A new way to study one of the hardest senses to understand

The human eye contains more than 100 million light-sensing photoreceptors. By comparison, each human ear has only about 15,000 to 16,000 sensory hair cells, including just 3,500 inner hair cells that send most of the sound information to the brain.

That scarcity, and the instability of the molecules that sense force, makes hearing one of the more difficult senses to study at the molecular level—a challenge becoming more urgent as hearing loss becomes increasingly common. The World Health Organization estimates that by 2050, nearly 2.5 billion people will have some degree of hearing loss, with 700 million people needing hearing rehabilitation.

Now, researchers at the University of Chicago have identified a much older and more abundant version of the cellular machinery that allows hair cells to sense the mechanical forces behind hearing. The discovery, published recently in Proceedings of the National Academy of Science (PNAS), could give scientists a new model for studying how the machinery behind hearing works.

“Inner-ear hair cells are so scarce that the normal cycle of testing how a molecule works and then determining its structure is very difficult to do,” said Eduardo Perozo, PhD, Lillian Eichelberger Cannon Professor of Biochemistry and Molecular Biology and study co-author. “Our goal was to find a similar system that is amenable to biochemical, functional, structural and mechanistic analysis. This study points to a much more accessible and evolutionarily-related system opening a new path to understanding how these molecular machines sense force—and ultimately, how that process allows us to hear.”

A cellular machine for sensing movement 

Hair cells in the inner ear perform a remarkable task: they convert mechanical forces—such as sound waves or movements of the head—into electrical signals that the brain can interpret. At the top of each hair cell are bundles of tiny membrane projections called stereocilia. 

When those projections move, they pull on molecular machinery that includes ion channels called TMC proteins. The channels allow ions to flow into the cell, changing its electrical state and ultimately sending information to the brain allowing us to hear and maintain our balance.

Studying that machinery in humans is difficult because there are so few hair cells and they do not regenerate, so the UChicago research team looked elsewhere in the animal kingdom for cells that might contain a similar system in much greater abundance. 

They turned to cnidarians—a group that includes jellyfish, sea anemones, corals and Hydra. Cnidarians have specialized stinging cells called nematocytes. These cells use mechanical stimulation to detect potential prey or other physical disturbances. When activated, the cells rapidly discharge a microscopic structure used to capture or defend against threats. 

“When you see these stinging cells, and if you know anything about the way the hair cells are arranged in the inner ear, you realize that there is a clear morphological similarity,” said Zeeshan Banday, postdoctoral fellow in the Perozo Lab and lead author of the study. 

The researchers wanted to determine whether that resemblance was more than superficial.

From resemblance to common ancestry 

The researchers found that cnidarian cells contain TMC proteins, the key molecular force sensors in the inner ear, in locations comparable to those found in human hair cells. They then conducted two experiments to determine whether those proteins convert mechanical stimulation into an electronic signal in cnidarian cells, like they do in human ones.

First, researchers reduced the activity of two cnidarian TMC proteins, TMC5 and TMC7, by genetically manipulating jellyfish. The stinging cells could no longer respond normally to mechanical stimulation and lost their ability to discharge. In a second experiment, the researchers used a fluorescent dye that enters cells through the mechanically activated TMC channels. When the stinging cells were mechanically stimulated, the dye entered only through their hair-like bundles, providing further evidence that the bundles contain the machinery responsible for mechanotransduction.

Together, these findings suggest that cnidarian cells and human hair cells share an ancient molecular toolkit for converting mechanical force into electrical activity. 

“It’s a very intriguing example of how evolution at the molecular level can develop these molecular machines, and how they can be used and co-opted in different ways,” Perozo said. 

The researchers estimate that this mechanosensory toolkit dates back hundreds of millions of years, long before the evolution of human ears. Over time, evolution appears to have adapted the machinery for different sensory tasks—including the systems that allow us to hear and maintain balance.

Because cnidarian cells are more abundant and accessible than human hair cells, the findings could also provide a new pathway for understanding human hearing at the molecular level. Researchers could use cnidarian cells to investigate questions such as: How is the molecular complex assembled? How does it respond to force? And which parts of the complex are responsible for sensing that force? 

A better understanding of how these channels work could help explain how mutations in them cause hearing loss—and potentially inform future approaches to treating hearing impairment.