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Genome editing (left) prevented damage in a mouse cochlea with mutations in Tmc1 (right). Scale bar = 50 µm.
NEUROSCIENCE
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he year 2018 was a roaring one for hearing loss research. A study published at the end of 2017 reverberated throughout the field. A team led by David R. Liu of Harvard University and ZhengYi Chen of Harvard Medical School and Massachusetts Eye and Ear used CRISPR-Cas9 genome editing to prevent mutation-related ear damage and protect hearing in mice (Nature 2017, DOI:10.1038/ nature25164). The edited gene in that study—Tmc1—drew more attention this year when a different team confirmed that the protein it encodes plays a key role in converting sound vibrations to electrical signals (Neuron 2018, DOI:10.1016/j. neuron.2018.07.033), a detail scientists had been trying to nail down for almost two decades. The protein, TMC1, helps form the pore of an ion channel on inner-ear sensory cells. The channel’s pore opens in response to vibrations caused by sound waves. Once the channel opens, ions flow into the sensory cell, generating electric currents that trigger a series of signaling events that convert the sound waves into something the brain can process. Chemistry played a key role in this discovery. Led by David Corey of Harvard Medical School and Jeffrey Holt of Boston Children’s Hospital, the scientists systematically modified one amino acid residue after another in the TMC1 protein in mice. They wanted to know whether adding a
Hearing loss research made headway
C R E D I T: NAT UR E
Insight into hearing loss mechanisms could lead to better treatments
bulky charged group to each amino acid would block the ion flow and prevent the sound-induced electric currents. Because most of these chemical modifications inhibited the currents, the researchers were able to conclude that TMC1 forms the ion channel’s pore. This discovery is great news for the 400 million people around the world who experience hearing loss, says Karen Avraham of Tel Aviv University. Corey notes that gene therapies that replace the mutant gene or correct it could be helpful for treating naturally occurring TMC1 mutations in humans. The genome-editing research performed by Liu and Chen in mice is an early-stage demonstration of that approach.
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O AZD5438 AZD5438 is a compound with potent protective abilities against cisplatininduced hearing loss in mice. In related work, Jian Zuo and coworkers at St. Jude Children’s Research Hospital showed the potential of using small molecules, such as AZD5438, to treat hearing loss in mice (J. Exp. Med. 2018, DOI:10.1084/ jem.20172246). The research focused on hearing loss induced by the cancer drug cisplatin, but, as Alan Cheng of Stanford University points out, the targets the group identified with its molecules may hold promise for treating other forms of hearing damage.—CICI ZHANG, special to C&EN DECEMBER 10/17, 2018 | CEN.ACS.ORG | C&EN
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