So far, testing on mammals, not to mention humans, is preliminary. Each human cochlea has only those 15,000 hair cells (the other 15,000 are in the vestibular system), and they are inaccessible in a living person. These generally decrease as we age, although not always. “Some animals and some humans seem resistant to noise and drugs and some humans hear perfectly until old age,” Rubel said. “What grants this protection? Do some people have genetically ‘tough’ ears and others have ‘weak’ ears? If so, what are the genes responsible for this difference, and can we use them to protect hearing?” By doing genetic screening in zebrafish, it may be possible to find these genes and then find the cellular pathways to turn “weak ears” into “tough ears.”
In March of 2012, I met with Rubel and a group of younger fellow researchers at the Virginia Merrill Bloedel Center. Rubel is a charismatic leader, but he insisted on referring to these researchers not as part of his lab but as independent scientists, with their own NIH grants, some with their own Hearing Restoration projects. David Raible was out of town. Raible, Jennifer Stone, and Elizabeth Oesterle collaborate on different projects with each other and with Rubel. But, Rubel said, “Having sort of started the hair-cell regeneration field, I feel very comfortable getting out of it and doing other things.”
Jennifer Stone is a cell biologist and neuroanatomist, who works primarily on avian hair cell regeneration. About five or six years ago she started working with mice, with several of the other participants, including Rubel and Elizabeth Oesterle, a cell biologist, and Clifford Hume, an M.D./Ph.D. clinician scientist. Stone led a recent study which found that after virtually all the vestibular hair cells in adult mice are killed, 16 percent of the hair cell population comes back spontaneously.
“It’s a new discovery,” Stone said. “It’s not entirely surprising, but I think we’ve demonstrated it pretty definitively.” Because spontaneous regeneration happens in only certain regions of the vestibular system, it helps the researchers narrow the field. By comparing the tissue in this region to tissue in others, they may understand the factor that allows regeneration in one place but not in another. Once we understand what allows the tissue to make new hair cells in these regions, Stone said, we can determine what would be needed to “release the brake,” as she put it.
The p27 gene, which regulates cell division and helps prevent cancer, is one such molecule. To allow these hair cells to divide, the p27 gene would need to be turned off. Or maybe, she added, “it could be that we need to push the pedal on the gas: add something to promote division. It could be that we have to both put on the brakes and push on the pedal to start this process in mammals.”
Julian Simon is a chemist, a Ph.D. pharmacologist, who got interested in the toxicity of cancer therapeutic drugs when clinicians at the Seattle Cancer Care Alliance, the patient arm of the Fred Hutchinson Cancer Research Center and the University of Washington, complained about the ototoxicity of certain chemotherapy drugs, Cisplatin prominently among them. Simon said that 30 to 40 percent of patients who go on Cisplatin regimens for lung cancer sustain significant and permanent hearing loss. (Rubel told me that some reports suggest an even higher percentage, up to 80 percent.) Simon’s approach is to use small molecules to “perturb” biological systems. “We know what we’d like the cells to do, and in this case we’d like to take cells that would otherwise die and keep them living.” Because the whole process of sensory hair cell death is—“with all due respect to present company” (meaning his fellow researchers)—“poorly understood, by learning how we can protect these cells from dying, maybe we can also learn something about the way cells die. Why they die.”