From hype to hope

PROFESSOR PETER ANDREWS discusses the range of medical possibilities that will be opened up by stem cells

Every so often new facets of biology capture the popular imagination – transplantation biology, gene therapy, GM crops. Over the past few years, stem cell biology has hit the headlines: the derivation of human embryonic stem (ES) cells in 1998 provoked endless speculation about the potential for ‘stem cell therapies’, or regenerative medicine, to provide cures for a host of currently incurable conditions resulting from the loss of tissues and organs to disease, resulting from aging or accident.

Examples ranged from diseases such as type 1 diabetes, to neurological diseases like Parkinson’s or Huntington’s disease, to heart disease. But what is the reality?

In fact, regenerative medicine has been with us for years, and bone marrow transplantation for treating various diseases, especially leukaemias, has become a practical treatment. But it is a treatment that developed slowly over more than forty years, from the first recognition of blood stem cells by Till and McCullogh in Canada in the early 1960s. The current interest in stem cells, however, was sparked by the derivation of human ES cells.

These cells can be established as permanent cell lines by placing an early embryo, about four days after fertilisation, into culture. This was first achieved by Martin Evans (one of this year’s Nobel Prize winners) with embryos of the laboratory mouse, over 25 years ago; it was finally achieved with human embryos just nine years ago, by Dr James Thomson at the University of Wisconsin in Madison.

ES cells are cells that grow indefinitely in culture but retain the properties of cells that appear in the embryo soon after fertilisation. Most importantly, they retain the ability to differentiate into all cell types found in the body – hence the hope that, if we could control the process of their differentiation, ES cells would allow us to produce indefinite amounts of particular cells that could be transplanted to patients to replace diseased or damaged tissues.

For many this is seen as a worthy goal, but for others the destruction of an embryo to produce ES cells is unacceptable. However, most if not all current lines of human ES cells have been derived from embryos produced by In Vitro Fertilisation (IVF) to enable infertile couples to have babies. Inevitably, this process produces more embryos than can be used and these would otherwise be destroyed.

To those of us in the field, it seems more ethically acceptable to use these for advancing biomedical science, than to destroy them to no useful purpose. In addition, at the time they are used to produce ES cells embryo are only four to six days old and certainly not recognisable as a person. In the 1980s the Warnock Commission concluded that experimentation on IVF embryos up to 14 days after fertilisation is ethically acceptable, if the work is for a purpose with real potential benefits.

Those conclusions were enshrined in UK law in the 1990 Human Embryo and Fertilisation Act, after which the Human Fertilisation and Embryo Authority (HFEA) was set up to regulate research with human embryos. This effectively included the possibility of deriving ES cells, although that was not explicitly acknowledged by Parliament until regulations were subsequently approved.

So where are we today? After nine years’ work with human ES cell lines, the promise remains, but all now recognise that considerable research is necessary before this promise can be realised. Many human ES cell lines have now been derived and characterised by many groups around the world. Indeed, I have had the privilege to lead an international consortium, the International Stem Cell Initiative, comprising 17 laboratories from 11 countries, which recently undertook to compare the properties of 59 human ES lines and establish criteria for working with them, a study recently published in Nature Biotechnology.

But that represents only one small piece of a larger jigsaw puzzle. Working with these and other lines, many groups are now making slow progress to work out techniques for harnessing the ability of ES cells to make particular cell types. However, much work remains to be done.

In this respect stem cells are no different from other advances in biomedicine. Bone marrow transplantation is one example. Others include monoclonal antibodies were first produced in 1975, yet it was almost 30 year later that monoclonal antibody-based drugs for treating cancer and other conditions began to appear in a robust and usable form.

But in reality ES cells offer many more opportunities to improve medical practice, than simply to be a source of cells for transplantation. They may give us a source of standardised human cells of different types that can be used for both drug discovery and testing for the unwanted side effects of new drugs (toxicology) in ways that have hitherto not been available. For example, ES cells with different genotypes will offer new tools for pharmacogenomics – the testing of how genetically different individuals may respond differently to particular therapeutic drugs.

Beyond this, ES cells offer us the opportunity to establish new models of different human diseases from which we can hope to better understand the causes of the pathology and develop new approaches to treatment. In my own case, I am particularly interested in aspects of human ES cells that might give us new insights into cancer.

Finally, from the opportunities that ES cells give us to explore normal processes by which our bodies develop during embryogenesis and in adult life, we may find ways to active endogenous stem cells that will allow us to stimulate our bodies to repair themselves without resort to transplantation.

In the end, ES cell biology offers many possibilities for eventual applications in human medicine. But they will not come over night and they are much broader than the popular notion of applications in transplantation.

Peter Andrews is Arthur Jackson professor of biomedical science at the University of Sheffield. He works at the Centre for Stem Cell Biology and the Department of Biomedical Science. Since 2003, he has lead the International Stem Cell Initiative, which links the work of more than 80 leading scientists from around the world.