The RNA world in early formulations (White 1976) as discussed by Penny (2005). This envisages RNA-like cofactors performing essential catalyses early, with continued utility as part of larger RNA molecules, and with the original RNA scaffold of the ribozyme being replaced piece-by-piece by proteins over evolutionary time, sometimes more than once independently, with the cofactor still doing the catalytic job, but with better positioning of substrates and intermediates within a handed catalytic site of a protein. Some cofactors representing the red dot are redrawn from Graham & White (2002) and Stryer (1975). Note the conspicuous absence of chiral centres in the catalytically active moieties of the cofactors. NAD, nicotinamide adenine dinucleotide; FAD, flavin adenine dinucleotide.