Why animal model studies are lost in translation.

The development of novel therapies based on understanding the pathophysiologic basis of disease is a major goal of biomedical research. Despite an explosion in new knowledge on the molecular mechanisms of disease derived from animal model investigations, translation into effective treatment for human patients has been disappointingly slow. Several fundamental problems may explain the translational failures. First, the emphasis on novel and highly significant findings selectively rewards implausible, low-probability observations and high-magnitude effects, providing a biased perspective of the pathophysiology of disease that underappreciates the complexity and redundancy of biological systems. Second, even when a sound targetable mechanism is identified, animal models cannot recapitulate the pathophysiologic heterogeneity of the human disease, and are poor predictors of therapeutic success. Third, traditional classifications of most complex diseases are based primarily on clinical criteria and do not reflect the diverse pathophysiologic mechanisms that may be involved. The development of a flexible and dynamic conceptual paradigm that takes into account the totality of the evidence on the mechanisms of disease, and pathophysiologic stratification of patients to identify subpopulations with distinct pathogenetic mechanisms, are crucial for the development of new therapeutics.