By David N. Leff
If you want to win a risk-free barroom wager, just bet the bartender that he or she has electrical hearing aids in both ears.
In fact, we're all born with these microscopic, battery-like contrivances on the sensory hair cells of our inner ears' cochlea. "There is a fluid space - the endolymph fluid bathing the sensory hair cells of the cochlea," explained British hearing geneticist Karen Steel, "that is normally maintained at a high electrical resting potential. In a mouse it's about 100 millivolts." Steel directs a laboratory at the Medical Research Council's Institute of Hearing Research, affiliated with the University of Nottingham.
"This endocochlear potential," she explained, "sets up a positive potential difference across the tops of the hair cells, so that the fluid bathing their upper surface is maintained at 100mv. The interior of the cells has a negative potential. That means there is a potential difference across the top of the hair cell, which acts like a battery, like a driving force that presumably helps the process of potassium ions flowing into the hair cells when their channels are opened. This occurs in response to sound stimulation."
Potassium recycling back to the endolymph, Steel pointed out, is critical to the entire machinery of hearing.
"The cochlea," she pointed out, "is the end organ, the periphery, of the auditory system. When a sensory hair cell detects sound, potassium floods into the hair cell, and because its ions are positively charged, the effect of this is to depolarize the cell. That means its normally negative potential inside is reduced, because positive ions are flowing in.
"This process of depolarization," she went on, "triggers synaptic activity at the other end of the cell. And some of those sensory hair cells within the cochlea have synapses with neurons of the cochlear nerve, which terminates in the brain. The details of those various connections are still being worked out."
Steel is the author of a "Perspective" in today's issue of Science, dated Aug. 27, 1999, titled: "The benefits of recycling." It comment on a research paper in the same issue, which bears the title: "Altered cochlear fibrocytes in a mouse model of DFN3 nonsyndromic deafness." That article's 20 co-authors are at the Japanese Foundation for Cancer Research in Tokyo, and five other academic and industrial institutions in Japan.
"What they report," Steel told BioWorld Today, "is having identified a transcription factor that seems to cause a specific cellular defect in a part of the inner ear that is involved in recycling potassium, and is associated with deafness."
DFN3 - A Deafness Gene On Chromosome X
"DFN3," Steel pointed out, "is the name given to a very specific sort of deafness. If a gene has DFN, that just stands for deafness. Then an added number means it's located on the human X chromosome. We now know," she went on, "that DFN3 is caused by mutations in this transcription factor gene, which the Japanese co-authors knocked out in their mouse experiments."
About one child in 2,000 is born with inherited deafness, their Science paper notes. Of this number, 70 percent occur nonsyndromically - that is, without any other signs or symptoms except the progressive hearing impairment itself. "Genetic studies," the co-authors observe, "have shown that DFN3 is caused by mutations in BRN-4. . . . The role of Brn-4 [its protein] in the development of auditory function, however, remains unclear."
To clarify this role, Steel related, "The co-authors generated knockout mice, from which they removed the coding part of the BRN-4 gene, this transcription-factor gene, and just put a marker gene in its place. The essential point," she pointed out, "is that they removed the gene, so the mice could not make the protein.
"The reason why they are interested in this particular gene," Steel observed, "is that the same gene has been shown to be involved in deafness in humans. So making a mouse model of a human form of deafness gives us a handle on understanding what's going on in humans with mutations in BRN-4.
"I think their results are very interesting," she continued, "in that this is the latest in a series of genes that seem to involve this process of potassium recycling. There are probably six different proteins, encoded by six different genes, that are involved directly in the process of potassium recycling. And there are undoubtedly going to be more that we haven't found yet. (See BioWorld Today, March 20, 1998, p. 1.)
"But this one is not a channel or a pump or anything like that; it's a transcription factor. So it's probably implicated in the development of that part of the inner ear that's involved in the process. And if those cochlear cells don't develop properly, it means that they are not able to participate fully in the recycling of potassium. And the result of that is reduction in size of the electrical endocochlear potential that's maintained within the cochlear duct."
Treatment? Someday - Maybe
Steel's commentary ends with the observation, "Therapeutic intervention to bypass the dysfunctional protein, and to restore a benevolent environment before the hair cells die, might halt the progression of deafness." To which she added in conversation, "Any gene that's identified in causing deafness, particularly when it's a progressive deafness, is a potential candidate for some sort of treatment in the future. If we only understood what's wrong inside the cochlea, we could perhaps do something about it. But it's very much in the long term. Right now, we have no specific idea as to how this might be done.
"I think that at the moment," Steel observed, "people involved in biotechnology, and certainly pharmaceutical companies, don't think of hearing impairment as something that's treatable. In writing commentaries," she concluded, "I try to make people think that hearing impairment may one day be treatable in some way - other then just wearing hearing aids, which are not a very good solution to hearing impairment."