In the mid-1980s two and two were not equaling four in Ed Rubel’s lab. Rubel, a UW professor who was conducting research on hearing loss, could not understand why Raul Cruz, a surgery resident working with him, kept coming up with results that made no sense.
Rubel was a new arrival from the University of Virginia, where he’d conducted hearing loss research for years. He told Cruz to add up the dead cells inside the ears of chickens after giving the birds doses of antibiotics. Scientists already knew that some patients receiving therapeutic doses of certain antibiotics suffered hearing loss. Rubel wanted to know when and how that loss occurred, so he focused on chickens, which suffer the same pattern of hearing loss when exposed to the same drugs.
Yet Cruz presented Rubel with an impossible result—he counted more living cells at the end of the experiment than at the beginning.
“My first reaction was that he must have done something wrong—counted incorrectly or mixed up his animals,” says Rubel. “I told him to go back to the lab and to keep his animals straight.”
Cruz returned with the same data. Rubel was surprised and perplexed that the promising resident didn’t seem to be getting it right.
“We all knew that there was a progressive loss of cells after this kind of treatment,” says Rubel. “So we decided to use different counting criteria.”
The third time Rubel saw the same data, he realized that something unexpected was happening. What he was observing contradicted everything known at the time about neurobiology and hearing.
“Somehow cells were coming back to life after they’d already been gone,” he explains.
The resurrection of hair cells in the inner ear of chickens might sound esoteric to the average American—but for the 28 million people who suffer from hearing loss, it could be the beginning of a new way of life. About 80 percent have irreversible hearing loss, and the number one cause is the death of hair cells—the very cells Cruz was counting. If Rubel could find out how these cells return to life, perhaps he could apply that knowledge to humans.
He found that the secret of the regrowth was in the birds’ genes. Using DNA technology, Rubel and his colleagues went on to show that, after the damage, new cells were produced by cell division. “But that was really a confirmation of what we’d been seeing all along when we were actually counting cells,” he says. “I don’t think that most of the world believed that birds actually produced new cells until the early 1990s. It takes a while for other people to replicate the work and realize that this wasn’t just a freak of a chicken.”
Rubel—whose joint appointments span three UW departments: otolaryngology—head and neck surgery, physiology and biophysics, and neurosurgery—adds, “We haven’t cured anybody yet. What we’ve found is a potential pathway—our hair cell work has opened a new area of research in the effort to treat hearing disorders.”
These hearing disorders don’t just attack the elderly. Kay Sterner, ’00, first noticed her hearing loss at age 11. When lying on her right side, she couldn’t hear crickets chirping at night. Sterner, 26, has what she describes as “old man hearing” and what doctors call “presbycusis.”
Usually presbycusis is an age-related condition where the cells in the ear are thought to wear out. “Hearing loss is associated with grandpas saying, ‘Eh?’“ says Sterner. “A lot of people joke about it and associate it with old age.”
In high school, Sterner wore her first hearing aid—only in one ear and only during class. Today she wears digital hearing aids that are virtually invisible. In face-to-face conversation, her hearing loss is not immediately apparent.
“People have said to me that it’s no different than wearing glasses,” says Sterner, but she disagrees. “It is much different. This is not something we’ve completely figured out how to correct. Even with the hearing aids, I don’t have normal hearing. I have to wear the hearing aids and I have to ask people to change their behavior for me.”
Much of the basic research that may someday help Sterner and others takes place at the UW’s Virginia Merrill Bloedel Hearing Research Center. Founded in 1988, the center brings together the research interests of 55 clinical and basic scientists from the School of Medicine, the College of Engineering, and the College of Arts and Sciences. It is one of the largest hearing research collaborations in the country.
The center started with a $5 million gift from Northwest lumber-company magnate Prentice Bloedel during the Campaign for Washington, the UW’s first major fund drive. The center honors his wife, Virginia, who suffered from hearing loss. Rubel was the center’s first director, and much of its basic research involves hair cell regeneration.
Hair cells are crucial to detecting the vibration of air molecules, what we call “sound.” A vibration may be produced, for instance, by a bow on a violin string or a person’s voice. Hearing begins when the air disturbance impinges on the eardrums, deep in each ear canal. The eardrum is attached to a series of three, tiny, middle-ear bones whose movements are transmitted to the cochlea, a snail-shaped organ about the size of a pea, located in the skull behind the eye. Fluid inside the cochlea is moved by the actions of the middle ear bones.
Within the cochlea are 15,000-16,000 hair cells, so called because under a powerful microscope protrusions on the cells resemble hairs—but they have no relation to the hairs on your head. In the inner ear, these groups of small “hairs” bend and yield according to the movement of fluid in the cochlea, much like reeds in the current of a river. The movement of the hairs generates neural signals, which are carried to the brain. Highly complex combinations of neural signals are interpreted by the brain as, perhaps, Beethoven’s Ninth Symphony or Mom on the other end of the telephone.
“Ultimately the goal is to compare what we find in the chicken to what is known about mammals.”
Jennifer Stone, research assistant professor
In humans, hair cells come in four rows within the cochlea. There are inner hair cells and outer hair cells. Inner hair cells detect sound. The outer hair cells are still a bit of a mystery, but they seem to strengthen sound by amplifying the response of inner hair cells. Outer hair cells are the most vulnerable to drugs, excessive noise and aging. When they wear out and die, a hearing aid may act as an amplifier to boost the sound signals—but without the precision of the original cells.
“If the inner hair cells die, you’re deaf,” explains George Gates, an otolaryngology professor and current director of the Bloedel Center. “But hearing aids supplement the function of outer hair cells by making sounds louder. Hearing aids are an extra power source. You are putting acoustic energy into the ear.”
One important question, according to Gates and Rubel, is why do adults lose hearing as they age? Scientists think there is a combination of causes involving genetics, cellular biology and biochemistry. Much of the effort is focused on genetics, although no one would say that gene therapy is a viable option, yet. “Gene therapy is a long and rugged road to explore,” says Gates.
Researchers at the Bloedel Center have identified genes that may be involved in presbycusis. This work corresponds with analyses of data from the famous Framingham Heart Study. The study of more than 5,000 men and women between the ages of 30 and 62 from the town of Framingham, Mass., began in 1948 to track common factors of cardiovascular disease. Every two years the subjects, and now their children, have had extensive physical examinations and lifestyle interviews. The study gives medical researchers an invaluable pool of genetic data to analyze for a variety of illnesses.
In the Framingham study, according to Gates, children of parents with presbycusis suffer similar patterns of hearing loss at the same time in life. Perhaps in the next 10 to 20 years, researchers may be able to prescribe drugs that specifically target and manipulate the genes that control cell division and death in the inner ear.
While some look at prevention of hearing loss through gene therapy, others investigate restoring a weakened sense of hearing. In Rubel’s lab, researchers found that birds regenerate damaged hair cells seemingly spontaneously. Jennifer Stone, a research assistant professor in otolaryngology, wants to track the step-by-step biochemical process that enables chickens to regenerate hair cells. Understanding each step in birds would eventually allow researchers to identify what steps are missing in mammals.
Stone works mainly with chickens. Besides being less complicated in general, the hearing apparatus in birds is more easily accessible than that of mammals. The spiral-shaped human cochlea is encased in very dense bone. Birds have a relatively straight cochlea that can be preserved outside of the body.
“Ultimately the goal is to compare what we find in the chicken to what is known about mammals,” Stone explains. She wants to know why mammals do not have the natural ability to regenerate hair cells.
Scientists speculate that this ability was lost in something like an evolutionary compromise. Mammals have the ability to hear higher frequencies than chickens, but they no longer regenerate hair cells. Researchers theorize nature selected mammals that could hear better in their youth—rather than those that could regenerate hearing as they age.
“The amount of mass on a tissue affects how the tissue vibrates,” says Elizabeth Oesterle, a research associate professor in Rubel’s group. “A sensory system that is encoding high frequency sounds does not have the luxury of having extra cells.”
Dogs and bats are other examples of animals with sensitive hearing that do not regenerate hair cells. Oesterle, who has been a pioneer in understanding hair cell regeneration in mammals, has been able to induce the first stages of hair cell regeneration to a limited extent in the inner ear of rodents. She’s looking for molecules that can kick in the production of larger numbers of hair cells—but not too many. Mammalian organs have a very elaborate way of putting the brakes on cell division, whether it is cells in the heart or the retina. The overproduction of cells, after all, results in cancer. The molecules responsible for signaling cell division are similar across tissue types and even across species.
The same molecules expressed in cancer may one day be important in stimulating the regeneration of hair cells in the inner ear after damage. In order for the process to be clinically applicable in hearing loss research, scientists must be able to turn these molecules on and off.
In one experiment, published by Rubel’s group in collaboration with investigators at the Fred Hutchinson Cancer Research Center, mice that lacked one of the genes controlling cell division were shown to produce extra inner- ear hair cells. The indiscriminate overproduction, the group reported, eventually caused a severe hearing loss.
Will hearing loss be “cured” in the next few years? Probably not. But work at the Bloedel Center is helping the process along. Rubel envisions a kind of Manhattan Project—with researchers from many different disciplines working at the UW on the problem of inner-ear hair cell regeneration in mammals.
“Any small bits of knowledge that we can gain about the biology and the physiology of hearing, and cellular biology of the inner ear or brain pathways may be critical down the line for clinical applications,” says Rubel.
“When human beings first decided to ride a horse, rather than walk from one place to another, could we have predicted the current land speed record?” asks Rubel. “I doubt it. We’re at that level. Just 15 years ago nobody believed that regeneration of the hair cells in the inner ear could possibly happen—let alone restore hearing. Now we know hair cell regeneration almost perfectly restores hearing in all of the other vertebrates that hear complex sounds. The challenge that lies ahead is to make that happen in us. “
When Miss Alabama won the Miss America pageant in 1995, another contestant had to tap her on the shoulder to tell her. Heather Whitestone, Miss America 1995, lost her hearing after suffering a reaction to medication when she was 18 months old. The 21-year-old accounting major was the first woman with a disability to be crowned Miss America. Her first-place winning talent was a ballet dance that she performed while wearing a white chiffon dress and a hearing aid.
Whitestone joins a growing list of hearing-impaired celebrities including Montreal Expos outfielder Curtis Pride, musician Pete Townsend, “Guiding Light” soap-opera actress Amy Ecklund, and bodybuilder / “Incredible Hulk” Lou Ferrigno.
Most prominent these days is actress Marlee Matlin, a frequent face on the prime-time television drama The West Wing. After contracting German measles as a toddler, Matlin lost her hearing completely in one ear and only retained 20 percent in the other.
At age 21 Matlin’s first feature film role in Children of a Lesser God won her an Academy Award for best actress. Since then she has won Emmy awards for guest roles on Seinfeld and Picket Fences. Matlin also helped successfully lobby the U.S. Congress to mandate close captioning on newly manufactured television sets.