By Katerina Kanevche & Amr Sobeh

The function of all living cells depends on the subcellular compartmentalization and spatial distribution of a broad range of small molecules, from metabolites to signaling molecules and cellular building blocks. Determining the spatial distribution of small molecules within cells is therefore crucial for understanding fundamental cellular mechanisms. And yet, we presently lack the ability to determine the subcellular distribution of the vast majority of these molecules.

This project aims to develop an instrument of unprecedented capability that will, for the first time, allow for the identification and mapping of any small molecule within its native cellular environment at nanometer resolution. The successful development of this technology will immediately provide access to a host of unsolved problems in biology and has the potential to revolutionize our understanding of metabolism in healthy and diseased cells.

Our approach involves a unique combination of a quantum-based technique for discrimination between molecular species with scanning tip-enhanced spectroscopy for nanometer-scale resolution. An atomic force microscopy (AFM) tip is scanned across the sample, providing a sensing volume of a few cubic nanometers. We employ high-resolution vibrational spectroscopy, along with the quantum optimal dynamic discrimination (ODD) technique to detect the molecule of interest within the crowded cellular environment.