Center for Molecular Biology of RNA
University of California, Santa Cruz
The UCSC COVID Ribozyme Project
Coronaviruses, which cause SARS, MERS and COVID-19 are RNA viruses - that is, their genetic information is encoded in RNA instead of DNA. This fact has caught the attention of researchers in the Center for Molecular Biology of RNA at UCSC. The Center is the largest and most prominent grouping of RNA researchers in the world, with 20 RNA research groups, three members of the National Academy of Sciences, a Nobel laureate and a Breakthrough laureate. The two research groups of William Scott and Harry Noller are leading the COVID Ribozyme Project, whose goal is to design a 'ribozyme' (a catalytic RNA molecule) to attack the RNA genome of SARS-CoV-2, the coronavirus responsible for the world-wide COVID-19 pandemic.
Professor Scott, who is a world leader in the field of ribozyme research, has developed a small, powerful ribozyme that can be designed to attack and cut virtually any viral RNA. In the case of coronaviruses, the cut will disable the virus's ability to replicate itself during infection. Initial experiments, in collaboration with Noller's group, have already identified four ribozyme designs that rapidly and specifically cut SARS-CoV-2 RNA targets in the test tube. Preliminary experiments now show that at least one of these ribozymes can attack its RNA target in human cells. Future experiments will be aimed toward asking whether these ribozymes can inactivate a live virus in infected cells and animal models. In addition to Profs. Noller and Scott, the collaboration has been critically dependent on the expertise of Dr. Sara O’Rourke, a UCSC virologist with extensive previous background working with human RNA viruses, and Dr. Laura Lancaster, an RNA Center molecular biologist whose focus is on ribosomes and protein synthesis.
The ribozymes are designed to target the most vulnerable and invariant sequences of SARS-CoV-2, including the gene encoding the infamous 'spike protein', which forms the knobs seen on the surface of the virus seen in electron microscope images. The spike protein is especially critical, because it recognizes and binds to a receptor on the surfaces of cells in the human respiratory tract, contributing to the unusually high infectiousness of the virus. However, researchers believe that even a cut anywhere in the virus RNA will inactivate its infectious capabilities.
Although several research groups and companies around the world are attempting to fast-track the development of a vaccine against SARS-CoV-2, effective treatments are nevertheless urgently needed for the millions currently infected world-wide. Furthermore, fast-tracking vaccine development will require shortcuts in testing such as human-challenge trials. In this type of trial, healthy patients are treated with a candidate vaccine, and then challenged with exposure to live virus to see if they have developed immunity. However, human-challenge trials can only be safely conducted if there is a treatment in case the vaccine fails. Development of an effective anti-COVID ribozyme could provide precisely such a treatment, allowing accelerated development of an effective vaccine.
Ribozymes are an especially attractive potential therapy for other reasons. First, they only target RNAs, so even if a ribozyme inadvertantly attacks a human RNA, RNAs are constantly being replaced in cells, and so our systems will rapidly recover. Second, we are further protected from any potential side-effects by the fact that that the ribozyme itself, being RNA, will soon be degraded. Third, RNAs have been found to enter human cells relatively easily, and effective RNA delivery systems have been developed in recent years. Because the SARS-CoV-2 virus infects the respiratory tract, delivery of an anti-COVID ribozyme could be as simple as using a nasal spray.
Importantly, RNA viruses, such as influenza, are well known to develop resistance to vaccines because they undergo mutations over time in the human population. These are usually mutations that cause changes in proteins on the surface of the virus. But Professor Scott has designed his ribozymes to attack RNA sequences that are completely invariant in all coronaviruses. So even when the next deadly coronavirus emerges, its target sequences will almost surely be unchanged, so will be knocked out by the ribozyme.
Finally, it is worth noting that most human viruses, including HIV, polio, influenza, rabies and even the common cold, are RNA viruses. Accordingly, there is no obvious reason why Scott's ribozymes could not be designed to attack any human RNA virus. In fact, Scott's group and his associated startup company IncisiveRNA, founded at the local Startup Sandbox incubator in Santa Cruz, are already developing candidate HIV-specific ribozymes for treatment of AIDS.
Since its founding in 1992 with a grant from the Markey Trust, the Center has
grown to 16 RNA faculty laboratories, distributed between the Departments of
MCD Biology, Chemistry & Biochemistry and Biomolecular Engineering, now
representing the largest grouping of RNA laboratories in the world. A hallmark of
the Center is the opportunity for interdisciplinary research. One notable example
lies at the interface between the study of RNA structure and its biological
functions. The presence of the UCSC Genomics Institute, faculty of which are
represented in the RNA Center, provides a unique and powerful infrastructure for
connecting experimental RNA science with computational biology.
Interdisciplinary interaction is encouraged through monthly RNA Club meetings,
where researchers from the RNA Center as well as invited outside speakers from
the Bay Area RNA community present their findings. Among the research topics
under investigation in the Center are the functions of long non-coding RNAs ('lnc
RNAs'), catalytic RNAs ('ribozymes'), ribosome structure and function,
spliceosomes and the mechanism of pre-mRNA splicing, protein-RNA
interactions in regulation of alternative splicing, gene regulation by micro RNAs,
RNA genomics, expression of RNA in single cells in different tissues and
nanopore sequencing of single RNA molecules.
Prospective postdoctoral candidates should apply directly to individual RNA
Center faculty via their email addresses as listed here.
Prospective graduate students should apply to the UCSC Graduate Program in Biomedical Science and Engineering
, or to the graduate programs in MCD Biology ,
Chemistry and Biochemistry , or