Howard Jones, 1910-2015
It was with great sadness that ESHRE learned of the death of Howard Jones. He was 104 years old and a pioneer of IVF in the USA in much the same way as his friend and colleague Robert Edwards was in Britain.
However, Howard, with his wife Georgeanna, did not begin their IVF programme until 1980. Following 'retirement' from Johns Hopkins in Baltimore in 1978, they were moving to a new division of reproductive endocrinology at the Eastern Virginia Medical School in Norfolk, Virginia, on the very day of Louise Brown’s birth in England. Invited to comment on the news by a local journalist, and asked what it would take to have a test-tube baby in the USA, Howard replied in his characteristic laconic way, 'Just a little money'. That proved enough to set the Norfolk programme in motion and, after a frustrating year pursuing pregnancies in a natural cycle, Norfolk finally achieved its first success in its 13th patient to receive gonadotrophins. Delivery by Cesarean section followed on 28th December 1981.
Howard and Georgeanna were frequent and welcome visitors to ESHRE's annual meetings, and in 1998 in Gothenburg were jointly awarded honorary membership of ESHRE. Like Bob Edwards, Howard was ever sensitive to the ethical issues raised by assisted reproduction, and their initial work in Norfolk had been delayed by public protest. Howard was a founding father of the ASRM's ethics committee and, even at the age of 102, self-published a book on the religious, legal and bioethical implications of ART for defining 'personhood'. His last book appeared just a few months ago, a memoir of the early days of IVF in the USA.
Today, the eponymous Jones Institute for Reproductive Medicine in Norfolk is named in honour of Howard and Georgeanna. Together, they demonstrated the validity of ovarian stimulation with hMG in what would become the forerunner of today's universal low dose protocols.
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The referendum will also kick out restrictions on the number of embryos generated in an IVF cycle, which have so far been limited to those that "can be immediately implanted". The vote, if confirmed and incorporated into the constitution, will now make embryo freezing legal and encourage single embryo transfer.
Commenting on the developments, Dr Edith Coonen, Chair of ESHRE'sPGD Consortium said: "It's great news for Swiss people, because it provides another reproductive option for those who need it in their trusted home environment and without having to go abroad. The vote indicates broad public support, and in professional support the PGD Consortium is committed to the exchange of knowledge and promotion of best practice."
In advance of studies thought to involve the modification of DNA in human embryos, experts in genome-editing technology have called for a moratorium in any research which aims to modify the human germline. Describing such work as "dangerous and ethically unacceptable", they write: " In our view, genome editing in human embryos using current technologies could have unpredictable effects on future generations . . . Such research could be exploited for non-therapeutic modifications."
They add that genomic editing of human non-reproductive cells - using the same basic technology - aims to repair or eliminate a mutation underlying a monogenic disease. The principle is that corrective changes to a number of cells carrying the mutation — in which the genetic correction would last the lifetimes of the modified cells and their progeny — could provide a once-and-for-all curative treatment for patients with some types of genetic disease.
Thus, according to an accompanying editorial in Nature, these gene-editing tools are being used to develop therapies to correct genetic defects in people (such as by editing white blood cells). Researchers "fear that attempts to produce ‘designer babies’ by applying the methods to embryos will create a backlash against all use of the technology."
A report recently published in MIT Technology Review described experiments in animals in which the genomes of pigs and cattle had been modified to incorporate useful genes and remove the bad ones using a genome editing technology known as CRISPR-Cas9.(2)
Most countries, including the EU but not the USA (where government approval is required), have banned germline engineering, mainly because the genetic changes created by germline editing would be passed on to future generations.
1. Lanphier E, Urnov F, Haecker SE. Don't edit the human germ line. Nature 2015; 519: 410-411.
2. Regalado A. Engineering the perfect baby. MIT Technology Review, 5 March 2015.
UK to allow mitochondrial donation
The UK is poised to become the world's first country to allow clinical trials of mitochondrial donation in couples known to be at high risk of passing on mitochondrial diseases to their children. The move follows a vote in the UK's lower Parliament (the House of Commons) which approved the measure by a considerable majority; if the measure now succeeds in passing the House of Lords and meeting the regulatory requirements of the HFEA, the first trials could begin towards the end of this year. The trials are likely to be at the Wellcome Trust Centre for Mitochondrial Research at Newcastle University, under the direction of Professor Doug Turnbull, which would need to apply for a research license from the HFEA.
The possibilities of preventing the transmission of mitochondrial diseases (which are said to affect around 2500 women in Britain) has already been the subject of a favourable public consultation by the HFEA.
Two techniques have been explored so far: nuclear transfer from the intended parents' affected zygote to an enucleated donor zygote with healthy mitochondria; and maternal meiotic spindle transfer in which the meiotic spindle from the mother's affected oocyte is transferred to a healthy donor oocyte (whose spindle has been removed) before fertilisation with the partner's sperm. Both techniques involve genetically modifying a human oocyte, which is not currently permitted in any treatment in the UK.
The controversial issue, however, as demonstrated in the consultations and Parliamentary debates, is not the technique, but the ethics of gene modification - and the inevitability that in each of these techniques the healthy reconstructed embryo will contain the donor's mitochondria as well as the intended parents' own DNA. It was for this reason that the ever inventive British press dubbed the technique 'three-parent IVF' and rightly raised the question of future genetic inheritance in these families - even though the proportion of donor DNA in these embryos would be very small (around 0.2% of the total genetic material).
While ESHRE has made no formal statement on mitochondrial donation (or any contribution to the consultations), Anna Veiga, ESHRE's former Chairman and currently Scientific Director at Hospital Universitari Quiron Dexeus in Barcelona, said: 'After extensive scientific review and public consultation, the technique of mitochondrial donation will be ready for clinical application if approved by the UK's House of Lords.
'This represents an important step in the prevention of mitochondrial disease and the possibility of reproduction with their own gametes for affected couples. The minor contribution from the donor’s mitochondria to the genetic constitution is not expected to cause any adverse outcome in the offspring. In my opinion, no major ethical concern arises in such cases, considering that oocyte donation is a frequently used alternative in affected couples. As in any other ART procedure, couples must receive complete and detailed information.'
If you are interested in this topic, you can also read the special issue of MHR: Basic Science of Reproductive Medicine "‘Mitochondria: their genome and their contribution to well-being and disease". The issue can be found here.
'Low' rates of ART complications found in analysis of US database
A study described as the first to quantify ART-associated patient risks in the USA has found that complication rates are "low", with "no concerning trends or patterns identified". The report was published in the Journal of the American Medical Association.(1)
The findings were based on data submitted to the Centers for Disease Control and Prevention National ART Surveillance System (NASS) for treatments between 2000 and 2011, a total of more than 1.1 million autologous cycles. Reported complications (defined as having been directly related to ART and occurring within 12 weeks of cycle initiation) included infection, haemorrhage requiring transfusion, moderate or severe ovarian hyperstimulation syndrome (OHSS), medication adverse event, anaesthetic complication, hospitalisation, patient death within 12 weeks of stimulation, and other complications.
As expected, the most common complication (without multiple pregnancy) was OHSS, occurring at a peak rate of 153.5/10,000 autologous cycles (1.53%), with hospitalisations peaking at 34.8/10,000 autologous cycles; rates of other complications remained below 10/10,000 cycles. Reported complications following donor cycles were less frequent; none showed a significant trend.
Fifty-eight total deaths were reported (18 stimulationrelated and 40 maternal deaths prior to infant birth). No donor deaths were reported.
However, the authors warn - as did experts speaking at a workshop of ESHRE's EIM Consotrium last year - that "underreporting of complications remains an inherent limitation of surveillance systems and must be considered when interpreting our findings".
1. Kawwass JF, Kissin DM, Kulkarni AD, et al. Safety of Assisted Reproductive Technology in the United States, 2000-2011. JAMA 2015; 313: 88-90.