Biomedical research aims to identify mechanisms underlying clinical pathologies, with the goal of developing novel treatments. In most cases, these mechanisms are examined in commercially available rodent models due to ease of use, homogeneous genetic backgrounds, and a strong foundation of previous research in these animals. While it is undeniable that these approaches are valuable, we can learn a great deal by examining the unique and elegant mechanisms that evolved in wild animal models that have responded and adapted to clinically relevant environmental and ecological stressors like hypoxia. Identifying these latent mechanisms can stimulate creative ideas for innovative therapeutic approaches that cannot be identified in traditional rodent models.

This approach embodies the spirit of the Krogh Principal of comparative physiology. In 1929, August Krogh wrote “For a large number of problems there will be some animal of choice or a few such animals on which it can be most conveniently studied.” Krogh believed that if it were possible to obtain an understanding of “essential characteristics of matter in the living state” that we must study vital physiological functions “in all their aspects throughout the myriads of organisms” [8]. Krogh understood that to successfully comprehend the mechanisms behind universal physiological concepts tied to human health and medicine, there would need to be decades of research with unique model systems to properly study certain questions. Consequently, this philosophy guided the larger field of physiology until recent decades.

Indeed, many of the most important discoveries in physiology and medicine were revealed through studies of diverse and unique animal models. For example, by examining pH-temperature relationships across a diversity of organisms, including ectotherms, with body temperatures spanning a much larger range than mammals alone, the “alphastat hypothesis” was revealed. This was a groundbreaking hypothesis which helped to eventually explain why protein function was conserved in conditions of changing temperature and how proteins respond to changes in isothermal pH. In fact, the observations in ectotherms corrected an erroneous view that many proteins functioned only within a narrow range of pH around 7.4. Another example of contributions of comparative physiology to medicine came from Krogh himself, who received a Nobel Prize for elucidating the structure and function of capillaries based on studies in another ectotherm, frogs. Krogh examined capillary networks in the frog tongue because of its translucent color (which allowed direct view of the capillaries and their associated arteries and veins) as well as the highly developed capillary tone in this tissue.

Unfortunately, in recent years, the fields of biomedical science and comparative physiology seem to have lost their intimate link. However, as we reach the centennial of Krogh’s evaluation of “The Progress of Physiology,” perhaps it is time to revisit more diverse experimental approaches. It has become clear that many discoveries made in rodent models are not replicated in humans, leading to low rates of successful translation to clinical trials [9]. In fact, many studies in rodent models are not successfully replicated by separate research teams using the same models and experimental design, due to lack of rigor in study design and insufficient considerations of statistical power. This is not a new problem, as Krogh himself proposed in 1929 that the field of physiology was beginning to suffer from a lack of critical thought in experimental design and hypothesis formulation, which lead to early signs of an unwieldy literature, poor replication, and waste of resources and animals. One solution to the overuse of animals in research is to choose better models geared toward answering a particular question. These models may include in vitro human cell-based assays or novel animal models which either better represent the human phenotype or provide unique insight into a question because of specific adaptations in that model.

Many comparative physiologists have begun reemphasizing the importance of approaching biomedical questions by examining physiological solutions to challenging environments that already exist in nature [10]. This philosophy extends not only to diverse animal models but also within-group comparisons by examining physiological plasticity and long-term adaptation to various stressors. Indeed, studies with humans exposed to extreme environments, as well as human populations that have undergone evolutionary adaptation to these environments, such as high-altitude native groups on the Tibetan Plateau, Andean Altiplano, and Ethiopian highlands, can be informative for discovering protective mechanisms against hypoxia that already exist and can provide insight into novel therapeutic targets.

In conclusion, many lessons can be learned about human pathologies and treatment options by studying wild animal models. Many species, some mentioned above, are known to avoid certain injuries or diseases that humans or other species would be susceptible to. These species provide a unique opportunity to advance our understanding of both human and veterinary medicine. With the advancement of technology, capacity to study these species in controlled settings, and ability to link genotypes and phenotypes, new techniques can be used to address previously unanswered questions. Biomedical research should embrace a comparative approach to identify these unique mechanisms and test their therapeutic potential.