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Flipping the genetic switch

Secret found in genes of petunias and worms has potential to turn off human disease

When the human genome was sequenced two years ago, researchers held the blueprint of a human being in their hands -- a nonsensical string of 3 billion DNA letters. But the project's promise of curing disease and explaining the workings of the human body would depend in part on a curious phenomenon first observed in microscopic worms and in petunias -- cells' natural ability to ''turn off" genes.

Over the past few years, scientists have turned the once-puzzling research result into a powerful tool now poised to bridge the gap between the genome project and the medicine cabinet.

The tool, called RNA interference, or RNAi, is ubiquitous in biology laboratories, and in the span of just a few years has leapt from the journal Science's list of top-10 basic science breakthroughs in 2002 and 2003 literally into the eyes of its first patients.

''It's a transforming technology. You can't do a [genetic] experiment without doing RNAi," said Dr. William Hahn, an associate professor at Harvard Medical School who uses the tool to study the genetics of cancer.

RNA interference, often called ''gene silencing," is like a genetic dimmer switch, a natural mechanism that allows a cell to regulate its genetic climate, turning one gene up during a crucial part of development, or turning another down, as a defense against mutations. Researchers are now harnessing the mechanism with the hope of crafting drugs that will turn off the genes essential for diseases like HIV, cancer, or influenza.

RNA carries instructions for making proteins from the DNA in the nucleus to the outer reaches of the cell. There the RNA churns out proteins that give rise to basic traits such as green eyes and blond hair, and lead to disease.

Scientists once thought if they inserted a gene, for example, for purple, they could turn a flower more purple. Instead, in 1990, they discovered that inserting the ''purple" gene actually made the flower more white -- they had accidentally watched RNAi at work, but didn't yet know what it was. Later that decade, another group stumbled across the same effect in a microscopic roundworm.

''We observed this bizarre silencing effect. It was like the organism was fighting back and didn't want to express the gene we were putting in," said Craig Mello, a cell biologist at the University of Massachusetts Medical School who saw the worms reject the gene. He later found that he could trigger the effect by adding a special kind of double-stranded RNA to the worms.

But it was the discovery in 2001 that this RNAi mechanism worked in human cells, and could be studied in a test tube, that began to transform the landscape of biology.

In March, a group of researchers and private companies began collaborating in the public-private RNAi Consortium, an $18 million joint effort to write an RNAi recipe book, instructing scientists how to quickly and efficiently turn off 15,000 human genes to speed up drug discovery.

''We can create a set of tools that allows us to do high-level genetics in human cells in a way we've never done before," said Hahn, a co-investigator in the consortium, which includes Harvard, MIT, the Dana-Farber Cancer Institute, and international biotechnology companies, among others.

Using RNAi technology, scientists can do rapid, accurate genome-wide screens one gene at a time -- which just wasn't possible a few years ago. In labs, researchers are now systematically shutting off each gene in humans and other species, allowing them to zero in on a possible genetic Achilles' heel for HIV, Alzheimer's, and dozens of other devastating diseases.

Since RNAi is shared by all flora and fauna, scientists believe that once they make this work in a petri dish or a mouse, it's only a matter of time until an RNAi drug will do the same thing in a person.

The first clinical trials of such drugs are in progress, testing whether RNAi is safe and could work in humans. Sirna Therapeutics, a pharmaceutical company based in Boulder, Colo., is testing a drug that uses tiny strands of RNA to shut down genes that trigger macular degeneration, an age-related disease that causes blindness. This month, the company presented the interim results of the first stages of a clinical trial: In the 14 patients tested, the drug appeared effective and safe after a maximum of 157 days of followup.

Many more treatments are in the works: Alnylam, a Cambridge-based pharmaceutical company, is planning to launch a macular degeneration trial by the end of this year and is also gearing up to fight a respiratory virus by early 2006. In the next few weeks, Los Angeles-based CytRx plans to begin a clinical trial of an RNAi drug to treat Lou Gehrig's disease, a fatal disease that causes a progressive loss of motor control. Sirna is partnering with Massachusetts General Hospital to find an RNAi therapy to combat hearing loss.

The market for such therapies could grow to nearly $6 billion within the next decade, according to a study by Research and Markets, an Irish marketing firm.

''There are so many doors open right now, you can't even begin to do all the research," said Mello, who, like many leaders in the field, is still fleshing out exactly how RNAi works, and why.

The road to RNAi therapies could be long: All gene therapy carries unknown risks, RNAi is notoriously difficult to package into a safe and effective drug, and since many of the diseases being targeted are chronic or incurable -- like Huntington's or HIV -- the drugs will need to be proven safe over months, years, or even a whole lifetime before they reach the market.

But RNAi is already being used in conventional drug development to locate new targets for medications.

Most scientists who work in yeast, bacteria, and fruit flies are used to waiting decades if not longer for their findings to have an impact on people. RNAi has given their work new immediacy.

Before, ''we had a bizarre and pretty cool phenomenon" in a worm, Mello said. Now, scientists have realized it's an essential biological process essential to all cells. ''This is really why RNAi is totally, mind-bogglingly cool: Only a few years ago, we didn't know it existed."

Carolyn Y. Johnson can be reached at cjohnson@globe.com.

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