EMERGING RESEARCH GRANTS ALUMNI
The cornerstone of Hearing Health Foundation for six decades has been funding early-career hearing and balance researchers through its Emerging Research Grants (ERG) program. Many ERG scientists have gone on to obtain prestigious National Institutes of Health (NIH) funding to continue their HHF-funded research; since 1958, each dollar awarded to ERG scientists by HHF has been matched by NIH investments of more than $90. Within the scientific community, ERG is a competitive grant awarded to the most promising investigators.
ERG alumni continue to make headlines in the mainstream news for their scientific breakthroughs. Here are details about notable recently published papers.
Moving Beyond Wnt and Notch Pathways for Hair Cell Regeneration
There are several active human clinical trials evaluating the safety of inner ear hair cell regeneration therapies, but these therapies’ target mechanisms may be insufficient to stimulate hair cell growth in the adult mammalian cochlea. These approaches rely on the canonical Wnt and Notch signaling pathways and the Atoh1 molecule, which is necessary for hair cell regeneration and is regulated by these pathways.
However, a report published in Molecular Therapy in May 2019 by Anshula Samarajeewa, Bonnie E. Jacques, Ph.D., and Hearing Restoration Project member Alain Dabdoub, Ph.D. (a 2009 ERG scientist), notes that there has been very limited success thus far in regenerating hair cells in adult mammalian cochlea using these signaling pathways. This likely means, the authors write, that researchers will need combined approaches that also use epigenome-editing techniques to address changes to the genetic material and activity that occurs with age.
Both the Wnt and Notch pathways play a role in determining how inner ear cells develop into specific types of cells and multiply, and they are also important in the development of the cochlea as a whole. Activating Wnt pathways and inhibiting Notch pathways can turn supporting cells into hair cells in fetuses and newborn mammals, making these key targets for hair cell regeneration. But both become much less effective as the body ages. Manipulating these pathways in adult animals has led to some success in regenerating hair cells, but these new hair cells tend not to develop fully, do not form necessary connections with auditory neurons, or even survive.
This lack of success is not because these pathways no longer exist in adults; researchers have found that they are still functional. This suggests that there are epigenetic changes that occur as a result of aging to make the adult cochlea less receptive to regeneration. Targeting epigenetic enzymes in addition to the Wnt and Notch signaling pathways may therefore prove more successful, but researchers still need to determine which part of the chromosome to target. This process would involve gene-editing techniques like CRISPR. This type of epigenome editing has slowed hearing loss in newborn mice, but it has yet to be tried in adult mice. If successful, this technique has the potential to treat hereditary and acquired forms of hearing loss. —Christopher Geissler, Ph.D.
Genome Editing Protects Hearing in Mice
Massachusetts Eye and Ear/Harvard Medical School associate professor Zheng-Yi Chen, D.Phil. (1995 ERG), and colleagues delivered a CRISPR/Cas9 genome editing complex directly into the inner ear hair cells of mice, preventing hearing loss in an animal model of genetic progressive deafness. The CRISPR/Cas9 therapy disabled a mutated form of the gene Tmc1, the first time that a gene editing protein has been ferried directly into the relevant cells to halt progression of genetic hearing loss.
A single-letter mutation in the gene Tmc1 and carrying only one of two copies of the mutated gene both lead to progressive hearing loss in mice and humans. With the mutated gene disabled, the inner ear hair cells survive, and mice otherwise genetically destined to become deaf retained a portion of their hearing. In a report published in Nature in December 2017, the team says that at four weeks, untreated mice were unresponsive to sound below an average of 80 decibels, while treated mice responded to sound at approximately 65 decibels. At eight weeks, treated mice also retained their instinctive physical “startle” response to sudden loud sound, while the untreated mice did not respond. The researchers said delivering the Cas9 protein itself locally, instead of DNA elements that the cell can use to build Cas9, improved the DNA specificity and potential safety of the treatment. —Massachusetts Eye and Ear
Researchers Discover Key Gene in Cells Associated With Age-Related Hearing Loss
Hearing Restoration Project consortium member Ronna Hertzano, M.D., Ph.D. (2009–10 ERG), an associate professor at the University of Maryland School of Medicine, and colleagues identified a gene, Ikzf2, that acts as a key regulator for outer hair cells whose loss is a major cause of age-related hearing loss. The Ikzf2 gene encodes helios, a transcription factor (a protein that controls the expression of other genes). The mutation of the gene in mice impairs the activity of helios in the mice, leading to an outer hair cell deficit.
As published in Nature in November 2018, the team tested whether the opposite effect could be created—if an abundance of helios could boost the population of outer hair cells. They introduced a virus engineered to overexpress helios into the inner ear hair cells of newborn mice, and found that some mature inner hair cells became more like outer hair cells by exhibiting electromotility, a property limited to outer hair cells. The finding that helios can drive inner hair cells to adopt critical outer hair cell characteristics holds promise for future treatments of age-related hearing loss. —University of Maryland
Specially Timed Signals Reduce Tinnitus Symptoms
In a double-blind clinical trial with 21 subjects, University of Michigan Medical School professor Susan Shore, Ph.D. (1987 and 1992–95 ERG) and team showed an experimental device could help people with tinnitus (hearing ringing or buzzing in the absence of an external sound source). Fusiform cells, the main neurons in the brainstem’s dorsal cochlear nucleus region, help the brain focus on where sounds are coming from, and help tune out sensations that result from the movement of our own head and neck (known as somatosensory inputs). The team’s previous work in animals showed that loud noise can trigger a change in the nerve cells’ activity—altering its timing so that the cells fire off synchronized signals spontaneously instead of waiting for an actual sound from the environment.
This phantom signal is transmitted into other centers where perception occurs. To stop the signal, the device uses “bimodal auditory-somatosensory stimulation,” which plays a sound into the ears, alternating it with precisely timed, mild electrical pulses delivered to the cheek or neck. Both are aimed at pushing the damaged nerve cells back to typical activity. In the trial, whose results were published in Science Translational Medicine on Jan. 3, 2018, participants using a sham treatment experienced no effect, but those who used the device daily for four weeks reported a decrease in tinnitus and an improved quality of life. —University of Michigan
Study Points to Possible New Therapy for Hearing Loss
University of Rochester Medical Center research associate professor Patricia White, Ph.D. (2009 and 2011 ERG), with Hearing Restoration Project member and Harvard Medical School professor Albert Edge, Ph.D., and team have been able to regrow the sensory hair cells found in the mouse cochlea. The study, published in the European Journal of Neuroscience on Sep. 30, 2018, builds on White’s prior research that identified a family of receptors called epidermal growth factor (EGF) that is responsible for activating supporting cells in the auditory organs of birds. When triggered, these cells proliferate and foster the generation of new sensory hair cells. In mice, EGF receptors are expressed but do not drive regeneration of hair cells, so it could be that as mammals evolved, the signaling pathway was altered.
The new study aimed to unblock the regeneration of hair cells and also integrate them with nerve cells, so they are functional, by switching the EGF signaling pathway to act as it does in birds. The team focused on a specific receptor called ERBB2, found in supporting cells. They used a number of methods to activate the EGF signaling pathway: a virus targeting ERBB2 receptors; mice genetically altered to overexpress activated ERBB2; and two drugs developed to stimulate stem cell activity in the eye and pancreas that are already known to activate ERBB2 signaling. The researchers found that activating the ERBB2 pathway triggered a cascading series of cellular events: Supporting cells began to proliferate and started the process of activating other neighboring stem cells to lead to “apparent supernumerary hair cell formation,” and these hair cells’ integration with the network of neurons was also supported. —University of Rochester
Age Effects on Speech Recognition
Age-related changes in perceptual organization have received less attention than other potential sources of decline in hearing ability. Perceptual organization is the process by which the auditory system interprets acoustic input from multiple sources to create an auditory scene. In daily life this is essential, because speech communication occurs in environments in which background sounds fluctuate and can mask the intended message.
Perceptual organization includes three interrelated auditory processes: glimpsing, speech segregation, and phonemic restoration. Glimpsing is the process of identifying recognizable fragments of speech and connecting them across gaps to create a coherent stream. Speech segregation refers to the process where the glimpses (speech fragments) are separated from background speech, to focus on a single target when the background includes multiple talkers. Phonemic restoration refers to the process of filling in missing information using prior knowledge of language, conversational context, and acoustic cues.
A July 2018 study in The Journal of the Acoustical Society of America by William J. Bologna, Au.D., Ph.D., Kenneth I. Vaden, Jr., Ph.D. (2015 ERG), Jayne B. Ahlstrom, M.S., and HHF board of directors member Judy R. Dubno, Ph.D. (1986–88 ERG), investigated these components to determine how their declines may contribute to increased speech recognition difficulty with age. As expected, older adults performed more poorly than younger adults. Older adults were less able to make use of limited speech information and reduced continuity. A competing talker created hearing challenges regardless of age. The study concludes, “Taken together, these results suggest that age-related declines in speech recognition may be partially explained by difficulty grouping short glimpses of speech into a coherent message.” —Elizabeth Crofts
Healthy Diet May Lower Risk of Hearing Loss in Women
Roland Eavey, M.D. (1987–88 ERG), the chair of the otolaryngology department at Vanderbilt University coauthored a report in The Journal of Nutrition on May 11, 2018, that showed women with healthier diets had a lower risk of hearing loss. The healthier diets emphasized fruits, vegetables, fish, seafood, nuts, beans, legumes, and olive oil over dairy, meat, and poultry. The longitudinal study spanning 22 years and including more than 70,000 women showed those with a better eating habits cut their risk for moderate or worse hearing loss by 30 percent. —Yishane Lee
RNA Injection Restores Hearing in Guinea Pigs
The CEO of Oklahoma’s Hough Ear Institute and a 26-year U.S. Army veteran, Richard Kopke, M.D. (1996 ERG), coauthored a March 2018 paper in Molecular Therapy about the use of small interfering RNAs (siRNAs) to block the activity of the Notch signaling pathway gene Hes1. Hes1 has been shown to itself block supporting cells from converting into hair cells. The team found that a sustained release of siRNAs in mouse cochleae through nanoparticles after deafening resulted in the recovery of some hearing ability, measured using auditory brainstem responses. Compared with the control mice, the 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. —Y.L.
Simple Treatment May Minimize Hearing Loss Caused by Loud Noises
John Oghalai, M.D. (a 1996–97 ERG scientist), of the University of Southern California, coauthored a May 7, 2018, study in the Proceedings of the National Academy of Sciences showing promise for preventing noise-induced hearing loss. Using a mouse model, the investigators found that in addition to immediate hair cell death after loud noise exposure, a fluid buildup in the inner ear occurs, eventually leading to nerve cell loss. Because the extra fluid shows a high potassium level, the researchers saw a method to rebalance the fluid by injecting a salt and sugar solution into the ear. Nerve cell loss was reduced by 45 to 64 percent, which the team says may preserve hearing. The team sees future applications for military service members exposed to blast trauma and patients with the hearing and balance disorder Ménière’s disease. —Y.L.
Anthony Ricci, Ph.D. (1999–2000 ERG), a professor of otolaryngology–head and neck surgery at Stanford University, and Alan Cheng, M.D. (2002–03 ERG), a Stanford associate professor of otolaryngology, are developing a new type of aminoglycosides, a widely used, life-saving class of antibiotic that fights a broad range of serious infections and diseases such as cystic fibrosis and tuberculosis, but that also has the side effect of hearing loss in one in five patients. The pair have been collaborating since 2008, leveraging Ricci’s knowledge of mechanotransduction (how sound wave vibrations are converted into electrical signals) and ion channels. Of the 18 potential replacement antibiotics they created, three show the most promise for preserving hearing while remaining effective in killing bacteria and will be tested further. —Y.L.
Moving Toward a Future Free of Drug-Induced Hearing Loss
A special publication orchestrated by five of the nation’s leading hearing experts compiles the latest research into hearing loss caused by drugs and solvents—how it occurs, how to treat it, and how to prevent it.
A free e-book comprising 23 scientific articles from 93 authors, “Cellular Mechanisms of Ototoxicity” was published by Frontiers in Cellular Neuroscience in March 2018. “We’re trying to elevate ways for the human population to avoid losing this important sensation for experiencing and communicating with the world around us,” says co-editor Peter Steyger, Ph.D. (1995–96 ERG), a professor of otolaryngology–head and neck surgery in the Oregon Health & Science University (OHSU) School of Medicine. A member of HHF’s Council of Scientific Trustees, Steyger lost hearing at age 14 months after being treated with antibiotics for meningitis.
“Ototoxicity is a threat to hearing at any age, and hearing loss remains a significant side effect of chemotherapy,” says co-editor Jian Zuo, Ph.D., of St. Jude Children’s Research Hospital in Memphis, Tennessee. Additional editors included experts from the Department of Defense Hearing Center of Excellence and the National Institute on Deafness and Other Communication Disorders. —OHSU News