Protein-based nano-‘computer’ evolves in its ability to influence cell behavior

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Traditional synthetic biology approaches to cell-based therapies, such as those that kill cancer cells or promote tissue regeneration after injury, rely on the expression or suppression of proteins that produce a desired action within a cell. This approach can take time (for proteins to be expressed and degraded) and costs cellular energy in the process. A team of researchers from the Penn State School of Medicine and the Huck Institutes of Life Sciences are taking a different approach.

“We are engineering proteins that directly produce a desired action,” said Nikolay Dokholyan, the G. Thomas Passananti Professor and vice chair for research in the Department of Pharmacology. “Our protein-based devices or nanocomputing agents respond directly to stimuli (inputs) and then produce a desired action (outputs).”

In a study published in Progress of science today (May 26) Dokholyan and bioinformatics and genomics doctoral student Jiaxing Chen describe their approach to creating their nanocomputing agent. They designed a target protein by integrating two sensor 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 modified protein into living cells in culture. By exposing the cultured cells to the stimuli, they used equipment to measure changes in cell orientation after the cells were exposed to stimuli from the sensor domains.

Previously, your nanocomputing agent required two inputs to produce one output. Now Chen says that there are two possible outputs and that the output depends on the order in which the inputs are received. If rapamycin is detected first, followed by light, the cell will assume one cell orientation angle, but if the stimuli are received in reverse order, the cell will assume a different orientation angle. Chen says this experimental proof-of-concept opens the door for the development of more complex nanocomputing agents.

“Theoretically, the more inputs you feed into a nanocomputing agent, the more potential results could result from different combinations,” Chen said. “Potential inputs could include physical or chemical stimuli and outputs could include changes in cell behaviors, such as cell steering, migration, modification of gene expression, and immune cell cytotoxicity against cancer cells.”

The team plans to further develop their nanocomputing agents and experiment with different applications of the technology. Dokholyan, a researcher at the Penn State Cancer Institute and the Penn State Neuroscience Institute, said his concept could one day form the basis of next-generation cell-based therapies for various diseases, including autoimmune diseases, viral infections, diabetes , nerve damage and cancer. .

Yashavantha Vishweshwaraiah, Richard Mailman, and Erdem Tabdanov of Penn State School of Medicine also contributed to this research. The authors declare not to have any interest conflicts.

This work was supported by the National Institutes of Health (grant 1R35GM134864) and the Passan Foundation.