Mice models inadequate for human inflammatory disease
The laboratory mouse is the corner-stone scientific research. The ease with which it can be housed, genetically manipulated and its close similarity to humans has made it the go-to animal for medical researchers. Over 3 million mice were used in scientific experiments in the UK in 2012. But there are important limitations to this ubiquitous animal, as a paper published earlier this year showed, much to the surprise of many scientists.
The large-scale study, which re-analysed data from previous studies and combined it with new research, found huge variation in gene activity in mice with sepsis, burns and other types of trauma. Despite showing the same inflammatory responses under a microscope, inside the cells, at the molecular level of genes, it was a different story. This variation is not seen in people – whether the patient is suffering from infection or burns, the gene activity is essentially the same. Even more surprising, the paper concluded that the molecular similarity of the studied diseases induced in mice compared to their human counterparts came close to that expected by random chance alone.
Nobody claims animals are the perfect models of human disease, but these results came as a shock to many in the field. They may explain why every one of nearly 150 drugs tested at huge expense in patients with sepsis has failed. But rather than turn their backs completely on mice in their experiments, the authors of the study propose building on the findings to improve their use. They propose comprehensively studying gene activity in patients first and using this as a blue-print to “design” mice to match. Not only is it possible to artificially alter the activity of mouse genes but new techniques allow scientists to insert multiple human genes into the mice to recreate human responses to disease at the molecular level.
For some diseases the differences between mice and men have been long-known. This is particularly true for neurodegenerative conditions such as Alzheimer’s and Parkinson’s. Although they can be used for some research into these diseases, mice might simply not be complex enough to display some of the cognitive symptoms observed in dementia. This is why some researchers must use primates despite the considerable cost and technical limitations – they are far more difficult to genetically manipulate for example. Social behaviour is another area where mice are just too-far removed from people. 50 years of observing rhesus monkeys interacting with one-another in the wild, combined with lab experiments reaching almost as far back, has provided a wealth of understanding for researchers studying autism spectrum disorders, for example. Mice do not have the social structures, reliance on vision for social signalling, and deep similarity in brain circuitry controlling social behaviour and instincts.
Researchers using animals must constantly ask themselves whether the use is necessary. Indeed UK and European law demands they use as few animals as possible and alternatives where they exist. They also have a duty to make sure that use is as likely as possible to yield valuable results. Initiatives such as the Collaborative Cross programme, which has generated a collection of mice to reflect the genetic diversity seen in human populations, might help. “Humanised” mice containing human genes, cells, tissues and/or organs could also lead to more accurate models of disease. They have already led to a better understanding of the immune system complications underlying type 1 diabetes and multiple sclerosis.
Scientists strive above all else to get accurate results; that means employing cutting edge techniques and keeping abreast of the latest findings that could influence their own experiments. Although animals are undoubtedly invaluable in medical research, it’s important to remember the limit to which they can replicate complex human conditions.
Perhaps unsurprisingly, this paper gave an opportunity for some to argue against all animal research, a response countered in this blog piece from the Jackson Laboratory.