Two of Horvitz's postdocs, Victor Ambros and Gary Ruvkun, continued analyses of these genes as they launched their own labs.

By 1993, Ambros had moved to Dartmouth College in Hanover, New Hampshire, where he cloned lin-4 and discovered that it encoded not a protein but a 22-base RNA. “The world did not jump up and take notice,” Horvitz recalls. “Nobody cared about tiny RNAs in an obscure nematode.” Ruvkun, at the Massachusetts General Hospital, analyzed the gene lin-14, which Ambros had shown to be genetically regulated by lin-4. The combined efforts of Ambros and Ruvkun led to the important discovery that lin-4 regulates the activity of lin-14 by “sticking” to the messenger RNA it produces and then preventing it from making its protein.

In 2000, Ruvkun discovered that let-7 also encodes a miRNA that acts by regulating the expression of other C. elegans genes, showing that lin-4 was not unique. In separate work, Ruvkun showed that this miRNA was broadly conserved across a wide variety of species, including humans. “Now,” Horvitz says, “the scientific world noticed.”

Once Ruvkun discovered the widespread nature of miRNAs, concerted work on them began. Scientists have now identified more than 200 miRNA genes in humans, and they predict there may be 250 or more.

“This was an experiment screaming to be done,” says Horvitz of the recent collaboration between his lab and Todd Golub's lab at the Dana-Farber Cancer Institute. “Biology said it was plausible that miRNA expression patterns and cancer are related, and modern techniques being used to categorize tumors were not sufficient. Looking at miRNA expression patterns in tumors was an obvious thing to do. Todd was nearby and one of the foremost leaders in fingerprinting tumors. He was expert with relevant techniques, and he had the tumor samples.” Golub's lab had shown how to classify tumors by using microarrays—a tool that analyzes the structure and function of tens of thousands of genes at a time—to determine the unique patterns of expression of all protein-coding genes.

The study opened up a new area of research for Golub. “Our lab hadn't been thinking about miRNAs at all prior to this project,” he admits. “No one would mistake us for being miRNA aficionados. But we have spent a lot of time thinking about the cancer genome in general and how one might learn something about cancer by taking global views of the genome of a cancer cell as opposed to studying the details of your favorite gene.”

A staff scientist in Golub's lab, Justin Lamb, was developing a technique for using color-coded plastic beads to profile protein-coding RNAs. The beads stick to specific RNAs in solution, giving researchers an improved tool to differentiate among thousands of tiny, genetically similar RNAs. Two members of Horvitz's lab, postdoc Eric Miska and graduate student Ezequiel Alvarez-Saavedra, had developed a microarray method for profiling miRNA expression patterns. Lamb and Miska were friends and talked about using the plastic beads for profiling miRNAs. Meanwhile, Horvitz contacted Golub about his long-held interest in the possible relationship between miRNAs and cancer and suggested profiling miRNAs in tumors. The two labs worked together, with Golub's postdoc Jun Lu taking the lead to adapt the beads for miRNAs, and the study began.

The plastic bead technique helped them to “define the landscape of miRNA expression over many different cancers,” Golub says, and to distinguish different kinds of cancers and classify normal versus cancer cells. Perhaps most important, the researchers were able to group tumors according to the developmental origin of the tumor's cells. Here was at least the suggestion, as the researchers wrote in their paper, that “miRNA expression patterns encode the developmental history of human cancers.” Golub credits the contributions to the work of several postdocs and staff scientists in both labs—especially Jun Lu, Gad Getz, Eric A. Miska, and Justin Lamb.

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