Spindle Self-Organization and Bioenergetics in Vivo

Harvard University, Cambridge MA

Investigators

Abstract

There is no established framework capable of understanding the structure and behaviors of organelles, specialized structures within a cell that can contain millions of dynamic, energy-transducing molecules. Similarly, cellular metabolism is extremely complex, involving hundreds of proteins, intricate networks, and numerous intermediate metabolic compounds, and we currently lack the ability to predict the flux through different pathways. This project employs the paradigm used to study complex systems in physics of integrating quantitative experiments with phenomenological theories, but applies these methods to study the spindle, oocyte bioenergetics, and the interactions between the two. This work will provide fundamental insight into cell division and energy metabolism, and will help pave the way towards an understanding of the nonequilibrium thermodynamics of living matter. The goal of the project is to develop a quantitative understanding of the spindle, energy metabolism, and the interaction between the two. The knowledge gained will help explain how metabolic defects disrupt cell division and cytoskeletal organization, which is believed to cause diverse pathologies, including cancer, neurological diseases, and infertility. Furthermore, if the nonequilibrium thermodynamics of living, active matter become sufficiently well understood, it will eventually become possible to engineer manmade active materials with lifelike properties. Graduate students, undergraduates, and high school students will be trained in interdisciplinary research, both through working on the project, and in classes, summer courses, and tutorials. A strong effort will be taken to enhance the involvement of women and underrepresented minorities in these activities. The results obtained, will be disseminated in research journals, on the lab web site, and at conferences (including new, interdisciplinary conferences). The PI will create a monthly series of events on scientific communication that will help give graduate students and postdocs valuable skills and enhance their engagement with public outreach. These will include collaborations with high school teachers, writers, entrepreneurs and artists, and will help create a community of people who are passionate about scientific communication. Life is a nonequilibrium phenomenon. Metabolism provides a continuous flux of energy that dictates the form and function of many subcellular structures. These subcellular structures are active materials, composed of molecules which use chemical energy to perform mechanical work and locally violate detailed balance. One of the most dramatic examples of such a self-organizing structure is the spindle, which segregates chromosomes during cell division. Despite its central role, very little is known about the nonequilibrium thermodynamics of active subcellular matter, such as the spindle. In this project the PI will study the interplay between spindle behaviors and bioenergetics in mouse oocytes using a combination of quantitative experiments and theory. The goal of this project is to provide a systematic basis to understand and predict the behaviors of the spindle and energy metabolism in vivo, and how perturbing one impacts the other. This work also aims to contribute to physics through the quantitative study of the nonequilibrium thermodynamics of living, active matter. 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.