- Institute Professor, Massachusetts Institute of Technology
- Professor of Biology, Massachusetts Institute of Technology
A world leader of research in molecular biology and biochemistry, Dr. Phillip A. Sharp is Institute Professor at the Massachusetts Institute of Technology, the highest academic rank at the Institute.
Much of Dr. Sharp’s scientific work has been conducted at MIT’s Center for Cancer Research (now the Koch Institute), which he joined in 1974 and directed from 1985 to 1991. He subsequently led the Department of Biology from 1991 to 1999 before assuming the directorship of the McGovern Institute from 2000 to 2004. His research interests have centered on the molecular biology of gene expression relevant to cancer and the mechanisms of RNA splicing. His landmark achievement was the discovery of RNA splicing in 1977. This work provided one of the first indications of the startling phenomenon of “discontinuous genes” in mammalian cells. The discovery that genes contain nonsense segments that are edited out by cells in the course of utilizing genetic information is important in understanding the genetic causes of cancer and other diseases. This discovery, which fundamentally changed scientists’ understanding of the structure of genes, earned Dr. Sharp the 1993 Nobel Prize in Physiology or Medicine. His lab has now turned its attention to understanding how RNA molecules act as switches to turn genes on and off (RNA interference). These newly discovered processes have revolutionized cell biology and could potentially generate a new class of therapeutics.
Dr. Sharp has authored over 400 scientific papers. He has received numerous awards and honorary degrees, and has served on many advisory boards for the government, academic institutions, scientific societies, and companies, including the presidency of the AAAS (2013); Chair of the Scientific Advisory Committee; and SU2C Project, AACR.
A native of Kentucky, Dr. Sharp earned a BA degree from Union College, KY in 1966, and a PhD in chemistry from the University of Illinois, Champaign-Urbana in 1969. He did his postdoctoral training at the California Institute of Technology, where he studied the molecular biology of plasmids from bacteria in Professor Norman Davidson’s laboratory. Prior to joining MIT, he was Senior Scientist at Cold Spring Harbor Laboratory. In 1978 Dr. Sharp co-founded Biogen (now Biogen Idec) and in 2002 he co-founded Alnylam Pharmaceuticals, an early-stage therapeutics company.
- PhD in Chemistry, University of Illinois at Champaign-Urbana, 1969
- BA in Chemistry and Mathematics, Union College, 1966
- Double Helix Medal, CSHL, 2006
- National Medal of Science, 2004
- Benjamin Franklin Medal for Distinguished Achievement in the Sciences, 1999
- Nobel Prize in Physiology or Medicine, 1993
- Dickson Prize, 1991
- Albert Lasker Basic Medical Research Award, 1988
- Louisa Gross Horowitz Prize, 1988
- Gairdner Foundation International Award, 1986
- General Motors Research Foundation Alfred P. Sloan, Jr. Prize for Cancer Research, 1986
- NAS Award in Molecular Biology, 1980
- Member, National Academy of Sciences
- Member, Institute of Medicine
- Member, American Academy of Arts and Sciences
- Member, American Philosophical Society
- Foreign Member, Royal Society, UK
MicroRNAs (miRNAs) are encoded by endogenous genes and regulate over half of all genes in mammalian cells. They regulate gene expression at the stages of translation and mRNA stability. Developing methods to physically identify the target mRNAs for particular miRNAs is ongoing. RNA interference (RNAi) has dramatically expanded the possibilities for genotype/phenotype analyses in cell biology. Investigations into the mechanisms responsible for the activities of short interfering RNAs (siRNAs) are underway with the objective of increasing their effectiveness in gene silencing. High throughput sequencing of RNA populations revealed the generation of small RNAs from divergent transcription in mammalian cells. The role of this pervasive transcription from the anti-sense strand is under investigation. It is likely that these anti-sense transcripts are unstable because, in contrast to the sense transcript, they are not adequately recognized by certain RNA splicing factors. However, some of the non-coding RNAs generated by divergent transcription are processed by splicing and polyadenylation and are sufficiently abundant to be considered long non-coding RNAs (lncRNAs). The same high throughput technology allows definition of alternatively spliced isoforms. Shifts in isoforms are common in cancer versus normal cells. Also, recent results from other labs have suggested that chromatin structure is related to control of alternative splicing. We are investigating these processes and, in particular, the relationship between elongation of transcription, RNA splicing and chromatin modifications.
MicroRNAs (21-22 nt) are processed from hairpin RNAs encoded by cellular DNA and regulate gene expression primarily by inhibiting translation and promoting mRNA degradation. Some 250-350 conserved miRNA genes are encoded in the human genome (see Figure 1). siRNAs function through the miRNA-pathway and these RNAs will inhibit the translation of a reporter gene that contains multiple partially complementary target sites. We have developed methods for identifying the targets of the RNP complex containing miRNAs and we surprisingly found that mRNAs appear to be bound to components of the miRNP in the absence of miRNAs. miRNA regulation is not essential for survival, not even for some tumorigenic properties of mammalian cells. We have recently isolated a sarcoma tumor cell line that is null for dicer, devoid of miRNAs, and yet can produce a tumor in vivo. However this cell line is very sensitive to stresses.
We have recently reported that divergent transcription is common of promoter sites for genes in embryonic stem cells (see Figure 2). These promoters have an RNA polymerase initiated in the sense direction immediately downstream of the transcription start site and a second polymerase initiated in the antisense direction, about 250 base pairs upstream. The evidence for this structure is multifold. It includes the identification of small RNAs from these two regions of many promoters, detection of small RNAs by Northerns and mapping of RNA polymerase and modifications of chromatin in these regions. This research has been done in collaboration with Professor Richard Young. Surprisingly, the anti-sense polymerase is controlled by elongation processes very similar to those of sense polymerase. For example, both require P-TEFb for elongation beyond about 50 nts. The nature of factors or sequences that differentiate the effective elongation of the polymerase in the sense direction as compared to the ineffective elongation in the anti-sense direction remains to be identified.
Long non-coding RNAs (lncRNAs) have been described from analysis of deep RNA sequencing from many types of mammalian cells. Comparable RNA species have also been reported from sequencing data of yeast and Drosophila. Recent analysis of several large data sets of RNA sequences expressed in embryonic stem cells shows that a majority of long non-coding RNAs originated from initiation sites that are divergent from known protein-encoding genes or sites with chromatin marks indicating enhancer elements. Thus, synthesis of some long non-coding RNAs is probably a manifestation of general transcriptional processes. However, these lncRNAs could function in regulation of genes in cis to the site of transcription or in trans at other sites in the genome. In the latter case, the lncRNAs would probably need to be more abundant then the 1-2 copies per cells for most divergent transcripts.
Gene sequences important for accurate splicing of the nuclear precursors to mRNAs are commonly conserved during evolution. We are using computational methods to identify, by comparison of genomic sequences from multiple organisms, intron and exon sequences which are important for accurate splicing and for control of alternative RNA splicing. The cell surface protein CD44 is expressed as a variety of isoforms in tumor and activated cells but is present in a constitutive form in quiescent cells. These isoforms influence the cells’ motility, invasiveness and recognition of extracellular factors. Accordingly, shifts in the prevalence of these isoforms occur as tumor cells become more invasive such as in the epithelial to mesenchymal transition. RNA binding proteins and signaling pathways controlling alternative RNA splicing of CD44 are being investigated using high throughput sequencing methods to define transcriptomes. We are also investigating the relationship between chromatin structure and alternative RNA splicing.
Research Areas of Focus
- P. L. Boutz, A. Bhutkar, and P. A. Sharp. “Detained introns are a novel, widespread class of post-transcriptionally spliced introns.” Genes Dev. 29.1 (2015): 63-80.
- S. Chen, N. E. Sanjana, K. Zheng, O. Shalem, K. Lee, X. Shi, D. A. Scott, J. Song, J. Q. Pan, R. Weissleder, H. Lee, F. Zhang, and P. A. Sharp. “Genome-wide CRISPR Screen in a Mouse Model of Tumor Growth and Metastasis.” Cell 160.6 (2015): 1246-60.
- A. D. Bosson, J. R. Zamudio, and P. A. Sharp. “Endogenous miRNA and target concentrations determine susceptibility to potential ceRNA competition.” Mol. Cell 56.3 (2014): 347-59.
- S. Chen, Y. Xue, X. Wu, C. Le, A. Bhutkar, E. L. Bell, F. Zhang, R. Langer, and P. A. Sharp. “Global microRNA depletion suppresses tumor angiogenesis.” Genes Dev. 28.10 (2014): 1054-67.
- M. Jangi, P. L. Boutz, P. Paul, and P. A. Sharp. “Rbfox2 controls autoregulation in RNA-binding protein networks.” Genes Dev. 28.6 (2014): 637-51.
A full list of Dr. Sharp’s publications can be found on PubMed.