This book illustrates the mechanisms and models linking the realms of molecular interactions and biological processes or functions. It addresses the need of mathematical modelers to learn how to formulate models of cellular processes and to understand how quantitative modeling can help sort through the complexities of molecular regulatory networks.
The purpose of DARPA's BioSPICE Program was to provide a new and useful set of software tools for modeling biochemical pathways and molecular regulatory networks within living cells. Using nonlinear ordinary differential equations to capture the temporal dynamics of molecular control systems, the modeling team built successful computer models of cell cycle regulation in a variety of organisms, including yeast cells, amphibian embryos, bacterial cells and human cells. These models accurately reproduce the physiological properties of normal cell division, and the bizarre properties of 200+ mutant cells that have been studied. The models predict phenotypes of novel mutants and unintuitive properties of the cell cycle machinery, which have been confirmed by the experimental teams on the project. The theorists used one- and two-parameter bifurcation diagrams to link gene-protein interaction networks to the physiological properties of cells. The Software Team developed tools for building mathematical models from a chemical reaction network, for associating experimental data with a model, for managing simulations of the data by the model, for evaluating how well the simulation fits the data, and for automatic parameter estimation. In addition a powerful tool for numerical bifurcation analysis was created. The major accomplishments of the Virginia Tech Consortium are (1) a set of downloadable, open-source computer programs that embody a Problem Solving Environment for dynamic modeling of macromolecular regulatory networks in living cells, and (2) an integrated set of models of cell cycle regulation in bacteria, yeasts, and metazoans that are accurate, predictive and informative. The models are described in the peer-reviewed literature and are freely available from web sites maintained at Virginia Tech. Some of the experimental tests carried out by the group are cited as classic examples of modern molecular systems biology.
Current Topics in Cellular Regulation, Volume 11 focuses on the biochemical mechanisms and key role of the liver in the homeostasis of blood glucose. This book begins with a discussion of glucokinase that is known to play a key role in glucose uptake by liver, followed by a broad overview of the mechanisms that control both glucose uptake by and release from the liver and enzymes involved in glycogen synthesis and breakdown. The classical enzyme models for allosteric regulatory mechanisms known as the biodegradative threonine deaminase are also elaborated. Other topics include the control of blood cholesterol levels, use of cultured mammalian cells, and studies of mutant cell lines. A model for protein turnover is likewise presented, including other mechanisms for the selective degradation of protein, selective uptake by lysosomes, and possible role of stabilizing factors. This publication concludes with an evaluation of complex regulatory mechanisms proposed for the regulation of photosynthetic carbon assimilation. This volume is recommended for biologists and researchers interested in advances in the general area of cellular regulation.
Tumors can be induced by a variety of physical and chemical carcinogens. The resulting tumor cells are usually abnormal in their morphology and behavior and transmit their abnormalities to their daughter tumor cells. Most theories of the pathogenesis of tumors suggest that carcinogens in some way cause alterations either of the genomes or of inheritable patterns of gene expression in normal cells, which then cause morphological and behavioral changes. This volume presents a collection of articles aimed at the question by what genetic or epigenetic mechanisms carcinogens can cause morphological abnormalities of tumor cells. It includes reviews of cellular targets of known carcinogens, and presents varying viewpoints of how morphological abnormalities and the actions of carcinogens might be related. The volume will be of interest to all those who are involved in cancer research or in the prevention, diagnosis or management of tumors in humans or animals.
In 1974 The National Institute on Aging established a somatic cell genetic resource for aging research at the Institute for Medical Research in Camden, New Jersey. Within this program there is a yearly workshop to promote theory and concept develop ment in aging research with the specific purpose of addressing the use of genetically marked cells for aging research and to stimulate interest in aging research by workers in a variety of disciplines. This monograph, The Regulation of Cell Proliferation and Differentiation, is the result of the first workshop held May 15-17, 1975. The concept of the workshop was to consider two main areas: First, a discussion of clinical syndromes expressing as a major manifestation excessive growth, deficient growth or failure to thrive; and second, to present work in cellular and molecular biology on a model system suitable for in vitro study of regulation of cell proliferation and diff2rentiation. The model selected for this was skeletal muscle. It has been widely accepted that normal somatic cells from individual human donors display limited replicative lifespans when cultivated in vitro (1,2). That such "clonal senescence" may be related to in vivo aging is suggested by observations relating the replicative lifespans of cultures to donor age (3-5,13) donor genotype (4-7) and donor's tissue of origin (5,8). A variety of theories have been developed to explain in vitro clonal senescence (9).
Over the last decade a huge amount of experimental data on biological systems has been generated by modern high-throughput methods. Aided by bioinformatics, the '-omics' (genomics, transcriptomics, proteomics, metabolomics and interactomics) have listed, quantif ed and analyzed molecular components and interactions on all levels of cellular regulation. However, a comprehensive framework, that does not only list, but links all those components, is still largely missing. The biology-based but highly interdisciplinary field of systems biology aims at such a holistic understanding of complex biological systems covering the length scales from molecules to whole organisms. Spanning the length scales, it has to integrate the data from very different fields and to bring together scientists from those fields. For linking experiments and theory, hypothesis-driven research is an indispensable concept, formulating a cycle of experiment, modeling, model predictions for new experiments and, fi nally, their experimental validation as the start of the new iteration. On the hierarchy of length scales certain unique entities can be identi fied. At the nanometer scale such functional entities are molecules and at the micrometer level these are the cells. Cells can be studied in vitro as independent individuals isolated from an organism, but their interplay and communication in vivo is crucial for tissue function. Control over such regulation mechanisms is therefore a main goal of medical research. The requirements for understanding cellular interplay also illustrate the interdisciplinarity of systems biology, because chemical, physical and biological knowledge is needed simultaneously. Following the notion of cells as the basic units of life, the focus of this thesis are mathematical multi-scale models of multi-cellular systems employing the concept of individual (or agent) based modeling (IBM). This concept accounts for the entity cell and their individuality in function and space. M.
Current biological research demands the extensive use of sophisticated mathematical methods and computer-aided analysis of experiments and data. This highly interdisciplinary volume focuses on structural, dynamical and functional aspects of cellular systems and presents corresponding experiments and mathematical models. The book may serve as an introduction for biologists, mathematicians and physicists to key questions in cellular systems which can be studied with mathematical models. Recent model approaches are presented with applications in cellular metabolism, intra- and intercellular signaling, cellular mechanics, network dynamics and pattern formation. In addition, applied issues such as tumor cell growth, dynamics of the immune system and biotechnology are included.
Provides excellent overviews highlighting the research results of leading scientists as well as young investigators in the field of cellular and molecular regulatory mechanisms. How each cell grows and develops at the appropriate time and place is thoroughly covered along with such issues as culturing the types of cells which represent excellent model systems for studies on tumor formation, proliferation and differentiation; cell cycle control; molecular control of DNA replication and repair and much more.
The scientific basis, inference assumptions, regulatory uses, and research needs in risk assessment are considered in this two-part volume. The first part, Use of Maximum Tolerated Dose in Animal Bioassays for Carcinogenicity, focuses on whether the maximum tolerated dose should continue to be used in carcinogenesis bioassays. The committee considers several options for modifying current bioassay procedures. The second part, Two-Stage Models of Carcinogenesis, stems from efforts to identify improved means of cancer risk assessment that have resulted in the development of a mathematical dose-response model based on a paradigm for the biologic phenomena thought to be associated with carcinogenesis.
