Britain has set out a road map towards the first clinical tests of reproductive techniques that combine parents’ genes with DNA from a third party. The approach raises ethical questions, but could spare children from inheriting some rare diseases, including forms of muscular dystrophy and neurodegenerative disorders that affect around 1 in 5,000 people.
These conditions are caused by defects in the mitochondria, the ‘power packs’ of the cell, which are inherited from a child’s mother through the egg. Experiments on primates, and with defective human eggs, have already shown that genetic material can be removed from an egg that has faulty mitochondria and transferred to a healthy donor ovum, leaving the flawed mitochondrial DNA behind. In principle, the resulting egg could then develop into a healthy child carrying both the parents’ nuclear genes and mitochondrial DNA from the donor. But the work amounts to genetic modification of embryos — which is currently illegal in the United Kingdom — and also involves destroying fertilized eggs.
Two procedures are being developed: pronuclear transfer and maternal spindle transfer. Nature – Scientists and politicians are working together to bring new reproductive techniques to Britain.
US researchers have already used maternal spindle transfer to produce two healthy rhesus monkeys.
Mitochondria are found in all eukaryotic cells and contain their own genome (mitochondrial DNA or mtDNA). Unlike the nuclear genome, which is derived from both the egg and sperm at fertilization, the mtDNA in the embryo is derived almost exclusively from the egg; that is, it is of maternal origin. Mutations in mtDNA contribute to a diverse range of currently incurable human diseases and disorders. To establish preclinical models for new therapeutic approaches, we demonstrate here that the mitochondrial genome can be efficiently replaced in mature non-human primate oocytes (Macaca mulatta) by spindle–chromosomal complex transfer from one egg to an enucleated, mitochondrial-replete egg. The reconstructed oocytes with the mitochondrial replacement were capable of supporting normal fertilization, embryo development and produced healthy offspring. Genetic analysis confirmed that nuclear DNA in the three infants born so far originated from the spindle donors whereas mtDNA came from the cytoplast donors. No contribution of spindle donor mtDNA was detected in offspring. Spindle replacement is shown here as an efficient protocol replacing the full complement of mitochondria in newly generated embryonic stem cell lines. This approach may offer a reproductive option to prevent mtDNA disease transmission in affected families.
Neurologist Douglass Turnbull of Newcastle University, UK, and his team have performed pronuclear transfer on defective human eggs, and found that normal development occurred in a small minority.
Mutations in mitochondrial DNA (mtDNA) are a common cause of genetic disease. Pathogenic mutations in mtDNA are detected in approximately 1 in 250 live births and at least 1 in 10,000 adults in the UK are affected by mtDNA disease. Treatment options for patients with mtDNA disease are extremely limited and are predominantly supportive in nature. Mitochondrial DNA is transmitted maternally and it has been proposed that nuclear transfer techniques may be an approach for the prevention of transmission of human mtDNA disease. Here we show that transfer of pronuclei between abnormally fertilized human zygotes results in minimal carry-over of donor zygote mtDNA and is compatible with onward development to the blastocyst stage in vitro. By optimizing the procedure we found the average level of carry-over after transfer of two pronuclei is less than 2.0%, with many of the embryos containing no detectable donor mtDNA. We believe that pronuclear transfer between zygotes, as well as the recently described metaphase II spindle transfer, has the potential to prevent the transmission of mtDNA disease in humans.
Schematic representation of pronuclear transfer in abnormally fertilised human embryos. The main findings are potential development to blastocyst stage in vitro and very low levels of donor mtDNA carry over (less than 2%)
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