During the development of vertebrates, including humans, the fertilized egg develops into the embryo, and the cells in the embryo then proceed to differentiate to form somatic cells of different tissues and organs. The fertilized egg is considered totipotent, as it can develop into a whole organism, while the cells in the embryo are pluripotent because they are capable of differentiating into somatic cells that make up all the organs. Half a century ago, it was found by John Gurdon that this developmental clock can be reversed, and that differentiated somatic cells in a frog model could regain their pluripotency or totipotency. Attempts were then made to show that mammalian cells – and human cells in particular – could also be reprogrammed back to a pluripotent state, because it is believed that such knowledge may advance our understanding of developmental mechanisms, and yield new approaches for disease treatment. The breakthroughs came within the last 15 years. The scientists honoured by the 2008 Shaw Prize in Life Science and Medicine used different approaches to reprogramme an adult cell into the totipotent or pluripotent state, and in doing so made important contributions to potential new approaches to improve agriculture practices and to treat human diseases.
Ian Wilmut and Keith H S Campbell worked together in the Roslin Institute near Edinburgh for many years, using sheep as the model, in order to understand the early physiology of the egg and how laboratory manipulations can improve our knowledge of the development from egg to birth. They pioneered a new technique of starving embryo cells before transferring their nucleus to fertilized egg cells. The technique synchronized the cell cycles of both cells and the results led Wilmut and Campbell to believe that any type of cell could be used to produce a clone. In 1995, they produced a pair of lambs called Megan and Morag from embryonic cells. They performed nuclear transfer experiments in which nuclei from embryonic, foetal and adult cells of the sheep were transplanted into fertilized eggs derived from ewes. Although the yield was low, they were successful in obtaining live newborn lambs from these transfers. One of the live-born lambs, Dolly, was derived from the transplantation of the nucleus of an adult mammary cell. Thus, Dolly was the first example of the reprogramming of the adult cell back to totipotency in a mammal. They further created a sheep called Polly in which they showed that it was possible to incorporate a human gene into the donor's DNA before cloning, thus indicating that it may be possible to use animals to produce human proteins for the benefit of mankind. Since then, the work of Wilmut and Campbell has been duplicated in many other animal species and has provided approaches to produce useful therapeutic products with cloned animals and to improve agricultural practices.
Shinya Yamanaka focuses his research on ways to reprogramme adult somatic cells to generate cells that resemble embryonic stem cells. The experiments of Wilmut and Campbell indicate that adult mammalian cells can be reprogrammed into pluripotent embryonic stem cells by nuclear transfer. Building on these insights, Yamanaka sought a different and more direct way to reprogramme adult cells. He systematically analyzed hundreds of genes that are expressed differently in embryonic and somatic cells. In 2006, he startled the scientific community by reporting that the addition of just four genes could induce adult mouse skin cells back to embryonic-like cells that he called induced pluripotent stem (iPS) cells.
He further showed that these pluripotent stem cells could produce fully reproductive mice, proving definitively that these cells are totipotent. His work was rapidly duplicated and validated by researchers in many laboratories. The next question was whether his method would work in human skin fibroblasts. In November 2007, Yamanaka's laboratory, concurrently with James Thomson's of Wisconsin, startled the world with the news that pluripotent stem cells can also be induced from human skin cells in a similar fashion. Based on his discovery in the mouse, animal experiments by others have already shown that it was possible to cure mouse models of sickle cell anaemia and Parkinson Disease. While more work needs to be done for human therapeutic applications, his discovery opens up the possibility of generating from a patient's own skin pluripotent stem cells that can be manipulated for the treatment in a host of human diseases. Since the DNA is the patient's own, immunological rejection of donor's cells can be circumvented. It is an improvement on therapeutic cloning, which requires nuclear transfer into human donor eggs to derive stem cells, a procedure which raises ethical concerns and which has not yet been successful with human cells.
The discoveries of Wilmut and Campbell and of Yamanaka have ushered in a new era of studying mammalian development and cell differentiation. They have also provided new approaches of improving agriculture practices, and novel treatment of human diseases.
Life Science and Medicine Selection Committee
The Shaw Prize
9 September 2008, Hong Kong