When Bob Waterston decided to go to medical school after completing an engineering degree at Princeton, there were two small problems. One: He had taken no biology courses. Two: He hadn't fulfilled the foreign language requirement.
The solution was obvious -- to Waterston. He and his wife went to Europe for biology classes in German, a language they had only just begun to study.
Waterston has always thrived on challenge. In the middle of his medical degree at the University of Chicago, he paused to do a Ph.D. After jogging with his oldest daughter, he became a marathon runner. Now he is running the most ambitious marathon of all --the effort to decipher the human genetic blueprint.
Robert H. Waterston, M.D., Ph.D., is the James S. McDonnell Professor of Genetics and head of the Department of Genetics in the School of Medicine. He also directs the Genome Sequencing Center, where more than 200 researchers, computer specialists, technicians and students work day and night to sequence DNA.
The team is contributing to an international effort called the Human Genome Project, which is systematically finding human genes by spelling out the order of the genetic letters in our DNA. Sequencing the DNA -- the genomes -- of other organisms also is part of the plan because experiments with genetically similar creatures can reveal human gene function.
This expensive project is essential, Waterston explained, because biologists currently are working with most information hidden from view. "Sure, you can study one gene and its local landscape," he said. "But if you really want to understand how an organism works, you need all the information on the table."
The complete sequence of human DNA should be in hand by 2005, and it will profoundly affect our knowledge of ourselves. "By the middle of the next century, we'll have a good understanding of how genes contribute to all aspects of human health, well-being and behavior," Waterston said. "Eventually, there'll be genetic alleviation of many inherited diseases."
Since the 1960s, Brenner had studied the developmental genetics of a graceful nematode worm named Caenorhabditis elegans, which lives in soil, and he had several mutants that moved in an awkward manner. Fascinated with the exquisite order of proteins in muscle cells, Waterston decided to explore the muscle defects in these worms.
Joining the School of Medicine as an assistant professor in 1976, he continued to study C. elegans, whose muscles are surprisingly similar to those of humans. His group has since defined the role of a major protein called myosin in muscle assembly and contraction. It also has located about 25 muscle genes and their proteins. "Eventually, it became clear that, to understand the many genes involved in muscle assembly, we needed to get much better at the molecular level," Waterston said. "The genome project created a systematic and efficient way of identifying genes."
Waterston's lab was next to that of Maynard Olson, Ph.D., who was on the faculty from 1979 until 1992. "Watching Maynard alternately struggle and succeed in developing methods for mapping yeast made me realize that one could actually think about the genome of the worm," Waterston said. "But at that time it seemed like an audacious idea."
With the aid of a John Simon Guggenheim Fellowship, Waterston returned to Cambridge in 1985 for a sabbatical. There he began to work with John E. Sulston, Ph.D., and Alan R. Coulson, Ph.D., who had begun to create a physical map of the worm's DNA. Their collaboration continues to this day.
Returning to St. Louis in 1986, Waterston found that David T. Burke, one of Olson's graduate students, had found a way to convert large segments of DNA into artificial chromosomes that yeast cells would copy. These yeast artificial chromosomes, or YACs, provided a way to get sufficient amounts of DNA for analysis and, overlapped, would generate a map. The YACs, combined with a previously developed map made from overlapping bacterial clones, led to extensive coverage of a physical map of the worm by 1989.
At a meeting at Cold Spring Harbor, N.Y., that summer, Coulson, Sulston and Waterston pinned six long pieces of paper, each corresponding to a C. elegans chromosome, across one room's entire wall. Their impressive map persuaded influential geneticists that it was time to spell out the details of the genome with DNA sequence.
In August 1990, Waterston received a grant from the newly created National Center for Human Genome Research -- now the National Human Genome Research Institute. Sulston, his collaborator and now head of Cambridge's Sanger Centre, received funding from Britain's Medical Research Council and through a National Institutes of Health grant. "But several people told us we were crazy even to contemplate this project," Waterston recalled.
If every letter in the genetic code were 1 mm wide, he said, the worm genome would stretch from St. Louis to Columbia, Mo. The longest contiguous sequence anyone had obtained in 1990 would stretch the length of a couple of football fields.
During the first year, the St. Louis group sequenced 40,000 of the worm's 100 million nucleotide base pairs --its genetic letters. But they were constantly testing ways to speed up sequencing. Advances in computer software and increasing mechanization of the biochemistry were helpful in increasing speed. The center now has finished a total of 59 million base pairs from various organisms and has reached a rate of 3.3 million base pairs per month. As well as worm DNA, the researchers are working on DNA from humans, mice and a plant. It also contributed to the complete sequence of yeast, which was announced in April 1996.
Waterston finds this work as intellectually challenging as his muscle research. "I approach it in the same hypothesis-driven manner, having ideas about how to make the process work better and devising experiments to test those ideas," he said.
To date, the St. Louis and Cambridge groups have jointly sequenced nearly three-fourths of the worm's DNA, and the collaboration still is thriving. "Bob Waterston is an excellent and innovative research scientist who also has a tremendous flair for organization," Sulston said. "He is utterly honest, straightforward and fun to be with and is committed to getting things done rather than just talking about them. All of these attributes make him the best collaborator one could hope to find and explain why Washington University has spawned the most effective genome center in the United States."
Apart from some small, incoherent sections, the worm project will be finished next summer. Biologists then will have access to a genome that is eight times larger than any previously sequenced. They also will have the first genome of an organism with more than one cell.
To find out how this genome turns a fertilized egg into a 959-cell animal with organs, Waterston wants to know when and where each gene becomes active. He also hopes to uncover new aspects of gene regulation. The group therefore is sequencing a second roundworm that is as genetically different from C. elegans as mice are from humans. By comparing the two genomes, they hope to identify likely regulatory elements.
The success of the worm project has been so spectacular that Waterston and Sulston convinced their funding agencies to go ahead with human genome sequencing. "Three years ago, Bob Waterston rattled the scientific community by urging the Human Genome Project to get on with our most daunting goal: the letter-by-letter sequencing of the entire human genome," said Francis Collins, M.D., Ph.D., director of the National Human Genome Research Institute. "Most people thought that beginning such a momentous task was several years away. But it should have been no surprise to have this challenge come from Bob. In addition to being wise, thoughtful and generous-spirited when it comes to genome matters, he leads the most successful DNA sequencing partnership in the world. He's a big part of the reason I am confident that we'll finish the human sequence on time."
In April 1996, the Genome Sequencing Center received a three-year $24 million grant, the largest of six grants for sequencing human DNA. To date, researchers around the world have completed about 2 percent of the human genome, which, with 3 billion base pairs, is 30 times larger than that of C. elegans. "If the worm genome were to stretch from St. Louis to Columbia, the human genome would stretch from St. Louis to L.A.," Waterston pointed out.
The upshot was that, in 1994, Merck & Co. Inc. funded Washington University's efforts to sequence snippets of human gene copies, agreeing that the data should go to a publicly accessible database at the National Library of Medicine in Bethesda, Md. The center also sends raw data straight from its sequencing machines to its own Web site each day, sometimes with spectacular results. On Nov. 23, 1995, it posted the sequence of a region of human DNA known to contain a breast cancer gene, BRCA2. On Dec. 5, 1995, an international group submitted a paper to the journal Nature identifying the gene's exact location.
Between his involvement with the genomics community and hands-on work in the lab, Waterston has little spare time --these days, he keeps fit by riding his bike to work. But he supports the efforts of his wife, Pat, who is president of the board of Coalition for the Environment, a board member of the Missouri Parks Association and a former head of Citizens to Protect Forest Park.
The Waterstons' youngest daughter, a junior at Washington University, hopes to make a career in environmental policy. Their oldest daughter is a graphic designer in Palo Alto, Calif. Their middle daughter is looking for a teaching position in Chicago. Six years ago, the Waterstons took their nephew, now 7, into their home.
This month, the Waterstons went to Pakistan to hike in the Himalayas. Climbing the smaller peaks, they glimpsed the bigger ones above. Waterston will remember that view as he and his colleagues labor up the biggest peak in the genomic landscape, aiming for the top by 2005.
-- Linda Sage
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