"The quest for biomarkers": are we on the right technical track?

The discovery phase of biomarkers of diagnostic or therapeutic interest started a decade ago with the very rapid development of proteomic investigations. In spite of the development of innovative technologies and multiple approaches, the "harvest" is still modest. Various reasons justified the encountered difficulties and most of them have been circumvented by specific sample treatments or dedicated analytical approaches. Nevertheless, the situation of very modest biomarker discovery level did not change much. This review intends to specifically analyze the main approaches used for biomarker discovery phase and evaluate related advantages and disadvantages. Thus, preliminary sample treatments such as fractionation, depletion and reduction of dynamic concentration range will critically be discussed and then the main differential expression investigation methods analyzed. Combinations of technologies are also discussed along with possible proposals to federate associations of complementary technologies for better chances of success.