In a new study, human immune cells were engineered to generate a different output than they ordinarily would in response to an environmental input. Specifically, molecular components were installed that allowed the cells to recognize a tumor-derived protein and produce an immune-stimulating factor. This sort of rewiring of cellular input-output shows promise not only in cancer immunotherapy, but in other translational applications, as well as in basic biological research. MESA: modular extracellular sensor architecture. [Northwestern University]
In a new study, human immune cells were engineered to generate a different output than they ordinarily would in response to an environmental input. Specifically, molecular components were installed that allowed the cells to recognize a tumor-derived protein and produce an immune-stimulating factor. This sort of rewiring of cellular input-output shows promise not only in cancer immunotherapy, but in other translational applications, as well as in basic biological research. MESA: modular extracellular sensor architecture. [Northwestern University]

Cells are often reprogrammed to alter their output and churn out desirable products. And, increasingly, they are being reprogrammed to sense external cues, and thereby accept new input. But imagine what could be accomplished if both kinds of reprogramming were accomplished at once, so that cells could respond however we desired to whatever input we might specify?

That’s the approach being explored by synthetic biologists based at Northwestern University. In a recent study, these scientists demonstrated how modular components could be engineered into cells to “rewire” their input/output behavior. The scientists, led by Joshua N. Leonard, Ph.D., used their modules to create immune cells capable of sensing and responding to a tumor signal, a signal that would, ordinarily, have deactivated the cells.

The cells’ revised functionality has direct implications for fighting cancer. More important, the approach used to rewire the cells could be applied in other contexts.

Details of the scientists’ work appeared December 12 in the journal Nature Chemical Biology, in an article entitled, “Rewiring Human Cellular Input–Output Using Modular Extracellular Sensors.”

“Here, we report such a biosensor engineering strategy, leveraging a self-contained receptor–signal transduction system termed modular extracellular sensor architecture (MESA),” wrote the article’s authors. “We developed MESA receptors that enable cells to sense vascular endothelial growth factor (VEGF) and, in response, secrete interleukin 2 (IL-2).”

Essentially, the engineered cells sense VEGF, a protein found in tumors that directly manipulates and in some ways suppresses the immune response. When the rewired cells sense VEGF in their environment, these cells, instead of being suppressed, respond by secreting IL-2, a protein that stimulates nearby immune cells to become activated specifically at that site. Normal unmodified T cells do not produce IL-2 when exposed to VEGF, so the engineered behavior is both useful and novel.

“This work is motivated by clinical observations, in which we may know why something goes wrong in the body, and how this may be corrected, but we lack the tools to translate those insights into a therapy,” said Dr. Leonard. “With the technology we have developed, we can first imagine a cell function we wish existed, and then our approach enables us to build—by design—a cell that carries out that function.”

The technology developed by Dr. Leonard’s team is intentionally modular, such that its “parts” can be combined with other synthetic biology innovations to write more sophisticated cellular programs. “Because this platform utilizes modular, engineerable domains for ligand binding (antibodies) and output (programmable transcription factors based upon Cas9), this approach may be readily extended to novel inputs and outputs,” the article’s authors explained.

“To truly accelerate the rate at which we can translate scientific insights into treatments, we need technologies that let us rapidly try out new ideas, in this case by building living cells that manifest a desired biological function,” asserted Dr. Leonard. “Our technology also provides a powerful new tool for fundamental research, enabling biologists to test otherwise untestable theories about how cells coordinate their functions in complex, multicellular organisms.”








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