Escaping the Rat Race
Over-reliance on rodent models could be leading drug discovery in the wrong direction
Stefan Amisten |
When I was working at Oxford, a professor I knew said something that really stayed with me: “Mouse diabetes is not a big clinical problem.”
There are only three real frontiers left to explore – deep space, the deep ocean, and the mysteries of biomedical science. And that made biomedical science an obvious career choice for me; it’s where individuals and small groups can come together and create new things or discover new knowledge – all without a huge budget or the support of a large organization. Biomedical science truly is the final frontier. But I believe there is a huge knowledge gap in our field. Why? Two words: rodent models.
I focus on drug targets for diabetes and cardiovascular disease; and, in my experience, too much research focuses on what has come before. The same drug targets and receptors are given all the attention, and we’re failing to look elsewhere. It also struck me that the vast majority of research – especially in diabetes – is conducted using mice and rats. But how well do rodent models really reflect their human counterparts? Looking further, I found that in-depth research into the similarities between mice and humans in this context is severely lacking – even though millions of pounds are spent studying mice and rats with diabetes.
There seems to be an assumption that the mouse is more or less the same as the human. But if you look at things from an evolutionary perspective, mouse and man had their last common ancestor around 10 million years before the dinosaurs died out! So besides the very obvious differences like our increased size and lack of tail, there are huge differences in our pharmacology – but no one seems to be working to comprehensively map these differences.
My colleagues and I set out to address the gap; after all, we all want to treat human disease, not simply learn more about mice. Our initial study found that some quite important and well-known receptors differ a great deal in terms of expression in mouse and man (1). I find this both worrying, because a lot of conclusions are being drawn using mouse models, and comforting, because it means there is much untapped potential in human tissues that we’ve missed by only looking at rodents.
Clearly, the availability of human tissue is an issue – and it’s important to remember that behind every human tissue donation there is an individual tragedy. So, from a practical perspective, it isn’t possible to sidestep the use of animal models for most research. But there are things researchers can do to address the issue, and this can be applied to any disease or tissue: look at human tissue first, then move to an animal model if necessary, and then once you have finished your mouse studies, go back to human tissue to validate your findings. There’s no point spending three years coming up with a fantastic drug target in rodent models if that particular target is not present in humans. Don’t waste precious time and resources studying animal-only phenomena.
I plan to continue my work in this area; my colleagues and I are currently working to publish a follow-up study looking at the peptides and proteins that interact with cell surface receptors, and how they differ in mice and humans. Based on our findings so far, it seems that some of the textbooks (which were created with the help of mouse data) will need to be rewritten, as there are many big differences that have been overlooked. I would urge all researchers using mice as part of their work to consider how well their findings will translate – if you jump to conclusions based on your findings in mice, you run the risk of making discoveries that will only benefit mice!
After all - “Mouse diabetes is not a big clinical problem.”
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- S Amisten et al., “A comparative analysis of human and mouse islet G-protein coupled receptor expression”, Sci Rep, 7, 46600 (2017). PMID: 28422162.