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Hamilton Smith's Second Chance

 Douglas Birch

From the moment he learned he had won the Nobel Prize for medicine, Hamilton Smith dreaded what was to come.

On that October morning 21years ago, Smith numbly performed the rituals of celebration—sipping champagne, nodding at well-wisher, posing for photos—at Johns Hopkins University School of Medicine in Baltimore. Finally, he fled.

Smith wondered if there had been some mistake. His award-winning discovery came after a brief experiment, done almost on impulse, "Are you kidding?" he's gasped when a reporter told him about the prize.

Standing 196 centimetres tall, with sloppy posture and a goofy laugh, Smith lacked the confidence to be much of a teacher and regarded himself as just a "kitchen chemist." But in his lab, Hamilton Smith was one of the master craftsmen of science. What he had done was discover the first tools for dissecting DNA, the stuff from which all life springs.

Winning the Nobel Prize might have been the most triumphant moment of Smith's life. Instead it overwhelmed hem. His wife, Liz, would never forget his anguished reaction. "Gee, I got this thing," he told her. "I have to earn it now."

Seeds of the future. Smith's scientific career began in his parents' house in Urbana, Illinois. His father, Bunnie Smith, was a professor of education at the University of Illinois. His mother, Tommie, who was often tense and withdrawn, had been a secondary school teacher. In the early 1940s, Ham, ten, and his brother Norman, 11, set up a lab in the basement. Both shy, the boys would work wordlessly, side by side, for hours. It was their fortress of solitude.

Using castoffs and scraps, they built their own centrifuge, blowtorch and telescope. A few years later, after the first jet engines were built, the Smith boys tried to rig one from an old carburetor.

Ham was Norman's student, confidant and best friend. Both skipped a grade in secondary school. Both wound up at the University of California at Berkeley, where they studied at desks jammed next to each other in the room they shared, calling each other the same nickname, Butch.

During Ham's last year at Berkeley, Norman started to hear a persistent noise, like the clatter of dishes atop an old refrigerator. He also grew increasingly wary and decided someone was trying to poison him.

He went to a psychiatrist, who diagnosed schizophrenia, which can cause hallucinations and delusional thinking. Devastated, Ham was also worried about himself. Schizophrenia runs in families. For 20 years, he and his brother had shared almost everything. What if they shared this illness too?

By the time he finished medical school in 1956, Ham had only a few close friends and had gone on a couple of disastrous blind dates. One evening, when he was a resident at Barnes Hospital in St Louis, a blonde student nurse invited him to go bowling. "He was unassuming," Liz Smith recalls.

Their courtship did not include deep confidences or emotional declarations. But they were comfortable with each other. The following year they were married.

Demystifying DNA. Soon after, Smith saw a newspaper story about a new test for some inherited illnesses. He hadn't even heard DNA mentioned when he was in medical school, but by the late 1950s scientists recognized links between genes and disease. Intrigued, he read every research paper he could find on this new field, molecular biology.

Scientists understood that DNA is the recipe for life and genes are made of it. They knew that DNA is a chain of four chemical compounds—adenine, thymine, cytosine and guanine, abbreviated A, T, C and G. Depending on the number and sequence of its four chemical letters, the recipe can call for a bacterium or a beetle, a blue whale or a human.

Abandoning his medical career to study DNA, Smith became an assistant professor at Johns Hopkins, where he based his study of genetics on the bacterium Haemophilus influenzae. Smith's postgraduate student, Kent Wilcox, noticed that when he combined viral DNA with an extract of bacterial proteins, the viral DNA seemed to vanish.

"Look, we can do an experiment," Smith told Wilcox. They took a solution of bacterial enzymes and added it to a test tube containing viral DNA. They say the viral DNA break down and Smith knew instantly that something was destroying it. He later found that, to protect itself against infection, the bacterium produced chemicals that sliced up the invader's DNA, cutting it at predictable points.

His important discovery of the chemicals—"restriction enzymes"—would revolutionise genetics. For years scientists had been searching for a way to locate genes, remove them and determine how they worked. Now they had it.

Following Smith's example, two California scientists used restriction enzymes in 1973 to plug a frog's gene into another organism, and the field of genetic engineering was born. Smith's discovery would lead to tests for inherited illnesses, such as some forms of colon cancer, and the development of synthetic hormones such as insulin.

Chaos at home. Smith's five children—four boys and a girl—had always felt an unspoken pressure to match their father's success. After he won the Nobel Prize, and hopes of doing so evaporated.

For Derek, then 14 and the third oldest, teasing began immediately. Kids would say, "If your dad's so smart, how come you're so stupid?"

Smith seldom issued orders to his children or set any limits. He never had the confidence, he says, to tell his children what he expected of them.

The Smith's home in suburban Riderwood, Maryland, "was a zoo," says eldest son, Joel, who dropped out of university and drove a truck. At 16, Barry, the second oldest, was in open revolt: he'd sneak into bars and join boys who committed vandalism. After failing the eleventh grade twice, he dropped out.

Derek was the most precocious (at the age of five he could take a telephone apart and put it back together). But by secondary school, he was diagnosed as "hyperkinetic" and given drugs to calm him. He dropped out of school at age 15. Only the youngest children—Bryan and Kirsten—made it through university.

His children's failures baffled and frustrated Smith. His attitude was, If I can get it, why can't you? What he couldn't cope with, he ignored.

Smith continued to study his bacterium in his Hopkins lab, where most of his research was paid for by the National Cancer Institute, a division of the National Institutes of Health (NIH). But officials grew skeptical that Haemophilus would lead to new cancer treatments. By 1989, his grant applications were rejected.

Humiliated, Smith now scrounged supplies and accepted financial help from the school. It wasn't enough. By 1993, he decided to phase out his lab and mark time until retirement.

With fewer obligations, Ham became involved with Norman again. Though hospitalized three times for schizophrenia, Norman had earned a master's degree in engineering, married and raised two children. Mostly he worked as his father's researcher.

For 20 years Ham had rarely seen Norman. "I denied my brother's illness," he says. It was more than an irrational sense of shame or fear. He knew the laws of inheritance: if the position of a few chemical letters had been switched, Norman might have the Nobel. It made no sense, of course, but Ham felt guilty.

Dark prince. In 1993, the all-but-forgotten Nobel winner attended a genetics conference in Bilbao, Spain. There he spotted researcher Craig Venter. "Where are your horns?" Smith joked.

With piercing blue eyes, wild eyebrows and grey spikes of hair, Venter, then 46, didn't just look devilish. Many of his colleagues regarded the scientist as the dark prince of molecular biology, bent on plundering the treasures in human DNA. He had angered them when, as a scientist at NIH, he filed patent applications for hundreds of genes that he'd identified. After leaving NIH, he would reap $13.8 million conducting research for a new private venture.

That night in Spain, Venter talked about his love of science, insisting he was miscast as a mercenary. To Smith's surprise, he found himself sympathizing. Venter invited Smith to become an adviser to the Institute for Genomic Research in Montgomery County, Maryland. He accepted.

Scientists had long dreamed of sequencing the genome of a cellular organism—that is, identifying all the genes. It's an important step to understanding how chemistry creates life. The first to finish would make history.

At a 1993 meeting at Venter's institute, Smith asked, "would you be interested in doing an actual genome sequence?" He suggested his "lab pet," Haemophilus.

"Yes," Venter said. "I am very interested." Thirteen months after the work began, Venter's team completed the sequencing.

At a meeting in Washington, in May 1995, Venter reported that he and Smith and their team had recorded all 1,830,137 chemical letters in the genome of Haemophilus. Encoded in that string of letters were 1743 genes. The breakthrough electrified geneticists. Scientists knew it was only a matter of time before they unlocked the genetic text of every life form.

Race of his life. Smith had never imagined trying to answer biology's grandest questions. He assumed the breakthrough of sequencing human DNA—some 3 billion chemical letters long—would be made by the hundreds of researchers with the NIH-led Human Genome Project. Yet after eight years, NIH had mapped the genome, but sequence only six percent. Its $4.6─billion effort was to be completed in 2005.

Then last year Venter shocked Smith with his latest inspiration. "We're going to ‘shotgun' the human genome," Venter said.

Shotgunning was a shortcut technique the team used to sequence the Haemophilus genome. But Smith thought it too crude to use on human DNA. Silently he panicked.

Not only was Venter proposing that they take on the government and beat it, but he also claimed the pair could reach the goal four years faster and for only $461.5 million. As Venter's plan splashed onto front pages, Francis Collins, a leader of the Human Genome Project, scoffed. He told one reporter that Venter's strategy would create "the Cliffs Notes or the Mad magazine version" of humanity's book of life. In September 1998 Collins moved up the NIH deadline to 2003.

So at 66, an age when most people retire, Smith was drawn into one of history's most ambitious scientific efforts. To produce a complete genome by December 2001, the computers of Celera Genomics Corporation, Venter's new company, must juggle data from tens of millions of DNA fragments. That's never been done, but Smith tries to be optimistic. "We just know that we are going to do it," he says.

At ease. Walking over stubbled fields at sunset, Smith surveys his new home in Baltimore County, Maryland. He calls it Epoch Farm and hopes it represents a "new epoch" for the Smith family.

He and Liz moved to the worker's cottage and gave the big farmhouse to their daughter, Kirsten, and her husband for a horse-boarding business. Pointing to the hills close to his home, Ham says he's asked his sons to build houses there so they and their families can live nearby.

It's not an unlikely dream. Last year several of the Smiths got together at a restaurant. As they posed for a family portrait, everyone pushed closer. No-one kissed or hugged; that was something another family might do. Still, they seemed pleased to touch, to bump knees, to fit together.

After years of wandering in a scientific wilderness trying to prove himself to others, Smith is back helping to propel biology forward. Nothing would thrill him as much as completing the human genetic text. "It's going to be the absolute foundation of biology and medicine for 100 or 200 years," he says.

Even if he does not, Hamilton Smith can take comfort. He's engaged in some of the most important research in science, doing what he loves doing. And he no longer faces the world alone.

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