From mouse egg to mouse embryo: polarities, axes, and tissues.

This review describes the three classical models (mosaic, positional, and polarization) proposed to explain blastocyst formation and summarizes the evidence concerning them. It concludes that the polarization model incorporates elements of the other two models and best explains most known information. I discuss key requirements of a molecular basis for the generation and stabilization of polarity and identify ezrin/E-cadherin, PAR proteins, and Cdx2 as plausible key molecular players. I also discuss the idea of a network process operating to build cell allocations progressively into committed differences. Finally, this review critically considers the possibility of developmental information being encoded within the oocyte and zygote. No final decision can be reached on a mechanism of action underlying any encoded information, but a cell interaction process model is preferred over one that relies solely on differential inheritance.

Variation of maternal KIR and fetal HLA-C genes in reproductive failure: too early for clinical intervention.

A distinctive type of (uterine) natural killer (NK) cell is present in the uterine decidua during the period of placental formation. Uterine NK cells express members of the killer immunoglobulin-like receptor (KIR) family that bind to parental HLA-C molecules on the invading placental trophoblast cells. The maternal KIR genes and their fetal ligands are highly variable, so different KIR/HLA-C genetic combinations occur in each pregnancy. Some women only possess inhibitory KIR genes, whereas other women also express activating KIR genes. The overall signal that NK cells receive from paternal HLA-C on trophoblast depends on the ratio of activating and inhibitory KIR genes expressed by them. Therefore, NK cells provide a balance during placentation to ensure maternal survival and an adequately nourished fetus. Because inhibitory KIRs are found more frequently in women with defective placentation, e.g. pre-eclampsia, fetal growth restriction or recurrent spontaneous abortion, some fertility clinics suggest that women should be 'tissue typed' for their KIR genotypes. We explain why, presently, it is premature to introduce KIR and HLA-C typing to predict pregnancy outcome. In future, however, selecting for certain combinations of KIR and HLA-C variants in surrogacy, egg or sperm donation may prove useful to reduce disorders of pregnancy.

Attitudes to Male Homosexuality Within the British Medical Association in the 1950s.

The British Government appointed a departmental committee to review anti-homosexuality laws in 1954 following a marked increase in the number of arrests for homosexuality after World War II. The committee invited the British Medical Association (BMA) and other institutions to provide scientific and medical evidence relating to homosexuality. In 1954, the BMA established the Committee on Homosexuality and Prostitution to present its view on how the law impacted upon homosexuals and society. This paper analyses the BMA's attitudes to homosexuality by examining its submission to the Departmental Committee. Whilst the BMA supported implicitly the decriminalization of certain homosexual acts, it remained strongly opposed to homosexuality from a moral perspective and insisted that it was an illness. It is concluded that the BMA's submission was driven primarily by a desire to control the "unnatural deviant" behavior of homosexuals and to protect society from that behavior rather than to protect homosexuals.

The early history of evidence-based reproductive medicine.

The origins of evidence-based medicine as understood today are traceable to 1972 and the publication of Archie Cochrane's book Effectiveness and Efficiency: Random Reflections on Health Services. This book attempted to bridge the divide between scientific medicine and clinical judgment that had developed since the mid-19th century. Its genesis was stimulated by Cochrane's experiences as a prisoner-of-war medical officer and of the demands placed after the 1939-1945 war on the UK National Health Service. In the 1960s, reproductive medicine was considered by the UK Medical Research Council to be relatively 'unscientific' in its approach to care delivery and was described as such by Cochrane in the 1970s. Evidence is presented here that reproductive medicine responded, becoming by 1989 a pioneering clinical discipline in the application of evidence to practice. This was achieved largely through the efforts of Iain Chalmers, who was a key player in the development of the systematic review and in the foundation of the Cochrane collection.

Investigating the specificity of endothelin-traps as a potential therapeutic tool for endothelin-1 related disorders.

BACKGROUND: Endothelin (ET)-traps are Fc-fusion proteins with a design based on the physiological receptors of ET-1. Previous work has shown that use of the selected ET-traps potently and significantly reduces different markers of diabetes pathology back to normal, non-disease levels. AIM: To demonstrate the selected ET-traps potently and significantly bind to ET-1. METHODS: We performed phage display experiments to test different constructs of ET-traps, and conducted bio-layer interferometry binding assays to verify that the selected ET-traps bind specifically to ET-1 and display binding affinity in the double-digit picomolar range (an average of 73.8 rM, n = 6). RESULTS: These experiments have confirmed our choice of the final ET-traps and provided proof-of-concept for the potential use of constructs as effective biologics for diseases associated with pathologically elevated ET-1. CONCLUSION: There is increased need for such therapeutics as they could help save millions of lives around the world.

Robert Edwards: the path to IVF.

The early influences on Robert Edwards' approach to the scientific research that led to human IVF are described. His interest as a graduate student in the genetics of early mammalian development stimulated him later to investigate whether the origins of human genetic diseases such as Down, Klinefelter and Turner syndromes might be explained by events during egg maturation. This clinical problem provided the most powerful stimulus to achieve both oocyte maturation and fertilization in vitro in humans. Indeed,preimplantation genetic diagnosis was his main goal until he met Patrick Steptoe in 1968. A re-evaluation of his meeting with Steptoe suggests that initially Steptoe's laparoscopic skill was of interest for its potential to solve the sperm capacitation problem. Steptoe'simpact on Edwards was twofold. First, Steptoe's long-held interest in infertility raised this application of IVF higher in Edwards'priorities. Second, Steptoe offered a long-term partnership, in which oocyte collection without in-vitro maturation was a possibility.The professional criticism generated by their work together encouraged Edwards to pursue a deliberate programme of public education about the issues raised and to challenge and develop professional bioethical thought and discourse about reproduction.

The politics of human embryo research and the motivation to achieve PGD.

This article reports a historical study of factors influencing the achievement of clinical preimplantation genetic diagnosis (PGD) in 1990, 22 years after its first demonstration in animals. During the 1970s, research on PGD continued in large farm animals, but serious interest in human PGD was not evident until 1986. First, interest in PGD during the 1970s waned with the advent of prenatal testing, which for gynaecologists was clinically more familiar, technically simpler and ethically less challenging than IVF. Indeed, IVF was viewed with widespread suspicion until the first IVF births in 1978. Second, interest in clinical PGD was stimulated by the UK Parliamentary reaction against human embryo research that greeted the Warnock Report in 1984. This hostility led scientists to initiate a pro-research campaign, further galvanized in 1985 by MP Enoch Powell's bid to ban such research. However, while Powell abhorred embryo research, he approved of PGD, a stance that divided the anti-research lobby. Accordingly, the campaigners for research emphasized that it was needed to achieve PGD. Powell demanded evidence of such projects and PGD research increased from 1986. It is concluded that UK political debates on embryo research played a critical role in stimulating the achievement of clinical PGD. Human pregnancies following preimplantation genetic diagnosis (PGD) for embryo sex were announced in 1990, 22 years after the technique was pioneered in animals. PGD in humans required not only technological advances, such as IVF and sensitive diagnostic tests, but also the motivation to develop and apply them. Our historical analysis shows that, although research on PGD continued in large farm animals during the 1970s, and techniques of the required sensitivity were developed on mouse embryo models, interest in clinical PGD was not evident until 1986. Two factors stimulated this sudden change in motivation. First, interest in PGD was depressed during the 1970s by the advent of prenatal diagnostic techniques, which for gynaecologists were clinically, technically and ethically less challenging than IVF. IVF was then regarded with a suspicion that only started to wane in the early 1980s following the first IVF births. Second, the UK Parliamentary reaction against human embryo research that greeted the Warnock Report in 1984 provided a positive stimulus to clinical PGD by prompting scientists to form a pro-research lobby, which was further galvanized in early 1985 by MP Enoch Powell's almost-successful bid to ban human embryo research. We show that while Powell abhorred embryo research, he approved of PGD, a stance that fractured the unity of the anti-research lobby. Accordingly, the pro-research lobby emphasized that embryo research was needed to achieve PGD. Powell demanded evidence of such projects, thereby, we argue, stimulating PGD research from 1986. Our evidence shows that UK political debates about PGD played a critical role in stimulating the achievement of PGD clinically.

Why the Medical Research Council refused Robert Edwards and Patrick Steptoe support for research on human conception in 1971.

BACKGROUND: In 1971, Cambridge physiologist Robert Edwards and Oldham gynaecologist Patrick Steptoe applied to the UK Medical Research Council (MRC) for long-term support for a programme of scientific and clinical 'Studies on Human Reproduction'. The MRC, then the major British funder of medical research, declined support on ethical grounds and maintained this policy throughout the 1970s. The work continued with private money, leading to the birth of Louise Brown in 1978 and transforming research in obstetrics, gynaecology and human embryology. METHODS: The MRC decision has been criticized, but the processes by which it was reached have yet to be explored. Here, we present an archive-based analysis of the MRC decision. RESULTS: We find evidence of initial support for Edwards and Steptoe, including from within the MRC, which invited the applicants to join its new directly funded Clinical Research Centre at Northwick Park Hospital. They declined the offer, preferring long-term grant support at the University of Cambridge, and so exposed the project to competitive funding mode. Referees and the Clinical Research Board saw the institutional set-up in Cambridge as problematic with respect to clinical facilities and patient management; gave infertility a low priority compared with population control; assessed interventions as purely experimental rather than potential treatments, and so set the bar for safety high; feared fatal abnormalities and so wanted primate experiments first; and were antagonized by the applicants' high media profile. The rejection set MRC policy on IVF for 8 years, until, after the birth of just two healthy babies, the Council rapidly converted to enthusiastic support. CONCLUSIONS: This analysis enriches our view of a crucial decision, highlights institutional opportunities and constraints and provides insight into the then dominant attitudes of reproductive scientists and clinicians towards human conception research.