Researchers bring “protein circuits” one step closer to cell-cell communication

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Through synthetic biology, scientists can add new functions to cells, such as the ability to generate new materials and detect and respond to diseases in specific ways. The application is exciting, but there are some inefficiencies in the process. One of them is being evaded by Xiaojing Gao, a chemical engineer at Stanford University.

Scientists have been using these new capabilities for years cell Through a genetic circuit — a synthetic network of genes that can be integrated into cells to sense specific triggers and provide the desired response. But as part of this process Genetic circuit To respond, you first need to translate it into a protein. A faster option is the “protein circuit,” says Gao, who eliminates intermediaries by building circuits from the protein itself. However, this also has major drawbacks. Protein circuits operate entirely within the cell, but most biological processes require cells to communicate with each other.

Gao and his team of researchers are now one step closer to cell-cell communication in protein circuits. In a paper published on February 17th Nature CommunicationsResearchers describe a new platform they have developed that allows circuits to release proteins from cells and display them on the surface of cells. In the future, researchers hope that cells will be able to respond to these proteins. The effect is that “a very small subset of cells that can affect other cells can be designed,” said Alexander Vlajos, Ph.D. scholar of chemical engineering and lead author of the paper. I am saying.

New process

Vlahos says this new process mimics the way cells function naturally. Every cell has a normal circuit where a protein receives information and passes it to the next protein. This allows you to change the next protein in the path: One way to make these kinds of modifications naturally is to use proteases, which are enzymes that cleave proteins at specific sites. This activates or deactivates the protein in the process. Synthetic protein circuits function much like adding new functions to a cell, but can do it stealthically without interacting with the normal function of the cell.

The new platform also emulates how cells normally communicate with each other. Many cells use proteins to communicate. That is, it secretes or displays proteins so that adjacent cells can sense and respond to these proteins. The platform, known as RELEASE or Retained Endoplasmic Cleavable Secretion, adds this ability to secrete and display proteins in protein circuits, extending what these circuits can do. “We haven’t reinvented the wheel,” says Vlahos.

In a sense, the inside of a cell is like a crowded city, with tens of millions of proteins running around to its destination. Proteins generally know exactly where they need to go, with the help of short tags that indicate where they should go. In RELEASE, Vlahos and Gao utilize these tags to add one of them to the protein they want to secrete. This particular tag keeps the protein sequestered inside the cell, but can be removed by a particular protease. When this protease is added to a cell with a protein circuit, the tag is cleaved in two and the protein is released or “released” and secreted.

“Circuit as a medicine”

One of the potential uses of their research is to attack cancers caused by mutant proteins that are difficult to target with conventional medicines. For these cancers, the lead authors of the paper, Vlahos and Gao, envision a “circuit as a circuit” approach. In this approach, a subset of cells that carry the circuit sense the mutant protein and respond in two ways. It also secretes proteins that activate the immune response to cancer.

Protein circuits and releases are steps 1 and 2 to achieve a “circuit as a drug” approach. In other steps, in the future, we will develop additional platforms that allow protein circuits to fully participate in cell-cell communication. These include adding sensors that allow the manipulated cells to respond to changes in the environment and investigating how cells adjacent to the proteins secreted by the circuit respond.

For Vlahos with a background in regenerative medicine, the next step is to continue optimizing RELEASE. protein circuit Create better programmable cells that can be introduced into regenerative medicine and cell therapy. “Xiaojing and I developed RELEASE with the ultimate goal in mind. It’s about creating programmable cells that can communicate with others. That’s basically the big picture.”

Modeling how cells choose their destiny

For more information:
Alexander E. Vlahos et al, Protease Controlled Secretion and Display of Intercellular Signals, Nature Communications (2022). DOI: 10.1038 / s41467-022-28623-y

Quote: Researchers in cell-cell communication (February 18, 2022) obtained from https: // on February 18, 2022. “Protein circuit” is one step closer to-cell.html

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Researchers bring “protein circuits” one step closer to cell-cell communication

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