2015 New Investigator Grant
Matthew Good, Ph.D. Assistant Professor, Department of Cell and Development Biology, University of Pennsylvania
Building Synthetic Cell-Like Compartments to Investigate the Impacts of Cell Size and Shape on Intracellular Function
Size in biological systems is coordinated at multiple levels, from organisms and tissues to cells and their internal components. However, how size-regulation is achieved is a largely unanswered question. The goals of my research program are to understand how subcellular structures adapt to changes in cell geometry, and how cell size controls cellular function. A stunning example of size scaling occurs after fertilization of eggs from the vertebrate Xenopus laevis - cells undergo a 1,000,000-fold reduction is cell volume, due to rapid cell division in the absence of growth. As cell size is reduced, internal structures, such as organelles, must also shrink to match the decreasing dimensions of a cell, while also maintaining function. To put this problem in real-world context, imagine if a 1:10th scale toy model of an automobile was fully functional and contained a working combustion engine. This nearly impossible engineering feat has been accomplished in cells through the evolution of various intracellular structures, such as the mitotic spindle - a molecular machine that uses force to segregate chromosomes using force - and the nucleus, which acts as the command center of the cell. Amazingly, these structures are able to maintain their necessary functions even after miniaturization. This result begs the question of how a coupling between cell size and organelle size is achieved. One hypothesis is that intracellular structures sense and respond to intrinsic physical features of a cell, such as volume or position of the boundary. However, it has proven nearly impossible to address this question due to the difficulty of manipulating cell size in an embryo. To overcome this hurdle I have developed a microfluidic technology for building synthetic celllike compartments whose dimensions can be specified with ease and precision. With the support of the Charles E. Kaufman Foundation, my goal is to use this system to this dissect how cell geometry regulates the assembly and size of organelles, and even which genes a cell turns on or off. The larger significance of this work lies in the intimate connection between cell size and embryo development, and the observation that cell and organelle size are often misregulated in disease.