Biology is continually throwing up ethical dilemmas. And the thorniest issue of 2000 was that surrounding research on human embryonic stem cells.

These cells can, in theory, give rise to any of the body's tissues — and so have enormous potential in regenerative medicine. But 'pro-life' activists are bitterly opposed to their use, as cultures of embryonic stem cells can only be created by destroying a pre-implantation human embryo.

 

JOE READLE/NEWSMAKERS/EYE OF SCIENCE/SPL

Culture shock: with George W. Bush installed in the White House, US stem-cell researchers may turn to using adult stem cells, such as bone marrow stem cells (right), rather than embryonic cultures.

The freedom of researchers to work with embryonic stem cells rests on a knife-edge in many countries. In the United States, home to the largest community of stem- cell researchers, the National Institutes of Health proposed in August that federal funds could be used to support the research, provided the cells had been isolated using private money. But with the election of George W. Bush to the presidency, this decision might be rescinded.

Campaigners against embryonic-stem-cell research have made much of experiments suggesting that adult stem cells, which reside in and help regenerate many tissues, can give rise to a much wider variety of cell types than was thought. Given this remarkable plasticity, they argue, attempts to develop stem-cell therapies should not need human embryonic stem cells.

This unexpected phenomenon became well known in 1999, when a team led by Angelo Vescovi of the San Raffaele Hospital in Milan showed that neural stem cells taken from the brains of mice, cultured, and injected into bone marrow could give rise to apparently normal blood cells¹. This finding has proved difficult to replicate. But the past year has seen further demonstrations of plasticity, including two papers earlier this month that showed the reverse transformation — mouse bone-marrow stem cells giving rise to cells that resemble neurons^{2, 3}. Vescovi's group encored in October by showing the mouse and human neural stem cells could produce muscle cells⁴.

Although these experiments hint that adult stem cells have great therapeutic potential, most researchers in the field argue that this may never be realized if the door to research on human embryonic stem cells is closed. The problem, they say, is that stem-cell science is in its infancy — its practitioners know little of the molecular mechanisms that underlie the plasticity of stem cells, or that cause them to travel down particular developmental pathways. For some tissues, they are still arguing over the precise identity of the stem cells involved. "We're in the Dark Ages," observes Leonard Zon, a developmental biologist at the Children's Hospital in Boston.

 

YORGOS NIKAS/SPL

Divide and conquer: embryonic stem cells could be a source of any tissue type.

Many researchers agree that, in the long term, adult stem cells may be preferred for therapeutic applications. But experiments with embryonic stem cells, which have the greatest developmental potential, will almost certainly be needed for these therapies to see the light of day. Stem-cell biologists reject the notion that research on embryonic stem cells from mice will be enough. John Gearhart of Johns Hopkins University in Baltimore points out that human and mouse embryonic stem cells behave differently in culture. "These cells do vary considerably," he says.

Ron McKay, a stem-cell biologist at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, believes that the potential of adult stem cells will vary from disease to disease. "It depends absolutely on what you're interested in," he says.

For liver regeneration, work in mice suggests that adult stem cells have great clinical promise: in November, researchers with the company StemCells in Sunnyvale, California, cured animals of a lethal liver disease by transforming bone-marrow stem cells into liver cells⁵. Preliminary data from humans are also encouraging⁶.

But McKay's work, on therapies for Parkinson's disease that require the production of neurons that release the neurotransmitter dopamine, suggests that adult stem cells have their limits. McKay can generate large numbers of dopamine-producing neurons from mouse embryonic stem cells⁷, but he has so far failed to achieve this using adult neural stem cells.

Researchers agree that the key to developing therapies is the fundamental understanding needed to drag the field out of its Dark Ages. And although this process is still in its early days, some papers published in 2000 gave chinks of light.

For instance, it is becoming clear that signals requiring cell-to-cell contact help determine stem cells' eventual fate^{4, 8}. Meanwhile, researchers are starting to discover the intracellular factors involved. In March, a team at the Massachusetts General Hospital showed that a protein called p21 is vital for maintaining bone-marrow stem cells — without it, the cells proliferate rapidly and are soon exhausted⁹. And in September, a Canadian– German team showed that a transcription factor called Pax7 prevents the stem cells in muscle from developing into other tissues¹⁰.

Despite these advances, stem-cell researchers warn that there is a mountain still to climb. "To manipulate the variables is extremely difficult," says Vescovi.