Research by pilot awardee Zheng-Yi Chen, D.Phil may hold the Holy Grail of hearing loss: how to regenerate hair cells, the inner-ear sensory cells that detect sound. After two decades of foundational basic-science discoveries and translational work in animal models, Chen, an associate professor of otolaryngology at the Massachusetts Eye and Ear Infirmary, thinks his laboratory has found a formula for hair-cell regeneration, which could lead to the recovery of hearing. He needs one more piece of data in a preclinical model to move the work to the next stage, a clinical trial in humans. Pilot funding via our Five Senses: Input & Response program is helping bridge that crucial translational gap.

The public health impact of a solution to hearing loss, which has no effective treatment, would be transformative for millions. In the U.S. alone, 36 million people suffer hearing loss, which can lead to social isolation, anxiety, depression, and even dementia. Solving hearing loss is a primary objective of the Chen lab, and the end goal is in sight. We caught up with Chen shortly after the Five Senses awardees were announced.

You’re taking an audacious approach to solving hearing loss by trying to regenerate the sensory cells that enable hearing. Why target these hair cells?

Hair cells are one of the inner ear’s most important cells for the functioning of hearing, used for detecting sound and for sense of balance. Hearing loss has many different causes–environment, noise, certain drugs, viral infection, genetic mutations–but the loss of these sensory cells is one of the primary reasons.

Like other mammals, humans are born with a certain number of hair cells in each ear, about 16,000. That’s it. If you lose one hair cell, you lose it forever. Whereas many cells in our body do regenerate, even if at a very slow rate, inner ear cells never regenerate. They can be damaged easily, and damage accumulates to ultimately lead to hearing loss of different degrees. There is no replacement mechanism. That’s the reason hearing loss is permanent, and why we want to regenerate hair cells to regain function.

“With this pilot opportunity, the process is very streamlined, which I love. The people who reviewed our project really understand the potential value. It’s a very coherent community of investigators; we can bounce ideas off one another and learn from each other.”

Your work falls under the broad umbrella of regenerative medicine, but your approach is different than most. Why?

The goal of regenerative medicine is, basically, to find a way to regenerate tissues or repair damage to cells in lasting ways. We know that is intrinsically difficult to do. Everything has to be regenerated perfectly in the right place and order to regain function. The most advanced work in the field uses stem cells that are grown in a dish and differentiated into the cell you want, then transplanted into the body. In the ear, that approach is extremely difficult if not impossible, because the inner ear has a very intricate structure with a delicate, integrated, hierarchical organization. So while transplanting stem cells is viable in tissue such as blood or skin, or even heart, that’d be very challenging to do in the inner ear.

Instead, we want to reprogram the inner ear cells to turn their biological clock backwards. A highly mature differentiated cell normally doesn’t have any capacity to either repair or regenerate. However if you turn the biological clock backwards to a very young stage, the progenitor cell state, suddenly they have many amazing capacities, including regeneration and repair. So we’re trying to use this reprogramming approach to coerce the inner ear cells to revert to relatively young, immature cells. From there they can regain the property to regenerate.

Where are you now with this work and what’s the next step?

We have shown that we can regenerate hair cells in vitro; we can put the cochlea of the mature inner ear in a petri dish, and we can regenerate hair cells by using this component that we discovered. We can also induce regeneration in vivo in transgenic animals, where we can use a genetic manipulation to activate certain genes.

But our human ears are not transgenic, and we cannot just turn on a gene at will. We really need to find a drug-like molecule able to regenerate hair cells, ultimately, in humans. That means we first have to demonstrate that we can do it in a wild-type animal in vivo. This is why receiving pilot funding from Harvard Catalyst is important: it allows us to test proof of concept, different formulations and modalities so we can come up with the best possible combination of drug-like molecule that will induce hair cell regeneration.

What is the value of pilot funding to fill the translational research gaps that you’re facing right now?

“I think hair cell regeneration is one of the most important projects in the lab because it solves the most fundamental question and will have the most profound impact on people.”

We’ve been able to make major progress, but we need to do some more groundwork, like identifying the best combination, optimization — all those crucial aspects of therapeutic development. It’s very difficult to get NIH funding for those things, because NIH wants you to either do some very “safe” work or meet a very steep goal to demonstrate groundbreaking findings, if you can get to that. We come in between. We’re clearly far more advanced than what exists out there, but we’re not yet at the stage where we can say to the NIH: “We have shown it works in mouse models and now we can use it to regain hearing; fund us for that work.” When we reach a new stage with our pilot funding of demonstrating our findings, then I have no doubt we can obtain major funding. This initial funding provides a critical stepping stone to get there.

These days, funding is always tight. To find funding for this kind of research takes a lot of work and sometimes you don’t get anything, which becomes a total waste of time. But with this pilot opportunity, the process is very streamlined, which I love. The people who reviewed our project really understand the potential value. It’s a very coherent community of investigators; we can bounce ideas off one another and learn from each other. All of that really adds value not only to the grant itself but also for the investigators. We can help each other to fulfill the overall goal.

How does this fit into your lab’s broader work?

We have multiple projects including gene therapy and genome editing for treatment of hearing loss, and have shown very good results along that line. But I think hair cell regeneration is one of the most important projects in the lab because it solves the most fundamental question and will have the most profound impact on people. That’s why this has been our main goal.

If we are able to do this, we really hope society will have a more productive and self-sustained elderly population who are able to enjoy life more, which will also lessen the burden of hearing loss on society. We are very optimistic that something good will happen, not only through my own lab but through collaborative efforts.