Ian Wilmut, Keith H S Campbell and Shinya Yamanaka through their pioneering work have shown that mammalian cells can be reprogrammed into early stem cells, and in the process have made important contributions to potential new approaches for the treatment of human diseases and to the improvement of agriculture.
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 later made to show that mammalian cells – and human cells in particular – could also be reprogrammed back to a pluripotent state, both to advance our understanding of developmental mechanisms and because of the belief that great therapeutic benefits would flow from such knowledge. The breakthroughs came in the last 15 years. The landmark contributions by the scientists that are honoured with the Shaw Prize have thereby ushered in a new era in stem cell research, with huge potential benefits to mankind.
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. In 1995, they produced a pair of lambs called Megan and Morag from embryonic cells. They also 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 is 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 work of Wilmut and Campbell indicates that adult mammalian cells can be reprogrammed into pluripotent embryonic stem cells. Since embryonic stem cells are pluripotent, they have the potential of differentiating into many cell types for the treatment of diseases. Building on these insights, Yamanaka 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 pluripotent. His work was rapidly duplicated and validated by researchers at MIT, Harvard, UCLA and UCSF. The next question was whether his method would work in human 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 fibroblasts in a similar fashion. Based on this discovery, 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 avoided. 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.
Life Science and Medicine Selection Committee
The Shaw Prize
10 June 2008, Hong Kong