The Mechanics of Hearing

Membrane People

Anyone with a memory of high school science classes probably can recall the basic anatomy of the human ear. Its most striking feature is the snail-shaped cochlea, a spiraling chamber filled with fluid and two types of sensory cells. Confusingly, these sensory cells are called inner and outer hair cells, even though the cells are both located in the inner ear and aren’t hairs at all but, instead, consist of a bundle of stiff fibers known as stereocilia (see Figure 1).

Inner hair cells perform like any average sensory cell. As fluid moves around in the cochlea because of air-pressure induced vibrations in the outer and middle ear, it deflects the stereocilia on inner hair cells, causing the cells to send an auditory nerve signal to the brain. The brain processes these signals, which we perceive as sound.

Figure 1. Scanning electron micrograph of cochlea showing outer hair cells.

Outer hair cells respond differently, however. When their stereocilia deflect, the entire cell contracts and shortens. Rather than simply responding to stimuli, outer hair cells do work in a purely physical sense: like a tiny motor, the cells convert electrical energy into mechanical energy, a phenomenon known as electromotility.

Raphael compares outer hair cell electromotility to turbochargers in a car engine. Because outer hair cells are rooted alongside inner hair cells in the cochlea’s basilar membrane, outer hair cell contractions are in turn sensed by inner hair cells. The outer hair cells add an active element to the system, boosting and amplifying inner hair cell response. The result is the oft-described “exquisite sensitivity” unique to mammalian hearing.

While electromotility can be observed and even set to music—Raphael eagerly shows visitors a video made by a British researcher of an outer hair cell grooving to “Rock Around the Clock”—researchers know little about exactly how outer cells contract and transfer force within the structure. That’s because, on the whole, scientists have misunderstood how cell membranes work, something that Raphael’s group is working hard to change.

“We’re all essentially membrane people,” says Jennifer Greeson, a third-year graduate student who entered Raphael’s group with a BS in electrical engineering. Yong Zhou, a biochemist in his fourth year with Raphael, explains that scientists have long considered membranes to be static entities: barriers that isolate or protect cells from invasion or foundational structures upon which other proteins function. Raphael’s group, though, is demonstrating that changes in the membrane itself may regulate key biological functions.

In the outer hair cell, for instance, it’s a protein lodged in the cellular membrane that powers electromotility. This protein, called prestin, has puzzled scientists since its discovery in 2000. How can such an aggressive motor protein function in the fluid, five-nanometer thick environment of the cellular membrane?

Raphael has developed a promising model of prestin’s function, one that considers the membrane as arched or bent rather than flat. Shifts in electric potential can increase the curvature of the membrane and, like pressure inflating a blimp, enable the force generated by prestin to be transmitted to the other proteins within the cell’s interior scaffolding (see Figure 2). Raphael borrowed the term “flexoelectricity” from liquid crystal studies to describe this action. His membrane-bending model is applicable not just to outer hair cells but possibly to motile bacteria and other biological systems. More importantly, it’s an engineering principle that has ramifications beyond biology. “We may have discovered a new design principle for nanoscale motors,” Raphael posits. “So I ended up with a Grand Unified Theory after all—only for outer hair cells rather than fundamental particles,” he adds with a wink.

Figure 2. Raphael has posited that flexoelectricity acting through a protein called prestin (beige cone in inset circles above) may be responsible for the unique mechanics of the ear's outer hair cell. Prestin is lodged in the plasma membrane (blue) of outer hair cells; the rest of the cellular scaffolding consists of spectrin and actin molecules (red and purple). When the electric field surrounding the cell changes, it causes the prestin molecules to realign (note inward curvature of the prestin molecules in inset b vs. inset a). This realignment creates bends in the membrane itself, causing the entire cell to contract.

Like their mechanical counterparts, biological motors need tuning, and Raphael’s group is investigating how to use chemistry to modulate membrane-based motors. Physicians have long known that patients taking high doses of aspirin can experience short-term hearing loss. Raphael figured out a possible reason why: He found that salicylate, a by-product of aspirin, softens lipid membranes. Prestin’s forces have less impact in a squishier environment, and membrane softening may explain why aspirin causes stomach problems—the stomach lining is essentially one large membrane.

Graduate student Zhou is researching how salicylate chemically modifies membranes. His work may one day provide a way to control membranes in living cells and synthetic microelectromechanical systems. An exciting potential outgrowth of membrane bioengineering is drug delivery. Membranes fuse with other membranes or let materials through as their composition and mechanical properties change. The ability to tweak membranes on demand could provide new ways to deliver drugs or even genes for treating a range of diseases and disorders.

And on the subject of gene therapy, Raphael’s group is collaborating with researchers at Baylor College of Medicine who are specifically investigating a particular genetic form of hearing loss caused by a lack of prestin. The researchers are working to deliver the genes encoding for prestin directly to outer hair cells—to provide what graduate student Greeson calls a “biological fix” for this type of hearing loss as opposed to the man-made, mechanical fixes represented by hearing aids and cochlear implants. Raphael’s group is providing technical expertise and equipment to this auditory bioengineering project—particularly a Zeiss LSM 510 multiphoton and multispectral confocal microscope that Raphael and his students refer to as “the new toy.” Obtained in 2003 through a major research instrumentation grant from the National Science Foundation, the microscope in Raphael’s lab is one of the most powerful available in the Houston area. Greeson uses the microscope to image and decipher the nanoscale conformational changes that occur in prestin when the membrane’s electric field is changed.