HRP

A Powerful New Bioinformatics Tool

By Stefan Heller, Ph.D.

Our paper describing a new bioinformatics tool—and to showcase the software, a very detailed investigation as to how inner ear hair cells assemble their hair bundles—appeared in Cell Reports on June 5, 2018.

The creation of the CellTrails tool was supported in part by Hearing Health Foundation’s Hearing Restoration Project (HRP) but moreover, it is the product of recognizing existing limitations of data analysis, going back to the drawing board multiple times, and finally getting to a “product” that is going to be the workhorse to analyze a good part of the bioinformatics data that the HRP has been accumulating for years.

  An image taken at 40x magnification using a confocal microscope in the Stefan Heller lab shows a 7-day-old chicken cochlea. Credit: Amanda Janesick, Ph.D.

An image taken at 40x magnification using a confocal microscope in the Stefan Heller lab shows a 7-day-old chicken cochlea. Credit: Amanda Janesick, Ph.D.

The ideas came from conversations between HRP scientific director Peter Barr-Gillespie, Ph.D., and me and our getting stuck with trying to make sense of all the data—so the tool is the direct product of interactions through the HRP.  It follows on our work utilizing single-cell gene expression analysis to examine the genetic instructions allowing individual cells to differentiate (change) into other types of cells, such as inner ear supporting cells that turn into hair cells in species other than mammals, and thereby restoring hearing.

The tool helps us pinpoint where specific single cells are located in an organ, and their trajectories as they undergo transformations, information that was lost or fuzzy before. With it we can create a more robust, visually rendered gene expression landscape. Two postdoctoral fellows in my lab were instrumental in CellTrails: bioinformatics researcher Daniel Ellwanger, Ph.D., the tool’s primary developer, and Mirko Scheibinger, Ph.D., who validated its predictions.

I hope many researchers make use of CellTrails, accessible online, to analyze their own mountains of data. As I told Stanford’s SCOPE Blog, “Single cell transcriptome analysis and reconstruction of spatial and temporal relationships among cells is an exploding new technology. A lot of labs are faced with the challenge of analyzing the data from single cells. This study is a rather extensive study that goes beyond the inner ear field because it provides a new way to analyze single cell transcriptomic data.”

I truly feel that the seeds that were planted years ago are now growing into sizable plants—we have a massive "chick regeneration inner ear plant” that is starting to thrive!

HRP_logo for web.png

Find the tool at hellerlab.stanford.edu/celltrails.

Stanford University’s Stefan Heller, Ph.D., is a member of HHF’s Hearing Restoration Project, where Oregon Health & Science University’s Peter Barr-Gillespie, Ph.D., is the scientific director.

Print Friendly and PDF

Uncovering a Signaling Molecule That Modulates Avian Hair Cell Regeneration

By Rebecca M. Lewis, Au.D., Ph.D., and Jennifer Stone, Ph.D.

Mammals including humans cannot regenerate hair cells, but other species such as birds and fish readily regenerate hair cells after damage to restore auditory function. The gene ATOH1 produces a protein that pushes supporting cells—cells that neighbor hair cells—to either directly convert into a hair cell or to divide and form a new hair cell. However, ATOH1 expression (when the gene is turned on) does not guarantee that hair cells develop in birds or mammals, which suggests that there are factors that prevent supporting cells from changing into hair cells. Identifying these factors in birds may help us better understand the lack of hair cell regeneration in mammals.

  This schematic depicts our current ideas for how BMP4 regulates ATOH1 expression and therefore hair cell regeneration in the avian hearing organ. It shows (from left) typical hair cells, hair cell damage, and hair cell regeneration. Typical hair cells secrete BMP4. When hair cells die, BMP4 signaling is reduced, which allows ATOH1 to be expressed in supporting cells and pushes supporting cells to turn into hair cells. The newly regenerated hair cells secrete BMP4, suppressing ATOH1 in supporting cells and restoring the normal condition.

This schematic depicts our current ideas for how BMP4 regulates ATOH1 expression and therefore hair cell regeneration in the avian hearing organ. It shows (from left) typical hair cells, hair cell damage, and hair cell regeneration. Typical hair cells secrete BMP4. When hair cells die, BMP4 signaling is reduced, which allows ATOH1 to be expressed in supporting cells and pushes supporting cells to turn into hair cells. The newly regenerated hair cells secrete BMP4, suppressing ATOH1 in supporting cells and restoring the normal condition.

We examined the avian auditory system to characterize a potential inhibitor to ATOH1 during hair cell regeneration: bone morphogenetic protein 4 (BMP4). Bone morphogenetic proteins are secreted signaling molecules that regulate cellular processes in many regions of the body, including the nervous system. We found that BMP4 localizes to hair cells of the mature avian hearing organ and disappears when hair cells die or sustain damage. From this, we hypothesized that BMP4 may prevent ATOH1 expression in supporting cells and loss of BMP4 when hair cells die may enable ATOH1 to be expressed in supporting cells, driving them to convert into hair cells.

When we exposed avian auditory organs to BMP4 after selectively killing hair cells, this prevented ATOH1 expression and hair cell regeneration. When we antagonized BMP4 using an inhibitor, we found a generally opposite result: an increase in the number of regenerated hair cells.

We conclude that BMP4 is a potent inhibitor of ATOH1 and therefore suppresses hair cell regeneration. We recommend that BMP4 be explored further in studies of mammalian hair cell regeneration.

Published in Hearing Research on May 2, 2018, this study detailing BMP4’s negative effect on ATOH1 expands our knowledge of signaling molecules that suppress hair cell regeneration in birds and may also modulate hair cell regeneration in humans.

Rebecca M. Lewis, Au.D., Ph.D., is a clinical audiologist and auditory neuroscientist at Massachusetts Eye and Ear/Harvard Medical School in Boston. HRP researcher Jennifer Stone, Ph.D., is the director of research in the department of otolaryngology–head and neck surgery at the Virginia Merrill Bloedel Hearing Research Center at the University of Washington.

Print Friendly and PDF

The Countdown to Operation Regrow

By Gina Russo

Hearing Health Foundation (HHF) is counting down the days until the start of Operation Regrow, a two-week movement when you can help us to further progress toward better treatments and cures for hearing loss.

Beginning Tuesday, June 5, at 8:00 AM EDT, you can support the team of scientists conducting life-changing research to restore lost hearing, and more importantly, your generosity will have double the impact! All contributions received by 11:59 PM EDT on Tuesday, June 19 will be matched by an anonymous donor.

  Transverse section through the embryonic day 20 chicken utricle (inner ear organ) at 20X magnification. Photo by Amanda Janesick, Ph.D., of the lab of Stefan Heller, Ph.D., a Hearing Restoration Project consortium member

Transverse section through the embryonic day 20 chicken utricle (inner ear organ) at 20X magnification. Photo by Amanda Janesick, Ph.D., of the lab of Stefan Heller, Ph.D., a Hearing Restoration Project consortium member

With just five days remaining until launch, you can share the five most important facts about Operation Regrow with friends and family:

  1. The Hearing Restoration Project (HRP) is the HHF-funded scientific consortium dedicated to finding biological cures for hearing loss.

  2. Damage to the sensory cells in the human inner ear causes irreversible hearing loss.

  3. The HRP members know that the key to hearing loss cures is the human ability to regrow cells in the inner ear. This phenomenon is already possible in certain species. The HRP has observed cell regrowth in chickens, fish, and young mice.

  4. The HRP is comprised of 15 senior scientists who work collaboratively by openly sharing data and ideas, and this collaboration helps to speed up the research process.

  5. HHF maintains stellar charity ratings from Better Business Bureau Wise Giving Alliance, Guidestar, Charity Navigator, and CharityWatch for using 100% of donations to support critical research, ensuring that all Operation Regrow contributions will directly help the HRP.

If you are able to make a gift to Operation Regrow, please visit www.hhf.org/regrow between June 5 and June 19. Gifts may also be made by phone during business hours, 9:00 AM to 5:30 PM EDT, at 212-257-6140. We’ll be sure to keep you updated on our progress. Thank you for supporting HRP and hearing health!

Print Friendly and PDF

New Method Enables Systematic Study of Hair Cell Loss and Regeneration in Chickens

By Carol Stoll

Most forms of hearing loss are permanent because damage to inner ear sensory hair cells is irreversible in mammals, including humans. Mammalian vestibular hair cells have the potential to regenerate albeit at a low rate, but the hair cells of the adult mammalian cochlea are not regenerated. Birds, however, have a robust regenerative response to hair cell damage and are able to restore structure and function in inner ear organs. Consequently, the study of the molecular mechanisms that trigger the onset of avian hair cell regeneration in the balance organs as well as in the cochlea is important and may lead to therapies for hearing loss in humans.

  This image shows the undamaged and damaged utricle, an inner ear balance organ, in a chicken. HRP researchers have devised a new method to study the precise timing of hair cell regeneration in chickens using a single surgical application of an ototoxic drug. Photo by   Amanda Janesick, Ph.D.

This image shows the undamaged and damaged utricle, an inner ear balance organ, in a chicken. HRP researchers have devised a new method to study the precise timing of hair cell regeneration in chickens using a single surgical application of an ototoxic drug. Photo by Amanda Janesick, Ph.D.

Past experiments that investigate these regeneration mechanisms in living chickens required multiple injections of a drug to induce hair cell loss, making it difficult to determine the exact timing of the regeneration response. A collaboration of two Hearing Restoration Project researchers, Stefan Heller, Ph.D. and Jennifer Stone, Ph.D., and two talented postdoctoral fellows from their laboratories was recently published in Journal of the Association for Research in Otolaryngology identifying a potential solution to this problem. They developed an experimental framework that uses a single ototoxic drug application, enabling them to study the precise onset and timing of hair cell regeneration in vivo.

Heller, Stone, and colleagues performed their experiments on a total of 75 chickens. At seven days of age, the chickens were anesthetized and underwent surgery to eliminate hair cells in the inner ear organs. During the surgery, streptomycin (an ototoxic antibiotic) was delivered to the chicken’s inner ear. At various time points after the surgery, two sensory organs—the utricle, a vestibular organ; and the basilar papilla, the hearing organ—were dissected, labeled for various cellular markers, and analyzed under a microscope. Hair cells and their surrounding supporting cells were counted and observed for damage. EdU, a marker of cell division, was administered to the chickens to determine whether or not new hair cells were generated by cell division. These techniques enabled the researchers to quantitatively characterize the regenerative response of the utricle after damage.

The results of the study demonstrate that surgical application of a single streptomycin dose is a feasible approach to elicit hair cell loss and regeneration in the chicken utricle and basilar papilla. Just hours after streptomycin delivery, hair cell numbers significantly declined and DNA replication was activated. The team was then able to record specific events of the regeneration process, which get initiated around 12 hours after streptomycin-induced hair cell loss, and continue over the course of several days.

Supporting cells produce new hair cells either by converting into a hair cell (direct transdifferentiation), or by dividing, usually asymmetrically, into a supporting cell and a hair cell.  Throughout this regenerative response, supporting cell numbers and density in the utricle remain relatively constant, suggesting that there is a mechanism that responds to specific levels of damage and coordinates the individual events of the regeneration process.

The study establishes a framework for the refined study of the two modes of hair cell regeneration in the chicken utricle. The next steps of the work will focus on understanding the exact timing and mechanism of coordination of the regeneration response. With only a single application of streptomycin necessary to induce near-complete hair cell loss in hearing and balance organs, the new animal model allows for study of the entire process including initiation, realization, and termination. The fundamental understanding of the avian regenerative mechanisms may lead to future development of therapies for loss of hearing and balance in humans.

WE NEED YOUR HELP IN FUNDING THE EXCITING WORK OF HEARING AND BALANCE SCIENTISTS. DONATE TODAY TO HEARING HEALTH FOUNDATION AND SUPPORT GROUNDBREAKING RESEARCH: HHF.ORG/DONATE.

Print Friendly and PDF

Therapies for Hearing Loss: What Is Being Tested?

By Pranav Parikh

regenerated hair cells.png

Untreated hearing loss is linked to a lower quality of life, physical functionality, and communicative ability. The most common type of hearing loss, sensorineural, is often a result of damage to the delicate sensory hair cells in the inner ear. Because hair cell loss is irreversible, and hearing impairment therefore permanent, new treatment strategies are a welcome sign. In the July 2017 issue of Otology & Neurotology, Hearing Restoration Project (HRP) consortium member Ronna Hertzano, M.D., Ph.D., and Debara L. Tucci, M.D., a member of Hearing Health Foundation’s Council of Scientific Trustees (CST), along with Matthew Gordon Crowson, M.D., examined the field of emerging therapies for sensorineural hearing loss.

The team identified 22 active clinical drug trials in the U.S., and reviewed six potential therapies. Four use mechanisms to reduce oxidative stress believed to be involved in the inner ear cell death. Three of the therapeutic molecules being tested—D-methionine, N-acetylcysteine (NAC), and glutathione peroxidase mimicry (ebselen)—act as antioxidants to mop up free radicals caused by noise or other trauma to the inner ear. (For more about D-methionine, see page 11.) The fourth, sodium thiosulfate, is a chemical found to counteract the ototoxic effects of chemotherapy drugs.

The fifth approach is to manipulate the “cell death cascade.” This occurs when cells endure significant stress or injury, leading to the release of free radicals and changes in pH and protein that then kill the cell. Since hair cells do not regenerate like other cells, the cell death cascade causes permanent hearing loss. A trial is underway to make the cochlear neuroepithelium (inner ear tissue) more resilient to cell death signaling, using an inhibitor called AM-111 to block the chain of events leading to cell death. Finally, the sixth approach is a novel hair cell replacement therapy using the gene Atoh1, known to be a vital regulator of hair cell regeneration, causing cells to differentiate (change) into hair cells. Using mouse models, it has been shown that if Atoh1 is blocked, hair cell differentiation does not occur, and if it is induced, hair cell formation occurs, at least in the ears of very young mice.

Drug delivery methods to the inner ear are also being investigated. In addition to orally, delivery methods include a topical ear gel, intravenous infusion, and, most revolutionarily, direct injection of viruses to deliver genes to the inner ear. And while many of the drugs had to overcome hurdles to reach late-phase clinical trials, questions about safety, efficacy, and side effects remain, in addition to whether animal model results translate to human biology.

Ronna Hertzano.jpeg

HRP consortium member Ronna Hertzano, M.D., Ph.D. (far left), is an assistant professor at the University of Maryland School of Medicine. HHF CST member Debara L. Tucci, M.D., is a professor at Duke University Medical Center in North Carolina.

WE NEED YOUR HELP IN FUNDING THE EXCITING WORK OF HEARING AND BALANCE SCIENTISTS. DONATE TODAY TO HEARING HEALTH FOUNDATION AND SUPPORT GROUNDBREAKING RESEARCH: HHF.ORG/DONATE.

This article originally appeared in the Fall 2017 issue of Hearing Health magazine. Find it here, along with many other innovative research updates. 

Print Friendly and PDF

That Annoying Ringing in Your Ears Has a Name: Tinnitus

HHF's communications and programs manager, Laura Friedman, shared her knowledge of tinnitus treatments with Boomer in "Have You Heard? That Annoying Ringing in Your Ears has a Name: Tinnitus."

noisemakers.jpg


There are currently no permanent solutions to cure this constant, unexplained noise, but the efforts of HHF's Hearing Restoration Project, an international scientific consortium working collaboratively in search of a biological cure for hearing loss, may produce one.

"One of the more interesting experimental treatment possibilities for tinnitus is reported by Laura Friedman...Since hair cell loss in the Corti (the organ containing sensory hair cells required for hearing) leads to hearing reduction, missing hairs may cause persistent imbalances in the auditory nerve, resulting in tinnitus. To address this possibility, the HHF’s Hearing Restoration Project is working to discover factors that would allow new human hair cells to be regenerated and restored in the Corti, or to convert non-sensory cells into hair cells."

Read the full article from Boomer, here.

 

 

Print Friendly and PDF

The HRP Shifts Gears for Greater Impact

By Peter Barr-Gillespie, Ph.D.

It’s remarkable to me that the Hearing Restoration Project (HRP) is five years old! While the past five years revealed that regeneration of sensory hair cells is more complex than anticipated, our scientists have nonetheless made significant progress. Several notable HRP research projects supported by Hearing Health Foundation (HHF) were published in 2016, and more are on the way.

Financial investment in the HRP is crucial for our success. Through the HRP, HHF supports promising innovative research areas that due to the lack of available funds are not adequately financed by other agencies. We continue to acquire large-scale genomics datasets, and the more we generate the more valuable they all are—comparing the results from different types of experiments is a key approach of the HRP.

In 2017 we will see a change in the way the HRP conducts its research. At our HRP meeting this past November, the consortium updated its research methods for the upcoming year, choosing to focus and devote more resources on two promising, major experimental strategies. This is a shift from the approach over the past five years, when the HRP followed various independent paths to understanding hair cell regeneration.

The first project will use “single-cell sequencing” experiments, which will reveal the molecular processes of hair cell regeneration in chicks and fish with unprecedented resolution. Single-cell methods allow us to examine thousands of genes in hundreds of individually isolated supporting cells, some of which are responding to hair cell damage.

With these voluminous datasets, we will then describe the succession of molecular changes needed to regenerate hair cells. Results from these experiments will be compared with similar experiments examining hair cell damage in mice, which like all mammals, including humans, do not regenerate hair cells.

The second project will examine whether epigenetic DNA modification (the inactivation of genes by chemical changes to the DNA) is why mice supporting cells are unable to transform into hair cells after damage to the ear. Our existing data suggests this is the case, and so a strategy for hearing restoration may involve the reversal of these epigenetic modifications.

The first project will allow us to identify the genes involved, and the second project will help us understand how to effectively manipulate those genes despite their DNA modifications—and to biologically restore hearing.

The consortium approach funded by HHF provides a unique opportunity; the collaboration of 15 outstanding hearing investigators will lead to results far more quickly than traditional projects that rely on a single investigator. All HRP investigators plan projects and interpret data arising from them, allowing us to collectively utilize our 200-plus years of experience we have studying the ear.

HHF has been able to increase HRP funding for 2017 compared with 2016—for this I am grateful. However, there are several research needs unmet. Increased funding levels would speed our deeper understanding of hair cell regeneration, which will ultimately lead us to find therapies to treat human hearing loss and tinnitus.

Most of all, we are looking to add additional scientists to HRP labs to increase productivity and significantly accelerate research progress. There is also an urgent need for more “bioinformatics” scientists to thoroughly examine our data and identify common threads buried deep within our results. In addition, the HRP has research projects that have been placed on hold until funding is found for them.

We are excited about the coming year’s planned research, and eagerly await the results. On behalf of myself and the other scientists who make up the HRP, I thank you for your investment and interest in our work. I look forward to giving you further updates.

HRP scientific director Peter Barr-Gillespie, Ph.D., is the associate vice president for Basic Research and a professor of otolaryngology at the Oregon Hearing Research Center, and a senior scientist at the Vollum Institute, all at Oregon Health & Science University. 

We need your help in funding the exciting work of hearing and balance scientists.

To donate today to support HHF's groundbreaking research,

please visit hhf.org/donate.

Print Friendly and PDF

Unraveling Genes Critical for Inner Ear Development

By Albert Edge, Ph.D., and Alain Dabdoub, Ph.D

The goal of the Hearing Restoration Project (HRP) is to determine how to regenerate inner ear sensory cells in humans to eventually restore hearing for millions of people worldwide. These sensory cells, called hair cells, in the cochlea detect and turn sound waves into electrical impulses that are sent to the brain. Once hair cells are damaged or die, hearing is impaired, but in most species, hair cells spontaneously regrow and hearing is restored. The HRP is aiming to enable this ability in humans. 

All cells develop through a chain of events triggered by chemical signals (proteins) from outside the cell. The signals kick off responses inside the cell that can change the cell’s ability to proliferate (grow and divide) and differentiate (take on specialized functions).

The Wnt signaling pathway, a sequence of events triggered by the Wnt protein, helps guide inner ear cell development, including the proliferation of cells that differentiate into the hair cells and supporting cells necessary for hearing and balance. But in mice and other mammals, inner ear cell proliferation does not continue past newborn stages.

Underscoring their importance in evolutionary terms, Wnt signals occur across species, from fruit flies to humans—the “W” in Wnt refers to “wingless”—and Wnt signaling is guided by dozens of genes. Albert Edge, Ph.D., Alain Dabdoub, Ph.D., and colleagues performed a comprehensive screen of 84 Wnt signaling-related genes and identified 72 that are expressed (turned on) during mouse inner ear development and maturation. Their results appeared in the journal PLoS One this February.

The Wnt signaling network has three primary pathways. Two are known to be integral to the formation of the mammalian inner ear, including the determination of a cell’s “fate,” or what type of cell it ultimately turns into. This is particularly significant because the inner ear’s sensory epithelium tissue is a highly organized structure with specific numbers and types of cells in an exact order. The precise arrangement and number of hair cells and supporting cells is essential for optimal hearing.

The relationship between the Wnt-related genes, the timing of their expression, and the various signaling pathways that act on inner ear cells is extremely complex. For instance, the composition of components inside a cell in addition to the cell’s context (which tissue the cell is in, and the tissue’s stage of development) will influence which pathway Wnt signaling will take. It is known that inhibiting the action of Wnt signaling causes hair cells to fail to differentiate.

 

The new research complements previous chicken inner ear studies of Wnt-related genes as well as a recent single-cell analysis of the newborn sensory epithelium in mice (conducted by HRP scientist Stefan Heller, Ph.D., and colleagues). Comprehensively detailing these 72 Wnt-related genes in the mouse cochlea across four developmental and postnatal time periods provides a deeper understanding of a critical component of hair cell development, bringing the HRP closer to identifying genes for their potential in hair cell regeneration.

Your Support Is Needed!

Hair cell regeneration is a plausible goal for eventual treatment of hearing and balance disorders.

The question is not if we will regenerate hair cells in humans, but when.  

However, we need your support to continue this vital research and find a cure!

Please make your gift today.  

Print Friendly and PDF

Spotlight On: Andy Groves, Ph.D.

CURRENT INSTITUTION: 

Baylor College of Medicine, Houston, Texas

EDUCATION:

Undergraduate from the University of Cambridge

Ph.D. from the Ludwig Institute for Cancer Research, London

Postdoc at the California Institute of Technology 

This new feature aims to connect Hearing Health Foundation (HHF) supporters and constituents to its Hearing Restoration Project (HRP) consortium researchers. Spotlight On provides an opportunity to get to know the life and work of the leading researchers working collaboratively in pursuit of a cure for hearing loss and tinnitus. 

What is your area of focus?

I am a developmental biologist who uses the ear as a model system to understand the general problem of embryonic development—how do you form something very complicated from very simple beginnings. The inner ear is a tissue that receives extremely precise instructions to form just the right number of cells in the right place at the right time. My lab studies where the ear comes from embryonically, how the cochlea acquires its exquisite pattern, and why sensory hair cells are not replaced in mammals after damage.

Why did you decide to get in to scientific research?

I always enjoyed biology and chemistry as a kid and thought it would be more fun than studying medicine. I had a very enthusiastic high school biology teacher who loaned me books on biology and evolution, which made an enormous impression. When I was an undergraduate at Cambridge, I was lucky to have two professors who both won Nobel Prizes, and during my senior year I had the opportunity to do research with one of them. After that, scientific research seemed like the only game in town….

Why hearing research?

I started to study ear development as a postdoctoral fellow in the 1990s because it had received very little attention for decades. The ear appeals to my love of extremes in biology: It has one of the most elaborate three-dimensional structures of any organ; it possesses cells of astonishing mechanical sensitivity; and it can detect sounds over a trillion-fold power range. It is also remarkable to think that our entire auditory experience—conversation, music, the natural world—is captured by just a few thousand sensory cells in each ear!

What is the most exciting part of your research?

Experiments can take months or years to carry out. But every now and then you find something new, and the thrill of realizing that you have found out something that no one else in the world knows about is quite addictive.

What do you enjoy doing when you’re not in the lab?

I am a huge music fan and have a large CD collection. Right now my playlist includes Beethoven sonatas played on a fortepiano, some rare Miles Davis live concerts from 1965, and Howlin’ Wolf albums. As a grad student, I sang at Cambridge and with the London Philharmonic Orchestra. I also love reading. Despite living in the U.S. for over two decades, I know very little about its history, so I have been trying to educate myself about the Civil War Era. I just finished reading “The Half Has Never Been Told” by Edward Baptist.

What is a memorable moment from your career?

For me, it is the “firsts”—seeing students or postdocs publish their first paper or when someone in my lab gets their first academic position. The nature of science means that most of what is discovered will become obsolete or surpassed, but the achievements and careers of the people who have come through the lab will hopefully last for much longer.

If you weren’t a scientist, what would you have done?

To be honest, I never had a “plan B.” I love teaching, and so if I had to give up research, it might be nice to teach biology to undergraduates.

Hearing Restoration Project

What has been a highlight from the HRP consortium collaboration?

The biggest help has been having collaborators on hand to do experiments that are outside the scope of my own lab. We recently published a paper with another HRP researcher, Stefan Heller, Ph.D., at Stanford, where he helped us analyze gene expression of single cells in the cochlea. We showed that blocking the Notch pathway could cause new hair cells to form in very young animals, but that this approach stops working as animals get older. The explosion of new technology and techniques means it is harder to do all the experiments you want in your own lab—so collaboration is key.

What do you hope to have happen with the HRP over the next year, two years, five years?

I hope we can begin a large-scale testing of candidate drugs or gene manipulations in the next two years. This initial screening will likely be in cell culture systems or in the zebrafish system that some members of the HRP helped to pioneer. In five years, I hope we have lead compounds that have been validated independently in several HRP labs.

What is needed to help make HRP goals happen?

Frankly, funding to keep our research moving forward. A postdoctoral fellow with five to six years of training starts out on a modest salary of about $45,000, plus $12,000 in benefits. So that’s $57,000 before they even pick up a test tube in the lab. Each person will typically use between $15,000-$20,000 a year in supplies and chemicals. Simply maintaining a single cage of mice for one year costs $210, and my lab can use between 300-500 cages of mice for our experiments! HHF and its donors have been extremely generous in their support, however with additional funding the output from the consortium could be significantly greater and accelerate the pace to a cure.

Which scientist or mentor was the most inspirational?

My two postdoctoral mentors at Caltech, David Anderson and Marianne Bronner, were both instrumental in making me the scientist I am today. As I was moving into the ear field, I was also lucky to meet Ed Rubel while he was on a sabbatical at Caltech and now as a fellow member of the HRP. More broadly, my two scientific heroes are Seymour Benzer and Francis Crick. Both were gifted scientists who laid the foundations of modern biology and were able to make seminal contributions to every field they worked in, from developmental and molecular biology to the study of aging, behavior, and consciousness. 

Your financial support will help ensure we can continue this vital research in order to find a cure for hearing loss and tinnitus in our lifetime. Please donate today to fund the top scientific minds working collaboratively toward a common goal. For more information or to make a donation, email us at info@hhf.org.

Your help provides hope.

Print Friendly and PDF

The Path to a Cure for Hearing Loss and Tinnitus

By Laura Friedman

On May 21, 2015, Hearing Health Foundation hosted its first live-video research briefing as part of our effort to provide regular updates on our research programs and progress. Through these briefings, our goal is for our attendees to obtain new information and understanding about hearing loss, prevention and research toward a cure.

During this inaugural research briefing, Dr. Peter Barr-Gillespie, Scientific Director, Hearing Restoration Project presented the Hearing Restoration Project (HRP). The HRP was founded in 2011 and is the first and only international research consortium focused on investigating hair cell regeneration as a cure for hearing loss and tinnitus. The overarching principle of the consortium is collaboration: open sharing of data and ideas. The HRP consortium consists of 14 of the top investigators in the audiological space, as well as a scientific director, Dr. Barr-Gillespie.

We wanted to share with you highlights from the presentation, which is available to watch with live captioning or to read with notes summarizing each slide

  1. History of Hearing Health Foundation

    • Founded in 1958, established reputation for pioneering breakthroughs in hearing and balance research.

      • Early supporters of the revolutionary cochlear implant. Today, over 220,000 children and adults benefit.

      • Advocated for the passage of Universal Newborn Hearing Screening legislation in the 1990s. Today, 97% of newborns are tested for hearing loss at birth.

      • The Emerging Research Grants Program provides seed funding for researchers in hearing and balance science such as discoveries in hair cell regeneration, tinnitus, hyperacusis, and Ménière’s research. 

  2. The Challenge

    • In the past century, the primary treatment for hearing loss has been hearing aids and cochlear implants. While these have been very successful treatments, they have limitations.

    • For this century, we have a number of different avenues for more effective therapy. 

      • Preventing the damage to the hair cells to preserve hearing. By generating greater awareness of the effects of hearing loss, we aim encourage people of all ages to protect their ears.

      • Gene therapy, targeting those who have lost hearing due to genetic disorders.

      • The majority of people who have lost hearing have done so through noise damage or aging, and may be candidates for hair cell regeneration/restoration.

  3. HRP Consortium History & Model

    • One of the key facets of the HRP’s approach is that we use three different animal models for studying hair cell regeneration
      • Two of those models, the chick and the zebrafish, show robust hair cell regeneration.
        • f you damage the hair cells of a chick or a fish, within a short time—only a day or two for the fish, a few weeks for the chick—the hair cells come back; new hair cells are formed.
          • So, that's spectacular, because it tells us that animals are capable of regenerating hair cells. 
      • y contrast, the mouse is our other experimental model. Like in the human, the mouse shows no hair cell regeneration after a few days following birth.
        • You can damage the hair cells in the mouse and as far as we can tell, nothing much happens in terms of restoring hair cells. So, if we can figure out how to regenerate hair cells in the mouse, then we will be able to regenerate hair cells in people.
  4. HRP Strategic Research Plan

    • Our strategic plan consists of three separate phases. We have already made a lot of progress on Phase 1 and we have initiated Phase 2:

      • Phase 1 – Discovery research:  Compare the fish, chick, and mouse to discover pro- or anti-regeneration pathways and determine supporting cell fates.

      • Phase 2 – Pathway validation: Verify pathways using fish, chick, and mouse models and describe regeneration strategies.

      • Phase 3 – Develop therapies and treatment options: Identify drugs that trigger hair cell regeneration in the mouse model.

  5. Progress To-Date

    • Progress on Phase 1: We've identified a variety of candidates for hair cell regeneration and the pathways that are necessary. 

      • We have too many, so we really are continuing to use bioinformatics methods to winnow down and determine which are most important.

      • We have definitively shown, at least in the mouse, the specialized supporting cells remain.

      • We know now what our target cells are for triggering hair cell regeneration. 

    • Phase 2 has begun, but we haven’t stopped Phase 1: 

      • We've got multiple approaches to try and see whether or not we can block regeneration in the fish and chick or stimulate regeneration in the mouse.

    • Phase 3 is in sight:

      • Experimental models from Phase 2 will be used to screen for drugs—using the mouse first

  6. The Next Five Years

    • With your help, we can continue to quicken the pace towards a cure. Here’s our plan for the next five years: 

      • Phase 1 will continue: more candidate generation for Phase 2

      • Phase 2 (pathway verification) already initiated in zebrafish, mouse, chick (low throughput)

      • Phase 2 must be scaled up: many more genes, combinatorial approaches; cell lines for screening

      • Phase 3 (drug screening) requires the right screening model, which will come out of Phase 2.

The Future is Very Bright – But we need your support!

Hair cell regeneration is a plausible goal for eventual treatment of hearing and balance disorders. The question is not if we will regenerate hair cells in humans, but when.  However, we need your support to continue this vital research and find a cure! Please make your gift today.  

 

Print Friendly and PDF