How can supporting cells be coaxed into making more hair cells? Almost twenty years ago, it was proposed that hair cells and support cells, side by side, participate in an ongoing conversation using an evolutionarily ancient communication system called the Notch signaling pathway. The hair cell commands the support cell not to divide and prevents it from becoming a hair cell. Because the mammalian cochlea has evolved to have only four rows of cells, Groves explained, the creation of more cells would disrupt the mechanical properties of the cochlea, possibly preventing it from working properly.
The role of the Notch pathway in regulating the activity of the p27 gene is controversial. Groves mentioned work that Amy Kiernan, currently on the faculty at the University of Rochester, carried out when she was a postdoc with Tom Gridley at the Jackson Laboratory in Bar Harbor, Maine. She managed to inactivate the Notch signaling pathway in mice genetically. Her mice produced extra hair cells and showed some precocious cell division in the cochlea. Another researcher working with Groves and Segil, Angelika Doetzlhofer, did the same, using a pharmacological approach with drugs that blocked Notch signaling. When they blocked the signaling in newborn mice, they saw a 50 percent increase in hair cells and fewer supporting cells. These findings are preliminary, Groves cautioned, and the role of the Notch pathway is still being studied.
Following up on this, Groves and colleagues repeated their Notch blocking experiments in older mice. By the time the mice were three days old, the increase in hair cells had dropped to 30 percent. In six-day-old mice, new hair cells were no longer produced. Although extrapolating this timetable to humans is tricky, the current data suggests that the human cochlea may no longer respond to Notch inhibitors by the time the fetus is five to six months old.
“So here is the take-home message,” Groves concluded. “Our challenge—if you want to set a ten-year challenge—is to understand these roadblocks and then devise methods to get rid of them, and ultimately to apply these methods in a clinical setting.” A clinical setting populated by humans. As Groves said at the beginning of his talk, “We’re not here to treat hearing loss in birds.”
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Stefan Heller and his colleagues are taking a different approach to regenerating hair cells. They are attempting to get stem cells—undifferentiated cells that can develop into various specialized cells—to turn into hair cells, by mimicking the naturally occurring developmental processes that lead to formation of the inner ear. They do this in a culture dish and in a laboratory setting, which allows them to learn a lot about the process, such as what it actually takes to make sensory hair cells from scratch.
In March 2012, I visited Heller’s lab at Stanford in Palo Alto. We literally ran into each other as I was looking for his office. Heller is formidably smart but completely unimposing in manner. He was wearing a well-worn T-shirt with a coffee cup on it (half full? half empty? “Definitely half full,” he said), jeans, and sneakers. We talked in his office with a huge humming fish tank taking up about a sixth of the office. I asked if he had zebrafish. He said he didn’t, but Dr. Robert Jackler, the chair of the Stanford Otolaryngology Department and the force behind the accumulation of brain power that makes Stanford’s one of the most important hearing research departments in the world, told me that Heller raises anemones to get novel fluorochromes for his research.