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Flawed tests on mice for human illnesses reinforce need for alternatives

Mice fall short as test subjects for humans’ deadly ills, according to a study published in the journal for the Proceedings of the National Academy of Sciences (PNAS).

The article, which was subsequently reported in the New York Times, is based on a 10-year study of human inflammation that occurs during trauma, burn injuries and bacterial infection.  It found that the way humans respond to these events is totally different to how mice respond.

Humans typically respond to different acute inflammatory stresses in highly similar ways, unlike mice. In humans, the genomic response to burn injuries and trauma has a 91% correlation while in mice this ‘correlation’ is just 13%.

Direct comparisons between humans and mice for all three responses show an 8% correlation at best between results and in some cases show no correlation at all.

The immune system reacts immediately in response to trauma, burn injuries or bacterial infection in order to protect the cells and tissues that have been damaged and in order to limit the damage that these events can cause. In acute cases, the immune system over-reacts with potentially fatal consequences. There are currently no drugs available that can alleviate this overreaction by the immune system.

According to the authors of the study: “There are multiple considerations to our finding that transcriptional response in mouse models reflects human diseases so poorly, including the evolutional distance between mice and humans, the complexity of the human disease, the inbred nature of the mouse model, and often, the use of single mechanistic models.

“In addition, differences in cellular composition between mouse and human tissues can contribute to the differences seen in the molecular response.”

The study also pointed out that, as mice do not live as long as humans, long-term diseases and long-term recovery strategies cannot be modelled in a mouse: “Additionally, the different temporal spans of recovery from disease between patients and mouse models are an inherent problem in the use of mouse models. Late events related to the clinical care of the patients (such as fluids, drugs, surgery, and life support) likely alter genomic responses that are not captured in murine models.”

Drugs that combat the serious effects of elevated inflammatory responses in critically ill or injured patients have never been successful in clinical trials. To date there have been nearly 150 clinical trials for drugs that block the inflammatory response and in all cases the drugs have failed even though a response had been seen in the animal model.

When asked how difficult it was to publish this study, given that many journals had refused or rejected to publish the work, one of the lead authors said: “They were so used to doing mouse studies that they thought that was how you validate things. They are so ingrained in trying to cure mice that they forget we are trying to cure humans.”

The study comes at a time when the call for finding alternatives to animal experiments is at its highest point for many years. 

The UK’s leading humane medical research charity, the Dr Hadwen Trust (DHT), and Queen Mary, University of London, recently joined forces to lead the global development of human-relevant methods and alternatives to animal use in diverse areas of bio-medical research.

They have created the world’s first Professorial Chair in Animal Replacement Science which will see the UK spearhead a collaborative global search for more ethical, human-relevant alternatives to animal experiments.

Kailah Eglington, Chief Executive of the Dr Hadwen Trust, said: “This marks an important stage in animal alternatives.  Although the DHT has been making the case for alternatives for many years, this takes animal replacement science to a new level.”

The DHT is to fund the Chair, along with a dedicated unit and PhD student, thanks to a £1m legacy left to the charity specifically for this purpose by lifelong supporter Alan Stross.  The Chair is a major stepping stone towards creating a global community of scientists working together towards finding techniques that replace the use of animals and that are more human-relevant.

A change in UK legislation directed by the EU, which came into force this year, also ensures that alternative, non-animal research techniques are used in medical research if they are available.

Kailah Eglington added: “The PNAS study highlights how poor the mouse is as a human-analogue system for inflammation studies, so the question naturally arises as to its relevance in other areas of medical research.

“Now, with this new legislation, it is vital that new and existing scientists and researchers are aware that successful alternatives to animal experiments are available today and that more are needed.”

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