Biomarker

Biomarkers used for medicine, or precision medicine, are a part of a relatively new clinical toolset. They are categorized in 3 primary ways according to their clinical applications. They are classified as molecular biomarkers, cellular biomarkers or imaging biomarkers. All 3 types of biomarkers have a clinical role in narrowing or guiding treatment decisions and follow a sub-categorization of being either predictive, prognostic, or diagnostic.

Diagnostic

Diagnostic biomarkers that meet a burden of proof can serve a role in narrowing down diagnosis. This can lead to diagnosis that are significantly more specific to individual patients.

After a heart attack a number of different cardiac biomarkers can be measured to determine exactly when an attack occurred and how severe it was.

A biomarker can be a traceable substance that is introduced into an organism as a means to examine organ function or other aspects of health.[5] For example, rubidium chloride is used as a radioactive isotope to evaluate perfusion of heart muscle.

It can also be a substance whose detection indicates a particular disease state, for example, the presence of an antibody may indicate an infection.[5] More specifically, a biomarker indicates a change in expression or state of a protein that correlates with the risk or progression of a disease, or with the susceptibility of the disease to a given treatment.[5]

One example of a commonly used biomarker in medicine is prostate-specific antigen (PSA). This marker can be measured as a proxy of prostate size with rapid changes potentially indicating cancer. The most extreme case would be to detect mutant proteins as cancer specific biomarkers through Selected reaction monitoring (SRM), since mutant proteins can only come from an existing tumor, thus providing ultimately the best specificity for medical purposes.[6]

Another example is KRAS, an oncogene that encodes a GTPase involved in several signal transduction pathways. Biomarkers for precision oncology are typically utilized in the molecular diagnostics of chronic myeloid leukemia, colon, breast, and lung cancer, and in melanoma.[7]

Biomarkers for precision medicine are a part of a relatively new clinical toolset. In the case of metastatic colorectal cancer (mCRC) only two predictive biomarkers have so far been identified and implemented clinically.[3] In this case, the lack of data beyond retrospective studies and successful biomarker-driven approaches was suggested to be principal cause behind a need for novel biomarker studies within the medical field due to the severe attrition that accompanies clinical trials.

The field of biomarker research is also expanding to include a combinatorial approach to identifying biomarkers from multi-omic sources. Combining groups of biomarkers from various omic data allows for the possibility of developing panels that evaluate treatment response based on many biomarkers at a single time. One such area of expanding research in multi-omic biomarkers is mitochondrial DNA sequencing. Mutations in mitochondrial DNA have been shown to correlate to risk, progression, and treatment response of head and neck squamous cell carcinoma.[8] In this example, a relatively low cost sequencing pipeline was shown to be able to detect low frequency mutations within tumor-associated cells. This highlights the general snapshot capability of mitochondrial DNA-based biomarkers in capturing heterogeneity amongst individuals.[8]

The Early Detection Research Network (EDNR) compiled a list of seven criteria by which biomarkers can be assessed in order to streamline clinical validation.[9]

In 1997 the National Institute of Health suggested a need for guidelines and legislation development that would regulate the ethical dimensions of biomarker studies.[9] Similar to the way that the Human Genome Project collaborated with the U.S. Office of Technology Assessment, biomarker susceptibility studies should collaborate to create ethical guidelines that can be implemented into the groundwork and proposal requirements of the studies.

Ensuring that all of the participants that are included each step of the project (i.e. planning, implementation, and the compilation of the results) are provided with the protection of ethical principles that are put in place prior to beginning the project. These ethical protections should not only protect the participants in the study, but also the non participants, researchers, sponsors, regulators, and all other persons or groups involved in the study.[9] Some ethical protections could include but are not limited to:[9]

• Informed consent of the participant
• Access to participation opportunities independent of race, socio-economic status, gender, sexuality, etc. (within the range allowed by the experimental protocol)
• Scientific integrity
• Confidentiality of data (anonymity)
• Acknowledgement of conflict of interest in terms of funding and sponsorship by given sponsors
• Transparency and recognition of health and legal risks involved in participation

In cell biology, a biomarker is a molecule that allows the detection and isolation of a particular cell type (for example, the protein Oct-4 is used as a biomarker to identify embryonic stem cells).[13]

In genetics, a biomarker (identified as genetic marker) is a DNA sequence that causes disease or is associated with susceptibility to disease. They can be used to create genetic maps of whatever organism is being studied.

A biomarker can be any kind of molecule indicating the existence, past or present, of living organisms. In the fields of geology and astrobiology, biomarkers, versus geomarkers, are also known as biosignatures. The term biomarker is also used to describe biological involvement in the generation of petroleum. Biomarkers were used in the geo-chemical investigation of an oil spill in the San Francisco Bay, California in 1988.[14] On April 22–23 around 400,000 gallons of crude oil was accidentally released into the San Joaquin Valley by a refinery and manufacturing complex of the Shell Oil Company. The oil affected many surrounding areas. Samples of the crude oil were collected in the various regions where it had spread and compared to samples that were unreleased in an attempt to distinguish between the spilled oil and the petrogenic background present in the spill area.[14] Mass Spectra was performed to identify biomarkers and cyclic aliphatic hydrocarbons within the samples. Variations in the concentration of constituents of the crude oil samples and sediments were found.[14]

Rachel Carson, the author of Silent Spring, raised the issue of using organochlorine pesticides and discussed the possible negative effects that said pesticides have on living organisms.[15] Her book raised ethical issues against chemical corporations that were controlling the general reception of the effect of pesticides on the environment, which pioneered the need for ecotoxicological studies. Ecotoxicologial studies could be considered the precursors to biomarker studies.[16] Biomarkers are used to indicate an exposure to or the effect of xenobiotics which are present in the environment and in organisms. The biomarker may be an external substance itself (e.g. asbestos particles or NNK from tobacco), or a variant of the external substance processed by the body (a metabolite) that usually can be quantified.

The widespread use of the term "biomarker" dates back to as early as 1980.[17] The manner in which the environment was monitored and studied near the end of the 1980’s was still mainly reliant on the study of chemical substances that were considered dangerous or toxic when found in moderate concentrations in water, sediments, and aquatic organisms.[16] The methods used to identify these chemical compounds were chromatography, spectrophotometry, electrochemistry, and radiochemistry.[16] Although these methods were successful in elucidating the chemical makeup and concentrations present in the environment of the contaminants and the compounds in question, the tests did not provide data that was informative on the impact of a certain pollutant or chemical on a living organism or ecosystem. It was proposed that characterizing biomarkers could create a warning system to check in on the well being of a population or an ecosystem before a pollutant or compound could wreak havoc on the system. Now, due to the development of biomarker studies, biomarkers can be used and applied in the fields of human medicine and in the detection of diseases.[16]

De Kock and Kramer developed the concept of active biomonitoring in 1994. Active biomonitoring is a comparison of the chemical/biological properties of a sample that has been relocated to a new environment that contains different conditions than its original environment.[27]