John Gurdon's share of the 2012 Nobel Prize in Physiology or Medicine with Shinya Yamanaka is a timely reminder of Europe's deep roots in the biological science underlying stem cell research.
Gurdon's recognition comes fully 50 years after his classic 1962 nuclear transfer experiment, which demonstrated that the nucleus of a fully differentiated cell from the intestine of a tadpole remains totipotent and capable of generating a complete organism.
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Europe is still at the forefront of stem cell research, with international leaders, such as Hans Schöler and Oliver Brüstle in Germany; Hans Clevers in the Netherlands; Elena Cattaneo in Italy; Petr Dvorak in the Czech Republic; and Austin Smith and Ian Wilmut in the UK. But Gurdon's Nobel prize comes at a time of real anxiety for European stem cell scientists, as the political debates that will determine the overall European Union budget for the 2014–2020 period, as well as the budget for the European Commission's (EC's) Horizon 2020 programme, start to heat up.
Four members of the 754-member European Parliament are threatening a legal challenge to Horizon 2020 if it continues support for human embryonic stem cell (hESC) research. "It is a real concern that they won't allow human embryonic stem cell research," says Christine Mummery, Professor of Developmental Biology at Leiden University Medical Centre.
Patent ruling
The four MEPs, Peter Liese (EPP, Germany), Miroslav Mikolasik (EPP, Slovakia), Gerald Häfner (Greens-EFA, Germany) and Konrad Szymanski (ECR, Poland) and other opponents of hESC research have been energised by the controversial October 2011 ruling of the Court of Justice of the European Union (CJEU), which holds that any innovations derived from hESC research are unpatentable.
These opponents are now seeking to tear up the rules under which hESC research has been conducted in Europe for the past decade. The European Commission’s Directorate for Research & Innovation is keen to maintain the status quo, a compromise originally hammered out during the Sixth Framework Programme (FP6) and carried forward to Framework Programme 7 (FP7). This requires researchers to follow the national rules governing hESC research in their respective countries, which takes account of the contrasting attitudes to the research across the EU's 27 member states.
Ireland, the home country of the Commissioner for Research & Innovation, Máire Geoghegan-Quinn, will have a key role in the political debate on the future of stem cell research, as it will hold the EU Presidency for the first six months of 2013, during which many of the finer details of Horizon 2020 will be thrashed out.
Ireland is one of Europe's laggards in engaging with hESC research - it has yet to pass legislation on the issue, and summarily disbanded the Irish Bioethics Council in 2009 after its publication of a report calling for the introduction of a liberal regime. "Ireland is now important to the future of all European research for the next ten years at least," says Stephen Sullivan, chief scientific officer of the Irish Stem Cell Foundation. "My fear is that officials from Ireland won't have a full appreciation of the issues that European stem cell research is facing."
In general, the position of most countries on hESC research has not shifted greatly during the lifetime of FP7 - national laws, where they exist, were laid down earlier. According to data from the EC-funded site eurostemcell.org, eleven EU member states permit the derivation of hESC lines from embryos generated during in vitro fertilisation procedures that either are unsuitable for or are not needed for implantation.
Generation of cell lines
Three of these countries, Belgium, Sweden and the UK, also permit, in limited circumstances, the generation of cell lines from embryos created by somatic cell nuclear transfer. This is essentially the same technique pioneered 50 years earlier by Gurdon and involves inserting the nucleus of an adult cell into an egg cell and then stimulating it to start dividing.
Germany does not permit the derivation of hESC lines, but it does allow work on imported lines generated before 1 May 2007. The country remains one of Europe's powerhouses in stem cell research, although its strengths in the field have been overshadowed by controversies, foremost among them being Greenpeace's legal challenge to patents on neural precursor cells, which Oliver Brüstle, of the University of Bonn Medical Centre, derived from hESCs.
That case is continuing. The German supreme court had sought legal clarification from the CJEU last year, and is hearing further legal arguments this month (November 2012) before finalising its decision. Although many feared that the 2011 ruling would dampen prospects for commercial stem cell therapies in Europe, the issue is far from settled, according to Nick Bassil, a partner at London-based patent attorneys Kilburn & Strode. "It does leave open the door for further challenges. It's not as fixed as some people suggest," he says. "It will be interesting to see how other national courts approach this when they have similar cases before them."
Embryonic stem research remains essential
If Europe is to remain internationally competitive in stem cell research, continued support for hESC research is necessary. Although Shinya Yamanaka's development in 2006 of a simple technique to induce pluripotentcy in adult somatic cells has shifted the focus of stem cell research considerably, hESC research remains essential at this point in the field's development. "We still need human embryonic stem cells as a benchmark," Mummery says.
That scientific reality is reflected in funding for stem cell research under FP7. Between 2007 and 2011, 55 research projects involving some aspect of stem cells received €338 million; eighteen of these involved hESCs and received €107 million. Final figures for 2012 are not yet available, but foremost among the new clutch of projects is StemBancc, an ambitious €52 million initiative, led by Zam Cader at Oxford University.
Funded under the pharmaceutical industry-backed Innovative Medicines Initiative, StemBancc will recruit some 500 patients and healthy volunteers, from whom it will generate over 1,500 human induced pluripotent stem (iPS) cell lines for use as probes in drug discovery and drug toxicology research. "Genomic studies of disease have got a bit stuck," Mummery says. "iPS cells can exhibit phenotypes that allow comparisons between diseased and healthy cells."
Basic stem cell biology
Large-scale EC-funded stem cell collaborations of this kind represent a kind of 'champions league' for stem cell researchers in Europe. They complement national initiatives, which, inevitably, vary in scale and focus. Philanthropic funding has been an important source of cash for some of them. DanStem, the Danish Centre for Stem Cell Research, established in Copenhagen in 2011, received a ten-year DKK350 million (€47 million) grant from the Novo Nordisk Foundation, for example. The centre is focused on basic stem cell biology, but it also has ambitions to translate its findings into new approaches to cancer and diabetes therapy.
Software entrepreneur Dietmar Hopp, a stalwart supporter of Germany's commercial biotechnology sector, has also backed his country's stem cell research efforts. In October, his foundation announced that it was doubling its support for the Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), bringing its total commitment to €15 million.
HI-STEM, which the Dietmar Hopp Foundation jointly established in 2008 with the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), is focused on the detailed study of cancer stem cells and has ambitions to develop therapies particularly for patients with late-stage cancer.
Industrialising production of stem cell therapies
Industrialisation initiatives, which will move cell and stem cell therapies from academic laboratories into full-scale manufacturing environments, are also getting underway. CellforCure is leading a French consortium that investing €80 million in a facility at Les Ulis, near Paris. It will initially take on five clinical stage programmes which consortium members are developing. A similar UK initiative, the Cell Therapy Catapult Centre, is being developed at Guy's Hospital in London.
Translating stem cell science into clinically useful therapies remains an early stage effort, and many companies across Europe are struggling to raise the necessary finance. "We have a very good academic base," says Michael Hunt, CEO of Guildford, UK-based stem cell therapy developer ReNeuron plc. "We just don't seem to be very good at translating that into commercial businesses."
Nevertheless, one company, TiGenix has gained approval for a cell therapy, and several others are conducting clinical trials. For stem cell therapy to deliver on its enormous promise will require continuing investment at all stages of research, from the academic lab through to the clinic. The future shape of Europe's participation in much of this will be determined in the coming months.
Cormac Sheridan has covered the European and global biotechnology industry for the past 15 years, during which time he has been a correspondent for BioWorld and a regular contributor to many other international publications.
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