Medical ethics is a field of expertise that has developed alongside increasingly powerful technologies that have changed medical practice significantly over the past decades. From artificial ventilation and the possibility of resuscitation after cardiac arrest in the 1960s to the big-data-driven medicine of today, increasingly supported by artificial intelligence (AI), modern medicine is loaded with ethical dilemmas and complex decisions. Four principles, namely respect for autonomy, non-maleficence, beneficence and justice, were identified in the 1970s as guiding concepts of an ethics of biomedicine, the then emerging clinical practice that is informed by biological and physiological evidence from basic research. However, as the cultural and historical context affects the understanding of these principles, their implementation in clinical practice and healthcare is not trivial. Here, we highlight additional principles and values that back up these four core principles in the European context, particularly solidarity, human dignity, pluralism, tolerance, non-discrimination and gender equality. We further summarize how European Union law reflects such principles and values, and refer to existing instruments to support their implementation. Focusing on solidarity, we highlight its understanding in the European context and some challenges for its realization, particularly in the context of using AI in medicine and healthcare.

Alkylglycerol monooxygenase (AGMO) and plasmanylethanolamine desaturase (PEDS1) are enzymes involved in ether lipid metabolism. While AGMO degrades plasmanyl lipids by oxidative cleavage of the ether bond, PEDS1 exclusively synthesizes a specific subclass of ether lipids, the plasmalogens, by introducing a vinyl ether double bond into plasmanylethanolamine phospholipids. Ether lipids are characterized by an ether linkage at the sn-1 position of the glycerol backbone and they are found in membranes of different cell types. Decreased plasmalogen levels have been associated with neurological diseases like Alzheimer's disease. Agmo-deficient mice do not present an obvious phenotype under unchallenged conditions. In contrast, Peds1 knockout mice display a growth phenotype. To investigate the molecular consequences of Agmo and Peds1 deficiency on the mouse lipidome, five tissues from each mouse model were isolated and subjected to high resolution mass spectrometry allowing the characterization of up to 2013 lipid species from 42 lipid subclasses. Agmo knockout mice moderately accumulated plasmanyl and plasmenyl lipid species. Peds1-deficient mice manifested striking changes characterized by a strong reduction of plasmenyl lipids and a concomitant massive accumulation of plasmanyl lipids resulting in increased total ether lipid levels in the analyzed tissues except for the class of phosphatidylethanolamines where total levels remained remarkably constant also in Peds1 knockout mice. The rate-limiting enzyme in ether lipid metabolism, FAR1, was not upregulated in Peds1-deficient mice, indicating that the selective loss of plasmalogens is not sufficient to activate the feedback mechanism observed in total ether lipid deficiency.

EDITORIAL article Front. Genet., 07 September 2023Sec. ELSI in Science and Genetics Volume 14 - 2023 | https://doi.org/10.3389/fgene.2023.1280344

Plasmalogens are an abundant class of glycerophospholipids in the mammalian body, with special occurrence in the brain and in immune cell membranes. Plasmanylethanolamine desaturase (PEDS1) is the final enzyme of plasmalogen biosynthesis, which introduces the characteristic 1-O-alk-1 '-enyl double bond. The recent sequence identification of PEDS1 as transmembrane protein 189 showed that its protein sequence is related to a special class of plant desaturases (FAD4), with whom it shares a motif of 8 conserved histidines, which are essential for the enzymatic activity. In the present work, we wanted to gain more insight into the sequence-function relationship of this enzyme and mutated to alanine additional 28 amino acid residues of murine plasmanylethanolamine desaturase including those 20 residues, which are also totally conserved-in addition to the eight-histidine-motif-among the animal PEDS1 and plant FAD4 plant desaturases. We measured the enzymatic activity by transient transfection of tagged murine PEDS1 expression clones to a PEDS1-deficient human HAP1 cell line by monitoring of labeled plasmalogens formed from supplemented 1-O-pyrenedecyl-sn-glycerol in relation to recombinant protein expression. Surprisingly, only a single mutation, namely aspartate 100, led to a total loss of PEDS1 activity. The second strongest impact on enzymatic activity had mutation of phenylalanine 118, leaving only 6% residual activity. A structural model obtained by homology modelling to available structures of stearoyl-CoA reductase predicted that this aspartate 100 residue interacts with histidine 96, and phenylalanine 118 interacts with histidine 187, both being essential histidines assumed to be involved in the coordination of the di-metal center of the enzyme.

BACKGROUND:European countries are increasingly harmonising their organ donation and transplantation policies. Although a growing number of nations are moving to presumed consent to deceased organ donation, no attempts have been made to harmonise policies on individual consent and the role of the family in the decision-making process. Little is known about public awareness of and attitudes towards the role of the family in their own country and European harmonisation on these health policy dimensions. To improve understanding of these issues, we examined what university students think about the role of the family in decision-making in deceased organ donation and about harmonising consent policies within Europe.METHODS:Using LimeSurvey© software, we conducted a comparative cross-sectional international survey of 2193 university students of health sciences and humanities/social sciences from Austria (339), Belgium (439), Denmark (230), Germany (424), Greece (159), Romania (190), Slovenia (190), and Spain (222).RESULTS:Participants from opt-in countries may have a better awareness of the family's legal role than those from opt-out countries. Most respondents opposed the family veto, but they were more ambivalent towards the role of the family as a surrogate decision-maker. The majority of participants were satisfied with the family's legal role. However, those who were unsatisfied preferred to limit family involvement. Overall, participants were opposed to the idea of national sovereignty over consent policies. They favoured an opt-out policy harmonisation and were divided over opt-in. Their views on harmonisation of family involvement were consistent with their personal preferences.CONCLUSIONS:There is overall division on whether families should have a surrogate role, and substantial opposition to granting them sole authority over decision-making. If European countries were to harmonise their policies on consent for organ donation, an opt-out system that grants families a surrogate decision-making role may enjoy the widest public support.

Vascularized Composite Allotransplantation (VCA) has evolved in recent years, encompassing hand, face, uterus, penile, and lower extremity transplantation. Accordingly, without centralized oversight by United States Organ Procurement and Transplantation Network (OPTN) or European Programs, centers have developed their own practices and procedures that likely vary, and accordingly, present different levels of rigor to the evaluation process, internationally. The importance of psychosocial factors in the selection process and treatment course has been widely recognized, and therefore, several approaches have been developed to standardize and guide care of VCA candidates and recipients. We propose to develop an international multidisciplinary platform for the exchange of expertise that includes clinical, patient, and research perspectives. Patient perspectives would derive from peer education and the assessment of patient-reported outcomes. To establish a foundation for such a platform, future research should review and combine current VCA protocols, to develop the ethical framework for a standardized psychosocial evaluation and follow-up of VCA candidates and recipients. This review presents a comprehensive overview of recent results in the field of VCA, developments in structural aspects of VCA, and provides viewpoints driven from clinical experience.

Little is known about the physiological role of alkylglycerol monooxygenase (AGMO), the only enzyme capable of cleaving the 1-O-alkyl ether bond of ether lipids. Expression and enzymatic activity of this enzyme can be detected in a variety of tissues including adipose tissue. This labile lipolytic membrane-bound protein uses tetrahydrobiopterin as a cofactor, and mice with reduced tetrahydrobiopterin levels have alterations in body fat distribution and blood lipid concentrations. In addition, manipulation of AGMO in macrophages led to significant changes in the cellular lipidome, and alkylglycerolipids, the preferred substrates of AGMO, were shown to accumulate in mature adipocytes. Here, we investigated the roles of AGMO in lipid metabolism by studying 3T3-L1 adipogenesis. AGMO activity was induced over 11 days using an adipocyte differentiation protocol. We show that RNA interference-mediated knockdown of AGMO did not interfere with adipocyte differentiation or affect lipid droplet formation. Furthermore, lipidomics revealed that plasmalogen phospholipids were preferentially accumulated upon Agmo knockdown, and a significant shift toward longer and more polyunsaturated acyl side chains of diacylglycerols and triacylglycerols could be detected by mass spectrometry. Our results indicate that alkylglycerol catabolism has an influence not only on ether-linked species but also on the degree of unsaturation in the massive amounts of triacylglycerols formed during in vitro 3T3-L1 adipocyte differentiation.

Clinical ethics consultation is a relatively young field of expertise that supports ethically reflected decision-making. This process shakes up the existing hierarchy in two ways; first, by involving further perspectives in a structured and transparent way, and, second, by shifting the focus to a more comprehensive, interdisciplinary view. A major challenge for those providing clinical ethics consultation is building trust, which involves being considerate towards the needs of patients, relatives and healthcare professionals as well as towards customs and organizational culture. As this service emphasizes the relational aspect of medical care, it is difficult to realize within existing institutional frameworks. This paper explores how clinical ethics consultation developed and changed over the past few decades alongside an evolving understanding of respect for patient autonomy within an ethics of care approach. One of the most influential images related to clinical ethics consultation marks the beginning of this era, however, it also signifies some of the limitations and challenges of the practice still valid nearly 60 years after the first clinical ethics committee had been installed.

Abstract Background Genome editing in mice using either classical approaches like homologous recombination or CRISPR/Cas9 has been reported to harbor off target effects (insertion/deletion, frame shifts or gene segment duplications) that lead to mutations not only in close proximity to the target site but also outside. Only the genomes of few engineered mouse strains have been sequenced. Since the role of the ether-lipid cleaving enzyme alkylglycerol monooxygenase (AGMO) in physiology and pathophysiology remains enigmatic, we created a knockout mouse model for AGMO using EUCOMM stem cells but unforeseen genotyping issues that did not agree with Mendelian distribution and enzyme activity data prompted an in-depth genomic validation of the mouse model. Results We report a gene segment tandem duplication event that occurred during the generation of an Agmo knockout-first allele by homologous recombination. Only low homology was seen between the breakpoints. While a single copy of the recombinant 18 kb cassette was integrated correctly around exon 2 of the Agmo gene, whole genome nanopore sequencing revealed a 94 kb duplication in the Agmo locus that contains Agmo wild-type exons 1–3. The duplication fooled genotyping by routine PCR, but could be resolved using qPCR-based genotyping, targeted locus amplification sequencing and nanopore sequencing. Despite this event, this Agmo knockout mouse model lacks AGMO enzyme activity and can therefore be used to study its physiological role. Conclusions A duplication event occurred at the exact locus of the homologous recombination and was not detected by conventional quality control filters such as FISH or long-range PCR over the recombination sites. Nanopore sequencing provides a cost convenient method to detect such underrated off-target effects, suggesting its use for additional quality assessment of gene editing in mice and also other model organisms.

Purpose Gamete donors and recipients of such donations have been explored by previous studies, which mostly focus on post-donation scenarios. Our study analyses the general willingness to donate oocytes or sperm and focuses on differences between potential female and male donors in attitudes, meanings, and motives in a pre-donation setting. Methods An electronic survey (n = 555 students) was used in this anonymous observational study. To enable comparisons between men and women regarding their attitudes, meanings, and motives and their willingness to donate gametes, we designed two separate questionnaires. Results The sample was divided into three groups based on the willingness to donate: potential donors (n = 133; women: 48.1%, men: 51.9%); doubtful donors (n = 207; women: 75.8%, men: 24.2%); and non-donors (n = 215; women: 68.3%, men: 31.7%). The group of potential male donors (39.2%) was significantly larger than the group of potential female donors (16.9%). Significant differences regarding altruism, the meaning of one's self-worth, and passing on the own genes were found between doubtful and potential donors. Potential donors attached less value to altruism but more value to the enhancement of one's self-worth and passing on one's genes than doubtful donors. The motive of passing on one's genes and altruistic motives were more important to men than to women. Conclusion This study helps to create a better understanding of potential donors in the existing donation framework and supports the evaluation of the given regimes in the context of designing an improved framework.

As public interest advocates, policy experts, bioethicists, and scientists, we call for a course correction in public discussions about heritable human genome editing. Clarifying misrepresentations, centering societal consequences and concerns, and fostering public empowerment will support robust, global public engagement and meaningful deliberation about altering the genes of future generations.

Medical ethics is a field of expertise that has developed alongside increasingly powerful technologies that have changed medical practice significantly over the past decades. From artificial ventilation and the possibility of resuscitation after cardiac arrest in the 1960s to big data-driven genomic medicine of today, modern medicine is loaded with ethical dilemmas and complex decisions. Four principles, namely respect for autonomy, non-maleficence, beneficence and justice, were identified in the 1970s as guiding concepts of an ethics of biomedicine, the then emerging clinical practice that is informed by biological and physiological evidence from basic research. However, as cultural and historical context affects understanding of these principles, their implementation in clinical practice and healthcare is not trivial. Here, we highlight additional principles and values that back up these four core principles in the European context, particularly solidarity, human dignity, pluralism, tolerance, non-discrimination and gender equality. We further summarize how European Union law reflects such principles and values, and refer to existing instruments to support their implementation. Focusing on solidarity, we highlight its understanding in the European context as well as some challenges for its realization.

Zielsetzung Diese Studie analysiert die Spendebereitschaft für Gameten vor dem Hintergrund, dass seit der Änderung des Fortpflanzungsmedizingesetzes 2015 die Eizellspende in Österreich erlaubt ist und die Samenspendeoptionen erweitert wurden. Es werden die Einstellungen und Motive von potentiellen, von noch unentschlossenen SpenderInnen und von Nicht- SpenderInnen miteinander verglichen.

Die Beitrage des Bandes beschaftigen sich mit Begutachtungspraktiken verschiedener Epochen und zeigen die Entwicklung des Gutachtens als einen Prozess auf, der zunehmend der Diskussion, Ausverhandlung und dem Einfluss von Wissen und Gegenwissen um soziokulturelle Normen unterliegt. Ausgehend von der Annahme, dass der Medizin in der Klassifikation, Bewertung und Einschatzung bzw. in der Subjektivierung von Einzelnen und Gruppen eine besondere Bedeutung zukommt, ruckt insbesondere jenes Verhaltnis in den Fokus, das durch die Tatigkeit des Gutachtens zwischen und fur Menschen hergestellt wird.

A significant fraction of the glycerophospholipids in the human body is composed of plasmalogens, particularly in the brain, cardiac, and immune cell membranes. A decline in these lipids has been observed in such diseases as Alzheimer's and chronic obstructive pulmonary disease. Plasmalogens contain a characteristic 1-O-alk-1'-enyl ether (vinyl ether) double bond that confers special biophysical, biochemical, and chemical properties to these lipids. However, the genetics of their biosynthesis is not fully understood, since no gene has been identified that encodes plasmanylethanolamine desaturase (E.C. 1.14.99.19), the enzyme introducing the crucial alk-1'-enyl ether double bond. The present work identifies this gene as transmembrane protein 189 (TMEM189). Inactivation of the TMEM189 gene in human HAP1 cells led to a total loss of plasmanylethanolamine desaturase activity, strongly decreased plasmalogen levels, and accumulation of plasmanylethanolamine substrates and resulted in an inability of these cells to form labeled plasmalogens from labeled alkylglycerols. Transient expression of TMEM189 protein, but not of other selected desaturases, recovered this deficit. TMEM189 proteins contain a conserved protein motif (pfam10520) with eight conserved histidines that is shared by an alternative type of plant desaturase but not by other mammalian proteins. Each of these histidines is essential for plasmanylethanolamine desaturase activity. Mice homozygous for an inactivated Tmem189 gene lacked plasmanylethanolamine desaturase activity and had dramatically lowered plasmalogen levels in their tissues. These results assign the TMEM189 gene to plasmanylethanolamine desaturase and suggest that the previously characterized phenotype of Tmem189-deficient mice may be caused by a lack of plasmalogens.

The effective collection and management of personal data of rapidly migrating populations is important for ensuring adequate healthcare and monitoring of a displaced peoples' health status. With developments in ICT data sharing capabilities, electronic personal health records (ePHRs) are increasingly replacing less transportable paper records. ePHRs offer further advantages of improving accuracy and completeness of information and seem tailored for rapidly displaced and mobile populations. Various emerging initiatives in Europe are seeking to develop migrant-centric ePHR responses. This paper highlights their importance and benefits, but also identifies a number of significant ethical, legal and social issues (ELSI) and challenges to their design and implementation, regarding (1) the kind of information that should be stored, (2) who should have access to information, and (3) potential misuse of information. These challenges need to be urgently addressed to make possible the beneficial use of ePHRs for vulnerable migrants in Europe.

In current biomedicine, omics technologies drive systems-oriented modes of research to achieve a more holistic and personalized view of health and disease. This shift in scientific approach co-occurs with an era of biocapitalism characterized by markets for biomaterial (e.g., DNA, cells, and tissues) as exploitable resources, high-throughput technologies as tools, and “Big Data” as currency. Prediagnostics and genomics-based analyses successfully entered the public domain more or less unfiltered, offering numerous business opportunities envisioning individuals to contribute to the health sector by providing biomaterial and data as well as by using technology, thus becoming participants and informed coproducers of health. Exploring strengths and weaknesses, as well as opportunities and threats by S.W.O.T. analysis, we highlight some chances, pitfalls, and biases of this sector from a bioscience ethics stance. We conclude that the shift from diagnostic to predictive interpretation of data that comes along with integrative biology seems to escape the general and sometimes the experts' awareness. Moreover, rapid translation into products for the global health market is based on marketable views on health and disease that in turn affect basic research through, for example, funding policies and the research questions being asked. Along with this, biological reductionism is revived fuelling simplified understandings of the genotype phenotype relationship in terms of biology and the human dimension in a broader sense, as well as visions of achieving human perfection through novel biotechnologies.

Plasmanylethanolamine desaturase (PEDS) (EC 1.14.99.19) introduces the 1-prime double bond into plasmalogens, one of the most abundant phospholipids in the human body. This labile membrane enzyme has not been purified and its coding sequence is unknown. Previous assays for this enzyme used radiolabeled substrates followed by multistep processing. We describe here a straight-forward method for the quantification of PEDS in enzyme incubation mixtures using pyrene-labeled substrates and reversed-phase HPLC with fluorescence detection. After stopping the reaction with hydrochloric acid in acetonitrile, the mixture was directly injected into the HPLC system without the need of lipid extraction. The substrate, 1-O-pyrenedecyl-2-acyl-sn-glycero-3-phosphoethanolamine, and the lyso-substrate, 1-O-pyrenedecyl-sn-glycero-3-phosphoethanolamine, were prepared from RAW-12 cells deficient in PEDS activity and were compared for their performance in the assay. Plasmalogen levels in mouse tissues and in cultured cells did not correlate with PEDS levels, indicating that the desaturase might not be the rate limiting step for plasmalogen biosynthesis. Among selected mouse organs, the highest activities were found in kidney and in spleen. Incubation of intact cultivated mammalian cells with 1-O-pyrenedecyl-sn-glycerol, extraction of lipids, and treatment with hydrochloric or acetic acid in acetonitrile allowed sensitive monitoring of PEDS activity in intact cells.