The results were tantalizing—after all, it is not every day that a new class of genes is discovered—but it wasn't clear what role these miniature genes might play in people's lives.
That's when Carlo Croce and George Calin decided to take a fresh look at the mysterious case of the missing leukemia gene. Calin, who is now a molecular biologist at the University of Texas MD Anderson Cancer Center, typed the known microRNA gene sequences into his computer, comparing them with the stretch of DNA that many CLL patients' cancer cells lack. "They were exactly there," he recalls: two microRNA genes sat right where the CLL-suppressing gene was presumed to be.
Calin called Croce into the lab right away: "Dr. Croce, these are the genes!"
Croce looked at Calin and blinked. "S---!," Calin recalls him saying. "These are the genes!'"
Calin and Croce tested blood samples from leukemia patients and found that 68 percent contained little or none of the two microRNAs, while blood cells from people without the cancer had many of the molecules. Calin and Croce were convinced: these two tiny genes made microRNAs that suppressed cancer.
"I was stunned," says Croce. "We had the dogma that all the cancer genes were protein-coding genes," says Croce. MicroRNA "explained a lot that we couldn't explain before. It changed the way we looked at the problem."
Calin and Croce published their finding in 2002—the first time anyone had implicated microRNAs in human disease.
Since then, "every cancer we look at, we find an alteration in microRNA," says Croce. "In probably every human tumor there are alterations in microRNA."
Croce lives in a stately mansion in Columbus' Upper Arlington suburb. Mounds of mail are scattered on the kitchen table when we arrive. Croce has been away from home for weeks, attending conferences and giving talks at the National Institutes of Health in Bethesda, Maryland, the National Academy of Sciences in Washington, D.C., a cancer meeting in San Diego, Johns Hopkins University in Baltimore and three meetings in Italy. The house feels empty and unused.
"Essentially, it's just for sleeping," Croce's son, Roberto, 29, says later about his father's house. "He mostly just parks his possessions there. If he's in town, he's at work, or he hangs out with me." Roberto is working toward a PhD in economics at Ohio State. (Carlo, who has never married, also has a 12-year-old daughter who lives in Buenos Aires.)