Hope behind the stem cell hype

Within the next week or so, couples attending an NHS fertility clinic in Newcastle upon Tyne will be asked a question that, in Britain at least, has never been asked before. Will they donate their spare eggs for cloning experiments, so that scientists can create human embryos and use them as sources of stem cells?

Triggered by this month's decision by the Human Fertility and Embryology Authority to grant the first licence for therapeutic cloning, the question marks the beginning of a lengthy and uncertain research process. But it does a lot more, placing Britain, and more specifically Alison Murdoch at Newcastle NHS Fertility Clinic and Miodrag Stojkovich at the university's Institute for Human Genetics, at the orefront of one of the most powerful yet controversial areas of science.

Scratch the surface of scientific opinion, and the announcement seems to have been met with unalloyed approval. As reflected in the media, this was therapeutic cloning's first step towards a viable treatment for conditions such as diabetes, Parkinson's and Alzheimer's.

An examination of every incremental step of any endeavour would lead to exaggeration, and therapeutic cloning is no exception. But behind the optimism lies a deep divide among scientists about the real benefits that therapeutic cloning could bring. Many of those working in the field believe that the technique is too elaborate, too complex and too expensive to succeed as a commonplace therapy.

"If you look within the scientific community, there's a sharp division between those who see what has rather prematurely been called therapeutic cloning as a viable clinical procedure, and those who regard it as purely a useful research tool," says Richard Gardner, the Oxford University embryologist and chair of the Royal Society's working group on stem cells and therapeutic cloning.

The principles behind therapeutic cloning are relatively straightforward. Take diabetes, a disease in which pancreatic cells degenerate and fail to produce insulin. Doctors would take a few skin cells from the diabetic and extract their cell nuclei, the biological pouches that contain DNA. These nuclei would then be implanted into donated eggs which have been hollowed out, so they have no DNA of their own. A tiny jolt of electricity or a squirt of chemicals then stimulates the eggs to divide into a tiny ball of cells no bigger than a pinhead.

From this tiny clump of cells, scientists can extract stem cells, which potentially can form any of the hundreds of different tissues in the body. In the case of diabetes, scientists will try to nudge the stem cells down the right developmental path to turn them into fully functioning pancreatic cells. Because the cells were created using the patient's own DNA, they could be implanted into his or her pancreas without the risk of immune rejection.

Research into therapeutic cloning is at such an early stage that almost every step of the process is fraught with difficulty. Cloning is so inefficient that typically hundreds of eggs are used in trying to create one embryo from which stem cells can then be harvested. Last year Korean scientists who created the first stem cell line from cloned human embryos used more than 200 eggs.

The high failure rate is often blamed on genetic abnormalities, themselves a result of the "cell nuclear transfer" process. Quite what goes wrong is a question that has for the most part baffled scientists. "At the moment, we just don't know how to increase the efficiency of nuclear transfer, and that remains the biggest problem there is," says Konrad Hochedlinger, a cloning expert at the Whitehead Institute in Cambridge, Massachusetts.

If therapeutic cloning is ever going to be a widespread clinical procedure, scientists need to make at least one huge advance. "We either have to find another source of eggs, or we'll have to get the efficiency up to 25% or 50%," says Stephen Minger, a lecturer in bio-medical sciences at King's College London, who recently deposited the first stem cell lines in a new bank in Hertfordshire that will reduce the number of eggs needed for basic research.

Work is continuing to improve the efficiency of cloning, but some groups are hunting for alternatives to donated eggs. One option is to take biopsies of ovarian tissue and use them to produce mature eggs in the lab.

Even if scientists can come up with an alternative source of eggs, they must still work out how to convert stem cells taken from early-stage embryos into human tissues. Scientists know that chemicals released by nearby cells and molecules within the stem cells themselves play a role in determining the type of tissue the cells will eventually grow into, but so far it has proved tough to mimic the process in the lab. Researchers working with animals have had some successes, among them differentiating mouse stem cells into neural tissue.

But, according to Minger, no firm recipes of how to turn stem cells into one tissue or another have been published. "The consensus- is that it is more to do with chance than anything else," he says. "To be clinically relevant, we need procedures people can replicate in 50 labs around the world. Otherwise, they might as well not work."

For all the difficulties in trying to make therapeutic cloning work, some tantalising successes in animals are fuelling optimism. In 2002, Hochedlinger and Rudolph Jaenisch at the Whitehead Institute showed for the first time that therapeutic cloning could be used to cure a genetic disease. The scientists took skin cells from a mouse with a genetic disease similar to "bubble boy" syndrome, which renders immune systems so weak that sufferers have to be kept in sterile environments. Using cell nuclear transfer, the scientists created early-stage embryos from which they took stem cells, all of which carried the genetic defect that caused the immune disease. In something of a master stroke, Jaenisch and his team then succeeded in correcting the defect in the stem cells, which, when injected into the mouse, cured it of the disease. The process was elaborate, but it worked for a disease for which there are few effective treatments.

Rather than therapeutic cloning becoming a therapy in its own right, it is its usefulness as a tool for studying disease that will really have an impact, says Irving Weissman, a developmental biologist at Stanford University.

"For me, the greatest and most important thing that'll come from this is a whole new platform to understand human genetic diseases," he says. "For the first time ever, you can have the authentic human disease to work on, right there in cells in front of you." Weissman says the technique will allow scientists to study some of the best known genetic diseases, from diabetes to early-onset heart disease, find out precisely what genetic fault is responsible, and from that develop ways of treating them.

Weissman is one of the optimists: "Anyone- who says therapeutic cloning won't happen based on where we are today is naive. It's wrong to hype it as something that will happen in the next five years, but it will happen."

At Newcastle Murdoch and Stojkovich now have the chance to see just how difficult human therapeutic cloning will be. "It could be that it works in humans straightaway, or it could turn out to be much tougher than doing it in animals," says Murdoch. "There are big hurdles, but none is insurmountable. If you think back 25 years to when IVF first started, if we'd given up when the first few attempts didn't work, we'd never have the routine service we have now. The potential benefits of what we are doing are so great, we'd have to have several years of it not working at all before we'd even think of giving up on it."