Gene Mapper

By MICHAEL D. LEMONICK

When President Clinton held a press conference last June to mark what was billed as one of the most important scientific milestones of the century--the cracking of the human genetic code--two men stood together on a White House podium to share the credit. As leaders of competing genome projects, Francis Collins, director of the National Human Genome Research Institute, and J. Craig Venter, president of Celera Genomics, were recognized, correctly, as the two most important players in the worldwide effort to spell out the 3 billion "letters" of the human genome--the biochemical recipe, encoded in our DNA, for manufacturing and operating a complete human being.

Yet while scientific diplomacy required that Venter and Collins get equal recognition for this epochal achievement, insiders knew that, to paraphrase George Orwell, one man was more equal than the other. The genome would certainly have been sequenced if Craig Venter had never been born. But if he hadn't decided to attack the problem with a radical approach, using the most sophisticated computer technology available, and to drive the effort with the full force of his rebellious personality, it would have taken years longer to complete. By forcing Collins and his colleagues to double and redouble the pace of their work, Venter guaranteed that the scientific rewards and potentially lifesaving medical treatments derived from decoding our genes would start to pour in almost half a decade earlier than anyone had expected.

Beyond that, their equal billing at last summer's announcement belied the fact that Venter's version of the genome was more complete than Collins'. Venter's contribution, asserts Victor McKusick, the Johns Hopkins researcher who is considered the grandfather of medical genetics, was "spectacular."

That is an understatement. Having the genome in hand will almost certainly be seen as one of the crowning achievements of the new century, no matter what else happens in the next 100 years. The genome--or, more precisely, the individual genes it contains--spell out the instructions for constructing the protein building blocks of every cell in every tissue of the body. This so-called book of life will inevitably reveal secrets of both health and disease, promising new treatments for virtually every malady that afflicts us. Heart disease, cancer, diabetes, Alzheimer's, Parkinson's, mental illnesses of all sorts will almost certainly yield to a new generation of genome-based medicines that will make antibiotics and other modern drugs seem prehistoric.

Comparing the human genome with those of other organisms, from bacteria to insects to mammals, will help biologists understand how more complex species evolved from simpler ones--and even pinpoint the precise bits of genetic information that are uniquely human. "It has to be a milestone in human history when you have a first look at your instruction book," says James Watson, who with Francis Crick discovered the structure of DNA a half-century ago. "Having this book will change the world."

As followers of the genome saga know, Venter's restless intellect and his tendency to buck authority were evident from the start. After barely graduating from high school in the 1960s, for example, he headed not for college but for the surfing beaches of Southern California. That made him a prime target for the draft, and the Navy sent him to Vietnam as a medical corpsman--an experience that taught him indelible lessons about the fragility of human life and the colossal ineptitude of big bureaucracies. Says Venter: "If you suffered fools, you died. I dealt with thousands of people dying because of stupid government policies."

Never one to keep his opinions quiet, Venter did two stints in the brig for refusing to follow orders. When he returned to the U.S., his laid-back surfer-boy mentality was gone. He signed up at the University of California, San Diego, and emerged six years later with a Ph.D. in physiology and pharmacology. Within a few years, he landed at the National Institutes of Health, where he began trying to locate and decode a gene that governs production of a brain-cell protein. The work was agonizingly slow, and when he heard about a computerized machine that used lasers to automatically identify the chemical letters in DNA, he went out and bought a prototype--even though his NIH bosses wouldn't pay for it.

If that purchase became a symbol of Venter's disdain for authority, the new technique he developed for finding genes with it demonstrated his brilliance. By focusing on those bits of DNA that were actually doing something--as opposed to the long strings that had no obvious function--he was able to tag the relevant parts and decode them. These "expressed-sequence tags" enabled Venter to start identifying genes at a hitherto unimaginable pace of 25 or so a day.

But he was increasingly unhappy within NIH, with its bureaucracy, limited funds and intramural sniping (Watson, Collins' predecessor as head of the agency's genome project, had derided Venter for his work on machines that "could be run by monkeys"). So he and Claire Fraser, his wife and collaborator, left to found a private research firm, called the Institute for Genomic Research (TIGR), where in 1994 he upped the gene-sequencing ante to a new level. At the urging of medicine Nobelist Hamilton Smith, now a Celera scientist, Venter decided to use a technique called shotgunning to sequence the entire genome of a living organism, the H. influenzae bacterium (a bug that causes ear and respiratory infections).

The idea was to shred the creature's DNA, sequence each of the millions of tiny fragments, then (the hard part) reassemble the sequences in their proper order. Critics argued that it was too difficult a task, and the project failed to get federal funding. But within a year TIGR published the bacterial genome--the first free-living organism to be fully sequenced.

And then, in 1998, Venter took his most audacious gamble. Armed with a more powerful set of gene-sequencing machines and heading a new company called Celera Genomics, he boldly declared that he was going after the biggest prize of all--the human genome. Not only would he sequence the whole thing, but he'd also do it by 2001, several years before the expected completion of the official Human Genome Project. While he insisted he'd make his genome map public, Venter said he'd sell proprietary analytical software to plumb it for information.

That arrogant challenge, coupled with Venter's high-flying profile on Wall Street, where his company was publicly traded, didn't sit well with Collins, by now the project's unofficial leader. Collins claimed at one point that Venter's genome map would be so incomplete and full of errors it would read like Mad magazine. Not to be bested in a war of words, Venter called the genome project's directors the "liars' club."

Eventually, even his bitterest critics had to face the fact that Venter had not been dealing in hype. And, in the end, the genome project was forced to adopt some of Venter's ideas to avoid being left behind. "It was," admits Watson, "the correct way to go." Thanks to Venter's maverick ways, says Phillip Sharp, director of the McGovern Institute for Brain Research at the Massachusetts Institute of Technology, "we have the human genome four years early, and it's spectacular. Craig is to be applauded for doing this."

Some of the discoveries that will flow from the genome sequence (and from the necessary next steps of identifying its genes and specifying their functions) are more or less predictable. By noting which genes are inactive--or inappropriately active--in people with cancer, heart disease and dozens of other illnesses, for example, scientists will be able to devise powerful, narrowly targeted drugs, tailored to an individual's own genetic makeup, that can correct the problem without serious side effects.

But that's just the start. By looking at the genome as a whole, scientists can begin addressing broader questions about who we are and how we got here. They're learning, for example, that humans have far fewer genes than the 100,000 to 140,000 scientists believed as recently as last summer. The real count, says Celera geneticist Mani Subramanian, turns out to be more like 30,000 or 35,000--a number that seems shockingly low to many scientists. "We think we're superior beings," he says. "But we have the same number of genes as a plant."

The genome seems to carry amazingly detailed evidence of our evolutionary history, including traces of viruses that long ago invaded our DNA and became a permanent part of us. Says Smith: "We hope over the years to get a clear picture of how our genome was put together and even see where it might be going." Not just how, but when. For example, the genome evidently contains a molecular clock in the form of sequences of letters that are repeated between the genes and have mutated over time. The rate of these changes could serve to time-stamp specific traits. We may someday be able to pinpoint the epoch in which the traits that make us uniquely human emerged.

Although the details will take decades to unravel, the genetic evidence is coming in at a remarkable pace. In the months since Venter and Collins stood together at the White House last June, Celera scientists have rushed ahead and sequenced the genome of the mouse. Astonishingly, mouse and human genomes are almost identical, with only a few hundred genes separating the two.

How can nature build two such different organisms from what is essentially the same blueprint? No one knows for sure, though scientists are formulating theories. One is that when a gene sets out to make proteins it can splice itself together in alternative ways; another is that some genes in man are left running longer than they are in a mouse--so that our bodies grow bigger, our brain cells more numerous and so on. "It's not as if a new kind of brain cell were invented 150 million years ago [when mice and men diverged]," says Robert Weinberg, a professor at M.I.T.'s Whitehead Institute. "The arguments will be settled only 10 or 20 years from now."

But long before then, whole new categories of questions will emerge. For where scientists once studied genetics--the structure and function of individual genes--they've now entered the age of genomics, in which they will study huge numbers of genes acting in concert. "The gene is like a piano key," says James Shreeve, author of an upcoming book, The Golden Code. "Up to this point, we've been going after notes. Now we have the keyboard. You had to have that level of detail to understand the music."

Venter will undoubtedly continue to irritate. He sparked a new controversy just two weeks ago by negotiating an agreement with Science whereby the prestigious journal will publish his genome sequence without insisting that he take the customary parallel step of uploading the data to NIH's GenBank website. Leaders of the competing genome project symbolically chastised Science by taking their own version of the genome to the rival journal Nature. But it's thanks to Venter, aggressive and hard-nosed as he is, that the world can read the score of the human symphony--and those of some 40 other organisms--not three or four or five years from now but today.

--Reported by Dick Thompson/Washington

With reporting by Dick Thompson/Washington