Multimodal Investigation of Cellular Adaptation Across Timescales

ABSTRACT/SUMMARY The Center for Cellular Adaptation is an interdisciplinary team comprised of biologists, physicists, and data scientists embarking a comprehensive project to develop a multiscale, predictive understanding of how cells adapt to changes in their environment. This research could potentially lead to innovative, holistic therapeutic interventions for a range of diseases that reprogram maladaptive cellular states. The project is divided into three main scientific thrusts, each exploring different timescales of cellular adaptation. The first thrust aims to understand the adaptive roles of stress-induced biomolecular condensates in physiological adaptation. Membrane-free assemblies of macromolecules induced during stress were previously thought to be toxic but are now known at least in some cases to be adaptive assemblies with physical properties shaped by evolution. By studying condensates in diverse environmental contexts, we aim to link the properties of these condensates to cellular function and fitness. The second thrust seeks to understand how cells prioritize environmental responses at the transcriptomic level. Cells typically respond to single environmental stressors by repressing growth-related genes and activating stress-specific genes. However, it is unknown how cells respond in complex environments with multiple stressors. We will generate single-cell transcriptomes from yeast and pancreatic cancer cells under a wide range of environmental conditions to understand how cells prioritize – and how malignant cancer reprioritize – environmental signals. The third thrust will explore the relationship between physiological and evolutionary adaptation, aiming to understand how stress responses contribute to evolutionary adaptation. We will use CRISPRi screening coupled to single cell transcriptomics (Perturb-seq) to test the hypothesis that the effects of genetic mutations on the transcriptome will be similar to the effects of environmental perturbations. We will also identify novel phenotypic capacitors that promote genetic diversity in cell populations to enable long-term adaptation. The challenging nature of these research goals necessitates the diverse collaboration of expertise involved in The Center for Cellular Adaptation. Our highly collaborative research model will be coordinated by regular monthly meetings involving all Center PIs, collaborators, and trainees to discuss ongoing research. Additionally, the PIs will meet monthly to evaluate progress as well as elicit feedback from an advisory board of experts on an annual basis. This integrated, multi-scale approach to understanding cells may provide a novel unified framework connecting adaptive processes across timescales and the maladaptive processes that culminate in aging, cancer, and neurodegeneration.