Research Where Science and Art Meet: Jennifer Stone, Ph.D

Where Science and Art Meet The Hearing Restoration Project’s Jennifer Stone, Ph.D., shares how she pivoted from studio art to neuroscience, combining two passions.

The path from student to researcher is not set in stone. Most researchers take the more traditional route where they choose a field during their undergraduate years and keep with it through master’s and doctoral degrees. Then, there are others who happen upon the field and, unsuspectingly, fall in love with it.

Jennifer Stone, Ph.D., a research professor at the University of Washington, falls into the latter category. A self-described “prolific drawer” as a teenager, Stone started her college career as a studio art major at Skidmore College in New York.

Stone switched to biology after taking an introductory course she was dreading, after uninspiring experiences in high school. She found herself connecting with the professors in the department and realized biology’s potential as an outlet to continue to express her artistic side.

“One of the earliest projects I was involved in was doing scientific illustration with insects,” Stone says. She went out in the winter and collected insect nymphs from the brook near her house, then sketched them at college during January term.

Stone says she felt a connection with the faculty and biologists with whom she had studied or worked with and felt a sense of support.

“I learned that biology was a nice intersection between arts and science,” Stone says, “and I had really strong interactions with women biologists at Skidmore. Both of these features reinforced my love of biology.”

After college, she took two years to explore biomedical research, working in a lab that was studying development of the brain. At that time, her life took another turn— toward neuroscience.

After finishing graduate school at Boston University, Stone settled at the University of Washington. Stone conducts research on the sensory hair cells of the inner ear, which she calls the most beautiful cells in the body—

and continues to dabble in art, incorporating illustrations into her papers and teaching.

Today, Stone’s research is focused on regenerating hair cells in mammals during adulthood. Hair cells are required for hearing and balance because they are specialized to sense sound waves and head motions. Hair cells die as we age and when we are exposed to ototoxic drugs or high noise levels. Hearing and balance deficits arising from hair cell loss are widespread, particularly in elderly people. Both types of sensory deficit make it hard to socialize and can lead to isolation.

Hearing aids amplify sounds in the cochlea and are useful in some types of hearing loss. When hearing loss is severe or profound, cochlear implants can bypass the injured cochlea altogether and directly stimulate the nerve to allow people to hear. Investigators are also developing vestibular implants to provide relief for balance problems such as vertigo.

Opposite page: This striking microscopic view of the mouse utricle, a balance organ in the inner ear, is an example of how Hearing Restoration Project’s Jennifer Stone, Ph.D., has been able to combine her interest in science with her art (also shown on this page).

Stone conducts research on the sensory hair cells of the inner ear, which she calls the most beautiful cells in the body— and continues to dabble in art, incorporating illustrations into her papers and teaching.

“But, no treatment cures the problem—the loss of hair cells,” Stone says. “We want to find a way to do that.”

The Stone lab focuses on vestibular hair cells, which are required for balance. Although there is no natural regeneration in the auditory sensory organ (the cochlea), vestibular organs have a natural capacity to regenerate some hair cells. This process is limited, but the Stone lab is studying it carefully, with the hope of applying what they learn to promote full hair cell regeneration in both the hearing and balance organs.

While her path may have diverged from the typical model, Stone found ways to blend both of her interests, finding a place for biology and art in her career.

Jennifer Stone, Ph.D., a member of HHF’s Hearing Restoration Project, is a research professor in the University of Washington’s department of otolaryngology–head and neck surgery, where she is also the director of research. She is a 1995, 1996, and 2000 Emerging Research Grants alumnus. For more, see hhf.org/research.

This is adapted from a story by Ash Shah, the science editor of The Daily, the University of Washington’s student newspaper, at dailyuw.com.

A team of researchers has generated a developmental map of a key soundsensing structure in the mouse inner ear. Scientists at the National Institute on Deafness and Other Communication Disorders (NIDCD), part of the National Institutes of Health, and their collaborators analyzed data from 30,000 cells from mouse cochlea, the snail-shaped structure of the inner ear. The results provide insights into the genetic programs that drive the formation of cells important for detecting sounds.

The study datasets are shared on a unique platform open to any researcher, creating an unprecedented resource that could catalyze future research on hearing loss. Led by Matthew W. Kelley, Ph.D., chief of the Section on Developmental Neuroscience at the NIDCD, the study appeared online in Nature Communications on May 13, 2020. The research team includes investigators at the University of Maryland School of Medicine, Baltimore; Decibel Therapeutics, Boston; and King’s College London.

“Unlike many other types of cells in the body, the sensory cells that enable us to hear do not have the capacity to regenerate when they become damaged or diseased,” says NIDCD Director Debara L. Tucci, M.D., who is also an otolaryngology–head and neck surgeon. “By clarifying our understanding of how these cells are formed in the developing inner ear, this work is an important asset for scientists working on stem cell-based therapeutics that may treat or reverse some forms of inner ear hearing loss.”

In mammals, the primary transducers of sound are hair cells, which are spread across a thin ribbon of tissue (the organ of Corti) that runs the length of the coiled cochlea. There are two kinds of hair cells, inner hair cells and outer hair cells, and they are structurally and functionally sustained by several types of supporting cells. During development, a pool of nearly identical progenitor cells gives rise to these different cell types, but the factors that guide the transformation of progenitors into hair cells are not fully understood.

To learn more about how the cochlea forms, Kelley’s team took advantage of a method called single-cell RNA sequencing. This powerful technique enables researchers to analyze the gene activity patterns of single cells. Scientists can learn a lot about a cell from its pattern of active genes because genes encode proteins, which define a cell’s function. Cells’ gene activity patterns change during development or in response to the environment.

“There are only a few thousand hair cells in the cochlea, and they are arrayed close together in a complex mosaic, an arrangement that makes the cells hard to isolate and characterize,” Kelley says. “Single-cell RNA sequencing has provided us with a valuable tool to track individual cells’ behaviors as they take their places in the intricate structure of the developing cochlea.”

Building on their earlier work on 301 cells, Kelley’s team set out to examine the gene activity profiles of 30,000 cells from mouse cochleae collected at four time points, beginning with the 14th day of embryonic development and ending with the seventh postnatal day. Collectively, the data represents a vast

Single-cell RNA sequencing helps scientists map how sensory hair cells (pink) develop in a newborn mouse cochlea.

catalog of information that researchers can use to explore cochlear development and to study the genes that underlie inherited forms of hearing loss.

Kelley’s team focused on one such gene, Tgfbr1, which has been linked to two conditions associated with hearing loss, Ehlers-Danlos syndrome and Loeys-Dietz syndrome. The data showed that Tgfbr1 is active in outer hair cell precursors as early as the 14th day of embryonic development, suggesting that the gene is important for initiating the formation of these cells.

To explore Tgfbr1’s role, the researchers blocked the Tgfbr1 protein’s activity in cochleae from 14.5-day-old mouse embryos. When they examined the cochleae five days later, they saw fewer outer hair cells compared to the embryonic mouse cochleae that had not been treated with the Tgfbr1 blocker. This finding suggests that hearing loss in people with Tgfbr1 mutations could stem from impaired outer hair cell formation during development.

The study revealed additional insights into the early stages of cochlear development. The developmental pathways of inner and outer hair cells diverge early on; researchers observed distinct gene activity patterns at the earliest time point in the study, the 14th day of embryonic development. This suggests that the precursors from which these cells derive are not as uniform as previously believed. Additional research on cells collected at earlier stages is needed to characterize the initial steps in the formation of hair cells.

In the future, scientists may be able to use the data to steer stem cells toward the hair cell lineage, helping to produce the specialized cells they need to test cell replacement approaches for reversing some forms of hearing loss. The study’s results also represent a valuable resource for research on the hearing mechanism and how it goes awry in congenital forms of hearing loss.

The authors have made their data available through the gEAR portal (gene Expression Analysis Resource), a webbased platform for sharing, visualizing, and analyzing large multi-omic datasets. The portal is maintained by Ronna Hertzano, M.D., Ph.D., and her team in the department of otorhinolaryngology and the Institute for Genome Sciences at the University of Maryland School of Medicine.

“Single-cell RNA sequencing data is highly complex and typically requires significant skill to access,” Hertzano says. “By disseminating this study data via the gEAR, we are creating an ‘encyclopedia’ of the genes expressed in the developing inner ear, transforming the knowledge base of our field and making this robust information open and understandable to biologists and other researchers.”

This originally appeared on the National Institutes of Health website, at nih.gov. Matthew W. Kelley, Ph.D., is a 1997 Emerging Research Grants (ERG) alumnus and a member of HHF’s Council of Scientific Trustees (CST), the ERG’s governing body; Debara L. Tucci, M.D., is a 1992–93 ERG alumnus and a former CST member; and Ronna Hertzano, M.D., Ph.D., is a 2009–10 ERG alumnus and a member of HHF’s Hearing Restoration Project. For references, see hhf.org/summer2020-references.

It turns out that to hear a person yapping, you need a protein called Yap. Working as part of what is known as the Yap/Tead complex, this important protein sends signals to the hearing organ to attain the correct size during embryonic development, according to a June 2020 study published in Proceedings of the National Academy of Sciences (PNAS) from the University of Southern California (USC) Stem Cell Initiative laboratory of Neil Segil, Ph.D.

“Our study provides insights into how the hearing organ develops in utero, and offers clues about how to regenerate damaged cells to restore hearing later in life,” says lead author Ksenia Gnedeva, Ph.D. Gnedeva performed the research during her postdoctoral training in the Segil Lab, and is now an assistant professor in the USC Caruso Department of Otolaryngology–Head and Neck Surgery, where Segil is also a professor.

As the organ of Corti forms in the embryonic mouse, a population of progenitor cells self-renews and proliferates to achieve the correct size. Then, after approximately two weeks, the progenitor cells begin differentiating into various specialized cell types.

The scientists found that the Yap/Tead protein complex plays a major role in this intricate developmental process by regulating the activity of hundreds of genes that control self-renewal and proliferation.

The Yap protein serves as a key signal to promote the proliferation of the progenitor cells during the first two weeks of development. If Yap signaling drives proliferation for longer than two weeks, then the inner ear sensory organs grow too large. If Yap signaling breaks down prematurely, then the organ of Corti ends up being too small.

By the time mice are born, the progenitor cells in the organ of Corti have finished both proliferation and differentiation, and cannot regenerate if they are damaged—causing permanent hearing loss.

Remarkably, when the scientists activated Yap in newborn mice with hearing loss, some of the cells in the organ of Corti began proliferating again, suggesting that regeneration might be possible.

“This study provides the first support for the possibility of restoring lost sensory cells for hearing and balance by activating Yap in mice,” says Segil, who is also a professor in USC’s department of stem cell biology and regenerative medicine. “Although we can’t permanently activate Yap in human patients for a variety of practical reasons, we might be able to locally administer a drug targeting related groups of molecules.” —Cristy Lytal By the time mice are born, the progenitor cells in the organ of Corti have finished both proliferation and differentiation, and cannot regenerate if they are damaged—causing permanent hearing loss. Remarkably, when the scientists activated Yap in newborn mice with hearing loss, some cells in the organ of Corti began proliferating again, suggesting that regeneration may be possible.

This originally appeared on the USC Stem Cell website, part of the Keck School of Medicine of USC, stemcell.keck.usc.edu. Neil Segil, Ph.D. (above far left), is a member of Hearing Health Foundation’s Hearing Restoration Project (HRP), which helped fund this research. HRP members Andy Groves, Ph.D. (center), from Baylor College of Medicine, and Mark Warchol, Ph.D., from Washington University in St. Louis, are among the coauthors on the PNAS paper. For more, see hhf.org/hrp. For references, see hhf.org/summer2020-references.