2 U.S. Scientists Share Nobel

In experiments on millimeter-long worms, Mello and Fire found that injections of paired strands of RNA -- which they included as "controls" because pairs would be expected to cancel each other out and have no effect -- inhibited genes far more efficiently than single strands of antisense RNA.

That made no sense, said Thomas R. Cech, who won a Nobel prize in 1989 for his work on RNA and is now president of the Howard Hughes Medical Institute, which funds Mello's work.

" 'Who mixed up these tubes, anyway?' That must have been what they were saying," Cech said. "The whole thing was so damned surprising."

Further experiments revealed that cells of virtually all organisms are endowed with a mechanism that detects double-stranded RNA and breaks it into little pieces. At first it was probably a way of defending against viruses, most of which use RNA rather than DNA as their genetic material.

Later, it appears, evolution helped organisms use elements of that system to turn off their own genes. The system involves the production of "short interfering RNAs" and "microRNAs," short pieces of RNA that can attach to messenger RNA, thus making double-stranded RNA.

Some of the RNAs interact with one or both of a pair of proteins -- dubbed "dicer" and "slicer" by scientists who apparently spent too much time watching late-night advertisements for food processors. From there, a chain reaction of events ends up destroying the targeted messenger RNA and snuffing that gene's impact on the body.

Several companies have begun to design therapies that take advantage of RNAi.

Acuity Pharmaceuticals of Philadelphia has completed phase two efficacy studies of an RNAi that shuts down a gene responsible for new blood vessel growth. Injected into the eyes of patients with age-related macular degeneration (AMD), a common cause of blindness in older adults, it blocked the overgrowth of blood vessels that is the cause of that disease.

Sirna Therapeutics Inc. of San Francisco has completed safety studies for AMD and is developing RNAi against hepatitis C virus. And Alnylam Pharmaceuticals of Cambridge, Mass., has been testing an RNAi against respiratory syncytial virus, which is especially deadly in infants.

The approach is not without challenges, though. Interfering RNA molecules are about 50 times the size of conventional drug molecules, posing difficulties getting them to where they are needed in the body. Some have also proven toxic in animal tests.