On a Data-Driven Mission

By Peter G. Barr-Gillespie, Ph.D.

The annual meeting of Hearing Health Foundation’s (HHF) Hearing Restoration Project was held in Seattle November 11-12, 2018. We used this meeting to update one another on recent progress on HHF-funded projects, discuss in detail the implications of new data, evaluate the directions of ongoing projects, and plan for the next funding period.

As you may recall, in November 2016 the Hearing Restoration Project (HRP) made a deliberate turn toward funding only the highest-impact science that our group leads the world in researching—we have termed this the “Seattle Plan.” We therefore devoted a substantial portion of our efforts to cross-species comparisons that contrast molecular responses to inner ear sensory hair cell damage in species that regenerate their hair cells, especially chickens and fish, with responses in mice, which like other mammals do not regenerate their hair cells. We also have been examining the “epigenetic” structure of key genes in the mouse, as one hypothesis is that epigenetic modifications of the DNA—that is, the inactivation of genes through chemical changes to the DNA—causes mouse (and human) cells of the cochlea to no longer respond to hair cell damage by regenerating hair cells.

Avian and mammal supporting cell subtypes differ, but Stefan Heller, Ph.D., and team are investigating if an evolutionary homogenous equivalent exists in the organ of Corti, and if this knowledge could be used for hair cell regeneration. Credit: Chris Gralapp / Otolaryngology Head and Neck Surgery (OHNS) - Stanford University School of Medicine

I am happy to report that progress over the past two years on these two major projects has been outstanding. For the cross-species comparisons, Stefan Heller, Ph.D., and Tatjana Piotrowski, Ph.D., reported on single cell analysis of, respectively, chick and fish hair cell organs responding to damage. Using single cell analysis—isolating hundreds to thousands of individual cells and quantifying all of the protein-assembly messages they express—we can determine the molecular pathways by which hair cells are formed during development and regeneration. This approach has always been promising, but this year we have begun to reap the expected benefits, as those projects have given us an unprecedented view of hair cell formation.

The epigenetics project overseen by Neil Segil, Ph.D., has now reached maturity, and using the voluminous data acquired over the past several years his lab has shown how supporting cells (from which we intend to regenerate hair cells) change the epigenetic modification of their DNA so they no longer are able to switch on key genes used for turning them into hair cells. A topic of great interest at the meeting was that of genetic reprogramming: Can we use genes (like transcription factors, proteins that control the transfer of genetic information) or small molecules (which often can be taken orally and still reach their targets) to overcome the epigenetic modification and push supporting cells to turn into hair cells? Preliminary results from Segil’s lab and from others in the field make us optimistic that the reprogramming approach will eventually be part of a regeneration strategy.

We also heard from Seth Ament, Ph.D., a bioinformatics expert we recently recruited to the HRP to explicitly compare our various datasets and find the common threads between them. Ament has used gene expression data from the chick, fish, and mouse, as well as the epigenetic data from the mouse, to hypothesize which genes may be important for hair cell regeneration. As a systems biology specialist, Ament brings a fresh eye to the field of auditory science and has not only identified some of the genes we expected to be important, but new ones as well. His success nicely justifies our cross-species approach, and the bioinformatics comparisons that he has been able to achieve in his initial HRP project have been impressive.

Finally, two other Seattle Plan projects have gone well, including our data-sharing platform called the gEAR (gene Expression Analysis Resource), developed by Ronna Hertzano, M.D., Ph.D., which allows us to analyze our data privately but also to efficiently share data with the public. In addition, John Brigande, Ph.D., reported on his project developing mouse models for testing interesting new genes; his group will be adding several powerful models in the year to come.

The excitement at the meeting extended to our future plans. We agreed that the Seattle Plan was the still the proper course, and we eagerly anticipate more data and results to come from our consortium of researchers. We are truly getting a clearer picture of hair cell regeneration due to the HRP’s efforts. That said, there is a long way to go; our efforts show us how surprisingly intricate biology is, despite knowing from the start that systems like the inner ear are remarkably complex. Nature always has surprises for us, by turns dashing treasured hypotheses while revealing unexpected mechanisms. The HRP is most definitely on track for success, and all of us in the HRP sincerely thank you for your continued support.

HRP scientific director Peter G. Barr-Gillespie, Ph.D., is a professor of otolaryngology at the Oregon Hearing Research Center, a senior scientist at the Vollum Institute, and the interim senior vice president for research, all at Oregon Health & Science University. For more, see hhf.org/hrp.

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Women’s History Through the Lens of HHF

By C. Adrean Mejia

Before Women’s History Month concludes, Hearing Health Foundation (HHF) would like to highlight the accomplishments of women in science, technology, engineering, and mathematics (STEM), including those who have been instrumental to our own progress toward preventing, treating, and curing hearing loss and related conditions.

Historically, STEM has been majority male, but the growing inclusion of women in the industry is closing the gender gap. In fact, LinkedIn reports the percentage of women entering STEM roles in the last four decades is greater than that of any other professional sector. In 1978, the STEM workforce was only 10% female, while today about a third of this field is comprised of women.

Emerging Research Grants (ERG) recipient Dr. Wafaa Kaf administers a hearing screening. Credit: Missouri State University.

As individuals and as an organization that values inclusiveness, we all at HHF applaud the trend of growing opportunity for women in scientific professions, while remaining equally grateful to the male researchers and Board members who offer their commitment, support, and expertise. Our founder was a woman; 60 years ago, Mrs. Collette Ramsey Baker began a quest to find better treatments and cures for hearing and balance conditions which is championed by all today.

We would like to acknowledge the outstanding women on HHF’s Board of Directors, whose altruism and intelligence have furthered hearing research and HHF’s growth. Our Board Chair, Elizabeth Keithley, Ph.D., who has been an auditory researcher for more than 30 years, began her association with HHF as a grant reviewer. Dr. Keithley has conducted and published a number of studies related to the mechanisms of inflammation and aging on the inner ear.

From left: HHF Board Chair Elizabeth Keithley, Ph.D., and Board member Judy Dubno, Ph.D.

Board member Judy Dubno, Ph.D., professor at the Medical University of South Carolina, is considered one of the most important otolaryngology researchers in the nation. Her work has focused on auditory perception, hearing loss, and speech recognition. Dr. Dubno was also a contributor to the report that successfully urged the FDA to create a category of over-the-counter hearing aids to make hearing loss treatment more accessible to American adults.

Also serving on the Board is Ruth Anne Eatock, Ph.D., of the University of Chicago, who studies sensory signaling by hair cells and neurons in the inner ear. She was recently published in The Journal of Neuroscience for her investigation of inner ear sensory cells in rodents.

HHF is also thankful for the three female scientists who are part of our Hearing Restoration Project (HRP) consortium working to permanently cure hearing loss: Ronna Hertzano, M.D., Ph.D., Tatjana Piotrowski, Ph.D., and Jennifer S. Stone, Ph.D. Their labs at the University of Maryland, Stowers Institute for Medical Research, and the University of Washington, respectively, have uncovered valuable insights related to a biological cure for hearing loss.

Our Emerging Research Grants (ERG) program has empowered many brilliant, female researchers, including those recently published: Wafaa Kaf, Ph.D., researching new techniques to diagnose Ménière's disease; Michelle Hastings, Ph.D., investigating early genetic intervention for Usher syndrome; Elizabeth McCullagh, Ph.D., examining the connection between sound localization difficulties and Fragile X Syndrome; and Samira Anderson, Au.D., Ph.D., working to improve hearing aid fit to enhance usage.

Finally, we are fortunate to have Nadine Dehgan serving as our CEO. Ms. Dehgan plays a crucial role in our growth and programming efficiency, and her leadership experience and passion for how hearing science can better people’s lives has made her a strong fit to drive HHF forward.

HHF deeply values the work of all individuals who bring us closer to a world without hearing loss and tinnitus. For Women’s History Month, we’re honored to call special attention to the women who have been part of these life-changing efforts in the spirit of Mrs. Ramsey Baker, whose determination and selflessness still inspires us today.