While growing up on a small farm in Vermont during the 1950s and 1960s, Victor Ambros became intrigued by biographies about scientists and inventors. “I remember in particular reading about Clyde Tombaugh, who discovered Pluto,” Ambros recalls. “He was a farm boy who took up amateur astronomy and ended up becoming a professional astronomer. I really identified with that as a boy, and I became enthralled with the idea of trying to join that tradition and be a scientist.”
Encouraged in his scientific interests by his parents (who bought him, for example, the equipment to build an amateur telescope as well as a subscription to the Time-Life “Library of Science” book series), Ambros set off after high school for the Massachusetts Institute of Technology (MIT), where he received both a bachelor of science and a PhD in biology. During that time Ambros was graduate research assistant to biologist and Nobel laureate David Baltimore, where he studied the molecular properties of the poliovirus.
In 1979, Ambros took a postdoctoral position in the MIT lab of biologist (and future Gruber and Nobel laureate) H. Robert Horvitz. “Bob was using [a nematode worm called Caenorhabditis elegans] as a genetic model to study development, and I just got really captivated by the potential of finding out new things about developing animals using a really simple animal,” Ambros recalls.
In Horvitz’s lab, Ambros studied two genes, lin-4 and lin-14, which had opposite effects on developmental timing: Mutations of lin-4 caused developing larvae to repeat early developmental stages, whereas mutations of lin-14 caused larvae to skip those early stages and mature prematurely."This suggested that the two mutated genes had opposite effects in the developing worm’s cells. Further research, done in conjunction with Gary Ruvkun, who joined Horvitz’s lab as a postdoctoral fellow in 1982, revealed that lin-4 represses lin-14, but the molecular mechanisms behind that activity remained a mystery.
In 1984, Ambros took a faculty position at Harvard University, and in 1992, he moved to Dartmouth College. At both places, he continued his work on lin-4, which included successfully isolating and cloning the gene. Ambros expected that the product of the gene would be a standard regulatory protein, but much to his surprise, it instead turned out to be a tiny non-protein-coding strand of RNA only about 22 nucleotides (nt) long. This was a seminal moment in molecular biology, for it marked the first discovery of a microRNA, although the term would not be coined for almost a decade.
Meanwhile, Ruvkun, now in his own lab at Harvard, had identified the specific area of the lin-14 gene that lin-4 targets: a section known as the 3' untranslated region (3' UTR). One evening, Ambros and Ruvkun, who still communicated regularly with each other, decided to compare the lin-4 and lin-14 sequences. They discovered, much to their amazement, that the 22-nucleotide lin-4 RNA and the 3' UTR were partially complementary, which suggested that lin-4 was regulating lin-14 by binding to these sequences. In addition, the matching sequences were on evolutionarily conserved areas of the genes, “so we instantly knew it was real,” says Ambros. “That was what was really cool about it.”
In 1993, Ambros and his lab colleagues, Rhonda Feinbaum and Rosalind Lee (Ambros’ wife since 1976), published in the journal Cell their discovery that the regulatory product of lin-4 was a tiny strand of RNA. In the same issue, Ruvkun described how lin-4 was regulated by lin-14. They had successfully identified the mechanism that kept C. elegans larvae with the lin-4 mutation from fully developing. At the time, though, most researchers—including Ambros—suspected that this process was restricted to C. elegans, as it was the only organism with lin-4 in its genetic makeup. But then, in 1999, British plant biologist David Baulcombe reported, for the first time, that a similar class of RNAs demonstrating a related silencing process existed in plants. A year later, Ambros’s lab discovered that lin-4 regulated a second gene in C. elegans, lin-28—a finding that suggested that microRNA might be functioning throughout the C. elegans genome. Then, in 2000, Ruvkun announced the discovery of a second microRNA—let-7—in C. elegans. He also demonstrated that let-7, unlike let-4, was evolutionarily conserved across the animal kingdom. It was now clear that microRNAs were not just a peculiarity of C. elegans.
“When I read that paper, I got a jolt,” recalls Ambros. “I thought, ‘Oh, my god. There must be many more of these small RNAs. It was one of those moments when you know your life is changing.”
In the ensuing years, Ambros has continued his research on microRNA function and gene regulation during development. He has received numerous honors and awards for his scientific achievements, including memberships in the National Academy of Sciences and the American Academy of Arts and Sciences. Since 2008, he has been at the University of Massachusetts Medical School, where he is the Silverman Professor of Natural Science and co-director of the RNA Therapeutic Institute. The enthusiasm Ambros developed for science when he was growing up on his family’s Vermont farm has never left him. Every day in his lab is an “adventure,” he says. “When I was a kid, I wanted to belong to something important, and I feel I’m incredibly lucky to have been able to do that,” he adds.
Ambros lives in the Worcester Massachusetts area with his wife and long-time collaborator, Rosalind Lee. They have three grown sons.