Rice University bioengineers have made a significant breakthrough in the field of synthetic biology by developing a new construction kit for building custom sense-and-respond circuits in human cells. This research has the potential to revolutionize therapies for complex conditions like autoimmune disease and cancer. The new approach to artificial cellular circuit design relies on phosphorylation, a natural process cells use to respond to their environment by adding a phosphate group to a protein. This process plays a crucial role in various cellular functions, such as converting extracellular signals into intracellular responses.
Previous attempts at utilizing phosphorylation for therapeutic purposes in human cells focused on re-engineering native signaling pathways but faced limitations due to the complexity of the pathways. However, the Rice researchers’ new perspective on phosphorylation as a series of interconnected cycles has enabled them to construct entirely novel pathways for engineering “smart cells” that can detect and respond to disease signals. By treating each cycle in a cascade as an elementary unit and linking them together in new ways, the researchers have expanded the signaling circuit design space.
The researchers’ design strategy has enabled them to engineer synthetic phosphorylation circuits that are highly tunable and can function in parallel with cells’ natural processes without impacting their viability or growth rate. The modular approach to cellular circuit design proved capable of reproducing the systems-level ability of native phosphorylation cascades to amplify weak input signals into macroscopic outputs. This new framework provides a foundational tool for synthetic biology and presents a way to program cells to respond to physiological events that occur rapidly within seconds or minutes.
One of the advantages of the new approach is that synthetic phospho-signaling circuits can potentially be programmed to respond to physiological events on a similar timescale, unlike previous synthetic circuit designs based on slower molecular processes. The researchers tested the circuits for sensitivity and ability to respond to external signals like inflammatory factors, demonstrating its potential translational applications. They engineered a cellular circuit that can detect inflammatory factors and could be used to control autoimmune flare-ups and reduce immunotherapy-associated toxicity.
The research conducted by the Rice University bioengineers represents a significant advancement in the field of synthetic biology and paves the way for the development of programmable circuits in human cells that can respond quickly and accurately to signals. The study is the first report of a construction kit for engineering synthetic phosphorylation circuits, highlighting the transformative work being done at Rice University in synthetic biology. The framework developed by the researchers has the potential to control mammalian cells’ immediate response to change, providing new opportunities for therapeutic interventions in complex diseases like autoimmune disorders and cancer.
