Photo by Bo Jungmayer / Fred Hutch News Service
Fred Hutchinson Cancer Research Center’s Dr. Adam Geballe has been named a fellow of the American Association for the Advancement of Science (AAAS). Fellows are elected by their peers for their scientifically or socially distinguished efforts to advance science or its applications. Geballe, who is associate director of the Hutch’s Human Biology Division, was recognized for identifying two key proteins in a virus called cytomegalovirus (CMV) that counteract the defenses of the humans it infects.
CMV causes a common and usually symptom-free infection. But it can be dangerous in individuals whose immune function is weak, such as newborns or those undergoing transplant. As the human body has evolved strategies to block CMV, the virus has evolved its own methods to circumvent these barriers.
It was Geballe’s contributions to our understanding of this struggle, by revealing the molecular determinants of the ‘arms race’ between CMV and humans, which led to his election as AAAS Fellow. He joins 13 other Fred Hutch researchers who have also been honored by AAAS, the world’s largest general scientific society, dedicated to advancing science for the benefit of all.
Pinpointing key players in molecular tug-of-war
Once it’s infected a cell, CMV must create more copies of itself to spread to more cells and further the infection. To do this, the virus co-opts our cells’ own machinery to create a virus-producing factory. But the products from a virus factory look a little different than usual. Our cells take advantage of what Geballe calls a “weak link in the virus life cycle” to sense a viral takeover and develop a targeted counterattack.
One of those virus sensors in human cells is protein kinase R (PKR). Once PKR is triggered by viral products, it pulls the emergency brake on the cellular machinery the viruses have appropriated and shuts down the virus factory. It’s not necessarily that great for the individual cell (which can no longer use its own machinery), but it’s a small price to pay for the organism, explained Geballe, who has studied large DNA viruses like CMV throughout his 30 years at Fred Hutch.
“This stops viruses, but viruses have ways to counteract that in the arms race scenario,” he said. “We know that a lot of viruses have one, two, three genes to block that pathway.”
Geballe and his team pinpointed the two proteins that human CMV uses to block PKR in the ongoing tug-of-war between virus and host. When the researchers removed the genes for those proteins from CMV, it could no longer grow in the lab. But when they also removed PKR from the human cells, the defanged viruses grew normally.
Various types of CMV infect different organisms, from humans to guinea pigs to a wide range of monkeys. Geballe aims to understand how their different PKR-blocking proteins work and how they evolve. He has explored the evolutionary shifts of PKR and viral inhibitors of PKR in different species and species-specific viruses to see how changes affect each molecule’s effectiveness. Ultimately, he hopes to better understand the molecular interactions underpinning the viruses’ ability to counteract PKR. It’s possible that doing so could reveal how manipulating such a critical pathway could be used to improve human health.
“My longer term goal is to be able to control the pathway,” he said.
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Sabrina Richards, a staff writer at Fred Hutchinson Cancer Research Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a Ph.D. in immunology from the University of Washington, an M.A. in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at firstname.lastname@example.org.