Benjamin tenOever had just earned tenure at the Icahn School of Medicine at Mount Sinai when The Scientist first profiled him. He had overcome the first major obstacle in his career; after a year of failed experiments that disproved his hypothesis about the role of microRNAs in mammalian cellular responses to viral infection, he used synthetic biology to turn microRNAs into an antiviral system in mice. “I still to this day love viruses,” he said at the time. “They’re the things I love the most.”
Now, tenOever harnesses his virology skills in applications from rare disease therapeutics to xenotransplantation. For The Scientist’s 40th anniversary, tenOever shared how he has spent the last decade or so following his data down some interesting and unexpected roads, creating microRNA circuits to alter cell behavior and deliver new therapeutics.
“I definitely would never have thought that I'd be talking to you today about making cell-specific delivery systems for prime editors using viruses if you had asked me [12] years ago,” he laughed. “And I would never have been able to predict the path that brought me here.”
MicroRNA Circuits Inside a Virus Enable Cell-Specific Delivery
There have been two major shifts in tenOever’s research approach over the years. The first has been a shift in focus from pursuing very specific questions—such as how the mammalian immune system responds to viral infection—to attempting to understand the bigger picture. The second shift has been methods-based. “I've really moved away from observing biology to try and understand it, to programming biology to understand it,” tenOever explained. “[It’s] a really different way to approach science, but it's one that I really enjoy doing. And it really has moved my program in very different directions.”
His earlier work with microRNAs and reprogramming them into an antiviral system has been career-defining, and tenOever has come back to this field again and again.1 While other approaches can encounter reproducibility issues when transitioning from in vitro to in vivo models, tenOever said microRNAs are exactly the opposite: “The more in vivo you go, the better it works.”
Recently, tenOever and his team have been working with microRNA switches called on- and off-gates to build circuitry, much like the hardware inside a computer. Among other applications, these logic gates are used to trigger responses, like the identification of specific cell types. “[It can] change the behavior of how much protein comes off an RNA, whether an RNA gets cleaved, degraded, [or] saved,” he remarked. “And you can start multiplexing these things on top of each other. So, with each passing year, we find another way to multiplex it.”
tenOever is now the Chair of the Department of Microbiology at NYU School of Medicine, where his laboratory explores virus-host interactions and therapeutic strategies.
NYU School of Medicine
After building this circuitry, they can add gene editing components, such as prime editors and guide RNAs, and package it all within a virus-like particle for cell-specific delivery. “It looks like a virus, but it causes no disease,” tenOever said. “It only runs its program when a certain microRNA profile is present, which means that we can [deliver it] specifically to the exact terminal cell that you want and nothing else.” He hopes this highly programmable delivery system will allow his team to produce life-saving therapies for rare diseases. Because the system shows promise in localized delivery to the lungs via intranasal administration in preclinical animal models, their current targets include inherited pulmonary diseases such as primary ciliary dyskinesia.
Moving to NYU has also been a defining moment in tenOever’s career; the seamless integration of the academic research and medical arms of the university has allowed him to develop meaningful multidisciplinary collaborations and put his microRNA system to good use in addressing unmet patient needs. One of those needs is xenotransplantation, the transplantation of cells, tissues, or organs from one species to another; it’s a field that is poised for a much-needed breakthrough. “We have really created a very comprehensive tool set that allows us to build what once was a virus, but now is essentially a microRNA-controlled computer, to deliver things like Cas9,” he said.
When pig organs are harvested, they can be placed on an ex vivo perfusion system, which keeps them alive for days or weeks outside of the body with no immune system. This, tenOever said, is the perfect window in which to perform multiplexed gene editing that will help make the organs suitable for transplantation into humans. “The idea is that you can then immediately test them, rather than having to wait to find what the next bottleneck is going to be,” he said.
When it comes to his microRNA computer system, tenOever said there are myriad future directions he is keen to pursue. “The truth is that once you have these tools in place, there are so many applications, and it's so easy to just change the software and then apply it somewhere else,” he said.
Pivoting During the Pandemic and Harnessing AI
During the COVID-19 pandemic, tenOever and his team worked with animal models to try to understand the SARS-CoV-2 virus and identify an approved compound that could provide therapeutic benefit to patients in the intensive care unit.2 Unfortunately, none of their early leads panned out, but scientifically, it was an invaluable experience. Aside from their testing of therapeutic compounds in animal models and sequencing viral variants, the team also explored the virus’s immune evasion strategies, host susceptibility genes, and the effects of Long COVID. “We were working 110-hour weeks, every week, for two years straight,” he said. “It was insane. We were bringing cadavers into our [lab]. We were just so outside of our wheelhouse, but it was just so clear how important it was.”
In terms of technology, artificial intelligence has helped tenOever and his team integrate and analyze massive datasets from spatial and single-cell transcriptomics to proteomics.3 Programs like AlphaFold have also allowed him to reverse-engineer proteins and create mimetics with the same three-dimensional structure. In the context of their therapeutic delivery system, creating a biological mimetic of a viral entry component allows them to avoid issues of an immune response to the original virus due to prior exposure—a common problem with viral vectors like adeno-associated viruses. “It allows you to actually kind of fit into this idea of moving away from just observing biology but trying to program it and see if you can control it in a predictable way,” said tenOever. “It's a really powerful tool.”
Reflecting on his earlier profile, tenOever said it was immensely transformative at a stressful time, helping him gain valuable career momentum. “Once that momentum starts, a journal or magazine like The Scientist then catches wind of you, and they put you out there and expand you a little bit more. Then you get the attention of people who are organizing meetings or looking for their seminar speakers,” he recalled. However, the best advice that helped him through tough stretches came from his mentor and Mount Sinai virologist Peter Palese: “Don't think about failure. Just assume you're going to succeed and just keep going full throttle.”
- tenOever BR. RNA viruses and the host microRNA machinery. Nat Rev Microbiol. 2013;11(3):169-180. 2.
- Daniloski Z, et al. Identification of required host factors for SARS-CoV-2 infection in human cells.Cell. 2021;184(1):92-105.e16
- Frere JJ, et al. Quantitative tissue proteomics reveals protein signatures associated with SARS-CoV-2 variant infection in hamsters. J Proteome Res. 2026;25(2):920-935.
