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Conventional wisdom held that only a huge stretch of DNA could function as a gene. The discovery of an overlooked genetic entity upends that view. Croce "was stunned." (Greg Ruffing / Redux)

High Hopes for a New Kind of Gene

Scientists believe that microRNA may lead to breakthroughs in diagnosing and treating cancer

Inside the house, art, not science, takes center stage. Croce owns more than 400 paintings by 16th- to 18th-century Italian masters. He built a cavernous 5,000-square-foot wing—21-foot ceilings and all—to display some of the largest paintings.

Croce says he bought his first painting when he was 12 years old, for $100. He likes to buy paintings when he has a suspicion about who the artist is but doesn't know for sure. "I never ask someone," he says. "I just buy it and then I may be wrong or I may be right." He bought one painting for $11,500 from a gallery in Naples. He thought it might be by a Baroque painter named Bartolomeo Schedoni. "I made a picture after it was restored, and sent it to the expert on Schedoni. He said, 'Oh yeah, that is the Schedoni.'" The painting, Croce says, is probably worth 100 times what he paid for it.

"His art collecting has the same experimental bent that his science has," says Peter Vogt, a cancer researcher at the Scripps Research Institute in La Jolla and a friend of Croce's.

Over the years, Croce has patented several discoveries and co-founded three companies. His lab at Ohio State is on the top two floors of a ten-story building. With a staff of about 50 people, the lab has a budget of about $5 million a year, which is on par with a small biotechnology company. His funding comes from federal and private grants.

"There are a lot of people who would say he is entirely successful because he has a huge amount of resources. I actually think it's the other way around; I think he has huge amounts of resources because he is successful," Cavenee says.

As soon as Croce suspected a connection between microRNAs and cancer, he started asking questions: Would cancer cells have different amounts of microRNAs than normal cells have? Would some microRNAs be more common than others in certain types of cancer? "He was really the first person to make that leap," says Slack about Croce's early bet on microRNAs. "It took somebody with Carlos' vision and money to really move the field forward."

In 2003, Croce recruited Chang-Gong Liu, then a microchip developer at Motorola, to design a tool that can test for the presence of microRNAs in a sample of cells or tissues. Using the tool, called a microarray, Croce's laboratory has found microRNAs that seem to be unique to certain types of cancers. For the 3 to 5 percent of patients whose cancer has metastasized, or spread, from an unknown source within the body, the implications of this finding are huge. Because knowing where the cancer began is a key to optimal treatment—tumors arising in different tissues respond to different approaches—microRNAs may be able to help oncologists prescribe the best treatments for such patients.

MicroRNAs may also be able to estimate a cancer's severity. Croce and his collaborators found that the levels of two microRNAs—called Let-7 and mir-155—predicted survival in lung cancer patients. Croce's group has also found microRNAs that predict whether a patient's CLL will become aggressive or stay mild. In the future, a patient's microRNA profile might indicate whether he or she should undergo an aggressive and risky treatment or a milder, safer one.

Today, researchers have identified about 40 microRNA genes associated with cancers, including those of the breast, lung, pancreas and colon. Like conventional genes that produce proteins, microRNA genes can also be cancer promoters, causing the disease if they produce too many microRNAs. Or they can be cancer suppressors; if they are damaged or lost, cancer ensues. Moreover, scientists have begun to understand how microRNAs interact with traditional cancer genes, revealing a complex switchboard of connections that seem to happen inside cells as the disease takes over.

Croce's biggest hope is that microRNAs might one day be used as therapies. "I am convinced, absolutely convinced," he says, "that microRNAs will become drugs." In some recent experiments, he and a colleague have injected microRNAs into mice with leukemia or lung cancer. The injections, he says, stopped the cancer growth.

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