A Powerful New Bioinformatics Tool

By Stefan Heller, Ph.D.

Our paper describing a new bioinformatics tool—and to showcase the software, a very detailed investigation as to how inner ear hair cells assemble their hair bundles—appeared in Cell Reports on June 5, 2018.

The creation of the CellTrails tool was supported in part by Hearing Health Foundation’s Hearing Restoration Project (HRP) but moreover, it is the product of recognizing existing limitations of data analysis, going back to the drawing board multiple times, and finally getting to a “product” that is going to be the workhorse to analyze a good part of the bioinformatics data that the HRP has been accumulating for years.

An image taken at 40x magnification using a confocal microscope in the Stefan Heller lab shows a 7-day-old chicken cochlea. Credit: Amanda Janesick, Ph.D.

The ideas came from conversations between HRP scientific director Peter Barr-Gillespie, Ph.D., and me and our getting stuck with trying to make sense of all the data—so the tool is the direct product of interactions through the HRP.  It follows on our work utilizing single-cell gene expression analysis to examine the genetic instructions allowing individual cells to differentiate (change) into other types of cells, such as inner ear supporting cells that turn into hair cells in species other than mammals, and thereby restoring hearing.

The tool helps us pinpoint where specific single cells are located in an organ, and their trajectories as they undergo transformations, information that was lost or fuzzy before. With it we can create a more robust, visually rendered gene expression landscape. Two postdoctoral fellows in my lab were instrumental in CellTrails: bioinformatics researcher Daniel Ellwanger, Ph.D., the tool’s primary developer, and Mirko Scheibinger, Ph.D., who validated its predictions.

I hope many researchers make use of CellTrails, accessible online, to analyze their own mountains of data. As I told Stanford’s SCOPE Blog, “Single cell transcriptome analysis and reconstruction of spatial and temporal relationships among cells is an exploding new technology. A lot of labs are faced with the challenge of analyzing the data from single cells. This study is a rather extensive study that goes beyond the inner ear field because it provides a new way to analyze single cell transcriptomic data.”

I truly feel that the seeds that were planted years ago are now growing into sizable plants—we have a massive "chick regeneration inner ear plant” that is starting to thrive!

Find the tool at hellerlab.stanford.edu/celltrails.

Stanford University’s Stefan Heller, Ph.D., is a member of HHF’s Hearing Restoration Project, where Oregon Health & Science University’s Peter Barr-Gillespie, Ph.D., is the scientific director.

Empower the Hearing Restoration Project's life-changing research. If you are able, please make a contribution today.

HHF Attends HLAA 2018 Convention

By Nadine Dehgan

I was fortunate to attend my very first Hearing Loss Association of America (HLAA) Convention last week in Minneapolis, MN with Hearing Health Foundation (HHF)’s Program Associate, Maria Bibi.

Nadine Dehgan and Maria Bibi at HLAA 2018.

We spent much of our time serving as resources to the highly engaged attendees. In the exhibit hall at our HHF booth, we answered questions related to our critical research and awareness programming. Maria and I were humbled to learn of the deep appreciation for our work from our booth’s visitors.

Several educational sessions were held beyond the exhibit hall. I was particularly grateful to witness John Brigande, Ph.D., and Ronna Hertzano, M.D., Ph.D., speak about HHF’s Hearing Restoration Project (HRP), the international scientific consortium dedicated to identifying better treatments and cures for hearing loss and tinnitus. Here, I met a supporter of HHF, who said, “[Drs. Brigande and Hertzano] were both informative, encouraging, and enthusiastic about their work and the possible outcomes. I will continue to follow their progress even more closely now.”

HHF Emerging Research Grants (ERG) 2018 recipient Evelyn Davies Venn, Au.D, Ph.D, also delivered a compelling presentation. An Assistant Professor at the University of Minnesota, Dr. Venn’s research focuses on a highly personalized hearing technology to help individuals better understand speech in noise. She discussed a new hearing aid in concept phase that will convert the sense of touch into sound electricity.

A shift from typical days in our quiet New York City office, the four-day convention connected us with many inspirational people—folks with hearing loss and scientists alike. Buzzing with energy, optimism, and knowledge about hearing loss, the convention was an important representation of how HHF’s work impacts so many individuals.

Uncovering a Signaling Molecule That Modulates Avian Hair Cell Regeneration

By Rebecca M. Lewis, Au.D., Ph.D., and Jennifer Stone, Ph.D.

Mammals including humans cannot regenerate hair cells, but other species such as birds and fish readily regenerate hair cells after damage to restore auditory function. The gene ATOH1 produces a protein that pushes supporting cells—cells that neighbor hair cells—to either directly convert into a hair cell or to divide and form a new hair cell. However, ATOH1 expression (when the gene is turned on) does not guarantee that hair cells develop in birds or mammals, which suggests that there are factors that prevent supporting cells from changing into hair cells. Identifying these factors in birds may help us better understand the lack of hair cell regeneration in mammals.

This schematic depicts our current ideas for how BMP4 regulates ATOH1 expression and therefore hair cell regeneration in the avian hearing organ. It shows (from left) typical hair cells, hair cell damage, and hair cell regeneration. Typical hair cells secrete BMP4. When hair cells die, BMP4 signaling is reduced, which allows ATOH1 to be expressed in supporting cells and pushes supporting cells to turn into hair cells. The newly regenerated hair cells secrete BMP4, suppressing ATOH1 in supporting cells and restoring the normal condition.

We examined the avian auditory system to characterize a potential inhibitor to ATOH1 during hair cell regeneration: bone morphogenetic protein 4 (BMP4). Bone morphogenetic proteins are secreted signaling molecules that regulate cellular processes in many regions of the body, including the nervous system. We found that BMP4 localizes to hair cells of the mature avian hearing organ and disappears when hair cells die or sustain damage. From this, we hypothesized that BMP4 may prevent ATOH1 expression in supporting cells and loss of BMP4 when hair cells die may enable ATOH1 to be expressed in supporting cells, driving them to convert into hair cells.

When we exposed avian auditory organs to BMP4 after selectively killing hair cells, this prevented ATOH1 expression and hair cell regeneration. When we antagonized BMP4 using an inhibitor, we found a generally opposite result: an increase in the number of regenerated hair cells.

We conclude that BMP4 is a potent inhibitor of ATOH1 and therefore suppresses hair cell regeneration. We recommend that BMP4 be explored further in studies of mammalian hair cell regeneration.

Published in Hearing Research on May 2, 2018, this study detailing BMP4’s negative effect on ATOH1 expands our knowledge of signaling molecules that suppress hair cell regeneration in birds and may also modulate hair cell regeneration in humans.

Rebecca M. Lewis, Au.D., Ph.D., is a clinical audiologist and auditory neuroscientist at Massachusetts Eye and Ear/Harvard Medical School in Boston. HRP researcher Jennifer Stone, Ph.D., is the director of research in the department of otolaryngology–head and neck surgery at the Virginia Merrill Bloedel Hearing Research Center at the University of Washington.

Empower the Hearing Restoration Project's life-changing research. If you are able, please make a contribution today.

Why So Many Can’t Afford to Hear Better

Only about 14 percent of Americans with hearing loss use hearing aids. For many others, this vital, life-changing treatment that facilitates participation in meaningful conversations with friends and family is out of reach financially.

Hearing Health Foundation (HHF)’s 2017 hearing loss survey, created to better understand our constituents’ opinions related to hearing loss, was cited by a WBUR-FM Here & Now radio segment highlighting the barriers to hearing loss treatment that Americans encounter.

The news story opens with commentary from retiree Betty Hauck, 72, who was shocked when her first pair of hearing aids cost her $5,600—with no assistance from Medicare.

“A price tag like that is often a surprise to people buying hearing aids for the first time. Four states—Arkansas, Connecticut, New Hampshire and Rhode Island—require health plans to cover hearing aids for children and adults,” explains reporter Peter O’Dowd.

“But those benefits are rare. A 2017 survey by the Hearing Health Foundation, a group that funds research and advocates for treatments and cures for hearing loss, found that 40 percent of the people they asked had no hearing aid coverage through health insurance.”

Kevin Franck, director of audiology at Massachusetts Eye and Ear, among other experts, are hopeful that the Over-the-Counter Hearing Aid Act of 2017 will reduce barriers—cost, stigma, and hassle—encouraging greater adoption.

You can access the full WBUR segment, here.

Note: The audio segment is not captioned but is summarized in print.

The Listening Project

By Vicky Chan and Lauren McGrath

“Most people still assume that if a person is deaf, they’re not able to speak,” narrates Jane Madell, Ph.D., in the opening moments of her documentary film “The Listening Project,” released in March 2018. Her statement sets the tone for the following 38 minutes of personal stories that shatter stigmas about hearing loss.

A New York City-based pediatric audiologist, speech language pathologist, and auditory verbal therapist, Madell created the documentary with award-winning filmmaker Irene Taylor Brodsky to reveal how technology has improved communication—and life—for people with hearing loss.  

Richard, a cochlear implant recipient, is one of the participants in "The Listening Project" who works as a software engineer.

Brodsky captured interviews of 15 individuals with hearing loss, most of whom Madell treated when they were children. Madell says filming  allowed her to reconnect with her former patients to “see what they had to say about growing up with a hearing loss and what advice they might have for parents of newly identified children with hearing loss.”

The subjects of “The Listening Project” are vibrant young adults living and working all over the world—connected by their gratitude for the technologies and treatments that enable them to hear and talk. The majority are cochlear implant recipients, while the remainder wear hearing aids. They experienced similar anxieties, including not being able to hear everything in social settings, disclosing hearing loss to new acquaintances, and accepting their hearing loss.

If not for modern medical progress, the film’s subjects may not ever have been able to overcome these hurdles. When Madell began her career in audiology 45 years ago, hearing loss treatments were very restrictive. Only children with mild to moderate hearing loss could hear well with hearing aids, and the Food and Drug Administration had not yet approved cochlear implants. Such limitations challenged Madell emotionally early in her practice. Though she smiled and appeared optimistic in front of her patients and their families following a hearing loss diagnosis, she knew how hard they would need to work with inadequate accommodations for their children to succeed.

Madell’s former patients and millions of others are fortunate  changes in hearing technology and policies in recent decades have been dramatic. “We are so lucky we live now and not 30 years ago, 40 years ago,” says one. Another young man adds that the ability to communicate and feel comfortable doing so is “a core human value.” Advancements have made it possible for children with hearing loss to learn spoken language, which Madell believes is critical for educational, social, and professional development and gives them options they would not have otherwise.

Madell hopes the personal stories in “The Listening Project” will help parents of newly diagnosed children, as well as legislators, educators, and healthcare workers. “Parents of children with hearing loss have told me that if they had seen the film before the diagnosis, it would have been easier to deal with,” she says. It shows parents that with the resources and hearing technology available today, hearing and speech are possible for every child.

To learn more about the film for either personal or educational use, visit thelisteningprojectfilm.org.

On a Quest

By Sue Baker

From his earliest days, the concept of sound consumed musician and inventor Les Paul. How did sound work? Why did the record player produce sounds different from the player piano? Why does the sound of the train change as it moved down the tracks? Why did the body of his acoustic guitar vibrate when he plucked the strings? How could he make just the strings vibrate?

Although best known for his solid body electric guitar and industry-changing recording inventions, for Les the quest always came back to sound, even in his later years. “I’ve spent my life looking for the perfect sound, trying to build the perfect guitar to play the perfect note,” he wrote in his 2005 autobiography, “Les Paul in His Own Words.”

One of Les Paul's hearing-related inventions.

In the 1960s, Les’s eardrums were ruptured due to playful roughhousing. The resulting infection and, later, mastoidectomy surgery, left him with a hearing loss. He wasn’t happy about the hearing aids’ sound quality for music.

I met Les when I was the executive director at a museum in his hometown of Waukesha, Wisconsin. We were creating an exhibit about his career. Over the course of what would be the last decade of his life, our friendship grew. Two years after Les passed away at age 94 in 2009, his business manager Michael Braunstein asked me to work at the Les Paul Foundation.

During one of my visits to Les’s home in 2001, I asked him about an unusual piece of equipment in a corner. “Oh, it’s just an experiment I was doing,” he said. “I was trying to replicate how the human ears work.” He was a tinkerer by nature and necessity, always wanting to invent something to fill a void or to improve what was available.

Musician Jon Paris says Les’s audiologist (whom he met at New York City’s Iridium Jazz Club, where Les performed every Monday night) told him that Les “drove him nuts—in a good way—constantly demanding better quality from his hearing aids.”

Another friend, Chris Lentz, says that Les worked with Marty Garcia of Future Sonics to improve his hearing aids. In a note to Chris, Marty wrote, “Throughout our years together, Les validated just about every voice coil transducer Future Sonics developed.”

In a 2008 interview in Audiology Today, Les talked about how he wanted to improve hearing aids for music. He cited the importance of extending the audio range to capture more of the harmonic structure than what is needed for speech. Les also wanted hearing aids that could be worn in the shower and would work optimally when using the telephone.

Les Paul’s 103rd birthday would have been this June 9. He would have been gratified to see how far hearing aid technology has come.

Sue Baker is the program director for the Les Paul Foundation. For more, see lespaulfoundation.org.

Researchers Fighting the Effects of Noise

By Yishane Lee

The cornerstone of Hearing Health Foundation, ever since its founding in 1958 as the Deafness Research Foundation, has been funding early-career researchers who bring innovative thinking to hearing and balance research. HHF’s Emerging Research Grants (ERG) are awarded to the most promising scientists in the field, with many going on to earn prestigious National Institutes of Health backing.

HHF is always proud to see ERG grantees thrive in their careers and research. Most recently, two ERG scientists funded in the mid-1990s have made headlines, each for treatments for noise-induced hearing loss (NIHL).

1996 and 1997 ERG scientist John Oghalai, M.D., of the University of Southern California, coauthored a study showing promise for preventing NIHL. Published May 7, 2018, in the Proceedings of the National Academy of Sciences, Oghalai and team used miniature optics to examine the mouse cochlea after exposure to extremely loud noise, and found that in addition to immediate hair cell death, a fluid buildup in the inner ear over several hours eventually led to nerve cell loss. The fluid buildup, or endolymph hydrops, contributes to synaptopathy, or damage to the auditory nerve cell synapse. In a USC News press release, Oghalai described the excess fluid as a feeling of fullness and ringing in the ear that a person may experience after attending a loud concert.

Because the extra fluid showed a high concentration of potassium, the team saw a method to re-balance the fluids that naturally occur in the inner ear by injecting a salt (sodium) and sugar solution into the middle ear three hours after exposure. Nerve cell loss was reduced by 45 to 64 percent, which may help preserve hearing. The researchers see applications for this treatment for military service members who experience blast trauma as well as for people who have Ménière’s disease, the hearing and balance condition that is associated with inner ear fluid buildup.

Images from the cochleae of guinea pigs show the presence of more hair cells in animals treated with a short interfering RNA that interrupts a gene upregulated after damage (right; control on left). Inner and outer hair cells (IHC and OHC) are labeled in green, stereocilia in yellow, and nuclei in blue. Arrowheads indicate ectopic hair cells. Credit: The Scientist via Molecular Therapy.

1996 ERG scientist Richard Kopke, M.D., FACS, of the Hough Ear Institute in Oklahoma, spent more than 20 years serving with the U.S. Army, becoming well aware of the dangers of NIHL for service members. In a paper in Molecular Therapy, published online in March 2018, Kopke and colleagues used “small interfering RNAs” (siRNAs) to block the activity of the Notch signaling pathway gene Hes1 that itself blocks hair cell differentiation in developing supporting cells and may contribute to the failure of hair cells to regenerate after injury.

These siRNAs were delivered using nanoparticles directly injected to the cochleae of live, adult guinea pigs. Kopke’s team had previously shown using siRNAs to block Hes1 to be effective in regenerating hair cells in cultured mouse cochlea. In the current study, the 24-hour, sustained-release of siRNAs through nanoparticles three days after deafening resulted in the recovery of some hearing ability, measured using auditory brainstem responses, at three weeks and continuing to nine weeks, when the study ended. Compared with the control mice, the RNA-injected mice showed less overall hair cell loss and early signs of immature hair cell development, which the authors say may signal hair cell regeneration. Hearing loss caused by noise, chemotherapy drugs, or aging that damages or kills hair cells are all targets for this potential treatment.

In an article in The Scientist, HHF’s Hearing Restoration Project consortium member Jennifer Stone, Ph.D., who was not involved in the paper, echoed the study authors in saying further research should work to determine which cells are turning into hair cells, and whether the observed hair cell development is truly new hair cells and not the repair of damaged hair cells. Kopke and team plan to test the treatment using longer periods between deafening and injection, while also modifying dose and delivery.

We need your help supporting innovative hearing and balance science through our Emerging Research Grants program. Please make a contribution today.

The Countdown to Operation Regrow

By Gina Russo

Hearing Health Foundation (HHF) is counting down the days until the start of Operation Regrow, a two-week movement when you can help us to further progress toward better treatments and cures for hearing loss.

Beginning Tuesday, June 5, at 8:00 AM EDT, you can support the team of scientists conducting life-changing research to restore lost hearing, and more importantly, your generosity will have double the impact! All contributions received by 11:59 PM EDT on Tuesday, June 19 will be matched by an anonymous donor.

Transverse section through the embryonic day 20 chicken utricle (inner ear organ) at 20X magnification. Photo by Amanda Janesick, Ph.D., of the lab of Stefan Heller, Ph.D., a Hearing Restoration Project consortium member

With just five days remaining until launch, you can share the five most important facts about Operation Regrow with friends and family:

1. The Hearing Restoration Project (HRP) is the HHF-funded scientific consortium dedicated to finding biological cures for hearing loss.

2. Damage to the sensory cells in the human inner ear causes irreversible hearing loss.

3. The HRP members know that the key to hearing loss cures is the human ability to regrow cells in the inner ear. This phenomenon is already possible in certain species. The HRP has observed cell regrowth in chickens, fish, and young mice.

4. The HRP is comprised of 15 senior scientists who work collaboratively by openly sharing data and ideas, and this collaboration helps to speed up the research process.

5. HHF maintains stellar charity ratings from Better Business Bureau Wise Giving Alliance, Guidestar, Charity Navigator, and CharityWatch for using 100% of donations to support critical research, ensuring that all Operation Regrow contributions will directly help the HRP.

If you are able to make a gift to Operation Regrow, please visit www.hhf.org/regrow between June 5 and June 19. Gifts may also be made by phone during business hours, 9:00 AM to 5:30 PM EDT, at 212-257-6140. We’ll be sure to keep you updated on our progress. Thank you for supporting HRP and hearing health!