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.
"What's the best microRNA to choose? Which segment should I target? Is it better to target one segment with two microRNAs? Academically, it might not publish very well, but those details are important if you want to make clinical product." -Benjamin tenOever
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.
Half of tenOever's lab now works in bioengineering and vaccine development. The work sprung out of tenOever's deeply rooted enthusiasm for viruses and medicine and his grounding in molecular and cellular biology -- and it earned him a 2009 Presidential Early Career Award for Scientists and Engineers (PECASE). Now that he has added this new component to his scientific repertoire, tenOever has a foot firmly planted in translational research. "We patent things now," he says. "It's an obvious move toward making products that people can actually use."
Medicine to viruses
Growing up in small-town Ontario, Canada, with a veterinarian father, tenOever was surrounded by medical science from an early age. As an undergraduate at McGill University in Montreal, he planned to become a physician, initially taking the normal round of large, impersonal premed science courses. But when he took an elective course in microbiology, one fantastic professor outlined the workings of bacteriophages, the viruses that attack bacteria, with flair and passion. His interest piqued, tenOever sought out the popular science book, Invisible Invaders: Viruses and the Scientists Who Pursue Them by Peter Radetsky. The book, he says, "changed my life forever."
After that, he took every microbiology course he could. He proposed an independent study project in 1998, during his last year of his undergraduate work: studying hantaviruses within the rodent population in Montreal. The lethal Sin Nombre variant of hantavirus had emerged in the Southwestern United States years earlier, and tenOever wanted to compare the endemic local virus with that strain. He persuaded a faculty member who had equipment, space, and money (but a different research focus) to sponsor his research project -- on the condition that tenOever apply for a permit from the Canadian government to carry out the work.
"My last year of undergrad schooling and classes became a side note," he says. "I was essentially the exterminator for McGill." He got permission to set up mouse traps around campus -- in the morgue, in chemistry labs, and in offices where workers stored food in their desk. He got up at 5 a.m. each day to retrieve the traps.
By the time he heard back from the Canadian government about the permit, he had dissected the lungs of a couple hundred mice. However, because of concerns that he wasn't qualified and didn't have adequate biosafety facilities if he found a dangerous virus, officials apologetically pulled the plug on the project. It was disappointing, he says, "but I was addicted to virology from then on."
An unconventional virologist
He stayed at McGill for his Ph.D., working in virologist John Hiscott's laboratory. But instead of studying viruses using the classical approach -- how a virus replicates -- he studied how a cell recognizes that it is infected. "I had a freezer full of viruses, and I was ecstatic," he says.
When he looked for a postdoc in 2004, he weighed options, which included working with a more traditional molecular biologist, Tom Maniatis, then at Harvard University, or with a virologist, Adolfo García-Sastre at Mount Sinai School of Medicine, whom he'd met through Hiscott in the early days of his Ph.D. He proposed an option that allowed him to work with both. Based primarily at Harvard with Maniatis, tenOever developed a knockout mouse model to study a particular protein, IKKε, that's involved in the immune response to viral infection. He needed a virologist's expertise to study viral infection in vivo, so he brought the knockout mice to García-Sastre's lab to carry out the viral infection studies.
The work confirmed the expected role of this protein: helping a cell respond to viral infection by producing interferon. In addition, they also found a second -- and possibly more important -- role that they hadn't expected, Maniatis says: IKKε was actively involved in turning on other antiviral genes within a cell. Had tenOever not pursued the viral infection studies at Mount Sinai, he adds, "we simply wouldn't have discovered this [second] role of the kinase, because you'd never detect this in cell culture."
The work with García-Sastre helped tenOever land a faculty position at Mount Sinai in 2007. With his unconventional virology training -- studying cellular responses to viruses rather than viral infection -- "I've always had something to prove in calling myself a virologist," he says. But he is now surrounded by more virologists than at any other point in his career. TenOever's broader, almost outsider perspective is part of what makes his work creative, García-Sastre says.
TenOever is always willing to sift through unexpected results, interpret them, and figure out how they might lead to new research directions, says Jasmine Perez, a third-year Ph.D. student who has worked on tenOever's microRNA project from its earliest days. "We call him the Superscientist," she says, "Any project he picks up, he can make something out of."
A translational focus
At first, adapting his microRNA project to make it more translational meant puzzling through the question of how to tweak the flu virus's genetic code. In other models, microRNAs bind to untranslated regions of messenger RNA. However, influenza viruses don't contain any spare nucleotides: The viruses translate every bit of their genetic information. Therefore, tenOever and his colleagues had to figure out how to make sequence modifications that still produced functional viral proteins.
To fund the new approach to the work, tenOever contacted the Army Research Office, which sponsors new technology for vaccine development. The agency was so enthusiastic about the work that they funded the project within months and nominated his work for the PECASE.
Now that the initial idea has been published, the translational goal has also shifted tenOever's big-picture thinking. As a basic researcher, he has been most interested in looking for ideas that point toward new directions in the field: a new role for a protein or a new understanding of how cellular proteins drive the immune response. But designing solutions to real-world vaccine problems requires him to answer questions that he might not have pursued in the past: "What's the best microRNA to choose? Which segment should I target? Is it better to target one segment with two microRNAs?" tenOever says. "Academically, it might not publish very well, but those details are important if you want to make clinical product."
While many life scientists react to the growing complexity of the field by focusing narrowly, tenOever is an example of how doing creative science means finding new connections outside your original research niche, says Maniatis, who is now the incoming chair of the Department of Biochemistry and Molecular Biophysics at the Columbia University College of Physicians and Surgeons. "It's clear that the wider your understanding is, the more likely it will be that you will take your research in new directions."
The basic science of innate immunity and the more translational focus on vaccine development dovetail nicely in his laboratory, tenOever says. And the benefits of carrying out his research at a medical school and at Mount Sinai, in particular, go beyond working among a community of virologists. Although he doesn't currently take advantage of it, affiliation with a hospital offers tenOever access to primary blood and tissue samples, he says. More important for his work, he adds, is that Mount Sinai's Office of Technology and Business Development is particularly supportive of patenting research, making his findings usable to the public and advertising them to companies that might be interested in the technology. The feedback from companies is also valuable, both financially and scientifically. TenOever is already taking advice from researchers in the vaccine industry about the limitations of current products, such as FluMist, so that he can learn how to improve them.
"It's great that I can make a virus that grows great in eggs and dies in a mouse, but that wouldn't do any good if we didn't, one, have a patent for it and, two, spread the word to a company that might be interested and say, 'Hey, we can give you this technology if you want it,' " he says. Although you don't need to be at a medical school to have a great technology transfer office, tenOever notes, "That, to me, is a very good push toward clinical relevance."
Photo (top): Three-dimensional image of the Penicillium stoloniferum virus. W.F. Ochoa, UC San Diego; Source: San Diego Supercomputer Center, UC San Diego. (Courtesy, National Science Foundation.)
Sarah A. Webb writes from Brooklyn, New York.