Programmable Protein Circuits Between Living Cells

Synthetic biologists at Stanford University, Howard Hughes Medical Institute, and Caltech have developed a new technology for protein circuits between living cells.

Gene circuits are synthetic networks of genes that can be integrated into cells to sense specific triggers and deliver a desired response. Gene circuit engineering permits adding new functions to cells, such as the ability to detect and respond to diseases.

However, because genes must be translated into proteins to act, synthetic networks made directly of proteins would be more efficient. But natural protein circuits operate entirely within a particular cell. And the majority of biological processes require cells to be in communication with one another.

The Stanford-led synthetic biologists have found a way for protein circuits to release proteins from the cell, or to display them on the cell surface. Other cells can then respond to these proteins.

Researcher Alexander Vlahos describes the hoped-for end result of this research. In a press release issued by Stanford University, he says, “you can engineer a very small subset of cells that can then have an effect on other cells.”

Synthetic protein circuits extend natural protein circuits found in living cells. A protein receives information and then passes the information along to the next protein. Efficient synthetic protein circuits would permit adding new functions to cells without changing with the cells' normal functions.

Scientists have developed a new synthetic biology platform known as RELEASE (Retained Endoplasmic Cleavable Secretion). It is described in a research paper published in Nature Communications. It enables synthetic protein circuits to secrete and display proteins.

The scientists “developed RELEASE with an end goal in mind: trying to have programmable cells that can talk to other things,” says Vlahos. “That’s fundamentally the big picture.”

Vlahos and research leader Xiaojing Gao hope that engineered protein circuits will be able to attack cancers caused by mutant proteins that are difficult to target with traditional drugs.

For these cancers, Vlahos and Gao envision a “circuit as medicine” approach. A subset of cells carrying the circuit would sense the mutant protein and respond in two ways. They would kill the mutant cell. And they would also secrete proteins that activate an immune response against the cancer.

In the paper, the Stanford-led researchers argue that RELEASE could also have therapeutic applications in neurobiology, developmental biology, immunology, tissue engineering, and transplantation. RELEASE could be used to create sense-and-respond cells to control biological factors in order to facilitate the acceptance of engineered tissue implants.

The proposed plug-and-play platform for sensing and secreting proteins would enable programming of such communications with unprecedented precision.