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 benefi 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 fl 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.
  如何提出合作请求

• 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.” 说起来容易做起来难

• 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如果老板给一个这种课题，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 fl oors away.

交流和保密？

• 申请专利

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.

• 各类药企游说积极接触NIH的主管，想要弄清楚风向，是否对DNA合成药物有特别的监管，是否有政策风险。

---- 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 从 Asilomar 会议上拿到合成DNA实验室的名单，一个个打电话推销，询问他们是否觉得此技术已经可以商业化。大部分人都说需要十到二十年，最后Boyer的回答是马上就可以商业化，但他心事重重. Swanson 感觉劝说他见一面。

见面后Swason惊讶的发现Boyer自己也在考虑商业化，走的还很远。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。两人志趣相投，Swason介绍的风投也给Boyer留下了深刻印象。

初生牛犊的天真让他们很快开始。 28 Naïveté, 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 naïveté. . . . I think if we had known about all the problems we were going to encounter, we would have thought twice about starting. . . . Naïveté was the extra added ingredient in biotechnology.”

Boyer 想开公司，但对如何运营信心不足。Swason 弥补了这一点。By aligning himself with a company, perhaps he could mitigate the perennially pressing problem of raising funds for his lab
开公司进行成果转换？清华大学的那位教授...风险、成本、政策、如何考虑

• 经过调研，Swason 选择了胰岛素。
• 风投Kleiner & Perkins 对这项技术一无所知。但是Boyer 分析的很好，思路清晰。需要什么设备、原料，如何进行，让投资人相信，就算实验无法成功，这个也是有价值的。
• 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三人构成了一个非常小但高效的董事会。

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

• 向大学购买专利
• 二轮融资

3. PROVING THE TECHNOLOGY

Genentech 的特殊点在于当时它的技术完全是全新的，而且尚未有任何一款药物能在近期生产

---- A PORTENTOUS EXPERIMENT ----

第一个实验目的在于确定流程能够工业生产。两组合作大规模克隆特定DNA。结果证明人工合成的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 ----

生长激素抑制剂，更小，更容易合成.Riggs 和 Itakura 从科学的角度想要做这个，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

他们正在申请NIH基金，这时Boyer打电话来想要第二次合作，合成胰岛素。Riggs劝说先做 Somatostatin 生长激素抑制剂，Boyer很容易就同意了。

但是劝说 Swanson 同意比较难，他全身心投入到胰岛素这个已经被证实有巨大市场前景的蛋白质上。而Somatostatin尚无清晰的临床价值。他更看重产品，能给公司带来价值、吸引投资人的产品，而不像三名科学家一样从实验规律、可行性考虑。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 接下来又找了律师 Kiley 完成和 City of Hope 以及大学方面的专利协议。 Kiley 会给这个年轻的、以自己的技术为唯一命脉的公司，灌输技术专利是多么重要。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。

后来 City of Hope 果然和 Genentech 就授权费打官司，要求对引申出去的其他技术、药品也要授权；但 Genentech 认为只有二者合作的 生长激素以及胰岛素需要。某个案件中陪审团 7：5 赞同 Genentech，但是另一场里 Genentech 被惩罚性地要求赔偿。上诉后减少赔偿但依然败诉。

---- MAKING SOMATOSTATIN ----

尽管合成 somatostatin 的基金不来自 NIH ，他们依然派出人审查，并要求在更高的生物危害防护实验室中进行。科学家们一开始不顺利，后来重新设计 gene ， 添加启动子，终于合成。但蛋白质很快被细胞酶分解，他们又通过设计，让 somatostatin 在一个大蛋白质的尾部悬挂，这样就不会被分解。这种思路也避免 somatostatin 在细胞中发挥生物活性，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! *

所有科学家都欣喜若狂， 这也证明 Genentech 的技术可行，在未来有极大的前景。

Kiley 马上着手申请专利。而大家又因为一作二作的问题有了争执。

---- WIDER ISSUES ----

政策风险依然很大，政府可能会要求更加繁琐的生物安全限制。

而研究发布后，也迅速引起了争议。主要领导者 Boyer 毁誉参半。亦有人开始讨论科学家-企业的关系，毕竟 Boyer 以“全职合伙人”的身份加入到企业中，并非以前大多数教授的那种轻度合作。UCSF 的报告认为这一行为给学院带来了不好的声誉和嫉妒。 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 ----

由于缺少制药经验，他们想于胰岛素制药公司合作。先后联系了 Novo Industri, Hoechst ，最终 Lilly 有意生产人胰岛素。

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

Swanson 招募了一个发酵专家作为生产总监，千金市马骨的作用。 Boyer 则在学校找到了一些有异于投身工业界的博后。以及有经验的资深学者

随着 UCSF 发布招待会，成功克隆了老鼠的胰岛素基因。他们招人的紧迫性也大了起来。

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

他们随后和LILLY公司签订合同，但随后Boyer才知道前几天LILLY也和另一个团队签订了数额更大的合同。他担心LILLY只是暂时买下自己的技术，但为的是保证另一套技术能够不受竞争，又或者Genentech的技术生产另一套产品。于是他和Swason又和LILLY签订了另一套限制合同。

---- PUBLICITY AND EXPANSION ----

是否要申请专利？ Swanson 想要保护公司机密，但科学家想要发表在同行评议的论文上。最终 Boyer 发表了，这也使得学界迅速跟进。公众也更加相信这一技术得到了科学共同体的承认。对公司的快速打响名声有很大帮助。这也是吸引科学家的一个好方法。

与此相反，有些制药公司会在专利申请后才让科学家发表论文，损害了后者和科学共同体的利益。

Swanson 后来也开始同意这一原则。因为华尔街会用引用数评估小科技公司的创新实力。只要让文章发表，科研界也愿意过来工作。

Boyer 自己却不愿意署名。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.

沿着Genentech的路径，不少 DNA 合成的生物技术小公司产生了。这一模式也被业界接受。

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.

各大公司都开始与研究所、大学合作，开始向生长激素进发。不同组之间竞争相当激烈，Swanson and Kleid wrote to Goodman 要材料，被拒绝。 Goodman 告诉 Seeburg 严禁不经允许就把任何材料拿出实验室。后来 Seeburg 受不了这种氛围，某次接口清理试剂，直接把样品拿到了 Genentech 。但 Seeburg 随后就酗酒，没有什么进展。因此To rescue the stalled project, Swanson turned to Goeddel, fast becoming Genentech’s prized cloner

这种行为怎么看待？当时是一种灰色地带。整个公司建立过程中的知识产权问题

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

这意义无疑十分巨大：In short, the making of growth hormone indicated a far clearer path, albeit with inevitable detours and impediments, to a viable commercial future.

于此同时，前往法国的UCSF 研究组也成功的克隆了人类生长激素基因，离他们也很近了。不过UCSF并不想商业化，而是为了研究基因表达。而无论怎么说，Genentech 还是第三次成功地克隆了基因，表明了他们在生物技术上的强大实力，也说明生物科研不仅仅是大学研究所的事情。 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 认为，只有完全把研发、生产、销售掌握到一起，才能够获得最大利益并支持后续的研究。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. 为了达成这个目标，就需要长期的、一步一步的计划。

他计划首先把生长激素卖给原有的生产商，避免直接的市场开发。

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

第一个问题就是如何把实验室规模的合成扩大为工业生产。为此聘请了一批生产工程师和发酵专家作为骨干。a cadre of process engineers and fermentation experts to handle the development and scale-up of insulin and growth hormone。

但随后遇到了 NIH 的限制——细菌培养不能超过10升。 Swanson 最初标榜公司完全符合最严苛的限制以获得民众认同，但这些却影响了目前的生产问题。为此他和LILLY公司甚至去华盛顿游说。最后，胰岛素、生长激素的生产不被细菌培养所限制。

胰岛素终于被FDA批准；In October 1982 the FDA approved the sale of the Genentech-Lilly insulin, under the trade name Humulin. 而生长激素更难一些。

---- CORPORATE EXPANSION ----

从1970到1979，公司的规模和复杂度都有了剧烈提高，也需要管理规模的扩大。

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

但年轻的 Swason 牢牢把握了公司的方向。第一是产品导向，第二是收支平衡，Genentech had been operating in the black since the third quarter of 1978 。他的管理风格不那么正式、严苛，而与科学家关系友好，注重互动。 he was mainly a facilitator and cheerleader。

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

直到1983年他们都没有科研主管，研究者们自由而平等。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 ----

硅谷的企业文化：重视创新、快速研究、知识产权的创造和保护 emphasis on innovation, fast-moving research, and intellectual property creation and protection

但这些企业和研究所的关系不如 genentech 与大学研究的关系密切。Boyer 鼓励公司的研究员参与到学术界的科研活动中。

而GenenTech则是科学价值观和企业价值观的融合。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

学术界和科研界的不同价值观

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没什么两样：等实验结果的间隙玩桌上足球、给保龄球下注。

每个人都是公司的一份子。每周五都有聚餐。

平等主义，无差别对待。

Swanson 要求很严格。如果你的手头的工作没有堆起来，你就没有好好努力工作！

创业公司的精神：

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.

没有约束，没有边界

6. WALL STREET DEBUT

---- BIOMANIA ----
70年代末，美国民众、华尔街对于生物科技开始大力追捧。政府以及NIH对相关的研究也放宽了显著。对潜在用途和可能危害的权衡开始偏向其巨大意义。

---- EXIT STRATEGIES ----

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

他们找投资人谈了两场，都没能成功拿到进一步投资。最后总结是自己的技术太先进还没有量产。因此，他们开始考虑IPO，去股市。

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

干扰素前景巨大，但是用普通方法生产成本太高。在此热潮下，用生物技术生产是一个很自然的考虑。 Cetus, DuPont, Hoffmann–La Roche, Harvard, Caltech, 以及其他研究者都在竞争克隆干扰素基因。

Genentech 很早就想过开发干扰素，但抵制住了随大流的诱惑，在完成了比较容易、结构已知、且有巨大市场的胰岛素和生长激素后，他们才开始加入研发干扰素的行列。1979年中，他们开始了计划，1980年1月6日和 Hoffmann–La Roche 签订了合作协议。这一举动相当及时，因为当月16日 Charles Weissmann’s lab at the University of Geneva就发布消息成功克隆并表达了干扰素前体。但是事后 Weiss 也被人质疑利用大学实验室完成商业内容，Biogen也违反了科学准则，在干扰素基因测序结果出来前就抢先发布新闻（他们担心被Genentech抢走Scoop）。

公司的 Goeddel 团队则不为所动。

最终 genentech 率先实现了干扰素的研发。尽管其潜在机制、效用尚不明确，但投资者依然蜂拥而来，另外几家生物技术公司同样受到追捧。

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

Perkins 认为要尽早上市，尽一切代价劝说 Swason 和 Boyer，并开启投票。不过没有成功。后者的担忧在于法律阻碍

---- LEGAL IMPEDIMENTS ----

1. 专利问题。不再保护生物，只能把合成方法作为专利申请。公司能够保护自己的技术，维持技术优势吗？

Kiley 上诉至最高法院，高院以5：4认为，技术体现了智力上的独创，可以被保护。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的法律诉讼

Ullrich’s and Seeburg’s 的转化材料。经过协商，支付给大学$350,000以平息，避免对上市产生影响。

但这只是暂时的，1999年UCSF还是把genentech 告上法庭。Seeburg突然推翻自己先前的证言，称自己和Ullrich并未合成DNA，而是使用的UCSF的。他们当时觉得做不出来很尴尬，因此秘密协定满了下来。但是Ullrich激烈地反对这一说法，用实验记录本证明原创性。法院决定二审，双方在此期间决定和解。 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

接下来他们开始写上市报告。当时还没有类似的企业，没法参考成功经验。 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

最后的计划书还是通过了，尽管写满了“谨慎投资”

---- THE IPO ----

上市后一分钟，股价从 $35 to $80，二十分钟后到达$89 ，当天以$71收盘。创始人名利双收，记者纷纷采访。

对Genentech的员工来说，IPO是一个惊人的发现。令他们吃惊的是，这家苦苦挣扎的初创企业曾努力维持现金流，如今却获得了一笔即时的现金，并成为公认的“前跑者”——现在看来，这是一个新兴的工业领域。

Cetus 的创始人也被他们震动，考虑上市。

科学界也很重视，有人重新提起科学与商业的界限。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?

科研界和工业界的关系前所未有的紧密。 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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