Protein misfolding toxicity is a major factor in neurological disease. The high load of misfolded proteins in tumors has also been called cancer’s ‘Achilles heel.’ But to understand how misfolding impacts health, we need to quantify how cell fitness declines as misfolded proteins accumulate. A hypothesis as to why misfolded proteins are toxic is that they steal resources (eg, chaperones), implying toxicity depends on the availability of resources. Our goal is to make accurate predictions about the context-dependent costs of misfolding mutations by quantifying the relationship between the number of misfolded proteins in a cell and cell fitness. We do so through a combination of novel methods, some of which utilize DNA barcodes and CRISPR gene-editing, some of which hunt for subpopulations of cells that are sensitive to misfolding, and some of which involve technologies that we developed ourselves. Deciphering how the cost of misfolding scales with the number of misfolded proteins will improve predictions about the combined costs of multiple misfolding mutations. It will also reveal when and how these extremely common, but typically small-effect, mutations contribute to evolutionary processes.

Relevant Papers:
-A novel system to identify mutations that cause protein misfolding link
-Our review of mechanistic hypotheses underlying context-dependence link
-Quantifying the toxicity of misfolded proteins link
-Chaperone levels go up in lock step with the number of misfolded proteins link