Development of a European Human Embryonic

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Englert, Yvon. Université Libre de Bruxelles. Belgium. Tanner, Klaus. Ruprechts-Karl University, Heidelberg Germany. Steering Committee members provide ...
SPECIAL REPORT Development of a European Human Embryonic Stem Cell Registry The number of human embryonic stem cell (hESC) lines that are available and that are subsequently being used in numerous research projects is increasing steadily. However, there is little coordination of hESC line derivation, and comparative information on the characteristics and quality of these cells is sparse. Obtaining consistent information on hESCs is hampered further by legislative fragmentation, particularly in Europe. Recognizing these obstacles, the European Commission has set up a Human Embryonic Stem Cell Registry (hESCreg) to make hESCs and their characterizing information accessible and to ensure that the results of research become more quickly available to the public. The primary objectives of hESCreg are to provide freely accessible information on existing hESC lines, their derivation, molecular characteristics, use and quality. Successful research with listed hESC lines will be used to evaluate clinical potential and thus directly influence policy decisions. The developing integration with other initiatives, such as characterization projects, registries and cell banks, is expected to lead to a common and internationally accepted central reference. The hESCreg provides a first step in this direction and might grow into an internationally funded and administered project. KEYWORDS: characterization, database, harmonization, human embryonic stem cells, registry, website

Human embryonic stem cell (hESC) research holds unprecedented promise for the development of cell therapies for degenerative pathologies and trauma. It may also provide new tools for drug discovery and toxicity testing, as well as for studying human development, disease physiology and gene control. The number of hESC lines that are available and that are subsequently being used in numerous research projects is increasing steadily [1–3] . However, there is little coordination of hESC line derivation and comparative information on the characteristics and quality of these cells is sparse. This has severely hindered reproducibility of findings and obscured transparency in the field. Obtaining consistent information on hESCs is hampered further by legislative fragmentation, particularly in Europe. This reflects the continent’s historic pluralism and the different ethical, philosophical and political positions (FIGURE 1) . Recognizing these obstacles, the European Commission has set up a Human Embryonic Stem Cell Registry (hESCreg) to make hESCs and their characterizing information accessible and to ensure that the results of research become more quickly available to the public. hESCreg has the mandate to improve coordination and rationalization of hESC research in Europe. The aim of using a comprehensive data source for measuring reproducibility and enabling comparability and transparency in the field has indeed received strong support from

the research community. A Steering Committee (StC), a Scientific Advisory Board (SAB) and an Ethics Advisory Board of leading hESC researchers has been established to provide this support to hESCreg (TABLE 1) . The primary objectives of hESCreg are to provide information on existing hESC lines, their derivation, molecular characteristics, use and quality. By doing so it will act as a platform for coordination and cooperation. A desirable outcome – accessibility of the information to governmental bodies, regulators and the public at large – may be further rationalization of the field. It will also help to avoid redundancy and ensure comparable quality standards.

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Registry of hESC lines & projects It is widely recognized that the complex and multidisciplinary nature of hESC research requires comparable information about the origin and availability of the cell lines, the methodology and standards for their derivation and their functional and molecular characteristics. Questions of reproducibility and standardization will be even more crucial when clinical or pharmacological applications are to become a reality. The registry aims to collect extensive information on every available hESC line. The major areas of hESC-related information are, therefore, cell derivation and culture methods,

J Borstlap1†*, A Kurtz2*, G Stacey3, A Elstner2, A Damaschun1, B Arán4, JC Gerlach5, JC Izpisúa5 & A Veiga4,6 †

Author for correspondence CellNet Ini a ve, Berlin–Brandenburg Center for Regenera ve Therapies (BCRT), Charité – Universitätsmedizin Campus Virchow-Klinikum, BCRT, Augustenburger Platz 1, D-13353 Berlin, Germany Tel.: +49 304 5053 9400; E-mail: joeri.borstlap@ charite.de 2 Cell Therapy Group, Berlin–Brandenburg Center for Regenera ve Therapies, Berlin, Germany 3 The UK Stem Cell Bank, South Mimms, UK 4 Center of Regenera ve Medicine, Barcelona, Spain 5 Gene Expression Laboratory, Salk Ins tute for Biological Studies, La Jolla, CA, USA 6 Ins tut Universitari Dexeus, Barcelona, Spain * Both authors contributed equally. 1

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A hESC research and derivation (IVF), SCNT hESC research and derivation (IVF) hESC research on imported cell lines No hESC-specific legislation in place No hESC-specific legislation in place, any kind of hESC research forbidden

B

Country

Number of hESC lines derived

Belgium

17

Czech Republic

7

Denmark

26

Finland

10

France

1

Israel

15

Netherlands

4

Spain

10

Sweden

64

Switzerland

1

Turkey

11

UK

34

Total

200

Figure 1. Legislative status and number of human embryonic stem cell lines derived in Europe. (A) Legislative Status of hESC derivation and research in EU27 and Switzerland, Norway, Turkey and Israel. (B) Number of hESC lines derived in countries that are represented by members of the hESCreg Steering Committee and Scientific Advisory Board. The information on the number of derived hESC lines were provided by the members of the hESCreg Steering Committee. hESC: Human embryonic stem cell; SCNT: Somatic cell nuclear transfer.

including donation of embryos and consenting aspects. Data on stem cell lines will include gene and protein expression, potency in vitro and in vivo and, fi nally, hESC application in research, medicine and industry. Numerous protocols for derivation and expansion have been used so far, but information on the comparative quality of cell lines generated by different approaches remains inconsistent [4–7] . ESCs have been derived with varying efficiency from single cells, morula-stage embryos, as well as from the inner cell masses of blastocysts, all of diverse morphological qualities [8] , and variable success rates have been reported [2,6] . hESCs were originally derived and cultured on mouse feeder cells with bovine serum supplements, but human feeder cells are now widely used and there has been progress towards feeder-free and clinical-grade culture systems [9,10] . In addition, it is foreseeable that hybrid and somatic cell nuclear transfer (SCNT) hESC lines will be derived, with 946

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the additional need to develop standardized characterization methods and means for comparability. The registry will therefore provide information for every single cell line regarding the source, stage, quality of the embryo, derivation procedure, culture methods and media used, and the current status of available lines. Alternative pluripotent cells such as parthenogenetic stem cell lines [11] , spermatogonial stem cells [12] and hESC-like pluripotent cell lines from reprogrammed somatic cells [13,14] are also under consideration for registration. Importantly, the hESCreg database will also provide information on the provenance of the cells, confirming that the embryos used to derive cell lines were obtained with informed consent from the donors. Pluripotent hESCs are characterized by their ability to differentiate into all cell types of the endodermal, ectodermal and mesodermal lineages and the expression of a typical set of genes and proteins. Several methods have been used to future science group

Development of a European Human Embryonic Stem Cell Registry

demonstrate pluripotency of hESCs, including in vivo teratoma as well as in vitro differentiation protocols. These characteristics appear to be extremely important for the future clinical or commercial use of these cells, since they allow directed, defined and, therefore, controllable and standardized manipulation. Standardization and comparability are also critically dependent on the data available regarding molecular markers for hESCs and their differentiated progeny. The typical and sufficient expression profile for the characterization of hESCs still remains an intense area of study. Recent research has compared hESC lines at the gene-expression level to understand molecular profiles of pluripotency and signatures of typical hESC lines [15] . The identity of the pathways that are essential for the pluripotent state is still not completely understood. Accordingly, the activity of relevant pathways in specific hESC lines will be registered in hESCreg. Data analysis & mining tools The molecular and biological data regarding each cell line will be included in a data mining tool using gene and cell ontologies. The complete hESCreg dataset will be formatted for comparative analysis, data mining and scrutiny. The aim is to enable researchers to use hESCreg as an instrument to independently derive and test hypotheses and associations about the features and potencies of the cells. Regulatory harmonization and standardization efforts may also be based on this information. Scientists can inform and choose from available cell lines, submit new findings about these cells and compare their own results with other groups. An example of this mechanism is the representation of the UK Stem Cell Bank in the hESC registry. The information generated by the bank on the cell lines it stores is treated as a data ‘supplement’ to the originally registered cell line information. Thus, independent and repetitive confirmation of cell-specific data will be visible to the user through active participation of scientists. This external validation process is aimed at transparently assessing the quality of a specific line in relation to other lines. The registry has implemented criteria for the registration of hESC lines. These basic criteria (‘registration information’) include information on the provider/owner and availability, cell derivation and culture methods, and gene- and protein-expression features that are necessary for the basic assessment of a hESC line (TABLE 2) . Registration of a hESC line requires submission of information to show that the cell is a pluripotent hESC. It includes embryo data future science group

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Table 1. Members of the Scientific Advisory Board, Steering Committee and Ethics Advisory Board of hESCreg. Name

Institution

Country

Andersen, Claus Yding

University Hospital Copenhagen

Denmark

de Guerra, Arnaud

Agence de la Biomedicine

France

Dvorák, Petr

Masayrk University Brno

Czech Republic

Hovatta, Outi

Karolinska Institutet

Sweden

Jaconi, Marisa

University of Geneva

Switzerland

Kurtz, Andreas

Charité Universitätsmedizin Berlin

Germany

Mummery, Christine

Netherlands Institute for Developmental Biology

Netherlands

Reubinoff, Benjamin

Hadassah University Hospital

Isreal

Sermon, Karen

Vrije Universiteit Brussel

Belgium

Stacey, Glyn

NIBSC, UK Stem Cell Bank

UK

Tuuri, Timo

University of Helsinki

Finland

González, Victor

Instituto de Salud Carlos III

Spain

Steering committee

Scientific advisory board Andrews, Peter

University of Sheffield

UK

Braude, Peter

King’s College London

UK

de Sousa, Paul

Roslin Cells Ltd.

UK

Dinnyes, Andras

Szent Istvan University

Hungary

Findikli, Necati

International Hospital Istanbul

Turkey

Ganten, Detlev

Charité Universitätsmedizin Berlin

Germany

Gerlach, Jörg

University of Pittsburgh

USA

Henriche, Domingos

Faculty of Medicine of Lisbon

Portugal

Hyllner, Johan

Cellartis AB

Sweden

Izpisúa, Juan Carlos

Salk Institute for Biological Studies

USA

Lako, Majlinda

International Centre for Life – Newcastle University

UK

McKay, Ronald

NINDS Porter Neuroscience Research USA Center

Menéndez, Pablo

Andalucía Stem Cell Bank

Spain

Michalska, Anna

Monash Medical Centre Stem Cell Laboratory

Australia

Peschanski, Marc

INSERM U421/IM3

France

Robertson, Marylin

Scottish Stem Cell Network (SSCN)

UK

Savatier, Pierre

INSERM U846

France

Simón, Carlos

Centro de Investigacion Príncipe Felipe Spain

Sunde, Arne

University Hospital of Trondheim

van Steirteghem, Andre European Society Human Reproduction & Embryology

Norway Belgium

Ethics advisory board Casado, Maria

Universitat de Barcelona

Spain

Englert, Yvon

Université Libre de Bruxelles

Belgium

Tanner, Klaus

Ruprechts-Karl University, Heidelberg Germany

Steering Committee members provide information regarding the human embryonic stem cell research in each country. Scientists of the Scientific Advisory Board represent the scientific core of the registry and have a determinant role in ensuring that adequate scientific criteria have been implemented and adhered to during the preparation and management of the registry.

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Table 2. Registration Information. Registration information

Categories

General

Information on the original cell line name and if the cell line is a subset of an already existing cell line. The provider also indicates if informed donor’s consent exists and if the donor is traceable. The cell line will be given a systematic registry name for traceablility within the registry. Information on whether the origin of the cell line is an embryo or an induced pluripotent stem cell. Information on the derivation method of the embryo (in vitro fertilization, somatic cell nuclear transfer, parthenogenesis). Information on the embryo stage for single-cell preparation. Information on whether the cell line is available or not. Information on the karyotype of the cell line, on the passage number at which the karyotype was determined and on any change of karyotype. Information on the genetic modification of the hESC cells whether it was inherited (genetic disorders) or induced (knockout, transgene). In vitro: Information on the method of in vitro differentiation into cells of all germ layers (e.g., spontaneous differentiation, embryoid bodies or directed differentiation). In vivo: Information on the method of in vivo differentiation (teratomas or chimeras indicating whether one, two or three germ layers were formed). hESC markers proposed as hESCreg standard: ALPL/CD9/DNMT3B/GABRB3/GCTM2/GCT343/ GDF3/NANOG/POU5F1 (OCT-4)/SSEA-3/SSEA-4/ TRA1–60/ TRA1–81/TDGF1/THY1 (CD90) Other hESC markers: REX-1/ SSEA-1/SOX-2

Derivation data

Availability Karyotyping Genetic modification Differentiation

Cell markers

Information on characteristics that are necessary for the basic assessment of a hESC line in Human Embryonic Stem Cell Registry. Registration and addititional information, as well as specific contents are dynamic and will therefore be adjusted as hESC research and the project develop. hESC: Human embryonic stem cell.

regarding the use of fresh or frozen embryos and if they have been obtained by in vitro fertilization, SCNT, parthenogenesis or other means. Karyotype data are requested and both in vitro and in vivo differentiation potency and markers of pluripotency have to be reported. A second level of information (‘additional information’) includes data from the screening of embryo donors, embryo quality information and derivation methodology details. Special attention is given to culture conditions, regulatory documents and publications. It is planned to extend this level of information with additional geneand protein-expression profi les and biological data, as well as with information on preclinical and clinical applications. Both ‘registration information’ and ‘additional information’ are regularly reviewed and updated. The database provides a public online ‘front end’, or homepage (FIGURE 2) , with listings of lines according to defined criteria and quality standards, search features and general background information, for example, regarding politics, ethics and news. A secure ‘back end’ can be reached after accepted registration. Here, providers can register cell lines and researchers can register research projects or enter publications. A data evaluation bar system indicates how much data are available on each registered hESC line [16] . With regards to hESC-specific characterization, a hESC line in hESCreg receives one bar if at least four markers proposed within 948

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the registration information of hESCreg have been evaluated by the provider together with the proof of differentiation into all three germ layers. The cell line receives another bar if the expression of a core set of markers (including NANOG, TDGF, POU5F1, GABRB3, GDF3 and DNMT3B) as proposed by the International Stem Cell Initiative [15] has been evaluated by the provider. Integration between the hESCreg and other registries may initially be facilitated by providing links to the respective sites. In the long term, however, a globally shared database should be established. Implementation of the logistic effort for this kind of global registry is presently in preparation. Quality assessment The quality of the data available from hESCreg is critical to its international scientific impact and its ethical acceptability within Europe. The registry first established criteria for ‘quality’ and, most importantly, what that means to the intended users. In addition, it is also responsive to how it will be perceived by the public and pressure groups who will wish to see a demonstration of correct handling of ethical issues. Strict evaluation of data provided for the project in an open, fair and scientifically rigorous process is essential. Sustaining a neutral position on the science and ethics is also essential, and the input of various advisors consulted in future science group

Development of a European Human Embryonic Stem Cell Registry

the development of the registry will be handled carefully. This will be vital to ensure that the natural debates that must be allowed in science and ethics are enabled whilst ethical matters are dealt with appropriately from a European perspective, acknowledging national differences, without compromising the value of the data accommodated on the database. There is strong focus on seeking quantifiable data that can be standardized for the different lines to enable direct comparison of data and

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information on the registry. Existing standards will be employed wherever possible and a consensus will be sought from the StC and SAB and other qualified sources where no standards exist. Protocols are established to deal with differences of opinion and other conflicts so that relevant discussions and alternate positions are dealt with in an open and fair way. In order to deliver various aspirations the key features of this project include a code of practice and detailed protocols for its operation and

Figure 2. Screenshot of the Human Embryonic Stem Cell Registry database homepage. The online access to information on hESC lines, research projects and publications is free. General background information, for example ethical issues, hESC research and funding, is available on the public front end. hESC: Human embryonic stem cell; hESCreg: Human Embryonic Stem Cell Registry. Taken from [106] .

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careful evaluation of risks for the quality of the registry for all stakeholder groups. In this way, it is intended that the registry will command the highest level of respect on an international level and could provide a model for resolution of international data on stem cells in a way that is scientifically robust and accommodates cultural diversity. Last, hESC lines generated in Europe will, for the first time, be listed and be accessible from a central database. International harmonization Since the field of hESC research is still in its infancy and expected to develop, the consortium is explicit in its openness to incorporate additional partners and to closely collaborate with European and international initiatives in the field. Cooperation and networking with European and global initiatives is facilitated through the SAB, workshops and scientific meetings. Furthermore, the European Commission has requested that the 18 ongoing projects that use hESC within the 6th Framework Programme for Research and Technological Development [101] should register these lines with hESCreg. Since there are a several non-European hESC lines under research in these projects, this documentation extends beyond Europe. In general, hESCreg aims to facilitate co-operations through modular extensions of the database. These extensions meet the specific requirements to cover the information from the respective projects and initiatives. These modules may be outsourced to external websites in which they can function as autonomous platforms that synchronize with the registry through defined interfaces. Within the hESCreg website, modules function as add-ons and modes of operation that may be switched on or off. Currently, this concept is being developed with the International Stem Cell Initiative (ISCI) and the International Cell Banking Initiative of the International Stem Cell Forum (ISCF) [102] , the UK Stem Cell Bank [103] , the International Society for Stem Cell Research (ISSCR), which plans to develop an international registry about the ethics and political conditions of hESC research [104] , as well as with the Ethics Initiative from the ISCF, which is coordinated by the Canadian Stem Cell Network. The registry aims to establish similar cooperations with further international developments such as: The Interstate Alliance on Stem Cell Research (IASCR), which also includes the California Institute for Regenerative Medicine (CIRM), and in which the US National Academies of Science play a central role [105]; 950

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The National hESC Bank in Wisconsin, USA, which is providing the cell lines that are available for use in projects of the NIH [102] ; The Stem Cell Network of the Asia–Pacific region (SNAP), including relations to China, the Academies of Science in Taiwan, the Center for Developmental Biology in Japan and the Australian Stem Cell Center [17] ; The International Consortium of Stem Cell Networks (ICSCN), a consortium of 14 national stem cell networks and an ideal forum to disseminate information about the project and to initiate international collaborations. The ICSCN has compiled a table of global regulations, policies and organizations regarding hESC research for its members [106] . Future perspective We expect the registry to promote knowledge exchange on the availability of hESC lines, but also to enhance transparency in the field on a scientific as well as on the socio–ethical, legal and policy levels. Successful research with listed hESC lines will be used to evaluate clinical potential, and thus directly influence policy decisions. It will also identify centers for certain cell applications that can improve training and exchange for European scientists. The developing integration with other initiatives such as characterization projects, registries and cell banks is expected to lead to a common and internationally accepted central reference. The hESCreg provides a first step in this direction and might grow into an internationally funded and administered project. Acknowledgements We would like to thank the members of the Steering Committee, Scientific Advisory and Ethics Advisory Board of hESCreg for their help in obtaining information on hESC lines derived and on the status of hESC legislation in their countries. We thank M Walthert (Berlin, Germany) and K Schenk for database design and Q Vinh Phan for support in graphical design.

Financial & competing interests disclosure hESCreg is supported by a grant from the European Commission as a Specific Support Action within the 6th Framework Programme for Research and Technological Development, contract number 037820. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial confl ict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

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Development of a European Human Embryonic Stem Cell Registry

SPECIAL REPORT

Executive summary Need for a registry The promise of new life-saving therapies through human embryonic stem cell (hESC) research is challenged by ethical issues that create a dilemma for some. This issue establishes the need for careful control of this work. A registry would provide a central reference for acceptability of use of hESCs in the EU. The Human Embryonic Stem Cell Registry (hESCreg) coordinates scientific, technical and ethical issues. Data hESCreg has established criteria for a registry. A front-end public area is presented with a certain data set. A back-end secure area enables access after registration and permits downloading project and banking data. A ‘bar’ system evaluates spread and depth of data available on each line. Links to other databases are anticipated and have been built into the planning. Quality Quality can be viewed from many perspectives, but it is vital that the perspective of database users are foremost. The public are primarily concerned with appropriate handling of ethical governance and promotion of therapeutic progress. Stringent evaluation of data is vital, and this is delivered by seeking expert advice and dealing with ethical and scientific debate in a way that captures the debate where there is no clear resolution. The hESCreg project seeks to quantify data and utilize existing standards or develop these through the Steering Committee and Scientific Advisory Board input. A Code of Practice will be established to demonstrate accountability for operation of hESCreg. International harmonization All FP6 projects are requested to input to hESCreg by the European Commission. Modular design enables effective links with other databases, for example, the International Stem Cell Initiative. Plans are established to coordinate with other developing databases: International Society for Stem Cell Research, the Interstate Alliance on Stem Cell Research, International Stem Cell Forum and Banks. 8

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Websites 101 Rapid Press Release: European Commission

proposes strict ethical guidelines on EU funding of human embryonic stem cell research (2003). http://europa.eu/rapid/pressReleasesAction.d o?reference=IP/03/969&format=HTML&ag ed=0&language=EN&guiLanguage=en 102 International Stem Cell Forum.

www.stemcellforum.org 103 UK Stem Cell Bank.

www.ukstemcellbank.org 104 International Society for Stem Cell Research.

www.isscr.org 105 Interstate Alliance on Stem Cell Research,

International Consortium on Stem Cell Networks. www.stemcellconsortium.org 106 Human Embryonic Stem Cell Registry.

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