Turning proteins into PROSE

The ability to rapidly detect and identify unknown proteins remains a critical gap for a number of areas, such as healthcare, biotechnology, and national security. Existing tools can characterize proteins with known sequences, but they struggle to read long, chemically complex, and modified proteins, including toxins and engineered threats designed to evade detection methods. 

As advances in synthetic biology and artificial intelligence accelerate the creation of novel proteins, this gap is expected to widen. Addressing it will require not only biological insight, but engineered platforms capable of directly measuring and interpreting molecular information at scale.

DARPA launched the PROtein SEquencing (PROSE) program to pursue fundamentally new approaches to this challenge. 

Today’s protein sequencing methods are largely adaptations of tools designed for other tasks: Mass spectrometry performs well for short proteins but becomes less reliable as proteins grow longer, while optical and nanopore techniques developed for DNA and RNA struggle with proteins’ far greater chemical diversity. 

By contrast, PROSE performers will design integrated microsystems from the ground up to interact with individual molecules and convert their physical and chemical signatures into digital information. Successful PROSE technologies will read protein diversity directly, without relying on reference sequences. 

“Reading proteins requires coordinated and integrated advances in biophysics, molecular design, nanofabrication, sensing architectures and computer science,” explains John M. Hoffman, PROSE program manager at DARPA. “PROSE brings these pieces together in single, integrated microsystems designed to accommodate the full chemical complexity of proteins.”

PROSE kicked off earlier this month, and the first phase of the 36-month program is now underway. In this phase, three performer teams led by Electronic Biosciences, the Kostas Research Institute at Northeastern University, and Pumpkinseed, will focus on demonstrating protein sequencing approaches and defining paths toward scalable microsystem integration. 

PROSE’s second phase will emphasize the development of integrated systems capable of sequencing long proteins with high fidelity without a reference.

Beyond its immediate objectives, PROSE supports DARPA’s broader interest in exploring how biological and organic systems can be integrated with microsystems to enable new sensing and computation paradigms. Biological systems have evolved information processing capabilities with properties not available to many conventional electronic and/or photonic approaches. By investigating how biomolecules can be engineered to function as active elements within microsystems, PROSE contributes to longer-term research into molecular integrated circuits and hybrid bio-compute platforms.

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