Editor's Note: This is part three of a three-part series on global stem cell research. Parts one and two ran in Wednesday's and Thursday's issues.

EDINBURGH, Scotland - More than 200 scientists worldwide convened in early March at a two-day conference to discuss not only the science of stem cell research, but also the regulatory, financial and ethical implications of the field.

The Scottish Stem Cell Sciences Network, a two-year-old organization funded by a government arm called Scottish Enterprise, brought leading scientists here in an effort to capitalize on the innovation in the region, and to educate potential investors.

While those scientists work to find applications for their research, they all need money. And with more countries - like the U.S. - providing public funds for that research, the competition is rising.

"Like everybody else, I don't want to be second or third," said Austin Smith, head of the Institute for Stem Cell Research in Edinburgh.

Who would, when the research is so painstakingly hard and the promise so great? Embryonic stem cells are attained from pre-implantation embryos about a week old, making them ethically controversial. But it's the potential of stem cells, in general, that propels forward the research. Stem cells divide, producing copies of themselves and other cell types, and could be used to repair tissue such as skin, muscle and gut. They could bring to light what controls normal cell development. They could be used to replace damaged cells that can't be replenished on their own. Through differentiation, they could become blood cells and muscle cells, nerve cells, heart cells or insulin-producing cells, playing a crucial role in treating Parkinson's disease, heart disease, diabetes, cystic fibrosis, multiple sclerosis - the list goes on.

U.S. Tempts European Scientists With Stem Cell Dollars

At one time, Europeans saw the U.S. as no threat in the race to find a scientific application for stem cell research, in part because President Bush's decision to limit federal funding to certain pre-determined cell lines hurt the science in the States. But that merely was a bump in the road, they say, and California's Proposition 71 has changed things.

"The Americans are just so flexible, so even though they have a ridiculous federal policy, they just get around it," Smith said. "They just move to California."

Now some European scientists, struggling to conduct research on tight budgets, are being lured by the Americans.

"The California institutions are just going around knocking on people's doors," Smith said, "and that's going to really ramp up in the next 12 months."

Edinburgh's Stem Cell Sciences Ltd. (SCS) soon plans to establish an American office where it will license out its stem cell assays for use with drug discovery. The company has offers from seven U.S. states. While CEO Peter Mountford would not say which states made the offers, he noted that several are earmarking public funds for stem cell research. In addition to California's $3 billion, Illinois and New York each are setting aside $1 billion, while Wisconsin is budgeting $750 million for its scientists. New Jersey and Massachusetts are expected to supply money, as well, Mountford said, adding that public funding is an important component to stem cell research since the science is in the early stages and a financial return is not imminent.

"It's a long time to market," he said, "and unattractive to investors."

Scientists Work Around Ethical Concerns

While state government support is increasing in the U.S., public opposition of using embryos for research remains strong. Some scientists are trying to find ways to conduct research with the support of conservative political and religious leaders. Professor William Hurlbut, of Stanford University, who serves on the president's Council on Bioethics, is developing a proposal that could bring Americans closer to a consensus. He suggests using a process called altered nuclear transfer. By genetically modifying a human egg cell, the process could create embryonic stem cells without creating embryos.

"I think it's a pragmatic move in the environment that he's got to work [in]," Mountford said.

The scientific possibility has gotten the attention of Gov. Mitt Romney, of Massachusetts, a potential candidate for the 2008 presidency and a staunch opponent of creating embryos for the purpose of stem cell research. Romney is trying to find ways to support stem cell research in his state without compromising the ethics of working with embryos.

Swedish company NeuroNova AB avoids some of the pitfalls of stem cells in two ways. First, the company is working on the therapeutic potential of adult stem cells, which do not carry any of the ethical concerns that embryonic stem cells do. Second, rather than having transplantation as a main goal, the company is focused on therapeutic neurogenesis, the stimulation of endogenous cells to generate new neurons via therapeutic proteins and small molecules.

The company has a cell-therapy program, as well, but is focusing its efforts mainly on therapeutic neurogenesis to investigate orphan indications, cognitive impairment, Alzheimer's disease, Parkinson's disease and stroke. It expects to be in the clinic by 2006.

"We are absolutely exploiting what stem cells can do," Ulf Ljungberg, CEO of NeuroNova, told BioWorld Today. "But it is easier to use substances because you don't need to worry as much about what people think about stem cells - rationally or irrationally."

The advantage of therapeutic neurogenesis is that it is a pharmaceutical approach, and thus somewhat immune to the ups and downs of stem cell regulation on embryonic stem cells. But there is the power of association, and scientific concerns over one type of stem cell, such as the motor side effects of fetal stem cell transplants or the tumorigenic effects of embryonic cells, likely are to cast a pall on all types of stem cells for both regulators and investors. Using therapeutic neurogenesis as an approach, rather than cell transplants, is one way to get around those concerns.

Tight Controls Needed For Public Comfort

Europeans feel strongly that the U.S. government needs to get a system in place to better govern companies and researchers. The UK, for instance, gives out a limited number of licenses to its scientists.

"In the U.S., we find it quite strange that companies can do whatever they want to do," Mountford said. "We think it should be very transparent, very regulated."

And that regulation should be equal for everyone, said Anders Bjorklund, head of the Swedish section of EuroStemCell, a pan-European stem cell research effort.

"In Sweden, it's the same legal framework whether you are in a company or in academia," he said.

While some believe the government should step aside and allow businesses to operate, many Europeans feel that tighter regulation of stem cell research is an advantage and the lack of control in the U.S. is fueling the public outcry against embryonic stem cell research. That public dissent, they say, is not so readily found in Europe.

"I think that's actually why it's supported by the community, because they know it is tightly regulated," said Marilyn Moore, coordinator of the Scottish Stem Cell Sciences Network. "Nobody is going to be allowed to go off and do anything without it being rigorously reviewed, scientifically reviewed, ethically reviewed and morally reviewed. It's very tightly controlled, and I think that's an important aspect of the public's faith in this."

Boo Edgar, founder and head of business development of Cellartis, a Swedish company that has the largest number of embryonic stem cell lines available, agrees, at least partially.

"It depends on where you are supported from," he told BioWorld Today. "But we are very fortunate in that sense - lawmakers have put forward laws on how to deal with stem cell research. Swedish laws have regulated research with fertilized eggs since 1991," he said. "For both companies and investors, this legal framework limits our risk."

However, tight control is not uniform across Europe, Bjorklund said, but "it is true that in some countries, particularly in Northern Europe, regulatory conditions are quite favorable."

In other countries, not so much: Germany has put restrictions on embryonic stem cell research that are similar to U.S. federal restrictions, except that, as Bjorklund dryly noted, "they are tougher on the legal consequences" of ignoring those laws.

Bjorklund said the situation in the U.S. ultimately might resemble Europe, with different regulations coexisting in different jurisdictions.

Regulations Not Enough; Scientists Secure IP

In the UK, Roslin Institute's Ian Wilmut holds licenses for his research in the area of stem cells and cloning. He led the team that cloned Dolly the sheep in 1996.

"One of the things that we had to demonstrate to the regulatory community was that cloning would provide opportunities that you could not get in any other way," he said.

But while Wilmut has his licenses, some European stem cell advocates say the current controls in Europe are not enough. Scientists could encounter the same protests they saw in the 1990s, when genetically modified organisms were introduced to the food supply. And if the public protest is not enough, scientists also could face litigation.

"If you can get sued for getting burned with hot coffee at McDonald's, imagine what can happen with something as complex as this," said Alan Colman, a molecular embryologist who once worked at Edinburgh-based PPL Therapeutics plc.

Colman moved to Singapore a few years ago after being offered a $6 million grant for research focused on creating insulin-producing stem cells for diabetics. To be successful as a commercial entity, scientists need to establish their intellectual property early and thus draw investments, Colman said

Geron Corp., for example, holds licenses to some of the University of Wisconsin's WARF (Wisconsin Alumni Research Foundation) patents, which permit the Menlo Park, Calif.-based company to use cardiomyocytes, islet cells and neural cells for therapeutic purposes. While some scientists complain that IP restricts independent research, companies such as SCS and Geron have said they would allow non-commercial academic researchers free access to cell lines and proprietary information.

"It is not something that we're trying to withhold people from doing," said Jane Lebkowski, Geron's senior vice president of regenerative medicine. "Many different firms, many different universities, many different groups hold little pieces of the puzzle."