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The Human Proteome Vidal et al. Clinical Proteomics 2012, 9:6 http://www.clinicalproteomicsjournal.com/content/9/1/6 CLINICAL PROTEOMICS MEETING REPORT Open Access The human proteome – a scientific opportunity for transforming diagnostics, therapeutics, and healthcare Marc Vidal1, Daniel W Chan2, Mark Gerstein3, Matthias Mann4, Gilbert S Omenn5*, Danilo Tagle6, Salvatore Sechi7* and Workshop Participants Abstract A National Institutes of Health (NIH) workshop was convened in Bethesda, MD on September 26–27, 2011, with representative scientific leaders in the field of proteomics and its applications to clinical settings. The main purpose of this workshop was to articulate ways in which the biomedical research community can capitalize on recent technology advances and synergize with ongoing efforts to advance the field of human proteomics. This executive summary and the following full report describe the main discussions and outcomes of the workshop. Executive summary human proteome, including the antibody-based Human A National Institutes of Health (NIH) workshop was Protein Atlas, the NIH Common Fund Protein Capture convened in Bethesda, MD on September 26–27, 2011, Reagents, the mass spectrometry-based Peptide Atlas with representative scientific leaders in the field of pro- and Selected Reaction Monitoring (SRM) Atlas, and the teomics and its applications to clinical settings. The main Human Proteome Project organized by the Human purpose of this workshop was to articulate ways in which Proteome Organization. Several leading laboratories the biomedical research community can capitalize on re- have demonstrated that about 10,000 protein products, cent technology advances and synergize with ongoing of the about 20,000 protein-coding human genes, can efforts to advance the field of human proteomics. be identified and quantified in a single experimental Proteins are the major components of biological net- specimen; this figure may represent nearly the complete works and molecular machines, and proteins are the tar- complement of proteins actually expressed in a single gets for the large majority of drugs available today. cell type. In yeast the complete expressed proteome has Participants in this Workshop recognized that a deeper been identified. Even though a more comprehensive knowledge of the human proteome could help fill the characterization of the dynamic aspect of the proteome gap between genomes and phenotypes, transform the will require further technology development, it is a dis- way we develop diagnostics and therapeutics, and ruptive concept that almost all of the primary products thereby enhance overall biomedical research and future of the genome can be detected at the protein level in healthcare. The Human Genome Project and its many one single experiment. follow-on initiatives, including the HapMap and The Workshop was organized in five sessions: (1) pro- ENCODE, together with advances in protein sciences, tein networks; (2) integrating proteomics with other have provided a foundation for proteomic technologies omics; (3) quantitative proteomics by exploratory and and informatics resources. Several major initiatives are targeted methodologies; (4) study design and statistical already moving toward deep characterization of the challenges in clinical proteomics; and (5) proteomic technologies in a clinical setting. Sessions 1–3 consti- – * Correspondence: [email protected]; [email protected] tuted a main theme on systems biology; sessions 4 5 5University of Michigan, Ann Arbor, MI, USA represent a theme on strategies for clinical proteomics. 7 National Institute of Diabetes and Digestive and Kidney Diseases, The full agenda is at http://www3.niddk.nih.gov/fund/ National Institutes of Health, 6707 Democracy Blvd. Rm 611, Bethesda, MD 20892-5460, USA other/HumanProteome2011. This executive summary Full list of author information is available at the end of the article © 2012 Vidal et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Vidal et al. Clinical Proteomics 2012, 9:6 Page 2 of 11 http://www.clinicalproteomicsjournal.com/content/9/1/6 and the following full report describe the main discus- approximately 10,000 proteins from different genes in sions and outcomes of the workshop. human cell lines, for example. Such deep analyses per- mit direct comparison with deep sequencing of the Protein networks: toward a comprehensive wiring transcriptome, as well as with protein expression based diagram of human cells on immunohistochemistry, as documented in the The interactome network of cells is the complete set of Human Protein Atlas. macromolecular interactions that take place between genes and gene products; it is mostly mediated by pro- Study design and statistical challenges in clinical teins. Pull-down of diverse protein complexes and se- proteomics quencing of the components, plus other direct For the past decade, many of the individual institutes of measurements of protein-protein, protein-nucleic acid, the NIH have supported programs and projects to gen- and protein–lipids interactions now make it feasible to erate potential protein biomarkers for early or more create wiring diagrams for systems biology. The capabil- specific diagnosis or prognosis of a wide array of dis- ity of quantifying the main gene products and providing eases. There are many complex challenges in developing information on post-translational modifications and such omics-based tests. Heterogeneity of etiology, splice variants of proteins addresses the dynamic nature pathogenesis, and responses to therapy among patients of the networks. Experimental and natural perturbations with identical diagnoses, is common. Knowledge of of cultured cells and of whole organisms can then reveal mechanisms, mediated by pathways and networks, is connectivity and can test hypotheses of the blueprint fundamental to moving beyond statistical correlation as and dynamic regulation of phenotypes. Informatics tools a basis for biomarker development. Integration of data such as Cytoscape and databases such as BioGRID pro- across multiple levels of omics analyses should facilitate vide means of visualizing pathways, networks, and such knowledge development. Several general recom- interactomes. mendations for biomarker discovery projects were also made during the discussion. Participants emphasized Integrating proteomics with other omics the importance of specifying as early as possible in the Detailed integration of data and knowledge from mul- process the intended clinical use, and the importance of tiple omics technology platforms is essential for building proper study design in order to avoid introducing bias. and understanding the pathways from genome to pheno- Finally, it is important for translational scientists to types and the influence of environmental and behavioral understand the long path of discovery, confirmation, variables. The influence of allelic variants, splice variants, validation, clinical trials, and FDA approval to establish and post-translational modifications must be assessed in test validity and utility and gain reimbursement of the combined analyses of mRNA and protein abundance and laboratory service. response to perturbations. Single nucleotide polymorph- isms and alternative splicing can influence sites of post- translational modifications, magnifying their downstream Proteomic technologies in a clinical setting effects. Linking gene expression, protein expression, and The late-stage translation of proteomic technologies and metabolomics has become an attractive approach, facili- protein biomarker candidates into clinical tests requires tated by new bioinformatics tools. specification of the intended clinical use, sufficient evi- dence in preliminary studies to support the investment Quantitative proteomics by exploratory and targeted for a large-scale validation trial, demonstration of reliable mass spectrometry methods test performance characteristics, and sufficient clinical There has been stunning progress in mass spectrom- benefit to gain acceptance by the clinical community. It etry-based proteomics, with new technologies and com- is counterproductive to try to short-circuit these com- binations of instrumentation for bottom-up peptide plex steps, especially in the absence of a strong biological analysis, top-down protein analysis, and targeted quanti- foundation for the biomarker candidate or panel of bio- tative analysis of proteotypic peptides of selected pro- markers. The development of a roadmap for the transla- teins. The equipment and reagent sector for proteomics tion of proteomics technologies into clinical settings will is a major economic engine. These advances enable require close collaboration between researchers, indus- much more potent approaches for biomarker develop- tries, regulators, clinical chemists and clinicians, includ- ment and protein targeting with therapeutic agents. In ing private-public partnerships to leverage existing NIH contrast to recent studies limited to the most abundant programs. Such a partnership would accelerate the devel- dozens or hundreds of proteins in a biological speci- opment of clinically useful technologies and biomarkers men, current experiments are identifying, with a false and make a significant impact to fulfill the unmet clinical discovery
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