Computational methods in synthetic biology

We discuss how a theoretical synthetic biology research programme may liberate empiricism in biological sciences beyond the unaided human brain. Because synthetic biological systems are relatively small and largely independent of evolutionary contexts, they can be represented with mathematical models strongly founded on first principles of molecular biology and laws of statistical thermodynamics. A universal mathematical formalism for describing synthetic constructs may then be plausibly used to explain in unambiguous, quantitative terms how biological phenotypic complexity emerges as a result of well-defined biomolecular interactions. SynBioSS, a publicly available software package, is described that implements this mathematical formalism.     

Cellular automaton simulation of tumour growth -- equivocal relationships between simulation parameters and morphologic pattern features.

OBJECTIVE: To develop an interpretation procedure which estimates simulation parameters (tumour cell motility, tumour cell adhesion, autocrine and paracrine growth control, stroma destruction) of simulated patterns solely based on morphometric features of the morphologic pattern. METHODS: A cellular automaton computer simulation program was developed which produces morphologic patterns by growth of a seed of tumour cells. At the beginning of each simulation run certain simulation parameters are assigned to the tumour cells. After the run has been completed, the resulting pattern is evaluated by a set of morphometric features. Simulation parameters and resulting morphometric features of 27,800 simulations were stored in a database and were used for the evaluation of potential relationships. RESULTS: Correlation analysis showed highly significant correlations between morphometric features on the one hand and the preset simulation parameters (tumour cell motility, tumour cell adhesion, autocrine and paracrine growth control, stroma destruction) on the other. Correlation coefficients, however, varied from 0.72 to 0.99. When only one simulation parameter varied while all others were kept constant, morphometric features yielded a highly reliable estimate of the particular simulation parameter. When variability was extended to 4 simulation parameters, morphometric features were less effective in estimating the setting of the parameters. Though in all patterns tested several possible simulation parameter constellations could be ruled out, morphometric features were usually compatible with more than one set of simulation parameters thus preventing a straightforward interpretation. CONCLUSIONS: Though simulation parameters significantly and reproducibly influence the resulting morphologic pattern as characterized by morphometric features, estimates of the simulation parameters based on morphometric features yield equivocal results.     

The role of simulation in biomathematical modeling

This paper is a general introduction to the field of biomathematical modeling. Biomathematical modeling is divided into three parts: the derivation of models, the fitting of models to data, and the simulation of data from models. This paper focuses on the simulation of data from models. The uses of simulation, the potential users of simulation, and simulation software are described.     

情景模拟与传统教学法在手术室护理教学中的对比研究

目的:探讨情景模拟与传统教学方法在手术室护理教学中的应用效果。方法:抽选我科实习护生240人,分别采用情景模拟教学(120人)和传统教学(120人)。传统教学以讲授为主,不予术前模拟练习。结果:比较无菌操作、动手、手术配合、紧急处理、沟通交流、理论考核和综合考核等指标,情景教学法优于传统教学法,组间有明显的统计差异(P<0.05),满意度调查和教师测评也认为情景教学法更优。结论:情景模拟教学使护生在演练中获得更多理论知识和实践体验,优于传统教学方法。     

ElePhant: an anatomic-electronic simulation system for the evaluation of computer assisted interventions and surgical education]

BACKGROUND: Suitable simulation systems providing realistic conditions are required for preclinical evaluation of computer assisted interventions and surgical training. Techniques are necessary for an objective detection of injuries to the structures at risk. The aim of this study was the technical realization of a simulation system for the ENT intervention, mastoidectomy.MATERIALS AND METHODS: The basis of the simulation system was a CT scan of a cadaver skull. Using 3D printing, an anatomical phantom with realistic bone-like properties was created. Electronic detection systems were integrated into the structures at risk. A study with 16 ENT surgeons was conducted to prove the system's suitability for surgical training.RESULTS: The creation of simulation systems for the objective evaluation of surgical intervention qualities is feasible. A modular structure enables economic and simple replacement of the simulation area. The modules are cost effective and reproducible with high accuracy. The present study shows that the simulation system can be applied in surgical education and evaluation as an alternative to cadavers.CONCLUSION: Objective evaluation of injured structures at risk can be realized in real time. The simulation system permits preclinical evaluation studies of computer assisted instruments and surgical education. Reproducibility of the results makes multi-center studies possible.     

OBIYagns: a grid-based biochemical simulator with a parameter estimator

SUMMARY: OBIYagns (yet another gene network simulator) is a biochemical system simulator that comprises a multiple-user Web-based graphical interface, an ordinary differential equation solver and a parameter estimators distributed over an open bioinformatics grid (OBIGrid). This grid-based biochemical simulation system can achieve high performance and provide a secure simulation environment for estimating kinetic parameters in an acceptable time period. OBIYagns can be applied to larger system biology-oriented simulation projects. AVAILABILITY: OBIYagns example models, methods and user guide are available at https://access.obigrid.org/yagns/ SUPPLEMENTARY INFORMATION: Please refer to Bioinformatics online.     

Simulation studies on bacteriorhodopsin α-helices

Bacteriorhodopsin (BR) is a membrane protein which pumps protons through the plasma membrane. Transmembrane BR helical segments are subjected to simulation studies in order to investigate the effect of bilayer environment in various simulation conditions. A bilayer potential is introduced to the system to mimic the lipid membrane. The structures from the simulations are compared with the experimentally determined structures in terms of geometrical properties. Electrostatic contribution to the helix packing is also investigated. The simulation results show that the packing geometry of the transmembrane helices is highly affected by the bilayer potential. The results obtained from the simulations may be used for further simulation studies and analysis in investigating transmembrane helix packing. Received: 5 July 1999 / Revised version: 5 October 1999 / Accepted: 15 October 1999     

Simulation tools for biochemical networks: evaluation of performance and usability

MOTIVATION: Simulation of dynamic biochemical systems is receiving considerable attention due to increasing availability of experimental data of complex cellular functions. Numerous simulation tools have been developed for numerical simulation of the behavior of a system described in mathematical form. However, there exist only a few evaluation studies of these tools. Knowledge of the properties and capabilities of the simulation tools would help bioscientists in building models based on experimental data. RESULTS: We examine selected simulation tools that are intended for the simulation of biochemical systems. We choose four of them for more detailed study and perform time series simulations using a specific pathway describing the concentration of the active form of protein kinase C. We conclude that the simulation results are convergent between the chosen simulation tools. However, the tools differ in their usability, support for data transfer to other programs and support for automatic parameter estimation. From the experimentalists' point of view, all these are properties that need to be emphasized in the future.     

COPASI--a COmplex PAthway SImulator

MOTIVATION: Simulation and modeling is becoming a standard approach to understand complex biochemical processes. Therefore, there is a big need for software tools that allow access to diverse simulation and modeling methods as well as support for the usage of these methods. RESULTS: Here, we present COPASI, a platform-independent and user-friendly biochemical simulator that offers several unique features. We discuss numerical issues with these features; in particular, the criteria to switch between stochastic and deterministic simulation methods, hybrid deterministic-stochastic methods, and the importance of random number generator numerical resolution in stochastic simulation. AVAILABILITY: The complete software is available in binary (executable) for MS Windows, OS X, Linux (Intel) and Sun Solaris (SPARC), as well as the full source code under an open source license from http://www.copasi.org.     

Modular modeling of cellular systems with ProMoT/Diva

MOTIVATION: Need for software to setup and analyze complex mathematical models for cellular systems in a modular way, that also integrates the experimental environment of the cells. RESULTS: A computer framework is described which allows the building of modularly structured models using an abstract, modular and general modeling methodology. With this methodology, reusable modeling entities are introduced which lead to the development of a modeling library within the modeling tool ProMot. The simulation environment Diva is used for numerical analysis and parameter identification of the models. The simulation environment provides a number of tools and algorithms to simulate and analyze complex biochemical networks. The described tools are the first steps towards an integrated computer-based modeling, simulation and visualization environment Availability: Available on request to the authors. The software itself is free for scientific purposes but requires commercial libraries. SUPPLEMENTARY INFORMATION: http://www.mpi-magdeburg.mpg.de/projects/promot     

Hybrid simulation of cellular behavior

MOTIVATION: To be valuable to biological or biomedical research, in silico methods must be scaled to complex pathways and large numbers of interacting molecular species. The correct method for performing such simulations, discrete event simulation by Monte Carlo generation, is computationally costly for large complex systems. Approximation of molecular behavior by continuous models fails to capture stochastic behavior that is essential to many biological phenomena. RESULTS: We present a novel approach to building hybrid simulations in which some processes are simulated discretely, while other processes are handled in a continuous simulation by differential equations. This approach preserves the stochastic behavior of cellular pathways, yet enables scaling to large populations of molecules. We present an algorithm for synchronizing data in a hybrid simulation and discuss the trade-offs in such simulation. We have implemented the hybrid simulation algorithm and have validated it by simulating the statistical behavior of the well-known lambda phage switch. Hybrid simulation provides a new method for exploring the sources and nature of stochastic behavior in cells.     

Practical aspects of Monte Carlo simulation of charged particle transport: Mixed algorithms and variance reduction techniques

This paper is concerned with the practical implementation of Monte Carlo simulation methods for charged particle transport. The emphasis is on light particles (electrons and positrons) because of the larger scattering and energy straggling effects. Differential cross sections (DCS) for the various interaction mechanisms are described. As the average number of interactions along the particle track increases with the initial energy, detailed simulation becomes unfeasible at high energies. We can then rely on mixed simulation algorithms: hard events (i.e. individual interactions with angular deflection or energy loss larger than given cutoff values) are sampled from the DCS whereas soft events are simulated by means of a multiple scattering approach. Too frequently, the statistical uncertainty of analogue simulation (i.e. strict simulation of the physical interaction process) is found to be so large that results are meaningless. This problem can be partially solved by applying simple variance reduction techniques. Received: 10 September 1998 / Accepted in revised form: 10 November 1998     

Genetic Network Analyzer: qualitative simulation of genetic regulatory networks

MOTIVATION: The study of genetic regulatory networks has received a major impetus from the recent development of experimental techniques allowing the measurement of patterns of gene expression in a massively parallel way. This experimental progress calls for the development of appropriate computer tools for the modeling and simulation of gene regulation processes. RESULTS: We present Genetic Network Analyzer (GNA), a computer tool for the modeling and simulation of genetic regulatory networks. The tool is based on a qualitative simulation method that employs coarse-grained models of regulatory networks. The use of GNA is illustrated by a case study of the network of genes and interactions regulating the initiation of sporulation in Bacillus subtilis. AVAILABILITY: GNA and the model of the sporulation network are available at http://www-helix.inrialpes.fr/gna.     

MARLIN, software to create, run, and analyse spatially realistic simulations

MARLIN is a software to create, run, analyse, and visualize spatially explicit population genetic simulations. It provides an intuitive user interface with which the geographical layout of a metapopulation can be drawn by hand or loaded from a map. Furthermore, the interface allows easy selection of the many different simulation settings. MARLIN then uses the program QuantiNemo to run the simulation in the background. When simulations are finished, MARLIN directly analyses and plots the results, thereby greatly simplifying the simulation workflow. This combination of simulation and analysis makes MARLIN ideal for teaching and for scientists who are interested in doing simulations without having to learn command-line operations. MARLIN is available for computers running Mac OS X and can be downloaded from: http://www.patrickmeirmans.com/software.     

A general computational model of mitochondrial metabolism in a whole organelle scale

SUMMARY: A computational tool for mitochondrial systems biology has been developed as a simulation model of E-Cell2, a publicly available simulation system. The general model consists of 58 enzymatic reactions and 117 metabolites, representing the respiratory chain, the TCA cycle, the fatty acid beta-oxidation and the inner-membrane transport system. It is based on previously published enzyme kinetics studies in the literature; we have successfully integrated and packaged them into a single large model. The model can be easily extended and modified so that mitochondrial biologists/physiologists can integrate their own models and evaluate them in the context of the whole organelle metabolism. AVAILABILITY: The mitochondrial model is bundled up with E-Cell2 simulation system, which can be downloaded from http://www.e-cell.org. CD-ROMs are also available and are distributed at major conferences. SUPPLEMENTARY INFORMATION: All the kinetic data are available via http://www.e-cell.org     

Evaluation of Tools for Modeling Manufacturing Systems Design with Multiple Levels of Detail

This paper presents an investigation of simulation packages regarding their ability to model business processes related to manufacturing systems. Three simulation packages are investigated: VS7, SIMAN/CINEMA IV, and SIMFACTORY II.5. These packages are evaluated with regard to their capabily of modeling problems related to the manufacturing systems design (MSD) framework, which involves different levels of detail: the conceptual modeling level and the detailed design level. The investigation is based on a case study related to manufacturing systems. The main objective of this investigation is to examine the manufacturing simulation packages and their ability to offer variable detail modeling. Research findings suggest that no simulation environment offers sufficiently flexible facilities for the variable detailed modeling of manufacturing systems design. The paper proposes a method for systems entity classification to increase the levels of detail in an effective manner without duplication of data collection and model building efforts.     

Drug transport in artery walls: a sequential porohyperelastic-transport approach

A simulation framework for drug-eluting stents (DES) is presented that simulates the two distinct operational phases of a DES: stent deployment is simulated first, a mechanical porohyperelastic/elasto-plastic/contact analysis. This analysis calculates the interstitial fluid velocity as the result of interstitial fluid pressure gradients and mechanical deformations of the vessel wall. The deformed geometry, interstitial fluid velocity field and porosity field are extracted and used as input for the drug release simulation: a reaction-advection-diffusion (RAD) transport analysis calculating the spatial and temporal drug distribution. The advantage of this approach is that the deformed geometry and interstitial fluid velocity field are not assumed a priori, but are actually calculated using a stent deployment simulation. The framework is demonstrated simulating a DES in an idealised, 3D vessel. Varying mechanical and transport properties based on literature data are assigned to each of the three layers in the wall. The results of the drug release simulation for a period of one week show that the drug distributes longitudinally but will remain in the proximity of the stented area.     

Computer simulation is an undervalued tool for genetic analysis: a historical view and presentation of SHIMSHON--a Web-based genetic simulation package

Computer simulation methods are under-used tools in genetic analysis because simulation approaches have been portrayed as inferior to analytic methods. Even when simulation is used, its advantages are not fully exploited. Here, I present SHIMSHON, our package of genetic simulation programs that have been developed, tested, used for research, and used to generated data for Genetic Analysis Workshops (GAW). These simulation programs, now web-accessible, can be used by anyone to answer questions about designing and analyzing genetic disease studies for locus identification. This work has three foci: (1) the historical context of SHIMSHON's development, suggesting why simulation has not been more widely used so far. (2) Advantages of simulation: computer simulation helps us to understand how genetic analysis methods work. It has advantages for understanding disease inheritance and methods for gene searches. Furthermore, simulation methods can be used to answer fundamental questions that either cannot be answered by analytical approaches or cannot even be defined until the problems are identified and studied, using simulation. (3) I argue that, because simulation was not accepted, there was a failure to grasp the meaning of some simulation-based studies of linkage. This may have contributed to perceived weaknesses in linkage analysis; weaknesses that did not, in fact, exist.     

Serial NetEvolve: a flexible utility for generating serially-sampled sequences along a tree or recombinant network

SUMMARY: Serial NetEvolve is a flexible simulation program that generates DNA sequences evolved along a tree or recombinant network. It offers a user-friendly Windows graphical interface and a Windows or Linux simulator with a diverse selection of parameters to control the evolutionary model. Serial NetEvolve is a modification of the Treevolve program with the following additional features: simulation of serially-sampled data, the choice of either a clock-like or a variable rate model of sequence evolution, sampling from the internal nodes and the output of the randomly generated tree or network in our newly proposed NeTwick format. AVAILABILITY: From website http://biorg.cis.fiu.edu/SNE Contacts: giri@cis.fiu.edu SUPPLEMENTARY INFORMATION: Manual and examples available from http://biorg.cis.fiu.edu/SNE.