At the VMBHRC, collaborative research is the rule, leading to a natural and fruitful sharing of ideas. A broad-based multidisciplinary team of researchers has been in place for many years, bringing a wide range of strategies and expertise to bear in unraveling the complex questions of how best to prevent, repair, and reverse inner-ear disease including hearing loss, tinnitus, and vestibular disorders.

New Hope for Hearing Loss

Hearing loss is the common chronic human disability: one in 10 Americans has enough hearing loss to cause serious communication problems. In people over the age of 60, this number increases to 30 percent and then to more than 50 percent for those over 80 years of age. During the past two decades, progress toward understanding the biological foundations of both normal and impaired hearing has been rapid. UW scientists have played major roles in these advances, including pioneering the field of inner-ear hair cell regeneration and significantly advancing knowledge in the areas of cochlear implants, hearing development, genetics of hearing loss, vestibular testing, and early diagnosis of hearing loss in children.

Better Hearing Through Research

The University of Washington's Virginia Merrill Bloedel Hearing Research Center (VMBHRC) houses an interdisciplinary group of researchers who study hearing, hearing loss, and related communication disorders. The center's motto is 'Better Hearing Through Research', its goal to advance knowledge in the auditory field so that all may hear. The Bloedel Center was established in 1988 with a generous gift from Prentice Bloedel and his wife, Virginia Merrill Bloedel, who suffered from a progressive, and ultimately profound, hearing loss. Today, through the center, 15 University departments and more than 60 affiliated research scientists from a variety of disciplines in three UW schools and colleges (the School of Medicine, the College of Engineering, and the College of Arts and Sciences) are working together. We seek to conquer deafness and disequilibrium by preventing hearing loss and through repair and regeneration once damage has occurred. The Bloedel Center now comprises the largest hearing research group in the country.

Research at the Bloedel Center

Scientists whose research is conducted at the laboratories of the VMBHRC are investigating several innovative approaches to understanding hearing resilience, repair, and regeneration. Efforts are under way to understand cellular and molecular mechanisms, including genetic triggers. Our researchers are working to improve technologies that are currently available, such as the cochlear implant. Other technologies, such as hair-cell regeneration, are an exciting approach that holds promise for tomorrow.

Resilience

Approximately one in 1,000 babies is born with significant hearing loss; about half of these cases are due to an inherited genetic condition. Over the past decade, research in the laboratory of Dr. Bruce Tempel has contributed to identifying these ?deafness genes? in mice and by extension in humans. Of particular interest are genes that regulate calcium concentrations in hair cells (sensory cells of the inner ear necessary for normal hearing), thereby affecting the transduction of sound. Of equal interest are genes that maintain high-resolution action potential encoding of auditory information in neurons of the auditory brainstem. Dr. Helen Brew uses mice lacking specific ion channel genes to determine the role of these genes in normal auditory transmission and their potential contribution to disease states including tinnitus. Dr. Valerie Street uses molecular genetic techniques to identify genes that cause low-frequency and progressive hearing loss in families where the loss is first observed in teenagers or young adults. Research continues to identify the genetic basis of these familial forms of hearing loss and to search for ways to minimize their effects through hearing aids, training, drug development, cochlear implants, and eventually gene therapy aimed at gene supplementation or hair cell regeneration.

Cross-section image of a chick's auditory brain stem. Recent discoveries about avian hearing have exciting implications for the future of hearing-loss treatment in humans.

In comparison to frank mutations that are familial, much less is known about the complex genetic contributions to hearing loss associated with aging or exposure to noise. Age-related or noise-induced hearing loss comes on slowly in most people but has a major impact, causing hearing loss and difficulties in communication in roughly 50 percent of the population at retirement age.What can be done to help prevent or resist these forms of cumulative hearing loss? Several research projects at the VMBHRC are aimed at identifying gene targets and methods for preventing hearing loss.

In the laboratory of Dr. Tempel, strains of mice that show age-related hearing loss or are resistant to noise exposure are being analyzed using a whole genome approach aimed at identifying each of the multiple genes that contribute to making these mice uniquely susceptible to aging or resilient to noise. Homologous genes in humans are likely to also contribute to similar types of hearing loss in humans.

In Dr. Edwin Rubel's lab, zebrafish are being used to identify genes and chemical compounds that influence the sensitivity of the inner ear to aging and potentially toxic agents such as therapeutic drugs, noise exposure and environmental toxins. High throughput genetic screening and high throughput testing with large chemical libraries are allowing VMBHRC scientists to detect molecules and cellular pathways that alter the sensitivity of the inner ear to damage and degeneration.

Efforts by these and other investigators will eventually identify basic mechanisms and provide therapies aimed at increasing resilience and resistance to hearing loss.

Repair

Cochlear implants have proven to be an important advance in the quest to restore hearing. Using this device, most deaf people can gain understanding of speech, provided the speech is heard against a quiet background. Cochlear implants are limited, however. Currently they do not provide good speech perception in noise, nor do they typically produce enough pitch perception for a full appreciation of music. VMBHRC scientist Dr. Jay Rubinstein and his team are studying ways to improve cochlear implant technology to reduce these limitations. Their research is focusing on a signal processing approach for cochlear implants, which induces a nerve response that is closer to that in normal hearing.Using recently developed sound-processing algorithms, music perception, spatial hearing, and speech perception in noise can be improved, providing a better quality of life for cochlear implant users. It is possible that certain vestibular disorders and forms of tinnitus may be treatable using advances in these technologies.

Although cochlear implants have made a remarkable impact on the rehabilitation of hearing loss, they do not reproduce the temporal and spectral sensitivity of normal hearing. Dr. Rubinstein?s work demonstrates that increased temporal sensitivity with cochlear implants can be produced with improved sound processing. Improving spectral sensitivity (the ability to discriminate pitch) demands a more biological approach such as that provided by work described in the next section. Dr. Clifford Hume,working with Dr. Rubel, is identifying molecular mechanisms causing auditory neurons to connect to appropriate hair cells during normal development. This knowledge can be exploited to cause auditory neurons to grow toward and attach to cochlear implant electrodes. The results should lead to marked improvement in spectral resolution.

Dr. Olivia Bermingham-McDonogh is using tissue-specific knockout technology to look at the post-natal requirement of neurotrophins for spiral ganglion cell survival. Investigating what growth factors are important in the survival of spiral ganglion cells in the adult will provide us the ability to engineer cochlear implants that may be coated with the appropriate factors to encourage and enhance the survival of these ganglion cells.While it has been demonstrated that electrical stimulation provides some trophic support to the spiral ganglion, it is known that normal hair cells provide such support through a variety of other mechanisms that could be emulated with such knowledge.

Regeneration

Loss of hair cells (the orange structures in this photo) is the cause of most hearing loss. Researchers at VMBHRC were the first to discover that these cells can be regenerated in birds.

Most cases of hearing loss and balance dysfunction result from loss of sensory cells (hair cells) in the inner ear. Hair cells are very sensitive and fragile. Loud noise, aging, toxic medications, trauma, and genetic conditions can all destroy hair cells. Over the past decade, regrowth of certain human cells has become a clinical reality. For example, new skin can be grown in the laboratory and used to resurface burns. We now know that new hair cells are produced after injury in some animals and can be formed in the mammal inner ear under certain laboratory conditions. The search to identify the conditions and factors that regulate cell regrowth is at the heart of one of our research initiatives at the center.While the primary focus of the initiative is on hair-cell regeneration, all the cell types in the inner ear will be examined.

Researchers at the VMBHRC at the University ofWashington were the first to discover hair-cell regeneration in birds, and they continue to be the leaders in the field of hair-cell regeneration research. They have validated that regeneration of inner-ear structures in mammals (as well as birds) is possible. Dr. Rubel and his colleagues are now poised to take the next step in bringing this possibility closer to reality.

Currently,VMBHRC scientists are working on distinct but complementary aspects of the haircell regeneration puzzle.

• Dr. Elizabeth Oesterle is studying the role of leukocytes, growth factors, and transcription factors in promoting progenitor-cell division and hair-cell differentiation in mammalian and avian inner ears.
• Dr. Jennifer Stone is characterizing hair cell progenitors and stem cells from the mature avian inner ear and the role of transcription factors in promoting cell-cycle exit and haircell differentiation in birds.
• Dr. Olivia Bermingham-McDonogh is delineating the role of growth factors and their receptors in the development and maintenance of the differentiated cells in the cochlea. In addition to studies on the mammalian cochlea, Dr. Bermingham-McDonogh, in collaboration with Drs. Rubel, Stone and Oesterle, is investigating the gene expression changes that occur during regeneration of the avian cochlea using microarray analysis.
• Dr. Clifford Hume is using molecular biology to design and test molecules to promote the transition of undifferentiated stem cells into functional inner ear hair cells.

Other Research

Schematic drawing of the ear in relation to surrounding structures. The inner ear (in blue) is located deep within the bones of the skull.

As we get older, our hearing begins to lose some of its sharpness and clarity. This process of age-related hearing loss is known as presbycusis. Dr. George Gates and his research team are studying the relationship between certain types of hearing tests and dementia in people who are 65 years of age or older. They are investigating the use of central behavioral auditory tests, such as the synthetic sentence identification test, in which a patient must identify sentences in the presence of a background story being presented simultaneously to one ear. Dr. Gates believes this test may be a predictor of Alzheimer?s disease. Findings from this research may be applied to the development of clinical hearing tests that can help screen for early stages of Alzheimer?s disease during routine hearing evaluations.

Dr. Patrick Feeney's research interest is the diagnosis of hearing loss due to middle- ear disorders. Currently, techniques for testing and diagnosing middle-ear function employ narrowband low-frequency sounds. Dr. Feeney's research focuses on using wideband energy reflectance to study middle-ear function and development. This method allows an earlier and more accurate diagnosis of hearing complications in newborns, infants, and adults.

Dr. James Phillips studies the ear's contribution to balance and vision. Dr. Phillips is researching the creation of new testing methods for the diagnosis of vestibular disorders, the co-development of the vestibular and visual systems in infants and children, and the neurophysiology of central brainstem mechanisms controlling eye and head coordination.