The August Krogh Principle: Seeking Unity in Diversity
To the Editor
In 1929, Nobel Laureate August Krogh wrote the following on the importance of comparative animal physiology to medicine: “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” (1). The August Krogh principle has as its fundamental core the concept of “seeking unity in diversity” among all life forms. It is a powerful and underserved method of thinking or philosophy that taps into hundreds and millions of years of evolution in nature’s own laboratory to foster scientific creativity, discovery, and innovation (2).
I read with interest the review titled: “Abandon the Mouse Research Ship? Not Just Yet!” written by 27 distinguished scientists from around the world and across many disciplines (3). The authors are to be commended for discussing the pros and cons of the mouse model as an experimental platform for answering clinically relevant questions. I remain, however, unconvinced that the mouse model is optimally suited for questions on human trauma, sepsis, and resuscitation science in light of the mouse’s ability to enter torpid states during hypoxic or ischemic stress (4).
Torpor is the ability of an animal to “fall off” the standard “mouse-to-elephant curve” and lower their core temperature and metabolic rate to extreme values during times of stress and return when conditions are more favorable (2). In addition, torpor is known to profoundly affect the innate and adaptive immune systems including reducing the numbers of circulating leukocytes, lowering complement levels, and diminishing the animal’s response to bacterial lipopolysaccharide, phagocytotic capacity, cytokine production, lymphocyte proliferation, and antibody production (5). In those severe trauma states such as hemorrhagic shock, septic shock, and cardiac arrest, the mouse model may not be an appropriate model if it elicits a “torpor response” or a variation of that response. In 2005, hydrogen sulfide was reported to be revolutionary for emergency trauma care and treating soldiers on the battlefield based on its extraordinary ability to place a mouse in suspended animation for many hours with apparent complete recovery of function (6). However, the hydrogen sulfide concept failed to translate into larger animal models because the mouse was the wrong animal model for the translation of that particular question. The mouse model may, however, be a useful model for studying the underlying mechanisms of torpor with potential human relevance.
The key point is that all small animal models are not equal. The ability of the mouse to enter torpor does not apply to rats, guinea pigs, white rabbits, and most large mammals (4). The review failed to address this particular “trick” the mouse has over other small or large experimental animal models and the potential impact that this may have in answering clinically relevant questions in trauma and sepsis research. In contrast, rat models remain valid for critical care research, as they do not drop their resting active-phase body temperature or metabolism, even in food-deprived states (4). Caution should therefore be exercised in grouping the mouse with other rodents or other mammals when studying severe regional or global hypoxia and ischemia in critical care research. This caution might well be extended to other areas of translational research, as new or repurposed drugs should be examined in multiple animal models before undertaking clinical trials.
Geoffrey P. Dobson, PhD
Heart, Trauma and Sepsis Laboratory
Australian Institute of Tropical Health and Medicine
College of Medicine, James Cook University
Townsville, Queensland, Australia
1. Krogh A: The progress of physiology. Science 70 (1809): 200–204, 1929, p. 202.
2. Dobson GP: Organ arrest, protection and preservation: natural hibernation to cardiac surgery: a review. Comp Biochem Physiol B 139: 469–485, 2004.
3. Osuchowski MF, Remick DG, Lederer JA, et al.: Abandon the mouse research ship? Not just yet! Shock 41 (6): 463–475, 2014.
4. Schubert KA, Boerema AS, Vaanholt LM, de Boer SF, Strijkstra AM, Daan S: Daily torpor in mice: high foraging costs trigger energy-saving hypothermia. Biol Lett 6 (1): 132–135, 2010.
5. Bouma HR, Carey HV, Kroese GM: Hibernation: the immune system at rest? J Leukoc Biol 88 (4): 619–624, 2010.
6. Blackstone E, Roth MB: Suspended animation-like state protects mice from lethal hypoxia. Shock 27 (4): 370–372, 2007.