A new switch for the cell therapies of the future

The body regulates its metabolism precisely and continuously, with specialised cells in the pancreas constantly monitoring the amount of sugar in the blood, for example. When this blood sugar level increases after a meal, the body sets a signal cascade in motion in order to bring it back down.

In people suffering from diabetes, this regulatory mechanism no longer works exactly as it should. Those affected therefore have too much sugar in their blood and need to measure their blood sugar level and inject themselves with insulin in order to regulate it. This is a relatively imprecise approach compared to the body’s own mechanism.

Equipping cells with special functions

Martin Fussenegger is Professor of Biotechnology and Bioengineering at the Department of Biosystems Science and Engineering of ETH Zurich in Basel. With the above situation in mind, he and his team have been working on cell therapies for some time. One day, the hope is that these therapies will allow metabolic diseases such as diabetes to be treated individually and precisely – or even cured.

But how do these cell therapies work? First, the researchers modify human cells by incorporating a network of genes that give the cells special abilities. These cells are implanted under the skin, for example, and the network is activated by a specific external stimulus.

A suitable switch is key

To that end, the researchers have developed various types of switches over recent years. Some can be controlled electrically, others with light, and one even using music by the British rock band Queen (see ETH News).

The researchers in Basel have now developed another variant, which they have presented in the journal external page Nature Biomedical Engineering.

“For me, this solution is the best gene switch that my group and I have built so far,” says Fussenegger. The reason is that the switch can be triggered using the long-established active ingredient nitroglycerine, and that the means of application – sticking a patch to the skin – is very simple. Corresponding patches are already available to buy in various sizes in any pharmacy.

Nitroglycerine quickly diffuses out of the patch and into the skin, where it encounters an implant that contains modified human kidney cells.

Network activated by nitric oxide

These cells specifically intercept the nitroglycerine and have a built-in enzyme that converts it into nitric oxide (NO), a natural signalling molecule. In the body, NO normally causes blood vessels to dilate, leading to increased blood flow. It is broken down within a few seconds and therefore only affects a very localised area.

The implanted cells are modified so that NO triggers the production and release of the chemical messenger GLP-1, which in turn boosts insulin release by the beta cells of the pancreas and thus regulates blood sugar level. GLP-1 also triggers a feeling of satiety, thereby reducing food intake.

The new switch is made exclusively of human constituents – that is, it contains no components from other species. “That’s a new and groundbreaking feature,” says Fussenegger. With components from other species, there is always a risk of false triggering, interference with the body’s own processes, or immune reactions. “Here, we’re able to rule that out.”

A whole arsenal of switches

In the last 20 years, the ETH professor has developed various different gene switches, some of which respond to physical triggers such as current, sound waves or light. Which type has the best chance of being implemented one day?

“Physical triggers are interesting because we don’t need to use molecules that interfere with the body’s own processes,” the biotechnologist says. He explains that electrical signals are ideal for controlling switches and gene networks using portable electronics such as smartphones or smartwatches – and AI can then be incorporated, too. “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,” says Fussenegger.

However, the further development of these cell therapies based on gene switches is a complex and lengthy process. “Developing a cell therapy to market maturity not only takes decades but also requires lots of staff and sufficient resources,” says the researcher. “There’s no shortcut.”

Until now, Fussenegger’s work has focused mainly on cell therapies for diabetes, which is one of the world’s most prevalent metabolic diseases, affecting one in ten people. “That’s the model disease we work with. Fundamentally, however, it’s also possible to develop cell therapies for other metabolic, autoimmune or even neurodegenerative diseases – in principle, for everything that requires dynamic regulation.” According to Fussenegger, many drugs are like a hammer that is used to strike at a problem blindly. “Cell therapies, on the other hand, solve the problem in a similar way to the body,” he says.