Christy Landes

Molecular Mechanisms of Disease Development
Mechanistic chemistry is capable of relating a product to the precursors with precision at nearly every scale. The relative amounts and chemical structure of each reactant are known; the energy and structure of the intermediates are classified; and even the electrons can be assigned to respective wave functions depending on the resources available to the researcher. Disease inception, although governed by chemical interactions, represents a much more complicated problem. Each step in such a complex scenario involves pathogen-cell interactions and immune responses that are poorly understood from a chemical perspective.

Single molecule spectroscopy, SMS, provides an opportunity to characterize complex biological processes without the ensemble averaging associated with bulk techniques. The simple example of a single ligand binding to a substrate by simultaneous specific and non-specific interactions illustrates the type of convolution intrinsic to even the most elementary biological processes. Our group will use single molecule fluorescence resonance energy transfer, SMFRET, and fluorescence correlation spectroscopy, FCS, to deconvolute chemical responses within biological processes that relate to disease inception and chronic inflammation.

Development of Next-Generation Single Molecule Spectroscopic Tools
The latest SMS techniques can monitor single biological events such as binding, translation, or folding. Many biological processes, such as signal transduction, involve multiple entangled events. For example, in response to viral binding to a cell surface receptor, the corresponding cellular transmembrane protein undergoes a chemical (and/or physical) change to signal protective responses.

Our goal is to image these separate, but entangled, events simultaneously in single biomolecules, on time frames that allow us to monitor the associated chemical processes. We hope to exploit newly synthesized nonlinear optical dyes, and combine both confocal and wide-field microscopic techniques to attain this goal. By switching from linear to nonlinear optical dyes, we can measure single molecule two-photon fluorescence (and FRET) as well as second harmonic generation. In this way, we hope to be able to resolve events such as signal transduction at cell surfaces, as illustrated above, or diffusion through a membrane, as shown below.