HOUSTON — Researchers at Rice University have unveiled a breakthrough platform for engineering custom “sense-and-respond” circuits inside human cells, creating a powerful new toolkit for next-generation cell therapies. Published in the journal Science, this pioneering work enables scientists to construct synthetic signaling pathways that allow cells to detect disease markers and trigger precise therapeutic actions within minutes. The development marks a significant leap in synthetic biology, potentially opening the door to "smart" cell-based treatments for complex conditions like autoimmune disorders and cancer.

The research team, led by graduate student Xiaoyu Yang and corresponding author Caleb Bashor, an assistant professor of bioengineering and biosciences, has developed a modular assembly system for phosphorylation-based circuits. Phosphorylation, the process of adding a phosphate group to a protein, is a fundamental and rapid signaling mechanism human cells naturally use to react to their environment.

“Imagine tiny processors inside cells made of proteins that can ‘decide’ how to respond to specific signals like inflammation, tumor growth markers or blood sugar levels,” said Yang, the study's lead author. “This work brings us a whole lot closer to being able to build ‘smart cells’ that can detect signs of disease and immediately release customizable treatments in response”.

A New Design Philosophy for Cellular Circuits

The breakthrough centers on a key conceptual shift. In nature, phosphorylation signals travel through complex, cascading pathways. Historically, bioengineers tried to rewire these existing, intricate native pathways with limited success. The Rice team’s innovation was to treat each step in the phosphorylation cascade as a standalone, standardized unit.

They discovered these core units are not just interconnected in nature but are fundamentally interconnectable. By creating engineered versions of these units, researchers can now link them together in novel combinations to design entirely new pathways from the ground up. This turns cellular circuit design into a more predictable, modular engineering discipline.

“This opens up the signaling circuit design space dramatically,” Bashor said. “It turns out, phosphorylation cycles are not just interconnected but interconnectable... Our design strategy enabled us to engineer synthetic phosphorylation circuits that are not only highly tunable but that can also function in parallel with cells’ own processes without impacting their viability or growth rate”.

Speed, Precision, and Proven Therapeutic Potential

A major advantage of this phosphorylation-based approach is its remarkable speed. While many synthetic biology tools rely on slower processes like gene transcription, which can take hours, phosphorylation circuits can activate in seconds or minutes. This allows them to respond to fast-changing physiological conditions in real time.

To demonstrate the platform's immediate medical relevance, the team engineered a proof-of-concept circuit designed to combat harmful inflammation. The synthetic circuit was programmed to detect specific inflammatory factors and, in response, activate a process to control autoimmune flare-ups and reduce toxicity associated with some immunotherapies. This successful test underscores the technology's potential to create sophisticated cellular therapies that autonomously manage complex diseases.

“Our research proves that it is possible to build programmable circuits in human cells that respond to signals quickly and accurately, and it is the first report of a construction kit for engineering synthetic phosphorylation circuits,” Bashor said.

A Foundational Tool for a Growing Field

The achievement is seen as a foundational advance for the broader field of synthetic biology. Caroline Ajo-Franklin, director of the Rice Synthetic Biology Institute, highlighted the leap forward this represents. She noted that if past decades taught researchers how to program simple, gradual responses in bacteria, this work “vaults us forward to a new frontier — controlling mammalian cells’ immediate response to change”.

The research also validated its quantitative models by demonstrating a key feature of natural systems: signal amplification. The engineered circuits could detect weak molecular inputs and transform them into strong, macroscopic cellular responses, just as natural pathways do. This reliability between prediction and real-world function strengthens the platform's value as a trustworthy engineering tool.

The Road Ahead for "Smart Cell" Therapies

While the therapeutic applications are still in the early stages, the research provides a robust and flexible framework that is now available to the global scientific community. Researchers worldwide can use this “construction kit” to design custom circuits for a wide array of diseases, moving beyond inflammation to target cancer cells, metabolic disorders, and more.

The work, supported by multiple National Institutes of Health grants and other foundations, establishes a new paradigm. By mastering the language of rapid cellular signaling, bioengineers are now equipped to program human cells with an unprecedented level of sophistication, paving the way for a future where living cells become dynamic, self-regulating medicines.