Diabetes is a condition in which the body produces too little or no insulin. Diabetics therefore depend on an external supply of this hormone by injection or pump. Researchers led by Martin Fusenegger from the Department of Biosystem Sciences and Engineering at ETH Zurich in Basel want to make life easier for these people and are looking for solutions to produce and administer insulin directly into the body.
One such solution that scientists are looking for is enclosing designer insulin-producing cells in capsules that can be implanted into the body. To be able to externally control when and how much insulin the cells release into the blood, researchers have studied and applied various triggers in recent years: light, temperature and electric fields.
Fussenegger and his colleagues have already developed another, novel stimulation method: they use music to trigger cells to release insulin within minutes. This worked particularly well with “We Will Rock You,” a global hit by British rock group Queen.
Cell equipment for receiving sound waves
To make insulin-producing cells sensitive to sound waves, the researchers used a protein from the bacterium E. coli. Such proteins respond to mechanical stimuli and are common in animals and bacteria. The protein is located in the bacterial membrane and regulates the flow of calcium ions into the cell. The researchers incorporated the blueprint of this bacterial ion channel into human insulin-producing cells. This allows these cells to create the ion channel themselves and embed it in their membrane.
As the scientists were able to show, the channel in these cells opens in response to sound, allowing positively charged calcium ions to flow into the cell. This causes a reversal of charge in the cell membrane, which in turn causes the tiny insulin-filled vesicles inside the cell to fuse with the cell membrane and release insulin to the outside.
Booming bass boosts insulin secretion
In cell cultures, the researchers first determined which frequencies and volume levels activated the ion channels most strongly. They found that sound levels around 60 decibels (dB) and bass frequencies of 50 hertz were most effective at triggering the ion channels. To induce maximal insulin release, the sound or music had to last a minimum of three seconds and pause for a maximum of five seconds. If the intervals are too far apart, significantly less insulin is released.
Finally, the researchers examined which music genres elicited the strongest insulin response at a volume of 85 dB. Bass-thumping rock music like Queen’s “We Will Rock You” came out on top, followed by action movie soundtracks The Avengers. The insulin response to classical music and guitar music is quite poor by comparison.
“We Will Rock You” triggers approximately 70 percent of the insulin response within 5 minutes, and all within 15 minutes. This is comparable to the natural glucose-induced insulin response of healthy individuals, Fusenegger says.
The sound source should be directly above the implant
To test the system as a whole, the researchers implanted the insulin-producing cells into mice and positioned the animals so that their bellies were directly over the speaker. This was the only way the researchers could observe an insulin response. However, if the animals were allowed to move freely in a “mouse disco”, the music failed to induce insulin release.
“Our designer cells only release insulin when a sound source with the right pitch is played directly on the skin over the implant,” Fusseneger explains. The release of the hormone is not triggered by ambient noise such as the noise of airplanes, lawnmowers, fire sirens, or conversations.
No ambient noise triggering
As far as he can tell from tests on cell cultures and mice, Fussenegger sees little risk that the implanted cells in humans will release insulin consistently at the slightest noise.
Another safety buffer is that insulin depots need four hours to fully replenish after they have been depleted. So even if the cells were exposed to sound at hourly intervals, they would not be able to release a full load of insulin each time and thus cause life-threatening hypoglycemia. “However, this can cover the typical needs of a diabetic patient who eats three meals a day,” Fussenegger says. He explains that insulin remains in the vesicles for a long time, even if a person does not eat for more than four hours. “No depletion or accidental disposal.”
But clinical application is far away. The researchers simply provided a proof of concept, showing that genetic networks can be controlled by mechanical stimuli such as sound waves. Whether this principle will ever be put into practice depends on whether the pharmaceutical company is interested in doing so. After all, it can be widely applied: the system works not only with insulin, but also with any protein that lends itself to therapeutic use.