Should the Human Proteome Project Be Gene- or Protein-centric?
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iseases are due to gene defects (mutations, deletions, etc.) and/or the environment, which can then be divided into two components: toxicants and microbes. The etiology of all human diseases belongs to these three categoriessgenes, toxicants, and microbesswith a variable involvement for each one. For example, Huntington’s disease is essentially caused by a single gene defect, whereas hypertension and diabetes are the result of multiple gene defects and, often, food “toxicity” or overabundance. Pneumonia is frequently caused by microbes, but genetic predisposition and the uptake of toxic products, such as in alcoholism, can be factors, too. Therefore, it is essential to measure the predominant effects of microbes and of the environment in addition to genetic predisposition for many diseases. The latter is most efficiently detected at the genetic or transcriptomic level, as well as with host antibody production (serology testing) or immune-cell responses. The former can be unraveled at many levels, depending on the offending chemicals, some of which modify DNA, RNA, proteins, or metabolites. The analysis depends on the reactivity of the chemicals and the biological system that is implicated. Thus, a gene-centric Human Proteome Project (HPP) would capture only a fraction of the changes that can occur in human disease. Clearly, we need to expand an HPP to include the study of environmental factors. Biology and medicine. Genetic material, at the DNA level, seems to be mobile among living species but relatively static within individuals, except in cancer proliferation and certain cell types. However, proteins are dynamic. The processes of protein remodeling, biodegradation, and synthesis are regulated in diverse ways, and for some proteins, these processes occur constantly. As demonstrated in one of Nobel Prize winner Aaron Ciechanover’s pioneering papers (Biochem. Biophys. Res. Commun. 1978, 81, 1100-1105), intracellular protein degradation is tightly controlled and requires energy. Protein half-lives, concentration levels, and modifications are intimately linked to cell metabolism and are probably less directly linked to gene expression level. For example, deregulation of intracellular polypeptide degradation can lead to Alzheimer’s disease or cancer because of the abnormal accumulation of certain proteins or because of the too-rapid degradation of others. The protein degradation system is even a domain of small-molecule target searching in pharmaceutical research. The understanding of normal and physiopathological responses of cells in biology and medicine has to involve the application of a systems science approach to the study of proteins and their modifications, as well as environmental effects. Bioinformatics. The final verification of exon prediction and of protein structure and function can be done only at the protein level. Although Swiss-Prot/UniProtKB now lists most,
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© 2008 American Chemical Society
if not all, of the proteins predicted from the human genome, the protein products of the identified gene sequences need to be expressed or synthesized to unravel the products’ structure, associations, and functions. In addition, new transcripts have been discovered that cover longer distances than previously predicted, and the protein counterparts need to be found to prove these transcripts’ existence. Clinical practice. For many years, clinicians have interpreted the level of measured isoenzymes, such as alkaline phosphatase, to diagnose and to monitor the treatment of liver or bone diseases. Modified proteins, such as glycated hemoglobin (hemoglobin A1c) or carbohydrate-deficient transferrin, are measured to monitor diabetes treatment or alcohol abstinence. Currently, the blood level of the propeptide procalcitonin best predicts a septic event or severe pneumonia and guides the use of antibiotics in the emergency room. Indeed, procalcitonin is a great new biomarker for severe inflammation and sepsis. The workup of hypoglycemia often requires the measurement of the cleaved peptide of native insulin, the c peptide. In pulmonary embolism, the most frequently used tests with an excellent negative-predictive value are those that assay for cross-linked peptides from fibrin called D-dimers. None of the protein levels and modifications mentioned above can be predicted from the gene or gene transcript. A gene or gene transcript’s diagnostic, prognostic, or therapeutic value has to be discovered at the protein, peptide, and metabolomic levels. In a different domain, in clinical pharmacotoxicology, phenotypes often differ from genotypes because of environmental effects. For example, despite excellent genotype prediction of cytochrome P450 2D6 and C19 by DNA array, phenotypic differences in hospitalized patients are so tremendous that they diminish or eliminate the utility of such expensive technology in daily or common practice. Proteomic perspective. The elements summarized above demonstrate the critical need to encourage and support, on a large scale, an HPP, despite its tremendous complexity. Matthias Mann has recently published an editorial saying, “Can proteomics retire the western blot?” (J. Proteome Res. 2008, 7, 3065). His work demonstrates that recent MS improvements in his laboratory and elsewhere provide the identification and quantification of most peptides in a very complex mixture, including many protein modifications. In conclusion, the listed arguments favor a project that would be protein- and not gene-centric. Today, an HPP should be technology-driven by MS. It should be based on clinical pathology and anchored in biology and medicine. DENIS HOCHSTRASSER Geneva University and University Hospital
Journal of Proteome Research • Vol. 7, No. 12, 2008 5071
