Questioning the preclinical paradigm: natural, extreme biology as an alternative discovery platform

Abstract

The pace at which science continues to advance is astonishing. From cosmology, microprocessors, structural engineering, and DNA sequencing our lives are continually affected by science-based technology. However, progress in treating human ailments, especially age-related conditions such as cancer and Alzheimer's disease, moves at a relative snail's pace. Given that the amount of investment is not disproportionately low, one has to question why our hopes for the development of efficacious drugs for such grievous illnesses have been frustratingly unrealized. Here we discuss one aspect of drug development –rodent models – and propose an alternative approach to discovery research rooted in evolutionary experimentation. Our goal is to accelerate the conversation around how we can move towards more translative preclinical work.

Towards a personalised approach in exercise-based cardiovascular rehabilitation: How can translational research help? A ‘call to action’ from the Section on Secondary Prevention and Cardiac Rehabilitation of the European Association of Preventive Cardiology

“…Nevertheless, a certain scepticism is warranted based on whether animal models appropriately translate to humans, which has resulted (and rightly so) in the value of such research being questioned. [154][155][156] An ideal disease model should mimic the human condition genetically, experimentally and physiologically. Therefore, using inbred mouse strains may not reflect the response generated in a genetically polymorphic human population, which may be one reason for the failure of many promising preclinical drugs when translated into human clinical trials.…”

Mechanisms of oxidative stress resistance in the brain: Lessons learned from hypoxia tolerant extremophilic vertebrates

“…Moreover, while most rodents in the wild rest in thermally buffered burrows or crevices, mice in captivity usually are exposed to the same thermal conditions when resting and active and are chronically cold-stressed. In most animal facilities mice are housed at temperatures (20–24°C) well below thermoneutrality (30–32°C) and thus are required to expend considerable energy on facultative thermogenesis [57, 58]. With no opportunity for physical exercise and little mental stimulation these cold-stressed rodents often consume vast amounts of food relative to animals in the wild and become obese.…”

“…Given that many of the concerns raised in the role of oxidative stress, aging and neurodegeneration commonly arise through studies solely using mice and rats in a tightly controlled laboratory environment, there is a dire need for additional animal models that show different ecophysiological strategies as well as longevity traits. Species that have adapted to extreme environments (e.g., with pronounced seasonal thermal fluctuations or low oxygen) or that are extremely long-lived such as the naked mole-rat [64] may be particularly useful [57, 65–67]. Such unusual, highly adapted species enable one to test the ubiquity of findings observed in traditional laboratory models, and evaluate whether nature has already evolved the appropriate mechanisms to overcome the cellular and molecular challenges posed by oxidative stress.…”

Regulation of Nrf2 signaling and longevity in naturally long-lived rodents

“…Surprisingly little is known about the mechanism(s) responsible. Lack of progress in this regard could reflect the predominant choice of short-lived animal models that are likely to have an inadequate molecular arsenal to naturally protect against the vagaries of aging (8). Comparative biology provides a powerful tool to evaluate whether nature, through millions of years of "evolutionary experimentation," has evolved cellular mechanisms that may abrogate physiological declines during aging in long-lived species.…”