Synthetic lethality

Synthetic lethality is defined as a type of genetic interaction where the combination of two genetic events results in cell death or death of an organism. Although the foregoing explanation is wider than this, it is common when referring to synthetic lethality to mean the situation arising by virtue of a combination of deficiencies of two or more genes leading to cell death (whether by means of apoptosis or otherwise), whereas a deficiency of only one of these genes does not. In a synthetic lethal genetic screen, it is necessary to begin with a mutation that does not result in cell death, although the effect of that mutation could result in a differing phenotype (slow growth for example), and then systematically test other mutations at additional loci to determine which, in combination with the first mutation, causes cell death arising by way of deficiency or abolition of expression. Synthetic lethality has utility for purposes of molecular targeted cancer therapy. The first example of a molecular targeted therapeutic agent, which exploited a synthetic lethal approach, arose by means of an inactivated tumor suppressor gene (BRCA1 and 2), a treatment which received FDA approval in 2016 (PARP inhibitor). A sub-case of synthetic lethality, where vulnerabilities are exposed by the deletion of passenger genes rather than tumor suppressor is the so-called "collateral lethality". The phenomenon of synthetic lethality was first described by Calvin Bridges in 1922, who noticed that some combinations of mutations in the model organism Drosophila melanogaster (the common fruit fly) confer lethality. Theodore Dobzhansky coined the term "synthetic lethality" in 1946 to describe the same type of genetic interaction in wildtype populations of Drosophila. If the combination of genetic events results in a non-lethal reduction in fitness, the interaction is called synthetic sickness.