2020 Nobel Prize in Medicine awarded to RNA Society member, Charlie Rice
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Written by Brett Lindenbach

In a decision that underscores the fundamental role of RNA science in biomedicine, Charlie Rice has been awarded the 2020 Nobel Prize in Medicine for his work on cloning, culturing and characterizing the RNA genome of hepatitis C virus (HCV).   Through work led by co-awardees Harvey Alter at NIH and Michael Houghton at Chiron Corporation, a single immunoreactive cDNA of the HCV genome was initially obtained, revealing a ~10-kb positive-strand RNA genome that is distantly related to mosquito-borne flaviviruses, such as yellow fever virus.  Although this was a landmark discovery, further progress was initially slow because the virus was not culturable and only infected chimpanzees. These discoveries piqued the interest of Charlie Rice at Washington University, who set out to construct a functional cDNA clone of HCV.  However, after assembling a full-length clone based on the reported sequence, they found that RNA transcripts failed to produce signs of HCV infection after injection into chimpanzees. Suspecting that the reported 3´-end was incorrect, Charlie’s lab went back and resequenced the HCV genome with more sensitive methods, finding that the HCV 3´ noncoding region consisted of a short variable region, a homopolymeric polyuridine/polycytidine region, and a novel, highly structured 98-nt region. Lo and behold, in vitro transcripts containing this authentic 3´ end were now infectious in chimpanzees, validating the functionality of the cDNA clone that the Rice lab had reconstructed. These efforts then led to the construction of self-replicating “replicons” that could be used to study HCV RNA replication in cell culture and enabled drug screening efforts that ultimately led to potent virus-specific antiviral compounds that have cured millions of HCV patients.  As we now know, the HCV genome is a goldmine of functional RNA structures, including an uncapped 5´ end that is protected from 5´-3´ exonuclease degradation by a host microRNA, an elaborately structured ribosome entry site, and numerous conserved and functionally important RNA structures embedded within the coding and noncoding regions.