The Prize of RNAi

The recently discovered role of small RNAs could mean new drugs and a new understanding of fundamental biology.

By Phillip Sharp

November 1, 2006

Only eight years after their 1998 paper in Nature announced the discovery of RNA interference (RNAi), in which double-stranded RNA is used to silence genes, Andrew Fire and Craig Mello awoke in the wee hours of the morning of October 2 to the news that they were the 2006 recipients of the Nobel Prize in Physiology or Medicine. Such a short time between discovery and prize often signifies a finding’s importance: it took only nine years for Watson and Crick to win the Nobel for discovering the structure of DNA. The Nobel Assembly’s confidence in the importance of RNAi is obvious.

The initial experiment by Fire and Mello, showing that double-stranded RNA injected into worms would silence the gene with the corresponding sequence, was a clarion call to labs around the world, announcing a new method for investigating gene functions. After the initial discovery, other labs showed that small double-stranded RNAs could be used to selectively silence genes in human cells, providing a much-sought-after general approach to exploring the functions of all 21,000 human genes.

Over the past five years, the science of RNAi has advanced research in almost all areas of human biology, including work on cancer, obesity, and autoimmune diseases. Several biotech organizations are developing RNAi-type therapeutics to silence genes that cause diseases: drugs that treat macular degeneration, a leading cause of blindness, and respiratory syncytial virus, a cause of death in premature newborns, are already in clinical trials. Since the technology can in theory silence any gene, it might enable a new category of therapeutics similar in breadth to the class of monoclonal antibodies, which now account for billions of dollars in biotech sales.

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RNAi also provoked the startling insight that small RNAs could be a key regulator of gene expression. Indeed, other scientists subsequently discovered that genes encoding small RNAs are common; there are approximately 300 to 500 of them in human cells. These are now called microRNA genes and are known to influence the expression of at least a quarter of all human genes. This is a newly discovered level of molecular control. Alterations in control by microRNAs have now been associated with many diseases, and the subject has only begun to be investigated.

The study of small RNAs is still in its infancy. In fact, this past summer, a family of small RNAs, called piRNAs, was discovered in the germline of vertebrates; it is a new field of science. Textbooks in cell biology are literally being rewritten.

Phillip Sharp, MIT Institute Professor and 1993 Nobel laureate, is a cofounder of Alnylam Pharmaceuticals, which is developing drugs based on RNAi. He is also a cofounder of Biogen. This year’s Nobel laureate Andrew Fire received his PhD from MIT in 1983, working in Sharp’s lab.

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