Heads of Laboratories
Investigator, Howard Hughes Medical Institute
F.M. Kirby Professor
Laboratory of Sensory Neuroscience
A.James.Hudspeth@rockefeller.edu
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 grow back 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 20 to 300 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 the possibility that human hearing benefits from a tiny mechanical amplifier in each hair bundle. They have found that bundles from the frog’s inner ear are spontaneously active, oscillating through a distance of ±30 nm. This unprovoked activity may underlie the spontaneous emission of sound measured from many normal ears, including those of most humans. When a small stimulus force is applied to an active bundle, the oscillation is entrained: The bundle’s motion becomes synchronized with the stimulus. Measurement of the mechanical work performed during entrainment confirms that a hair bundle can amplify its mechanical input. In experiments now in progress, Dr. Hudspeth is attempting to extend these results to the mammalian ear. Using a theoretical approach to model the mammalian ear, Dr. Hudspeth and his colleagues have pointed to a ratchet mechanism by which low-frequency sounds are amplified. Identification of the active process in the human cochlea is especially important because hearing loss usually begins with deterioration of this amplifier.
To identify proteins important in the hair cell’s operation, some members of Dr. Hudspeth’s group are using the zebrafish model system for biochemical, genetic, and molecular-biological experiments. In an effort to understand how human hair cells might be replaced, other individuals are investigating the development and regeneration of hair cells in the lateral-line system. They have identified precursors—transit amplifying cells—each of which undergoes a single mitotic division to produce a pair of hair cells of opposite orientation. Moreover, they have established that every afferent nerve fiber selectivity innervates hair cells of a particular orientation, and does so by an activity-independent mechanism that involves chemical cues.
Dr. Hudspeth’s research has led to a deeper 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 human deafness, an affliction that affects one-tenth of our population.
CAREER
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 has received the Charles A. Dana Award for Pioneering Achievements in Health, the K. S. Cole Award in Membrane Biophysics from the Biophysical Society, the Ralph W. Gerard Prize from the Society for Neuroscience, the Award of Merit from the Association for Research in Otolaryngology, the Award of Recognition from the Otological Society of Japan, the W. Alden Spencer Award from the Columbia University College of Physicians and Surgeons, the L. S. Rosenstiel Award from Brandeis University, the Hugh Knowles Prize from Northwestern University, the John and Samuel Bard Award in Medicine and Science from Bard College, and the Guyot Prize from the Rijksuniversiteit Groningen. An Investigator of Howard Hughes Medical Institute, Dr. Hudspeth is a member of the National Academy of Sciences and the American Academy of Arts and Sciences.
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