SAN DIEGO-The remarkable new tools of the genomic generation have been used by researchers at the House Ear Institute in Los Angeles, Translational Genomics Research Institute in Phoenix, and the University of Antwerp, Belgium, to zero in on genes that cause presbycusis, or age-related hearing loss.
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June 2007
Rick A. Friedman, MD, PhD, of the House Ear Institute, described the scientists’ work at the Triological Society’s Otology Forum April 26 at the Combined Otolaryngology Spring Meetings. He and his collaborators (not in attendance at COSM) studying the genetics of presbycusis included Dietrich Stephan, PhD, of Translational Genomics, Guy Van Camp, PhD, University of Antwerp, and the company Affymetrix.
While tempting the hundreds of COSM attendees with this exciting, sneak-peek look at the yet unpublished research, Dr. Friedman also explained the rationale behind genomic studies into complex traits where multiple pathways lead to common diseases such as hypertension, diabetes, and presbycusis.
His presentation was the lead talk in the research update. Additional presenters included Neil Segil, PhD, also from the House Ear Institute, who discussed the potential of hair cell regeneration with endogenous progenitor cells-specifically supporting cells; Allen Ryan, PhD, Professor of Otolaryngology at the University of California, San Diego (UCSD), who addressed the progress and challenges of stem cell therapy for the inner ear; and Bryan A. Liang, MD, PhD, JD, a medical ethics and legal expert based in San Diego, who reminded colleagues about liability, medical board sanctions, and the slime factor associated with judgment errors in today’s cutting-edge, genomic basic and clinical research.
Whole Genome Association Studies
Noting that his goal in organizing the forum was to convey the importance of this era of genomic medicine and potential stem cell therapies, Dr. Friedman based his remarks on his recent whole genome association studies. He said that since common diseases such as presbycusis result from common variations within the human genome, special tools are needed to detect the subtle differences that result in a variation of the expression of the gene, but not necessarily by its absence.
Key to the discovery of these subtle differences was the Affymetrix DNA microarrays, tiny silicon microchips with 500,000 bits of DNA information. The newest version of these microarrays was utilized by Dr. Friedman and his team as they searched for the gene or genes responsible for age-related hearing loss. The genes of more than 800 European subjects (with and without presbycusis) were subjected to the analysis of single nucleotide polymorphisms (SNPs) in an expensive ($1,000 per chip) study. The team has identified several markers at locations throughout the genome, all showing statistical significance and interplay to create the genetic risk for presbycusis.
The exciting part of this-and it will be coming soon-is that we have candidate genes that stand out across all nine of these European populations studied, he said. Eventually, we expect to find additional genes of significance in presbycusis.
He noted that the discovery of disease-causing genes could potentially allow for diagnostics and biomolecules for the treatment of age-related hearing loss.
Sensory Hair Cell Function
Following Dr. Friedman, Dr. Segil described his studies, which could potentially lead to the genetic treatment of individuals who’ve lost sensory hair cell function. Noting that there are currently no therapies that can be claimed successful, he said research such as his provides hope for the future.
Unfortunately, mammalian hair cells do not regenerate and researchers don’t know why. It is possible that mammalian supporting cells may lack the capacity for regeneration of hair cells, or there may be a specialized type of supporting cell in vertebrates such as birds, which are capable of hair cell regeneration. Another possibility is that a signal for regeneration may be missing or blocked.
Dr. Segil noted that there are two possibilities for generating lost hair cells: (1) stimulating self-repair by targeting endogenous progenitors, i.e., supporting cells; or (2) the transplantation of exogenous stem cells or progenitors. His team studies supporting cell stimulation by focusing on the identification of cells that might be susceptible to manipulation.
In mice, Dr. Segil’s team tested the capacity of cochlear supporting cells to divide and transdifferentiate by using green fluorescent markers expressed only in supporting cells in the inner ear. With the resulting purified supporting cells, the scientists discovered that the cells were still capable of self-division. And, although these cells normally wouldn’t actively divide, under the culture conditions in the lab, they did.
If we keep these cells in culture for six days, some of the cells begin to differentiate as hair cells, he said, adding that they have not yet identified the stimulus for the division. What they did determine is that self-division is age-dependent, in early cells. It is important, Dr. Segil said, to further test whether self-division can be stimulated in mature cells.
In another study, Dr. Segil’s team is targeting one pathway that keeps cells next to each other from differentiating as the same cell type. They believe that supporting cells are being actively inhibited from becoming hair cells by this pathway. Additional projects look at cell differentiation to better understand the process by which the supporting cell differentiated state is maintained.
Hair Cell Transplantation
As for transplantation as a method to regenerate lost hair cells, Dr. Ryan described the work by his team at UCSD.
Transplantation is the reverse side of the regeneration story in that there is considerable interest now in the role of hair cell replacement through stem cells, he said. It has been found that many types of stem cells tolerate transplantation into the inner ear, and sometimes will integrate into target tissues. However, inner ear tissue appears to have limited ability to induce stem cells to adopt an appropriate phenotype for the site without extra help.
His team found that in the case of sensory cells, transplanted immature hair cells can integrate into a damaged sensory epithelium if the appropriate access is provided, which they did in vitro. He said that there also appears to be a ‘critical period’ for transplantation; cells that are too immature or too mature cannot integrate to repair a damaged epithelium.
That suggests to us that if there is going to be a transplantational strategy for replacement of cells in the inner ear, we will have to be very careful about the developmental stage at which these cells are transplanted, he said.
In contrast to these in vitro results, Dr. Ryan’s team had much less success with in vivo delivery in rats. And yet, we think that cellular therapy has a lot of potential applications in the inner ear, with most transplanted stem cells surviving, and even integrating into some tissues. Access to some tissue sites-especially the organ of Corti and spiral ganglion-is a critical factor. And, achieving the appropriate cellular phenotype is the most significant challenge to transplantation, he said.
Legal Issues
In the final presentation, Dr. Liang lauded the advent of genomic medicine, but warned the audience about legal issues and conflict of interest in this new era.
It is estimated that in five years, by 2012, half of all drugs and devices will be bioproducts, he said, adding that basic science and clinical use need commercial development to enhance and further the application of discoveries.
The law has recognized that cutting-edge basic science and clinical research create issues of conflict of interest, he said, noting that physicians have a fiduciary duty to their patients to disclose all conflicts of interest-even if the financial or other benefit to the physician is concurrent with effective patient treatment.
He said established ethical norms dictate that we assess these circumstances using both a subjective test and objective test. Subjectively, would this conflict affect your recommendations and/or care for this patient? Objectively, would a reasonable person believe that this conflict would affect your recommendations and/or care for this patient?
Ethically, we must also scrutinize the potential conflict using the sunshine test, Dr. Liang said. Would you want this financial or other arrangement known by your patients and/or published in your local newspaper?
Finally, he warned physicians about the slime factor, noting that slime slips and slides with you the rest of your life, and if you take advantage of a temporary financial benefit that represents a conflict, that’s what you’ll be known for the rest of your life.
©2007 The Triological Society