The body carefully and continuously regulates its metabolism, with specialized cells in the pancreas constantly monitoring the blood sugar levels, for instance. When blood sugar rises after a meal, the body initiates a signal cascade to lower it back to normal levels. However, in individuals with diabetes, this regulatory mechanism no longer functions properly. As a result, they experience high blood sugar and must measure their levels regularly and inject insulin to manage it. This method, while effective, is less precise compared to the body's natural regulation. Researchers are focusing on cell therapies, where they modify cells to restore disrupted metabolic functions. These therapies require suitable switches, created through biotechnology, to prompt modified cells to release chemical messengers that regulate metabolism. Now, researchers have developed a gene switch that can be activated with commercially available nitroglycerine patches. The long-term goal is to bring this cell therapy to market, although it will take at least ten years to achieve.

Researchers at ETH Zurich (Zurich, Switzerland) have been working on cell therapies with the hope of one day treating or even curing metabolic diseases like diabetes in a personalized and precise manner. To make cell therapies work, the researchers alter human cells by incorporating a network of genes that grant the cells specific abilities. These cells are then implanted under the skin, and the network is activated by a particular external trigger. Over the past two decades, the ETH professor has developed various gene switches that respond to physical stimuli such as electricity, sound waves, or light. The research team at ETH has now developed a new variant, which they introduced in the journal Nature Biomedical Engineering.

The researchers believe that this latest solution is the most advanced gene switch they have created. The switch is activated using nitroglycerine, a well-known and widely used substance, and its application is simple: it only requires applying a patch to the skin. These patches are readily available in pharmacies in different sizes. Nitroglycerine quickly diffuses from the patch into the skin, where it interacts with an implant containing modified human kidney cells. These cells are designed to capture the nitroglycerine and have an enzyme that converts it into nitric oxide (NO), a natural signaling molecule. In the body, NO normally causes blood vessels to expand, increasing blood flow, but it is broken down within seconds, limiting its effect to a very localized area.

The modified cells in the implant are engineered so that NO triggers the production and release of GLP-1, a chemical messenger that enhances insulin secretion from the pancreas’s beta cells, helping regulate blood sugar. GLP-1 also induces a feeling of fullness, reducing food intake. This new switch is made entirely of human components—there are no materials from other species involved. The development of these gene-switch-based cell therapies is complex and time-consuming. Thus far, the focus has been primarily on diabetes, one of the most widespread metabolic diseases affecting one in ten people. However, these cell therapies could also be applied to treat other metabolic, autoimmune, or even neurodegenerative diseases, as they all require dynamic regulation.

“Physical triggers are interesting because we don’t need to use molecules that interfere with the body’s own processes,” said Martin Fussenegger, Professor of Biotechnology and Bioengineering at the Department of Biosystems Science and Engineering of ETH Zurich. “I therefore think electrogenetic cell therapies have the best chances of implementation. In terms of chemical switches, I see the new solution as being in pole position.” 

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