The first protein-based nano-computing agent that acts as a circuit has been developed by researchers at Penn State University. This milestone brings them one step closer to developing next-generation cell-based therapies to treat diseases such as diabetes and cancer.
Traditional synthetic biology approaches to cell-based therapies, such as those that destroy cancer cells or promote tissue regeneration after injury, rely on the expression or repression of proteins that produce a desired effect within a cell. This approach can take time (until proteins are expressed and degraded) and cost cellular energy in the process. A team of researchers from Penn State College of Medicine and the Huck Institute of the Life Sciences takes a different approach.
“We are designing proteins that produce a desired effect directly,” said Nikolay Dokholyan, G. Thomas Passananti professor and associate researcher in the Department of Pharmacology. “Our protein-based devices, or nano-computing agents, respond directly to stimuli (inputs) and then produce a desired action (outputs).”
In a study published today (May 26) in Science Advances, Dokholyan and bioinformatics and genomics graduate student Jiaxing Chen describe their approach to developing their nano-computing agent. They constructed a target protein by integrating two sensory domains, or areas that respond to stimuli. In this case, the target protein responds to light and a drug called rapamycin by adjusting its orientation, or position in space.
To test their design, the team introduced their engineered protein into live cells in culture. By exposing the cultured cells to the stimuli, they used devices to measure changes in cell orientation after the cells were exposed to the sensory domain stimuli.
Previously, their nano computing agent required two inputs to produce an output. Now Chen says there are two possible outputs and the output depends on the order in which the inputs are received. If rapamycin is detected first and then light, the cell assumes a certain orientation angle. However, when the stimuli are received in reverse order, the cell adopts a different orientation angle. According to Chen, this experimental proof-of-concept opens the door to the development of more complex nano-computing agents.
“Theoretically, the more inputs you embed into a nano-computing agent, the more potential outcomes could result from different combinations,” Chen said. “Possible inputs could be physical or chemical stimuli, and outputs could be changes in cellular behavior, such as B. Cell direction, migration, alteration of gene expression and cytotoxicity of immune cells towards cancer cells.”
The team plans to further develop its nano-computing agents and experiment with different applications of the technology. Dokholyan, a researcher at Penn State Cancer Institute and Penn State Neuroscience Institute, said their concept could one day form the basis of next-generation cell-based therapies for various diseases, including autoimmune diseases, viral infections, diabetes, nerve injuries and cancer.
Yashavantha Vishweshwaraiah, Richard Mailman, and Erdem Tabdanov of Penn State College of Medicine also contributed to this research. The authors declare no conflicts of interest.
This work was funded by the National Institutes of Health (grant 1R35GM134864) and the Passan Foundation.