Abstract
Over 60% of NIH extramural funding involves animal-related research. Mice represent approximately 80–90% of the animals used in biomedical research, yet mice are often the least understood laboratory animal species. The number of genetically engineered mouse (GEM) mutants has risen substantially and the use of GEM models for hypothesis-driven research has also increased. However, the scientific community lacks sufficient numbers of adequately trained experts to accurately characterize these animals and validate the models. This letter is intended to increase awareness of the pending disaster and to solicit support in finding solutions.
Laboratory mouse populations are straining (pun intended) the housing capacity of research institutions. This growth remains unabated. On the heels of several large-scale mouse mutagenesis programs and considerable growth in GEMs created by individual laboratories, the National Institutes of Health is embarking upon the “knock out mouse project (KOMP),” with the goal of knocking out every functional gene in the mouse genome. Similar large-scale efforts are launching in Canada (NorCOMM: North American Conditional Mouse Mutagenesis Project), Europe (EUCOMM: European Conditional Mouse Mutagenesis Programme) and Asia. These trends have created rich opportunities and critical demand for expert comparative pathologists who are knowledgeable in mouse biology and human disease.
The genomics era has demonstrated the conservation of genetic information across species that gives credence to Osler's suggestion of there being only “One Medicine.” While the body systems do similar things across the spectrum of mammals, each species has its own characteristics in responding to various diseases. In this context, the mouse as a model of human disease has to be interpreted by pathologists who have knowledge of specific disease conditions in both humans and mice, and can evaluate mouse tissues knowing their unique similarities to and differences from humans. Thus, a unique specialty in pathology is required for the immense use of mouse models to be accurately evaluated in terms of comparative medicine.
The scientific literature is replete with erroneous interpretation of phenotype by scientists, (including pathologists) who lack expertise in mouse pathology. As much as it would be unacceptable to analyze structure of a molecule using x-ray diffraction data without a formally trained expert, it should be unacceptable to publish papers and fund grants purporting to model human disease without the expert review of a formally trained, knowledgeable pathologist. However, pathologists are frequently missing from important applications and papers. Effective mouse pathology requires a global understanding of mouse biology, euphemistically termed “Muromics” (for a more thorough discussion of Muromics, see Barthold, Comp Med. 2002 52:206–23.). In addition to comparative medical pathologists, there is a critical shortage of veterinary pathologists with expertise in the mouse. The scarcity of pathologists to serve biomedical research, and mouse-related research in particular, has been emphasized in several recent National Academy reports.
NIH recognizes this problem, but is attempting to address this shortage with only scant investment of resources. Furthermore, NIH funding mechanisms allow for scientific training and research, but not for discipline training, such as pathology. Financial austerity of the NIH budget does not bode well for solving the problem. Partnership and investment by industry, which waits at the doors of academic institutions to hire what few pathologists are being trained, is critically needed.
Why comparative pathologists? They are the gatekeepers of translational research. If mouse models are to be valid models of human disease, they must be accurately and adequately characterized. Comparative mouse pathology requires a unique set of skills and knowledge base that is not possessed by most investigators, or for that matter, the standard pathologist. It requires familiarity with the nuances of the mouse, and knowledge of the human condition that the mouse model purports to emulate. NIH is investing significantly into mouse-related research, but it is all for naught without validation, effective application, and translation toward the advancement of human health. Pathologists provide validation.
A 2004 Workshop sponsored by NCRR concluded that the United States has fewer than a dozen individuals that can be identified as legitimate “mouse pathologists” or more correctly, Veterinary or Physician Pathologists trained in or experienced in pathology of mice. Further, most of these dozen or so individuals are approaching retirement age. Where are the mouse pathologists of the future and who is going to train them? The mouse genetics community, encouraged by national and international organizations, is creating a glut of mice but not the human resources necessary for their characterization.
One solution to our dilemma is to develop an “electronic consortium” of existing “experts” in various aspects of mouse pathology whose collective wisdom would be shared, using appropriate distant-learning tools, with interested young pathologists. A panel of such experts will also provide the confirmatory “second opinion” that guarantees the investigator a source for rigorous review. While the technology for such a distant-learning consortium is currently available, a stable funding base needs to be identified and developed. The solution also should include: 1. NIH funding for training veterinary and physician pathologists in the specialty of mouse pathology; and 2. funds for workshops and courses in mouse pathology (independent meetings or at society meetings as CME courses), money for publication of additional materials in mouse pathology, not already published.
How can those of you who will benefit most from the study of disease with this huge population of mice pay for the education of the future generation of pathologists? The US government is funding the impending mouse glut, but will not pay for the human resource. We ask that the scientific community recognize the impending predicament and help address the issue before it becomes catastrophic. We need your understanding and support.
Ted Valli, D.V.M.
Stephen W. Barthold, D.V.M., Ph.D
Jerrold E. Ward, D.V.M. Ph.D
Cory Brayton, D.V.M.
Alex Nikitin, M.D. Ph.D.
Alexander D. Borowsky, M.D.
Roderick T. Bronson, D.V.M.
Robert D. Cardiff, M.D., Ph.D.
John Sundberg, D.V.M., Ph.D.
Tan Ince, M.D., Ph.D.