Yehoash Raphael, Ph.D.
Member: Hearing Restoration Project
Current Institution: The University of Michigan
Education: Tel Aviv University B.Sc., M.Sc., Ph.D.; The University of Michigan, Postdoctoral training
What is your area of focus?
My lab focuses on developing mechanisms to protect, repair, and regenerate cells in the inner ear. We use mammalian models for genetic deafness and for environmentally caused hearing loss such as overstimulation or ototoxicity (medications that are toxic to the ear).
Our main mode of intervention is gene therapy, a method that utilizes modified viruses to shuttle therapeutic genes into cells. We are also studying the biology of inner ears that receive cochlear implants and developing methods for enhancing the health of the neurons in these ears, with the goal of improving the quality of sound perception by the implant user.
Why did you decide to get in to scientific research?
I was trained as an audiologist, and although I enjoyed the clinical aspects of audiology, I found research even more fascinating and realized that scientific curiosity was leading me toward the research path. The unique and highly organized structure of sensory cells in the cochlea is among the features of the auditory system that truly captured my enthusiasm and piqued my interest, leading me to switch my focus and enroll in graduate studies that were more biology oriented. My choice to work in the field of protection and regeneration was influenced in part by my experience in the military, which involved many years in artillery and frequent exposure to loud explosions.
What is the most exciting part of your research?
Data analysis is by far the most exciting part of my research. I enjoy observing the tissues under the microscope and analyzing results of every experiment; it is the highlight at the end of every experiment, sometimes yielding unexpected results.
Tell us something you enjoy doing when you are not in the lab or presenting your research.
I enjoy my family first and foremost, and I read fiction in both English and Hebrew. Among books that left a strong impression in recent years are The Glass Castle, Defending Jacob, The Signature of All Things, The Art of Hearing Heartbeats, and several historical fiction novels such as The Shadow of the Wind and Pope Joan. I listen to music, especially well recorded albums of jazz, pop, and classical music (opera, orchestral, chamber) and enjoy vocalists, such as Esperanza Spalding, Diana Krall, Jazzmeia Horn, Sarah McLachlan and Cecile McLorin Salvant.
What has been a highlight or memorable moment of your career?
I will always remember in the early 1990’s when we first saw supporting cells dividing in the chick hearing organ, implicating those cells as a source for new hair cells in noise- traumatized ears. In 1991 we also observed supporting cells that began to exhibit hair cell features without having had a chance to divide, suggesting they can convert their identity. Influenced by these two findings, we started focusing our work on supporting cells and ways to induce their conversion to new hair cells in the mammal. About 10 years later, we started seeing new hair cells in the living, mature mammalian inner ear, in response to Atoh1 gene therapy. This was a very rewarding outcome after spending decades
developing the approach and technology to accomplish regeneration, not knowing whether it would ever work.
What has been a highlight or something valuable you’ve gotten from the HRP consortium thus far?
The approach of sharing ideas and data is a very positive part of the HRP culture. Collaboration is important because it allows for open discussion and direct feedback, enhancing the likelihood of success. The atmosphere of the HRP consortium facilitates this rare opportunity for scientists to openly discuss novel approaches and technology.
How has the collaborative effort helped/furthered your research?
My area of expertise is in manipulating the inner ear and assessing the outcomes. Support from the HRP has allowed me to improve and advance our surgical approach for injecting reagents into the tiny inner ear of the mouse. The HRP is now supporting extensive data analysis that could lead to identification of pathways and specific molecules that will enhance hearing restoration. Once candidate molecules are formulated, my expertise in inner ear surgeries and histological analysis will become very useful.
What is needed to help make HRP goals happen?
With the continued financial support of HHF’s supporters, the HRP will be able to further expand experimental work on hearing restoration, to develop therapies for treating a variety of causes of hearing loss, such as those caused by environmental reasons (noise or side effect of medications). The HRP will also be able to expand its focus to include finding cures for genetic deafness.
Which scientist or mentor do you find the most inspirational?
My Ph.D. mentor Benny Geiger, Ph.D., was very inspirational with his deep knowledge of cell biology, admirable wisdom, and endless patience. Josef Miller, Ph.D. (who, sadly, passed away in early 2017), also left a strong impression on me, for his intellectual approach to life and science. With both Joe and Benny, in addition to discussion of data and experimental plans, I was able to enjoy and benefit from shared interests in music, art and books.
Reprogramming and Gene Delivery
Andy Groves, Ph.D. (chair), Baylor College of Medicine
John Brigande, Ph.D., Oregon Health & Science University
Yehoash Raphael, Ph.D., University of Michigan
Segil Lab, University of Southern California
This group will take the lead on transitioning to Phase II, testing candidate genes. They will study the effects of current transcription factor reprogramming cocktails on supporting cell behavior, including the collection of additional transcriptomic and epigenetic data that will be shared with the CSE group. These experiments will be performed in a variety of systems, including a flattened epithelium guinea pig model that shares features with chronic human deafness. The Groves lab will use transgenic mice to detail the effects of the reprogramming cocktails in the organ of Corti. The Brigande lab will continue its work on creating efficient mouse model systems to interrogate candidate genes for sensory hair cell regeneration, as pioneered by testing whether viral delivery of these same reprogramming factors is also efficacious. The Raphael lab will take a similar approach in the guinea pig model, in this case using a virus designed and generated by the Groves and Segil labs. These experiments are part of the group’s broader efforts to develop new methods to deliver molecules and/or genes, for example by endogenous activation of reprogramming factors via CRISPR/Cas-9.