Targeting versus tinkering: Explaining why the clinic is frustrated with molecular mapping of disease mechanisms.

We argue that our common diseases should not necessarily be taken as a sign of physiological error. Regulatory networks developed by evolutionary forces to support reproductive fitness happen to include disease as a side-effect. For example, inflammatory and autoimmune diseases are secondary to a strong defence against infections. An evolutionary perspective can help us understand why many drugs targeted to single molecules or linear signaling pathways fail in clinical trials. We present the hypothesis that a tinkering research strategy, as compared with the prevailing reductionist approach, may be more likely to help us find the tools needed to interfere optimally with disease-generating networks. One application of the hypothesis can be to analyze how manipulation with diet and gut microbial flora influences multiple sclerosis patients, rather than to first map in detail the molecular disease mechanism and then develop targeting drugs.