Fundamental and translational insights from short-term, single-cell growth measurements

Abstract

Cell growth is a fundamental process that is intrinsically linked to our understanding of biology. As a central process in the propagation of single cells, changes to cell growth are a reflection of changes to cell state, and to their robust internal programming. Furthermore, cell growth is a key characteristic in a variety of physiological situations, including development, immune response, and diseases such as cancer. Consequently, growth has been a critical metric used to understand a wide range of biological subjects, but our ability to measure it on short timescales matching those of newer molecular assays has been limited. Within this thesis we exhibit two applications of short-term growth measurements, demonstrating their value in both the study of fundamental biology of the cell and in translational applications. By using a suspended microchannel resonator to take precise mass measurements on single cells over time, we are able to describe for the first time the nature of single-cell growth response dynamics over minute-timescale intervals in response to perturbations. Metabolic depletion studies show that growth on short timescales is unique from canonical measurements of cell growth on longer timescales, and that the two timescales are not always directly coupled, suggesting that single-cell growth is far more plastic than generally acknowledged. Translational studies show that rapid growth measurements demonstrate promise in assessing single-cell growth heterogeneity and therapeutic susceptibility prior to loss of cell viability.