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A key feature of the transcription factor network which controls human development is that only a tiny fraction of the network’s vast number of potential gene expression states is stable. This subset includes a few hundred states that encode and specify all the cell phenotypes arising in the mature organism and during development. An implication is that if expression of the cellular transcriptional network can be forced into a state which approaches one of these stable ‘attractor’ states, the network might collapse towards the attractor, redefining cellular identity. That this is possible is demonstrated in somatic nuclear transfer, in natural and artificially-induced cell fusion, and most remarkably, in cellular reprogramming based on ectopic expression of a handful of master regulators, as in the case of induced pluripotency. What if we could modulate the levels of transcription factors simply by adding appropriate cocktails of messenger RNA to cell culture media? Then we might be able to play the transcriptional network like a keyboard, guiding cells towards any fate we chose – and, we could do it without leaving a mark on the genome. The demonstration that long-term administration of mRNA encoding Yamanaka factors can rapidly and efficiently turn somatic fibroblasts into pluripotent stem cells suggests that this approach will emerge as important new paradigm for future work in regenerative medicine.
