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Topics: Five Questions, Funding, Pilot Funding

Young Investigator Takes Aim at Genetics of Hearing Loss

Five Questions with Samuel Mathias on overcoming study feasibility hurdles.

Sameul Mathias holding his newborn twins.
Samuel Mathias holding his twins.

Samuel Mathias’s story represents virtually every young investigator’s. Junior faculty as an instructor in the department of psychiatry at Boston Children’s Hospital, he’s vying for his first big RO1–again–and hitting a wall with the feasibility dilemma: How to prove you can do the study when you haven’t completed it yet.

Enter Five Senses: Input and Response, our 2022 pilot funding opportunity. Now he’s directing his own study, collecting data, analyzing it, and calling the shots independently, but with the support of expert guidance. It’s already proved its value for Mathias by improving his score on an NIH grant resubmission.

His aim is high: unraveling the genetics of one of the most common sensory disorders of all, age-related hearing loss. We caught up with him a couple of months after he became a first-time father to twins and was suffering from sleep deprivation.

What is the big-picture goal of this project?

The big picture is sorting out the genetics of hearing loss and deafness.

Childhood deafness is one of the success stories of modern genomics. If a child is born with hearing loss not caused by infection or part of a syndrome, there’s about an 80% chance you can identify the genetic variant causing it. That’s the current state of our understanding. In the next five or 10 years we might be able to reverse some forms of deafness by editing the genome. Those investigations are going on now.

“We really don’t know much about the genetics of age-related hearing loss. We know it is controlled by genes to some extent, but we don’t know which genes.”

However, childhood hearing loss or congenital deafness is rare, affecting two or three of every thousand children. The overwhelming majority of hearing loss affects adults – about 40% of people over age 65. We really don’t know much about the genetics of age-related hearing loss. We know it is controlled by genes to some extent, but we don’t know which genes.

To understand the more common disorder, we’re looking at rare or extreme cases to discover whether there is an early kind of prodromal phase to age-related hearing loss.

That’s a new strategy for unraveling genetic questions in hearing loss. Why this approach?

After the Human Genome Project, the big idea was to do large genome-wide association studies (GWAS) where you measure the genomes of hundreds of thousands of participants and then look for genes that influence common conditions or traits. Generally, you get lots of hits–many correlations between genes and the phenotype you’re looking at–but the effect of any individual gene is usually tiny. So, where do you go with that?

What we’re doing is a compromise between the classical approach of looking at rare diseases, like congenital deafness, where the focus is on individual variants that have strong effects, and the GWAS approach, which looks at common conditions in huge samples and finds many variants that have tiny effects. We’re somewhere in the middle, looking at extreme cases of common diseases, where individual variant effects might be stronger than in more typical cases. This approach has been used for other diseases in which the genetic role has been hard to pin down.

In this case, we’re investigating people who developed age-related hearing loss unusually early in life, say in their 40s. In the absence of clear environmental exposure to high-impact noise or other causes, their hearing loss is most likely genetic, so we anticipate finding stronger effects than in GWAS. That makes the results potentially more actionable down the line.

We’re also looking at the offspring  of people with early-onset age-related hearing loss, specifically their adolescent or young adult children, who are most likely too young to have hearing loss now but are at high risk of developing it later on due to their family history. Studying these individuals will allow us to discover the early or prodromal characteristics of age-relating hearing loss.

How might this work change our understanding of hearing loss?

If we discover that there is an early phase to hearing loss, that’s a massive boon. You could potentially predict which people are going to develop these problems years in advance, and try to prevent or at least minimize those problems with lifestyle changes, medications, etc.

As it is now, by the time the primary symptoms of hearing loss appear, it’s too late to do anything. If the inner ear hair cells have already died, there’s nothing you can do besides a prosthesis like a Cochlear implant or hearing aid. You can’t get them back.

So anything we can do to figure out who’s going to develop hearing loss before it happens will be critical.

What’s the value of pilot funding like this to you?

I’m basically a new investigator. I’ve applied for big RO1 NIH grants for a few years now, and the major limitation is always demonstrating feasibility. Practically, they want to know: Can this person do this?

“When you’re starting a new lab for the first time and you don’t have that preliminary data, it’s very difficult to make a compelling argument that you can get the work done. These kinds of small grants are instrumental in demonstrating that.”

When you’re starting a new lab for the first time and you don’t have that preliminary data, it’s very difficult to make a compelling argument that you can get the work done. These kinds of small grants are instrumental in demonstrating that.

This pilot is the first study for which I am collecting my own data, independently of other researchers. Just writing about it in a resubmission application for an R01 improved my application score. So it has already helped me, even before we collected any data.

Another great aspect of this pilot grant is that it comes with a huge amount of support; the Harvard Catalyst program managers  are extremely hands-on. I have a meeting at least every month to check in and talk through the nitty gritty details. They have access to resources and people who can help troubleshoot problems. That’s been very useful for me.

Every three months or so Harvard Catalyst organizes “all-hands” progress meetings where you get to see what the other awardees are doing, and that’s been incredibly helpful for me as well. With a small grant it can be quite easy to get siloed, completely focused on your own work. Connecting with other investigators made me feel like I was part of a much larger community of people who are conducting research on a comparable scale.

You’re the new parent of infant twins – congratulations! What has the transition to parenthood been like for you and your wife?

Rough. Just really rough. We’re not American so we don’t have any family here. There’s no support at all. I didn’t realize how much of an issue that was going to be. We sort of intellectually knew, but it’s a different thing when you have to emotionally endure sleeping just three hours a day.

Boston Children’s Hospital has been super helpful. Because their focus is on children, it’s kind of natural that they’ve been accommodating when it comes to life changes around kids. My wife is assistant professor in the same department, and she has medical leave as well as parental leave. I took half of my leave and then went back to work to minimize how much we spend on daycare, because it is more than my paycheck and more than our rent. When her leave expires, I’ll take the rest of my leave.

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