ABOVE: Queen’s “We Will Rock You” and other pop songs trigger insulin release, thanks to the field of sonogenetics. © iStock, delihayat

When Queen wrote the floor-stomping, hand-clapping hit “We Will Rock You,” they probably never imagined that it might one day be used to tame blood sugar levels. But by exploiting proteins that respond to sound, researchers at ETH Zurich took a step toward making pop music a prescribable therapy. The team published a study in The Lancet describing how membrane channels that are sensitive to low-bass pop music can be rigged to regulate insulin release from human cells implanted into mice.1 If adopted in people with type I diabetes, this approach could allow insulin levels to be controlled with music, potentially doing away with injections.

“This is revolutionary work,” said Lei Sun, a biomedical engineer at Hong Kong Polytechnic University who was not involved with the study. “The clinical translation is still far away, at least from my point of view, so I’m conservatively excited,” he added, highlighting that the system hasn’t been tested and finetuned in humans.

Bioengineers have developed a variety of methods to remotely trigger cellular functions in mice. With optogenetics, researchers switch on excitable cells like neurons under the precise control of a light beam.2 Similarly, scientists developed sonogenetics to stimulate cells using sound waves—typically ultrasound frequencies that are outside the human audible range.3 Martin Fussenegger, a bioengineer at ETH Zurich, and his colleagues set out to use music instead of ultrasound to control cells so that patients wouldn’t need an ultrasound device.

See also “Stimulating Neurons with Sound”  

To remotely control cells with sound, researchers rely on mechanosensitive ion channels in the cell membrane. When sound vibrations warp the membrane, the ion channels open, allowing ions to flood into the cell and trigger cellular processes. Fussenegger and his team used a Ca2+ ion channel from Escherichia coli bacteria that responds to sound in the human auditory range.4 

They introduced this large conductance mechanosensitive channel (MscL) into an insulin-producing human cell line adapted from pancreatic β cells that no longer responded to glucose,5 so that insulin release could be singularly controlled with sound. With this setup, music vibrations triggered an influx of Ca2+ ions into the cells, which led to insulin release. Aside from the bacterial channel, “everything that replicates the dynamics for insulin release is of human origin, so we expect this system really to interface with humans,” Fussenegger said. 

With their modified cell line in hand, Fussenegger and his team determined how volume and genre affected insulin release in the cultured cells. They saw the best results using 65 decibels, a volume louder than a conversation but quieter than a vacuum cleaner. Low-bass pop songs like “Billie Jean,” “Hotel California,” and “We Will Rock You” were potent triggers, but piano or guitar renditions of the same songs and classical music elicited a weaker response. Fortunately, environmental sounds such as wind, rain, or BBC News left on in the background did not trigger the cells. Fussenegger explained that environmental noise, classical music, and treble-heavy acoustic songs don’t typically produce the low-bass thump common in pop music that hits the 65 decibels needed for optimal insulin release.

See also “Researchers Use Ultrasound to Control Neurons in Mice”  

Next, the team implanted these musically controlled cells into the mice peritoneum, a membrane that lines the abdomen. “We Will Rock You” was one of the best pop songs for triggering insulin release from cultured cells, so the team played this rock anthem for the mice. 

Unlike the stationary cells grown in a dish, mice scurry around, so the researchers wondered if movement would complicate the effectiveness of the treatment. Indeed, mice laying still and facing the speaker secreted more insulin than mice that were allowed to roam around. Music only had an effect if it was played out loud as well; mice wearing earphones did not secrete insulin, probably because the sound vibrations were concentrated in the ears and didn’t reach the cells in the abdomen. 

“It’s fascinating,” said Sreekanth Chalasani, a neuroscientist at the Salk Institute who works with sonogenetics but was not involved with the study. He found the proof-of-concept study promising because he believes remotely controlling medical processes is the future. However, he expects that a clinical committee would ask for several queries to be addressed before trying the system in humans. In particular, he posed these questions: “How long are the cells alive? How effective are you at producing insulin six months out or one year out? Can you make insulin only in high glucose?” 

Sun would also like to know whether attending concerts or other music events would inadvertently trigger insulin release even if blood glucose levels are normal.

He hopes that a safety mechanism can be installed in the musically controlled β cells that only allows insulin to be released if blood glucose levels are high. “You have to have some sort of sensing circuitry to adjust your insulin secretion depending on your glucose level,” he explained.

Mice listening to “We Will Rock You” released all of the insulin from the implanted cells within five minutes, and it took four hours to replenish those insulin stores. Fussenegger suggested that listening to music during that replenish period would be equivalent to snacking in between meals, during which they release insulin prematurely and don’t have enough stored away to control blood sugar levels during the next meal.6 

Going forward, Fussenegger is upbeat about the prospects of this technology. He noted that it has the potential to be used with any therapeutic protein, not just insulin. “You could link it to the expression of therapeutic antibodies. You could link it to the release of other hormones. So, anything that can be genetically encoded can be controlled,” he said.

References

  1. Zhao H, et al. Tuning of cellular insulin release by music for real-time diabetes control. The Lancet. 2023;11:637-640.
  2. Emiliani V, et al. Optogenetics for light control of biological systems. Nat Rev Methods Primers. 2022;2(55).
  3. Ibsen S, et al. Sonogenetics is a non-invasive approach to activating neurons in Caenorhabditis elegans. Nat Comms. 2015;6(8264).
  4. Sukharev SI, et al. A large-conductance mechanosensitive channel in E. coli encoded by mscL alone. Nature. 1993;368(6468):265-268.
  5. McCluskey JT, et al. Development and functional characterization of insulin-releasing human pancreatic beta cell lines produced by electrofusion. JBC. 2011;286(25): 21982-21992.
  6. Solomon TPJ, et al. The effect of feeding frequency on insulin and ghrelin responses in human subjects. BJN. 2008;100(4):810-819.