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Tyler Jacks is inhibiting lung tumors in mice by introducing the microRNA called let-7.
RNA, a nucleic acid, is still best known for its role as a messenger, relaying instructions from the DNA of genes to the parts of the cell that make proteins. But its many other talents keep surprising researchers. MicroRNAs, for instance—short stretches of 21 to 22 nucleotides, compared with the thousands of nucleotides that contain the recipe for making a protein—come from parts of the genome once considered worthless.
When the human genome was sequenced, only a small fraction of it—the “coding” part—seemed important. The coding DNA is first transcribed into RNA and then translated into proteins. Yet this part makes up only 1.2 percent of the 3 billion nucleotides in our genome. The rest was sometimes called “junk DNA” because it didn't seem to do anything. As David P. Bartel, an HHMI investigator at the Massachusetts Institute of Technology (MIT) points out, however, “You know it's not junk if evolution has retained it.” In fact, “noncoding” DNA is beginning to look more like a gold mine—a source of many kinds of potent RNA, including forms such as microRNAs (and the different but structurally related small interfering RNAs) that help regulate gene activity.
MicroRNAs influence nearly all aspects of health and disease—the “stemness” of stem cells, cancer, early development, diabetes, viral infections, schizophrenia, heart disease, aging, and Alzheimer's disease, for example. Bartel calculates that more than half of human genes are regulated by microRNAs.
Cancer researchers in particular are excited by recently uncovered connections between microRNAs and major pathways of the disease. As many as 50 percent of all cancers involve a cellular pathway governed by the p53 gene, a tumor suppressor. When this gene is mutated and fails to produce normal protein, malignant cells can grow wildly. In 2007, five lab groups independently reported that a family of microRNAs called miR-34 sits in the middle of the p53 pathway.
One team, led by HHMI investigators Gregory J. Hannon and Scott W. Lowe at Cold Spring Harbor Laboratory in New York, found that when they switched on these microRNAs in mouse cells there was a rise in cell senescence (a kind of genetic death in which cells lose the ability to replicate—see “When Cells Grow Old”). Other teams showed that miR-34 could also promote apoptosis (cell death). Both of these responses protect the organism when a particular cell's DNA is damaged through environmental exposures. By contrast, when researchers decreased the activity of miR-34 microRNAs, cancerous cells survived and proliferated. The scientists hope that before long these microRNAs can be medically delivered to living animals in a safe and efficient manner, to disrupt cancer pathways. Their success could be a step toward preventing or treating the disease in humans.
Tyler Jacks, a cancer researcher and HHMI investigator at MIT, is also looking into the therapeutic potential of microRNAs—particularly those of the let-7 family, which are extremely scarce in cells from mice with lung tumors. To find out whether increasing these microRNAs would reduce the development of cancer, he turned to a mouse model of lung cancer. He had already used such a model in 2005 in a landmark study of the relationship between microRNAs and cancer. (Led by HHMI investigators Todd R. Golub at the Dana-Farber Cancer Institute in Boston and H. Robert Horvitz at MIT, the study showed that microRNAs are expressed at a much lower level in various tumor cells than in normal tissue, but it was not clear why.)
This time Jacks chose mice whose lung tumors looked like those of humans with advanced, non-small cell lung cancer. When researchers in his lab activated let-7 microRNAs that they had delivered into the animals' lungs, “this dramatically inhibited the tumors' development,” says Jacks. Unfortunately, the tumors later became resistant to the microRNAs. His group is trying to analyze why that happened.
Photo: Leah Fasten