Abstract
A completely new area of research was established by Shinya Yamanaka and his colleagues when they demonstrated that, simply by introducing four transcription factors, it is possible to reprogram skin cells from mice so that they become equivalent to embryo stem cells. Extensive research since then has confirmed this important new observation and extended the result to other species and other donor cells.
This most spectacular demonstration of Cellular Reprogramming has important implications for many aspects of biological research and extraordinary practical applications. It is likely that in the future other entirely new approaches to manipulation of cell phenotype will lead to further dramatic developments. The limits to reprogramming are not yet clearly defined.
The emphasis of the Journal will be different, as more articles will provide new approaches and novel insights to understand the cellular and molecular mechanisms of reprogramming. However, the Journal will continue to publish articles concerned with nuclear transfer, pluripotent stem cell derivation, genetic modification through nuclear transfer, and the practical application of this knowledge in research, medicine, and agriculture, just as it always has done. In addition, other articles will be concerned with essential enabling techniques such as those for oocyte maturation, parthenogenetic activation, cell fusion, cell culture, and micromanipulation. Other articles will focus on the development of novel vectors or small molecules that facilitate reprogramming.
It is appropriate that these changes are occurring with a Special Issue that has many exciting articles that describe important studies of “reprogramming.” There are research articles concerned with DNA methylation, loss of specific histone from the transferred nucleus, and abnormal levels of transcript of key genes in preimplantation in cloned embryos. Several other articles describe interventions to enhance reprogramming in cloned embryos and so increase the efficacy of nuclear transfer.
A great deal has been learned about nuclear transfer and cellular reprogramming during the past 25 years, but far more remains to be discovered. There are still species, such as the rat and nonhuman primate, for which there is no reliable protocol for production of cloned offspring. Clearly, the reasons for the failure are not clear or they would be overcome. The efficiency has not changed dramatically during the last 10 years, although some of the new articles suggest ways forward.
We know even less about direct reprogramming of cells where, in fact, the potential benefits are far greater. At present the process is slow, reprograms only a very small proportion of the cells, and it seems that induced pluripotent stem (iPS) cell lines are less uniform than comparable embryonic stem (ES) cell lines. Is it possible by understanding the process of reprogramming to increase the speed and efficiency of the reprogramming? It might be expected that this change would also improve the uniformity of iPS cell lines.
What limits are there to our ability to change phenotype directly? We know that change can be made within germ layers, but it is sometimes suggested that direct change from one germ layer to another is not possible. The practical implication would be that such a change could only be achieved by an intermediary step through the pluripotent state.
The practical value of reprogrammed human cells remains to be fully explored. Many laboratories have projects to create models of human inherited diseases by reprogramming cells from patients and directing the pluripotent cells to the tissue that is affected in the disease. Can patient-specific cells be used to correct human inherited diseases, such as sickle cell anemia? Is it appropriate to consider patient-specific cells for cell therapy to avoid immune rejection? Or would it be more appropriate to establish libraries of cells with carefully selected genotypes? It is argued that in this way a modest number of lines would provide an acceptable match for a very significant proportion of the population.
These and many other matters, both biological and practical, will provide important subjects for future research. We hope that this Journal, now suitably renamed, will provide a forum for all of these subjects and discussions, and we welcome your active participation and manuscript submissions.