The ethics of preconception expanded carrier screening in patients seeking assisted reproduction.

Expanded carrier screening (ECS) entails a screening offer for carrier status for multiple recessive disorders simultaneously and allows testing of couples or individuals regardless of ancestry or geographic origin. Although universal ECS-referring to a screening offer for the general population-has generated considerable ethical debate, little attention has been given to the ethics of preconception ECS for patients applying for assisted reproduction using their own gametes. There are several reasons why it is time for a systematic reflection on this practice. Firstly, various European fertility clinics already offer preconception ECS on a routine basis, and others are considering such a screening offer. Professionals involved in assisted reproduction have indicated a need for ethical guidance for ECS. Secondly, it is expected that patients seeking assisted reproduction will be particularly interested in preconception ECS, as they are already undertaking the physical, emotional and economic burdens of such reproduction. Thirdly, an offer of preconception ECS to patients seeking assisted reproduction raises particular ethical questions that do not arise in the context of universal ECS: the professional's involvement in the conception implies that both parental and professional responsibilities should be taken into account. This paper reflects on and provides ethical guidance for a responsible implementation of preconception ECS to patients seeking assisted reproduction using their own gametes by assessing the proportionality of such a screening offer: do the possible benefits clearly outweigh the possible harms and disadvantages? If so, for what kinds of disorders and under what conditions

Human germline gene editing: Recommendations of ESHG and ESHRE

Technological developments in gene editing raise high expectations for clinical applications, first of all for somatic gene editing but in theory also for germline gene editing (GLGE). GLGE is currently not allowed in many countries. This makes clinical applications in these countries impossible now, even if GLGE would become safe and effective. What were the arguments behind this legislation, and are they still convincing? If a technique can help to avoid serious genetic disorders, in a safe and effective way, would this be a reason to reconsider earlier standpoints? The European Society of Human Reproduction and Embryology (ESHRE) and the European Society of Human Genetics (ESHG) together developed a Background document and Recommendations to inform and stimulate ongoing societal debates. After consulting its membership and experts, this final version of the Recommendations was endorsed by the Executive Committee and the Board of the respective Societies in May 2017. Taking account of ethical arguments, we argue that both basic and pre-clinical research regarding GLGE can be justified, with conditions. Furthermore, while clinical GLGE would be totally premature, it might become a responsible intervention in the future, but only after adequate pre-clinical research. Safety of the child and future generations is a major concern. Future discussions must also address priorities among reproductive and potential non-reproductive alternatives, such as PGD and somatic editing, if that would be safe and successful. The prohibition of human germline modification, however, needs renewed discussion among relevant stakeholders, including the general public and legislators

Responsible innovation in human germline gene editing: Background document to the recommendations of ESHG and ESHRE

Technological developments in gene editing raise high expectations for clinical applications, including editing of the germline. The European Society of Human Reproduction and Embryology (ESHRE) and the European Society of Human Genetics (ESHG) together developed a Background document and Recommendations to inform and stimulate ongoing societal debates. This document provides the background to the Recommendations. Germline gene editing is currently not allowed in many countries. This makes clinical applications in these countries impossible now, even if germline gene editing would become safe and effective. What were the arguments behind this legislation, and are they still convincing? If a technique could help to avoid serious genetic disorders, in a safe and effective way, would this be a reason to reconsider earlier standpoints? This Background document summarizes the scientific developments and expectations regarding germline gene editing, legal regulations at the European level, and ethics for three different settings (basic research, preclinical research and clinical applications). In ethical terms, we argue that the deontological objections (e.g., gene editing goes against nature) do not seem convincing while consequentialist objections (e.g., safety for the children thus conceived and following generations) require research, not all of which is allowed in the current legal situation in European countries. Development of this Background document and Recommendations reflects the responsibility to help society understand and debate the full range of possible implications of the new technologies, and to contribute to regulations that are adapted to the dynamics of the field while taking account of ethical considerations and societal concerns

Environmental and Molecular Mutagenesis Meeting Report Assessing Human Germ-Cell Mutagenesis in the Post-Genome Era: A Celebration of the Legacy of William Lawson (Bill) Russell

ABSTRACT Although numerous germ-cell mutagens have been identified in animal model systems, to date, no human germ-cell mutagens have been confirmed. Because the genomic integrity of our germ cells is essential for the continuation of the human species, a resolution of this enduring conundrum is needed. To facilitate such a resolution, we organized a workshop at The Jackson Laboratory in Bar Harbor, Maine on September [28][29][30] 2004. This interactive workshop brought together scientists from a wide range of disciplines to assess the applicability of emerging molecular methods for genomic analysis to the field of human germ-cell mutagenesis. Participants recommended that focused, coordinated human germ-cell mutation studies be conducted in relation to important societal exposures. Because cancer survivors represent a unique cohort with well-defined exposures, there was a consensus that studies should be designed to assess the mutational impact on children born to parents who had received certain types of mutagenic cancer chemotherapy prior to conceiving their children. Within this high-risk cohort, parents and children could be evaluated for inherited changes in (a) gene sequences and chromosomal structure, (b) repeat sequences and minisatellite regions, and (c) global gene expression and chromatin. Participants also recommended studies to examine trans-generational effects in humans involving mechanisms such as changes in imprinting and methylation patterns, expansion of nucleotide repeats, or induction of mitochondrial DNA mutations. Workshop participants advocated establishment of a bio-bank of human tissue samples that could be used to conduct a multiple-endpoint, comprehensive, and collaborative effort to detect exposure-induced heritable alterations in the human genome. Appropriate animal models of human germ-cell mutagenesis should be used in parallel with human studies to provide insights into the mechanisms of mammalian germ-cell mutagenesis. Finally, participants recommended that 4 scientific specialty groups be convened to address specific questions regarding the potential germ-cell mutagenicity of environmental, occupational, and lifestyle exposures. Strong support from relevant funding agencies and engagement of scientists outside the fields of genomics and germ-cell mutagenesis will be required to launch a full-scale assault on some of the most pressing and enduring questions in environmental mutagenesis: Do human germ-cell mutagens exist, what risk do they pose to future generations, and are some parents at higher risk than others for acquiring and transmitting germ-cell mutations?

Reconstitution of gametes for assisted reproduction

Eichenlaub-Ritter U. Reconstitution of gametes for assisted reproduction. HUMAN REPRODUCTION. 2003;18(3):473-475.There are basically two major problems in the genesis of 'cloned' gametes in mammals, which have not been addressed in the original debate article. There is no adequate discussion on the mechanisms providing for high fidelity of chromosome segregation in mitosis and meiosis, and for proper imprinting in construction of 'reconstituted gametes'. The original debate article is uncritical with respect to the currently insufficient database and the incomplete documentation of results

Development of female germcells

Eichenlaub-Ritter U. Development of female germcells. Gynäkologische Endokrinologie . 2018;16(4):220-229

Genetics of oocyte ageing

Eichenlaub-Ritter U. Genetics of oocyte ageing. MATURITAS. 1998;30(2):143-169.Objectives: Correlations between parental age, aneuploidy in germ cells and recent findings on aetiological factors in mammalian trisomy formation are reviewed. Methods: Data from observations in human oocytes: molecular studies on the origin of extra chromosomes in trisomies, experiments in a mouse model system, and transgenic approaches are shown. Results: Errors in chromosome segregation are most frequent in meiosis I of oogenesis in mammals and predominantly predispose specific chromosomes and susceptible chiasmate configurations to maternal age-related nondisjunction. Studies on spindle structure, cell cycle and chromosome behaviour in oocytes of the CBA/Ca mouse used as a model for the maternal age-effect suggest that hormonal homeostasis and size of the follicle pool influence the quality, maturation competence and spindle size of the mammalian oocyte. Predisposition to errors in chromosome segregation are critically dependent on altered cell cycles. Compromized protein synthesis and mitochondrial function affect maturation kinetics and spindle formation, and cause untimely segregation of chromosomes (predivision), mimicking an aged phenotype. Conclusions: Altered cell cycles and untimely resolution of chiasmata but also nondisjunction of late segregating homologues caused by asynchrony in cytoplasmic and nuclear maturation appear to be causal to errors in chromosome segregation with advanced maternal age. Oocytes appear to lack checkpoints guarding against untimely chromosome segregation. Genes and exposures affecting pool size. hormonal homeostasis and interactions between oocytes and their somatic compartment and thus quality of follicles and oocytes have the potential to critically influence chromosome distribution in female meiosis and affect fertility in humans and other mammals. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved

Expression in in-vivo and in-vitro growing and maturing oocytes: focus on regulation of expression at the translational level

Eichenlaub-Ritter U, Peschke M. Expression in in-vivo and in-vitro growing and maturing oocytes: focus on regulation of expression at the translational level. HUMAN REPRODUCTION UPDATE. 2002;8(1):21-41.Studies of expression in in-vivo and in-vitro maturing oocytes have the potential to elucidate signalling pathways involved in the intricate crosstalk between the oocyte and its somatic compartment during differentiation and morphogenetic processes, and the origin of disturbances in oocyte maturation possibly involved in reduced fertility. This review summarizes data on expression studies with focus on regulation of expression at the translational level in the maturing oocyte. The regulation of gene expression at the translational level as analysed in in-vitro maturing oocytes is complex and highly conserved between different species. It is characterized by differential degradation, and by storage and recruitment of distinct maternal mRNAs involving conserved consensus sequences in the 5' or 3' untranslated regions (UTRs) of mRNAs. Proteins interacting with such sequences affect the temporal 3' polyadenylation, and bring the 5' and, 3' UTRs of mRNAs into close proximity for efficient initiation of translation. Post-translational modifications of mRNA-associated proteins contribute to maturation- and developmentally controlled and to cell cycle-dependent expression. New methodologies for analysis of ovary-specific gene expression and function of genes in oogenesis,are also reviewed, e.g. RT-PCR, SAGE-PCR, real-time rapid cycle fluorescence monitored RT-PCR, differential display techniques, and microinjection of anti-sense RNA, double-stranded RNAs or mRNAs expressing green fluorescent protein-tagged proteins into maturing oocytes

Environmental Hazard in the Aetiology of Somatic and Germ Cell Aneuploidy

Pacchierotti F, Eichenlaub-Ritter U. Environmental Hazard in the Aetiology of Somatic and Germ Cell Aneuploidy. Cytogenetic and Genome Research. 2011;133(2-4):254-268