Animal Rights

Breaking News: Animal Models Do Not Predict Human Response

| by Dr Ray Greek

Headlines from a August 3, 2011, press release from Washington University in St. Louis: New study calls into question reliance on animal models in cardiovascular research, Human hearts respond differently than mouse hearts to two cardiovascular drugs

Studies have revealed that there are differences between mouse and human hearts in the distribution of potassium ion channels. This is important because some drugs act on these potassium channels. The press release continues:

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Anyone who follows science has read enthusiastic stories about medical breakthroughs that include the standard disclaimer that the results were obtained in mice and might not carry over to humans. Much later, there might be reports that a drug has been abandoned because clinical trials turned up unforeseen side effects or responses in humans. Given the delay, most readers probably don't connect the initial success and the eventual failure. But Igor Efimov, PhD, a biomedical engineer at Washington University in St. Louis who studies the biophysical and physiological mechanisms that underlie heart rhythm disorders, is acutely aware of the failure of once-promising drugs to pass clinical trials. "The problem is the difference in gene expression between the mouse and the human is very very large," Efimov says. Mice are the most popular animal model in cardiovascular research in part because it is easy and cheap to create a transgenic mouse, and these mice allow research questions to be asked and answered precisely and quickly. To avoid the "mouse trap," Efimov has established connections with local institutions that supply his lab with human hearts. The hearts are either diseased ones removed from patients undergoing heart transplants or "non-failing" hearts that have been donated for research but are considered unsuitable for transplantation. An article in the August issue of the Journal of Molecular and Cellular Cardiology beautifully demonstrates the importance of working with human hearts. It reports on studies in human hearts of two drugs that had already been studied in the mouse heart (work also published in the Journal of Molecular and Cellular Cardiology). The results show that a drug target that looked promising in the mouse model would not work in humans.

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The abstracts for the articles in the Journal of Molecular and Cellular Cardiology can be accessed here and here. The press release continues:

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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, Efimov says. 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," Efimov says. "It has resulted in the discovery of almost no successful drugs. Clinical trial after clinical trial has ended in failure." Mice are the most popular animal model in physiology, but the mouse is not a very good model for cardiac physiology. "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," Efimov says. "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," Efimov says. "So, unfortunately, even with the help of transgenic mice, very few results made it from the animal model to the clinic." . . . "Since we've begun to work with human hearts," he says, "we're finally starting to catch up with animal physiology."

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I should here note that the researchers mentioned above are probably not going to abandon animal models and indeed probably still support animal modeling. But I will let the above speak for itself in terms of the value of using animal models to predict human response to drugs and disease.