Overarching theme: Hosted by the Institute of Medical Chemistry, our lab investigates the physical chemistry of cells living on or in the human body. The human body is a constantly changing and stress-prone environment, subjecting its constituent cells to a barrage of chemical, mechanical, and thermal stresses. These perturbations disrupt the homeostatic setpoints that cells strive to maintain. To preserve fitness under environmental stress, cells actively modify their growth rates, proliferation dynamics, and metabolic fluxes as part of a larger adaptive change in their morphogenetic behavior.

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Conventionally, an adaptive morphophenotype that confers a fitness advantage is considered the result of environment-genotype interactions. In recent years, however, evidence has shown that the environment can directly modify cell phenotype without engaging the canonical flow of genetic information (DNA → RNA → Protein → Phenotype). In many cases, these environment-phenotype interactions are driven directly by physicochemical reactions among stress-sensitive cellular proteins. Yet, the “molecular grammar” rules that govern how individual proteins detect stress and convert it into actionable forces to reshape the whole cell and modify its growth remain only partially understood. This is a universal, scale-bridging problem that nearly all biological cells must solve. Deciphering how they achieve this task is the global objective of our research program.

 

To this end, we employ an interdisciplinary approach that integrates molecular multi-omics with data analysis of cells before and after perturbation. This allows us to uncover molecular-scale patterns that predict the rules governing a cell's adaptive response. These rules are then incorporated into a physically-grounded computer model to simulate a virtual, whole-cell-scale morphophenotype. The model's predictions are experimentally validated through a suite of techniques, including quantitative microscopy, bioimage informatics, analytical biochemistry, molecular genetics, and physicochemical analyses.

 

We hope that this work will ultimately reveal new targetable mechanisms behind stress adaptations in pathogenic cells. This is especially important in the context of ever-increasing drug resistance/tolerance, one of the main threats to global health.

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