First Nano-Computing Agent That Uses Two-Input Protein Device Provides Key Solutions in Cell-Based Therapies

In the pharmaceutical industry, cell-based therapies use traditional synthetic biology methods that depend on expressing or suppressing proteins that produce a desired action within a cell. By nature, cells cancel mechanical and structural environmental signals and use them in making decisions and changing their behavior.

In carrying out these processes, complex computational methods are performed by protein networks that process information and create functional outputs. This approach used in destroying cancer cells or encouraging tissue regeneration usually takes time and consumes cellular energy in the process.

To address this challenge, a team of researchers took a different approach by directly engineering proteins that produce a desired action.

Designing a Two-Input Protein Device

Researchers from Penn State College of Medicine and Huck Institutes of the Life Sciences developed the first protein-based nano-computing agent, which functions as a circuit—their device works by responding directly to inputs and producing desired outputs.

Lead author Nikolay Dokholyan created the agent by integrating two sensor domains that will respond to the stimuli. The target protein can respond to stimuli and a drug called rapamycin by adjusting its orientation or position in space. The design was tested by introducing the engineered protein into live cells in culture. Equipment was used to measure cellular orientation changes after exposure to the stimuli.

In their previous works, the nano-computing agent produces only one output using two inputs. In their recent study, two possible outputs can be created based on the order in which the inputs are received. This means that if the nano-computing agent detects rapamycin and then light, the cell will adopt one orientation angle. At the same time, if the stimuli are received in reverse order, a different orientation angle will be adopted.

The researchers claim their protein device can reversibly manipulate cell orientation by applying appropriate input signals. When used in the industry, the potential inputs could include physical or chemical stimuli, while outputs could comprise changes in cellular behaviors. In the future, the researchers plan to improve their nano-computing agents for various technologies, such as treating autoimmune diseases, viral infections, and nerve injury.

Understanding Cellular Orientation

Cellular orientation results from the interaction between the cell and its complex biophysical surroundings. This is done by continuously detecting and transducing environmental biophysical cues to the nucleus of the cells through a network of mechanotransduction pathways.

In the laboratory, it is widely known that cultured mammalian cells can respond to topographical signals in their surroundings. The physical topography of a substrate to which the cells connect could affect not only cell orientation but cell morphology as well.

This has inspired regenerative medicine, which was developed to replace damaged tissues. Applying the mechanism to engineering and life sciences offers the potential to restore normal functions of body organs with the use of living cells combined with biomaterials such as genes or drugs.