What are biomarkers – different types and applications

What are biomarkers

Biological marker are usually more commonly abbreviated to as biomarkers, these are specific target markers that are used to measure what is actually occurring within a cell or an organism at a specific given moment (this is often referred to as a biological state). These biological characteristics can be accurately measured and objectively evaluated.

Biomarkers are molecular, biochemical, physiologic and anatomic in nature. Providing an indicator to either normal or a biological pathogenic process which can potentially allow the assessment of a pharmacological response to a specific therapeutic intervention. In majority of cases biomarkers are used to measure the presence or in some cases the progression of a disease or the effectiveness of a particular treatment.

Essentially, biological markers do not define how a person functions or feels but instead are measurable entities. Some of the most common examples include: blood pressure, heart rate, metabolic studies, x-ray studies, genetic and histologic tests. During many clinical trials, biological marker serve as important intermediate markers of a specific disease and can help to identify a particular therapy that may be effective in the treatment of that disease. There are also lots of evidence to suggest that many biomarker-driven approaches have led to shortening of the clinical trial time and have accelerated the product development phase and regulatory approval process. Generally, a biomarker displays a particular physical trait or a measurable biologically formed change within that body that is associated to a specific health condition or a disease. Some potential biomarkers include: proteins, antibodies, protein fragments, carbohydrates, genomics (RNA or DNA), cellular, metabolites and imaging.

Types of biomarkers

Biological markers can be classified into essentially 4 groups.

• Molecular: these can be measured within a biological sample (for example: serum, plasma, biopsy, cerebrospinal fluid and bronchoalveolar lavage). Essentially they display a biophysical property. The classical example of this is blood glucose.
• Physiologic: this involves that measurement of a particular body process. For example is blood pressure.
• Radiographic: this is obtained predominately from imaging investigations. A common example is measuring bone mineral density.
• Histologic: this study reflects on the molecular or biochemical alteration within fluids, cells or tissues. Popular examples include grading and staging of specific cancers.

Applications for biomarkers

Biological markers play a major role in the health care profession, which is known to include detection and prevention of a disease, individual disease risk determination and future monitoring and treatment of disease. Biomarkers are fundamentally used to measure the toxicity and safely of a specific therapeutic treatment or exposure to a particular environment.

The most common applications are listed below.

1. Screening: These procedures are used to find individuals that are of a higher risk of developing a health problem and those that do not show any symptoms of the disease. The ultimate goal is achieving early detection and surveillance or lifestyle changes which will help to minimise the risk of the disease or even allow a more effective treatment procedure being undertaken. Screening tests are not regarded as being diagnostic but instead are vital in identification of a small group of population who should undergo further tests in order to identify the presence or absence of the disease. Some common biomarker used for screening include: prostate specific antigen (PSA) for prostate cancer, fecal occult blood (FOB) for testing colon cancer, mammography for breast cancer, pap test for cervical cancer, cholesterol for cardiovascular disease and diabetes or prediabetes.
2. Risk and Susceptibility: These are biomarker that are linked with either an increase or decrease in the chance of developing a medical condition or a disease in a person who from a clinical standpoint is not showing any signs of the disease or medical condition. These markers essentially indicate if an individual has a greater chance of developing this condition later in life. Some of the most common examples include: BRCA1/2 mutation can be used to evaluate the chances of developing ovarian and breast cancers, elevated levels of low-density lipoprotein (LDL) cholesterol levels can indicate a greater risk of coronary artery disease, monitoring apolipoprotein C levels can show pre-disposition to developing Alzeimer’s disease and human papillomavirus (HPV) to developing cervical cancer.
3. Diagnostic: These often refer to as specific biological parameters that help in the diagnosis of the disease and in many cases can also serve to identify progression of disease and potential success of any treatment undertaken. These procedures can be anatomical, laboratory, physiological, genetic, radiological and any other findings that can aid in differentiating one disease from another. Examples include: sweat chloride for cystic fibrosis, troponin-I for coronary ischemia, glomerular filtration rate (GFR) for chronic kidney disease and ejection fraction (EF) for cardiomyopathy and congestive heart failure.
4. Prognostic: This is a biological or clinical characteristic that can be used to generate information on the possible likely health outcome of the individual (for example chances of disease recurrence) irrespective of the treatment undertaken. Examples include: TP53 mutations and chromosome 17p deletions leading to patient death with chronic lymphocytic leukemia and BRCA 1/2 on the chances of a second cancer reoccurring in women with breast cancer.
5. Monitoring: These are biomarker that can be used repeatedly over time to assess disease progression (looking at change in disease severity, worsening of existing abnormalities and occurrence of new disease effects) or it could assess the response of a condition or disease to a specific treatment (this can either be favourable or unfavourable). These markers play a vital role throughout medical product development, for example, during therapeutics processes, preventative trials of a new drug, devices or biologics. Examples include: cancer antigen 125 (CA125) for ovarian cancer disease burden or status, viral load for response to anti-retroviral treatment for HIV, serum LDL for response to lipid lowering drugs, haemoglobin A1C for response to anti-hyperglycemic agents or life style changes and international normalised ration (INR) for efficacy of anti-coagulant therapy.
6. Safety: Defined as a biological marker that can be used in measuring before and/or after exposure to an environmental agent or medical product in order to determine the presence, likelihood and the extent of toxicity as an adverse effect. Examples include: serum creatinine for nephrotoxicity, bilirubin and hepatic aminotransferases for hepatotoxicity, serum potassium for hyper or hypokalemia, serum bisphenol A (BPA) is measured in pregnant women and corrected QT interval (QTc) to assess potential for drugs to induce ventricular tachycardia.

Useful biomarkers

A biological marker is regarded as a measurement that helps in the diagnostic process or in predicting the response to a drug in order to effectively treat a specific disease. Over time the use of biomarkers during routine investigation has grown to the extent that now it is being used virtually in all areas of medicine. Cardiac biomarkers and tumor biomarkers are two of the most frequently used categories in the field of medical practise.

Cardiac markers
Generally, cardiac biomarkers can be described as endogenous substances that are released by the body into circulation during period when the heart becomes stressed or damaged. Acute coronary syndrome is the result of the formation of plaque during the process of atherosclerosis, this is mainly caused by the formation of thrombus within the coronary arteries that have been damaged and this leads to a sudden reduction in blood and oxygen travelling to the heart. Angina is caused by a reduction in blood supply to the heart, in many cases when this blood flow is interrupted from 30 mins to 60 mins then this can result in heart muscle necrosis and this eventually leads to myocardial infarction.

There are essentially 4 well established biomarkers that are used for the detection of myocardial necrosis.

(A). Myoglobin: Myoglobin is described as a small protein that is present in skeletal and heart muscles, it has the ability to bind oxygen. In the muscle cells it is able to trap oxygen which is used by the cells to generate energy in order to make the muscles contract. During periods when the heart or skeletal muscles become damaged, the body is able to release myoglobin is release into the blood stream. Within a couple of hours after the injury, elevated levels of myoglobin can be detected.

The kidneys play an important function in filtering myoglobin which is then released through urine. However, high levels of myoglobin are found to be toxic to the kidneys and can result in damaging the kidneys or in some cases lead to kidney failure. The detection of myoglobin in the urine can help to detect and prevent these conditions.

(B) Cardiac Troponin I (cTnI): Troponin I is a protein that is globular in nature and has the ability to bind actin on its own and also inhibit myosin binding. The function of inhibiting the contractile interaction between actin and myosin only is possible in the presence of tropomyosin. The letter I is given at the end due to its characteristic of being an inhibitor. Troponin I is also widely accepted as the “gold standard” for evaluating patients that are displaying acute myocardial infarction. Also, in veterinary medicine, elevated levels of cTnI has been observed during myocardial damage but in these cases this is only after ionophore toxicity in cattle.

(C). Cardiac Troponin T (cTnT): Troponin T has a main role of binding tropomyosin and helping to position it on the actin molecule, this leads to modulating striated muscle contraction. In the laboratory TnT is fundamental in diagnosing a heart attack due to the nature that it released into the blood stream when the hearth muscle becomes damaged. Another important function of troponin T is during the transduction of calcium signals in the process of contraction regulation.

(D). Creatine Kinase Isoenzymes: Creatine kinase (CK) we previous referred to as creatine phosphokinase, it is described as an intracellular enzyme which is predominately present in skeletal muscles, the brain and myocardium and in smaller quantities in various visceral tissues. The function of this enzyme is to catalyse the reaction of creatine and ATP to form phosphocreatine and ADP. It is a reversible reaction. The levels of CK are found to be elevated during periods when the muscle cells in the body become damaged. There are 3 isoenzymes of CK that exist, these are CK-MM which is present in the heat and skeletal muscles; CK-MB this is found in the heart and CK-BB that is mainly found in the brain.

Tumor markers
A tumor biomarker is defined as a substance that can be found in blood, urine, body tissues and various other biological fluids. These are mostly proteins that are generated by either the cancer tissue themselves or by the body in order to respond to cancer growth. There are many different types of tumor markers that are found for various cancers types. Some of these biomarkers are known to be only linked to one type of cancer whereas others can be associated with a many cancers. However, researcher are always on the look out to discovered new tumor markers since many cancers that exist do not have any known tumor biomarkers.

Some of the common know tumor markers and the common cancers they are found in are listed below.

• Alpha-Fetoprotein (AFP): Cancer of liver, testes and ovaries. It is also found to be elevated during pregnancy.
• Cancer Antigen 15-3 (CA 15-3): Cancer of breast, lungs and ovarian. Elevated levels also present in benign breast conditions.
• Cancer Antigen 19-9 (CA 19-9): Cancer of pancreas, bile ducts and bowel. Elevated levels displayed in inflammatory bowel disease and pancreatitis.
• Cancer Antigen 125 (CA 125): Cancer ovarian. Elevated levels during endometriosis.
• Calcitonin: Medullary thyroid carcinoma. Elevated in thyroiditis, pernicious and anaemia.
• Carcinoembryonic Antigen (CEA): Cancer of liver, thyroid, lung, bowel, pancreatic, bladder, breast and cervix. Elevated levels in condition such as COPD, hepatitis, colitis and pancreatitis.
• Human Chorionic Gonadotropin (hCG): Testicular cancer and trophoblastic disease. Elevated levels during testicular failure and pregnancy.
• Prostate Specific Antigen (PSA): Cancer of prostate. Elevated levels displayed in prostatitis and benign prostatic hyperplasia.
• Thyroglobulin: Thyroid cancer.
• Neuron Specific Enolase (NSE): Cancer of neuroblastoma and small cell lung.

Final thoughts

Validated biomarkers play a pivotal role in basic and clinical based research this can also be found in clinical practices. They provide important information which allows a better understanding of the disease process and how specific drugs work in order to combat particular diseases. The knowledge generated can be used in the early diagnosis of the disease and in many cases can prevent the disease even before it starts. Biological markers can improve the safety and efficacy of existing medicines and any new markers that are developed. Furthermore, new novel biomarkers offer the potential to personalise disease management and prevention, this will make the delivery of healthcare service more cost effective, safe and precise. The ultimate target and goal is to improve the overall health outcomes.

References

1. Advantages and Limitations of Current Biomarker Research: From Experimental Research to Clinical Application. Curr Pharm Biotechnol. 2017;18 (6): 445-455. Review. Kim SH et al.
2. Complex network-based approaches to biomarker discovery. Biomark Med. 2016 Jun;10 (6): 621-32. Review. Hayashida M and Akutsu T.
3. Latest advances in biomarker discovery and development. Drugs Today (Barc). 2012 Nov;48 (11): 735-9. Review. Tracy M.
4. Emerging Concepts and Methodologies in Cancer Biomarker Discovery. Crit Rev Oncog. 2017;22 (5-6): 371-388. Review. Lu M, Zhang J, Zhang L.
5. Sources of variability in biomarker concentrations. J Toxicol Environ Health B Crit Rev. 2014;17 (1): 45-61. Review. Aylward LL et al.
6. Biomarker discovery: validation and decision-making in product development. Sex Transm Dis. 2009 Mar;36 (3 Suppl): S76-80. Review. Niedbala RS et al.
7. Metabolomics and cardiovascular biomarker discovery. Clin Chem. 2012 Jan;58 (1): 139-47. Review. Rhee EP and Gerszten RE.
8. Stable feature selection for biomarker discovery. Comput Biol Chem. 2010 Aug; 34 (4): 215-25. Review. He Z and Yu W.
9. Cardiac markers: from enzymes to proteins, diagnosis to prognosis, laboratory to bedside. Ann Clin Lab Sci. 1999 Jan-Mar; 29 (1): 18-23. Review. Wu AH.
10. Role of cytokines and inflammation in heart function during health and disease. Heart Fail Rev. 2018 Sep; 23 (5): 733-758. Review. Bartekova M et al.
11. Cardiac biomarkers in heart failure. Clin Biochem. 2014 Apr; 47 (6): 327-37. Review. Liquori ME et al.
12. Advances in cardiac biomarkers. Emerg Med Clin North Am. 2005 Nov; 23 (4): 959-75. Review. Aviles JM and Aviles RJ.
13. The role of tumor markers in the early detection of cancer. Semin Surg Oncol. 1989;5 (3): 186-93. Review. Humphrey PA.
14. Tumor markers in cancer diagnosis and prognosis. CA Cancer J Clin. 1988 Mar-Apr;38 (2): 104-26. Virji MA et al.
15. The clinical usefulness and limitations of tumor markers. Surg Gynecol Obstet. 1988 Jun;166 (6): 567-79. Review. Torosian MH.

Related ELISA Kits

Cardiac Markers ELISA Kits:

ACE2, ANP, BNP, Cardiac Troponin I, Cardiotrophin-1, CK-MB, CRP, Haptoglobin, Homocysteine, Lipocalin-2,  Malondialdehyde, Superoxide Dismutase, Myoglobin, Troponin T

Tumor Markers ELISA Kits:

4-Hydroxynoneal, AFP, Beta hCG, CA 15-3, CA 19-9, CA 72-4, CA-125, Calcitonin, CEA, Chromogranin A, Free PSA, NSE, PRKCE, Thyroglobulin, Total PSA, VDBP