Ph.D., Physics, University of Cambridge
BSc, Maths and Physics, Univ of Bristol
Our Research: Cytokinesis in cell division, cell force production and mechanosensing, cell motility, membrane fusion in cell trafficking and secretion, viral membrane fusion. Using analytical and computational methods, we develop quantitative models aiming to elucidate basic cellular mechanisms. We are also interested in mechanisms of disease and therapeutic strategies. Modeling and joint modeling-experimental approaches are employed. Our group welcomes theory and experimental students and postdocs.
CYTOKINESIS. Cell division is fundamental to life, from development of the embryo to regeneration of cells in adults. Cytokinesis is the final stage of the cell cycle in which physical separation into two daughter cells occurs. Defects in this process are associated with cancer, neurological disease and birth defects. Animals and fungi accomplish cytokinesis by constriction of an actomyosin contractile ring built from force-producing myosin motor proteins, actin filaments and other components. The goal of our research is to quantitatively understand the mechanisms cells have evolved to assemble and constrict this contractile machine. The machine spatiotemporally coordinates its components to control internal stresses, actin polymerization and turnover so stable constriction results.
FORCE PRODUCTION AND MECHANOSENSING BY CELLS. In processes such as cell migration and wound healing cells interact with their environment both chemically and mechanically. Mechanical interactions are two-way: response to external force and exertion of force. By exerting force cells can couple to or modify the environment or measure its mechanical properties. Broadly, our research aims to understand different cellular contractile actomyosin machines used for these purposes and to identify common principles. We have modeled the stress fiber, a relatively well characterized tension-producing machine used in wound healing and matrix remodeling whose organization is related to that of muscle myofibrils. Predicted stress fiber kinetics reflect the organization of known components and mechanical feedback from the surroundings. A key principle which emerges is coupling between internal stresses and turnover rates. A related focus of our work is force fields produced by migrating cells and their measurement using nanostructured substrates.
CELL MOTILITY. How do cells move around? What machinery is used and how does it work? How does this machinery malfunction in cancer metastastis? Cell motility is crucial for embryonic development, wound healing and defense against pathogens while metastasis, the most devastating aspect of cancer, is associated with misregulated motility. Cell motion involves forward pushing against the leading edge plasma membrane by actin polymerization, adhesion of the protrusion to the extracellular matrix and forward pulling of the cell body. We study the underlying mechanisms to understand how the cell coordinates these processes to sense the mechanical properties of its surroundings and generate traction. Spatiotemporal traction patterns are of particular interest and novel nanofabricated substrates are being developed to measure cell-generated forces at submicron resolution and compare with model predictions.
MEMBRANE FUSION IN CELLULAR TRAFFICKING AND SECRETION. Many materials are transported around the cell in membrane-enclosed compartments. Delivery of cargo at the final destination requires controlled fusion of membrane surfaces. Examples include neurotransmitter release at synapses interconnecting neurons in the central nervous system and trafficking between organelles such as the endoplasmic reticulum and golgi. Efficient and specific fusion is achieved through a conserved fusion machinery whose core includes the SNARE proteins. Spatial and temporal control results from the action of this machinery in the context of the physical properties of phospholipid membrane bilayers. Our research explores the mechanisms and pathways to fusion mediated by SNARES and other participants. The pathway includes membrane adhesion, hemifusion where outer leaflets fuse and a hemifusion diaphragm may grow and finally creation of a fusion pore.
VIRAL MEMBRANE FUSION. Enveloped viruses such as HIV and influenza invade cells by membrane fusion mediated by protein machinery. HIV's GP160 protein and influenza's hemagluttinin exhibit structural similarities to cellular SNARE proteins and are thought to effect membrane adhesion and trigger fusion through hemifused intermediates. Our research addresses physical mechanisms of viral fusion which may help drug development and lead to novel strategies of disease therapy.
Distinguished Scientist Lecture Series, Institute for Research in Immunology and Cancer, University of Montreal, Canada, February 2010. Soft Matter Center, Department of Physics, New York University, "Mechanisms of Actomyosin Contractility."
Soft Matter Center, Department of Physics, New York University, December 2009. "How Cells and Viruses Fuse Membranes."
Department of Physics, Lehigh University, April 2009. "Physics of Intracellular and Viral Membrane Fusion."
Recent Advances in Biophysical Chemistry of Transport by Biomolecular Motors and Machines symposium, American Chemical Society National Meeting, Philadelphia, August 2008. "Cytoskeletal Contractile Machines."
Department of Physics, University of Wisconsin-Madison, May 2008. "Force-Producing Machines in Living Cells."
Department of Microbiology, Columbia University, April 2008. "Assembly and Mechanisms of Contrac-tile Cellular Machines.