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Ever since a 1960s' Flash Gordon comic strip featured space medics using a dose of interferon to instantly cure a patient of an alien virus, the public has been primed for a miracle drug. Professor Phillip A. Sharp, director of the McGovern Institute for Brain Research, says a method of controlling gene expression called RNA interference (RNAi) may provide such drugs.
Speaking to an overflow crowd at the Department of Chemical Engineering's Frontiers of Biotechnology Lecture, Sharp said using double-stranded small RNAs to silence genes "will fundamentally change the way we do cell biology. We have to understand how an organism's genes interact if we are to understand disease processes."
Interferons are a family of proteins that human cells release when invaded by a virus. Small interfering RNAs (siRNAs) are 21- to 23-nucleotide RNA molecules that can cause targeted gene silencing in mammalian cells without triggering any interferon response, leading researchers on a quest to create RNA medicines to treat a host of disorders from high cholesterol to cancer, as well as viral diseases such as AIDS.
MIT and the Whitehead Institute for Biomedical Research have been involved from the start in exploring RNAi.
RNAi has been used to control viral infections in plants, as a tool to probe cell biology by observing the effects of silencing specific genes, as a means to see if potential drugs are having their desired effect and for potential new therapeutic approaches, said Sharp, a Nobel laureate in biology. He said his longtime goal has been to silence genes in mammalian cells.
Sharp's own recent work in the field uses RNAi methods to interfere with cell surface receptors to make an individual more resistant to viral infections like HIV. He is one of the founders of a Cambridge company started in 2002 that aims to use small RNAs to silence genes in disease states.
Sharp described RNAi-related work in several other laboratories around campus.
David P. Bartel, associate professor of biology and a member of Whitehead, studies RNA-mediated cellular processes, including RNAi and microRNAs, small RNA molecules that also seem to silence genes. Bartel has identified hundreds of genes that code for them in a wide range of organisms. It was Thomas Tuschl, formerly a postdoctoral associate under Bartel, who announced at a 2001 meeting of the RNA Society that RNA fragments quickly and efficiently turn off genes in human cells.
The laboratory of 2002 Nobel laureate H. Robert Horvitz, professor of biology and a Howard Hughes Medical Institute investigator, has initiated a genomics/robotics project to analyze the more than 100 micro-RNAs encoded by the C. elegans (roundworm) genome.
Luk Van Parijs, the Ivan R. Cottrell Career Development Assistant Professor in Immunology, looks at how cell growth and cell death signals control immune function and disease. His laboratory is testing whether autoimmune disease or cancer can be cured by specifically targeting immune cell survival molecules using RNA interference methods.
Other researchers around the world are exploring ways to silence genes in animals' hearts, kidneys and livers, and injecting short RNAs into animals' retinas to suppress a gene that causes a condition that leads to blindness. A danger sign that has surfaced in some research is that even if these short RNAs are designed for a specific target, they may generate off-target results, silencing genes at multiple sites rather than just one.
A version of this article appeared in MIT Tech Talk on October 8, 2003.