The cover artwork represents Popper’s postulate: If several observations of swans always show swans to be white, then the conclusion is that all swans are white. The dogma that all swans are white, held until the discovery in the eighteenth-century of black swans in Australia. We used this as an analogy for the interpretation of proteomics experiments in this article.

It struck us, when analysing proteomic data from ours and other studies, that several well-characterised intracellular proteins consistently appeared in secretomes (e.g. conditioned medium). Although at first it is tempting to attribute these to cell lysis during the assay and ignore them, we probed the literature and discovered that many intracellular proteins are multifunctional as well as present in multiple locations. Some of these proteins have been independently discovered, named and characterised and it was not until sequencing of the human genome that they were discovered to be one and the same. Glucose-6-phosphate is a prime example of this, being independently discovered as neuroleukin, autocrine motility factor and sperm surface antigen 36, all extracellular or cell surface proteins with unique functions. Others proteins have been discovered in one location or to carry out a particular role and other locations or functions which are less easily detected have been missed, or discounted based upon dogma or a lack of understanding (such as the absence of a secretion signal sequence in an extracellular protein).

We have the proteomics techniques to reveal the goings-on of a cell in an unbiased manner. Thus this article is intended to convey the message not to ignore proteins based upon dogma, but to investigate the unexpected, since this is where much of the interesting biology remains to be discovered. We discuss how pharmacoproteomics represents a useful tool for drug target validation and may be useful for highlighting novel and specific drug targets.

Get the whole story in Nature Reviews Drug Discovery 2009;8(12):935-48