In the news

  • Newsletter Edition
The PHG Foundation monthly newsletter features news and views about genetics and genetics research, from a public health perspective. The newsletter is written by staff of the PHG Foundation.

In the news

News story   |   Published 7 May 2004

A survey by the Genetics and Public Policy Center at the Johns Hopkins University, Baltimore, Maryland, has found that a majority of Americans polled approve of the use of preimplantation genetic diagnosis (PGD) to choose a ‘saviour sibling’ for an ill child but do not approve of choosing embryos based on a desire to choose one sex of child over another. The survey of 4,005 Americans showed that 61% approve of PGD, the process in which a women’s embryos are genetically tested to see which are free of an inherited disease. Subsequently, the healthy embryos can be tissue-typed to find ones that will match that of the ailing sibling. Once the ‘saviour’ child is born, their cord blood can be used in a bone marrow transplant for the sibling.

However, PGD can also be used to determine the sex of a child. ‘Social sex selection’ occurs when individuals deliberately choose one gender over the other. In the poll, 57% of Americans rejected this use of genetic testing. This echoes the position of British people. A MORI poll, as part of a consultation carried out by the Human Fertilisation and Embryology Authority (HFEA) on sex selection, showed that 69% of Britains believed that unrestricted sex selection should not be allowed and that 80% believed that PGD should not be allowed for non-medical reasons.

In the United Kingdom applications for PGD combined with tissue typing must be approved by the HFEA. In contrast, in the US, PGD services are not regulated and this concerns 80% of Americans polled. They worry that if unregulated, such reproductive genetic technologies might “get out of control.” Whether this study will prompt legislative action in the future is unknown. A detailed evaluation of the survey results should be available in the summer.


News story   |   By Dr Philippa Brice   |   Published 20 May 2004

In its White Paper of June 2003, ‘Our inheritance, our future - realising the potential of genetics in the NHS’, the Government asked the Human Genetics Commission (HGC) to work with the National Screening Committee (NSC) to consider the idea of genetic profiling of newborns. This concept is based around existing newborn screening programmes in the UK; it has been suggested that to take DNA samples from new babies and store a genetic profile (whether in the form of key genetic markers or theoretically a complete genome sequence) as part of their NHS electronic patient record. This reference could potentially be used to tailor treatments and direct preventative interventions as knowledge about genetic influences on health develops, so that potential health benefits could be rapidly realized. The White Paper noted that ‘public debate on many of the wider issues’ was an essential prerequisite for consideration of implementing such a programme, and therefore requested the HGC and NSC to work together in performing an initial analysis of the ethical, social, scientific, economic, and practical considerations of genetic profiling at birth.

As part of this analysis, the HGC held a meeting held in Bristol on the 11th-12th May, during which they heard from scientists involved in the 'Children of the Nineties' project. The Avon Longitudinal Study of Parents and Children (ALSPAC), based at the University of Bristol and funded by the Wellcome Trust and Medical Research Council, is a large-scale study of population genetics looking at the genetic and environmental influences on the health of a large cohort of children in the Avon region. DNA samples from 25,000 parents and children are being collected, stored and analysed as part of this initiative. Professor Jean Golding, director of ALSPAC, said that a national databank of genetic information for every newborn child could be created based around the ALSPC DNA bank, and stressed that the potential benefits of such a scheme were enormous, with the caveat that proper safeguards to prevent unauthorised access and misuse of the data would have to be established. She proposed that in the future, by accessing a patient’s genetic profile, health providers could help them reduce the risk of "heart attack, diabetes, or any other genetically related illness". A report on the findings of the HGC is due to be released by the end of the year.


News story   |   By Dr Philippa Brice   |   Published 6 May 2004
The South Korean team of scientists led by Professor Woo Suk Hwang who made the headlines following the publication of a paper in Science outlining the production of embryonic stem cell lines from cloned human embryos (see newsletter item from February 2004) are now at the centre of controversy over the source of the human egg cells used for the experiments. The paper reported the use of 242 eggs from 16 anonymous women donors; other researchers have expressed surprise at the large supply of eggs, because the treatments required to induce super-ovulation in donors are painful and carry associated risks, making recruitment of volunteers to donate eggs difficult. One of the paper’s co-authors, female PhD student Ja Min Koo, reportedly told the journal Nature that the donors included herself and another female team member. She subsequently retracted this claim, attributing it to a misunderstanding caused by her poor English, but concern is growing that she or other female team members may have contributed eggs to the research project. This would be inappropriate because co-authors of the paper could be said to have benefited from the high-profile research results, contrary to the declaration by contributing authors that there were no conflicts of interest. The Korean Bioethics Association is reportedly investigating whether donor recruitment was performed ethically, and particularly whether young female researchers were involved in donation [see Nature news report: Cyraniski D (2004) Nature 429, 12-14].

News story   |   Published 21 May 2004

The European Patent Office (EPO) has decided to revoke a patent granted in 2001 to Myriad Genetics Inc. and other collaborators on a “Method for diagnosing a predisposition to breast and ovarian cancer.” Myriad had been granted patent EP 699754 on methods used to detect mutations in the BRCA1 gene that might predispose one to cancer. The patent was originally granted because the EPO decided that the isolation of the BRCA1 gene was new, involved an inventive step and was capable of industrial application, requirements for any European patent. However, opponents have charged that the ‘invention’ was not novel under European patent law and the patent will impede research. An ‘opposition division’ within the EPO, a panel of three patent examiners and a legal expert, agreed with proceedings brought by opposition groups and decided to revoke the patent. However, this ruling may be challenged in second-instance proceedings in front of an EPO board of appeal.

It is not stated whether the patents awarded to Myriad for other uses of the BRCA1 gene as well as on the BRCA2 gene have also been challenged. The patents have been controversial and opposed to by many organisations. Together these patents are seen to be extremely broad as they cover the areas of laboratory testing services, diagnostic kits and therapeutic products. As it is believed that 5-10% of cases of breast cancer are caused by a genetic mutation, the potential of economic gain from a monopoly on this market could be great. The Institut Curie in France has fought against the patents since 2001 (a timeline of their activities in this fight is available on their website) together with other organisations across Europe. They argue that Myriad’s patents on the BRCA1 and 2 genes will block research into any new (as possibly less expensive) genetic tests. There has been concern that as Myriad has created a monopoly on BRCA testing in the US, that they will try to impede work in Europe. This fear has been lessened as the EPO has granted a patent to Cancer Research UK (CRUK) on BRCA2, covering sequencing of the gene and testing for damaged an inactive variants (see newsletter article February 2004). CRUK announced that it would allow public laboratories across Europe use the patent for free.

The EPO will now be open to arguments both for and against the contested Myriad patent. A written statement discussing the opposition division’s decision revoking the patent will be available from the EPO in a few months.


News story   |   Published 25 May 2004
A couple have successfully given birth to a child conceived using 21-year old sperm. Dr Elizabeth Pease at St Mary’s Hospital, Manchester, has said, “We believe this is the longest period of sperm cryopreservation resulting in a live birth so far reported.” The man had had his sperm frozen at age 17 when he was diagnosed with testicular cancer. The cancer treatment rendered him infertile. As UK regulations allow men to freeze sperm until they are aged 55, he was able to store it until he was interested in having a family. The man’s partner underwent four rounds of IVF treatment using his frozen sperm before conceiving. This success will reassure other young men facing cancer treatment that long-term freezing can be successful. However, as Dr Pease noted, the couple would not have been able to have their child on the NHS as new guidance, to be in force by April 2005, will only allow one free round of IVF for infertile couples. The National Institute for Clinical Excellence (NICE) has recommended three rounds of IVF be given for couples with proven infertility (see newsletter article February 2004)

News story   |   By Dr Philippa Brice   |   Published 4 May 2004

A recent publication in the European Journal of Cancer sets out guidelines for the management of women at increased risk of familial breast cancer [Sauven P (2004) Eur J Cancer 40, 653-665]. Commissioned by the Association of Breast Surgery, these guidelines were developed by a panel of experts from specialities including oncology, clinical and cancer genetics, radiology and clinical psychology, on behalf of the Association of Breast Surgery. Seven panel members are from the UK and two from the New York Strang Cancer Prevention Center, US. The guidelines are based on the UK model of healthcare, although the report states that the recommendations (summarised below) are intended to be more widely applicable.

Summary of recommendations

bullet All Breast Units should have a protocol for the management of women at familial risk.

bullet Women at potentially increased familial risk of breast cancer should be defined according to standard, moderate or high-risk groups.

bullet Women who are eligible should be offered the opportunity to participate in prospective chemo-prevention studies.

bullet Women at high-risk of familial breast cancer should be referred to a genetics clinic, according to an agreed protocol.

bullet Risk-reducing mastectomy may significantly reduce, but not eliminate, the risk of subsequent breast cancer and should be offered to women where appropriate.

bullet Units undertaking risk-reducing mastectomy should have agreed protocols.

bullet Prophylactic oophorectomy should not be routinely recommended solely to reduce breast cancer risk.

bullet Prophylactic oophorectomy should be discussed as an option to reduce ovarian cancer risk in BRCA1and BRCA2 carriers.

bullet Mammographic screening of women at familial risk is of unproven benefit and should only be undertaken according to strict unit protocols or, preferably, within a clinical trial.

The functions of a Family History Clinic are outlined – to assess and communicate risk, to refer patients as appropriate, and to provide information for patients, their families and GPs. However, the existence of a Family History Clinic within all Breast Units is not considered essential, provided there are clear protocols for the management of women potentially at increased risk of breast cancer. It is suggested that familial risk should be assessed with reference to the guidelines of Eccles et al. [Eccles DM, Evans DGR and Mackay J (2000) J Med Genet 37, 203-209] to classify all women as standard, moderate or high-risk. Those who fall into the moderate/high or high-risk categories should be referred to a genetics clinic. It is noted that ovarian cancer is a marker of higher genetic risk and brings most women into the high-risk category, so that reported familial cases of ovarian cancer should be verified. The UK criterion for genetic testing is probability of at least 20% that a mutation is present; current American Society of Clinical Oncologists (ASCO) guidelines suggest a probability of at least 10%. The report summarises the UK criteria for testing for BRCA1/2 mutations, and for mutations in the genes TP53, PTEN and ATM, which are associated with Li-Fraumeni syndrome, Cowden’s syndrome and Ataxia Telangiectasia respectively. The distinction between diagnostic and predictive genetic testing is underlined; the authors note that in general a diagnostic test from an affected relative (and the subsequent identification of a relevant mutation associated with increased predisposition to breast cancer) must precede any predictive testing of unaffected family members.

Current preventative measures available to women found to have a high genetic risk of breast cancer and who have received appropriate counselling are reviewed, including chemoprevention; based on current evidence the authors conclude that the use of drugs such as tamoxifen should be confined to women who have a high risk of developing breast cancer but a low risk of side-effects (such as deep vein thrombosis or pulmonary embolism) from the chemotherapy. Surgical risk-reduction measures (prophylactic mastectomy and oophorectomy) are also considered. The authors stipulate that bilateral risk-reducing mastectomy (BRMx) should only be offered on the basis of strict selection criteria such as those set out in the Manchester Protocol [Lalloo F et al. (2000) Eur J Surg Oncol 26, 711-713], and that oophorectomy should not be recommended solely for a reduction in breast cancer risk, although it remains an option for a reduction in ovarian cancer risk for BRCA1/2 mutation carriers. The latter recommendation is made on the basis that chemoprevention studies are underway that may show this to be at least as effective as oophorectomy in reducing breast cancer risks. Screening options (breast imaging, mammographic screening and self-examination) are also discussed.

Comment: The authors of this paper have provided grading for their principal recommendations according to the type of evidence available and on what sort of evidence each recommendation is based. Of note, the only recommendation directly based on the most robust category of evidence (from a meta-analysis of randomised controlled trials) is that suggesting that eligible women should be offered the opportunity to participate in clinical trials, underlining the need for more well designed and properly controlled trials of breast cancer risk and preventative interventions. Whilst providing a useful summary of some of the key issues in the identification and management of women with increased risk of breast cancer, this report is likely to be superseded in the UK by the new National Institute for Clinical Excellence (NICE) guidelines on Familial breast cancer: identification and management of genetic risk, which are due for release later this month (May 2004).


For more information on familial breast and ovarian cancer, see the Disease Profiles section.


News story   |   By Dr Philippa Brice   |   Published 6 May 2004

Health Secretary John Reid has announced that funding to establish and run the new Genetics Education and Development Centre has been awarded to the Birmingham Women's Healthcare Trust (see press release). The new centre is to be formed as part of the commitment to developing knowledge and skills in genetics within the NHS set out in the 2003 White Paper Our Inheritance, Our Future: realising the potential of genetics in the NHS, which allocated funds of £50 million to help ensure that the NHS will be able to effectively harness advances in genetics for the benefit of patients. Announcing Birmingham’s winning bid, John Reid said: "Improving the understanding and knowledge of staff is key if NHS patients are to fully benefit from the genetics revolution. Clinical staff need to know how genetic technology can be used in diagnosis, prevention and treatment so that they can help patients make informed choices about whether to take a genetic test or which treatment to choose. This centre will mean that education in genetics will become an integral part of all professional training programmes, not only for undergraduates but also for existing staff".

The Genetics Education and Development Centre, which will receive funding of £600,000 a year for the next three years, will work with training providers, professional and academic bodies to educate NHS staff in genetics and the role of genetics in healthcare. Key objectives are to identify core skills in genetics for different groups of staff (particularly GPs), produce materials and courses to enable staff to access genetics education and training and toprovide support for the service development initiatives, announced at the same time, and aimed at bringing the benefits of genetics into mainstream medicine. The centre is to be led by Professor Peter Farndon and will be affiliated to the NHS corporate university (NHSU), which aims to improve health and social care by providing learning opportunities for NHS staff.

The Public Health Genetics Unit (PHGU) provided input to Birmingham’s winning bid, and will be associated with the new centre. Hilary Burton, PHGU Consultant in Public Health Medicine and author of the 2003 report Addressing genetics, delivering health: A framework for developing competency in genetics for health professionals in the UK will act as consultant for the centre; Hilary is secretary of the UK Strategic Steering Group for Genetics Education for Health Professionals, chaired by Professor Sian Griffiths, the President of the Faculty of Public Health.


News story   |   Published 11 May 2004

The new Spanish government and the Andalusian state government have simultaneously dropped lawsuits over the creation of the Spain’s first public stem cell bank (see Newsletter March 2004). This should allow the parties to debate revisions to the national law passed last October that placed strict limits on stem cell research. The law requires that researchers only use surplus embryos that had been stored for more than 5 years at the time the law took effect. The Andalusians had previously passed their own state law that was less restrictive and in addition created a regional centre for a new stem cell bank. However, the previous conservative Spanish government sought to limit stem cell research in the country and in reaction filed a lawsuit claiming that the state law was unconstitutional. The Andalusian state government replied by filing their own lawsuit charging the Spanish government with interfering in the way they governed in their region. The impasse was expected to stay in place until the Constitutional Court had delivered their verdict, expected in the summer.

Now, with the Socialists in power in both the Andalusian and Spanish governments, the lawsuits have been dropped and there is consensus that stem cell research in Andalusia, and elsewhere, should take place. It is expected that the national law will be revised accordingly.


News story   |   Published 5 May 2004

A majority of members of the US House of Representatives support changing the current federal policy restricting stem cell research. A letter to President Bush, signed by 206 House members, asks him to reconsider his 2001 executive order that restricts federal funding for stem cell research. The 2001 order requires that any research conducted be limited to using stem cell lines that were in existence at the time the order came into force. No other research can be done using federal funds. While government officials believed these cell lines would be sufficient at the time, they are now seen to be inadequate. The National Institutes of Health estimates that of the 78 cell lines available in 2001, only 19 are viable and some, if not all, are contaminated with animal cells, which makes them potentially unusable. Researchers are creating new cell lines but only privately funded research projects can make use of them.

House members are hoping that Bush will reconsider his position and revise his order when faced with this show of significant bipartisan support. No new legislation has been drafted as an alternative. In the meantime, there are examples of support for more research using stem cells across the country. US states, such as New Jersey and California, are passing laws to commit state funds to stem cell research. Other states are considering such laws in order to remain competitive in this scientific field, as they fear the best researchers will move to states where money is available. A poll [PDF file] conducted on behalf of the Results for America project of the Civil Society Institute, an organisation in favour of regenerative medicine, found that 2 out of 3 voters in 18 states believe Bush should override the current limits on federal funding and expand the government’s support of stem cell research. Whether these signs of support by the American public will sway Bush is unclear, however it will no doubt be used as a campaign issue over the coming months.


News story   |   Published 19 May 2004

Today marks the opening in the UK of the world’s first embryonic stem cell bank. The UK Stem Cell Bank, hosted by the National Institute of Biological Standards and Control in Hertfordshire, will provide resources for researchers wishing to conduct experiments in this field. Funded by the Medical Research Council (MRC) and the Biotechnology and Biological Sciences Research Council (BBSRC), it currently holds two stem cell lines, developed at King’s College London and the Centre for Life in Newcastle, with other lines to be deposited in the future. Two laboratories were granted licenses by the Human Fertilisation and Embryology Authority (HFEA) in 2002 to generate human embryonic stem cell lines. The Bank will validate and screen cell lines being deposited for viability and quality. It will store as well as distribute the cell lines, as happens at other banks for other types of cells. In addition, it will track where stem cells are being used, a requirement raised in the new European Directive on human tissues and cells. The stem cells are expected to be used for basic research and the development of clinical applications, such as repairing damaged and diseased tissue to treat Parkinson’s, diabetes or cancer. As Professor Colin Blakemore, Chief Executive of the MRC, said, “The Bank will ensure that researchers can explore the enormous potential of this exciting science for the future benefit of patients.”

Researchers applying to the Bank to either deposit stem cells or gain access to stem cells for their research will need to receive approval from the Bank’s Steering Committee. The Steering Committee includes experts in obstetrics, surgery, clinical embryology, bioethics, law, theology, midwifery, cell banking and sociology, as well as lay members and representatives from regulatory and funding agencies. Through strong oversight, the Bank will aim to ensure that the stem cell lines are a useful resource for research. A viable stem cell line will replicate providing a continuing supply of material. Using cells from a central resource negates the need for researchers to create their own cells, thus helping to limit the number of embryos used for research purposes.

This final argument should aid the acceptance of stem cell research by the public. Support for stem cell research is growing, in the UK as well as in other countries in the world. There have been calls in the United States for President Bush to relax his restrictive policy; several US states have passed laws to enable state funding for research, bypassing federal prohibitions. In Spain, the Socialist government is considering changing its law and supports the creation of a stem cell bank in Andalusia (see newsletter May 2004). The UK is also a part of the International Stem Cell Forum, with other countries such as Australia, Canada, France, Germany, Israel, Singapore and the United States. However, the UK is justifiably proud of its achievements in this field. As the Health Minister, Lord Warner, stated, “This Bank is the first of its kind in the world and confirms the UK’s position as a leader in stem cell research.”


News story   |   Published 26 May 2004

The US Food and Drug Administration (FDA) has introduced new regulations to help prevent the transmission of disease through donated tissues and cells. The new rule, effective in May 2005, will require that virtually all donated tissues and cells, including sperm and stem cells, now must be screened for diseases such as AIDS, Creutzfeldt-Jakob disease (CJD, the human form of mad-cow disease), and SARS. Currently, the FDA only requires that some donated tissues, such as skin and eye tissue, be screened for hepatitis and AIDS. However, there have been hundreds of lawsuits on behalf of individuals who have been harmed or died from infections caused by contaminated tissue brought against the FDA and companies that sell tissue. Additionally, the number of tissue transplants has grown to more than a million a year in the US. Therefore the FDA has increased screening to include new infectious agents as well as added new types of tissue to the list of those being screened, in order to better protect tissue recipients.

The rule also includes tighter restrictions on who may be suitable donors. Individuals who lived in Britain during the 1980s and height of the mad cow disease epidemic will not be able to donate certain tissues as they are seen to be at a higher risk of developing CJD. Controversially, homosexual men who admit to having had sex with another man in the past five years will not be able to donate sperm if it is to be used by strangers. They can donate for use by family members or friends. Restrictions of this type have been in place in some states but now will apply to the entire US. While officials state that this will further reduce the possibility of transmitting HIV to the tissue recipient, gay activist groups claim that this is bigotry and ignores scientific research showing that there are tests that can adequately screen for HIV. “There is a 72 hour test which would provide information as to whether a person was HIV positive, we know that even the International Red Cross accepts blood from men who have sex with men,” Roberta Sklar, of the National Gay and Lesbian Taskforce, has stated to the press. However, the FDA maintains that the suitability of some individuals to donate may need to be judged based on their lifestyle choices


News story   |   Published 4 May 2004

A group of US federal agencies are collaborating on a new project designed to study how genetic and environmental factors affect children. Researchers plan to use that information to identify potential threats to their health. The National Children’s Study (NCS) combines the efforts of the National Institute of Child Health and Human Development, the National Institute of Environmental Health Sciences, the Centers for Disease Control and Prevention, and the Environmental Protection Agency. Approval for the NCS came as part of US legislation, the Children’s Health Act 2000.

The NCS will follow 100,000 children from before birth to age 21. Pregnant women will be recruited in the beginning stages of the study. Early information, such as the woman’s antenatal diet, any exposure to chemicals, and their general health and emotional state will be recorded. Over the years, researchers will examine environmental factors that may affect the children. ‘Environmental’ is defined broadly, including natural and man-made environmental factors, biological and chemical factors, physical surroundings, social factors, behavioural influences and outcomes, genetics, and cultural and family influences and differences. This will be done by conducting physical, mental, emotional and developmental examinations of the children, as well as interviewing parents and environmental sampling of their homes, with a hope to understanding the role of such factors in health and disease. For example, they will ask parents to report such things as how much television the child watches, whether they attend a day-care, how the child is disciplined and what kind of foods the child eats. With this data, researchers may be able to answer questions such as does attending a day-care influence a child’s developmental growth or do vaccines cause autism?

Several working groups on specialist subjects have been set up, including ones that will focus on specific areas such as exposure to chemical agents, injury, gene-environment interactions, medicines and pharmaceuticals, fertility and early pregnancy, birth defects, development and behaviour, repository issues, and ethics. The Ethics Working Group will be looking at the ethics of how the study will be conducted, such as issues of recruitment, confidentiality of data and samples and feedback of information to participants. An Ethics Resource Guide for the NCS will be prepared. The Repository Working Group will be responsible for how samples will be collected, recorded, stored, etc. Planning work continues but the NCS sponsors are planning to begin work in 2006.


Research articles

Research article   |   Published 7 May 2004

Determining the molecular basis of complex diseases, such as myocardial infarction (MI), is the subject of numerous genetic epidemiological studies. Recently, a letter published in the journal Nature (Nature 2004:429;72-75.) has suggested an association between a single nucleotide polymorphism (SNP) in the LGALS2 gene, which codes for galectin-2, and MI in Japanese individuals. These findings have received media coverage by both the BBC and Reuters news agencies.

The authors identified seventeen LGALS2 SNPs in a small number of MI patients and proceeded to compare the genotype frequencies of these SNPs using a case-control study design. This analysis revealed a potential association between one SNP (3279C¨T) and MI in Japanese patients. The authors provide further support for this finding by confirming the association in two further case-control studies on different patients. The SNP lowers the transcriptional activity of the LGALS2 gene, resulting in a reduction in the amount of galectin-2, and may alter the secretion of lymphotoxin-a (LTA), a protein previously shown to be associated with risk of MI. The authors suggest that the less frequent allele (3279T) may be associated with a protective effect against MI on the basis of a lower frequency in patients compared to controls. Subsequent to the identification of the 3279C¨T SNP, a detailed series of biochemical and molecular experiments are presented to confirm the association between galectin-2 and LTA. Galectin-2 appears to regulate the secretion of LTA, and may therefore play a role in the pathogenesis of MI, although the functional correlation between these two proteins and the development of atherosclerotic plaques remains to be determined.

Comment: Molecular genetic studies provide an important insight into the link between genetics and disease. The expansion in this field has led to a large number of potential associations being reported in the literature. It is imperative that each study be judged on its merits, in particular when attempting to identify associations between single polymorphisms and complex, multi-genic disease(s), with due care given to the chance of misleading associations (such as the SNP identified being in linkage disequilibrium with the true functional variant). Despite the limited epidemiological information available in the article, the study provides good initial evidence for a potential association between this LGALS2 SNP and MI in Japanese. The authors acknowledge that further work is required to determine both the relevance of these findings to non-Japanese populations and to clarify the functional correlation between galectin-2, LTA and MI.


Research article   |   By Dr Philippa Brice   |   Published 25 May 2004

A brief report published in the Online First electronic version of BMJ (which releases papers in advance of their publication in the print journal) links a common genetic polymorphism with an increased risk of neural tube defects in babies. The gene in question encodes a folate dependent enzyme, 5, 10-methylenetetrahydrofolate reductase (MTHFR); the common genetic variant, C677T, substitutes an alanine residue in place of a valine at position 222 in the enzyme, with an associated decrease in levels of enzyme activity. The effect of decreased enzyme activity is reduced levels of folate in the tissues, and increased levels of homocysteine in the plasma. This polymorphism may be homozygous (TT genotype) or heterozygous (CT genotype); these genotypes are present in around 10% and 38% of the population, respectively. The TT genotype affects enzyme activity, folate and homocysteine levels more markedly than the heterozygous CT form, and has previously been associated with an increased risk of neural tube defects such as spina bifida in pregnancy, as well as a modestly increased risk of cardiovascular disease. The BMJ paper reports an Irish study to investigate whether the heterozygous CT genotype is also associated with an increased risk of neural tube defects [Kirke, PN et al. (2004) BMJ, doi:10.1136/ bmj.38036.646030.EE] .

DNA from 395 individuals with neural tube defects spina bifida aperta or encephalocele, and 855 randomly selected newborn controls was genotyped for the MTHFR polymorphism. From their results, the authors calculated that both the TT and CT genotypes were associated with a small increased risk of neural tube defects; although the increased risk associated with the heterozygous genotype (around 50%) was lower than that for the homozygous TT genotype (around 150%), it was nevertheless proposed to represent a significant fraction of neural tube defects in the population, because the CT genotype is more common. Taken together, the authors propose that the TT and CT genotypes may account for over a quarter of all neural tube defects in Ireland. They claim that the potential adverse effect of these genotypes on neural development in foetuses can be corrected by maternal folic acid supplementation in pregnancy, leading them to suggest that these results underline the importance of taking folic acid prior to conception and in the early stages of pregnancy. They also argue that fortification of foods (such as bread) with folic acid may have additional public health benefits, by reducing the risk of cardiovascular disease in as much as half of the population.

Comment: This study confirms and extends previous work rather than identifying a novel gene-disease association, but is interesting to consider that even a mildly increased level of risk, if affecting a large proportion of the population, may be significant in public health terms. It is also a good example of how environmental changes (taking folic acid in early pregnancy when the neural tube of the foetus is developing) may in some cases balance out genetic effects, although in fact this study does not present any evidence connecting maternal folic acid supplementation directly with foetal MTHFR genotype and risk of neural tube defects. The maternal genotype with respect to the MTHFR polymorphism may also be relevant, and additional environmental and foetal genetic factors probably also influence neural tube formation.


Research article   |   By Dr Philippa Brice   |   Published 26 May 2004

Genomic imprinting is a process of differential expression of certain genes in the foetus based on whether they are present on the paternal or maternal alleles. Imprinting is mediated by epigenetic modifications, of which the most common is differential methylation of DNA sequences associated with imprinted genes in oocytes and spermatozoa. Major changes in genomic methylation occur following fertilisation, but imprinted alleles are protected from these effects. Imprinting disorders can lead to abnormal foetal development and diseases such as Angelman's and Beckwith-Wiedemann's syndromes. Angelman syndrome results in severe learning difficulties, epilepsy, unsteady gait and an unusually happy disposition. In some cases the syndrome is caused by DNA mutations that disrupt the imprinting process in a region of chromosome 15. Beckwith-Wiedemann syndrome is a condition associated with excessive growth before and after birth; this can cause a range of physical abnormalities, and also confers a greatly increased risk of malignant tumour development. In up to 60% of cases it is thought to result from disruption of imprinting in a region of chromosome 11.

Concern over the risk of imprinting disease in children conceived using assisted reproductive technologies (ARTs) such as in vitro fertilisation has been raised due to an unexpectedly high incidence of these syndromes. This has previously been attributed to the loss of maternal imprinting in the oocyte or embryo caused by ART procedures such as oocyte maturation or embryonic culture. A new study published in the Lancet presents evidence linking genetic imprinting disorders with abnormal spermatogenesis in men with low sperm counts [Marques CJ et al. (2004) Lancet 363, 1700-1702].

The Portugese team analysed spermatozoa from semen samples from 123 men undergoing routine investigations for infertility. Of these, 27 were found to have normal sperm and were used as a control group, whilst the remainder had moderate (46 individuals) or severe (50 individuals) oligozoospermia – that is, low sperm count. Sperm that showed normal morphology and motility were isolated from these samples, and DNA was extracted from them for analysis of methylation status in two oppositely imprinted genes: the paternally expressed MEST gene, and the maternally expressed H19 gene. Normally, for the MEST gene the maternal allele is methylated and inactive whilst the paternal allele is not, and for the H19 gene the paternal allele is methylated and inactive whilst the maternal allele is not.

Analysis of the MEST gene showed that the maternal imprint had been correctly erased in all of the normozoospermic (normal) and oligozoospermic samples. However, analysis of the methylation profiles of H19, which is paternally imprinted in early stages of spermatogenesis, revealed differences. Although all of the normal sperm DNA samples were correctly methylated, 24% of the oligozoospermic samples showed incomplete methylation. These samples represented 17% of the moderate and 30% of the severe oligozoospermic groups, with the degree of incomplete methylation being generally greater in the severe as composed to the moderate groups, in terms of the number of unmethylated sites. The authors conclude that abnormal spermatogenesis resulting in low sperm counts is associated with a rise in defective paternal imprinting of the H19 gene. They propose that infertility treatment may therefore promote transmission of paternal imprinting errors, with potentially detrimental developmental effects for embryos conceived following such treatment.

Comment: Although genetic imprinting disorders are generally rare, this paper presents evidence that a significant proportion of men with low sperm counts may have sperm with imprinting defects. The study is very small; extending the analysis to larger sample populations and additional paternally imprinted genes would strengthen the evidence base, as would long-term follow up of children born to men involved in such a study. Nevertheless, this is potentially an important issue in terms of increased risk of disorders among children born following assisted reproduction, though the absolute risk would remain very small. It may be desirable to evaluate current and potential new technologies used in assisted reproduction in terms of the relative risk of imprinting disorders they may represent, both maternal and paternal.


Research article   |   By Dr Philippa Brice   |   Published 14 May 2004

Researchers at Harvard University have published findings that question the potential use of adult stem cell therapies to regenerate damaged tissues, in particular specialized ß-cells in the pancreas. The researchers found that pancreatic ß-cells, which produce insulin, were derived primarily from pre existing pancreatic ß-cells, as opposed to multipotent adult stem cells [Dor Y et al. (2004). Nature 429, 41 46]. The hormone insulin is produced by pancreatic ß-cells in response to excess glucose in the bloodstream; insulin induces muscle, liver and fat cells to store glucose as an energy reserve for the body. In type I diabetes, the pancreatic ß-cells are destroyed by an autoimmune response. At present the only available treatment is the regular administration of insulin, without which patients would die; transplantation of pancreatic islets (clusters of ß-cells) can successfully treat the disease, but this option is severely limited by the lack of donated organs available for transplant. There is therefore considerable interest in stimulating the production of new ß-cells as a therapeutic strategy.

Adult stem cells (precursors of multiple different types of cell within a tissue) are known to exist in certain tissues such as the skin, and therapeutic transplantation of adult stem cells is an approach being investigated for a range of diseases. Previous evidence has suggested that highly proliferative pancreatic duct cells may function as stem cells and give rise to new ß-cells. By using a method of genetic lineage tracing, the scientists sought to trace the origin of new cells generated in response to pancreatic tissue damage in mice. Tracing was achieved using a ‘pulse chase’ labelling method; transgenic mice were created in which fully differentiated (adult) ß-cells were labelled with a heritable genetic insert that can direct expression of the human placenta alkaline phosphatase (HPAP) protein in progeny cells, when induced to do so by the presence of tamoxifen. New ß cells cells derived from cells other than the labelled adult ß-cells - including stem cells - will not express this protein label, whereas new ß-cells that have arisen from the original labelled cells will. Control experiments confirmed that injection of tamoxifen to the transgenic mice caused specific labelling of only differentiated pancreatic ß-cells.

A test group of 6 8 week old transgenic mice were then induced by tamoxifen injection to express HPAP from labelled cells. Pancreatic tissue samples from these mice were stained for insulin expression (to identify ß-cells) and for HPAP (to identify labelled ß-cells) following the initial labelling ‘pulse’ and at different time points over a twelve month period (the ‘chase’). Analysis showed that around 30% of ß-cells expressed HPAP at the start of the experiment. During the chase period, it would be expected that wholly new islets derived from non differentiated stem cells would contain no HPAP expressing cells. Within existing islets, maintenance by stem cells would be expected to result in a gradually decreasing proportion of labelled ß-cells, whereas maintenance by self duplication of ß-cells would result in a constant proportion of labelled ß-cells over time. The team compared the number of islets (here defined as a group of more than ten ß-cells) that contained labelled ß-cells following the initial pulse and during the chase period. Out of a total of 485 islets examined from the pulse and 744 islets from the chase periods of the experiment, all contained numerous HPAP positive ß-cells. It was therefore concluded that no new ß cell islets were formed in the mice during adult life.

The analysis was then extended to smaller clusters of 1–10 ß-cells, reportedly often supposed to represent newly formed, stem cell derived ß-cells growing into mature islets; again, these clusters would be expected to be completely HPAP negative if comprised of cells produced from stem cell precursors. However, a constant proportion (70-80%) of the clusters contained ß-cells expressing HPAP throughout the experiment, leading the researchers to conclude that no new ß-cell islets were formed by stem cells over the 12-month period. Single cell analysis was performed in order to determine the mechanism by which existing ß-cell islets were maintained. Tissue samples stained for HPAP and insulin expression were scored for the percentage of ß-cells that expressed HPAP; this percentage remained effectively stable in the chased mice (27.4% following the initial pulse compared with 29.54% during the chase period). The researchers deduce that any new ß-cells in pancreatic islets must have been derived from the replication of pre existing ß-cells.

Finally, the team addressed the question of whether stem cells might be involved in circumstances other than normal growth and maintenance of ß-cells – in particular, whether injury might stimulate them to proliferate and give rise to new ß-cells. They used a model of injury induced by the removal of a large portion of the pancreas from transgenic mice; two months after this injury the remaining pancreatic tissue was removed and analysed for insulin and HPAP expression. All islets were found to contain numerous HPAP positive ß-cells, and the frequency of HPAP expressing ß-cells did not change after injury, suggesting that stem cells (or other non ß- cells) made no significant contribution to the generation of new ß cells following injury. An article accompanying the report [Zaret K (2004). Nature 429, 30 31] notes that it fails to address the nature of pancreatic regeneration in a situation of long term damage, but the evidence presented nevertheless strongly points to generation of pancreatic ß-cells primarily, and possibly exclusively, from pre-existing pancreatic ß-cells and not adult stem cells.

Comment: The findings presented in this report are of direct relevance to research into potential therapies for diabetes, suggesting that they should perhaps focus on stimulating existing pancreatic ß-cells to generate new cells as opposed to previous efforts to create new cells from adult stem cells from various tissues. An obvious caveat is that all the experiments were performed in mice, making it important to determine whether human pancreatic ß- cells are generated in the same way. This paper also serves to emphasise the potential importance of embryonic stem (ES) cell research; if adult stem cell lines cannot be used for regeneration of pancreatic ß-cells, to how many other tissues may this also apply? For individuals with diabetes who lack any pancreatic ß-cells, the only feasible remaining therapeutic option could be the use of pluripotent human embryonic stem (ES) cells. It is also possible that ES cells used to create pancreatic ß-cells could be manipulated to avoid triggering the destructive autoimmune response against ß-cells seen in individuals with type I diabetes.