As part of our review of the past 5 years of SICHL’s collaborative research, Dr. Alan Cheng gives us some insight into his predictions for the future of his lab’s research, and into what his lab has achieved and goals they are working towards in the coming years:
Q) What has your lab learned about hearing and/or hearing loss over the last 5 years?
A) Our lab has made major discoveries in the areas of hair cell regeneration and aminoglycoside ototoxicity in the last few years.
First, it has been long understood that the mammalian cochlea does not regenerate, yet in young mammals, stem-cell-like cells can be isolated. Through a series of work using transgenic animals, we have found the identity of these stem-cell-like cells that can contribute to a modest degree of regeneration. While the time window is limited to the young animal, this discovery has established one of the first models of mammalian cochlear hair cell regeneration and also defines the genetic signature of these naturally occurring stem-cell-like cells.
Based on this work, we have discovered another model of mammalian hair cell regeneration by studying the balance organ (utricle). While this organ is responsible for detecting acceleration(not hearing), it too relies on sensory hair cells for proper function. Again, by using transgenic mice, we have defined the precursors that regenerate hair cells. But importantly, we have now established reliable models of regeneration where a functional recovery can be systematically examined. Thus, in addition to studying the anatomy of hair cell regeneration, we are able to simultaneously study the degree of functional recovery as a result of hair cell regeneration.
While several other labs study hair cell regeneration including that in non-mammalian species, our approach is unique in that we have several models of mammalian hair cell regeneration and also the ability to compare regeneration to functional recovery. Since our ultimate goal is to regenerate hair cells to restore hearing in humans, I believe our approach is the most practical, direct and promising.
In a second direction, aminoglycoside antibiotics are well known to cause irreversible hair cell damage and hearing loss. Years of research in this area has focused on ways to negate this ototoxic side effect. In collaboration with Tony Ricci, we have identified the transport mechanism by which aminoglycosides enter inner ear hair cells. Using our understanding of this transport avenue, we have designed and synthesized a new generation of aminoglycoside-derivatives that are no longer toxic to the inner ear while still killing bacteria both in the petri dish and whole animals. This critical discovery has allowed us to create a pipeline to synthesize non-toxic antibiotics with the ultimate goal of eliminating this source of preventable hearing loss.
Q) What has been your lab’s biggest challenge?
A) We are fortunate to have funding from the NIH and other federal agencies because they look for well grounded, hypothesis testing research. However, we are motivated to accelerate our research so we can translate our discoveries sooner to improving patients’ lives. For example, some of the experiments that can catapult forward our knowledge are high risk, high reward. Moreover, having additional personnel (i.e. research assistants or postdocs) can also help accelerate discovery. Newer technology/equipment are essential to cutting edge research, and such expenses are often not covered by grant dollars. Lastly, funding from federal agencies is extremely competitive and often fluctuates. Although we are fortunate that we haven’t suffered from such a tragedy, a more sustained source of support such as an endowment can ensure that our research moves forward regardless of the federal funding climate.
Q) What are your goals for the research in the coming 5 years?
A) There are 3 main important goals for our lab in the coming years. The first two pertain to regeneration to restore hearing and balance functions. Based on our discovery of multiple hair cell progenitor cell types, we are poised to acquire their genetic signatures which likely hold the clues to initiating and completing hair cell regeneration. The work to analyze these genes and test them takes time but our results could reveal gene(s) that drive mammalian hair cell regeneration.
The 2nd goal is to understand how hair cell regeneration relates to functional recovery, a topic that is immensely important yet poorly understood. Our approach is designed to unveil the anatomy and function of the regenerating vestibular organ in the next 5 years.
Lastly, we hope to synthesize additional nonototoxic antibiotics. Based on our initial work where one chemical pathway was used to modify existing aminoglycosides, we now have designed additional compounds and also additional chemical pathways. We hope to identify non-ototoxic antibiotics in animal experiments that can be considered for clinical trials in 5 years’ time.