2 Share Nobel Prize for Finding ‘Split Genes’

An American and a Briton whose career has been spent in the United States will share the 1993 Nobel Prize for medicine or physiology for their discovery of “split genes,” the Swedish Nobel Assembly announced Monday.

Richard J. Roberts of New England Biolabs in Beverly, Mass., and Phillip A. Sharp of the Massachusetts Institute of Technology independently discovered in 1977 that most genes are not simple, continuous pieces of DNA. Rather, genes are composed of multiple segments of DNA interspersed with stretches of DNA with no apparent function--a finding that foreshadowed the development of genetic engineering technology.

“The discovery of split genes has been of fundamental importance for today’s basic research in biology, as well as for more medically oriented research concerning the development of cancer and other diseases,” said the Nobel Assembly of the Karolinska Institutet, which awarded the $825,000 prize that the two will split. “Roberts’ and Sharp’s discovery has changed our view on how genes in higher organisms develop during evolution.”

“It was a surprise,” Sharp, 49, said at a news conference. “It feels good this morning, folks. Things don’t get better than this.”

“Everybody doing science wants to feel they are going to make a discovery that everybody will look up to,” Roberts, 50, a native of England, said at a separate news conference. “But I think there’s a different kind of satisfaction that comes when you realize that all of your colleagues also think it was a great discovery.”

Roberts and Sharp studied adenoviruses, causes of common colds, because it was thought that the virus’s genes shared important similarities with those of higher organisms. Both were attempting to identify the locations of individual genes in the virus’s DNA--deoxyribonucleic acid, the genetic blueprint of life.

To their surprise, they found that each gene was not located at one discrete site, but was spread out over a large region interspersed with regions--now called introns--of so-called nonsense DNA with no discernible function. Many other researchers quickly showed that genes of most other organisms, up to and including humans, had a similar organization.

“Next to the discovery of the structure of DNA, this (was) probably the greatest discovery in genetics in the last 70 to 80 years,” molecular biologist Sidney Altman of Yale University said Monday.

“It was a completely seminal observation . . . that changed the whole thinking about our concept of gene organization,” said molecular biologist Eric J. Stanbridge of UC Irvine College of Medicine.

Sharp said he and Roberts were “fortunate to be in the right place at the right time, doing the right experiment.” But the time was ripe for the discovery, he added, and “if we hadn’t made this discovery, within six months there would have been 10 other labs making the discovery. The field was so primed to look at the structure of genes that it would have been made by many other laboratories.”

Their findings also led to the discovery of a new genetic process called splicing, in which the gene segments are cut away from the nonsense material and then stitched together to form an intact gene. This splicing does not occur with DNA, however, but with RNA, or ribonucleic acid, which carries information from DNA to the cell’s protein-producing machinery.

The recognition of RNA splicing led directly to the discovery that RNA itself could be a catalyst for chemical reactions in a cell--a discovery that won the 1989 Nobel Prize for chemistry for Altman and Thomas Cech of the University of Colorado.

The discoveries about splicing have “ultimately led to a whole new set of approaches to the treatment of cancer and viral infections, such as HIV, through use of ribozymes, which take advantage of RNA splicing chemistry” to kill the cancer cells or viruses, said molecular biologist Laurence Kedes of USC.

Sharp’s and Roberts’ discovery also provided insight into evolution. Researchers had believed that evolution occurred when single chemicals in a gene mutated, producing subtle changes in the protein for which the gene is a blueprint. The accumulation of many such changes over a long period of time were thought to be necessary for a significant change in the function of a protein.

But the recognition that genes existed in segments led to the understanding that those segments can be randomly shuffled before assembly, leading to new proteins in a much shorter period of time and thereby speeding up evolution. “This knowledge has radically changed our view . . . of evolution,” the Nobel Assembly said.

Such shuffling is also thought to be the cause of some genetic diseases, such as chronic myeloid leukemia, a cancer of the blood, and beta-thalassemia, a form of anemia common in Mediterranean countries.

Most of the two researchers’ work has been publicly funded. The National Institutes of Health reported Monday that during their careers, Sharp has received $20 million from the agency and Roberts $18 million.

Unraveling ‘Nonsense’ DNA

The discovery by Nobel laureates Phillip Sharp and Richard Roberts of “nonsense DNA” radically changed the prevailing view of genetic structure and paved the way for gene-splicing technology. Here is a look at the gene structure they discovered:

1) Chromosomes in a nucleus are packed with tightly coiled DNA, which consists of two matching strands linked somewhat like a twisted zipper.

2) At intervals along the DNA strands are surplus DNA segments that have no apparent protein message, called “nonsense” DNA. A gene may comprise several segments separated by the “nonsense” DNA.

3) The DNA passes on its instructions to the cell via messenger RNA. The RNA has the machinery to cut out the nonsense sections and splice genetic material together as a model for assembling proteins in the cell.

Researched by VICKY McCARGAR / Los Angeles Times

Profile: Richard Roberts

* Age: 50

* Education: Bachelor of science degree and doctorate from University of Sheffield, Britain.

* Career highlights: Research director of New England Biolabs since 1992. Worked at Cold Spring Harbor Laboratory from 1972 to 1992 and was a research fellow at Harvard University.

* Quote: “No one had anticipated that it was . . . one of those discoveries that come, really, once in a lifetime, where dogma is completely overthrown.”

Profile: Phillip Sharp

* Age: 49

* Education: Studied at Union College in Barbourville, Ky., doctorate in chemistry from University of Illinois at Champaign-Urbana, post-doctorate fellow at Caltech.

* Career highlights: Head of biology department at Massachusetts Institute of Technology. Director of MIT Center for Cancer Research from 1985 to 1991.

* Quote: “It was a surprise (but) I knew it was very important work and very interesting work.”