Kary Mullis goes surfing after learning that he has won the Nobel Prize.

THE QUIRKY GENIUS WHO IS CHANGING OUR LIVES

by Jim Dwyer

Kary Mullis is not likely to fit most people's profile of a serious scientist. He is a man who quit the lab to work in a restaurant a man who had a midnight brawl on a beach with a fellow researcher, a man who elicits both giggles and awe from other scientists.

Yet Mullis, a slightly built man with thinning blond hair, is responsible for what many consider the most important advance in genetic research since the discovery of DNA's double helix four decades ago. Many expect him to be named when the Nobel Prizes are announced this week (or at least in the next few years), because his invention- the polymerase chain reaction, or PCR has revolutionized microbiology, medical diagnostics, criminal investigation, even evolution (see box).

His invention, in fact, made the idea behind Jurassic Park that people can manipulate tiny fragments of ancient DNA to create full- grown dinosaurs at least scientifically plausible.

The procedure devised by Mullis makes it possible to reproduce a single gene or DNA fragment a billion times in a few hours. It has become a standard tool in most important biological laboratories in the world.

"What he has going for him to get the Nobel is that PCR is a revolutionary technique with vast impact on medicine and basic science," says Thomas White, head of research and development at Roche Molecular Systems, which paid $300 million, a record in the health-care field--for the PCR patent and associated technology.

White pauses a beat. "What he has going against him is his outlandishness." I was curious to learn more about this man who some think is too weird to win a Nobel. "The later at night, the better," Mullis said, agreeing to see me. "I'm a night person. I talk better then." His home, a ranch named The Institute for Further Study (after the words that follow most scientific papers: "This calls for further study"), is in the Anderson Valley, twisting from the Napa Valley to the Pacific Ocean near Mendocino. It is four miles up a dirt road, and no lights shine in his windows on this moonless night.

"Ssshh," someone whispers. "We're being watched." Pause. "The satellites," says the voice. "They're watching us, so we have all the lights out. That way, we can see them before they see us."

The voice is that of Mullis, and he is with four others in a hot tub, watching the skittering light of satellites across the sky. Sipping red wine from a nearby vineyard, served in mugs, Mullis and guests discuss the nature of space junk, how a green tinge in a light passing overhead probably means there's a lot of copper wire on board that manmade asteroid, and when exactly science replaced religion in some people's lives.

Later, he talks about his discovery. "PCR was my road into the world," he says in the soft accent of his Columbia, SC, childhood, fidgeting like a bashful country boy. "It's as if your fairy godmother said, "Hey, this invention will make your life a lot easier." People started recognizing I was a bright guy ."

At the time, Mullis was working as a chemist for one of the first big biotech firms, the Cetus Corporation in Emeryville, Calif. (the company was bought out in 1991), synthesizing chemicals that were used by other scientists in genetic cloning. The work bored him. In fact he spent most of his time sunning himself on the roof or puttering in the lab, even writing computer programs to automatically answer his colleagues' requests.

"I was playing," he says. "I think really good science doesn't come from hard work. The striking advances come from people on the fringes, being playful." Mullis was being playful on an April evening in 1983 as he drove up to his ranch. "My hands were occupied, but my mind was free," he says.

He remembers the fragrance of the flowering roadside buckeye that washed in the car windows as its white stalks bobbed in the headlights. How, he was pondering, could you find a single spot on the long, fragile DNA molecule? In a series of acrobatic chemical leaps, he realized that a section of DNA containing a gene or fragment could be marked off, then forced into copying itself using replicating techniques similar to those DNA employs when a cell divides. Then he realized something so startling, he had to pull the car to the side of the road. When he had been messing with computer programs, he had been impressed by the power of a reiterative computer loop, in which the same process is repeated over and over. He saw how fast numbers can climb when they increase exponentially. Replicating DNA could work about the same way: By adding the right chemicals, the little section of DNA could keep reproducing itself automatically and exponentially--so that the fragment would double, from two pieces, to four, to eight...and ever onward. In practical terms, he saw that, after eight doublings, he would have 256 copies of the gene. By the 20th cycle, he'd have 1,048,576. By the 30th, he'd be up to 1,073,741,824--a billion copies of a single gene in three hours. Bottomless vats of DNA, and easy to find. Ten years later, scientific papers using PCR or a variation of it are being published at the rate of 500 a month.

Mullis speaks with some bitterness about the years that followed his discovery. He was turned down flat by prestigious journals when he tried to publish his findings. He remembers the reception to his idea by colleagues at Cetus as ice cold. Then, he maintains, as PCR was taking off, they sought to attach themselves to its development.

"PCR was rapidly developed by all kinds of people," he says. "The people at Cetus were the lucky ones who got first crack. Instead of appreciating that, and appreciating me, they overstated the role they played." Mullis crafts his lab assistant, Fred Faloona, as being his primary collaborator.

Others who were at Cetus maintain that PCR would not have developed as quickly from off-the-wall brainstorm to off-the-shelf technology without the backing of other scientists. Just as Mullis is acknowledged to be PCR's intellectual author, they feel entitled to credit for serving as midwives.

Mullis left Cetus with a $10,000 bonus for his invention. Financially, there's also the $400,000 he received for winning this year's Japan Prize, one of international science's highest honors. But PCR has not made him wealthy. The main patent for the process is in his name but was owned by Cetus, as his employer, which sold it to Roche. Mullis now works as a consultant and writer. He spends time at his ranch and an apartment in La Jolla, where he rollerblades at sunset and surfs at dawn.

He is playing with some new ideas. The most exciting is called "atomic tags," a proposed test of multiple blood factors for serum, viruses, enzymes, cell counts--done with a small blood sample and kept in a database that would provide quick diagnosis and treatment. More offbeat is "star genes," in which bits of celebrity DNA would be embedded in trading cards and jewelry, then sold. "Suppose you had some gene that had to do with Mick Jagger's lip," Mullis suggests. But most of his ideas are still on the drawing board.

"There's two kinds of stuff in science," he says, "the thinking and the doing. I'm not good at accomplishing things."

Mullis has been having fun with science since he was a boy. At 17, using a rocket fuel he made out of potassium and sugar, he sent a frog into the sky and brought it down safely with a parachute.

He studied biochemistry at graduate school at the University of California at Berkeley and later moved to Kansas. After his second marriage failed (he has been married and divorced three times and is the father, he says, "of three children that I know about and a bunch more from the artificial insemination program in Kansas City"), he moved back to Berkeley, where--disheartened with a lot of things, including science--he took a job in a restaurant. One day, he says, his graduate school adviser came to see him. "He said, "Mullis, we put a lot of effort into you." After a while, his argument convinced me it was harder working in a restaurant than in a lab."

That brought him to Cetus and put him on the road to his thrilling discovery.

"People ask me what's the future of PCR," Mullis says. "I tell them, 'What's the future of the screwdriver?' As long as people use screws in wood, they'll be using the screwdriver. PCR is to DNA as the screwdriver is to carpentry."

UNLOCKING THE PAST, IMPROVING THE FUTURE

With PCR, scientists can roll ,back the stone from the tomb of extinction and read genes from creatures that died 120 million years ago. Even if it doesn't mean recreating dinosaurs, this ability is solving old mysteries. For example, the remains of Russia's last czar, Nicholas II--executed in 1918--were positively identified this year using a PCR test that matched DNA in the bones with DNA of members of the British royal family, who are distant relatives of the czar.

PCR also has helped free at least a dozen men wrongly convicted of rape.

It can be used to decipher parts of chromosomes at the earliest stages of life. Will a child have cystic fibrosis? Does he or she carry a gene that might be associated with homosexuality? And, by the way--is it he or she?

Adults can learn if they're doomed to a fatal disease, such as Huntington's chorea.

PCR can tell within hours if a person is infected with the HIV virus. Before, the standard test looked for antibodies produced in response to the virus; now, doctors can look for HIV directly by searching for genetic codes unique to it.

And there is a new PCR-based test for chlamydia a venereal disease that can cause infertility. Instead of the uncomfortable old test a urine sample now provides the same information.