DNA decoding draws competition

The federal government's Human Genome Project (HGP), a 15-year, $3 billion venture launched in 1990 to map out and catalog human DNA, has proceeded exceedingly well. And while the project— which uses computers to identify DNA fragments— has reached its halfway point ahead of schedule, it has met with some unexpected competition from private companies that claim to be able to do the work faster and less expensively.

In May, Celera Genomics Corp., Rockville, Md., said it would complete the same work at one-tenth the cost of the public program and within three years— about four years before the government is scheduled to finish. Three months later, Incyte Pharmaceuticals Inc., Palo Alto, Calif., surprised both groups by stating it would crack the human code within two years, also at a lower cost.

Federal HGP officials and other observers assert that the government's work is more intensive than that of the private companies and will produce more accurate results.

Scientists have fallen into a match of sorts, each side eyeing the ultimate prize: the achievement of a scientific feat possibly greater than the creation of the periodic table of elements. The complete map of human DNA promises to provide a key to unlock doors to diseases— a key that has evaded scientists for years.

Francis Collins, director of the National Human Genome Research Institute (NHGRI), said geneticists around the world will use HGP data to define, diagnose and develop treatments for diseases. Research information already has led to new discoveries for disorders such as relapsing multiple sclerosis, human growth deficiency, diabetes, hemophilia A, cystic fibrosis and Parkinson's disease.

"The isolation of a gene for Parkinson's disease last year demonstrated the power of this new discovery method and showed conclusively that changes in DNA can cause [Parkinson's disease] in some families," Collins said in June in testimony before the House Science Committee's Energy and Environment Subcommittee. "In just a few months, the researchers showed conclusively that an altered gene caused Parkinson's disease in the study families. Many have hailed this as the most significant advance in Parkinson's disease research in 30 years. Genome project tools have underpinned virtually all gene discoveries of this century," Collins told the subcommittee.

Effects of the A-Bomb

The sequencing of the human genome began in the mid-1980s as an Energy Department effort to study the effects of radiation on survivors of the Hiroshima and Nagasaki bombings. The National Institutes of Health eventually joined forces with DOE as the scope of this research grew. The two agencies signed a memorandum of understanding in 1988 and officially launched HGP two years later.

DOE works on the project at three of its national laboratories: Lawrence Berkeley, Lawrence Livermore and Los Alamos. The Joint Genome Institute, created in 1997, manages these three labs, providing services such as budgetary control and a peer review system. NIH carries out most of its research through university-based research grants. While 22 institutes and centers comprise the agency, NHGRI maintains lead responsibility for the project.

The initial DOE/NIH plan for the proj-ect set goals for creating physical and genetic maps; conducting experimental DNA sequencing of the fruit fly, a round worm yeast and E. coli bacteria; establishing computer management of research data; and undertaking studies of HGP's ethical, legal and social implications. Scientists met these objectives ahead of schedule and under budget, and the effort cost almost 25 percent less than the original $1 billion estimate for 1991 to 1997.

But as NIH and DOE scientists congratulated each other, the private sector prepared to release even more exciting news. On May 11, 1998, Perkin-Elmer Corp., a scientific instrument manufacturer, and The Institute for Genomic Research (TIGR) reported that their new company, Celera Genomics, will "substantially complete the sequencing of the human genome in three years [using] breakthrough DNA analysis technology." Company chairman Ken Clavert said this technology will allow the company to "operate a genomic sequencing facility with an expected capacity greater than that of the combined world output."

Craig Venter founded TIGR, an independent nonprofit research institute, in 1992 after leaving his job at NIH. While working on the federally funded project, Venter and his colleagues developed a new sequencing technique that offered a faster way to identify genes. He told the House subcommittee that when circumstances surrounding funding and patenting of this technology made it difficult for him to use it in his lab at NIH, he decided to take it elsewhere.

Differing Approaches

At TIGR, Venter employed this technology to identify more than 50 percent of the genes in the human genome. He published his results in 1995. During the same year, TIGR released the first complete sequence of a self-replicating, living organism that the institute determined using another new sequencing technique: the whole-genome shotgun approach. This strategy takes a wide view of human DNA, as opposed to the shotgun-sequencing approach used by the government to home in on the precise location of each fragment. Using the shotgun-sequencing approach, NIH and DOE researchers identify the fragment's position in the larger strand of DNA before sequencing to ensure that they can put it back in order— a practice not used by their private-sector counterparts.

Celera will employ the whole-genome shotgun strategy— coupled with a new, fully automated sequencing machine developed by Perkin-Elmer— to finish mapping the human genome. Although company officials express confidence in their approach, others question it. Marv Frasier, division director for the Health Effects and Life Sciences Research Division of DOE's Office of Biological Environmental Research, said Celera's method will produce "more of an intermediate product that will have some gaps.

"We don't know how well that will work for human genomes," Frasier said. "It has worked very well for microbes."

Maynard Olson, a professor of medicine at the University of Washington's Division of Medical Genetics, told the House subcommittee that the Celera approach will offer only short-term benefits because the data it will produce probably will be "poor" in quality. "The [Celera] initiative offers the possibility that the immediate needs of the biological community over a period of two to three years— roughly the interval of 2000 to 2003— may be better met than would otherwise have been the case," Olson said. "I hope that the project is successful and that the data are sufficiently accessible to the scientific community that this promise is met. However, in the larger scheme of the Human Genome Project, we would all be unwise to focus on so transient a contribution."

In addition to different standards of quality, critics of Celera also point to the lack of access to information the company will provide. While the government project shares DNA sequence data daily, Celera will only provide it quarterly.

But Venter believes his strategy will get the job done, asserting that his "grand experiment" will each day catalog 100 million base pairs— the four chemicals that make up DNA pairs and that are repeated millions of time throughout a genome. At such a rapid clip, this output will far exceed that of NIH and of DOE. The federal program has deposited more than 300 million base pairs in GenBank, the publicly funded database maintained by the National Library of Medicine.

Venter also defended the quality of his product in his testimony to the subcommittee. "The accuracy of this sequence will be comparable to the standard now used in the genome sequencing community of fewer than one error in 10,000 base pairs," he said.

Gillian Woollett, associate vice president of biologics and biotechnology at the Pharmaceutical Research and Manufacturers of America, told the subcommittee that companies such as Celera have a great incentive to use the fastest approach: Pharmaceutical companies are eager to buy genetic information. "The whole of drug development is changing," she said. "We are very interested in genomics across the board."

Despite the different approaches, the federal program has invited the participation of other parties. "We welcome Venter's plan," DOE's Frasier said. "NIH and DOE invested in much of the technology that Perkin-Elmer will use. We'll use that new technology as it's made available to us."

For his part, Venter told the subcommittee that it should not pull the plug on the federal program. "The safe bet is to keep funding it," Venter said. "Once I show [the Celera approach] works and we're making progress, then I'll argue that they are probably wasting money."

Two months after the hearing, Incyte Pharmaceuticals announced it will sequence the genome in less time than it will take Celera. Like its competition, the California company will use a riskier sequencing technique than the federally funded program and will not produce an entirely comprehensive map.

Officials from Incyte were unavailable for comment.

All three groups have traveled far from the days when sequencing was done by hand as a string of chemical reactions. And as the race to decode the human genome continues, the groups are pushing the envelope on developing new sequencing technologies.

Both the private ventures and the federal program have geared up to finish the project in less time then anyone previously imagined possible.

This goal, however, represents only the first milestone in a series of events. More of a triathlon than a dash, the next step for researchers is to begin studying genetic diseases and developing treatments.

"The beautiful thing about genomics is having the data and doing something with it," Venter said. "Sequencing is the beginning, not the end of anything."