Lessons from Toxicology: Developing a 21st-Century Paradigm for Medical Research

Abstract

Biomedical developments in the 21st century provide an unprecedented opportunity to gain a dynamic systems-level and human-specific understanding of the causes and pathophysiologies of disease. This understanding is a vital need, in view of continuing failures in health research, drug discovery, and clinical translation. The full potential of advanced approaches may not be achieved within a 20th-century conceptual framework dominated by animal models. Novel technologies are being integrated into environmental health research and are also applicable to disease research, but these advances need a new medical research and drug discovery paradigm to gain maximal benefits. We suggest a new conceptual framework that repurposes the 21st-century transition underway in toxicology. Human disease should be conceived as resulting from integrated extrinsic and intrinsic causes, with research focused on modern human-specific models to understand disease pathways at multiple biological levels that are analogous to adverse outcome pathways in toxicology. Systems biology tools should be used to integrate and interpret data about disease causation and pathophysiology. Such an approach promises progress in overcoming the current roadblocks to understanding human disease and successful drug discovery and translation. A discourse should begin now to identify and consider the many challenges and questions that need to be solved.

Figure 1

Integrating data on extrinsic and intrinsic causes of disease using systems biology provides a more comprehensive understanding of human illnesses. The adverse outcome pathway (AOP) concept links exposure, via chemical structure (or structures), the molecular initiating event, and key events, to an adverse outcome.

Figure 2

Diagram showing different pathways concepts, including the well-characterized adverse outcome pathway (AOP) for chemically induced skin allergy, from chemical structure through molecular initiating event, key events and adverse outcome. DCs, dendritic cells; QSAR, quantitative structure–activity relationships. Reprinted from Encyclopedia of Toxicology, Vol. 1, 3rd ed. Adverse outcome pathways: development and use in toxicology, pp. 95–99, 2014, with permission from Elsevier.