Michaela Gack Vilcek Dropdown Arrows
Michaela Gack
The Vilcek Prize for Creative Promise in Biomedical Science
Michaela Gack, Ph.D.

Early success is a recurring theme in Michaela Gack’s scientific career. From her high school days in her native Germany to her current position as associate professor at the University of Chicago, Gack’s ambition has fueled her meteoric rise through the ranks of molecular biology. Her work has unraveled the intricacies of how viruses evade the human immune system and uncovered molecular targets for the development of drugs and vaccines for a range of infectious diseases.

Raised in a small town in the German state of Bavaria, Gack became enamored with human biology as an undergraduate student at Friedrich Alexander University in Erlangen-Nuremberg. There, she became fascinated with the nuances of the molecular arms race between cancer-causing viruses and the human immune system. She pursued her interest through a collaborative graduate training program between her university and Harvard Medical School, where she arrived in 2005 to begin PhD studies in the lab of molecular biologist Jae Jung.

While working with Jung at Harvard, she identified a novel molecular mechanism through which a protein in human cells called RIG-I mediates defense against viruses. The role of the protein in detecting viruses had been previously established. “RIG-I essentially alerts the immune system to the presence of viruses and sets off an immune response, but many aspects of its mechanism of activation were unclear,” explains Gack. Using biochemical methods, Gack found that an enzyme called TRIM25 activates RIG-I by tagging it with a protein called ubiquitin. Once tagged, RIG-I triggers the production of antiviral defense molecules known as interferons.

Researchers had long known that ubiquitin-tagging of proteins earmarks them for destruction by cells. Gack’s work, published in Nature, surprisingly revealed that such protein modification can also play a crucial role in immune defense against invading viruses. “In the wake of our discovery, this kind of atypical ubiquitin-tagging by TRIM enzymes was found to be fairly common in antiviral immunity, and many TRIM proteins are now implicated in immune sensing and signaling,” says Gack. More importantly, Gack found that avian, swine, and human flu viruses block TRIM25 to evade immune defense by RIG-I, unraveling a molecular target for the design of antiviral drugs and vaccines.

“The discovery that TRIM25 activates RIG-I happened soon after I started my PhD,” recalls Gack. And it promptly earned her wide acclaim and a faculty appointment at Harvard Medical School, where she rose to an associate professorship in an uncommonly brief span of six years. In 2015, she accepted an associate professorship at the University of Chicago.

Meanwhile, Gack’s work has also shed light on the mechanisms through which mosquito-borne viruses such as dengue virus and West Nile virus evade the human immune response. Previous studies had established that antiviral defense triggered by RIG-I depends on the protein’s proper intracellular localization and transport, which are mediated by a partner-protein called 14-3-3 epsilon. By directly binding to RIG-I’s partner, dengue and related viruses dampen its protective action. Gack’s team found that mutating the dengue virus protein that binds to 14-3-3 epsilon essentially overrides the subversive action of the virus. More to the point, by genetically stripping dengue virus of its ability to bind 14-3-3 epsilon, Gack has generated a crippled virus that can elicit a strong human immune response, providing a framework for rational vaccine design against emerging infectious diseases. Extending those findings, Gack and her collaborators are now investigating the physiological role of this immune evasion strategy for other mosquito-borne viruses.

Gack says her goal is to continue to unravel molecular mechanisms that might someday yield antiviral vaccines and drugs not only for emerging and re-emerging viruses but also tumor-inducing viruses, such as certain herpesviruses and human papillomaviruses. Judging by her past accomplishments, she is destined for future success. Early success, she says, was the result of her unremitting drive and the unconditional support she received in the United States. “The US is so multicultural, it gave me so many new perspectives—for research and for life. I think it’s the diversity of people and opinions that keeps me in this country,” she adds.

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