Imagine tiny molecular “factories” stationed inside your cells that can sense dangerous signals—like inflammation or cancer markers—and instantly release precisely the right therapeutic compounds. Far from science fiction, this vision is edging closer to reality thanks to a groundbreaking “construction kit” from Rice University bioengineers that allows for building customizable, programmable circuits in human cells.

Rice researchers published details of their work in Science, heralding a major leap forward in synthetic biology that could spark transformative therapies for complex conditions such as autoimmune disorders and cancer.

“This is like embedding tiny processors in cells, made entirely of proteins, that can ‘decide’ how to respond to specific signals such as inflammation, tumor growth, or high blood sugar,” explained graduate student Xiaoyu Yang, the study’s lead author in Rice’s Systems, Synthetic and Physical Biology Ph.D. program. “Our work moves us significantly closer to constructing ‘smart cells’ that can detect disease indicators and instantly produce tailor-made treatments.”

A Natural Mechanism Repurposed

The new technique centers on phosphorylation, a normal cellular process in which proteins are activated by the addition of a phosphate group. Phosphorylation enables cells to sense their surroundings and translates external cues into internal actions, such as movement, secretion, immune defense, or gene expression.

In multicellular organisms, phosphorylation often proceeds in a domino-like chain, with one event triggering the next. Previous efforts to harness phosphorylation for therapeutic applications have generally involved retooling existing cellular pathways, but their inherent complexity has limited practical use.

Now, Rice researchers have shown a different way forward by zeroing in on how phosphorylation unfolds sequentially in interconnected cycles. Each cycle can be treated like a building block and recombined to form entirely new pathways connecting cellular inputs to desired outputs.

“This dramatically broadens the space for signaling circuit design,” said Caleb Bashor, an assistant professor of bioengineering and biosciences at Rice and corresponding author on the study. “Previously, we weren’t certain we could rearrange these phosphorylation cycles with such precision. Our framework has let us construct synthetic phosphorylation circuits that are exceptionally adaptable yet still function alongside a cell’s natural processes without affecting its viability or growth.”

Constructing and Testing the Circuits

Though the idea seems straightforward, working out the principles for building, linking, and fine-tuning phosphorylation-based circuits—plus verifying they could indeed be introduced into living cells—was a formidable challenge.

“We weren’t sure that circuits composed entirely of engineered protein parts would be able to function as smoothly and quickly as the innate pathways in human cells,” Yang said. “It took a great deal of collaboration and experimentation, but we were thrilled to see them perform on par with natural systems.”

As part of their investigation, the researchers demonstrated that the synthetic circuits they assembled could replicate an important feature of natural phosphorylation cascades: amplifying weak input signals into robust responses. Observing this ability in practice confirmed the team’s mathematical modeling predictions, highlighting the toolkit’s potential as a foundation for synthetic biology work.

Faster Response Times

A notable benefit of the new approach is speed. Phosphorylation can occur within seconds or minutes, which means these engineered circuits could be tuned to react to swiftly changing physiological conditions—like rapid shifts in inflammatory signals. By comparison, many existing synthetic circuits rely on slower processes, such as gene transcription, that take hours to kick in.

In addition, the team tested how the circuits detect and respond to external signals, such as inflammatory molecules. To illustrate the real-world potential, the researchers showed that their phosphorylation-based circuit can sense these signals, which may help control autoimmune flare-ups or lessen immune-related side effects in cancer immunotherapy.

“This is the first published example of a construction kit for engineering synthetic phosphorylation circuits in human cells,” said Bashor, who also serves as deputy director of the newly formed Rice Synthetic Biology Institute. “Our findings prove it’s possible to create programmable, rapid, and precise cellular systems.”

Expanding the Frontiers of Synthetic Biology

Caroline Ajo-Franklin, director of the Rice Synthetic Biology Institute, characterized this work as emblematic of the pioneering research underway at Rice. “Over the last two decades, synthetic biologists have become adept at tweaking the slow, incremental responses of bacteria to their environments,” she said. “The Bashor lab’s findings catapult us to a new frontier, where we can now control mammalian cells’ immediate reactions to shifting conditions.”

Ajo-Franklin, who holds appointments in biosciences, bioengineering, chemical, and biomolecular engineering and also serves as a Cancer Prevention and Research Institute of Texas Scholar, underscored the significance of this achievement: “These insights into phosphorylation-mediated circuit design transform how we think about engineering mammalian cells, offering fresh possibilities for tackling complex diseases with targeted, rapid, and customizable treatments.”