A decade of progress since the birth of Dolly

Abstract

The greatest effect of the birth Dolly, the first cloned animal derived from an adult, has been in prompting biologists to consider ways of reprogramming adult nuclei to a pluripotent state directly. The first procedure depends upon use of viral vectors to introduce selected transcription factors, but this procedure is slow and very inefficient. Research in our laboratory has demonstrated that exposure of differentiated nuclei to an extract of embryo stem cells induces expression of key pluripotency genes within 8 h, suggesting that it may be possible to identify and use other factors to enhance direct reprogramming. A study of mechanisms that bring about changes in DNA methylation in early sheep embryos identified a developmental isoform of Dnmt1, the expression of which was limited to early stages of pregnancy. Reduction in the level of transcript of this isoform at the time of fertilisation caused sheep embryo development to cease at the early morula stage, revealing a key role for the isoform that remains to be characterised. The ability to obtain pluripotent cells from specific patients is providing important new opportunities to study inherited diseases when the causative mutation is not known. The initial objective of this research is not cell therapy, but to use cells with the characteristics of those in a patient who has inherited the disease to establish a high-throughput screen to identify drugs that are able to prevent progression of the symptoms of the disease. Research is in progress with cells from patients with amyotropic lateral sclerosis.