Award for Outstanding Doctoral Thesis Research in Biological Physics: Fundamental limits to cell replication in extreme heat and cold

An important challenge is explaining how myriad cellular processes together dictate a "pace" at which a cell's life progresses. We intuitively think of life progressing at some pace, but it is unclear how to quantitatively define that pace and mathematically derive it from cellular processes. Several systems-level quantities may represent the pace. Important examples are a cell's doubling time or how rapidly a cell irreversibly loses its viability. Here, we focus on these two quantities in the context of temperature. Temperature is a universal parameter that affects the rates of virtually all cellular processes and thus the pace of a cell's life. Increasing or decreasing the temperature beyond some "optimal" range causes a cell to replicate more slowly. However, it remains unclear whether there is a limit to how slowly the cell can grow and replicate. More generally, it is unclear how temperature quantitatively constrains replication and the viability of a cell. We answer these open questions for the budding yeast, Saccharomyces cerevisiae, through an interplay of mathematical modeling and experiments at single-cell and genome-wide levels. Our findings revise the textbook view – yeast die at extreme temperatures due to protein misfolding or other damages that cells cannot autonomously repair – by revealing that cells help each other survive and replicate. These cooperative behaviors emerge from cells collectively fighting heat- and cold-induced reactive oxygen species. We quantify power-laws and phase diagrams that summarize the population dynamics of yeast in extreme heat and cold, and reveal "speed limits" – a fastest and slowest possible pace at which yeast can complete the cell cycle – for yeast's life at frigid temperatures. Together, our findings uncover quantitative, fundamental principles governing viability and replication of cells at extreme temperatures, and encourage further explorations of how thermal energy drives and constrains life.