September 15, 2007 (Vol. 27, No. 16)

Without Proper Training and Organization, Research Dollars Will Be Wasted

The biotechnology industry faces a major problem; too many genetically modified mice and too few comparative pathologists. National and international programs aimed at unraveling the mysteries of the genome will produce a flood of transgenic and knockout mice but not the resources for their characterization.

Compounding the problem, for each gene multiple technologies will be used to generate mice, and reporter genes will be used to monitor tissue-expression patterns in the presence or absence of discernable histological changes. Yet these consortia have no plans for developing the intellectual and scientific workforce needed to phenotype these mutant mice. Without accurate and consistent phenotyping of the projected glut of new mouse strains, the scientific community will be unable to take advantage of these remarkable animals.

We cannot rely on individual investigators to comprehensively phenotype a mouse strain of interest. Genetically modified mice have numerous unexpected and hidden phenotypes that have often been missed or unappreciated by the untrained, unaware observer. Few investigators have the training necessary for proper analysis and they frequently have to rely on inadequately trained colleagues. The threat this poses can be seen in the egregious errors of interpretation already in the literature due to under-trained individuals.

Examples are numerous. Results of misdiagnoses are far reaching and can impact years of research and millions of dollars in lost opportunity costs. Clearly, industry cannot afford these expensive errors. The concerns become even more critical with the formation of the International Knockout Mouse Consortium aimed at knocking out the entire mouse genome and creating as many as 200,000 additional new mouse strains.

Importance of Pathologists

How are we to address this problem? The challenge for industry is to make effective, efficient use of the resources provided by our governments. The current plans do not include the resources necessary to phenotype the over-abundance of animals. Most alarming, comparative pathologists, an essential resource, are in increasingly short supply and in danger of extinction.

Comparative pathologists are the gatekeepers of translational research. Without them, genomic changes cannot be properly understood or appreciated. To be valid models of human disease, the mice must be accurate replicas. Their validation requires expert comparative pathologists with experience in both mouse and human histopathology. Comparative mouse pathology requires a unique set of skills and a knowledge base not possessed by most investigators or, for that matter, the standard pathologist. Validation requires familiarity with the nuances of the mouse, and the knowledge of the human condition to be emulated by the mouse model.

The NIH is investing significantly in mouse-related research, but the investment will be all for naught without the validation, effective application, and translation toward the advancement of human health that is provided by comparative pathologists. NIH recognizes this problem but has not made the necessary investment of resources to correct it. Furthermore, NIH funding mechanisms allow for scientific training and research but not discipline training such as pathology.

The austerity of the NIH budget does not bode well for solving the problem. Veterinary pathology training programs are also poorly positioned to address this need. This leaves the private sector with little option other than hiring pathology graduates at exorbitant prices and hoping to provide the necessary training on the job. Our experience, unfortunately, is that this does not happen. Leadership from and investment by industry is still critically needed.

The government has created some useful, though inadequate, resources through various loosely organized networks of expert comparative pathologists. They currently consist of informal, unsupported fellowships of kindred souls sharing common interests and expertise. These networks represent a tremendous asset but they need to be organized, formalized, and better utilized.

An effective solution to the problem is to develop an electronic consortium of these existing experts in mouse pathology whose collective wisdom could be shared with interested young pathologists using appropriate distance-learning tools. A panel of such experts would also provide the confirmatory second opinion that guarantees the private sector a source for rigorous independent review.

While the technology for such a distance-learning consortium is currently available, a stable funding base needs to be developed. The solution also should include: NIH funding for workshops and continuing education courses in mouse pathology, support for publication of additional materials in mouse comparative pathology, and a review of all comparative pathology grant proposals and manuscripts by competent comparative pathologists. The net effect of these initiatives would not be constraining but rather would streamline the analysis of new strains and the training of new personnel.

How can the private sector, a major benefactor of these programs, best access and support the education of a future generation of pathologists? The U.S. government has no plan to pay for the training required to characterize the mice. We suggest that the biotechnology industry needs to recognize the pending predicament and join with us in addressing the issues before they become catastrophic. As active participants, the biotech industry stands to derive numerous benefits, including the education of pathologists that it will need to exploit the promise of genomic information.

The burden can be minimized for individual companies by the formation of a consortium supported by the private sector. This consortium can sponsor the development of more formal networks of comparative pathologists, which will provide the training platform for young pathologists who will oversee the complete and accurate phenotyping of the expected mouse glut. Without this initiative, the future will be an expensive disaster.

Robert D. Cardiff, M.D., Ph.D., is a distinguished
professor of pathology in the School of Medicine and Center for Comparative Medicine at the University of California, Davis, and Bruce W. Altrock, Ph.D., is an adjunct professor in the biomolecular science and engineering program at the University of California, Santa Barbara. E-mail: [email protected].

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