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Synthetic Biology

Cool-mint-triggered gene switch makes insulin in diabetic mice

Synthetic biologists design genetic circuit made from all human components to expresses therapeutic proteins

by Alla Katsnelson, special to C&EN
July 11, 2019

 

20190711lnp2-circuit.jpg
Credit: Adapted from Nat. Med.
A synthetic gene circuit produces a therapeutic protein (yellow star) when activated by menthol. The minty molecule opens a pore in TRPM8 receptors, allowing calcium ions to flow into the cell. The flood of calcium activates a transcription factor (purple oval), which then turns on the promoter for the gene coding for the therapeutic protein.

Menthol provides a cooling minty sensation to chewing gum, cough medicine, and tooth paste. Now researchers want to use it to trigger the production of insulin or other therapeutic proteins in engineered human cells.

The team of scientists report a gene circuit that consists entirely of human genes and proteins and is activated by menthol to control the synthesis of a desired protein (Nat. Med. 2019, DOI: 10.1038/s41591-019-0501-8). Scientists could engineer cells with this circuit and then doctors could implant those cells into patients who need the specific therapeutic protein. Most gene and cell therapies developed to date have contained components from bacteria or yeast, which makes them vulnerable to attack and destruction by our immune systems, says Martin Fussenegger of the Swiss Federal Institute of Technology, Zurich. His team’s fully human switch should be able to deliver its therapeutic punch without incurring the wrath of the immune system.

Fussenegger and his team settled on menthol as the molecular cue to switch on their gene circuit because it is both highly specific and can be delivered in multiple ways. “It’s a very convenient trigger molecule because we only encounter it if we want to be exposed to it,” he says.

Our sensory system picks up menthol’s cooling sensation through a specialized receptor called TRPM8. When menthol activates TRPM8, the receptor’s pore opens and allows a flood of calcium ions into the cell. In cells engineered with the new gene circuit, this calcium torrent revs up a genetic element called a promoter, which then turns on the gene for the desired therapeutic protein.

The researchers created cells in which their menthol gene circuit was hooked up to the gene that produces insulin. They then implanted the cells in diabetic mice. When they rubbed the skin of the mice with menthol, the engineered cells made insulin and regulated the animals’ blood sugar. “That was our first proof of concept that the menthol system could work in animals,” Fussenegger says. He envisions that people with implants of such cells could brush their teeth with menthol toothpaste or dab on some essential oil containing the minty compound to activate insulin production instead of giving themselves an injection.

In another test of the circuit, the team created cells with the gene switch controlling expression of a protein that sponges up myostatin, a molecule that drives muscle degradation. The engineered cells successfully treated mice with a muscle wasting disease.

Researchers have previously made these kinds of trigger-driven gene switches, but this is the first such gene circuit made exclusively from human parts, says Joshua Leonard, a synthetic biologist at Northwestern University. “It’s an important first step.”

Fussenegger’s team hopes to eventually test the insulin-making cells in humans, possibly by partnering with a pharmaceutical company.

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