Daring Sprint to the Summit

The Quest: A determined Hamilton Smith attempts to scale a scientific pinnacle -- and reconcile with family

April 13, 1999|By Douglas Birch | Douglas Birch,Sun Staff

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.

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