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Appendix 7: Written Comments from Johns Hopkins University

The Department of Otolaryngology-Head & Neck Surgery
The Johns Hopkins University

General Comments

Traditional temporal bone (TB) laboratory research can be defined as the procurement and processing of human temporal bones for light microscopic analysis. TB laboratories offer valuable translational research material. There is no substitute for TB histology paired with history and audiometry in describing anatomic phenotypes associated with hearing and balance disorders in humans. More, light-microscopic characterization of phenotype may prove essential to future genomic and proteomic characterizations and molecular therapy. Despite potential opportunities offered by TB laboratories, dedicated effort in maintaining and expanding traditional TB research laboratories is isolated to few sites nationally.

Reasons underlying the lack of concerted development of TB laboratories likely relate to methods employed. Limitations of TB research are well recognized: (1) Procuring TBs on cases with existing detailed, prospective historical records is problematic and (2) conditions surrounding death, particularly prefixation times and temperature, hamper optimal tissue fixation. Due to processing limitations, TB laboratory research has not often advantaged developments in molecular research (particularly genomic and proteomic approaches) and, as a result, may contribute little to hypothesis-driven, basic science that emphasizes gene expression and proteomics.

Though the future of our own TB research laboratory appears secure, its growth is not likely under present circumstances. We believe, however, that there are prospects for improving this outlook. New approaches to training and support for advanced research that incorporates TB laboratory resources offer opportunities for expanding insights. Consideration should be given to supporting a national TB bank effort that offers improved access and promotes collaborations of neurotologic clinician-researchers unified by particular research themes.

Training

The TB laboratory provides an ideal milieu for the early training of neurotologic clinician-scientists. A primary goal should be to expand the scope of TB research by enabling greater access to existing temporal bone material and encouraging the application of newer research methods. Methods applied should optimize the amount of information we can derive from existing specimens. Research opportunities utilizing existing TB collections should be readily available to young neurotologic clinician-researchers.

One approach to training might make better use of existing TB research laboratories by improving access for neurotology fellowship trainees. Opportunities to conduct TB research would seem to be a natural fit for neurotology trainees given their career focus on surgical anatomy of the skull base. Fellows accepted into approved neurotology fellowships represent a potentially valuable pool of young clinician-researchers. For example, the NIDCD could fund competitive research fellowships for fellows to travel to an institution with an existing TB research lab.

The research fellowship could be part of an ACGME-accredited neurotology fellowship, fulfilling requirements for time in research. One attractive feature of this proposal is that it would help to address a national challenge in funding ACGME-approved fellowships in neurotology. Direct billing for services by approved fellowship-trainees is not allowable under CMS guidelines. In particular, fellows with prior training in research techniques could expand the scope of work carried out in existing laboratories.

Other training initiatives might encourage the use and development of TB research laboratories through incentives for training in the analysis of TB specimens as corollary projects in "R" and "K" grant applications, and in resident training through "T" grant applications.

Future directions for TB Research Support

Support for TB research should encourage the use of emerging approaches to extend both the depth and breadth of data acquired from TB specimens. Expanded applications of immunohistochemistry and electron microscopy can augment conventional histopathologic characterizations. The breadth of TB research can be widened with greater application of molecular methodologies, robotics, and morphometry. The preservation of the capability to effectively process TB material may prove valuable to the development of minimally invasive surgical procedures and implantable device design.

Enhanced access through digital imaging
If support for digitization, storage, and retrieval of images were available, wider utilization of TB specimens would result. That is, TB collections would be utilized more frequently if they were accessible with searchable queries over the Internet, with a resource to allow someone to purchase a high quality LM image of a particular section or TB. Low resolution images can certainly be made available over broadband Internet as well.

Protease-mediated degeneration of subcellular components in TB material imposes a fundamental limitation. TB research should be recast to enable molecular characterizations of hearing and balance disorders. With increased understanding of the genetics of disorders of hearing and balance, collected material for study should allow for DNA sequencing. Archived TB specimens offer both nuclear and mitochondrial DNA. Basic DNA sequencing would identify candidate mutations allowing for the detection of known genetic causes of ear pathology and would help to identify new disorders. One approach would include genetic sequencing of suspected genes in donors, in addition to TB harvesting. Obtaining blood is easier than harvesting TBs, so a dedicated program of blood collection is needed. We believe that individuals interested in donating their temporal bones are likely to agree to DNA testing. Searches of collected genetic info can be expanded as our understanding increases. Thus we believe it makes sense to start developing this source of data now as it may be of great benefit to future research.

Evolving capabilities afforded by radiologic and molecular techniques are such that the most effective specimens to bank for studying TB pathology may not the TBs themselves, but rather high resolution CT and blood for DNA studies. Such specimens are also much less costly and time intensive to obtain, store, and disseminate than is bone histology. While having bone histologic specimens available for correlation with radiologic, genetic, audiographic, and clinical outcomes data is undoubtedly useful, funds should be directed toward building archives of blood and radiologic images for each new temporal bone added to the archive.

Since blood is not always available from TB donors post-mortem, marrow (or other soft tissue) from each new temporal bone logged would at least save some DNA for later studies.

Alternative approaches to embedding and sectioning TB tissue should be explored. Thought needs to be given to the fixatives and embedding media used. New approaches might examine post-decalcification stages of embedding and sectioning employing techniques that facilitate immunohistochemical and ultrastructural analysis.

The feasibility of extending temporal bone processing beyond current light microscopic studies can be examined in controlled animal studies that investigate the effects of post-fixation delay, for example.

Development of TB research collaborations
We encourage discussion as to whether consortia of TB researchers should be organized to pursue particular research themes, promoting interactions between basic and applied scientists. Models of such consortia exist (e.g. SPORE-supported collaborations), with the expressed intent of supporting a translational research focus. For example, a systematic approach to exploring TB pathology may be guided by morphometry and DNA analysis using archived specimens from existing TB laboratories whose combined collections would offer stronger research material.

Approaches to TB procurement
Currently most TB labs receive no NIDCD financial support for procurement efforts. Potential donors are directed to have their families contact us upon death. To expand current collections we will have to come up with the resources to harvest, decalcify, section, stain, and store new temporal bones. A centralized repository of data on candidate donors might facilitate an organized approached to TB procurement.

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