A. James Hudspeth, M.D., Ph.D.
F. M. Kirby Professor; Investigator, HHMI
Laboratory of Sensory Neuroscience
E-mail: hudspaj@rockefeller.edu
The majority of the hearing impaired suffer from sensorineural hearing loss, also referred to as “nerve deafness.” But 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’ve 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.
Such extraordinary sensitivity to sound 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. 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, especially those essential for the development and functioning of the hair bundle, Dr. Hudspeth’s group is using zebra-fish genetics. They have screened the progeny of mutagenized fish for abnormalities of aural development, hearing, balance and lateral-line organ structure. Following the isolation of 42 mutant lines, members of his group have begun positional cloning of the affected genes. Because heritable human deafness stems from abnormalities in more than 100 genes, they believe that some of the genes identified in the zebrafish will be orthologues of those affected in humans.
Dr. Hudspeth’s research has already led to a more in-depth understanding of the intricacies of the inner ear and how they contribute to hearing and hearing loss. He hopes that further investigation could indicate both the causes of and potential remedies for certain forms of human deafness — an affliction that affects 1 child in 1,000 at birth, and an additional 1 in 1,000 before maturity.
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 year-long 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
at Rockefeller.
Dr. Hudspeth received the Charles A. Dana
Award for Pioneering Achievements in Health
in 1994 and the W. Alden Spencer Award from
the Columbia University College of Physicians
and Surgeons in 1985. He is also a recipient
of the Ralph A. Gerard Prize from the Society
for Neuroscience, the K.C. Cole Award in
Membrane Biophysics from the Biophysical
Society and an Award of Merit from the
Association for Research in Otolaryngology.
Dr. Hudspeth is a member of the National
Academy of Sciences and the American Academy
of Arts and Sciences, and is a Howard
Hughes Medical Institute investigator.
