The line between the Internet of Things (IoT) and the Internet of the Body (IoB) just got a little blurrier. In the IoT, everyday devices are interconnected so that they may exchange data and respond accordingly. In the IoB, networked devices include living cells, such as insulin-producing cells. Whereas IoT applications are often pedestrian, such as sensitizing an apartment’s air conditioner to the apartment dweller’s GPS information, IoB applications raise the possibility of remote-controlled therapeutics.

To demonstrate the potential of the IoB, scientists based at ETH Zurich have introduced a device that uses external electric fields to trigger on-demand insulin release inside the body. When tested in mouse models of type 1 diabetes, the device wirelessly coaxed bioengineered cells to release insulin, stabilizing the animals’ blood glucose levels within minutes.

Now, suppose that such a device—one containing insulin-producing cells and an electronic control unit—is implanted in the body of a diabetic. As soon as the patient eats something and their blood sugar starts to rise, they use an app on their smartphone to trigger an electrical signal, or they rely on a preconfigured app to send the signal automatically, provided information about the meal was entered in advance. A short while after the signal is sent, the cells release the necessary amount of insulin to regulate the patient’s blood sugar level.

This scenario might sound like science fiction, but it could soon become reality, argue the ETH scientists. Led by Martin Fussenegger, PhD, professor of biotechnology and bioengineering, they have demonstrated that a wireless electronic device can be used to directly activate gene expression. In other words, they have developed an advanced form of electrogenetics. Unlike current remote-controlled electrogenetic medical devices, the new prototype can do without sophisticated bioelectronic interfaces, that is, interfaces that require electrical conduction between device electrodes and bioengineered cells.

Direct electronic input can be used to control cellular behavior, but this approach is awkward and has limited potential. In contrast, the new prototype incorporates a bioelectronic interface that uses electric fields to control cell function in vivo via a wearable device.

Details appeared May 29 in the journal Science, in an article titled, “Electrogenetic cellular insulin release for real-time glycemic control in type 1 diabetic mice.” The article describes how the ETH Zurich team leveraged a voltage-gated calcium channel to achieve a high degree of control over electrostimulation-driven insulin production and secretion in engineered human pancreatic β cells.

“We present a cofactor-free bioelectronic interface that directly links wireless-powered electrical stimulation of human cells to either synthetic promoter–driven transgene expression or rapid secretion of constitutively expressed protein therapeutics from vesicular stores,” the article’s authors wrote. “Electrogenetic control was achieved by coupling ectopic expression of the L-type voltage-gated channel CaV1.2 and the inwardly rectifying potassium channel Kir2.1 to the desired output through endogenous calcium signaling.”

The modified β cells within the device were able to be reused for several weeks and capable of rapidly restoring normal glycemic levels in mice.

A wearable, wireless device has been developed that uses an electric current to directly control gene expression. The device, which has been tested in mice, suggests that medical implants could be switched on and off using electronic devices outside the body. [Katja Schubert, after Krawczyk et al., Science 2020]
The Basel-based scientists have a wealth of experience in developing genetic networks and implants that respond to specific physiological states of the body, such as blood lipid levels that are too high or blood sugar levels that are too low. Although such networks respond to biochemical stimuli, they can also be controlled by alternative, external influences like light—as in optogenetic applications, which use precise wavelengths of light as a means to control cell function remotely.

Similarly, electrogenetic applications may use electrical stimulation to directly influence the expression of voltage-dependent receptors in electrosensitive designer cells. “We’ve wanted to directly control gene expression using electricity for a long time; now we’ve finally succeeded,” Fussenegger said.

The implant the researchers have designed is made up of several parts. On one side, it has a printed circuit board (PCB) that accommodates the receiver and control electronics; on the other is a capsule containing human cells. Connecting the PCB to the cell container is a tiny cable.

A radio signal from outside the body activates the electronics in the implant, which then transmits electrical signals directly to the cells. The electrical signals stimulate a special combination of calcium and potassium channels; in turn, this triggers a signaling cascade in the cell that controls the insulin gene. Subsequently, the cellular machinery loads the insulin into vesicles that the electrical signals cause to fuse with the cell membrane, releasing the insulin within a matter of minutes.

Fussenegger sees several advantages in this latest development. “Our implant could be connected to the cyber universe,” he explained. Doctors or patients could use an app to intervene directly and trigger insulin production, something they could also do remotely over the internet as soon as the implant has transmitted the requisite physiological data. “A device of this kind,” Fussenegger continued, “would enable people to be fully integrated into the digital world and become part of the Internet of Things—or even the Internet of the Body.”

When asked about the potential risk of attacks by hackers, he drew a comparison to pacemakers: “People already wear pacemakers that are theoretically vulnerable to cyberattacks, but these devices have sufficient protection. That’s something we would have to incorporate in our implants, too.”

As things stand, the greatest challenge he sees is on the genetic side of things. To ensure that no damage is caused to the cells and genes, he and his group need to conduct further research into the maximum current that can be used. The researchers must also optimize the connection between the electronics and the cells.

And a final hurdle to overcome is finding a new, easier, and more convenient way to replace the cells used in the implant, something that must be done approximately every three weeks. For their experiments, Fussenegger and his team of researchers attached two filler necks to their prototype in order to replace the cells; they want to find a more practical solution.

Before their system can be used in humans, however, it must still pass a whole series of clinical tests.

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