Racing the feds to the genetic moon Genetics: Using new technology, an upstart entrepreneur claims he can create a nearly complete blueprint of a human gene four years earlier than the federal government.

THE BALTIMORE SUN

ROCKVILLE -- When J. Craig Venter said a few days ago that he would try to complete the first human genetic blueprint faster than the federal Human Genome Project, it was as if some aerospace executive had vowed in the mid-1960s to overtake NASA and be the first to put humans on the moon.

Of course, the upstart entrepreneur who tried to launch a private Apollo mission would have been ridiculed, his sanity seriously questioned. But Venter, who pioneered a widely used method for rapidly identifying genes, has a history of silencing skeptics.

At a press conference in Bethesda this week, Venter sketched a plan to sprint ahead of the $3 billion government project and record all but a tiny fraction of the human genetic code by 2001.

"It's going to rely on doing everything faster and better than everybody else," he said, his quiet voice belying the audacity of his boast.

Venter, head of the Institute for Genomic Research (TIGR) in Rockville, said this private-sector genome project will be conducted by a new, for-profit company that doesn't have a name yet. Perkin-Elmer Corp., of Norwalk, Conn., will own 80 percent of the firm, with Venter and others controlling the remaining 20 percent.

If Venter succeeds, he'll have a nearly complete transcription of the human genetic code four years earlier than the deadline set for the federal effort. That collaboration includes researchers at a dozen universities and institutes, led by the Department of Energy and the National Institutes of Health.

The Human Genome Project has been called the most ambitious biological research program ever launched. Some scientists predict that it will become the basis for the hunt for new drugs, diagnostic tests and preventive therapies for the next century.

From 1990 until last year, federal researchers were busy scouting out landmarks on the vast landscape of human DNA. They were preparing for sequencing, the inch-by-inch survey that is the project's ultimate goal. Sequencing began in 1997, and it's about 4 percent completed.

Some scientists think that the federal effort is moving too slowly, and that it will never complete its work by the 2005 deadline.

The problem is that reading the genetic code takes very $H expensive equipment, factory-style discipline and lots of manual labor.

"Sequencing is very much a brute-force kind of enterprise," says Dr. Matthew Heil, a consultant for the Delphi Group Ltd. of White Plains, N.Y., a biotech consulting firm. "It's a straightforward, cookbook kind of thing. Universities have been the centers for innovation. Actually implementing the sequencing effort, I think,

has been a little hard for them."

Any suggestion that the effort is behind schedule is "ridiculous," according to Dr. Eric Green, chief of the genome technology branch of the NIH's National Human Genome Research Institute, which runs the genome project.

Venter didn't criticize the pace of federal research. He just said he could complete the work much faster, and provide crucial data to researchers all over the world at a very attractive price. "It's free," he said.

Perkin-Elmer is expected to pick up most of the $300 million cost of project.

The payoff for Venter and Perkin-Elmer, he said, would be first crack at patenting between 100 and 300 of the 60,000 to 80,000 genes uncovered by the sequencing effort. But he said his firm would publish all its data once every three months, and would not seek any fees from researchers who create new products from unpatented sequences.

The stakes are enormous, in money as well as in human health.

So far, genetic research has yielded a dozen widely used pharmaceuticals, including man-made human growth hormone and insulin.

Four patents held by Amgen, a biotech firm, on genes that stimulate the production of red blood cells produced $1.1 billion in revenue last year. Among the hundreds of other genes patented are several controlling bone formation and parts of the immune system.

Once the human genome is sequenced, of course, sequencing it again would be like re-inventing the wheel. Some scientists wonder if the federal government will continue to pay for a multibillion-dollar project in competition with a private firm.

But Dr. Francis Collins, director of the National Human Genome Research Institute at the NIH, says it "really remains to be seen" if Venter can succeed. He predicts that the public genome project will plow ahead, at least for the next 18 months, while Venter tries to prove he can make his private effort work.

Venter says he'll know by next April if he's on the right track.

Perkin-Elmer first approached Venter with the idea several months ago, telling him it had developed a DNA sequencing machine that works 24 times faster than existing machines.

The most widely used DNA analyzers look at snippets of DNA that have been trapped in slabs of a gelatin-like substance and separated by running an electric current through the gel. This is time-consuming work.

But Perkin-Elmer's Model 3700 analyzer employs a new capillary technology that uses thin tubes or channels in place of the gels.

Venter did not describe the new technology in detail, but said that a lab worker using a Model 3700 could sequence as much DNA in 20 minutes as that same worker can now do in eight hours.

Venter also plans to use a controversial technique to prepare the DNA for scanning by the machines. It's called whole-genome shotgunning.

Basically, it means taking all the DNA to be analyzed and shattering it into tens of thousands of pieces small enough to be read quickly. Supercomputers then compare these fragments and figure out how they should fit back together.

The federal genome project is using a more conservative method, where sections of DNA are removed from known locations along the genome, then shattered, sequenced and reconstructed. The government's approach is more methodical, and makes fewer demands on computers to reassemble the bits of genetic material.

There is no question that the approach by Venter's institute is much faster and cheaper. But some scientists fear it may also be less accurate and comprehensive. The problem is the structure of human DNA, which makes it hard to transcribe.

For one thing, long stretches of the genome contain thousands of repeats of the same two molecules. For example: AGAGAG. It is hard or impossible, even for supercomputers, to fit these stuttering strings into the overall puzzle.

Also, human DNA contains twists, loops and kinks, like a tiny roller coaster, which can disorient researchers looking for the order of molecules.

But Venter and other researchers at his institute say they are confident that they can overcome the problems and sequence most of the genome. A computer analysis, Venter said, showed that his method would leave only 3,000 tiny gaps in the 3 billion-molecule-long DNA chain.

Several firms, including Human Genome Sciences of Rockville and Incyte Pharmaceuticals of Palo Alto, Calif., already claim to have found the vast majority of genes and are filing patents. It isn't clear how many more valuable genes are still out there.

"They've taken the juicy bits already," says Robert Cook-Deegan, a scientist with the National Institute of Medicine and author of "The Gene Wars," a history of the Human Genome Project.

But Heil, the industry consultant, says that a lot of conflicting claims have been made about how many genes have been discovered.

"Those are just misleading statements," he says. "The fact of the matter is that there's still a lot of work to be done."

Transcribing human DNA is only the first step toward developing new drugs, Heil points out. Figuring out what the genes do and how to exploit them will be another monumental task.

But just getting the sequence in hand could prove critical to the advance of medicine.

"There's no doubt at all this is an incredibly important tool," Cook-Deegan says. "What this is going to do is move biology up one level in complexity."

Pub Date: 5/14/98

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