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May 12, 1998
Beyond Sequencing of Human DNA
By NICHOLAS WADE
he sequencing of the human genome, a historic goal in biomedical research, was snatched away last Friday from its government sponsor, the National Institutes of Health, by a private venture that says it can get the job done faster.
Government officials are scrambling to adjust to the stunning turn of events, saying that the task of interpreting the genome may begin much sooner now, and that there is every reason for Congress to continue to fund the project.
Adjusting to a bold new entry in the genome race.
Having the human DNA sequence in hand much earlier than anticipated will significantly accelerate the pace of biomedical research. "People will sign on to the concept that genome sequences are the underpinning of biology," said Dr. Richard Roberts, a Nobel prize winner who is the research director of New England Biolabs. "I think we are entering the most exciting era of biology. Finally we might understand what life is and how it works. The genome is just a start."The takeover of the human-genome project is a venture of unusual audacity. Almost equally remarkable is that other genome experts seem to accept with little reservation that the abductors have a reasonable chance of making good on their claim to substantially complete the human genome, starting from scratch, in three years. The National Institutes of Health had planned to complete the sequence by the year 2005, after a 15-year program costing $3 billion.
The new venture will be financed by Perkin-Elmer, the scientific-instrument maker, at an estimated cost of only $200 million. The idea was conceived by Michael Hunkapiller, head of Perkin-Elmer's Applied Biosystems division. "I won't say Mike is a genius, because he'd hit me up for a raise," Tony White, the chief executive of Perkin-Elmer, said last week. An aide added, "Let's just say he is smart."
Hunkapiller is one of the co-inventors, along with Dr. Leroy Hood of the University of Washington, of the DNA sequencing machines that determine the order of the chemical units in the genetic material. His division recently developed a new model of their standard sequencing machine, one that is more highly automated and allows the machines to work round the clock with very little attendance.
Hunkapiller realized the new machines were so much more efficient than their predecessors that a roomful of 200 or so might be able to complete the whole human genome in just a few years.
The human genome, with 3 billion units of DNA altogether, is distributed over 23 chromosomes, each of which is a single DNA molecule about 100 million units long. Hunkapiller's machines can determine the order of units in fragments of DNA, which are about 500 units in length. Some 60 million of these overlapping, 500-unit pieces of DNA must then be reassembled to give the sequence of the full-length chromosomes from which they are derived.
The reassembly process is far from straightforward, and Hunkapiller turned to Dr. Craig Venter, a leading DNA sequencer who heads the Institute for Genomic Research in Rockville, Md. He invited Venter to a meeting and told him he thought it might be possible to sequence the whole genome.
"Craig said, 'You've got to be crazy,"' Hunkapiller said. "We spent a few days working through the math and came away thinking maybe it's doable. They went back and redid the calculations, and so did we."
The idea of a single organization cracking the genome in a single procedure, known as a shotgun experiment, is extremely bold. Under the approach adopted by the National Institutes of Health, half a dozen university laboratories are working on the sequence, each tackling a different chromosome.
Dr. Francis Collins, the NIH director of the human-genome project, is proud of their progress, noting that 4 percent of the genome has already been sequenced, whereas the initial plan called for only 1 percent to be completed by this stage. But some scientists in the biotechnology industry say NIH's management of this industrial-scale project has been flawed from the start.
"There have been serious problems of organization and management both at the Department of Energy and at NIH," together with internal dissension among the senior scientists involved, said Dr. William Haseltine, chief of Human Genome Sciences, a genome-sequencing company in Rockville, Md.
That issue will be moot if the sequencing of human DNA is assumed by the new private venture. However, it is hard to see how the new venture could have started without the substantial groundwork laid by NIH and by the university programs it funded, particularly the team at Washington University at St. Louis, led by Dr. Robert Waterston.
Recognizing the credibility of the new venture by Venter and Perkin-Elmer, NIH officials are preparing to persuade Congress to continue funding the genome project but to switch the focus from getting the sequence to the enormous tasking of interpreting it. Venter plans to enter his findings in a public database.
One essential aid to understanding the human genome is to sequence the surprisingly similar genome of the mouse. Though all biologists recognize the need for such a project, it may not be immediately clear to members of Congress that having forfeited the grand prize of human-genome sequence, they should now be equally happy with the glory of paying for similar research on mice.
The new venture accentuates the emerging importance of genomics as the central framework of biology and medicine. "There is a real treasure trove to be found in the total genome and its evolutionary history, particularly as other genomes, those of chimpanzees, new and old world monkeys and mice, become sequenced," said Haseltine. "Once that picture is put together we'll have a very good idea of our evolutionary history."
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