Rice University bioengineers have made a groundbreaking advancement in synthetic biology with the development of a novel construction kit designed to build custom sense-and-respond circuits within human cells. This research, published in the prestigious journal Science, represents a major step forward in harnessing the power of synthetic biology for therapeutic applications, particularly for the treatment of complex diseases like autoimmune conditions and cancer.
At the heart of this breakthrough is a concept known as phosphorylation, a natural biochemical process that is crucial in how cells sense and respond to their environment. Phosphorylation involves adding a phosphate group to a protein, which can dramatically change the behavior of the protein and, by extension, influence various cellular functions. In living organisms, this process is integral to a range of cellular activities, including moving, secreting substances, reacting to pathogens, or expressing genes.
In multicellular organisms like humans, phosphorylation-driven signaling pathways often operate through multistage cascades. These cascades consist of a series of interrelated events that amplify and propagate signals within the cell. Traditionally, efforts to engineer human cells to harness these cascades have focused on modifying existing signaling pathways to introduce therapeutic functionality. However, the inherent complexity of these pathways has posed significant challenges, limiting their potential for broad therapeutic use.
The recent study from Rice University bioengineers marks a departure from this conventional approach. The team was able to conceptualize a new way to leverage phosphorylation-based circuits by treating each cycle in the signaling cascade as an independent, interconnected unit. They hypothesized that these individual units could be combined in innovative ways to create entirely new pathways that link cellular inputs—such as the detection of a disease marker—with cellular outputs, such as the release of a treatment.
This insight opened up a vast new design space for building synthetic circuits within living cells. According to Caleb Bashor, an assistant professor of bioengineering and the corresponding author on the study, the new design strategy enabled them to create synthetic phosphorylation circuits that are not only highly tunable but also function in parallel with the cells’ native biological processes. The synthetic circuits were able to maintain the viability and growth rates of the cells, ensuring they did not disrupt their normal functions.
Building these synthetic circuits in human cells turned out to be far from a straightforward endeavor. Researchers initially didn’t expect their custom-designed signaling circuits to perform as quickly or efficiently as natural signaling pathways, which are complex and finely tuned by evolution. However, much to their delight, the engineered protein parts performed with remarkable speed, rivaling that of naturally occurring cellular processes.
Part of what made the new approach so effective was its ability to reproduce one of the essential functions of native signaling cascades: amplifying weak input signals into large-scale cellular responses. In their experiments, the team observed how weak external signals, such as the presence of inflammatory factors, were amplified into significant changes in cellular behavior. This amplification, which is a key feature of natural signaling cascades, was predicted by the team’s computational models and then confirmed in their experiments.
Another significant advantage of this new approach is the speed at which the synthetic circuits can respond. Phosphorylation, unlike other molecular processes such as transcription (which may take hours to initiate a response), operates on a much faster timescale—often in seconds or minutes. As a result, the new synthetic circuits could be engineered to respond rapidly to physiological events such as changes in blood sugar levels or tumor growth. This speed makes the approach highly appealing for creating cells that can react to conditions in real time, providing more immediate therapeutic responses.
One of the most exciting prospects of this new framework is its potential for treating autoimmune diseases. In a proof-of-concept experiment, the researchers engineered a cellular circuit that could detect inflammatory factors commonly associated with autoimmune flare-ups. The circuit could then release a therapeutic response, essentially programming cells to “treat” inflammation or immune-related conditions right when they are detected.
This work represents the first successful demonstration of a construction kit for building synthetic phosphorylation circuits. By using the kit, researchers could create “smart cells” that respond to specific inputs, such as inflammation or tumor markers, and react by releasing customizable treatments. This innovation has tremendous implications for precision medicine, where highly specific, tailored therapies could be delivered only when and where they are needed.
Caroline Ajo-Franklin, the director of the Rice Synthetic Biology Institute and co-author of the study, emphasized the significance of the breakthrough, noting how it advances the field of synthetic biology. Ajo-Franklin, a professor of biosciences, bioengineering, and chemical and biomolecular engineering, praised the work as marking a new frontier in synthetic biology. “If over the past 20 years, synthetic biologists have learned how to manipulate the way bacteria respond to environmental cues, the Bashor lab’s work has vaulted us forward into a new era where we can control mammalian cells’ immediate responses to change,” she explained.
The potential for this research to revolutionize treatments for diseases is immense. By harnessing the power of synthetic biology and enabling “smart” human cells that can sense their environment and respond with targeted therapeutic interventions, the team opens the door to personalized medicine approaches that could offer treatments tailored to individuals’ specific needs. This could be particularly impactful in diseases like cancer, where precise targeting of tumor markers could allow for highly effective and localized treatments, sparing healthy tissues from unnecessary damage.
Moreover, the precision and speed with which these synthetic circuits can operate could vastly improve the efficacy of existing immunotherapies. The ability to control immune responses and autoimmune flare-ups in real-time could offer significant advances in treating conditions that currently lack effective therapeutic options.
Overall, the work at Rice University represents a significant leap forward in the field of synthetic biology, demonstrating the potential of engineered cellular circuits to act as finely tuned, responsive systems. As the research continues to evolve, it may well pave the way for groundbreaking treatments and therapies that could reshape the future of medicine. These smart cells could one day be capable of detecting and responding to a host of diseases—bringing us one step closer to solving some of the most complex medical challenges of our time.
Reference: Xiaoyu Yang et al, Engineering synthetic phosphorylation signaling networks in human cells, Science (2025). DOI: 10.1126/science.adm8485