Experimental insulin implant uses electricity to control genes

Lilly Tozer

An insulin crystal viewed under a light microscope. People with type 1 diabetes do not make enough insulin, which helps to control blood sugar levels. Credit: Alfred Pasieka/Science Photo Library

Genetically engineered human cells that produce insulin when stimulated by a small electric current could one day be used to develop better treatments for type 1 diabetes.

Researchers generated cells that undergo a chain reaction in response to reactive oxygen species (ROS) — unstable oxygen-containing radicals produced when a current is applied — that ultimately switches on the gene needed to make insulin.

In a proof-of-concept experiment, they then implanted the engineered cells into mice and showed that the cells released insulin when a current was applied using electrified acupuncture needles.

The findings, published in Nature Metabolism on 31 July1, offer hope that this technology could one day be incorporated into medical implants, says co-author Martin Fussenegger, a bioengineer at the Swiss Federal Institute of Technology in Zurich.

The technique “can use normal batteries and lower voltages that are compatible with implantable devices”, says Rodrigo Ledesma Amaro, a synthetic biologist at Imperial College London who was not involved in the research.

Electric gene switch

The idea of using electricity to control biological processes has been around since the 1980s, when researchers began to develop the concept using microbes. Fussenegger and his team have been working on human cells with a view to developing “an interface between the electrical world and the genetic world”, Fussenegger says. This could be used to target genetic diseases by switching specific genes on or off in implanted cells, allowing them to deliver crucial proteins.

For example, people with type 1 diabetes make little or no insulin, a key hormone responsible for the control of the body’s blood sugar levels. The ability to stimulate cells to produce insulin on demand could help those with the condition to avoid hyperglycaemia, when blood sugar levels become dangerously high.

Fussenegger and his colleagues engineered insulin-producing cells that could be activated electrically by manipulating their response to ROS. These toxic molecules are produced naturally during cell metabolism but their formation can also be induced by applying a direct current to the cells. “At low levels, ROS can function as an important signalling molecule and a critical regulator of gene expression,” says Esma Isenovic, who researches the implications of ROS in disease at the University of Belgrade. But during oxidative stress, when ROS are in excess, they can attack other molecules and disrupt normal functioning. To avoid this, cells normally produce antioxidant proteins to neutralize ROS.

In the engineered cells, researchers ‘disguise’ the gene that produces insulin by placing it after a synthetic promoter sequence, a region of DNA associated with antioxidant-producing genes that are switched on in response to ROS. The sequence comprised repeated ‘antioxidant response elements’ which naturally enhance the expression of antioxidant proteins during oxidative stress.

Insulin implant

Once the authors had shown that this approach could work, they went one step further, incorporating the reprogrammed human cells into a device that they implanted into mice with hyperglycaemia. They delivered current to the cells — which sat in a capsule just under the skin — using acupuncture needles. When the device was stimulated, the animals’ blood insulin levels increased, and their blood sugar levels normalized. The amount of insulin released could be controlled by varying the length and strength of the current.

The team hopes that one day this system could be adapted into wearable medical devices controlled by a computer or smartphone.

But the technology is still at a very early stage, and more work is needed before it can be tested in people. Isenovic says that it is too early to contemplate therapeutic applications. She points out that the next step — studying the technology in different mouse models with larger sample sizes — will help to “provide a complete picture” of the system’s potential applications.