US scientists win Nobel Prize for RNA interference discovery

American geneticists Andrew Fire and Craig Mello have won the 2006 Nobel Prize in Physiology or Medicine for their discovery of RNA interference, a mechanism for controlling the flow of genetic information.

Fire, a 47-year-old professor of pathology and genetics at Stanford University School of Medicine, and Mello, 46, professor of molecular medicine at the University of Massachusetts Medical School and a Howard Hughes Medical Institute investigator, first published their findings in the journal Nature on February 19, 1998.

Fire and Mello had discovered a mechanism that can degrade messenger RNA (mRNA), the form of RNA that carries information from DNA in the nucleus to the sites of protein synthesis in the cell, from a specific gene. This mechanism, RNA interference (RNAi), is activated when RNA molecules occur as double-stranded pairs in the cell.

Double-stranded RNA activates biochemical machinery which degrades those mRNA molecules. When such mRNA molecules disappear, the corresponding gene is silenced and no protein of the encoded type is made.

Fire and Mello first worked out the role of RNAi while investigating how gene expression is regulated in the worm C. elegans.

Injecting mRNA molecules encoding a muscle protein led to no changes in the behaviour of the worms. 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, they observed that the worms displayed peculiar, twitching movements. Similar movements were seen in worms that completely lacked a functioning gene for the muscle protein.

They found that when sense and antisense RNA molecules meet, they bind to each other and form double-stranded RNA. Hypothesising that such a double-stranded RNA molecule silences the gene carrying the same code as this particular RNA, they injected double-stranded RNA molecules containing the genetic codes for several other worm proteins. In every experiment, injection of double-stranded RNA carrying a genetic code led to silencing of the gene containing that particular code. The protein encoded by that gene was no longer formed.

According to the Nobel committee at the Karolinska Institute, after a series of simple but elegant experiments, Fire and Mello deduced that double-stranded RNA can silence genes, that this RNA interference is specific for the gene whose code matches that of the injected RNA molecule, and that RNA interference can 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 RNA interference is a catalytic process," the committee's citation reads.

"RNA interference opens up exciting possibilities for use in gene technology. Double-stranded RNA molecules have been designed to activate the silencing of specific genes in humans, animals or plants. Such silencing RNA molecules are introduced into the cell and activate the RNA interference machinery to break down mRNA with an identical code.

"This method has already become an important research tool in biology and biomedicine. In the future, it is hoped that it will be used in many disciplines including clinical medicine and agriculture."

In an interview with the editor of the Nobel Prize organisation's website, Mello said he was surprised that the breakthrough had been awarded so soon after its discovery.

"I felt I was sort of too young to get it this soon and thought, if it happened, it would be a few years from now," Mello said. "So I wasn't ready at all."

Asked if there was a Eureka moment for the duo when they realised what was happening, Mello said there really wasn't until they began to understand the nature of the first gene they cloned. "[F]or me that was very much like a Eureka moment because the phenomenology was exciting and interesting - the fact that this silencing was occurring and the fact that it could be transmitted from one generation to the next and spread from tissue to tissue," he said.

"[N]ot until we cloned the first gene, which we had called rde1 for RNAi decision gene number one, did we realise that the gene had homologues in essentially every organism including humans and plants and even fungi. And that, to me, was extremely exciting, especially because it was a novel gene and yet highly conserved, with extensive sequence conservations."

He said he was now thinking in terms of the role of this type of silencing in evolutionary change, rather than simply as something involved in regulating gene expression.

"Actually I think it has an impact, or a potential impact, on evolution on a broader scale as a source of inheritance and variation. And that's something that I'm thinking about writing right now, a paper, essentially a hypothesis, that this may play a very important role in evolutionary change."