Training Mouse Pathologists: Ten Years of Workshops on the Pathology of Mouse Models of Human Disease

On September 23–29, 2011 the 10th annual workshop, Pathology of Mouse Models of Human Disease, for veterinary and human pathologists, was held at the Indiana University-Purdue University-Indianapolis (IUPUI) campus in Indianapolis, Indiana. In this report we outline the rationale for setting up this workshop series, summarize our experience in its development, and outline our main goals and perspectives.

The laboratory mouse has been critical to biomedical research since Clarence Cook Little defied the thoughts of the day nearly a century ago by creating the first inbred mouse strain (Holstein 1979). Nearly 100 years later, mice, or more recently, genetically engineered mice (GEMs) (Peters et al. 2007; Rosenthal and Brown 2007; Ward et al. 2000), have become the primary biomedical tool for major genetic-based medical breakthroughs. This trend continues even more so with the international knockout mouse project (KOMP), which aims to create GEMs in which every known gene in the mouse is inactivated (Abbott 2010). Other exciting breakthroughs, ranging from large-scale aging projects (Sundberg et al. 2011; Yuan et al. 2009) to mutagenesis strategies (Clark et al. 2004; Goldowitz et al. 2004) to new genetic tools such as the diversity outcross (Svenson et al. 2012) and collaborative cross (Chesler et al. 2008) mice, will further expand the value of mice and the need for detailed and accurate histopathological phenotyping (Schofield et al. 2011). Although the technology to create mutant mice has become more or less routine, there is a critical shortage of expert pathologists to do the requisite pathology phenotyping in which accurate comparisons are made with human diseases (Schofield et al. 2009).

Veterinary pathologists are trained in the pathology of multiple species but have only limited knowledge of human pathology, and their experience with laboratory mice is generally restricted to the diagnosis of infectious disease and standard domestic and research animals. Many veterinary pathologists gain expertise in toxicologic pathology while evaluating rodent tissues for the pharmaceutical and chemical industries, but few are trained in the nuances of mouse genetic-based pathology and the validation of human disease models. By contrast, physicians have extensive knowledge of human pathology, but many are not well versed in the intricacies of mouse anatomy, pathology, and genetics or comparative pathology in general. We have made a great effort to redefine a pathology training program and services that integrate veterinary and human pathologists into a cohesive interdisciplinary approach on an institutional basis (Sundberg et al. 2004); however, the traditional Hippocratean, mentor–student approach to teaching medicine remains one of the most effective approaches. To focus on this topic, in 1999, Drs. Jerrold Ward and John Sundberg organized the first large meeting to focus on this topic, Pathology of Genetically Engineered Mice, which was held at the National Institutes of Health in Bethesda, Maryland. Although this semicomprehensive meeting resulted in the production of a well-regarded textbook (Ward et al. 2000), the conference itself was not accessible to many practicing pathologists who needed training and confidence to meet the new demands. Further large meetings, which were held on different continents, eventually evolved into a state of the art program on GEMs. It was problematic that mouse pathology was no longer the emphasis of this program, since genetics played a major role at these meetings.

To meet the specific needs of pathologists, we recognized that a different approach was required. To encourage direct open interaction and network development, the format was changed to small, focused meetings, each of which was led by a core group of veterinary and medical pathologists who enlisted the help of other world authorities in medical research. The annual meetings, each of which featured approximately fifteen faculty members, were limited to twenty to twenty-five participants on average, and they occurred in different research institutions at locations throughout the United States. Since the fifth meeting (Sundberg et al. 2007), we have held meetings at The Jackson Laboratory (2007, 2009), Cornell University (2008), the University of Washington (2010), and IUPUI (2011). The next meeting will be at The Jackson Laboratory, September 9–15, 2012. The goal has been to encourage pathology residents and veterinary and human pathologists to attend and to encourage investigators to take advantage of the opportunity to interact with the world authorities who visit their campuses.

The basic format has remained the same each year. However, workshop location–based faculty contributions provide the diversity of additionally covered topics, making each workshop a unique event. Each workshop provides a week of intensive lectures in pathology and histopathology and with some lectures on related disciplines and methods, including mouse genetics and didactic sessions in which particular disease areas and models are discussed. Wet labs on necropsy procedures or new technologies are also provided. We developed interactive digital slide sessions and discussion sessions on other aspects of pathology, including career development and running a mouse pathology service. The core faculty consists of experts in their respective areas of mouse pathology, and they describe the latest breakthroughs in their fields. Additionally, world experts, such as Dr. Matthew H. Kaufman from the University of Edinburgh in Scotland, well known for his classic texts (Kaufman et al. 2010; Kaufman 1992; Kaufman and Bard 1999), covered mouse embryology. Dr. Xavier Montagutelli, from the Institut Pasteur in Paris, France, covered basic mouse genetics. These and other distinguished scientists provide an international flavor that attracts an intercontinental list of participants to the meeting. Other speakers, such as Dr. Peter Vogel, formerly the chief pathologist at Lexicon and now at St. Jude’s in Memphis, Tennessee, were former attendees who are now regular presenters in their areas of expertise.

Speakers cover public databases such as The Mouse Genome Informatics Database (http://informatics.jax.org/); the Mouse Tumor Biology Database (http://tumor.informatics.jax.org/); Mouse Phenome Database (http://phenome.jax.org/), Pathbase (http://pathbase.net/); The National Cancer Institute Mouse Models of Human Cancer (http://emice.nci.nih.gov/); and The University of California Comparative Medicine virtual slide site for mouse models of cancer (http://imagearchive.compmed.ucdavis.edu/). This information provides the participants access to mouse anatomy and pathology resources of which they were often previously unaware (Sundberg, Ward et al. 2009). Textbooks were made available to acquaint participants with the classics in the field (Hedrich and Bullock 2004; Holland 2004; Maronpot et al. 1999; Mohr et al. 1996; Percy and Barthold 2007; Smith et al. 2002; Sundberg 1994; Sundberg and Boggess 2000; Sundberg and Ichiki 2005; Treuting and Dintzis 2011). In addition, the organizers contributed to the development of the latest classification systems for mouse proliferative lesions; such classifications have been published in Cancer Research and other top-ranking journals during the past few years. These classification systems were discussed in the context of integration with pathology ontology databases, such as MPATH, that can be used to expedite daily diagnostic workflow (Schofield, Bard, Boniver et al. 2004; Schofield, Bard, Booth et al. 2004; Schofield et al. 2010; Sundberg, Schofield et al. 2009; Sundberg et al. 2008).

These annual workshops provide a state of the art overview of the pathology of GEMs as well as spontaneous diseases affecting inbred strains and results of experimental manipulations. More importantly, they allow for the integration of this field with other research areas, such as genetics and molecular biology. Of even greater significance, the workshops promote effective working relationships between veterinary and human pathologists, in which they join forces to make the most accurate histopathologic interpretations and the most creative uses of these fantastic biomedical tools. Given that the number of applicants consistently exceeds the number of available slots, we look forward to the continuation of these workshops as an important contribution to the research community.