GENENTECH: The Beginnings of Biotech by Smith 2011

Prologue

• Genentech's success is by no means straight forward, pre ordained, or inevitable events.
• The making of Genentech was in fact racked by problems, internal and external. The science did not always work.
• He needed to somehow balance a freewheeling, university-like culture against the dire need to eke out a profi t, fi le for patents, and above all make marketable products
• Genentech in large measure recast the aspirations, direction, and culture of life science and set the stage for the formation of a biotechnology industry

1. INVENTING RECOMBINANT DNA TECHNOLOGY

• He（ Cohen） regularly attended biochemistry seminars and bene? ted from the chance “to bounce
  ideas off people in that department.” 18

• Seeing its possible relevance to characterizing plasmid DNA, he issued Boyer, whom he had never met, a last-minute invita-
  tion to attend the conference

• The walk gave Cohen and Boyer a chance to talk about the ongoing
  experiments in their labs. In a ? ash it struck them that they might have
  between them the makings of a method for joining and cloning DNA
  molecules

• Boyerlab A graduate student had isolated EcoRI that cut DNA predictably

• CohenLab By mid-1972 he and two assistants had developed a system for removing plasmid DNA from bacterial cells, shearing it into pieces in a blender, and inserting single molecules of plasmid DNA into bacteria to study plasmid structure and antibiotic resistance

• Boyer’s first impulse was to donate some of his enzyme, as he had done for the Stanford scientists, and let Cohen conduct the experiment on his own. Cohen recalled saying, “Well, that doesn’t seem quite fair. Your lab has spent a lot of time isolating the enzyme and we should do this as a collaboration.” Also to the point, Cohen needed the Boyer lab’s expertise in restriction enzymes for the experiment to transpire as conceived. Boyer agreed to collaborate.
  如何提出合作請求

• Shared interests and the need for combined expertise and resources brought together two very different personalities. In many ways, they were polar opposites—in manner, demeanor, and approach to life

• There are some people who think that once a method of biochemical joining DNA ends was worked out, it was obvious that the chimeric [recombinant] DNA could be cloned. That’s easy to say in retrospect, but in actuality it was not the case—especially for DNA molecules that contain components derived from different biological species.” 說起來容易做起來難

• Uncertain of the experiment’s success, Cohen assigned it to his research assistant Annie Chang, rather than to one of his postdoctoral students whose career might suffer if the project failed如果老板給一個這種課題羡宙，如何取舍

• Cohen, a cautious foil to the outgoing Boyer, pressed to keep the research quiet until it was published and their priority established. It was not an unreasonable request, particularly considering the fearsomely competitive Stanford biochemists working a few ? oors away.

交流和保密质涛？

• 申請專利

2. CREATING GENENTECH

---- BOB SWANSON ----

• In 1970 Swanson graduated from MIT with an undergraduate degree in chemistry and a master of science degree in management

  • Taking a measure of Swanson, Kleiner was impressed, according to Perkins, with the young man’s ability “to think straight and get things done.” 9 When Swanson decided to leave Citibank and seek a new position, Kleiner recommended him to Perkins to fill a vacancy at the partnership

  • Swanson spent the next few weeks reading up on recombinant DNA technology and urging Cape and Farley to take it up at Cetus—to no avail.

  • After the denouement over Cetus, Kleiner and Perkins began to question Swanson’s suitability as an associate

• Pharmaceutical and chemical corporations, conservative institutions at heart, also had reservations, anxious not to lose out if the radical approach proved competitive but also aware of the many unanswered questions concerning its industrial implementation and productivity.

• 各類藥企游說積極接觸NIH的主管经磅，想要弄清楚風向蛮拔，是否對DNA合成藥物有特別的監(jiān)管，是否有政策風險晃财。

---- FOUNDING GENENTECH ----

His(Swanson) seven years in venture capital had provided valuable training in raising money and advising new companies, but the experience had also made him feel “l(fā)ike a coach on the sidelines.”He wanted a piece of the action; he wanted a company of his own

Swanson 從 Asilomar 會議上拿到合成DNA實驗室的名單叨橱，一個個打電話推銷，詢問他們是否覺得此技術已經可以商業(yè)化断盛。大部分人都說需要十到二十年罗洗，最后Boyer的回答是馬上就可以商業(yè)化，但他心事重重. Swanson 感覺勸說他見一面钢猛。

見面后Swason驚訝的發(fā)現Boyer自己也在考慮商業(yè)化伙菜，走的還很遠。he found that Boyer had gone so far as to arrange a research
collaboration with a German chemist to test its industrial possibilities. It had not worked out, but he and Boyer seemed of one mind regarding the technology’s commercial possibilities厢洞。兩人志趣相投仇让，Swason介紹的風投也給Boyer留下了深刻印象。

初生牛犢的天真讓他們很快開始躺翻。 28 Na?veté, in fact, was a salient quality of their concept for a company. “I always maintain,” Boyer reminisced, “that the best attribute we had was our na?veté. . . . I think if we had known about all the problems we were going to encounter, we would have thought twice about starting. . . . Na?veté was the extra added ingredient in biotechnology.”

Boyer 想開公司，但對如何運營信心不足卫玖。Swason 彌補了這一點公你。By aligning himself with a company, perhaps he could mitigate the perennially pressing problem of raising funds for his lab
開公司進行成果轉換？清華大學的那位教授...風險假瞬、成本陕靠、政策、如何考慮

• 經過調研脱茉，Swason 選擇了胰島素剪芥。
• 風投Kleiner & Perkins 對這項技術一無所知。但是Boyer 分析的很好琴许，思路清晰税肪。需要什么設備、原料榜田，如何進行益兄，讓投資人相信，就算實驗無法成功箭券，這個也是有價值的净捅。
• On the promise of the Kleiner & Perkins seed money, Swanson and Boyer dissolved their partnership and on April 7, 1976, signed incorporation papers creating a legal entity known as Genentech
• Perkins、Boyer辩块、Swason三人構成了一個非常小但高效的董事會蛔六。

---- LEGAL AND POLITICAL OBSTACLES ----

• 向大學購買專利
• 二輪融資

3. PROVING THE TECHNOLOGY

Genentech 的特殊點在于當時它的技術完全是全新的荆永，而且尚未有任何一款藥物能在近期生產

---- A PORTENTOUS EXPERIMENT ----

第一個實驗目的在于確定流程能夠工業(yè)生產。兩組合作大規(guī)墓拢克隆特定DNA具钥。結果證明人工合成的DNA具有相同的活性。

• Boyer and his lab had collaborated with Arthur Riggs, and his colleague Keiichi Itakura
• Itakura contributed the synthetic DNA fragment, and Heyneker managed to splice it into plasmids and clone it in bacteria

---- SWITCHING TARGETS ----

生長激素抑制劑捉腥，更小氓拼，更容易合成.Riggs 和 Itakura 從科學的角度想要做這個，man-design抵碟。 Riggs attended a seminar in which an endocrinologist presented his work on a number of brain hormones, including one called somatostatin. It struck Riggs that somatostatin, composed of a single chain of fourteen amino acids in contrast to insulin’s double chain of fi fty-one, was a far better choice for the time-consuming process of chemical DNA synthesis. He and Itakura decided to give it a try

他們正在申請NIH基金桃漾，這時Boyer打電話來想要第二次合作，合成胰島素拟逮。Riggs勸說先做 Somatostatin 生長激素抑制劑撬统，Boyer很容易就同意了。

但是勸說 Swanson 同意比較難敦迄，他全身心投入到胰島素這個已經被證實有巨大市場前景的蛋白質上恋追。而Somatostatin尚無清晰的臨床價值。他更看重產品罚屋，能給公司帶來價值苦囱、吸引投資人的產品，而不像三名科學家一樣從實驗規(guī)律脾猛、可行性考慮撕彤。It was not only a battle of wills; it was a contest between scientific and business objectives—a conflict that research-driven companies repeatedly experience

---- NEGOTIATING RESEARCH AGREEMENTS ----

Swason 接下來又找了律師 Kiley 完成和 City of Hope 以及大學方面的專利協(xié)議。 Kiley 會給這個年輕的猛拴、以自己的技術為唯一命脈的公司羹铅，灌輸技術專利是多么重要。It would fall to him to indoctrinate the fi rm’s future scientists, predictably naive in business matters, on the central importance of patenting, especially critical for a fl edgling company in which the basic “products” were their own technical know-how and innovative power愉昆。

后來 City of Hope 果然和 Genentech 就授權費打官司职员，要求對引申出去的其他技術、藥品也要授權跛溉；但 Genentech 認為只有二者合作的 生長激素以及胰島素需要焊切。某個案件中陪審團 7：5 贊同 Genentech，但是另一場里 Genentech 被懲罰性地要求賠償倒谷。上訴后減少賠償但依然敗訴蛛蒙。

---- MAKING SOMATOSTATIN ----

盡管合成 somatostatin 的基金不來自 NIH ，他們依然派出人審查渤愁，并要求在更高的生物危害防護實驗室中進行牵祟。科學家們一開始不順利抖格，后來重新設計 gene 诺苹， 添加啟動子咕晋，終于合成。但蛋白質很快被細胞酶分解收奔，他們又通過設計掌呜，讓 somatostatin 在一個大蛋白質的尾部懸掛，這樣就不會被分解坪哄。這種思路也避免 somatostatin 在細胞中發(fā)揮生物活性质蕉，更加安全。

• They had installed an artifi cial gene in bacteria and made a mammalian protein—and it worked like the real thing! *

所有科學家都欣喜若狂翩肌， 這也證明 Genentech 的技術可行模暗，在未來有極大的前景。

Kiley 馬上著手申請專利念祭。而大家又因為一作二作的問題有了爭執(zhí)兑宇。

---- WIDER ISSUES ----

政策風險依然很大，政府可能會要求更加繁瑣的生物安全限制粱坤。

而研究發(fā)布后隶糕，也迅速引起了爭議。主要領導者 Boyer 毀譽參半站玄。亦有人開始討論科學家-企業(yè)的關系枚驻，畢竟 Boyer 以“全職合伙人”的身份加入到企業(yè)中，并非以前大多數教授的那種輕度合作株旷。UCSF 的報告認為這一行為給學院帶來了不好的聲譽和嫉妒测秸。 It advised that “in the future it would be wise to refrain from making contracts in which work will be done by a university faculty member who also has a major financial interest in a concern, as this amounts to a contract between the person and himself, with the university’s role only being incidental

4. HUMAN INSULIN: GENENTECH MAKES ITS MARK

---- SEEKING CORPORATE CONTRACTS ----

由于缺少制藥經驗，他們想于胰島素制藥公司合作灾常。先后聯(lián)系了 Novo Industri, Hoechst ，最終 Lilly 有意生產人胰島素铃拇。

---- PROCURING A FACILITY AND STAFF ----

Swanson 招募了一個發(fā)酵專家作為生產總監(jiān)钞瀑，千金市馬骨的作用。 Boyer 則在學校找到了一些有異于投身工業(yè)界的博后慷荔。以及有經驗的資深學者

隨著 UCSF 發(fā)布招待會雕什，成功克隆了老鼠的胰島素基因。他們招人的緊迫性也大了起來显晶。

---- THE ELI LILLY CONTRACT -----

他們隨后和LILLY公司簽訂合同贷岸，但隨后Boyer才知道前幾天LILLY也和另一個團隊簽訂了數額更大的合同。他擔心LILLY只是暫時買下自己的技術磷雇，但為的是保證另一套技術能夠不受競爭偿警，又或者Genentech的技術生產另一套產品。于是他和Swason又和LILLY簽訂了另一套限制合同唯笙。

---- PUBLICITY AND EXPANSION ----

是否要申請專利螟蒸？ Swanson 想要保護公司機密盒使，但科學家想要發(fā)表在同行評議的論文上。最終 Boyer 發(fā)表了七嫌，這也使得學界迅速跟進少办。公眾也更加相信這一技術得到了科學共同體的承認。對公司的快速打響名聲有很大幫助诵原。這也是吸引科學家的一個好方法英妓。

與此相反，有些制藥公司會在專利申請后才讓科學家發(fā)表論文绍赛，損害了后者和科學共同體的利益蔓纠。

Swanson 后來也開始同意這一原則。因為華爾街會用引用數評估小科技公司的創(chuàng)新實力惹资。只要讓文章發(fā)表贺纲，科研界也愿意過來工作。

Boyer 自己卻不愿意署名褪测。One [reason] is I wanted to continue my own [UCSF] research, which I couldn’t do at the company. . . . Another reason was I didn’t want to manage a large group of scientists. I had enough of a taste of doing that at a small level to know that I didn’t like it. And third, . . . I wanted to make sure that the young scientists at the company were getting the recognition. I didn’t want my fi gurehead overshadowing anything they did. So it was a conscious decision, and I think a good one.

沿著Genentech的路徑猴誊，不少 DNA 合成的生物技術小公司產生了。這一模式也被業(yè)界接受侮措。

5. HUMAN GROWTH HORMONE: SHAPING A COMMERCIAL FUTURE

---- COMPETING FOR HUMAN GROWTH HORMONE ----

Peter Seeburg had joined Boyer’s lab in the spring of 1975 to begin a post-doctoral fellowship.
- Seeburg spent his days doing experiments in Goodman’s lab. At night, with Baxter’s permission and encouragement, he took to working secretly on growth hormone with Baxter’s postdoc Joseph Martial.

各大公司都開始與研究所懈叹、大學合作，開始向生長激素進發(fā)分扎。不同組之間競爭相當激烈澄成，Swanson and Kleid wrote to Goodman 要材料，被拒絕畏吓。 Goodman 告訴 Seeburg 嚴禁不經允許就把任何材料拿出實驗室墨状。后來 Seeburg 受不了這種氛圍，某次接口清理試劑菲饼，直接把樣品拿到了 Genentech 肾砂。但 Seeburg 隨后就酗酒，沒有什么進展宏悦。因此To rescue the stalled project, Swanson turned to Goeddel, fast becoming Genentech’s prized cloner

這種行為怎么看待镐确？當時是一種灰色地帶。整個公司建立過程中的知識產權問題

最后果然成功了饼煞。The company’s fi rst two projects had fallen short of establishing that its technology was widely applicable for the bacterial production of useful proteins

這意義無疑十分巨大：In short, the making of growth hormone indicated a far clearer path, albeit with inevitable detours and impediments, to a viable commercial future.

于此同時源葫，前往法國的UCSF 研究組也成功的克隆了人類生長激素基因，離他們也很近了砖瞧。不過UCSF并不想商業(yè)化息堂，而是為了研究基因表達。而無論怎么說芭届，Genentech 還是第三次成功地克隆了基因储矩，表明了他們在生物技術上的強大實力感耙，也說明生物科研不僅僅是大學研究所的事情。 Genentech wanted first and foremost a commercial growth hormone product; the UCSF group, in no way adverse to producing a marketable hormone, was nonetheless primarily concerned to elucidate the mechanisms behind mammalian gene expression in bacteria. However interpreted, Genentech in its triple gene clonings—somatostatin, human insulin, and growth hormone—had demonstrated that top-fl ight biology was no longer the sole province of academe. Clearly, Genentech had moved into the hallowed circle, with other upstart companies to follow.

---- MOVING TOWARD CORPORATE INTEGRATION ----

Swanson 認為持隧，只有完全把研發(fā)即硼、生產、銷售掌握到一起屡拨，才能夠獲得最大利益并支持后續(xù)的研究只酥。He believed that only by making and
selling its own pharmaceuticals could Genentech capture full monetary value from the heavy cost of pharmaceutical research and development. 為了達成這個目標，就需要長期的呀狼、一步一步的計劃裂允。

他計劃首先把生長激素賣給原有的生產商，避免直接的市場開發(fā)哥艇。

---- SCALING UP INSULIN AND GROWTH HORMONE ----

第一個問題就是如何把實驗室規(guī)模的合成擴大為工業(yè)生產绝编。為此聘請了一批生產工程師和發(fā)酵專家作為骨干貌踏。a cadre of process engineers and fermentation experts to handle the development and scale-up of insulin and growth hormone十饥。

但隨后遇到了 NIH 的限制——細菌培養(yǎng)不能超過10升。 Swanson 最初標榜公司完全符合最嚴苛的限制以獲得民眾認同眷昆，但這些卻影響了目前的生產問題蜒秤。為此他和LILLY公司甚至去華盛頓游說。最后亚斋，胰島素作媚、生長激素的生產不被細菌培養(yǎng)所限制。

胰島素終于被FDA批準帅刊；In October 1982 the FDA approved the sale of the Genentech-Lilly insulin, under the trade name Humulin. 而生長激素更難一些掂骏。

---- CORPORATE EXPANSION ----

從1970到1979，公司的規(guī)模和復雜度都有了劇烈提高厚掷，也需要管理規(guī)模的擴大。

• In January 1979 Robert Byrnes arrived to become Genentech’s first vice president of sales and marketing

但年輕的 Swason 牢牢把握了公司的方向级解。第一是產品導向冒黑，第二是收支平衡，Genentech had been operating in the black since the third quarter of 1978 勤哗。他的管理風格不那么正式抡爹、嚴苛，而與科學家關系友好芒划，注重互動冬竟。 he was mainly a facilitator and cheerleader欧穴。

Boyer 的風格也是如此。 Boyer was also casually contributory and helpfully communicative泵殴，always interactive涮帘。

直到1983年他們都沒有科研主管，研究者們自由而平等笑诅。Only in 1983 did Genentech create the formal position of vice president of research and appoint a UCSF professor of molecular biology to fi ll it

---- AN EMERGING CULTURE ----

硅谷的企業(yè)文化：重視創(chuàng)新调缨、快速研究、知識產權的創(chuàng)造和保護 emphasis on innovation, fast-moving research, and intellectual property creation and protection

但這些企業(yè)和研究所的關系不如 genentech 與大學研究的關系密切吆你。Boyer 鼓勵公司的研究員參與到學術界的科研活動中弦叶。

而GenenTech則是科學價值觀和企業(yè)價值觀的融合。But academic values had to accommodate corporate realities: at Swanson’s insistence, research was to lead to strong patents, marketable products, and profi t. Genentech’s culture was in short a hybrid of academic values brought in line with commercial objectives and practices

學術界和科研界的不同價值觀

In academe, the motivation is quite different. Graduate students are there to get a PhD thesis, so they focus on their little aspect. That’s all there is to it. They don’t have to integrate into a bigger project. The postdocs are there to make a name for themselves because they want to become assistant professors, so they have to publish. Those are the most productive years. But again, the goal is very personal. “What contribution can I make to a certain understanding of whatever.” It can be very individualistic.In industry, the goals are more clearly defi ned, but often you need different disciplines to reach them. So, indeed, out of Genentech came articles with twelve or fi fteen names on them, and it was always viewed by academe as a funny way of doing science. I found the contrary; it was a very different way of doing science, because this was a demonstration that you can accomplish a lot by working together with different disciplines.

在公司妇多，研究者的生活和普通人沒什么兩樣：等實驗結果的間隙玩桌上足球伤哺、給保齡球下注。

每個人都是公司的一份子者祖。每周五都有聚餐立莉。

平等主義，無差別對待咸包。

Swanson 要求很嚴格桃序。如果你的手頭的工作沒有堆起來，你就沒有好好努力工作烂瘫！

創(chuàng)業(yè)公司的精神：

Go get it; be there fi rst; we have to beat everybody else. . . . We were small, undercapitalized, and relatively unknown to the world. We had to perform better than anybody else to gain legitimacy in the new industry. Once we did, we wanted to maintain the leadership.

沒有約束媒熊，沒有邊界

6. WALL STREET DEBUT

---- BIOMANIA ----
70年代末，美國民眾坟比、華爾街對于生物科技開始大力追捧芦鳍。政府以及NIH對相關的研究也放寬了顯著。對潛在用途和可能危害的權衡開始偏向其巨大意義葛账。

---- EXIT STRATEGIES ----

But a company substantially supported by venture capital needed more than technological achievement; it needed to provide financial return to its investors

他們找投資人談了兩場柠衅，都沒能成功拿到進一步投資。最后總結是自己的技術太先進還沒有量產籍琳。因此菲宴，他們開始考慮IPO，去股市趋急。

---- INTERFERON: THE NEW WONDER DRUG? ----

干擾素前景巨大喝峦，但是用普通方法生產成本太高。在此熱潮下呜达，用生物技術生產是一個很自然的考慮谣蠢。 Cetus, DuPont, Hoffmann–La Roche, Harvard, Caltech, 以及其他研究者都在競爭克隆干擾素基因。

Genentech 很早就想過開發(fā)干擾素，但抵制住了隨大流的誘惑眉踱，在完成了比較容易挤忙、結構已知、且有巨大市場的胰島素和生長激素后谈喳，他們才開始加入研發(fā)干擾素的行列册烈。1979年中，他們開始了計劃叁执，1980年1月6日和 Hoffmann–La Roche 簽訂了合作協(xié)議茄厘。這一舉動相當及時，因為當月16日 Charles Weissmann’s lab at the University of Geneva就發(fā)布消息成功克隆并表達了干擾素前體谈宛。但是事后 Weiss 也被人質疑利用大學實驗室完成商業(yè)內容次哈，Biogen也違反了科學準則，在干擾素基因測序結果出來前就搶先發(fā)布新聞（他們擔心被Genentech搶走Scoop）吆录。

公司的 Goeddel 團隊則不為所動窑滞。

最終 genentech 率先實現了干擾素的研發(fā)。盡管其潛在機制恢筝、效用尚不明確哀卫，但投資者依然蜂擁而來，另外幾家生物技術公司同樣受到追捧撬槽。

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Perkins 認為要盡早上市此改，盡一切代價勸說 Swason 和 Boyer，并開啟投票侄柔。不過沒有成功共啃。后者的擔憂在于法律阻礙

---- LEGAL IMPEDIMENTS ----

1. 專利問題。不再保護生物暂题，只能把合成方法作為專利申請移剪。公司能夠保護自己的技術，維持技術優(yōu)勢嗎薪者？

Kiley 上訴至最高法院纵苛，高院以5：4認為，技術體現了智力上的獨創(chuàng)言津，可以被保護攻人。the distinction was not between living and inanimate things, but rather between products of nature, whether living or not, and human-made inventions

2. UCSF的法律訴訟

Ullrich’s and Seeburg’s 的轉化材料。經過協(xié)商悬槽，支付給大學$350,000以平息贝椿，避免對上市產生影響。

但這只是暫時的陷谱，1999年UCSF還是把genentech 告上法庭。Seeburg突然推翻自己先前的證言，稱自己和Ullrich并未合成DNA烟逊，而是使用的UCSF的渣窜。他們當時覺得做不出來很尷尬，因此秘密協(xié)定滿了下來宪躯。但是Ullrich激烈地反對這一說法乔宿，用實驗記錄本證明原創(chuàng)性。法院決定二審访雪，雙方在此期間決定和解详瑞。 Genentech agreed to pay the university $150 million and to make a $50 million contribution toward construction of a research building at UCSF’s new Mission Bay campus in San Francisco

接下來他們開始寫上市報告。當時還沒有類似的企業(yè)臣缀，沒法參考成功經驗坝橡。 With no model to follow, no protocol for due diligence, no industry standards to guide them, the group quibbled among themselves and with the SEC over which risks it should disclose and how much it had to reveal of Genentech’s heavily guarded contracts

最后的計劃書還是通過了，盡管寫滿了“謹慎投資”

---- THE IPO ----

上市后一分鐘精置，股價從 $35 to $80计寇，二十分鐘后到達$89 ，當天以$71收盤脂倦。創(chuàng)始人名利雙收番宁，記者紛紛采訪。

對Genentech的員工來說赖阻，IPO是一個驚人的發(fā)現蝶押。令他們吃驚的是，這家苦苦掙扎的初創(chuàng)企業(yè)曾努力維持現金流火欧，如今卻獲得了一筆即時的現金棋电，并成為公認的“前跑者”——現在看來，這是一個新興的工業(yè)領域布隔。

Cetus 的創(chuàng)始人也被他們震動离陶，考慮上市。

科學界也很重視衅檀，有人重新提起科學與商業(yè)的界限招刨。To some, the flip side of the icon was mercenary scientists turning research funded by the public into private commercial and personal gain. The contention was but an early stage in an issue still debated in biotechnology: how best to balance basic and commercial interests in academic research?

科研界和工業(yè)界的關系前所未有的緊密。 A path had been broken for the growth of a far-flung, interactive network of relationships between academic biology and an expanding fl eet of biotechnology companies. Although university-industry associations were in no way new, either in the United States or abroad, what was new was the explosive growth and significance of such connections in biomedical research from the 1980s onward

EPILOGUE