Final Report Summary - EU-HPSCREG (European human Pluripotent Stem Cell Registry)
Executive Summary:
Human embryonic stem cell (hESC) research holds promise for regenerative therapies, offers a tool for drug discovery and toxicity tests, for studying human development, disease physiology and gene control. hESC lines are derived in an increasing number of laboratories accompanied by a widening scope of usage and application. This trend has not diminished since human induced pluripotent stem cells (hiPSC) became available as research and use of hESC and hiPSC rapidly co-develop. The advancing scope of the field, the increasing count of researchers, laboratories and institutions working with pluripotent stem cells (hPSC) and the ever growing number of hESC and hiPSC lines poses novel challenges on ethical provenance and quality validation of the cells. These challenges have been addressed by establishing the European hESC registry (EU-hESCreg). The proposed project aimed at sustaining and improving operability of EU-hESCreg, and to expand its content and usability in order to respond to the existing and anticipated needs in the field for a transparent and validated registry of PSC-lines. The European human pluripotent stem cell registry (hPSCreg) has adapted its registration content and requirements to accommodate hESC and hiPSC. The inclusion of the relevant pluripotent stem cells (hPSC) broadened comparability and standardization of cell lines, advance knowledge dissemination and hence provided information that is useful to reduced the need for generating new hESC lines. The objective of the EU-hPSCreg was to promote access to hPSC lines and to provide transparency about their characteristics, to contribute to the harmonization of hPSC usage and develop it into an international hub. The project implemented (i) transparent and detailed criteria for registration, qualification and validation of hPSC, (ii) established efficient means and tools for internal and external communication and dissemination of information and (iii) provided a reliable technical and regulatory basis for operationa as wel as a completely reworked web - interface. hPSCreg collaborated with the IMI project EBiSC to share information and integration of EBiSC lines in hPSCreg. In addition, hPSCreg has hooked up with ELSEVIER to mpromote publication of its cell lines. The number of registered lines increased significantly.
Project Context and Objectives:
Human embryonic and other pluripotent stem cells (PSC) are the basic for the development of precision medicine, personalized drug testing, disease modeling and a tool for studying human development. The derivation of PSC involves the donation of human biological samples, or the destruction of human embryos at the preimplantation stage. Critical for the utilization of these cells is a verifiable procurement, based on ethical approval of documented consent procedures. Another critical issue is the verification of thee pluripotent capacity of the cells, e.g. their potency to differentiate of cells of all germ layers. Only when these criteria are fulfiled, PSC are confidentially usable. Moreover, because of the diverse sources and applications of the cells, there is an increasing need for exchange of data to support collaboration and for the setting of standards regarding their derivation, characterization and to support best choice of a PSC line for application. Only a small fraction of PSC-lines has been banked and are thus characterized under standard conditions. But even then there is a strong need for providing central registries and standardized cells that allow to search through a global network of banks and registries. In order for the European Union to remain competitive in the global arena, continuation and expansion of the hPSCreg is required to be prepared for the current and foreseeable challenges in the area of pluripotent stem cell research and application.
Research with human pluripotent stem cells has advanced dramatically since the first establishment of hESC more than 10 years ago. Currently there are at >2000 hESC lines that were derived in 32 countries. Of these, about a quarter was derived in Europe. The invention of revolutionary technologies to induce pluripotency in virtually any human somatic cell provided the field with even more assets for studies into basic questions of development and for regenerative medicine. Our analysis showed that iPSC and ESC co-exist as necessary and essential resources in this respect. The annual numbers of experimental hiPSC and hESC studies continues to dramatically increase, showing that both research fields develop independently, further expand and partially overlap. In fact hESC have enabled the establishment of all methodologies to which iPSC lines are now being applied and hESCs continue to be used for primary rsearch and method development and as comparators of “normal” human cell function against which the performance of iPSCs is measured. It is important to recognize that there is a concensus amongst the scienetific community that the true nature of iPSCs has yet to be elucidated and performance of work on both iPSC and hESC will need to continue in parallel. This has impact on the validation criteria used by hPSCreg. In summary, the hPSCreg project is driven by the need for ethical and scientific validation of hPSC - lines and the gap between our ability to compare and select human PSC. These are essential to justify the promises we make for basic and applied research with these cells. The ability to monitor the hPSC quality will allow to select the most suitable cells, reduce the need for new ESC generation and to promote development of this dynamic field.
It has been recognized by the pioneering work of hPSCreg that centralized registries can address some of the mentioned challenges faced by researchers. In addition, registries provide a validated resource for scientists but also inform the public about the status of stem cell research. Furthermore, a stem cell registry has the potential to act as a hub for coordinative and collaborative Interaction between scientists on the status, standards and directions of the research area. This can be facilitated by direct hyperlinks between registries and data bases of molecular and other data.The hPSCreg monitors 3 main fields of information at the start of the project:
1. hPSC lines derived in Europe and internationally
2. Source (including ethical procurement), characteristics and availability of hPSC lines
3. Research activities with PSC in Europe, especially funded by the EC
The information covered in the online database has accordingly been structured and special filters have been developed to distinguish the information available between the different PSC lines reported. Acceptance of hPSCreg’s online platform was reflected by a steady increase of page impressions. Other hESC-registries have been developed subsequently after hPSCreg’s implementation. Notably, these are regsitries associated with cell banks or registries to validate regulatory complience (e.g.NIH-registry). The National Institutes of Health (NIH) registry, which has been in place since 2001 with initially only 21 registered cell lines, has been greatly expanded and provides a validated site for cells eligible for federal funding. Interestingly, the NIH-registered WiCell lines H1 and H9 are still by far most widely used lines internationally The International Society for Stem Cell Research (ISSCR)'s Registry of (4, 10-13). Their early availability together with registration in a public site let to extended use of these cell lines, which are now among the best characterized hESC lines available. The comparison of these different systems in Table 1 shows the comprehensive nature of the current hESCreg database and its strength against all aother similar databases internationally.
Whilst the main focus of hPSCreg is on hESC lines, the integration of other types of PSC, especially of iPSC is a key goal of the project.this includes to provide as much information as needed by users, which can be diovided into several categories:
Source Qualification
There is a need to provide information about the origin of hESC and hiPSC as one of the most important characteristics of the cell type and constitutes a requirement with fundamental ethical implications. The fast-growing number of lines and their increased use in research, cell therapies, and pharmacological studies, make it mandatory to develop qualification criteria. In the case of hPSC, source qualification refers to tissue source and provision of the cell, access to the cell, source of reprogramming genes and vectors, whether it is available from an accredited bank or provided from a research laboratory, and whether the biological characteristics of the cells have been independently verified. Albeit differences between hESC and hiPSC, there are ethical requirements which apply, such as informed consent, data and privacy protection, traceability, dissemination and consented scope of application. Knowledge about these mandatory requirements and adherence needs to be documented and may become a decisive qualification criteria for the use of a particular cell.
Quality control and scientific characterization
Information needs to be provided and criteria developed to evaluate the potency and quality of the cells. With the growing number and sources of pluripotent cell lines, and inability of researchers to secure resources to fully charaacterise all isolated hPSC lines, the need increases for information about their potency and quality. Moreover, criteria are required to evaluate and compare the cells with respect to their performance in a specific application. The basic criteria to evaluate all hPSC are the same that apply to hESC – the gold standard for pluripotent cells. These are then supplemented by information regarding the cell origin and details of the method used for derivation, e.g. reprogramming in the case of hiPSC. For example, the availability of disease specific, GMP and clinical grade hPSC demands the set up of relevant registration information guidelines for these cells. To directly compare between hESC and pluripotent cells from other sources requires systematic collection of key data and their representation to define the distinct characteristics of each hPSC, and to highlight the advantages and disadvantages for their use in specific applications. On this note, access will be provided to information about research projects with hESC and hiPSC, as well as the distinct lines used in these projects. This essential transparency task will answer questions like: ‘What is being done where with which hPSC, and what are the outcomes?’
Technology transparency
PSC can be generated by an increasing number of technologies and methods, and they can be cultured, differentiated, characterized and stored using very diverse protocols. The technologies used for a specific cell line add strongly to its biological characteristics and variability. It is therefore of importance to make the information on the technologies and protocols used for the generation and further manipulation of PSC available and to develop consent on respective standards.
Research and Cell Application
Data derived by researcher after a line has been registerd should be made available as a means to assess hPSC characteristics and to rigorously compare hESC with each other and with hiPSC. Further direct comparison of iPSC and hESC data will also enable resolution of iPSC diversity and consistency with hESC characteristics. Since comparison of cells is a key function of EU-hPSCreg as it reduces the need for the establishment of novel cells and refines research, a comprehensive backbone for the annotation of each cell line with research data will be implemented. Moreover, a registry of projects that work with specific hESC-lines, a task to be implemented for EC-supported projects at a minimum, will complement the research data. The searchable data and project database will help to reduce redundancy of research with hESC and to motivate collaborations.
Communication and harmonization
For hPSCreg to maintain its position as a prime information hub for hESC and hiPSC, it is essential to have close communication with the providers of the cells (e.g. scientists, labs, banks, registries), the users of the cells (e.g. clinicians, industry, research labs) and stakeholders in need for information on cell usage, status of the field or regulatory and standardization status (e.g. stem cell societies, regulators). Efficient communication will also be required to keep registry information up to date and to foresee and ract in a timely fashion to new developments in the field. As research on PSC is a global endeavor and can only succeed through international cooperation, hPSCreg can promote internationalized, standards, validation criteria and ethical guidelines within the international discourse.
Dissemination and Public awareness
Novel technologies are often met with skepticism, including technologies using hESC and hiPS. The rise of hESC and hiPSC technology has generated public interest, and at the same time produced anticipations that are not always realistic. By providing information on research results and transparency on where the field stands, realism can be injected into the public debate. Moreover, public awareness includes the information about the scientific progress in a field, regenerative medicine and stem cells. This has been evident for hESC, and is now required for informed decisions on other types of pluripotent stem cells, such as hiPS. Another aspect of awareness concerns the scientific community. An informational hub, which interlinks several information sources, and provides qualified commentaries on novel scientific, ethical or regulatory developments will benefit both, researchers as well as the general public, regulators, clinicians and industry.
Based on these goals and tasks, the project has 4 objectives as described below.
Objective 1: Acquisition, Registration and Qualification of hPSC data. The key task of hPSCreg is the provision of information on and about hESC and hiPSC lines. The first task therefore is to define the content of the information to be acquired and to determine registration, quality and validation requirements. The second task is the collection of this information in an efficient and systematic manner and the third task is to check quality, completeness of the data and validation of the registered cell lines. The content of the information is allocated into several packages, such as a basic package containing necessary information to determine whether the cell is a PSC, an ethics package that provides information on ethical provenance of the cells, a science and technology package that provides protocols and results, and an application package containing information on the use of these cells e.g. in research or medicine. The registration collection of the information will be facilitated through the hPSCreg network of national contact points, the scientific committee, but most importantly by the researchers. Quality check and validation of information will be provided by the hPSCreg team and its partners by assessing the completeness and plausibility of cell-related information according to predetermined criteria. This step will allow users to assess whether a cell line complies with ethical and scientific standards required for their usage. Developing and applying scientific and ethical criteria regarding the criteria for the inclusion of hPSC lines will constitute one of the main tasks of this objective. Periodic update of the available information is essential. Validation of the data is required to assure users that the information provided by the Registry is reliable. This is most important if the Registry is to be used as a European and globally accepted resource for qualified cell lines, as a standard tool and hub for other registries. The project would also offer to establish and host registries for countries who do not have formal registries. Validation mechanisms are provided for the qualification information (basic and ethics packages) though a multistep confirmation and feedback procedure. All data are also validated through the use of comparison tools and plausibility checks by the Registry team. Moreover, feedback from the community will provide independent evaluation of the provided data. If provided data are confirmed by several provides / users, this will increase confidence in them and increase the validation level of the respective cell line.
Objective 2: Communication, Dissemination and Harmonization. An important element of EU-PSCreg is to facilitate scientific networking, international cooperation, knowledge dissemination and promotion of public awareness. These tasks will be implemented through online tools for direct interaction and exchange with the Registry and with the community, through publications and newsletters, and by the active contribution to international standardization and harmonization efforts in the framework of conferences, relevant organizations and societies such as the International Stem Cell Initiative (ISCI). EU-PSCreg will seek interaction and participate in related EU-funded projects as a key resource. A hub will be developed that serves as a communication and dissemination platform toward the scientific community, stakeholders from political and patient organizations and to the general public. This hub will also serve as a contact and access point for international registries with similar scopes. Operation procedures and scope, standards, content and results of the Registry work will also be published. Regular commentaries and newsletters will be directed not only at researchers, but also at other stakeholders and the general public and educational organisations. Content will be dynamic and will be presented to ensure that data compariswon is availa through the DB that is not available elsewhere without considerable work. Collaboration and communication with other registries and banks (e.g. NIH, ISCR-UMASS, NIH/Korea, NIBIO/Japan) will be actively enforced.
Harmonization refers to the need for adjustment of differences and inconsistencies among different measurements, methods, procedures, schedules, specifications, or systems to make them uniform or mutually compatible. In this respect, harmonization promotes standardization. Thus, hPSCreg is in a unique position to direct harmonization in the stem cell field by applying the same criteria e.g. nomenclature, cell characterization, qualification and procurement. While different laboratories use currently diverse protocols, tools and measurements, the Registry provides a means to evaluate and compare them. By providing open access to information it contributes to harmonization, yet importantly, the Registry will actively promote harmonization and standardization through its publications and communications as part of its dissemination efforts. Harmonization in these areas, also in terms of nomenclature, protocols, markers, is required to compare the different cells and the Registry aims at setting up and support respective efforts actively.
Objective 3: Implement Governance and safe Technical Conduct. The EU-PSCreg will not be operational and sustainable without an efficient and safe technical backbone and clear governance and code of conduct policies. Hence, the main task of this objective is to assure that the Registry is safe, technically secured, publicly accessible, and has a transparent, controlled and standardized procedure to operate. Safe technical conduct is provided by building on the existing EU-hESCreg server, which is embedded into a secured and serviced IT-environment of Charité University Medicine Berlin. Related and necessary tasks are the development and maintenance of the database and interface, compliance with data safety and data security regulations and technical service provision to users such as feedback management and cell registration. We will implement novel tools that are not yet integrated into hESCreg to search and compare registered information on all levels, to link to other registries and to assemble documentation about each cell line. Governance is provided by adjusting, implementing and controlling transparent principles for quality assurance, with a formal code of conduct and operating procedures for the acquisition and registration of data, to insure quality and adherence to scientific and ethical requirements. This also includes implementation of standard procedures for communication and inclusion / harmonization of data from other registries. Technical conduct requires maintaining a stable, secure and efficient technical backbone that is hosting the Registry. We will build on the same system that has been implemented for hESCreg and upgraded as required. Data are deposited on a virtual server, which is continuously serviced, controlled and backed up by the institution (Charité), providing long term sustainability and public access. Database and interface of EU-hPSCreg are based on those established hESCreg. However, upgrades and improvements will be implemented in order to increase efficiency and flexibility of searches and comparisons, and to enable the compilation of cell-specific data sheets (e.g. cell line documentation). In addition, feedback and forum areas will be improved with tools for follow up, especially for feedback on the status of cell registration and qualification. Finally, procedures for linking with other registries and banks for the sharing of data will be developed and implemented.
Open Source/Access Model: Selected standard and customized tools for stem cell biology will be provided. This will involve algorithms for data comparison, statistical analysis and export modules for work with the data in local systems (API). Provision of these functionalities may serve as an additional incentive for researchers to download their stem cell data. All characterization and analysis functions will operate under the Open Source/Access model. Compliance with data safety/protection and data security regulations is a necessity for the Registry. Since only anonymized data about cells will be registered, there is no traceability provided to any donor. These may only be accessible via the data providers and the Registry will indicate whether a cell line is traceable (via the provider), or not. The provider contact information, or links to cell banks, will also be provided. Data security is provided via the firewall and backup services of the IT-environment of Charité University Medicine Berlin.
Objective 4: Effective project management: The task of establishing an efficient and competent management structure will rely on the established structure of EU-hESCreg, where the project management team is supported by a steering committee and an advisory board. Together, these will provide the appropriate means of control, independence and sustainability of the EU-PSC Registry. Project management will provide daily, operational management, strategic management involving the Steering Committee (StC) and the Ethics Advisor, as well as management of external cooperation and communication tasks such as workshop and meeting organization. Project management is furthermore responsible for adherence to governance rules, for internal controlling, review and reporting obligations. Importantly, the management will be responsible for the implementation of measures for sustainability of the Registry. Regular consortium meetings or telephone conferences will be organized to facilitate the oversight and review function by the coordinator. Sustainable platform operation: Specific concepts will be drafted to allow for the transition of the registry from temporary to permanent and sustainable operation. This will include offering specific services such as cloud computing, software-as-a-service models, service based cell line search, selection and validation, participation in international research and infrastructure projects or permanent affiliation with a large public research funding institutions as possible options.
The EU-hPSCreg will not be operational and sustainable without clear governance and code of conduct policies. Governance is provided by adjusting, implementing and controlling transparent principles for quality assurance, code of conduct (CoC) and standard operating procedures (SOP) for the acquisition and registration of data, to insure quality and adherence to scientific and ethical requirements. Evaluation and review mechanism for cell line data need to be implemented and standard operating procedures (SOP) developed. Governance also includes implementation of standard procedures for communication and inclusion / harmonization of data from other registries. A quality management system (QMS, including CoC and SOPs) and governance procedures for the Registry will be developed and implemented to ensure coordinated, effective and controlled data entry, validation and feedback management. The procedures will detail the formal roles and internal cooperation of the Registry management, the partners and Steering Committee (StC). The QMS will ensure continuous commentary on effectiveness of the Project and implementation of proposals for improvement. The management will implement the QMS by organizing a work stream of open meetings and reviews with partners and StC. The mainframe governance procedures were already developed for the hESCreg project and will provide basis for the development and maintenance of this platform into hPSCreg.
Regulation and ethical issues are part of the governance document aim at delivering their appropriate representation as a guide for managing the Registry. This will provide assurance that central ethics and regulatory themes are maintained within the project as a whole. An independent ethics and legal advisors will be included in the project for that aim. SOPs for source qualification. Source information refers to criteria that serve to verify the scientific and ethics data posted by the providers to the Registry. Source information is thus important for the user of the Registry to verify whether a cell line adheres to the benchmark criteria set by the researcher or its funding agency for usage of hPSC. Comprehensive summaries for source information will, in addition, provide a resource for assessment of ethical standards, scientific scrutiny and reliability of hPSC research. The SOPs will provide definitions on scope and content for source information for the providers. The Registry will enable the user to specifically access these source data to search for benchmark criteria fit for specific research applications. As benchmark criteria for hPSC usage will depend on the potential application of the cell, a rather broad frame that allows for different levels of scrutiny will be provided. The SOPs will set rules and procedures for the acquisition, qualification and validation of source information. The Registry co-ordination will, however, actively recruit providers of cells to submit verifiable source information for their hPSC. The level to which source information will be required to make a public listing of a PSC will be regularly evaluated and approved by the StC as outlined in the governance rules (code of conduct) of the Registry. As active Validation of source information e.g. by re-assessing the claims and data provided is not practicable, validation will be provided by cross referencing on the scientific level using the Registry database itself. On the regulatory and ethical levels, validation will be promoted by harmonizing the provided information with the information in the Registry on the legal and regulatory environment in the specific source country.
Project Results:
The work plan was oriented along the aim to sustain and further develop a Registry for human embryonic stem cells (hESC), supplemented with human induced pluripotent stem cells (hiPSC). It was structured into four closely linked work packages on (i) cell-line data acquisition and validation, (ii) communication and dissemination, (iii) technical implementation and (iv) management and administration.
The hPSCreg consortium continued the work laid down in the previous EU-hESCreg project. However, due to lack of funding and of progressive developments in the field, the database, backend, frontend, registration tools and validation procedures had to be completely renewed. These tasks needed to be performed without jeopardizing the existing data. In addition, more functions and tasks were taken on by hPSCreg, including certification of PSC-lines, publication of lines, implementation of standardization tools (e.g. nomenclature) and the development of modules to allow interaction with PSC banks.
The first key objective was the provision of information on and about hESC and hiPSC lines. The first task to reach this objective was to define the content of the information to be acquired and to determine registration, quality and validation requirements. This objective has been achieved, although it was also realized that the selected criteria require continuous updating as the field progresses and user requirements develop. Hence, we consider the definition of content and validation requirements as ongoing tasks. Moreover, the initiated collaboration with EBiSC (European bank of Induced Pluripotent Stem Cells) turned out to be extremely fruitful in terms of user requirement assessment. Consequently, we have installed mechanism to continuously update the information content and react to demands for new information requirements. In addition, we have integrated means to add and annotate cell lines with new information even after validation. Most important were the collection of the defined cell-line information in an efficient and systematic manner and the third task to check quality, completeness of the data and validate the registered cell lines. The required information to be registered has been allocated into several packages. The basic package contains information that is absolutely necessary for registration of a cell line (minimal requirements). This includes evidence of ethical provenance, evidence of pluripotency and traceability to a generator of the cell line. The extended package includes information on cell characterization, protocols and results, and an application package containing information on the use of these cells e.g. in research or medicine. This includes a list of EU-funded projects in which hESC and hiPSC are used. A standard procedure for quality check and validation of information has been developed as part of the standard operation procedures (SOPs).
In the continuously ongoing Task 2, cell-lines and associated data were acquired and registered and cell-information according to the defined requirements was organized. We have developed a new registration tool (see also WP2) to facilitate data entry according to the registration requirements as defined in task 1. In a first step, all existing hESCreg lines were transferred to the new database and the respective fields used and information validated. Secondly, the hPSCreg team has registered a batch of new cell lines manually. Post launching of the registration tool in November 2014, the cell line - registration became publically available. It has since then further developed and is under constant revision to add new features, functions and allow for the systematic annotation of information to cell lines. The registration tool can be visited at http://hpscreg.eu.
In Task 3, we checked quality and completeness of the provided information or validation. We developed a multistep process for assessment of the cell-related information, which involves the management. Originally, the Committee of National Representatives (CNR) and the Ethics Advisor was involved in this process, but this procedure has not been effective and was changed. Now, the hPSCreg team alone validates lines based on strict fulfilment of registration requirements. To that end a valuation system was developed, which determines transparently the completeness and validation of the cell related information. Only in case a provider of information for a cell line is unknown and cannot be verified by the hPSCreg team, the CNR will be involved.
In Task 4, we have developed a review process for registry information as a continuous task as outlined in the code of practise (CoP). In general, information will be reviewed by the hPSCreg team. The CNR will alert the management of any changes in regulation and on scientific breakthroughs that require changes in the review mechanism.
Validation of PSC lines by the hPSCreg team is the prerequisite for public release of the line. In addition, the registry is providing Certificates to each cell line that fulfils requirements to use them in Horizon 2020 funded research. In addition to cell-line certificates, hPSCreg provides project certificates (certifying that the project is registered and which PSC lines are being used).
The second key objective was the facilitation of efficient mechanisms for internal and external communication and feedback, scientific networking, international cooperation, knowledge dissemination and promotion of public awareness. In the reporting period, we developed a dissemination and communication concept based on electronic means. A helpdesk and online communication standard via a contact form was implemented as a first step. Mechanisms for communication between hPSCreg and other registries and PSC-banks were developed. Further refinement and implementations of dissemination activities were implemented by an egreement with ELSEVIER to publish hPSCreg lines in the journal ‘Stem Cell Research – Lab Notes’. The Registry acts as a reviewer for hPSClines and facilitates their expedited publication. More than 60 lines have already been published in this open access journal. In addition hPSCreg has published several papers describing the Registry’s purposes, role and structure. Moreover, hESCreg has participated and presented at a number of conferences and meetings.
In Task 1, we determined means and rules for internal and external communication (appendix Operation concept communication and dissemination). Internal communication between WPs, the management team, the national representatives and Ethics Advisor were regularly (monthly) performed by email and teleconferencing (skype). External communications are focused on web-based solutions (online tools), electronic communications (email) and meetings. For efficient communication and exchange of data, web services and web applications were determined as the preferred solution. Two-way communication channels were implemented for user registration and user feedback embedded in the registration tool.
In Tasks 2 and 3, we have implemented collaborations with the registries eagle-I (USA), the NIMH PSC-Bank at Rudgers (USA) and the Korean NIH Registry on an informative level. This includes the registration of hPSC-lines in hPSCreg and the exchange of information regarding implementation of standards (ethics consent, ontologies) and nomenclature. Furthermore, we have set up collaboration with the International Stem Cell Banking Initiative (ISCBI) and the UK Cell Therapy Catapult (CTC) regarding the development, dissemination and application of guidelines and rules regarding the procurement, handling and application of hPSC-lines for clinical application. Finally, we have established close links to the European Bank for Induced Pluripotent Stem Cells (EBiSC), where hPSCreg is the key portal for the registration of EBiSC cell lines. Members of CTC, ISCBI and EBiSC are members of the hPSCreg CNR.
In Task 4 hESCreg is providing on its website links to relevant regulatory information, to publications, projects working with hESC and hiPSC and maintain a News feature (http://hpscreg.eu). In Task 5 we established a standardized naming convention (Nomenclature) for pluripotent stem cells.
The third key objective was the establishment of an accurate carefully constructed technical platform and portal as well as robust government structures. In connection with establishing the database, we completely revised the original version, eliminated flaws and security issues, which were related and caused by the intermediate lack of funding and developed and implemented a new website (including design, new user management and new search and browse functionalities). This work took significantly more effort that originally planned. The reasons were a 2-yar gap in technical maintenance due to lack of funding for hESCreg, a fault-prone web interface, which was not usable for the newly implemented registration items and functionalities and a backend that was unsuited for registration of cell lines and related information by users. Basically, the whole registry was rebuilt from scratch while the old version had to be maintained and running and transferred without data loss to the new back/frontends.
Although these tasks took more effort than anticipated and remain a central to acceptance of the Registry. They are critical to long term sustainability and for implementing a solid quality assurance process, robust traceability and scientific quality of data.
With respect to governance and code of conduct (CoC), we have developed and implemented internal and external policies, which are transparently laid down in the CoC document. The CoC document provides the governing guidelines to quality assurance. Together with the Standard Operating Procedures (SOPs) they detail the protocols for the acquisition and registration of data, to insure quality and adherence to scientific and ethical requirements, evaluation and review mechanism for cell line data. Rules and standard procedures for communication, dissemination and inclusion / harmonization of data from other registries have been detailed in the Communications and Dissemination Guide document. In addition, to strictly adhere to ethical standards of Horizon2020 and to trace and confirm ethical procurement of the registered cell lines, we have established a Procedure for Management of Key Ethics Information and Risks Relating to Registration of Pluripotent Stem Cell Lines and an Ethics Evaluation Form. The latter has been implemented as part of the registration tool facilitating search and immediate assessment of the relevant consent information and ethics approvals.
In Task 1 we performed a requirements analysis to determine adjustments needed for the current technical backbone, database and interface in relation to objectives of the project and strategic Registry tasks. We have determined that all technical elements must be newly established, programmed and tested as the status quo version was not fit to provide the needed stability, capacity and usability. We have developed and implemented the required elements (database, server, interface), tested them and validated basic functionalities (to register, curate, service, backup and update the database, search, browsing and user management). The new hESCreg has been publicly launched in Heidelberg and in San Antonio (USA) in 2014. The interface/portal has been redesigned and implemented. The further improvement of the front- and backends is a continuing, iterative process.
In Task 2 we have developed several tools for standardization and analysis. We developed and implemented a standardized nomenclature of pluripotent stem cells. This tool automatically assigns names to registered cells and thus supports search, comparison and exchange of data and cells across multiple platforms. Via the platform CellFinder we developed comparison tools between cells based on transcriptomics data, which are usable for hPSCreg. In addition, we implemented a visualization tool to provide easy and intuitive access to the status of PSC-research and application by country, cell type and also informs about the ethics/regulatory requirements in these countries.
All functions operate under the Open Source/Access model. Efficient data integration routines are ontology-based where ontologies were available and validated. The expansion of the ontology implementation, and term curation is ongoing. Primary and secondary research data can be uploaded and made available to the community. Provision of the generator, owner and distributer (e.g. banks) is available.
In Task 3, we implemented means for compliance with data safety/protection and data security regulations as outlined in the Procedure for Management of Key Ethics Information and Risks Relating to Registration of Pluripotent Stem Cell Lines document. Data security and data traceability is implemented via a logbook mechanism. This includes the necessary provisions for data security such as firewall and password protection of data, division of the platform in front- and backend and clear access regulations.
In Task 4 we developed and implement the quality management system and governance procedures for the Registry. The procedures detail the formal roles and internal cooperation of the Registry management, the partners and CNR. These are outlined in the Code of Conduct and Standard Operating Procedures documents.
Regulations and rules of operation for co-operation with institutions outside of the Registry (cell banks, other registries, initiatives such as ISCI, other EU-projects, sponsors), especially concerning direct data transfer or exchange are outlined in the Operation Procedures for Communication and Cooperation document.
In Task 5 we described and implemented regulation of ethical issues as part of the governance document and integrated these in the governance document as guide for managing the Registry to assure that central ethics and regulatory themes are maintained within the project as a whole (Procedure for Management of Key Ethics Information and Risks Relating to Registration of Pluripotent Stem Cell Lines document). We have appointed the Ethics Advisor Dr.Rosario Isasis (see hPSCreg website) and collaborate with the Ethics Working Party of the International Stem Cell Initiative.
In Task 6 we developed and implement SOPs for source qualification and criteria that serve to verify the scientific and ethics data posted by the providers to the Registry, including a comprehensive summary for source information for assessment of ethical standards, scientific scrutiny and data reliability. The SOPs provide definitions on scope and content for source information for the providers. The Registry enables the user to specifically access these source data to search for benchmark criteria fit for specific research applications. The SOPs include rules and procedures for the acquisition, qualification and validation of source information. An appropriate portal and search functionality is implemented for cross-referencing.
In Task 7, we have participated in meetings, including conferences on large scale PSC-banking and on harmonization in the field. Targeted and dissemination materials include posters and presentations at conferences. Two specific hPSCreg sessions were held at international conferences.
The fourth objective included the overall planning, administration, financial controlling, managing and coordinating the work and communication with the European Commission. The Code of Conduct documents as well as Standard Operating Procedures outline the procedures implemented for management. Other documents include emergency plans and duty booklet.
The coordinator controlled and coordinated the partners and work packages mainly through monthly meetings and by ad hoc email/teleconferences. Each meeting was documented by minutes which were documented and approved by all participants.
Strategic management is based on advice from CNR and the Ethics Advisor. Meetings and advisory notes by members of these bodies are also documented and circulated as described in the SOPs.
A list of project meeting is provided in the table below:
Date Type of meeting
20.03.13 TC (telephone conference)
16.04.13 TC
13.06.13 Boston ISSCR. Personal meeting
25.06.13 TC
17.07.13 TC
22.07.13 Berlin. Personal meeting
23.07.13 Berlin. Personal meeting
1.10.13 TC
22.10.13 TC
26.11.13 TC
5.12.13 TC
23.01.14 TC
06.03.14 TC
01.04.14 TC
10.06.14 TC
18.06.14 Vancouver ISSCR. Personal meeting
04.08.14 TC
We developed a work plan for the CNR and circulated a questionnaire to elucidate status of hESC/hiPSC research and regulation. Internal communication (with WP leaders, CNR) is organized via email and teleconferencing. For external communication, we use contact forms provided at the website (helpdesk). The management has initiated several collaborations with the aim to ensure sustainability and expansion. This includes the IMI project EBiSC and the ISCBI. The management has established an active CNR (as provided at the hPSCreg website) and Ethics Advisory mechanism (see website). Task management within the project was controlled via an online task management system (redmine), which allowed for transparent task assignment, monitoring, commenting and updating. All partners had password protected access to redmine.
There was an original underestimation of work related to technical implementation (database design, portal and website development and server implementation), which was due to surprisingly malfunctioning of many elements of the old hESCeg database. This again was due to a gap in funding and thus incomplete maintenance capabilities. On top of this problem, the programmer we hired for this task quit and a new staff member needed to be hired and made familiar with the tasks. Despite these obstacles, we were able to fulfil all deliverables. The hPSCreg website is available at www.hPSCreg.eu. It is continually updated and improved.
The management included intensive communication with stakeholders and beneficiaries in order to test, validate and improve the database and website. This included
• participation in workshops and presentation of hSCreg in the IMI projects EBiSC, StemBANCC and the International Stem Cell Initiative / ISCBI.
• Collaboration with the European Bioinformatics Institute (EBI)
• Collaboration with Kyoto University and National Institutes of Health of Korea, both hosting the relevant national registries
• Collaboration with the UK stem cell bank, WiCell, Rudgers (USA)
Potential Impact:
hPSCreg Statistics
2015
6.917 visits with action (e.g downloads)
5 Minutes 31s average time at the website
5,5 actions in average per visit
0,61 s average time to generate the website
34.232 views of the site, 21.212 direct visits
1.797 internal searches, 500 unambigous search terms
551 downloads, 434 unambigous downloads
Access by equipment:
Desktop: 6.391
Smartphone: 302
Tablet:175
Unknown: 40
Phablet: 8
Feature-Phone: 1
Access by continent:
Europe: 4.307
Asia: 1.245
North Amerika: 1.054
Unbekannt: 113
South Amerika: 102
Oceania: 45
Africa: 41
Middle America: 10
Access by country top 50:
United Kingdom 1562
USA 980
Germany 857
Spain 461
Soputh Korea 268
Japan 243
France 238
India 226
Slowenia 138
Belgium 127
Italy 116
China 115
Netherlande 111
Norway 110
Thailand 109
Sweden 92
unknown 110
Brasilia 72
Switzerland 68
Russia 63
Israel 60
Canada 60
Chech Republic 49
Australia 43
Hongkong 37
Finland 36
Kuwait 35
Poland 30
Greece 29
Portugal 28
Denmark 27
Turkey27
Iran 26
Austria 25
Taiwan 24
Singapur 23
Irland 22
Egypt 19
Hungary 18
Malaysia 14
Mexico 14
Luxemburg 13
Rumania 13
Pakistan 12
Philippines 11
Peru 9
Ukrainia 8
Columbia 7
Nigeria 7
Search terms top 50:
spain 29
h9 28
H9 23
iPS 15
trisomy 13 15
MIFF1 12
NCRM 9
wa09 9
France 7
h1 7
hues8 7
ips 7
MIFF 7
Shef 7
cancer 6
CRMi001-A 6
ED 6
HES3 6
hues9 6
Seoul 6
trisomy 6
United Kingdom 6
ESi001-A 5
hues 5
ipsc 5
NCRM-5 5
RCi68 5
shef 5
Shef-3 5
shef-3 5
Shef-6 5
shef-6 5
Spain 5
UNEW 5
bcrt 4
cambridge 4
China 4
CRMi001 4
H1 4
h7 4
HES-3 4
miff1 4
ncrm 4
NCRM-1 4
NCRM1 4
newcastle 4
Oscar 4
RCi 4
SNU 4
uk 4
2014
3.320 visits
5 Minutes 44s average time at website
6,2 Actions per visit
1,08 s average generation time of website
19.388 views, 12.417 unambiguous views
160 internal searches, 138 unambigous search terms
294 downloads, 274 unambigous downloads
Access by equipment:
Desktop: 2.856
Tablet:212
Smartphone: 211
unknown: 41
Access by continent:
Europe 2.005
Asia 626
North America 425
South Aamerica 108
unknown 106
Oceania 27
Africa 17
Middle America 6
Access by country:
United Kingdom 588
Germany 587
USA 361
Spain 223
South Korea 188
India 185
France 105
Brasilia 93
unknown 93
Italy 76
Japan 65
Belgium 61
Switzerland 61
Canada 55
Sweden 49
China 34
Chech Republic 34
Kuwait 29
Netherlands 29
Australia 25
Israel 20
Denmark 18
Turkey 18
Finland 17
Poland 17
Singapur 17
Taiwan 17
Thailand 17
Iran 16
Russia 15
Austria 12
Luxemburg 11
Philippines 10
Hungary 10
Mexico 9
Bulgaria 8
Portugal 8
Egypt 8
Greece 7
Irland 7
Kroatia 6
Slowenia 6
Ecuador 5
Serbia 5
Hongkong 5
Indonesia 4
Lettland 4
Norway 4
Puerto Rico 4
Search terms top 50:
name searches
H1 4
spain 4
edi 3
h1 3
i3 3
roslin 3
h2 2
h4 2
H9 2
HS 2
HSF-6 2
netherlands 2
rc 2
trisomy 13 2
201B1 1
201B2 1
201B3 1
201B6 1
243h7 1
246G1 1
246G3 1
246G4 1
246G5 1
bonn 1
ca1 1
cancer 1
CCTL 1
cFA404-KiPS4F-1 1
CHA-hES3 1
che- 1
ches 1
chHES-8 1
chim 1
chimaeric 1
chimeric 1
cho 1
cryo save 1
CyT203 1
cyth25 1
EBNA1 H9 1
Edi 1
Edi1 1
Endeavour 1 1
envy 1
ES 1
esi-017 1
europe 1
fat cell 1
fertility unit sweden 1
Germany 1
Alltogether since start of statistical documentation
10.247 visits
5 Minutes 35s average time at site
5,7 actions per visit
0,78 s average generation time of site
53.642 views, 33.649 unambigous views
1.959 internal searches, 604 unambigous search terms
846 downloads, 709 unambigous downloads
List of Websites:
http://hpscreg.eu
Contact:
Human pluripotent stem cell registry
BCRT
Augustenburger Platz 1
13353 Berlin, Germany
Phone: +4930 450539424
Email: hpscreg@charite.de
Human embryonic stem cell (hESC) research holds promise for regenerative therapies, offers a tool for drug discovery and toxicity tests, for studying human development, disease physiology and gene control. hESC lines are derived in an increasing number of laboratories accompanied by a widening scope of usage and application. This trend has not diminished since human induced pluripotent stem cells (hiPSC) became available as research and use of hESC and hiPSC rapidly co-develop. The advancing scope of the field, the increasing count of researchers, laboratories and institutions working with pluripotent stem cells (hPSC) and the ever growing number of hESC and hiPSC lines poses novel challenges on ethical provenance and quality validation of the cells. These challenges have been addressed by establishing the European hESC registry (EU-hESCreg). The proposed project aimed at sustaining and improving operability of EU-hESCreg, and to expand its content and usability in order to respond to the existing and anticipated needs in the field for a transparent and validated registry of PSC-lines. The European human pluripotent stem cell registry (hPSCreg) has adapted its registration content and requirements to accommodate hESC and hiPSC. The inclusion of the relevant pluripotent stem cells (hPSC) broadened comparability and standardization of cell lines, advance knowledge dissemination and hence provided information that is useful to reduced the need for generating new hESC lines. The objective of the EU-hPSCreg was to promote access to hPSC lines and to provide transparency about their characteristics, to contribute to the harmonization of hPSC usage and develop it into an international hub. The project implemented (i) transparent and detailed criteria for registration, qualification and validation of hPSC, (ii) established efficient means and tools for internal and external communication and dissemination of information and (iii) provided a reliable technical and regulatory basis for operationa as wel as a completely reworked web - interface. hPSCreg collaborated with the IMI project EBiSC to share information and integration of EBiSC lines in hPSCreg. In addition, hPSCreg has hooked up with ELSEVIER to mpromote publication of its cell lines. The number of registered lines increased significantly.
Project Context and Objectives:
Human embryonic and other pluripotent stem cells (PSC) are the basic for the development of precision medicine, personalized drug testing, disease modeling and a tool for studying human development. The derivation of PSC involves the donation of human biological samples, or the destruction of human embryos at the preimplantation stage. Critical for the utilization of these cells is a verifiable procurement, based on ethical approval of documented consent procedures. Another critical issue is the verification of thee pluripotent capacity of the cells, e.g. their potency to differentiate of cells of all germ layers. Only when these criteria are fulfiled, PSC are confidentially usable. Moreover, because of the diverse sources and applications of the cells, there is an increasing need for exchange of data to support collaboration and for the setting of standards regarding their derivation, characterization and to support best choice of a PSC line for application. Only a small fraction of PSC-lines has been banked and are thus characterized under standard conditions. But even then there is a strong need for providing central registries and standardized cells that allow to search through a global network of banks and registries. In order for the European Union to remain competitive in the global arena, continuation and expansion of the hPSCreg is required to be prepared for the current and foreseeable challenges in the area of pluripotent stem cell research and application.
Research with human pluripotent stem cells has advanced dramatically since the first establishment of hESC more than 10 years ago. Currently there are at >2000 hESC lines that were derived in 32 countries. Of these, about a quarter was derived in Europe. The invention of revolutionary technologies to induce pluripotency in virtually any human somatic cell provided the field with even more assets for studies into basic questions of development and for regenerative medicine. Our analysis showed that iPSC and ESC co-exist as necessary and essential resources in this respect. The annual numbers of experimental hiPSC and hESC studies continues to dramatically increase, showing that both research fields develop independently, further expand and partially overlap. In fact hESC have enabled the establishment of all methodologies to which iPSC lines are now being applied and hESCs continue to be used for primary rsearch and method development and as comparators of “normal” human cell function against which the performance of iPSCs is measured. It is important to recognize that there is a concensus amongst the scienetific community that the true nature of iPSCs has yet to be elucidated and performance of work on both iPSC and hESC will need to continue in parallel. This has impact on the validation criteria used by hPSCreg. In summary, the hPSCreg project is driven by the need for ethical and scientific validation of hPSC - lines and the gap between our ability to compare and select human PSC. These are essential to justify the promises we make for basic and applied research with these cells. The ability to monitor the hPSC quality will allow to select the most suitable cells, reduce the need for new ESC generation and to promote development of this dynamic field.
It has been recognized by the pioneering work of hPSCreg that centralized registries can address some of the mentioned challenges faced by researchers. In addition, registries provide a validated resource for scientists but also inform the public about the status of stem cell research. Furthermore, a stem cell registry has the potential to act as a hub for coordinative and collaborative Interaction between scientists on the status, standards and directions of the research area. This can be facilitated by direct hyperlinks between registries and data bases of molecular and other data.The hPSCreg monitors 3 main fields of information at the start of the project:
1. hPSC lines derived in Europe and internationally
2. Source (including ethical procurement), characteristics and availability of hPSC lines
3. Research activities with PSC in Europe, especially funded by the EC
The information covered in the online database has accordingly been structured and special filters have been developed to distinguish the information available between the different PSC lines reported. Acceptance of hPSCreg’s online platform was reflected by a steady increase of page impressions. Other hESC-registries have been developed subsequently after hPSCreg’s implementation. Notably, these are regsitries associated with cell banks or registries to validate regulatory complience (e.g.NIH-registry). The National Institutes of Health (NIH) registry, which has been in place since 2001 with initially only 21 registered cell lines, has been greatly expanded and provides a validated site for cells eligible for federal funding. Interestingly, the NIH-registered WiCell lines H1 and H9 are still by far most widely used lines internationally The International Society for Stem Cell Research (ISSCR)'s Registry of (4, 10-13). Their early availability together with registration in a public site let to extended use of these cell lines, which are now among the best characterized hESC lines available. The comparison of these different systems in Table 1 shows the comprehensive nature of the current hESCreg database and its strength against all aother similar databases internationally.
Whilst the main focus of hPSCreg is on hESC lines, the integration of other types of PSC, especially of iPSC is a key goal of the project.this includes to provide as much information as needed by users, which can be diovided into several categories:
Source Qualification
There is a need to provide information about the origin of hESC and hiPSC as one of the most important characteristics of the cell type and constitutes a requirement with fundamental ethical implications. The fast-growing number of lines and their increased use in research, cell therapies, and pharmacological studies, make it mandatory to develop qualification criteria. In the case of hPSC, source qualification refers to tissue source and provision of the cell, access to the cell, source of reprogramming genes and vectors, whether it is available from an accredited bank or provided from a research laboratory, and whether the biological characteristics of the cells have been independently verified. Albeit differences between hESC and hiPSC, there are ethical requirements which apply, such as informed consent, data and privacy protection, traceability, dissemination and consented scope of application. Knowledge about these mandatory requirements and adherence needs to be documented and may become a decisive qualification criteria for the use of a particular cell.
Quality control and scientific characterization
Information needs to be provided and criteria developed to evaluate the potency and quality of the cells. With the growing number and sources of pluripotent cell lines, and inability of researchers to secure resources to fully charaacterise all isolated hPSC lines, the need increases for information about their potency and quality. Moreover, criteria are required to evaluate and compare the cells with respect to their performance in a specific application. The basic criteria to evaluate all hPSC are the same that apply to hESC – the gold standard for pluripotent cells. These are then supplemented by information regarding the cell origin and details of the method used for derivation, e.g. reprogramming in the case of hiPSC. For example, the availability of disease specific, GMP and clinical grade hPSC demands the set up of relevant registration information guidelines for these cells. To directly compare between hESC and pluripotent cells from other sources requires systematic collection of key data and their representation to define the distinct characteristics of each hPSC, and to highlight the advantages and disadvantages for their use in specific applications. On this note, access will be provided to information about research projects with hESC and hiPSC, as well as the distinct lines used in these projects. This essential transparency task will answer questions like: ‘What is being done where with which hPSC, and what are the outcomes?’
Technology transparency
PSC can be generated by an increasing number of technologies and methods, and they can be cultured, differentiated, characterized and stored using very diverse protocols. The technologies used for a specific cell line add strongly to its biological characteristics and variability. It is therefore of importance to make the information on the technologies and protocols used for the generation and further manipulation of PSC available and to develop consent on respective standards.
Research and Cell Application
Data derived by researcher after a line has been registerd should be made available as a means to assess hPSC characteristics and to rigorously compare hESC with each other and with hiPSC. Further direct comparison of iPSC and hESC data will also enable resolution of iPSC diversity and consistency with hESC characteristics. Since comparison of cells is a key function of EU-hPSCreg as it reduces the need for the establishment of novel cells and refines research, a comprehensive backbone for the annotation of each cell line with research data will be implemented. Moreover, a registry of projects that work with specific hESC-lines, a task to be implemented for EC-supported projects at a minimum, will complement the research data. The searchable data and project database will help to reduce redundancy of research with hESC and to motivate collaborations.
Communication and harmonization
For hPSCreg to maintain its position as a prime information hub for hESC and hiPSC, it is essential to have close communication with the providers of the cells (e.g. scientists, labs, banks, registries), the users of the cells (e.g. clinicians, industry, research labs) and stakeholders in need for information on cell usage, status of the field or regulatory and standardization status (e.g. stem cell societies, regulators). Efficient communication will also be required to keep registry information up to date and to foresee and ract in a timely fashion to new developments in the field. As research on PSC is a global endeavor and can only succeed through international cooperation, hPSCreg can promote internationalized, standards, validation criteria and ethical guidelines within the international discourse.
Dissemination and Public awareness
Novel technologies are often met with skepticism, including technologies using hESC and hiPS. The rise of hESC and hiPSC technology has generated public interest, and at the same time produced anticipations that are not always realistic. By providing information on research results and transparency on where the field stands, realism can be injected into the public debate. Moreover, public awareness includes the information about the scientific progress in a field, regenerative medicine and stem cells. This has been evident for hESC, and is now required for informed decisions on other types of pluripotent stem cells, such as hiPS. Another aspect of awareness concerns the scientific community. An informational hub, which interlinks several information sources, and provides qualified commentaries on novel scientific, ethical or regulatory developments will benefit both, researchers as well as the general public, regulators, clinicians and industry.
Based on these goals and tasks, the project has 4 objectives as described below.
Objective 1: Acquisition, Registration and Qualification of hPSC data. The key task of hPSCreg is the provision of information on and about hESC and hiPSC lines. The first task therefore is to define the content of the information to be acquired and to determine registration, quality and validation requirements. The second task is the collection of this information in an efficient and systematic manner and the third task is to check quality, completeness of the data and validation of the registered cell lines. The content of the information is allocated into several packages, such as a basic package containing necessary information to determine whether the cell is a PSC, an ethics package that provides information on ethical provenance of the cells, a science and technology package that provides protocols and results, and an application package containing information on the use of these cells e.g. in research or medicine. The registration collection of the information will be facilitated through the hPSCreg network of national contact points, the scientific committee, but most importantly by the researchers. Quality check and validation of information will be provided by the hPSCreg team and its partners by assessing the completeness and plausibility of cell-related information according to predetermined criteria. This step will allow users to assess whether a cell line complies with ethical and scientific standards required for their usage. Developing and applying scientific and ethical criteria regarding the criteria for the inclusion of hPSC lines will constitute one of the main tasks of this objective. Periodic update of the available information is essential. Validation of the data is required to assure users that the information provided by the Registry is reliable. This is most important if the Registry is to be used as a European and globally accepted resource for qualified cell lines, as a standard tool and hub for other registries. The project would also offer to establish and host registries for countries who do not have formal registries. Validation mechanisms are provided for the qualification information (basic and ethics packages) though a multistep confirmation and feedback procedure. All data are also validated through the use of comparison tools and plausibility checks by the Registry team. Moreover, feedback from the community will provide independent evaluation of the provided data. If provided data are confirmed by several provides / users, this will increase confidence in them and increase the validation level of the respective cell line.
Objective 2: Communication, Dissemination and Harmonization. An important element of EU-PSCreg is to facilitate scientific networking, international cooperation, knowledge dissemination and promotion of public awareness. These tasks will be implemented through online tools for direct interaction and exchange with the Registry and with the community, through publications and newsletters, and by the active contribution to international standardization and harmonization efforts in the framework of conferences, relevant organizations and societies such as the International Stem Cell Initiative (ISCI). EU-PSCreg will seek interaction and participate in related EU-funded projects as a key resource. A hub will be developed that serves as a communication and dissemination platform toward the scientific community, stakeholders from political and patient organizations and to the general public. This hub will also serve as a contact and access point for international registries with similar scopes. Operation procedures and scope, standards, content and results of the Registry work will also be published. Regular commentaries and newsletters will be directed not only at researchers, but also at other stakeholders and the general public and educational organisations. Content will be dynamic and will be presented to ensure that data compariswon is availa through the DB that is not available elsewhere without considerable work. Collaboration and communication with other registries and banks (e.g. NIH, ISCR-UMASS, NIH/Korea, NIBIO/Japan) will be actively enforced.
Harmonization refers to the need for adjustment of differences and inconsistencies among different measurements, methods, procedures, schedules, specifications, or systems to make them uniform or mutually compatible. In this respect, harmonization promotes standardization. Thus, hPSCreg is in a unique position to direct harmonization in the stem cell field by applying the same criteria e.g. nomenclature, cell characterization, qualification and procurement. While different laboratories use currently diverse protocols, tools and measurements, the Registry provides a means to evaluate and compare them. By providing open access to information it contributes to harmonization, yet importantly, the Registry will actively promote harmonization and standardization through its publications and communications as part of its dissemination efforts. Harmonization in these areas, also in terms of nomenclature, protocols, markers, is required to compare the different cells and the Registry aims at setting up and support respective efforts actively.
Objective 3: Implement Governance and safe Technical Conduct. The EU-PSCreg will not be operational and sustainable without an efficient and safe technical backbone and clear governance and code of conduct policies. Hence, the main task of this objective is to assure that the Registry is safe, technically secured, publicly accessible, and has a transparent, controlled and standardized procedure to operate. Safe technical conduct is provided by building on the existing EU-hESCreg server, which is embedded into a secured and serviced IT-environment of Charité University Medicine Berlin. Related and necessary tasks are the development and maintenance of the database and interface, compliance with data safety and data security regulations and technical service provision to users such as feedback management and cell registration. We will implement novel tools that are not yet integrated into hESCreg to search and compare registered information on all levels, to link to other registries and to assemble documentation about each cell line. Governance is provided by adjusting, implementing and controlling transparent principles for quality assurance, with a formal code of conduct and operating procedures for the acquisition and registration of data, to insure quality and adherence to scientific and ethical requirements. This also includes implementation of standard procedures for communication and inclusion / harmonization of data from other registries. Technical conduct requires maintaining a stable, secure and efficient technical backbone that is hosting the Registry. We will build on the same system that has been implemented for hESCreg and upgraded as required. Data are deposited on a virtual server, which is continuously serviced, controlled and backed up by the institution (Charité), providing long term sustainability and public access. Database and interface of EU-hPSCreg are based on those established hESCreg. However, upgrades and improvements will be implemented in order to increase efficiency and flexibility of searches and comparisons, and to enable the compilation of cell-specific data sheets (e.g. cell line documentation). In addition, feedback and forum areas will be improved with tools for follow up, especially for feedback on the status of cell registration and qualification. Finally, procedures for linking with other registries and banks for the sharing of data will be developed and implemented.
Open Source/Access Model: Selected standard and customized tools for stem cell biology will be provided. This will involve algorithms for data comparison, statistical analysis and export modules for work with the data in local systems (API). Provision of these functionalities may serve as an additional incentive for researchers to download their stem cell data. All characterization and analysis functions will operate under the Open Source/Access model. Compliance with data safety/protection and data security regulations is a necessity for the Registry. Since only anonymized data about cells will be registered, there is no traceability provided to any donor. These may only be accessible via the data providers and the Registry will indicate whether a cell line is traceable (via the provider), or not. The provider contact information, or links to cell banks, will also be provided. Data security is provided via the firewall and backup services of the IT-environment of Charité University Medicine Berlin.
Objective 4: Effective project management: The task of establishing an efficient and competent management structure will rely on the established structure of EU-hESCreg, where the project management team is supported by a steering committee and an advisory board. Together, these will provide the appropriate means of control, independence and sustainability of the EU-PSC Registry. Project management will provide daily, operational management, strategic management involving the Steering Committee (StC) and the Ethics Advisor, as well as management of external cooperation and communication tasks such as workshop and meeting organization. Project management is furthermore responsible for adherence to governance rules, for internal controlling, review and reporting obligations. Importantly, the management will be responsible for the implementation of measures for sustainability of the Registry. Regular consortium meetings or telephone conferences will be organized to facilitate the oversight and review function by the coordinator. Sustainable platform operation: Specific concepts will be drafted to allow for the transition of the registry from temporary to permanent and sustainable operation. This will include offering specific services such as cloud computing, software-as-a-service models, service based cell line search, selection and validation, participation in international research and infrastructure projects or permanent affiliation with a large public research funding institutions as possible options.
The EU-hPSCreg will not be operational and sustainable without clear governance and code of conduct policies. Governance is provided by adjusting, implementing and controlling transparent principles for quality assurance, code of conduct (CoC) and standard operating procedures (SOP) for the acquisition and registration of data, to insure quality and adherence to scientific and ethical requirements. Evaluation and review mechanism for cell line data need to be implemented and standard operating procedures (SOP) developed. Governance also includes implementation of standard procedures for communication and inclusion / harmonization of data from other registries. A quality management system (QMS, including CoC and SOPs) and governance procedures for the Registry will be developed and implemented to ensure coordinated, effective and controlled data entry, validation and feedback management. The procedures will detail the formal roles and internal cooperation of the Registry management, the partners and Steering Committee (StC). The QMS will ensure continuous commentary on effectiveness of the Project and implementation of proposals for improvement. The management will implement the QMS by organizing a work stream of open meetings and reviews with partners and StC. The mainframe governance procedures were already developed for the hESCreg project and will provide basis for the development and maintenance of this platform into hPSCreg.
Regulation and ethical issues are part of the governance document aim at delivering their appropriate representation as a guide for managing the Registry. This will provide assurance that central ethics and regulatory themes are maintained within the project as a whole. An independent ethics and legal advisors will be included in the project for that aim. SOPs for source qualification. Source information refers to criteria that serve to verify the scientific and ethics data posted by the providers to the Registry. Source information is thus important for the user of the Registry to verify whether a cell line adheres to the benchmark criteria set by the researcher or its funding agency for usage of hPSC. Comprehensive summaries for source information will, in addition, provide a resource for assessment of ethical standards, scientific scrutiny and reliability of hPSC research. The SOPs will provide definitions on scope and content for source information for the providers. The Registry will enable the user to specifically access these source data to search for benchmark criteria fit for specific research applications. As benchmark criteria for hPSC usage will depend on the potential application of the cell, a rather broad frame that allows for different levels of scrutiny will be provided. The SOPs will set rules and procedures for the acquisition, qualification and validation of source information. The Registry co-ordination will, however, actively recruit providers of cells to submit verifiable source information for their hPSC. The level to which source information will be required to make a public listing of a PSC will be regularly evaluated and approved by the StC as outlined in the governance rules (code of conduct) of the Registry. As active Validation of source information e.g. by re-assessing the claims and data provided is not practicable, validation will be provided by cross referencing on the scientific level using the Registry database itself. On the regulatory and ethical levels, validation will be promoted by harmonizing the provided information with the information in the Registry on the legal and regulatory environment in the specific source country.
Project Results:
The work plan was oriented along the aim to sustain and further develop a Registry for human embryonic stem cells (hESC), supplemented with human induced pluripotent stem cells (hiPSC). It was structured into four closely linked work packages on (i) cell-line data acquisition and validation, (ii) communication and dissemination, (iii) technical implementation and (iv) management and administration.
The hPSCreg consortium continued the work laid down in the previous EU-hESCreg project. However, due to lack of funding and of progressive developments in the field, the database, backend, frontend, registration tools and validation procedures had to be completely renewed. These tasks needed to be performed without jeopardizing the existing data. In addition, more functions and tasks were taken on by hPSCreg, including certification of PSC-lines, publication of lines, implementation of standardization tools (e.g. nomenclature) and the development of modules to allow interaction with PSC banks.
The first key objective was the provision of information on and about hESC and hiPSC lines. The first task to reach this objective was to define the content of the information to be acquired and to determine registration, quality and validation requirements. This objective has been achieved, although it was also realized that the selected criteria require continuous updating as the field progresses and user requirements develop. Hence, we consider the definition of content and validation requirements as ongoing tasks. Moreover, the initiated collaboration with EBiSC (European bank of Induced Pluripotent Stem Cells) turned out to be extremely fruitful in terms of user requirement assessment. Consequently, we have installed mechanism to continuously update the information content and react to demands for new information requirements. In addition, we have integrated means to add and annotate cell lines with new information even after validation. Most important were the collection of the defined cell-line information in an efficient and systematic manner and the third task to check quality, completeness of the data and validate the registered cell lines. The required information to be registered has been allocated into several packages. The basic package contains information that is absolutely necessary for registration of a cell line (minimal requirements). This includes evidence of ethical provenance, evidence of pluripotency and traceability to a generator of the cell line. The extended package includes information on cell characterization, protocols and results, and an application package containing information on the use of these cells e.g. in research or medicine. This includes a list of EU-funded projects in which hESC and hiPSC are used. A standard procedure for quality check and validation of information has been developed as part of the standard operation procedures (SOPs).
In the continuously ongoing Task 2, cell-lines and associated data were acquired and registered and cell-information according to the defined requirements was organized. We have developed a new registration tool (see also WP2) to facilitate data entry according to the registration requirements as defined in task 1. In a first step, all existing hESCreg lines were transferred to the new database and the respective fields used and information validated. Secondly, the hPSCreg team has registered a batch of new cell lines manually. Post launching of the registration tool in November 2014, the cell line - registration became publically available. It has since then further developed and is under constant revision to add new features, functions and allow for the systematic annotation of information to cell lines. The registration tool can be visited at http://hpscreg.eu.
In Task 3, we checked quality and completeness of the provided information or validation. We developed a multistep process for assessment of the cell-related information, which involves the management. Originally, the Committee of National Representatives (CNR) and the Ethics Advisor was involved in this process, but this procedure has not been effective and was changed. Now, the hPSCreg team alone validates lines based on strict fulfilment of registration requirements. To that end a valuation system was developed, which determines transparently the completeness and validation of the cell related information. Only in case a provider of information for a cell line is unknown and cannot be verified by the hPSCreg team, the CNR will be involved.
In Task 4, we have developed a review process for registry information as a continuous task as outlined in the code of practise (CoP). In general, information will be reviewed by the hPSCreg team. The CNR will alert the management of any changes in regulation and on scientific breakthroughs that require changes in the review mechanism.
Validation of PSC lines by the hPSCreg team is the prerequisite for public release of the line. In addition, the registry is providing Certificates to each cell line that fulfils requirements to use them in Horizon 2020 funded research. In addition to cell-line certificates, hPSCreg provides project certificates (certifying that the project is registered and which PSC lines are being used).
The second key objective was the facilitation of efficient mechanisms for internal and external communication and feedback, scientific networking, international cooperation, knowledge dissemination and promotion of public awareness. In the reporting period, we developed a dissemination and communication concept based on electronic means. A helpdesk and online communication standard via a contact form was implemented as a first step. Mechanisms for communication between hPSCreg and other registries and PSC-banks were developed. Further refinement and implementations of dissemination activities were implemented by an egreement with ELSEVIER to publish hPSCreg lines in the journal ‘Stem Cell Research – Lab Notes’. The Registry acts as a reviewer for hPSClines and facilitates their expedited publication. More than 60 lines have already been published in this open access journal. In addition hPSCreg has published several papers describing the Registry’s purposes, role and structure. Moreover, hESCreg has participated and presented at a number of conferences and meetings.
In Task 1, we determined means and rules for internal and external communication (appendix Operation concept communication and dissemination). Internal communication between WPs, the management team, the national representatives and Ethics Advisor were regularly (monthly) performed by email and teleconferencing (skype). External communications are focused on web-based solutions (online tools), electronic communications (email) and meetings. For efficient communication and exchange of data, web services and web applications were determined as the preferred solution. Two-way communication channels were implemented for user registration and user feedback embedded in the registration tool.
In Tasks 2 and 3, we have implemented collaborations with the registries eagle-I (USA), the NIMH PSC-Bank at Rudgers (USA) and the Korean NIH Registry on an informative level. This includes the registration of hPSC-lines in hPSCreg and the exchange of information regarding implementation of standards (ethics consent, ontologies) and nomenclature. Furthermore, we have set up collaboration with the International Stem Cell Banking Initiative (ISCBI) and the UK Cell Therapy Catapult (CTC) regarding the development, dissemination and application of guidelines and rules regarding the procurement, handling and application of hPSC-lines for clinical application. Finally, we have established close links to the European Bank for Induced Pluripotent Stem Cells (EBiSC), where hPSCreg is the key portal for the registration of EBiSC cell lines. Members of CTC, ISCBI and EBiSC are members of the hPSCreg CNR.
In Task 4 hESCreg is providing on its website links to relevant regulatory information, to publications, projects working with hESC and hiPSC and maintain a News feature (http://hpscreg.eu). In Task 5 we established a standardized naming convention (Nomenclature) for pluripotent stem cells.
The third key objective was the establishment of an accurate carefully constructed technical platform and portal as well as robust government structures. In connection with establishing the database, we completely revised the original version, eliminated flaws and security issues, which were related and caused by the intermediate lack of funding and developed and implemented a new website (including design, new user management and new search and browse functionalities). This work took significantly more effort that originally planned. The reasons were a 2-yar gap in technical maintenance due to lack of funding for hESCreg, a fault-prone web interface, which was not usable for the newly implemented registration items and functionalities and a backend that was unsuited for registration of cell lines and related information by users. Basically, the whole registry was rebuilt from scratch while the old version had to be maintained and running and transferred without data loss to the new back/frontends.
Although these tasks took more effort than anticipated and remain a central to acceptance of the Registry. They are critical to long term sustainability and for implementing a solid quality assurance process, robust traceability and scientific quality of data.
With respect to governance and code of conduct (CoC), we have developed and implemented internal and external policies, which are transparently laid down in the CoC document. The CoC document provides the governing guidelines to quality assurance. Together with the Standard Operating Procedures (SOPs) they detail the protocols for the acquisition and registration of data, to insure quality and adherence to scientific and ethical requirements, evaluation and review mechanism for cell line data. Rules and standard procedures for communication, dissemination and inclusion / harmonization of data from other registries have been detailed in the Communications and Dissemination Guide document. In addition, to strictly adhere to ethical standards of Horizon2020 and to trace and confirm ethical procurement of the registered cell lines, we have established a Procedure for Management of Key Ethics Information and Risks Relating to Registration of Pluripotent Stem Cell Lines and an Ethics Evaluation Form. The latter has been implemented as part of the registration tool facilitating search and immediate assessment of the relevant consent information and ethics approvals.
In Task 1 we performed a requirements analysis to determine adjustments needed for the current technical backbone, database and interface in relation to objectives of the project and strategic Registry tasks. We have determined that all technical elements must be newly established, programmed and tested as the status quo version was not fit to provide the needed stability, capacity and usability. We have developed and implemented the required elements (database, server, interface), tested them and validated basic functionalities (to register, curate, service, backup and update the database, search, browsing and user management). The new hESCreg has been publicly launched in Heidelberg and in San Antonio (USA) in 2014. The interface/portal has been redesigned and implemented. The further improvement of the front- and backends is a continuing, iterative process.
In Task 2 we have developed several tools for standardization and analysis. We developed and implemented a standardized nomenclature of pluripotent stem cells. This tool automatically assigns names to registered cells and thus supports search, comparison and exchange of data and cells across multiple platforms. Via the platform CellFinder we developed comparison tools between cells based on transcriptomics data, which are usable for hPSCreg. In addition, we implemented a visualization tool to provide easy and intuitive access to the status of PSC-research and application by country, cell type and also informs about the ethics/regulatory requirements in these countries.
All functions operate under the Open Source/Access model. Efficient data integration routines are ontology-based where ontologies were available and validated. The expansion of the ontology implementation, and term curation is ongoing. Primary and secondary research data can be uploaded and made available to the community. Provision of the generator, owner and distributer (e.g. banks) is available.
In Task 3, we implemented means for compliance with data safety/protection and data security regulations as outlined in the Procedure for Management of Key Ethics Information and Risks Relating to Registration of Pluripotent Stem Cell Lines document. Data security and data traceability is implemented via a logbook mechanism. This includes the necessary provisions for data security such as firewall and password protection of data, division of the platform in front- and backend and clear access regulations.
In Task 4 we developed and implement the quality management system and governance procedures for the Registry. The procedures detail the formal roles and internal cooperation of the Registry management, the partners and CNR. These are outlined in the Code of Conduct and Standard Operating Procedures documents.
Regulations and rules of operation for co-operation with institutions outside of the Registry (cell banks, other registries, initiatives such as ISCI, other EU-projects, sponsors), especially concerning direct data transfer or exchange are outlined in the Operation Procedures for Communication and Cooperation document.
In Task 5 we described and implemented regulation of ethical issues as part of the governance document and integrated these in the governance document as guide for managing the Registry to assure that central ethics and regulatory themes are maintained within the project as a whole (Procedure for Management of Key Ethics Information and Risks Relating to Registration of Pluripotent Stem Cell Lines document). We have appointed the Ethics Advisor Dr.Rosario Isasis (see hPSCreg website) and collaborate with the Ethics Working Party of the International Stem Cell Initiative.
In Task 6 we developed and implement SOPs for source qualification and criteria that serve to verify the scientific and ethics data posted by the providers to the Registry, including a comprehensive summary for source information for assessment of ethical standards, scientific scrutiny and data reliability. The SOPs provide definitions on scope and content for source information for the providers. The Registry enables the user to specifically access these source data to search for benchmark criteria fit for specific research applications. The SOPs include rules and procedures for the acquisition, qualification and validation of source information. An appropriate portal and search functionality is implemented for cross-referencing.
In Task 7, we have participated in meetings, including conferences on large scale PSC-banking and on harmonization in the field. Targeted and dissemination materials include posters and presentations at conferences. Two specific hPSCreg sessions were held at international conferences.
The fourth objective included the overall planning, administration, financial controlling, managing and coordinating the work and communication with the European Commission. The Code of Conduct documents as well as Standard Operating Procedures outline the procedures implemented for management. Other documents include emergency plans and duty booklet.
The coordinator controlled and coordinated the partners and work packages mainly through monthly meetings and by ad hoc email/teleconferences. Each meeting was documented by minutes which were documented and approved by all participants.
Strategic management is based on advice from CNR and the Ethics Advisor. Meetings and advisory notes by members of these bodies are also documented and circulated as described in the SOPs.
A list of project meeting is provided in the table below:
Date Type of meeting
20.03.13 TC (telephone conference)
16.04.13 TC
13.06.13 Boston ISSCR. Personal meeting
25.06.13 TC
17.07.13 TC
22.07.13 Berlin. Personal meeting
23.07.13 Berlin. Personal meeting
1.10.13 TC
22.10.13 TC
26.11.13 TC
5.12.13 TC
23.01.14 TC
06.03.14 TC
01.04.14 TC
10.06.14 TC
18.06.14 Vancouver ISSCR. Personal meeting
04.08.14 TC
We developed a work plan for the CNR and circulated a questionnaire to elucidate status of hESC/hiPSC research and regulation. Internal communication (with WP leaders, CNR) is organized via email and teleconferencing. For external communication, we use contact forms provided at the website (helpdesk). The management has initiated several collaborations with the aim to ensure sustainability and expansion. This includes the IMI project EBiSC and the ISCBI. The management has established an active CNR (as provided at the hPSCreg website) and Ethics Advisory mechanism (see website). Task management within the project was controlled via an online task management system (redmine), which allowed for transparent task assignment, monitoring, commenting and updating. All partners had password protected access to redmine.
There was an original underestimation of work related to technical implementation (database design, portal and website development and server implementation), which was due to surprisingly malfunctioning of many elements of the old hESCeg database. This again was due to a gap in funding and thus incomplete maintenance capabilities. On top of this problem, the programmer we hired for this task quit and a new staff member needed to be hired and made familiar with the tasks. Despite these obstacles, we were able to fulfil all deliverables. The hPSCreg website is available at www.hPSCreg.eu. It is continually updated and improved.
The management included intensive communication with stakeholders and beneficiaries in order to test, validate and improve the database and website. This included
• participation in workshops and presentation of hSCreg in the IMI projects EBiSC, StemBANCC and the International Stem Cell Initiative / ISCBI.
• Collaboration with the European Bioinformatics Institute (EBI)
• Collaboration with Kyoto University and National Institutes of Health of Korea, both hosting the relevant national registries
• Collaboration with the UK stem cell bank, WiCell, Rudgers (USA)
Potential Impact:
hPSCreg Statistics
2015
6.917 visits with action (e.g downloads)
5 Minutes 31s average time at the website
5,5 actions in average per visit
0,61 s average time to generate the website
34.232 views of the site, 21.212 direct visits
1.797 internal searches, 500 unambigous search terms
551 downloads, 434 unambigous downloads
Access by equipment:
Desktop: 6.391
Smartphone: 302
Tablet:175
Unknown: 40
Phablet: 8
Feature-Phone: 1
Access by continent:
Europe: 4.307
Asia: 1.245
North Amerika: 1.054
Unbekannt: 113
South Amerika: 102
Oceania: 45
Africa: 41
Middle America: 10
Access by country top 50:
United Kingdom 1562
USA 980
Germany 857
Spain 461
Soputh Korea 268
Japan 243
France 238
India 226
Slowenia 138
Belgium 127
Italy 116
China 115
Netherlande 111
Norway 110
Thailand 109
Sweden 92
unknown 110
Brasilia 72
Switzerland 68
Russia 63
Israel 60
Canada 60
Chech Republic 49
Australia 43
Hongkong 37
Finland 36
Kuwait 35
Poland 30
Greece 29
Portugal 28
Denmark 27
Turkey27
Iran 26
Austria 25
Taiwan 24
Singapur 23
Irland 22
Egypt 19
Hungary 18
Malaysia 14
Mexico 14
Luxemburg 13
Rumania 13
Pakistan 12
Philippines 11
Peru 9
Ukrainia 8
Columbia 7
Nigeria 7
Search terms top 50:
spain 29
h9 28
H9 23
iPS 15
trisomy 13 15
MIFF1 12
NCRM 9
wa09 9
France 7
h1 7
hues8 7
ips 7
MIFF 7
Shef 7
cancer 6
CRMi001-A 6
ED 6
HES3 6
hues9 6
Seoul 6
trisomy 6
United Kingdom 6
ESi001-A 5
hues 5
ipsc 5
NCRM-5 5
RCi68 5
shef 5
Shef-3 5
shef-3 5
Shef-6 5
shef-6 5
Spain 5
UNEW 5
bcrt 4
cambridge 4
China 4
CRMi001 4
H1 4
h7 4
HES-3 4
miff1 4
ncrm 4
NCRM-1 4
NCRM1 4
newcastle 4
Oscar 4
RCi 4
SNU 4
uk 4
2014
3.320 visits
5 Minutes 44s average time at website
6,2 Actions per visit
1,08 s average generation time of website
19.388 views, 12.417 unambiguous views
160 internal searches, 138 unambigous search terms
294 downloads, 274 unambigous downloads
Access by equipment:
Desktop: 2.856
Tablet:212
Smartphone: 211
unknown: 41
Access by continent:
Europe 2.005
Asia 626
North America 425
South Aamerica 108
unknown 106
Oceania 27
Africa 17
Middle America 6
Access by country:
United Kingdom 588
Germany 587
USA 361
Spain 223
South Korea 188
India 185
France 105
Brasilia 93
unknown 93
Italy 76
Japan 65
Belgium 61
Switzerland 61
Canada 55
Sweden 49
China 34
Chech Republic 34
Kuwait 29
Netherlands 29
Australia 25
Israel 20
Denmark 18
Turkey 18
Finland 17
Poland 17
Singapur 17
Taiwan 17
Thailand 17
Iran 16
Russia 15
Austria 12
Luxemburg 11
Philippines 10
Hungary 10
Mexico 9
Bulgaria 8
Portugal 8
Egypt 8
Greece 7
Irland 7
Kroatia 6
Slowenia 6
Ecuador 5
Serbia 5
Hongkong 5
Indonesia 4
Lettland 4
Norway 4
Puerto Rico 4
Search terms top 50:
name searches
H1 4
spain 4
edi 3
h1 3
i3 3
roslin 3
h2 2
h4 2
H9 2
HS 2
HSF-6 2
netherlands 2
rc 2
trisomy 13 2
201B1 1
201B2 1
201B3 1
201B6 1
243h7 1
246G1 1
246G3 1
246G4 1
246G5 1
bonn 1
ca1 1
cancer 1
CCTL 1
cFA404-KiPS4F-1 1
CHA-hES3 1
che- 1
ches 1
chHES-8 1
chim 1
chimaeric 1
chimeric 1
cho 1
cryo save 1
CyT203 1
cyth25 1
EBNA1 H9 1
Edi 1
Edi1 1
Endeavour 1 1
envy 1
ES 1
esi-017 1
europe 1
fat cell 1
fertility unit sweden 1
Germany 1
Alltogether since start of statistical documentation
10.247 visits
5 Minutes 35s average time at site
5,7 actions per visit
0,78 s average generation time of site
53.642 views, 33.649 unambigous views
1.959 internal searches, 604 unambigous search terms
846 downloads, 709 unambigous downloads
List of Websites:
http://hpscreg.eu
Contact:
Human pluripotent stem cell registry
BCRT
Augustenburger Platz 1
13353 Berlin, Germany
Phone: +4930 450539424
Email: hpscreg@charite.de