Putting the "Bio" Back Into Biomarkers: Orienting Proteomic Discovery Toward Biology and Away from the Measurement Platform (Editorial‪)‬

The discipline of mass spectrometry (MS)-based serum biomarker profiling is a relatively young field that was launched in a flourish of scientific hope and the clinical promise of a better cancer test (1-5). Nevertheless, the field has already undergone a rollercoaster cycle of optimism and disappointment and renewed enthusiasm during its brief 7-year history (1-8). Before 1999 very little effort was made to directly use MS (MALDI-TOF or ES) as a means to discover new blood biomarkers. Many scientists thought that serum was too complex for MS analysis, and dominated by contaminants, rendering these samples unacceptable for direct introduction into expensive and sophisticated MS research instruments. All of these arguments seemed to be overturned in 1998 when a new class of MALDI-TOF, surface-enhanced laser desorption and ionization (SELDI) was commercialized. Scientists with no formal training in MS saw SELDI as an opportunity to explore the application of MALDI MS to biomarker discovery. Although this method had relatively low resolution, it appeared to provide a fresh, one-step approach to the search for ion signatures of hundreds of candidate biomarkers. Importantly, SELDI-TOF offered a means to support a critical new hypothesis that was emerging in the protein biomarker field. This hypothesis abandoned the assumption that a single specific tumor cell-derived cancer biomarker existed. Instead, cascades of biomarkers were generated from the tumor tissue microenvironment through interactions between the tumor cells and the host cells (e.g., endothelial cells, stroma cells, and immune cells) (1, 5). The tissue-microenvironment hypothesis predicted that a panel of biomarkers could achieve a sensitivity and specificity superior to previous failed cancer biomarker searches (1, 5-8). In 2002 SELDI provided a means for discovering the ion signatures of these putative biomarkers, although their identity was unknown (1, 2).