Researchers warn of clinical mousetrap

Two new studies that compare the immune systems of humans and mice and gene expression in humans and mice directly challenge the notion that rodents provide a reliable and safe human analog for clinical research.

In the first study, published in Molecular Ecology, Norwegian researchers examining the immune systems of lab mice and wild mice found that the lab mice were usually never exposed to the bacteria and pathogens that would “exercise” their immune systems.

Study author Preben Boysen explained that natural killer (NK) cells are pivotal players in the onset of important immune defences in response to vaccines, infections or cancer. But NK cells are generally not seen in lab mouse lymph nodes. These findings correspond with the hypothesis that NK cells need a microbial priming phase – such as in the wild – in order to become fully responsive.

The increased NK cell activity in wild mice could reflect the recent discovery that NK cells carry imprints of previous microbial encounters and act for long periods as “memory-like” cells, challenging the previous notion that such cells are normally short-lived immune cells.

From these findings, Boysen contends that the lab mouse research model neglects environmental factors that are needed to fully represent the immune system of mice and humans. “The traditional [lab] mouse model may miss out important NK based immune responses, since these important cellular players will not have gone through the microbial priming that would normally occur in a mouse or a human’s natural environment.”

The second study, by medical researchers at Washington University in St. Louis, calls into question researchers’ reliance on rodent models in cardiovascular research. “The problem is the difference in gene expression between the mouse and the human is very very large,” said study co-author Igor Efimov.

Efimov investigates the biophysical and physiological mechanisms that underlie heart rhythm disorders. His study reports on the failure in human hearts of two drugs that had already been studied in the mouse heart. The results show that a drug target that looked promising in the mouse model would not work in humans.

Efimov said the drug being tested did the opposite in humans of what happened in mice. Specifically, it would cause fatal arrhythmias in people. Efimov sees the results as indicative of a larger problem with cardiovascular research, one that has blocked the development of effective therapies for many years.

The current approach to studying arrhythmia and many other diseases goes back to a three-step protocol worked out by the German scientist Rudolf Virchow. The first step is to identify the clinical signs and symptoms of the disease; the second is to recreate those symptoms and identify a therapy in an animal model; and the third evaluate the safety and efficacy of the therapy in clinical trials.

“The problem is that at least in the cardiac arrhythmia field, this paradigm has had very few successes,” lamented Efimov. “It has resulted in the discovery of almost no successful drugs. Clinical trial after clinical trial has ended in failure. A mouse’s heart beats about 600 times per minute, so you can imagine it is a little different from humans, whose hearts beat on average 72 times per minute. You can mutate in mice the gene thought to cause heart failure in humans and you don’t get the same disease, because the mouse is so different. So, unfortunately, even with the help of transgenic mice, very few results made it from the animal model to the clinic.”

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Source: Washington University in St. Louis, Norwegian School of Veterinary Science

 

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