In 2011, a team led by Jeffrey Holt, PhD, demonstrated that a protein called TMC1 is required for hearing and balance, following the 2002 discovery that mutations in the TMC1 gene cause deafness. Holt’s team proposed that TMC1 proteins form channels that enable electrically charged ions such as calcium and potassium to enter the delicate hair cells of the inner ear. This, in turn, enables the cells to convert sound waves and head movement into electrical signals that talk to the brain.
In a new study published today in Neuron, Holt and colleagues teamed with the lab of David Corey, PhD, at Harvard Medical School. Together, they confirmed TMC1’s essential role in hearing, ending a 40-year quest, and mapped out its working parts.
Working with living hair cells in mice, they made substitutions in 17 amino acids within the TMC1 protein, one at a time, to see which substitutions altered hair cells’ ability to respond to stimuli and allow the flow of ions. Eleven amino acid substitutions altered the influx of ions, and five did so dramatically, reducing ion flow by up to 80 percent. One substitution blocked calcium flow completely, thereby revealing the location of the pore within TMC1 that enables ion influx.
Down the road, the study could have implications for reversing hearing loss, which affects more than 460 million people worldwide.
“To design optimal treatments for hearing loss, we need to know the molecules and their structures where disease-causing malfunctions arise, and our findings are an important step in that direction,” Holt said in this press release from Harvard Medical School.
The ear is a part of the body that’s readily accessible to gene therapy: You can inject a gene delivery vector (typically a harmless virus) and it has a good chance of staying put. But will it ferry the corrected gene into the cells of the hearing and/or vestibular organs where it’s most needed?
Back in 2015, a Boston Children’s Hospital/Harvard Medical School team reported using gene therapy to restore rudimentary hearing in mice with genetic deafness. Previously unresponsive mice began jumping when exposed to abrupt loud sounds. But the vector used could get the corrected genes only into the cochlea’s inner hair cells. To really restore significant hearing, the outer hair cells need to be treated too. …
Could regenerative techniques restore hearing or balance by replacing lost sensory cells in the inner ear? Lab-created inner-ear organs, described today in Nature Communications, could provide helpful three-dimensional models for testing potential therapies.
The lab-built sac-like structure above, about 1 millimeter in size, contains fully-formed balance organs resembling the utricle and saccule, which sense head orientation and movement and send impulses to the brain. The tiny organs were built from mouse embryonic stem cells in a 3-D tissue culture in work led by Jeffrey Holt, PhD, of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital and Eri Hashino, PhD, of the University of Indiana. …
One of my very favorite images in science, Dr. Wilder Penfield’s classic motor homunculus, shows how much brain real estate is devoted to controlling movement of different parts of the body. Notice the huge hands and the tiny feet. As the World Cup gets underway, soccer fan Jeffrey Holt, PhD, also a Boston Children’s Hospital neuroscientist, writes that soccer is more than just a great sport, it’s “a triumphant display of the incredible plasticity of the human brain… because the soccer player is limited by one simple rule: no hands!”
Though no one’s actually taken a look, Holt imagines that the brains of great soccer players like Cristiano Ronaldo, Lionel Messi or Neymar would have much expanded neural representation of the feet. Read more in his post on WBUR-Boston’s Cognoscenti blog.
Hearing loss affects more than 300 million people worldwide, making it the most common sensory disorder. While there are no cures, recent efforts to develop biological treatments for hearing loss provide reason for cautious optimism. Three strategies—gene therapy, stem cells and drugs—have shown encouraging results in animal models, poising them for translation into potential therapies for humans.
Hearing loss can arise from many different causes, so it is unlikely that a single “magic bullet” will be developed to treat all forms of deafness. Rather, each individual cause may require a tailored and specific treatment strategy. …
Ending a 30-year search by scientists, researchers have identified two proteins in the inner ear that are critical for hearing, which, when damaged by genetic mutations, cause a form of delayed, progressive hearing loss.
The proteins are essentially transducers: They form channels that convert mechanical sound waves entering the inner ear into electrical signals that talk to the brain. Corresponding channels for each of the other senses were identified years ago, but the sensory transduction channel for both hearing and the sense of balance had been unknown.
The channels are the product of two related genes known as TMC1 and TMC2. TMC1 mutations were first reported in people with a prominent form of hereditary deafness back in 2002 by Andrew Griffith, MD, PhD, of the National Institute on Deafness and Other Communication Disorders (NIDCD) and collaborators. Children with recessive mutations in TMC1 are completely deaf at birth. …
Sound waves produce the sensation of hearing by vibrating hair-like structures on the inner ear’s sensory hair cells. But how this mechanical motion gets converted into electrical signals that go to our brains has long been a mystery.
Scientists have believed some undiscovered protein is involved. Such proteins have been identified for taste, smell and sight, but the protein required for hearing has been elusive. In part, that’s because it’s hard to get enough cells from the inner ear to study – they’re embedded deep in the cochlea.
“People have been looking for more than 30 years,” says Jeffrey Holt of the department of otolaryngology at Boston Children’s Hospital. “Five or six possibilities have come up, but didn’t pan out.”
Last week, in the Journal of Clinical Investigation, team led by Holt and Andrew Griffith, of the National Institute on Deafness and Other Communication Disorders (NIDCD), demonstrated that two related proteins, TMC1 and TMC2, are essential for normal hearing – paving the way for a test of gene therapy to reverse a type of genetic deafness. …