Elucidation and Control of the Hybridization Chain Reaction

The programmable chemistry of nucleic acid base pairing enables the design and construction of hybridization chain reactions (HCR) in which metastable DNA or RNA molecules undergo conditional polymerization in the presence of a target nucleic acid. Employed as programmable in situ amplifiers, HCR enables simultaneous mapping of multiple target mRNAs within intact vertebrate embryos. Employed as programmable mechanical transducers, HCR enables selective killing of cultured human cancer cells containing targeted cancer mutations. To elucidate and improve the properties of HCR systems, we use a combination of theory and experiments to probe and perturb HCR equilibrium behavior and self-assembly pathways. We find that HCR is appropriately modeled as a seeded nucleation-elongation polymerization and use this theoretical framework to re-engineer the equilibrium and kinetic properties of the mechanism.