Biomarker discovery

Biomarker discovery is a medical term describing the process by which biomarkers are discovered. Many commonly used blood tests in medicine are biomarkers. There is interest in biomarker discovery on the part of the pharmaceutical industry; blood-test or other biomarkers could serve as intermediate markers of disease in clinical trials, and as possible drug targets.

Mechanism of action

The way that these tests have been found can be viewed as biomarker discovery; however, their identification has primarily been made one at a time. Many well-known tests have been identified based on biological insight from the fields of physiology or biochemistry; therefore, only a few markers at a time have been considered. An example of biomarker discovery is the use of inulin to assess kidney function. From this process a naturally occurring molecule (creatinine) was discovered, enabling the same measurements to be made without inulin injections.

The recent interest in biomarker discovery is spurred by new molecular biologic techniques, which promise to find relevant markers rapidly without detailed insight into the mechanisms of a disease. By screening many possible biomolecules at a time, a parallel approach can be attempted; genomics and proteomics are some technologies used in this process. Secretomics has also emerged as an important technology in the high-throughput search for biomarkers;[1] however, significant technical difficulties remain.

The identification of clinically significant protein biomarkers of phenotype and biological function is an expanding area of research which will extend diagnostic capabilities. Biomarkers for a number of diseases have recently emerged, including prostate specific antigen (PSA) for prostate cancer[2] and C-reactive protein (CRP) for heart disease.[3] The epigenetic clock which measures the age of cells/tissues/organs based on DNA methylation levels is arguably the most accurate genomic biomarker. Using biomarkers from easily assessable biofluids (e.g. blood and urine) is beneficial in evaluating the state of harder-to-reach tissues and organs. Biofluids are more readily accessible, unlike more invasive or unfeasible techniques (such as tissue biopsy).

Biofluids contain proteins from tissues and serve as effective hormonal communicators. The tissue acts as a transmitter of information, and the biofluid (sampled by physician) acts as a receiver. The informativeness of the biofluid relies on the fidelity of the channel. Sources of noise which decrease fidelity include the addition of proteins derived from other tissues (or from the biofluid itself); proteins may also be lost through glomerular filtration.[4] These factors can significantly influence the protein composition of a biofluid.[5] In addition, simply looking at protein overlap would miss information transmission occurring through classes of proteins and protein-protein interactions.

Instead, the proteins' projection onto functional, drug, and disease spaces allow measurement of the functional distance between tissue and biofluids. Proximity in these abstract spaces signifies a low level of distortion across the information channel (and, hence, high performance by the biofluid). However, current approaches to biomarker prediction have analyzed tissues and biofluids separately.[6]

Research

An information-theoretic framework for biomarker discovery, integrating biofluid and tissue information, has been introduced; this approach takes advantage of functional synergy between certain biofluids and tissues, with the potential for clinically significant findings (not possible if tissues and biofluids were considered separately).[7] By conceptualizing tissue biofluids as information channels, significant biofluid proxies were identified and then used for guided development of clinical diagnostics. Candidate biomarkers were then predicted, based on information-transfer criteria across the tissue-biofluid channels. Significant biofluid-tissue relationships can be used to prioritize the clinical validation of biomarkers.

Ex vivo blood stimulation

Ex vivo blood stimulation is the process by which researchers can analyse the immunological biomarkers of drug effects in healthy volunteers. Blood samples (taken from healthy volunteers) are stimulated in the laboratory to activate the immune system. Ex vivo blood stimulation studies, therefore, allow the evaluation of the effect of a new compound in a "living system" in which the immune system has been challenged.[8] Most research using this method is carried out by Phase I clinical research organisations, allowing them to collect blood samples and analyse them instantly so they do not deteriorate.

See also

References

  1. ↑ Hathout, Yetrib (2007). "Approaches to the study of the cell secretome". Expert Review of Proteomics 4 (2): 239–48. doi:10.1586/14789450.4.2.239. PMID 17425459.
  2. ↑ Singer, E. A.; Penson, D. F.; Palapattu, G. S. (2007). "PSA Screening and Elderly Men". JAMA 297 (9): 949; author reply 949–50. doi:10.1001/jama.297.9.949-a.
  3. ↑ Crawford, D. C.; Sanders, C. L.; Qin, X.; Smith, J. D.; Shephard, C.; Wong, M.; Witrak, L.; Rieder, M. J.; Nickerson, D. A. (2006). "Genetic Variation is Associated with C-Reactive Protein Levels in the Third National Health and Nutrition Examination Survey". Circulation 114 (23): 2458–65. doi:10.1161/CIRCULATIONAHA.106.615740. PMID 17101857.
  4. ↑ Jacobs, Jon M.; Adkins, Joshua N.; Qian, Wei-Jun; Liu, Tao; Shen, Yufeng; Camp, David G.; Smith, Richard D. (2005). "Utilizing Human Blood Plasma for Proteomic Biomarker Discovery†". Journal of Proteome Research 4 (4): 1073–85. doi:10.1021/pr0500657. PMID 16083256.
  5. ↑ Anderson, NL; Anderson, NG (2002). "The human plasma proteome: history, character, and diagnostic prospects". Molecular & Cellular Proteomics 1 (11): 845–67. doi:10.1074/mcp.R200007-MCP200. PMID 12488461.
  6. ↑ He, YD (2006). "Genomic approach to biomarker identification and its recent applications". Cancer biomarkers : section a of Disease markers 2 (3–4): 103–33. PMID 17192065.
  7. ↑ Alterovitz, G; Xiang, M; Liu, J; Chang, A; Ramoni, MF (2008). "System-wide peripheral biomarker discovery using information theory". Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing: 231–42. doi:10.1142/9789812776136_0024. PMID 18229689.
  8. ↑ Ex Vivo Blood Stimulation in Biomarker Discovery

External links

Academic journals in the field