Collaborative Research: DMS/NIGMS 1: Mesoscale Kinetic Theory of Early Mitotic Spindle Organization

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For life to proliferate, cells must faithfully divide their genetic material equally into two new daughter cells during cell division. The highly dynamic bipolar mitotic spindle, built from protein filaments called microtubules, is the cellular machine needed to accomplish this essential task. Errors in the spindle assembly process have been linked to diseases such as cancer. A critical initial step in building the spindle involves the separation of duplicated centrosomes that form the spindle poles. This involves a variety of proteins that bind and generate a force on the microtubules. While the mechanical interplay is complex, the relevant factors appear small enough in number that their collective action can be analyzed in precise biophysical terms. This project will combine biophysical laboratory experiments, computational physical models, and statistical parameterization frameworks in order to build detailed understanding of how spindle formation is affected by the interaction of the diverse protein components. Methodologically, the research aims to coherently evolve a physically interpretable structural theory of early spindle formation that is built bottom-up with clear linkages between stages of complexity. Additionally, the research team from mathematical sciences, biology, and physics will develop educational outreach activities for students at the universities and local high schools, emphasizing how collaborative methodologies from mathematics, physics, and biology can be deployed to better understand vital processes in the life sciences.The key technical novelty of this project will be the construction of a mesoscale kinetic theory framework. The framework will treat the spindle and associated protein concentrations through statistical summaries and be parameterized in increasing stages of complexity through in vitro experimental configurations designed for this project. The theoretical model will be developed through interaction with computational simulations and newly proposed in vitro experiments involving microtubule bundles with virtual asters in simplified geometries, probed by optical tweezers. The project will exploit the coarse-grains existing kinetic theory to model crosslinker-mediated interactions between pairs of microtubules to aligned and non-aligned bundles of microtubules. A reduced statistical description will be sought relative to highly detailed kinetic theories and direct simulation based on a detailed accounting of individual crosslinkers and microtubules. The research will identify and exploit key collective variables for a more computationally tractable and transparent connection between regulatory and environmental factors and the resulting spindle dynamics, which can aid in generating hypotheses for future experiments. The graded complexity integration process will enable interrogation of and corrections to physical assumptions regarding understanding how crosslinker behavior for microtubule pairs scales up quantitatively to microtubule bundles.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.