Nobel breakthrough launched a race for genetic cures

University of Massachusetts Medical School researcher Craig C. Mello shared the Nobel Prize in medicine last week for discovering a way to turn off individual genes -- a finding that has transformed the field of biology.

Mello and his colleague, Andrew Z. Fire of Stanford University, found in 1998 that a special kind of double-stranded molecule called RNA could be used to shut off genes in the microscopic roundworm C. elegans.

Since then the technique -- called ``RNA interference" or gene silencing -- has opened the doors to new therapies and given scientists unprecedented insight into basic gene function in all living beings, from primitive organisms to people.

Biotech companies are racing to develop drugs that will shut off errant genes to treat diseases. Researchers are using the technique to find genes that are crucial for organisms to wreak havoc. Scientists are examining the role that RNA interference plays in normal cells as a kind of thermostat that regulates the genetic climate.

Globe reporter Carolyn Y. Johnson spoke with Mello late last week.

Q: What's next for your research?

We're still trying to understand the mechanism of RNA [interference] . . . identifying the genes and the proteins that function in the process.

A: We're digging deep into the mechanism, and we still feel like the little worm has a lot to teach us.

Q: Did you have any inkling when you and Andrew Fire published the 1998 paper in Nature that you had discovered something that was so fundamental to biology that it would change things so rapidly?

A: No, we didn't. . . . We were like: This is cool stuff. Will it be applicable in other systems? We didn't know yet whether it was going to be universal.

It became clear [later] when we cloned the first gene that we identified as required for the silencing effect and found that in fact that gene [has an equivalent in human cells] . . . that was when for me I started thinking, ``Wow."

Q: What do you think are the most promising applications of RNA interference?

A: There are a lot of diseases that are good candidates. . . . Probably the best targets are those where RNA can be delivered directly into the tissue. . . . Our company that we're starting will focus on ALS [a neurodegenerative disease]. . . . It's a devastating disease, and this is the kind of disease I'm most passionate about trying to attack because it's fatal, and there really aren't drugs that cure it.

Q: Is there anyone else whose work was a major factor in the discovery and, perhaps, should have shared the prize?

A: The problem with this particular area is if you take one more step out and give the prize to three people, then there's a real argument it should really be six people or eight people. . . . It's possible there'll be further prizes down the road for understanding additional aspects of the mechanism. . . .

I wouldn't be surprised if there's a prize that focuses on the discovery of the small RNA molecules themselves [that trigger silencing in mammal cells and were discovered later]. I think that needs to be looked at carefully as a potential prize.

I think this is a first step in the process. . . . We had a part of the puzzle.

Q: >Why have you stayed at UMass, an underfunded public university, and are you going to stay there now?

A: Absolutely. UMass is up and coming, and I think the cost of doing research here is so much lower than in the Boston area. I'm not sure what it works out to per square foot, but it's quite significant -- the cost of space is lower, the cost of living for employees. . . . As a colleague here at UMass, I think my voice is heard and listened to a lot more than if I was another small cog in a big wheel. I feel like I can help plan and grow this institution.

Q: What drew you to work on the genetics of a microscopic roundworm?

A: What fascinated me in high school was the fact that you could do what we call cloning now in biology -- that's when you take a piece of DNA from one organism and put it into bacteria or another organism. I was fascinated by that whole kind of technology from the very beginning. . . .