Research Focus

Our laboratory studies the chemistry and biology of the elements. We advance new concepts in imaging, proteomics, drug discovery, and catalysis by drawing from core disciplines of inorganic, organic, and biological chemistry. For example, we have developed activity-based sensing as a general platform to identify transition metals, reactive oxygen species, and one-carbon units as new classes of single-atom signals for allosteric regulation of protein function. These chemical tools also reveal unique metal and redox disease vulnerabilities as targets for innovative drug discovery efforts to treat neurodegeneration, cancer, and metabolic disorders. Representative project areas are summarized below.

Transition Metal Signaling: Bioinorganic Chemistry of the Brain and Body. We are advancing a new paradigm of transition metal signaling, where nutrients like copper and iron serve as dynamic signals to regulate protein function by metalloallostery beyond their traditional roles as active site cofactors. We develop activity-based sensing probes for imaging mobile transition metal pools and activity-based proteomics probes for identifying allosteric metal sites in proteins. These chemical tools enable us to decipher the complex biology of sleep, cognition, and obesity in cell, zebrafish, mouse, and non-human primate models. We also develop medicines to target cuproplasia and cuproptosis, newly recognized forms of copper-dependent cell proliferation and cell death, respectively, as metal-dependent disease vulnerabilities in cancer, neurodegeneration, and metabolic liver disorders.

Activity-Based Sensing: Illuminating One- and Two-Carbon Signaling. We have pioneered the field of activity-based sensing by developing chemical sensors for biological analytes that achieve high selectivity using reaction chemistry rather than conventional lock-and-key binding approaches. Building upon our previous work on selective reactive oxygen and sulfur species detection, we are imaging one- and two-carbon metabolites in organelles, cells, tissues, and animals to elucidate principles of how these signals influence genetic and epigenetic control of cancer metabolism, neurodegeneration, and immune response.

Activity-Based Proteomics: Decoding and Drugging Single-Atom Signaling. We are establishing a field of single-atom signaling, focusing on understanding how reversible addition or removal of a single oxygen atom on proteins can influence their function. We develop activity-based proteomics probes to identify new targets of methionine oxidation as well as writers and erasers that regulate their single-atom biology. Our broader work on protein bioconjugation methods reveal new ligandable hotspots for undruggable protein targets to accelerate the development of next-generation precision medicines that target redox disease vulnerabilities in cancer and neurodegeneration.