Tuesday, November 22, 2011

0 Article: The Mouse Trap: How One Rodent Rules The Lab

Slate recently posted a three part series on the use of mice in biomedical research and how that use has helped as well as hindered drug development and scientific understanding of human illness.

This three part series kicks off with "The Mouse Trap: the dangers of using one lab animal to study every disease", which examines the rise in the use of the murine (mouse) model  to test new pharmaceuticals and get a better understanding of human processes in illness. We also learn that this model - useful as it has been - has its drawbacks.

 Mark Mattson, neuroscientist, finds that murine studies may not accurately represent what happens between the study and control group when the control group is often overfed, sedentary, and develops cancer, renal problems, and diabetes - unlike a wild mouse living in its normal habitat. It was later discovered that medication which worked in chubby rodents did not go on to work in rodents with a normal weight and activity level.

Furthermore, in clinical trials on humans later on, the difference between plump mice and a diverse group of humans was too great. A drug which worked in the rodents did not work in humans at all.

Cheap, efficient, and mass produced, these mice are raised in germ-free barrier rooms and sometimes pumped with antibiotics. The ease in which they can be raised, bred, and genetically modified to single out specific processes similar to those in the human body to study has made mice very popular for researchers. While they can closely model many processes in the human body, are they a close enough match for modeling and testing everything?

Mattson argues they are not, and that science needs to wake up and take a closer look at how heavily mice have been used to make decisions that affect human medicine. He's not the only one, either - Clif Barry, the nation's leading expert on tuberculosis, thinks the murine model has shortcomings too. This is no clearer than in work in his own field: The latent form of TB that humans get is not one which can be found in mice. Mice do not experience a latent stage of TB - they only get progressively weaker, age, and die.

This particular passage from the article gave me a moment to pause and reflect:
"[...] for some patients a latent case of tuberculosis can suddenly become active. The granulomas rupture and propagate, spilling thousands of organisms into the lungs, where they can be aerosolized, coughed up, and passed on to a new host. Left untreated, the infection migrates into the bloodstream and other organs; widespread inflammation leads to burst arteries or a ruptured esophagus; and in about half of all cases, the patient dies.

The layered granuloma is the defining feature of human tuberculosis: The place where the host fights the infection (successfully or not), and the necessary site of action for any drug. To cure the disease, a treatment must be able to penetrate each ball of cells, whatever its type or composition; every last bacterium must be destroyed. "It's the structure of those granulomas that makes it so difficult to treat TB," says Barry. And they simply don't exist in mice.

If you infect a mouse with TB—if you spritz a puff of infected air into its nostrils through a trumpet, as so many labs do around the world—the animal's lungs quickly fill up with bacteria and immune cells, like a nasty case of pneumonia. There are no discrete balls of tissue, no well-defined granulomas sheathed in fibrin, no array of structures that harbor the bugs at various stages of development. The mice have no special, latent form of TB, either, and no way to pass on the disease. They simply die, after a year or two, of a slow and progressive decline.

That's why we've made so little progress using mice to generate new drugs and treatments, Barry tells me."
The article continues to outline the history behind why mice have become the dominant research model to use to determine whether or not a drug or treatment plan will be tried in clinical trials on people, and also discusses the setbacks generated by this decision. In the end, the verdict is that using mice has distinct limitations and a number of studies may be invalidated and useless because of it.

It does get me to wondering, of course, as to how useful the murine model is for studying Borrelia burgdorferi. Perhaps in some ways it is useful, but in others it is less so: Dr. Stephen Barthold has said mice are a poor model for neuroborreliosis.

And this does raise the question of which details are important in a study that the layperson will miss when reading it. The average person will read about the study design, and perhaps some discussion and the conclusion - but will one question the decision to use one research animal model over another? What about primers? What about media? What about any number of small details that once changed could result in a different outcome?

Read the full Slate article, and continue with the next two articles in the series. It is a fascinating look into the world of biomedical research, tradition, and profit.

Reference: http://www.slate.com/articles/health_and_science/the_mouse_trap/2011/11/lab_mice_are_they_limiting_our_understanding_of_human_disease_.html


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