Birds can naturally restore their hearing after damage, a remarkable ability that has inspired cutting-edge research that could eventually lead to treatments for human hearing loss. In Hearing Health Foundation’s (HHF) April 28 research webinar, Hearing Restoration Project member Stefan Heller, Ph.D., of Stanford University shares fascinating insights into his team's groundbreaking work on hair cell regeneration.
For the 450 million people worldwide suffering from debilitating hearing loss, the root cause is often the same: damaged or dead sensory hair cells in the inner ear. These sensory cells convert sound vibrations into electrical signals that our brain interprets as sound.
When they die—whether from aging, noise exposure, certain medications, or genetic conditions—mammals (including humans) cannot naturally replace them like other species can, such as birds and fish.
Stefan Heller, Ph.D., during his April 28 HHF research webinar.
“No more hair cells means hearing loss,” Heller says. “It’s like having a stage performance where someone steals all the microphones—there’s simply no way to hear the performance anymore.”
We know that salamanders can regrow their tails, Heller says. What’s interesting is that part of the tail includes a structure called the lateral line, which has hair cells similar to the ones in our inner ear. When the tail grows back, these hair cells grow back too. That was an early sign that hair cell regeneration might be possible.
The scientific breakthrough came in 1988 when researchers discovered that birds like chickens and quails could regenerate hair cells after acoustic trauma.
These discoveries were made by scientists who had been funded by Hearing Health Foundation, including Brenda Ryals, Ph.D., now on HHF’s board, and Doug Cotanche, Ph.D. And they led to the creation of HHF’s Hearing Restoration Project, a collaborative research consortium whose mission is to unlock hair cell regeneration in humans.
Heller’s lab has meticulously documented this regeneration process in chickens:
After damage, hair cells die within 12 to 24 hours
Supporting cells begin dividing around 38 to 48 hours
New hair bundles—the mechanosensitive structures on top of hair cells—appear within 7 days
These bundles mature to normal appearance by day 11
Synaptic connections with nerves are reestablished by days 11 to 14
Complete hearing restoration occurs within 4 to 5 weeks
When a hair cell dies, one nearby supporting cell re-enters the cell cycle and divides into a new hair cell and a new supporting cell. This process begins 4–11 days after damage, with the new hair cell becoming functional by days 11–14. The epithelial wound closes rapidly to prevent fluid leakage.
When hair cells die, the surrounding cells must quickly seal the gap to prevent fluids from leaking through the damaged area, Heller explains. In this process, exactly one supporting cell near the dead hair cell is activated.
This single supporting cell begins to divide, creating two new cells: one replacement hair cell and one new supporting cell. This division happens within 2 to 4 days. The new hair cell is initially immature and nonfunctional, but becomes fully functional after 11 to 14 days.
Cracking the Molecular Code
Using advanced single-cell technology, Heller’s team identified the specific signaling pathway that triggers this regeneration. When hair cells die in birds, they release enzymes that activate a receptor called F2RL1 on supporting cells. This triggers a cascade involving a gene called HBEGF, ultimately leading to supporting cell division and regeneration.
And the smoking gun, according to Heller? When researchers blocked this pathway with inhibitors, the supporting cells no longer divided, and no new hair cells appeared.
“We’re seeing the tip of the iceberg,” Heller says. “There’s likely a second pathway involved as well, but we’ve identified key molecular signals that drive this regenerative process.”
The next frontier is applying these findings to mammals. Heller’s team has successfully developed methods to ablate hair cells in adult mice and is currently studying why mouse supporting cells don’t naturally divide and regenerate after damage.
“The time course of hair cell death in mice is slightly different from chickens,” Heller says. “Outer hair cells die within 14 hours, while inner hair cells survive until day three before dying.”
The team is exploring several approaches:
Using gene therapy tools to deliver the regenerative genes identified in birds
Testing drug treatments that activate the proteins in the regenerative pathway
Conducting molecular analyses to understand what’s missing in the mammalian response
Looking Toward a Cure
Will there be a universal cure for hearing loss? Heller is cautiously optimistic but realistic.
“Looking at the different causes for hearing loss—aging, genetics, noise exposure, drug toxicity—it becomes clear that a one-size-fits-all cure is unlikely,” he says.
Recent breakthroughs in gene therapy for deafness due to the single gene otoferlin demonstrate that targeted treatments are possible. In clinical trials in the U.S., Europe, and China, children with OTOF gene variants who received gene therapy can now hear—a remarkable achievement that shows the potential of precision medicine approaches.
When asked about the outlook for a cure for human hearing loss, Heller says, “We’re already there for some patients, but we don’t realize it.” He explains that if we break down the 450 million patients with hearing loss into a pie chart, some pieces of this pie will be large and some relatively small.
We can now treat otoferlin-related hearing loss, he says, which affects a very small slice of the pie. Those patients have a working treatment, although we’re still learning how long it lasts. Heller adds that in the next 10 years, we’ll continue to reach more groups with specific causes of hearing loss—creating a momentum that will help accelerate the process for everyone.
Significant challenges remain, including:
Efficiency and safety of potential regenerative treatments
Cellular aging issues that affect the whole auditory system
Ensuring proper nerve connections with newly generated hair cells
Developing proper diagnostics to identify specific causes of hearing loss
Heller reiterates that while progress is accelerating, patience is needed, and the gold standard for severe to profound hearing loss is the cochlear implant, itself a technology that has improved dramatically in the past several decades. “If I were affected by profound hearing loss at my age, I wouldn’t hesitate to get a cochlear implant while continuing to work on treatments to help people in the future,” he says.
Crucial Funding
HHF’s support has been crucial for this groundbreaking work, Heller says, estimating that for $1 received from the foundation, he has been able to leverage $8 from other sources like the National Institutes of Health and other foundations.
“Without HHF funding, we would not have been able to do this work,” Heller says. “It took seven years until we began to get funded from the NIH. HHF supported the careers of several researchers who now lead their own labs, expanding the group of scientists working on this problem.”
As research continues to advance, there’s real hope that the lessons learned from our feathered friends might someday restore natural hearing in humans. While we may not see universal treatments in the immediate future, targeted approaches for specific types of hearing loss are already becoming reality.
Please click here to get the transcript, bibliography, and captioned video.
Hearing Restoration Project member Stefan Heller, Ph.D., is a professor of otolaryngology–head & neck surgery at Stanford University and the Edward C. and Amy H. Sewall Professor at Stanford’s School of Medicine, as well as a faculty member at their Institute for Stem Cell Biology and Regenerative Medicine. He is also a 2001–2002 Emerging Research Grants scientist.
HHF appreciates your support of hearing and balance research at hhf.org/donate.
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We can now treat otoferlin-related hearing loss. Those patients have a working treatment, although we’re still learning how long it lasts. In the next 10 years, we will continue to reach more groups with specific causes of hearing loss—momentum that will help accelerate the process for everyone.