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A team led by Harvard Medical School (HMS) researchers is exploring the possibility of creating an entire new class of medicines, with up to $4.4 million in federal funding from the Advanced Research Projects Agency for Health (ARPA-H) under its PROPEL project.
The award, in the form of a contract to HMS, supports a one-year, multi-institution pilot project to accelerate the development of RNA medications that would use genetic switches called riboswitches to regulate genes within the human body. If the ambitious effort pans out, this platform could eventually apply to many different diseases, including cancer, metabolic diseases such as diabetes, autoimmune disorders, neurodegeneration, and rare genetic diseases.
Led by principal investigator Silvi Rouskin, assistant professor of microbiology in the Blavatnik Institute at HMS, the team includes collaborators at MIT’s Whitehead Institute and RNAV8 Bio (pronounced “renovate”), a biotech firm that specializes in mRNA engineering. The PROPEL project is managed by Program Manager Dr. Shannon Greene in ARPA-H’s Health Science Futures Office.
The project launched in late July 2026.
Simple switches that manage complex biological processes
Riboswitches alter gene activity in response to simple chemical cues from small molecules. This last detail makes them ideal candidates for potential therapeutic approaches.
The discovery of riboswitches by Yale University’s Ronald Breaker and others in 2002 was extremely exciting, Rouskin said. While it was originally thought that a given piece of RNA could only fold into a single shape, riboswitches work because they can form alternative shapes, depending on the presence or absence of specific chemical signals. These shifting RNA shapes regulate basic metabolic functions by switching genes on and off.
Many riboswitches have been found in bacteria and some in fungi, but they have been harder to locate in more complex organisms. No riboswitches have been verified in humans, although Rouskin’s previous work has hinted toward candidates.
Acknowledging that the work ahead is extremely challenging, Rouskin said that recent advances by her and colleagues on the PROPEL project have uniquely positioned the group to uncover how riboswitches regulate gene expression and begin to find ways to use them.
PROPEL’s long-term goal is to discover and design RNA switches that function in human cells so they can be used as the foundation for highly precise medicines that turn specific genes on or off only at the right time and in the right cell types. For example, if a switch is identified in the human genome that activates a metabolic response that might be helpful to treat some symptom of a disease, the small molecule that flips the switch could be delivered as a medication, or a natural or engineered switch might be built into a therapeutic RNA to target or amplify the therapeutic’s impact.
If the project is successful, doctors could eventually use these personalized, targeted mRNA therapies to improve treatment effectiveness and limit side effects.
Collaboration will be key to success
For the one-year pilot project, the goals are to identify or engineer a riboswitch that can function in a human cell and to build a map of other riboswitches — or genes that might be amenable to switching using this technology.
Rouskin’s lab uses methods from biochemistry, computational biology, and machine learning to explore the dynamics of folded RNA inside living cells, which illuminates the broader question of how RNA structure controls biological processes. The resources from the PROPEL award will enable the team to deploy more powerful tools and a more diverse set of approaches to the problem and speed up the search, she said.
To overcome the challenges inherent in identifying these tiny molecular machines hidden in the vastness of the human genome, PROPEL will use powerful AI models, rapid RNA structural analysis, and large-scale screening. The team aims to identify and engineer riboswitches that detect chemical signals associated with many different diseases.
Whitehead Institute member Jonathan Weissman, also a professor of biology at MIT and an investigator of the Howard Hughes Medical Institute, will lead an effort to screen for regulatory sequences in the untranslated regions of the genome, focusing on the areas adjacent to genes which contain proteins that control when and how those genes are expressed.
RNAV8 Bio will focus on engineering and testing mechanisms for the delivery of potential medications.
“Working with the Weissman Lab and RNAV8 Bio means combining strengths, with each team bringing something crucial to the project,” Rouskin said, pointing out that the Weissman Lab brings world-class expertise in genome-wide screening and RNAV8 knows how to deliver RNA as a drug.
“Pairing academic discovery with industry’s ability to execute is, honestly, the only way I see this becoming a real therapy instead of just another paper,” Rouskin said. “That’s the best part for me, building something together that none of us could built alone.”
The road from scientific discovery to better human health
Rouskin’s curiosity-driven, basic science work — using computational models to understand the fundamental rules that govern the ways RNA molecules twist and fold to perform the regulatory functions for the basic processes of life — has always been aimed at finding ways to put that machinery to work to improve human health.
“I came to the United States alone at 15, with a lot of aspirations for my science and no map for how to get there,” Rouskin said.
Recalling the sacrifice her mother made, letting Rouskin grow up an ocean away from her and the rest of her family, Rouskin said that her mother often asked how this research would actually help people.
“This project is a big step toward being able to answer this question with something that I built,” Rouskin said.
