Peter Barr-Gillespie

Hearing Restoration Project Scientific Director to Lead University’s Research Enterprise

By Tamara Hargens-Bradley, OHSU News

OHSU/Kristyna Wentz-Graff

OHSU/Kristyna Wentz-Graff

Peter Barr-Gillespie, Ph.D., will be Oregon Health & Science University’s (OHSU) first chief research officer and executive vice president, effective Jan. 1, 2019. Barr-Gillespie has served as interim senior vice president for research at OHSU since 2017.

In his new role, Barr-Gillespie will be principal adviser to OHSU President Danny Jacobs, M.D., FACS, on research strategy and research resource allocation. He will lead and manage OHSU’s research enterprise—comprising dozens of internationally and nationally acclaimed basic, translational, clinical, and public health research programs—and serve on the president’s executive leadership team.

“Dr. Barr-Gillespie has done a tremendous job leading the OHSU research mission on an interim basis. I’m delighted to appoint him to a new, permanent position that reflects his contributions and capabilities as well as the vital role of research at OHSU,” Jacobs says.

Barr-Gillespie also will collaborate with external academic, industrial and community research partners, and the various funding, regulatory and accrediting bodies. Moreover, he will represent OHSU in research collaborations with other universities in Oregon and the northwest region.

“I am excited to support Dr. Jacobs in developing OHSU’s 2025 strategic plan for research,” Barr-Gillespie says. “To be among the top-ranked research universities for NIH funding in the country and maintain our national reputation for cutting-edge research, we need to empower our researchers to do their best science by smartly investing in people, core resources, and space, and enhancing our graduate programs.”

OHSU/Kristyna Wentz-Graff

OHSU/Kristyna Wentz-Graff

Barr-Gillespie is an internationally recognized scholar, biomedical researcher and visionary academic leader who has been on faculty at OHSU since 1999. He currently holds faculty appointments in the departments of Otolaryngology/Head and Neck Surgery, Biochemistry and Molecular Biology, and Cell and Developmental Biology in OHSU’s School of Medicine and Oregon Hearing Research Center. He also is a senior scientist in the OHSU Vollum Institute.

An NIH-funded investigator, Barr-Gillespie’s research focus, his passion, is understanding the molecular mechanisms that enable our sense of hearing. Specifically, the Barr-Gillespie lab endeavors to determine how sensory cells in the inner ear called hair cells allow humans to perceive sound. Barr-Gillespie will maintain his active research program while serving as chief research officer.

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Barr-Gillespie is also the scientific director of the Hearing Restoration Project (HRP), an international consortium of 14 investigators funded by Hearing Health Foundation. The HRP’s goal is to develop a biological therapy for hearing loss arising from destruction of hair cells, which are not regenerated after damage from noise, ototoxic drugs, or aging.

Barr-Gillespie earned his bachelor’s degree in chemistry from Reed College in 1981, carrying out his senior undergraduate thesis at OHSU after a summer fellowship in OHSU’s biochemistry department. He received his doctorate in pharmacology at the University of Washington in 1988, and completed a postdoctoral fellowship in physiology, cell biology and neuroscience with Jim Hudspeth, M.D., Ph.D., at the University of California San Francisco and the University of Texas Southwestern Medical Center in 1993.

Following his fellowship, he accepted a faculty position in physiology at Johns Hopkins and remained there until accepting the position of scientist at the OHSU Vollum Institute and associate professor of otolaryngology/head and neck surgery in the OHSU School of Medicine in 1999. In 2014, Barr-Gillespie was appointed associate vice president for basic research at OHSU.

As a young investigator, Barr-Gillespie was named a Pew Scholar in Biomedical Sciences, a program that funds research “that shows outstanding promise in science relevant to the advancement of human health.” During his tenure at OHSU, he has been honored with the Faculty Excellence in Education Award and the John A. Resko Faculty Research Achievement and Mentoring Award.

Over his distinguished career, he has published more than 115 scholarly articles, chapters, and reviews, and has been an invited lecturer at dozens of research universities, academic conferences, and scientific events.

Barr-Gillespie and his wife, Ann Barr-Gillespie, D.P.T., Ph.D., live in Portland. She is the vice provost and executive dean of the College of Health Professions at the Pacific University Hillsboro campus. Their children are Aidan Gillespie, 17, and Katie Gillespie, 24, whom Peter and Ann share with their mother, Susan Gillespie. In their spare time, Peter and Ann enjoy cycling and hiking.

This is republished with permission from OHSU News.

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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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The Hearing Restoration Project: Update on the Seattle Plan and More

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

Hearing Health Foundation launched the Hearing Restoration Project (HRP) to understand how to regenerate inner ear sensory cells in humans to restore hearing. These sensory hair cells detect and turn sound waves into electrical impulses that are sent to the brain for decoding. Once hair cells are damaged or die, hearing is impaired, but in most species, such as birds and fish, hair cells spontaneously regrow and hearing is restored.

The overarching principle of the HRP consortium is cross-discipline collaboration: open sharing of data and ideas. By having almost immediate access to one another’s data, HRP scientists are able to perform follow-up experiments much faster, rather than having to wait years until data is published.

Regenerated hair cells from chicken auditory organs, with the cell body, nucleus and hair bundle labeled with various colored markers. Image courtesy of Jennifer Stone, Ph.D.

Regenerated hair cells from chicken auditory organs, with the cell body, nucleus and hair bundle labeled with various colored markers. Image courtesy of Jennifer Stone, Ph.D.

You may remember that two years ago, we changed how we develop our projects. We decided together on a group of four projects—the “Seattle Plan”—that are the most fundamental to the consortium’s progress. These projects, which grew out of previous HRP projects, have now been funded for two years, and considerable progress has been made. We have also funded several other projects that have bubbled up out of new observations and capabilities, and they have added considerably to our knowledge base. With this in mind, I am pleased to share with you the latest updates for our 2018–19 projects.

SEATTLE PLAN PROJECTS

Transcriptome changes in single chick cells
Stefan Heller, Ph.D.

  • Found that all “tall” hair cells are exclusively regenerated mitotically in this animal model.

  • Compiled evidence for different supporting cell subtypes.

  • Obtained good quality single cell RNA sequencing (scRNA-seq) data and are in the process of evolving an analysis strategy for the baseline cell types (control group). Identified about 50 novel marker genes for hair cells, supporting cells, and homogene cells, including subgroups.

  • Developed a strategy to finish all scRNA-seq using a novel peeling technique and latest generation library construction methods.

  •  Established two methods for multi-color in situ hybridization (PLISH, proximity ligation in situ hybridization) and SGA (sequential genomic analysis) for spatial and temporal mRNA expression validation.

Epigenetics of the mouse inner ear
Michael Lovett, Ph.D., David Raible, Ph.D., Neil Segil, Ph,D., Jennifer Stone, Ph.D.

  • Completed epigenetic, chromatin structure, and RNA-seq datasets for FACS-purified cochlear hair cells and supporting cells from postnatal day 1 and postnatal day 6 mice, and provision of these data sets to the gEAR (gene Expression Analysis Resource portal) for mounting on their webpage through EpiViz for access by the HRP consortium.

  • Established a webpage (EarCode) so that HRP consortium members can access the current data directly through a University of California, Santa Cruz, genome browser.

  • Discovered maintenance of the transcriptionally silent state of the hair cell gene regulatory network in perinatal supporting cells is dependent on a combination of H3K27me3 and active H3k27-deacetylation, and that during transdifferentiation, these epigenetic marks are modified to an active state.



Mouse functional testing
John Brigande, Ph.D.

  • Defined in vitro and in vivo model systems to interrogate genome editing efficacy using CRISPR/Cas9.

Implementing the gEAR for data sharing within the HRP
Ronna Hertzano, M.D., Ph.D.

  • Added scRNA-seq workbench for easy sharing and viewing of scRNA-seq data. Such data, which are now driving the field forward, have been particularly difficult to share

  • Created additional public datasets to improve data sharing.

  • Completely rewrote the gEAR backbone to be updated to the latest technologies, allowing the portal to now to handle a much larger number of datasets and users.

  • Performed hands-on gEAR workshops at the Association for Research in Otolaryngology and the Gordon Research Conference, increasing the number of users with accounts to greater than 300.


Single Cell RNA-seq of homeostatic neuromasts
Tatjana Piotrowski, Ph.D.

  • Optimized protocols for fluorescent-activated cell sorting and scRNA-seq; obtained high quality scRNA-seq transcriptome results from 1,400 neuromast cells; clustered all cells into seven groups; and performed analyses to align the cells along developmental time, providing a temporal readout of gene expressions during hair cell development.

OTHER PROJECTS

Integrated systems biology of hearing restoration
Seth Ament, Ph.D.

  • Discovered 29 novel risk loci for age-related hearing difficulty through new analyses of genome-wide association studies of multiple hearing-related traits in the U.K. Biobank (comprising 330,000 people), and predicted the causal genes and variants at these loci through integration with transcriptomics and epigenomics data from HRP consortium members.

  • Generated scRNA-seq of 9,472 cells in the neonatal mouse cochlea and utricle (postnatal days 2 and 7).

  • Conducted systems biology analyses that integrate multiple HRP datasets to characterize gene regulatory networks and predict driver genes associated with the development and regeneration of hair cells. These analyses utilize scRNA-seq of sensory epithelial cells in mouse, chicken, and zebrafish hearing and vestibular organs, as well as epigenomic data (ATAC-seq) from hair cells, support cells, and non-epithelial cells in the mouse cochlea.


Comparison of three reprogramming cocktails
Andy Groves, Ph.D.

  • Created and validated transgenic mouse lines expressing three different combinations of reprogramming transcription factors.

  • Demonstrated these lines can produce new hair cell–like cells in the undamaged and damaged cochlea of the immature mouse.

  • Compiled preliminary data showing Atoh1 and Gfi1 genes can create ectopic hair cells in the adult mouse cochlea.


Signaling molecules controlling avian auditory hair cell regeneration
Jennifer Stone, Ph.D.

  • Identified four molecular pathways (FGF, BMP, VEGF, and Wnt) that control hair cell regeneration in the bird auditory organ. These pathways were identified in Phase I (gene discovery) as being transcriptionally dynamic in birds, fish, and mice during regeneration, which indicated they may be universal regulators of hair cell regeneration.

  • Determined that the Notch signaling pathway (a powerful inhibitor of stem cells) also blocks supporting cell division in the chicken auditory organ after damage. This discovery shows that Notch is a negative regulator of regeneration, conserved in birds, fish, and mice.

  • Identified signaling molecules in birds that are correlated with either mitotic or non-mitotic modes of hair cell regeneration, and are now exploring how these signaling molecules interact to determine which mode of regeneration occurs. Since mammals only exhibit non-mitotic regeneration, we are particularly interested in determining how this mode is controlled.

UP NEXT

We look forward to our annual meeting, which will be held in Seattle in November. There we will discuss and integrate these data to develop our plans for our 2019–20 projects.

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As always we are very grateful for the donations we receive to fund this groundbreaking research to find better treatments for hearing loss and related conditions. Every dollar counts, and we sincerely thank our supporters.

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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