Evolutionary Aspects of Animal Models

Abstract

The 8th American College of Veterinary Pathologists (ACVP) symposium, held at the 2012 Experimental Biology meeting in San Diego, California (http://experimentalbiology.org/ content/AboutEP.aspx), was organized by the ACVP Intersociety Experimental Pathology Committee in conjunction with the American Society for Investigative Pathology (ASIP; http://www.asip.org/). The symposium facilitates interactions and cross-disciplinary collaborations between veterinary and physician pathologists, scientists, and basic researchers. The American Society for Nutrition cosponsored this year’s symposium. The symposium topic was evolutionary aspects of animal models. An evolutionary perspective is increasingly being embraced as essential for a comprehensive understanding of disease. The symposium highlighted the importance of an evolutionary perspective in the development and use of animal models of human disease. Speakers emphasized how evolution has differentially molded cardiovascular physiology, response to infectious agents, and aging in both man and animals. In addition, the evolutionary trade-offs between phenotypic selection and disease, which has provided many spontaneous animal models of human diseases, were discussed. Dr Robert Hamlin, The Ohio State University, opened with the challenges for studying cardiovascular disease in a talk entitled: ‘‘Animals as models of human cardiovascular disease: the search to overcome outdated evolutionary homeostatic mechanisms.’’ He addressed the fact that animals used to model human diseases often have very different cardiovascular physiology from humans and how these differences affect the predictive value of safety studies. As an example, cardiovascular drug safety testing was expanded significantly upon discovering that the antihistamine terfenadine is cardiotoxic when not completely metabolized. Its toxic effect is induced by the inhibition of the cytochrome P450 3A4 (CYP 3A4) isoform, a circumstance that caused death in a small percentage of people due to an unexpected interaction with other medications. CYP 3A4 is inhibited by a variety of commonly prescribed drugs as well as grapefruit. In its toxic form, terfenadine induces a prolonged QT interval and thus can trigger a fatal arrhythmia; however, this effect could not be modeled in rats and mice since they do not have the hERG ion channel that caused the human arrhythmia. Dr Hamlin further emphasized the importance of matching characteristics of the experimental animal with those of the human phenotype. In listing several animals that should not be used to model specific human diseases, he included guinea pigs and dogs as poor subjects for studies of coronary collateralization as their coronary arteries have a much more extensive collateral circulation than is present in human beings. An interesting theme was how many cardiovascular diseases arise or worsen due to outmoded ‘‘protective’’ homeostatic mechanisms. For example, volume depletion was the primary mode of death for prehistoric man; however, in the developed world, the mechanisms that evolved to assist survival in conditions of volume depletion (thirst, decreased urine production, and vasoconstriction) now complicate more modern maladies such as diabetes, congestive heart failure, and pulmonary disease. Such examples emphasize the need for careful consideration of the evolutionary similarities and differences between man and the animals used in research. To summarize, Dr Hamlin questioned how we can expect to model a heterogeneous population with a homogeneous animal model when disease characteristics may be determined by population heterogeneity. He concluded that selecting surrogates to study human pathophysiology should