In retrospect: Flowers for Algernon
Ananyo Bhattacharya looks back at a science-fiction touchstone on the ethics of experimental biology.
Fat rats skew research results
Failure to recognize that many laboratory animals live unhealthy lives may be leading researchers to misinterpret their findings, potentially misdirecting efforts to develop theraputic drugs. The problem, reports a group at the US National Institute on Aging in Bethesda, Maryland, is that many rats and mice used in experiments are so overweight that they are glucose intolerant and heading for an early death (B. Martin et al. Proc. Natl Acad. Sci. USA doi:10.1073/pnas.0912955107; 2010). As a result, data from the animals — about, for example, the effects of an anti-cancer drug — may not apply to normal-weight animals. “The vast majority of investigators who use rats and mice don’t recognize that their normal conditions are relatively unhealthy,” says Mark Mattson, chief of the National Institute on Aging’s Laboratory of Neurosciences and a co-author on the paper. “The most logical way to extrapolate is to say any data we obtain in the animal model would be more relevant to overweight, sedentary humans than normalweight, active individuals.” Mattson and his colleagues note that the standard lab practice of allowing rats and mice continuous access to food without much opportunity to exercise can cause some to balloon in weight to up to 1 kilogram. Beneficial effects of a potential drug or behaviour could simply result from its effect on the consequences of an animal’s unhealthy lifestyle, they say, and studies showing that caloric restriction can extend lifespan may have to be reinterpreted. “A major reason the lifespan of rats and mice is extended by caloric restriction is they started from an unhealthy baseline,” argues Mattson. He and his co-workers identify areas as diverse as immune function, cancer and neurological disorders that could be affected by the problem. Mattson says that including running wheels in cages and feeding only on alternate days could solve the ‘fat rat’ problem, adding that the institutional committees that oversee and approve such experiments should encourage researchers to tackle the problem. The fat-rat hypothesis is certainly credible, says Robin Franklin, a neuroscientist and director of research at the Department of Veterinary Medicine , University of Cambridge, UK. “But I suspect it’s one of many factors that are responsible for the difference between animal models and human diseases,” he says, adding that the problem has not been apparent in his research. Still, Mattson and his colleagues have penned “hundreds of papers using rodent models and are widely known in their field”, says Christian Newcomer, executive director of the Association for Assessment and Accreditation of Laboratory Animal Care, a non-profit organization based in Frederick, Maryland, that accredits animal use in many laboratories, including those of the US National Institutes of Health. “I think [the paper] is going to carry a lot of weight.” ■ Daniel Cressey Fat rats skew research results IS TO C KP H O TO
Use of a body condition score technique to assess health status in a rat model of polycystic kidney disease.
Dear Editor 
 
We read with great interest the recent article in the March issue of JAALAS by Hickman and Swan.3 The results of this study demonstrate that body condition score is an effective noninvasive tool for assessing the health status and wellbeing in a rat model of polycystic kidney disease. This study emphasizes the importance of empirical study of the evaluation criteria within a specific animal model, as the standard approach used to score mouse body condition required modification to accommodate the fat deposition in obese rats.3 
 
This finding is relevant to more general considerations of the potential impact of obesity on rodent models, as discussed in recent articles in the Proceedings of the National Academy of Sciences1 and Nature.2 These articles describe how the use of sedentary, overweight, glucose intolerant rodents as control animals can influence studies of immune function, carcinogenesis, and neurologic disorders. These articles effectively make the point that the type of control animal used (that is, a healthy, normal weight control versus an obese, glucose intolerant control) can skew interpretation of the experimental results. This is of critical concern in drug development, where therapeutic interventions may be effective in sedentary, overweight animals, but ineffective, or produce different side effects, in normal weight, active subjects.1 
 
As the authors of the PNAS article demonstrate, dietary energy intake and exercise level may be critical variables influencing experimental outcomes due to the numerous signaling and metabolic pathways that are affected by dietary intake and exercise.1 Standard housing for rodents provides ad libitum access to food and limited floor space without access to a means of voluntary exercise (like a running wheel).4 These conditions encourage continuous weight gain.1 As the authors point out, our knowledge of how diet and exercise affect basic biological processes and disease pathogenesis needs to be expanded.1 
 
As laboratory animal veterinarians, animal care professionals, and investigators, we need to critically evaluate the environmental conditions of research animals and how weight and exercise level may impact the collection and interpretation of experimental data. The modification of the body condition score technique to accommodate genetically obese rats, as described by Hickman and Swan, is a good example of addressing experimental issues that arise when working with obese research animals.3 
 
Sincerely, 
 
 
Naomi M Gades, DVM, MS, CPIA, DACLAM 
 
Consultant, Department of Comparative Medicine, Mayo Clinic 
 
Nicole Murray, PhD 
 
Senior Associate Consultant, Department of Cancer Biology, Mayo Clinic 
 
 
 
Letters to the Editor 
Letters discuss material published in JAALAS in the previous 3 issues. They can be submitted through email (gro.salaa@slanruoj) or by regular mail (9190 Crestwyn Hills Dr, Memphis, TN 38125). Letters are not necessarily acknowledged upon receipt nor are the authors necessarily consulted before publication. Whether published in full or part, letters are subject to editing for clarity and space. The authors of the cited article will generally be given an opportunity to respond in the same issue in which the letter is published.