An Overview of Biomarkers (I)

  • Before being used in the field of biomedicine, the term "Biomarker" was more common in geological literature. It was once translated as "biomarker compound", which refers to some organic compounds in geological materials derived from living organisms. In the 1960s, this term began to appear in medical literature. In the 1980s, it was officially introduced into the biomedical field. In the field of biomedicine, it has also been described differently. In 2001, the Biomarkers Definitions Working Group convened by the NIH in the United States gave a definition to biomarker: it refers to "a characteristic that can be objectively detected and evaluated, which can be used as a normal biological indicator for the pharmacological response of the pharmacological process, pathological process or therapeutic intervention".

    The definition of biomarker means that people have a clearer understanding of it, and it also reflects people's concern about it. More than ten years after this definition was proposed, it has also been more than ten years of rapid development of high-throughput technologies such as biochips and next-generation sequencing. With the development of these detection technologies, a huge amount of biomarker data has been produced, and a large number of related documents have been published. The market surrounding the discovery, screening, verification and application of biomarkers is also expanding. Biomarkers are mainly used in the fields of medical diagnosis and drug development, and it has become an important theme in these fields.

    1. Classification of biomarkers

    From the definition of biomarkers, it can be seen that biomarkers cover a wide range, and with the advancement of detection technology, more specific detection results can be regarded as biomarkers. People have classified it from different angles.

    According to their potential uses, biomarkers can be divided into four categories.

    1). Biomarkers for disease diagnosis. It includes early diagnosis or prognostic markers of the disease. Such markers are currently the most widely used, the most influential, and the most familiar to people. For example, blood pressure, blood sugar and other test indicators detected by routine physical examination. It reflects the existence of the disease and sometimes the course of the disease. With the advancement of technology, such markers are no longer just some biochemical indicators. Some genetic indicators are also regarded as such biomarkers.

    2). Biomarkers used to detect disease activity. Such markers are used to assess the severity of the disease, or to evaluate the efficacy. Sometimes it is also used to detect the side effects of drugs. Some biomarkers have multiple roles and also have diagnostic functions. For example, the blood pressure and blood glucose indicators mentioned above. C-Reaction Protein (CRP) is a representative of this type of marker. It can perfectly reflect the course of rheumatoid arthritis and the effect of interferon on the disease.

    3). Biomarkers that reflect the effects of drugs. Such markers are the most valued by the pharmaceutical industry. There is also some overlap with the previous type. They directly reflect the binding of the drug to the target (receptor or enzyme) and the pharmacological effects. For example, some imaging results can be used as markers of drug action. D2 receptor imaging of the brain of patients with neurodegenerative diseases can prove the effects of related drugs; the measurement of blood glucose drift in patients with type II diabetes can confirm the efficacy of the DPP4 inhibitor drug sitagliptin. Such markers can be used as direct evidence to prove the mechanism and effect of the drug when applying for a new drug, and can significantly shorten the application period.

    4). Biomarkers related to pharmacokinetics. The transportation and metabolism of drugs involve the efficacy of drugs, as well as the side effects of drugs. The efficiency of transport or metabolic process may vary among individuals, which is related to heredity. Therefore, sometimes it is necessary to refer to biomarkers at the molecular genetics level to rationally select drugs or determine drug dosages. This requires special attention in the use of certain anti-cancer drugs. For example, the anti-cancer drug Irinotecan is catalyzed by UDP-glucuronosyltransferase (UGT1A1) and then excreted through bile and urine. However, patients with UGT1A1*28 genotype need to be cautious when using this drug. Because the UGT1A1*28 allele is related to drug metabolism. For another example, when using the immunosuppressive drug Azathioprine (Azathioprine), it is necessary to check the TPMP gene locus to reduce the side effects of the drug. .

    From the perspective of the natural properties of biomarkers, they can be divided into different types such as nucleic acids (DNA, RNA), proteins, sugars and their derivatives.

    The research progress of nucleic acid markers has been very fast in the past ten years, thanks to the rapid development of nucleic acid sequencing and other technologies. After all, the composition and structure of nucleic acids are simpler than proteins. DNA type markers represent the following changes or phenomena: SNPs, InDels, CNVs, methylation and other modifications, chromosome insertions, deletions, rearrangements or duplications at the cytogenetic level, haplotypes, short sequence duplications, etc. Markers of RNA type include RNA sequence, RNA expression level, transcriptome, RNA processing, non-coding RNA (microRNA, lncRNA), etc.

    People have known and used protein biomarkers for a long time. As mentioned earlier, some protein indicators (enzymes) used in routine physical examinations belong to this type of markers. The samples used to detect these markers, such as blood and saliva, are easy to obtain, and the detection procedures are not cumbersome. Therefore, they are widely used clinically. In recent years, the development of proteome science has promoted the research of such markers.

    The glycome, similar to the genome or proteome, is the sum of all sugars in an organism or cell, including simple sugars and conjugated sugars. The sugar chain part in glycoconjugates (glycoprotein, glycolipid, etc.) has a huge amount of information. Glycosylation of some proteins is related to disease. Certain polysaccharides can be used as breast cancer markers.

    In addition to the above types, some metabolomics research results are also used in the development of biomarkers. Metabolome refers to the dynamic overall of the body's endogenous metabolites. Theoretically, metabolites include nucleic acids, proteins, lipids, biological macromolecules and other small molecular metabolites. But currently only small molecular metabolites with a relative molecular mass of less than 1,000 are involved. Changes in the number and amount of metabolites can be used as an indication for certain diseases.