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Antibody microarray technology, imageScientists at PNNL are developing antibody microarray technology for the validation of biomarker profiles. The image above is of an antibody microarray analysis of a serum sample taken from a woman with stage 3 breast cancer. The scale on the bottom indicates the relationship between increased signal intensity and color.

Characteristic protein expression patterns are observable in individual cells, communities of cells, organs, and whole organisms. Importantly, there are detectable differences in the patterns of protein expression in healthy versus compromised systems. Biomarkers can be used to measure the characteristic and dynamic pattern of protein expression that reflects the state of biological systems. At Pacific Northwest National Laboratory (PNNL) we are exploring the potential of biomarkers for medical applications, risk assessment, and early detection of disease and damage. Scientists at PNNL are working to use biomarkers to detect cancers and diabetes, predict ecosystem change and damage, understand nanomaterial impact on respiratory health, and measure the response to zoonotic agents.

Disease Biomarkers

Biomarkers can serve a variety of medical needs. They can be used to detect a disease in an individual in the early stages before that disease advances to become a serious illness. In this role, biomarkers are used to screen either the general population or individuals who are considered at high risk for developing a disease. For example, levels of prostate-specific antigen (PSA) in the blood are used as a general marker of prostate cancer in men over 40 years old. Similarly, elevated glucose levels in the blood are indicative of diabetes. Biomarkers can also be used to monitor a patient's response to drugs or other types of therapy. PSA levels generally are undetectable after prostate cancer surgery and glucose levels return to normal in properly treated diabetics.

Although biomarkers are commonly used to detect a few diseases and to monitor some therapies, good protein biomarkers have not been identified for most medical needs. One of the greatest problems with finding useful biomarkers is that normal protein levels are highly variable among individuals. Factors such as age, race, and diet can alter biomarker levels in both healthy and diseased individuals. Because of this variability, it is difficult to distinguish whether a person has a disease based on a single biomarker. It is believed that the use of multiple biomarkers, in other words, a biomarker profile, will be more useful.

Recent advances in proteomic technologies, such as mass spectrometry, have greatly improved the ability to discover and validate protein profiles as biomarkers. Mass spectrometry is now widely used in proteomic studies and is being applied to routine analysis of proteins in blood and other clinical samples to discover new protein profiles. However, proteomic technology cannot yet be used to clearly define biomarker profiles that will be truly useful in a clinical setting, because it cannot efficiently process a large enough sample number nor provide true quantitative data. PNNL researchers are working to overcome these deficits by developing a Next Generation Proteomics Platform using new gas phase separation technologies that vastly improve throughput. Another approach to this problem uses technological advances in microarrays that use antibodies to quantify protein levels. Antibody microarrays provide clinically relevant data and have the potential for the efficient analysis of large numbers of samples. Therefore, antibody microarrays can be used in targeted studies to determine which potential biomarkers discovered by proteomics are clinically useful.

Researchers at PNNL are using existing technologies and developing new antibody microarray technologies to study biomarkers of disease. In particular, we are working to identify clinically relevant biomarker profiles for breast cancer, ovarian cancer, chronic obstructive pulmonary disease and diabetes.

Environmental Biomarkers

Ellyn Murphy, Point of Contact

Environmental Biomarkers, logo

An environmental biomarker is multiple biomolecular signatures that when examined together present a unique pattern of molecular change in an organism and identify an exposure or response to a specific environmental stressor. Environmental biomarkers may signal a specific biological response to pollution, subtle changes in the environment, or deliberate release of toxic substances as an act of terrorism. These biomarkers are the next generation of risk assessment tools, replacing whole-organism measures of response with sub-cellular responses acquired along the pathway of disease progression from first exposure to terminal disease state.

PNNL scientists are discovering and implementing environmental biomarkers to transform environmental assessment and management into a predictive, systems-based science. This work includes (1) identifying biosignatures of response, (2) selecting and validating biomarkers, (3) developing tools based on these biomarkers for collecting information on the status of an organism or ecosystem, (4) using these tools in surveillance and detection, and (5) applying this information in predictive models.

PNNL's environmental biomarkers research focuses on three areas for which the discovery and application of environmental biomarkers may provide early, pre-symptomatic indicators of disease and damage.

Predicting Ecosystem Change and Damage - Scientists at PNNL are addressing the challenges inherent in developing molecular-level biomarkers that can quantitatively describe biodiversity, system behavior and multiple stressors across levels, in the absence of genomic data. The goal is to identify biomolecular signatures associated with specific functions within an ecosystem to aid in recognizing early warning signs of ecosystem stress and damage.

Systems Toxicology of Nanomaterials - Because of the increasing production and use of nanomaterials and our lack of knowledge regarding the acute and chronic health effects, PNNL scientists are striving to understand the properties of nanomaterials that lead to toxicity and advance the field of biomarker discovery for respiratory diseases associated with exposure to nanomaterials.

Response to Biological Agents - At PNNL, researchers are focusing on biomarkers of response to biological agents to gather intelligence on infectious agent dissemination. In addition, they are working to discriminate between the truly affected and the worried well during an exposure.

Read more about PNNL's environmental biomarkers research by visiting our Environmental Biomarkers website.

PNNL's Biomarkers Research Efforts Are Supported by by the National Institutes of Health.

Advanced Proteomics and Metabolomics: Type 2 Diabetes and Pre-Diabetes – Researchers are applying advanced proteomic and metabolomic technologies to study both plasma and blood cells from individuals with normal glucose tolerance, impaired glucose tolerance, and recently diagnosed type 2 diabetes. This project team endeavors to advance the study of Type 2 diabetes and pre-diabetes by identifying biomarkers at the level of the proteome and metabolome that are predictive of Type 2 diabetes and pre-diabetes in vivo.

Center for Novel Biomarkers of Response – Established at PNNL, the NIH National Institute of Environmental Health Sciences’ Center for Novel Biomarkers of Response is part of the Genes, Environment, and Health Initiative. Research through the Center is focused on identifying and validating proteins in plasma related to two important risk factors for human morbidity and mortality: the stressors cigarette smoke and obesity.

Development of Antibody Microarrays for the National Cancer Institute Early Detection Research Network – Researchers are developing an antibody microarray capable of simultaneously assaying up to 50 different cancer biomarkers in a single test.

High Dynamic Range Quantitative Proteomic Profiling of Plasma Samples from Pre-diagnostic Colon Cancer Patients and Controls - Researchers at PNNL are using a global quantitative proteomic strategy to try and identifiy protein biomarkers for the early detection of colon cancer.

High-Throughput Evaluation of Breast Cancer Markers – A number of blood proteins have been reported to be altered in women with breast cancer. Researchers are using sophisticated proteomic methodologies to identify possible biomarkers of breast cancer in plasma.

Proteomic Identification of NAF Biomarkers – We hypothesize that nipple aspirate fluid (NAF) is a concentrated and selective source of protein biomarkers for breast cancer. Using proteomic approaches, researchers are characterizing the proteome of NAF and undertaking preliminary analyses to identify potential protein biomarkers.

Proteomics and Metabolomics Studies of Type 1 Diabetes – Members of this project team are applying advanced proteomic and metabolomic technologies to study plasma and serum from Type 1 diabetes patients and isolated human pancreatic islets. The team endeavors to advance the study of Type 1 diabetes and human islet transplantation by identifying biomarkers at the level of the proteome and metabolome that are predictive of both Type 1 diabetes and islet performance in vivo.

PNNL's Biomarkers Research Efforts Are Supported by the Life Sciences Discovery Fund

Next Generation Clinical Proteomics to Target Human Health Challenges - Scientists are developing new proteomics technology to search for blood biomarkers for liver disease. In subsequent studies, the new technology will be used to study cancer, diabetes, and other conditions.

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