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 Bruce Stillman, Ph.D.
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There are times when it is exhilarating, but also humbling, to be a member of a privileged fellowship who collectively call themselves scientists. The year 2000 was such a moment, for we saw extraordinary progress in understanding the fabric of life, the sequence of bases in DNA that encode our genetic information. Following past successes in the sequencing of the genomes of many microbes–the yeast Saccharomyces cerevisiae and the small worm Caenorhabditis elegans–a flurry of important genome sequences emerged during 2000, all with great fanfare. Early in the year, we saw the publication of the sequence of the genome of the fruit fly Drosophila melanogaster, which was a result of a successful collaboration between academic scientists and the private sector, a harbinger of future genome projects. In the middle of the year came the highly coordinated, multinational announcement that the drafts of the human genome were complete, following intervention and direction from President Clinton in this country and Prime Minister Blair in the U.K. The publication of the draft human sequences appeared in early 2001, again with much public attention. With lesser blowing of the trumpet, the last month of the year saw the publication of the complete sequence of the first plant genome from Arabidopsis thaliana. Thus, for the first time, it is possible to gaze into the intimate genetic details of organisms from all kingdoms of life. As a consequence, public interest in biology and medicine is at an all-time high and probably rivals public interest in science following other monumental scientific and engineering feats, such as landing a man on the moon and the splitting of the atom. We have been fortunate to witness and participate in these dramatic advances. A new era of biology has blossomed that will long have profound consequences for science and indeed for society as a whole.
The revolution of recombinant DNA that emerged in the early 1970s made it possible to obtain unlimited amounts of virtually any DNA. Imaginations ran wild, but like so many endeavors in science, technical limitations still kept biologists at bay. Perhaps the clearest and most difficult technical challenge was to figure out how to read the sequence of individual genes. By the mid 1970s, just as I was entering graduate school in Australia, two vastly different approaches to DNA sequencing emerged. One from Wally Gilbert's laboratory in Cambridge in the U.S. used a chemical sequencing approach, whereas that from Fred Sanger's laboratory in Cambridge in the U.K. employed enzymatic methods. The two different technologies from the two Cambridges were complementary, but early on, each had its advocates as to which one was best. It was rather amusing to listen to young Australian scientists returning from studies in either the U.S. or the U.K. tout the virtues of their favorite approach to gene sequencing, depending on the country of origin. In those days, both methods were important, and it was necessary to learn both to be a successful graduate student. In retrospect, these developments proved, unwittingly, to be the first multinational collaboration in the DNA sequencing era, for the sequencing problem was essentially solved and now could be scaled up.
Progress was rapid, and within a year, the genome of a bacteriophage (a virus of bacteria) called fX174, which contains approximately 5375 nucleotides, was reported from Sanger's group. It was equally exciting to learn in 1978, during my first visit to Cold Spring Harbor for the annual Symposium, of Greg Sutcliffe's determination of the complete sequence of the then-favorite bacterial cloning plasmid, pBR322, using the Maxam and Gilbert technique. It was only a matter of time before the concept of sequencing the whole human genome began to be discussed, notably at a meeting organized by Robert Sinsheimer in 1985 at the University of California, Santa Cruz. But the idea of determining the complete sequence of the human genome was controversial, as many biologists saw the cost as being too high. This was a time when grants were particularly difficult to obtain because of limited funding, and there was considerable concern that such an ambitious project could not be completed for technical reasons, even if sufficient funds could be found. During the Cold Spring Harbor Symposium in 1986, Jim Watson brought together some of the leading biologists to discuss the genome sequencing proposal: Was it feasible and, of particular importance, who should fund the considerable cost? Those days now seem far in the distant past, but it was only 14 years ago, a short time in the history of molecular biology. Wally Gilbert's prediction at that meeting that we would all carry our genetic sequence on a credit card then seemed far too fanciful, but it is now well within the realm of possibility.
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