Trends in Biotechnology
ReviewUnderstanding human metabolic physiology: a genome-to-systems approach
Section snippets
The human genome: a system defined
The human genome sequence is generally touted as a blueprint for the physiological functions of the human body. However, the translation from the annotated sequence to cellular physiology remains elusive. The annotated sequence contains a wealth of information about the gene products (proteins) and the biochemical processes that they mediate. This information essentially provides a ‘parts’ list of biological components that exist in human cells, but it is the interplay among these components
Metabolism: foundational to human health and disease
Metabolism is widely known to play an important part in human physiology. Its function is important for understanding disease states and progression 5, 6, aging and nutrition 7, 8, 9, 10 and improving the performance of individuals such as athletes, astronauts and soldiers 11, 12, 13. In particular, metabolism has been known to be involved in many major disease states, such as diabetes, obesity and cardiovascular disease 14, 15. Cancers display highly abnormal metabolic phenotypes, and
Collecting metabolic knowledge: a reaction network point-of-view
The annotated human genome, along with literature (or ‘bibliome’) data, defines the known biological components present in the human body. Because this information exists in many different domains, there is a need to compile the data in a structured format that catalogs genes, their associated protein products and related biological functions. A component-by-component, or ‘bottom-up’, approach to network reconstruction results in a biochemically, genetically and genomically (BiGG) structured
Community approach to reconstructing the human metabolic network
Reconstruction efforts by multiple research groups have resulted in human metabolic network representations that vary in content owing to differences in reconstruction approaches and literature interpretation 2, 3, 4. Thus, the development of a human network reconstruction whose content is agreed upon necessitates a collective community effort to formalize such a network. The notion of a two-dimensional annotation jamboree for a consensus network reconstruction was first articulated at a
Advancing systems-level analysis of human metabolism
Reconstruction of genome-scale human metabolic networks has initiated development towards studying human physiology in silico at a systems level. Four crucial steps to this process have been described [1], with the biological representation becoming more focused and detailed at each level and thus culminating in a systems framework for analyzing and modeling human metabolic phenotypes (Figure 2).
Two general approaches used to study metabolic network systems are (i) topology-based analysis and
Towards comprehensive human modeling
Human metabolic physiology arises collectively from different levels of biological organization, as illustrated in Figure 3, and thus requires a systems perspective to understand it as a whole. Whole-body metabolic functions are mediated by the interactions and exchange among various compartments (i.e. among different cell or tissue types); thus, a multi-compartment human model can provide a better depiction of physiologically relevant metabolic states. Efforts have been initiated towards
Concluding remarks
We have reached a mature stage in the development of metabolic systems biology in microbes, and the extension of this approach to human metabolism has now been initiated. A key component is the bottom-up reconstruction of genome-scale metabolic networks based on our current knowledge, a process that requires detailed curation and incorporation of genomic and biochemical information into a mathematically structured network. Recent network applications have shown that it is possible to analyze
Acknowledgements
We thank Neema Jamshidi and Ines Thiele for their valuable comments and suggestions during preparation of the manuscript.
Glossary
- Bibliome
- the comprehensive compilation of published literature text and associated information.
- Genome-scale model
- a computational model converted from a genome-scale network reconstruction by defining and implementing mathematical parameters to calculate phenotypic behavior of the reconstructed organism.
- Genome-scale network reconstruction
- a genome annotation-based, manually-curated assembly of biochemical transformations that describe specific biological processes (e.g. metabolism, transcriptional
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