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 Animals cannot predict human responses to drugs and disease. How often has a headline caught your eye, promising cures for everything from cancer to Alzheimer's disease? Then, upon reading the article, you are disappointed to realize that the "advance" was made on a laboratory mouse. It has long been appreciated that animals cannot predict human responses to drugs and disease. Dr. BB Brodie said in the August 13, 1963 issue of The Pharmacologist: "It is often a matter of pure luck that animal experiments lead to clinically useful drugs." More recently, then-U.S. Secretary of Health and Human Services Mike Leavitt stated on January 12, 2006: "Currently, nine out of ten experimental drugs fail in clinical studies because we cannot accurately predict how they will behave in people based on laboratory and animal studies." Vaccines against AIDS have worked well in monkeys but failed in humans. The way HIV affects animals differs significantly from the way it affects humans. These examples could be easily multiplied.
Recent developments in biology and physics have now provided a framework or theory to support the clinical evidence. For decades, scientists studied animals in hopes of learning about humans under the paradigm of reductionism. Reductionism is the idea that you can learn about big, complicated systems by taking apart the components that make them up, studying them, and then applying what you have learned to the system as a whole. Biomedical research has historically been based on the notion that if you know how all the components of an organism function, you can make predictions about the organism as a whole. Moreover, if you know how the components of organism A function, you can also predict how those same components will function in organism B. This worked very well in the early days of biology as many aspects of a living system can be successfully studied piece by piece and many pieces did in fact serve the same function in mice, monkeys and humans. Simple systems, or complex systems at certain levels, are amenable to being studied under reductionism.
Complex systems as a whole however, are not. Complexity as a science is related to chaos; a butterfly in Asia flaps its wings and it rains in the U.S. Very small pertubations in chaotic or complex systems can result in dramatic changes over time. A complex system is different from a simple system in that a complex system is greater than the sum of its parts. Therein lies the problem. Studying one complex system will not allow you to extrapolate to another even very similar complex system. For example, studying how mice respond to a drug will not allow you to predict what the drug will do in humans. Why is this?
 Complex systems have many characteristics including the fact that they are extremely sensitive to initial conditions and are nonlinear. Nonlinearity means that the output of the system is not proportional to the input; like the butterfly example. Some small inputs or changes may lead to a very different system as a whole, while some large inputs may not affect the system at all.
Complex systems also exhibit emergent properties. Emergent properties cannot be predicted by studying isolated components. This is another reason predictions about the whole cannot be made based on reductionism (breaking down the whole into its parts). Humans and animals are examples of complex systems. In the past, scientists could study mice and extrapolate the findings to humans because at the more basic levels of examination reductionism worked. Reductionism fails when studying complex systems as the level of examination becomes more fine-grained. This is the level scientists are studying when trying to predict human response to drugs and disease.
This is why even monozygotic (formerly called identical) twins do not always suffer from the same diseases and may react differently to the same drug. It is also why scientists have cured cancer in mice hundreds of times but those same cancers are still killing humans. An appreciation for the implications of complex systems is sufficient to explain why animals cannot predict human response to drugs and disease.
The second aspect of science that explains why animals are not predictive for humans is evolutionary biology. The Human Genome Project and the various spin off projects have taught us that most mammals have more or less the same genes. Dog, human, or rat, we are all composed of more or less the same genes. Humans even have the gene that, in mice, results in a tail. The genes themselves do not make us different from rats (although there are a very few dissimilarities). It is the regulation and expression of the genes that account for the differences. The reason we do not grow a tail is that the gene that results in tails in mice is turned off in us during our development in the womb. So, voila no tail.
Think of genes as the keys on of a piano. Your piano has exactly the same keys as mine. But the way you press (or express) your keys may result in Mozart while my expression of my keys might result in jazz. Same keys but very different outcomes. Evolutionary biology has shown that differences in gene regulation and expression may be a mechanism for how some species evolved. As animals evolved into different species the same genes were used but by regulating and expressing them differently new niches were filled.
We also now know that the environment can cause certain genes to be expressed. This means that even very small differences between the environments of two people, such as their position in the womb, can result in one suffering from a disease while the other does not. This probably explains some of the differences between monozygotic twins.
The background that a gene functions in also influences what the gene does. For example, mutations in the genes that cause phenylketonuria and Sanfilippo syndrome in humans do not cause these diseases in macaque monkeys. Background-specific modifier genes may be responsible for this.
Animals and humans have taken distinct evolutionary trajectories, adapting and solving different problems, and filling different niches in the course of evolution. Structural similarities can deceive us into thinking mice are merely humans writ small. They are not!
Empirically, we have known for decades that animals cannot predict human response to drugs or disease. An appreciation of complex systems and an understanding of evolutionary biology vis-à-vis gene regulation and expression allow us to place the empirical evidence in a broader context. 
Ray Greek has raised his voice against animal experimentation. He is President of Americans for Medical Advancement, Los Angeles and Europeans for Medical Advancement, London.
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