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Bioorganic Mass Spectrometry

Working Group 3.21




The basic task of the group is providing measurements in the area of Clinical Chemistry at state of the art, high precision and high reliability. The spectrum of analytes covers small organic molecules, as glucose, creatinine, cholesterol or steroid hormones, as well as proteins, referred to as Health-Status Markers. These measurements constitute a link between the network of Reference Laboratories, as organized by the German Medical Association, and the National Metrology Institute (PTB) safeguarding SI-traceability and international comparability, this way, of results. Research and development are driven by the need in this area, either for measurands presently available in unsatisfying precision only, or unavailable at all. Beyond this, methods are being developed for novel measurands providing a metrological basis for their exploration, thus supporting research in molecular medicine. Mass spectrometry is pivotal a technology in this context.

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Quantifying diagnostic protein markers

Mass-spectrometry based Reference Methods, well established for small molecules as glucose, cholesterol or steroid hormones, have not been available, until recently, for quantification of proteins. However, quite a number, perhaps the vast majority of biomarkers in diagnostic use, or being discovered, are proteins. Therefore, PTB has developed Isotope Dilution Mass Spectrometry (ID-MS) for protein markers, expanding the scope of  SI-traceable Reference Measurement to this important class of clinical measurands. Fundamentally, the methodology has the potential to provide antibody-independent results, that can be used as reference data in quality control. PTB is among the leading National Metrology Institutes in this area.

Discriminating protein isoforms

Proteins often exist as families of molecules with small differences among the members, leaving their properties similar, however, on the whole. Different isoforms, e.g., result by either skipping or including part of the amino acid sequence 'stored' for that protein in the genome, or if different genes are coding for the same (basic) protein. For instance, several isoforms have been detected for somatotropin (growth hormone, GH). Little is known about perhaps slightly varying biological functions of these GH-forms and their specific diagnostic potential. Antibodies, presently used for quantification are subject to cross-reactivity and limited thus for the purpose of distinct measurement. Mass spectrometry, with its inherently high selectivity, has the promise to furnish much better resolution and is being investigated as a tool for detection and evaluation of isoforms. Also, ID-MS methods will then be at hands for the measurands needed for (potentially) improved diagnostics.

Further into novel measurands

Mass spectrometric protein quantification is used to explore measurands for research purposes in general. One present study is about mass spectrometric quantification of viral proteins. This, if successful, could open another option to calibrating measurement of viral load in therapeutic monitoring. Potentially, this could be used as independent approach to backup (or calibrate) routine PCR-methods used in hospitals. Another project recently started is intended to support research in Gene Therapy. Small stretches of RNA (siRNA) are used as drugs to suppress cellular expression (production) of certain target proteins. A generic ID-MS method is being developed for reliable quantification of protein expression levels. This, eventually, may provide a metrological sound basis for benchmarking different drug delivery / cell / target protein systems. Improved inter-laboratory comparability of data, as anticipated, would support optimization in drug development.

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Quality Control in Clinical Chemistry

Laboratories providing clinical measurements for patient samples are required to regularly participate in External Quality Control Schemes (EQAS). Control samples are sent to the participants, and their results checked against target values. For many diagnostic markers, as e.g. glucose, creatinine, cholesterol or steroid hormones, such target values are determined by isotope-dilution mass spectrometry (ID-MS), a Primary Reference Method. In practice, these measurements are performed by contracted Reference Laboratories. PTB, on the other hand, monitors proficiency of Reference Laboratories by intercomparison on ID-MS level.

Auditing Reference Laboratories

Reference Measurement Laboratories, according to Guidelines of the German Medical Association, have to comply with DIN EN ISO/IEC 17025 and 15195. PTB supports accreditation bodies by technical evaluation of instrumentation, equipment, and measurement procedures. Audits are based on manuals, inspection of the laboratory, and monitoring results of regular intercomparison for key measurands.

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