Understanding Animal Models in Translational Research

During the last decades, basic and translational research have used animal models to explore pathophysiological conditions to better understand the mechanisms behind the disease and to develop novel therapies for prevention and treatment. Today we are going to talk you through the different types of animal models used in biomedical research. We hope that this will provide an overview on how widely different animals models are used in science.

Cardiovascular physiology is a complex and deeply integrated network of hemodynamic, neuro-hormonal, and metabolic mechanisms. It is tempting to think that only ‘higher’ animal models, such as pigs are suitable to study the cardiovascular system. Different models have, however, different advantages that complement one other. Data and knowledge of these models combined will help find therapies related to the cardiovascular field.

Invertebrate models: Despite the vast morphological and cellular differences between humans and invertebrate animals, the Drosophila melanogaster model, for example, retains many internal organ systems and molecular mechanisms functionally analogous to those in vertebrates. The fly’s simple heart shares molecular and structural similarities to the human heart, with both experiencing age-related decline, and with specific genes involved in cardiac ageing identified in flies and mammalian hearts.   Easily and quickly bred and housed, Drosophila may be a suitable model to generate preliminary data to test a hypothesis.  The proper interpretation and use of these findings are, of course, key to designing subsequent experiments in a next level model.

Rodent models: Rats and mice have been extensively used to develop and study different pathologies. Let’s use the heart failure models as example. Overall, the disorder can be genetically related as seen in knock-in/out strains and condition prone lineages, or stimulus-induced by myocardial injury or by pressure overload. In genetically depended models, although one gene and/or protein mostly defines the strain, it is unfortunately usually not limited to that specific pathway. Secondary over or under expression of different proteins can affect other regulatory mechanisms and hinder the translational relevance of the study. These limitations are addressed to certain extent when tissue specific promoter elements are built in these transgenic models to target the genetic alterations to a specific tissue, aiming to minimize broader effects of genetic alterations. When tissue specific promotor elements are combined with stimulus-induced models, a tissue specific time-controlled transgenic model is created. Combine this with inducing, for instance, hypertension via aortic constriction and you have a powerful model to investigate hypertension.   In stimulus -induced models, the nature and onset of the stimulus must be considered when designing a study. For example, in the aortic constriction induced heart failure murine model, the hypertension onset is acute and therefore not adequate to explore underlying mechanism related to a gradual disease onset. While rodents are used extensively and are extremely helpful in answering many basic research questions, data translation is limited by distinct responses, motor skills and cognitive function, among other traits.

Large animal models: Although no model can completely replicate the intricacies seen in human pathologies, large animal models share more human similarities in terms of anatomy, physiology, and size, therefore increasing the chances of bench findings translating to effective clinical applications. This not only applies to pathophysiological processes, but also to human/clinical surgical techniques and device development. A good example can be observed in valvular heart disease research. Semilunar valve disorders, such as congenital malformations in infants and calcification in elderly patients, often require surgical replacement using mechanical or bioprosthetic valves. This, in turn, requires replacement compatibility and replacement surgery tailored to age, size and disease etiology. Even with the higher translational advantage, there are significant challenges to the use of large animal models. Besides costs due to size and all specialized husbandry needs, many of the immunoassay’s tools, such as specific antibodies so prolifically available in small animal research, are not as available for large species. Transgenic models, another hallmark of small animal research, has yet to be widespread in large animals.

Non-human primate models: As the most phylogenetically proximate model to humans, these models represent the first and sometimes the only choice for research related to immunology and neurological disorders. The number of non-human primates used in research is less than 1% and it is highly regulated. Non-human primate research is allowed only when no other research model can provide the required information. For example, transplant tolerance differs greatly by species. A lot was learned about transplant tolerance in mice and studies then progressed to swine models. However, the step to some  specific human studies could not be safely made without non-human primate models.

It is crucial to have a thorough understanding of the disease mechanisms and how they align with each model’s specificities. Besides the disparities in animal species, strains, metabolic pathways, diseases onset and progression, there are many other sources of methodological pitfalls that can minimize data translation such as: variations in drug dosing schedules and regimen; proper sample size, randomization, age and sex matching and control groups; distinctions in laboratory technique; proper outcome factors selection. In future blogs we will discuss these topics, since they are as important to high quality research as today’s topic.

Research must be guided by well-planned experimental design and careful interpretation of results to harvest the full value of any data. The process behind virtually every medical discovery process is a long one, probably extending through decades. Every step in the process is essential to the next, from basic research to human clinical trials. Transonic has been working with the life science and clinical communities for over 35 years, providing guidance and support where requested. So have a look at our video in which we celebrate all those years of research. You may find inspiration for your own research.