Jennifer Stone, Ph.D.

Member: Hearing Restoration Project
Current Institution: University of Washington School of Medicine
Education: Skidmore College, B.A. in Biology and Studio Art Boston University School of Medicine, Ph.D. in Anatomy and Neurobiology

The Stone Lab

What is your area of focus?
The major goal of our research is to develop a biological therapy for hearing and balance deficits through hair cell regeneration, using two approaches: First, we study chickens, which are able to replace all of the hair cells in the inner ear after damage and regain hearing and balance functions. Then, we study adult mice, which can replace about one in five hair cells in their balance organs. Using these approaches, we are identifying signals that direct the formation of new hair cells in mature birds and rodents. Some signals may ultimately be effective in promoting hair cell regeneration and restoring hearing in humans.

If you had not become a researcher what would you have done?
At one point, I wanted to be a dentist, like my father. I worked with him in high school, and I loved spending time with patients and watching him work. I also love architecture—a great blend of art and science. In some ways what I am doing blends both interests: helping people and learning how the architecture of the human body is regenerated after damage.

Why did you decide to get into scientific research?
In college, I was a studio art major, drawn to the beauty of nature and the human form. Along the way, I was encouraged to explore biology because it is aesthetically appealing and has many secrets to unlock. After college, I spent two years doing neuroscience research at Beth Israel Hospital in Boston, and this experience pushed me to become a scientist.

Why hearing research? What is the most exciting part of your research?
A few things drew me to the inner ear. One was the intricacy and beauty of hair cells, the sensory receptor cells used for hearing and balance. Second, I met my graduate studies mentor, Douglas Cotanche, Ph.D., at Boston University School of Medicine. At that time and along with a few other scientists, Doug had recently discovered hair cell regeneration in birds. It wasn’t until I wrote my first application for funding that I began to appreciate how many people are affected by hearing and balance disabilities. A lack of media attention has meant a general unawareness about these disorders. As for the most exciting—it’s hard to choose! It’s thrilling when, after a long period of trying
to solve a technical or conceptual problem, the solution emerges and it is unexpected! I also
love to watch young scientists fall in love with research and begin to form their own ideas
and make discoveries.

What has been a highlight of your career?
I was honored to receive the Burt Evans Young Investigator Award from the National Organization for Hearing Research when I became an assistant professor at the University of Washington School of Medicine. This award boosted my confidence, and I have since pushed myself even harder to be an effective researcher.

How has the collaborative effort helped your research?
Working with the HRP has “upped my game,” as I have learned so much from my colleagues about applying new techniques to my research, as well as mentoring and presenting work publicly. By collaborating with HRP investigators who have expertise different from mine—such as Neil Segil, Ph.D., and Mike Lovett, Ph.D.—my lab has more effectively utilized genomics to identify and
study signaling pathways that promote hair cell regeneration, allowing us to refine experiments and accelerate our pace toward discoveries.

What do you hope to have happen with the HRP over the next few years?
I am excited to see how the public release of HRP’s Phase I data will spur investigators around the world to take their research on hair cell regeneration in new directions. I anticipate HRP members will identify one or more drugs that can promote hair cell regeneration in mice, an important step toward stimulating regeneration in humans.

What is needed to help make HRP goals happen?
Scientists in the consortium must remain committed to working extremely hard toward figuring out mammalian hair cell regeneration, and they must receive continuous funding for these efforts. Research is not effective when it happens in fits and starts. It is going to take several years of hard work to find a safe and effective way to promote the lasting recovery of hearing in humans. I am so grateful to HHF and its donors for their continued generosity and support of my and the HRP’s research efforts. With additional funding at the same—and hopefully increased—levels, our research efforts can be accelerated significantly and ultimately lead us faster to better treatments for hearing loss and tinnitus.

Research

Featured

2022

Integrative Analysis
Seth Ament, Ph.D. (co-chair), University of Maryland
Ronna Hertzano, M.D., Ph.D. (co-chair), National Institute on Deafness and Other Communication Disorders
Albert Edge, Ph.D., Mass Eye & Ear
Stefan Heller, Ph.D., Stanford University
David Raible, Ph.D., University of Washington
Jennifer Stone, Ph.D., University of Washington

This group will take the lead on data curation and analysis. A dedicated full-time HRP analyst is working across groups to help collect and process data, thereby facilitating a broader analysis of cell states and trajectories across species. The group will start by annotating hair cell types from all species so that anyone in the field can assess what kind of hair cell their regeneration approaches may produce, while also easing identification of common hair cell genes, which will help the Cross-Species Epigenetics group. Analysis of the hair cells produced in mouse organoids will be performed as an example. The Ament lab will leverage their expertise in bioinformatics, while the Hertzano lab will continue to oversee upkeep of gEAR, with a goal of making it even easier for HRP members to post their new data and for others in the community to analyze those data. The Edge lab will take the lead on the development of organoids as a screening platform for the future. The Heller, Hertzano, Raible, and Stone labs will validate markers by in situ hybridization across species, and all working group members will help direct the analysis.

2022

2018

Epigenetics of the mouse inner ear
Michael Lovett, Ph.D., Imperial College London
David Raible, Ph.D., University of Washington
Neil Segil, Ph.D., University of Southern California
Jennifer Stone, Ph.D., University of Washington

Inner ear supporting cells from newborn mice harbor a latent capacity for some regenerative responses, but these disappear within the first few weeks of life. This observation provides an experimental window this proposal will exploit to address fundamental questions about the failure of hair cell regeneration in mammals. Specifically, we propose experiments to identify those changes in the genetic material, the chromatin, that are responsible for orchestrating the differentiation of new hair cells within the perinatal organ of Corti; and investigating the changes in the chromatin, the epigenome, that lead to the failure of regeneration in the adult inner ear.

2018

Signaling molecules controlling avian hair cell regeneration
Jennifer Stone, Ph.D., University of Washington

HRP members have spent the past three years gathering information about genes that are turned on or off after inner ear hair cell damage in the chick, fish, and mouse. Some of these genes may encode therapeutic agents that can be applied to stimulate hair cell regeneration in humans. Our HRP studies and others have found that five signaling pathways (Wnt, VEGF, BMP4, Notch, and FGF) are important regulators of hair cell regeneration in the chick cochlea (the basilar papilla). The expression and activity of these pathways change significantly after hair cell damage, and the experimental manipulation of activity in each pathway either boosts or dampens hair cell regeneration. Furthermore, each pathway shows distinct regional expression patterns in the basilar papilla, which implicates it in either mitotic regeneration or non-mitotic regeneration—two distinct ways in which hair cells are replaced after damage. Studies in other growing tissues demonstrate that these five pathways regulate one another in temporally and spatially restricted patterns, in order to coordinate cell growth, differentiation, and patterning. Thus, it is likely that any therapy leading to safe and stable hair cell regeneration will require coordinated manipulation of more than one gene or pathway in the cochlea. In this study, we propose to begin to determine how these five powerful pathways interact to enable and control hair cell regeneration in the chick basilar papilla after hair cell damage.

2018

2017

Identification of candidate regulators of hair cell regeneration in the chick cochlea and utricle
Jennifer Stone, Ph.D. University of Washington
Mark Warchol, Ph.D. Washington University in St. Louis

This project has two components. In the first, the investigators will focus on validation of miRNA-seq data recently acquired by the HRP consortium; these new experiments will determine whether the genomics experiments accurately reflected miRNA fluctuations in the tissue, and may suggest candidate miRNA modulators of hair cell regeneration. In the second component, this project will test which specific signaling pathways are important for the proliferation of supporting cells and the regeneration of hair cells using pharmacological approaches.

2017

Epigenetics of mouse inner ear maturation and transdifferentiation
Neil Segil, Ph.D. University of Southern California
Jennifer Stone, Ph.D. University of Washington
Michael Lovett, Ph.D. Imperial College London
David Raible, Ph.D. University of Washington

Many genes are turned off by chemical modifications (epigenetic marks) that prevent activation of the gene. One hypothesis is that mammals cannot activate a hair cell regeneration program after the first few postnatal days because the responsible genes have been epigenetically silenced. This second-year project looks at these epigenetic marks in the ear for every gene, during both early and late development. The investigators will use this analysis to find candidate promoter regions, which control gene activity. Preliminary data support the idea that supporting cells turn off expression of key hair cell genes (e.g., Atoh1), and so a plausible approach to triggering regeneration in the mammalian ear is to reverse such changes.

2017

Transcriptomics-based analysis of hair cell regeneration in non-mammals
Stefan Heller, Ph.D. Stanford University
Tatjana Piotrowski, Ph.D. Stowers Institute for Medical Research
Jennifer Stone, Ph.D. University of Washington
Mark Warchol, Ph.D. Washington University in St. Louis
Michael Lovett, Ph.D. Imperial College London

In this third-year project, we will disrupt hair cells, then analyze how gene expression changes in single cells from species that show robust hair cell regeneration. Heller’s lab will examine the consequences of aminoglycoside damage at the single-cell level in the chick utricle, while the Piotrowski lab will examine fish lateral-line cells. In another component, the project will add two time points to the chick cochlea and utricle bulk RNA-seq datasets that were generated by Lovett and Warchol and which are extremely valuable datasets for the HRP consortium.

2017

2016

An epigenetic framework for regulating HC regeneration
David Raible, Ph.D. University of Washington
Neil Segil, Ph.D. University of Southern California
Jennifer S. Stone, Ph.D. University of Washington

Many genes are turned off by chemical modifications (epigenetic marks) that prevent activation of the gene. One hypothesis is that mammals cannot activate a hair cell regeneration program after the first few postnatal days because the responsible genes have been epigenetically silenced. This project uses HRP data that looks at these epigenetic marks in the ear for every gene, both during early and late development. The investigators will use this analysis to find candidate promoter regions, which control gene activity. Candidate genetic sequences from the mouse experiments will then be tested in zebrafish. These experiments will allow us to better understand how key hair cell regeneration genes are controlled.

2016

A cross-species approach toward functional testing for hair cell regeneration
Andy Groves, Ph.D. Baylor College of Medicine
David Raible, Ph.D. University of Washington
Jennifer S. Stone, Ph.D. University of Washington

This multi-modal, cross-species analysis project allows the HRP to test the role of molecules identified in our previous and ongoing experiments. Experience gained in the first year has led to first screening pathway inhibitors in chicks, then validating these initial hits by generating gene knockouts in zebrafish using CRISPR technology. Targets that pass both screens will then be assessed in the mouse. This project exemplifies the consortium’s shift toward Phase II of the HRP’s strategic research plan.

2016

RNA-seq analysis of vestibular supporting cells during hair cell regeneration in adult mouse vestibular organs
Neil Segil, Ph.D. University of Southern California
Jennifer S. Stone, Ph.D. University of Washington

Because the adult mouse utricle, a vestibular organ, shows limited hair cell regeneration, the investigators will examine which genes are active in supporting cells that allow this activity. They will first complete RNA-seq analysis for adult mouse utricular supporting cells, to learn how gene expression is altered in these cells after hair cell damage. Second, they will perform ATAC-seq to locate regions in mouse chromatin that are altered after utricle damage, and correlate these data with RNA-seq results. Finally, they will define genes that are only expressed in type I or type II vestibular hair cells, which will help them determine strategies to promote regeneration of both cell types after damage in adult mammals. The data they generate from these three sets of experiments will be highly useful for defining potential therapeutic strategies for hair cell regeneration in humans.

2016

Single-cell transcriptional profiling of chicken utricle and basilar papilla sensory epithelium cells after aminoglycoside-induced hair cell loss
Stefan Heller, Ph.D. Stanford University School of Medicine
Jennifer S. Stone, Ph.D. University of Washington
Michael Lovett, Ph.D. Imperial College London
Mark Warchol, Ph.D. Washington University School of Medicine

The broad premise of the HRP is to identify molecules that could control hair cell regeneration. To do this, we are studying cell types and regenerative processes in multiple contexts and species, then integrating these data together to identify mechanisms that could potentially be turned on in the mouse cochlea to drive transdifferentiation (activating the correct set of hair cell–promoting genes in supporting cells). The role of this systems biology project is to provide the necessary data integration “glue,” binding together the results from the data generation projects. We will combine much of the data that is being generated by the HRP to advance our knowledge of hair cells, supporting cells, conversion of one cell type to another, and the potential for regeneration. By modeling all of the available HRP data, we will identify regulatory molecules that may contribute to regeneration.

2016

Jennifer Stone, Ph.D.

Research

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