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.