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2
Progress and Opportunities in Veterinary Research

This chapter outlines some of the contributions of veterinary research and the promise it holds for the improvement of public health and food safety, animal health, and the advancement of comparative medicine. Because animal welfare—defined as the well-being of individual animals, that is, normal functioning and freedom from disease and injury—is an extension of animal health that involves veterinary research, it is appropriate to include it in the field of animal health. Research in several subdisciplines of the three fields has been identified as critical for advancing and protecting animal and human health. In addition, several emerging issues span two or more fields, so they cannot be neatly categorized as subdisciplines of public health and food safety, animal health and welfare, or comparative medicine (Box 2-1). Although the different aspects of veterinary research are grouped under four headings—public health and food safety, animal health and welfare, comparative medicine and emerging issues, they are intertwined. For example, research in comparative medicine contributes to animal health through development of preventive medicine and treatment. Study of wildlife diseases contributes not only to wildlife health and conservation but also to the study of emerging infectious diseases, many of which are zoonotic.

PUBLIC HEALTH AND FOOD SAFETY

Food Safety

Foodborne illnesses, as defined by the World Health Organization, are diseases—usually infectious or toxic—caused by agents that enter the body through



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Critical Needs for Research in Veterinary Science 2 Progress and Opportunities in Veterinary Research This chapter outlines some of the contributions of veterinary research and the promise it holds for the improvement of public health and food safety, animal health, and the advancement of comparative medicine. Because animal welfare—defined as the well-being of individual animals, that is, normal functioning and freedom from disease and injury—is an extension of animal health that involves veterinary research, it is appropriate to include it in the field of animal health. Research in several subdisciplines of the three fields has been identified as critical for advancing and protecting animal and human health. In addition, several emerging issues span two or more fields, so they cannot be neatly categorized as subdisciplines of public health and food safety, animal health and welfare, or comparative medicine (Box 2-1). Although the different aspects of veterinary research are grouped under four headings—public health and food safety, animal health and welfare, comparative medicine and emerging issues, they are intertwined. For example, research in comparative medicine contributes to animal health through development of preventive medicine and treatment. Study of wildlife diseases contributes not only to wildlife health and conservation but also to the study of emerging infectious diseases, many of which are zoonotic. PUBLIC HEALTH AND FOOD SAFETY Food Safety Foodborne illnesses, as defined by the World Health Organization, are diseases—usually infectious or toxic—caused by agents that enter the body through

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Critical Needs for Research in Veterinary Science BOX 2-1 Subdisciplines of Veterinary Research that are Critical to Improving Public Health and Food Safety, and Animal Health and Advancing Comparative Medicine Public Health and Food Safety Food Safety Biosecurity Animal Health and Welfare Food-Producing Animals Aquaculture Companion Animals Laboratory Animals Wildlife and Conservation Comparative Medicine Animal Modeling Emerging Areas of Research in Comparative Medicine Emerging Issues Emerging Infectious Diseases Ecosystem Health Social Policies, Societal Needs and Expectations Exotic and Caged Pet Medicine the ingestion of food. They are a major cause of human morbidity and mortality in the United States, responsible for an estimated 76 million illnesses, 325,000 hospitalizations, and 5,000 deaths a year (Mead et al., 1999). Animals—both domesticated and wild—are frequent reservoirs of foodborne pathogens that can cause human illness and animals are among the most common vehicles of enteric bacterial infections in humans (http://www.cdc.gov/foodnet/). For example, more than 70% of sporadic Campylobacter infections in the United States have been associated with eating foods of animal origin or contact with animals (Friedman et al., 2004). Eating contaminated poultry products is largely responsible for cases of Salmonella enteritidis infection (Kimura et al., 2004). Escherichia coli O157:H7 infections are associated principally with eating products of bovine origin, contact with ruminants, and consumption of water contaminated with bovine feces (Kennedy et al., 2002; Kassenborg et al., 2004). Primary risk factors for multiple drug-resistant Salmonella newport infections are contact with cattle and consumption of bovine products (Gupta et al., 2003). Most of those microorganisms are commensals that reside in the animal gastrointestinal tract and cause no apparent symptoms of illness and had no adverse effects on weight gain or milk or egg production. Most foodborne pathogen infections have no effect on

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Critical Needs for Research in Veterinary Science animal health or on economic factors associated with animal production so there has been considerably less emphasis on veterinary food-safety research than on research to improve animal health, and greater advances have been made in controlling diseases of livestock and poultry than in reducing the occurrence of pathogens in these animals. Animal-associated pathogen contamination of food occurs both before and after harvest. Livestock and poultry are the primary sources of many harmful microorganisms that are transmitted to foods and on the farm during harvesting, slaughter, and processing. Such foods as meat and poultry can be directly contaminated with pathogens through contact with animal manure during production and processing, and other foodstuffs, such as fruits and vegetables, can be indirectly contaminated through the environment, for example via irrigation water tainted with livestock manure. Various determinants influence the carriage and transmission of foodborne pathogens during animal production and processing. For example, an animal’s diet can affect the microbial composition of its intestinal tract and can serve as a source of harmful agents, such as prions related to bovine spongiform encephalopathy from ruminant neurological tissue; in free-range conditions, outdoor exposure to wildlife presents a greater opportunity for transmission of indigenous pathogens of vermin, pests, and wild animals than does controlled indoor housing, which largely excludes vermin and wild animals; in some times of the year, such as summer, there is a dramatic increase in pathogen carriage by livestock and poultry; shipping of animals can induce stress and greater susceptibility to pathogen shedding; and slaughtering practices, such as cold-water chilling of poultry, can disseminate pathogens among carcasses during processing. There are many gaps in our understanding of where in the production and processing chain interventions will have the greatest effect on reducing pathogen loads and ultimately providing the greatest public-health protection. Of the estimated 76 million cases of foodborne illness that occur each year in the United States, CDC estimates that there are 62 million cases of food-associated acute gastroenteritis of unknown etiology (Mead et al., 1999). Although the causative agents of many well-documented foodborne outbreaks of distinctive illness (such as Brainerd diarrhea) remain unknown (Bean et al., 1996), many new foodborne pathogens were identified in recent years. For example, during the late 1970s and early 1980s, three major bacterial pathogens were first identified by microbiologists and public-health epidemiologists as agents of foodborne illness: Campylobacter jejuni, E. coli O157:H7, and Listeria monocytogenes. Since then, C. jejuni has become recognized as the leading cause of acute bacterial gastroenteritis in many developed countries, E. coli O157:H7 has been identified as the leading cause of hemolytic uremic syndrome, and L. monocytogenes has become a primary cause of death among recognized foodborne pathogens. It is possible that many emerging foodborne pathogens are not newly evolved but already exist in nature and have yet to be identified or associated with foodborne disease.

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Critical Needs for Research in Veterinary Science Resistance to antimicrobial agents has become a major public health concern and subtherapeutic use of antibiotics as growth promoters in animals has been alleged to be one of the major factors in antibiotic resistance. Arguments for and against that association have been presented (Turnidge, 2004; Phillips et al., 2004), but surveillance systems that monitor the distribution, occurrence, and trends in numbers of antimicrobial-resistant pathogens in humans, animals, and environmental sources will be critical for resolving this issue. The United States, in 1996, created the National Antimicrobial Resistance Monitoring Systems (NARMS), which was a collaborative effort of the Center for Veterinary Medicine in the Food and Drug Administration (FDA), the US Department of Agriculture (USDA), and the Centers for Disease Control and Prevention (CDC). Major contributions to the field of antimicrobial resistance among pathogens of animal and human significance have been achieved through elucidation of mechanisms of development of antimicrobial resistance. The principal genetic force responsible for induction of antibiotic resistance in bacteria has been found to be horizontal gene transfer of plasmids, transposons, and integrons. Although it is known that the emergence and dissemination of bacterial antimicrobial resistance result from numerous complex interactions among antimicrobials, microorganisms, and the surrounding environment, the relative importance of specific factors in mobilization of these genetic factors between organisms is unknown. The genetics revolution has led to potential introduction of desirable characteristics in food-producing animals, such as developing transgenic lines of food animals intrinsically resistant to traditional foodborne pathogens. However, methods used to modify animals genetically may introduce compositional changes, some of which may be undesirable. Potential hazards include toxicity, allergy, nutrient deficiencies and imbalances, and risks associated with endocrine activity. Research is needed to assess the safety and nutritional values of transgenic and cloned food animals. Continuing veterinary research on food safety is needed to improve detection and surveillance of foodborne pathogens associated with livestock and poultry production, define the ecology of foodborne pathogens in food-producing animals and their environment, develop interventions to reduce the dissemination of foodborne pathogens by poultry and livestock, study the development and mechanisms of antibiotic resistance of foodborne pathogens associated with animals in the food chain, and develop methods to assess the safety and nutritional value of transgenic and cloned animals. Examples of Critical Research Needs Rapid, sensitive, and accurate assays for detecting foodborne pathogens. Epidemiological approaches to identifying risk factors and intervention strategies that have the greatest effect on reducing foodborne pathogens and

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Critical Needs for Research in Veterinary Science antimicrobial-resistant microorganisms associated with livestock, poultry, and aquaculture. This includes a more comprehensive understanding of the epidemiology and genetic elements of the foodborne zoonotic agents, especially of those agents that have recently emerged. Practical and effective interventions for minimizing carriage of and contamination with food-associated pathogens of animal origin. Methods to assess the safety and nutritional value of transgenic and cloned food-producing animals. Identification of previously unrecognized foodborne pathogens of animal origin. Importance and Contribution of Research The US Department of Agriculture (USDA) Economic Research Service estimates more than $15 billion in annual medical expenses and lost productivity resulting from salmonellosis, Campylobacter enteritis, and enterohemorrhagic E. coli infections alone (USDA-ERS 2004). A concerted research effort to address food safety can prevent the recurrence and reduce the effects of the more than 3.5 million estimated cases of foodborne illness each year of which livestock and poultry are the primary sources of causative agents. Veterinary research will contribute to eliminating transmission of pathogens to foods of animal origin. Biosecurity Biosecurity is the integrated system of policies, training, and procedures designed to deter, interdict, detect, respond to, and recover from intentional introduction of biological agents or related products that can cause disease or death in humans, animals, or plants. Until 1997, almost all US research done for the purpose of developing countermeasures to biological warfare was done in the Department of Defense (DOD) (Zajtchuk, 1997). Veterinarians with board certification in laboratory animal medicine or comparative pathology or with doctoral degrees in specialty fields—such as physiology, pharmacology, toxicology, and microbiology—played an important role in that research. Research conducted at the US Army Medical Research Institute of Infectious Disease (USAMRIID) at Fort Detrick, MD—the lead DOD laboratory for medical biological defense—and in other laboratories led to important vaccines, drugs, and diagnostics for military personnel. Other government departments became involved in biodefense research—first the Centers for Disease Control and Prevention (CDC) in 1998 and then the National Institute of Allergy and Infectious Diseases (NIAID) in 2002. Several medical countermeasures developed at USAMRIID—such as cell-culture-derived smallpox vaccine and recombinant anthrax vaccine—have now been moved into advanced development by the Department of Health and Human Services.

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Critical Needs for Research in Veterinary Science Although food safety has been an integral part of veterinary medicine throughout history, food biosecurity is an emerging issue that affects the entire food chain. Preharvest biosecurity research is concerned with protection of animal health and production, and postharvest biosecurity research is related to food microbiology and toxicology (refer to food safety section above). Examples of agricultural and food-biosecurity research being conducted by veterinary scientists include the development of preharvest and postharvest surveillance systems, diagnostic and detection systems, vaccines, immunomodulating drugs, animal and product tracking systems, and ecologically sound means of disposal of animal carcasses. A new awareness of the need for food and agricultural biosecurity research arose after September 11 and the “anthrax letter” attacks of 2001 because biosecurity research is closely related to maintaining a safe agricultural sector and food supply. The US food and fiber industry generates over $200 billion a year in farm cash receipts (USDA, 2003). From an economic standpoint, adulteration of food could alter market sentiment through fear and thus have substantial economic impact with enormous potential ripple effects. Furthermore, sequential or multifocal attacks on our food supply could undermine the trust of the American people in their government. Agricultural bioterrorism and the vulnerability of the food-producing animal industries in the United States to such activity are addressed in a National Research Council report (NRC 2003a). That report provides an in-depth analysis of the known agents that could be used to disrupt food-animal production and discusses the research and infrastructure needed to develop countermeasures. The fact that animals cannot be easily protected from the group of diseases suggested as primary agents of agricultural bioterrorism is indicative that those conditions should be among those given high priority for veterinary research. (See Appendix D for list of bioterrorism agents.) In 2004, the Department of Homeland Security (DHS) awarded 3-year grants to two university consortia to study preharvest and postharvest agricultural biosecurity (DHS 2004). In addition, several academic centers—typically in land-grant universities—have established their own centers, and some have or are constructing biosafety level 3 laboratories in which to conduct agricultural research (see Appendix E). Examples of Critical Research Needs Improved ability to detect and identify disease and pathogens in animal populations. Improved ability to detect pathogens and toxicants in food along the processing chain. Improved understanding of interactions between pathogens and hosts so that effective preventive measures and countermeasures can be developed. Rational development of cost-effective countermeasures, both vaccines and nonspecific therapeutic agents.

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Critical Needs for Research in Veterinary Science BOX 2-2 Species-Neutral Disease Surveillance Species-neutral surveillance is defined as monitoring diseases of all animal species, including humans and domestic and wild animals, and communicating the findings throughout the health-care community. Animal health and human health are more closely related than has been recognized in the past. Therefore, monitoring animal diseases could provide foresight with respect to disease emergence in humans. For example, the emergence of West Nile virus in June 1999 was characterized by an unusual number of dead birds in the borough of Queens, New York City. Some 6-7 weeks later, local hospitals received an unusual number of patients with encephalitis—then diagnosed as St. Louis encephalitis, which is a mosquito-borne viral encephalitis that does not produce disease in birds. The misdiagnosis was not recognized until the animal and human disease findings were integrated. The West Nile virus case illustrates the utility of species-neutral disease surveillance. One of the most important public-health lessons learned in recent years is that communication between animal health and human health professionals should be improved and maintained and that surveillance systems should be integrated to discover disease as early as possible irrespective of the host (GAO, 2000). Had such a system been in place for West Nile virus and monkey pox in the United States and for SARS internationally, our responses would have been more rapid and effective. Whether a disease develops naturally or is introduced by a terrorist, an integrated network of research, surveillance, and response that covers all species in the United States and internationally will save lives. Veterinary research is central to the development of such a system. Importance and Contribution of Research Although veterinary researchers are already addressing important research issues related to agricultural terrorism and emerging disease, we are slowly gaining an appreciation of the importance of integrating human and animal health issues through “species-neutral” disease surveillance (Box 2-2) and of combining findings internationally rather than only nationally. ANIMAL HEALTH AND WELFARE Food-Producing Animals Food-producing animals include all species of mammals and birds (including wildlife) that are raised in captivity or domestic conditions primarily as sources of human food. Research on infectious diseases and noninfectious health problems of metabolic or genetic origin in food-producing animals has been

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Critical Needs for Research in Veterinary Science going on for many years, conducted by a combination of veterinary and nonveterinary medical scientists and animal scientists. Much of the knowledge of nutrition, metabolism, and nutritional deficiencies that applies to humans was discovered as a result of observations on animals. Although frank clinical symptoms of specific nutrient deficiencies are rare today in food-producing animals because of the extensive knowledge of nutrient requirements, research on food and feed is needed because it represents the largest cost associated with handling food-producing animals. As genetic modifications in animals are made and metabolic manipulation is imposed through pharmaceuticals to enhance or focus production, it will be increasingly important to meet the nutrient needs of these “harder-working” animals. (Safety of genetically modified animals as food is discussed in the “Public Health and Food Safety” section above.) Historically, such efforts focused on diseases that affected single animals or individual herds or flocks and addressed issues associated with production, such as reproductive diseases, nutritional deficiencies, and mammary gland infections; but zoonotic diseases, such as tuberculosis and brucellosis, and their eradication were also of great concern. New information, vaccines, and technologies have led to continued advances in understanding and improved early detection, prevention, control, and eradication. The success of that work has helped the United States to become the largest source of food-producing animals. Such contemporary issues as the increasingly important subject of zoonotic diseases have shown the need for new approaches to ensuring the health and well-being of food animals. Food-animal production is often near areas occupied by wildlife or other domestic species (such as companion animals), which can contribute to the transmission of zoonotic or other diseases. This is a complex issue that requires expertise in comparative medicine and epidemiology. (See also the sections in this chapter on “Animal Health and Welfare” under subsection “Wildlife and Conservation” and on “Emerging Issues” under subsection and “Emerging Infectious Diseases” for discussions of zoonotic disease transmission.) Examples of the importance attached to those needs are found in recent documents published by the National Research Council (NRC 2002b). Emerging animal diseases and their effect on markets and the economy and on global animal and human health and safety have been addressed, with emphasis on foot-and-mouth disease (FMD) and bovine spongiform encephalopathy (BSE), (the international concerns of the time), each of which had an enormous economic impact. The cost of BSE in the United Kingdom in direct compensation was reported to be in billions of US dollars in 2002 (NRC 2003b), and there were substantial additional effects in international markets. The cost to North American cattle markets has been estimated at $3 to $5 billion. To add to the seriousness of the BSE and general prion issues, it has recently been reported that some people may act as subclinical carriers of variant Creutzfeldt-Jakob disease (vCJD) (Carrell 2004; Head and Ironside 2005); that BSE has been naturally transmitted

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Critical Needs for Research in Veterinary Science to goats (Anon. 2005) and an array of zoo animals, including kudus, antelopes, and cheetahs (Kirkwood and Cunningham, 1994); and that in naturally infected captive greater kudu, BSE prions have an unprecedented wide distribution throughout tissues (Cunningham et al., 2004). The reports suggest that the impact of vCJD may be difficult to predict, that the potential host range for the BSE prion is very wide, and that transmission to humans or other animals through novel pathways is possible. In the case of FMD, a disease not known to be transmitted to humans (and thus primarily an issue of animal health and economics), the estimated cost in the United Kingdom in 2001 has been set at $30 billion (NRC 2003b). Examples of Critical Research Needs Development of capacity and implementation of broad programs in comparative medicine to understand, rapidly detect, and control zoonotic and nonzoonotic diseases in food-producing animals raised in concentrated production units, with emphasis on techniques and technologies for field use in large animal populations. Evaluation of the implications of increases in productivity achieved through genetic or pharmaceutical means for animal health, nutrient, and metabolic requirements. Monitoring and assessment of trans-species disease transmission, epidemiology, and the delineation of resistance, susceptibility, and virulence factors across animals and pathogenic organisms. Importance and Contribution of Research A thorough understanding of diseases in food animals would improve our ability to detect diseases rapidly and control them effectively. Otherwise, the food-producing animal system will continue to be vulnerable to disease outbreaks with major consequences for animal health and the economy. Failure to address the issues above noted will erode the ability of the food-animal industries of the United States to be globally competitive and economically viable and will subject them to the potential devastation created by natural or human-made biodisasters. A critical issue on the global level is the understanding, detection, and control of the various diseases that are associated with prions (such as BSE and CJD). Aquaculture For the purposes of this report, aquaculture is defined as the farming of aquatic animals including finfish (such as salmon and catfish) and shellfish (such as clams, mussels, and shrimp). Freshwater catfish production dominates aqua-

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Critical Needs for Research in Veterinary Science culture in the United States and generates about $1 billion per year. Marine aquaculture—involving primarily salmon, clams, and shrimp—represents about one-third of aquaculture production by weight. From 1989 to 1998, there were marked increases in the aquaculture production of catfish (by 40%), salmon (468%), clams (379%), and shrimp (193%) (Goldburg et al., 2001). Aquaculture has only recently involved veterinary research. Increases in the quantity and economic importance of farmed species and in intensive production practices, have led to a rising need for disease detection, treatment, and prevention. Veterinary researchers have contributed substantially to the identification and characterization of important aquaculture diseases, such as infectious salmon anemia (Kibenge, et al., 2004). In addition, scientists of the FDA Center for Veterinary Medicine have been conducting studies on the effectiveness of treatment of fungal infection and internal parasites in fish (FDA 2003). Examples of Critical Research Needs Improved understanding of immune responses (especially cell-mediated) in fish to facilitate the development of effective vaccines and appropriate delivery systems. Improved methods of pathogen detection. Increased effectiveness and safety of medications used to treat diseases in aquaculture species. Enhanced understanding of the impact of aquatic animal production systems on marine and freshwater ecosystems. Importance and Contribution of Research Lack of effective disease identification, prevention, and control strategies (for example, efficacious vaccines) in aquaculture species results in the overuse of antibiotics and chemicals. Overuse leads to economic losses (for example, high mortality in fish production facilities), human health hazards (for example, compromised food safety because of drug or pollutant residues and zoonotic pathogens) (Benbrook, 2002), and adverse environmental effects (for example, antimicrobial and pesticide use, and transmission of disease to wild populations). Companion Animals Over the last several decades, veterinarians and animal scientists have contributed to advancing the diagnosis and treatment of disease and to the understanding of companion-animal welfare and the human-animal bond (Badylak et al., 1998; Dodds, 1995a,b; Lawrence, 1994; Ostrander et al., 1993; Parker et al., 2004; Patterson et al., 1988; Smith, 1994). Advances in companion-animal research have led to markedly increased expectations for animal and human medi-

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Critical Needs for Research in Veterinary Science cal services (Lawrence, 1994; Eyre et al., 2004). The breadth and sophistication of veterinary diagnostic and treatment methods have increased the need for timely high-quality research (Boothe and Slater, 1995; Smith, 1994; Dodds, 1995a). Research involving companion animals has been conducted by many investigators at a wide array of institutions and organizations. Companion animal-research has typically been in three categories: research on the diseases or conditions of companion animals for their direct benefit, research on diseases of comparative medical or pathological significance that provides direct benefits to companion animals and indirect benefits to humans, and research on basic physiological, pharmacological, molecular, or pathological processes that primarily benefits humans but benefits companion animals indirectly. (See section on Comparative Medicine for details on animal models for biomedical research.) Basic-science researchers, pathologists, and clinicians have all made useful contributions to companion-animal research. The scope of companion-animal research has increased considerably over the last several decades. There are still important disease-related problems in most of the traditional medical disciplines (for example, pharmacology, immunology, pathology, internal medicine, orthopedics, cardiology, oncology, and ophthalmology), but attention is increasingly directed at emerging matters related to animal welfare (such as quality-of-life determination and animal abuse), animal-shelter medicine and control of unowned and feral animal populations, the human-animal bond (including the role of service animals), complementary medicine, and the cause and treatment of behavioral disorders. Companion animals play important roles in service work, not only in assisting people with special needs but also in herding, search and rescue, drug and chemical detection, police and military assistance, and hunting and retrieving. Research into the behavioral and training needs of this special group of companion animals will increase their quality of life and enhance their performance as assistants, protectors, and life-savers. Horses have historically been used as companion animals and performance. Therefore, equine research has been directed primarily at improving overall health and soundness by developing diagnostic screening tests for heritable traits and studying the causes of common debilitating diseases, such as laminitis (founder) and exercise-induced pulmonary hemorrhage. Of specific importance to the viability of some horse breeds is the need to restrict breeding of horses that carry deleterious genetic traits. For example, hyperkalemic periodic paralysis in quarterhorses can be traced to one famous foundation sire, combined immunodeficiency of Arabians is traceable to a particular group of animals, and the lethal white gene of paint foals is produced by matings of the overo-to-overo color pattern. Companion-animal research improved the health of animals and humans by the enhanced control of infectious diseases through vaccines (such as distemper, parvovirus, and rabies), development of pharmaceutical agents, and the study of

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Critical Needs for Research in Veterinary Science BOX 2-4 Medical Advances Achieved Through Animal Research 1790 Vaccine for smallpox developed (cow) 1880 Vaccine for anthrax developed (sheep) 1888 Vaccine for rabies developed (dog and rabbit) 1902 Malarial life cycle discovered (pigeon) 1919 Mechanisms of immunity discovered (guinea pig, horse, and rabbit) 1923 Insulin discovered (dog and fish) 1932 Function of neurons discovered (cat and dog) 1933 Vaccine for tetanus developed (horse) 1939 Anticoagulants developed (cat) 1945 Penicillin tested (mouse) 1954 Polio vaccine developed (mouse and monkey) 1956 Open-heart surgery and cardiac pacemakers developed (dog) 1968 Rubella vaccine developed (monkey) 1984 Monoclonal antibodies developed (mouse) 1989 Organ transplantation advances developed (dog, sheep, cow, and pig) 1992 Laproscopic surgical techniques developed (pig) 1995 Gene transfer for cystic fibrosis developed (mouse and nonhuman primate) 2000 Brain signal transduction discovered (mouse, rat, and sea slug) 2001 Promising drug for prevention of AIDS developed (monkey) SOURCE: Foundation for Biomedical Research, 2001. Animal Models for Animal Diseases Information generated by animal-based experiments has been used primarily to benefit human health and well-being, but parallel benefits have been accorded to animals (Dodds, 1995a; Wagner, 1992); for example, with respect to inherited bleeding disorders (Dodds, 1995b), congenital cardiac disease and inborn errors of metabolism (Patterson et al., 1988), neuromuscular and copper-storage disorders (Brewer et al., 1992), and inherited eye diseases (Smith, 1994). These basic and comparative medical advances have improved diagnosis and treatment in clinical veterinary medicine. Emerging Areas of Research in Comparative Medicine Molecular Markers for Research and Clinical Applications For 4 decades, veterinary and comparative geneticists have developed and relied on biochemical markers of specific genetic traits to identify carrier and affected animals can be used as models of human disease (Patterson et al., 1988; Dodds, 1995a,b; Dodds and Womack, 1997). More recently, molecular ap-

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Critical Needs for Research in Veterinary Science proaches have been developed used to study gene-therapeutic approaches for advancing human health and well-being (Ostrander et al., 1993). Examples of diseases that commonly affect humans and companion animals and lend themselves to molecular and gene therapy are autoimmune thyroid disease (Happ, 1995), such inherited bleeding disorders as hemophilia and von Willebrand disease (Dodds, 1995b; Kay et al., 1993), and organ-specific autoimmune disease (Ford, 2001; Schultz, 1999). Future technological developments, particularly in gene delivery and cell transplantation, will be critical for the successful practice of gene therapy (Dodds and Womack, 1997). Animal Genome and Phenome Research Substantial advances have been made in sequencing the genomes of humans and other mammalian species. Large-scale genome-sequencing projects have focused on completing the sequencing of the genome of the human (Freimer and Sabatti, 2003), the chimpanzee, the dog (Parker et al., 2004), the cow (Gibbs, et al., 2002), the mouse, the rat and the chicken, several insects, nematodes, fungi, yeast, and bacteria (AVMA, 2004a). In the near future, scientists will begin to sequence the genomes of nine more mammals, including the domestic cat, the guinea pig, the rabbit, the orangutan, and the elephant (AVMA, 2004a). Interest in the human and canine genomes has spawned related research in “phenomics” to identify specific genotypes that are associated with the species phenotype. The purpose of the human, mouse, and canine phenome projects is to learn about both genetic and nongenetic factors that contribute to the variability of the species (Bogue, 2003; Freimer and Sabatti, 2003; Grubb et al., 2004; Pletcher et al., 2004). For example, dog research will focus on the phenotypic characteristics that distinguish one breed from another and that distinguish one animal from another in the same breed. Size, anatomy and appearance, composition and metabolism, behavior and temperament, and disease susceptibility will be investigated. Effective Animal Models to Establish Safety and Efficacy of Therapeutic Compounds The challenge today is to develop better treatments for the many serious diseases that afflict human and animal populations. FDA’s Critical Path Initiative focuses on targeted scientific efforts to modernize methods to evaluate the safety, efficacy, and quality of medical products as they move from product selection and design to mass manufacture. Critical-path research complements basic research, but results in the creation of new tools for product development. Medical-product development starts with basic research that leads to discovery and prototype design and then proceeds to preclinical trials in animal models to test for efficacy and finally clinical trials and FDA approval. The costs of that process are

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Critical Needs for Research in Veterinary Science increasing rapidly, but the failure rate of candidate drugs in clinical development has increased. Extensive use of computer modeling (“silicotechnology”) could improve predictability, shorten time for drug development, and reduce the overall cost of drug development by as much as 50%. Improved data-mining efforts to combine in vitro and in vivo animal studies with human clinical outcomes (while protecting proprietary data effectively) could form the basis of useful predictive safety models. Animal models have been informative for efficacy and safety studies of new lead compounds and therapeutics, but improvements are still needed. Further characterization of existing and newly developed disease models in rodents and other laboratory animal species will lead to better validation of potential therapeutic disease targets and analysis and understanding of disease pathways in animal models (Kinkler, 2004). Stem-Cell Research The goal of stem-cell research is to engineer cell lines for use in tissue, organ, or cell transplantation or for gene therapy for treatment of diseases (NIH, 2004). The future of regenerative medicine depends on further exploration of the biological, ethical, and funding questions prompted by the therapeutic potential of adult and embryonic human and mouse stem cells (NRC, 2002c). Stem-cell transplantation has been effective in treating diseases in animal models. However, although effective outcomes of stem-cell transplantation have been obtained—for example, in neurodegenerative diseases—the underlying mechanisms leading to re-establishment of neurological function are still unclear. Such mechanisms as stem-cell promotion of growth-factor release, cell fusion, and transdifferentiation are some explanations of the favorable outcomes. Additional work with animal models of disease will result in a better understanding of the mechanisms of stem-cell therapies. Genetically Engineered Animals The capacity to manipulate the DNA of mammals by adding or deleting specific genes has made the laboratory mouse a robust tool for advancing biomedical research. Genetic engineering has substantially increased the number of mutant strains available compared with induced-mutagenesis methods, such as N-ethyl-N-nitrosourea (ENU) mutagenesis. For example, genetically engineered mouse models have advanced the understanding of such neurodegenerative diseases as Alzheimer’s disease, Parkinson’s disease, and motor neuron disease (Wong et al., 2002). Transgenic sheep and goats express foreign proteins in their milk that may be used to treat such genetic defects as human and canine hemophilia. Transgenic pigs may serve as a source of organs for transplantation into humans (xeno-transplantation). Further development of transgenic animals will permit investi-

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Critical Needs for Research in Veterinary Science gations that will eludicidate the cellular components of tissue remodeling that are essential to regenerative medicine. Advanced Surgical Techniques (Microsurgery) and Biomedical Devices Research in advanced surgical techniques includes the development of the skills needed for microvascular, microneural, and microtubular surgery, which are used in plastic and orthopedic surgery, urology, general surgery, neurosurgery, otolaryngology, obstetrics and gynecology, and cardiothoracic surgery. Training courses typically use rabbits and rats as experimental models. A research model of arterial thrombosis that mimics human vascular thrombosis (for example, coronary arterial occlusion) has been used extensively by investigators interested in the development of thrombolytic agents, particularly urokinase and tissue plasminogen activators, for human use (Badylak et al, 1998). A biomaterial derived from porcine small intestinal submucosa was developed from a throw-away product of the pork industry; this “bioscaffold” material has been used in a variety of animal models and in human patients for repair, replacement, and reconstruction of the esophagus, dura mater, lower urinary tract, acutely and chronically injured skin, and the cardiovascular system (Badylak et al, 2000). Vaccine-Related Research Understanding of basic immune mechanisms in laboratory animals has made it possible to design vaccines that protect against infectious diseases, to induce effective responses to tumor antigens, and to control graft rejection and autoimmune diseases (Tizard, 1990; Lanzavecchia, 1993). However, there is an emerging need for new approaches to protect against immunological and infectious challenges (Cohen, 1994) and to understand adverse reactions to vaccines in humans and animals (Oehen et al., 1991; Paul et al., 2003; Schultz, 1999; Scott-Moncreieff et al., 2002; Tizard, 1990; Vascellari et al., 2003). Examples of Critical Research Needs Advanced training of comparative-medicine scientists to support and facilitate biomedical research, with emphasis on expertise in phenotype and behavior assessment of unique rodent strains. Further development and refinement of animal models to advance biomedical research. Expansion of resources and methods for characterizing the genetic background, phenotype, and behavior of unique mouse and rat strains. Enhanced methods for preserving valuable models and improving the reproductive efficiency of laboratory animals. Improved methods for genetic engineering in laboratory animal species other than the mouse to advance understanding of select diseases.

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Critical Needs for Research in Veterinary Science Importance and Contribution of Research Research in comparative medicine is critical to the advancement of biomedical research, which will lead to improvements in human and animal health. Comparative-medicine research contributes to the improved quality of laboratory animals and the quality of research that uses them. EMERGING ISSUES IN VETERINARY SCIENCE Emerging Infectious Diseases Emerging infectious diseases (EIDs) have become recognized as one of the most important threats to public health over the last 30 years (Binder et al., 1999; IOM, 1992; NRC, 2003b). Emerging diseases are those which have recently expanded in geographic range, moved from one host species to another, increased in impact or severity, or undergone a change in pathogenesis, or were caused by recently evolved pathogens (other definitions are available in IOM, 1992). Combating emerging diseases is a key goal of public-health efforts nationally and globally, and it is hindered by poor knowledge of potential emerging zoonoses—for example, diseases caused by wildlife parasites, viruses, and other microorganisms that move into humans (Morse, 1993). The reason emerging diseases (most of which are zoonotic) require and attract so much attention is that they are usually complex and not well understood, are not susceptible to rapid diagnostic or detection methods, and usually not subject to vaccines, other therapeutics, or readily applied prevention programs. Of the 175 organisms considered to be pathogenic in humans and commonly cited as emerging, 132, or 75% are zoonotic (Taylor et al., 2001). The emergence of new diseases, such as SARS, has been linked to increased contact between humans and the animals carrying the diseases. The spread of H5N1 avian influenza virus in Asia that infected domestic poultry, swine, cats, wild birds (pigeons and crows), and humans is related to changes in agricultural practices of livestock industries. Animals are also carriers of many insect-transmitted pathogens. When the uncertainties associated with transmission from one species to another are added to the ever-increasing mobility of society, the potential interface between those conditions and human food safety, and the heightened concerns about possible effect of bioterrorism on animals (intentional introduction of an animal disease with the intention of causing economic consequences or transmission of disease to humans), the urgency of comprehensive research and implementation becomes obvious. Veterinary researchers are employed in a number of capacities in EID research. Because of the predominance of zoonotic pathogens in EID outbreaks, veterinarians have been key parts of the teams attempting to identify wildlife

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Critical Needs for Research in Veterinary Science reservoirs of hantavirus, Lyme disease, West Nile virus, leptospirosis, Lassa fever, Ebola virus, Nipah virus, Hendra virus, and others. Veterinarians with epidemiological training have been involved in most of the major outbreak investigations undertaken by CDC. Outbreaks of new zoonotic agents occur almost every year, and they have serious health and economic consequences. For instance, SARS coronavirus, which appears to have wildlife origins, caused over 700 deaths and $50 billion in losses to the global economy in 2003 (Guan et al., 2003; Rota et al., 2003). The zoonotic predominance among EIDs suggests a growing need for veterinary researchers to understand dynamics of wildlife pathogens that have emerged or are likely to emerge into human populations (for example, West Nile virus and viruses related to SARS coronavirus or Nipah virus). The ability of these emerging pathogens to spread rapidly across the planet is enhanced by a large and increasing volume of trade in wildlife species that can act as introduction vectors. For example, monkeypox was imported into Wisconsin through the exotic-pet trade industry. The scope of EID research has been widened to include emerging diseases of marine and terrestrial wildlife and domestic animals (Anon, 1998; Daszak et al., 2000; Dobson and Foufopoulos, 2001; Harvell et al., 1999; Nettles, 1996). EIDs are responsible for population declines and mass mortality of wildlife (Daszak et al., 2000), loss of coral reefs and other marine resources globally (Harvell et al, 1999), and threats to global food-animal markets (NRC, 2002b; see also section on food-producing animals). Veterinary involvement in EID research is critical. For example, BSE was originally discovered by veterinary pathologists, and the dynamics of its spread were understood by veterinary epidemiologists working with mathematical modelers, all before it emerged in the human population. In addition, veterinary institutes and veterinary medical researchers were critical in studying the pathogenesis of the 1918 human pandemic influenza virus in animal models to understand the molecular development and prevention of human influenza pandemics (Kash et al., 2004; Tumpey et al., 2004). Understanding how environmental or population changes select for emergence of new zoonotic pathogens from the “zoonotic pool” (Morse, 1993) is a goal discussed in both National Research Council reports on EIDs (NRC, 2003b). Useful models are a number of studies funded through the National Institutes of Health/National Science Foundation initiative in ecology of infectious diseases (NIH, 2002) and a recent study of retrovirus emergence in bush meat-hunters in west Africa (Wolfe et al., 2004). Examples of Critical Research Issues A preemptive approach to predict and prevent infectious diseases. New tools to identify novel, potentially zoonotic pathogens in wildlife populations that may be the next HIV/AIDS or SARS coronavirus. Such tools will include microarrays and other sophisticated biotechnological applications based on the pool of known zoonotic EIDs that wildlife populations harbor.

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Critical Needs for Research in Veterinary Science Increased involvement of veterinary researchers in understanding the wildlife trade as a mechanism of EID introduction and in understanding how zoonotic bioterrorism agents may behave if released in the United States. The causes, anthropogenic, ecological and environmental drivers, and effects of emerging diseases of livestock and wildlife. Importance and Contribution of Research Veterinary research in EID would reduce human mortality due to new emerging diseases, help to prevent future outbreaks of unknown diseases, and help to prevent or deter the introduction and dissemination of pathogens into the United States. This research will also have important economic benefits in reducing public-health costs and disruption of trade and industry. Ecosystem Health The field of ecosystem health developed in Canada with the formation of the International Society for Ecosystem Health in 1994 and the launch of its journal Ecosystem Health (superseded by Ecohealth). The field approaches health as a metaphor in that a healthy ecosystem is one with the full assemblage of species, each with healthy populations. Research in ecosystem health allows a more complete understanding of how disease organisms, toxicants, and health issues affect animal and human populations and the functioning of ecosystems. Ultimately, breakdown of ecosystem health leads to loss of ecosystem functions and affects human health and welfare through effects on agriculture, hunting, fishing and livestock production, and food animal safety. Veterinary researchers have an important role to play in the advancement of ecosystem health and can contribute in numerous and diverse ways. For example, veterinary researchers have been involved in the characterization of a multispecies (human, companion animal, and marine mammal) outbreak of cryptococcosis (Stephen et al., 2002), in identifying indicators of ecosystem health (Stephen and Ribble, 2001), and in using ecosystem-health concepts for wildlife conservation (for example, Wildlife Conservation Society Field Veterinary Program). Understanding the effects or ecological footprint of terrestrial and aquatic animal agriculture on ecosystems and social systems and how sustainable practices can be developed is critical in both developed and developing nations (Tilman et al, 2003). Examples of Critical Research Needs Definition of what constitutes a healthy ecosystem. Development of reliable and predictive indicators of ecosystem health. Characterization of the complex interaction between humans, domestic and wild animals, and the environment to predict risks to the health of these populations.

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Critical Needs for Research in Veterinary Science Studies of the interaction between human and animal communities by multidisciplinary teams that include zoo veterinarians, ecologists and toxicologists, and public-policy experts to understand how human activities affect ecosystems and all their inhabitants, including humans. Importance and Contribution of Research Failure to address research in ecosystem health would lead to substantial and unpredictable risks (such as infectious disease, food safety, water-borne illness, toxins) to the health of humans and domestic and wild animals. Biodiversity in wild animal and plant populations would be at risk as a result of unhealthy and unsustainable ecosystems. Social Policies, Societal Needs, and Expectations Including Animal Welfare The care and use of research animals are governed by USDA regulations and PHS policy, which were implemented to address societal concerns about laboratory animal welfare. These regulations and standards include requirements for the oversight of animal research by Institutional Animal Care and Use Committees and standards for laboratory animal husbandry, housing and enrichment, environmental conditions, and veterinary medical care. However, some of the standards are not supported by scientific analysis. In particular, studies that objectively define, measure, and validate the benefits of social housing and environmental enrichment are inadequate. In the absence of scientific studies that support animal care standards, arbitrary guidelines can lead to inappropriate care, cause undesirable changes in an animal’s physiological or behavioral status, produce confounding research results, and unnecessarily increase the cost of animal research. It is imperative that the guidelines and recommendations be strongly supported by scientific study. (See subsection on Laboratory Animals under the Animal Health section.) Although government standards have been established for laboratory animals, the management of food-producing animals is based largely on practices developed and implemented by animal scientists and food-animal producers. The science-based, objective literature on the impact of physical environment—such as space requirements and the impact of confinement or group housing—on food-producing animals is far from adequate and represents a major and critical area for future comprehensive research (Mench, 1992; Fraser, 2003). Pressure from major users of animal food products (such as fast-food chains) is expected to advance the urgency of the need, but the expertise needed to achieve the needed results is lacking in the scientific community, although excellent progress is being made in animal handling and transportation, livestock behavior and facility design, and humane slaughter practices (Grandin, 2000; see also http://www.grandin.com/). In addition, research is being conducted in Europe, notably the

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Critical Needs for Research in Veterinary Science Netherlands, on the physical environments of pigs and poultry. Some common management practices—such as veal calf production; sow gestation crates; beak-dubbing and comb removal in chickens; and dehorning, castration, and branding of cattle—were developed to improve production or prevent injuries to other animals and humans, but have also raised public concerns about animal welfare. In addition, the effects of new products and technologies used to enhance animal production, including growth hormones and genetic modification, have caused some public concerns. In addition to laboratory animals and food-producing animals, welfare is an important consideration for animals used for entertainment, racing, hunting, military and police activities, pet therapy, service (such as Eye Seeing dogs), recreation, and companionship. Science-based methods for measuring stress and distress and stress-related effects in animals are essential if substantial progress is to be made in ensuring the welfare of various species. Such efforts require complex multifaceted studies involving expertise in veterinary medicine, animal science, animal behavior, endocrinology, neurology, and pharmacology. Scientifically based studies can and should be used to make sound public policy and to set responsible regulatory standards. For example, research data have demonstrated that commercially available rabies vaccines will protect dogs for at least 3 years and are therefore federally licensed for a 3-year duration. However, some individual states and counties have established regulations that require more frequent vaccination, despite research evidence that demonstrates the potential adverse effects of such practices. Rabies vaccination can produce tumors in dogs and cats at the injection site, cause serious neurological and immunological adverse effects and death in any species, and induce autoimmune thyroiditis in dogs (Paul et al., 2003; Schultz, 1999; Scott-Moncrieff et al., 2002; Vascellari et al., 2003). Guidelines for canine and feline vaccination have also been developed by the AVMA Council on Biologic and Therapeutic Agents and AAHA task force the American Association of Feline Practitioners and the Academy of Feline Medicine Advisory Panel on Feline Vaccines, on the basis of evidence from veterinary research and published studies (Elston et al., 1998; Klingborg, 2002; Paul et al., 2003). Risk analysis is an important public-policy framework being used both nationally and internationally to make regulatory decisions regarding food safety and to formulate animal trade policies. Science-based risk assessments on the relation of specific pathogens or toxicants to animal and human health are a critical component of the risk analysis. Findings derived from research to identify and characterize hazards and assess exposures are the bases of modeling risk assessments. Sound risk assessments will require a wide array of research on the hazards of and exposure to diseases. Valid scientific studies should also help to determine the outcome of legal decisions, which may otherwise be driven by emotionally based considerations. During the last decade, for example, several municipalities have adopted the term

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Critical Needs for Research in Veterinary Science guardian instead of pet owner. Such changes may eventually lead to court challenges regarding the legal standing of animals and how they are used by society. In addition, many law schools have established centers that specialize in animal “rights”. Again, scientific evidence will be important to validate or refute legal challenges with respect to animals. Examples of Critical Research Needs Studies that objectively define, measure, and validate the benefits of social housing and environment enrichment. Science-based methods to measure stress and distress and stress-related effects in animals. Scientific analysis that uses quantifiable indicators to measure the effects of pharmaceutical agents and genetic modifications on animal welfare. Multidisciplinary studies of detection, control and prevention of large-scale zoonotic disease outbreaks that require disposal of large numbers of animals. Importance and Contribution of Research Additional research is required to determine the optimal care and use of animals and to support the development of sound public policies governing animal welfare. Research is also required to ensure best management practices of animals in the face of a widespread disaster involving animals and to protect human health. Exotic and Caged Pets Exotic and caged pets typically include birds, small mammals (such as ferrets, rabbits, hamsters, guinea pigs, and gerbils), reptiles (such as turtles, lizards, and snakes), and amphibians (such as frogs). Exotic-pet trade is a growing industry that is estimated to be worth more than $10 billion (Kuehn, 2004a). In the case of most species—such as reptiles, amphibians, marsupials, exotic birds, and mammals—little research has been done on their behavioral and husbandry needs. Many medical problems in exotic pets are related to poor husbandry (Kuehn, 2004b). In addition, limited information is available on the treatment of their diseases. Although the volume of information available on exotic and caged pets has increased considerably over the last few decades, most of it is anecdotal or derived from case reports, because most veterinarians involved with exotic pets provide clinical services and are not actively engaged in research. The recent outbreak of monkeypox transmitted by prairie dogs that were housed or transported with African rodents from Ghana and the resurgence of salmonellosis contracted from reptiles (iguanas and turtles), marsupials (sugar gliders), and small mammals (hedgehogs) readily illustrate the potential risk that exotic-pet ownership poses (Check, 2004; Gross, 2003; Woodward et al., 1997). There has

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Critical Needs for Research in Veterinary Science been considerable growth in the demand for and ownership of exotic and caged pets (Doolen, 1996; http://epw.senate.gov/hearing_statements.cfm?id2=212880). The demand is putting increasing pressure on veterinarians who treat exotic and caged animals to keep up with the highly species-specific needs of their patients. Examples of Critical Research Needs Characterization of the zoonotic pathogens capable of being carried by exotic species and also those pathogens that may be transmitted to domestic and wild animal populations. Improved methods of diagnosis and treatment of exotic animal diseases, especially in regards to safe and effective anesthetic and analgesic protocols. Determination of appropriate husbandry requirements for many exotic species. Importance and Contribution of Research Given the increasing number and diversity of exotic pets, veterinary research is necessary to identify important infectious diseases that may pose a risk of transmission to humans and domestic and wild animals. Research on the behavioral, husbandry, and medical needs of exotic pets is also necessary to enhance their quality of life and to contribute to the comparative understanding of diseases in other species. CONCLUSION This chapter illustrates that veterinary research is a diverse enterprise that involves many disciplines and species and has a substantial effect on human health and the economy. In many fields, veterinary research is about characterizing the health implications of changing relationships and the boundaries between species and their environments. The compelling but difficult question is, What is the most important? Although research priorities have been outlined in each area, the different areas of veterinary research were not prioritized against each other. Clearly, issues related to homeland security (such as biosecurity) and food safety stand out because of the potential for catastrophic effects on human and animal health. However, problems often arise from fields that have been overlooked (for example, exotic pets) and many important advances come from fields that may not be recognized by some as priorities so that a balanced approach to support research in the above areas must be sought. The key question regarding research priorities is not what topic should be investigated first, but how a strong and flexible national capacity for veterinary research can be built and maintained to maximize the contribution of veterinary research to the health and welfare of animals and people.