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Right Now | Sounds Like a Good Hair Day

Cilia in C-Major

March-April 2005

In the human ear, it takes only a few millionths of a second from the time a sound wave vibrates the receiving "hair cells" to the time the cells generate a neural response. The equivalent process in the human eye, from photon absorption to cellular response, takes a thousand times longer. Hearing "is fast because it's simple," says professor of neurobiology David P. Corey of Harvard Medical School.

Now: Three hair cells from the inner ear, greatly magnified. These cells are from the balance, rather than hearing, part of the inner ear, but the differences are minor.

View larger image.

Then: An 1884 German lithograph depicts structures of the inner ear.
Photograph and medical illustration courtesy of David Corey

Well, yes and no. On a basic level, it's easy to explain how we hear: sound waves, traveling through the air, vibrate the eardrum at certain frequencies and magnitudes, which the brain interprets to identify the sound's pitch and volume. Betwixt vibration and human perception, though, lie several intermediate steps. Hair cells in the inner ear convert sound waves -- a form of mechanical energy -- into electrical signals. In the brain, those messages make several transformations between electrical and chemical signals and back again, bouncing from neuron to neuron until they reach a final resting point where we perceive them as sound.

It was 30 years ago when Corey, as a graduate student at the California Institute of Technology, began applying his undergraduate background in physics -- and his childhood drive to take things apart and figure out how they work -- to the mystery of hearing. In a recent article in Nature, he and his colleagues describe a protein they believe adds a crucial piece to this intricate puzzle.

Scientists have long known that the eardrum vibrates and transmits the vibration to the inner-ear bones, touching off a mechanical process in the cochlea, the snail-shaped organ containing hair cells with bristly cilia that vibrate back and forth in response to sound waves -- the greater the cilia vibration, the louder the sound. (A video clip on this magazine's website, www.harvardmagazine.com/av/hearing.html, shows these cilia vibrating in response to a piece of music.) Different areas along the cochlea's length correspond to different sound frequencies: the brain determines pitch according to the location of the hair cells activated. Timbre derives from pitch, and reflects a sound's characteristic profile of harmonics or overtones: a flute's sweet sound signals its pure fundamental pitch, while the violin's more raspy notes include many harmonics.

When a sound wave enters the inner ear, cilia all along the cochlea's length vibrate. So how do hair cells detect the vibration of their cilia? In the 1970s, Corey and his graduate adviser at Caltech, A. James Hudspeth, found that moving the cilia directly opens pores called ion channels at the tips of the cilia. Electrically charged potassium ions enter the hair cells through open ion channels and change the cells' voltage.

Then, in 1984, British neurobiologist James Pickles discovered "tip links," microscopic connectors that stretch between the tips of cilia. When sound waves move the cilia back and forth, the tip links alternately stretch to pull open ion channels and relax to allow the channels to close. "This," Corey says, "is where things stood for a long time," until the mapping of human and animal genomes enabled more precise description, and even manipulation, of genes and the proteins they encode. Suddenly, scientists had a way to find the protein that makes the ion channel, forging the link between vibration and perception.

From a family of proteins called TRP channels, Corey's team identified one, TRPA1, as their prime suspect. They knew that the 33 channels of the TRP (pronounced trip) family often appeared in other human sensory systems, and that they allowed the same ions to flow in, at the same rate, as observed in hair cells. TRPA1's unusual molecular structure intrigued them: unlike other TRPs -- but like a TRP channel that mediates fruit flies' sense of touch -- TRPA1 contains a chain-like stretch of 17 identical links (called ankyrin repeats) leading up to the channel part of the protein. (Corey sometimes subtitles lectures "What a Long, Strange TRP It's Been.") Maybe, they posited, the hair cell uses this chain to pull the channel open.

Studies of the inner-ear cells of frogs, fish, and mice have confirmed TRPA1's presence, and indicate that TRPA1 probably plays the same role in all vertebrates. The next step is to move from correlation to causation. Corey's lab is therefore breeding mice that are genetically engineered to have defective TRPA1-production genes. If the mice are deaf, that will support their findings thus far.

Researchers at Harvard and elsewhere have already begun screening deaf humans for genetic defects in TRPA1. Corey takes care, though, not to create false hope. Because there are more than 300 types of inherited deafness, he says this discovery simply adds one more entry to a long and incomplete list of possible genetic causes for the disability, and he cautions, "We're not going to cure deafness right away."

~Elizabeth Gudrais

 

David Corey e-mail address [email protected]