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The Cantoni Memorial Lecture Series
A native of Kentucky, Dr. Sharp earned a B.A. degree from Union College, KY and a Ph.D. in Chemistry from the University of Illinois, Champaign-Urbana. He did his postdoctoral training at the California Institute of Technology, studying molecular biology of plasmids from bacteria in Professor Norman Davidson's laboratory. Prior to MIT, he was a Senior Scientist at Cold Spring Harbor Laboratory.
In 1978, Dr. Sharp co-founded Biogen (now Biogen Idec), in 2002, he co-founded Alnylam Pharmaceuticals, an early-stage therapeutics company, and in 2006, he co-founded Magen Biosciences Inc., a biotechnology company developing agents to promote the health of human skin. He serves on the boards of all three companies.
Much of Dr. Sharp's scientific work has been conducted at MIT's Center for Cancer Research, beginning in 1974 and directed from 1985 to 1991. He subsequently led the Department of Biology 1991 to 1999 before assuming the directorship of the McGovern Institute from 2000-2004. His research interests focused on molecular biology of gene expression relevant to cancer and mechanisms of RNA splicing. His landmark achievement was the discovery of RNA splicing. This work provided one of the first indications of the startling phenomenon of discontinuous genes in mammalian cells. Dr. Sharp's research opened an entire new area in molecular biology, forever changing the field, leading to his 1993 Nobel Prize in Physiology/Medicine. His lab now focuses on understanding how RNA molecules act as switches to turn genes on and off.
Dr. Sharp has a distinguished record of public service, including having served as a member of the President's Advisory Council on Science and Technology, as co-chairman of the Director of NIH Strategic Plan and as a member of the Committee on Science, Engineering and Public Policy.
RNA has emerged as a common factor in the regulation of genes. The concept of RNA as a single messenger carrying information from gene to ribosome was significantly modified when processes such as alternative RNA splicing, alternative polyadenylation, and RNA editing were discovered. All of these processes modify, depending on cellular environment and type of cell, the nature of the information transferred from the DNA sequence to the ribosome. More recently, discovery of processes such as RNA interference (RNAi) and the existence of hundreds of genes for non-coding RNAs, microRNAs dramatically changed our concept of the roles of RNA in cells. Here, short RNAs are regulating expression of genes as transacting regulatory factors, a class of activities that had previously been reserved for protein factors.
Bioinformatics analyses supported by some biochemical results indicate that over a quarter of all genes in vertebrates is regulated by microRNAs. Further, alterations in this regulation have been related to many disease processes such as cancer. Cells frequently encounter stress such as depletion of oxygen or glucose. Subcellular complexes containing microRNAs and Argonaute proteins are concentrated in stress granules under these conditions. These and other results suggest regulation of gene expression by microRNAs during stress could be an important and common aspect of their functions.
Embryonic stem (ES) cells are multi-potent and can be induced to undergo differentiation into many cell types characterized by the expression of subsets of genes. To explore the possible roles of short RNAs in these processes, ES cells were examined by deep sequencing. The population of short RNAs in Dicer-negative cells was compared to the population of short RNAs in its parental Dicer-positive ES cell lines. MicroRNAs are the major--if not the only--type of short RNA expressed through a Dicer-dependent pathway in ES cells. The following new insights emerged from these results. A population of Dicer-dependent microRNAs overlaps repetitive elements and could be signals for their silencing. |