The term biomarker refers to a broad category of objective medical indicators—signs of a patient's health that can be observed and measured from outside the body. These indicators are both accurate and reproducible.

Biomarkers are valuable tools for detecting changes in a patient's physiological state that may signal the risk or progression of a disease or indicate how a condition might respond to a particular treatment. They hold significant potential for personalised medicine, as diagnostic or progression markers can provide crucial information that helps tailor treatments to the individual, enabling more precise and effective interventions in the disease or condition process.

There is an urgent need for better biomarkers to enhance diagnosis, guide molecularly targeted therapies, and monitor disease activity and treatment responses across a broad range of conditions. Proteomics techniques, particularly those based on mass spectrometry, offer great potential for discovering new biomarkers that could serve as the basis for innovative clinical blood tests. However, their contribution to diagnostics so far has been underwhelming, largely due to the lack of a well-defined pipeline connecting marker discovery to reliable validation methods.

Recent advancements in technology now allow for the creation of a comprehensive biomarker development pipeline consisting of six critical stages: candidate discovery, qualification, verification, research assay optimisation, biomarker validation, and commercialisation. A deeper understanding of the entire biomarker discovery and validation process—along with the challenges and strategies involved at each stage—can improve experimental study designs, increase the efficiency of biomarker development, and ultimately help bring new clinical tests to market more effectively.1.

Biomarkers can be measured in nearly any body fluid. Traditionally, blood has been the preferred matrix for analysis. However, certain obstacles, such as the Blood-Brain Barrier (BBB) and specific cells, membranes, or systems like the lymphatics, can prevent some analytes from being present in the fluids associated with these systems. Despite these challenges, advancements in detection technology are allowing previously undetectable analytes to be identified in these fluids. One such fluid gaining attention is saliva, which is increasingly recognised as a promising, non-invasive, real-time matrix for biomarker detection.

As mentioned earlier, changes in individual genes or groups of genes can lead to the production of "abnormal signals." This results in the formation of proteins that may be indicative of a specific disease or condition. For example, Prostate-Specific Antigen (PSA) is a protein commonly associated with prostate hypertrophy or cancer.

The challenge then becomes whether this protein biomarker is both sensitive (i.e., can changes in its levels accurately reflect disease progression or response to treatment) and specific (i.e., is the biomarker unique to that particular disease, or can it also appear in other conditions?).

Overall, medicine is gradually moving away from a "one-size-fits-all" approach and increasingly focusing on validating the use of multiple biomarkers to enhance specificity, particularly for accurate disease diagnosis.

In addition to biological fluid-based measures, non-biological methods, such as Transcranial Magnetic Stimulation (TMS) used in traumatic brain injury (TBI) analysis, are also being incorporated. These techniques help strengthen diagnostic validity and provide more comprehensive insights for accurate diagnosis.

'The True Path'

The true "golden egg" in the pursuit of understanding and defining traumatic brain injury (TBI) is not simply diagnosing the condition, but rather the quantification, individualization, and development of a definitive tool to aid decision-making regarding return-to-play, return-to-school, return-to-work, and return-to-duty scenarios.

While protein biomarkers have garnered much attention, they do not yet hold the promise of fulfilling this role. They are not even reliable enough as true diagnostic tools, as shown in the figure above (click to view). On the other hand, miRNA(microRNA) holds significant promise in both the diagnostic space and as a monitor of drug response, especially as specific TBI treatments are developed and tested.

The ultimate biomarker will be one that directly reflects DNA outcomes following injury, which in turn correlates with the pathology of TBI. While this breakthrough may still be years away, the logical next step is to focus on advancing our understanding and use of small RNA-based analysis, while moving away from reliance on protein biomarkers (or using them in combination). This shift could accelerate progress and lead to more effective outcomes for individuals currently affected by or at risk for TBI-related conditions.

1, Nader Rifai, et al. Nature Biotechnology 24, 971 - 983 (2006)