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Two simple reasons why experiments on lab mouse do not adequately recreate physiologically relevant human disease models

These days we frequently come across of discussions about relevance or non-relevance of laboratory mouse models to study human diseases. Mouse models have their supporters and opponents.

Usually, those in favor say that it’s the cheapest model at hand. However, this is not exactly true. Genetically modified mice that actually represent the main attractiveness of using mouse models can easily cost $200 per one male and female pair. And we are talking about the simplest genetic modifications. More fancy mutants can cost $500 or above apiece.

In the US, the FDA’s position is important to consider. FDA’s Investigational New Drug (IND) application requires incorporation of pre-clinical studies (related to proof of concept and toxicology). However, except mice and rats (and some birds), all other mammals are USDA covered species and hence fall under more complex guidelines. For example, USDA covered species include non-human primates, dogs, cats, guinea pigs, hamsters, rabbits, and any other warm-blooded animal. So, basically USDA and FDA regulations naturally make mouse the main experimental target animal for drug testing or academic laboratory manipulation.

Now, those who oppose mouse experimentation say that mouse models are waste and inhumane since they do not adequately represent human disease models. There are sufficient data to make such conclusion. Without going into detailed analysis, I want to suggest two simple reasons that many people haven’t even heard of.

1. Laboratory mice in any university or research organizations are kept in plastic cages at room temperature, around 22-25℃ (72-77℉). However, this is sub-optimal temperature for mouse whose natural affinity is for higher temperature (30℃). Basically lab mice are constantly feeling a little “cold”. And we know enough that this can affect their physiology, for example development of insulin sensitivity, obesity, type 2 immunity, overall inflammatory response.

2. Laboratory mice are fed only specially formulated dry pellets and water. Nothing else. However, in natural environment, mice eat almost everything including vegetables and fruits. Now, such non-natural food composition for lab mice affects their GI tract physiology and of course their microbiota. Research articles are full of protocols where mice are treated with antibiotic and combination of different antibiotics. It appears that this type of antibiotic treatment does not affect lab mice behavior such as their appetite and does not induce loss of weight or other GI tract disturbance that one would expect to happen from antibiotic treatment in ordinary mammals, including humans. Now, would you still think that testing new antibiotics safety profile in mouse could predict any side effects in humans?

The real issue is not whether mouse model is “representative” or not, but rather the question is, if not mouse, what else should we use for pre-clinical studies?

posted by David Usharauli