Ethics of modifying the mitochondrial genome

Recent preclinical studies have shown the feasibility of specific variants of nuclear transfer to prevent mitochondrial DNA disorders. Nuclear transfer could be a valuable reproductive option for carriers of mitochondrial mutations. A clinical application of nuclear transfer, however, would entail germ-line modification, more specifically a germ-line modification of the mitochondrial genome. One of the most prominent objections against germ-line modification is the fear that it would become possible to alter 'essential characteristics' of a future person, thereby possibly violating the child's right to an open future. As only the nuclear DNA would contain the ingredients for individual characteristics, modification of the mtDNA is often considered less controversial than modification of the nuclear DNA. This paper discusses the tenability of this dichotomy. After having clarified the concept of germ-line modification, it argues that modification of the mtDNA is not substantively different from modification of the nuclear DNA in terms of its effects on the identity of the future person. Subsequently the paper assesses how this conclusion affects the moral evaluation of nuclear transfer to prevent mtDNA disorders. It concludes that the moral acceptability of germ-line modification does not depend on whether it alters the identity of the future child-all germ-line modifications do-but on whether it safeguards the child's right to an open future. If nuclear transfer to prevent mtDNA disorders becomes safe and effective, then dismissing it because it involves germ-line modification is unjustified

The spread of antimalarial drug resistance: A mathematical model with practical implications for ACT drug policies

Most malaria-endemic countries are implementing a change in antimalarial drug policy to artemisinin combination therapy (ACT). The impact of different drug choices and implementation strategies is uncertain. A comprehensive model was constructed incorporating important epidemiological and biological factors and used to illustrate the spread of resistance in low and high transmission settings. The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and that in low transmission areas ACTs slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. A major obstacle to achieving the benefits of high coverage is the current cost of the drugs. This argues strongly for a global subsidy to make ACTs generally available and affordable in endemic areas

Authors' Reply: Response to Ian Clark

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A leap of faith? An interview study with professionals on the use of mitochondrial replacement to avoid transfer of mitochondrial diseases

STUDY QUESTION: What are the opinions of professionals in the field of genetics, reproductive science and metabolic diseases on the development of mitochondrial replacement technologies to be used in the context of medically assisted reproduction? SUMMARY ANSWER: Although concerns regarding safety remain, interviewees supported the development of nuclear transfer techniques to help women who are at risk of transferring a mitochondrial DNA disease to their offspring conceive a genetically related child. WHAT IS KNOWN ALREADY: Technological developments in the field of nuclear transfer have sparked new interest in the debate on the acceptability of the use of donor oocytes to prevent the transmission of mitochondrial diseases. For example, in the UK, extensive public consultations have been done to investigate whether such techniques would allow the passing of a law that involves making changes to a human oocyte or embryo before transfer to a woman's body. Until now, continental European countries seem to await the outcome of the British debate before themselves considering the arguments for and against this technology. STUDY DESIGN, SIZE, AND DURATION: We interviewed 12 professionals from Belgium and The Netherlands. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: We conducted 12 interviews with fertility specialists, scientists, clinical geneticists, a pediatrician specialized in metabolic diseases and a specialist in metabolic diseases. The profiles of the interviewees varied but all had experience with mitochondrial diseases, either in treating patients or in providing counseling to patients or to prospective parents. The interviews were conducted face-to-face and took 30-45 min. The language of the interviews was Dutch. We analyzed the transcript of these interviews using QSR NVIVO 10 software to extract themes and categories. MAIN RESULTS AND THE ROLE OF CHANCE: This study has shown that, although amongst the professionals we interviewed there was support for the development and deployment of nuclear transfer, this support does not necessarily correspond to uniform opinions about the importance of having a genetically own child or the contribution of mitochondrial DNA to essential characteristics of an individual. LIMITATIONS, REASONS FOR CAUTION: In translating the quotes from Dutch to English some of the linguistic nuances may have been lost. We only interviewed 12 individuals, in two countries, whose view may not be representative of existing values and opinions that may be held by professionals worldwide on this matter. To further explore the issue at hand, a subsequent investigation of the opinions of people affected by mitochondrial diseases and of the general public is necessary. WIDER IMPLICATIONS OF THE FINDINGS: With this study we have demonstrated there is in principle support for the nuclear transfer technique from Dutch and Belgian professionals. Further research, both scientific and ethical, is needed to define the modalities of its possible introduction in the fertility clinic

Identifying risk factors for the development of sepsis during adult severe malaria.

BACKGROUND: Severe falciparum malaria can be compounded by bacterial sepsis, necessitating antibiotics in addition to anti-malarial treatment. The objective of this analysis was to develop a prognostic model to identify patients admitted with severe malaria at higher risk of developing bacterial sepsis. METHODS: A retrospective data analysis using trial data from the South East Asian Quinine Artesunate Malaria Trial. Variables correlating with development of clinically defined sepsis were identified by univariable analysis, and subsequently included into a multivariable logistic regression model. Internal validation was performed by bootstrapping. Discrimination and goodness-of-fit were assessed using the area under the curve (AUC) and a calibration plot, respectively. RESULTS: Of the 1187 adults with severe malaria, 86 (7.3%) developed clinical sepsis during admission. Predictors for developing sepsis were: female sex, high blood urea nitrogen, high plasma anion gap, respiratory distress, shock on admission, high parasitaemia, coma and jaundice. The AUC of the model was 0.789, signifying modest differentiation for identifying patients developing sepsis. The model was well-calibrated (Hosmer-Lemeshow Chi squared = 1.02). The 25th percentile of the distribution of risk scores among those who developed sepsis could identify a high-risk group with a sensitivity and specificity of 70.0 and 69.4%, respectively. CONCLUSIONS: The proposed model identifies patients with severe malaria at risk of developing clinical sepsis, potentially benefiting from antibiotic treatment in addition to anti-malarials. The model will need further evaluation with more strictly defined bacterial sepsis as outcome measure

Respect voor (toekomstige) personen:Humanisme en repro-genetics

Valedictory Lecture, Maastricht University, 1-9-202