Tuning in to how genes control hearing development.
The hair cells of the inner ear translate sounds into nerve signals. They are a key part of the apparatus that converts thuds, hums, swishes and voices into data that can be interpreted by the mammalian brain. But the delicate tufts of stereocilia — microscopic hairs that jut out from the surfaces of hair cells, giving them their fuzzy appearance and name — are vulnerable to loud noises, infections, drugs and ageing. Once damaged or destroyed, they are unable to regenerate spontaneously, and their loss leads to impaired hearing.
Although earlier experiments showed that a transcription factor called ATOH1 (also known as MATH1) controlled the expression of developmental genes to generate cells with the shape and characteristics of hair cells, no one knew if they were functional. But a team led by John Brigande, a developmental neurobiologist at the Oregon Health and Science University in Portland, has shown that in mouse embryos in utero, transferring the Atoh1 gene into cells that will become the cochlea creates additional working hair cells that form connections with nerve cells (see page 537). “A lot of people had done work on this gene, but no one had ever interrogated the behaviour of the cells, or done a direct recording of their properties,” says Brigande.
The biggest challenge, he says, was convincing Anthony Ricci, a hair-cell biophysicist at Stanford University School of Medicine in California, to join him on the project. “It's not that easy to find a person with the skill set, drive and passion to pursue such a difficult question,” Brigande says.
Their first meeting might have been disastrous. Ricci entered Brigande's office wearing a New York Yankees baseball cap. “How could he come into the office of a Boston Red Sox fan wearing that?” Brigande jests. After chatting about this most bitter of baseball-team rivalries, Ricci agreed that the hair-cell study would be a unique opportunity to understand the functionality of the cells induced by ATOH1. Brigande says that he and Ricci are kindred spirits in the way they approach science. “We're both in the experimental trenches.”
Brigande has a progressive form of hearing loss in both ears that was detected at age ten. He became interested in studying hearing when he joined Donna Fekete's lab at Purdue University in Indiana for his postdoctoral training. At that point, he realized that his hearing loss had progressed to a point where he needed a supportive environment in which to continue his academic career. Fekete's hair-cell development lab and the field of hearing research offered just that.
Brigande, who describes himself as profoundly hard of hearing, admits that he has personal motivations for his work. But he says it is his deep fascination with mouse embryonic development that drives him. “Living with profound hearing loss does add some inspiration, but I didn't need the extra kick. Even as a student, I would wake up far too early in the morning and drift into the lab,” he says.
Now that Brigande and his colleagues have shown that Atoh1 gene transfer produces working hair cells, they plan to use mouse models of human deafness to answer the question of whether a gene-replacement strategy can restore hearing. “The questions that remain now rely on creativity, passion and hard work,” he says. “Such questions are not intractable any more, and that's exciting.”