Biological Physics (CPLC) Seminar: Hyun Youk

1/24/2020 10:01:13 AM

 “At the cusp of life and death: transitions at single cell level”


Abstract:   Understanding how living cells and organisms behave at the boundary of life and death may help us in rigorously defining what being “alive” and being “dead” each mean. Studying life-death boundary (i.e., life pushed to its limits) is inherently challenging because one must first discover a “knob” that one can tune to have cells or organisms transition between life and death. One would then need to finely tune this knob to place the living system right at the boundary, which would require having a degree of quantification and control that might be difficult to achieve. In this talk, I will present three studies - two on budding yeast and one on murine Embryonic Stem (ES) cells - that explore this topic with a combination of experiments, mathematical models, and ideas inspired by dynamical systems and statistical mechanics. First, I will show that budding yeasts, despite being single-celled organisms, collectively combat rising temperatures - this is contrary to the textbook view of yeasts autonomously combatting heat shocks. We found that when temperature increases above a certain value, budding yeasts secrete and extracellularly accumulate an antioxidant (glutathione) that reduces heat-induced damagaes caused by harmful, extracellular agents (i.e., yeasts collectively clean up their extracellular environment). In this way, yeasts help each other and their future generations of cells replicate and avoid population extinctions at high temperatures. We measured a "phase diagram" which summaries, as a function of temperature, when yeasts can replicate and when they cannot. A population goes extinct at a high temperature unless it has enough yeasts cooperatively cleaning their extracellular environment. Next, I will describe our work on dormant yeast spores. Here we sought to better understand how one arrested form of life remains alive while another arrested form of life is dead. Specifically, we addressed how some dormant yeast spores maintain the capacity to “wake-up” when an external source of energy (glucose) appears while others have lost that ability. We show that yeast spores possess an intrinsic ability to express genes while still dormant and without any nutrients (i.e., in plain water). The spores gradually lose this ability. The decrease in the gene-expressing ability is correlated with an increase in the amount of glucose required for waking up. Thus, once the gene-expressing ability becomes sufficiently low, the spore requires more than saturating amounts of glucose to wake-up (i.e., spore cannot wake up anymore). We thus discovered how dormancy gradually transitions to death and what sets this lifetime. In this investigation, we inadvertently discovered that dormant yeast spores exhibit unusual gene-expression dynamics, which raises the question of how the central dogma of molecular biology functions in dormant spores and cells (dormant yeast spores were widely assumed to not express any genes). I will present an on-going work that investigates this question with single-molecule based techniques for measuring transcription (single-molecule FISH). Finally, I will describe our discovery of quorum sensing by murine ES cells that cause the cells to either collectively proliferate or die - leading to population proliferation or extinction - solely based on their initial population-density. Crucially, we found that this quorum sensing is absent while ES cells are pluripotent but become active at the moment the cells are triggered to differentiate towards any cell fate. We found that the quorum sensing occurs over a macroscopic (millimeter) lengthscale and describe the molecule that the differentiating cells secrete and sense to achieve quorum sensing. The three studies mentioned above, despite invovling very different settings, point to common features. Together, these studies suggest that it may be worthwhile to search for common cellular dynamics that underlie living systems at the boundary of being alive and being dead.