Protein-based nanocomputers are evolving in the ability to influence cell behavior


May 26, 2023

(Nanowerk NewsThe first protein-based nanocomputing agent that functions as a circuit has been created by Penn State researchers. This achievement brings them one step closer to developing the next generation of 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 suppression of proteins that produce desired actions within cells. This approach can be time consuming (for proteins to be expressed and degraded) and consume cellular energy in the process. A team from Penn State College of Medicine and Huck Institutes of the Life Sciences researchers took a different approach.

“We engineered a protein that directly produces the desired action,” said Nikolay Dokholian, Professor G. Thomas Passananti and co-lead research in the Department of Pharmacology. “Our protein-based devices or nanocomputing agents respond directly to stimuli (input) and then produce the desired action (output).

In a study published in Science Advances (“Noncommutative combinatorial protein logic circuits control cell orientation in a nanoenvironment”), Dokholian and bioinformatics and genomics doctoral student Jiaxing Chen describe their approach to creating their nanocomputing agent. They engineered 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 engineered protein into living cells in culture. By exposing cultured cells to stimuli, they used equipment to measure changes in cellular orientation after cells were exposed to sensory domain stimuli.

Previously, their nanocomputing agents 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 the reverse order, then the cell adopts a different orientation angle. Chen said this experimental proof-of-concept opens the door for the development of more complex nanocomputing agents.

“Theoretically, the more inputs you embed into a nanocomputing agent, the more potential outcomes result from different combinations,” said Chen. “Potential inputs can include physical or chemical stimuli and outputs can include changes in cellular behavior, such as cell orientation, migration, modification of gene expression, and cytotoxicity of immune cells against cancer cells.”

The team plans to further develop their nanocomputing agent and experiment with different applications of the technology. Dokholian, a researcher from the Penn State Cancer Institute and Penn State Neuroscience Institute, said their concept could one day form the basis of the next generation of cell-based therapies for various diseases, such as autoimmune diseases, viral infections, diabetes, nerve injury and cancer. .


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