Systematized Serendipity: Fishing Expeditions for Anesthetic Drugs and Targets

Most of science involves making observations, forming hypotheses, and testing those hypotheses, to form valid conclusions. However, a distinct, longstanding, and very productive scientific approach does not follow this paradigm; rather, it begins with a screen through a random collection of drugs or genetic variations for a particular effect or phenotype. Subsequently, the identity of the drug or gene is determined, and only then are hypotheses formed and the more standard scientific method employed. This alternative approach is called forward screening and includes methods such as genetic mutant screens, small molecule screens, metabolomics, proteomics, and transcriptomics. This review explains the rational for forward screening approaches and uses examples of screens for mutants with altered anesthetic sensitivities and for novel anesthetics to illustrate the methods and impact of the approach. Forward screening approaches are becoming even more powerful with advances in bioinformatics aided by artificial intelligence.