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Youthful duo snags a swift Nobel for RNA control of genes

Nature volume 443, page 488 (05 October 2006) | Download Citation

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Award comes just eight years after publication.

The call from Stockholm was received by two unusually young scientists, an impressively short time after they demonstrated a fundamental control of gene expression.

Silence is golden: Craig Mello (left) and Andrew Fire. Image: STANFORD UNIV.; UNIV. OF MASSACHUSETTS

The 2006 Nobel Prize in Physiology or Medicine has gone to Andrew Fire, now at Stanford University, California, and Craig Mello, now at the University of Massachusetts Medical Center in Worcester. Both are in their forties. It honours a discovery that has transformed biological research and may, in the future, prove useful in treating human disease.

The discovery is called RNA interference, or RNAi. When a gene is to be expressed, it sends instructions to the cell's protein synthesis machinery. The intermediary is messenger RNA (mRNA), which has a structure complementary to that of the gene. In their breakthrough paper, published in Nature in 1998, Fire and Mello, and colleagues, demonstrated that these mRNAs can be targeted for destruction by specific double-stranded forms of RNA (A. Fire et al. Nature 391, 806–811; 1998 ).

Researchers already knew that 'antisense' RNA — an artificial molecule whose sequence complements the mRNA — could silence specific genes when taken up by a cell. But the effect was modest and inconsistent. And, confusingly, the same effect was seen with 'sense' RNA.

In a series of simple and elegant experiments on a muscle gene in the nematode worm Caenorhabditis elegans, Fire and Mello showed that a powerful and consistent effect required the sense and antisense RNAs to be stuck together, as double-stranded RNA. When injected with the double-stranded RNA, the worms twitched awkwardly, just like mutant worms lacking the muscle gene. The researchers also showed that mRNA was destroyed by the treatment, rather than being masked as others had believed. And they showed that the double-stranded RNA can cause more copies of itself to be made, can spread between cells and can even be inherited by progeny.

In the Nature paper the researchers speculated that organisms might use this mechanism to control expression of their genes — a fact soon shown to be true. RNAi turned out to be an important way of controlling 'jumping genes', which can insert themselves throughout the genome and disrupt gene function. It is also thought to help protect against viral infections, at least in simple organisms.

Fire and Mello's subsequent research, and that of the many researchers who flooded the field after them, have since filled in the details. The RNAi pathway has been fully worked out and shown to apply to all genes — not just in worms but in nearly all other species.

“There is hardly a lab not using the tools of RNAi to turn off the genes that they are studying,” says Tom Tuschl of Rockerfeller University, New York, who joined the RNAi élite soon after the Fire and Mello discovery. RNAi reagents have been used to find genes involved in everything from ageing to cancer. Clinical hopes are pinned on finding ways to use RNAi to reduce the activity of genes that cause disease.

Most Nobel prizes are given many years after the relevant discovery. The Fire and Mello award, given just eight years after publication of their paper, is reminiscent of Kary Mullis's 1993 chemistry Nobel. That prize was awarded for his 1985 invention of the polymerase chain reaction — a method of gene amplification that invaded research labs just as fast and comprehensively as the RNAi technique has.

Ronald Plasterk of the University of Utrecht in the Netherlands, who worked with Fire when they were young researchers at the Laboratory of Molecular Biology in Cambridge, UK, says he felt that a Nobel was around the corner. But he didn't think it would be so soon. For a laugh, on the morning of the announcement Plasterk asked his postdoc to call Fire in a pronounced Swedish accent. “But then we heard he had really won, so the joke had to be dropped.”

Mello seemed stunned when interviewed on the Nobel webcast, not long after he had heard the news. “I seem too young,” he said. “And isn't the gap unusually short?”

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