Volume 89 Issue 51 | p. 19
Issue Date: December 19, 2011

Cover Stories: Chemical Year In Review 2011

Genomics: RNAi Adapted For Mammals

Biotech companies are now actively using RNA interference to develop drugs for viral infections, cancer, and other diseases
Department: Science & Technology
Keywords: RNA interference, RNAi, gene silencing, small interfering RNA

In 2001, the then-nascent field of RNA interference took a leap forward when scientists showed that the gene-silencing method worked in human cells, not just in lower organisms.

In RNAi, short pieces of double-stranded RNA guide complementary strands of messenger RNA to a protein complex known as RISC, the RNA-induced silencing complex. RISC cleaves the mRNA, preventing its translation into protein.

In earlier work, scientists had shown that gene-length strands of RNA shut down all protein synthesis in mammalian cells. Thomas Tuschl, then at the Max Planck Institute for Biophysical Chemistry, in Göttingen, Germany, and now at Rockefeller University, showed that scientists could instead use short, synthetic strands of RNA—called small interfering RNAs (siRNAs). These siRNAs allowed scientists to use RNAi in human and other mammalian cells.

“Since the demonstration in 2001 by Tuschl and colleagues that siRNAs trigger sequence-specific degradation of mRNAs with concomitant gene silencing, there has been an explosion of applications in basic studies and therapeutics,” says John J. Rossi, an RNAi expert at the Beckman Research Institute of City of Hope, a cancer center in Duarte, Calif. “At least a half-dozen biotech companies are actively developing siRNA therapeutics for diseases ranging from viral infections to hypercholesterolemia and cancer.”

But it hasn’t been all smooth sailing, Rossi notes. Unwanted immune responses and poor delivery have hampered development, he says.

Phillip D. Zamore, an RNA silencing expert at the University of Massachusetts Medical School, finds the most important RNA silencing advance in the past decade to be the “old-fashioned scientific discovery” of Piwi-interacting RNAs (piRNAs) made independently by Tuschl’s group and Gregory J. Hannon and coworkers at Cold Spring Harbor Lab in 2006. These short RNA sequences silence DNA sequences known as transposons, which can move around within the genome. The mechanism by which piRNAs work is not yet known, but they are clearly important because male mice that lack them are sterile.

 
Chemical & Engineering News
ISSN 0009-2347
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