The Race to Crack the Gene Code

Suppose that halfway through the U.S. effort to land the first man on the moon, a private company boasted it would beat the government-financed Apollo program by several years, doing the job for less money and at no expense to taxpayers.

Although private industry never raced NASA to the moon, something similar is happening with the government-sponsored Human Genome Project, an international effort to spell out the entire human genetic code within the next five years.

The project, begun in 1990 and backed by $3 billion in federal funds, seeks a fundamental understanding of how the human machine works and, all too often, malfunctions. The task has been compared to the great scientific achievements of this century, the equivalent of the lunar landing or the Manhattan Project that developed the atomic bomb.

But unlike the Apollo program, there are huge profits lurking in the 3 billion chemicals that are strung together to form DNA, the human blueprint contained in each living cell’s 46 chromosomes.

By mapping all of the human genes, researchers hope to discover new ways of identifying and treating not only the birth defects caused by simple genetic errors, but such complex diseases as cancer and diabetes. Any company that identifies and patents the genes implicated in heart disease, for example, could get a share of the billions of dollars to be made from new drugs based on the discoveries.

What began as a cooperative effort--carefully parceled out among university, government and nonprofit laboratories--has become a spirited race, with several companies working furiously to beat the public project.

The government-backed scientists are skeptical and angry, worried that their private competitors will stake claims to the human genome, the complete map of heredity, and stifle future research. The fears are not unfounded: Companies have been taking their gene discoveries to the U.S. Patent and Trademark Office to claim ownership of their new findings. In contrast, scientists receiving government grants publish their discoveries daily on the Internet, guaranteeing that the results will remain in the public domain.

Learning the complete genetic code and finding the 70,000 to 100,000 genes scattered throughout the chromosomes of every human cell could pave the way to a more complete understanding of illness--aging, cancer and arthritis, for instance. And it could move medicine closer to the day it can predict--perhaps prevent--health problems such as heart attack, stroke and Alzheimer’s disease.

Those advances could mean big payoffs for pharmaceutical and biotechnology companies that can turn such knowledge into useful medical tests and treatments.

At Maryland-based Celera Genomics, Craig Venter, flamboyant-scientist-turned entrepreneur, triggered the footrace mentality last spring when he boasted that his new company would complete the letter-by-letter spelling out of the genetic code by 2001, four years earlier than the government-backed program forecasts.

“We’ll do in three years what was taking 15, for hundreds of millions rather than billions” of dollars, Venter said in an interview.

In the months that followed, another company, Incyte Pharmaceuticals, declared it would finish sequencing the human chromosomes even faster--by the end of next year. A third company, Genset Corp., also asserts that it is well ahead of Celera and government-sponsored researchers in mapping the code.

For its part, the federal government recently announced it is accelerating its efforts.

Assembling 800 ‘Don Quixotes’

The finished product of the Human Genome Project has been dubbed the Holy Grail of biology. In a profusion of competing metaphors, it has also been called a map, a gigantic jigsaw puzzle, a blueprint, a book, even “the bible of life.” When finished, it will be a multivolume encyclopedia of human heredity written in the four letters, or bases, of the DNA code.

Just reading out the letters, at 10 per second, would take more than a decade. And making sense of it all--figuring out what all those instructions mean--will give scientists plenty to do for another century.

Sequencing the human genome begins by taking DNA from white blood cells or sperm cells. Most DNA used in the government-backed Human Genome Project will be drawn from a small number of randomly chosen volunteers, their identities kept secret to protect their privacy.

The actual sequencing work is akin to being given multiple copies of a lengthy novel that have been cut into sentence fragments and attempting to reconstruct the entire story, said Richard M. Myers, director of the Stanford Genome Center, one of several government-funded sequencing projects. By looking for overlapping words and phrases, it should be possible to paste together the complete book.

To make the task more manageable, the federally supported centers have spent considerable time dividing the genome into segments 100,000 to 200,000 letters long.

Enter Craig Venter and his partners at Perkin-Elmer Corp., a $1.5-billion-a-year manufacturer of analytical instruments, which plans to spend up to $300 million on the new venture. Venter says he has a shortcut to sequencing chromosomes.

By next spring, Venter’s Celera Genomics will take delivery of 230 high-speed gene-sequencing machines from a Perkin-Elmer division. That’s more raw sequencing power than currently exists in the world, said Celera Vice President Peter Barrett.

In the interest of speed, Venter plans to cut up the full genome all at once, deciphering the DNA code of the tiny fragments, then use new software to reconstruct the genome as a whole.

Celera plans to publish its genetic sequence data every three months on the Internet--after filing claims to commercially promising genes. The company will sell software to help pharmaceutical and biotechnology companies mine the formidable body of data.

Venter has impressive credentials. He founded the nonprofit Institute for Genomic Research in 1992, and in 1995 he co-published the complete DNA code for a disease-causing bacterium, the first living organism, other than viruses, ever sequenced.

But a number of scientists raise doubts about his ability to deliver on this grander scheme.

The sequencing machines Venter plans to install have yet to be manufactured. The computer software he will need to assemble small bits of information into the completed books is still being developed. And critics say the shortcuts he plans to take will leave numerous gaps in the sequence and tend to connect pieces of code that don’t belong together.

“Imagine with all those words and sentences, if you switched Page 500 with Page 553,” said Stanford’s Myers. But the human genome has many more letters than even a lengthy novel. “It’s 800 ‘Don Quixotes,’ ” Myers said--virtually guaranteeing lots of mismatches and gaps.

Some scientists believe that Venter’s boastful predictions are simply attempts to promote his company or sell Perkin-Elmer sequencing machines.

But Venter contends that the economic arguments work both ways. “Some scientists had to attack me. It’s a constant theme to preserve their budgets. . . . Science is fundamentally driven by economic interests, by definition.”

Incyte Pharmaceuticals in Palo Alto--whose corporate credo is “Cheaper, better, faster”--says it has no intention of completing the human sequencing with the degree of accuracy sought by the federally funded project. Instead, the company plans to complete a “rough draft” of the genome by the end of next year and to do the job with just enough accuracy to find the genes.

“Our game is not to claim the human genome but to identify all the genes, getting every gene over the full length of the genome, and then look at the genetic differences between individuals and how these individuals react to disease,” said Incyte President Randal W. Scott.

If the company succeeds, it will provide its pharmaceutical company clients with tests that can quickly determine how a particular patient will respond to a particular drug.

Meanwhile, scientists at Genset have set up a huge sequencing factory of their own, more than 150,000 square feet in size, near Paris.

All the hoopla over Venter’s announcement “made me sick,” said Genset Vice President Jay Lichter, who is based in La Jolla. “Craig Venter is trying to do with this new company something we started as an organization over two years ago: build up a very high-density map [of the human genome], and in the end we will sequence it,” Lichter said.

Genset is racing to develop a set of genetic markers spread out among the chromosomes that should prove useful in identifying which patients will respond positively to various drugs and predicting conditions such as high blood pressure and heart disease.

Analysts who follow these companies say the competition to establish intellectual-property rights to the human genome is fierce. “While immense, the human genome is finite,” said Michael G. King Jr. of BancBoston Robertson Stephens. “Companies don’t want to be locked out of intellectual property by not having the rights to a particular gene.”

Incyte has emerged as one of the few profitable biotechnology companies by selling access to its growing database of genetic information and the software to analyze it, King said. “Celera is getting in the game a little bit late,” he said. “It remains to be seen what the company can actually achieve, but I don’t want to count them out.”

The Genome as Intellectual Property

In the face of the commercial push, the two federal agencies that are coordinating the government-sponsored effort, the National Human Genome Research Institute in Bethesda, Md., and the Energy Department, announced in September that their international collaboration would finish the complete sequencing of the human genome by 2003--two years ahead of schedule. What’s more, they plan to finish a “working draft” that will cover 90% of human DNA by the end of 2001.

The final product of the federal effort will be a carefully proofread transcription of all the letters in the human genetic code, spelled out chromosome by chromosome, with less than one error in 10,000. The government-sponsored researchers are convinced that none of the private companies either want to, or are able to, produce such a product.

“This is what we really want finished, a highly accurate sequence, going all the way to a product that will withstand the test of time over the centuries,” said Dr. Francis S. Collins, director of the National Human Genome Research Institute. Researchers note that many genetic disorders, such as sickle cell disease, are caused by a change in only one base in the several thousand that constitute a gene. Errors in deciphering the structure of genes could send researchers off on wild goose chases.

Martha Krebs, director of the Energy Department’s office of energy research, pointed out that the first eight years of the federal project funded advances that have made the mapping of the complete genome possible. Venter’s nonprofit institute, for example, has received more than $26 million from federal agencies. “Venter couldn’t have gotten here without the investments of the national program,” Krebs said.

One reason the public effort is moving ahead more quickly is to preempt the efforts of private companies to stake claims on individual genes.

“If all these sequences are patented, it creates a situation where companies with patents could dictate who gets to work on them,” said Dr. Robert Waterson, director of the Washington University Genome Sequencing Center in St. Louis. “That’s clearly not healthy. It will not produce the best use of the genome sequence.”

In 1996, a number of participants in a Human Genome Project meeting in Bermuda agreed that scientists in the collaborative effort should publish their new data as quickly as possible. As a result, the government now requires the centers it sponsors to post their data every night on the Internet.

The aim, says Maynard Olson, director of the University of Washington’s Human Genome Center, is to prevent private interests from patenting the basic information, “to preempt the capturing of intellectual property.”

Ari Patrinos, who manages the Energy Department’s human genome program, said he welcomed the rivalry as a spur to getting the job done.

“We all want to see the sequence done,” Patrinos said, “but clearly there are huge egos. They all want to finish first in one form or another. Who would blame them? This is both a collaborative effort and a competition.”

Venter is confident that his team will complete the job first, but he believes the federally funded effort should continue.

“I’m willing to gamble that this [private effort] will work,” he said. “That doesn’t mean that taxpayers should.”

Times staff writer Thomas Maugh II contributed to this report.

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The Building Blocks

The complete set of instructions for making an organism is called its genome. It contains the blueprint for all cellular structures and activities. Found in every nucleus of a person’s trillions of cells, the human genome consists of coiled threads of deoxyribonucleic acid (DNA) and protein molecules, organized into structures called chromosomes.

In humans, as in other higher organisms, a DNA molecule consists of two strands that wrap around each other to resemble a twisted ladder whose sides are connected by rungs of nitrogen-containing chemicals called bases. Four different bases are present in DNA: adenine, thymine, cytosine and guanine.

The particular order of the bases is called the DNA sequence; the sequence specifies the exact genetic instructions required to create a particular organism with its own unique traits.

Each DNA molecule contains many genes, the basic units of heredity. A gene is a specific sequence of bases, whose patterns carry the data required for constructing proteins, which provide the structural components of cells and tissues. The human genome is estimated to comprise at least 100,000 genes.