Hearing Hairs

Damaged auditory hair cells cause hearing loss. Other vertebrates can regenerate the hairs. Could humans?



A microscopic substance designed to affect tissue development is implanted into the ear of a chick embryo. The specimen will be incubated for three to 10 days, then studied for its effects.

Download the cell recovery graphic.

If it were reasonable to name the body's most valuable cells, the sensory receptors in the ear — the hair cells that translate sound pressure into electric signals that the brain can interpret — would be good candidates for the top 10 list:

  • They total about 16,000 per ear, so there are none to spare. By contrast, each eye has 130 million photoreceptors.
  • They're subject to damage by noise, the side effects of certain antibiotics, infection and, inevitably, aging.
  • When they are lost, profound deafness is the result. And they don't grow back.

At least they don't regenerate in mammals. In other vertebrates, damaged hair cells in the inner ear regrow in an accelerated process that's otherwise almost identical to the one by which they were originally created during embryonic development.

The difference in regenerative ability drives the research of Mark E. Warchol, PhD, a research associate professor of otolaryngology working at Central Institute for the Deaf at Washington University School of Medicine, and Michael Lovett, PhD, professor of genetics. The two collaborate to understand what changes take place to shut down mammals' ability to regenerate hair cells.

Mark E. Warchol, PhD, right, and Michael Lovett, PhD, examine a network of gene interactions they have observed during chicken hair cell regeneration and also in the normal development of the mouse inner ear.

Why is there this difference; what makes mammals the exception?" Warchol asks. "The regenerative mechanism is present in other vertebrates, and the cells are so similar."

Warchol believes that an inhibitor is at work in mammals, and the goal is to understand the mechanism with an eye toward re-evoking the process of hair cell regeneration. The death of hair cells is "the bottom line of deafness," and the "holy grail" is to improve or even cure hearing loss by regrowing them, Lovett says. The work is representative of the university's BioMed 21 initiative, designed to bring together collaborators to speed clinical solutions from research discoveries.

Working with hair cells and the cells that support them from chicks, the researchers see regeneration begin 12 to 16 hours after injury. The process starts when supporting cells revert to a state that resembles a stem cell. Then, "the genetic regulatory pathways are re-activated, and new hair cells differentiate. They look mature and are functional within 10 days," Warchol says. The process also appears to stop as it should, again mimicking embryonic development.

It takes about another 20 days to make final connections between hair cells and the brain, as chemical signaling molecules guide nerves to their targets. For example, the neuron responsible for delivering a 1-kHz signal has to connect to the 1-kHz-specific spot on the cochlea and, at the other end, to the 1-kHz-region of the brain. But by the time four weeks has passed, a completely deaf chick will again be hearing the infernal peeping of his or her clutch-mates.

Work done elsewhere shows that it may be possible to elicit the same reversal in lower mammals and, the hope is, ultimately in humans. Yehoash Raphael at the University of Michigan has introduced a virus that carries a critical gene for hair-cell development into the inner ears of deaf guinea pigs. New cells grow, Warchol says, and they look much like hair cells, though the full extent of recovery is not yet clear and awaits further study. "But that's a profound effect, nonetheless" he says.

Why no regeneration for mammals?

If the hair cells used to hear are otherwise so similar in other vertebrates and mammals, why is it that evolution has denied mammals the ability to regenerate damaged or lost sensory cells?

Warchol and Lovett say several explanations are in wide circulation. First, an adaptation that mammals possess — the ability to hear high frequencies that other vertebrates cannot sense — required more highly specialized support cells that serve as stressed mechanical structures. That specialization may have made it impossible for mammalian support cells to revert to a type from which they can differentiate into hair cells.

The evolved ability to hear high pitches could have been important for vocalizing without attracting the attention of predators.

It's also possible that in a world before gunshots, MP3 players and Aerosmith, the regeneration of lost hearing was not a critically important capability and could be sacrificed for other advantages.

The Warchol/Lovett approach is different. Having first developed methods for maintaining sensory cells in vitro, they employ gene array technology to identify genes that are either activated or inhibited shortly after cell damage or cell death. By developing their own gene chips, they control costs and can perform large numbers of comparisons. They study sensory cells from both the chick's ear and vestibular organ.

To simulate both cell death and the trauma of loud noise, the investigators apply a toxic antibiotic to kill or a laser to damage the two subsets of cells. Working in vitro, they precisely control timing, examining the cells at critical points. Recording changes in genetic activity from each of the four scenarios, they then create a Venn diagram of the overlap. About 20 genes are always perturbed, and "those are likely to be the important players," Warchol says.

Then, a powerful genetic manipulation technique that selectively knocks down an individual gene's protein product for a period of two to three days allows the researchers to rerun the experimental protocol and observe results. "We'd like to identify those genes that act as supressors of the regeneration process," Warchol says, "and temporarily knock them down." But the process is tedious; the research began with 1,700 candidate transcription factor genes that act as switches, and the network of protein interaction is complex. The tough question is: "If we bring down one factor, how does that change reverberate through the network of activation?" Warchol says.

Next, they plan similar investigations in the mouse to observe which genes in that mammal are inhibiting regeneration and how they are interacting. "We'll overlay results from the mouse experiments on the chick data to compare and contrast genetic activity," Lovett says. If they can find transcription-factor genes specific to the mammalian ear, the potential exists to remove the innate inhibition to regeneration. "If we can suppress the suppressor, it may be possible to allow the natural regeneration of hair cells," Warchol says.

The day on which that is possible in humans may be far off, but the promise to reinstate what seems otherwise to be a lost capability could help those whose hearing has been damaged or eradicated by an increasingly noisy world, trauma or the aging that eventually affects everyone.

The research reported here is funded in large part by the National Organization for Hearing Research Foundation and the National Institutes of Health.

Natural defenses can silence a gene

One way to discern the effect of a gene and the protein it expresses is to turn it off and observe the process in which you're interested, noting any changes. Medical scientists have devised a powerful process that uses the cell's own defenses to switch off individual genes.

Called small interfering RNA, the technique introduces into a cell a fragment of double-stranded RNA from the gene-of-interest's instruction for protein building. All cells have defenses against double-stranded RNA, because it usually is encountered only when a virus is present. As the cell's immune defense chops up what it believes is an invader, it also eliminates the similar protein product of its own genes. The result: expression of a single protein is suppressed. The effect lasts a few days, long enough to explore the effects, and appears to leave no side effects. "By using the normal cellular mechanism, there's no longer a need to genetically engineer an entire organism and grow it," says Michael Lovett.