As molecular geneticist François Jacob wrote, living organisms reflect “the very nature of a historical process full of contingency” . Evolutionary contingency constrains relationships between genome sequence, organization, and function. However, technologies for engineering ever-larger stretches of DNA now enable synthetic regulatory reconstitution experiments (–) in which foreign DNA, freed from historical contingency, can be placed directly into a host cell. Such “in hostia” reconstitutions complement classic in vitro approaches for determining the rules of genomic regulation. Notably, in hostia reconstitutions assess the regulatory “ground state” of a host cellular environment—that is, the propensity for inserted DNA to be active or silent. On page 627 of this issue, Meneu et al. describe what happens when bacterial DNA is introduced into yeast cell nuclei as synthetic chromosomes. The spontaneous formation of …