UPDATES FROM THE SCIENTIFIC DIRECTOR
Where We Are, and Where We Are Going
By: Peter G. Barr-Gillespie, Ph.D., scientific director of the HRP consortium and a scientist at the Vollum Institute at Oregon Health & Science University
Hearing Health Foundation’s Hearing Restoration Project (HRP) is an international research consortium comprising 14 leading scientists in the hearing and balance space. They are collectively searching for a biological cure for hearing loss and tinnitus through inner ear hair cell regeneration.
The HRP has three phases of research. Phase I, underway since our inception in 2011, uses “discovery science” methods to identify molecules that may be involved in hair cell regeneration. Phase I also includes bioinformatics (the analysis of discovery data), which allows us to compare results from different experiments with our three different model systems (fish, bird, and mammalian hair cells).
Last year marked the HRP’s foray into Phase II, testing candidate molecules found in Phase I to determine if they are truly part of the regeneration response in fish or birds or if they block regeneration in mammals. Phase II projects are very important, both for validation of the data from Phase I and for the transition to Phase III. Phase III involves screening for drugs that can stimulate hair-cell regeneration.
The HRP meets annually in person each fall in Seattle. In this article we review accomplishments and next steps from the meeting held November 15–17, 2015.
For HRP consortium members, our annual in-person meeting is the highlight of the year. The two days of exchanging information often leads to fresh insights into our data and stimulates dialogue about new research areas for future pursuit.
On the first day of the meeting, investigators of the 2015 funded projects discussed the significant progress made. The Phase II project by the University of Washington’s Jennifer S. Stone, Ph.D., and David Raible, Ph.D., along with Andy Groves, Ph.D., of Baylor College of Medicine, was successful in using a system known as CRISPR/Cas9 to test genes in zebrafish, and then extending those observations to mice and chicks.
In addition, the Phase I project of single-cell transcript analysis by Stefan Heller, Ph.D., of Stanford University, is nearing completion, which will allow us to see the molecules used during hair cell regeneration in chicks.
We also discussed several ongoing projects, most importantly the X-cells project, which arose out of the 2014 annual HRP meeting (see Spring 2015’s “Examining X-Cells,” at hearinghealthmag.com). Several HRP investigators had noticed that cells with some characteristics of hair cells, which we dubbed X-cells, could be seen weeks or months after damage to the mouse cochlea that had fully eliminated hair cells. The consortium was excited, as X-cells could be supporting cells that had begun to turn into hair cells, but were unable to fully turn into hair cells. After finding that these cells proved to be rare and that their properties were difficult to define, it was agreed that research into X-cells should not receive additional HRP funding.
However, the X-cell observations are important and notable, and having the research published would be a service for the field. This is a great example of science at its best: an unexpected observation, followed by experiments to test whether the observation is relevant. It’s worth noting that I expect that the number of HHF-supported research papers from HRP consortium members will substantially increase in 2016 and beyond. Publishing the HRP’s work is important because dissemination of research is considered a major benchmark of progress and defines success within the scientific community.
One of the key goals of the meeting was to have strategic, forward-looking discussions. We agreed that the consortium needs to focus on additional discovery experiments; deeper bioinformatics analysis of existing data; and the development of suitable model systems for testing candidate pathways. Biological processes usually follow pathways, which are sequential steps that transform a signal or chemical from one state to another. We hypothesize that there are pathways in bird and fish hair cells that promote hair cell regeneration, and pathways in mammalian hair cells that prevent it.
The key objective in stimulating hair cell regeneration in humans is to understand which pathways are relevant. Do humans lack pathways that promote regeneration, or do they have an overly active pathway that inhibits it? Our next steps depend on addressing this question.
Consortium members proposed two new methods for testing pathways, which include specialized methods for turning on genes in the mouse ear and assessing the growth and differentiation of supporting cells in vitro. In addition, the consortium endorsed continued support of a separate Raible-Groves-Stone project (different from the X-cells project previously mentioned) that tests pathways in fish (using CRISPR, an extremely precise gene manipulation method), in genetically modified mice, and in birds, using drugs that activate or disrupt pathways.
Our November 2015 meeting capped off a very active year of research for the HRP consortium and set the stage for exciting research in the coming year. The more we learn about hair cell regeneration, the more we see how complex the challenge is. It is important to remember the HRP has made significant progress toward our goal—we are getting closer to finding the key to unlock a cure for hearing loss and tinnitus.
As we ask you to stay tuned for ongoing updates in 2016, we’d like to sincerely thank you for your continued support of HHF and the HRP.