Hamilton Smith never imagined himself trying to answer biology's grandest question.

For more than 30 years, he'd been content to study bacteria, hunching over colonies of germs. He left it to others to tease out the secrets in the twisted, tangled and nearly endless coils of human DNA.

Hidden there are the answers to the central mysteries of biology and medicine -- how we grow up and grow old, fall ill and get well, how genes influence our instincts and intellects. Inscribed in our DNA is the saga of 4 billion years of evolution and the story of mankind's dispersal across the Earth. Encrypted in its text are strategies for defeating ancient scourges and, someday, correcting nature's mistakes.

No one knew better than Smith the value of sequencing human DNA. But he had always assumed that this breakthrough would be made by the hundreds of researchers with the Human Genome Project, a global effort led by the National Institutes of Health.

Then, last year, Craig Venter, Smith's collaborator, returned from California and shocked Smith with his latest inspiration. "We're going to shotgun the human genome," Venter said.

Not only was Venter proposing that they take on the huge government project and beat it. But the pair could reach the goal, he claimed, four years faster and hundreds of millions of dollars cheaper than their rivals.

To play David to the government's Goliath, Venter needed a clever strategy. He thought he had one, he told Smith. They would use sophisticated new machines he'd just seen in California and the "shotgun" -- a rapid-fire sequencing technique Smith had pioneered.

Smith silently panicked. The shotgun, he felt, was too crude to use on human DNA. "Nobody thought it would be worth trying," Smith says. "Including me."

To succeed, Venter's plan would require lab techniques that hadn't been invented, technology that hadn't been tested, computer software that hadn't been written. "It wasn't a rational approach," Smith says.

At 66, an age when most people consider retiring, he still had important work to do. At Venter's research institute in Rockville, Smith was helping create history's first genetic blueprints of scores of microbes, including those that cause malaria, syphilis, tuberculosis and sleeping sickness. It was work that could lead to an arsenal of new drugs and vaccines to protect against these relentless killers.

And after years of neglecting his family, Smith was trying to make amends. He hoped to devote more of himself to his wife, Elizabeth, and his children, especially a son struggling with drug abuse and another who was seriously ill.

Still, Venter needed Smith's help, and Smith felt he couldn't turn his friend down. "He did a tremendous amount for me by kind of waking me up," he says.

So, before Smith could voice all his doubts, raise all his objections -- before he really had a chance to think things through -- he found himself dragged into one of history's most ambitious scientific efforts.

He never heard the starting gun, but he was off and running the race of his life.

The shotgun approach

Before Smith became one of the Human Genome Project's chief competitors, he was one of its founders. In Los Alamos, N.M., in 1986, he and 40 other scientists had gathered to discuss what was then little more than an intriguing idea.

The site was symbolic. This, scientists knew, would be biology's equivalent of the Manhattan Project, which produced the first atomic bombs, or of NASA's Apollo program to put men on the moon.

Some biologists questioned the effort. Sequencing doesn't specify what genes do, nor does it explain how they work.

Smith, though, was convinced that creating a catalog of human genes was a crucial first step. With the genetic text in hand, he believed, scientists would one day learn to correct the errors that cause thousands of inherited disorders. They could tinker with the scattered genetic flaws that may determine susceptibility to major killers, including cancer and heart disease. They could learn to control, and perhaps eradicate, such widespread sources of suffering as retardation, alcoholism and mental illness -- including schizophrenia, the disorder that afflicts Smith's brother.

Understanding the human genome could permit doctors to regenerate organs and do a hundred other things that no one today can anticipate.

"It's going to be the absolute foundation of biology and medicine for 100 or 200 years," Smith says. "It's going to be the reference point, the framework for everything we do."

When the National Institutes of Health created the Human Genome Project in 1990, it funneled most of its money into scores of university labs. Some analyzed the DNA of smaller organisms -- a microscopic worm, a weed, a mouse -- searching for genes similar to those in humans.

Work on human DNA progressed slowly, and some scientists, including Smith, proposed shifting the money to a few large labs. For years, that advice was ignored. By last fall, the NIH had spent eight years and more than $1.8 billion -- and had mapped only 6 percent of the human genome.

"It's just a disaster," said Steven L. McKnight, a biochemist at the University of Texas-Southwestern Medical Center. "There is no cohesion, no focus, no game plan. To me, it's typical government work."

The glacial pace was dictated, in part, by the choice of strategy. To sequence the approximately 3 billion chemical letters in human DNA, researchers had to pick one of two basic approaches: the map-based technique or the so-called shotgun.

Mapping DNA is like translating a manuscript in a foreign language written on a long scroll. (A machine does the translating, but can only handle a few hundred letters at a time.) Genetic linguists could scan this scroll, which might stretch for 100 miles, using the machine to translate several sentences every few yards, then every few feet, then every few inches. Ever so slowly, they would complete the text.

Using the shotgun, the linguists would make multiple copies of the scroll and rip them to shreds. After translating the millions of snippets, they would compare them and piece them alltogether.

Shotgunning is much faster than mapping. But by the late 1980s, the shotgun strategy had never been attempted on long stretches of DNA. Scientists figured that assembling the blizzard of pieces generated by shotgunning human DNA was beyond the fastest computers.

Even with the latest machines, Venter knew he was taking an enormous risk. To improve the odds, he tried to head off his competition. So he met Francis Collins, head of the Human Genome Project, at a lounge at Dulles Airport last May.

In a few hours, Venter told Collins, he would announce plans to beat the genome project. His sequence information, he said, would be available free to any scientist. All Venter and his corporate partner, the Perkin-Elmer Corp., wanted was patents on about 200 of the estimated 100,000 human genes, and the first chance to develop drugs and diagnostic tests.

Why not join forces? he asked. "If you want to consider it a co- project that we jointly lead," he recalls saying, "I would be willing to accept that."

Venter said he would do the bulk of the work. NIH researchers, he suggested, would tackle the less rewarding job of filling in the many expected gaps in the sequence.

And if Collins was worried about keeping the government scientists busy, Venter had one more suggestion:

"We can do the human," he said. "The NIH can do the mouse."

Collins sat speechless. "I was stunned," he recalls.

"He just thought that my proposal was the height of arrogance," Venter says. "His view was that he was already the head of the Human Genome Project. He didn't need to share his crown with me."

That afternoon, Venter pushed ahead. He pledged to sequence the human genome by the year 2001 at a cost of $300 million. The $3 billion federal effort was scheduled to be completed in 2005. As Venter's plan splashed onto front pages, Collins retaliated. He told one reporter the shotgun would create "the Cliff's Notes or the Mad magazine version" of humanity's "Book of Life." And he questioned Venter's commitment to making the data public.

Stung by the comments, Venter dismissed Collins as "a government bureaucrat." Soon after, an NIH panel canceled a $6 million grant to his institute. "Francis is very vindictive," he fumes.

Collins says he didn't make the decision, adding: "This is not a personal vendetta of mine."

Challenged by Venter and Smith, labs across the country accelerated their efforts. Congress gave Collins more money for this year alone than Venter plans to spend in the next three. In August, Collins moved up the NIH deadline to 2003 and promised a "rough draft" covering a third of the human genome by the spring of 2001.

In making the announcement, the professorial Collins sounded oddly like Venter. "We are talking about big and ambitious, even audacious plans," he declared.

Last month, Collins turned up the pressure again, vowing to deliver a draft covering 90 percent of the genome by next spring. The aim is not just to beat Venter. It's to prevent him and other biotech entrepreneurs from patenting large stretches of the genome, according to Leroy Hood, an adviser to the government effort.

Venter set out to commandeer the federal Human Genome Project, but only succeeded in rousing it from its torpor. He often portrays himself as a beleaguered leader, battling superior forces.

This time, there's no doubt he is.

The clone library

When Venter decided to jump from sequencing bacteria to sequencing humans, he was proposing, in effect, to fast-forward through 4 billion years of evolution. Smith insisted that they test the shotgun strategy on an organism that was bigger than a microbe but smaller than a man.

Someone suggested the fruit fly, Drosophila, long a favorite of genetic researchers. The notion appealed to Venter. Transcribing the fly's DNA would be a scientific landmark. Not only would it be the largest genome sequenced thus far, but it could advance human genetics.

As strange as it sounds, humans and these tiny insects have a lot in common. About half the fly's estimated 12,000 genes are thought to have counterparts in humans. Genetic experiments in people would be unthinkable, but with the fly, scientists could manipulate genes and see the effects.

The project could also help Smith and Venter solve their biggest problem. Ninety-seven percent of human DNA is so-called "junk" -- seemingly meaningless stretches of genes and stuttering strings of chemical letters (for example, ATATATATATATATA...). Geneticists must determine the length and location of these nearly indistinguishable regions.

By sequencing the fly -- one-third of its 150 million chemical letters is junk -- Smith and Venter can test new methods for sorting through the junk in human DNA.

The first, critical step in sequencing is Smith's responsibility: the creation of a clone library, the archive of genetic raw material that is later copied, cut up and transcribed.

As he stood in his gleaming lab last fall, Smith dipped a pipette into a test tube to extract DNA. "The really pure stuff is crystal clear," Smith said, holding the tube up to the light. "It's beautiful."

Handling DNA is delicate work: A strand of DNA is brittle, slippery and 37,000 times thinner than a human hair. Smith must be careful not to splice pieces together accidentally, creating a false sequence. Letting one slip through would be like writing a wrong answer, in pen, in a giant crossword puzzle: A single mistake can lead to many others.

When Smith made the clone library for the first bacterial genome, Haemophilus, one out of every 200 pieces was spliced that way. But the microbe's genome was small enough that researchers could screen out those mistakes.

If errors cropped up as frequently in the fly or human genome projects, hundreds of thousands of false pieces would result. Smith is trying to reduce the number of false fragments to one in a million, a nearly impossible degree of precision.

Plenty of scientists could create a clone library. But none could do it better than Smith. Biology is a squishy science that demands a practiced hand. Subtle factors -- fluctuations in temperature or humidity or in the content of tap water -- can ruin an experiment. A scientist once spent weeks in his lab watching helplessly as DNA turned into glop. Smith quickly diagnosed the problem: a high-power ultraviolet light that switched on at the wrong moment.

"The business of making libraries has always been as much of an art as a science," says David Botstein, a Stanford geneticist. "Ham Smith is one of the premier craftsmen of molecular biology."

When Smith retired from Hopkins last year, he turned down a part-time post, saying he didn't want to feel as if he were freeloading. (When he balked at an emeritus professorship, Hopkins would not take no for an answer.) At Venter's new biotech company, Celera Genomics Corp., Smith considers himself just another member of the team. But his young colleagues regard him as a kind of living-legend-in-residence.

"A lot of us are users of the molecular biology tool kit," says Mark Adams. "Ham has been, to a large extent, a creator of that tool kit."

Smith, who advises Celera's computer scientists, knows the hidden landscape of DNA -- the shallows and sandbars lurking just below the surface -- as well as any can.

By mid-February, the first advanced sequencing machines had arrived at Celera, weeks behind schedule. Technicians are still struggling to get them to work, and a key piece of software has not yet been written. It could take until July, Smith says, to start sequencing the fly.

Despite the glitches, Maryland's upstart effort has drawn worldwide attention. Smith remains in the background, but Venter has appeared on the cover of USA Today's magazine in January, pictured with Copernicus, Galileo, Newton and Einstein. "Will This Maverick Unlock the Greatest Discovery of Our Age?" the headline wonders. (Copies are available outside Venter's office.) He has been interviewed by Japanese and Canadian film crews, featured in a public television special, profiled in British magazines and written about in scientific publications.

After Venter and Smith took on the government, several other biotechnology companies have jumped into the genome race, increasing the level of competition.

Sometimes, Venter sounds less than confident. "I wish we were talking about this after we accomplish it," he says. "I'm used to talking about what I've done, not what I'm going to do."

Smith feels the pressure, too, and knows he is risking his reputation on something he once thought impossible. "We're throwing the gauntlet out there," he says.

A key measure of success will be the number of gaps left in the genome by December 2001, the company's self-imposed deadline. Last year, Venter estimated that the shotgun strategy might leave 3,000 gaps in the sequence.

Other scientists said Venter and Smith are likely to wind up with 100,000 or more, leaving the genome so full of holes as to be worthless.

Venter shrugs at that claim. "They're hoping we will fail," he says.

To produce a complete genome, Celera's computers must juggle data from tens of millions of DNA fragments. That's never been done before, Smith concedes, and it worries him. But he tries to be optimistic.

"We just know we're going to do it," he says.

Family reunion

Walking over stubbled fields at sunset, Smith surveys his new home in northern Baltimore County. He calls it Epoch Farm, and hopes it represents a "new epoch" in the history of the Smith family. He and Liz moved to the field hand's place on the 138-acre property last spring and gave the big farmhouse up the road to their daughter, Kirsten, 31, and her husband. The newlyweds are trying to start a horse-boarding business.

Pointing to hills above a wooded stream, Ham says he's asked a couple of his sons to build houses there, so they and their families can live nearby. He says this matter-of-factly, as if it weren't the unlikeliest of dreams.

After years of struggle, his family is not yet whole. Ham's youngest son, Bryan, succeeded where his brothers did not, graduating from high school and college. But Bryan drifted into drug use. Undercover police caught him buying crack cocaine on a Govans street corner in April 1997.

The 33-year-old was arrested again last spring at his parents' home after failing to complete treatment for addiction. To avoid jail, he spent time in a residential drug treatment program. Family members try to be hopeful, but say Bryan blames Ham for most of his troubles. For now, there is only silence between them.

With his other children, Ham has reached an understanding. Perhaps it was simply that they grew up. Perhaps it was that Ham, grieving over his parents' deaths, recognized the importance of his family and how isolated he had become. Somehow, without speaking of it, they learned to accept one another.

Ham's children have cast off their anger. And their father, at last, has released them from the weight of his disapproval. With Derek, for example, Ham once saw only a great gift squandered. "I recognized in Dirk the potential of being a first-class scientist," he says.

After dropping out of high school, Dirk earned his GED and a degree from a technical college. Today, he works for a computer firm in Columbus, Ohio. Like Ham, he's a father of five. Not long ago, Dirk, 35, turned down a high-paying job in Seattle because it would have taken time from his family. Ham couldn't be prouder. "I would rate Dirk as a superior father," he says.

With his children, Smith has become an itinerant visitor, an awkward but amiable presence. "Dad comes down here once a month," says Joel, who lives in Winchester, Va. "Brings a paper by. Goes helps Barry work on his house. Sees Dirk in Ohio. He'll always ask: 'Short a few bucks this month?' "

"We do things now," says Barry. "Stuff father and son like to do together. I just think that he's had more time."

No chasm in the Smith family was wider than that between Ham and Barry, now 37, a stocky man with flowing brown hair and a gallery of tattoos. When Barry was a teen-ager, getting in trouble and dropping out of school, his father banished him from the house. He seemed to swerve as sharply as he could from the intellectual path his father had chosen, working first as a landscaper, then in a slaughterhouse. Today, Barry lives far from any neighbors, in an old schoolhouse he restored in the shadow of Virginia's Blue Ridge Mountains.

Three years ago, while helping his father move a heavy springhouse door, Barry clutched his chest. "I feel faint," he said. "I've got to sit down." Ham saw immediately that his son was having a heart attack. It was the first of several. Chronically ill, he can't do strenuous work or hold a regular job. Instead, he does occasional chores or yard work for family members.

Now, when he visits Barry's farm in Coal Mine Hollow, Ham goes fishing with his son, or works on Barry's house or helps pick beans from the garden. Barry once ignored his father's accomplishments, but now takes pride in them. By degrees, the years have taught them both forgiveness.

"We get along great now," Barry says. "We're doing all the stuff now that I wish we had done when I was a kid."

Last August, the Smith family staged a reunion of sorts on Joel's birthday. They gathered in Winchester at the Cork Street Tavern, the restaurant Joel and friends started with the help of a loan from Ham.

Sitting on the patio, the family ate ribs, drank iced tea and ate sheet cake. Joel cheerfully played host and honored guest, supervising the waitress even as he read cards with lame 40th birthday jokes. From across the patio, Ham waved at one of Dirk's five children, who call their grandfather "Opa." The little girl buried her face in her mother's shoulder.

There was, at first, something stiff and tentative about this gathering. But as they posed for a rare family portrait, the Smiths good-naturedly scrunched together. The children climbed on laps, and everyone pushed closer to Ham.

No one kissed or hugged; that was something another family might do. Still, they seemed secretly pleased to touch shoulders, to bump knees, to finally fit together.

Moving biology forward

Shortly after dawn last fall, Smith pushed through the door to the nearly empty ballroom at the Fontainebleau Hotel in Miami Beach. While others slept, Smith and his confederates plotted strategy.

During the four-day genetics conference, Smith bolted from one talk to another, furiously scribbling notes. As always, he was the most diligent student. While others gossipped or angled for jobs, Smith scouted for insights or scraps of information -- anything that might help.

The human genome has become Smith's obsession. When he renovated his house at Epoch Farm, he had high-speed Internet connections installed in several rooms so he can work on his computers anytime he gets an idea. While driving to work or eating lunch, Smith puzzles over the problems ahead.

During a lecture last fall, he began doodling and suddenly saw a new way to prepare his clone libraries. Back in his lab, he did some calculations. He figured he could reduce the number of stuck-together pieces of DNA from one in 200 to one in 10,000, maybe even one in 100,000. It wasn't yet the one in a million he was shooting for, but it was a major advance.

It would be quickly followed by another. With Smith's aid, Celera's computer scientists recently finished writing a powerful new program for assembling DNA. The ultimate goal -- the complete human genetic encyclopedia -- may be that much closer.

"When the idea first hit me, it just seemed like such an incredible undertaking," Smith says. "But I've seen how we can work together and get these things done. My experience has been that things that look impossible, if you keep thinking about them and moving one step at a time, usually they're doable."

Not long ago, the partners were joking around when Venter turned suddenly to Smith. Wouldn't it be fantastic, he asked, if they could share a Nobel? Smith grew sober, and shook his head firmly.

"You can have it," he said.

After years of feeling he had to act like someone he wasn't, of trying to prove himself to others, Smith was back where he started, where he felt he belonged. The work, he realized, was all that mattered. He is helping, once again, to propel biology forward. He's engaged in some of the most important research in science, doing things he always dreamed of doing, and no longer faces the world alone.

Nothing would thrill Smith as much as completing the human genetic text, taking our ultimate biological measure, understanding this most remarkable of species down to its molecular foundations. If his team can pull it off, the achievement will stand for all time. If they can't, Smith can take comfort. Through faith and perseverance, he's done his best to fulfill his promise, as a scientist, a brother, a father and a man.

What are his plans? "Sequence," he says. "Sequence, sequence, sequence. That's what's needed to set the stage for the 21st century. That's my religion."

And in it, he sees his redemption.

"It's going to be the absolute foundation of biology and medicine for 100 or 200 years."

Four Letters That Define Us

Written in the 13,957 letters on this page is a potential human tragedy.

The letters represent a gene that, when flawed, can cause Duchenne muscular dystrophy, a disease that cripples and gradually kills.

Like all our 100,000 genes, this one is written in a chemical alphabet. Its four letters -- A, T, G and C -- represent adenine, thymine, guanine and cytosine. Chained together, they form DNA.

The number and arrangement of those chemical letters determine what we are and who we are. The sequence dictates our shape and sex, predicts our height and, to some extent, our health. It influences almost everything about us.

Spelled out on this page is the dystrophin gene, which makes a protein vital to muscle structure. In some people, a single "G" -- shown in bold above -- is replaced by a "T," triggering the disorder.

By sequencing all 3 billion letters in human DNA, scientists hope someday to understand how the body works. The task is mind-boggling. Printing that entire sequence would fill almost 215,000 of these pages.

ABOUT THE SERIES

Sunday: After winning the Nobel, Hamilton Smith struggles against failure -- in his work and with his family.

Yesterday: Smith gets a second chance through an unlikely alliance with a controversial researcher.

Today: Smith and his partner take on the scientific establishment, pursuing one of the most ambitious research goals in biology.

Reprints: Copies of this series are available from SunSource at 410-332-6800. The cost is $7.95.

Pub Date: 04/13/99