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Navigating the Stem-Cell Research Maze

credit: NIH

After completing a Ph.D. in biochemistry at the University of Patras in Greece, her home country, Evangelia Papadimou decided to switch to embryonic stem cell research. She spent two post-doctoral years working on mouse embryonic stem cells in France with a Marie Curie Fellowship. "My hope was to work on human embryonic stem cells" and stay in France, she says. It didn't work out that way.

Although many young European scientists weigh good opportunities to do research against proximity to home when deciding on their next position, Papadimou also had to take into account another factor: the political climate of potential host countries. "I wanted to do this in France, but ... they didn't have the right to work on" human embryonic stem (hES) cells--until it was time for her to leave. Surprisingly, it was in Italy--one of the least permissive countries for stem cell research--that she found the opportunity that suited both her professional and personal aspirations. "I came to Italy because of the strong tradition of the University of Milan Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases and its participation to the exciting, E.U.-funded EuroStemCell project. I saw I would have the chance to work on human embryonic cells ... and stay in Europe." Still, in such a strong Catholic country, the climate for her research is "a bit difficult," she says.

Evangelia Papadimou

Papadimou's experience illustrates the maze of opportunities--and obstacles--that Europe offers embryonic stem cell researchers. Opportunities are strong, but it is often necessary to adapt attitudes--and sometimes the work--to radically different policies when crossing otherwise open national borders. Whereas places like the United Kingdom and Sweden allow researchers to pursue hES cell research with few restrictions, researchers in other countries, like Italy and Germany, worry that local restrictions will push the field's most important advances out of their laboratories and outside their nation's borders. Researchers looking to build a career in the field must learn to navigate the European policy maze and adapt to the research and funding climates within the countries they end up in.

The European policy maze

These days it is common--especially for outsiders--to view Western Europe as a somewhat homogeneous place. But every European country has its own culture, religious beliefs, and history--so it isn't really surprising that each country also has its own way of dealing with a subject as sensitive as research involving human embryos. With scientists, ethicists, policymakers, and sometimes the Catholic Church weighing in, the spectrum of policies for stem cell research across Europe is complex and constantly evolving--which makes it even harder for scientists to choose a country and adapt to the local research climate.

On one end, countries like the United Kingdom and Sweden are among the most liberal in the world when it comes to hES cell research. Like most other countries, these two forbid reproductive cloning but allow both the destruction of embryos for the derivation of new cell lines and the creation of embryos by somatic cell nuclear transfer for therapeutic cloning. After the first hES cells were isolated in 1998 in the United States, Swedish researchers began working with hES cells under the guidance of a 1991 law that allowed the use of embryos to study early development. Although the research has always been legal in Sweden, further laws passed in 2003 and 2005 have clarified this initial law and formalised the ethical guidelines for this research. Therapeutic cloning was legalised in 2005.

Angel Raya

The United Kingdom amended its in vitro fertilisation (IVF) laws to legalise hES cell research in 2001. The Czech Republic also got an early start: The first cell lines available in this country were derived by Petr Dvorák and his group in Brno in 2003. A June 2006 law formalised the Czech regulations to authorise work with surplus embryos but forbids the creation of new embryos for research. (Editor's note: Here is some additional discussion of the situation in the Czech Republic.)

Not far behind is Spain, where the public and political climate is positive. Spain's political leaders are keen to help the nation's scientists join the field's leaders. The Spanish Act on Assisted Reproduction, passed in November 2003, made it possible for researchers to work on hES cells and derive new cell lines for the first time. Spanish researchers now eagerly await approval of a new biomedicine law, which, if passed, will authorise nuclear transfer experiments. France has also entered the field, but cautiously: With its new Loi de Bioéthique du 6 Août 2004, France still bans embryo research but grants 5-year exemptions to work on hES cells--and, since February this year, to derive new cell lines. The law will be reviewed in 5 years.

At the other end of the policy spectrum sit Germany and Italy. The German Stem Cell Act passed in July 2002 forbids either importing or deriving new stem cell lines, forcing researchers to work with cell lines derived before January 2002. The Italian IVF law of February 2004 bans the creation or destruction of an embryo for research purposes. But by not specifying any regulations regarding human stem cells, the law leaves researchers free to work on cell lines that are already established. By comparison, current U.S. policy prohibits researchers from using federal funding or infrastructure to derive new stem cell lines or work with stem cell lines derived after 9 August 2001 but allows researchers to do this research with private or state funding.

Funding: The bottom line

In a field like embryonic stem cell research, in which large initial investments are required, funding is even more important than in other scientific fields. Even in Sweden--where the government and the public see the importance of embryonic stem cell research and where government funding for research hovers around 4% of gross domestic product--researchers feel they need more resources. "Basically, the economy is the limiting factor here because it's a very, very expensive experiment," says Ernest Arenas, a professor at the Karolinska Institute in Stockholm. In December 2005, the British government increased its investment in stem cell research from 50 million pounds ($85 million) to 100 million pounds ($170 million). But even that investment doesn't come close to matching California's $3 billion funding over 10 years.

The wealthier and more permissive countries like the United Kingdom and Sweden have pots of money set aside for stem cell research. Even Germany, with its restrictive policies toward hES cell work, devotes national funding to stem cell research; its priority, however, is work on adult stem cells. Most researchers in Spain and the Czech Republic must compete for national research funds against scientists in other fields, although Spain has opened three new research centres for human stem cell research with funding from the central and local Spanish governments. The Center for Regenerative Medicine in Barcelona received 9 million euros for its building and first 4 years of operation. The Czech Republic lacks the money for such initiatives; developing its stem-cell infrastructure will require deeper pockets, like those of the E.U., says Eva Sykova, a professor at Charles University in Prague.

In Italy, the road is more difficult still. Given the unfavourable climate, "all [public] funding agencies and most private agencies exclude research on human lines," says Elena Cattaneo, head of the Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases at the University of Milan, where Papadimou also works. "If you want to work on human embryonic stem cell lines, the only hope is to get an E.U. grant. But these are very competitive grants, and young Italian groups that start on hES require first national money to develop the scientific competence necessary to then apply to E.U.," which makes it almost impossible for them to break in.

Although the E.U. offers funding aimed at facilitating stem-cell collaborations, the funds are tightly regulated. In addition to the usual scientific evaluation, to be funded, research proposals must also pass the scrutiny of the European Group of Ethics. The E.U. then requests an ethical approval from the host country--even if the research is legal there--and the research finally needs to be voted on favourably by a delegation of the 25 European governments. "This is a very careful way of the E.U. to deal with the diversity of opinions" in Europe, says Cattaneo.

Researchers in the less permissive countries fear they will be left out altogether. Oliver Brüstle, a professor at the University of Bonn and a stem-cell-research advocate in Germany, worries that German restrictions will limit his access to E.U. support and cripple Germany's competitiveness in the field. "We can only do limited work on imported cell lines generated before 2002," he says. "International projects such as E.U. consortia are switching to more superior, recently derived cell lines, which will systematically isolate countries such as Germany." Ironically, the funding Germany contributes to the E.U. is used to support research on newly generated hES cell lines in other countries, he adds--while German scientists carrying out such research could be prosecuted and imprisoned for up to 3 years.

A European culture of accountability and transparency

Malin Parmar

Even in permissive countries, European researchers have to get approvals to do their research and stick to strict regulations. "Even in the U.K., there's a lot of sensitivity about embryo research, and we do a lot of bioethical work despite the fact that we're scientists and we're not bioethicists," says Stephen Minger, director of the Stem Cell Biology Laboratory at King's College in London.

Although such regulations are bureaucratic headaches, Minger sees advantages in the European model in comparison to the policies in the United States that leave privately funded research unregulated."From early on, British researchers--and certainly researchers in Germany and Italy and France and Spain--have stuck their head up and said [hES cell research] is really important. And, yes, it is ethically contentious, and, yes, there are reasons that you might be opposed to this. But let's regulate it. Let's do it in a way where it's not hidden away [in] privately funded ... labs where there's no accountability. Let's do this in a way where there is total accountability and where everybody is aware of what's going on."

But even if they agree with the necessity of oversight, some scientists still worry that the regulations will stifle research. In France for example, researchers relish the opportunity they now have to do human stem cell research, but most would welcome some simplification in the regulations. The authorisation process in France takes about 4 months, and in 2006, there were only three calls for proposals. "If the project changes, ... you have to apply again; it's very cumbersome," says John De Vos of INSERM/University Hospital of Montpellier. "A control [from the Agence de la Biomédecine is possible any time," says Samir Hamamah, De Vos's boss. If irregularities are found, the authorisation may be suspended or taken away. The new law is "salutary," says Hamamah. Still, "the conditions are draconian. It explains why there aren't that many groups working on these projects." So far, only 20 or so research teams have been granted the authorisation to work on hES cell lines in France.

In the most permissive countries, the public is typically supportive of the work and well informed about its potential scientific and medical benefits. Still, human stem cell researchers should be prepared not to be the most popular scientists in town. Minger, for example, says he has received angry messages and even a death threat since he was granted one of the first two U.K. licences in 2002. In less permissive countries, researchers encounter one more obstacle: "the idea ... that what you are doing is wrong"--even among scientists, Cattaneo says. In some fortunately rare cases, her research has been boycotted at national meetings, she says.

So far in Italy, only six labs, including Cattaneo's, have publicly declared that they work on hES cell lines; these six went public in June as they defended their research against claims from politicians that hES cell research was illegal in Italy. "The way to solve these things is to diffuse the knowledge about human embryonic stem cells and what they can do," says Cattaneo. Together with three other colleagues at the university of Milan, in July, Cattaneo launched the Centre for Stem Cell Research to share knowledge with scientists and promote exchange and dialogue with the public.

A wealth of training opportunities

Vitezslav Bryja

The liberal policies in some countries and the wealth of cross-cultural collaborations have made Europe a good destination for researchers from around the world--including the United States, Australia, and Asia--to train in hES cell research.

European grants often facilitate collaborations among research groups. EuroStemCell, to which the Arenas, Brüstle, and Cattaneo labs belong, has a funding programme to help researchers exchange data and learn new techniques. Although short exchanges sometimes get the job done, some researchers have decided to pursue longer stays. The joint meetings of consortia such as EuroStemCell also offer young researchers opportunities to learn about the field and build connections with more-established researchers. "You know what people are doing ... [and] who to contact. And they will know you, which makes a big difference," says Malin Parmar, a Swedish postdoctoral researcher at the University of Edinburgh who is also taking part in EuroStemCell.

The choice of options makes researchers in countries with more restrictive policies worry that their brightest scientists might not return from postdoctoral stints in other European countries or even in the United States--specifically, California. Convinced of the promise of the plasticity of hES cells, Ilyas Singec, a German postdoc at the Burnham Institute for Medical Research in San Diego, California, sees far more opportunities in California than he does in his homeland. If he returns to Europe, he says, "it could well be that the U.K. would be the most attractive place in Europe to do ES cell research. Going back to Europe is one option, but not necessarily to Germany."

But where to settle?

Like Papadimou and Singec, many European researchers will ultimately have to find a balance between research and funding opportunities on the one hand and proximity to home on the other. Isabel Liste, a Spanish postdoc currently in Arenas's lab at the Karolinska Institute in Stockholm, has done postdoctoral work in Spain, France, and the United States. She plans to return home to take a junior faculty position in Madrid next year. Even though interest in embryonic stem cell research in Spain is growing, she worries that she may not get the funding opportunities there that she would in Sweden.

Still, Angel Raya, who returned to Spain in February 2006 after working at the Salk Institute for Biological Studies in California, notes that many expatriated Spaniards and young embryonic stem cell scientists from European countries like Germany, Italy, and France choose to work in Spain. "It's not so easy to work in the United States. Overall, the new legal and regulatory framework in Spain permits and, even more importantly, fosters research on hES cells, thus making our country a very attractive place for young scientists interested in being trained and/or pursuing these kind of activities," says Raya. Although he admits he was initially concerned about the longer-term funding prospects, in the current favourable political and public climate he now feels confident that the Spanish effort to fund and foster hES cell research will continue.

Vitezslav Bryja, a postdoc at the Karolinska Institute, also plans to return to his home country, the Czech Republic, to start his independent career. With permissive stem cell regulations and a growing investment in stem cell research, he sees far more positions available to him there than in other countries. Still, he's realistic about the risks that he and his young colleagues throughout Europe must take in pursuing the work. Because of the expense, small labs have to show results quickly to keep their funding, he says. Watching one small lab in Sweden dissolve after the researchers' funding wasn't renewed, he says, showed him that it's "important to be in a network. One cannot work alone, because this can be lethal."

Sarah Webb has a Ph.D. in bioorganic chemistry. She writes from Brooklyn, New York.

Elisabeth Pain is contributing editor for South and West Europe.

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