Ryan Flynn, Assistant Professor of Stem Cell and Regenerative Biology, Principal investigator in the Stem Cell Program at Boston Children’s Hospital, and faculty member of the Harvard Stem Cell Institute, has been recognized with the NIH Director’s Transformative Research Award. He shares the award with collaborator Eliezer Calo an Associate Professor at MIT and the Koch Institute.
The Transformative Research Award, established in 2009, promotes cross-cutting, interdisciplinary approaches and supports individuals and teams of investigators who propose research that could potentially create new, or challenge existing, paradigms. This prestigious accolade highlights Flynn’s work in cell surface RNA biology—an emerging field he has played a pivotal role in establishing. The award supports his and Calo’s research into understanding how and why RNA and RNA-binding proteins (RBPs) function on the surface of cells, a question that could lead to transformative insights in cell biology and disease mechanisms.
The focus of the NIH-awarded project is on investigating the functions and properties of cell surface RNA binding proteins (csRBPs) and determining whether csRBPs may play a role in human disease.
Flynn, who has been leading pioneering research into this topic, describes the NIH grant as a critical milestone in his career. “The goal of my lab is to understand why cells make glycosylated RNAs, place them and RNA-binding proteins on their surfaces, and to uncover the biological roles they play in normal cellular functions and disease contexts,” he said. “The Transformative Research Award is unique because it supports high-risk, high-reward research, which is exactly what we’re doing.”
A New Frontier in RNA Biology
The work in Flynn’s lab centers around a novel and unconventional area of study: the biology of cell surface RNA. Historically, RNA was believed to be confined to the inside of the cell, performing its well-known role in protein synthesis. However, Flynn’s research has revealed that RNA is glycosylated and present on the surface of cells, a discovery that challenges the current understanding of cell biology.
Flynn’s investigation began with a groundbreaking discovery in 2021 when he identified “glycoRNAs,” RNA molecules conjugated with sugars, on the surface of cells. “This was a surprising discovery because it defied what we previously understood about how RNA behaves in cells. We showed that RNA could be modified with glycans, which typically attach to proteins or lipids,” Flynn explained. This finding opened up an entirely new area of exploration into how RNA may be involved in processes at the cell membrane. A paper describing the conclusive proof of how glycoRNAs are formed was published in Cell in August.
The central goal of Flynn’s research, which the NIH grant will help support, is to uncover the mechanisms that govern the presence of RNA and RNA-binding proteins on the cell surface. “We want to understand how these molecules get to the surface, what their functions are once they’re there, and how they might contribute to disease,” Flynn said.
While Flynn’s research remains at the frontier of basic biological discovery, it holds promise for future applications in disease understanding and treatment. According to Flynn, studying cell surface RNA and RNA-binding proteins could help illuminate how cells communicate with one another and how diseases such as cancer hijack these processes.
One of the most intriguing findings from Flynn’s lab is the role of RNA-binding proteins in facilitating the entry of molecules into cells, a phenomenon known as “cell penetration.” Flynn has observed that certain RNA-binding proteins, which were thought to be confined to the interior of the cell, can function outside the cell as well. “One of the key questions we’re asking is: how do these proteins get from the inside to the outside of the cell without traditional membrane-targeting signals?” Flynn said.
This area of research could have far-reaching implications, especially in the field of drug delivery. “If we can understand how RNA-binding proteins are trafficked to the cell surface and how they control what enters and exits the cell, we might be able to harness these processes for therapeutic purposes, such as improving the delivery of drugs to target cells,” Flynn added.
Ten-Year Collaboration
The NIH Director’s Award recognizes Flynn’s research collaboration with Calo who he has worked with for 10 years after first meeting when Flynn was a graduate student and Calo was a postdoctoral researcher. “We both study RNA-based mechanisms, and he studies a lot of the nucleolar processes. And now I’m studying the cell surface,” says Flynn. “This grant is the culmination of years of joint work, and it’s exciting to think about what we’ll uncover by combining our expertise,” Flynn said. Their collaboration aims to address the fundamental question of how RNA-binding proteins are trafficked to the surface of the cell and how their roles differ from their well-understood functions within the cell.
Flynn acknowledges that his work stands at the edge of conventional understanding, and this is precisely why the NIH chose to support it. “The NIH reviewers noted that the study has the potential to be highly transformative because it challenges existing dogma and explores a field that is virtually uncharted,” he said. “It’s one of the most innovative areas of cell biology right now because we’re discovering entirely new processes that no one thought could exist.”
Shaping a New Scientific Paradigm
Flynn is optimistic that his research will lead to a paradigm shift in how scientists think about cellular biology. “There’s a growing body of evidence showing that RNA and RNA-binding proteins are much more dynamic than we ever thought,” Flynn said. “When we think about the cell surface, we usually think about protein-protein interactions. But now, we need to consider RNA as part of that picture.”
This paradigm shift is reflected in the broader goals of Flynn’s research, which include developing new models of the cell membrane that incorporate RNA biology. “We’re building a framework where RNA plays an active role in mediating how cells communicate and interact with their environment,” he said.
The Transformative Research Award comes with five years of funding, providing Flynn and Calo’s labs the necessary resources to take their research to the next level. “It’s a five-year grant, split between our labs at Harvard and MIT. This will allow us to continue our deep investigation into cell surface RNA biology, explore its role in disease, and, hopefully, pioneer new therapeutic strategies,” Flynn said.
As the research progresses, Flynn hopes to attract more attention to this burgeoning field, which remains in its infancy. “There are only a handful of labs in the world studying cell surface RNA biology, but I believe that’s about to change,” Flynn said. “The more we uncover, the clearer it becomes that this is an integral part of how cells function, and it could be key to unlocking new treatments for diseases that currently have limited options.”
For Ryan Flynn, the NIH Director’s Transformative Research Award is not just a personal achievement—it’s an affirmation that the future of science lies in the unknown. “This is exactly what science is about: pushing boundaries, questioning assumptions, and discovering new truths,” he said.
