Alexander Vlahos, Assistant Professor of Biomedical Engineering in the Wallace H. Coulter Department of Bio-medical Engineering (BME) at Georgia Tech and Emory University, has been awarded an R21 Trailblazer Award for New and Early-Stage Investigators by the National Institute for Biomedical Imaging and Bioengineering (NIBIB), a part of the National Institutes of Health (NIH), for the project Stress-Responsive Protein Sensors for Precision Cancer Immunotherapy.
This highly competitive, three-year award provides up to $400,000 in direct costs to early-career investigators to establish and support independent research programs at the intersection of engineering, physical sciences, and biomedical sciences. Designed to support bold, high-risk, high-reward ideas, it enables investigators to pursue innovative approaches that could transform the biomedical sciences while generating foundational data needed for larger NIH research grants and initiatives in the future.
The award will enable Vlahos to pursue an ambitious idea: engineer synthetic protein circuits that can enable cells to sense when they are under stress and activate appropriate, precise therapeutic responses.
In cancer, ischemia, fibrosis, and other diseased states, cells are placed under immense physiological stress. In solid tumors, for example, rapidly dividing cells often outpace their blood supply, causing cells to become hypoxic due to chronically low oxygen levels and limited nutrients. These stress conditions have long been recognized as hallmarks of disease, yet they have largely remained underexplored as a guide for enhancing the targeting of immunotherapies.
Rather than relying on conventional, static molecular markers found in healthy tissue, or even relying on protein markers that many cancer cells can develop resistance mechanisms to over time, Vlahos aims to exploit physio-logical stress signals—e.g. hypoxia and the stress that disrupts protein folding in the endoplasmic reticulum (ER)—as biological cues that indicate when and where a therapeutic response should occur. This means engineering cells that only activate their programmed outputs when the appropriate intracellular disease-associated signals—whether individual or combinatorial—are present.
To accomplish this, his lab is engineering modular synthetic protein sensors that are capable of sensing these signals and integrating them into logical protein circuits. These synthetic protein circuits are like the biological version of the electrical circuits inside of a laptop computer. However, instead of using copper wires and electricity, protein circuits use interacting proteins to transmit information within a cell. Scientists can program cells to detect specific biological signals and trigger precise cellular responses, giving living cells the ability to function as tiny biological computers.
“Since synthetic protein circuits function entirely at the protein-level, they are inherently faster than the traditional gene circuits because they rely on post-translational modifications – something that can happen in the span of minutes, rather than hours or even days,” Vlahos explains.
Another advantage is that they can be delivered via mRNA, allowing for non-integrative delivery of synthetic protein circuits. Recent advances in lipid nanoparticle technology—the same technology that enable many of the COVID-19 vaccines to be approved for use—have made this strategy much more practical for therapeutic applications, such as this. If successful, this approach could provide a novel framework for enhancing the specificity of existing cancer immunotherapies, while reducing the unintended off-target effects to the body.
Although the initial focus of this project is on solid tumors, this technology could have applications far beyond cancer. Similar responses to cellular stress are observed in fibrotic diseases, autoimmune diseases, neurodegenerative diseases, and even chronic kidney disease, corroborating the potential utility of such a programmable plat-form across multiple areas of medicine.
“Receiving the Trailblazer Award is an important milestone for my independent research program,” Vlahos ex-plained. “It provides the support to pursue bold, high-risk ideas at the intersection of synthetic biology and regenerative medicine, while enabling my laboratory to develop new approaches that can transform how we improve the specificity of cancer immunotherapies.”
The Vlahos Lab conducts research that synergizes synthetic biology and tissue engineering to develop programmable gene and cell therapies for a variety of different biomedical applications. The new award builds on his lab’s broader vision of developing programmable biomedical technologies that enable cells to sense and respond to complex disease environments with greater efficacy than conventional therapeutics.
“Receiving the NIH Trailblazer Award was transformative for my research program,” added Professor Tara Deans, an Associate Professor of Biomedical Engineering in the Coulter BME Department and previous recipient of the Trailblazer Award. “It provided the resources and confidence to pursue a high-risk, high-reward idea at a critical stage in my career, and it helped us accelerate work that would have been difficult to launch through more traditional funding mechanisms. Equally important, the award created momentum by opening doors to new collaborations, helped establish the direction of my lab, and signaled this kind of bold, interdisciplinary research was worth investing in.”
The award not only highlights the strength of Vlahos’ research program but also Coulter BME’s commitment to advancing transformative biomedical engineering research.
As Vlahos begins this three-year project, the research could establish proof-of-concept of an entirely new way of designing therapies—one that allows them to continuously “listen” to their surroundings and respond directly to disease specific signals. If successful, this research could lay the foundation for programmable immunotherapies that adapt to the biology of individual patients and diseases in the future.
