By Peter Barr-Gillespie, Ph.D.
The annual meeting of Hearing Health Foundation’s (HHF) Hearing Restoration Project (HRP) was held in Seattle Dec. 12–14, 2019. As always, we use this extended in-person meeting to discuss in detail the progress of the consortium over the past year and to develop our plan for the upcoming year.
From the lab of Stefan Heller, Ph.D., this image shows a transverse section through the middle of an embryonic day 20 chicken cochlea that shows neuronal connections to hair cells colored green and red. Spherical green structures are the nerve cell bodies. Courtesy of Amanda Janesick and Stanford Otolaryngology Imaging Core Facility.
In 2016 the HRP developed the Seattle Plan, in which we shifted our focus on what the consortium does best: cross-species comparisons of inner ear sensory hair cells and their ability to regenerate, or not. These studies contrast molecular responses to hair cell damage in species that regenerate their hair cells (such as birds and fish) with animals that do not (all mammals including mice and humans).
We also directed considerable resources to determine the epigenetic structure of key genes in the mouse. Epigenetic modifications are chemical changes to DNA that affect whether a gene is “turned on” or “turned off.” Our evidence shows that, in the cells we intend to target to make new hair cells, mouse ears turn off key hair cell genes using epigenetic changes, preventing us from regenerating their hair cells. The goal of the Seattle Plan is to use the information coming from this concerted effort to understand how to develop a strategy to regenerate hair cells in mammals.
Stefan Heller, Ph.D., and Tatjana Piotrowski, Ph.D., reported considerable progress on the first major goal, showing the damage response in birds (Heller’s lab) and fish (Piotrowski’s lab). Their single-cell transcriptomics experiments allow us to see the molecular events that occur in both hair cells and supporting cells as the hair cells die, are removed, and then are replaced by supporting cells. The data from these experiments are extremely thorough. While they will require considerably more analysis to understand, the data will ultimately give us a vivid picture of how genes are regulated during hair cell regeneration.
Neil Segil, Ph.D., shared that his work on the mouse—examining the epigenetic changes occurring in the inner ear during development, as well as in very young cochlear cells that do show some regeneration—is nearly complete and will be submitted for publication soon. These data crucially reveal one aspect of why hair cells do not regenerate in the adult mouse hearing organ and suggest some therapeutic approaches that may form part of a hair cell regeneration strategy. Reversing the epigenetic block will be essential to coax the mouse supporting cells within the cochlea to convert to hair cells.
Seth Ament, Ph.D., discussed the bioinformatics analyses of these cross-species comparisons, a crucial aspect of the Seattle Plan. His group has shown key gene regulatory networks active during development of hair cells; these gene networks may need to be activated if we are to stimulate hair cell regeneration in adult mammalian cochleas. Ament will be working closely with Heller, Piotrowski, Segil, and others to carry out further bioinformatics dissection of our data.
Ronna Hertzano, M.D., Ph.D., shared the ongoing progress of the gEAR website tools, which enable HRP consortium members and other auditory researchers to share, analyze, and compare datasets from many different types of experiments. The gEAR is easy to use and now contains many—if not most—datasets from experiments using the auditory system and is designed for the easy addition of additional datasets. The gEAR website will continue to be a major tool for knitting together the disparate data that the HRP consortium has generated.
John Brigande, Ph.D., presents his research at the December 2019 Hearing Restoration Project meeting.
John Brigande, Ph.D., reviewed the success using i-GONAD, a rapid way to inactivate or modify any gene using the CRISPR/Cas9 genome editing approach. i-GONAD will allow Brigande to screen dozens of genes per year to determine whether inactivation can augment regeneration strategies. He discussed additional methods that will allow us to activate genes, a strategy that may be required in order to regenerate hair cells.
As a group we decided the Seattle Plan will require at least one more year to gather and analyze all of the data needed for a complete comparison of the damage response in chick and fish compared with the damage response in mice. Our effort will focus on rounding out the data we need for this analysis. We have complete datasets for the chick and fish responses to hair cell death, as well as a thorough description of the epigenetic events that transpire in the mouse during inner ear development. But our understanding of how supporting cells in the mouse cochlea respond—or don't—to the loss of hair cells, especially in adult mice, is limited.
Moreover, we are only now beginning to compare the damage response in human inner ear tissues (in this case, the utricle, a vestibular organ) to that of the mouse. Demonstrating similarities will justify the continued use of the mouse as a model system. We expect that the upcoming year will fill in these gaps, allowing us to identify the next steps in the Hearing Restoration Project’s goal of developing therapies for hearing loss.
HRP scientific director Peter G. Barr-Gillespie, Ph.D., is a professor of otolaryngology and a chief research officer and executive vice president at Oregon Health & Science University. For more, see hhf.org/hrp.
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