One cell for all, and all from one

The biology of stem cells is one of the two most important areas of biomedical research, the other being molecular genetics. The concentration of research and teaching effort on these two themes reflects the belief that these subjects each have the potential to offer revolutionary opportunities in research and medicine - a view shared by many biologists.

The handbook's two volumes follow a similar sequence in dealing with embryo (volume one) and adult (volume two) stem cells. After a general introduction to the subject, each is concerned with the basic biology of their population of cells. In volume one, the mechanisms that regulate differentiation of cell types during normal development are described. In volume two, the concern is with stem cells from different tissues. Final chapters cover regulations and commercial and ethical aspects. Clearly this is an all-encompassing work, and it is impossible to mention each chapter in this review.

Mouse embryo stem cells have the characteristic that they are able to form all of the tissues of an adult. Although this can never be confirmed, it is assumed that human embryo stem cells also have this ability. Embryo stem cells of both species are also able to divide many times in culture. It is for these reasons that much research is concerned with derivation, maintenance and differentiation of human embryo stem cells.

Although mouse embryo stem cells have been available for more than 20 years, the molecular mechanisms that give them their unique characteristics are not understood. Current perspectives are provided before an analysis of the early stages of development from which embryo stem cells originate.

While methods have been established for the derivation of human embryo stem cells, they are inefficient and carry the risk of infection. One objective of much research is to be able to use chemically defined culture conditions to guarantee quality and improve reproducibility.

In parallel with this research there is a major effort to establish reliable procedures for the derivation of different cell types. This often involves empirical cookery, but there is a more systematic approach in which analyses of patterns of gene expression reveal expression indicative of particular progenitors.

These genes may then be used as "reporters" to provide a more precise assessment of the effect of varying culture conditions on the path of differentiation. Before cells are transplanted into patients, it is essential that all cells differentiate. Stem cells are able to form tumours, so the transplantation of just one remaining embryo stem cell could be fatal.

Other major challenges remain before embryo-derived cells can be used routinely in therapy. So far, relatively small numbers of cells have been cultured for research. The procedures must now be scaled up for clinical requirements. Strategies must be devised to deal with immune rejection where it occurs, and several approaches are being considered to avoid the use of immunosuppressive drugs, including induction of tolerance or use of cloned embryo cells. A solution is urgently required. Cells derived from the patients themselves would be immunologically matched, and they are the subject of the second volume. In recent months, cells with the ability to divide in culture for prolonged periods and to give rise to more than one cell type have been derived from different tissues, including skin, mammary gland, heart and liver. While cells from the patient would be matched, it would take time and involve notable cost to multiply the number of cells adequately, cause them to differentiate and confirm their normality. In this volume, the characteristics of many adult stem cells, method of culture and potential are described.

One of the key issues that is hotly debated in this rapidly moving field is: what exactly do we mean by stem cells? Do adult and embryo stem cells share any common characteristics, such as patterns of gene expression? It is argued that this information might facilitate a decision as to which of the newly isolated populations deserves to be characterised as a stem cell.

Experience so far suggests that the biology of stem cells is too complex for this approach to be valid. Embryo-derived cells retain the ability to form all tissues, whereas those derived from a differentiated tissue have a more restricted potential.

Of course, that potential depends on what is done to the cells. Murine embryo stem cells may themselves be considered an artefact of culture as they are not exactly like cells at any stage of embryo development and their derivation may depend on epigenetic changes in gene expression. There may be similar effects of prolonged culture on cells from any source.

Cells derived from adult tissue may have two limitations that must be overcome. First, they may have a limited lifespan either in culture or after transfer to a patient. Second, they are unlikely to be able to form all tissue types without considerable modification in culture.

Many researchers believe that, if treated appropriately, cells derived from adult tissue will have the potential to form many adult cell types, perhaps all cell types. A variety of treatments applied with this objective in mind include exposure to inhibitors of enzymes that maintain chromatin structure, such as methyltransferases. Clearly cytokines that regulate differentiation of cells can influence phenotype, and most cell cultures include a rich source of such factors - serum. A further inventive approach is to introduce into the treated cells factors from the cytoplasm of cells of the desired phenotype by permeabilising the cell membrane and dunking the cells in extract. In this way, fibroblast cells acquire some of the characteristics of lymphocytes or neurons.

It seems very likely that, in future, it will be possible to obtain stem cells from a patient and treat them with a combination of drugs, cytokines and intracellular factors to change their phenotype. In the meantime, research with embryo-derived cells seems the most likely to provide effective therapies. We are a long way from being able to make informed judgements about the use of stem cells in therapy, but we should not overlook their more immediate value in studies of early development and disease.

Assessment of new drugs derived from embryo stem cells is already beginning. Inevitably, ethical and political issues will continue to influence this area of research. So far, little consideration has been given to the cost of potential treatments or the means of delivery.

This work contains 155 chapters by world experts on many different aspects of stem-cell biology. In such a rapidly moving field, it is inevitable that some chapters will soon seem out of date, but the work is still excellent and informative. It does not provide protocols but rather summarises our present understanding of the key mechanisms. It will provide an excellent introduction to researchers or students who are new to the field and will be a source for people wishing to learn about a cell type outside their area of research. Bruce Alberts, the eminent molecular biologist who is president of the National Academy of Sciences in the US, provides a foreword. After noting his concern that it is not possible to predict the precise outcome of research, he comments: "Nevertheless, the history of science makes it certain that knowledge derived from research on stem cells will eventually lead to enormous benefits for human health, even if they are unpredictable."

These books make an invaluable contribution to the education of researchers and clinicians both of the present day and of the future. They should be available in libraries of all biology and medical schools as well as those of companies and research institutes.

Ian Wilmut is group leader of gene function and development, Roslin Institute.