EU Science Hub

Adapting the Adverse Outcome Pathway concept to biomedical research

Jan 15 2018

JRC scientists have explored the application of Adverse Outcome Pathways (AOP) to improve mechanistic understanding of human disease pathophysiology in order to advance biomedical research and inform the development of new drugs.

The AOP concept was originally developed to facilitate better use of mechanistic understanding in determining the toxicological properties of chemicals. 

In particular, the goal has been to deliver reliable, animal-free methodologies for the hazard and risk assessment of chemicals, making greater use of in vitro and in silico methods.

In this context the AOP framework offers an efficient and effective means for capturing mechanistic knowledge, to link a molecular initiating event triggered by a chemical, through a sequence of key biological events, to an adverse health effect relevant for regulatory decisions.

In a recent publication JRC scientists suggest that the AOP concept could also have great value for biological research and drug discovery.

By giving examples of Parkinson's disease and impairment of learning and memory abilities in children, it is shown that the AOP concept can be applied to understanding human disease pathophysiology. Based on these two examples it is proposed to move towards mechanistically based taxonomies of human disease using the AOP concept.

Human diseases are currently classified based on clinical features rather than on the underlying pathophysiological processes that cause different symptoms in affected individuals. Mechanistic understanding of these pathways described in an AOP format could contribute to the establishment of "mechanistically-based" taxonomies of disease. Such knowledge could potentially lead therefore to the re-classification of certain pathological states thus aiding better diagnosis and treatment.

In addition, it is suggested that the use of human induced pluripotent stem cell-derived neurons originating from patients with neurological conditions could facilitate the development of better targeted (personalised) treatments. Moreover, this would also help reduce the reliance on animal models which are often poor in accurately recapitulating aspects of human biology and disease.

Read more in: Bal-Price A and Meek ME: "Adverse outcome pathways: Application to enhance mechanistic understanding of neurotoxicity", Pharmacology & Therapeutics 179 (2017) 84-95. doi: 10.1016/j.pharmthera.2017.05.006