Massachusetts General Hospital (MGH) and Harvard Medical School (HMS) investigator Gary Ruvkun is one of three co-recipients of the 2008 Lasker Award for Basic Medical Research. Presented by the Albert and Mary Lasker Foundation, the Lasker Awards are often considered the American version of the Nobel Prize, and many Lasker recipients have gone on to win the Nobel. The award will be presented in New York on Sept. 26.
Ruvkun and his co-recipients — Victor Ambros of the University of Massachusetts Medical School and David Baulcombe of the University of Cambridge in the United Kingdom — are being honored for discovering that tiny molecules of RNA can control the activity of critical genes in animals and plants. Instead of being translated into proteins as messenger RNAs are, single-stranded microRNAs bind to regulatory segments of their target genes’ RNA and block gene expression. Current knowledge suggests that microRNAs may control one-third of human protein-coding genes.
In the early 1980s Ruvkun and Ambros were both fellows in the Massachusetts Institute of Technology (MIT) laboratory of Robert Horvitz, investigating genes that control development in the C. elegans roundworm. They worked together to isolate a gene called lin-14 that operates in concert with a gene called lin-4 to regulate the worms’ transition through key developmental stages.
As the two researchers established their own laboratories — Ruvkun in the MGH Department of Molecular Biology and Ambros initially at Harvard — they continued collaborating to uncover how the two regulatory genes interacted, and made some surprising discoveries. Lin-4 did not block the activity of lin-14 through the protein it coded for but in a manner never seen before: by direct interaction between the two genes’ RNA strands. These critical RNA molecules also appeared to be extremely small, around 20 nucleotides long. In the meantime, Baulcombe was pursuing similar research in plants. His discovery that plant genes could be silenced by the action of tiny RNAs — similar to the worm sequences studied by Ruvkun and Ambros — implied that the same mechanism operated in plants and animals.
In 2000, Ruvkun’s team discovered let-7, another tiny regulatory RNA that shuts down its target gene the same way that lin-4 silences lin-14. The researchers also found that the let-7 RNA sequence had been snipped out of a larger RNA molecule that folds back on itself in a hairpin shape. Later that year Ruvkun published evidence that animals from fish to flies to humans have their own versions of let-7, implying that the mechanism is universal to all but the most primitive animal species.
In 2001, Ruvkun collaborated with Craig Mello, of the University of Massachusetts, and Andrew Fire, then at the Carnegie Institution, to show that the microRNAs of both lin-4 and let-7 are released from their precursor hairpin RNA molecules by the enzyme Dicer. This enzyme is also critical to the RNA interference process that Mello and Fire had discovered and for which they received the 2006 Nobel Prize.
It now appears that the human genome contains between 500 and 1,000 microRNAs involved in a broad range of normal and disease-related activities. Researchers have just begun exploring their potential for the diagnosis, prognosis, and treatment of disorders. In addition to continuing investigation of RNA’s role in controlling gene expression, Ruvkun’s team studies other mechanisms involved in the development, metabolism, and longevity of C. elegans, including genes involved in the regulation and storage of fat.