The late 1990s was the most productive period in the history of biological research. The birth of Dolly, the first cloned mammal, was quickly followed by the first successful derivation of human embryonic stem cells and then, as the new millennium dawned, the completion of the Human Genome Project.

Since then the media have amplified these achievements, with the enthusiastic encouragement of many of the researchers involved, to create intense public excitement about a new era of regenerative medicine. Some people imagine that within a few years it will be possible, through some still obscure combination of stem cells, cloning and genetic engineering, to create new cells and eventually whole organs to replace those that fail through disease, accident or old age.

That promise is counterbalanced by ethical and religious objections to stem cell research--particularly to the idea that embryos could be created especially for research and then destroyed--and fears that therapeutic cloning could open the door to reproductive cloning.

For many people the very phrase "stem cells" sums up all the excitement and fears. But there is widespread ignorance about stem cells and wishful thinking about how quickly their potential will be achieved. This report is intended to shed scientific light on the future of stem cell research--and the associated policy issues that are driving national and state governments to commit billions of dollars of public funds to the field.

First, then, some basic definitions. Stem cells serve as a biological repair system, with the potential to develop into many types of specialised cells in the body. They can theoretically divide without limit to replenish other cells. When a stem cell divides, each daughter can remain a stem cell or adopt a more specialised role such as a muscle, blood or brain cell, depending on the presence or absence of biochemical signals. Controlling this differentiation process is one of the biggest challenges in stem cell research.

There is nothing new about stem cells per se. Stem cell therapies have been used for decades. The best known example is bone marrow transplantation to treat leukaemia and other blood disorders; this works because marrow is full of blood stem cells. But all therapies so far have used what are often called adult stem cells--a term that is fine when the source is actually an adult but misleading when, as often happens, the cells come from an infant or foetus. Somatic stem cells may be a better name for these cells.

The range of specialised cells that can be obtained from somatic stem cells is limited--how limited is currently the subject of intense scientific debate that will be considered in a later article [see "Repair Workers Within," on page A12]. Early embryos are potentially a better source because all their cells are still unspecialised. Embryonic stem cells (commonly abbreviated to ES cells) are pluripotent: they can differentiate into almost any type of cell.

The first line (stable replicating population) of human ES cells was created in 1998 by James Thomson of the University of Wisconsin. The procedure involves taking cells from inside a week-old embryo (or blastocyst)--a microscopic ball of 50 to 100 cells--and culturing them in a laboratory dish with nutrients and growth factors. Embryos are normally donated by couples undergoing IVF treatment and would otherwise be discarded.

Even now, after seven years of intensive work worldwide, the world has fewer than 150 well-characterised ES cell lines, because the process of establishing them is extremely tricky. Only 22 lines are available for federally funded research in the US, where the Bush administration has decreed that the National Institutes of Health should not support work on lines created after August 2001. Once established, a stem cell line is essentially immortal. It can be frozen for storage in a cell bank, such as the one established last year in the UK, and for distribution to other researchers.

In an attempt to get round ethical objections to the destruction of human embryos for research, some scientists have been exploring alternative sources of ES cells. One approach would be to identify the least differentiated adult stem cells and wind back their developmental clock, so that they behaved as pluripotent ES cells. Another is through parthenogenesis--activating an unfertilised human egg so that it starts to divide like an early embryo. But it is not clear whether either approach will work in practice.

Until very recently, researchers have grown human ES cells on layers of mouse skin cells, known as feeder cells, which inhibit their differentiation into more specialised cells. They have also been nourished with blood serum derived from calf foetuses. Unfortunately, these nonhuman components carry a risk of contamination with animal proteins or pathogens, as in xenotransplantation, which could prevent the stem cells being used safely in the clinic.

This year several research groups have announced successful substitution of human for animal components, but some scientists maintain that contamination of the specialised media used for ES cell growth and differentiation is so pervasive that it will be hard to eliminate completely [see box on page A11].

ES cells, unlike adult stem cells, cannot be used directly in therapy because they cause cancer. Indeed, one laboratory test for ES cells is to inject them into mice and analyse the teratoma (a tumour formed of foetal tissue) that arises. So any therapeutic application will require scientists to drive the ES cells' differentiation into particular specialised cells for transplantation into patients--for instance, beta cells to produce insulin for diabetics or dopamine-producing neurones to treat Parkinson's disease. And rigorous screening will be required to make sure that no ES cells are still present.

If establishing ES cell lines is tricky, guiding their differentiation is a scientific nightmare. Researchers are only just beginning to understand the environmental conditions and the combinations of growth factors and other proteins required to guide human ES cells so that they become stable nerve or muscle or whatever other specialist cells are required for treatment.

Producing embryonic stem cell lines is tricky. Fewer than 150 lines have resulted from seven years of hard work.

Yet experience with mouse ES cells suggests that it will be possible to develop safe and effective therapies from their human counterparts. Researchers around the world are making a great effort to do so, because cell-based therapies are so immensely promising. Biologists believe most degenerative diseases are too complex to treat effectively just by giving patients drugs or even gene therapy. Living cells, which produce a far larger number of biologically active molecules, stand a better chance of success.

Although no clinical trials of ES cells have taken place yet, other types of cell therapy have shown that this kind of transplantation can work in people. Examples, besides the ubiquitous bone marrow transplant, include the use of neural stem cells from foetuses to treat brain disease and insulin-producing beta cells from cadavers to treat diabetes. Successes with somatic cells lie behind the hope that ES cells will eventually work even better, but a lot more research will be needed to prove the point.

The obstacles that ES cell researchers need to overcome include better ways of obtaining ES cells efficiently; better methods to identify ES cells and their true developmental potential; ways to control their differentiation and growth inside the body; understanding whether the immune system attacks ES cells or ones differentiated from them; and learning more about the comparative advantages of ES cells and somatic cells for various applications.

While direct use of stem cells in patients is what most excites politicians and the public, many scientists say their main medical benefits may be delivered indirectly, through their use in research to advance other therapies. If researchers can work out the complex chemical and genetic signals that control the growth and differentiation of stem cells, the results would be enormously useful in medicine. ES cells should make it possible to develop models of tissue development and function that will enable chemists to test potential drugs more effectively.

For example, if ES cells derived from embryos known by genetic screening to carry cystic fibrosis genes can be guided to become CF lung cells, these would open a new window for studying the disease and testing treatments for it. For pharmaceutical chemists, unlike biologists, the vision of regenerative medicine involves finding drugs--ideally small molecules that patients can take by mouth to stimulate their own tissues to regenerate--rather than messing around with cell therapy.

The science is still far too uncertain for us to tell how stem cell research and regenerative medicine will develop. It may take another generation or two before we derive much clinical benefit from the great biological advances of the late 1990s. But the medical payoff could eventually be spectacular.