PAGE 3 OF 6
David Bartel calculates that more than half of human genes are regulated by microRNAs.
Other researchers want to use microRNAs as early markers of cancer. Muneesh Tewari and his colleagues at the Fred Hutchinson Cancer Research Center in Seattle showed that microRNAs are present in samples of plasma and serum “in a remarkably stable form.” Thus, it may be possible to monitor tumor-derived microRNAs, which are present in different amounts in healthy individuals and cancer patients, the group reported in the July 29, 2008, issue of Proceedings of the National Academy of Sciences.
Most promising, perhaps, are recent findings that raise the possibility of stopping a cancer's metastasis—the spread to other organs, which ultimately kills the patient. Last year, HHMI investigator Joan Massagué and colleagues at Memorial Sloan-Kettering Cancer Center identified two microRNAs (miR-126 and miR-335) that were missing in the most aggressive mouse and human breast tumors. When they delivered these critical microRNAs to the breast cancer cells, the tumors lost the ability to spread. And on December 12, 2008, Arul M. Chinnaiyan, an HHMI investigator at the University of Michigan Medical School, reported in Science that his team had discovered that a microRNA called miR-101 must be active to prevent the spread of prostate cancer. When this microRNA is lost, an enzyme called EZH2 that promotes the spread of cancer cells springs into action.
Thus, “for treatment purposes,” Chinnaiyan says, “replacing miR-101 in solid tumors that have lost it could reduce their metastatic properties.” This procedure might apply not only to prostate cancer but also to breast, ovarian, and colon cancers as well as to certain forms of brain and lung cancers and leukemia. “The problem is the delivery issue,” he says. “Several drug companies are now working on ways to put specific microRNAs into ailing cells while avoiding healthy cells, where [the agents] might produce some damage.”
Many other diseases besides cancer have been linked to microRNAs. For example, at the Gladstone Institute of the University of California, San Francisco, Deepak Srivastava produced genetically engineered mice that lacked miR-1-2, a microRNA normally found in the animals' heart cells. These mutants produced offspring with life-threatening holes in their hearts or fatal disruptions in their cardiac rhythms. Srivastava found that other microRNAs were deficient in mice with cardiac hypertrophy, a condition that can lead to heart failure.
In diabetes, however, scientists see the opposite problem: an overabundance of microRNAs. The goal in that case is to silence the microRNAs involved. For instance, researcher Markus Stoffel of the Swiss Federal Institute of Technology in Zurich is collaborating with an American drug company, Alnylam Pharmaceuticals, to develop what they call “antagomirs”—small fragments of RNA that can travel through the body and reduce the expression of certain microRNAs in specific organs. (HHMI investigators Phillip D. Zamore and Thomas Tuschl invented antagomirs in 2004. Zamore, Tuschl, and Bartel are among the founders of Alnylam.)
No one realized that microRNAs would be so important when the first one was discovered, in 1993, in the microscopic worm Caenorhabditis elegans. Since his time as a postdoctoral fellow in Horvitz's MIT lab, Victor Ambros had been trying to determine how the mutant gene lin-4 made worms develop abnormally. The gene controlled developmental timing, Ambros (now on the faculty of the University of Massachusetts Medical School) and Horvitz concluded. When lin-4's function was missing, this timing was off and cells that were supposed to behave as if they belonged to older larvae got stuck at an earlier stage, repeating cell-fate programs that they should have expressed only once.
Photo: Robert E. Klein / AP, ©HHMI