With 3 AA batteries and 2 acupuncture needles, a device controls gene expression in live mice

Researchers have created a battery-powered device that stimulates gene expression and prompts cells to produce insulin in diabetic mice, cracking open a door to a future where wearable electronics could program cell and gene therapies. 

In a study published July 31 in Nature Metabolism, researchers from Swiss university ETH Zurich described how they developed an interface called direct current (DC)-actuated regulation technology, or DART, that uses an electric current to stimulate bioengineered cells. In a proof-of-concept study in mice with Type 1 diabetes, a once-daily stimulation of implanted insulin-sensing human cells was enough to correct their blood sugar.

“We believe this technology will enable wearable electronic devices to directly program metabolic interventions,” the scientists wrote in their paper.

Electricity already has applications in gene therapy in the form of electroporation, a technique used to deliver DNA into cells without the need for a viral vector. But until now, it appears that no one has successfully created a battery-powered device that can fine-tune gene expression in cells implanted in live animals. Previous attempts were marred by cytotoxicity, poor performance and devices that burned out quickly.

To get around those issues, the ETH Zurich team looked to a type of compound that’s already produced naturally in the body: reactive oxygen species, or ROS. While ROS are often associated with inflammation, as they’re a byproduct of immune cell activity, the researchers knew from previous studies by other teams that it was possible to generate nontoxic levels of them in cells via stimulation with electrodes delivering a low-voltage DC current. Furthermore, scientists from the University of Maryland had recently devised a system that altered gene expression in bacteria by upregulating ROS with an electric current.

For their new device, the researchers developed a system that uses battery power to stimulate low-level ROS formation and trigger gene expression in bioengineered cells. First, they added ROS-sensing proteins to human embryonic kidney cells that had been engineered to secrete insulin. When triggered by an electrical current, the proteins would upregulate gene expression inside the cells, stimulating a cascade that resulted in insulin production.

After verifying that the system worked in cell cultures, they moved to testing it in live mice. They used three off-the-shelf AA batteries to send a 4.5-volt charge through their device into acupuncture needles, which were inserted into the backs of male mice with Type 1 diabetes that had been implanted with the bioengineered ROS-sensing, insulin-secreting kidney cells. A simple on-off switch controlled the device.

The researchers found stimulating the cells once a day for 10 seconds was enough to increase insulin production to the point that the mice didn’t experience episodes of hyper- or hypoglycemia for the next 24 hours. Additional experiments showed that the system could be tuned further and activated multiple times a day to give tighter control over blood glucose levels, mimicking insulin injection patterns sometimes needed to control blood sugar in human patients. By checking the mice’s glucose levels every three hours, the researchers found that one to four activations a day were sufficient to optimize glucose levels without side effects.

The researchers noted that the system has several advantages. For one, it requires very little power and overall energy to control glucose levels. They estimated that a triple AA battery pack would be enough to give a single therapeutic injection of insulin every day for as long as five years. On top of that, charged acupuncture needles like the ones used in the experiment are already used in traditional Chinese medicine in practices approved by the World Health Organization.

“Thus, we believe rapid, electronics-free direct battery-powered low-voltage DC control of therapeutic transgenes in human cells is a leap forward, representing the missing link that will enable wearables to control genes in the not-so-distant future,” the scientists wrote.