Low-Bass Music Controls Insulin Release From Designer Cells
By Deborah Borfitz
October 11, 2023 | Scientists in Switzerland have figured out how to remotely control genes in a way that could one day enable diabetics to produce and administer insulin directly in their body rather than relying on injections, inhalers, and pumps. Low-bass heavy popular music and movie soundtracks are being used to trigger insulin release from designer cells in implantable capsules when intentionally directed at the implant site, according to Martin Fussenegger, professor of biotechnology and bioengineering at ETH Zurich in Basel, who is leading the research project.
Insulin release can be fine-tuned based on the type of music being played. Queen's song “We Will Rock You” famously released almost 70% of insulin within five minutes and the remainder within 15 minutes, comparable to the dynamics of glucose-triggered insulin release by human pancreatic islets, as recently reported in The Lancet: Diabetes & Endocrinology (DOI: 10.1016/S2213-8587(23)00153-5). The second strongest insulin response was elicited by the soundtrack to the action movie The Avengers. Beethoven could instead be used for a lower insulin dose, Fussenegger says, noting that ambient noises (e.g., wind, bird songs, and rain) and speech do not have enough bass power to induce release of the hormone at all.
The music-inducible cellular control (MUSIC) device contains cells engineered to be receptive to sound waves, also known as “longitudinal air pressure waves,” by repurposing a protein from E. coli that normally regulates the influx of calcium ions, he explains. Although the system could and ultimately will utilize a human mechanosensitive receptor if deployed in the clinic, the bacterial option worked particularly well for the proof-of-concept study by providing a broad range of triggerable doses.
Bass frequencies of 50 hertz and a volume level of about 65 decibels—a loudness that compares to people speaking normally to each other within five meters—proved to be the most effective in triggering the ion channels, says Fussenegger. The low-bass frequencies also had to persist for at least three seconds and be a reappearing component of a song between brief pauses.
Importantly, the sound source also had to be directly above the implant. A “clear and significant” induction of insulin could be seen after three minutes of music exposure, he notes, although the effects were detectable almost instantaneously.
In the future, individuals with diabetes might simply listen to a “joyful sequence of different tunes” to keep their glucose level in check, says Fussenegger. The Lancet article contains a list of tunes ranked by their ability to trigger insulin release during experiments with mice, but guitar or piano versions of original songs didn’t perform well because they no longer had sufficient bass.
Over time, new songs will no doubt be added to the playlist as new bass-heavy releases are cut, he adds. Presumably, no special permissions would be needed from the musical artists for the tunes deemed to be medically useful.
But it might not always be music that triggers insulin dosing. As Fussenegger and his colleagues most recently discovered, off-the-shelf sonic toothbrushes that stimulate in the same frequency range could also be used—maybe after a meal when individuals don’t happen to be near a loudspeaker.
Fussenegger and his colleagues have been working on gene control switches for many years now to provide dosing and adjustable expression dynamics for gene- and cell-based therapies. Insulin is but one example of a therapeutic protein that can be controlled using a gene switch, he says.
As gene switches have become more refined, so has interest in remotely controlling those gene control systems—meaning no drugs and no injections. Scientists working in the field of optogenetics have succeeded in doing this by shining light on cells.
“But if you want to control these cells over longer periods of time, the light uses up too much electricity,” says Fussenegger. To cut out the “middleman” (the light), he and his team have managed to directly link electric signals to gene expression. Among the multiple strategies they have investigated is a system where light therapy served as a wireless switch for human brain activities and mental states controlling gene expression (Nature Communications, DOI: 10.1038/ncomms6392).
Music as the gene switch takes that line of investigation to the next level, since many people have a music source nearby and use it to jam out to their favorite tunes. “We can foresee diabetics sitting down and listening to music while having their meal and having music interventions whenever they need to combat a glucose spike,” Fussenegger says.
As anyone who has used music for relaxation and stress reduction purposes is aware, musical exposure can be emotionally impactful, but the reason for this is not entirely clear, he continues. What’s now apparent is that the effects are more powerful than previously thought and capable of altering the body at a metabolic level.
To date, small molecules have been the triggers for most of the gene switches developed for cell-based therapies, says Fussenegger. And they have invariably suffered from pharmacokinetic challenges or undesirable side effects because they didn’t have a good off switch, referencing the off-target effects on bone and teeth encountered 20 years ago with tetracycline.
Remote gene switches hold the promise of longer-term gene regulation because they fine-tune expression from outside of the implanted cells. Light and sound can both be localized to the implant site whereas drugs are systemically delivered and thus reach parts of the body where they are not needed and create problems.
For a complex chronic disease like diabetes, dynamic control of insulin delivery to the right location and in the right amount is crucial. Type 1 diabetics need to avoid any glycemic excursion, be it from dietary intake or stress, Fussenegger says. Over the years, glycemic excursions enhance the odds of side effects that include fatigue, depression, blindness, and lower-extremity amputations.
It’s the reason type 1 diabetics typically wear a continuous glucose monitor (CGM) on their arm with a companion smartphone app alerting them of a glucose peak, so they know to immediately inject a short-acting insulin. They are experienced at injecting insulin before and after meals to avoid the repercussions and, in the future, a more palatable option would be to instead stabilize their blood sugar level by turning on some music—still relying on the CGM to stay ahead of sugar spikes and crashes, he explains.
Technology of this type would be particularly beneficial to children with type 1 diabetes and reduce some of the burden on their caregivers, Fussenegger adds. Having well-controlled glucose levels is “even more important” in this population since the risk of side effects are directly related to the length of time they've had the disease.
In the latest study, sound waves began with the membrane of a vibrating loudspeaker that shaped the air and produced music, says Fussenegger. They functioned as a mechanical stimulus that distorted the designer cells, much like what happens to hair cells when air pressure waves are being funneled through the inner ear, but in this case the mechanosensitive receptor was E. coli.
The protein is in the membrane of the bacterium and regulates the influx of calcium ions into the cell interior, he explains. The blueprint of this bacterial ion channel was incorporated into human insulin-producing cells, enabling them to create the ion channel themselves and embed it in their membrane.
The ion channel in the cells would open in response to sound, thereby allowing the inflow of positively charged calcium ions. This caused the tiny insulin-filled vesicles inside the cell to fuse with the cell membrane and release the insulin to the outside.
Several bacterial mechanosensitive receptors were tested by the study team, in addition to human proteins, he adds.
“We could, with further developments, certainly humanize the system with human components,” says Fussenegger. But it was “interesting to see the [best-in-class] bacterial channel work so perfectly in human cell membranes.” Since the researchers were dealing with engineered cells that get encapsulated for implantation, it was not critical to use only human components at this stage of technology development.
The mice with the implanted insulin-producing cells were placed so that their bellies were directly on the loudspeaker, he says, which was the only way an insulin response was triggered. When the animals were allowed to move freely in a “disco environment,” the music did not induce the insulin release.
The fact that the loudspeaker must be in the line of sight of the implant site is “kind of an inherent safety measure,” says Fussenegger. As people using the device are walking around their daily life and being exposed to low-bass frequencies, they don’t want to accidentally induce an insulin release. The MUSIC device would not be triggered by environmental noise from aircraft, lawnmowers, and emergency vehicles “as long as either the patient or the sound source is changing positions and do not remain in the direct line of the pressure wave,” he notes.
The segue to clinical trials may be challenging, says Fussenegger. To advance cell-based therapies would first require producing the engineered cells at an industrial plant certified in Good Manufacturing Practices. He and his team would then need to partner up with medical specialists having the industrial know-how and financial resources to drive the project forward.
Venture capital is also hard to come by, he says. Big pharma generally won’t take over a technology’s development until it has completed phase 2 clinical trials. Researchers would therefore welcome partnership opportunities, from anywhere in the world, and will design new cell types as needed to keep the momentum going.
The clinical potential of the system extends to “anything you can genetically encode,” says Fussenegger. “What we have invented here is the music control, which impinges either on the promoter or on the depolarization of the cell [and] both are typical signaling moieties of every human cell.”
If the music control can manage a chronic disease as dynamically complex as diabetes, then it can control “just about everything,” Fussenegger says. Insulin could be replaced by any biopharmaceutical, including another hormone, an antibody targeting cancer or a virus, or an anti-infective protein clearing some parasite or bacterial infection.