Heads of Laboratories
A. James Hudspeth, M.D., Ph.D.
Investigator, Howard Hughes Medical Institute
F.M. Kirby Professor
Laboratory of Sensory Neuroscience
The majority of the hearing impaired suffer from sensorineural hearing loss, also referred to as “nerve deafness.” Despite its name, this type of hearing loss usually results from damage to the hair cells of the inner ear. The human cochlea contains about 16,000 of these hair cells, which do not regenerate once they have been damaged. Dr. Hudspeth’s laboratory is working to better understand the normal hearing process and causes of hearing deterioration as an initial step toward the prevention or reversal of deafness.
Sound consists of rapid pressure fluctuations in the air, and hearing commences when these signals impinge upon the external ear, setting the eardrum into oscillatory motion. This movement is relayed through the three miniscule bones of the middle ear — the hammer, anvil and stirrup — to the snail-shaped cochlea. Within the cochlea, these mechanical signals are converted into vibrations along the basilar membrane, upon which the hair cells stand in four ranks. Each hair cell is endowed with a few hundred fine “feelers,” or stereocilia, that collectively constitute its hair bundle. Sound-induced vibrations set the hair bundles in motion, evoking electrical responses by opening and closing mechanically sensitive ion channels in the stimulated bundles. As a result of the direct mechanical connection between the hair bundle and ion channels, the transduction process of hair cells is remarkably rapid; we can consequently hear sounds at frequencies as great as 20 kHz. The direct nature of auditory transduction also makes the process highly sensitive.
The extraordinary sensitivity of our hearing suggests that the cochlea amplifies its mechanical inputs, and researchers in Dr. Hudspeth’s lab are exploring how human hearing benefits from a tiny mechanical amplifier in each hair bundle. They have found that bundles are spontaneously active, oscillating through a distance of ±30 nm. This unprovoked activity likely underlies the spontaneous emission of sound measured from many normal ears, including those of 70 percent of humans. When a small stimulus force is applied to an active bundle, the bundle’s motion becomes synchronized with the stimulus. Measurement of the mechanical work performed in this situation confirms that a hair bundle can amplify and tune its mechanical inputs. Members of the research group are now extending these results to the mammalian ear. Using a theoretical approach to model the mammalian ear, they are also exploring the mechanism by which low-frequency sounds are amplified. Identifying the active process in the human cochlea is especially important because hearing loss usually begins with deterioration of this amplifier.
In an effort to learn how hair cells develop, Dr. Hudspeth’s group is conducting molecular-biological experiments on the larval zebra-fish. In the lateral line of this species, new hair cells arise continually to replace those that die as a result of aging or chemical toxicity. The division of a precursor cell consistently produces a pair of hair cells of opposite polarity, one of which responds to water movement toward the animal’s anterior, the other sensitive to posterior flow. In the hope of establishing what signaling pathways lead to the production of new hair cells, members of the group are isolating both hair cells and their precursors and examining their gene expression. The investigators hope to identify pathways that might be activated in the human ear to foster hair cell replacement. Other experimenters are studying how individual nerve fibers distinguish between hair cells of the two polarities, selectively innervating only one of the two sets.
Dr. Hudspeth’s research has led to a deepened understanding of the intricacies of the inner ear and how they contribute to hearing and hearing loss. He hopes that further investigation will indicate both the causes of and potential remedies for certain forms of human hearing impairment, an affliction that affects 10 percent of the American population.
Dr. Hudspeth received his bachelor’s degree in biochemistry from Harvard University in 1967 and his M.D. in 1973 and Ph.D. in 1974 from the same institution. After a postdoctoral fellowship at the Karolinska Institute in Stockholm, he accepted a faculty position at the California Institute of Technology. He relocated to the University of California, San Francisco, in 1983, and in 1989 he moved to The University of Texas Southwestern Medical Center at Dallas, where he founded the school’s neuroscience program. Dr. Hudspeth came to Rockefeller in 1995 and was named the F.M. Kirby Professor. He is also director of the F.M. Kirby Center for Sensory Neuroscience.
Dr. Hudspeth received the Charles A. Dana Award for Pioneering Achievements in Health and the W. Alden Spencer Award from the Columbia University College of Physicians and Surgeons. He is also a recipient of the Ralph W. Gerard Prize from the Society for Neuroscience, the K.S. Cole Award in membrane biophysics from the Biophysical Society, the Award of Merit from the Association for Research in Otolaryngology, and the Guyot Prize from the University of Groningen. Dr. Hudspeth is a member of the National Academy of Sciences and the American Academy of Arts and Sciences and is an investigator at the Howard Hughes Medical Institute.
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