In late 2007, during the early months of his faculty position at Mount Sinai School of Medicine in New York City, Benjamin tenOever faced a wrinkle in his research plans. Experienced in looking at how cells respond to viruses, he'd set his sights on microRNA and how these small molecular segments that tweak protein expression might help cells fight off infection. After months of work, the project looked like it might be a dead end: They had found that microRNAs are produced as a virus infects a cell, but those sequences didn't make a difference in how a cell responded to its invader.
With the dilemma percolating in the back of his mind, tenOever had a eureka moment while shopping with his wife along Lexington Avenue in Manhattan: “Every cell has a pool of microRNAs, even if they didn't target the viruses,” he explains. So, he wondered, what if he flipped the idea around and engineered viruses that bound to the existing cellular microRNAs? Instead of trying to harness a cell's microRNAs to fight infection, he would be creating tools to tweak the immune response of an altered vaccine. The strategy could provide a stealth way to build attenuated viruses for producing vaccines. Since then, he and his colleagues have modified the sequences of influenza viruses to bind to a natural microRNA expressed in humans and mice, in essence developing a virus that's knocked down by the body's natural microRNA. What's more, the microRNA they chose is not expressed in chickens; therefore, the modified virus reproduces well in chicken eggs, potentially solving a common flu vaccine-production problem. They reported the work in the June issue of Nature Biotechnology.