The early period described above set the stage for the next era in the development of organoid and 3D cultures. By 1980, researchers had the tools (both material and conceptual) to start unraveling the mysteries that govern tissue-specific function and morphogenesis. In 1981, Bissell et al. submitted a paper to the Journal of Theoretical Biology hypothesizing that ECM regulates gene expression. The article titled “How does extracellular matrix regulate gene expression” (Bissell et al., 1982) was published the same year Hall et al. (1982) determined that if MDCK or normal murine mammary gland cells cultured on top of collagen I gels, once confluent, were overlaid with another collagen layer (the epithelium in response to a collagen cocoon), cells rearranged to form tissue-like structures, which is compatible with the notion that it is the matrix that pulls the strings. A similar phenomena was described for follicle formation from isolated thyroid cells (Chambard et al., 1981). Using floating collagen gels as described by Emerman and Pitelka (1977) and radioactive carbon, Lee et al. (1984, 1985) showed that the milk that was produced
