Contact us to receive a monthly email listing new additions to the PHG Foundation newsletter and site.
Researchers at the University of Edinburgh have announced the launch of a new two-year study that seeks to recruit 1000 adults from the North Isles of Orkney to look at risk factors for cardiovascular disease (see press release). The study, funded by the Chief Scientist Office of the Scottish Executive and supported by The Royal Society and the Medical Research Council Human Genetics Unit, will investigate the role of genes and the environment in the development of heart disease, stroke and diabetes. The islands' isolated population is particularly appropriate for the study, because they share a much greater degree of environmental factors such as diet and lifestyle than mainland populations. The population is also very stable, with some family trees traceable as far back as eight generations, so that shared genetic factors are likely to exert significant and detectable effects on disease risk.
The study’s lead investigator Dr Jim Wilson, of the university's Public Health Sciences department, commented: “The Orkney Cardiovascular Disease Study (ORCADES) will increase our understanding of the relative roles of inheritance and the environment in causing these diseases, and will include a search for any genes that predispose strongly to illness” (see BBC news report). Ultimately, by identifying key genetic factors involved in the three life-threatening diseases, researchers hope to develop improved therapeutic interventions.
22 October 2004Doctors are reporting that Charlie Whitaker has been ‘effectively cured’ of Diamond Blackfan Anaemia (DBA), as a result of a bone marrow transplant from his genetically selected brother. Three months on from his transplant, Charlie’s bone marrow looks normal although longer follow-up is needed to be certain that he no longer suffers from DBA. DBA is a rare blood disorder where sufferers cannot produce their own red blood cells. It can be treated by a bone marrow transplant but no one in Charlie’s family was a match for his tissue type. His parents had approached the Human Fertilisation and Embryology Authority (HFEA) for permission to use pre-implantation genetic diagnosis (PGD) and tissue typing to genetically select an embryo that would produce a child who would be a match for Charlie and could provide bone marrow. The HFEA originally refused their application on the basis that as Charlie did not inherit his DBA, the child to be selected might not suffer from it and therefore would not benefit personally from being chosen through PGD. The Whitakers travelled to the United States to have the procedure and Jamie was born as a result. His cord blood was collected and stored until it was determined that he did not also have DBA and the time was appropriate to conduct the bone marrow treatment. Now, three months on, both boys appear healthy and happy.
The HFEA has now relaxed its stance on ‘saviour siblings’ and several other families are in the process of applying to have PGD and tissue typing done here in the UK. Ethicists and others are divided on the appropriateness of this move towards a looser stance on ‘designer babies.’ Some believe that the success of the procedure in the case of the Whitakers justifies the HFEA’s decision. Others continue to argue that children should never be produced simply to be a donor for another. However, if the success stories continue, no doubt more families will follow the Whitaker’s lead. Doctors have estimated that up to a hundred children could be treated using donated bone marrow from genetically selected babies.
25 October 2004As part of a package of measures addressing genetic engineering and biotechnology, the German government has drafted legislation to allow employers to require job seekers to take genetic tests. This move has raised concerns with the German National Ethics Council which worries that this could take Germans down the ‘slippery slope’ towards a more widespread use of genetic tests required for job seekers, potentially leading to discrimination in work and the inability to get insurance or other benefits. The government counters that this legislation would not open the way for routine genetic testing. The tests would be confined to identifying people for whom a genetic disorder might adversely affect their ability to perform a specific job.
However, this is not the first time this issue has arisen in Germany. Last year, a German teacher was refused a permanent position after being identified as being at risk for Huntington’s Disease (HD), based on a family history of the condition (BMJ 2003;327:827). Her employer claimed that she might have a higher rate of absenteeism and increased medical bills if she did develop the disease and was therefore denied the position. She has pursued the case in court. Ironically, Germany’s current employment practices prohibit discrimination on the grounds of genetic make-up.
4 October 2004Dr Mary Archer is to chair the new East of England Stem Cell Network, an initiative funded by the East of England Development Agency (EEDA) and co-ordinated by the Cambridge Genetics Knowledge Park (CGKP) in partnership with the Cambridge Network, the Cambridge Stem Cell Institute, and the Eastern Region Biotechnology Initiative (ERBI).The Eastern region has a large number of centres of excellence in all aspects of stem cell medicine and research, and the new network links academic, medical and commercial partners to foster collaboration and ensure that the region continues to play a key role in this area both nationally and internationally.
Stem cells are cells that have the ability to divide (replicate) indefinitely; under certain conditions they can also give rise to different types of specialised mature cells that make up tissues – for example, heart or muscle cells. Stem cells are present in certain human tissues such as the bone marrow, skin and pancreas, and also in human embryos, and are of interest as a potential source of cells for regeneration of damaged tissue. Dr Archer noted the importance of stem cell research as having potential to lead to the development of novel therapeutics for a broad range of diseases, commenting that the new network would “help spread knowledge and encourage greater collaboration between researchers, funding bodies, biotechnology and pharmaceutical companies and regulatory bodies” and also "promote the East of England as a leading area for stem cell research and create an environment which encourages investment in further research” (see BBC news report).
[Dr Philippa Brice and Dr Ireena Dutta]
13 October 2004Pre-eclampsia is a serious complication of pregnancy, affecting around 1 in 10 pregnancies. It is a hypertensive disorder that affects multiple systems and causes significant morbidity and mortality among affected women and neonates. When pregnancies are established, fetal trophoblast cells (which give rise to the placenta) invade the uterus and remodel the maternal arteries to create blood vessels to sustain blood supply to the fetus. In pre-eclampsia the fetus receives an inadequate placental blood supply due to failing trophoblast invasion, which causes growth retardation. The only cure for pre-eclampsia is delivery, making it a major cause of premature birth. Between 3-5 mothers and 500-600 babies die annually in the UK as a result of pre-eclampsia, but a much greater number will suffer from long-term health problems, with a concomitant burden on the NHS.
The causes of pre-eclampsia remain poorly understood, although immunological responses against the invading trophoblast tissue have been proposed to play a role. There is a genetic component to the disease, which frequently runs in families, but the nature of this genetic aspect remains unclear. It has been suggested that pre-eclampsia may be a multigenic disease, influenced by environmental factors. It is also thought that a combination of maternal and fetal genetic factors may cause the condition. A new study has looked at genetic polymorphisms affecting fetal trophoblast cells and maternal uterine natural killer (NK) immune cells as risk factors for pre eclampsia. [Hiby SE et al (2004). J. Exp. Med. advance online publication 10.1084/jem.20041214]. The researchers reasoned that the only immune recognition components (histocompatibility antigens) on fetal trophoblast cells known to be polymorphic are HLA-C molecules, which are recognised by killer immunoglobulin receptors (KIRs) on maternal NK cells. These cells play a key role in establishing placental blood vessels. They postulated that this interaction could be a key factor in the development of pre-eclampsia.
Two key KIR genotypes (A and B) can be distinguished, such that all individuals can be classed as AA, AB or BB with respect to the KIR genes; the A genotype lacks activating KIR receptors. HLA-C genes fall into two major groups, C1 and C2. The study looked at maternal and fetal genotypes with respect to KIR and HLC-A in 200 women with pre-eclampsia and 201 matched controls. It was established that the frequencies of HLA-C alleles did not differ significantly among the test and control groups. However, a statistically significant increase in the frequency of the AA genotype (from 25% to 35%) was observed among pre-eclamptic pregnancies compared with controls. Analysis of combinations of maternal KIR genotypes with fetal HLA-C subgroups C1 and C2 revealed that the increased frequency of the AA genotype in mothers with pre eclampsia was present only where the fetal C2 HLA-C subgroup was also present (ie. where the fetus was heterozygous or homozygous for C2).
It was concluded that mothers with an AA genotype (lacking all or most activating KIR) were at a greatly increased risk of pre-eclampsia where the fetus possessed HLA-C2 group genes, even if the mother herself possessed such genes. The researchers postulate that in this situation, fetal trophoblast HLA-C2 molecules only interact with inhibitory killer immunoglobulin receptors, resulting in excessive inhibition of maternal uterine NK cells and poor trophosblast invasion. An examination of the relative frequencies of HLA-C2 and the KIR AA genotype in a range of ethnic populations revealed an inverse relationship between HLA-C2 and AA frequencies, suggesting evolutionary selection against this genetic combination.
Comment: This report is only one further contribution to the studies on possible genetic factors involved in the development of pre eclampsia, and the authors themselves concede that further research is required (see BBC news report); a much larger study size would be desirable. Although they cannot represent the sole genetic interaction important in the disorder, if validated these results could have potential application in the development of a screening test to identify pregnant women at high risk for pre-eclampsia. Presently the condition cannot be diagnosed until overt symptoms develop, but if it could be identified earlier in pregnancy then careful clinical management would be likely to improve outcomes for both mothers and babies.
22 October 2004Researchers in Newcastle have applied to the Human Fertility and Embryology Authority (HFEA) for a second license to clone human embryos for therapeutic purposes. The HFEA granted a license for the fertilisation and cloning of human eggs, the first of its kind in Europe, to scientists at the University of Newcastle in August for research into human embryonic stem cells as a therapeutic tool (see newsletter item). A second team is now seeking approval to transfer the nucleus of a human embryo into an unfertilized donor egg. Professor Doug Turnbull of the University of Newcastle and Dr Mary Herbert of the Newcastle Fertility Centre hope this research will help in the development of techniques to avoid the transmission of mitochondrial disease from mother to child. In a joint statement they said: "'People with defects of mitochondrial DNA have a number of different clinical problems including severe muscle disease, epilepsy, dementia, stokes and heart failure…For many people there is no effective treatment and there is progressive disability leading to death” (BBC report).
It is hoped that by using a donor egg with healthy mitochondria (structures that provide energy for cells, including egg cells) and implanting the nucleus of an embryo from a mother with defective mitochondria, the resulting embryo will grow into a baby unaffected by mitochondrial defects. However, such embryos would effectively have three biological parents (the mother, the father and the egg donor), since there is a small amount of heritable genetic material in mitochondria. Opponents of human cloning believe the procedure to be ethically unacceptable, and some claim it represents an unacceptable initial step towards the genetic engineering of human beings. The HFEA has declined to comment on the application but many experts expect that it will be successful.
26 October 2004The world will have to wait a bit longer to see if the United Nations will vote for or against a treaty banning all types of cloning. After two days of debate on the issues, there is no word on when the Sixth Committee (Legal) of the General Assembly will convene to vote on opposing resolutions in the cloning debate. As with the debates last year (see PHGU newsletter articles October 2003, December 2003), two draft resolutions were presented. The Costa Rican delegation, with the support of many countries including the United States, have proposed a total ban on both reproductive and therapeutic cloning, calling cloning for whatever practice “…contrary to due respect for the human person….” The Belgium delegation proposed a second resolution supporting "...the development of the life sciences for the benefit of mankind..." It would ban reproductive cloning but allow countries to regulate therapeutic cloning according to their own laws. This is the position supported by the United Kingdom. Asked when the committee would meet again to vote on the opposing propositions, a UN official said he did not have any information available to him.
One explanation for the delay in voting is the recognition that the issue might have a bearing on the upcoming US presidential elections. The candidates are split in their support of embryonic stem cell research; President Bush supports limited Federal funding for research while Senator Kerry claims he would expand funding if he were elected. Whether the UN vote would influence what is an already close election is unclear, but it has been reported by the Reuters News Agency that the vote will be delayed because “…Washington hopes to avoid an embarrassing loss just days before the election…” There are several indication that a support for a total ban on cloning is waning. Secretary General Kofi Annan told the press that he personally supports therapeutic cloning, but the decision should be left to the countries to decide. The 12-country Southern African Development Community, which had supported the total ban when the debate was held last year, now has changed its stance. Speaking on behalf of the group, Ambassador Alfred Dube of Botswana stated, "We shall not be party to any decision that will have us act hastily without measuring the benefits that medical science can provide to improve the quality of life of our people."
No date is set for a vote; U.N. Ambassador Mohamed Bennouna, the committee chairman, has told Reuters that “..he planned to meet informally with the two sides next week in hopes of narrowing their differences…”
26 October 2004The US Advisory Committee on Heritable Disorders and Genetic Diseases in Newborns and Children, an expert panel created by the Department of Health and Human Services (HHS) to develop a list of conditions for screening, has released its recommendations. It was proposed last week that all fifty US states should begin an expanded newborn screening programme to perform blood tests for at least 30 genetic disorders. These disorders all have effective interventions to avoid or improve adverse health outcomes for affected babies, if detected early enough, and can be reliably diagnosed by laboratory tests. Current estimates suggest that around 1000 newborn babies with treatable genetic disorders go undiagnosed in the US each year; it is hoped that expansion of current screening practice will identify these children in time to provide treatment (see Genome News Network report). The report also details an additional 25 conditions for which there is presently a reliable screening test, but no effective therapy; it proposes further expansion of routine newborn screening to include these conditions and urges states to report these test results.
Presently, the provision of newborn screening for genetic disorders in the US varies widely between different states. The recommendations, the result of a three-year study on newborn genetic conditions and screening performed by the American College of Medical Genetics (ACMG) on behalf of HHS, aim to establish parity across the US. However, the federal government cannot enforce the guidelines, and the decision on whether or not to implement them will rest with individual state health departments. Expansion of screening programmes will have associated cost implications, not so much for the tests themselves (which can be performed simultaneously and without additional expense using a technique called tandem mass spectrometry) as for the increased costs of re-testing and follow-up for babies with positive screening results. The situation with respect to fees is also complicated; most patients meet fees themselves but the costs for Medicaid patients are split between the state and federal governments.
4 October 2004The first global analysis of human microarray data has been released. DNA microarrays or gene chips are used to study patterns of cellular gene expression, and have been widely used in the investigation of tumour-specific genetic profiles. A new study has used a global approach to look at a total of 1975 datasets from microarray analyses of cancer cells, comprising 22 different types of tumour, from the Stanford Microarray Database and Whitehead Institute Center for Genomic Research database. The 14,145 genes analysed were assigned to modules, groups of genes that act together to perform specific functions. A total of 456 modules found to represent statistically significant gene expression patterns associated with various functions were analysed with biological and clinical data, to identify conditions in which particular modules were induced or repressed.
The end-product of this process was a map showing the status of modules in different forms of cancer. Some modules were shown to be present in a range of tumour types; for example, an osteoblastic module comprising genes associated with the proliferation and differentiation of cells that produce bone was implicated in breast cancer, lung cancer, hepatocellular carcinoma and acute lymphoblastic leukemia. These tumours may therefore share pathological mechanisms of progression and metastasis. Other modules showed tumour-specific associations, such as a growth inhibitory module found to be repressed in acute leukemia. Only one of the eleven growth suppressor genes present within the module was previously implicated in acute leukaemia; the other ten represent potential novel therapeutic targets. The researchers, whose work is published in the October edition of Nature Genetics, say that the study “provides a comprehensive roadmap for cancer, offering multiple research directions for diagnostic, prognostic and therapeutic studies” [Segal E et al. (2004) Nat. Genet. 36, 1090-1098], although findings from the project will require verification. GeneXPress, the data analysis and visualization engine used to create the cancer map, is also publicly accessible. Project team member Daphne Koller from Stanford University commented: "The whole thing is done in an automated fashion and can work on gene sets from other species besides humans and processes that are not cancer" (see The Scientist report).
5 October 2004The US National Institute of Environmental Health Sciences (NIEHS) set up the Environmental Genome Project (EGP) in 1997 to investigate the role of common genetic polymorphisms in environmentally induced disease. The project has focused on the discovery and annotation of single nucleotide polymorphisms (SNPs) in candidate environmental disease genes, with the creation of databases that integrate this data with annotated gene models. A total of 213 candidate genes with a possible role in environmental susceptibility to disease were analysed to determine whether functionally significant polymorphisms in the genes affected individuals’ susceptibility to genotoxic environmental agents. These genes were selected because they were known to be involved in biological processes that are influenced by environmental exposures (such as gene expression, DNA repair, and metabolism). In many cases loss-of-function mutations in these genes have previously been associated with serious disease states.
In a recent publication arising from the project, researchers report the discovery of a total of 23,443 SNPs in DNA from the polymorphism discovery resource (PDR) panel [Livingston RJ et al. (2004) Genome Research 14, 1821-1831]. The PDR is a representative panel of individuals of different ethnic groups from the United States population. The researchers found a "significant number" of polymorphisms that may confer sensitivity to environmental agents. Using techniques to identify potentially functional variations in coding sequence, they identified a total of 65 SNPs likely to cause altered protein function, with potentially deleterious phenotypic effects. Only seven of these variants were common polymorphisms, having a minor allele frequency (MAF) of greater than 5% (that is, the variant allele is present in at least 5% of the population). A few of these SNPs had previously been associated with known phenotypes, including an increased risk of neural tube defects in one case and several cases of increased cancer risk. The other 65 SNPs are suggested to represent high priority candidates for disease association studies. The authors note that, according to the common disease/common variant hypothesis, the genetic risk factors underlying common diseases are likely common, modest-risk alleles in the human population. Of the seven common variants identified, four have not previously been linked with any known phenotypes.
The total number of human genes is presently estimated to be around 25,000. Using an earlier estimate of 24,000 to 35,000 genes, the researchers present an extrapolation of their findings to predict the existence of a total of 7300 to 18,500 SNPs that alter protein function (with potentially harmful effects) in the human genome. The total number of commonly occurring deleterious SNPs is proposed to be between 790-1150. The future focus of the EGP is also outlined in the paper; a further 350 genes involved in metabolism, cell signalling, structure and division are to be analysed. The biological relevance and functional significance of the 23,443 SNPs already identified are to be investigated in molecular epidemiology studies of environmentally induced disease.
Comment: Although these first results from the Environmental Genome Project provide only candidate genetic variants that may be involved in harmful responses to environmental exposures, the potential benefits of this initiative may be realised as some polymorphisms are shown to be risk factors for specific diseases. The authors of this paper claim that the ultimate aim of the EGP is for these studies to "translate into the decision-making that creates better environmental health policy and health monitoring practices with sensitivity and specificity for at-risk individuals". Given the vast number of common genetic variants in the human population, using new techniques to mine the human genome for those with key roles in human health and disease is an important approach to reaching this goal.
21 October 2004The International Human Genome Sequencing Consortium has released an analysis of the ‘gold standard’ version of the human genome sequence in the latest edition of the journal Nature [Nature 431, 931 - 945]. The current genome sequence, published last year, contains 2.85 billion nucleotides. It encompasses around 99% of gene containing regions of the genome and is 99.999% accurate. Notably, the predicted total number of genes has fallen to just 22,287: 19,599 known protein-coding genes and a further 2,188 sections of DNA predicted to be protein-coding genes. Original estimates of gene number when the draft genome sequence was released were between 30 and 40,000, a figure that was considered surprisingly small. Now, researchers are confident that the key to the biological complexity of humans is gene regulation, rather than gene number. Dr Tim Hubbard, of the Wellcome Trust Sanger Institute in Cambridge (major partner in the international sequencing project) commented: "It means that each gene can be used in a variety of different ways depending on how it is regulated" (see BBC news report).
Dr Jane Rogers, Head of Sequencing at the Wellcome Trust Sanger Institute commented: "The task of identifying genes remains challenging, but the finished human genome sequence, genome sequences from other organisms, better computational models and other improved resources, have combined to give a much clearer and more reliable picture of our genomic landscape" (see press release). The authors of the paper note that the accuracy and completeness of the gold standard genome sequence allows systematic searches for the causes of disease with confidence that few predisposing genetic factors will escape detection. The gold standard genome sequence is interrupted by only 341 gaps, many of them reportedly associated with segmental duplications of DNA. These are large near-identical DNA sequences present in at least two locations in the genome, which will require novel methods to complete.
25 October 2004Down's Syndrome is the most common chromosomal abnormality that affects live born babies; it is caused by trisomy of human chromosome 21. Usually this trisomy is complete (the presence of a complete additional copy of chromosome 21) but in some cases only partial trisomy with respect to this chromosome is observed. Down's Syndrome results in mental retardation in association with certain characteristic facial and physical features, as well as other medical conditions affecting the heart and gastrointestinal tract. These clinical features of the syndrome are presumed to be the result of abnormally increased levels of gene expression from the additional copy of chromosome 21; previous research has suggested that a certain subset of genes are likely to be key in causing disease. Together these genes are referred to as the Down Syndrome Critical Region (DSCR) of chromosome 21.
A new paper in Science reports that this region does not account for the craniofacial abnormalities associated with Down syndrome [Olson LE et al. (2004) Science 306, 687-690]. Researchers from Johns Hopkins in the US created mouse models for DS by engineering mice that were trisomic for the murine equivalent of the DSCR only, with a view to producing improved disease models. Mouse models for Down syndrome exist, but have been complicated to develop; most of the orthologous murine genes for tho