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7 INCENTIVES AND FOCUS IN UNIVERSITY AND INDUSTRIAL RESEARCH: THE CASE OF SYNTHETIC INSULIN
7 INCENTIVES AND FOCUS IN UNIVERSITY AND INDUSTRIAL RESEARCH: THE CASE OF SYNTHETIC INSULIN
Pages 157-187
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From page 157... ...
view each other as competitors for ce funding and academic prestige, while similarly sized firms compete ugh markets and the development of appropriable products or processes. i, then, do biotechnology firms and universities regard each other as complets, and is this relationship the result of the particular historical sequence that fed the early days of biotechnology?
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From page 158... ...
However, Genentech, a small start-up biotechnology firm with no income and limited resources, was the organization first able to synthesize and patent human insulin, resulting in a royalty agreement with Eli Lilly. This paper contends that Genentech's commercial success can be understood through contrasting and comparing its goals with those of university departments, such as Harvard or UCSF.
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From page 159... ...
Activation and repression of protein production, the intergenerational transmission of genetic instructions, and the relationship between the sequence of genetic information and the production of amino acids presented fundamental but manageable puzzles to research ers. Before 1970, most of the important advances within molecular genetics were the result of studying prokaryotic (lower)
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From page 160... ...
Perhaps a bit more SThe definition and boundaries of each of these disciplines have changed over time, but the textbook definition or the relative scope of each has not changed nearly as much as that of molecular biology. 6Restriction enzymes are the critical material in "cutting" up genetic material for the purpose of extracting specific DNA strands.
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From page 161... ...
P4, the strictest standard, was reserved for experiments with dangerous or human genetic material and could only be performed in the equivalent of a military biowarfare lab. 8Adenine, cytosine, thymine, and guanine, respectively.
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From page 162... ...
In Stephen Hall's popular account of the "race" to synthesize human insulin,~4 he divides the research activities into three groups. The groups' coordinators were Walter Gilbert, the team of William Rutter and Howard Goodman, and Herbert Boyer, respectively.ls Organizing analysis of the insulin research by lab chief provides 12This is by no means an exhaustive review of the major advances that took place in the mid1970s.
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From page 163... ...
The respective labs of Howard Goodman and William Rutter, both of UCSF, decided to collaborate on the insulin research. The collaboration was initiated because members of both labs were independently attempting to express rat insulin in E
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From page 164... ...
A SHORT HISTORY OF THE rDNA INSULIN RESEARCH PROJECTS The expression of human insulin in bacteria was identified as a feasible research goal by the time that rDNA experimentation resumed in the summer of 1976. The most influential labs, equipped with a novel set of procedures, tools, and questions, attempted to carve out important but "doable" research projects.
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From page 165... ...
Alex Ullrich, a postdoctoral researcher in Goodman's lab, then "backwards-engineered" the MRNA into the original DNA strands utilizing reverse transcriptase.21 These DNA strands were then spliced into a plasmid utilizing the Cohen-Boyer technique. The vector was then in 19It may be instructive to note that cDNA cloning, the most elegant method for isolation, begins with messenger RNA (mRNA)
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From page 166... ...
cold colony did, indeed, possess the genetic material for rat insulin (Ullrich et al., 1977~. To put the experiment in perspective, the insertion of a eukaryotic gene into E
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From page 167... ...
Genentech contracted with Herbert Boyer's own gene cloning and plasmid construction lab at UCSF, as well as with Arthur Riggs and Keiichi Itakura of City of Hope National Medical Center just outside of Los Angeles. Upon the advice and requests of Riggs and Itakura, Genentech funded experiments whose goal was the expression of synthetic somatostatin, a simpler human hormone than insulin.24 While somatostatin was not perceived to have any direct commercial value, it was viewed by its Genentech funders as an acceptable first step toward the synthesis of the insulin gene.
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From page 168... ...
Much of the scientific insight from cDNA cloning did not require the use of natural human genetic material, however. The Gilbert group at Harvard continued to pursue expression of rat insulin in bacteria.
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From page 169... ...
For expression of human insulin, Genentech was able to establish its own laboratory in South San Francisco and hire its first full-time researchers, Dennis Kleid and David Goeddel. The Harvard researchers, in contrast, reached 29Globin is an essential protein in the construction of red blood cells and had been utilized by the Harvard researchers in earlier research.
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From page 170... ...
The UCSF researchers involved in the rat insulin insertion experiment, most notably Alex Ullrich, agreed with Lilly to pursue research on expression of human insulin.33 By focusing on the expression of human genetic material, those researchers utilizing cDNA cloning methods were required to satisfy far more stringent RAC guidelines than were necessary for the rat insulin experiments. As mentioned earlier, very few locations possessed sufficient safety precautions to satisfy the regulation, and most of the acceptable locations were military biowarfare labs.
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From page 171... ...
Gilbert's group, in contrast to the UCSF researchers, was intent on the expression of human insulin during the summer and early autumn of 1978. Four Harvard researchers, Gilbert, Efstratiadis, Villa-Komaroff, and Broome,36 secured a one-month research stay at Porton Down Microbiology Research Labs in England.
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From page 172... ...
A research contract, ensuring a steady stream of income, was negotiated with Eli Lilly after the successful achievement of expression of human insulin in bacteria. The research strategy utilized mirrored the somatostatin project, though additional players were brought onto the team, such as David Goeddel and Dennis Kleid, for the actual cloning.
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From page 173... ...
Isolation of the rat insulin gene provided key insights into the interaction between introns, exons, and the modes of intergenerational transmissions of genetic information. On the commercial side, Genentech and Eli Lilly signed a research and royalty agreement shortly after the Genentech expression experiment.
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From page 174... ...
As mentioned above, Paul Berg claims that molecular biology was an approach and philosophy toward bioresearch adopted by an increasing number of experimenters during the 1970s, and that the increase in this adoption was partially a function of the increasing availability of tools and technology (telephone interview with Paul Berg, Professor of Biochemistry, Stanford University, February 17, 1993~. Gilbert, on the other hand, notes that while particular distinctions do not do justice to the set of skills possessed by a researcher in either field, biochemists might be more interested in activities such as the purification of proteins while molecular biologists would be more interested in the manipulation of DNA through the use of enzymes (telephone interview with Walter Gilbert, Professor, Department of Molecular Biology and Biochemistry, Harvard University, February 18, 1993~.
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From page 175... ...
that "99.9 percent of organic chemists work on other and different topics; 0.1 percent of organic chemists work on DNA synthesis" (telephone interview with Keiichi Itakura, Department of Molecular Genetics, City of Hope National Medical Center, February 18, 1993~. In other words, the proper role for an organic chemist in genetic engineering research was not obvious before the insulin research.
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From page 176... ...
However, the deeper insight is best stated by Walter Gilbert: "When one is working on the frontier, nearly anything that one puts one's fingerprint on will be interdisciplinary" (telephone interview with Walter Gilbert, Professor, Department of Molecular Biology and Biochemistry, Harvard University, February 18, 19931. Only a small number of researchers had mastered the emerging techniques of genetic engineering at the time of this case study.
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From page 177... ...
William Rutter notes three of these characteristics: "complementing your own research objective," "believing you will get an answer faster," and introducing "specific expertise" (telephone interview with William Rutter, Professor of Biochemistry, University of California, San Francisco, and President, Chiron Corporation, June 14, 1993~. For example, the UCSF group pursued, for a while, a collaboration with researchers at the University of Texas (most notably Peter Lomedico)
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From page 178... ...
Indeed, as discussed above, the Gilbert group arranged their stay at Porton Down through Biogen connections, and Alex Ullrich completed a stay at Eli Lilly's French research facility. These connections were critical for these researchers, as there were very few sites at which experiments with human genetic material could be conducted.
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From page 179... ...
In contrast, the Harvard and UCSF researchers needed to alter their funding arrangements as well as their base of operation as soon as they began experiments with human genetic material. ANALYSIS AND CONCLUSIONS This case study has focused upon rDNA insulin research in the late 1970s.
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From page 180... ...
For exarr~ple, while the Harvard effort was pushed by Walter Gilbert in particular directions, Gilbert notes that "we were limited by the practicalities of what graduate students and postdocs were interested in" (telephone interview with Walter Gilbert, Professor, Department of Molecular Biology and Biochemistry, Harvard University, February 18, 1993~. Additionally, the insulin research at the academic labs was conducted with a set of biological questions in mind.38 These restrictions did not bind Genentech.
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From page 181... ...
In conjunction with the focus on nonhuman genetic material, the cDNA strategy leveraged the disciplinary focus of these labs: molecular biology and biochemistry. The synthetic process, while "a quick way to get a result" (telephone interview, W
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Rutter, 1993~. Thus, in contrast with the Genentech strategy, the cluster of characteristics that identify the academic researchers (cDNA cloning, the focus on nonhuman genetic material, and relative disciplinary insularity)
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From page 183... ...
Bob Swanson at Genentech, in contrast, exploited the competitive nature of his researchers to focus organizational resources on the successful expression of human insulin in bacteria. "Definitely the name Wally Gilbert was in Swanson's mouth all the time.
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The university researchers, on the other hand, attempted to exploit the commercial properties of their research in conjunction with the production of important biological information. This resulted in the use of cDNA methods, which re 4lSome of the more public contemporary work included the human growth hormone research, as well as the highly publicized debate at Harvard University concerning the university's potential exploitation of genetic engineering.
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From page 185... ...
However, the development of the Genentech corporate research culture took time to cultivate. Indeed, the somatostatin experiment represents an important transition period for the Genentech researchers as they performed an experiment with little direct commercial value in the context of a corporate funding relationship.
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From page 186... ...
Instead, molecular biology and biochemistry departments have become important training sites for industrial researchers as well as serving as a nexus for information dissemination. Moreover, university labs have continued to push forward the boundaries of fundamental scientific knowledge (perhaps best exemplified by the Human Genome Project)
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From page 187... ...
1977. Rat insulin genes: Construction of plasmids containing the coding sequences.
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