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14 February 2003The membership has been announced for an Interim Advisory Group that will advise the funders of the UK BioBank project on ethics and governance issues (see press release). Chair of the group is William Lowrance, a Geneva-based independent consultant in health policy and ethics, and author of a recent report on the secondary use of medical information in research. The eight other members include experts in ethics (Baroness Onora N’Neill and Professor Alastair Campbell), sociology (Professor Erica Haimes), law (Dr Graeme Laurie and Professor Jean McHale) and biomedical research (Professor Chris Mathew), as well as two lay members with experience in consumer affairs and voluntary and community work (Mrs Helen Millar and Mrs Madeleine Wang). The group, which will meet over the course of the next 5-6 months, will comment on proposals for ethical oversight and governance by the BioBank funders and may also put forward its own proposals on these issues.

5 February 2003The European Commission has become frustrated by the lack of progress in many member states towards implementing the 1998 Directive on the legal protection of biotechnological inventions. Only six countries, including the UK, have incorporated the provisions of the Directive into their national legislation, despite the fact that the official deadline for implementation, 30 July 2000, is long past. In the remaining nine states, which include both France and Germany, moves towards implementation appear to have stalled during debate in the legislature or have been shelved because of national elections. The Commission, which last October issued its annual report on the development and implications of patent law in the field of biotechnology (a document that includes, for example, discussion of issues including the scope of patents, cloning and stem cell technology), decided in December to threaten the nine errant states with being taken to the European Court of Justice over their failure to comply with the directive. On 28 January it announced, in addition, that it has set up an expert group “to ensure that the Directive will work for research, innovation and the public interest not against them”. The 13-strong group will not consider ethical issues surrounding patents – these are the province of the European Group on Ethics – but will focus on legal and technical aspects, and the impact of the patenting system on research in science and technology. Its reports will be published at the same time as the Commission’s next annual monitoring report, towards the end of 2003.  

Note: The February 2003 issue of Nature Medicine contains a brief news/commentary article about the problems the European Commission faces in forging a common policy on patenting in the stem cell field. See Mitchell, P. (2003) Nature Medicine 9, 154

10 February 2003Expertise in ethics, the pharmaceutical industry, patients’ experience, genetic counselling and consumer affairs is represented by five new members appointed to the Human Genetics Commission (see press release). The five new members – respectively Professor Brenda Almond, Dr Celia Brazell, Mr Alastair Kent, Ms Christine Patch and Mr Peter Sayers – join 12 reappointed members and a further seven whose terms of appointment are still current, to form the full 24-strong Commission.

3 February 2003A meeting of key leaders in stem cell research from eight countries, hosted by the UK’s Medical Research Council, has agreed on some initiatives to speed advances in the field and improve communication and collaboration among researchers (see report in 24 January issue of Science, p. 493). The programme will be driven forward by an international stem cell task force, the membership of which is expected to be announced within the next few weeks. Initiatives that were discussed include the setting up of a web site to catalogue information on stem cell lines and how to work with them, and detailing the various regulatory restrictions on their use. Researchers would also like to see an international repository of high-quality stem cell lines; just such a resource is currently being established in the UK and this may in time become the nucleus of an international collection. Moves are also afoot to agree on international standards for the characterisation of stem cells but these have proved more contentious.

3 February 2003The US NHANES (National Health and Nutrition Examination Survey) study is a well-established programme that involves an annual survey of around 3000 people representing a cross-section of the US population. The survey collects data on factors such as disease prevalence, risk behaviours and environmental exposures, and includes both a comprehensive questionnaire and a medical examination.. In recent years those agreeing to participate have in addition been asked whether they consent to have a blood sample taken and stored for possible future use in genetic research. McQuillan et al have monitored the response to this last question in 1999 and 2000 [McQuillan, GM et al (2003) Genetics in Medicine 5, 35-42 (Abstract)]. Overall, they found that around 85% of participants consented to the use of their blood samples for genetic research. However, although consent to participate in the overall NHANES survey did not vary by sex or ethnic background, females and non-Hispanic blacks were slightly less likely than other groups to consent to have blood samples taken for genetic research.

Comment: The NHANES participants were given several reassurances concerning the use of their samples. For example, they were told that their health information would be kept private and that their samples would not be identifiable by “nonstaff researchers or anyone using the data files”. They were also told that they would not receive individual feedback about results obtained with their samples, but would be kept informed in a general way about the progress of any research, which would be subject to approval by ethics review boards. They were informed that they were free to withdraw from participation at any time. These provisions are broadly in line with those proposed for the UK Biobank project, whose organisers should find the results of this study encouraging. A study in Scandinavia that was reported last year (see item in September 2002 newsletter) also showed around 80% support for genetic research among participants in a WHO study on risk factors for cardiovascular disease. 

28 February 2003In autumn 2002, the UK’s Genetics Commissioning Advisory Group (GenCAG), a subgroup of the national group that advises commissioners of specialised services, itself acquired a new subgroup that is responsible for overseeing moves to coordinate and rationalise the genetic testing services provided by UK laboratories. The terms of reference of the UK Genetic Testing Network Steering Group have now been published on the Department of Health’s website, along with minutes of its first two meetings held in September and November last year. In a spirit of “open government”, the group intends to publish its work on both the genetics pages of the Department of Health website and  website of the British Society for Human Genetics.

Among other responsibilities, the UKGTN Steering Group has a remit to keep under review the range and distribution of testing services offered by the NHS, to develop criteria for GenCAG for the evaluation and prioritisation of tests, to “maintain an interest” in the quality of service patients receive (including how results are communicated), to encourage work aimed at ensuring that genetic test requests are appropriate, and to undertake a horizon-scanning function to identify new research developments that are likely to impinge on service provision in the future. It will also develop principles to guide commissioners of genetic services and streamline and clarify financial structures. The Steering Group is supported by a Development and Coordination Team based at Bexley Primary Care Trust along with the lead specialised commissioning team in genetics. 

14 February 2003Writing in the Lancet, Ioannidis et al have analysed the results of 55 meta-analyses of genetic association studies, to see if there was evidence that the magnitude of the genetic effect found in different studies depends on the size of the study or varies markedly between the first-published study and later ones [Ioannidis, JPA et al (2003) Lancet 361, 567-571]. They report that for somewhere between 20% and 40% of the meta-analyses (depending on the statistical method used to assess the heterogeneity) there was indeed a significant difference between the size of effect measured in large and small studies – in most cases, the larger studies found a more modest genetic effect. Similarly, in about a quarter of the meta-analyses the first-published study reported a stronger effect than was found in subsequent ones. Overall, only 16% of the associations that had been subjected to meta-analysis appeared to be robust and without evidence of heterogeneity or bias. The authors comment that the failure of reported associations to stand up to meta-analysis may be due to real genetic heterogeneity (for example, the association may vary in different populations) or to one or more of many possible sources of bias in individual studies.

Comment: This paper adds further strength to calls for all reported genetic associations to be viewed cautiously until they are confirmed by multiple replications and/or by well-designed studies involving large numbers (preferably thousands) of both cases and controls. (This theme is also explored in the following Journal Club item.)  

7 February 2003Two published studies have claimed that the E4 variant of the gene encoding apolipoprotein E (APOE) increases the risk of cardiovascular disease to a far greater extent in smokers than in non-smokers [Stengard, JH et al (1999) Clin Genet 56, 367-377 (Abstract); Humphries, SE et al (2001) Lancet 358, 115-119 (Abstract)]. The suggestion that there is a gene-environment interaction between the APOE genotype and smoking has been called into question by a new, much larger study in which 4484 patients with acute heart disease were compared with 5757 controls [Keavney, B et al (2003) Lancet 361, 396-398]. As in the earlier studies (involving a total of 174 disease cases), the researchers found that smoking significantly increased heart disease risk (hazard ratio 4.6) and that the APOE4 allele slightly increased risk (hazard ratio of 1.37 for the E3/E4 genotype compared to the E3/E2 genotype). However, in contrast to the earlier studies, the researchers found that the hazard ratio for smokers versus non-smokers was not affected by genotype. Keavney et al conclude that studies involving very large numbers of disease cases (typically thousands) are essential in order to obtain reliable estimates of the modest effects expected of most genetic polymorphisms.

Comment:  This study appears to bear out the increasingly-voiced concern that small studies and publication bias lead to the reporting of many associations between common genetic variants and disease susceptibility that cannot subsequently be replicated. This has led some to conclude that the chances of any real associations being found is slim. The outlook may not be completely gloomy, however. Lohmueller et al report that, out of 25 published positive associations they analysed, 11 had been replicated more often that would be expected by chance if there were no true association, and eight of these stood up to meta-analysis [Lohmueller, KE et al (2003) Nat Genet 33, 177-182 (Abstract). The conclusion they draw is that, among a considerable amount of dross, there are some real results. Small studies do not always turn out to be wrong, but very large, well designed studies have the best chance of finding polymorphisms with modest but significant effects on disease risk.  

12 February 2003As part of its Science in Society programme, the Royal Society is running a web-based discussion on issues raised by DNA patents and genetic testing. The discussion is accompanied by  “science briefs” that outline the key concepts; in the case of genetic testing, most of the information concerns the issues involved in the use of genetic tests in insurance underwriting. The discussion forum lists three current “talking points”: “Human genes belong to everyone. How can anyone claim to own a gene?”; “Does having a patent placed on a gene help or hinder medical research?”; and “Would you want a genetic test to tell you if you were at risk of developing a disease?”. Would-be participants need to register before contributing their views.

14 February 2003A collaborative project involving scientists funded by Cancer Research UK and the Netherlands Cancer Institute in Amsterdam will use the new technique of RNA interference (RNAi) to switch off the expression of one gene at a time in human cells and see how cellular function is affected (see Cancer Research UK press release). The RNAi method works by targeting the messenger RNA produced when a gene is expressed in a cell: destroying the mRNA permanently silences the gene. The group aims to produce a “library” of cell lines, each characterised by the silencing of one gene. An initial pilot phase will target about 8,000 genes; the hope is that if this is successful then cell lines silenced for each of the 35,000 genes in the full genome could be produced by mid-2004. The cells will be available for use by researchers in the two funding organisations who want to explore the functions of individual genes. Researchers from other organisations will be able to purchase them. There are limits on how much can be learned about gene function from experiments in isolated cell lines, but continuing work using RNAi in nematode worms – whose gene function is remarkably similar to our own – will add to the picture [see for example, Lee, SS et al (2003) Nature Genetics 33, 40-48 (Abstract)]. Human cancer cells will also be used as targets for RNAi: the hope is that the method may identify genes that, when switched off in tumours, make them revert to a non-cancerous state. Such genes may be fruitful targets for new cancer treatments.