Victor R. Ambros, PhD

Silverman Professor of Natural Sciences
Program in Molecular Medicine
University of Massachusetts Medical School

“From nearly dead to gold rush” is how Victor R. Ambros, PhD, describes the remarkable journey of microRNA research since its discovery in his lab 16 years ago. Since then, microRNAs—short, single-stranded RNA molecules that regulate gene expression—have come a long way from being regarded as little more than a scientific curiosity to our current understanding of their critical role in animal development and future therapeutic applications for human disease. Building on his discovery, Ambros has devoted his research career to studying the genetic regulatory mechanisms that control developmental timing in the Caenorhabditis elegans animal model.

Ambros was born in New Hampshire and grew up in Vermont. He completed his bachelor’s degree and PhD in biology at the Massachusetts Institute of Technology, studying poliovirus genome structure and replication as a graduate student in the lab of Nobel laureate David Baltimore. Continuing at MIT as a postdoctoral fellow in the lab of future Nobel laureate H. Robert Horvitz, PhD, Ambros began work on the genetic pathways that ensure proper timing of developmental events in C. elegans. In 1984, Ambros joined the faculty at Harvard University, moved to Dartmouth College in 1992, and was recruited to the University of Massachusetts Medical School in 2008. He currently holds the title of Silverman Professor of Natural Sciences in the Program in Molecular Medicine.

The story of microRNA has humble beginnings. In 1993, while still at Harvard, Ambros and his colleagues cloned the gene sequence for lin-4, a novel repressor of lin-14, both of which are heterochronic loci in C. elegans. It was expected that lin-4 would encode for a conventional regulatory protein. Much to the researchers’ surprise, however, the lin-4 gene product turned out not to be a protein but, rather, a short, 22-nucleotide, non-coding strand of RNA sharing partial sequence complementarity with lin-14. In a now-landmark 1993 study, Ambros and long-time collaborator Gary Ruvkun, PhD, published back-to-back papers in Cell reporting that this new “small antisense” lin-4 RNA was capable of downregulating gene expression by binding directly to lin-14 messenger RNA.

At the time, the discovery of this first microRNA went barely noticed by the scientific community. For the next seven years, despite exhaustive screening efforts by researchers in Ambros’s lab to identify other small RNA gene products like lin-4 in close relatives of C. elegans, none were found. It seemed that the RNA-RNA interaction of lin-4 and lin-14 was, at best, an intriguing phenomenon isolated to the worm world.

Beginning in 2000, a series of startling discoveries by Ambros and others rescued microRNA from languishing in the archives of worm biology. First, Ambros found that lin-4 regulated not only lin-14 but also lin-28, suggesting that microRNA functioned at multiple sites across the C. elegans genome. Then, botanists identified anti-sense RNAs of about the same short length as lin-4 in plants, the first evidence that RNA-mediated gene silencing occurs outside of worms. Meanwhile, Ruvkun discovered a second microRNA in C. elegans, let-7, whose sequence was shown to be evolutionarily conserved across the animal kingdom. From then on, Ambros and others have raced to unearth a wide variety of microRNAs involved in gene regulation in organisms ranging from flies to vertebrates, including humans.

The clinical implications of Ambros’s work are quickly becoming evident. Dysregulation of microRNA expression is implicated in the development of lymphoma, leukemia, and congenital heart disease. MicroRNA profiling is also proving useful as a biomarker and prognostic indicator for conditions ranging from ovarian cancer to nicotine addiction. Biotech companies are springing up to capitalize on microRNAs’ vast diagnostic and therapeutic potential.

The discovery of microRNA in the Ambros lab has overturned traditional paradigms of gene regulation and expression and created an exciting new field of scientific research. As Ambros reflects, “What I love most about science is that it is such a deeply, intensely human enterprise. The success of the enterprise of science, and of the individual scientist, is derived precisely from the fact that we do it together. Science is among the best things that we do as a species.”

Ambros, who was elected to the National Academy of Sciences in 2007, has received numerous honors and awards, including the Albert Lasker Basic Medical Research Award, the Gairdner Foundation International Award, the Franklin Institute’s Benjamin Franklin Medal in Life Science, the Genetics Society of America Medal, the Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Science, and the Newcomb Cleveland Prize from the American Association for the Advancement of Science.