Of ten medications withdrawn from the US market between 1998 and 2001, eight were withdrawn because they induced certain severe side effects more frequently in women than in men (1). Men and women are obviously similar in terms of evolutionary biology and gene regulation, but they responded very differently to these drugs. Studies have revealed that one strain of mice could have a gene removed, while another strain would die without the gene (2, 3). Iressa or gefitinib was thought to be ineffective as an anticancer drug but further analysis revealed it to be very effective for people with a specific genetic mutation. Today, because of pharmacogenetics, and other advances, we are on the verge of Personalized Medicine—drugs and treatments tailor made for the individual.
This again illustrates how very small differences between complex systems can result in profound differences in disease and drug response. If men do not respond the same as women, and one strain of mice does not respond the same as another why are we testing on animals in order to predict human response to drugs and disease?
Evolution, complexity theory and genetics explain why animal testing should not be an effective means of discovering what a drug will do in humans and how human will respond to diseases and most importantly empirical data supports this. Most physicians in clinical practice will tell you animal data is meaningless to them because it has no predictive ability.
Furthermore, the level of examination has changed since the 19th century when animals were primarily used to find commonalities across species lines. As our examination of living systems has become increasingly fine-grained, we have found that subtle differences between organisms tend to outweigh gross similarities. Science could and did use animals to shed light on shared functions such as the basic function of the liver and pancreas, but today we are studying drug response and disease at the level that defines not only a species, but in many cases the individual.
The intact systems argument has historically been the animal modelers’ main argument: “We must test on animals because no experimental system be it in vitro, in silico, mathematical modeling, and so forth can predict what a drug will do to the intact living human system.” Ironically, it is the fact that each intact living system is a differently complex system with unique evolutionary trajectories that invalidates the use of animal models. Complex systems are more than the sum of their parts, and almost identical complex systems respond differently to the same drug or disease. The implicit claim in the intact systems argument, that humans and other animal species are the same biochemical animals just dressed up differently, is simply not true. When we were ignorant of the function of a lung, the notion of trans-species extrapolation was used with some utility. The level of our examination has become more fine-grained and our knowledge has so greatly advanced that interspecies extrapolation is no longer valid.
In the 19th century, medical research was almost solely the domain of the experimental physiologist. But today, medical research, even the foundations supporting it, is multidisciplinary. Physicists and mathematicians are involved vis-à-vis complex systems analysis. Evolutionary biologists, molecular biologists, mathematicians, computer scientists, physicians and others all play different but vital roles. It is incumbent upon all involved to understand the implications of the knowledge gained from other fields. Researchers should abandon modes of inquiry based on unexamined assumptions from the 19th century.
1. General Accounting Office. (US General Accounting Office, Washington, DC, 2001).
2. H. F. Nijhout, American Scientist 91, 416 (2003).
3. H. Pearson, Nature 415, 8 (Jan 3, 2002).