The cytokines present in an organism dictate which cytokine receptors can form pairs: in this schematic example, cytokine 1 causes receptors R1 and R2 to form a pair (left), while cytokine 2 causes receptors R3 and R4 to form a pair (right). Moraga et al. made new molecules called synthekines, with each synthekine being a composite of two mutant cytokines that each bind only one of their related receptors. These synthekines trigger the formation of ‘unnatural’ pairs of receptors (R2 and R3 in this case). The Jak-STAT signaling cascade downstream of the synthekine is weaker than the cascades triggered by the parent cytokines: there are also other differences in the signaling cascades (see main text).