Modelling,abstraction, and computation in systems biology: A view from computer science

Systems biology is centrally engaged with computational modelling across multiple scales and at many levels of abstraction. Formal modelling, precise and formalised abstraction relationships, and computation also lie at the heart of computer science—and over the past decade a growing number of computer scientists have been bringing their discipline's core intellectual and computational tools to bear on biology in fascinating new ways. This paper explores some of the apparent points of contact between the two fields, in the context of a multi-disciplinary discussion on conceptual foundations of systems biology.     

Natural killer lymphocytes: biology,development, and function

Natural killer (NK) lymphocytes represent the first line of defense against virally infected cells and tumor cells. The role of NK cells in immune responses has been markedly explored, mainly due to the identification of NK cell receptors and their ligands, but also through the analysis of mechanisms underlying the effects of various cytokines on NK cell development and function. A population of lymphocytes that shares function and receptors with NK cells is represented by natural killer T (NKT) cells. NKT lymphocytes are regulators of both innate and adaptive immune responses, but have also been reported to function as effector antitumor cells. The marked progress in our understanding of the biology, development, and function of NK/NKT cells has provided the basis for their potential application in tumor clinical trials.This work was presented at the first Cancer Immunology and Immunotherapy Summer School, 8–13 September 2003, Ionian Village, Bartholomeio, Peloponnese, Greece.     

Distributed computation: the new wave of synthetic biology devices

Synthetic biology (SB) offers a unique opportunity for designing complex molecular circuits able to perform predefined functions. But the goal of achieving a flexible toolbox of reusable molecular components has been shown to be limited due to circuit unpredictability, incompatible parts or random fluctuations. Many of these problems arise from the challenges posed by engineering the molecular circuitry: multiple wires are usually difficult to implement reliably within one cell and the resulting systems cannot be reused in other modules. These problems are solved by means of a nonstandard approach to single cell devices, using cell consortia and allowing the output signal to be distributed among different cell types, which can be combined in multiple, reusable and scalable ways.     

Models in biology: form and function

The relationships between physical and biological sciences are important in science education. This is shown in the links between the structure of biological science and the use of models. Although the physical sciences contain many principles of wide application, much of biology consists of very distinct examples. When these examples are used as models of organisms or processes, misunderstanding can occur if the characteristics of the model are used to make inaccurate generalizations. In biological education, stress on the importance of unique features must continually accompany the demonstration of similarities.

Theoretical models are constructed and reconstructed by students learning science, particularly in relation to broadly applicable principles. In biology a student may build a theoretical model of a subject which is itself a model used as an example. Distinct features of biological science may influence a variety of learning situations including problem solving.     

Decorin biology, expression, function and therapy in the cornea

Decorin is a small leucine-rich proteoglycan (SLRP) that plays a vital role in many important cellular processes in several tissues including the cornea. A normal constituent of the corneal stroma, decorin is also found in the majority of connective tissues and is related structurally to other small proteoglycans. It interacts with various growth factors such as epidermal growth factor (EGF) and transforming growth factor beta (TGFβ) to regulate processes like collagen fibrillogenesis, extracellular matrix (ECM) compilation, and cell-cycle progression. Studies have linked decorin dysregulation to delayed tissue healing in patients with various diseases including cancer. In the cornea, decorin is involved in the regulation of transparency, a key function for normal vision. It has been reported that mutations in the decorin gene are associated with congenital stromal dystrophy, a disease that leads to corneal opacity and visual abnormalities. Decorin also antagonizes TGFβ in the cornea, a central regulatory cytokine in corneal wound healing. Following corneal injury, increased TGFβ levels induce keratocyte transdifferentiation to myofibroblasts and, subsequently, fibrosis (scarring) in the cornea. We recently reported that decorin overexpression in corneal fibroblasts blocks TGFβ-driven myofibroblast transformation and fibrosis development in the cornea in vitro suggesting that decorin gene therapy can be used for the treatment of corneal scarring in vivo.     

Alpha1-antitrypsin: Structure,function and molecular biology of the gene

Alpha₁-antitrypsin (AAT) deficiency is one of the commonest inherited disorders in white Caucasians. This association has provided major insights into the pathogenesis of chronic lung disease. The three dimensional structure of the protein and the structure of the gene have been determined. Some of the signals required for regulation of expression and tissue-specificity have been defined. Genetic manipulation of active site residues may provide a new generation of biological compounds with potential therapeutic applications.     

Unwrapping glial biology: Gcm target genes regulating glial development,diversification, and function

Glia are the most abundant cell type in the mammalian brain. They regulate neuronal development and function, CNS immune surveillance, and stem cell biology, yet we know surprisingly little about glia in any organism. Here we identify over 40 new Drosophila glial genes. We use glial cells missing (gcm) mutants and misexpression to verify they are Gcm regulated in vivo. Many genes show unique spatiotemporal responsiveness to Gcm in the CNS, and thus glial subtype diversification requires spatially or temporally restricted Gcm cofactors. These genes provide insights into glial biology: we show unc-5 (a repulsive netrin receptor) orients glial migrations and the draper gene mediates glial engulfment of apoptotic neurons and larval locomotion. Many identified Drosophila glial genes have homologs expressed in mammalian glia, revealing conserved molecular features of glial cells. 80% of these Drosophila glial genes have mammalian homologs; these are now excellent candidates for regulating human glial development, function, or disease.     

Structural biology of the chromodomain: form and function

The chromodomain motif is found among certain chromosomal proteins of all eukaryotes. The chromodomain fold - three beta strands packed against a C-terminal alpha helix - mediates protein-protein and/or protein-nucleic acid interactions. In some cases, the affinity of chromodomain binding is regulated by lysine methylation, which appears to target chromodomain proteins and associated complexes to specific sites in chromatin. In this review, our current knowledge of chromodomain structure and function is summarized.     

Metacognition and reasoning

This article considers the cognitive architecture of human meta-reasoning: that is, metacognition concerning one''s own reasoning and decision-making. The view we defend is that meta-reasoning is a cobbled-together skill comprising diverse self-management strategies acquired through individual and cultural learning. These approximate the monitoring-and-control functions of a postulated adaptive system for metacognition by recruiting mechanisms that were designed for quite other purposes.     

Metacognition and reasoning

This article considers the cognitive architecture of human meta-reasoning: that is, metacognition concerning one's own reasoning and decision-making. The view we defend is that meta-reasoning is a cobbled-together skill comprising diverse self-management strategies acquired through individual and cultural learning. These approximate the monitoring-and-control functions of a postulated adaptive system for metacognition by recruiting mechanisms that were designed for quite other purposes.     

Bone cell biology: the regulation of development, structure, and function in the skeleton

Bone cells compose a population of cells of heterogeneous origin but restricted function with respect to matrix formation, mineralization, and resorption. The local, mesenchymal origin of the cells which form the skeleton contrasts with their extraskeletal, hemopoietic relatives under which bone resorption takes place. However, the functions of these two diverse populations are remarkably related and interdependent. Bone cell regulation, presently in its infancy, is a complicated cascade involving a plethora of local and systemic factors, including some components of the skeletal matrices and other organ systems. Thus, any understanding of bone cell regulation is a key ingredient in understanding not only the development, maintenance, and repair of the skeleton but also the prevention and treatment of skeletal disorders.     

Electron microscopy in cell biology: integrating structure and function

Electron microscopy (EM) is at the highest-resolution limit of a spectrum of complementary morphological techniques. When combined with molecular detection methods, EM is the only technique with sufficient resolution to localize proteins to small membrane subdomains in the context of the cell. Recent procedural and technical developments have increasingly improved the power of EM as a cell-biological tool.     

Evolutionary systems biology: links between gene evolution and function

The recent accumulation of genome-wide data on various facets of gene expression, function and evolution stimulated the emergence of a new field, evolutionary systems biology. Many significant correlations were detected between variables that characterize the functioning of a gene, such as expression level, knockout effect, connectivity of genetic and protein-protein interaction networks, and variables that describe gene evolution, such as sequence evolution rate and propensity for gene loss. The first attempts on multidimensional analysis of genomic data yielded composite variables that describe the 'status' of a gene in the genomic community. However, it remains uncertain whether different functional variables affect gene evolution synergistically or there is a single, dominant factor. The number of translation events, linked to selection for translational robustness, was proposed as a candidate for such a major determinant of protein evolution. These developments show that, although the methodological basis of evolutionary systems biology is not yet fully solidified, this area of research is already starting to yield fundamental biological insights.     

Comparative genomics of pectinacetylesterases: Insight on function and biology

Pectin acetylation influences the gelling ability of this important plant polysaccharide for the food industry. Plant apoplastic pectinacetylesterases (PAEs) play a key role in regulating the degree of pectin acetylation and modifying their expression thus represents one way to engineer plant polysaccharides for food applications. Identifying the major active enzymes within the PAE gene family will aid in our understanding of this biological phenomena as well as provide the tools for direct trait manipulation. Using comparative genomics we propose that there is a minimal set of 4 distinct PAEs in plants. Possible functional diversification of the PAE family in the grasses is also explored with the identification of 3 groups of PAE genes specific to grasses.