What could Dr Finlay and Mr Herriot learn from each other?BMJ 2005; 331 doi: https://doi.org/10.1136/bmj.331.7527.1220 (Published 24 November 2005) Cite this as: BMJ 2005;331:1220
- Bob Michell, professor of comparative medicine ()
Comparisons of human and animal diseases can benefit patients of all species
The late 19th century brought recognition that normality and disease depended on similar mechanisms in humans and animals; leading scientists espoused the concept of “one medicine,” calling it the medicine of the future. Comparative medicine largely failed to realise these expectations during the 20th century, becoming narrowly equated with induced rodent models of human disease. But veterinary and medical research have plenty to learn from each other.
Comparative medicine is the study of comparable diseases in different species; similarities and differences are both informative. Induced models are useful for identifying potential disease mechanisms, but spontaneous models come into their own with multifactorial diseases combining genetic, dietary, environmental, toxic, immune, and other factors—which are inherently difficult to model—and for the assessment of new treatments ahead of human trials, thereby bringingveterinary patients faster access to clinical innovations.
For many diseases—such as asthma, cystic fibrosis, and various cancers—rodent models are misleading, and therapeutic responses may differ profoundly from humans.1 The dog, for example, has several advantages over the mouse as a model of human disease.2 Many human tumours have canine counterparts,3 and, unlike in mice, telomerase reactivation may herald the onset of malignancy in dogs, potentially offering a therapeutic target.4
Our understanding of human hypertension is a good example of the power of comparative research.Knowledge of hypertension predated clinical blood pressure measurements; salt and renal disease were implicated 3000 years ago. The earliest blood pressure measurements, by Hales in 1733, mainly relied on dogs, as did the “Goldblatt model” of hypertension 100 years later and the research underlying Guyton's concept of “pressure natriuresis” as the long term regulator of arterial pressure. Genetic and salt sensitive hypertension and the renal role in blood pressure regulation and in renovascular and other forms of hypertension all emerged from studies in animals, notably dogs.Differences between breeds of dog in arterial pressure may yet offer insights into mechanisms or evolutionary origins of human essential hypertension: did the same genes confer biological advantage when human life was shorter and more active?
Lack of a comparative perspective often flaws research on hypertension through the use of exorbitant sodium intakes—such as rats given a diet comprising 8% salt, equivalent to a human consuming 6400 mmol/day (a month's customary intake daily). Actually, mammalian requirement is probably below 0.6 mmol/kg/day, so the rat diet represents five months' nutritional requirement daily.5 The benefits of comparative research, exemplified by hypertension, include control over factors difficult to control in humans (such as diet and breeding), short generation time, and plentiful siblings (invaluable for studies of prenatal or perinatal factors in disease), and shorter lifespan and breed differences in lifespan (opportunities to study diseases of senescence and the biological basis of ageing).
Comparative medicine comes into its own in the field of genetics—genes shared between species far outnumber those that are unique. Alignment of genome sequences between dogs, horses, cats, and humans is well advanced,6 7 with progress also in pigs, cattle, and sheep. Dogs combine exceptional phenotypicdiversity, exemplified by breed differences in size and lifespan, with a relatively uniform genotype. Among some 370 canine genetic disorders, about half have exact human analogues.8 They generally resemble the human disease more closely than do rodentmodels, reflecting closer evolutionary kinship and DNA sequence identity.9 The National Human Genome Research Institute regards the canine genome as a key research priority. Molecular genetics adds new dimensions to comparative studies—identification of novel disease genes, new disease models, new molecular targets for drugs, evaluation of gene therapy, and elucidation of genotypic variation in therapeutic responses.
Comparative medicine emerged from the realisation that humans and animals shared similar cellular structures and mechanisms and faced challenges from similar microorganisms. But disease models were just that; resemblances between diseases. Now molecular science can show identical receptors, mediators, and genes. This should not surprise us, unless we are creationists; we share a rich evolutionary legacy of genes, many involved in diseases. Comparative medicine is no longer the study of mere similarities but of the same disease in different species. We need parallel development of comparative clinical studies and research in molecular genetics. The Comparative ClinicalScience Panel should provide the necessary strategic coherence to yield knowledge and reduce suffering, unfettered by species.10 In 1988 Stewart Cameron wrote: “Too little attention has been paid to comparison of human and spontaneous animal disease, either by veterinarians or physicians, and it is to be hoped that greater exchange of informationcan be organised in future.”11 With the development of theComparative Clinical Science Panel, this hope may now be fulfilled.
Clinical review p 1248
Competing interests None declared.