The complete sequence of the human genome, with its promise of new insights into disease and a host of novel drug targets, was announced to great fanfare in 2003. But a quieter genetic revolution began a full decade earlier, when Dartmouth College scientists studying the microscopic worm C. elegans discovered the first of the powerful genetic switches now known as microRNAs.
It’s Biology 101 that genes in DNA are transcribed into long strands of messenger RNA that carry the genes’ instructions to the protein-making machinery of the cell. But lin-4, the microRNA found at Dartmouth, rewrote the rules. For starters, lin-4 is only 22 genetic letters long, far shorter than a typical 1,000-letter RNA message—hence the “micro.” But more significantly, lin-4 doesn’t help to build proteins. Instead, it sticks to messenger RNA and jams up the works, shutting down the expression of a large assemblage of genes involved in early development and allowing C. elegans larvae to progress toward adulthood.
It would be seven years before South African-born Frank Slack, Ph.D., showed that lin-4 was no fluke. In 2000, while a postdoctoral fellow at Harvard Medical School, Slack, now associate professor of molecular, cellular and developmental biology at Yale, identified a second microRNA, let-7, that also governs development in C. elegans .
Then the floodgates opened. In a series of discoveries that are remarkable even in the dizzyingly fast-paced world of molecular biology, it has been demonstrated over the past five years that hundreds of gene-silencing microRNAs are at work in plants and in numerous animals, including over 200 in humans that may regulate more than a third of our genes. Because half the C. elegans genome matches our own, including the gene for let-7, Slack’s research is having an impact on our understanding of human development, aging and illness, especially cancer.
According to Slack, one of the primary roles of microRNAs is to put a brake on cell proliferation during development. “Initially in the human embryo, you’ve got cells just dividing, dividing, dividing—to make as many cells as possible,” he says. “But at some point you want to make an organ. MicroRNAs come on to tell cells to stop dividing and to start differentiating into organs. And they stay on all through life, to keep the cells from dividing again.” Slack believes that the uncontrolled cell division that is a hallmark of cancer might be caused when the check on cell growth imposed by microRNAs is somehow lifted. “In various cancers we’ve looked at, microRNAs have been shut off,” he says. “We think that causes cells to re-enter their cell division program and behave like they’re in the embryo.”
In a 2005 paper in the journal Cell, Slack showed that let-7 is tamped down in human tumors, which unleashes Ras, a cell-proliferation gene that has long been implicated in cancers of the lung and pancreas. “Frank is doing wonderful science relating gene regulation by micro-RNAs to control of cell growth,” says Philip A. Sharp, Ph.D., a Nobel Prize-winning expert on RNA gene silencing at the Massachusetts Institute of Technology. “His finding that the Ras gene is regulated by let-7 was one of the first indications that changes in the levels of small RNAs could be critical in cancer.”
Slack is now collaborating with Assistant Professor of Therapeutic Radiology and Yale Cancer Center researcher Joanne B. Weidhaas, M.D., Ph.D., to develop microRNA-based diagnostic tools and treatments. Weidhaas says that genomic analyses of tumors and cancer therapies that target single genes have been disappointing because hundreds of genes are faulty in any given cancer and it has been difficult to discern which mutations are most important. The excitement surrounding microRNAs, she says, stems from their ability to regulate entire suites of genes that underlie biological pathways.
A 2005 study in the journal Nature found that measuring the levels of just 217 microRNAs could generate clearer genetic signatures for tumors than 16,000 probes for messenger RNA. Encouraged by these results, Slack and Weidhaas hope within two years to perfect a microRNA-based screening device that could help tailor cancer treatments to patients’ tumor types, and they are in the early stages of testing a let-7 inhalant therapy to rein in uncontrolled cell growth in lung cancer.
In addition, Weidhaas has shown that raising let-7 levels in C. elegans makes the worm’s cells more sensitive to radiation, leading her to conclude that a let-7 treatment could be a powerful adjunct to standard radiotherapy. “Some tumors are simply tougher than normal tissue when we treat them with radiation,” Weidhaas says. “If we could make cancer cells more sensitive than normal cells, or even bring them up to the same level, we’d have an enormous advantage.”
When he discovered let-7, Slack says, he could not have imagined that microRNAs, completely unknown to biologists only 15 years ago, could come so far so fast. “I’ve been at it from the ground floor,” he says, “and it’s been a fun ride.”