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Silence is golden for two teams of RNA researchers

"Imagine finding a gene that is used by a bioterrorism agent and then modifying the cells of the body to no longer express that gene." - Luk Van Parijs
"Imagine finding a gene that is used by a bioterrorism agent and then modifying the cells of the body to no longer express that gene." - Luk Van Parijs
Photo / Donna Coveney

Scientists exploit interference to shut down mammal genes

MIT researchers have developed a way to exploit RNA interference for the first time to silence genes in a wide variety of mammalian cells, including embryonic cells. The study appeared in the Feb. 17 edition of Nature Genetics.

This new approach allows genes to be switched off by inserting short pieces of ribonucleic acid (RNA) into developing cells. It is currently being used to help researchers uncover the function of the more than 30,000 genes found in humans, as well as in animal models of important diseases.

"Imagine finding a gene that is used by a bioterrorism agent," said Luk Van Parijs, assistant professor of biology at MIT's Center for Cancer Research (CCR) and senior author of the study, "and then modifying the cells of the body to no longer express that gene. It's like being vaccinated: the agent can no longer harm the body."

RNA interference is a potentially powerful tool, but important cell types have been resistant to the introduction of short interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs) required to trigger this process.

Van Parijs and colleagues created a system based on a disarmed lentivirus--a retrovirus that can introduce genetic material into almost every cell or tissue, including stem cells and neurons--and have used this virus to successfully deliver shRNAs into mammalian cells and even induce RNA interference (RNAi) in transgenic animals.

Using lentiviruses to silence genes will allow researchers to systematically test how they function in virtually all cells of the body and create animal models that will allow them to quickly and efficiently determine which genes are important to the function of different tissues and organs and which might be effective therapeutic targets in diseases.

Using this new technology, the MIT researchers have created transgenic mice in which important immune genes or cancer genes, such as p53, have been silenced. These mice are now being studied to understand more about how these genes contribute to autoimmune disease and cancer.

New short-form messenger can turn off targeted gene

A short form of RNA designed by MIT researchers can turn off a targeted gene much the way naturally occurring microRNAs do, MIT researchers report in the Feb. 15 issue of Genes & Development.

RNA--ribonucleic acid--was long thought to be only DNA's messenger, an intermediary that delivered the blueprint for constructing proteins. Researchers have now found that tiny segments of double-stranded RNA, dubbed short interfering RNAs (siRNAs), can be designed to shut down any given gene.

RNA medicines could be developed to treat a host of disorders from high cholesterol to cancer, as well as viral diseases such as AIDS.

MicroRNAs are small, naturally occurring RNA molecules that are similar to siRNAs but that function differently to silence genes.

Small RNAs, 21-25 nucleotides long, work in animals in at least two distinct ways: siRNA pair exactly to mRNA and destroy it, while microRNAs partially pair with mRNAs and repress their translation without destroying the mRNA.

Biology graduate students John G. Doench and Christian P. Petersen and Phillip A. Sharp, Institute Professor and director of the McGovern Institute at MIT, hope to use their newfound information about siRNAs to understand how naturally occurring microRNAs work to stop the translation of certain genes in mammals.

"This study shows that the two silencing pathways are connected," Petersen said. "Researchers have always assumed that siRNAs only act on messenger RNAs to degrade them by RNA interference, but they can also turn off gene expression by halting translation."

Last June, Sharp and colleagues showed that siRNAs could stop HIV infection in cells grown in the lab. The researchers created siRNAs that inhibited the growth of HIV through gene silencing.

"A lot of really big questions surround the biology of these RNAs, and we think we'll be able to study many of them with this system," Petersen said.

A version of this article appeared in MIT Tech Talk on February 26, 2003.

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