New guidlines published as mouse models thrown into question

As guidelines for animal testing are published, new genetic data suggests mouse models may not be relevant for studying human disease

Just how relevant is the mouse as a model for human disease?

Five of the UK’s major funders of animal research have published guidelines for using animals in research stating that funding will only be granted if - when collaborating with laboratories outside the UK - welfare standards are consistent with the principles in UK legislation and the new guidelines.

Although some funders have published guidance previously, this is the first time that the MRC, BBSRC, NERC, Wellcome Trust and NC3Rs have collaborated to produce a common set of principles for using animals in research and applying the 3Rs (replacement, refinement and reduction).

Sir Leszek Borysiewicz, chief executive of MRC, said: “The booklet sets out very clearly what the funders expect of those who work with animals. Good animal welfare and full implementation of the 3Rs are essential for good science and for retaining the support of the public in the use of animals in research.”
UK research using protected animals in scientific procedures is regulated by Animals (Scientific Procedures Act) 1986, administered by the Home Office. Although the Act requires that researchers apply the 3Rs, it contains minimal detail as to how this should be done.

Steve Visscher, interim chief executive of BBSRC, said: “Basic science often reveals new options for replacing, refining and reducing the number of animals used in research, but that use remains necessary in many key areas of biomedical science. We welcome this opportunity to re-emphasise our commitment to ensure that scientists continue to work at the very high standards demanded by UK funders.”

These are sentiments that are generally shared throughout the scientific community, however new work from the US has prompted some to go even further and suggest that mouse models may not even be relevant to human disease.

The mouse is a well used stand-in for humans in medical research, thanks to genomes that are 85% identical. But identical genes may behave differently in mouse and man, a study by University of Michigan evolutionary biologists Ben-Yang Liao and Jianzhi Zhang reveals.

“Everyone assumes that deletion of the same gene in the mouse and in humans produces the same phenotype. That’s the basis of using the mouse to study human disease,” said Zhang, an associate professor of ecology and evolutionary biology. “Our results show that may not always be the case.”

Zhang and Liao homed in on 120 essential human genes for which the mouse has an identical counterpart that also has been studied. If those 120 essential human genes are also essential in the mouse, deleting any of them should result in infertility or death before reproductive age. But their experiments showed an unexpected discrepancy.

“To our surprise, 22% of the 120 human essential genes are nonessential in the mouse,” Zhang said. “I expected there would be some, but I never expected the percentage to be so high.”

Zhang acknowledges that the study involved a relatively small number of genes and hopes that other researchers will be able to confirm the results, however Nicky Gordon, science officer for the Dr Hadwen Trust - a medical research charity that funds non-animal techniques to replace animal experiments - has echoed his concerns with mouse models.

She told Laboratory News: “We have long been concerned that equivalent genes in humans and mice don’t have the same functional effects. Millions of genetically modified mice are used as research 'models' for human diseases every year but the relevance of this research to human patients is highly questionable.”

Zhang and Liao’s work appears in the Proceedings of the National Academy of Sciences.