June 27, 2000

READING THE BOOK OF LIFE

Double Landmarks for Watson: Helix and Genome

By NICHOLAS WADE

	Scott Goldsmith for The New York Times
	Dr. James D. Watson, president of Cold Spring Harbor Laboratory, in his office, has the distinction of playing a major role in two milestones in science history.
	Related Articles • The Human Genome Project Video • The Composition of Life narrated by Nicholas Wade, science reporter, The New York Times. (Requires Macromedia Flash Plugin) 3D Interactive Images • DNA Replication Process (Requires Hypercosm Player) • The Scale of DNA (Requires Hypercosm Player) Biographies • Francis Collins: Dedicated Researcher, Family Man Heads Public Project • Craig Venter: A Maverick Making Waves Chronology • Timeline: Journey to the Genome Glossary • Genetic Terms
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he genesis and history of the genome project has been intertwined to a remarkable degree with the career of one man, Dr. James D. Watson.

With Dr. Francis Crick, Dr. Watson discovered the structure of DNA in 1953, and later helped start the human genome project which, less than 50 years later, is coming to fruition.

"I would only once have the opportunity to let my scientific career encompass a path from the double helix to the three billion steps of the human genome," Dr. Watson wrote in explaining his decision to become the first director of the human genome project office at the National Institutes of Health in 1988. Announcing of the results of the project yesterday, President Clinton acknowledged Dr. Watson's contributions by telling him, "Thank you, sir," and the audience of scientists and journalists broke into applause. The human genome project may be the gateway to the biology and medicine of the 21st century, but it was at first bitterly opposed by many academic biologists.

They believed that the interesting genes would come to light one by one in the course of the research they were already doing, and that a federal project to decode the whole genome would siphon money from their own budgets, financed mostly by the National Institutes of Health.

The first serious proposals for decoding the human genome, according to Robert Cook-Deegan in "Gene Wars" (W. W. Norton & Company, 1994), a history of the genome project's early days, were made in 1985 by biologists like Dr. Robert Sinsheimer of the University of California at Santa Cruz and Dr. Walter Gilbert of Harvard. It was the Department of Energy that first picked up their ideas in 1987, with the rationale that its nuclear radiation experts needed to know whether the genome could be protected from mutation.

Academic biologists continued to scorn the project. Biology, in their view, was a science based on clear-cut experiments, not on Big Science-style extravaganzas that vacuumed up data just for the sake it.

Dr. Watson's former mentor, Dr. Salvador Luria, wrote in a 1989 letter to Science that the genome program "has been promoted without public discussion by a small coterie of power-seeking enthusiasts."

With senior biologists lukewarm or hostile to the program, Dr. Watson was one of the few leaders with the stature to quell opposition and guarantee that the project would be scientifically rigorous.

Then director and now president of the Cold Spring Harbor Laboratory on Long Island, he also helped persuade Congress to give the National Institutes of Health the money to start its own genome venture.

Because of these efforts, Dr. Watson emerged as the obvious candidate to lead the human genome project, and was appointed as the first director of the agency's human genome program, a post he held from 1988 to 1992.

In the late 1980's the longest piece of DNA that had been decoded was a few thousand units long. The DNA molecules in human chromosomes range from 40 million to 250 million units in length, presenting a different scale of difficulty. The task was daunting but not insuperable if the chromosomes could be broken down into smaller pieces for decoding and assembled through some kind of chromosome map that would show how the pieces fit together.

Dr. Watson laid out the elements of what has been the public consortium's strategy ever since.

He decreed that the project would be conducted at several universities, not by some central administration, a move that allowed different initial approaches to be tried.

It had the advantage of spreading out the money, winning political support.

Dr. Watson sought out international partners, particularly in Britain, where the roundworm genome project had already begun, and vigorously campaigned for Germany and Japan to join the project.

"It wouldn't be good if the Americans owned the genome," he said in an interview last month. As a result of his efforts, the consortium now includes laboratories in Britain, France, Germany, China and Japan.

Another stamp of his stewardship is the program of ethical and legal studies about the genome, which at first took up 3 percent and now 5 percent of the N.I.H.'s genome project budget.

Dr. Watson, long concerned that biology should dissociate itself from the stain of the eugenic movement, announced the program as one of his first official acts.

In an unusually accurate piece of technological forecasting, Dr. Watson estimated the overall cost would be $3 billion and that the project could be completed in 15 years from its official starting date of 1990.

The cost estimate assumed that methods of sequencing DNA would get rapidly cheaper as technology improved. In fact the cost has fallen from $10 per unit of DNA at the project's start to 4 cents a unit now.

In laying the basis for the enormous task of sequencing the human genome, Dr. Watson's consortium eventually brought into being a powerful competitor, the Celera Corporation.

The concept of Celera grew from a surprising source, a company then known as Applied Biosystems, which made the principal brand of DNA sequencing machine used by the consortium's centers.

In devising a new generation of the machines, the company's president, Michael W. Hunkapiller, calculated it should be possible for a single, industrial-scale center to start from scratch and decode the human genome before the consortium did so.

Dr. Hunkapiller's idea required getting into competition with his own customers. But it also meant doubling the market for his sequencing machines and their chemical reagents.

To direct the project, he signed up Dr. J. Craig Venter, whose maverick sequencing ideas regularly earned the disapproval of the academic establishment yet often proved to work. The venture was backed by Tony White, president of the Perkin Elmer Corporation, who quickly shed the company's old-time instrument-making plants and committed it, as the PE Corporation, to the brave but untested new world of genomics.

Celera was begun in May 1998, with Dr. Venter declaring he would complete the genome by 2001. This was a bombshell to the public consortium, where Dr. Watson had been replaced by Francis S. Collins, and the Wellcome Trust of London, a powerful new medical charity that had become an important player by financing the Sanger Center in England to decode one-third of the genome.

True to form, several of the consortium's experts on DNA sequencing pronounced that Dr. Venter's proposed fast method for decoding the human genome would not work. But Dr. Collins decided that the Celera challenge could not be ignored.

He advanced the consortium's target finishing date to 2003 from 2005. He also committed the consortium to producing a rough draft of the genome by June 2000. The draft would focus on the gene-rich regions of the genome (only 3 percent of human DNA codes for genes) and would make the most useful part of the genome available to gene hunters much earlier than otherwise.

In December 1998, the consortium's two leading production centers, those of Dr. Robert H. Waterston at Washington University in St. Louis and Dr. John E. Sulston at the Sanger Center, reached an important milestone by completing their pilot project on the roundworm genome, the first animal genome to be decoded.

A few months later it became clear that the consortium's major centers had ironed out their problems with the human genome and were producing large amounts of DNA sequence on schedule, giving the lie to Dr. Venter's mockery of their projections as those of a "Liars' Club."

Dr. Waterston and Dr. Sulston had predicted in October 1998 that Celera would decode a lot of DNA fragments but would stumble in its plan to piece the fragments together. "Assembly would likely be woefully inadequate," they wrote.

But last March, Celera published the results of its first project, the decoding of the Drosophila fruit fly's genome.

The fruit fly genome showed that Celera probably could assemble the human genome with its quick method, and sharply raised the level of tension between the two teams.

A neck-and-neck race ensued to see whether the consortium could announce completion of its draft genome before Celera could declare that it had finished its final genome assembly.

Though consortium scientists routinely deplore the attention given to the race, the competition has benefited the world's biologists.

Without Celera's challenge, the consortium would have had little reason to alter its academic flight path and produce the useful part of the genome three years ahead of the 2003 landing date.

Without the consortium's challenge, Celera could be commanding top dollar for its database, knowing customers had no alternative.

The two sides have adopted different strategies for sequencing the genome and have produced results that are quite complementary, meaning that there was always a underlying logic to combining their efforts.

But for many months of rivalry, no peacemaker succeeded in bringing the two sides together.

Dr. Watson, whose book "The Double Helix" famously described the passions of a scientific race, remained a committed supporter of the public program he had shaped.

The consortium had succeeded, he said in an interview last month, "because people liked and respected each other, and because the consortium wasn't out for personal glory." He also gave credit to Dr. Leroy Hood and Dr. Lloyd Smith, both then at the California Institute of Technology, who in the early 1980's pioneered the first DNA sequencing machines.

These slow early models reached their zenith in the latest generation of machines known as capillary sequencers, like PE Biosystems' Prism 3700, the machine that launched Celera, and Amersham Pharmacia's excellent though less widely used Megabace. If the human genome project were allowed a robotic hero, it would be the Prism 3700.

Only in the last month have the two sides moved nearer as Dr. Venter and Dr. Collins saw mutual advantage in at least making a joint announcement of progress.

Through prodigious efforts and expert management, both sides have achieved remarkable success with their chosen approaches. Celera's whole genome shotgun approach has proved faster, but both with its fruit fly and the human genome, Celera has made use of data obtained by the consortium's clone-by-clone approach. The best way of sequencing a genome may be to use both methods.

If Celera's version of the human genome proves as good as its fruit fly genome, scientists may judge it to have chosen the better path. Nonetheless, both sides can fairly claim credit for the final result.

That biology has progressed from near total ignorance of the hereditary material to possession of the entire human genome within 50 years is testament to a hectic pace of discovery.

Even more remarkable is that a single individual, James Watson, should have played such a signal role in both the opening of the drama and in its conclusion.