARS-CoV-1.

许多病毒是DNA的，SARS是RNA病毒。

RNA interference operates by deploying an enzyme known as “Dicer.” Dicer snips a long piece of RNA into short fragments. These little fragments can then embark on a search-and-destroy mission: they seek out a messenger RNA molecule that has matching letters, then they use a scissors-like enzyme to chop it up. The genetic information carried by that messenger RNA is thus silenced.”

Mojica was driving home from his lab one evening when he came up with the name CRISPR, for “clustered regularly interspaced short palindromic repeats.”

RNA干扰。

Indeed, phage viruses are by far the most plentiful biological entity on earth. There are 10^31 of them—a trillion phages for every grain of sand, and more than all organisms (including bacteria) combined. In one milliliter (0.03 ounces) of seawater there can be as many as 900 million of these viruses.

腺病毒广泛存在，1g泥土里有10^31个。1毫升海水能装下9亿个病毒。

It was an astonishing and elegant discovery, one that would have great repercussions. But Mojica had a ridiculously difficult time getting it published. He submitted a paper to Nature in October 2003 entitled “Prokaryotic Repeats Are Involved in an Immunity System.” In other words, CRISPR systems were a way that bacteria acquired immunity to viruses.

CRISPR系统是细菌对病毒的免疫系统。

In Conti’s lab, Jinek developed a passion for the star molecule of this book, RNA. “It’s such a versatile molecule—it can do catalysis, it can fold into 3D structures,” he later told Kevin Davies of the CRISPR Journal. “At the same time, it’s a carrier of information. It’s an all-rounder in the world of biomolecules!”His goal was to work in a lab where he could figure out the structure of complexes that combined RNA and enzymes.

CRISPR的神奇之处，可以当催化剂，还可以折叠出3D结构，还可以携带信息。

In other words, CRISPR did not work through RNA interference, which had been the general consensus when Banfield first approached Doudna. Instead, the CRISPR system targeted the DNA of the invading virus. That had a holy-cow implication.

However, as with the transistor, it was not simply a one-way linear progression. Instead, there was an iterative dance among basic scientists, practical inventors, and business leaders. Science can be the parent of invention. But as Matt Ridley points out in his book How Innovation Works, sometimes it’s a two-way street. “It is just as often the case that invention is the parent of science: techniques and processes are developed that work, but the understanding of them comes later,” he writes. “Steam engines led to the understanding of thermodynamics, not the other way round. Powered flight preceded almost all aerodynamics.”

发明是科学之母。先是技术发展把事情做出来，是后面再去理解和解释。

But a different approach was required in order to determine the essential components of the system: biochemists working with the molecules in vitro, in a test tube. By isolating the components in a test tube, biochemists could explain at the molecular level the discoveries made by microbiologists working in vivo and by computational geneticists comparing sequencing data in silico.

It began making genetically engineered drugs and, in August 1978, blasted into hypergrowth when it won a bet-the-company race to make a synthetic version of insulin to treat diabetes.Until then, one pound of insulin required eight thousand pounds of pancreas glands ripped from more than twenty-three thousand pigs or cows.

胰岛素前期的故事，2磅的动物提取要从8000磅胰腺中提取，需要23000只猪或者牛。

She was forty-four, happily married, with a smart and polite seven-year-old son. Yet despite all of her success, or maybe partly because of it, she was having a mild midlife crisis. “I’d been running an academic research lab for fifteen years, and I started to wonder, ‘Is there more?’ ” she recalls. “I wondered if my work was having an impact in the broader sense.”

科学家也会有中年危机，44岁的Jennifer+7岁儿子。

Swanson had an unbroken record of failure as a venture capitalist. At the time, he was living in a shared apartment, driving a beat-up Datsun, and surviving on cold-cut sandwiches. But he had read up on recombinant DNA and convinced himself that he had finally found a winning horse.

基因泰克创始人当年的窘境：投资工作遭遇连续失败、合租、吃冷面包混日子。

There are two components to scientific discovery: doing great research and building a lab that does great research. I once asked Steve Jobs what his best product was, thinking he would say the Macintosh or iPhone. Instead he said that creating great products is important, but what’s even more important is creating a team that can continually make such products.

科学发现的两个部分：做好研究和建一个能做好研究的实验室团队，好团队/好公司要更重要。

They had also established the essential role of another part of the complex: CRISPR RNAs, known as crRNAs. These are the small snippets of RNA that contain some genetic coding from a virus that had attacked the bacteria in the past. This crRNA guides the Cas enzymes to attack that virus when it tries to invade again. These two elements are the core of the CRISPR system: a small snippet of RNA that acts as a guide and an enzyme that acts as scissors.

It turns out that tracrRNA performs two important tasks. First, it facilitates the making of the crRNA, the sequence that carries the memory of a virus that previously attacked the bacteria. Then it serves as a handle to latch on to the invading virus so that the crRNA can target the right spot for the Cas9 enzyme to chop.

crRNA

There were lessons from the arts, she would discover, that applied to science. “Methodology is important in both,” she says. “You also must know the basics and master the methods. That requires persistence—repeating experiments and repeating them again, perfecting how to prepare the DNA when you clone a gene, and then doing it over and over again. It’s part of the training, just like the hard work of a ballet dancer, repeating all day long the same moves and methods.

了解基础常识+掌握方法论，不止艺术和生物如此，投资也如此。

“I enjoy the freedom of being on my own, of not depending on partnership,” she says. She hated the phrase “work-life balance” because it implied that work competes with life. Her work in the lab and her “passion for science,” she says, brought her a “happiness that is as fulfilling as any other passion.

工作生活不一定要冲突。

It worked: the three-component complex reliably chomped up the target DNA. Jinek immediately told Doudna the news: “Without the tracrRNA, the crRNA guide does not bind to the Cas9 enzyme.” After that breakthrough, Doudna and Charpentier became more involved in the daily work. Clearly they were heading to an important discovery: determining the essential components of a CRISPR gene-cutting system.

“We found this protein, an enzyme called Cas9,” she explained. “It can be programmed to find viruses and cut them up. It’s so incredible.”

It was immediately obvious that this single guide would make CRISPR-Cas9 an even more versatile, easy-to-use, and reprogrammable tool for gene editing. What made the single-guide system particularly significant—from both a scientific and an intellectual property standpoint—was that it was an actual human-made invention, not merely a discovery of a natural phenomenon.

The 3,500-word paper went into great detail on how the crRNA and the tracrRNA worked to bind the Cas9 protein onto the target DNA. It also showed how the structure of two Cas9 domains determined how each cut one of the DNA strands at a specific location. Finally, it described how they were able to fuse the crRNA and tracrRNA to engineer a single-guide RNA. This system, the authors noted, could be used to edit genes.

CRISPR的关键点。

Researchers were able to devise proteins that could serve as a guide to get the cutting domain to a targeted DNA sequence. One system, zinc-finger nucleases (ZFNs), came from fusing the cutting domain with a protein that has little fingers shaped by the presence of a zinc ion, which allow it to grasp on to a specified DNA sequence. A similar but even more reliable method, known as TALENs (transcription activator–like effector nucleases), came from fusing the cutting domain with a protein that could guide it to longer DNA sequences.”

“With ZFNs and TALENs, you had to construct a new protein guide every time you wanted to target a different genetic sequence to cut; it was difficult and time consuming. But with CRISPR you merely had to fiddle with the genetic sequence of the RNA guide. A good student could do it quickly in a lab.”

“In the Saturday enrichment class, the focus was on DNA and how RNA carried out its instructions, with an emphasis on the role played in this process by enzymes, those protein molecules that act as catalysts to spark actions in a cell. “My teacher loved enzymes,” Zhang says. “He told me that whenever you face a tough question in biology, just say ‘Enzymes.’ It’s the correct answer to most questions in biology.”

“In addition, he used a well-known technique called “codon optimization” to make the CRISPR-Cas9 system work in human cells. Codons are the three-letter snippets of DNA that provide instructions for the specific arrangement of amino acids, which are the building blocks used to make proteins. A variety of codons can code for the same amino acid. In different organisms, one or another of these alternative codons may work more efficiently. When trying to move a gene-expression system from one organism to another, such as from bacteria to a human, codon optimization switches the codon sequence to the one that works best.”

“In September 2013, Gengine, Inc. was founded. Two months later, it changed its name to Editas Medicine. “We have the ability to essentially target any gene,” said Kevin Bitterman, a principal at Polaris Partners who served as the interim president for the first few months. “And we have in our crosshairs any diseases with a genetic component. We can go in and fix the error.”

“On April 15, 2014, she received an email from a reporter asking for her reaction to the news that Zhang and the Broad had just been granted a patent for the use of CRISPR-Cas9 as an editing tool. Doudna and Charpentier still had a patent application pending, but Zhang and the Broad, who had put in their own application later, had paid to have their decision fast-tracked. Suddenly it became clear, to Doudna at least, that Zhang and Lander were trying to relegate her and Charpentier to minor players—both in history and in any commercial use of CRISPR-Cas9.”

“Within a few months, she decided that she would be most comfortable working with her trusted partner and former student Rachel Haurwitz, with whom she had started Caribou Biosciences in 2011. Caribou had created a spinoff called Intellia, with the mission of commercializing CRISPR-Cas9 tools. “I became very interested in Intellia, because the Caribou team was launching it with the academic scientists I most liked and trusted and respected,” Doudna says.  

As a result, the pioneers of CRISPR-Cas9 ended up in three competing companies: CRISPR Therapeutics, founded by Charpentier and Novak; Editas Medicine, which included Zhang and Church and Doudna until she resigned; and Intellia Therapeutics, founded by Doudna, Barrangou, Sontheimer, Marraffini, and Haurwitz.”

“As a result, other patent applications were deemed to have an earlier priority date, and the court revoked Zhang’s patent. “Feng’s European patent was nullified because of the way he took me off,” Marraffini says.28 By 2020, Doudna and Charpentier had been awarded the major patents also in Britain, China, Japan, Australia, New Zealand, and Mexico.”

“To an unnecessary extent, the prolonged fight was driven by emotions and resentments. Instead, Doudna and Zhang could have followed the example of Jack Kilby of Texas Instruments and Robert Noyce of Intel who, after five years of wrangling, agreed to share the patent rights for the microchip by cross-licensing their intellectual property to each other and splitting the royalties, which helped the microchip business grow exponentially and define a new age of technology. Unlike the CRISPR contestants, Noyce and Kilby obeyed an all-important business maxim: Don’t fight over divvying up the proceeds until you finish robbing the stagecoach.

“The primary scientific goal of the initiative is to find a method to edit the sickle-cell mutation inside of a patient without needing to extract bone marrow. One possibility is to inject into the patient’s blood a gene-editing molecule with an address label that directs it right to the cells in the bone marrow. The difficult part will be to find the right delivery mechanism, such as a virus-like particle, that won’t trigger the patient’s immune system.”

Cancer: In addition to treating blood disorders, such as sickle-cell anemia, CRISPR has been used to fight cancer. China has been the pioneer in this field, and it is two or three years ahead of the United States in devising treatments and getting them into clinical trials. The first person to be treated was a lung-cancer patient in Chengdu, a city of 14 million in the western Chinese province of Sichuan. In October 2016, a team removed from the patient’s blood some of his T-cells, which are the white blood cells that help fight off diseases and confer immunity. The doctors then used CRISPR-Cas9 to disable a gene that produces a protein, known as PD-1, which stops the cell’s immune response. Cancer cells sometimes trigger the PD-1 response, thus protecting themselves from the immune system. By using CRISPR to edit the gene, the patient’s T-cells become more effective in killing the cancer cells. Within a year, China had seven clinical trials using this technique.”

“Doudna assigned the project to two young postdoctoral students who had just joined her lab, Kyle Watters and Gavin Knott. They focused on a method that some viruses use to disable the CRISPR systems of the bacteria they are attacking. In other words, bacteria developed CRISPR systems to ward off viruses, but then the viruses developed a way to shut down those defenses. It was an arms race the Pentagon could understand: missiles being countered by defense systems being countered by anti–defense systems. The newly discovered systems were dubbed “anti-CRISPRs.”

“One of the primary organizers was a soft-spoken but gently commanding MIT biology professor named David Baltimore, who that year would win the Nobel Prize for his work showing that viruses containing RNA, such as coronaviruses, can insert their genetic material into the DNA of a host cell through a process known as “reverse transcription.” In other words, the RNA can be transcribed into DNA, thus modifying the central dogma of biology, which states that genetic information travels in only one direction, from DNA to RNA. ”

“Stock went on to write a pro-editing manifesto, Redesigning Humans: Our Inevitable Genetic Future. “A key aspect of human nature is our ability to manipulate the world,” he argued. “To turn away from germline selection and modification without even exploring them would be to deny our essential nature and perhaps our destiny.”

“Unlike some other scientists at the time,8 the participants had purposely decided against calling for a ban or moratorium, which can over time become hard to lift. Their goal was to keep open the possibility of germline editing if it was safe and medically necessary. That was why, in the title of the piece, they called for “a prudent path forward,” which had become the watchword of many of the scientific conferences ”

“Over the next six years, Jiankui’s company would receive about $5.7 million in funding from government sources. By 2017, its gene sequencer was on the market and the company, of which Jiankui had a one-third stake, was valued at $313 million. “We confirmed Nana’s CCR5 gene was edited successfully with frameshift mutations on both alleles and Lulu’s was heterozygous,” he admitted. In other words, Lulu had different gene versions on her two chromosomes, which meant that her system would still produce some of the CCR5 protein.”

“Somatic editing can be used on certain types of cells, such as those of the blood, muscles, and eyes. But it is expensive, doesn’t work on all cells, and may not be permanent. Germline edits could make a fix in all of the cells of the body. Thus it holds a lot more promise. And a lot more perceived peril.”

“Memory may be the first mental improvement we will be able to engineer, and fortunately it is a less fraught topic than IQ. It has already been improved in mice, such as by enhancing the genes for NMDA receptors in nerve cells. In humans, enhancing those genes could help prevent memory loss in old age, but it could also enhance memory in younger people as well”

“The role of sports, at least since the first Olympics in 776 BC, is to celebrate two things: natural talent combined with disciplined effort. Enhancements would shift that balance, making human effort less of a component of victory. Therefore the achievement becomes a little less praiseworthy and inspiring. There is a whiff of cheating if an athlete succeeds by obtaining some physical advantages through medical engineering.”

“Likewise, suppose I’m an average height. If I were enhanced by eight inches, I’d be way taller than most people, and that could be a benefit to me. But if everyone else got the same eight-inch enhancement I did, then I would get no real benefit. The enhancement wouldn’t make me or society as a whole better off, especially given the legroom of airline seats these days. The only sure beneficiaries would be carpenters who specialized in raising door frames. So enhanced height is a positional good, while enhanced resistance to viruses is an absolute good”

“At this point in our deliberations, we have to face the potential conflict between what is desired by the individual versus what is good for human civilization. A reduction in mood disorders would be seen as a benefit by most of the afflicted individuals, parents, and families. They would desire it. ”

“In the meantime, we will have to deploy the finite allocation of wisdom that nature has dealt us as we ponder how to use the gene-editing techniques that we’ve discovered. Ingenuity without wisdom is dangerous.”

“Our respect for nature and nature’s God should, indeed, instill some humility about meddling with our genes. But should it absolutely forbid it? After all, we Homo sapiens are part of nature, no less so than bacteria and sharks and butterflies. Through its infinite wisdom or blind stumbling, nature has endowed our species with an ability to edit our own genes. If it’s wrong for us to use CRISPR, the reason cannot merely be that it’s unnatural. It’s just as natural as all of the tricks that bacteria and viruses use.”

It didn’t happen. When the real 1984 actually rolled around, Apple introduced an easy-to-use personal computer, the Macintosh, and in the words that Steve Jobs wrote for its ad, “you’ll see why 1984 won’t be like 1984.” That phrase contained a deep truth. Instead of computers becoming an instrument for centralized repression, the combination of the personal computer and the decentralized nature of the internet became a way to devolve more power down to each individual, thus unleashing a gusher of free expression and radically democratized media. Perhaps too much so. The dark side of our new information technology is not that it allows government repression of free speech but just the opposite: it permits anyone to spread, with little risk of being held accountable, any idea, conspiracy, lie, hatred, scam, or scheme, with the result that societies become less civil and governable.”

“Although this sounds like a scene from Gattaca, a real-world version of this baby-designing service—using preimplantation diagnosis—was launched in 2019 by a New Jersey startup, Genomic Prediction. In vitro fertilization clinics can send the company genetic samples of prospective babies. ”

For all of history, humans (and every other species) have been battling rather than accepting nature’s poisoned offerings. Mother Nature has produced massive suffering and distributed it unequally. Thus we devise ways to combat plagues, cure diseases, fix disabilities, and breed better plants, animals, and children.”

“Evolution’s primary guide is reproductive fitness—what traits might cause an organism to reproduce more—which means it permits, and perhaps even encourages, all sorts of plagues, including coronaviruses and cancers, that afflict an organism once its childbearing use is over. This does not mean that, out of respect for nature, we should quit searching for ways to fight against coronaviruses and cancer.”

“I am not sure how to make a sharp distinction in medicine between what is natural and what is unnatural, and I think it’s dangerous to use that dichotomy to block something that could alleviate suffering and disability.”

“His nerve cells would soon start dying and eventually he would be unable to walk, speak, then swallow or eat. He was doomed to die an early and painful death. The note was a wrenching plea for help. “How could you not want to make progress on coming up with ways to prevent such a thing?” Doudna asks. “My heart broke.” If gene editing could prevent this in the future, it would be immoral not to pursue it, she decided.”

“By limiting gene edits to those that are truly “medically necessary,” she says, we can make it less likely that parents could seek to “enhance” their children, which she feels is morally and socially wrong. The line between medical treatment and enhancement can be blurry, she acknowledges, but it is not totally meaningless.”

“Instead of making a cut in the double-stranded DNA, the newly discovered CRISPR system would insert a new chunk of DNA by harnessing transposons, known as “jumping genes,” which are big segments of DNA that can hop from one place to another on chromosomes.”

“The challenge with human gene editing,” she tells me, “is to get your editing tools past the cell’s outer plasma membrane and past its nuclear membrane to get to where the DNA is, and then you also have to get your tools to find the location in the genome.”

“When the American Masters series on PBS decided to do a documentary on Watson in 2018, it set out to produce a balanced, intimate, complex, and nuanced look at both his scientific triumphs and his controversial views.“What matters now are his perfections, not his past imperfections.”12 Perhaps people may say that of Watson someday, but in 2019 he was an outcast.

“In SARS-CoV-2, the RNA is about 29,900 base letters long, compared to more than three billion in human DNA. The viral sequence provides the code for making a mere twenty-nine proteins.4”

“In addition to the previously known Cas9 and Cas12 enzymes that target DNA, Zhang and Koonin found a class of enzymes that target RNA.3 They became known as Cas13.

Cas13 had the same odd trait as Cas12: when it found its target, it went into a cutting frenzy. The Cas13 not only cut its targeted RNA, it then proceeded to cut up any other nearby RNA.”

“Zhang speculated that it was an evolutionary method to have the cell commit suicide if it got too infected by an invading virus, thus preventing the virus from spreading as fast.”

“Zhang decided to start a diagnostics company to commercialize SHERLOCK, just like Chen and Harrington had launched Mammoth. Zhang’s cofounders included the two graduate students who were the lead authors on many of the papers from his lab describing CRISPR-Cas13”.“You know, nature’s got a ton of amazing secrets in it,” he says.”

“It took a while to get Sherlock Biosciences funded and launched because Zhang and his two graduate students did not want profit to be the main goal of the company. They wanted the technologies to be affordable in the developing world. So the company was structured in a way that allowed it to profit on its innovations while still taking a nonprofit approach in places where there was great need.

“But then, at the beginning of 2020, the world suddenly changed. The ability to quickly detect an attacking virus became critical. And the best way to do it faster and cheaper than the conventional PCR tests, which required a lot of mixing steps and temperature cycles, was to deploy RNA-guided enzymes that had been programmed to detect the genetic material of the virus—in other words, adapt the CRISPR system that bacteria had been deploying for millions of years.”

“The CRISPR-based tests developed by Mammoth and Sherlock are cheaper and faster than conventional PCR tests. They also have an advantage over antigen tests, such as the one developed by Abbott Labs that was approved in August of the plague year. The CRISPR-based tests can detect the presence of the RNA of a virus as soon as a person has been infected. But the antigen tests, which detect the presence of proteins that exist on the surface of the virus, are most accurate only after a patient has become highly infectious to others.”

“The development of home testing kits has a potential impact beyond the fight against COVID: bringing biology into the home, the way that personal computers in the 1970s brought digital products and services—and an awareness of microchips and software code—into people’s daily lives and consciousness.”

“Marson and Wilson devised a way to address the DNA vaccine delivery problem using CRISPR-Cas9. They put together a Cas9 protein, a guide RNA, and a nuclear localization signal that helps the complex get into the nucleus. The result was a “shuttle” that could get the DNA vaccine into cells. The DNA then directs the cells to make coronavirus spike proteins and thus stimulate the immune system to fend off the real coronavirus.4 It’s a brilliant idea that could have uses for many treatments in the future, but it has been difficult to make work. By the beginning of 2021, Wilson and Marson were still trying to prove it could be effective.”

“An RNA vaccine has certain advantages over a DNA vaccine. Most notably, the RNA does not need to get into the nucleus of the cell, where DNA is headquartered. The RNA does its work in the outer region of cells, the cytoplasm, which is where proteins are constructed. So an RNA vaccine simply needs to deliver its payload into this outer region.”

“Afeyan instantly authorized him to start work without waiting for full board approval. Lacking Pfizer’s resources, Moderna had to depend on funding from the U.S. government. Anthony Fauci, the government’s infectious disease expert, was supportive. “Go for it,” he declared. “Whatever it costs, don’t worry about it.” It took Moderna only two days to create the desired RNA sequences that would produce the spike protein, and thirty-eight days later it shipped the first box of vials to the NIH to begin early-stage trials. Afeyan keeps a picture of that box on his cell phone.

“The invention of easily reprogrammable RNA vaccines was a lightning-fast triumph of human ingenuity, but it was based on decades of curiosity-driven research into one of the most fundamental aspects of life on planet earth: how genes encoded by DNA are transcribed into snippets of RNA that tell cells what proteins to assemble. Likewise, CRISPR gene-editing technology came from understanding the way that bacteria use snippets of RNA to guide enzymes to chop up dangerous viruses. Great inventions come from understanding basic science. Nature is beautiful that way.”

“The result was a burst of papers in the spring of 2020 for improving CRISPR-based detection technologies for viruses. These included a system known as CARMEN, designed to detect 169 viruses at one time,11 and a process that combined SHERLOCK’s detection capability with an RNA extraction method called HUDSON to create a single-step detection technique he named SHINE.12 In addition to its CRISPR wizardry, the Broad was a master at devising acronyms.”

“One of the transformations wrought by the coronavirus pandemic is that more meetings in the future will be done virtually. It’s a shame. If COVID doesn’t kill us, Zoom will. As Steve Jobs emphasized when he built a headquarters for Pixar and planned a new Apple campus, new ideas are born out of serendipitous encounters. In-person interactions are especially important in the initial brainstorming of new ideas and the forging of personal bonds. As Aristotle taught, we are a social animal, an instinct that cannot fully be satisfied online.”

“The awarding of the 2020 Nobel Prize in Chemistry to Doudna and Charpentier was not a complete surprise, but the recognition came with historic swiftness. Their CRISPR discovery was merely eight years old. The day before, Sir Roger Penrose had shared the Nobel in physics for a discovery about black holes he had made more than fifty years earlier.”

“All of the scientists I write about in this book say that their main motivation is not money, or even glory, but the chance to unlock the mysteries of nature and use those discoveries to make the world a better place. I believe them. And I think that may be one of the most important legacies of the pandemic: reminding scientists of the nobility of their mission.”

“After millions of centuries during which the evolution of organisms happened “naturally,” we humans now have the ability to hack the code of life and engineer our own genetic future. Or, to flummox those who would label gene editing as “unnatural” and “playing God,” let’s put it another way: Nature and nature’s God, in their infinite wisdom, have evolved a species that is able to modify its own genome, and that species happens to be ours.

Like any evolutionary trait, this new ability may help the species thrive and perhaps even produce successor species. Or it may not. It could be one of those evolutionary traits that, as sometimes happens, leads a species down a path that endangers its survival. Evolution is fickle that way.”