The virtuous cycle of human genetics and mouse models in drug discovery

• Published in: Nature reviews. Drug discovery Vol. 18; no. 4; pp. 255 - 272
• Main Authors: Nadeau, Joseph H., Auwerx, Johan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2019; Nature Publishing Group
• Subjects: 631/154; 631/1647/767/1424; 631/208; Analysis; Animal research models; Bioengineering; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cancer Research; Disease; Drug discovery; Drug targeting; Epigenetics; Experiments; Gene expression; Genetic aspects; Genetic research; Genetics; Genomes; Genomics; Genotype & phenotype; Health aspects; House mouse; Human genetics; Hypothesis testing; Medical research; Medicinal Chemistry; Molecular Medicine; Novels; Organismal biology; Pharmacology/Toxicology; Physiology; R&D; Research & development; Review Article
• ISSN: 1474-1776; 1474-1784; 1474-1784
• DOI: 10.1038/s41573-018-0009-9

Ongoing studies in many species seek to understand the origins, architecture and consequences of phenotypic variation under normal and dysfunctional conditions, with the aim of identifying targets for intervention that can prevent, stabilize or reverse disease. Some suggest that only humans are appropriate for studying these questions and argue that candidate drug targets identified in mouse models are largely unreliable. Here, we review the vast evidence showing that mouse models continue to make fundamental contributions to our understanding of genetic principles, pathogenic mechanisms and therapeutic modalities. We propose a virtuous cycle in which the power of observational studies and natural experiments in humans are closely integrated with the rigour of true experiments in model organisms. Understanding the genetic and phenotypic architecture of health and disease is vital to the identification of novel therapeutic targets and therapies. Here, Nadeau and Auwerx review the fundamentals of genotype–phenotype relations in mouse models and discuss how the integration of human and mouse genetic research remains essential to understanding disease pathogenesis, identifying potential therapeutic targets and developing new therapies