ASIA KEPKA FOR TIME Phil Sharp: A Nobel Prize Laureate for his work with RNA

The Pioneers of Molecular Biology: Phil Sharp
	Thanks to his groundbreaking research, once-lowly RNA finally gets the respect it so richly deserves
	By David Bjerklie

Posted Sunday, February 9, 2002; 10:31 a.m. EST
As a boy growing up on the family farm, tucked into a bend of the Licking River, near McKinneysburg, in the northern hill country of Kentucky, Phil Sharp was a long way from the rarefied debate over the structure of DNA taking place in Cambridge, England. But Sharp would manage to not only join the ranks of the DNA research pioneers, but also upset the applecart in the process. Sharp's gateway to the wider world was Kentucky's Union College, which lead to graduate school in physical chemistry at the University of Illinois, where he studied the polymer properties of DNA. In 1969, Sharp's growing interest in molecular biology and genetics ("I am a product of 1953," he laughs) resulted in positions at CalTech, Cold Spring Harbor Laboratory, under the mentorship of James Watson, and finally the Massachusetts Institute of Technology, where he has been since 1974. He is currently director of M.I.T.'s McGovern Institute for Brain Research.

During the mid-70s, the prevailing view of the gene was that it was a continuous stretch of code within a long, double-stranded DNA molecule. When the gene was activated, its information was copied into a single-stranded RNA molecule (known as messenger RNA), which in turn translated the information into the production of a protein.

What Sharp did was to complicate this elegant picture in a way that opened up new and powerful possibilities. In 1977 Sharp found that an individual gene doesn't have to be a single, continuous stretch of DNA, but can instead be made up of several DNA segments separated by all manner of irrelevant DNA. As it turned out, Richard Roberts at Cold Spring Harbor had come to the same conclusion. Other researchers would soon discover that a discontinuous gene structure is in fact the most common gene configuration in higher organisms.

The once-neat DNA-RNA-protein sequence now had a big new wrinkle. A large segment of DNA, containing both relevant sequences, exons, as well as irrelevant, intervening pieces of code, or introns, can be transcribed whole into a strand of RNA. But RNA can then edit out the junk, a process called splicing, leaving an intact length of RNA that contains the instructions for making a protein.

The implications are enormous. Evolution had long been thought to be solely dependent on alterations in DNA, the blueprint of life. But the discovery of split genes and RNA splicing opened up an entirely new evolutionary mechanism, one in which gene segments are rearranged or shuffled by RNA. By selectively editing exons, RNA can produce different proteins. The DNA hasn't changed; only the RNA splicing pattern. While RNA may offer an avenue of adaptive change, it can also create problems. Researchers have already identified several diseases, including forms of anemia and leukemia, that are due to RNA splicing errors.

The discoveries have also forced DNA to share the limelight with what was once its less glamorous cousin, RNA. RNA research has already produced nobels for Sharp, Roberts, Sid Altman and Tom Cech and it continues to demonstrate that RNA is, as Sharp puts it, "a much more central molecule in cell biology than we have previously thought." It's the little molecule that could, can and often does.

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