Thedevelopmentandhomeostasisoforganismsdependsonthebalancebetweencellsurvivalandcelldeath—simplyput,thereisnolifewithoutdeath.In1842,KarlVogt,whilestudyingthemetamorphosisofamphibians,realizedthattheresorptionofthenotochordanditsreplacementbyvertebraeinvolvedphysiologicalcelldeath1.Theconceptof‘programmedcelldeath’wasconceivedmorethanacenturylater,in1964,whenLockshinandWilliamsdescribedregulatedcelldeathduringinsectmetamorphosis2.SchweichelandMerkerweresubsequentlythefirsttoreportthepresenceofthreedistinctcelldeathmorphologiesinratembryos,afterexposuretotoxins,whichalsooccurwithverylowfrequencyinthedevelopingmouse:typeIcelldeathwasassociatedwithheterophagy(‘eatingofanother’);typeIIcelldeathwasassociatedwithautophagy(‘eatingofitself’);andtypeIIIcelldeathdidnotinvolvedigestion3.Today,thesecelldeathmodesarereferredtoasapoptosis,celldeathassociatedwithautophagyandnecrosis,respectively.PioneeringworkinCaenorhabditiselegansrevealedthegeneticprogrammeofapoptosis4,whereasitsbiochemicalmechanismshavebeenelucidatedinvariousanimalmodels5,6.Wecurrentlyunderstandcelldeathasafundamentalprocessthatisregulatedbymultipleinterconnectedsignallingpathways,andwearestartingtodecipherhowcelldeathinfluencesprocessesinadditiontodevelopment,suchaschemotaxis,phagocytosis,regenerationandimmunogenicity7.Fortwodecades,apoptosiswasconsideredtobethestandardcelldeathformduringdevelopment,homeostasis,infectionandpathogenesis6,8,whereasnecrosiswasmostlyconsideredtobean‘accidental’celldeaththatoccurredinresponsetophysicochemicalinsults.Recentgeneticevidence9–16,aswellasthediscoveryofchemicalinhibitorsofnecrosis10,17,18,havegreatlychangedthisview,andrevealedtheexistenceofmultiplepathwaysofregulatednecrosis.Regulatednecrosisisdefinedasageneticallycontrolledcelldeathprocessthateventuallyresultsincellularleakage,anditismorphologicallycharacterizedbycytoplasmicgranulation,aswellasorganelleand/orcellularswelling(‘oncosis’).Multiplemodesofcelldeathsharethesemorphologicalhallmar...
