The Nobel Prize in Physiology or Medicine for 2006 was awarded to Drs. Andrew Fire and Craig Mello for their discovery of RNAi
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A wayward petunia leads to the discovery of RNAi and it's potential for innovative medicines.
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Highlighted papers that have contributed to the development of RNAi as a novel therapeutic modality.
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RNAi is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. RNAi creates a direct opportunity to harness a natural mechanism to develop specific and potent drugs, and has the potential to become the foundation for a whole new class of therapeutic products.
RNA interference (RNAi)
The discovery of RNAi has been heralded as a major scientific breakthrough that happens once every decade or so, and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. RNAi therapeutics target the ‘root’ genetic cause of diseases by potently silencing specific messenger RNA, thereby preventing the disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.
The discovery of RNA interference
RNA interference is a natural mechanism for silencing specific genes. Genes provide cells with the instructions for making proteins, and when a gene is silenced, the cell stops making the protein specified by that gene. RNA interference was first observed in plants, but the first crucial breakthrough in understanding the RNAi mechanism came from studies of worms. This came in 1998 with the recognition that double-stranded RNA (dsRNA) played a pivotal role in RNAi.
Induction of RNA interference using dsRNA quickly became a powerful tool for scientists to study the function of genes in many lower organisms, including worms and fruit flies. However, this approach initially seemed unworkable in mammalian cells, because of the tendency of dsRNA to provoke the interferon response and cause cell suicide. Such cell suicide makes biological sense in the normal situation where dsRNA is encountered - viral infection - because it prevents replication and spread of the virus to neighboring cells. For a time, however, it was a major obstacle to experimental induction of RNAi in mammalian cells.
This obstacle was overcome by Alnylam scientific founders, who developed a new strategy to trigger RNAi in mammalan cells using relatively small synthetic dsRNAs - long enough to induce RNAi, but small enough to avoid inducing the interferon response. Alnylam founders were the first to show that smaller dsRNAs, known as "small interfering RNAs" (siRNAs), bind to messenger RNAs (mRNAs) with complementary sequences and trigger mRNA degradation with the RNAi mechanism.
