Many drugs try to deactivate disease-causing proteins. For example, scientists have engineered small molecules that bind to the active part of a cancer-causing protein and disable it. But only a relatively small number of proteins, probably no more than a few thousand, are treatable by these “small molecule” drugs. Other proteins tend to be inaccessible, with chemical structures not easily targeted. In contrast, with RNAi it’s theoretically possible to design a drug that could turn off any of the 30,000 or so human genes—each of which normally codes for a different protein. “RNAi opens up the possibility that the whole universe of genes becomes ‘druggable,’” says Harvard Medical School’s Lieberman.

There’s another potential advantage. Because many drugs are designed to knock out or alter a particular protein, researchers have to consider the target’s physical structure and model a drug that fits it perfectly. Even then, there’s a chance the drug could react with other, similar proteins. With RNAi, protein targeting becomes both simpler and more precise. Suppose a researcher wants to eliminate production of a protein associated with a particular gene. He could systematically test 21-nucleotide sections of that gene with corresponding dsRNA until he finds one that effectively silences the gene. “This gives you a ready-made drug,” says John J. Rossi of the Beckman Research Institute in Duarte, Calif. “It’s very easy to design siRNA for virtually any gene of interest. And with the whole genome now sequenced, we can identify a target instantaneously.”

A final advantage is that rather than attacking a problem protein, RNAi addresses disease at a fundamental level, turning off the gene that codes for production of that protein. “With RNAi, you’re preventing the protein from even being made, versus trying to mop up the protein’s activity,” says Akshay Vaishnaw, vice president of clinical research at Alnylam.

In 2002 Lieberman began a study attempting to cure HIV in a petri dish of human cells. First, she targeted a protein called CD4, a receptor on the outer membrane of human immune cells, to which the HIV virus attaches itself and into which it inserts its genetic material. Lieberman used siRNA to silence the gene that coded for CD4 and found that without CD4 receptors to bind to, the HIV virus was four times less able to enter a cell. This could halt the spread of the virus.

Next, Lieberman tried a different tack, targeting the virus itself. Using RNAi, she turned off a pivotal HIV gene, called gag, that codes for proteins essential to the virus’s structure. She found that this sharply reduced the amount of HIV in the cells, apparently because new copies of the virus could not be made without the gag gene. Finally, to see whether siRNA could treat infection as well as prevent it, she infected the cells with HIV and then dosed them with siRNA. That worked too.

But treating cells in a petri dish is a far cry from achieving the effect in humans. To see what was possible in a living creature, Lieberman moved on to mice. Because overabundance of a protein called Fas is often involved in liver disease, she designed siRNA for the gene that makes that protein and was able to protect mice with hepatitis from liver failure—the first time siRNA had alleviated disease in an animal.