In the news

Results from a study of sperm counts among men attending Scottish fertility clinics between 1989 and 2002 were announced recently at the fourth joint meeting of the Association of Clinical Embryologists and the British Fertility Society, 5-6 January 2004. The SPIN (Semen Parameters in the Northeast) study measured sperm counts in more than 16,000 semen samples from over 7,500 men attending the Aberdeen Fertility Centre. They found that among men with sperm counts within the normal range (above 20 million sperm per millilitre), the average sperm count had fallen over 14 years from around 87 million sperm per ml to 62 sperm per ml. Although still well within normal parameters, this decrease represented a 29% drop in average sperm levels over this period.

Although men attending a fertility clinic are not necessarily representative of the male population as a whole, the results contribute to fears that environmental and genetic factors may be having serious adverse effects on male potency. Multiple potential causes for falling sperm counts have been proposed, including environmental toxins and chemicals, obesity and lifestyle factors such as smoking, drinking and drug use. However, there are as yet no firm conclusions. Researchers commented that in themselves the results could not be used to determine a corresponding fall in male fertility, although this is an issue of obvious concern. They next aim to investigate aspects of sperm quality (such as motility) to determine whether this has also declined over recent years. A recent US study found that the quality of sperm declined with age, in terms of increasing levels of DNA damage in sperm. They also observed an age-related decrease in levels of apoptosis of sperm cells (a process of self-destruction designed to remove genetically damaged cells), but were unable to attribute these features directly to ageing or to increased exposure to harmful environmental factors.

The European Group on Ethics in Science and New Technologies (EGE) has published the second issue of their newsletter, ‘Ethically Speaking.’ The EGE advises the European Commission on issues related to the ethics of science and new technologies as they relate to Community legislation and policies. Each issue of their newsletter brings together contributions from European national ethics committees, detailing their objectives, past and current work, and contact information. This second issue is expanded to include information from some future Member States and organisations outside the European Union. The newsletter also has an update of the EGE’s latest activities.

The EGE's aim is to publicise the activities of the various committees in order to identify common areas of interest and perhaps foster collaborations. With the number of Member States increasing in May 2004, the EGE recognises the need to improve communication between national ethics committees and ‘facilitate contacts and exchange.’ The newsletter also could be a useful beginning resource for those seeking information on a country’s perspectives on ethics issues and their areas of specific national interest.

The first transgenic animal, and genetically engineered pet, has been sold to the US public over this holiday period. 'GloFish' is a transgenic zebrafish that fluoresces red under ultraviolet light. Sales of the fish have been brisk, however concerns have been raised as GloFish appears to have fallen outside the jurisdiction of any of the US regulatory bodies. The Environmental Protection Agency, the Department of Agriculture, and the Fish and Wildlife Service have all been approached and refused to consider the regulatory impact of Glofish. As it not for human consumption or used in medicines, the Food and Drug Administration (FDA) has also stated that they would not regulate it. This ‘loophole’ worries environmentalists concerned about accidental release of the fish. Others believe further research and thought is needed on this issue before there is a rush of similar products on the market and regulation is impossible. As a result, a lawsuit against the government is being prepared, led by the Center for Food Safety, an interest group that advocates for standards in food safety. Independent experts have indicated that they believe there is no greater environmental danger posed by GloFish than by non-transgenic zebrafish. However, Singapore, Japan, and the state of California have all banned the sale of GloFish.

The first transgenic animal, and genetically engineered pet, has been sold to the US public over this holiday period. 'GloFish' is a transgenic zebrafish that fluoresces red under ultraviolet light. Sales of the fish have been brisk, however concerns have been raised as GloFish appears to have fallen outside the jurisdiction of any of the US regulatory bodies. The Environmental Protection Agency, the Department of Agriculture, and the Fish and Wildlife Service have all been approached and refused to consider the regulatory impact of Glofish. As it not for human consumption or used in medicines, the Food and Drug Administration (FDA) has also stated that they would not regulate it. This ‘loophole’ worries environmentalists concerned about accidental release of the fish. Others believe further research and thought is needed on this issue before there is a rush of similar products on the market and regulation is impossible. As a result, a lawsuit against the government is being prepared, led by the Center for Food Safety, an interest group that advocates for standards in food safety. Independent experts have indicated that they believe there is no greater environmental danger posed by GloFish than by non-transgenic zebrafish. However, Singapore, Japan, and the state of California have all banned the sale of GloFish.

The Human Fertilisation and Embryology Authority (HFEA) has announced new guidance to help cut down on the number of multiple births resulting from IVF treatment. The new Code of Practice states that, from March 2004, women under the age of 40 will have only two, rather than three, embryos implanted during treatment. An accompanying report, ‘Avoiding Multiple Births,’ explains the reasons behind this change in practice. Research has shown that implanting a smaller number of embryos reduces multiple pregnancies but does not significantly decrease the overall pregnancy rate. Being pregnant with more than one baby, however, has been shown to be potentially harmful to women, as they are more likely to suffer from pre-eclampsia and dangerously high blood pressure. The babies are also more likely to be born prematurely with attendant medical problems and there is an increased risk of mortality. Limiting the embryos will give those foetuses that do develop a greater chance of becoming healthy babies. Women over age 40 will continue to be able to have three embryos implanted as they have a lower chance of conceiving.

However, women who have had multiple children successfully after rounds of IVF treatment disagree with the guidance (see BBC News article 6/1/04). After struggling to conceive, they feel it is unfair to reduce a woman’s possibility of having a child by one-third, even if this does mean risking multiple births. The new Code of Practice states that this policy will be followed with ‘no exceptions,’ but doctors may be able to overlook it in ‘exceptional circumstances.’ There are already rumours that doctors will flout the rules.

Strikingly, this guidance is in direct contrast to the new regulations legislating the conduct of artificial reproductive technologies in Italy (see newsletter item December 2003). There, a woman undergoing IVF treatment will be required by law to have all fertilised embryos implanted in her womb, no matter the number or if they are defective. A future comparison of the birth and mortality rates resulting from these two different approaches to regulating IVF treatment will make interesting reading.

In two areas of the world, legislators are taking the more liberal decision to encourage stem cell research, to the approval of some onlookers. The US state of New Jersey has just passed a new state law that permits stem cell research while outlawing human reproductive cloning. The state is only the second, after California, to enact such a law and shows the willingness of New Jersey legislators to take what is an unpopular political position. The law allows research involving, “human embryonic stem cells, human embryonic germ cells, and human adult stem cells from any source, including somatic cell nuclear transplantation.” It expressly forbids cloning to make a human being, making such activities subject to a jail sentence of up to twenty years. The law also requires that all infertility patients be informed that they can donate their unused embryos for research. While the law does not aid the cause of federally-funded researchers, who will still be required to only use stem cells from the White House-approved list (see newsletter item August 2001), some see its benefits. Those conducting privately-funded research will be welcomed to New Jersey, which may encourage investment and attract top-class researchers. The law will certainly make it easier to obtain embryos for research. It also sends out a signal that not all politicians are in favour of the strong stance against stem cell research taken by the US government. It is unclear whether other states will follow New Jersey’s lead.

In Spain, there are also moves to continue its commitment, made last summer, to stem cell research (see newsletter item October 2003). It has been announced that two centres will be created to carry out research in regenerative medicine. The National Center for Organ and Tissue Transplant and Regenerative Medicine will be based in either Madrid or Barcelona. At a second centre, scientists will use zebrafish in experiments to determine the genetic basis of tissue regeneration. This initiative will be headed by Juan Carols Izpisúa Belmonte, who has been repatriated to Spain after working at the Salk Institute in California.

When Spanish legislators approved their law last year, allowing research to be conducted on ‘left-over’ embryos with the consent of the donors, it was a controversial decision for a predominantly Catholic country such as Spain to make. With New Jersey and Spain defying convention, what will be the next legislature to take a politically-unpopular view supporting stem cell research?

A report released by the Newcastle Fertility Centre shows that there is a willingness by the public to consider donating their surplus embryos for stem cell research. In the study, 57% of couples attending the Newcastle centre said they would give their consent. However, the key to receiving consent was providing the couple with information explaining the research and its potential applications, such as in the creation of therapies for serious diseases. According to Professor Alison Murdoch, who chaired the study, this provision of information was vital. “When people understand this issue they tend to look on it favourably. Scientists should not be afraid to engage the public on this issue” (BBC news, 5/1/04).

Dr Mark Walport, Director of the Wellcome Trust, has warned that the Human Tissue Bill might outlaw research into life-threatening diseases. In a press release, Dr Walport has said: “Although the proposed legislation has admirable aims, it could have serious consequences for many patients because it is unclear what research can and cannot be done.” The Bill was written to address issues raised by the Alder Hey Children’s Hospital and the Bristol Royal Infirmary inquiries and has had its second reading in the House of Commons (15 January). However, there is concern that, as the Bill currently stands, the Bill might prevent certain types of research. For example, Dr Walport pointed out that studies such as that of post-mortem tissue samples used to identify new variant CJD might not be possible as using some tissue samples might be considered illegal in the future. Dr Walport called for more clarity in the Bill, noting “There is no definition of consent and it is vague about the analysis of fresh DNA samples, criminal liability and licensing.” The Wellcome Trust and others in the science community are currently in discussions with the government “in an effort to find a satisfactory solution with a view to shaping suitable legislation.”

The Australian state of New South Wales has introduced a draft bill on artificial reproductive technologies for consultation. Unlike other parts of Australia, under this bill the system for fertility treatments will not be formally licensed. The bill includes provisions to remove anonymity from sperm and egg donors with a central register created to hold information about the donated gametes. This will allow children at the age of 18 to trace their biological parent. Frozen eggs and sperm unused after ten years will be destroyed and a partner will be able to withdraw their consent for fertility treatment up to the time when an embryo is implanted. Commercial surrogacy will be illegal, as would the donation of genetic material between siblings. There would be a maximum of ten offspring from any one donor.

Fertility experts are concerned that the loss of donor anonymity will further reduce an already low donor rate. This has already led to novel approaches to encourage donors, such as advertising in other countries for free holidays (see newsletter item December 2003). However, it is yet to be seen if donors will continue to disappear under such rules or whether new measures will need to be introduced to encourage donors from other sectors of the population.

In a recent press release, the US National Institute of Environmental Health Sciences (NIEHS) announced a collaborative venture with the University of North Carolina (UNC) to create a registry of 20,00 patients in order to study the relationship between environmental exposures, genetic susceptibility, and human disease. The new Environmental Polymorphism Registry will store DNA samples for use in the study of environmentally sensitive genes by researchers at the National Institutes of Health (including the NIEHS), UNC and collaborators. A pilot study of 600 patients at UNC clinics, 80% of whom agreed to donate DNA for storage for a period of 25 years, forms the basis of the registry, which will now be expanded.

The registry is unusual in that although samples will be coded to protect the identity of donors, patient identifiers will be maintained so that participants can be contacted in the future for voluntary provision of additional information or participation in follow-up studies. It is hoped that these studies will provide valuable new insights into ecogenetics (the interaction between genes and the environment) by allowing the identification of genetic polymorphisms in environmentally sensitive genes and possible correlations with environmental exposures and health outcomes. Dr Perry Blackshear, NIEHS director of clinical research commented: "The data collected from these studies may be used to define environmental risk factors and develop preventative strategies to reduce the incidence of disease".

Family members are taking the NHS to the High Court for removing the body parts of their dead loved ones with consent, seeking compensation for their grief and suffering. The plaintiffs in the case, who number over 2000, have reportedly already rejected an offer of £1000 in compensation, which they say is not enough. The parents of children who died at the Alder Hey Children’s Hospital received £5000 in compensation. This difference in monetary levels has led to the charge by plaintiffs that the NHS does not consider the individuals harmed in this case 'as important' as the children in the Alder Hey case.

The Department of Health has stated that the practice of organ retention without consent no longer takes place in the NHS. The Human Tissue Bill, currently before Parliament (see newsletter item December 2003), will make the practice illegal, with doctors facing a prison sentence if found guilty. However, the plaintiffs in this case appear to feel the need for a higher level of compensation, in addition to changed practices. As one parent told the BBC, “We need to be treated fairly.”

GAIC, the Genetics and Insurance Committee, has published its second report covering September 2002 to December 2003. This is their first report since being reconstituted with an extended remit. The committee’s main role over the last year has been “…to make decisions on the validity of using predictive genetic test results in determining insurance premiums for a range of insurance products.” Currently, GAIC has only approved one genetic test from which results can be used in setting insurance premiums, the Huntington’s disease test, and only for life insurance policies over £500,000. GAIC has, however, advised the Association of British Insurers on how applications for 17 other tests should be rewritten so that they may be resubmitted for further consideration.

GAIC has also been concentrating on two of its new roles. First, it monitors the insurance industry’s compliance with the moratorium on using the results of predictive genetic tests in setting insurance premiums. The moratorium is in place until November 2006 and GAIC reports that the insurance companies have been complying as required. Plans do need to be made to determine the future of the moratorium and GAIC has noted that it will work with the Government, patient groups, the insurance industry, the Human Genetics Commission, and other interested parties, on a long-term policy solution. In its second role, GAIC considers complaints from individuals. They considered one complaint from a member of the public and it was resolved to the satisfaction of all concerned.

Some very interesting information is provided in the annexes to the report. ‘A Brief Guide to Life and Health Insurance in the UK’ provides details on five insurance products: life, critical illness, income protection, long term care, and private medical insurance. Each is explained thoroughly with a section on the market issues related to genetics that might be relevant to GAIC and the Human Genetics Commission in their deliberations. There is also information on the state of genetics and insurance in countries in the European Union, North America and outside the EU

Public Health Minister Melanie Johnson announced government plans to remove the current right of sperm, egg and embryo donors to anonymity, with effect from April 2005 (see Department of Health press release). The announcement at the Human Fertility and Embryology Authority (HFEA) annual conference today follows a two-year public consultation by the government on what information children conceived using donated sperm, eggs or embryos should be entitled to access. The present regulations, set out in the Human Fertility and Embryology Act of 1990, allow children to be told that they were conceived using donated material once they reach the age of eighteen, and allows the HFEA to check whether they are genetically related to prospective marriage partners. The 1990 Act will now be reviewed, and current regulations altered to allow children access to more information about biological donor parents, including their identity and personal details such as physical appearance, occupation and religion, once they reach eighteen. Donors will not be held to have any legal, moral or financial responsibility for children born following donation, nor will they be obliged to meet them. Donations prior to April 2005 will remain anonymous, so that the first children born following donation entitled to access the identity of the donor will be able to do so from 2023.

In a press release welcoming the announcement, HFEA chair Suzi Leather said: “We consider that sharing information about origins with our children is part of responsible parenting. Although it is right to respect the guarantees of anonymity that have been given to donors in the past, it also seems to me wrong that the state has information about someone’s origins which they want and cannot have. Secrecy in adoption has been discredited and secrecy in assisted reproduction will come to be too”. However, other experts are concerned that the changes will deter potential donors, and also cause patients who wish to receive anonymous donations to go abroad for treatment. Sweden changed its laws in 1985 to allow children born following donor insemination the right to access identifying information about the donor. This resulted in an initial reduction in the numbers of donors, but levels subsequently rose again. However, many Swedish couples now opt to travel to countries such as Denmark, where donors remain anonymous, for treatment (see BBC news article on ‘fertility tourists’).

Parliamentary approval will be required before the new UK regulations can come into force.

The House of Commons Select Committee on Science and Technology has opened its inquiry into human reproductive technologies and the law by launching a public e-consultation. It is the first time a select committee has had an online consultation and the first time such a consultation has shaped how an inquiry will progress. The public can join the debate on issues such as sex selection, surrogacy and donation, consent and confidentiality, and screening and therapy. The Committee will then decide if online contributors should be invited to give oral testimony at the House of Commons. The web site is www.tellparliament.net; individuals can sign in to join the discussion groups. In addition, the site has resources such as links to other relevant web sites, information about the Science and Technology Committee and a glossary of terms related to reproductive technologies.

The e-consultation was opened with a public debate on the topic, “Sex Selection – When and Why?” The debate, chaired by Baroness Helena Kennedy, brought together ethicist John Harris, pro-life campaigner Josephine Quintavalle, and medical geneticist Professor Marcus Pembrey for a lively discussion with the audience on the pro and cons of this emotive issue.

This inquiry by the Select Committee has been opened as a result of their July 2002 report on the Human Fertilisation and Embryology Act 1990. In that report, the Committee stated their concerns regarding the current status of the legislation in research involving embryos. They concluded that the Act needed amending, stating, “The Government’s apparent reluctance to enact new legislation in this sensitive area has led to a position where the 1990 Act is open to legal challenge. We recommend urgent action to remedy this and reconnect the Act with modern science.” The Government, however, responded that it was felt that the Act was sufficient as it stood. The Committee disagreed and decided to conduct the current inquiry to see where the Act was open to debate and what amendments might be suggested.

A US fertility specialist, Dr Panos Zavros, has claimed that he has implanted a cloned embryo into the womb of a 35 year-old woman. It is too early, he stated, to say if the woman is pregnant. Dr Zavros made his announcement at a news conference in London over the past weekend, but has not published scientific evidence to support his claim, which experts decry as unethical. The embryo is said to have been created from an immature egg from the woman from which the DNA had been removed. It was replaced with a skin cell from her husband. If a child is born it would be exact DNA match to the husband. While cloning to produce a child, or human reproductive cloning, might give hope to infertile couples, experts agree that cloning is unethical as well as risky for the child. Animal cloning experiments have shown a high risk of premature death and offspring being born with abnormalities.

In addition, Dr Zavros has stated that he is ‘ready’ to split a human embryo, allowing one half to grow into a baby and the other to be stored as a source of stem cells in case of future illness. While embryo splitting has been done in animals, again the success rate is low. As well, the procedure has ethical implications that need to be considered before experiments such as the one Dr Zavros has described are carried out.

The Human Fertilisation and Embryology Authority (HFEA) has released a statement reiterating their position on these issues. Human reproductive cloning is illegal in the UK. Embryo splitting must be done in a laboratory and those carrying out such work must be licensed by the HFEA. The HFEA does not 'expect' clinics to produce embryos for treatment by embryo splitting.

The EU Commission has awarded 12 million Euros to a network of 24 bioinformatics groups based in 14 countries across Europe, to establish a virtual research institute for genome annotation (see EBI press release). Information overload is becoming increasingly problematic as genome sequencing and related projects generate ever-larger bodies of data. Bioinformatics, the discipline of electronic data storage, retrieval and analysis, is being pushed to the limit by the increasing demands placed upon it, and is also contributing to the problem in generating predictions of gene function that need to be verified experimentally. The aim of the new European BioSapiens project is to optimize progress in bioinformatics. Janet Thornton, Director of the European Bioinformatics Institute (EBI) and coordinator of the BioSapiens project commented: “Europe has excellent bioinformatics environments in many countries, but in order to maximize the overall impact it needs to strengthen and reinforce that excellence by restructuring and coordinating existing research capacities and the way research is carried out”. The EU concept of a “Network of Excellence” (NoE) is part of the Sixth Framework Programme for research funding, and is designed to combat the current fragmentary state of European research by creating durable structures for future research in certain priority areas, including life sciences, genomics and biotechnology for health.

The BioSapiens research network project will co-ordinate bioinformatics research via a Virtual Institute for Genome Annotation, which will consist of multiple ‘nodes’ focused on different aspects of genome annotation, generating data for input to a single freely accessible web portal. The institute will foster greater collaboration among bioinformaticians from academia and industry, and between experimentalists and bioinformaticians via meetings and workshops The institute will also establish a permanent European School of Bioinformatics for training at all levels of bioinformatics, and to foster best practice in the exploitation of genome annotation data. It is hoped that a co-ordinated approach to bioinformatics will allow Europe to compete effectively with other global players such as Japan and the US.

In a recent press release, the US National Institute of Environmental Health Sciences (NIEHS) announced a collaborative venture with the University of North Carolina (UNC) to create a registry of 20,00 patients in order to study the relationship between environmental exposures, genetic susceptibility, and human disease. The new Environmental Polymorphism Registry will store DNA samples for use in the study of environmentally sensitive genes by researchers at the National Institutes of Health (including the NIEHS), UNC and collaborators. A pilot study of 600 patients at UNC clinics, 80% of whom agreed to donate DNA for storage for a period of 25 years, forms the basis of the registry, which will now be expanded.

The registry is unusual in that although samples will be coded to protect the identity of donors, patient identifiers will be maintained so that participants can be contacted in the future for voluntary provision of additional information or participation in follow-up studies. It is hoped that these studies will provide valuable new insights into ecogenetics (the interaction between genes and the environment) by allowing the identification of genetic polymorphisms in environmentally sensitive genes and possible correlations with environmental exposures and health outcomes. Dr Perry Blackshear, NIEHS director of clinical research commented: "The data collected from these studies may be used to define environmental risk factors and develop preventative strategies to reduce the incidence of disease".

A recent paper in Nature [Geijsen N et al. (2004) Nature 427, 148-153] reports the derivation of primordial mouse germ cell lines from embryonic stem cells. The group examined expression of specific genes involved in ES cell pluripotency and germ cell development (for instance, genes that are expressed in germ cells but not somatic cells) in embryoid bodies (EBs) formed from their ES cell lines over time. A rare population of differentiated EBs was identified that retained genetic markers of pluripotency, notably the surface antigen SSEA1. In order to establish whether this population comprised residual undifferentiated ES cells or primordial germ cells (PGCs), normal ES cells and cells from the EBs of interest were cultured separately for a week in the presence of retinoic acid, and resulting SSEA1+ cells were quantified. Retinoic acid causes rapid differentiation of ES cells but rapid proliferation of PGCs; in the treated ES cells, more than 99% lost expression of SSEA1 whereas 5-10% of the EB-derived cells retained SSEA1 expression.

The retinoic-acid resistant EB-derived cells were then analysed to determine whether they showed deletion of epigenetic imprints, a unique characteristic of PGCs. The methylation status of the DMR2 (differentially methylated region 2) of the Igf2r gene – hypermethylated on the maternal allele - was examined for a control ES cell line and the putative PGCs. The methylation pattern of the EB-derived cell clones gradually diverged from that of the ES cells, showing a complete loss of methylation (and hence imprinting) for all clones by day 10 whilst the ES cells remained methylated at DMR2. A similar loss of imprinting was also observed for another Igf2r marker, H19, strengthening the evidence that the EB-derived cells were true PGCs.

Next, the researchers investigated whether their EB-derived PGCs were capable of undergoing further differentiation to form functional gametes. Analysis showed the upregulation of male germ-cell specific genes over time. Immunostaining with an antibody that specifically recognizes male meiotic germ cells and subsequent DNA analysis of cells identified in this manner suggested that meiosis (leading to the production of haploid cells) was inefficient in the EB-derived male meiotic germ cells when compared with cells derived from adult mice testes. However, a significant proportion of EB-derived haploid male germ cells were observed, and found to show similar morphology to the testis-derived haploid cells, indicating that male germ cell maturation had occurred. Injection of these EB-derived sperm-like cells to mouse oocytes resulted in fertilization and cleavage to the 2-cell stage in 50% of the oocytes, and progression to blastocyst formation by 20% of the oocytes. The blastocysts showed normal diploid chromosome content. The paper states that efforts to determine whether or not these early embryos produced be fertilization with EB-derived male germ cells will develop normally in utero are underway.

This paper supports previous recent reports of the generation of functional male and female gametes from mouse ES cells [Toyooka Y et al. (2003) Proc. Natl Acad. Sci. USA 100, 11457–11462; Hübner K. et al. (2003) Science 300, 1251–1256].

Comment: This study makes an important contribution to the demonstration that egg and sperm cells can be created from ES cells in vitro. The potential applications of such a technological capability are wide, particularly if similar techniques could be used to produce human gametes. This would facilitate the study of human germ cells, with probable applications in the treatment of infertility. In a News and Views article accompanying the paper by Geijsen et al., Surani [Nature 427, 106-107] notes that insertion of nuclei from adult cells into ES-derived oocytes, if leading to blastocyst formation, could provide an unlimited supply of human ES cells for medical research and transplantation purposes. These might be healthy cells, for instance to provide bone marrow transplants, or cells from patients with diseases that could provide unique insight into underlying disease mechanisms. However, even putting aside the potential ethical barriers to such developments, important scientific barriers remain. Most notably, it is not yet known whether or not the ES-derived gametes and blastocysts will give rise to normal, healthy embryos.

Current practice in prenatal diagnosis in many developed countries is to offer invasive diagnostic testing procedures (chorionic villus sampling or amniocentesis) to pregnant women considered to have a high risk of carrying a foetus with chromosomal abnormalities. The most prevalent such abnormalities that can result in the birth of live affected children are trisomy 21 (Down's syndrome), trisomy 18 (Edward’s syndrome) and trisomy 13 (Patau's Syndrome). In the US, antenatal guidelines have for some years recommended that invasive testing should be reserved for mothers aged 35 or older. This restriction was imposed because the invasive procedures carry a 1-2% risk of miscarriage, and it was considered desirable to balance the probability of the birth of a chromosomally abnormal child with the risk of procedure-related miscarriage, on an economic basis; the risk of chromosomal abnormalities increases with maternal age. It is now possible to use antenatal serum testing and ultrasonography to refine risk estimates for chromosomal abnormalities, particularly the most common, Down's syndrome; pregnant women in the US and the UK are now offered routine screening for Down's and referred for the invasive diagnostic testing methods if their calculated risk of having an affected foetus exceeds a threshold level. The authors of a recent paper in The Lancet [Harris RA et al. (2003) Lancet 363, 276-282] propose that offering the invasive diagnostic procedures only to women with risks above the threshold level has inherent drawbacks, notably the potential discrepancy between risks and benefits assumed in standard economic calculations with the perception of risks and benefits by the pregnant women themselves.

The study performs a cost-utility analysis of amniocentesis and chorionic villus sampling for trisomies 13, 18 and 21 versus no invasive diagnostic testing; cost-utility analysis is an economic technique that compares healthcare costs with benefits gained in terms of Quality-Adjusted Life Years (QALY). A QALY is one year of life adjusted for its quality, such that a year in perfect health is considered equal to 1.0 QALY, but a year in ill health would be less than 1.0 QALY. Researchers combined epidemiological, cost and clinical efficacy data from multiple sources with the probability of different adverse outcomes and preference data from a socio-economically diverse sample of 534 pregnant women aged 16-47 from San Francisco to determine the merit of risk-based thresholds for prenatal diagnostic testing. The researchers used a decision-analytic framework, a method for making a qualitative assessment of multiple contributory factors in order to create an economic evaluation of a procedure. Harris and colleagues conclude from their analysis that prenatal diagnostic testing is cost-effective irrespective of maternal age or the relative risk of a foetus having a chromosomal abnormality, and argue that offering universal prenatal diagnostic testing can therefore be justified on economic grounds. They do not attempt to assess the cost utility of maternal screening practices such as those used routinely in the UK (serum and ultrasonographic screening), but their results do question the original assumptions underlying the adoption of a threshold below which the lower risk of foetal chromosomal abnormality makes diagnostic testing less beneficial in economic terms.

Comment: The report demonstrates that the cost-effectiveness of prenatal testing for common chromosomal abnormalities such as Down’s Syndrome is highly sensitive to the preferences of pregnant women for the potential outcomes. The San Francisco study group of pregnant women generally considered procedure-related miscarriage as preferable to having a baby with Down's syndrome, which heavily influenced the calculated cost per QALY gained for the invasive procedures. Relatively small variation in preference in a different group of women could produce significantly different results. A commentary [Petrou & Mugford (2003) Lancet 363, 258-259] also notes that the women's preferences for health states were recorded early in pregnancy, whereas experience of those health states would probably significantly alter their preference rating for those circumstances. For instance, a pregnant woman with no children might perceive the birth of a child with a chromosomal abnormality as a seriously adverse outcome, whereas in fact she might adjust well to such an event. The main suggestion of the report, however, is that antenatal guidelines should seek to support fully informed choices on testing options for pregnant women, because individual preferences and concerns have a significant effect on the cost-utility of testing.

For more information on antenatal screening for Down’s Syndrome, see the disease profile section.

Concerns have been raised by a recent Nature Biotechnology report on genetic instability observed in human embryonic stem cell (hES) lines [Draper JS et al. (2004). Nat. Biotechnol. 22, 53–54]. A team led by researchers in Sheffield demonstrated the emergence of specific chromosomal abnormalities in three different (and commonly used) hES cell lines on multiple occasions when cultures were repeatedly passaged under standard conditions over several months. In the Sheffield laboratories, researchers observed the gain of an additional chromosome 17q in four occasions; a gain of chromosome 12 was also noted, but only in subpopulations of cells. US collaborators in Wisconsin using similar culture techniques reported multiple observations of the gain of chromosome 12 in hES lines, and in one instance a range of changes including amplification of part of chromosome 17q. The chromosomal abnormalities reported are similar to those seen in human cells derived from testicular tumours; researchers speculate that chromosomes 17 and 12 contain genes that, when over-expressed, allow cells to proliferate and avoid normal apoptosis (programmed cell death).

Comment: It is not possible to draw any general conclusions from this report, because the data do not allow useful comparison with other studies; not only do the majority of results come from only two hES cell lines, but there is no qualitative data from which to estimate the frequency of chromosomal abnormalities. However, the report raises questions into the genetic stability of hES cells, hitherto believed to possess stable karyotypes. A news and views feature accompanying the research communication [Pera MF (2004). Nat. Biotechnol. 22, 42–43], noting these caveats, calls for a systematic analysis of the genetic stability of different hES cell lines in different laboratories, to determine the extent of the phenomenon and those cell culture conditions that may predispose towards it. On a more reassuring note, the author observes that mouse ES cells have been widely used for over 20 years to produce normal chimeric offspring without any such analysis of genetic stability.