The Human Physiome: how standards, software and innovative service infrastructures are providing the building blocks to make it achievable.

Reconstructing and understanding the Human Physiome virtually is a complex mathematical problem, and a highly demanding computational challenge. Mathematical models spanning from the molecular level through to whole populations of individuals must be integrated, then personalized. This requires interoperability with multiple disparate and geographically separated data sources, and myriad computational software tools. Extracting and producing knowledge from such sources, even when the databases and software are readily available, is a challenging task. Despite the difficulties, researchers must frequently perform these tasks so that available knowledge can be continually integrated into the common framework required to realize the Human Physiome. Software and infrastructures that support the communities that generate these, together with their underlying standards to format, describe and interlink the corresponding data and computer models, are pivotal to the Human Physiome being realized. They provide the foundations for integrating, exchanging and re-using data and models efficiently, and correctly, while also supporting the dissemination of growing knowledge in these forms. In this paper, we explore the standards, software tooling, repositories and infrastructures that support this work, and detail what makes them vital to realizing the Human Physiome.

A blessing in disguise: international standards for the biotechnology industry.

Regardless of the industry, standards are ubiquitous in our everyday lives and essential to the interconnection of people, businesses, and countries. Standardization seeks to consensually establish the best technical application forany given process in order to ensure consistent quality, minimization of risks,and interoperability. As a life scientist, I was surprised to see my natural reservation towards draconic documentation change. Life science standards aref undamentally important for the smooth transaction of data and repetition of experiments, and may help small and medium enterprises gain the international attention they deserve and require, in order to get their innovations noticed.

Analysis of metabolic flux phenotypes for two Arabidopsis mutants with severe impairment in seed storage lipid synthesis.

Major storage reserves of Arabidopsis (Arabidopsis thaliana) seeds are triacylglycerols (seed oils) and proteins. Seed oil content is severely reduced for the regulatory mutant wrinkled1 (wri1-1; At3g54320) and for a double mutant in two isoforms of plastidic pyruvate kinase (pkpbeta(1)pkpalpha; At5g52920 and At3g22960). Both already biochemically well-characterized mutants were now studied by (13)C metabolic flux analysis of cultured developing embryos based on comparison with their respective genetic wild-type backgrounds. For both mutations, in seeds as well as in cultured embryos, the oil fraction was strongly reduced while the fractions of proteins and free metabolites increased. Flux analysis in cultured embryos revealed changes in nutrient uptakes and fluxes into biomass as well as an increase in tricarboxylic acid cycle activity for both mutations. While in both wild types plastidic pyruvate kinase (PK(p)) provides most of the pyruvate for plastidic fatty acid synthesis, the flux through PK(p) is reduced in pkpbeta(1)pkpalpha by 43% of the wild-type value. In wri1-1, PK(p) flux is even more reduced (by 82%), although the genes PKpbeta(1) and PKpalpha are still expressed. Along a common paradigm of metabolic control theory, it is hypothesized that a large reduction in PK(p) enzyme activity in pkpbeta(1)pkpalpha has less effect on PK(p) flux than multiple smaller reductions in glycolytic enzymes in wri1-1. In addition, only in the wri1-1 mutant is the large reduction in PK(p) flux compensated in part by an increased import of cytosolic pyruvate and by plastidic malic enzyme. No such limited compensatory bypass could be observed in pkpbeta(1)pkpalpha.

Parallel determination of enzyme activities and in vivo fluxes in Brassica napus embryos grown on organic or inorganic nitrogen source.

After the completion of the genomic sequencing of model organisms, numerous post-genomic studies, integrating transcriptome and metabolome data, are aimed at developing a more complete understanding of cell physiology. Here, we measure in vivo metabolic fluxes by steady state labeling, and in parallel, the activity of enzymes in central metabolism in cultured developing embryos of Brassica napus. Embryos were grown on either the amino acids glutamine and alanine as an organic nitrogen source, or on ammonium nitrate as an inorganic nitrogen source. The type of nitrogen made available to developing embryos caused substantial differences in fluxes associated with the tricarboxylic acid cycle, including flux reversion. The changes observed in enzyme activity were not consistent with our estimates of metabolic flux. Furthermore, most extractable enzyme activities are in large surplus relative to the requirements for the observed in vivo fluxes. The results demonstrate that in this model system the metabolic response of central metabolism to changes in environmental conditions can be achieved largely without regulatory reprogramming of the enzyme machinery.