During the 1990s, as signaling pathways were being defined for a variety of specific cell surface receptors, the signaling community surprisingly found that only a few dozen ubiquitous signaling pathways seem to account for nearly all biologic and developmental responses (54). The community studying signal transduction expected specific pathways for specific receptors, and the general question of the biochemical basis of signaling specificity arose. Although still a matter of debate, much of the answer to this question now appears to be that genetic loci are made accessible for the binding of transcription factors at the terminus of a signaling pathway before or concurrently with the use of the signaling pathway. This result indicated that the nucleus and cell membrane somehow anticipated the next step in development. Almost certainly, the development of highly specific regions of the genome that are open to incoming signaling pathways is brought about through the actions of lineage-specifying transcription factors and specific cell membrane receptors, but other components must be present that are capable of reversing long-standing patterns of epigenetic repression. A biochemical search for proteins
