The components sound like the aftermath of a shopping and spa retreat: three AA batteries. Two electrical acupuncture needles. One plastic holder that’s usually attached to battery-powered fairy lights. But together they merge into a powerful stimulation device that uses household batteries to control gene expression in cells.
The idea seems wild, but a new study in Nature Metabolism this week showed that it’s possible. The team, led by Dr. Martin Fussenegger at ETH Zurich and the University of Basel in Switzerland, developed a system that uses direct-current electricity—in the form of batteries or portable battery banks—to turn on a gene in human cells in mice with a literal flip of a switch.
To be clear, the battery pack can’t regulate in vivo human genes. For now, it only works for lab-made genes inserted into living cells. Yet the interface has already had an impact. In a proof-of-concept test, the scientists implanted genetically engineered human cells into mice with Type 1 diabetes. These cells are normally silent, but can pump out insulin when activated with an electrical zap.
The team used acupuncture needles to deliver the trigger for 10 seconds a day, and the blood sugar levels in the mice returned to normal within a month. The rodents even regained the ability to manage blood sugar levels after a large meal without the need for external insulin, a normally difficult feat.
Called “electrogenetics,” these interfaces are still in their infancy. But the team is especially excited for their potential in wearables to directly guide therapeutics for metabolic and potentially other disorders. Because the setup requires very little power, three AA batteries could trigger a daily insulin shot for more than five years, they said.
The study is the latest to connect the body’s analogue controls—gene expression—with digital and programmable software such as smartphone apps. The system is “a leap forward, representing the missing link that will enable wearables to control genes in the not-so-distant future,” said the team.
The Trouble With Genetic Controls
Gene expression operates in analogue. DNA has four genetic letters (A, T, C, and G), which are reminiscent of a computer’s 0s and 1s. However, the genetic code can’t build and regulate life unless it’s translated into proteins. The process, called gene expression, recruits dozens of biomolecules, each of which is controlled by others. “Updates” to any genetic circuits are driven by evolution, which works on notoriously long time scales. While powerful, the biology playbook isn’t exactly efficient.
Enter synthetic biology. The field assembles new genes and taps into cells to form or rewire complex circuits using the logic of machines. Early experiments showed that synthetic circuits can control biological processes that normally result in cancer, infections, and pain. But activating them often requires molecules as the trigger—antibiotics, vitamins, food additives, or other molecules—keeping these systems in the realm of analogue biological computing.
Neural interfaces have already bridged the divide between neural networks—an analogue computing system—and digital computers. Can we do the same for synthetic biology?
Digital Synthetic Biology
The team’s solution is DC-actuated regulation technology, or DART.
Here’s how the setup works. At the core are reactive oxygen species (ROS), often known as the villain that drives aging and tissue wear and tear. However, our bodies normally produce these molecules during the metabolic process.
To minimize damage to the molecules, we have a natural protein biosensor to gauge ROS levels. The biosensor works closely with a protein called NRF2. The couple normally hangs out in the goopy part of the cell, isolated from most genetic material. When ROS levels rise to an alarming rate, the sensor releases NRF2, which tunnels into the cell’s DNA storage container—the nucleus—to turn on genes that clean up the ROS mess.
Why does it matter? NRF2 can be genetically engineered to turn on other genes using synthetic biology, the authors explained. A load of previous work showed electricity can trigger cells to pump out ROS at a safe level for genetic control. In other words, stimulating cells with electricity could release ROS, which then activates the NRF2 “secret agent” to flip on any gene of your choice.
DART combines all this previous work into a highly efficient, low-energy system for electrical gene control. Batteries are the trigger, ROS the messenger, and NRF2 the genetic “on” switch.
To build the system, human cells in Petri dishes first got a genetic tune-up to make them express more biosensor and NRF2 than their natural counterparts, in turn making the engineered cells more attuned to ROS levels.
Then came designing the trigger. Here, the team used electrical acupuncture needles already approved by the US Food and Drug Administration (FDA). To power the needles, the team explored using AA, AAA, or button batteries—the latter are normally inside wearables—and measured different battery configurations that produced a sufficient voltage to stimulate ROS in the engineered cells.
One trial used a glow-in-the-dark green protein as an indicator. Zapping the cells with brief bursts of electricity pumped out ROS molecules. The cell’s biosensors perked up, in turn releasing NRF2, which latched on to the synthetically-added genetic machinery that expresses green proteins and turned it on.
The electrical trigger was fully reversible, with the cells “resetting” into normal, healthy conditions and able to withstand another electrical go-around.
“We’ve wanted to directly control gene expression using electricity for a long time; now we’ve finally succeeded,” said Fussenegger.
A Battery Solution to Diabetes?
Encouraged, the team next tried using DART to control the insulin gene. Insulin is essential for regulating blood sugar, and its levels are disrupted in diabetes. The team is no stranger to the field, previously engineering designer cells that pump out insulin in response to voltage changes.
Using DART, the team genetically engineered insulin-producing genes into human cells, which only turned on in the presence of ROS after electrical stimulation. The setup worked perfectly in Petri dishes, with the cells releasing insulin after being zapped with electricity and subsequently showered in ROS.
The engineered cells were then encapsulated into a clinically licensed jelly-like substance and implanted under the skin on the backs of mice with Type 1 diabetes. These mice can’t normally produce insulin on their own.
The DART controller is relatively simple: two acupuncture needles coated with platinum powered by three AA batteries and wired to a 12V power switch that targets the implanted engineered cells. As a control, the team also pricked mice with acupuncture needles far away from the implanted cells. Each group was zapped for just 10 seconds a day.
Compared to the controls, in just four weeks the electrogenetic treatment showed promise. The mice could better battle low blood sugar from dieting, and eventually they restored their normal blood sugar levels. They were also adept at regulating blood sugar levels after a meal, something that’s difficult in people with diabetes without using insulin. Other metabolic measures also improved.
The next step is finding ways to replace the need for genetically engineered cells used in the implants with a more clinically viable solution.
But to the authors, DART represents a road map to further bridge biological bodies to the digital realm. It should be straightforward to link DART controls to a wide range of biopharmaceuticals inside cells. With more optimizing, these electrogenetic interfaces “hold great promise for a variety of future gene- and cell-based therapies,” said the authors.
Image Credit: Peggy und Marco Lachmann-Anke from Pixabay
