Harvard Scientists: 'Smoking-Gun Evidence' Of Key To Hearing In Ear's Hair Cells

The snail shell-shaped part of the inner ear that houses hair cells (Courtesy of Holt Lab)
The snail shell-shaped part of the inner ear that houses hair cells (Courtesy of Holt Lab)

You know how you hear. Sound enters your ear, gets funneled down your ear canal, goes through your ear drum, into your inner ear and then ... well, it gets a little murky there for most of us. Somehow, the sound is converted into signals our brains can understand.

New research in the journal Neuron converts that "somehow" into a very specific protein, called TMC1, a critical key for hearing. I spoke with Jeffrey Holt, a Harvard Medical School professor of otolaryngology and neurology and a senior author on the paper. Our edited conversation:

What did you find?

We discovered that a protein, known as TMC1, is a key protein that converts sound into electrical signals inside the inner ear.

We first presented this as a hypothesis back in 2011 and we've been working on it for the past several years. We think we now have the definitive evidence, the smoking-gun evidence, to prove that the TMC1 protein forms this essential component that converts sound into electrical signals.

And it's found on those delicate sensory cells in the inner ear called hair cells?

Yes, at the tips of each one of these hair cells are the TMC1 proteins that open and close in response to sound. When they open, they generate electrical signals that are then transmitted to the brain, where the sound is perceived. TMC1 is an ion channel protein, meaning that it allows ions like calcium and potassium to flow into the cell and generate an electrical signal.

And I gather that pinpointing how that conversion happens has been a long quest...

The idea that hair cells convert sound into electrical signals has been around for 40 years, but the proteins involved in that conversion process have been largely unknown. We've been searching for this for quite some time, and it's only in the past several years that we had some clue that the TMC proteins might be involved. But now we've got the definitive evidence that shows that is indeed the case.

So what can we do with this new understanding, what are the implications?

In the sensory field, with the senses of vision, touch, smell and taste, the molecules that convert these external-world stimuli into electrical signals have all been identified — except for hearing. This has been the holdout. But we've now got the evidence to show that the TMC1 protein is essential for hearing.

We think this is important for a number of reasons. First, we think that this protein is important in the ears of all vertebrates. We know it's expressed in mice, in humans, in fish, in birds, and it's been conserved because it's so important to the survival of these critters.

We also think that there may be implications for potential therapeutics in the future. TMC1 was identified initially because mutations in this protein lead to hearing loss in both humans and in mice. We're hopeful that by understanding how the protein works, we can design therapeutics to restore auditory function in humans.

Something like half a billion people have hearing loss. How many of those might be helped by some sort of TMC therapy?

We're trying to get a better handle on how many individuals might be affected. Right now, most hearing-loss patients have not been genetically sequenced, but preliminary estimates suggest that maybe 4 to 8 percent of genetic hearing loss may be due to mutations in TMC1.

What about age-related hearing loss?

Age-related hearing loss can arise from a few different sources, both genetic causes as well as environmental causes — when you listen to your iPod too loud, or there are a number of drugs that are also toxic to the ear. I'm not sure that a TMC1 therapy would be useful for those environmentally induced hearing losses but perhaps for the genetic hearing loss.

And you hold a patent on TMC1 gene therapy?

Yes, that's work that we've developed here at Boston Children's Hospital. That has not been licensed yet, but it is something we're continuing to work on.

There are biotechs here in Boston that focus on hearing loss — Decibel and Frequency — would this finding be relevant for their work?

Yes, on the gene therapy side it would be relevant. Frequency Therapeutics is working more on stem cells and trying to promote generation of new sensory hair cells. So I'm not sure it would be relevant for that. But anything in the gene therapy realm, where you're trying to restore function in patients with genetic hearing loss, it could be relevant.

I gather there has been some debate around TMC1 in recent years — what was the issue?

The debate was around TMC1's exact role. It was clear that it was important, because there were mutations that lead to deafness in humans in mice, but the exact role was not clear.

We presented this idea that it might be involved as part of the hair cell transduction channel. And that's what stirred up the debate: A lot of skeptical scientists thought no, it's probably not the case. We felt that it was. But now we have the definitive evidence that shows that indeed, that is the case.

And it's correct to say that it's "the" key protein?

Yes, we think it is the key protein. There are likely other proteins involved that are part of a chain of proteins that convert sound information into electrical signals. But TMC1 is forming a major part of the core of the ion channel that allows calcium and potassium to flow into the cell.

Why do you think hearing is the last of the senses to be understood at this level?

For one reason, the inner ear is embedded in the densest bone of the body — it's known as the temporal bone. So it's hard to get to. There are also very few sensory cells in the inner ear. In the human ear, for example, there are about 16,000 sensory hair cells, whereas in the eye's retina there are up to 100 million photoreceptor cells that are sensitive to light. That's why the retina was understood many years ago, and  why we're still sorting out the inner ear.

Why would there be such a big difference?

This is what evolution did. I don't have a better answer than that. But this is why you need to take good care of your ears. We're always advocating for hearing health and not listening to sounds too loud. You've only got to 16,000 of those hair cells and they're supposed to last a lifetime — so treat them gently.


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Carey Goldberg Editor, CommonHealth
Carey Goldberg is the editor of WBUR's CommonHealth section.



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