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Principal Investigator: Rhiju Das
Organization: STANFORD UNIVERSITY
Fiscal Year: 2023
Award: $684,690
Funding agency: National Institute of General Medical Sciences
PROJECT SUMMARY
The continuing discoveries of RNAs and their critical roles in cellular and viral machinery
are inspiring novel antibacterial, antitumor, antiviral, and genome-editing therapies
based on disabling, manipulating, and repurposing the RNAs involved. Unfortunately,
our poor biophysical understanding of `how RNAs work' is slowing the development of
these potentially life-saving efforts. A critical bottleneck has been the inapplicability of
crystallography, NMR, phylogenetic analysis, and biochemical methods to determine the
partly ordered conformations of non-coding RNAs in all their functional states. To
address this bottleneck, we bring together biophysical modeling, electron microscopy,
high throughput biochemical/sequencing experiments, machine learning, wet-lab-
integrated crowdsourcing, and a wide collaborative network. Current projects that
exemplify our approach involve the COVID-19 pandemic. With our Ribosolve hybrid
structure determination pipeline, we are discovering that numerous segments of the
SARS-CoV-2 RNA genome form well-defined 3D structures whose targeting by
antisense oligonucleotides inhibits viral replication. In the OpenVaccine challenge, we
are developing highly structured COVID-19 mRNA vaccines with sufficient in vitro
stability to enable world-wide shipping of mRNA in prefilled syringes. This COVID-19
research has benefited from our agile approach and the flexibility allowed by MIRA
support; many of the computational and experimental methods we use now did not exist
before the pandemic. Because RNA is so fundamental to life, tackling many of science's
further `big questions' in human disease could be accelerated if we could visualize and
design any RNA. My lab seeks to create the RNA computational and experimental
foundation needed to get all of us there in upcoming years.
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