Provision and Quality Assurance of Preimplantation Genetic Diagnosis in Europe

Preimplantation genetic diagnosis (PGD) is now well established and provided in many European countries. However, regulations, professional standards and accreditation requirements can differ notably. Furthermore, no comprehensive independent data exist either about practice and provision in Europe or about the quality assurance practices and procedures designed to optimize the quality of the results. Consequently, a study was launched to obtain knowledge, currently lacking, of the provision and quality assurance of PGD services and cross-border activities in Europe. An online questionnaire was developed and sent to PGD providers, and expert opinions were obtained through interviews with professionals in specific countries. Information was gathered from 53 centres offering PGD in 17 European countries. There is a diverse array of tests available, with a trend for custom-made services. Although half of the centres have a designated quality manager, just 33% have achieved or are preparing for accreditation or certification. About 66% of the centres responded that they did not participate in external quality assessment, a problem exacerbated by the lack of existing PGD-specific schemes. Approximately 19% of the centres do not keep data on accuracy and 9% do not even follow up until birth. PGD is an expanding activity with an increasing international flow that accounts for approximately one-third of the activity reported. The survey highlights a significant need for improvement in quality assurance in PGD centres. On the positive side, important improvements in the quality management of these services are expected with the European Tissue Directive entering into force.JRC.J.5-Agriculture and Life Sciences in the Econom

The Histone Acetyltransferase Domains of CREB-binding Protein (CBP) and p300/CBP-associated Factor Are Not Necessary for Cooperativity with the Class II Transactivator

The class II transactivator (CIITA) is a transcriptional co-activator regulating the constitutive and interferon-gamma-inducible expression of class II major histocompatibility complex (MHC) and related genes. Promoter remodeling occurs following CIITA induction, suggesting the involvement of chromatin remodeling factors. Transcription of numerous genes requires the histone acetyltransferase (HAT) activities of CREB-binding protein (CBP), p300, and/or p300/CBP-associated factor (pCAF). These co-activators cooperate with CIITA and are hypothesized to promote class II major histocompatibility complex transcription through their HAT activity. To directly test this, we used HAT-defective CBP and pCAF. We demonstrate that cooperation between CIITA and CBP is independent of CBP HAT activity. Further, although pCAF enhances CIITA-mediated transcription, pCAF HAT domain dependence appears contingent upon the concentration of available CIITA. When HAT-defective CBP and pCAF are both present, cooperativity with CIITA is maintained. Consistent with a recent report, we show that nuclear localization of CIITA is enhanced by lysine 144, an in vitro target of pCAF-mediated HAT. Yet we find that neither mutation of lysine 144 nor deletion of residues 132-209 affects transcriptional cooperation with CBP or pCAF. Thus, acetylation of this residue may not be the primary mechanism for pCAF/CBP cooperation with CIITA. In conclusion, the HAT activities of the co-activators are not necessary for cooperation with CIITA

Consequences, Opportunities and Challenges of Modern Biotechnology for Europe

Modern biotechnology products and processes are an integral part of the EU economy, mainly in manufacturing, including pharmaceuticals, agro-food and healthcare. While some products are not recognizable to the broader public (e.g. the use of genetic markers in livestock breeding), others are used on a daily basis (detergents with enzymes, recombinant insulin) or have become subject of public discussion (e.g. genetically modified crops). Modern bioetchnology contributes significantly to the achievement of major EU polciy objectives.JRC.J.5-Agriculture and Life Sciences in the Econom

Consequences, Opportunities and Challenges of Modern Biotechnology for Europe - The Analysis Report

Biotechnology is generally considered one of the key technologies of the 21st century, with a potentially wide range of applications in e.g. healthcare, agriculture, and industrial production processes. However, this notion has not yet been substantiated, as the diversity of sectors in which biotechnology is applied makes it difficult to investigate its actual degree of diffusion. Against this background and following a request from the European Parliament, the European Commission initiated the Biotechnology for Europe Study (Bio4EU Study). The study's objectives are to assess the contributions of modern biotechnology to the achievement of major European policy goals, and to increase public awareness and understanding of modern biotechnology.This report presents an analysis of the collected data with a view to assessing the contributions of modern biotechnology to major EU policy goals such as economic growth and job creation (Lisbon Agenda), and environmental sustainability and public health (Sustainable Development Strategy). As such, the report can be considered a background document of the Bio4EU synthesis report, which sets out the main findings of the study.JRC.J.5-Agriculture and Life Sciences in the Econom

Preimplantation Genetic Diagnosis in Europe

In vitro fertilisation (IVF) and preimplantation genetic diagnosis (PGD) are now well-established treatments and are provided in many European countries. However, regulations, practices, professional standards and accreditation requirements are often markedly different between Member States (MS). Differences between MS seem to be becoming especially pronounced because of the interface between assisted reproduction and genetics. To assess the extent of these differences and try to obtain an initial picture of the overall situation in Europe, in March 2005 the Institute for Prospective Technological Studies (IPTS) of the European Commission's Joint Research Centre (JRC), the European Society of Human Genetics (ESHG) and the European Society for Human Reproduction and Embryology (ESHRE) organised a workshop on the abovementioned interface . The two-day event brought together 50 experts from different specialities to review current practices in Europe and discuss potential needs in this area. The first thing that became clear was that no full picture was available of PGD practice and provision in Europe. Secondly, the lack of quality assurance for these services in general was perceived as a potential problem. The participants in the workshop unanimously agreed that European clinics should be certified or accredited and that licensing systems should be developed by professional self-regulation. Minimum quality standards should be set. The lack of common European rules and regulations to guarantee minimum standards was said to be adding to the problem. However, quality assurance and accreditation have taken on new significance in the light of the recent EU Directive 2004/23/EC on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells. Thirdly, as a result of the abovementioned differences between MS, patients are travelling abroad to gain access to treatment which is not available in their own country. This, in turn, sometimes requires movements of gametes (oocytes and sperm) and embryos within the EU. Whilst it is known that couples and reproductive tissue are moving around Europe, the extent is not known – especially in the new MS. Lastly, an overview of how the different regulatory frameworks are having an impact on the actual practices of PGD services was deemed necessary in order to gain a better understanding of the trans-border flows. Having pinpointed some of the needs in this area, the IPTS launched this study in an effort to address them and to obtain the missing knowledge on provision of PGD services in Europe. The aims of this study are two-fold: 1)to obtain a clear picture of current PGD practice in Europe, including the quality of the services and cross-border activities (flows of couples or reproductive tissue); 2)to carry out a comparative review of the different regulatory frameworks at MS level and identify potential gaps at European level and the impact these might have.JRC.J.5-Agriculture and Life Sciences in the Econom

Biobanks in Europe: Prospects for Harmonisation and Networking

Biobanks (i.e. the organised collections consisting of biological samples and associated data, have gained great significance for research and personalised medicine) are increasingly recognised as a crucial infrastructure for research. However, at the same time the widely varied practices in biobanking regarding for example collection, storage and consent procedures may also pose a barrier to cross-border research and collaboration by limiting access to samples and data. In this context, a recent study indicates that the limited sharing and linkage of samples is a key barrier for research, such as pharmacogenetics. Wide variation is observed in the implementation of relevant existing regulation, which may add further burden to harnessing the public health benefit of these collections. Therefore, it has been suggested that there is a strong need for a harmonised approach on biobanking practices and improved networking of existing and new collections. This Report shows information on the extent of biobanking in Europe, collected through a survey of existing European biobanks regarding both technical aspects (e.g. storage conditions) and aspects of governance and ethics (e.g. sample and data sharing, consent procedures, collaborations etc.). In total, 126 biobanks from 23 countries in Europe were surveyed. Significant lack of harmonisation has been found, especially in the legal aspects (e.g. data protection, consent). This may be partly attributed to the varied interpretation and implementation of EC directives covering aspects of biobanking by national authorities. One of the main complications is that, although the field of data protection is harmonised through the EC directive on data protection, the collection, storage, and sharing of samples is not. Furthermore, in countries that have introduced special biobanks acts it is not always clear where the borderline lies between the scope of these acts and that of the Directive. Indeed, according to the survey, biobanks within the same country reported different practices, suggesting that the problems of harmonization might be higher than expected and claimed. Not only are there different national laws, but apparently within EU member states biobanks do not implement homogenous practices on privacy and data protection issues. Desk research and expert interviews were done to complete the picture presented by the survey. Experts widely recognised the need to improve collaboration and networking among the numerous existing biobanks, as well as new initiatives in Europe (and world-wide). Efficient organisation of these resources through the development, for example, of an infrastructure would potentially facilitate financial sustainability and greatly contribute to the rapid progress of research and development of better diagnostic and therapeutic approaches. The most favoured model involved the development of a virtual biobank that would allow networking of biobanks across different countries and centralisation of data rather than samples. However, several organisational challenges (wide variation in biospecimen collection, storage techniques, data comparability, etc.) may hamper such an effort. The lack of uniform regulatory and ethical requirements and/or practices may pose an additional barrier. The European Commission has already recognised the importance of international biobank projects and many of them have been funded and established in the context of the EU Framework Programmes. To help promote networking of biobanks and thus maximise public health benefits, at least some degree of harmonisation must be achieved. Whether this should be achieved solely at the level of legal/regulatory requirements and practices and/or by technical standardisation requires further investigation. Experts suggested the establishment of an international (rathen than just a European) umbrella (or network) organization, which would establish common operating procedures.JRC.DDG.J.2-The economics of climate change, energy and transpor

Identification of the Ankyrin Repeat Proteins ANKRA and RFXANK as Novel Partners of Class IIa Histone Deacetylases

Eighteen human histone deacetylases (HDACs) have been identified, and according to their sequence similarity to yeast homologs, these enzymes are grouped into distinct classes. Within class II, HDAC4, HDAC5, HDAC7, and HDAC9 share similar domain organization both within the N-terminal extension and the C-terminal catalytic domain, thus forming a subclass known as class IIa. These HDACs function as signal-responsive transcriptional corepressors. To gain further insight into their function and regulation, we utilized an N-terminal fragment of HDAC4 as bait in yeast two-hybrid screens, which uncovered myocyte enhancer factor 2C, 14-3-3zeta, and ankyrin repeat family A protein (ANKRA). ANKRA is a poorly characterized protein with an ankyrin repeat domain similar to RFXANK, a subunit of the trimeric transcription factor RFX. Mutations on genes of the RFX subunits and the coactivator CIITA are responsible for the bare lymphocyte syndrome, an immunodeficiency disorder attributed to the lack of major histocompatibility complex class II (MHCII) antigens. Through its ankyrin repeat domain, RFXANK interacted with HDAC4. Two RFXANK-binding sites were found on HDAC4 with one located within residues 118-279 and another within residues 448-666. Interestingly, this deacetylase also interacted with CIITA. Consistent with the physical interaction with RFXANK and CIITA, HDAC4 and homologs repressed MHCII expression. These results identify ANKRA, RFXANK, and CIITA as novel targets of class IIa HDACs and suggest that these deacetylases play a role in regulating MHCII expression

Generation of a genomic tiling array of the human Major Histocompatibility Complex (MHC) and its application for DNA methylation analysis

Background: The major histocompatibility complex (MHC) is essential for human immunity and is highly associated with common diseases, including cancer. While the genetics of the MHC has been studied intensively for many decades, very little is known about the epigenetics of this most polymorphic and disease-associated region of the genome.Methods: To facilitate comprehensive epigenetic analyses of this region, we have generated a genomic tiling array of 2 Kb resolution covering the entire 4 Mb MHC region. The array has been designed to be compatible with chromatin immunoprecipitation (ChIP), methylated DNA immunoprecipitation (MeDIP), array comparative genomic hybridization (aCGH) and expression profiling, including of non-coding RNAs. The array comprises 7832 features, consisting of two replicates of both forward and reverse strands of MHC amplicons and appropriate controls.Results: Using MeDIP, we demonstrate the application of the MHC array for DNA methylation profiling and the identification of tissue-specific differentially methylated regions (tDMRs). Based on the analysis of two tissues and two cell types, we identified 90 tDMRs within the MHC and describe their characterisation.Conclusion: A tiling array covering the MHC region was developed and validated. Its successful application for DNA methylation profiling indicates that this array represents a useful tool for molecular analyses of the MHC in the context of medical genomics

Modern Biotechnology in Health

The article summarises the results of the Bio4EU study regarding contributions of modern biotechnology applications in health to EU policy objectives. It outlines emerging applications and challenges facing modern biotechnology applications in health.JRC.J.5-Agriculture and Life Sciences in the Econom