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Sharp garners share of Nobel prize

Professor Phillip A. Sharp, researcher, teacher and head of the Department of Biology at MIT, last week won the 1993 Nobel prize in physiology or medicine for work that fundamentally changed scientists' understanding of the structure of genes. He shares the prize of about $825,000 with Dr. Richard J. Roberts of New England Biolabs in Beverly, MA, who independently came to the same conclusions at about the same time.

At an MIT press conference packed with cheering students and colleagues, a beaming Professor Sharp answered questions about the work, which has had important implications for the evolution of organisms and the causes of some hereditary diseases and cancers.

Specifically, Drs. Sharp and Roberts were awarded the prize for their discovery in 1977 that some of the genes of higher organisms are "split," or present in several distinct segments along the DNA molecule. Those segments are separated by extraneous, "nonsense" DNA.

Prior to the discovery, biologists thought that the genes of all organisms were arranged in continuous segments along the DNA, as is the case with simple organisms like bacteria whose cells have no nuclei. Now scientists know that "a split gene structure is. the most common gene structure in higher organisms," the Nobel committee said in announcing the prize.

The discovery "has been of fundamental importance for today's basic research in biology, as well as for more medically oriented research." and "has changed our view on how genes in higher organisms develop during evolution," the Nobel committee said.

First reactions

Dr. Sharp received the call from Stockholm at around 6:30am Monday, October 11. "I was shaking," he told the New York Times. "I said, `Could you please repeat that?'"

When asked at the MIT press conference at 10am the same day how it felt to be a new Nobelist, Professor Sharp replied: "You walk in a room like this and all your colleagues and friends give you a standing O, and the days don't get better than this."

Adding to the air of celebration was a wall clock that had been adapted for the occasion with small oval photos of the new Nobel laureate pasted over the numbers. "It's Phil Sharp's hour!" proclaimed Kenneth D. Campbell, director of the News Office, pointing to the clock at the opening of the news conference.

Sitting at the press conference table with Professor Sharp were his colleagues Richard O. Hynes, professor of biology and director of the Center for Cancer Research, and Robert J. Birgeneau, dean of the School of Science and Cecil and Ida Green Professor of Physics.

Also among those at the press conference were Dr. Sharp's wife, Ann, two of their three daughters, and Margarita Siafaca, who has worked with Professor Sharp since 1974 and is now manager of his laboratory. Ms. Siafaca celebrated the Nobel by opening a bottle of champagne she's had on ice since 1977-the year Professor Sharp made his seminal discovery-in anticipation of the honor that finally came.

RNA splicing

According to the Nobel committee, the prize-winning work also almost immediately led to the prediction of a new genetic process. Coined "RNA splicing" by Dr. Sharp ("I can remember getting out my dictionary to see if this was going to be an appropriate term," he said), this process deletes the nonsense segments from the gene to create an understandable "blueprint" that the cell can read to produce a protein.

In this process the cell makes a copy (RNA) of the gene in question from the master blueprint (DNA). The nonsense segments (known as introns) are then clipped from this RNA, and the segments of real value (known as exons) are spliced together. The resulting molecule called messenger RNA then travels to a work site outside of the nucleus where it serves as the blueprint for assembly of the protein it codes for.

Evolutionary implications

But why do the genes of higher organisms have such a split structure? What advantage could there be? Although these questions are still being debated, Professor Sharp said, "I think the most likely possibility is that by having the gene in pieces, you can-in different cell types or through evolution-pick different pieces to make a [different] functional protein. And that. could have been very important in the evolution and adaptation of organisms."

Further, some scientists believe that by separating and recombining the hereditary message, DNA with nonsense segments may safeguard genetic coding better than unbroken genes, which could be damaged more easily.

"Split genes" and medicine

Professor Sharp's work has also had a major impact on medicine. Soon after the discovery of split genes and RNA splicing, scientists realized that some of the approximately 5,000 hereditary diseases "are due to errors in the splicing process," the Nobel committee said. Today, researchers know that "about 25 percent of the known mutations that give rise to hereditary diseases. affect the splicing process," Professor Sharp said at the MIT press conference. Examples of such diseases include beta-thalassemia, an anemia prevalent in some Mediterranean countries, and one type of leukemia.

The discovery of split genes "does not give us cures, but the possibility to know how we are going to do therapy with genes in the future," Gosta Gahrton, a professor of medicine at the Karolinska Institute (which awards the Nobel prize), was quoted as telling reporters in Stockholm.

Immediate impact

Professor Sharp's work on split genes and RNA splicing had an immediate impact on the field of molecular biology. "We helped initiate a revolution," Professor Sharp said at the MIT press conference. Did he realize the magnitude of the discovery at the time? "I knew it was different, but did I know that it was going to mushroom into the case where 99 percent of all our genes are expressed this way, and it would become a whole field of science? No."

The summer of `77 "was one of the most bizarre summers in my life," he remembered. "As I was moving around the country giving talks about the work, every day somebody else would walk up and say, `this gene has a discontinuous sequence in it and is expressed by RNA splicing.'

"Within months," he said, "the work was obsolete. Everybody everywhere knew about it. You work 10 years to make this discovery, and within two weeks you couldn't give a talk on it because everybody and anybody knew what you were going to say."

Professor Sharp also noted that "if we hadn't made this discovery, within six months there would have been 10 other labs making the discovery [because] the field was so primed for looking at the structure of the gene." His group was first (with Dr. Roberts') because "I had been worried about the problem [that gave rise to the discovery] for many years" and applied all his efforts there.

Dr. Sharp said that other key members of the MIT team that made the discovery were Susan M. Berget, then a postdoctoral fellow at the Center for Cancer Research, and Claire Moore, then a technician at the CCR. Dr. Berget is now a professor at Baylor College of Medicine; Dr. Moore is a professor at Tufts University Medical School. The work was conducted through the Center for Cancer Research and the Department of Biology. It was supported by grants from the American Cancer Society, the National Institutes of Health, the National Science Foundation and funds from the CCR.

Resume of a Nobelist

Professor Sharp, 49, grew up on a small farm in Kentucky. He told the New York Times that he developed an interest in science from "excellent teachers" in high school. The Times also reported that "his parents, who had not gone to college, gave him a piece of tobacco land to encourage him to save for college, and the earnings eventually paid for a year and a half at Union College in Kentucky," where he received his undergraduate degree in chemistry and mathematics.

He earned his PhD from the University of Illinois in chemistry, and later joined the MIT Center for Cancer Research and Department of Biology in 1974 after postdoctoral research at Caltech and Cold Spring Harbor (where he worked with 1962 Nobel laureate James D. Watson). For several years Professor Sharp was director of the Center for Cancer Research; he is currently the Salvador E. Luria Professor of Biology at MIT.

Other MIT Nobelists

The awarding of the 1993 Nobel prizes brings to 25 the number of Nobel laureates who have either been educated at or affiliated with MIT. Professor Sharp is one of 10 Nobel laureates currently at MIT.

The others are: Jerome I. Friedman (physics, 1990); Henry W. Kendall (physics, 1990); Robert M. Solow (economics, 1987); Susumu Tonegawa (medicine or physiology, 1987); Eric S. Chivian (peace, 1985); Franco Modigliani (economics, 1985); Samuel C.C. Ting (physics, 1976); Paul A. Samuelson (economics, 1970); and Har Gobind Khorana (medicine or physiology, 1968).

Professor Sharp is also the third MIT Nobelist from the Center for Cancer Research. The others are Professor Tonegawa and David Baltimore (who received the prize in 1975 and will be returning to MIT next year). The CCR was founded in 1974 by Salvador E. Luria, now deceased, who was himself a Nobel laureate in medicine or physiology (1969).

A version of this article appeared in MIT Tech Talk on October 20, 1993.

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