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

The first protein-based nanocomputing agent that works like a circuit has been created by researchers at Penn State. This step brings them closer to developing next-generation cell therapies to treat diseases like diabetes and cancer.

Traditional synthetic biology approaches to cell therapies, such as those that destroy cancer cells or promote tissue regeneration after injury, rely on the expression or suppression of proteins that produce a desired action in a cell. This approach can take time (for proteins to express and degrade) and cost cellular energy in the process. A team of researchers from Penn State College of Medicine and the Huck Institutes of the Life Sciences take a different approach.

“We are designing proteins that directly produce a desired action,” said Nikolay Dokholyan, Professor G. Thomas Passananti 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 Science Advances today (May 26), Dokholyan and bioinformatics and genomics PhD student Jiaxing Chen describe their approach to creating their nano-informatics 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 the stimuli from the sensor domains.

Previously, their nanocomputing agent required two inputs to produce one 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, followed by light, the cell will adopt one cell orientation angle, but if the stimuli are received in reverse order, the cell will adopt a different orientation angle. Chen says this experimental proof of concept opens the door to developing more complex nanocomputing agents.

“Theoretically, the more inputs you put into a nanoinformatics agent, the more potential outcomes there are that 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 direction, migration, altered gene expression, and cytotoxicity of immune cells against cancer cells. .”

The team plans to further develop its 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 their concept could one day form the basis of next-generation cell therapies for various diseases, such as autoimmune diseases, viral infections, diabetes. , nerve damage and cancer. .

Yashavantha Vishweshwaraiah, Richard Mailman and Erdem Tabdanov of Penn State College of Medicine also contributed to this research. The authors declare no conflict of interest.

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

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