OPUS: MCS Functional solutions to cell-size evolution's geometry problem

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All living things are composed of cells. Some organisms, like bacteria, are just a single cell. Others, including the plants, animals, and fungi that are large enough to be seen by the human eye, can consist of trillions of cells. The cells that make up different parts of a body are different from one another; skin cells are different from heart cells, just as root cells are different from leaf cells. Despite these differences, however, all cells have a lot in common. Much of the fundamental chemistry that underlies life takes place within cells, allowing organisms to grow, heal, and respond to their environment. This chemistry depends on the right molecules coming into contact with one another inside the cell, which requires complex coordination and transportation of millions of molecules. This molecular coordination and transportation is thus critical for life, but a major feature of a cell that affects how it works - the size of the cell itself - remains surprisingly understudied. In nature, cells exist in many sizes. The larger ones have a longer distance to travel from the cell surface to the nucleus, which is the cell's control center. Large cells also have more internal cellular space, which means that any two potentially interacting molecules can be farther apart from one another. Understanding how cells maintain function at different sizes is critical for understanding the fundamental question of how cells coordinate and transport the countless molecules required for life. This study will focus on 10 species of salamanders with an exceptionally broad range of large cell sizes. Comparison across these species will allow the researchers to meet the following objectives: 1) study how increase in cell size impacts the function of molecular networks (i.e. gene regulatory networks, signal transduction cascades, metabolic pathways) through increased randomness in the interactions among molecules, 2) study how cells maintain function in the face of the increased randomness, decreased surface area, and increased volume that accompany large cell size, and 3) study how these changes at the cellular level impact the central traits of metabolism and embryonic development. These objectives will be met using mathematical modeling, comparative RNA sequencing, and cell ultrastructure microscopy. The research team consists of a mid-career principal investigator and two mentors, other scientists chosen for their strengths in mathematical modeling and cell size. Synergy across these labs will strengthen the investigator's ability to mentor young scientists in quantitative biology, and it will foster new collaborations among scientists to increase creativity and output.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.