A basic function of cells is that they act in response to their environments. It makes sense, then, that a goal of scientists is to control that process, making cells respond how they want to what they want.
One avenue for this ambition is cell receptors, which function like ignition slots on a cell, requiring keys - such as specific hormones, drugs, or antigens - to start up specific cellular activities. There are already synthetic receptors that give us some control over this sequence of events, most famously the chimeric antigen receptors used in CAR-T cell cancer therapy. But existing synthetic receptors are limited in the variety of keys they can accept and the activities they can trigger.
Now, detailed in a paper published Dec. 4 in Nature, Stanford researchers have developed a new synthetic receptor that accommodates a broader range of inputs and produces a more diverse set of outputs.
This innovation, called "Programmable Antigen-gated G protein-coupled Engineered Receptors" (PAGER), is built around G protein-coupled receptors, a set of over 800 proteins in the human body that turn on molecular switches inside the cell, called G-proteins, to control many vital functions. The researchers demonstrated PAGER's versatility by successfully controlling neuronal activity, triggering immune responses, and delivering therapeutic treatments in lab experiments.
"I think PAGER has potential for impact, both in the G protein coupled receptor biology field, and in synthetic circuits or cell-based therapies," said Alice Ting, professor of genetics at the School of Medicine and of biology in the School of Humanities and Sciences and senior author of the paper. "When you put a technology out there, it's always exciting to see all the creative ways that people use and transform the technology in ways that you never even imagined. There's so much more that's possible."
Holding the keys
While G-protein coupled receptors can activate various cellular activities, researchers had previously avoided them for programmable applications because customizing their "keys" was challenging, literally requiring researchers to direct the evolution of the receptors for years to create just one desired option.
"G-protein coupled receptors, normally, can be activated by specific small molecules that bind in a pocket in the receptor," explained Nicholas Kalogriopoulos, a postdoctoral fellow in the Ting lab and co-lead author of the paper. "Essentially, what we did is fuse something that blocks that pocket, and it only opens up when it binds something you've chosen."
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Schematic that shows how PAGER adds extra controls to G protein-coupled receptors. | Nicholas Kalogriopoulos, Reika Tei, Alice Ting
