Dynamics of Cellular Communities: Insights from Antibiotic-Induced Biofilms, Self-Replicating Oscillators, and Spatially-Extended Communities

Abstract

Collective behavior is a fascinating phenomenon occurring at many scales in biology. From flocking of birds to synchronization in neural populations, examples abound where local interactions give rise to “macroscopic”, often counterintuitive behavior, at the level of the community. In this thesis, I investigate community behavior in three distinct systems using a combination of theoretical and experimental approaches. The work spans a broad range of topics inspired by dynamics in microbial communities. In Chapter II, we provide a comprehensive theoretical study of synchronization in coupled oscillators, a topic that is among the most widely studied in dynamical systems. However, while past work has focused almost exclusively on populations of a fixed size, I introduce a new model of self-dividing oscillator populations that exhibits a remarkable range of synchronization phenomena as growth rate is varied. Chapter III describes a largely experiment-driven effort to understand a specific and counterintuitive phenomenon: the promotion of microbial community (biofilm) growth by low doses of antibiotic drugs in a medically relevant bacterial species, E. faecalis. We show that for cell wall synthesis inhibitors–which have for decades been among the most widely prescribed classes of antibiotics–low doses stimulate cell lysis and are associated with an increase in extracellular DNA, long believed to be an important structural component of biofilms. We also develop a simple mathematical model that highlights the interplay between the toxicity of the drug and the “beneficial” effects of cell lysis and can be used to predict the impact of various chemical perturbations that impact optimal biofilm growth. Finally, Chapter IV is devoted to ongoing work on spatial pattern formation in two bacterial species, E. coli and E. faecalis, exhibiting cooperative antibiotic resistance via the production of a community good–an enzyme that targets and degrades antibiotics. The work draws on previous theoretical models to predict pattern formation in simple (non-cooperative) populations, which we quantify using customized experimental tools for quantitatively characterizing colony growth over time and space. In addition, we observe a range of new pattern-formation phenomena driven, in part, by the interplay between cell motility, cooperation, and density-dependent cell growth.