A new ‘master regulator’ could call the tune for hair cells essential to hearing

The act of hearing is like a ballroom dance, scientist Jaime García-Añoveros says. Tiny hair cells lined up in the outer ear leap and sway, transmitting sound’s vibrations to other hair cells in the inner ear that carry information via nerves to the brain. Exquisitely sensitive to frequency, these hair cells detect highs and lows, music and noise, in something like a ballet. But the music stops when these cells are damaged, by noise or some cancer drugs or antibiotics. The cells can live as long as we do, but once they die, they cannot be regenerated.

“The cells in your skin or cells in your intestines, they can live a couple of weeks. But these cells can live a century,” García-Añoveros said about hair cells in the ear. “It’s amazing, but they’re not immortal. And when they die, before we die, we lose our hearing.”

García-Añoveros, professor of anesthesia, neurology, and neuroscience at Northwestern University Feinberg School of Medicine, led a team that identified a master gene regulator that controls whether these hair cells made by the cochlea become inner or outer hair cells. The hope is that other cells surrounding them that provide a lattice of support could be reprogrammed to regain lost hair cell function.

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That crucial step in mouse experiments may be a decade away from helping people, García-Añoveros told STAT in an interview about his team’s paper published Wednesday in Nature describing the discovery. But given the widespread loss of hearing among people as they age, the stakes are high. Research has connected hearing loss late in life to mental decline and dementia, believed to be a casualty of social isolation. This interview has been lightly edited and condensed for clarity.

Why do you study this part of the ear?

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There are two reasons why I find the cochlea fascinating. One is the medical relevance it has: The most common degenerative condition in humans is the loss of the hair cells of the cochlea. They are not produced normally after we’re born so that means the deafness that occurs with age is irreversible. It’s only mammals and humans that [have] lost that ability, but we know that nature can do it. So we can find ways to tweak it and make it happen again in an artificial condition.

The other reason I really like to study the cochlea is that it has a structure, if you look at any picture, in which the cells have positioned themselves with a precision that no other organ in a human or I think maybe in any animal has. The cells are placed in a lattice with micrometrics precision. So you can look at hundreds of cells and find one that’s missing or disoriented, misplaced. Any minute defect can be detected.

What do you see when you look at the cochlea?

I would say it’s the most beautiful organ in the body. But it’s not just aesthetic. It’s an ideal system we can study at that level of detail. And whatever we learn, I think will transcend hearing. It will be useful to study in general any organ regeneration or any organ development.

How do the outer hair cells work?

This is a fascinating aspect of biology in mammals — they don’t exist in other organisms and they are, evolutionarily speaking, a young cell type. Inner hair cells do what sensory cells are supposed to do: They detect sound and send the information to the brain. Outer hair cells do something very unique. They actually can move when they get stimulated by sound. The outer hair cells are in a swing, they crouch and jump. They amplify the sound, allowing us to hear very, very soft sounds. Because they amplify it at the right frequency, we can distinguish very minor differences in frequency, meaning from high to low pitch noises.

And the inner hair cells?

These cells are innervated, meaning they’re contacted by different nerves, different neurons, and they send different information to the brain. We are beginning to use this ability to switch from one to the other to study how they get innervated.

These outer hair cells can be damaged by noise, right?

In some forms of deafness, you lose the inner hair cells. In many more other types of deafness, what you lose is the much more vulnerable outer hair cells. When we talk about regenerating the cells, what you really need to do is to make the right type of cell. Because if you put an inner hair cell in the position of an outer hair cell or an outer hair cell in the position of an inner hair cell, it’s not going to work.

Where did you begin?

There has been progress in regeneration, getting hair cells produced by other cells in the tissue that basically convert into hair cells. But these hair cells are neither an inner nor an outer hair cell. We need to know how to make one cell type versus the other and then make them in the right place.

How did you pinpoint the gene you call the master regulator of these two types of hair cells?

In our prior study in Nature, we found a mutant in which there were outer hair cells were converting into inner hair cells. We identified the genes that were misregulated in those cells that were converting from outer to inner. We thought we may have among these a master regulator, and that’s what we found. We went through a few of these genes and we found one of them that if we put it into an outer hair cell, it becomes an inner hair cell.

What does this mean for potential treatment?

We’re basically trying to find a key gene that’s a switch that tells you whether a cell is going to be an inner or an outer hair cell. So it will become a very useful tool in trying to regenerate. I don’t know when regeneration will be practical in terms of treating patients, but at least in animal models, we’re moving forward in the right direction.

How would you use what you’ve learned about the master regulator?

This opens up a whole new area of research. It shows that there is a lot of plasticity, the ability of cells to convert from one to the other, which is good news if we want to generate these cells, because it means that they’re malleable. We can generate them, hopefully with artificial means, and generate what we want to generate.

What are the challenges?

The real difficulty is not just going to be making inner or outer hair cells. These cells are interpolated with very specialized supporting cells, shaped to fill in the gaps. And we have now begun to use this discovery to identify how to make the right type of supporting cell. I think that is going to be essential for restoring hearing.

It’s not just regenerating the cell type. The cell has to be placed correctly with the right type of supporting cells, and it has to be properly innervated so that it is properly connected to the brain. If the cell is not sending information to the brain, we’re not hearing.

How long is the road ahead between your experiments in mice and potential treatment in people?

Even though it looks like a daunting task, we have tools to understand it. My goal is in the next decade to start at least understanding it. It’s very hard to know when a therapy is going to be working. Right now, we should be able to know how to make an outer versus an inner hair cell. That will be the next therapy approach. I’m not saying therapy in people, but in animal models. I’m being conservative. I just think given all the barriers that have to be overcome, with this we can overcome a major one. But there will be others.

It’s very hard to know scientifically how easy or difficult it’s going to be to overcome the next barrier. You know, a hundred years ago, people were already picturing flying cars. And we don’t have them.

Are you hopeful?

I am optimistic because I can visualize how this is going to happen.