Speaker: Jennifer Hurley, Professor, Rensselaer Polytechnic Institute

Circadian rhythms are highly conserved, 24-hour, oscillations that tune physiology to the day/night cycle, enhancing fitness by ensuring that appropriate activities occur at biologically advantageous times. Circadian rhythms are a phenomenon that exist across the tree of life and throughout biological scales, with broadly conserved atomic-level timekeepers enhancing fitness at the organismal level. Chronic disruption of proper circadian synchronization negatively impacts organisms throughout the kingdom of life, from disrupting metabolic networks in fungi to increasing the risk for Alzheimer’s disease and Related Dementias (ADRD) in humans. The paradigm for circadian regulation over physiology was that transcriptional programing via a transcription-translation based negative feedback loop (TTFL), or “clock”, drives temporally specific waves of gene expression to time cellular processes. However, using systems biological approaches in fungi, we have demonstrated that transcriptional programing from the TTFL cannot completely account for cellular circadian regulation. Our work has also begun to demonstrate the proteins involved in the repressive arm of the TTFL, enabled by their regions of protein disorder, act as “hub” proteins for the formation of large macromolecular complexes to impart circadian post-transcriptional regulation. Finally, we have used systems biology approaches to show that circadian post-transcriptional regulation tightly controls metabolism, affecting both fungal physiology and the mammalian immune response, the disruption of which increases the severity of ADRD symptoms. Our across-scales approach to studying circadian rhythms using fungi elucidates the fundamental principles of circadian timing, revealing the mechanisms of circadian control over molecular, cellular, and organismal physiology.

Microbial natural products remain an important source of lead compounds for drug discovery. Traditional approaches to microbial natural product discovery take a microbe first approach in which individual strains are cultured in the lab and bioassays used to guide the isolation of active compounds. While once productive, the limitations to this approach are now well documented and include the recognition that only a small percentage of the bacteria present in the environment are readily obtained in culture. We have developed a new approach to microbial natural product discovery in which compounds are isolated directly from the environments in which they are produced thus bypassing the initial need for laboratory cultivation. This culture independent approach, which we call Small Molecule In Situ Resin Capture (SMIRC), is agnostic to the biological source of the compounds and requires no up-front knowledge of cultivation requirements or the cues needed to induce biosynthesis. Initial SMIRC deployments have yielded extensive, biome specific chemical diversity including compounds previously reported from marine plants, invertebrates, and bacteria. Mining compounds that could not be identified has yielded unprecedented carbon skeletons and demonstrated that sufficient yields can be obtained for bioactivity testing and NMR-based structure elucidation. These results suggest a path forward to access new chemical space for drug discovery and to address the ecological functions of marine natural products.