title: 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.
authors.affiliation: Research and Toxicology Department, Humane Society International, London, United Kingdom.
authors.forename: Gill
authors.initials: G
authors.lastname: Langley
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
authors.forename: Anil K
authors.initials: AK
authors.lastname: Balapure
authors.forename: Linda S
authors.initials: LS
authors.lastname: Birnbaum
authors.forename: John R
authors.initials: JR
authors.lastname: Bucher
authors.forename: Julia
authors.initials: J
authors.lastname: Fentem
authors.forename: Suzanne C
authors.initials: SC
authors.lastname: Fitzpatrick
authors.forename: John R
authors.initials: JR
authors.lastname: Fowle
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kavlock
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kitano
authors.forename: Brett A
authors.initials: BA
authors.lastname: Lidbury
authors.forename: Alysson R
authors.initials: AR
authors.lastname: Muotri
authors.forename: Shuang-Qing
authors.initials: SQ
authors.lastname: Peng
authors.forename: Dmitry
authors.initials: D
authors.lastname: Sakharov
authors.forename: Troy
authors.initials: T
authors.lastname: Seidle
authors.forename: Thales
authors.initials: T
authors.lastname: Trez
authors.forename: Alexander
authors.initials: A
authors.lastname: Tonevitsky
authors.forename: Anja
authors.initials: A
authors.lastname: van de Stolpe
authors.forename: Maurice
authors.initials: M
authors.lastname: Whelan
authors.forename: Catherine
authors.initials: C
authors.lastname: Willett
mesh_terms: D000826:Animal Testing Alternatives; D035843:Biomedical Research / Q000379:methods*; D003198:Computer Simulation; D055808:Drug Discovery; D023281:Genomics; D006801:Humans; D049490:Systems Biology / Q000379:methods*; D014116:Toxicology / Q000379:methods*