By Cheryl Pellerin
Washington File Staff Writer

Washington - Two U.S. scientists received the 2006 Nobel Prize in physiology or medicine October 2 for their discovery of RNA interference (RNAi), a mechanism for "silencing" genes and controlling the flow of genetic information. That mechanism could lead to new disease treatments.

Andrew Fire, 47, of the Stanford University School of Medicine in California, and Craig Mello, 45, of the University of Massachusetts Medical School, were notified of the award by the Nobel Assembly at the Karolinska Institute.

The two researchers, both longtime grantees of the U.S. National Institutes of Health (NIH), will share a nearly $1.37 million prize.

"The most immediate benefit [of the discovery] is going to be doing experiments that teach us things," Fire told Adam Smith, editor in chief of the Nobel Prize Organization Web site, during an October 2 telephone interview.

"There's a wonderful study that Rene Bernard's group [at the Netherlands Cancer Institute] in Holland did," Fire said, "where they used RNA interference to characterize a given tumor type, and once they figured it out they said, 'You could treat this with aspirin.' And then they put aspirin on it. That wasn't using RNAi as a drug, it was using it to learn more about the [system]."

Eventually, he added, through early work now in progress, scientists will learn the risks and benefits of using RNAi as therapy.

Plans are already under way to use RNAi silencing as a treatment for virus infections, heart disease, cancer, endocrine disorders and other conditions.

GENE SILENCING

Proteins are involved in all the processes of life - as enzymes digesting food, receptors receiving signals in the brain and antibodies defending the body against bacteria.

A genome - a collection of all the genes that make up each life form - works by sending instructions for building proteins from the DNA in each cell nucleus (center) to protein-making machinery in the surrounding cytoplasm.

Messenger RNA (mRNA) carries these protein-building instructions from the nucleus to the cytoplasm. In 1998, Fire and Mello published their discovery of a mechanism called RNA interference that could degrade mRNA from a specific gene.

The mechanism is activated when RNA molecules occur as double-stranded pairs in the cell.

Double-stranded RNA activates biochemical machinery that degrades mRNA molecules that carry a genetic code identical to that of the double-stranded RNA. When such mRNA molecules disappear, the corresponding gene is silenced and no protein of the encoded type is made.

RNAi occurs in plants, animals and people. It is important for regulating gene expression, helping defend against viral infections and keeping jumping genes - which can change places on a chromosome and cause damage if they end up in the wrong place -under control.

The human genome consists of about 30,000 genes, but only a fraction are used in each cell. The machinery that copies DNA to mRNA controls which genes are expressed in a process called transcription.

SENSE AND ANTISENSE

Fire and Mello were investigating how gene expression is regulated in the worm Caenorhabditis elegans.

Injecting mRNA molecules coded to produce a muscle protein led to no changes in the worms' behavior. The genetic code in mRNA is described as being the "sense" sequence, and injecting "antisense" RNA, which can pair with the mRNA, also had no effect.

But when Fire and Mello injected sense and antisense RNA together, the worms displayed peculiar, twitching movements - the same movements seen in worms that completely lacked a functioning gene for the muscle protein.

When sense and antisense RNA molecules meet, they bind to each other and form double-stranded RNA. Could such a double-stranded RNA molecule silence the gene carrying the same code as this particular RNA?

Fire and Mello tested the hypothesis by injecting double-stranded RNA molecules containing the genetic codes for several other worm proteins.

In every experiment, injecting double-stranded RNA carrying a genetic code led to silencing of the gene containing that code. The protein coded for by that gene was no longer formed.

A NEW RESEARCH FIELD

After a series of experiments, Fire and Mello deduced the following:

- Double-stranded RNA could silence genes.

- This RNA interference was specific for the gene whose code matched that of the injected RNA molecule.

- RNA interference could spread between cells and even be inherited.

It was enough to inject tiny amounts of double-stranded RNA to achieve an effect, and Fire and Mello therefore proposed that RNAi was a catalytic process.

Fire and Mello published their findings in the journal Nature in 1998.

Their discovery clarified many confusing and contradictory experimental observations and revealed a natural mechanism for controlling the flow of genetic information. This heralded the start of a new research field.

FIRE, MELLO AND NIH

At NIH, the National Institute of General Medical Sciences (NIGMS) began supporting the work of Fire in 1987 and Mello in 1999. Over the years, NIGMS has provided nearly $8.5 million to support the two scientists.

The NIH National Institute of Child Health and Human Development also provided more than $3 million to support Mello's research.

Their accomplishment demonstrates the importance of supporting new investigators and sustaining support of investigator-initiated ideas, according to an NIH statement.

"Today's Nobelists used experiments with nematode worms to find a mechanism that can silence genes in humans," said NIH Director Elias Zerhouni, M.D.

"Many diseases develop when genes don't work properly," he added, "so RNA interference offers a tremendous potential to create a new generation of drugs targeted to these and other conditions."

"RNAi is both a powerful tool for studying gene function and a promising approach to treating a host of human diseases," said NIGMS Director Jeremy Berg, "from macular degeneration and cancer to flu and other infections."

More information about the Nobel Prize is available at the organization's Web site.