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ContributorsAbbas ArdehaliDivision of Cardiothoracic SurgeryUCLA Medical CenterSchool of MedicineLos Angeles, CaliforniaJörgen JönssonInstitute of OdontologyHuddinge University HospitalKarolinska InstituteStockholm, SwedenKarsten BuschardBartholin InstituteCopenhagen, DenmarkBjörn KlingeInstitute of OdontologyHuddinge University HospitalKarolinska InstituteStockholm, SwedenAnthony M. CarterDepartment of Physiology andPharmacologyUniversity of Southern DenmarkOdense, DenmarkOtto MeyerDanish Veterinary and Food AdministrationSoborg, DenmarkChristi M. CavaliereSection of Plastic SurgeryUniversity of MichiganAnn Arbor, MichiganJesper MogensenCognitive NeuroscienceDepartment of PsychologyUniversity of CopenhagenCopenhagen, DenmarkRyan P. FrankDepartment of Orthopedic SurgeryUniversity of MichiganAnn Arbor, MichiganCynthia E. GloverDepartment of Comparative MedicineUniversity of WashingtonSeattle, WashingtonKurt D. HankensonDepartments of Orthopedic Surgery and the Unitfor Laboratory Animal MedicineUniversity of MichiganAnn Arbor, MichiganJann HauUniversity of UppsalaUppsala, SwedenRobert MurisonDepartment of Biological and MedicalPsychologyUniversity of BergenBergen, NorwayJørgen RygaardBartholin InstituteCopenhagen, DenmarkOve SvendsenDepartment of Pharmacology andPathobiologyRoyal Veterinary and Agricultural UniversityFrederiksberg, DenmarkRikke ThonTaconic M & BLille Skensved, DenmarkHenrik Elvang JensenLaboratory of Veterinary PathologyRoyal Veterinary and Agricultural UniversityFrederiksberg, DenmarkGerald L. Van Hoosier, Jr.University of WashingtonSeattle, WashingtonDavid WhitingDivision of Cardiothoracic SurgeryUCLA Medical CenterSchool of MedicineLos Angeles, California

Table of ContentsChapter 1Animal Models.1Jann HauChapter 2Animal Models in Pharmacology and Toxicology.11Otto Meyer and Ove SvendsenChapter 3Animal Models in Fetal Growth and Development .41Anthony M. CarterChapter 4Animal Models of Nephrological Disorders .55Cynthia E. GloverChapter 5Animal Models for Xenotransplantation .81David Whiting and Abbas ArdehaliChapter 6Animal Models in Neuroscience .95Jesper MogensenChapter 7Animal Models for Psychological Disorders .111Robert MurisonChapter 8Animal Models in Mycology.125Henrik Elvang JensenChapter 9Diabetic Animal Models .153Karsten Buschard and Rikke ThonChapter 10Animal Models of Skeletal Disease .183Kurt D. Hankenson, Christi M. Cavaliere, and Ryan P. FrankChapter 11Animal Models in Cancer Research.225Jørgen RygaardChapter 12Animal Models in Oral Health Sciences.237Björn Klinge and Jörgen JönssonIndex .263

CHAPTER1Animal ModelsJann HauCONTENTSIntroduction .1The Concept of Animal Models .2Classification of Animal Models .2Classification of Disease Models.3Induced (Experimental) Disease Models .3Spontaneous Animal Disease Models.4Transgenic Disease Models.4Negative Animal Models.5Orphan Animal Models .5Extrapolation from Animals to Humans.5Model Body Size and Scaling .6Conclusion.7References .8INTRODUCTIONMost of our basic knowledge of human biochemistry, physiology, endocrinology, and pharmacology has been derived from initial studies of mechanisms in animal models.1 Throughout history,scientists have performed experiments on animals with the aim of obtaining knowledge of animaland human biological structure and function (see, e.g., Held;2 Loew3). Often such studies have notbeen and are not possible in the human. This may be due to ethical or religious considerations, butoften practical, economic, and scientific reasons make initial studies in animals the best solutionto studies of a biological phenomenon.Laboratory animal science may be defined as the study of the scientific, ethical, and legal useof animals in biomedical research, that is, a multidisciplinary field encompassing biological andpathobiological specialties for the optimal scientific use of animals as models for humans or otherspecies.Basic laboratory animal science is concerned with the quality of animals as sentient tools inbiomedical research. It encompasses comparative biology of laboratory animals, technical aspectsof breeding, housing and husbandry, anesthesia, euthanasia, and experimental techniques. Laboratory0-8493-1084-9/03/ 0.00 1.50 2003 by CRC Press LLC1

2HANDBOOK OF LABORATORY ANIMAL SCIENCE, SECOND EDITIONanimal medicine is a veterinary specialty, focusing on the diagnosis, treatment, and prevention ofdiseases in animals used as subjects in biomedical activities. High-quality animals and animal careensure the highest possible health and welfare status of the animals and are prerequisites for goodscience and public acceptance of the use of animals in research.Volume I of this handbook is an introduction to basic laboratory animal science, whereas thepresent volume focuses on applied laboratory animal science, which is the use of animals as modelsfor humans — or in some instances as models for other species.THE CONCEPT OF ANIMAL MODELSA model is an object of imitation, something that accurately resembles something else, a personor thing that is the likeness or image of another.4 Prometheus, who has been deigned by poets tohave first formed Man, formed a model from water and earth and then stole fire from the sun toanimate the model.5 An animal model is thus an animated object of imitation in the image ofhumans (or other species), used to investigate biological or pathobiological phenomena.A laboratory animal model describes a biological phenomenon that the species has in commonwith the target species.6 A more accurate definition has been given by Held on the basis of Wessler’soriginal definition:7 “a living organism in which normative biology or behavior can be studied, orin which a spontaneous or induced pathological process can be investigated, and in which thephenomenon in one or more respects resembles the same phenomenon in humans or other speciesof animal.” What is generally understood by the term “animal model” is modeling of humans. Itis not the image of the used animal that is the focus of research but the analogy of the physiologicalbehavior of this animal to our own (or another) species. It would thus be more correct to refer toanimals as “human models” in this context. Laboratory animal science, comparative medicine, andanimal experiments are indeed much more about humans than about any other animal species.8The significance and validity with respect to usefulness in terms of “extrapolatability” of resultsgenerated in an animal model depend on the selection of a suitable animal model. A good knowledgeof comparative anatomy and physiology is an obvious advantage when developing an animal model.Animal models may be found throughout the animal kingdom, and knowledge about humanphysiology has been achieved in species far removed from the human in terms of evolutionarydevelopment. A good example is the importance of the fruit fly for the original studies of basicgenetics. Animal models are used in virtually every field of biomedical research, as reflected in thechapters of this book.CLASSIFICATION OF ANIMAL MODELSA plethora of animal models has been used and is being used and developed for studies ofbiological structure and function in the human. The models may be exploratory, aiming to understand a biological mechanism, whether this is a mechanism operative in fundamental normal biologyor a mechanism associated with an abnormal biological function. Models may also be developedand applied as so-called explanatory models, aiming to understand a more or less complex biologicalproblem. Explanatory models need not necessarily be reliant on the use animals but may also bephysical or mathematical model systems developed to unravel complex mechanisms. A thirdimportant group of animal models is employed as predictive models. These models are used withthe aim of discovering and quantifying the impact of a treatment, whether this is to cure a diseaseor to assess toxicity of a chemical compound. The anatomy or morphology of the model structureof relevance to the studies may be of importance in all three of these model systems. The extentof resemblance of the biological structure in the animal with the corresponding structure in humans

ANIMAL MODELS3has been termed fidelity. A high-fidelity model with close resemblance to the human case may seeman obvious advantage when developing certain models. What is often more important, however, isthe discriminating ability of the models, in particular the predictive models. When using models,for instance to assess the carcinogenicity of a substance, it is of the essence that at least one of themodel species chosen responds in a manner that is predictive of the human response to thissubstance. Thus the similarity between humans and model species with respect to relevant biologicalmechanism is often more important than the fidelity of the model. Often the two go hand in hand,and high-fidelity models offer the best opportunity to study a particular biological function.An animal model may be considered homologous if the symptoms shown by the animal andthe course of the condition are identical to those of humans.9 Models fulfilling these requirementsare relatively few, but an example is well-defined lesion syndromes in, for instance, neuroscience.10An animal model is considered isomorphic if the animal symptoms are similar but the cause of thesymptoms differs between human and model. However, most models are neither homologous norisomorphic but may rather be termed “partial.” These models do not mimic the entire human diseasebut may be used to study certain aspects or treatments of the human disease.10CLASSIFICATION OF DISEASE MODELSThe majority of laboratory animal models are developed and used to study the cause, nature,and cure of human disorders. They may conveniently be categorized in one of the following fivegroups, of which the three first are the most important, as given in numerical order:1.2.3.4.5.Induced (experimental) disease modelsSpontaneous (genetic) disease modelsTransgenic disease modelsNegative disease modelsOrphan disease modelsInduced (Experimental) Disease ModelsAs the name implies, induced models are healthy animals in which the condition to be investigated is experimentally induced, for instance, the induction of diabetes mellitus with encephalomyocarditis virus,11 allergy against cow’s milk through immunization with minute doses ofprotein,12 or partial hepatectomy to study liver regeneration.13 The induced-model group is the onlycategory that theoretically allows a free choice of species. Although one might be tempted topresume that extrapolation from an animal species to the human is the better the closer this speciesresembles humans (high fidelity), phylogenetic closeness, as fulfilled by primate models, is not aguarantee for validity of extrapolation, as the unsuccessful chimpanzee models in acquired immunodeficiency syndrome (AIDS) research have demonstrated.14 It is just as decisive that the pathologyand outcome of an induced disease or disorder in the model species resembles the respective lesionsof the target species. Feline immunodeficiency virus infection in cats may therefore for many studiesbe a better model for human AIDS than is human immunodeficiency virus infection in simians.Although mice and rats have many biological characteristics in common, they do not necessarilyserve equally well as models of human disease. For example, schistosomiasis (mansoni ) infectionmay be studied in experimentally infected mice but not in rats, whose immune system is able tofight the infection effectively.15Most induced models are partial or isomorphic because the etiology of a disease experimentally induced in an animal is often different from that of the corresponding disease in the human.Few induced models completely mimic the etiology, course, and pathology of the target diseasein the human.

4HANDBOOK OF LABORATORY ANIMAL SCIENCE, SECOND EDITIONSpontaneous Animal Disease ModelsThese models of human disease use naturally occurring genetic variants (mutants). Manyhundreds of strains and stocks with inherited disorders modeling similar conditions in humans havebeen characterized and conserved (see, e.g., http://www.jax.org). A famous example of a spontaneous mutant model is the nude mouse,16 which was a turning point in the study of heterotransplanted tumors and, for instance, enabled the first description of natural killer cells. Other famousspontaneous models include Snell’s dwarf mice, without a functional pituitary,17 and the curly-tailmouse, in which fetuses develop a whole range of neural-tube defects.18 Many of the mutants areavailable in inbred strains, with corresponding coisogenic or congenic strains. This is very usefulbecause the influence of just one affected gene or locus may then be studied against a referencestrain with similar genetic background as the mutant (see also Volume I, Chapter 9).An extensive literature is available on spontaneous models, and the majority of these are miceand rat models, although a wide range of mutants in many different species has been described. Agood example of the amount of information available is the publication of Migaki,19 which references 200 diseases in animals exclusively caused by inborn errors of metabolism.The spontaneous models are often isomorphic, displaying phenotypic similarity between thedisease in the animal and the corresponding disease in the human — this is called face validity;for instance, type I diabetes in humans and insulin-requiring diabetes in the BB rat. This phenotypicsimilarity often extends to similar reactions to treatment in the model animal and the human patient,and spontaneous models have been important in the development of treatment regimens for humandiseases.However, if the object of a project is to study the genetic causes and etiology of a particulardisease, then comparable genomic segments involved in the etiology of the disorder — constructvalidity — is normally a requirement. It should be remembered, however, that an impaired geneor sequence of genes very often results in activation of other genes and mobilization of compensatingmetabolic processes. These compensatory mechanisms may of course differ between humans andthe animal model species.Transgenic Disease ModelsThe rapid developments in genetic engineering and embryo manipulation technology duringthe past decade have made transgenic disease models perhaps the most important category of animaldisease models. A multitude of animal models for important diseases have been developed sincethis technology became available, and the number of models seems to be increasing quickly. Miceare by far the most important animals for transgenic research purposes, but farm animals and fishare also receiving considerable interest.Many physiological functions are polygenic and controlled by more than one gene, and it willrequire considerable research activities to identify the contribution of multiple genes to normal aswell as abnormal biological mechanisms. The insertion of DNA into the genome of animals or thedeletion of specific genes gives rise to sometimes unpredictable outcomes in terms of scientificresults as well as in terms of animal well-being in the first generations of animals produced.Thereafter, transgenic lines can be selected and bred or cloned to avoid or select for a specificgenotype. It is not an accurate science, although the methodology is constantly improving with theaim of eliminating unwanted effects. The embryo manipulation procedures themselves do not appearto affect the welfare of offspring in the mouse,20 and the large-offspring syndrome observed in farmanimals has so far not been reported in rodents (see Volume I, Chapter 18 for welfare aspectsassociated with transgenic animals).Mutations induced by the use of mutagens such as ethyl-nitroso-urea represent another approachto the generation of new mutants, which may serve as models of human disorders. In many aspects,these mutants may be similar to spontaneous mutants and to the ones generated by transgenic

ANIMAL MODELS5embryo manipulation. The maintenance of a line raises similar issues for chemically induced geneticmutants as for animals that have been genetically modified through embryo manipu

Handbook of Laboratory Animal Science, Second Edition: Animal Models, Volume II is dedicated to the use of laboratory animals as models for humans. This book explains in great detail the comparative considerations underlying the choice of animal species and strains in different research disciplines.