Prolog : News : New York Times : 10 03 06

10 03 06 | New York Times article by Nicholas Wade

2 American “Worm People” Win Nobel for RNA Work

This year’s Nobel Prize in Physiology or Medicine has been awarded to two American researchers, Andrew Z. Fire and Craig C. Mello, for a far-reaching discovery about how genes are controlled within living cells.

The discovery was made in 1998, only eight years ago. It has been recognized with unusual speed by the Nobel Foundation in Stockholm, which sometimes lets decades elapse before awarding its accolade. The foundation’s caution, born of the fear of giving immediate recognition to research that may prove unfounded, may have been dispelled this year by the evident promise of the new field, several scientists said.

The finding by Drs. Fire and Mello made sense of a series of puzzling results obtained mostly by plant biologists, including some who were trying to change the color of petunias. By clarifying what was happening, they discovered an unexpected system of gene regulation in living cells and began an explosive phase of research in a field known variously as RNA interference or gene silencing.

This natural method of switching genes off has turned out to be a superb research tool, allowing scientists to understand the role of new genes by suppressing them. The method may also lead to a new class of drugs that switch off unwanted processes in disease. Two gene-silencing drugs designed to treat macular degeneration are already in clinical trials.

“This was such an obvious Nobel, on everybody’s list of discoveries that would receive the prize soon,” said Dr. Thomas Cech, an expert on RNA and president of the Howard Hughes Medical Institute.

Dr. Bruce Stillman, president of the Cold Spring Harbor Laboratory on Long Island, said the prize was to recognize a new field of research, which has had “a spectacular birth and expansion,” as well as the discovery by Drs. Fire and Mello that started it.

Dr. Fire, now at Stanford University, worked at the Carnegie Institution of Washington when he made the discovery. Dr. Mello, a frequent collaborator, is at the University of Massachusetts Medical School in Worcester. Both are “worm people,” as scientists who do their biology in the roundworm Caenorhabditis elegans call themselves.

Prior to their discovery, plant biologists over many decades had found odd exceptions to Mendel’s laws of heredity, including some unexplained effects produced by injecting RNA, the less-well-known cousin of DNA, into plants. Both are chemicals called nucleic acids, but DNA is longer and more stable and is used by the cell for the archival function of storing genetic information. RNA is shorter and more active, and performs many of the cell’s more difficult tasks, like making copies of the genes in DNA and directing the synthesis of the proteins specified by the genes.

The plant biologists supposed that injecting new RNA might somehow interfere with the protein-synthesizing process but did not understand how to make this happen reliably. Drs. Fire and Mello made a decisive advance by showing in roundworms that the injected RNA had to be double-stranded and that the sequence of chemical units had to be the same as or very similar to those of the gene being singled out. Under these conditions, any gene in the roundworm could be switched off by injecting double-stranded RNA with a sequence of units that corresponded to those in part of the gene’s DNA.

Other scientists soon figured out the evolutionary reason for this curious mechanism. It is a defense against viruses, many of which have double-stranded RNA as their genetic material. When a virus enters a cell, its RNA is chopped up and the fragments are used to battle the virus itself. The cell takes one strand of each fragment and tests all the messenger-RNA’s — those that direct synthesis of proteins — to see if they match it. Only the virus’s RNA’s will match, and they are destroyed before they can start making the virus’s proteins.

The perceived importance of the Fire-Mello finding increased even more when other researchers discovered that it had a second dimension. It seemed that cells, having evolved this handy mechanism for suppressing a virus’s genes, then adapted it to controlling their own genes.

Both plants and animals, probably independently, evolved genes that do not make proteins but simply generate an RNA molecule that loops back on itself to form a hairpin twist similar to a virus’s double-stranded RNA. These RNA’s, known as micro-RNA’s, use the same gene-silencing mechanism as is set off by viruses, and ratchet down the activity of many of the cell’s own genes.

The genes that make micro-RNA’s are a novel class, quite different from the conventional genes that direct the synthesis of proteins. Researchers are now busily exploring how many exist in the human and other genomes. Micro-RNA genes seem to be important in processes like embryonic development in cancer. Gene silencing and micro-RNA’s have become overnight a major field of biological research, and one that may well attract other Nobel Prizes in the future.

“I think it will be applied quite broadly in anticancer therapies in the next 10 years,” Dr. Stillman said.

Given that scientists are divided into communities who work on particular organisms, this year’s Nobel Prize is being crowed over by worm people, who also enjoyed a big victory with the 2002 Nobel Prize. It may be less welcome to weed people — those who work on mustard and other plant species — who were passed over despite having laid the basis of the field.

“In some ways, it’s a little disappointing not to see plants recognized,” said Robert Martienssen, a plant geneticist at the Cold Spring Harbor Laboratory.

Was it unfair for plant biologists to be excluded from the Nobel Prize, which can be given to up to three winners? “You have to say they had their chance, and yes, it was interesting biology, but they didn’t trace it to double-stranded RNA,” Dr. Cech said. “The field exploded after the Fire and Mello paper.”

Dr. Fire was born in 1959 and grew up in Sunnyvale, Calif. His father is a Silicon Valley engineer. “Coming from a household with a respect for learning was most important,” he said. He said he did not expect the prize to change his life of teaching and doing research. But the prize means that “one can open public debate on something and people will listen,” he said.

Dr. Mello, born in 1960, also comes from a scientific family. His father is a paleontologist and was the first in his family to go to college. After yesterday’s interruptions, Dr. Mello said, “I hope I can get right back to work — I’m still young, as my mom pointed out.”

He and Dr. Fire began collaborating in the late 1980’s because they had developed similar techniques for working on the roundworm. Their partnership, though long distance, is still in effect. “We spend hours and hours sharing information and talking about our work, so long that my ear would hurt,” Dr. Mello said.

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