When the optimal is not the best: parameter estimation in complex biological models

Background: The vast computational resources that became available during the past decade enabled the development and simulation of increasingly complex mathematical models of cancer growth. These models typically involve many free parameters whose determination is a substantial obstacle to model development. Direct measurement of biochemical parameters in vivo is often difficult and sometimes impracticable, while fitting them under data-poor conditions may result in biologically implausible values. Results: We discuss different methodological approaches to estimate parameters in complex biological models. We make use of the high computational power of the Blue Gene technology to perform an extensive study of the parameter space in a model of avascular tumor growth. We explicitly show that the landscape of the cost function used to optimize the model to the data has a very rugged surface in parameter space. This cost function has many local minima with unrealistic solutions, including the global minimum corresponding to the best fit. Conclusions: The case studied in this paper shows one example in which model parameters that optimally fit the data are not necessarily the best ones from a biological point of view. To avoid force-fitting a model to a dataset, we propose that the best model parameters should be found by choosing, among suboptimal parameters, those that match criteria other than the ones used to fit the model. We also conclude that the model, data and optimization approach form a new complex system, and point to the need of a theory that addresses this problem more generally

Systems Biology by the Rules: Hybrid Intelligent Systems for Pathway Modeling and Discovery

Background: Expert knowledge in journal articles is an important source of data for reconstructing biological pathways and creating new hypotheses. An important need for medical research is to integrate this data with high throughput sources to build useful models that span several scales. Researchers traditionally use mental models of pathways to integrate information and development new hypotheses. Unfortunately, the amount of information is often overwhelming and these are inadequate for predicting the dynamic response of complex pathways. Hierarchical computational models that allow exploration of semi-quantitative dynamics are useful systems biology tools for theoreticians, experimentalists and clinicians and may provide a means for cross-communication. Results: A novel approach for biological pathway modeling based on hybrid intelligent systems or soft computing technologies is presented here. Intelligent hybrid systems, which refers to several related computing methods such as fuzzy logic, neural nets, genetic algorithms, and statistical analysis, has become ubiquitous in engineering applications for complex control system modeling and design. Biological pathways may be considered to be complex control systems, which medicine tries to manipulate to achieve desired results. Thus, hybrid intelligent systems may provide a useful tool for modeling biological system dynamics and computational exploration of new drug targets. A new modeling approach based on these methods is presented in the context of hedgehog regulation of the cell cycle in granule cells. Code and input files can be found at the Bionet website: www.chip.ord/~wbosl/Software/Bionet. Conclusion: This paper presents the algorithmic methods needed for modeling complicated biochemical dynamics using rule-based models to represent expert knowledge in the context of cell cycle regulation and tumor growth. A notable feature of this modeling approach is that it allows biologists to build complex models from their knowledge base without the need to translate that knowledge into mathematical form. Dynamics on several levels, from molecular pathways to tissue growth, are seamlessly integrated. A number of common network motifs are examined and used to build a model of hedgehog regulation of the cell cycle in cerebellar neurons, which is believed to play a key role in the etiology of medulloblastoma, a devastating childhood brain cancer

The Potential and Challenges of Nanopore Sequencing

A nanopore-based device provides single-molecule detection and analytical capabilities that are achieved by electrophoretically driving molecules in solution through a nano-scale pore. The nanopore provides a highly confined space within which single nucleic acid polymers can be analyzed at high throughput by one of a variety of means, and the perfect processivity that can be enforced in a narrow pore ensures that the native order of the nucleobases in a polynucleotide is reflected in the sequence of signals that is detected. Kilobase length polymers (single-stranded genomic DNA or RNA) or small molecules (e.g., nucleosides) can be identified and characterized without amplification or labeling, a unique analytical capability that makes inexpensive, rapid DNA sequencing a possibility. Further research and development to overcome current challenges to nanopore identification of each successive nucleotide in a DNA strand offers the prospect of ‘third generation’ instruments that will sequence a diploid mammalian genome for ~$1,000 in ~24 h.Molecular and Cellular BiologyPhysic

Optimization in computational systems biology

Optimization aims to make a system or design as effective or functional as possible. Mathematical optimization methods are widely used in engineering, economics and science. This commentary is focused on applications of mathematical optimization in computational systems biology. Examples are given where optimization methods are used for topics ranging from model building and optimal experimental design to metabolic engineering and synthetic biology. Finally, several perspectives for future research are outlined

137Cs, 40K, 238Pu, 239+240Pu and 90Sr in biological samples from King George Island (Southern Shetlands) in Antarctica

There are few data reported on radionuclide contamination in Antarctica. The aim of this paper is to report 137Cs, 90Sr and 238,239+240Pu and 40K activity concentrations measured in biological samples collected from King George Island (Southern Shetlands, Antarctica), mostly during 2001–2002. The samples included: bones, eggshells and feathers of penguin Pygoscelis papua, bones and feathers of petrel Daption capense, bones and fur of seal Mirounga leonina, algae Himantothallus grandifolius, Desmarestia anceps and Cystosphaera jacquinotii, fish Notothenia corriceps, sea invertebrates Amphipoda, shells of limpet Nacella concina, lichen Usnea aurantiaco-atra, vascular plants Deschampsia antarctica and Colobanthus quitensis, fungi Omphalina pyxidata, moss Sanionia uncinata and soil. The results show a large variation in some activity concentrations. Samples from the marine environment had lower contamination levels than those from terrestrial ecosystems. The highest activity concentrations for all radionuclides were found in lichen and, to a lesser extent, in mosses, probably because lichens take up atmospheric pollutants and retain them. The only significant correlation (except for that expected between 238Pu and 239+240Pu) was noted for moss and lichen samples between plutonium and 90Sr. A tendency to a slow decrease with time seems to be occurring. Analyses of the activity ratios show varying fractionation between various radionuclides in different organisms. Algae were relatively more highly contaminated with plutonium and radiostrontium, and depleted with radiocesium. Feathers had the lowest plutonium concentrations. Radiostrontium and, to a lesser extent, Pu accumulated in bones. The present low intensity of fallout in Antarctic has a lower 238Pu/239+240Pu activity ratio than that expected for global fallout

Effectiveness of predator satiation in masting oaks is negatively affected by conspecific density

La variación en la disponibilidad de las semillas da forma a las comunidades de plantas, y se ve fuertemente afectada por la depredación de las semillas. En algunas especies de plantas, la variación temporal en la producción de semillas es especialmente alta y está sincronizada en grandes áreas, lo que se denomina "siembra en mástil". Una ventaja selectiva de este fenómeno es la saciedad de los depredadores, que supone que la siembra en mástil ayuda a las plantas a escapar de la depredación de las semillas mediante la inanición de los depredadores en los años de escasez y la saciedad en los años de mástil. Sin embargo, aunque se puede predecir que la depredación de la semilla tiene un fuerte componente espacial y depende de las densidades de las plantas, apenas se ha investigado si la eficacia de la saciedad de los depredadores en las plantas de mastelero cambia según el efecto Janzen-Connell. Estudiamos, durante un período de 8 años, la producción de semillas, los patrones espacio-temporales de depredación de semillas de gorgojos y la abundancia de gorgojos adultos en una población de encinas (Quercus ilex) que consiste en árboles intercalados en parches que cubren un continuo de densidad conespecífica. Los robles aislados sacian eficazmente a los depredadores, pero esto es superado por el aumento de la densidad de plantas conespecíficas. La falta de saciedad de los depredadores en los árboles que crecen en parches densos fue causada por la redistribución de los insectos entre las plantas que probablemente los atenuó contra la escasez de alimentos en los años de escasez, y cambió el tipo de respuesta funcional del gorgojo del tipo II en los árboles aislados al tipo III en los árboles que crecían en parches densos. Este estudio proporciona la primera evaluación empírica de la noción de que el apareamiento y la saciedad del depredador deberían ser más importantes en las poblaciones que empiezan a dominar sus comunidades, y es coherente con la observación de que el apareamiento es menos frecuente y menos intenso en bosques diversos.Variation in seed availability shapes plant communities, and is strongly affected by seed predation. In some plant species, temporal variation in seed production is especially high and synchronized over large areas, which is called ‘mast seeding’. One selective advantage of this phenomenon is predator satiation which posits that masting helps plants escape seed predation through starvation of predators in lean years, and satiation in mast years. However, even though seed predation can be predicted to have a strong spatial component and depend on plant densities, whether the effectiveness of predator satiation in masting plants changes according to the Janzen-Connell effect has been barely investigated. We studied, over an 8-year period, the seed production, the spatiotemporal patters of weevil seed predation, and the abundance of adult weevils in a holm oak (Quercus ilex) population that consists of trees interspersed at patches covering a continuum of conspecific density. Isolated oaks effectively satiate predators, but this is trumped by increasing conspecific plant density. Lack of predator satiation in trees growing in dense patches was caused by re-distribution of insects among plants that likely attenuated them against food shortage in lean years, and changed the type of weevil functional response from type II in isolated trees to type III in trees growing in dense patches. This study provides the first empirical evaluation of the notion that masting and predator satiation should be more important in populations that start to dominate their communities, and is consistent with the observation that masting is less frequent and less intense in diverse forests.• National Science Foundation (Polonia). Becas Preludio 2015/17/N/ NZ8/01565, y Etiuda no. 2015/16/T/NZ8/00018, para Michał Bogdziewicz • Foundation for Polish Science Start Scholarship. Ayuda para para Michał Bogdziewicz • Gobierno de Extremadura. Programa de Atracción de Talento Investigador. Ayuda TA13032, para Raúl Bonal Andrés • Junta de Comunidades de Castilla-La Mancha/Fondo Social Europeo. Proyectos PII1C09-0256-9052 y PPII-2014-01-P • Ministerio de Economía y Competitividad de España y la Unión Europea Fondo de Desarrollo Regional. Proyecto AGL2014-54739-R (I+D+i) • Generalitat de Catalunya. Proyecto BEEMED (SGR913)peerReviewe