Fire and Mello win Nobel Prize

Researchers are honored for discovering the mechanism of RNA interference

By | October 2, 2006

Andrew Z. Fire, a professor in Stanford University School of Medicine's Department of Pathology and Genetics, and Craig C. Mello, professor of Molecular Medicine at the University of Massachusetts Medical School, have won this year's Nobel Prize in Physiology or Medicine for uncovering the mechanism of RNA interference, a discovery that "heralded the start of a new research field," according to the Nobel Academy.

"They started a revolution with the discovery of RNA interference," Nobel Laureate Philip Sharp, who won the prize in 1993 and studies the interference role of microRNA at the Massachusetts Institute of Technology, told The Scientist. Sharp said Fire, Mello, and their colleagues' landmark Nature study in 1998 -- which has been cited more than 2,500 papers, according to Web of Science (Thomson Scientific) -- not only launched a new field in RNA research, but also has had "profound impacts" on the understanding of gene regulation and function.

This year's prize represents "one of the quickest recognitions of a discovery," said Nick Hastie, director of the Medical Research Council Human Genetics Unit in Edinburgh, in a statement. "To find this in 1998 and get a Nobel Prize in 2006 is remarkable."

Fire and Mello made their discoveries in the nematode, Caenorhabditis elegans. Richard Jorgensen, associate professor at the University of Arizona Tucson, had noted the powerful co-suppression of petunia pigmentation genes using RNA constructs in the early 1990s. Antisense effects couldn't account for the extreme knockdowns in expression that researchers saw. In 1998, Fire and Mello investigated whether in fact double-stranded RNAs might be the trigger, and thus opened a new facet of RNAs' many duties in the cell. They found that just a few molecules were sufficient for wiping out gene expression, and in a modest prediction, the authors concluded, "The use of dsRNA injection adds to the tools available for studying gene function in C. elegans."

RNAi has grown into an extremely powerful tool. In the years since Fire and Mello's discovery, RNAi has been applied not only to uncovering gene function in many other organisms, but also to understanding and potentially treating human diseases. The revolution has created a new sector in the biotechnology industry. Alnylam Pharmaceuticals, based in Cambridge, MA, is one of a number of companies using RNAi to develop therapeutics and has one product already in clinical development. CEO John Maraganore said he believes the award of the prize to Fire and Mello is a reflection of the fact that RNAi "has such enormous implications for basic biology and the promise for the discovery of new medicines." Maraganore estimates the market capitalization of therapeutic RNAi companies is well over one billion dollars. He expects RNAi can be applied to numerous diseases, including respiratory syncytial virus, Parkinson's disease, and influenza.

"It is extremely gratifying to see RNAi applied so broadly in labs around the globe," Mello said in a statement. "Our work was just one piece of a puzzle but I think it is opening a door to a whole new frontier from which we can learn so much more about our bodies' own protective mechanisms." Sharp says Fire and Mello's impact on the study of RNAi still reverberates. "This discovery is still unfolding. This summer there was a whole other class of RNAs uncovered call piRNAs. There is a whole RNA world in our cells that has (yet to be explored)."

Reference: Fire, et al. 1998 Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391:806-811. 


Avatar of: Bill Crane

Bill Crane

Posts: 2

October 3, 2006

Adds strength to any argument that American life scientists, and the institutions that support them, are among the best in the world - and deserve recognition, independence and proper funding!
Avatar of: Zhijun Wang

Zhijun Wang

Posts: 1

August 23, 2007

From catalytic RNA to RNAi: the contribution of plasmid-based RNA expression system\n\nZhijun Wang, Ph.D\nCAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, P.R. China E-mail:\n\n\nDrs Fire and Mello were awarded Nobel Prize in 2006 for the contribution of RNAi 1. From my viewpoints, the basic mechanism of RNAi was derived from the catalytic RNA and the application of plasmid-based RNA expression system. RNA molecules with catalytic activity are called catalytic RNAs or ribozymes. For a long time, it was believed that biological catalysis depended only on some special proteins called enzymes. However, one of the most important findings in molecular biology reveals that proteins are not the only molecules that can catalyze the chemical reactions. At the beginning of the 1980s, Cech's group found that the single intron of the gene has an autocatalytic splicing activity in vitro. The intron can excise itself from the pre-RNA and the flanking exons are joined to the mature RNA independent of proteins or additional energy 2. Altman's group showed that the RNA component of RNase P from Escherichia coli is able to process its substrate, a pre-tRNA, in the absence of its protein subunit 3. In 1989, Cech and Altman were awarded the Nobel Prize for the discoveries on the catalytic RNA. Then an extensive search for catalytic RNA began. It appeared that catalytic RNAs are widely existed in nature 4. These kinds of RNAs include self-cleaving RNAs (for example: hammerhead motif ribozyme, hairpin motif ribozyme, hepatitis delta virus ribozyme, varkud satellite ribozyme), and self-splicing RNAs (for example: group I introns and group II introns).\nWith the development of plasmid biology, plasmid-based RNA expression system really makes the catalytic RNA into practical application. It has been discovered that perfectly complementary short interfering RNA (siRNA) can cleave mRNA at the sites to which they bind 5. Although most RNAi mechanisms were not only depended on the binding of siRNA with the target mRNA, but also the functional proteins 6, a significantly similar mechanism of catalytic RNA and RNAi on the RNA cleavage should be classified.\nIn fact, it is plasmid-based RNA expression systems that make catalytic RNA into practical application. I suppose the Nobel Prize of RNAi in 2006 should include one of plasmid biologists, who made the catalytic RNA into practical application. Plasmid biologists have been made significant contributions on the modern Science, for example, the discovery of DNA vaccination should be definitely due to the contribution of plasmid biologists, while not only the first scientist who did the DNA vaccination experiments.\n\n1. Nature 443, 488 (2006).\n2. Cell 31, 147?157 (1982).\n3. Cell 35, 849?857 (1983).\n4. Nature 418, 222?228 (2002).\n5. Nat Rev Drug Discov 3, 318-329. (2004).\n6. Cell 117, 69-81. (2004).\n

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