Two Americans win Nobel Prize for silencing problem genes

NEW YORK — The phone call came at 4:40 in the morning at Craig Mello's home in Massachusetts. It was from Stockholm, telling him he'd won the Nobel Prize.

But Mello was already awake. He'd been checking the blood sugar of his 6-year-old daughter, Victoria. She has diabetes — one of the many diseases that Mello's work may someday help to treat.

The 45-year-old professor at the University of Massachusetts Medical School in Worcester, and Andrew Fire, 47, a professor at Stanford University, will share the $1.4 million prize in physiology or medicine for discovering a process that can silence specific genes.

Called RNA interference, it occurs in plants, animals and people. It's important for regulating gene activity and helping to defend against viruses.

Since Fire and Mello published their groundbreaking research in 1998, scientists have made "RNAi" their own tool. It's now a standard lab procedure for studying what genes do.

And researchers are using it to try to develop treatments for a long list of diseases beyond diabetes, including AIDS, cancer, heart disease, asthma, cystic fibrosis, influenza, Parkinson's and Huntington's diseases, and age-related macular degeneration, a major cause of blindness.

"This has been such a revolution in biomedicine, everybody is using it," said Thomas Cech, president of the Howard Hughes Medical Institute, for which Mello is an investigator.

"It's so important that people almost take it for granted already, even though it was discovered fairly recently," said Cech, who won a Nobel in 1989 for RNA research.

Nobel prizes are generally awarded decades after the work that they honor, so a prize now for a finding published just eight years ago is striking.

But it's appropriate, said Bruce Stillman, president of the Cold Spring Harbor Laboratory in Cold Spring Harbor, N.Y., because the work "is recognized now as one of the really revolutionary changes in the way we think about how genes are controlled."

Genes are stretches of DNA, each one bearing a molecular code that directs the production of a particular protein such as a hormone or enzyme. But for a gene to make a protein, it must work through an intermediary molecule called messenger RNA, which directs the protein-making machinery of a cell.

In RNA interference, certain molecules trigger the destruction or inactivation of the messenger RNA from a particular gene, so that no protein is produced. Thus the gene is effectively silenced.

For instance, researchers have shown they can lower cholesterol levels in lab animals by suppressing a gene through RNA interference.

Could this ability to block disease-causing genes produce new treatments?

"In principle it works. In controlled laboratory conditions it works," Cech said. "And the next five years will tell whether this is a whole new class of pharmaceuticals with the potential to defeat numerous human diseases."

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

Acuity Pharmaceuticals of Philadelphia has completed 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, it blocked the overgrowth of blood vessels that is the cause of that disease.

Sirna Therapeutics of San Francisco has completed safety studies for macular degeneration and is developing RNAi against the hepatitis C virus.

And Alnylam Pharmaceuticals of Cambridge, Mass., has been testing an RNAi against the respiratory syncytial virus, which is especially deadly in infants.

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

Mello, who is still working on RNA interference, said his daughter's diabetes is a driving force, although he had started his research before she was born.

Fire said the award showed the importance of publicly funding basic research that doesn't appear to have any near-term payoff.

Fire, who was working for the Washington, D.C.-based Carnegie Institution at the time of the discovery, and Mello did their groundbreaking experiment in a tiny worm called C. elegans. They found they could block the effect of a specific gene by injecting worms with a particular double-stranded version of RNA. Usually RNA — ribonucleic acid — has one strand.

"That was the breakthrough that set the whole field on fire, no pun intended," Cech said.

While scientists had already known that RNA played a role in gene silencing, they didn't understand the process. The prize-winning research "was like opening the blinds in the morning," said Erna Miller, a member of the Nobel committee. "Suddenly you can see everything clearly."

Monday's prize was the first Nobel of this year, to be followed by the awards for physics, chemistry, literature, peace and economics.