The riddle of protein diagnostics: future bleak or bright?

The 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 a major positive impact. Enormous strides have been made in the detection and identification of proteins, largely because of rapid improvements in mass spectrometry instrumentation and software, which are the foundation of modern proteomics. With these tools, very large numbers of candidate biomarkers have been tabulated in publications, amounting in aggregate to perhaps 25% of all human proteins (4). Unfortunately, the impact on clinical diagnostics thus far has been dismal. If anything, the rate at which new tests for protein analytes are cleared by the FDA has slightly declined over the past 15 years, and it seems stuck at 1.5 new tests per year (Fig. 2). This rate is clearly insufficient to address major unmet medical needs and reflects no improvement attributable to the advances made in biomarker research. The tests that have been cleared in this period are not the product of proteomics research and in many cases are neither very widely used nor widely recognized by clinical chemists and physicians. A survey conducted among the leadership in the clinical chemistry community [n 378, 69 respondents (18%)] revealed that 35% of the tests cleared by the FDA since 1993 are performed in 10% of the clinical laboratories surveyed; 60% of these tests were performed in 25% of laboratories. Furthermore, 50% of the respondents were not familiar with the clinical utility of 12 (45%) of these tests. Although the percentage of respondents in the survey is relatively small, the findings suggest that FDA clearance does not necessarily translate into clinical acceptance, further clouding the impact of the novel markers. Biomarker theory thus seems to have diverged from clinical practice to an alarming degree. Such a discrepancy in science usually points to a serious flaw in our understanding of the problem at hand and prompts a reexamination of our general approach. At this point, we can identify 2 major structural problems in the approach to protein biomarkers that has been pursued to date.