A novel building kit for creating unique sense-and-respond circuits in human cells has been created by bioengineers at Rice University. The study, which was published in the journal Science, is a significant advancement in synthetic biology that has the potential to transform treatments for difficult diseases including cancer and autoimmune illness.
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,
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.
Xiaoyu Yang
Phosphorylation, a natural process by which cells react to their surroundings by adding a phosphate group to a protein, is the basis for the novel method of designing artificial biological circuits. The translation of extracellular signals into intracellular reactions, such as moving, secreting a drug, responding to a pathogen, or expressing a gene, is one of the many cellular processes in which phosphorylation plays a role.
Phosphorylation-based signaling frequently has a multi-stage cascading effect, similar to falling dominoes, in multicellular animals. Re-engineering native, pre-existing signaling pathways has been the main focus of prior attempts to use this method therapeutically in human cells. However, applications have remained relatively limited due to the paths’ intricacy, which makes them challenging to deal with.
However, phosphorylation-based advancements in “smart cell” engineering may see a notable increase in the upcoming years as a result of the new discoveries made by Rice researchers. This discovery was made possible by a change of viewpoint.
From cellular input—that is, something the cell experiences or perceives in its surroundings—to output—that is, what the cell does in response—phosphorylation is a sequential process that develops as a sequence of interrelated cycles. Each cycle in a cascade may be viewed as an elementary unit, and these units can be connected in innovative ways to create whole new pathways that connect cellular inputs and outputs. This is what the study team discovered and set out to demonstrate.
This opens up the signaling circuit design space dramatically,
It turns out, phosphorylation cycles are not just interconnected but interconnectable — this is something that we were not sure could be done with this level of sophistication before,
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.
Caleb Bashor
Although this might seem simple, it was quite difficult to figure out the guidelines for constructing, connecting, and fine-tuning the units, including the design of the intracellular and extracellular outputs. Furthermore, it was not a given that artificial circuits could be constructed and used in living cells.
We didn’t necessarily expect that our synthetic signaling circuits, which are composed entirely of engineered protein parts, would perform with a similar speed and efficiency as natural signaling pathways found in human cells,
Needless to say, we were pleasantly surprised to find that to be the case. It took a lot of effort and collaboration to pull it off.
Xiaoyu Yang
The ability of native phosphorylation cascades to amp up weak input signals into macroscopic outputs is a key systems-level capability that can be replicated using a do-it-yourself, modular approach to cellular circuit design. The usefulness of the novel framework as a fundamental tool for synthetic biology was further supported by experimental observations of this impact, which confirmed the team’s quantitative modeling predictions.
Since phosphorylation happens quickly in just a few seconds or minutes The circuits’ sensitivity and responsiveness to outside stimuli, such as inflammatory chemicals, were also examined by the researchers. The scientists demonstrated the framework’s translational potential by using it to design a cellular circuit that can identify these variables, potentially reducing immunotherapy-associated toxicity and controlling autoimmune flare-ups.
the new synthetic phospho-signaling circuits may be able to be programmed to react to physiological events that take place on a comparable timescale. This is another clear benefit of the new approach to sense-and-respond cellular circuit design. On the other hand, a lot of earlier artificial circuit designs relied on various molecular mechanisms, such as transcription, which can take several hours to initiate.
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.
Caleb Bashor
If in the last 20 years synthetic biologists have learned how to manipulate the way bacteria gradually respond to environmental cues, the Bashor lab’s work vaults us forward to a new frontier — controlling mammalian cells’ immediate response to change.
Ajo-Franklin
Source: Rice University – News
Journal Reference: Yang, Xiaoyu, et al. “Engineering Synthetic Phosphorylation Signaling Networks in Human Cells.” Science, 2025, DOI: 10.1126/science.adm8485.
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