Bioengineers at Rice University have developed a new assembly kit that can be used to create custom synthetic sense-and-respond circuits in human cells.
The recently published research is an advancement in the field of synthetic biology that could transform therapies for complex conditions such as autoimmune disease and cancer.
The new approach to artificial cellular circuit design builds on phosphorylation, a natural process used by the cells to respond to their environment.
Phosphorylation is involved in a wide range of cellular functions, including the conversion of extracellular signals into intracellular responses.
According to the research, previous attempts to harness the phosphorylation mechanism for therapeutic purposes in human cells focused on re-engineering existing signalling pathways.
However, the previous attempts are limited due to the complexity of the signalling pathways.
Rice researchers’ new findings showed that phosphorylation-based innovations in smart cell engineering could see a significant uptick in the coming years.
The study lead author Xiaoyu Yang said: “Imagine tiny processors inside cells made of proteins that can ‘decide’ how to respond to specific signals like inflammation, tumour 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 customisable treatments in response.
“We didn’t necessarily expect that our synthetic signalling circuits, which are composed entirely of engineered protein parts, would perform with a similar speed and efficiency as natural signalling 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.”
According to the research, phosphorylation is a sequential process that unfolds as a series of interconnected cycles, from cellular input to output (response of the cell).
In the research, the team tried to treat each cycle in a cascade as an elementary unit and link the units in new methods to pathways that connect cellular inputs and outputs.
The modular approach to cellular circuit design replicated a key systems-level function of native phosphorylation cascades, amplifying weak input signals into macroscopic outputs.
Experimental observations confirmed the team’s quantitative modelling predictions, validating the framework as a powerful foundational tool for synthetic biology.
Phosphorylation occurring rapidly in only seconds or minutes is another distinct advantage of the new approach to sense-and-respond cellular circuit design.
It allowed the new synthetic phospho-signalling circuits to potentially be programmed to respond to physiological events that occur on a similar timescale.
The researchers also tested the circuits for sensitivity and ability to respond to external signals such as inflammatory factors.
The team used the framework to engineer a cellular circuit that can detect these factors, to control autoimmune flare-ups and reduce immunotherapy-associated toxicity.
The study’s corresponding author Caleb Bashor said: “This opens up the signalling 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.
“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.”
