Role of Biomarkers in Health Care

Questions are still being raised as to whether detecting diseases at their earliest stages actually improves health. Based on the information presented in various chapters of this report, it can be concluded that biomarkers will play an important role in future medicine. Biomarkers will have a considerable impact on diagnostics and will facilitate the development of personalized medicine. Role of biomarkers in the management of various diseases have also been discussed. Biomarkers are already playing an important role in management of cancer. Screening approaches have led to dramatic changes in the outcome of cervical cancer. A promising area in the future application of biomarkers is that in which diseases can be diagnosed in their earliest stages in hopes of effective intervention. The new classes of sensitive imaging technology such as spiral CT can be made more specific through combination with a biomarker in blood, and disease relapse can be detected earlier through entirely new types of protein biomarkers. One area not discussed so far is the role of biomarkers in preventive medicine and health education. Biomarker profile of a healthy individual may be used to guide individualized health counseling. Susceptibility to certain diseases may require modifications of the general preventive medicine advice. Future studies need to establish the effectiveness of such an approach.

Gene–environmental interactions play an important role in human disease, but they have not been studied systematically. The Genes, Environment, and Health Initiative (GEI) of NIH in 2006 has supported research that will lead to the understanding of genetic contributions and gene–environment interactions in common disease. NIH GEI awarded a $5.9 million grant to the Pacific Northwest National Laboratory (PNNL) that houses the Center for Novel Biomarkers of Response. Scientists at the center intend to create new exposure assessment tools to better understand the role of gene–environmental interactions in human disease. Development of these tools will enable precise measurements of personal exposure to environmental, chemical, and biological agents. Two of the most important risk factors for human morbidity and mortality – cigarette smoke and obesity – will be the primary targets of interest for PNNL scientists. Research will focus on biomarkers for systemic stress caused by mainstream and secondhand cigarette smoke, with obesity as a confounding physiological factor. This research is comprised of two basic elements. The genetic component will rely on newfound abilities to swiftly identify genetic differences between people with illnesses and those who are healthy, leading to a greater understanding of genetic contribution to the disease. The environmental biology component will focus on developing new technologies to accurately measure personal exposures with small, wearable nanobiosensors that can be used to assess environmental agents. The center will provide NIH NIEHS with a database of response biomarkers, as well as chemical substances for selected biomarkers that are tested and validated in humans and supported by parallel studies in mice. The researchers will also develop nanobio sensors for measurement of biomarkers at POC.

There are several potential applications of biomarkers beyond drug development and human health care. Proteomic biomarkers have been used in stem cell research. Applications of biomarkers of infections can be extended to detection of biological agents used in bioterrorism and monitoring human exposure to environmental toxins. An integrated rapid, semiportable, prototype point microbial detection/identification system was proposed for clinical specimens, which is also capable of differentiating microbial bioterrorism attacks from threats or hoaxes by defining the pathogen (White et al. 2002). The system utilizes “flash” extraction/analytical system capable of detection/identification of microbes from environmental and clinical matrices. The system couples demonstrated technologies to provide quantitative analysis of lipid biomarkers of microbes including spores in a system with near-single-cell (amol/microl) sensitivity. Tandem mass spectrometry increases specificity by providing the molecular structure of neutral lipids, phospholipids, and derivatized spore-specific bacterial biomarker, 2,6-dipicolinic acid as well as the lipopolysaccharide-amide-linked hydroxy-fatty acids of Gram-negative bacteria. The extraction should take about an hour for each sample but multiple samples can be processed simultaneously. MALDI-TOF MS-specific biomarkers have been shown to be an effective tool for identifying microorganisms. Feasibility of this technique was demonstrated by detecting the obligate intracellular bacterium Coxiella burnetii , a category B bioterrorism agent (Shaw et al. 2004). Establishing associations between environmental agents and disease presents challenges to both epidemiologists and toxicologists, particularly in cases of complex gene–environment interactions and when there is a long latency between exposure and disease. The epidemiologic value of a biomarker lies in its ability to predict backward toward exposure and forward toward risk of clinical outcome. In 1995, the World Health Organization recognized that biological markers can potentially improve the way in which exposure to environmental factors is assessed. However, only a few valid biological markers were available at that time, which could be effectively used in epidemiological studies and the assessment of risk. The need for new approaches to assess DNA damage has been increasing due to the implications that different insults on genetic material may have on human health. In this context, the identification of how chemical agents with different mechanisms of action (i.e., antineoplastic drugs) damage DNA provides a good model to investigate some cellular and molecular mechanisms underlying the basis of genetic toxicology. The nasal epithelium is the first barrier with which environmental pollutants interact, and for this reason this epithelium can be useful as a sentinel in order to assess the interactions between the environment and the living organisms. Taking these phenomena into account and using a simple, sensitive and rapid method such as the single-cell gel electrophoresis, we could obtain information and an initial approach on the DNA status. This assay in combination with other techniques that provide more information about other molecular parameters could give us a better view of the biological status of the living cell. Identification of how chemical agents with different mechanisms of action damage DNA provides a good model to investigate some cellular and molecular mechanisms underlying genetic toxicology. The nasal epithelium is the first barrier with which environmental pollutants interact and can be useful for assessing the interactions between the environment and the living organisms. It is possible to assess the DNA status by use of a simple, sensitive, and rapid method such as the single-cell gel electrophoresis (Mussali-Galante et al. 2005). This assay in combination with techniques that provide more information about other molecular biomarkers could provide a better view of the biological status of the living cell. Organophosphorus (OP) compounds are still among the most widely used insecticides, and their main mechanism of acute toxicity is associated with inhibition of acetylcholinesterase. Measurements of urine metabolites and of blood cholinesterase activity are established biomarkers of exposure to OPs and of early biological effects. In recent years, increasing attention has been given to biomarkers of susceptibility to OP toxicity. Polymorphisms of paraoxonase (PON1), a liver and serum enzyme that hydrolyzes a number of OP compounds, play a role in modulating the toxicity of Ops. It is important to determine PON1 status, which encompasses the PON1192Q/R polymorphism (that affects catalytic ability toward different substrates) and PON1 levels (which are modulated in part by a C-108T polymorphism) over straight genotyping. Epidemiological studies on OP-exposed workers that include assessment of PON1 status to validate in human populations the role of PON1 as a determinant of susceptibility to OPs, as indicated by animal studies, are needed. Documentation of exposure and of early health effects would be most relevant to increase the predictive value of the test. Many of the advances in human health care are being applied to animal health. In fact, some of the new technologies were tested in experimental animals before they were introduced into human medicine. Dogs suffer from many of the same disease as humans. The value of measuring blood levels of the myocardial protein cardiac troponin I (cTnl) was tested for the diagnosis of congenital and acquired heart disease in the dog and in the evaluation of the severity of heart failure (Spratt et al. 2005). Serum samples obtained from healthy dogs and from dogs diagnosed with a variety of congenital and acquired heart conditions were assayed for cTnl concentration using an automated immunoassay method. Results were also analyzed according to the degree of heart failure as assessed using the International Small Animal Cardiac Health Council’s scheme. Healthy dogs had very low or undetectable blood cTnl levels, as did dogs with congenital heart disease. However, cTnl levels were significantly elevated in dogs with acquired mitral valve disease, dilated cardiomyopathy, and pericardial effusion. Blood cTnl levels also varied with severity of heart failure. Measurement of blood cTnl levels may be a useful aid in the diagnosis of dogs with suspected heart disease and in indicating the severity of heart failure.

Study of biomarkers of various diseases will help to improve the management in three ways: By providing a better understanding of the disease pathomechanism By improving the diagnosis and determining the prognosis By providing a basis for development of therapeutics and monitoring the effect of therapeutics on the disease By providing a better understanding of the disease pathomechanism By improving the diagnosis and determining the prognosis By providing a basis for development of therapeutics and monitoring the effect of therapeutics on the disease Biomarkers that will be useful for either disease prediction or treatment should have one or more of several properties, including Specific and selective association with illness in a population Heritability Independently indicate the presence of the disease regardless of the presence or absence of the clinical phenotype Co-segregation with disease within families Presence in relatives of affected individuals at a higher rate than in the general population Specific and selective association with illness in a population Heritability Independently indicate the presence of the disease regardless of the presence or absence of the clinical phenotype Co-segregation with disease within families Presence in relatives of affected individuals at a higher rate than in the general population A biomarker should fulfill three criteria to be useful clinically: Accurate, repeated measurements must be available to the clinician at a reasonable cost and with short turnaround times. The biomarker must provide information that is not already available from a careful clinical assessment. The measured level should aid in medical decision making. Accurate, repeated measurements must be available to the clinician at a reasonable cost and with short turnaround times. The biomarker must provide information that is not already available from a careful clinical assessment. The measured level should aid in medical decision making. Although one single biomarker fulfills all these conditions, multiple relevant disease biomarkers that can be examined concurrently increase diagnostic specificity. Important therapeutic areas that are currently the focus of biomarker discovery are cancer, metabolic disorders, inflammatory disorders, and diseases of nervous system and cardiovascular system. Some diseases overlap within these categories. Many diseases have multiple biomarkers due to involvement of different pathways. Some biomarkers, e.g., those of inflammation, occur in several diseases characterized by inflammation.