June 26, 2000

Scientists Complete Rough Draft of Human Genome

By NICHOLAS WADE
NYT UPDATE 2:40 P.M.

	Reuters; Agence France-Presse
	President Clinton, center, was joined by Craig Venter of Cerlera Genomics and Dr. Francis Collins of the National Institutes of Health.
	Related Articles • The Human Genome Abounds in Complex Contradictions (July 27, 2000) • Most Ills Are a Matter of More Than One Gene (July 27, 2000) • Data From Genome Project Transforming Biology Research (July 27, 2000) • Text of the White House Statements (July 27, 2000) Issue in Depth • The Human Genome Project Video • President Bill Clinton spoke at a White House announcement on Monday morning. • 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 Glossary • Genetic Terms Chronology • Secrets of the Gene: A Timeline
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	The Genome Project What are the implications of a decoded human genome? Add your thoughts and see what other readers are saying in Abuzz. Predict the uses humankind will find for this knowledge. Compare this achievement to other milestones in science.

ASHINGTON -- In an achievement that represents a pinnacle of human self-knowledge, two rival groups of scientists said in a joint announcement today they had effectively deciphered the genome, the set of genetic instructions that defines the human organism.

The genome consists of two sets of 23 giant DNA molecules, or chromosomes, with each set containing a total of 3 billion chemical units. The successful decipherment of this vast genetic archive marks the extraordinary pace of biology's advance since 1953, when the structure of DNA was first discovered, and presages a post-genomic era of brisk progress.

"Today, we celebrate the revelation of the first draft of the human book of life," said Dr. Francis Collins, leader of the National Institutes of Health team that took part in the effort.

Understanding the human genome is expected to revolutionize the practice of medicine. Biologists expect in time to develop an array of genomic-based diagnostics and treatments tailored to individual patients, some of which will exploit the body's own mechanisms of self-repair. Knowledge from the project also has the potential to raise a host of ethical and social problems -- everything from discrimination by insurance companies or employers to the morality of designing babies to inherit particular traits.

Today's announcement was hailed not only by scientists but also by President Bill Clinton and Britain's Prime Minister Tony Blair, whose governments had jointly supported the mapping effort.

President Clinton, announcing the feat at the White House, called it "one of the most important, most wondrous maps ever produced by humankind," even more significant than the mapping of the American continent in the early 19th century.

"Today we are learning the language with which God created life," Mr. Clinton said.

Prime Minister Blair, in a televised linkup from London, said: "Let us be in no doubt about what we are witnessing today: A revolution in medical science whose implications far surpass even the discovery of antibiotics, the first great technological triumph of the 21st century."

Today's announcement heralds an unexpected truce between the two groups of scientists who have been racing to finish the genome. Veering away from the prospect of asserting rival claims of victory, the two have chosen to report simultaneously their attainment of different milestones in their quest.

"The only race we're interested in today is the human race," Dr. Collins said at a joint news conference with J. Craig Venter, president of the Celera Corporation.

Dr. Venter said he has assembled the complete, contiguous sequence of DNA units in the human genome, save for gaps that amount to 2 percent of the estimated 3.12 billion units. Most of these gaps contain DNA that does not code for genes.

A different result was reported by Celera's rival, the Human Genome Project, a consortium of academic centers supported largely by the National Institutes of Health and the Wellcome Trust, a medical philanthropy in London.

Dr. Collins, leader of the N.I.H.'s part of the consortium, said its scientists had sequenced 90 percent of the human genome in draft form, meaning its accuracy will be upgraded later.

Dr. Collins, speaking at the White House ceremony today, said, "Science is a voyage of exploration into the unknown. We are here today to celebrate a milestone on a truly wondrous voyage into ourselves."

Both versions of the human genome meet the important goal of allowing scientists to search them for desired genes, the genetic instructions encoded in the DNA. The consortium's genome data is freely available now. Celera has said it will make its human genome data freely available at a later date. Dr. Venter said his company would make money by "helping our clients interpret that data."

The two genome versions were obtained through prodigious efforts by each side, involving skilled management of teams of scientists working around the clock on a novel technological frontier.

Spurring their efforts was the glittering lure of the genome as a scientific prize, and a rivalry fueled by personal differences and conflicting agendas.

Dr. Venter, a genomics pioneer whose novel methods have regularly been scorned by experts in the consortium's camp, has often cast himself, not without reason, as an outsider battling a hostile establishment.

The consortium scientists were halfway through a successful 15-year program to complete the human by 2005, when Dr. Venter announced in May 1998 that as head of a new company, later called Celera, he would beat them to their goal by five years.

His bombshell entry turned an academic pursuit into a fierce race. Dr. Collins, the consortium's unofficial project manager, responded by moving his completion date forward to 2003 and setting this month as the target for the 90 percent draft. "These folks have pulled out all the stops," he said of his staff in an interview last week. "They have achieved a ramp-up that is beyond anything one would have imagined possible."

The consortium has spent $250 million on sequencing the human genome since January 1999, when its all-out production phase began, said Dr. Robert Waterston of Washington University, St. Louis, one of the principal researchers. Celera has not released its costs but Dr. Venter said in May last year that he expected Celera's human genome to cost from $200 to $250 million.

The race opened with mutual predictions of defeat.

The groups were divided by political as well as technical agendas. The consortium's two principal scientists, Dr. John E. Sulston of the Sanger Centre in England and Dr. Waterston insisted the genome data should be published nightly, an unusually generous policy because scientists generally harvest new data for their own discoveries before sharing it.

Both of the consortium's administrative leaders, Dr. James D. Watson and his successor Dr. Collins, made a point of seeking out international partners so that the rest of the world would not feel excluded from the genome triumph. Thus even though centers in the United States and Britain have done most of the heavy lifting, important contributions to the consortium's genome draft have been made by centers in Germany, France, Japan and China.

Academic scientists have felt some chagrin that an altruistic, open, and technically successful venture like the Human Genome Project should be upstaged by a commercial rival financed by the company that made the consortium's DNA sequencing machines.

But though Celera seeks to profit by operating a genomic data base, Dr. Venter also believed he could make the genome and its benefits available a lot sooner. He has succeeded in doing so, as well as in spurring the consortium to move faster.

"This is a triumph for public and private funding," Dr. Venter said. "Which, if it hadn't happened, decoding the human genome would be far off."

Today's truce between the two teams has been driven less by an outbreak of warm feelings than by calculation of its advantages. For Celera to claim victory over the consortium would risk alienating customers in the academic community. For the consortium, the surety of opting into a draw now may have seemed better than the risks of claiming victory with a complete genome much later.

Although Celera has a substantially complete sequence of the genome, which is considerably ahead of the consortium's 90 percent draft, its version incorporates and depends on the consortium's data. And the many small gaps in Celera's sequence will probably be filled by the consortium's scientists, adding further to their claim on credit for the final product.

The present truce between the two sides is limited to today's announcement and an agreement to publish their reports in the same journal, although the details remain to be worked out.

"All that has been discussed with Collins is just cooperation, not collaborative efforts," Dr. Venter said.

The versions of the human genome produced by the two teams are in different states of completion because of the different methods each used to determine the order of DNA units in the genome.

The consortium chose first to break the genome down into large chunks, called BACs, which are about 200,000 DNA letters long, and to sequence each BAC separately. This BAC-by-BAC strategy also required "mapping" the genome, or defining short sequences of milestone DNA that would help show where each BAC belonged on its parent chromosome, the 23 giant DNA molecules of which the genome is composed.

BACs are assembled from thousands of snippets of DNA, each about 500 DNA letters in length. This is the longest run of DNA letters that the DNA sequencing machines can analyze. A computer pieces together the snippets by looking for matches in the DNA sequence where one snippet overlaps another.

But the BACs do not assemble cleanly from their component snippets. One reason is that human DNA is full of repetitive sequences -- the same run of letters repeated over and over again -- and these repetitions baffle the computer algorithms set to assemble the pieces. The stage the consortium has now reached is that all its BACs are mapped, making the whole genome available in a nested set of smaller jigsaw puzzles. But the BACs are in varying stages of completion. The BACs covering the two smallest human chromosomes, numbers 21 and 22, are essentially complete. But many other BACs are in less immaculate states of assembly. Many consist of assembled pieces no more than 10,000 units long, and the order of these pieces within each BAC is not known.

The sum of the assembled pieces in each BAC now covers 90 percent of the genome. This working draft, as the consortium calls it, is maybe not a thing of beauty but is of great value to researchers looking for genes and represents a major accomplishment.

Celera's genome has been assembled by a different method, called a whole genome shotgun strategy.

Following a scheme proposed by Dr. Eugene Myers and Dr. J. L. Weber, Celera skips the time-consuming mapping stage and breaks the whole genome down into millions of the 500-letter fragments produced by the DNA sequencing machines. The fragments are then assembled in a single mammoth computer run, though with a handful of clever tricks to step across the repetitive sequence regions in the DNA. Though Celera's genome will probably be judged by scientists to be a much better version than the consortium's rough draft, the consortium can justifiably share the credit for it.

But the genome decoding is just the beginning.

"Having the genetic code is not a very important moment other than it's the begining of what we can do with it," Dr. Venter said.