It was rethinking the results of a "failed" experiment that first alerted Edwin Rubel to the possibility of correcting hearing loss at the cellular level. At the time, it was believed that damage to hair cells in the inner ear, which convert sound waves into nerve signals, was irreversible; once they were lost, the cells did not regenerate.

The ability of Rubel to recognize evidence to the contrary and run with it has set a new goal for research aimed at helping people with hearing loss. In the wake of that pioneering research, an entire center, spearheaded by Rubel, a professor in the departments of otolaryngology/head and neck surgery and of physiology and biophysics at the University of Washington in Seattle, was established at the university to support that effort as well as study other aspects of hearing.

The Virginia Merrill Bloedel Hearing Research Center serves as a focal point for research into the physiology, cell biology, and genetics of hearing and balance. Funding originated with the Bloedel family, back in the late 1980s. Virginia Bloedel was severely hearing-impaired for most of her life. Her husband, a Seattle philanthropist, appreciated the importance of basic research, and after reading an account of Rubel's work in a local newspaper, he contacted the scientist. He "asked what would we do with $5 million," Rubel recalls. "I fell off my chair."

The Bloedel gift has been translated into two endowed chairs and an endowed professorship that rotates among faculty in the arts and sciences. Several years later, a dean who encouraged interdisciplinary research tapped university funds to provide 15,000 square feet of space for Rubel, the director of research at the center, and a handful of colleagues. The result is a unique organization that draws on talent throughout the university, although it is administered jointly by the medical school's department of otolaryngology/head and neck surgery and the university's department of speech and hearing sciences. Rubel would like to expand this program manyfold, somewhat like a mini-Hubble-telescope project. All that is needed, he says, is adequate funding.

Rubel's reaction to an apparently botched experiment has already been key to a decade of new directions in manipulating the cellular basis of hearing. A medical resident's attempt 15 years ago to study changes in the chicken inner ear after antibiotic drug treatment was "a standard kind of experiment that got all the wrong results." But, Rubel says, "that's the time to look carefully." Rubel had directed the resident, Raul M. Cruz, to study gentamicin, a drug known to destroy the hair cells, and follow the time course of damage to these cells. At first, there was expected loss. When Cruz looked a few days later at the cells, instead of further loss, there was a gain in number.

"The dogma was, in any terrestrial vertebrate, when hair cells are lost, they are lost for life," Rubel says. But instead of disbelieving their results, the researchers decided to label the cells with radioactive thymidine to chart cell division. This maneuver enabled them to document true regeneration. Now, Rubel says, "the question is, Can we fool the mammalian ear into doing it?"

The microscopic tufts sported by cells in the inner ear are responsible for transducing compression waves in air into the nerve signals that enable us to hear. From the sighing of the breeze and the rustling of leaves to the concussive rattle of a jackhammer, sound waves are borne along by conducting processes of the outer and middle ears to delicate protein filaments called stereocilia, the "hairs" of hair cells in the inner ear, bending them a few nanometers. Too much loud noise or trauma and these delicate transducers break. Damaged or missing hair cells account for several types of hearing loss. Many genetic cases of deafness involve defects in these cells. Loss of hair cells is also responsible for the diminished hearing often experienced by people as they age.

Hearing loss is the most common disability of human beings, Rubel says, yet it is one of the least-funded areas of biomedical investigation. "People with communication difficulties do not make the best constituency," he says. The close-knit deaf community arose of necessity, he observes, from the stigma that in the past society placed on deafness - the difficulty in communicating that deaf people can sometimes experience has too often been perceived as a sign of mental deficiency. "If you are considered mentally retarded," Rubel says, it is not surprising that you would want to form a self-protective enclave, as many people with profound hearing loss have done.

Yet the deaf culture has costs for those who choose it. Many of the profoundly deaf, though of normal mental capacity, have difficulty reading, which further hampers communication with the rest of society, Rubel says. "People who learned American Sign Language on average do not develop reading [skills] beyond the fourth-grade level," he notes, while those given cochlear implants are often mainstreamed in schools. The deaf community frequently resists the offer of genetic screening and does not necessarily consider deafness a disability that needs to be corrected. "It's weird," Rubel observes. "You find that [deaf] people object to the cochlear implant, but they don't to hair cell regeneration. They see it as a natural reconstitution of function."

The first steps toward recouping hair cell loss in mammals have already been made. Spin-offs of the research into regenerating hair cells have meanwhile led to the design of in vitro preparations to study mature sensory epithelium, the lining of the inner ear's cochlea and semicircular canals, and spurred a search for the growth factors or genes that can be used to prompt the cells to regrow after damage.

Rubel says recent research at Bloedel and other centers shows that in mice missing the p27 gene, which helps control cell division, cells near the hair cells can be coaxed to reenter the cell cycle. These support cells continue to divide in such mice "long after they should have [stopped]," Rubel says. This finding hints at a similar possibility for hair cells of the mammalian inner ear, he adds.

P27 is likely to be just part of a complex set of factors that could be tapped to influence regeneration of hair cells, says George Gates, director of the Bloedel Center. "Regeneration offers promise [for restoring hearing], but it may be a decade or two away from reality," he cautions. "There's hope, and optimism, and lots of people working on it." At this juncture, what may be required is methodically looking in turn at every possible factor governing cell division in the inner ear, Gates says. To accelerate the process of discovery, the Bloedel Center has put together a hearing initiative, and is seeking $20 million in private funding to set up five new labs.

Different aspects of research into hearing repair have already been taken up by members of the broad-based, interdisciplinary effort at the Bloedel Center. These range from the epidemiology of human aging, led by Gates, using data from the well-known Framingham Heart Study, to the molecular genetics of potassium channels and their role in hearing, studied by Bruce Tempel. Mark Bothwell is seeking genes involved in hearing.

And then there are Bloedel-associated behavioral biologists who are working with birds. For example, behavioral psychologist Mike Beecher has collaborated with Rubel to study the return of hearing due to the regeneration of hair cells. Other experiments have shown that the songs of deafened songbirds deteriorate, just as does the speech of people who develop profound hearing loss. But such songbirds, whose hearing eventually returns because their hair cells regenerate after damage, can be taught new notes - even though ordinarily songbirds don't acquire new songs as adults. This new evidence for behavioral plasticity in adult birds, revealed by the work of Rubel’s former doctoral student, Sarah Woolley, has been submitted for publication.

Rubel, who earned a Ph.D. in physiological psychology and animal behavior from Michigan State University, feels entirely at ease in this far-flung, interdisciplinary enterprise. "If I have been criticized," he says, "it's been for being too broad. But that's what I enjoy."