Tatjana Piotrowski

HHF Scientists to Speak at New York Academy of Sciences Symposium

By Lauren McGrath

Hearing Health Foundation (HHF)’s Hearing Restoration Project (HRP) — the first international research consortium dedicated to investigating hair cell regeneration as a cure for hearing loss — was founded on the premise that collaboration is the key to innovation. “Although there is a romantic picture of a scientist slaving away in isolation, toiling toward ‘eureka’ moments, science works best with communication and sharing ideas,” says David Raible, Ph.D., an HRP consortium member based at University of Washington.

Peter Barr Gillespie, Ph.D., and Tatjana Piotrowski, Ph.D., of Hearing Health Foundation’s Hearing Restoration Project

Peter Barr Gillespie, Ph.D., and Tatjana Piotrowski, Ph.D., of Hearing Health Foundation’s Hearing Restoration Project

The New York Academy of Sciences (NYAS)’s Hearing Restoration and Hair Cell Regeneration symposium on Tuesday, October 8, will provide members of the HRP and other world-renowned hearing scientists an opportunity to collaborate as Raible describes. During an all-day event in New York City, auditory experts will convene to review recent advancements in the field, identify knowledge gaps, and outline future directions toward hearing loss cures.

The HRP and other scientists worldwide are dedicated to permanent cures for sensorineural hearing loss, which occurs when the sensory cells (hair cells) in the inner ear are damaged. “Current treatments for hearing loss including hearing aids and cochlear implants provide substantial benefits for many patients, but also have significant shortcomings and new options are needed,” explains Marie Samanovic-Golden, Ph.D., Program Manager, Life Sciences at NYAS.

The symposium is part of the NYAS’s well-respected Biochemical Pharmacology Discussion Group’s portfolio. To develop a robust agenda for this symposium, which is at the cutting-edge of the latest research and therapeutic developments on hair cell regeneration to restore age-related hearing loss, the Academy assembled a diverse Scientific Organizing Committee of eight experienced experts, including scientific researchers from both Academia and Industry. The Committee collaboratively developed the scientific agenda and learning goals for this conference and identified the best researchers in this field who were subsequently invited to speak at the symposium.

The full-day seminar will feature presentations from two prominent hearing loss researchers funded by HHF through the HRP: Peter Barr-Gillespie, Ph.D., and Tatjana Piotrowski, Ph.D., along with six other subject matter experts. Barr-Gillespie, the keynote speaker, will delve into the molecular basis of hair cell mechanotransduction unique to sensory hair cells and essential for hearing. He was also selected to discuss his current roles with Oregon Health & Science University and the HRP.

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Piotrowski was selected to present her latest findings in zebrafish, which — unlike humans — have been shown to have the ability to regenerate lost sensory hair cells. Her basic research on zebrafish is essential to map out how human’s regenerative abilities might be triggered towards a cure for deafness.

NYAS Scientific Organizing Committee member Michael Franti, Ph.D., Director of Regenerative Medicine Research Beyond Borders and Boehringer Ingelheim Pharmaceuticals, Inc., looks forward to the impact of the symposium. “Hearing loss affects an estimated 360 million people worldwide. The process of repairing hearing is a complex problem and regenerative therapies hold promise in novel treatments for deafness. Identifying the key aspects in hair cell regeneration is necessary to get us closer to a cure for hearing loss,” Franti says.

The Hearing Restoration and Hair Cell Regeneration symposium is open to the public. Constituents of HHF may register for a discounted fee using the promo code “HHF” after selecting “non-member academia.” The event will also be broadcast by webinar, for which details will follow. To learn more about the symposium or register as an attendee, see the event page.

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Single-Cell RNA Sequencing Reveals More Clues for Hair Cell Regeneration

By Mark E. Lush, Ph.D., and Daniel C. Diaz

Sensorineural hearing loss in mammals can often be attributed to damage or destruction of the delicate hair cells located within the inner ear. The microscopic hairlike projections on the surface of these cells are the key structure responsible for converting sound waves to electrical signals that travel to the brain through the auditory nerve. Unlike mammals, other vertebrates such as fish, birds, and reptiles routinely regenerate sensory hair cells during homeostasis and following injury. By studying the genetic program of hair cell regeneration in nonmammalian vertebrate organisms, researchers may discover therapeutic targets for treating hearing loss in humans.

The lateral line is a sensory system that allows aquatic vertebrates to orient themselves by detecting water motion. The lateral line organs (neuromasts), distributed on the head and along the body, contain approximately 60 cells, composed of central sensory hair cells surrounded by support cells and an outer ring of mantle cells. Using single-cell RNA sequencing, we combined some of the less well-defined clusters and identified major neuromast cell types, shown in this illustration, ranging from support cells to mature sensory hair cells. Credit: The lab of Tatiana Piotrowski, Ph.D., Stowers Institute for Medical Research, Kansas City

The lateral line is a sensory system that allows aquatic vertebrates to orient themselves by detecting water motion. The lateral line organs (neuromasts), distributed on the head and along the body, contain approximately 60 cells, composed of central sensory hair cells surrounded by support cells and an outer ring of mantle cells. Using single-cell RNA sequencing, we combined some of the less well-defined clusters and identified major neuromast cell types, shown in this illustration, ranging from support cells to mature sensory hair cells. Credit: The lab of Tatiana Piotrowski, Ph.D., Stowers Institute for Medical Research, Kansas City

One such organism, the zebrafish, has emerged as a powerful model for studying sensory hair cell regeneration. Like other fish, zebrafish contain a network of sensory hair cells throughout their body to detect changes in water movement. The hair cells are located in small organs in the skin called neuromasts, which also contains cell types that are remarkably similar to those found in the mammalian inner ear. To study the genetic program of hair cell regeneration in zebrafish, we sequenced the RNA of individual cells within neuromasts, allowing us to classify cell types based on their gene expression signature. This included cells transitioning from support cells to fully mature sensory hair cells, thereby identifying new genes that are expressed during hair cell development. In addition, we characterized the role of the growth factor fgf3, and found that it acts to inhibit hair cell progenitor proliferation. Our results were published in the journal eLife on Jan. 25, 2019. Future work will examine the function of these genes in sensory hair cell regeneration.

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Mark E. Lush, Ph.D., and Daniel C. Diaz both work in the lab of Tatjana Piotrowski, Ph.D., at Stowers Institute for Medical Research in Kansas City. Piotrowski is a member of the Hearing Restoration Project, which helped fund this study.

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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

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.

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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.

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.

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.

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