Joeri Borstlap

The public launch of the European Human Embryonic Stem Cell Registry this January in Berlin raised two important questions related to the controversial discussions in Germany about embryonic stem cell research: first, why is such a project coordinated by a German initiative in light of the restrictive human embryonic stem cell law, and second, is the registry a challenge to the strict German legislation on embryonic stem cell research? This commentary will answer those questions by explaining how the project came to be and what we hope it will do to advance stem cell science.

Information on nearly two hundred cell lines with input from many countries

The European Human Embryonic Stem Cell Registry (hESCreg) is not a cell bank. It is a registry holding a comprehensive collection of information on human embryonic stem cell (hESC) lines that have been derived in Europe or are being used in European Union (EU)-based projects. Among the explicit goals of the registry are to contribute to the development of international standards in the field and to harmonize with other international initiatives, banks and projects.

The European Human Embryonic Stem Cell Registry is now online

hESCreg is funded within the 6th Framework Programme for Research and Technological Development of the European Commission and is not based solely in Berlin. It is jointly coordinated by Joeri Borstlap, from the Berlin-Brandenburg Center for Regenerative Therapies (BCRT) at the Charité Universitätsmedizin Berlin, and Anna Veiga, from the Barcelona Stem Cell Bank at the Centre of Regenerative Medicine in Barcelona (CMRB), in Spain. Glyn Stacey, from the UK Stem Cell Bank, based in Hertfordshire, UK, who brings in expertise relating to quality assessment and banking issues, and Andreas Kurtz, also from the BCRT and former head of the competent authority regulating stem cell research in Germany at the Robert Koch Institute, in Berlin, are lead partners of hESCreg. A network of 12 individuals form the steering committee, serving as national contacts in all European countries that allow research with hESC.

When the database became publicly available, the project's steering committee, its Scientific and Ethics Advisory Boards, and many international representatives from hESC-related organizations celebrated the launch in Berlin. From that point until September, we are soliciting feedback and conducting our own evaluations on how to improve the technical structure of the registry and further develop its scientific content. The specifications of the basic scientific content and registration criteria are being coordinated in Barcelona. The technical specification of the database, design of the website, functional programming and data storage are being carried out at the BCRT in Berlin, as is the selection and collection of extended scientific, preclinical, clinical and other information, and the programming of both a knowledge base and dedicated data-evaluation tools.

Fully in line with the European Group on Ethics

The project originated from a recommendation of the European Group on Ethics, based in Brussels, which is an advisory board to the European Commission. Strict ethical guidelines adopted by the European Commission in 2003 called for proposals to set up a registry and contribute to public banks. “In this way,” the Commission stated, “the EU will contribute to an optimal access to and use of stem cells, ensuring that the results of research ultimately become more quickly available to all patients across Europe." A joint proposal from the groups in Berlin and Barcelona was submitted in November 2005. This was awarded funding in mid-2006, and contract preparations began in March 2007. We assembled information from the 12 national contacts, and we presented the first inventory of hESC lines in Europe at a meeting at the CRMB in June 2007 when the project was announced to the general public. An intermediate website with background information about the project has been available since then. The first access to the system was available to the providers of hESC lines by October 2007, when the database was enabled to accept cell-line data from providers. The goal is to reach full coverage of all European lines available by the end of 2008.

The biggest challenge of the project is not planning and implementing the database architecture, but reaching the providers of lines and supporting entry of information into the system. In June 2007, at the first hESCreg symposium, we had 176 cell lines listed, but already at the symposium in Berlin in January 2008, we found out about several additional ones. Of these 176 lines documented in the database, about 100 have detailed information either provided or authorized by their originators, which means that this project has already become a success, and we are very grateful for the tremendous support of all the scientists who painstakingly entered data and provided feedback in their spare time. I hope all these people will be recognized through a system in which it is possible to compare the characteristics of different lines in a systematic way.

A registry in Germany can inform debate across Europe

There are some areas of hESC research that the European Commission will not fund, including human cloning for reproductive purposes, research intended to modify the genetic heritage of human beings and research intended to create human embryos solely for the purpose of research or stem cell procurement. National policies do vary, however, and a comprehensive registry contributes to transparent mapping of differing national opportunities and restrictions for hESC research in Europe. For example, hESCreg provides a regularly updated map of Europe showing the cell lines available and the legislative environment in each country. We plan to link this map to the database and offer users country-specific filters.

In principle, research with hESCs is illegal in Germany according to the German Embryo Protection Act. However, the German Stem Cell Act grants certain exceptions after strict scientific and ethical reviews. As of February 2008, no research is permitted on hESC lines derived after 1 January 2002. Also, any violation of the act's provisions is a criminal offence (link in German) for which researchers may face imprisonment of up to three years. German stem cell researchers are effectively isolated from collaborations because even joint research within the context of international projects may be criminalized. Recent debates in the German parliament on amending the Stem Cell Act have been put forward by interest groups that go across all political party lines. The proposals range from an outright ban to upholding the present status quo, to shifting the cutoff date to May 2007, to the complete liberalization of hESC research, with the cutoff option deemed most likely to be adopted. Also very important for German researchers is the proposed weakening of the criminalization clause. This would allow researchers to work in international cooperation as long as the 'forbidden' cell material is stored outside Germany.

Because the hESCreg project carries out no direct research with hESC lines and does not work with actual cells, it would be fully legal in Germany no matter which of the proposed changes to the Stem Cell Act were adopted. The database provides a transparent source of information as a basis for further qualified political debate. Indeed, hESCreg is an infrastructure project, and its purpose is not to stimulate the derivation of new hESC lines but rather to prevent such production by informing researchers of lines that already exist and are available. The project also supports research by providing qualified scientific information in a standardized way with accompanying data-evaluation tools.

Germany's strong voice in the European Parliament influenced the debate in 2003 and pushed the demand for a hESC registry. In May 2007, the registry took an important role in the German debate and was recognized as an essential source for informed political decision making. Some politicians even argued that policies should only support research on lines included in the registry. In such cases, in Germany, only cells documented in the registry as complying with our guidelines would be legal for research. Elsewhere, EU funding would only be granted for cell lines in the registry, similar to the current situation for National Institutes of Health funding in the United States.

In both Germany and the United States, debate focuses on the status of the embryo and the value of life in terms of 'destroying' potential human beings. However, because the embryos used for hESC derivation would have been destroyed anyway and never have had a chance to be implanted and developed to birth, the discussion circles around the question of whether these embryos should be generated in the first place and to what extent human embryos should be exploited and used for the potential benefit of others. I personally think there is a sensible relation between the current legislative situation and both countries' historic pasts in which there were strong eugenistic programmes embedded in former political systems. Seen from this perspective, Germany provides a perfect political environment from which the hESCreg project could contribute to this debate as an information source for the scientific community and the general public.

Making cells broadly applicable in regenerative medicine and clinical projects

One positive effect of the restrictive German political situation is the creation of a 'German condition' with regard to regenerative medicine: compared with most other countries, work in Germany in this field is not primarily centred on embryonic stem cell research. Rather, the field is more broadly defined and there exists a tighter inclusion of other disciplines like cell-based therapies, immunology, material sciences and a wide range of surgical disciplines. The German 'art' of engineering also affects the direction of regenerative medicine and leads to a very competitive focus on translating basic research findings into medical products. hESC research offers ideal reference material to any kind of standardization necessary for stem cell therapy, whether it involves work with adult stem cells or stimulating endogenous cells.

In Germany today, 4 out of 20 groups are working within the genius loci of Berlin on hESC research projects. James Adjaye, at the department of Hans Lehrach, one of the contributors to the completion of the HUGO project at the Max Planck Institute for Molecular Genetics, recently was the first researcher in Europe to reprogramme adult cells back into the pluripotent state. The group of Daniel Besser works on signalling pathways, and Iduna Fichtner is testing the functionality of hESC in mouse models — both at the Max Delbrück Center for Molecular Medicine at the very same campus where Max Delbrück, together with K. G. Zimmer and N. W. Timofeev-Ressovsky, laid the foundations of molecular biology in the middle of the last century (Timofeev-Ressovsky, N. W., Zimmer, K. G. & Delbrück, On the Nature of Gene Mutation and Gene Structure , Weidmannsche Buchhandlung, Berlin, 1935; link in German). At the Charité Universitätsmedizin Berlin, one of the four campuses was named after Rudolph Virchow who, back in the nineteenth century, formulated the paradigm of modern cellular pathology. It is at this campus that the Bioreactor Group of Jörg Gerlach is working with hESCs in three-dimensional culture systems both for basic research as well as for scale-up in a clinical setting. For example, one of his aims is to differentiate hESCs into functional hepatocytes in ex vivo liver-support systems for cell and tissue transplantation or for the production of mediators.

One long-term goal of the hESCreg is to offer a platform to compare clinical research results in a standardized way. First steps in this direction are the partnership with the UK Stem Cell Bank and the collaboration with the International Stem Cell Initiative of the International Stem Cell Forum. Also, many further collaborations and contacts have been established with organizations in the field such as the Stem cell Network of the Asian-Pacific region (see Asian-Pacific researchers and officials form stem-cell network), the International Society of Stem Cell Research and the International Consortium of Stem Cell Networks. We are also planning a central German cell bank specially dedicated to cell-based therapies and clinical studies.

Even with the advent of nonembryonic pluripotent stem cells, I think hESC research is still necessary to verify hypotheses. As knowledge grows over the fundamental mechanisms of pluripotency, self-renewal, and differentiationI expect therapeutic approaches to shift from injecting cells to techniques that stimulate endogenous regenerative processes. This will be a long road, and many comparative and clinical studies will be necessary. Until we become able to more directly control regeneration, cell banks can set standards and provide common material to different labs. The registry might develop into a knowledge base providing both access to this material and comparison tools.

As our understanding of the mechanisms of regeneration advances, it may well be that the ethical debate will shift from the question about the status of the human embryo to the more fundamental questions related to the advantages and disadvantages of changing our very basic building blocks and human biological substance.