MRI: Development of a Highly-Multiplexed Cavity Optomechanical System for Single-Molecule Mass Spectrometry and Inertial Imaging

California Institute Of Technology, Pasadena CA

Investigators

Abstract

This project is to develop an unprecedented instrument for studying proteomics - the collection of proteins constituting the molecular machinery underlying all life forms. Genes are the molecular precursors of this cellular machinery; genes are the templates encoding how such proteins are constructed within cells. A profound technological revolution has recently enabled detailed studies of genomic templates; indeed, it has permitted decoding the human genome itself. Similar advances in technology for proteomics has not occurred. Underlying this is the fact that genomic studies are enabled by making billions of identical copies of individual genes. This gene amplification then enables their straightforward analysis en masse. No similar molecular amplification process exists for proteins. In fact, critical processes in health and disease are often determined by only a few copies of a protein molecule within a cell. Fundamental advances in biology and medicine can therefore only be made if proteins are studied molecule-by-molecule. A practical means for accomplishing this is identified in this effort, and assembly of novel instrumentation for such analyses is proposed. The research team has identified a unique technological path toward these ends that concatenates three key elements. First, single-molecule analysis of intact proteins and protein complexes. This is based on two novel approaches previously invented by this team - nanomechanical mass spectrometry and inertial imaging. Second, microwave-frequency cavity optomechanics. This enables ultrasensitive measurements upon the key nanomechanical devices, down to the quantum-mechanical limits of detection. Third, state-of-the-art high-resolution native mass spectrometry. This enables studies of intact (unfragmented) proteins and protein complexes. These three building-blocks will be assembled into a singular hybrid instrument to enable a new multi-physical approach for single-protein analyses that surmounts the limitations of all current methodologies. It offers realistic prospects for automated, high-throughput protein purification, and for identification of intact protein species. Further it is technology that could ultimately be widely disseminated. Deep proteomic profiling of individual cells will be transformational for biological research, clinical medicine, and pharmaceutical development. Surprisingly, no other technology is poised to enable this. The proposed work will be highly cross-disciplinary in nature, bringing together efforts of researchers spanning physics, engineering, chemistry, biology, and mathematics. This project's highly-collaborative and rich research environment will provide unparalleled opportunities for graduate students and postdocs involved in its broader efforts. The team and the collaborators are committed to providing long-term access to this instrument for biological and medical research - both in academia and industry. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.