4 August 2017
Disease-causing mutation successfully corrected by editing human embryos
An international group of scientists led by Shoukhrat Mitalipov of Oregon Health and Science University, USA, has successfully changed the DNA of a large number of one-cell human embryos with the CRISPR-Cas9 gene-editing technique.1 The researchers targeted a mutation in a gene called MYBPC3 known to cause hypertrophic cardiomyopathy, the leading cause of sudden death in young athletes.
According to the report, eggs were fertilised for the experiment using the donor sperm of men carrying this dominant mutations. The genetic correction was applied at the same time as the eggs were fertilised and before embryonic development. The report makes clear that the fertilised eggs were never intended for transfer.
There have been earlier reports - from China - of germline editing in human embryos, but these latest experiments appear to have been compromised by editing errors and mosaic response. The USlatest experiments are said to have "significantly reduced mosaicism" and to have taken germline editing in humans further than ever before.
The widely publicised report on germline editing from the US National Academics of Science, Engineering, and Medicine in February - and summarised by Robin Lovell-Badge at an invited session of this year's ESHRE Annual Meeting in Geneva - gave cautious support for the CRISPR-Cas9 technique, but subject to strict oversight and only in research.
Commenting on behalf of ESHRE's SIG Stem Cells, Cristina Eguizabal describes the report as "a major milestone in the field of gene editing" and adds: "Importantly, the researchers addressed several steps to improve the precision and safety of the technique. To date, the CRISPR-Cas9 technology used in embryos and pluripotent stem cells has frequently generated mosaics by repairing the mutation in some cells but also by introducing a high rate of unwanted genetic changes (known as off-target mutations) or extra mutations in the targeted gene (non-homologous repair). However, Mitalipov’s team considerably improved on previous efforts by injecting the CRISPR-Cas9 components together with the patient sperm directly into normal MII oocytes. Until now, the Cas9 complex has been injected directly into the zygote. Remarkably, they now found high efficiency of homologous-repair, no evidence of off-target genetic changes, and only a single mosaic generated in an experiment involving 58 human embryos.
Investigating applicability for targeting other gene mutations, increasing efficiency of homology-directed repair, abolishing mosaicism and defining with certainty whether off-target effects do occur in such contexts will now be imperative for future clinical applications. Moreover, correcting a gene mutation in the oocyte may pose more challenges than found in the sperm.
However, this medical breakthrough is undoubtedly an immense step forward, launching an exciting, yet controversial era in medicine.
1. Ma H, Marti-Gutierrez N, Park S-W, et al. Correction of a pathogenic gene mutation in human embryos. Nature 2017; doi:10.1038/nature23305.
In response to social media posts about breastfeeding at the ESHRE Annual Meeting in Geneva, ESHRE wants to clarify its policy about bringing children into the congress areas.
According to the terms and conditions which delegates agree to when registering to the ESHRE Annual Meeting, children under 18 are not allowed in the conference.
ESHRE’s rules seek to comply with the rules of the EFPIA regarding interactions with healthcare professionals and organisations.
Children and other relatives are allowed in the lobby / registration area of the congress. As such, mothers are free to breastfeed in this area of the congress.
We are aware that a number of our delegates and staff are breastfeeding mothers and we regret that facilities are not available in our current congress venue. So far, delegates have made their own childcare arrangements. We will provide breastfeeding facilities in future meetings.
Record impact factors for two ESHRE journals
ESHRE's two flagship journals, Human Reproduction and Human Reproduction Update, have each increased their impact factors in the citation categories of Reproductive Biology and O&G, the former from 4.621 to 5.020 and the latter from 11.194 to 11.748, in the latest journal analysis released 14 June. Both titles are now firmly established at the head of the Reproductive Biology category, while Human Reproduction Update also leads the O&G category by a substantial margin, with the highest recorded impact factor ever in both categories.
ESHRE's other print title Molecular Human Reproduction confirmed its high-ranking status in the category of Reproductive Biology with an impact factor of 3.585, thus placing all three ESHRE journals within the top four of this category.
Only last year did Human Reproduction's editor-in-chief Hans Evers make an impact factor of 5 his next stated ambition - and this has now been achieved in just 12 months. "The plan is working," he told us. "In a way this is our first 'own' impact factor, because this latest result - IF 2017 - is for citations in 2016 from publications of 2014 and 2015, and these of course result from our accept or reject decisions of 2013. It's a great achievement and everyone involved deserves congratulation."
Felice Petraglia, editor-in-chief of Human Reproduction Update, received the impact factor news en route from Shanghai airport to his hotel. "A young Chinese doctor told me with great enthusiasm," said Petraglia. "Still number one and still increasing the impact factor - and here in Shanghai confirmation that this ranking system is important worldwide. We have wonderful contributors to Update, and they deserve thanks - as do those who cited our papers. It's not easy staying on top for so long, but we'll keep trying."
Among other journals in the categories of Reproductive Biology and O&G, Fertility & Sterility fell slightly from 4.426 to 4.373, while Reproductive Biomedicine Online rose from 2.796 to 3.249. The biggest mover in the O&G category was BJOG, which saw its impact factor rise from 3.943 to 5.051.
According to Thomson Reuters, owners of the Journal Citation Reports, the impact factor is a measure of the frequency with which the "average article" in a journal has been cited in a specified period. It is calculated by dividing the number of current year citations to the source items published in that journal during the previous two years. The latest impact factors, for 2016, thus relate to all citable papers published in 2014-15. Despite emerging alternative metrics, impact factors remain the most reliable measure of journal quality.
Some of the highly cited papers contributing to the growing success of all three ESHRE journals can be read here.
Artificial mouse embryo developed in vitro
A structure whose composition and architecture very closely resemble a mouse embryo has been developed in vitro by scientists in the UK. Reporting their study in the journal Science, Professor Zernicka-Goetz and colleagues at the University of Cambridge describe how, using a combination of mouse embryonic and trophoblast stem cells, together with a 3D scaffold referred to an "extracellular matrix", they were able to grow a structure capable of assembling itself as a natural embryo.(1) After five days, the embryos resembled normal mouse embryos about to start their differentiation into various body tissues and organs.
Both the embryonic and extra-embryonic cells appeared to communicate and become organised into a structure that looked like and behaved like an embryo. "It has anatomically correct regions that develop in the right place and at the right time," explained Zernicka-Goetz in a press statement. "In a sense, the cells are telling each other where in the embryo to place themselves."
The investigators claim that the study demonstrates the ability of distinct stem cell types (a single embryonic and a cluster of trophoblast) to self-assemble in vitro to generate embryos whose morphogenesis, architecture and constituent cell-types resemble natural embryos. The culture system allowed interaction of these stem cells within a three-dimensional scaffold of extra-cellular matrix. "We found that in these culture conditions ESCs and TSCs developed into an elongated cylindrical architecture typical of the post-implantation mouse embryo," the authors reported.
They further proposes that this stem cell model of mammalian embryogenesis might provide "a potentially powerful platform" to dissect physical and molecular
mechanisms that mediate the critical crosstalk during natural embryogenesis, and thus shed a little more light on the biology of pregnancy.
Some non-involved commentators thought the experiments made a stronger case for extending the 14-day limit on embryo research, while Robin Lovell-Badge of the Francis Crick Institute in London said the artificial embryos developed in Cambridge lacked two cell types (ectoderm and endoderm) required for functional development.
Commenting on behalf of ESHRE, Rita Vassena, a former co-ordinator of the SIG Stem Cells, said: "This is an exciting study which sheds light on the ability of stem cells to communicate and arrange themselves in coherent structures not unlike a developing embryo. This will be an incredible tool to study stages of development which have so far been inaccessible, and even provide in vitro models aimed at understanding normal development or the origin of certain diseases. But given the possible ethical implications in translating this work to the human, scientific research should be accompanied by public discussion and a clear regulatory framework.”
The co-ordinator of ESHRE’s SIG Stem Cells added: "Despite the fundamental and clinical significance of these results, study of the implantation period and the events governing post-implantation in the human remain exceptionally challenging. Studies are often not feasible and curbed by bioethical and legal concerns. So the promise of investigating certain embryonic milestones without the need for human embryos may shed light on previously unattainable stages of human development. In theory, such research may eventually contribute to both reproductive medicine, by improving pregnancy outcomes, and regenerative medicine, by enhancing and uncovering new stem cell differentiation protocols. However, it is important to note that caution should be taken when translating findings from artificial models to the in vivo human environment. Although we are one step closer, further studies are crucial for more direct human clinical applications.”
1. Harrison SE, Sozen B, Christodoulou N, et al. Assembly of embryonic and extra-embryonic stem cells to mimic embryogenesis in vitro; Science; 2 March 2017; DOI: 10.1126/science.aal1810