New Frontier

For decades, scientists have neglected RNA molecules, assuming that they were little more than messengers carrying genetic instructions from DNA to manufacture the proteins that rule our lives.

Now, thanks to a spate of discoveries in recent years, it appears that humble RNA assumes a surprising variety of other forms that do much more than deliver messages. Snippets of RNA actually become enforcers in the cell, interfering with the instructions from certain genes or shutting them down altogether.

The discoveries have electrified biologists, shaking up long-held theories of genetics. Science magazine declared the rapidly expanding understanding of what are called "small RNAs" the research breakthrough of last year.

Much remains to be understood about how small RNAs work, but research suggests that they play a role in the development of plants and animals, as well as in fending off illnesses. Several biotechnology companies have begun to work on translating the findings into new medicines.

As their names suggest, RNA and DNA are related molecules, strings of chemical building blocks called nucleotides that make up the genetic code. The instructions for making proteins -- which "build" and maintain everything from our muscles to the hemoglobin in our blood -- are copied from genes in the double-stranded DNA onto a single-stranded RNA, which then conveys the blueprint to the cell's protein-making factories.

The excitement is focusing on short stretches of RNA just 21 to 28 base pairs in length, which had been largely overlooked by researchers.

In 1998, Andrew Z. Fire of the Carnegie Institution of Washington, a private nonprofit lab in Baltimore, and others injected worms with "double-stranded" RNA, so named because the single-stranded molecule bends back on itself. They saw that the new molecules silenced the genes responsible for producing that RNA.

Researchers have since probed deeper into RNA interference, identifying a "dicer" enzyme that chops the double-stranded RNA into bits, which then silence genes by latching onto messenger RNA.

Studying yeast and a microbe found in freshwater lakes and streams, researchers found last year that small RNAs can permanently shut down or delete whole sections of DNA. The observations suggest that small RNAs play a previously unrecognized role in regulating cell division.

Careers: The two young men responsible for the DNA breakthrough continued along different paths for decades after winning the Nobel Prize.

By Timothy B. Wheeler

For most scientists, a Nobel Prize is the capstone of a career.

But in the 50 years since their breakthrough discovery of the structure of DNA, James D. Watson and Francis H.C. Crick have continued to pursue the frontiers of knowledge, albeit along different paths.

Watson, once the brash whiz kid from Chicago, has become the "dean of DNA," as one colleague calls him. Buoyed by his gossipy 1968 bestseller The Double Helix, he abandoned his laboratory bench for an administrator's desk, pushing for a cancer cure and a complete map of the human genome.

He stands today as the most visible figure in the continuing genetics revolution, though his penchant for speaking his razor-sharp mind has left a trail of enemies -- and admirers.

Crick, who was raised in a middle-class English family, remains a researcher at 86 and co-wrote yet another scientific paper that was published just last month.

After the 1953 coup, Crick pushed on to work out the mechanics of DNA before his restless mind led him to explore more cosmic questions, such as the origins of life on Earth. For the past two decades, he has searched for the scientific basis of human consciousness.

As the world marks the 50th anniversary of the discovery of the double helix with celebrations this week in New York and this spring in England, Australia and elsewhere, admirers are honoring Watson's and Crick's lifelong contributions to science, not merely the discovery that earned them the 1962 Nobel Prize.

At 74, Watson crisscrosses the country attending scientific meetings and ceremonies. In rambling lectures and interviews, he extols the promise of genetic research even as he recalls with self-deprecating humor how he and Crick made history.

"I think the biggest opportunity is curing cancer," he said recently while sipping coffee in his office at Cold Spring Harbor Laboratory in New York. "We really know a lot about that disease."

Watson is president of Cold Spring Harbor, the former biological field station on the north shore of Long Island that he took over in 1968 and steered toward a genetic cure for cancer. He relinquished administrative oversight nine years ago, but the institution's 350 researchers remain among the most frequently cited in scientific literature.

His wispy white hair remains as unruly as it was in his youth, as does his willingness to say whatever comes to mind.

"I think it's very important to study intelligence," he said in a recent lecture, acknowledging the notion's political incorrectness. "Some people are stupid because of their genes."

Watson recalls growing up poor on the south side of Chicago, where he absorbed his parents' philosophical skepticism. "Don't believe anything unless there is evidence," he says.

An avid bird-watcher in his youth, he was drawn to molecular biology by a book on genetics that he read at the University of Chicago -- the same book that inspired his future partner, Crick.

As a researcher, Watson never achieved another breakthrough on the level of the double helix, despite nearly 20 years of lab work. Instead, he evolved into a scientific talent scout who attracted bright young minds and motivated them.

But Watson's passion for molecular biology -- and, to some, his arrogance -- got him into scrapes over the years. In the 1950s, while carving out a molecular biology department at Harvard University, he clashed with Edward O. Wilson, a Pulitzer Prize-winning author and noted expert on ants.

"I found him the most unpleasant human being I ever met," Wilson wrote in his memoir, Naturalist, dubbing Watson the "Caligula of biology."

Wilson and others, however, came to respect Watson's administrative abilities.

"The way he built up Cold Spring Harbor Laboratory was just extraordinary," says Dr. Victor A. McKusick, a pioneer of medical genetics at the Johns Hopkins University.

Among those impressed by Watson was Carol Greider, who spent 10 years at Cold Spring Harbor and found a potential clue to the cause of cancer in the ends of chromosomes, called telomeres.

"He would walk into my lab on a Saturday and ask me about a paper he had just read on telomeres," says Greider, now interim director of molecular biology and genetics at Johns Hopkins. "I was really just flabbergasted the first few times it happened, that he would follow so closely a field that was not really his specialty."

Watson's takeover of Cold Spring Harbor coincided with the successful conclusion of another obsessive quest -- finding a mate. At 40, he married a Radcliffe College sophomore named Elizabeth Lewis who was helping in his Harvard lab. They had two young sons, one of whom suffers from serious learning disabilities -- fueling Watson's belief in giving parents a chance to fix genetic flaws in their offspring.

"We have a son who's never had a chance to succeed, and that's awful, you know?" he said. "So I speak from a very personal viewpoint that evolution isn't kind, and we shouldn't let things as they are."

In the late 1980s, Watson lobbied Congress to fund an ambitious project to map all 3.2 billion chemical building blocks in human DNA. But he quit the Human Genome Project in 1992 in a dispute over plans to patent bits of genetic information that had been developed. Still, many credit his early vision and leadership of the genome effort, which is nearing conclusion.

"Watson had more influence than anyone else in strengthening the growth, the focus of biology," says biographer Victor McElheny.

Although Watson plans to attend many of the DNA anniversary celebrations, his one-time partner and old friend Crick is shunning them. Crick videotaped messages for this week's events in New York, but he declined a request to be interviewed.

The quick-witted, booming-voiced Crick, whom Watson describes as a "soul mate" during the race for the double helix, has curtailed his activities recently while undergoing treatment for colon cancer.

As president emeritus of the Salk Institute for Biological Studies in La Jolla, Calif., Crick continues to ponder how the brain works to make people aware of themselves and their surroundings -- a field until lately considered more the province of philosophers than scientists.

In his 1994 book The Astonishing Hypothesis, Crick suggested that "your joys and sorrows, your memories and your ambitions, your sense of personal identity and free will, are in fact no more than the behavior of a vast assembly of nerve cells and their associated molecules."

Trained as a physicist, Crick ventured into biology after developing mines for the British Navy during World War II. His outspokenness and hostility toward religion helped forge his famous partnership with the skeptical Watson.

Crick remained at the University of Cambridge after the DNA discovery, living in a house he dubbed the Golden Helix as he pursued DNA's underlying machinations. But by the mid-1960s, he concluded that the fundamental questions of genetics had been answered.

After moving to Southern California in the 1970s, he and fellow Briton Leslie Orgel developed the eyebrow-raising theory that life on Earth began with microorganisms from outer space -- probably seeded by an alien spaceship.

Crick later became a leading theorist in the study of how the brain works.

Watson thinks that neuroscience is one of the next big scientific frontiers, one that will keep reseasrchers racing for the rest of this century. Crick finds the field less developed than genetics was when he dove into research in the early 1950s.

"There seems no limit to the problems that now confront us," Crick said in his videotaped remarks. "I shall not live to see their solutions, but many of you should survive long enough to see many radically new techniques and striking discoveries."

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