THE FRANCIS S. COLLINS COLLEGIATE PROFESSORSHIP IN CHEMISTRY, BIOPHYSICS AND BIOLOGICAL CHEMISTRY, INAUGURAL LECTURE
Billions of safely given mRNA vaccine doses have saved millions of lives worldwide and proved beyond the shadow of a doubt that a transformative era of RNA Therapeutics is upon us, with great promise for overcoming virtually all diseases within this century through personalized medicines. Yet RNA can do so much more! Since the human genome project was completed, we know that at least 75% of our 3 billion DNA base pairs are transcribed into RNA, with the vast majority not coding for proteins but rather for “non-coding” RNAs (ncRNAs). Many of these ncRNAs remain uncharacterized in terms of their structure and function, spawning discussions of whether they are functional or not (and what “biological function” even is!). These applications and discoveries suggest that so far we have underestimated the far-reaching “RNA World” in our body, which may well also have spawned life on earth.
After an introduction to the power and benefits of these “new” and “old” RNA Worlds, this seminar will highlight some of the foundational work by the Walter lab, in which we use modern single molecule fluorescence microscopy to dissect and control the nanometer-sized RNA-protein assemblies that govern life, and particularly gene expression. Specifically, single molecule fluorescence resonance energy transfer (smFRET) allows us to measure distances at the 2-8 nm scale, whereas complementary super-resolution localization techniques measure distances in the 10 nm and longer range where biology occurs. Embracing the power of these technical advances, we have combined single-molecule, biochemical and computational simulation approaches to show that a bacterial riboswitch – controlled by a metabolite ligand – manipulates the speed of the much larger bacterial RNA polymerase. We posit that many more examples of such intimate coupling between RNA folding and gene expression remain to be discovered, leading to opportunities to identify new Achilles’ heels of the many pathogens that threaten human health. In addition, we are developing tools to observe single RNA nanomachines in action within their natural habitats inside living cells, leading to discoveries that may guide the development of novel cancer-fighting approaches.