Prof. Dr. Hannelore Daniel Lehrstuhl für Ernährungsphysiologie Technische Universität München Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt Nutritional systems biology - Systembiologie der Ernährung Von der Grundlagenforschung zur personalisierten Ernährung The age of Nutrigenomics is upon us. Numerous initiatives in Europe and the US have launched new programs in molecular nutrition research. Nutrigenomics seeks to provide a molecular understanding for how diets and common dietary constituents affect mammalian metabolism and health by altering gene/protein expression on basis of an individual’s genetic makeup. Although Nutrigenomics represents in the first place just another “omic”, it clearly induces a conceptual shift in nutritional sciences. Nutritional Sciences is functional genomics “par excellence”. Like no other environmental factor do nutrients, nonnutrient components of foods or natural xenobiotics with a huge variability in dose and time hit a rather static genome. Every nutritional process relies on the interplay of a large number of proteins encoded by the respective mRNA molecules that are expressed in a certain cell organ or organism. Alterations of mRNA levels and in turn of the corresponding protein levels are critical parameters in controlling the flux of a nutrient or metabolite through a biochemical pathway. Nutrients and non-nutrient components of foods, diets and lifestyle can affect essentially every step in the flow of genetic information from gene expression to protein synthesis and protein degradation and thereby alter metabolic functions in the most complex ways. Although a huge body of information on mammalian genes, their chromosomal localization, their genomic structure and in part also on the functions of the encoded proteins has been gathered, we are far from understanding the orchestrated way of how they make metabolism to work. Genomic data are in the first place compositional in nature and contain limited information about the dynamic behaviour of integrated cellular processes. Nevertheless, recent technological advancements have made it possible to analyze the variability and dynamic changes in the genetic response of a cell or organisms by determining the expression level of individual or huge sets of mRNA molecules. Whereas genomics describes large scale DNA-sequencing that provides basic genetic information and insights into sequence heterogeneity (i.e. SNP´s: single nucleotide polymorphisms) in coding regions of genes as well as in control elements (i.e. promotors), transcriptomics – also called mRNA expression profiling - assesses in a biological sample the mRNA-levels of up to several thousand open reading frames simultaneously and this is mainly done by DNA-hybridization arrays and/or by quantitative PCR-techniques Proteomics allows the proteome - as the protein complement of the genome that is expressed in a cell or an organ - to be identified and changes in protein expression patterns and levels to be determined simultaneously. Moreover, for individual proteins posttranslational modifications that are crucial for functions or even amino acid substitutions (polymorphisms) can here be detected. More recently, high-throughput applications of metabolomics (or metabonomics) based on the combination of gas or liquid chromatography separations with mass spectrometry or NMR techniques for detection of solutes allow hundreds of nutrients/metabolites to be detected simultaneously. These functional genomics tools in combination allow for the first time to assess all phenotypic changes in a biological system to alterations in its nutritional environment. Conceptually, functional genomics is either based on gene-driven or on phenotypedriven approaches. The gene-driven approaches use genomic information for identifying, cloning, expressing and characterizing genes at the molecular level. Phenotype-driven approaches characterize phenotypes from random mutation screens or naturally occurring variants to identify and clone the gene(s) responsible for the particular phenotype, without knowledge of the underlying molecular mechanisms. Of course, the two strategies are highly complementary at virtually all levels of analysis and lead collectively to the correlation of genotypes and phenotypes. As far as nature has not provided inborn errors of metabolism that demonstrate the phenotypical consequences of individual gene/protein malfunctions, the role of single genes or groups of genes in the make up of metabolism can be analyzed by gene inactivation (“knock-out”) or selective expression “knock-in” and overexpression models employing experimental animals from fruit flies (Drosophila melanogaster) to nematodes (Caenorhabditis elegans) to mice and rats or human cell lines. These approaches have already produced a large number of animal lines missing one or several genes or overexpressing others and have extended our knowledge on gene/protein functions substantially. These approaches are embedded into a rapidly evolving world of visual biology that allows the visualisation of the dynamics of all the processes underlying biological adaptations (i.e. automated image analysis of real-time laser confocal microscopic observations of GFP fusions, BAC transgenics and others). Moreover, nano-technology will provide miniaturized systems for on-line recording of metabolic and/or physiological processes in complex biological systems in real-time. In this respect, nutritional processes may become visible and the numerous “black-boxes” in human metabolism may see the first light. Nutritional systems biology rephrases the conceptual shift in nutritional sciences as a paradigm of the biology of genome-environment interactions. Nutritional systems biology employs the “omics” and uses model systems for the most comprehensive description of the interplay of genes and nutritional factors that make up metabolism in health and disease. That nutritional systems biology in its application may lead to a “new age of human nutrition” with genome-based personalized dietary recommendations or even personalized foods can easily be envisioned. However, we should not forget that eating foods is still more than applied nutritional systems biology.