AIM in Alternative Medicine

Given the functional interdependencies between the molecular components in a human cell, a disease is rarely a consequence of an abnormality in a single gene, but reflects the perturbations of the complex intracellular and intercellular network that links tissue and organ systems. The emerging tools of network medicine offer a platform to explore systematically not only the molecular complexity of a particular disease, leading to the identification of disease modules and pathways, but also the molecular relationships among apparently distinct (patho)phenotypes. Advances in this direction are essential for identifying new disease genes, for uncovering the biological significance of disease-associated mutations identified by genome-wide association studies and full-genome sequencing, and for identifying drug targets and biomarkers for complex diseases.

Network Medicine: A Network-Based Approach to Human Disease

This paper gives an overview of the development of the field of Knowledge Engineering over the last 15 years. We discuss the paradigm shift from a transfer view to a modeling view and describe two approaches which considerably shaped research in Knowledge Engineering: Role-limiting Methods and Generic Tasks. To illustrate various concepts and methods which evolved in recent years we describe three modeling frameworks: CommonKADS, MIKE and PROTEGE-II. This description is supplemented by discussing some important methodological developments in more detail: specification languages for knowledge-based systems, problem-solving methods and ontologies. We conclude by outlining the relationship of Knowledge Engineering to Software Engineering, Information Integration and Knowledge Management.

/pdf/knowledge-engineering-principles-and-methods-6do1hbj75r.pdf

Knowledge engineering: principles and methods

The dominant paradigm in drug discovery is the concept of designing maximally selective ligands to act on individual drug targets. However, many effective drugs act via modulation of multiple proteins rather than single targets. Advances in systems biology are revealing a phenotypic robustness and a network structure that strongly suggests that exquisitely selective compounds, compared with multitarget drugs, may exhibit lower than desired clinical efficacy. This new appreciation of the role of polypharmacology has significant implications for tackling the two major sources of attrition in drug development--efficacy and toxicity. Integrating network biology and polypharmacology holds the promise of expanding the current opportunity space for druggable targets. However, the rational design of polypharmacology faces considerable challenges in the need for new methods to validate target combinations and optimize multiple structure-activity relationships while maintaining drug-like properties. Advances in these areas are creating the foundation of the next paradigm in drug discovery: network pharmacology.

https://www.advancedmedicine.ca/wp-content/uploads/2013/09/Nature-Chemical-Biology.pdf

Network pharmacology: the next paradigm in drug discovery.

A network of disorders and disease genes linked by known disorder-gene associations offers a platform to explore in a single graph-theoretic framework all known phenotype and disease gene associations, indicating the common genetic origin of many diseases. Genes associated with similar disorders show both higher likelihood of physical interactions between their products and higher expression profiling similarity for their transcripts, supporting the existence of distinct disease-specific functional modules. We find that essential human genes are likely to encode hub proteins and are expressed widely in most tissues. This suggests that disease genes also would play a central role in the human interactome. In contrast, we find that the vast majority of disease genes are nonessential and show no tendency to encode hub proteins, and their expression pattern indicates that they are localized in the functional periphery of the network. A selection-based model explains the observed difference between essential and disease genes and also suggests that diseases caused by somatic mutations should not be peripheral, a prediction we confirm for cancer genes.

/pdf/the-human-disease-network-mm8yuib85g.pdf

AIM in Alternative Medicine

References

Network Medicine: A Network-Based Approach to Human Disease

Knowledge engineering: principles and methods

Network pharmacology: the next paradigm in drug discovery.

The human disease network

K-Nearest Neighbor

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