Induced and pathological developmental reprogramming

The theme of my 2014 lectures was cellular reprogramming. Since the advent of molecular genetics, biologists have been trying to understand how the fertilized egg forms an organism composed of hundreds of specialized cell types, each expressing a defined set of genes. Initially, the aim was to determine whether this specialization results from a progressive loss of the genetic information contained in the DNA sequence, or from differential gene expression during development. The pioneering nuclear transfer cloning experiments in amphibians by Robert Briggs and Thomas King in the 1950s, then by John Gurdon in 1962, validated the second hypothesis, demonstrating that embryogenesis proceeds by progressive restriction of gene expression potential, rather than by gene loss. Thus, cellular identity results from the expression of a specific combination of genes. This work was replicated several decades later in mammals: Dolly the sheep and Marguerite the cow were the first two successful examples of nuclear transfer cloning in this species group, and were followed by many others, including the mouse, the model species for most studies in mammalian biology. More recently, Shinya Yamanaka has demonstrated that it is possible to induce pluripotent stem cells (iPS cells) by dedifferentiation of adult stem cells, through forced expression of four key genes(Oct3/Oct4, SOX2, KLF4 and c-myc). This work, along with that of John Gurdon, by demonstrating that differentiated cells can be reprogrammed into pluripotent cells, earned these two researchers the Nobel Prize in Physiology and Medicine in 2012.