DEVELOPMENT OF ANIMAL MODELS FOR THE ENHANCEMENT OF ANIMAL AND HUMAN HEALTH (AVATARS FOR HUMANITY: CURRENT CONCEPTS AND LESSONS LEARNED)

摘要

An 'animal model' has been defined as "a living organism with an inherited, naturally acquired, or induced pathological process that in one or more respects closely resembles the same phenomenon occurring in man."1 While many would agree there is no ideal animal model, scientists have identified at least five classes of models2 useful to answer scientific questions. Considerations in choosing an animal model such as relevance to the human condition, accuracy of manifestation, predictability of outcome and species availability3 must be coupled with thorough understanding of the entity in humans to accurately compare manifestations. Achievement of an appropriate animal model, however, has recently been called into question by more than one group of investigators, whose concerns merit contemplation, even while continuing to design and work with animal models. Species selection depends on the exact scientific questions to be asked. The species that is phylogenetically closest to humans is not necessarily the best model to answer those questions. This 'high-fidelity fallacy'2 may lead to errors in species selection. Another error is lack of knowledge of differences in metabolic pathways between humans and potential animal models prior to species selection. Depending on the questions to be asked of the animal model, biomethods, microbiota, genetic characterization and even behavior may be important to know about potential model species as these factors may affect results of intervention.2 Basic concepts of design of an appropriate model, including scientific, ethical and regulatory considerations are readily available on-line, including the FDA's Animal Model Qualification process and the Animal Rule. Demonstrating this process, we will offer an example of a current U.S. Government (USG) animal model qualification effort, using an induced model of a biological threat. Despite widespread use of animals in biomedical research, the predictive value of animal models has begun to be questioned, increasingly seriously, ever since a 1994 statement declaring 'virtually every medical achievement of the last century has depended directly or indirectly on research with animals.'4 In the 21st century, innovations in safety, immunogenicity and toxicity testing of new or repurposed biological or chemical entities include in silico and in vitro testing systems which may supplement and, in the not-too-distant future, supplant certain aspects of animal model testing.