This project will investigate fundamental aspects of the ways that living cells interact with their physical environment. It is known that cells exhibit a wide range of mechanical responses to inputs such as external forces and the stiffness of the tissues in which they live, but models that attempt to describe the complex mechanical properties of cells are incomplete and cannot predict key aspects of cellular behavior. Improved physical understanding of cellular mechanical behavior is important as such activity drives both normal biological process, such as the development of embryos, as well as pathological ones including the spread of cancer. This project is a collaboration between researchers at Johns Hopkins University and the University of Pennsylvania. It will build on a recent discovery by the Investigators that promises new understanding of cell mechanics by exploiting analogies between the physics of cells and the dynamics of a class of materials termed soft glasses. These materials exhibit intermittent motion in response to external stresses, over a wide range of length and time scales, in a manner that is reminiscent of earthquakes or avalanches. The research team recently observed such phenomena in cells using a novel approach that can measure both cells’ intrinsic mechanical properties and the highly dynamic and fluctuating forces they exert on their environment with unprecedented accuracy. In this project, new experiments with this tool will be used to guide the development of a new physical model of key aspects of cellular mechanics. This model will then be used to advance understanding of the origin of cells’ physical responses to critical cues, such as the stiffness of their environment. An important outcome of this project will be the interdisciplinary research training it will provide for its participants, including a postdoctoral fellow, graduate students, Masters students and undergraduates, that will prepare them for careers in academia and industry. The project will also provide educational opportunities for Baltimore City high school students through research internships at Johns Hopkins University, and interactive instructional materials will be developed for K-12 use and for science outreach initiatives in Philadelphia sponsored by the University of Pennsylvania.
The actomyosin cortex and associated machinery of living cells is a remarkable example of a self-assembled active material. This project will develop a long-standing analogy between the actomyosin cortex and soft-glassy materials (SGMs). Co-PI Crocker has recently developed the first successful model to explain the unusual mechanics of SGMs from first principles. Initial experiments by the team, using active micropost array detectors recently developed by Co-PI Reich, which provide a uniquely powerful experimental platform for studying active cytoskeletal dynamics, suggest that cortical mechanics and fluctuations closely resemble those in the SGM model. The goals of this project are (i) to make a detailed experimental study of the mechanics and microscopic fluctuations of the cell cortex; (ii) to use that data to develop, refine and validate a new mechanistic model of emergent cortical mechanics that carries over the recent insights from SGMs to the cortex; and (iii) to use this model to understand cellular mechanical “outside-in†signaling in the context of cells’ ability to match their internal stiffness to that of their surroundings. This will enable testing a novel hypothesis: that like SGMs, cortical active matter behavior is the consequence of the system’s high-dimensional energy landscape giving rise to fractal energy minimizing paths, and that the evolution toward mechanical equilibrium in this fractal energy landscape leads to cells’ emergent dynamics and rheology. By moving the description of subcellular cortical dynamics beyond the phenomenological and providing a bridge between the well understood nanoscale molecular biophysics of actomyosin and cell-level mechanics, this work will help enable further understanding of more complex cell-level functions such as motility and tissue morphogenesis.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
