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Merchant

Funding of Temporal Bone Laboratories

By Saumil N. Merchant, M.D.
Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston, Massachusetts

August 21, 2003

Submitted to:
A. Julianna Gulya, M.D.
Workshop on Temporal Bone Histopathologic Research: Laboratories and Research Training
Organized by NIDCD
September 12, 2003

Importance of Studying Human Temporal Bones

A knowledge of the pathologic basis of disease is central to the study of medicine, including disorders affecting the auditory and vestibular systems. Otology is unique in that the inner ear is inaccessible during life and so, conventional techniques of pathologic study such as biopsy and surgical excision are not feasible. Consequently, insight into the pathologic basis of ear disease can only be obtained by postmortem study of temporal bones. The procurement, processing, and study of temporal bones is a time consuming and costly endeavor which lies outside the purview of clinical departments of pathology, and is therefore a research endeavor that is performed in temporal bone laboratories. There are several reasons why continued study of human temporal bones is warranted:

  1. There are a large number of auditory and vestibular disorders whose pathologic basis remains unknown. For example, there are over 500 syndromes with various kinds of hearing loss, many of them genetically determined. Yet, on a worldwide basis, temporal bones from less than 50 of these syndromes have been examined. While animal models can provide valuable information regarding the molecular bases of inner ear disorders, it will be important to verify the validity of these models by comparison with the otopathology, as determined in human cases. Studying human specimens can generate hypotheses regarding mechanisms of hearing loss which can then be tested experimentally in a suitable animal model. Thus, human and animal otopathology are complementary in terms of the information they can provide to researchers interested in genetics of inner ear disorders. There are also many auditory and vestibular syndromes for which no animal models exist, and so the study of human specimens in such cases becomes important.
  2. In addition to genetically determined labyrinthine disorders, there are a number of other common clinical conditions for which none or very few human temporal bone specimens exist anywhere in the world. Examples include Bell's palsy, sudden idiopathic deafness, vestibular neuritis, perilymphatic leak, etc. Unless we understand the pathologic bases for these disorders, it is difficult to implement rational diagnostic and therapeutic strategies.
  3. Another important area for study is to evaluate the efficacy of otologic surgery on the ear. For example, there are very few well documented specimens from patients who have undergone surgery for Meniere's disease. Hundreds of operations are performed annually for Meniere's disease and we do not know whether these procedures actually do what they are supposed to. Over 20,000 cochlear implants have been inserted in patients, and yet, less than 50 temporal bones with implants are available nationwide. Elucidation of the histopathologic changes can lead to a better understanding of the success or otherwise of surgical procedures and also lead to improvements in techniques and technologies.
  4. Finally, there are very few temporal bone specimens that have been procured from normal individuals with well-documented normal levels of hearing and balance function. Normal specimens are essential to serve as controls, especially in studies utilizing molecular and cellular methods of investigation. For example, in order to investigate whether mitochondrial mutations result in presbycusis, one needs temporal bone sections from well-defined normal controls.

Components of a Temporal Bone Laboratory

There are several factors that play in a role in establishment and maintenance of a successful and productive temporal bone laboratory (Schuknecht 1987; Ann Otol Rhinol Laryngol; Vol 96, Suppl 130).

  1. Source of temporal bones. A steady supply of normal and pathologic temporal bones with good documentation of vestibular and auditory function performed reasonably close to death is essential. In the U.S., temporal bones have come from two main sources: by harvesting specimens at routine autopsy and from the national temporal bone donor program of the NIDCD National Temporal Bone, Hearing and Balance Pathology Resource Registry (The Registry). Over the past several years, there has been a sharp decline in the number of specimens acquired at routine autopsy, because of a significant decrease in the number of autopsies and because temporal bone removal is not permitted in some cases by the next of kin. As a result, the importance of the Registry as a source of pathologic temporal bones has become even more critical.
  2. Research Assistants and Technicians. The preparation of temporal bones by various techniques including light microscopy, electron microscopy, and immunostaining requires special knowledge and skill and many years of experience. Skillful technicians and research assistants are critical to the success of any temporal bone laboratory.
  3. Director and Investigators. The personnel engaged in otopathology studies in a laboratory should include both MD and PhD researchers. The Director of a temporal bone laboratory should preferably be an otologist or a basic scientist who has active clinical collaboration. Knowledge of clinical problems can help to generate hypotheses and research questions that can be tested and explored using a temporal bone collection or using animal studies. Clinical knowledge also helps in more meaningful interpretation of findings observed during otopathologic studies.
  4. Research Fellows. The productivity of any laboratory is enhanced by research fellows that are engaged in projects pertaining to otopathology. Moreover, this is an important mechanism for training the temporal bone researcher and investigator of the future.
  5. Infrastructure for processing, storage, and retrieval of temporal bone specimens. A laboratory requires adequate space for processing new specimens. Facilities are also needed for storing both stained and unstained histologic slides in a manner that permits easy access for otopathologic studies. A computer-based database is necessary to record the otopathologic findings of each case in a manner that facilitates easy access and retrieval. A laboratory also needs audiovisual equipment to create and store images of interesting cases for research, publication, and teaching, preferably in digital format.

Budgetary Needs

A survey by Nadol (1989; Ann Otol Rhinol Laryngol; Vol 98, Suppl 143, 47-48) of temporal bone laboratories in the U.S. indicated that the average otopathology laboratory processed 40 temporal bones per year. Further, the personnel comprising a typical laboratory were 2 MD/PhD investigators, 2 technicians and 2-4 research fellows. At present, the approximate cost of acquisition and processing each new temporal bone specimen in our laboratory, including cost of chemicals and technician time, is $2,700 per temporal bone specimen. For 40 temporal bones per year, this translates into an annual expense of $108,000. Additional budget needs would include salary support for investigators and research fellows, funds for travel, publication costs, and funds for computers and audiovisual equipment. The budget for an average laboratory would be approximately $250,000 to $300,000 per year (direct cost), which is similar to that of a typical R01 grant.

Long Term Value of a Temporal Bone Collection

The hematoxylin and eosin stained slides from a temporal bone last for decades, thus allowing repeated studies on the processed specimens. In addition, the unstained slides, which are usually stored in 70% alcohol, also permit future studies using conventional and newer techniques of study (such as nucleic acid retrieval). The value of a temporal bone collection is enhanced with the acquisition of greater numbers of temporal bone specimens. As more specimens of a given diagnosis are acquired, hypothesis-driven studies can be performed and adequate assessments can be made of the variation in the histopathologic expression of a given disorder. Furthermore, the availability of unstained sections permits the application of techniques of study that are developed in the future in ways that cannot be predicted at the present time.

Role of the Registry

The NIDCD National Temporal Bone, Hearing and Balance Pathology Resource Registry was established in 1992 by the NIDCD to promote human temporal bone research by serving as a national resource for the researchers and the public. The Registry has a central office in Boston and its peripheral member network consists of all active and inactive temporal bone collections and laboratories that currently exist in the U.S. The Registry functions under a contract with the NIDCD and its main activities are as follows.

  1. The Registry has developed and maintains a computerized database cataloging information on temporal bone specimens contained in the various U.S. collections. Information is available on over 12,600 specimens from over 7,500 individuals and is easily retrievable using a search program similar to MEDLINE.
  2. The Registry maintains a nationwide temporal bone donor program. To date, over 5,000 individuals have been recruited to donate their temporal bones and central auditory and vestibular pathways. The Registry maintains up-to-date information about the auditory and vestibular disorders of its donors, which facilitates clinico-pathological correlations when the specimens are ultimately acquired.
  3. The Registry maintains a national tissue procurement network through which it has coordinated the retrieval of over 350 temporal bones and 100 brain specimens, all from donors with well-documented otologic disorders. These specimens were distributed amongst the active temporal bone laboratories in the U.S. for histologic processing and scientific study.
  4. The Registry maintains voice, TTY, and fax telephones and a website for the lay public and the scientific community to provide information regarding human temporal bone research and to respond to inquires. The Registry develops and disseminates information regarding temporal bone research via displays and exhibits at scientific and lay meetings, and articles in the lay media. The Registry also publishes a newsletter on advances and opportunities in otopathology research, with a circulation of over 12,000. The newsletter is published semi-annually.
  5. The Registry has organized several professional educational courses for the benefit of otopathologists, technicians, and students including half day didactic and full day, hands-on workshops.
  6. In its most recent project, the Registry has begun a program to obtain DNA during life from enrolled temporal bone donors using sterile buccal swab brushes. To date, over 1,100 donors have enrolled and provided such DNA. The DNA is frozen, in which state it will last for decades, and will provide a reliable source of genomic DNA to complement the histopathological studies on the donated specimens.

As will be evident from the above synopsis of the Registry's activities, the Registry facilitates the enrollment and tracking of temporal bone donors and the acquisition of their specimens upon their death. However, the Registry does not process temporal bone specimens. Rather, the specimens so procured are forwarded to the individual temporal bone laboratories for processing and scientific study. Prior to establishment of the Registry in 1992, one of the major problems in otopathology was the lack of a successful mechanism for procurement of pathologic temporal bones upon the death of a donor. At that time, there was a dearth of well-documented temporal bone specimens, but an abundance of laboratories willing to process and study such specimens. The Registry has been very successful in not only enrolling new donors but also in ensuring successful procurements of temporal bone and brain specimens upon the death of enrolled donors. Unfortunately, many previously active temporal bone laboratories have lost funding and have become dormant in the past several years. As a result, the Registry often finds itself in the situation where the temporal bone laboratory that was assigned to receive a particular individual's tissues is no longer active, and the Registry then has to locate an alternative laboratory for processing and scientific study.

Thoughts on Possible Mechanisms for Funding of Temporal Bone Laboratories

  1. A mechanism should be set up to fund the initial routine processing and study of prospectively acquired temporal bones ("core function"). This would consist of basic processing (fixation, decalcification, sectioning), staining of selected slides (every 10th or 20th), and a report containing a summary of the medical history and preliminary histologic findings. Thus, a library of temporal bone and brain specimens would be generated, which along with the DNA acquired during life by the Registry, would become a resource that can then be accessed by individual researchers and laboratories for more detailed scientific investigations. Such a core function could be entrusted to 3 or 4 designated laboratories in the U.S. or a special center could be set up for this purpose. Funding mechanisms that might support such a core function include an NIH contract, an R24 grant, or a P30 grant. Such a core could be administered by directors of active laboratories with oversight from the NIH.
  2. Consideration should also be given to developing a viable and long term funding mechanism to support the research activities of individual temporal bone laboratories (laboratories which are currently inactive or new laboratories). One of the biggest hurdles faced by otopathology researchers is the inability to compete successfully for NIH funding because temporal bone research, in general, is not hypothesis-driven. One cannot control or predict which temporal bones will be acquired at what point in time. As a result of the funding difficulties, it has become very difficult to recruit young investigators into temporal bone research. For the field to survive and grow, it is vital that budding investigators should feel that there is a future in otopathology research. Consideration should be given to a special study section to review applications from individual laboratories for temporal bone research.
  3. A mechanism should be established for the training of future otopathologists. For example, this might include funding of 1 or 2 trainee fellowships per year at each active laboratory in the country, perhaps via a T32 mechanism.

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