Single-molecule insights for DNA/RNA/protein interactions and drug discovery and development: the next level of resolution, for the next era of genetic medicines

Molecular interactions lie at the core of biochemistry and biology, and their understanding is crucial to the advancement of biotechnology, therapeutics, and diagnostics. Most existing tools make “ensemble” measurements and report a single result, typically averaged over millions of molecules or more. These measurements can miss rare events, averaging out the natural variations or sub-populations within biological samples, and consequently obscure insights into multi-step and multi-state reactions. The ability to make and connect robust and quantitative measurements on multiple scales - single molecules, cellular complexes, cells, tissues - is a critical unmet need. In this talk, I will introduce a general method called “CLiC” imaging to image molecular interactions one molecule at time with precision and control, and under cell-like conditions. CLiC works by mechanically confining molecules to the field of view in an optical microscope, isolating them in nanofabricated features, and eliminates the complexity and potential biases inherent to tethering molecules. By imaging the trajectories of many single molecules simultaneously and in a dynamic manner, CLiC allows us to investigate and discover the design rules and mechanisms which govern how therapeutic molecules or molecular probes interact with target sites on nucleic acids; and how molecular cargo is released inside cells from lipid nanoparticles. In this talk, I will discuss applications of our imaging platform to better understand DNA, RNA, protein interactions, as well as emerging classes of genetic medicines, gene editing and drug delivery systems. I will highlight current and potential future applications to connect our observations from the level of single molecule to single cells, and opportunities for collaboration as we set up our labs at UBC.