Vanderbilt researcher investigates viruses and mutations

MutationsBy Fleming Smith

Executive Staff

On November 17, Dr. Clint Smith, a visiting post-doctoral fellow from Vanderbilt University’s Denison Lab, gave a presentation on his research. His talk dealt with “How Mistakes Fuel Virus Evolution and Disease.” With undergraduate and graduate students at Vanderbilt, Smith has researched coronaviruses, common viruses that typically cause respiratory tract illnesses; two examples would be Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). His research could help develop vaccines for such diseases. “Biology is really integrated,” said Smith at the beginning of his presentation. “Enzymology and cell biology and virology and ecology all intertwine to really dictate how viruses infect us and how they cause disease…mutations are important for the evolution and adaptation of these organisms.”

RNA viruses lack proofreading and mismatch repair that can correct such mutations, but coronaviruses are a marked exception to this rule. “It’s really the balance here, both for cellular organisms and also for viruses; you want to be able to copy your information correctly so that you can transmit it, but then also have enough mutations to where if a virus is encountering an antibody in your body, it can mutate to avoid that,” explained Smith. Organisms that can replicate their DNA with few mistakes are said to have high fidelity.

A balance between correct replication and advantageous mutations means a virus will have a higher fitness, therefore able to infect more organisms and survive for a longer time in a host body. Coronaviruses like SARS and MERS have this balance, creating a high mortality rate. “SARS killed about 10% of the people that we knew were infected,” Smith mentioned. Of course, researchers are not always certain of the exact number of people infected. He continued, “MERS killed about 35% of the people we knew were infected. The 1918 influenza—3%.” Outbreaks of SARS and MERS, taking place in 2002 and 2012 respectively, were countered by effective, modern public safety measures likely not available in 1918, but the difference is still staggering. “Coronaviruses are positive-sense RNA viruses. And what that means is that their genome is essentially mRNA that would be floating around in your cytoplasm,” said Smith.

To find out more about coronaviruses, Smith and his fellow researches began conducting tests on the power of these viruses both to proofread and adapt. Two proteins in particular drew the scientists’ attention, and they experimented on viruses with different drugs, testing the resulting variations of the SARS virus on mice to see the varied fitness of each viral strain. Smith and his team discovered that one of the proteins, “a protein that coronaviruses have, that only they have, is really important in determining how many mistakes they make,” in Smith’s words. The more particles of the virus were injected into the mice, the lower the rate of mortality due to all the mistakes in replication; specifically, mice were injected with the SARS-ExoN (-) strain. Even if the same mice were afterwards introduced to a wild-type strain, the previous virus, riddled with mutations, would protect the mouse against SARS. “This could potentially be used as a way to design attenuated viruses for vaccines,” Smith explained. Smith’s experiments Photo courtesy of Google images led him to believe that there is a strong relationship between fidelity, fitness, and adaptive success. His research is not complete, but above all, he thanked his colleagues, both student and otherwise, for all of their work. He emphasized the importance of including many voices in scientific work. As he ended his presentation, he reminded the audience, “Science does not happen in isolation.”

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