Investigators are working to develop electrogenetic devices that use remote-controlled electrical stimulation to elicit specific behaviors in engineered cells. They are following in the footsteps of optogenetics, which use specific wavelengths of light to control cell function remotely.

A new study published in Science used such a device paired with encapsulated, engineered human pancreatic beta cells to express enough insulin to restore normal glycemic levels in mice models of diabetes. The devices were used over a period of several weeks.

A decade to humans

“We have shown that wireless electrical stimulation of insulin release by electrosensitive designer cells inside a bioelectronic implant was able to rapidly restore normoglycemia in type 1 diabetic mice,” summed up the paper. “The adoption of wireless electronic devices that can program the release of biopharmaceuticals, either via the secretory pathway or vesicular secretion, by means of direct communication between the device and implanted cells is expected to open up many new opportunities for advanced precision health care optimized for individuals.”

The academics are already working to further advance development with an undisclosed biopharma, almost certainly Glaxosmithkline plc which is the only major pharma to have a laser-focus on and massive investment in bioelectronics for many years. In its most ambitious effort, GSK partnered with Google sister company Verily Life Sciences LLC in mid-2016 to create bioelectronics joint venture Galvani Biosciences and fund it with more than $710 million over seven years.

Next, the researchers aim to continue to improve both the engineered cells and the implant; further testing in large animals is also planned. But it’s expected to take roughly another decade to get this sort of technology into human testing.

“We have worked for decades on deep switches and biosensors to engineer cells to send specific disease metabolite profiles and produce a therapeutic response,” Martin Fussenegger, a professor in the Department of Biosystems Science and Engineering at ETH Zurich in Basel, Switzerland told BioWorld. “As part of that, it has always been a question to communicate and to remotely control cellular behavior not by small molecules, but by remote cues.”

The eventual idea is to develop a closed-loop system based on data regarding food intake or blood glucose that would enable AI-based, automatic electrical stimulation of the engineered cells within the implant. Fussenegger is skeptical of existing continuous blood glucose monitors as part of this system, since they measure glucose oxidase. That measurement isn’t particularly useful in this context; rather, he is awaiting more optimal glucose data from a high-quality consumer device, such as the Apple watch, that also wouldn’t rely on microneedles.

Fussenegger expects that several different competing sophisticated diabetes solutions, such as the artificial or bionic pancreas as well as encapsulated cellular implants, will all continue to advance and compete alongside electrogenetics to the eventual benefit of patients.

Cellular manipulation

The engineered pancreatic beta cells have been designed to have insulin secretion function that is decoupled from glucose sensitivity, allowing their activation via electrostimulation. The cells can be stimulated to start to produce insulin, as well as to release existing insulin that has been produced and stored within them. In the study, peak secretion occurred about 10 minutes after the start of the stimulation. That combined mechanism of action could enable real-time insulin and control like natural beta cells.

The cells used in the experiment were human-derived. They are encapsulated to deter an immune response from the host, but long-term it’s expected that these cells could be autologous. If they are thus extracted, engineered and reimplanted within a device, that could help blunt any potential immune response as well.

“There are two different worlds, which work very similarly yet have no common interface: electronics and genetics,” said Fussenegger. “In nature, there's the electrical system like in the muscle or the brain--but that's not linked to gene expression, that's linked to just transfer information from A to B by an equalization of membranes. Other than that, there is nothing known in nature whereby living systems capture electric currents.”

“We thought, we need to bring these together,” he continued. “So, that’s why we got interested in this interface. From the beginning, it was clear that we need to do two things: we need to capitalize on our track record in engineered cells and we need to interface those cells with electronic devices. So, we have to go into two worlds and combine them.”

The stimulation works by depolarizing the cellular membrane, thereby opening up some of the ion channels and thereby allowing insulin secretion from the engineered cells. The technique could be effective with any type of hormone, such as adrenaline or growth hormone, with cells engineered to promote that particular expression.

The electrogenetic device is implanted subcutaneously and charged wirelessly. Although the ideal version ultimately would be powered by tapping directly into the body’s own electrical energy. The mouse implant is roughly the size of a small coin, or about 27 mm.

An essay accompanying the study in Science and offering perspective upon it noted four types of external manipulation of engineered cellular activity, of which optogenetics and electrogenetics are two. It also examines mechanogenetics, which is the use of deep tissue penetration such as focused ultrasound, and magnetogenetics, which uses magnetic nanoparticles to target cell receptors.

“We can now add electrogenetics to the mix of technologies for rapid and remote spatiotemporal control over complex biological functions. Electrogenetics represents the next tool in an expanding toolbox for engineering remote solutions for human therapeutics,” said authors Matthew Brier and Jonathan Dordick, who are both professors at Rensselaer Polytechnic Institute. “Despite their inherent limitation, each of these platforms has shown applicability, and the potential for combinations of these orthogonal platforms to exert fine-tuned control in complex systems is within our grasp.”

“Research into synergistic use of these approaches could be the next step,” they concluded. “For example, self-contained implants could act as multimodal monitoring and treatment devices for targeted diseases that have proven elusive to the current toolbox of modern medicine.”

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