Robert L. Sinsheimer

May, 1985. | Genomics. Volume 5, Issue 4, November 1989, Pages 954-956.

The Santa Cruz Workshop in May 1985 resulted from the convergence of several lines of thought.

The first complete genome to be sequenced was that of the bacterial virus ¢Xl 74 (5400 nucleotides) by Fred Sanger in 1977. Before that, my laboratory had been the first to purify, characterize, and genetically map this small virus, so that it was available to be the substrate upon which Sanger developed his elegant technique.

As one consequence, I had followed the further development of DNA sequencing and its application to larger and larger genomes. By 1985, the genomes of the bacterial viruses T7 (40,000 nucleotide pairs) and lambda (49,000 nucleotide pairs} had been sequenced and the sequencing of the genome of the Varicella-Zoster virus (125,000 nucleotide pairs) was far along. Early efforts were underway to sequence ultimately the DNA of the bacterium Escherichia coli (4.5 million nucleotide pairs) and, even more ambitious, the DNA of the nematode Caenorhabditis elegans (80 million nucleotide pairs). So I was cognizant of both the trend in sequencing and the evident limitations of the then-current methods.

In a different context, as Chancellor at the University of California at Santa Cruz, one of the nine campuses of the University of California system, I had come into contact, in varied modes, with “Big Science.” UC operates the nuclear weapons laboratories-Los Alamos and Livermore-for the Department of Energy. This relationship was a source of continuing controversy on the campus and throughout the UC system and I had, perforce, become informed in general about the programs of the Laboratories, each of which has a budget approaching a billion dollars per year. As Chancellor of UC Santa Cruz, I was also responsible for the operation of the Lick Observatory of UC. The astronomers at together with scientists and engineers at Lawrence Berkeley Laboratory, had been engaged for several years in a novel design for “the world’s largest telescope,” with a 10-m-diameter collecting mirror. I had been actively involved in securing the backing of the UC system for this project, which was expected to cost about $80 million. Lick astronomers were also involved in several aspects of the Hubble Space Telescope-a billion dollar project. And I was tangentially involved in the effort, led by UC, to attract the proposed Super-Conducting-Super-Collider particle accel­erator to California-a $6 billion project. It was thus evident to me that physicists and astronomers were not hesitant to ask for large sums of money to support programs they believed to be essential to advance their science.

Biology had always been “small science.” I wondered if there were scientific opportunities in biology that were being overlooked, simply because we were not thinking on an ad­equate scale.
For a number of years I had been simultaneously excited, frustrated, and concerned about the potential application of genetic knowledge to the human condition. I was excited, because it had become evident through the work of Victor McKusick and others that many human disorders had-as any geneticist would expect-genetic components, and, plausibly, so must many other human traits. Clearly, all of the phenomena of human growth and development and aging are genetically based. The evolutionary origin of Homo sap­iens assuredly involved significant genetic modification. But I was frustrated because a rational approach to the under­standing of these processes and any potential therapy of ge­netically based disorders would depend upon much greater knowledge of the human genome, knowledge that was ad­vancing all too slowly. I was concerned, too, over the potential that increased knowledge of the human genome would provide opportunity for social mischief-and, again, frustrated because very few would give such issues-which were certain to arise in the long run-much thought, as long as they seemed so remote.

As Chancellor of UC Santa Cruz, I had, of course, a major concern for the future of this young, growing campus. I wanted it to become the peer of other UC campuses such as Berkeley and Los Angeles, to become recognized in the world of science. It already was recognized in astronomy. As a biologist, I wanted similar recognition for its biology.

All of these nascent thoughts, visions, concerns, and am­bitions coalesced in the fall of 1984. The immediate impetus for their coalescence was the potential availability of funds for a Human Genome project. UC had received a large gift­$36 million-toward the construction of the 10-m telescope. Through a complex series of events, UC was at that time obliged to return the funds. A confluence of ideas led to the thought that this money might instead be used to launch an Institute to Sequence the Human Genome at UC Santa Cruz. I suggested this to UC President Gardner in a letter of No­vember 19, 1984.

Alas, it was not to be. But the basic idea seemed absolutely “right.” I would, however, need to seek other funds. To do this, I needed validation of my concept that this was a feasible project. I needed a rational plan of attack, a concept of pace and scale in monetary terms. To provide this, I next met with Harry Noller, Bob Edgar, and Bob Ludwig as the most rel­evant molecular biologists at UCSC to discuss convening a workshop on the feasibility of sequencing the human genome. We outlined the likely strategy for such a project. The de­velopment of more powerful methods for genetic mapping and cloning, the provision of automated means of sequencing, and the invention of improved means of data storage and access all seemed evident and essential stages. We then set about to invite leading scientists in each of these areas (Table 1). To our pleasure, most of those invited expressed interest and agreed to attend, although some indicated great skepti­cism.

The Workshop began on Friday evening, May 24, 1985, and ended on Sunday morning May 26. As it progressed, as the various scientists described the status of their work, and as we analyzed the problems to be solved and the likelihood of progress toward their resolution, the mood of the partic­ipants swung from extreme skepticism to confidence in the feasibility of such a program. Several participants had sig­nificant doubts whether such a program should be initiated­ whether it was a wise approach, whether the requisite funds could be justified. But feasibility was no longer the issue.

The sources of hesitation ranged from concerns over the introduction of Big Science into biology to arguments that most of the human DNA is “junk” -i.e., noncoding-so why sequence it? I disagreed with both objections. 

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TABLE 1: Participants in the May 1985 Santa Cruz Workshop

Off-campus participants

University of California at Santa Cruz participants