Department of Animal Science Advantages of Domestic Species As Dual Purpose Models

Domestic Species as Dual-Use Models in Animal Agriculture and Biomedicine Summary of Recommendations June 29, 2007

Introduction: Agriculturally important domestic species provide high quality human nutrition and have an enormous economic value to the US economy (excess of $100 billion annually; (http://www.ers.usda.gov/topics/animal-products.aspx) . Moreover, development of new animal models for human diseases is crucial to the pace of discovery of better diagnostic tools, preventative measures and therapies to eradicate economically and socially important problems such as obesity, infertility, infectious disease and cardiovascular disorders. The emergence of mouse models has allowed the scientific community to make rapid progress in understanding the genetic basis of disease. However, the application of findings in rodent models to human health has serious limitations. Agriculturally important animals, on the other hand, can be used not only for research to improve animal agriculture, but as biomedical models they more often mimic human disease states than rodent models because they more closely parallel the anatomy and physiology of human beings (Advantages). Because research using domestic species requires special facilities and expertise, it is important that highly qualified research scientists utilizing domestic species for research in animal agriculture and (or) as biomedical models be supported by federal funding agencies to ensure that their unique contributions to new medical and agricultural knowledge are enhanced. Consequently, the following important points relevant to domestic species, agriculture and human health also provide strong justification for why USDA and NIH should jointly advance domestic species as dual-purpose models to resolve high priority problems common to both animal agriculture and biomedicine: A) The missions of USDA and NIH are inextricably linked because health, well-being and fertility of domestic species are foundational to the availability and affordability of high quality, nutritious food, which in turn, contributes directly to human health. B) Genetic lines of agricultural animals, facilities and faculty expertise present at Land Grant Universities throughout the U.S. are valuable resources that are substantially underutilized for studies to benefit human health. Therefore, enhanced use of domestic species as biomedical models would have the additional benefit of generating important new information directly relevant to many areas of research in animal agriculture.

Previous Activities: Stakeholders, comprised of internationally recognized scientists funded both by NIH and USDA, university administrators, and officials at NIH and USDA conducted two workshops in the past three years. A white paper was developed and a series of meetings were conducted with officials at NIH and USDA. The most recent workshop was held at Lister Hill Auditorium on the NIH campus on April 19-21, 2007. The workshop featured presentations from three internationally recognized experts in each of the following areas of research that impact both biomedicine and agriculture: 1) reproduction and developmental biology, 2) developmental origins of disease, 3) metabolism, and 4) infectious diseases.

Recommendations: Agriculturally important domestic species have enormous value both to biomedicine and agriculture, but are underutilized as biomedical models in each of the aforementioned areas of research. Consequently, the workshop speakers and steering committee developed the following recommendations:

A. Recommendations to USDA and NIH for joint funding/program opportunities:

Stem cells: Development of a jointly funded program to improve methods to: a) promote genetic recombination in somatic cells to enhance efficiency of generation of genetic �knockout� animals through somatic cell nuclear transfer, and b) enhance efficiency of nuclear reprogramming to create stem cells and improve efficiency of cloning of domestic species is recommended. Tangible impacts relevant to the mission of the USDA and NIH include development of transgenic farm animals with economically important traits (e.g. disease resistance, high fertility, enhanced meat quality/growth) or nutraceutical value and development of new domestic species biomedical models for human diseases.

Oocyte quality: Development of a jointly funded program is recommended to understand the mechanisms that regulate competency of oocytes to develop into viable offspring (egg quality) and to identify reliable markers of high quality oocytes. Tangible impacts relevant to the mission of USDA and NIH include improved success of in vitro fertilization and embryo transfer and improved cloning efficiency in farm animals and enhanced success of assisted reproductive technologies in humans.

Developmental origins of adult disease: Development of a jointly funded program using domestic species is recommended to elucidate the impact of the environment in utero on developmental programming leading to onset of disease in adulthood, and to identify the mechanisms whereby the environment alters developmental programming of embryo/fetus and subsequent health, growth, and fertility of offspring. It is becoming more evident that the mother�s environment (e.g., nutrition, obesity, toxicants, drugs, disease) during pregnancy can have a major impact on mechanisms that regulate embryonic and fetal development (developmental programming), which in turn, may compromise health of the offspring. However, little, if any, attention has been paid to the impact of the environment during pregnancy of farm animals on subsequent economically important traits in the offspring such as growth rate, lactation, disease resistance and fertility. Moreover, biomedical models to investigate developmental origins of human disorders are scarce. Tangible benefits to USDA and NIH include development of new therapies to prevent or treat negative effects or enhance positive effects of the environment on embryo/fetal development and subsequent health of human beings and on economically important traits (e.g., growth, fertility, disease resistance) in farm animals.

Metabolism: Development of a jointly funded program to elucidate the biology of adipocytes, including the mechanisms regulating lipid metabolism and fat deposition in a tissue- and stage-specific fashion in domestic species is recommended. Tangible benefits to NIH and USDA include development of a better basic understanding of the causes of obesity in humans and improved meat quality and enhanced performance (e.g., lactation) in farm animals. This new information will not only provide a better understanding of how fat deposition is regulated and thus lead to treatments that improve consistency of meat products in farm animals and their nutritive value, but also provide valuable new insight into the mechanisms involved in human obesity, perhaps leading to novel therapies to combat this worldwide human disorder.

Infectious disease: Control of diseases in animal reservoirs prior to spread to humans has a tremendous impact on public health and provides unequaled cost-effectiveness. The control of rabies and milk-borne Mycobacterium and Brucella provide clear examples of this efficacy�approaches that can now be applied to other pathogens such as avian influenza, E. coli O157:H7, and Salmonella. This approach, clearly recognized in the recent AMA-AVMA initiative, requires new coordination between USDA and NIH and joint funding by both agencies is recommended to study pathogen transmission within animal populations and development of vaccine strategies to block transmission at the animal level�before emergence into the human population.

Development of reagents and resources including transgenic animals: Development of a jointly funded program that would provide a supplement to awarded grants that develop new reagents, resources and transgenic farm animals as part of the overall research plan (in place of �stand-alone� reagent/resource/transgenic animal development funding) is recommended. The supplement could include additional funds to develop critical antibodies, transgenic animals, tissue repositories, gene chips, high throughput genome screening, and complete genome sequencing of all food animal species of economic importance, e.g., the sheep.

B. Recommendations to NIH: Suggestions to strengthen the review practices at the NIH Center for Scientific Review: 1. Ensure that experts on biology and advantages of domestic species be represented on study sections. 2. Educate study section members on the need for outstanding integrative projects in domestic animal biology so that study section members will give them serious consideration. 3. Flag applications that fit in the large animal category for strong consideration by review panels. For example, indicate in reviewer instructions that alternative animal models may have important advantages that improve the translational quality of the research results compared with traditional rodent models and emphasize importance of alternative animal models to quality of applications.

C. Recommendations to stakeholder scientists and affiliated universities: 1. Publish articles that highlight the strengths and advantages of domestic species as dual- purpose models in animal agriculture and biomedicine, especially for vaccine studies; recapitulation of human disease for pathogenesis studies; elucidation of mechanisms that regulate growth, nutrition and metabolism; reproduction; and developmental origins of adult disease. 2. Enhance collaboration between centers with animal model expertise and medical schools/medical research institutes to facilitate both model development and new approaches to disease control at the animal-human interface. 3. Facilitate collaboration between biomedical and animal scientists to encourage development of new strategies to improve animal agriculture and human health. 4. Reorganize the land grant mission, philosophy and hiring practices to include and facilitate biomedical research. Refer to white paper for recommended ways land grant institutions can enhance use of domestic species as dual-purpose models in animal agriculture and biomedicine.