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The ears have it: Fero's genetic research produces unexpected insights on hearing
The most common forms of hearing loss and deafness caused by external injury or genetic mutations arise from damage to these delicate, ciliated, sensory cells located in the inner ear, or cochlea. "Hearing researchers were excited by the results," published recently in the Proceedings of the National Academy of Sciences, Fero says. He says one goal is to improve hearing by repairing damaged sensory cells or producing new ones. Though investigators are far from a true cure for deafness, Fero says that removing p27 function may allow production of new sensory cells in response to damage, at least in animal models. "Scientists have been trying to induce proliferation in the mammalian cochlea for a decade," he says. They have applied a battery of substances known to promote cell growth to the inner ear with little success, he says. The p27 gene produces the first known protein whose altered function induces proliferation in the inner ear. The key is not to apply p27 protein externally, but to eliminate its activity by knocking out the gene.
Washington, and collaborates at the Center with Fero and Dr. Chris Kemp, an investigator in the Human Biology Division, through a research contract. What led Fero's collaborators, including Dr. Hubert Löwenheim and others in Tübigen to peer into the inner ear of p27 knockout mice? Frustrated by attempts to induce cell growth, Löwenheim went after the basic biology, analyzing cochlea to see if they expressed a variety of genes known to affect cell proliferation, Fero says. "It's not an easy thing, because the cochlea is a complex, three-dimensional structure completely embedded in bone," Fero says. "It's not something people typically look at unless they have expertise in that field." Löwenheim found that the ears of rodents produced high levels of p27. His next logical step was to contact Fero and Center Basic Sciences Division investigator Dr. Jim Roberts, in whose lab p27 knockouts were created, to see if the high levels of p27 were associated with a function. "It was a revelation," says Kil, who performed some of the first experiments analyzing the ears of p27 mice. Kil says the result took them by surprise. Although many tissue types in the plus-size mice show slightly increased cell number, the amount of growth they observed in the ear was unexpectedly out of proportion to the limited overproliferation occurring in the rest of the animal. With Center scientists, Otogene researchers have begun answering the next crucial question: Will new sensory cells arise in response to damage in ear cells lacking p27? Kil and his group also are testing whether the application of other substances, such as growth factors, can modify production of sensory cells in ear tissue lacking p27. Although Fero is intrigued with the direction this research has gone, his main interest is still oncology. He devotes several months each year to patient care in the Center's marrow transplant services. The rest of his time, he primarily studies the role p27 may play in cancer and cell proliferation. The p27 protein physically interacts with protein complexes in the cell that permit cell division. Scientists in the Roberts lab, along with Fero, have studied the basic biochemistry of how p27's interactions with these protein complexes put the brakes on cell division. Fero, Kemp and other Center researchers also have discovered that p27 mice, because they lack proper control of cell proliferation, are susceptible to developing tumors. Their analyses support the idea that p27 may also play a role in human cancers. "Our collaboration with Otogene ultimately may benefit these other aspects of p27 research," Fero says. For example, Otogene is trying to selectively knock out p27 in ear cells with techniques that ultimately could be applied to hematopoietic stem cells. "It would be tremendous if we could expand stem cell numbers to improve the success rate of umbilical cord blood stem cell transplants," Fero says. "We might also be able to improve our ability to introduce new genes into stem cells, thus increasing the feasibility of hematopoietic gene therapy." With these and other ideas in mind, Fero insisted on independent funding for his and Kemp's collaboration with Otogene, to avoid detracting from cancer research. The research contract with Otogene and a joint small business technology transfer (STTR) award from the National Institutes of Health total nearly $500,000. Otogene has also committed to publish significant findings arising from the collaboration in a timely manner, so that the company can keep information flowing back to the source of its first insights basic research on cancer biology.
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