Making PCR explores the culture of biotechnology as it emerged at Certus Corporation during the 1980s and focuses on its distinctive configuration of scientific, technical, social, economic, political, and legal elements, each of which had its own separate trajectory over the preceding decade. The book contains interviews with the remarkable cast of characters who made PCR, including Kary Mullin, the maverick who received the Nobel prize for "discovering" it, as well as the team of young scientists and the company's business leaders.
This book shows how a contingently assembled practice emerged, composed of distinctive subjects, the site where they worked, and the object they invented.
"Paul Rabinow paints a . . . picture of the process of discovery in Making PCR: A Story of Biotechnology [and] teases out every possible detail. . . . Makes for an intriguing read that raises many questions about our understanding of the twisting process of discovery itself."—David Bradley, New Scientist
"Rabinow's book belongs to a burgeoning genre: ethnographic studies of what scientists actually do in the lab. . . . A bold move."—Daniel Zalewski, Lingua Franca
"[Making PCR is] exotic territory, biomedical research, explored. . . . Rabinow describes a dance: the immigration and repatriation of scientists to and from the academic and business worlds."—Nancy Maull, New York Times Book Review
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A Story Biotechnology
By Paul Rabinow
The University of Chicago PressCopyright © 1996 The University of Chicago
All rights reserved.
What would later be called the biotechnology industry emerged during the 1970s. The naming is itself significant because many of the projects the industry began with were old ones, some, such as fermentation processes, quite hoary. Whether projects such as beer making or producing antibiotics and vitamins should be considered precursors of the new biotechnology or holdovers from a previous time reflects the limits of epochal labels. Whether it was called "genetic engineering," "recombinant DNA," "cloning," or something else, the promise of a new era of efficiency and invention powered by scientific and technological advance provided the cachet and selling point for a series of diverse developments in science and commerce.
The main elements that contributed to the industry's initial appearance and the shape it has taken since, though familiar, are worth reviewing because they form the larger environment from which PCR emerged. These elements include: (a) the greatly enhanced technical ability to "recombine," "engineer," or simply "manipulate" DNA and other molecules; (b) a regulatory environment that encouraged the rapid application of research to applied problems, as well as changes in the patent laws directed at actively encouraging (almost forcing) the commercialization of inventions in both industrial and academic settings; and (c) the eventual dovetailing of governmentally funded research with venture capital looking for investments to form an expanded base for molecular biological research and development.
It was within this context of investments in scientific progress directly linked to new products and services in health that molecular biology came of age in the United States. The subtext of this story is the advance of technology, the ability to manipulate DNA under laboratory conditions. The importance of this subtext lies in its exemplarity: the truths of molecular biology emerge from model systems and the techniques used to create and study them. Biotechnology's hallmark, it could be said, lies in its potential to get away from nature, to construct artificial conditions in which specific variables can be known in such a way that they can be manipulated. This knowledge then forms the basis for remaking nature according to our norms.
A THRESHOLD CROSSED: 1979–82
In 1980 the Supreme Court of the United States ruled by a vote of 5 to 4 that new life forms fell under the jurisdiction of federal patent law. General Electric microbiologist Ananda Chakrabarty had developed a novel bacterial strain capable of digesting a component of oil slicks. Chakrabarty modified an existing bacterial strain by introducing a new DNA plasmid (a circular form of double-stranded DNA carrying a specific gene) into bacterial cells, thereby giving the organism the capacity to break down crude-oil components. In so doing, he produced a new bacterium with markedly different characteristics from any found previously in nature — one having the potential for significant utility. Chakrabarty having invented something "new, non-obvious and useful," the Court found it natural to protect his product with a patent.
A report from the U.S. Office of Technology Assessment concisely underlined the dimension of the Court's decision that has drawn the most public attention: "the question of whether or not an invention embraces living matter is irrelevant to the issue of patentability, as long as the invention is the result of human intervention." The Court's decision thereby establishes a broadened interpretation of the "product of nature" doctrine, which holds that for a naturally occurring being or process to be patentable it must contain a "substantially new form, quality, or property." While plant forms had been patentable since 1930, a variety of factors ranging from the organization of the seed industry to the slowness of existing methods for breeding new plant varieties prior to the advent of genetic engineering had contained the scope and impact of such patents until recently.
Until the 1980s, patents had generally been granted only in applied domains. The language of the Constitution, which authorizes Congress to "promote the Progress of Science and useful Arts, by securing for limited Times to Authors and Inventors the exclusive Right to their respective Writings and Discoveries," had been interpreted to mean that patent law should promote the progress of "useful arts," that is, applied technologies. Further, the Patent and Trademark Office had tended to restrict patents to operable inventions, not ideas; it had interpreted the Constitution to demand that an invention have a demonstrable and substantial "utility" in order to qualify for a patent. Finally, prior to the Chakrabarty case, it was generally held that living organisms and cells were "products of nature" and consequently not patentable. The requirement that patent protection be extended to the invention of "new forms" did not seem to apply to organisms (plants excepted). The patents on antibiotics had been awarded based on the isolation of these natural products in "pure form" rather than on the cells or organisms producing the antibiotics. "Nature" was public and available for all to use. The Chakrabarty decision validated a new dimension in the place "nature" would have in both the scientific and the cultural world.
The Supreme Court's ringing proclamation that "Congress intended statutory subject matter to include anything under the sun that is made by man," coming as it did in the same year as the election of Ronald Reagan as president of the United States and the massive influx of venture capital into the biotechnology world, not only opened up "new frontiers" in the law but can be appropriately seen as an emblem of an emerging new constellation of knowledge and power. Fredric Jameson's characterization of late capitalism as marked by its global reach as well as by the penetration of capital into nature on a transformatory scale never before possible is apposite. Claims of a similar sort, albeit employing a different jargon and rhetoric, became standard fare in biotechnology companies' annual reports.
In 1980 Congress also passed the Patent and Trademark Amendment Act "to prompt efforts to develop a uniform patent policy that would encourage cooperative relationships between universities and industry, and ultimately take government-sponsored inventions off the shelf and into the marketplace." At the time the government had some twenty-five different patent policies. This thicket of regulations tended to discourage exclusive licensing agreements, which in turn made industrial investment in product development less likely. The goal of the new policy was to encourage technological advance and a closer connection of university-based research with industry. Under the act's provisions, universities housing government-funded research were obliged to report any potentially patentable invention arising from that research. Failure to do so meant, under the so-called "march-in rights," that such rights automatically passed to the government. The universities responded with enthusiasm. An Office of Technology Assessment report on New Developments in Biotechnology: Ownership of Human Tissues and Cells states that from 1980 to 1984, President Reagan's first term in office, patent applications from universities in relevant human biological domains rose 300 percent.
The Role of Government
Although debates about the social and ethical consequences of the biosciences often turn on the pivotal role of business, it is worth remembering that the initial major impetus for bringing applied and pure research in the biosciences into a closer, more productive relationship came from the U.S. government. Government research facilities and foundations, created or expanded after World War II, from the National Institutes of Health (NIH) to the National Science Foundation (NSF), established a vastly expanded presence, eventually taking precedence in shaping policy over the older philanthropic foundations that had played this role in key sectors in the years between the two world wars. Improving the health of the American people through medical research became a national policy objective. It also became an arena of major economic and bureaucratic growth.
For example, the so-called "war on cancer," proclaimed in 1971, directed substantial research funds toward achieving practical results in the fields of health. It also buttressed the dominant role of the federal government in directing biomedical research. One has only to remember the largely private organization and funding of the campaign to discover the cause of and cure for polio in the 1950s to recognize the changes that took place in less than two decades. By the end of the 1970s, the federal government "was pouring 11 percent of all federally funded research-and-development moneys into basic biomedical research, compared to 2 to 4 percent for most other developed countries." However large such an investment in "health" may have been, it pales in comparison with the R&D budget allocated to the military, which remained constant at about 50 percent for most of the 1970s, rising to 60 percent in 1982 and 74 percent in 1987 (largely because of "Star Wars" and related high-tech weapons systems). The purpose of such a vast outpouring of money was to achieve practical results, to orient research by defining an agenda.
The first major change in the funding of recombinant DNA research came from the federal government. In 1975 only two projects had been funded, at an approximate cost of $20,000; in 1976 the National Institutes of Health were sponsoring 123 projects, at an approximate cost of $15 million. These were university-based projects. The motivation for increased spending was a combination of emergent and promising new technologies, such as cloning, and the spotlight focused on them by a growing national debate about their safety and broader social implications.
A Recombinant Configuration: 1974–79
A climacteric moment in the takeoff of the biotechnology industry was the extraordinarily swift and seemingly definitive resolution of the controversy over the safety of recombinant DNA. A whole range of technologies and research areas grouped under a single rubric became the focus of heated controversy that began in the early 1970s and peaked between 1975 and 1977. Because of an extremely rapid response by the leaders of the molecular biology world, by 1979 the debate had been all but silenced in the United States. The importance of this outcome for stabilizing the institutional and commercial horizons of recombinant DNA work can hardly be overestimated. Had it taken significantly longer to put regulatory mechanisms in place; or had the types of experiments defined as low, medium, and high risk been different; or had safety controls requiring substantial capital investments been imposed for experiments defined as low risk; or had there been a sustained split in elite scientific opinion over the advisability of pursuing the technological and scientific lines of research and development in question; or had there been a major accident with recombinant material — however representative of the "true risks" it may or may not have been — the consequences for funding what was then called recombinant DNA technologies, in both the public and commercial domains, would surely have been dramatic. It is worth remembering that there was nothing ineluctable about the course events took.
A preliminary debate on safety surfaced almost simultaneously with Paul Berg's successful recombinant DNA work in the early 1970s. This debate, originating in Berg's own laboratory, turned on determining what constituted laboratory safety. It included concern over the possible threat to environmental or public health by waste disposal or escape of recombinant organisms and materials. It expanded to more political and philosophical questions: what were the possible ecological and evolutionary implications of transferring DNA from one species to another? An initial voluntary moratorium suggested by Berg himself was followed in subsequent years by a series of high-level meetings attended by the leading players in the field. The emblem of these meetings, debates, and conjectures has now become the Asilomar Conference, held in February 1975. These meetings and consultations culminated in controls for recombinant DNA work in the U.S., Britain, and other countries. They represent a unique event in the regulation of technological applications. Elite scientists evaluated a new technology and developed regulatory guidelines that were subsequently adopted by the government. The regulations proved to be a very successful preemptive strategy that warded off further regulation by outsiders (to the scientific community or its elite informal groups). The molecular biology community's quick action assuaged many doubts (particularly in Congress), although it clearly did not provide definitive answers to a whole series of issues concerning either general risk analysis or broader ethical implications.
By 1977 and 1978, the argument prevailed that recombinant DNA was a supervised and safe technology as well as a potentially invaluable research tool with a huge potential for both profit and the improvement of health. As experience accumulated, work accelerated, and money was invested, the recombinant DNA guidelines were relaxed twice in 1980, again in 1981, and again in 1983. By this point, "The simultaneous growth of small biotechnology start-ups financed by venture capital and the increased interest of multinational corporations created a backdrop of intense entrepreneurial activity for the congressional hearings and NIH guideline revision meetings." Broader host-vector guidelines as well as a distinction between large-scale and small-scale experiments were introduced. Secret sessions of the Recombinant Advisory Committee (R.A.C.) were allowed in order to afford protection for proprietary interests. A corner had been turned. The safety issue had been contained. Government regulators, Congress, business, and a significant sector of the scientific community were satisfied.
Strategy: Patent and Publish
The early 1980s was a time of fierce competition during which the key arena for patenting and publishing was newly cloned genes. The status of the law in these areas was unsettled. Traditionally, in the academic system, publication and priority established scientific reputation. For business, the symbolic rewards for first publication were clearly secondary to the potential commercial advantages a patent offered. The management of biotech firms saw that publication could effectively prevent others from patenting a discovery. This realization led to the strategy of filing a U.S. patent application on a cloned gene and then publishing as rapidly as possible. Filing a patent application for an aspect of the work and subsequently publishing would serve as a means of establishing "prior art" and consequently barring others from obtaining a patent — especially outside the United States.
This strategy differed from older industrial strategies for success in cases where a slight variation in the structure or synthesis of a particular chemical might well be enough to get around a basic patent. Consequently, chemical structures were held secret for years until patents revealing that information were issued. The field of genetic research was so competitive that if one didn't publish findings quickly (often within a matter of weeks or months), there was a constant prospect that some other group would. Since the gene's cloning would be published anyway, the only effect of not publishing was to demoralize the company's scientists and to create the appearance of being second-rate.
A second aspect of this patent-and-publish policy was its use as a means of lessening the differences between the university and industrial milieux, a formerly large gap in the biosciences, closed or narrowed as a result of action on both sides. Many university scientists, led by the elite, responded eagerly to the new patent policies. Since the information was going to be made public rapidly in any case, it was beneficial to industry for its scientists to get credit in the larger world for their discoveries as a means of attracting and keeping high-level achievers. Further, such a policy facilitated work with university scientists by allaying the most commonly stated fear of those scientists that secrecy would be imposed for purposes of commercial gain.
Finally, the teams of bioscientists in companies like Cetus or Genentech often had a competitive advantage over their university colleagues because they were working in large teams with considerable resources of space, equipment, and staff flexibly available for timely use on specific projects. The scientific and commercial strategies concerning the flow of information were reflected in the design of biotech facilities. One of the architects hired by Biogen to design its new facilities observed: "To reinforce management's philosophy that the company is a synthesis of science and business ... we designed several informal meeting areas — for coffee, reading, etc. — where staff could gather and exchange ideas. Meeting rooms are glass enclosed to convey a sense of open communication." Of course, "a good physical environment is certainly to be desired, but it is not as important as a good informational environment. Scientists must be immersed in a constant flow of information and must be active participants in this process." Internal seminars were attended by attorneys alert for patentable ideas; all outside visitors attending the seminars were bound by confidentiality agreements.
Excerpted from Making PCR by Paul Rabinow. Copyright © 1996 The University of Chicago. Excerpted by permission of The University of Chicago Press.
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Table of ContentsIntroduction
1: Toward Biotechnology
2: Cetus Corporation: A Credible Force
3: PCR: Experimental Milieu + the Concept
4: From Concept to Tool
5: Reality Check
Conclusion: A Simple Little Thing
A Note on the Interviews