IBNAM Colloquium: Dennis Discher, PhD
Tuesday, April 21
3 PM
Baldwin Auditorium
Dennis E. Discher, Ph.D. is a Professor in Chemical & Biomolecular
Engineering and inthe Graduate Groups inPhysics and Cell & Molecular
Biology at the University of Pennsylvania. He earned his Ph.D. from
U.C. Berkeley (1993) and is co-author of 150 papers and book chapters ranging
in topic from polymer-based nano-delivery of drugs with development
of polymersomes and filomicelles to the biophysics of single molecules and
stem cells. His work emphasizes physical chemistry and statistical mechanics
as well as molecular and cell biology, and has appeared in a wide range of
journals, including Science, Cell, Nature Physics, Nature Nanotechnology,
Journal of Cell Biology, and PNAS. His past awards include an NSF-PECASE
Award, Friedrich Wilhelm Bessel Award from the Humboldt Foundation, and the
Best Paper Award 2004 Journal of Controlled Release.
Material Insights into Filamentous Viruses and Stem Cell Differentiation
From viruses to tissue matrices, biology is rife with systems that motivate mimicry with a goal toward clarifying principles. In order to reveal the important effects of shape and/or flexibility in bio-function, Dr. Discher will discuss two distinct systems. Filamentous viruses have inspired development and evaluation of polymer-based worm-like micelles to test and exploit non-spherical shapes in systemic delivery. Similar in morphology but distinct in function, fibrous protein matrices in tissues are imitated in their elasticity with crosslinked hydrogels, demonstrating the potent influence of elasticity E on biological processes such as cell differentiation.
He will describe the effects of synthetic carrier shape, which is largely unexplored in vivo. Recent findings have suggested that flexible filaments can persist in the circulation even if microns in length 1. To assess a functional effect, the hydrophobic drug paclitaxel (tax) was loaded into filomicelles and also sonication-generated spherical micelles of the same copolymer. Intravenous injection of tax-loaded filomicelles nearly doubles the maximum tolerated dose in normal mice, and in tumor-bearing mice the higher dose of tax produces greater and more sustained tumor shrinkage and tumor cell apoptosis. The results begin to lend insight into surprising advantages of the shapes of filamentous viruses.
He will also describe the effects of elasticity of synthetic hydrogels of tissue-mimetic elasticity on cell function. Tissues are ‘soft’, with the exception of calcified bone, but it is also true that gels composed of fibrous collagen – the most abundant protein in animals – are softer than most tissues. The effects of tissue-like elasticity on cell functions have only been studied for about a decade, with mechanisms seemingly based on the fact that cells make a number of key decisions by actively applying forces to the objects that they ‘touch’. Naive mesenchymal stem cells (MSCs) from human bone marrow will be shown to specify lineage and commit to phenotypes with extreme sensitivity to tissue level elasticity 2. Soft matrices that mimic brain appear neurogenic, stiffer matrices that mimic muscle are myogenic, and comparatively rigid matrices that mimic collagenous bone prove osteogenic. The results have significant implications for understanding physical effects of the in vivo microenvironment around cells.
REFERENCES
1. Y. Geng, P. Dalhaimer, S. Cai, R. Tsai, M. Tewari, T. Minko, and D.E. Discher. Shape effects of filaments versus spherical particles in flow and drug delivery. Nature Nanotechnology 2: 249-255 (2007).
2. A. Engler, S. Sen, H.L. Sweeney, and D.E. Discher. Matrix elasticity directs stem cell lineage specification. Cell 126: 677-689 (2006)
Professor Discher's Website
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