June 27, 2000

Genetic Code of Human Life Is Cracked by Scientists

By NICHOLAS WADE

	Reuters
	Top, Dr. Francis Collins and J. Craig Venter joined President Bill Clinton at the White House on Monday to announce the completion of the first draft of the human genome.
	From Tuesday's Times • Now, the Hard Part: Putting the Genome to Work • The Human Genome Abounds in Complex Contradictions • Most Ills Are a Matter of More Than One Gene • The Doctor's World: Genomic Chief Has High Hopes, and Great Fears, for Genetic Testing • Data From Genome Project Transforming Biology Research • Francis Collins: An Adroit Director of an Unwieldy Team • Craig Venter: A Maverick Making Waves • Who's Who on Celera's Team • Players on the Consortium Team: Scientists Turned Cartographers • Whose DNA Is It? In a Way, Nobody's • Double Landmarks for Watson: Helix and Genome • Studying Model Organisms 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 Chronology • Timeline: Journey to the Genome Glossary • Genetic Terms
	ADD YOUR THOUGHTS
	The Genome Project What are the implications of a decoded human genome? Predict the uses humankind will find for this knowledge. "Scientists should think carefully before 'discovering' a gene for IQ, sexuality, obesity, etc. Making these illnesses solidifies discrimination, intolerant worldviews, and implies that we need to cure people."  — schm "We will be able to see more clearly those things about us that are nature and those that are nurture."  — jashy Add your thoughts and see more reader comments in Abuzz.

ASHINGTON, June 26 -- In an achievement that represents a pinnacle of human self-knowledge, two rival groups of scientists said today that they had deciphered the hereditary script, the set of instructions that defines the human organism.

"Today we are learning the language in which God created life," President Clinton said at a White House ceremony attended by members of the two teams, Dr. James D. Watson, co-discoverer of the structure of DNA, and, via satellite, Prime Minister Tony Blair of Britain. [Excerpts, Page D8.]

The teams' leaders, Dr. J. Craig Venter, president of Celera Genomics, and Dr. Francis S. Collins, director of the National Human Genome Research Institute, praised each other's contributions and signaled a spirit of cooperation from now on, even though the two efforts will remain firmly independent.

The human genome, the ancient script that has now been deciphered, consists of two sets of 23 giant DNA molecules, or chromosomes, with each set -- one inherited from each parent -- containing more than three billion chemical units.

The successful deciphering of this vast genetic archive attests to the extraordinary pace of biology's advance since 1953, when the structure of DNA was first discovered and presages an era of even brisker progress.

Understanding the human genome is expected to revolutionize the practice of medicine. Biologists expect in time to develop an array of diagnostics and treatments based on it and tailored to individual patients, some of which will exploit the body's own mechanisms of self-repair.

The knowledge in the genome could also be used in harmful ways, particularly in revealing patients' disposition to disease if their privacy is not safeguarded, and in causing discrimination.

The joint announcement is something of a shotgun marriage because neither side's version of the human genome is complete, nor do they agree on the genome's size. Neither has sequenced -- meaning to determine the order of the chemical subunits -- the DNA of certain short structural regions of the genome, which cannot yet be analyzed.

With the rest of the genome, which contains the human genes and much else, both sides' versions have many small gaps, although these are thought to contain few or no genes. Today's versions are effectively complete representations of the genome but leave much more work to be done.

The two groups even differ on the size of the gene-coding part of the genome. Celera says it is 3.12 billion letters of DNA; the public consortium that it is 3.15 billion units, a letter difference of 30 million. Neither side can yet describe the genome's full size or determine the number of human genes.

The public consortium has also fallen somewhat behind in its goal of attaining a working draft in which 90 percent of the gene-containing part of the genome was sequenced. Its version today has reached only 85 percent, suggesting it was marching to Celera's timetable.

Today's announcement heralded 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 chose to report simultaneously their attainment of different milestones in their quest.

Celera, a unit of the PE Corporation, has obtained its 3.12 billion letters of the genome in the form of long continuous sequences, mostly about 2 million letters each, but with many small gaps.

A less complete version has been reported by 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, the consortium's leader, said its scientists had sequenced 85 percent of the genome in a "working draft," meaning its accuracy will be upgraded later.

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 a version of its genome sequence freely available at a later date.

In their remarks at the White House, Dr. Collins and Dr. Venter both sought to capture the wider meaning of their work in identifying the eye-glazing stream of A's, G's, C's and T's, the letters in the genome's four-letter code.

"We have caught the first glimpses of our instruction book, previously known only to God," Dr. Collins said.

Dr. Venter spoke of his conviction from seeing people die in Vietnam, where he served as a medic, that the human spirit transcended the physiology that is controlled by the genome.

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 innovative methods have at times 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 genome 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 5 years.

His bombshell entry turned an academic pursuit into a fierce race. Dr. Collins responded by moving his completion date forward to 2003 and setting this month as the target for a 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 15-year cost of the Human Genome Project, which began in 1990, has been estimated at $3 billion, but includes many incidental expenses. The consortium has spent only $300 million on sequencing the human genome since January 1999, when its all-out production phase began.

Celera has not released its costs, but Dr. Venter said a year ago that he expected Celera's human genome to cost $200 million to $250 million.

The race opened with mutual predictions of defeat. The consortium's senior scientists predicted in December 1998 that Dr. Venter's method of reassembling the sequenced fragments of genomic DNA was bound to fail. In May 1999, Dr. Venter, confident of Celera's impending success, observed that the National Institutes of Health and the Wellcome Trust were "putting good money after bad."

The groups were divided by political as well as technical agendas. The consortium's two principal scientists, Dr. John E. Sulston of the Sanger Center in England and Dr. Robert Waterston of Washington University in St. Louis, insisted that 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 database, Dr. Venter also believed that he could make the genome and its benefits available a lot sooner. He has succeeded in doing so, and in spurring the consortium to move faster.

Today's truce between the two teams offers several 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.

Celera's version of the genome 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 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. A joint workshop will be held to discuss the genome versions.

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 BAC's, which are about 150,000 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 giant DNA molecules of which the genome is composed.

BAC's 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 BAC's 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 BAC's are mapped, making the whole genome available in a nested set of smaller jigsaw puzzles.

But the BAC's are in varying stages of completion. The BAC's covering the two smallest human chromosomes, numbers 21 and 22, are essentially complete. But many other BAC's 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 85 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 a set of fragments that are 2,000, 10,000 and 50,000 letters long. These fragments are analyzed separately and then assembled in a single mammoth computer run, with a handful of clever tricks to step across the repetitive sequence regions in the DNA.

The approach ideally required sequencing 30 billions units of DNA -- 10 times that in a single genome.

Dr. Venter seems to have taken a considerable risk by starting his assembly at the end of March this year when he possessed only a threefold coverage of the genome. He has since raised his total to 4.6-fold coverage.

The decision may have been influenced by Celera's rate of capital expenditure -- the company's electric bill alone is $100,000 a month -- and by the need to sequence the mouse genome as well so as to offer database clients a two-genome package.

The mouse genome is expected to be invaluable for interpreting the human genome, and Dr. Venter said today that Celera would finish sequencing it by the end of the year.

Because of having relatively little of its own data, Celera made use of the consortium's publicly available sequence data and, indirectly, of the positional information contained in the consortium's mapped set of BAC's. The consortium can justifiably share in the credit for Celera's version of the genome, another cogent factor in the logic of today's truce.

Biotech Shares Rise and Fall

Stocks of biotechnology companies rose early yesterday after a White House announcement that the first survey of the human genome had been completed, but investors cashed in some of their profits before trading ended, causing several issues to fall.

Biotechnology shares peaked in March in a speculative frenzy, before backsliding sharply. In recent weeks, they again posted significant increases in anticipation of the genome announcement.

The Celera Genomics unit of the PE Corporation, which participated in the mapping project and has been one of the highest fliers, dropped $12.25, to $113 yesterday. The stock of the company, based in Rockville, Md., hit a record high of $252 a share on Feb. 25. Although well off its high, Celera shares are still up 1,400 percent from this time last year.