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New Technology for the Human Cytome Project Journal of Biological Regulators and Homeostatic Agents New technology for the human cytome project A. TÁRNOK Pediatric Cardiology, Heart Center Leipzig GmbH, University Hospital Leipzig, Leipzig, Germany ABSTRACT: Cytomes or cell systems are composed of various kinds of single-cells and constitute the elementary building units of organs and organisms. Their individualised (cytomic) analysis overcomes the problem of averaged results from cell and tissue homogenates where molecular changes in low frequency cell populations may be hidden and wrongly interpreted. Analysis of the cytome is of pivotal importance in basic research for the understanding of cells and their interrelations in complex environments like tissues and in predictive medicine where it is a prerequisite for individualised preventive therapy. Analysis of molecular phenotypes requires instrumentation that on the one hand provides high-throughput measurement of individual cells and is on the other hand highly multiplexed, enabling the simultaneous acquisition of many parameters on the single cell level. Upcoming technology suitable to this task, such as slide based cytometry is available or under development. The realisation of cytomic technology is important for the realisation of the human cytome project. (J Biol Regul Homeost Agents 2004; 18: ) KEY WORDS: Cytomics, Bioinformatics, Multilevel biocomplexity profiling, Slide based cytometry, Imaging, Human cytome project Received: Revised: Accepted: INTRODUCTION Slide based cytometry Cytomes, i.e. cell systems are composed of various Fluorescence microscopy represents a powerful kinds of single-cells and constitute the elementary technology for stoichiometric single cell based building blocks of organs and organisms (1, 2). Their analysis in smears or tissue sections. Whereas in the individualised (cytomic) analysis overcomes the past the major goal of microscopy and imaging was to problem of averaged results from cell and tissue produce high quality images of cells, in the last few homogenates where molecular changes in low years an increasing demand for quantitative and frequency cell populations may be hidden and wrongly reproducible microscopic analysis has arisen. This interpreted. Analysis of the cytome is of pivotal demand has come mostly from the drug discovery companies importance in basic research for the understanding of but also from clinical laboratories. Slide based cells and their interrelations in complex environments cytometry is an appropriate approach to fulfil this such as tissues and in predictive medicine which is a demand (6). Laser Scanning Cytometry (6-8) was the prerequisite for individualised preventive therapy (3, 4). first of this type of instrument to become commercially Cells within cytomes can be either uniform or available but today several different instruments are confined to particular cell subpopulations. In the latter on the market (9, 10). These instruments are built case changes in low frequency cell subpopulations may around scanning fluorescence microscopes that are be lost by dilution (5). This problem is overcome by either equipped with a laser (6) or a mercury arc lamp single-cell analysis of the molecular cell phenotypes as as the light source (9, 10). The generated images are they result from genotype and exposure (3). Analysis of processed by appropriate software algorithms to molecular phenotypes requires instrumentation that on produce data similar to flow cytometry. Slide based the one hand provides high throughput measurement of cytometry systems are intended to be high throughput individual cells and is on the other hand highly instruments although at present they have a lower multiplexed, enabling the simultaneous acquisition of throughput than flow cytometers. These instruments many parameters on the single cell level. In order to allow multicolour measurements of high complexity (7, unravel the human cytome on the road to a human 11) which is comparable to or even higher than with cytome project (1, 2) new technological approaches are flow cytometers. Another major advantage over flow of ncreasing importance. Upcoming technology is cytometry is that cells in adherent cell cultures and available or under development that is suitable to tissues as well can be analysed without prior this task. disintegration (12-15). In addition, due to the fixed 0393-974X/000-04 $15.00 © Wichtig Editore, 2004 Cytomic technology Fig. 1 - Idealised hypothetical design of a composite slide based cytometry instrument Slide based Functional analysis of living cells in and an experimental set-up for cytomic analysis of cells. cytometry their environmental context (Cytomes) restaining Slide based Highly multiplexed surface analysis cytometry with spectral and/or restaining confocal imaging, FLIM, FRET Intracellular structures Data pattern Identification of cells with expression analysis patterns of interest STED, SNOM, AFM Sub- m 3D analysis of individual cells Microdissection Isolation of cells of interest DNA/RNA array mass spectrometry Single cell Single cell electrophoresis Proteomics Genomics position of the cells on the slide or in the culture excitation (22), ultra sensitive fluorescence micro- chamber, cells can be relocated several times and scopes (23), stimulated emission depletion (STED) reanalysed. Even restaining and subsequent microscopy (24), spectral distance microscopy (25), reanalysis of each individual cell is feasible. Since by atomic force microscopy (AFM) scanning near-field slide based cytometry a high information density on optical microscopy (SNOM) (26) and image the morphological and molecular pattern of single restoration techniques (27). Using laser ablation in cells can be acquired, it is an ideal technology for combination with imaging, even thick tissue cytomics. specimens can be analysed on a cell by cell basis Although at present not realised, the information (28). density per cell can be increased even further by implementing technology such as spectral imaging Innovative preparation and labelling techniques (12), confocal cytometry (16), fluorescence resonance energy transfer (FRET) (12, 17, 18), near infrared Biomolecular analysis techniques like bead arrays Raman spectroscopy (19), fluorescence lifetime (29), layered expression imaging (30), single-cell imaging (FLIM) (18, 20) and second harmonic polymerase chain reaction (PCR) (31), tyramide imaging (21). All of these technological products mark signal amplification (32) or biomolecule labelling by progress in optical bioimaging. quantum dots (33), magnetic nanobeads (34) and In the future, limit breaking developments in aptamers (35) open new horizons of sensitivity, imaging far beyond the resolution limit down to the molecular specificity and multiplexed analysis. By nm-range are expected. These include multiphoton additional tools such as laser microdissection (31), 2 Tárnok laser catapulting (36) or fast electric single cell lysis the histological context. Serial optical imaging will (37) single cells can be rapidly isolated and further permit 3D-reconstruction of the molecular morphology subdued to genomic or proteomic analysis (31, 36, of cell membrane, nucleus, organelles and cytoplasm 38) or single cell capillary electrophoresis (37). including the parameterisation of 3D-shapes. Serial The dimensionality of measured molecular cell data histological sections taking stereological aspects of can be substantial, especially when repeated six or tissue architecture into account (42) will serve as eight colour staining protocols on many different cell basis for the standardised analysis of proximity and populations are performed (12, 39) and their spatial interaction patterns for intracellular structures like interrelationship within a tissue is taken into account nucleus and organelles as well as for different cell (11, 13, 14). The data density is multiplied if high den- types within the tissue architecture that can even sity single cell analysis like SNOM, AFM (26), STED include time as a parameter for 4D intravital (24) combined with single cell genomics (31, 36) or microscopy (43). proteomics (37,38) is added. One of the most important outcomes of the Human Genome Project is the realisation that there is CONCLUSION considerably more biocomplexity in the genome and the proteome than previously appreciated (40). Not The technical developments towards optimal only are there many splice variants of each gene technology for the analysis of cytomes and towards system, but some proteins can function in entirely the human cytome project are rapidly evolving. different ways not only in different cells but also in Already today several high quality instruments are different locations of the same cell, lending additional available. By combining different methods and importance to the single cell analysis of laser different types of instruments the way will be open in scanning cytometry and confocal microscopy. These the near future to bring high content single cell differences would be lost in the mass spectroscopy of analysis nearer to its limits. The establishment of such heterogeneous cell populations. Hence, cytomic a system using the various single-cell oriented approaches may be critical to the understanding of molecular technologies in conjunction with specific proteomics. In extending this from cells to tissue biomolecule labelling in a specially focused human architecture, machine vision protocols are a key in cytome project represents a combined challenge to conducting hyper-quantitative
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