The epigenetic view of development has long surpassed the theory of preformation (in which the gametes contain small but perfectly formed bodies waiting to grow). Epigenesis (or, in modern terms, lineage commitment) holds that differences in cells and tissues arise in development because gene-expression programmes change as cells differentiate. This view of development was most famously expressed by C. H. Waddington, who likened the path of a cell lineage towards terminal differentiation to a ball travelling downwards along branching valleys; once it has entered its final valley it cannot easily cross the mountain into the neighbouring one (transdifferentiation or plasticity) or return to the beginning (cloning or return to totipotency).

However, the differences in gene expression occur without any change in the sequence of DNA, which would render the process completely irreversible. Thus, although the model clearly envisaged difficulties with transdifferentiation or cloning, the reasons for these difficulties remained uncertain. The acid test of the prediction that changes in gene expression take place without underlying changes in the DNA sequence was to attempt to clone an animal by taking a differentiated nucleus (from the intestinal epithelium, say) and introducing it into an egg from which the nucleus had been removed. If the specialized transcriptional programme in a somatic nucleus is determined by the soup of transcription factors available to it, then by exposing the nucleus to the different soup that is present in the egg, reprogramming can occur. This was indeed demonstrated in the pioneering experiments by J. B. Gurdon, in which frogs were cloned from specialized cells, and more recently in several mammalian species (including Dolly the sheep). But despite these successes, the efficiency of cloning remains very low in all species in which it has been attempted. Has the right reprogramming soup not yet been found?

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