One usually sees and hears pipe organs pouring forth their music in churches. The source of these mellifluous sounds is a wall-sized array of cylindrical chambers, graduated in length from very short to very long. In their gently curving dimensions, pipe organs resemble the strings of a harp. Both variants dictate the pitch or frequency of the musical notes they invoke.

All mammals possess their own private pipe organs. These “hear” the auditory stimuli that reach the graduated inner-ear cylindrical chambers that control variations of pitch or frequency.

“This adaptation,’” explained research otolaryngologist Jeffrey Holt, “allows the cell to readjust its sensitivity range to static or tonic stimuli. For example, the stimulus of gravity is always present, and hair cells within the vestibular organs of the inner ear the organs responsible for the sense of balance must compensate for that constant stimulus of gravity. In an auditory organ in the ear,” he continued, “persistent stimuli might be the constant background noise in a crowded room full of conversation. So the sensory cells are able to adjust to these.”

Holt continued: “It’s a mechanical rearrangement of the mechano-sensitive apparatus in the ear. There is one channel that opens, something like a trapdoor, in the presence of a stimulus, and allows an electrical voltage to be generated. And the adaptation motor adjusts this channel so it’s not saturated. It all takes place,” he went on, “in the cochlea and vestibular organs, which are right next door to each other. They are the semicircular canals of the inner ear.”

Holt, an assistant professor at the University of Virginia in Charlottesville, is first author of the cover story in the current issue of Cell, dated Feb. 8, 2002. Its senior author is Peter Gillespie at the University of Oregon’s Hearing Research Center, in Portland. The Cell paper is titled, “A chemical-genetic strategy implicates myosin-1c in adaptation by hair cells.”

“The article’s principal finding,” Holt told BioWorld Today, “is the involvement of one protein, myosin-1c, in adaptation of sensory hair cells. It seems to be a key player for that process. What’s new in it is being able to conclusively identify this protein, playing this specific adaptation role. The problem is,” he pointed out, “that there are 40 or so different proteins within this superfamily of myosins. Attributing this adaptation function to one of those 40 has been a challenging task. Now we can apply this same approach to each of those 40 proteins, and elucidate their specific contributions.”

Chemical-Genetic Ploy Unveils Protein’s Role

“The proteins are located at the very tips of the hair bundles, at the site of sound transduction,” Holt noted. “Like a musical pipe organ, with its graded sound-chamber height, each different hair cell responds to a different pitch. There’s a cluster of these myosin proteins at the tip of each of these microscopic organ pipes. And myosin-1c had been localized to the tips of these stereocilia, or organ pipes. We knew it was here in the right spot, but we couldn’t say that it was involved in this adaptation process. Then Peter Gillespie devised this chemical-genetic strategy to identify myosin-1c’s specific role.

“The genetic aspect,” Holt recounted, “was to make a mutation in the DNA that encodes this protein. And the specific mutation we engineered did not alter the function of the protein at all. Myosin-1c functioned perfectly normally, but became sensitive to a chemical or drug to which we exposed it. That compound did not affect any of the other 40 myosins, but only this one, because of the mutation we introduced.

“To find that drug,” he recounted, “we had to screen a number of chemicals maybe 30 different compounds and found one. Our criterion was that it would block the action of myosin-1c but not any of the other myosins. It was designed just for this purpose.

“Hair cells of mice and humans are remarkably similar,” Holt remarked. “Having created that mutation, which sensitized the myosin-1c protein to the blocking drug, we generated transgenic mice by injecting the DNA that encodes this protein into their embryonic stem cells. We could then examine the sensory cells in the ears, in vitro, from neonatal mice. That allowed us to record the electrical properties of these vestibular cells by microscopically wiggling glass electrodes. The outcome was when we wiggled the hair bundle back and forth, we directly measured an electrical current to look at the adaptation process.

“Now that we’ve identified the function of myosin-1c,” Holt observed, “we want to begin looking at the other myosins in hair cells particularly those involved in deafnesses which 1c itself is not. And part of the issue,” he added, “is that myosin-1c is also found in other cells of the mammalian body for example kidney or lungs where it’s so critical that if there’s a mutation in the protein, then the mouse dies. It occurs mostly in the lining of the alveoli and bronchii in the lungs, but where in the kidney is not as clear.”

One In 1,000 Kids Born Incurably Deaf

Regarding hearing loss per se, Holt and his co-authors are focused mainly on congenital deafness. “I think one in a thousand infants around the world is born with some form of congenital hearing loss,” Holt observed. “There is no geographc or ethnic variation whatsoever, and no therapy for genetic deafness. Of five or six other myosin molecules expressed in the ear,” he continued, “three are associated with congenital hearing loss. Its inherited molecular etiology is not well understood. That’s one of the questions we hope to address. Now that we have this chemical-genetic strategy, we can use it to look at each of the myosins associated with deafnesses.

“Once the gene has been identified, and we can understand its function,” Holt said, “we hope to be able to take its correct form, put it into a biological vector, introduce that intact gene back into the sensory cells and hopefully restore function. Such experimental gene therapy in animals might come within a couple of years,” he surmised, “but I would guesstimate our goal of human trials at around 10 years in the future.”