The Riddle of Protein Diagnostics: Future Bleak or Bright?

> In theory, there is no difference between theory and practice. In practice, there is.> > —variously attributed to Andrew Tannenbaum, Jan L.A. van de Snepscheut, or Yogi BerraThe theory behind an exploding kaleidoscope of protein biomarker research is that reproducible molecular differences that correlate with important medical attributes can be discovered in patient samples and that these molecules can be measured with clinical tests to obtain useful medical information. How could this not be true? Chorionic gonadotropin and cardiac troponins are very good biomarkers indeed—for pregnancy and myocardial infarction, respectively—so proteins obviously can serve as useful clinical tests. Apparently the US Food and Drug Administration (FDA) agrees, because, through 2009, it has cleared commercial clinical tests for the measurement of 109 proteins in plasma or serum. Reference laboratories offer “home brew” tests that measure 96 more, for a total of 205 proteins (10% of the proteins known to exist in plasma and 1% of the baseline human proteome) with some recognized clinical importance (1).Of course many, perhaps most, of the chronic diseases that are really difficult to manage, as well as almost all cancers, remain beyond the reach of current clinical laboratory tests. To address this need, the NIH, guided by prevailing theory and the scientific community, has devoted increasing resources to the search for biomarkers via tried-and-true research support mechanisms. Over the past 2 decades, the numbers of research grants, research dollars, and published reports self-identified as biomarker related have increased dramatically (2). Fig. 1 shows the astonishing growth in funding and publication, which we obtained with updated key-word database searches (RePORT) (3). Although we do not know how much of this growth represents real effort directed at clinical biomarkers and how much is cosmetic “repurposing” of other lines of research, the aggregate total of >$1 billion spent over the last 3 years on biomarker discovery ought to have had …