Cathodoluminescence Electron Microscopy for Nanoscale Molecular and Ultrastructural Imaging of Brain Pathology

Our vision is to create new imaging platforms that reveal how biological structures give rise to function at the molecular level. Inspired by both fluorescence and electron microscopy, we are developing multicolor electron microscopy using cathodoluminescence, time‑resolved cryo‑vitrification methods to capture transient biological states, and tools to gently perturb proteins to capture their mechanical movements. Across all projects, we focus on inventing new hardware, sharing it openly with the scientific community, and using it to visualize and understand how complex biological systems are organized—from individual proteins to cells and tissues.

I am an Assistant Professor of Molecular and Cellular Biology and of Applied Physics at Harvard University. I obtained my HBSc in Chemistry and Physics from the University of Toronto. I then did my PhD with Dr. Martin Gruebele at the University of Illinois at Urbana-Champaign, where I studied the biophysics of protein folding using ultrafast lasers and molecular dynamics simulations. During my postdoctoral work with Dr. Steven Chu at Stanford University, I developed cathodoluminescent nanoprobes for multicolor electron microscopy. My lab at Harvard University is developing methods for multicolor and dynamic molecular imaging. To achieve multicolor electron microscopy, we are exploring the property of cathodoluminescence—optical emission induced by the electron beam. We are developing “cathodophores” for use as luminescent protein tags in electron microscopy. To capture the dynamics of biological processes, we cryo-vitrify samples after known time delays following stimulation using custom cryo-plunging and high-pressure freezing instruments. We are applying these new methods to visualize the formation of biomolecular condensates, and to map the organization of complex multicellular assemblies: bacterial biofilms, organoids, and brain circuits.

Scientists studying brain diseases like Alzheimer's face a frustrating problem: current microscopes force them to choose between seeing the tiny structures inside brain cells or identifying specific disease-related proteins, but not both at the same time—it's like having to choose between a high-resolution vision that can't distinguish colors, or a color vision with blurry images. Our team is developing a revolutionary microscopy technique that solves this problem by creating special molecular tags that glow when hit by an electron beam, allowing us to simultaneously capture incredibly detailed images of brain structures while pinpointing the exact locations of disease-causing proteins. Using this new method, we will study brain tissue from mice with Alzheimer's-like disease, creating the first-ever 3D color map showing where toxic proteins build up within the brain—like having Google Street View for the brain. This technology could transform how researchers study brain diseases, potentially accelerating the development of new treatments by revealing exactly what goes wrong inside diseased brains at a level of detail never before possible.

"Cathodoluminescence is emission of light induced by electrons. The MIND Prize will allow me to turn this phenomenon into a new contrast mechanism for neuroscience. It will give us nanometer‑scale registration between specific proteins and brain cells."