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，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？

• 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，想要弄清楚風向，是否對DNA合成藥物有特別的監管，是否有政策風險。

---- 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 “like 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，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化。大部分人都說需要十到二十年，最后Boyer的回答是馬上就可以商業化，但他心事重重. Swanson 感覺勸說他見一面。

見面后Swason驚訝的發現Boyer自己也在考慮商業化，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。兩人志趣相投，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。 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。Swason 彌補了這一點。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、成本、政策、如何考慮

• 經過調研，Swason 選擇了胰島素。
• 風投Kleiner & Perkins 對這項技術一無所知。但是Boyer 分析的很好，思路清晰。需要什么設備、原料，如何進行，讓投資人相信，就算實驗無法成功，這個也是有價值的。
• 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、Swason三人構成了一個非常小但高效的董事會。

---- 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，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生產。兩組合作大規模克隆特定DNA。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，更小，更容易合成.Riggs 和 Itakura 從科學的角度想要做這個，man-design。 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，這時Boyer打電話來想要第二次合作，合成胰島素。Riggs勸說先做 Somatostatin 生長激素抑制劑，Boyer很容易就同意了。

但是勸說 Swanson 同意比較難，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。而Somatostatin尚無清晰的臨床價值。他更看重產品，能給公司帶來價值、吸引投資人的產品，而不像三名科學家一樣從實驗規律、可行性考慮。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議。 Kiley 會給這個年輕的、以自己的技術為唯一命脈的公司，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。

后來 City of Hope 果然和 Genentech 就授權費打官司，要求對引申出去的其他技術、藥品也要授權；但 Genentech 認為只有二者合作的 生長激素以及胰島素需要。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。上訴后減少賠償但依然敗訴。

---- MAKING SOMATOSTATIN ----

盡管合成 somatostatin 的基金不來自 NIH ，他們依然派出人審查，并要求在更高的生物危害防護實驗室中進行。科學家們一開始不順利，后來重新設計 gene ， 添加啟動子，終于合成。但蛋白質很快被細胞酶分解，他們又通過設計，讓 somatostatin 在一個大蛋白質的尾部懸掛，這樣就不會被分解。這種思路也避免 somatostatin 在細胞中發揮生物活性，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， 這也證明 Genentech 的技術可行，在未來有極大的前景。

Kiley 馬上著手申請專利。而大家又因為一作二作的問題有了爭執。

---- 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。

而研究發布后，也迅速引起了爭議。主要領導者 Boyer 毀譽參半。亦有人開始討論科學家-企業的關系，畢竟 Boyer 以“全職合伙人”的身份加入到企業中，并非以前大多數教授的那種輕度合作。UCSF 的報告認為這一行為給學院帶來了不好的聲譽和嫉妒。 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。先后聯系了 Novo Industri, Hoechst ，最終 Lilly 有意生產人胰島素。

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

Swanson 招募了一個發酵專家作為生產總監，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界的博后。以及有經驗的資深學者

隨著 UCSF 發布招待會，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。

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

他們隨后和LILLY公司簽訂合同，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，但為的是保證另一套技術能夠不受競爭，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。

---- PUBLICITY AND EXPANSION ----

是否要申請專利？ Swanson 想要保護公司機密，但科學家想要發表在同行評議的論文上。最終 Boyer 發表了，這也使得學界迅速跟進。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。這也是吸引科學家的一個好方法。

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

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新實力。只要讓文章發表，科研界也愿意過來工作。

Boyer 自己卻不愿意署名。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，不少 DNA 合成的生物技術小公司產生了。這一模式也被業界接受。

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、大學合作，開始向生長激素進發。不同組之間競爭相當激烈，Swanson and Kleid wrote to Goodman 要材料，被拒絕。 Goodman 告訴 Seeburg 嚴禁不經允許就把任何材料拿出實驗室。后來 Seeburg 受不了這種氛圍，某次接口清理試劑，直接把樣品拿到了 Genentech 。但 Seeburg 隨后就酗酒，沒有什么進展。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？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。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，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。不過UCSF并不想商業化，而是為了研究基因表達。而無論怎么說，Genentech 還是第三次成功地克隆了基因，表明了他們在生物技術上的強大實力，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，只有完全把研發、生產、銷售掌握到一起，才能夠獲得最大利益并支持后續的研究。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、一步一步的計劃。

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。

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

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

但隨后遇到了 NIH 的限制——細菌培養不能超過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，但這些卻影響了目前的生產問題。為此他和LILLY公司甚至去華盛頓游說。最后，胰島素、生長激素的生產不被細菌培養所限制。

胰島素終于被FDA批準；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。

---- CORPORATE EXPANSION ----

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

• 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。第一是產品導向，第二是收支平衡，Genentech had been operating in the black since the third quarter of 1978 。他的管理風格不那么正式、嚴苛，而與科學家關系友好，注重互動。 he was mainly a facilitator and cheerleader。

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

直到1983年他們都沒有科研主管，研究者們自由而平等。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 ----

硅谷的企業文化：重視創新、快速研究、知識產權的創造和保護 emphasis on innovation, fast-moving research, and intellectual property creation and protection

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

而GenenTech則是科學價值觀和企業價值觀的融合。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，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、給保齡球下注。

每個人都是公司的一份子。每周五都有聚餐。

平等主義，無差別對待。

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

創業公司的精神：

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，沒有邊界

6. WALL STREET DEBUT

---- BIOMANIA ----
70年代末，美國民眾、華爾街對于生物科技開始大力追捧。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。

---- 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，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。因此，他們開始考慮IPO，去股市。

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

干擾素前景巨大，但是用普通方法生產成本太高。在此熱潮下，用生物技術生產是一個很自然的考慮。 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 很早就想過開發干擾素，但抵制住了隨大流的誘惑，在完成了比較容易、結構已知、且有巨大市場的胰島素和生長激素后，他們才開始加入研發干擾素的行列。1979年中，他們開始了計劃，1980年1月6日和 Hoffmann–La Roche 簽訂了合作協議。這一舉動相當及時，因為當月16日 Charles Weissmann’s lab at the University of Geneva就發布消息成功克隆并表達了干擾素前體。但是事后 Weiss 也被人質疑利用大學實驗室完成商業內容，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布新聞（他們擔心被Genentech搶走Scoop）。

公司的 Goeddel 團隊則不為所動。

最終 genentech 率先實現了干擾素的研發。盡管其潛在機制、效用尚不明確，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。

---- RUN-UP TO AN INITIAL PUBLIC OFFERING ----

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

---- LEGAL IMPEDIMENTS ----

1. 專利問題。不再保護生物，只能把合成方法作為專利申請。公司能夠保護自己的技術，維持技術優勢嗎？

Kiley 上訴至最高法院，高院以5：4認為，技術體現了智力上的獨創，可以被保護。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。經過協商，支付給大學$350,000以平息，避免對上市產生影響。

但這只是暫時的，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，而是使用的UCSF的。他們當時覺得做不出來很尷尬，因此秘密協定滿了下來。但是Ullrich激烈地反對這一說法，用實驗記錄本證明原創性。法院決定二審，雙方在此期間決定和解。 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，沒法參考成功經驗。 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，股價從 $35 to $80，二十分鐘后到達$89 ，當天以$71收盤。創始人名利雙收，記者紛紛采訪。

對Genentech的員工來說，IPO是一個驚人的發現。令他們吃驚的是，這家苦苦掙扎的初創企業曾努力維持現金流，如今卻獲得了一筆即時的現金，并成為公認的“前跑者”——現在看來，這是一個新興的工業領域。

Cetus 的創始人也被他們震動，考慮上市。

科學界也很重視，有人重新提起科學與商業的界限。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

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