Return on Investment

For the first 20 years of his research career, Mark Denison, MD, studied a virus that few of his colleagues considered important. He remembers hallway conversations that went something like: “You’re a smart guy, Mark, why don’t you study a different virus?”

Denison, director of the Division of Pediatric Infectious Diseases, was undeterred. He was interested in fundamental questions about virus biology, and his focus — mouse hepatitis virus — was a good model.

Plus, it was a coronavirus. At the time, it was known that coronaviruses that infected humans caused the common cold, and that other coronaviruses caused severe disease in animals. Denison and the handful of other researchers who studied this virus family through the 1980s and ‘90s thought that a coronavirus might someday cause severe disease in humans.

They were right.

In 2003, a coronavirus caused SARS (severe acute respiratory syndrome); another caused MERS (Middle East respiratory syndrome) in 2012; and a third caused this year’s COVID-19 global pandemic.

Denison didn’t set out to be a physician-scientist. He planned to be a general practice pediatrician, like his father. During his pediatrics residency at the University of Iowa, he got interested in infectious disease and thought it would be a useful addition to his practice, so he decided to complete fellowship training in the specialty.

“As I got into it clinically, I became very frustrated with the lack of answers to questions in infectious disease and how quickly it was changing, and I stepped into Stan Perlman’s lab at Iowa just to see what the research process was like,” he says. “I landed on this ‘side project’ he had looking at the biology of coronaviruses.”

Studying mouse hepatitis virus, Denison and Perlman were the first to identify coronavirus proteins that were required for the virus to reproduce. Denison continued to study coronavirus replication during his first faculty appointment at Thomas Jefferson University in Philadelphia, and after he arrived at Vanderbilt in 1991.

Despite the relative lack of interest in coronaviruses from some of his colleagues, Denison found continuous funding support from the National Institutes of Health and philanthropic sources and made steady progress defining essential features of coronavirus biology.

“At the level of the NIH, there has always been a recognition that fundamental research in virology is important for truly understanding how viruses are unique and what functions they have that can become targets for interference,” Denison says.

Using mouse hepatitis virus, and later the SARS and MERS coronaviruses, Denison and his team defined essential features of viral replication and pathogenesis. They discovered a novel proofreading mechanism that is active during replication and were the first to demonstrate that a compound from Gilead Sciences inhibited the replication of multiple coronaviruses.

That compound, remdesivir, received emergency approval from the Food and Drug Administration this spring as a treatment for patients who are severely ill with COVID-19.

With his 35-plus year history of contributions to understanding coronavirus biology, Denison is a sought-after source for journalists. He’s doing his best to help educate, he says, while also making sure that members of his research team stay healthy and rested. Working with dangerous viruses in a biosafety level 3 (BSL-3) laboratory requires “a level of vigilance and attention to detail that is physically and mentally exhausting.”

Denison relaxes by juggling, playing the tin whistle and enjoying long Saturday evening dinner chats with his three adult children and their significant others, separated into the four corners of a large screened porch.

He and his research team continue to search for new antiviral compounds that might work even better than remdesivir; they’ve already identified several good candidates in collaboration with the Emory Institute for Drug Development. They are also exploring ways to attenuate coronaviruses — as a strategy for future vaccine development.

“I hope that a simpler vaccine strategy, like the ones we’re involved in testing now, will work,” Denison says. “But this may not be the last coronavirus. We’re doing the work for the current one, but we’re always planning for the next one.”

Denison is the Edward Claiborne Stahlman Professor of Pediatrics, professor of Pathology, Microbiology and Immunology, and director of the Lamb Center for Pediatric Research.

— by Leigh MacMillan

Hope – Summer/Fall 2020