Can a Tiny Fish Save Your Ears?

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Researchers Use the Zebrafish in Efforts to Find Ways to Regenerate Hearing-Essential Cells

For many people, loss of hearing is irreversible.

For scientists trying to figure out what can be done about that, one answer may lie—or swim, actually—in freshwater aquariums.

About one of every 10 Americans suffers from hearing impairment, according to a survey conducted by the Better Hearing Institute, a nonprofit advocacy group. By far the most common cause of hearing loss is damage to the so-called hair cells in the inner ear as a result of excessive noise, certain illnesses and drugs, and simple aging. The problem is that once hair cells die, humans (like other mammals) aren’t able to grow new ones.

Hair cells, magnified 21,000 times, line the inside of the shell-like cochlea of the inner ear. Damage to these cells, which can’t regenerate, is a major cause of irreversible hearing loss in many people.

In recent years, a research team at the University of Washington in Seattle has been working on finding a way to resolve that problem in experiments involving the zebrafish, a common aquarium denizen. The zebrafish, like many aquatic creatures, has clusters of hair cells running along the outside of its body that help sense vibrations in the water, working in a similar way to hair cells in the human inner ear. But unlike humans, zebrafish are able to regenerate their damaged hair cells. Researchers hope their work can unlock secrets to protect human hair cells from becoming damaged and to stimulate the cells to regenerate.

Hair cells, which took their name because under the microscope they look like cells with little hairs growing out of them, are an essential link in hearing. The filament hairs, or cilia, bend with vibrations caused by sound waves entering the ear. That induces the hair cell to create an electrical signal that is passed on to the auditory nerve and sent to the brain. Devices such as hearing aids, which amplify sounds, and cochlear implants, which stimulate the auditory nerve directly, help people hear, but neither restores hearing to normal.

Until the mid-1980s, researchers thought warm-blooded vertebrates, including humans, weren’t able to regenerate hair cells. Then, researchers around the country began observing that hair cells grew back in birds whose hearing was damaged either by noise or drugs. They also determined that hair-cell regeneration can result in improved hearing; in experiments, song birds that had grown new hair cells were able to resume singing their original songs with perfect pitch again.

But there is no indication that mammals can regenerate hair cells. And why some animals, even within the same species, are more vulnerable to hair-cell death, while others are more resistant to it, is a mystery. “I literally walked around for years wondering about this variability,” says Ed Rubel, a professor of hearing sciences who leads part of the University of Washington research effort.

The zebrafish has hair cells on its body that work in a similar way to hair cells in the human inner ear.

There are two main approaches to efforts aimed at inducing hair cells to regenerate. Some research groups are attempting to get stem cells—undifferentiated cells that can develop into various specialized cells—to turn into hair cells, either by transplanting them from other parts of the body, or by stimulating stem cells naturally occurring in the inner ear to transform themselves. Albert Edge, an associate professor at Harvard Medical School and a researcher at the Massachusetts Eye and Ear Infirmary, says his team has been able to turn mouse stem cells into hair cells in a laboratory dish, though it isn’t clear whether those cells are functional or not.

Other researchers, like those at the University of Washington, are focused on understanding the molecules and genetics involved with hair-cell regeneration, and how to mimic this process in animals that don’t spontaneously regenerate hair cells. Scientists say aspects of such research, likely will be the first to have applications in humans. One encouraging angle: Dr. Rubel, in collaboration with another University of Washington scientist, David Raible, has identified chemicals that seem to protect hair cells from damage. In this experiment, zebrafish are exposed to a dye that highlights living hair cells. Then, one or two of the zebrafish—the young ones used in the lab measure just 1/8 of an inch long—are placed in each of 96 shallow holes contained on a plate. Different chemicals are administered to each fish group that might confer protection to the hair cells.

Finally, another chemical known to kill the fish hair cells is added. Under a microscope, researchers then examine the fish to look for cases where the dye is still evident, signaling that the cells are still alive and suggesting that the protective chemical appears to have done its job.

Those chemicals found to confer protection on fish hair cells are currently also being tested on mice and rats. The idea is that, once a drug is discovered that effectively protects hair cells from dying and is safe for humans, the medicine could be used to help protect the hearing of patients receiving drugs known for killing hair cells, like chemotherapeutic agents.

Dr. Rubel’s and Dr. Raible’s teams also are studying the genetics of zebrafish to identify markers that confer hair-cell protection.

Last year, their labs jointly identified several genetic mutations and drug-like compounds that seemed to protect hair cells from death, publishing their findings in the journal PLoS Genetics. In a separate study, published in 2007 in Hearing Research, they identified several drugs that also appear to be protective and were already approved for other purposes by the Food and Drug Administration. No tests have been performed on humans, however.

The teams also are working on a separate group of studies to understand the genes and other molecules that allow the regeneration of hair cells in zebrafish, birds and mice.

Surrounding cells known as support cells can both turn into hair cells or generate new hair cells. Dr. Rubel’s lab is investigating both processes. “If we understand the template of genes that are expressed by the cells we would want to divide, then we could tap into that template” to mimic regeneration efforts in mammals, he says.

One finding identified a developmental protein that appears to be turned on in animals able to regenerate hair cells. In one study, a team member found a type of protein increased in a chick (which can regenerate hair cells) after its cells were damaged. But in running the same experiment in a mouse (which can’t regenerate hair cells), the protein didn’t increase, suggesting the protein could be involved in regeneration.

Scientists involved in the experiments say there could be therapeutic trials to prevent hearing loss using drugs within a decade. However, finding a cure for hearing loss using hair-cell regeneration is likely to be at least 20 years away, they say.

“Hearing aids are Band-aids on a problem that already exists,” says Nancy Freeman, director of the regenerative and development program in hearing loss at the National Institute on Deafness and Other Communication Disorders.

“The hope with this type of [regeneration] approach is that at the end of the day you’d end up with something that natively restores function.”