Opinion VIEWPOINT Mkhaell J. Joyner, MD Laboratory of Human Integrative Physiology and Department of Anesthesiology. Mayo Clinic, Rochester, Minnesota. Nigel Paneth. MD. MPH Departments of Epidemiology and Biostatistics and Pediatrics and Human Development. College of Human Medicine. Michigan State UnNersay. East Lansing. JohnP.A.loannklis. MD. D5c Stanford Prevention Research Center. Department of Medone arelMeta. Research Innovation Center at Stanford. Stanford Universny. Stanford. California. Corresponding Author: John P. A. loannidis. MD. DSc. Stanford Prevention Research Center. Department of Me6cine and Meta-Research Innovation Center at Stanford. Stanford OnNersay.1265 Welch Rd. Medical School Office 13Iclg. Room X306, Stanford. CA 94305 (power! @stanford edu). What Happens When Underperforming Big Ideas in Research Become Entrenched? For several decades now the biomedical researchcom- munity has pursued a narrative positing that a combi- nation of ever-deeper knowledge of subcellular biol- ogy. especially genetics. coupled with information technology will lead to transformative improvements in healthcareand hu man health. In this Viewpoint. we pro- vide evidence for the extraordinary dominance of this narrative in biomedical funding and journal publica- tions; discuss several prominent themes embedded in the narrative to show that this approach has largely failed: and propose a wholesale reevaluation of the way forward in biomedical research. Primacy of the Narrative In 2016 approxi mately $15 billion of the $26 billion of ex- tramural research funding sponsored by the National In- stitutes of Health (NIH) could be linked to some version of search terms that include gene, genome, stem cells, or regenerative medicine.' These topics have also in- creasedgeometrically intheir representationarnang pub- khed articles. Between 1974 and 2014 the annual num- berof published articles indexed inPubMed increased