Editorial: Computational modelling of cell &; tissue processes &; function

Computational modelling of whole biological systems from cells to organs is gaining momentum in cell biology and disease studies. This pathway is essential for the derivation of explanatory frameworks that will facilitate the development of a predictive capacity for estimating outcomes or risk associated with particular disease processes and therapeutic or stressful treatments. This article introduces a series of invited papers covering a hierarchy of issues and modelling problems, ranging from crucial conceptual considerations of the validity of cellular modelling through to multi-scale modelling up to organ level. The challenges and approaches in cellular modelling are described, including the potential of in silico modelling applications for receptor–ligand interactions in cell signalling, simulated organ dysfunction (i.e., heart), human and environmental toxicity and the progress of the IUPS Physiome Project. A major challenge now facing biologists is how to translate the wealth of reductionist detail about cells and tissues into a real understanding of how these systems function and are perturbed in disease processes. In biomedicine, simulation models of biological systems now contain sufficient detail, not only to reconstruct normal functions, but also, to reconstruct major disease states. More widely, simulation modelling will aid the targeting of current knowledge gaps and how to fill them; and also provide a research tool for selecting critical factors from multiple simulated experiments for real experimental design. The envisaged longer-term end- product is the creation of simulation models for predicting drug interactions and harmful side-effects; and their use in therapeutic and environmental health risk management. Finally, we take a speculative look at possible future scenarios in cellular modelling, where it is envisioned that integrative biology will move from being largely qualitative and instead become a highly quantitative, computer-intensive discipline.     

Automated migration analysis based on cell texture: method &; reliability

Background  

In this paper, we present and validate a way to measure automatically the extent of cell migration based on automated examination of a series of digital photographs. It was designed specifically to identify the impact of Second Hand Smoke (SHS) on endothelial cell migration but has broader applications. The analysis has two stages: (1) preprocessing of image texture, and (2) migration analysis.     

Global diversity of cumaceans &; tanaidaceans (Crustacea: Cumacea &; Tanaidacea) in freshwater

Cumacea and Tanaidacea are marginal groups in continental waters. Although many euryhaline species from both groups are found in estuaries and coastal lagoons, most occur only temporarily in non-marine habitats, appearing unable to form stable populations there. A total of 21 genuinely non-marine cumaceans are known, mostly concentrated in the Ponto-Caspian region, and only four tanaids have been reported from non-marine environments. Most non-marine cumaceans (19 species) belong in the Pseudocumatidae and appear restricted to the Caspian Sea (with salinity up to 13‰) and its peripheral fluvial basins, including the northern, lower salinity zones of the Black Sea (Sea of Azov). There are nine Ponto-Caspian genera, all endemic to the region. Only two other taxa (in the family Nannastacidae) occur in areas free of any marine–water influence, in river basins in North and South America. Both seem able to survive in waters of raised salinity of the lower reaches of these fluvial systems; but neither has been recorded in full salinity marine environments. The only non-marine tanaidacean thus far known lives in a slightly brackish inland spring in Northern Australia. The genus includes a second species, from a brackish-water lake at the Bismarck Archipelago, tentatively included here as non-marine also. Two additional species of tanaidaceans have been reported from non-marine habitats but both also occur in the sea. Guest editors: E. V. Balian, C. Lévêque, H. Segers & K. Martens Freshwater Animal Diversity Assessment     

Evolutionary convergences and parallelisms: &;their theoretical differences and the difficulty &;of discriminating them in a practical &;phylogenetic context

The importance of evolutionary parallelisms and their differences from evolutionary convergences have been historically underappreciated, as recently noticed in Gould's last book `The structure of evolutionary history'. In that book, Gould make an effort to distinguish and to reinterpret these concepts in the light of the new discoveries of the last decades on developmental biology and genetics, presenting the elegant metaphor of `Pharaonic bricks versus Corinthian columns'. In this paper I will briefly discuss these concepts, and will argue that, despite the advances that have been made to define them in theory, it is rather hard to differentiate them in a practical phylogenetic context. In order to do so, I will provide some few examples from my own empirical studies on the last years of one of the most morphologically and taxonomically diverse groups of Vertebrates, the catfishes.     

Synchrony &; chaos in patchy ecosystems

The apparent synchronisation of spatially discrete populations is a well documented phenomenon. However, it is not clear what the governing mechanisms are for this synchrony, and whether they are robust over a range of environmental conditions and patch specific population dynamic behaviours. In this paper, we explore two (possibly interacting) modes of coupling, and investigate their theoretically discernible, and perhaps even experimentally measurable, signatures. To aid us in this investigation we employ a planktonic example system, with direct application to plankton patchiness. Furthermore, we address the role of chaos in complex spatio-temporal dynamics; we find that chaos associated with funnel attractors can play a distinguished role, over dynamics less sensitive to small variations, in being more susceptible to generalised synchronisation (such as phase synchronisation) in the presence of small local parameter variation. This is in contrast to the case for coupled systems with identical dynamics, and suggests that non-identically coupled systems are more vulnerable to global extinction events when exhibiting funnel-type chaotic dynamics.     

The acceptability of continuous cell lines: A personal & historical perspective

In the 1950s, only primary cell cultures were acceptable for the production of human biological products. This position was challenged in the late 1960s by human diploid cells (HDCs), and again in the 1980s by continuous cell lines (CCLs). The history of the HDC controversy is reviewed and lessons from that era that are relevant to the use of CCLs are pointed out. It became apparent in the early days of recombinant DNA technology in the 1980s that CCLs were needed for the development of some products. CCL acceptability therefore became more urgent, and several attempts were made to reach a consensus on regulatory issues. In 1986, the World Health Organization convened a Study Group to review the safety issues related to products derived from CCLs. The Study Group made a clear recommendation to pursue CCLs in product development because of the demonstrated capability of modern manufacturing processes to cope with contaminants. Issues such as acceptable levels of cellular DNA in products and the relationship of purity to safety are discussed in the context of the need for regulatory authorities, industry, and the general biomedical community to cooperate in addressing problems in a rational scientific manner.     

The antarctic diatom: Stellarima microtrias (Ehrenberg) Hasle & Sims cell structure and vegetative cell enlargement in culture

Summary On the whole, the ultrastructure of the vegetative cell of Stellarima microtrias (Ehrenberg) Hasle & Sims, is similar to that of other diatoms. The less common features are non membrane-limited pyrenoids crossed by two discs formed of three thylakoids and non perinuclear dictyosomal units. The enlargement of the cell is not related to sexuality and is the result of a purely vegetative process. Either one or two new vegetative cells are formed in a spherical cell depending on whether the parent cell, from which the spherical cell emerges, contains one or two vegetative nuclei (in mitotic cells before cytokinesis). Only one mitosis occurs with formation of a pycnotic nucleus, this being extruded. The ecological significance of the process is discussed.     

Cell Adhesion Molecules: Potential Therapeutic &; Diagnostic Implications

The role of cell adhesion molecules (CAM) and extracellular matrix proteins (ECM) in various pathological processes including angiogenesis, thrombosis, apoptosis, cell migration & proliferation are well documented. These processes can lead to both acute and chronic disease states such as ocular diseases, metastasis, unstable angina, myocardial infarction, stroke, osteoporosis, a wide range of inflammatory diseases, vascular remodeling, and neurodegenerative disorders. A key success in this field is evident from the potential role of the platelet GPIIb/IIIa integrin in the prevention and diagnosis of various thromboembolic disorders. Additionally, the use of soluble adhesion molecules as potential diagnostic markers for acute and chronic leukocyte, platelet, and endothelial cellular insult are increasingly utilized. The development of various therapeutic and diagnostic candidates based on the key role of CAM, with special emphasis on integrins in various diseases as well as the structure-function aspects of cell adhesion and signaling of the different CAM and ECM are highlighted.     

Lipid Rafts & Co.: an integrated model of membrane organization in T cell activation

The model of membrane compartmentalization by self-organizing functional lipid microdomains, named lipid rafts, has been a fruitful concept resulting in great progress in understanding T cell signal transduction. However, due to recent results it has become clear that lipid rafts describe only one out of several membrane organizing principles crucial for T cell activation besides fences and pickets and protein-protein interactions that take part in the formation of the immunological synapse as a highly organized structure at the T cell contact site to the antigen-presenting cell. This review describes the concepts of lipid rafts and other membrane organizing principles to evolve a novel integrated model on the functional role of microdomains in immunological synapse formation and T cell activation. Further research has to elucidate the relative contribution and interrelation of different modes of membrane organization in productive T cell activation.     

The stem cell code in oral epithelial tumorigenesis: ‘The cancer stem cell shift hypothesis’

Tumors of the oral cavity provide an ideal model to study various stages of epithelial tumor progression. A group of cancer cells termed cancer stem cells (CSCs) eludes therapy, persists and initiates recurrence augmenting malignant spread of the disease. Hitherto, accurate identification and separation of such minimal residual cells have proven futile due to lack of identifiable traits to single out these cells from the heterogeneous tumor bulk. In this review we have compiled comprehensive evidence from comparative phenotypic and genotypic studies on normal oral mucosa as well as tumors of different grades to elucidate that differential expression patterns of putative stem cells markers may identify ‘minimal residual disease’ in oral squamous cell carcinoma. We propose the “cancer stem cell shift hypothesis” to explain the exact identity and switch-over, tumor-promoting mechanisms adapted by putative CSCs with correlation to tumor staging.     

Signaling Functions of Free Radicals Superoxide &; Nitric Oxide under Physiological &; Pathological Conditions

Superoxide and nitric oxide are ubiquitous physiological free radicals that are responsible for many pathological disorders. Both radicals by themselves are relatively harmless but are the precursors of many toxic species such as peroxy and hydroxyl radicals, hydrogen peroxide, and peroxynitrite. However, it has been shown now that both superoxide and nitric oxide are also able to perform important signaling functions in physiological and pathophysiological processes. Wrongly named “superoxide,” the radical anion of dioxygen is not a super-oxidant but the strong super-nucleophile, an efficient catalyst of heterogenic nucleophilic reaction. Due to this, superoxide plays an important role in many enzymatic processes such as the phosphorylation and activation of numerous protein kinases. On the other hand, superoxide inhibits the activation of phosphatases, the enzymes catalyzed by dephosphorylation of protein kinases. We suggest that superoxide catalyzes these enzymatic processes as a result of its nucleophilic properties. Another important physiological function of superoxide and nitric oxide is their competition for the interaction with mitochondrial cytochrome c oxidase. Disturbance of superoxide/nitric oxide balance leads to the dysfunction of mitochondria and the enhancement of apoptosis and oxidative stress, which are primary causes of various pathological disorders and aging. In conclusion, interplay between superoxide and nitric oxide, one of major factors of aging development, is considered.     

Thrombin—Mast cell interactions : Binding and cell activation

Activation of mouse bone marrow-derived mast cells (BMMC) by thrombin (0.05-0.5 U/million cells) resulted in a concentration-dependent release of histamine, which levelled off by 0.1 U thrombin. Rat peritoneal mast cells (RMC) were not stimulated by thrombin, though in control experiments, both types of mast cells degranulated upon exposure to IgE-antigen. Pretreatment of thrombin with 0.2 mM diisopropylfluorophosphate (DFP), a specific serine protease inhibitor, resulted in 90% loss of thrombin degranulation and coagulant activity. Fluorescently labelled thrombin (FITC-thrombin) specifically bound to the BMMC surface, as measured by fluorescence cytometry. Pre-exposure of the BMMC to 20-fold excess of unlabelled thrombin prior to incubation with FITC-thrombin, prevented the binding of the labelled-thrombin to the cells. Incubation of thrombin with DFP or with antithrombin III (AT-III) resulted in losses of procoagulant and of BMMC degranulatory activities. DFP treatment of FITC-thrombin had no effect on the binding of the labelled enzyme to the cell surface. However, preincubation of the FITC-thrombin with AT-III prevented thrombin binding to the BMMC. Thus, the binding and the catalytic regions of the thrombin molecule are operationally distinct from one another. Kinetic analysis of the BMMC exposed to 0.5 U thrombin revealed a transient rise in intracellular cAMP, which peaked by 15 sec and was not measurable after 1 min. This suggests that differential activation of mast cells can occur at sites of tissue injury.