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10 April 2003In a surprise early statement, Appeal Court Judges on 8 April announced their decision that the Human Fertilisation and Embryology Authority does have the power to grant permission for a UK couple to use preimplantation genetic diagnosis (PGD) to select an embryo that would be both unaffected by the genetic disease beta-thalassaemia, and a tissue match for an existing sibling who is affected by the disease. The Appeal Court decision overturns an earlier ruling by the High Court, which accepted arguments by counsel for the campaigning group Comment on Reproductive Ethics that the HFEA had acted beyond its statutory powers and was effectively sanctioning the production of “designer babies”. The Appeal Court judges will release their full judgment at a later date. The couple, Raj and Shahana Hashmi, now plan to resume treatment as soon as possible, in the hope of having a healthy child whose cord blood would be a source of stem cells to treat their four-year-old son Zain. The HFEA has welcomed the Appeal Court decision, stressing that all applications to use PGD for this purpose will be assessed on an individual basis. The HFEA has already refused permission for another couple to use the procedure to select an embryo that would be a tissue match for an existing child, because in that case the procedure was not being used to avoid giving birth to a child with a serious genetic disease. 

28 April 2003In its report “Keeping science open: the effects of intellectual property policy on the conduct of science”, the Royal Society suggests some significant changes to the current regime for protecting intellectual property rights where they are applied to aspects of scientific research and knowledge dissemination. Concentrating on three areas of IPRs – patents, copyright and database protection – the Society concludes that, although IPRs are necessary to stimulate innovation and protect investment in research and development, many aspects of the current implementation of IPR legislation are not in the public interest. Its 25 key recommendations are tabulated together with a check-list of groups and organisations (Government, funding bodies, learned bodies, industry, courts etc) who need to take action on each point.

Many of the examples discussed in the report come from the area of biomedical science research. In the area of patents, for example (currently covered in the UK by implementation of an EU Directive on legal protection of biotechnological inventions), the Royal Society believes that the requirement to demonstrate both an inventive step and an industrial application should be interpreted much more rigorously by patent examiners, and that when a patent is granted its scope should be “no greater than that justified by the contribution made by the invention”. There should not be a presumption in favour of granting a patent and examiners should seek expert advice when assessing applications made in rapidly advancing fields of research. The report also recommends clarification of the current exemptions that allow researchers to use patented “inventions” for private and non-commercial use, the introduction of cheaper procedures for resolving patent disputes, and measures to protect the interests of developing countries.

In discussing copyright protection, the report points out new problems that have arisen with the growing use of electronic media for publishing scientific findings. The blanket application of a new European Directive originally designed to protect the interests of the entertainment industry (information about implementation of this Directive is available on the UK Patent Office website) is likely to hamper the need of scientific researchers for “fair dealing access for research and private study”. The Royal Society also urges scientists to publish their work in journals with liberal access policies, and recommends shortening the duration of copyright protection.

Database rights are protected in Europe under an EU "Database Directive" that may be suitable for stock market or horse racing databases but is inappropriate for application to scientific information, according to the report. For example, the “fair dealing” exceptions that allow extraction and/or use of the information in a database for non-commercial research, education and library use are vague, and could be seriously detrimental to science if rigorously enforced. It is also not in the public interest that data generated at great expense by publicly funded research should be made inaccessible by inclusion in a private database, so the report recommends that all such data should be placed in at least one repository that has liberal conditions of access and use. Specific mention is made of the need to clarify the terms of use of information to be generated by the UK Biobank project.

The report concludes that there is a need to take active measures to counteract a growing trend towards more stringent application of IPRs that is fettering scientific research and runs counter to the wider public interest. 

7 April 2003Newly appointed Chief Executive of UK Biobank, Dr John Newton, is scheduled to outline his vision for the project at an event organised by the Parliamentary and Scientific Committee on Monday 7 April. In his speech Dr Newton,  who is a specialist in public health and epidemiology, will draw attention to the need for large population-based studies to make sense, in epidemiological terms, of the vast amount of information flowing from the human genome project. An understanding of how genetic factors interact with environmental influences to cause disease will be essential if health benefits are to be achieved from advances in genetic science. Biobank is a long-term project, the value of which will not be apparent immediately, but it will be an important resource for biomedical research over the coming few decades. Dr Newton will stress that both the detailed study design and the arrangements for ethical oversight are still under development, and that there is determination to ensure that both scientific and ethical standards are robust. In speaking to parliamentarians, Dr Newton may feel he is entering the lion’s den, after a recent blistering on the Medical Research Council, and its role in Biobank, by the House of Commons Select Committee on Science and Technology (see item in March 2003 newsletter). 

4 April 2003A Working Party on Human Genetics, under the auspices of the Council of Europe, has produced a draft version of a proposed Additional Protocol to the Convention on Human Rights and Biomedicine, and is requesting comments on it. The draft text (see also explanatory notes) deals with “applications of genetics for health purposes”, though the intention is that the final Protocol will also cover non-medical applications of genetics. The Council’s Steering Group on Bioethics has not yet examined the draft text.

The  proposed Protocol covers “applications of genetics in the field of health including research, as well as in the fields of employment and insurance, which involve an intervention concerning the human genome, carried out on living persons or on the body of deceased persons”. It also covers such “interventions” carried out on “identified or identifiable human biological material, or the collection, processing or communication of personal genetic data”, but research use is excluded in this case. The Protocol does not apply to human embryos or fetuses.

The draft text includes general provisions on information, consent and authorisation, and on the conduct of genetic services. Services should, for example, have quality assurance programmes, ensure equitable access, and provide “genetic counselling and support appropriate to the … implications for the person concerned or the members of the person’s family”. Further sections deal with individual genetic tests on living people, tests on deceased people, genetic screening for health purposes, and “research”, which appears to be concerned mostly with somatic gene therapy. The sections on genetic tests cover not just diagnostics and predictive tests but also tests that may reveal a genetic predisposition or susceptibility to a disease: such tests, says the draft, should be performed “only for health purposes or for scientific research linked to health purposes”. Provisions on the consent that should be obtained include the statement that “appropriate information and consent or authorisation procedures” are necessary for tests carried out on biological material previously removed from a human body. Interestingly, another Article in this section, dealing with tests sold directly to the public, has three alternative texts, ranging from a flat prohibition of such tests to a requirement for adequate regulation and provision of information.

The UK has not adopted the Convention on Human Rights on Biomedicine because some aspects of it conflict with current law and practice in the UK. Similar difficulties may apply to the proposed Additional Protocol. For example, the prohibition on “discrimination” on the basis of genetic heritage would presumably preclude the use of any genetic test information in insurance, whereas tests approved by the Genetics and Insurance Committee in the UK can currently be used by insurers considering applications for high levels of life insurance and some other types of insurance cover. Some provisions of the Protocol might be interpreted as imposing quite draconian restrictions on the way research projects such as Biobank could operate, perhaps mandating individual feedback of all genotyping results. A weakness of the Protocol is that does not appear to make a clear distinction between predictive tests for highly-penetrant single-gene diseases, and tests that may reveal weaker predisposition to multifactorial disease. It is arguable that tests of the latter type do not need special regulation beyond that imposed on other, non-genetic types of medical test. The consultation closes on 30 April 2003. 

16 April 2003Because of heated controversy within the European Union over the ethics of embryonic stem cell research, the European Commission made an interim decision, in implementing the 6th Framework Programme for Research, not to fund any research involving the use of human embryos or human embryonic stem cells except where the project involved cells that had already been banked or cultured. A final decision about the ethical boundaries of EU-funded research in this field is to be made by December 2003. In preparation, the Commission has published a background report on stem cells that is designed to form a basis for discussion at an “inter-institutional seminar” on bioethics to be held on 24 April. The report outlines key features of stem cell biology and their potential therapeutic use. It also summarises the views of bodies such as the European Group on Ethics in Sciences and New Technologies on the ethical governance of stem cell research and includes a very useful survey of current legislation both in current EU member countries and in the countries set to join the EU within the next few years. It is clear that both attitudes and legislation on stem cells are in a state of flux, with some European countries settled on a very restrictive approach (for example Germany and Ireland), while others are moving towards allowing derivation of stem cells from “left over” IVF embryos that would otherwise be destroyed (for example, Belgium, Denmark, France and Spain). European Research Commissioner Philippe Busquin says “Regulating on ethical matters is the competence of Member States. In Europe, we have a legitimate diversity of rules and ethical frameworks in the field of human embryonic stem cell research”. It remains to be seen whether this approach will lead to the relaxing of restrictions on the types of stem cell research eligible for EU funding. It appears, in any case, that the European Parliament is not inclined to respect diversity of ethical views within the EU, with the recent passage of a draft Directive that explicitly bans the most controversial aspects of stem cell research (see Newsletter item and additional note). Clearly, it is proving difficult for the EU to reach consensus on which ethical principles should apply across the EU, and which should be a matter for decision by individual member states. 

8 April 2003Responses to the fifth (2002) Eurobarometer survey on biotechnology and the life sciences, published last month, suggest generally optimistic views about the impact of biotechnology on quality of life, though Europeans make clear distinctions among different applications of technology. Strong support is evident for medical uses of biotechnology, including the use of genetic testing to diagnose inherited disease and, perhaps surprisingly, for the “cloning of human cells or tissues to replace a patient’s diseases cells that are not functioning properly”. Positive attitudes to the latter suggest that the European public (including those in predominantly Catholic countries) may take a more liberal view than their legislators and policy-makers. Opinion is considerably more mixed about various uses of genetic information: the percentages supporting and not supporting forensic uses are almost equal, while substantial majorities do not support access to genetic information by government agencies or insurance companies. These views seem in line with a general suspicion of both industry and government. Continued opposition to genetically modified foods is evident, though attitudes seem to have softened a little since the last poll, in 1999, at least in some countries. There is evidence from the survey that, for many applications of technology, the largest group of supporters are those who also recognise some risk associated with the application, implying that support is not generally “blind” but is determined by a weighing of risks versus benefits. This trend is particularly clear among those who, by various measures, may be considered the “engaged public”. Nevertheless, responses to questions designed to measure understanding of genetics and genetic modification reveal a depressing level of ignorance: it seems that over 60% of people think that “ordinary tomatoes do not contain genes, while genetically modified tomatoes do” and about 50% think believe that “by eating a genetically modified fruit, a person’s genes could also become modified”.  

14 April 2003The much trailed report by the Human Genetics Commission on genetic testing services offered directly to the public has now been published. “Genes Direct”, subtitled “Ensuring the effective oversight of genetic tests supplied directly to the public”, is in fact rather less prescriptive than these phrases imply. The report contains useful discussion about many of the questions surrounding the issue, for example the need to seek a balance between respecting people’s right to seek information about themselves and protecting the vulnerable; the different levels of predictive certainty that apply to tests for highly-penetrant single-gene diseases and tests for weakly-penetrant variants involved in predisposition to common disease; the need for clarification of the degree to which existing regulatory regimes do or do not cover genetic tests; the difficulty of ensuring that consent has been obtained when home testing kits are used; the importance of commercial testing companies maintaining high standards of confidentiality and security in storing samples; the need for consumer education about the nature and limitations of genetic tests; and the role of professional regulation in ensuring best practice by groups such as pharmacists or nutritional therapists.

The Commission rejects the two extreme options of either allowing a free-for-all or banning direct-to-public/consumer tests altogether. It opts instead for a mixture of voluntary and statutory controls on such tests but is vague about which sorts of tests should attract which sorts of controls, saying only that "there needs to be a coherent review framework that can cover genetic tests across a spectrum that may range from the highly penetrant mutations in genes of large effect to those with loose associations with disease and those that are of relatively little health consequence". The Commission foresees roles for various agencies, such as the Office of Fair Trading, the soon-to-be-established Medicines and Healthcare Products Regulatory Agency, the proposed Human Tissue Authority, the Council for Regulation of Healthcare Professionals, and the UK Genetic Testing Network, in providing a network of points at which various levels of regulation could be brought to bear on genetic tests and the conduct of those involved in providing them. The report is categorical, however, in rejecting any regulatory role for the HGC itself. The Commission intends to publish an additional short report that will deal with the specific issues posed by paternity and genealogy testing services.  

24 April 2003The International Human Genome Sequencing Consortium has announced that the sequencing phase of the project is essentially over: the “reference” human genome sequence has been established to an accuracy of 99.9% and covers about 99% of the gene-containing regions of the genome [see press releases from the UK's Wellcome Trust Sanger Institute and the US National Human Genome Research Institute (NHGRI)]. Although some intractable regions of sequence remain unresolved, mostly in the mysterious 98% of the genome that does not code for protein, the current level of completion represents the limit of what can be achieved with current technology. Remarkably, the project has been completed ahead of time (by 2 years) and under budget, enabling the fanfares to coincide with the celebration of the 50th anniversary of the discovery of the double-helical structure of DNA by Watson and Crick.

But what next? In a 13-page feature article published in the 24 April issue of Nature, leading figures from the NHGRI outline their vision for the future of human genomics [Collins, FS et al (2003) Nature 422, 835-847]. They present a “blueprint for the genomic era” that consists of three major themes and six cross-cutting elements. The major themes – genomics to biology, genomics to health, and genomics to society – are set out in terms of 15 “grand challenges”, mainly for the research and health-care communities, but also for society as a whole.  The cross-cutting elements that run through all three of these priority areas are: generation and maintenance of resources (maps, sequences, clone libraries, cell lines etc); technology development; computational biology; training scientists in the new research skills they will need; ethical, legal and social implications (ELSI); and education of health professionals and the public.

The challenges for translating advances in genomics into benefits for health include a need to develop robust strategies for identifying and detecting genomic factors that influence disease risk, disease progression and response to treatment; using knowledge about the molecular basis of pathogenesis to develop new therapies; and developing genomics-based approaches to health care that are accessible to the developing world. NHGRI also sees a need to turn the disease-based focus on its head, by beginning to think about genomic factors that sustain good health. A need to be realistic about the practical potential of a possible future world of genomics-based prevention is also acknowledged: even if the science “delivers”, will people use genomically-based risk prediction to modify their behaviour, reduce their risk and so reduce health-care costs?  

23 April 2003A “Postnote” report by the UK Parliamentary Office of Science and Technology (POST) provides a welcome and timely antidote to an increasingly prevalent condition sometimes known as “genetic exceptionalism”. There has been a recent flurry of concern about genetic tests sold directly to the public, and the Human Genetics Commission has just published a detailed report on the subject (see also Newsletter item about this report). The Postnote report “Medical self-test kits” comments, tellingly, “There is an active debate about the supply of genetic tests direct-to-the-public. Less attention has been given to other medical tests, although many of the issues are the same”. In a concise four pages, the POST report defines the different types of test (screening, diagnostic, monitoring and predictive), outlines the regulatory regime that all medical tests will have to comply with from December 2003, and highlights the issues that will not be resolved by this regulatory system. Foremost among these is the “usefulness of the test result”, that is the clinical benefit, if any, to the person taking the test. The report also discusses the issues of counselling and support, and notes that the requirement for these services varies depending on the seriousness of the condition tested for. Implications for the NHS, such as possible increased demand on GPs and a need for pharmacists to be trained to interpret test results for consumers, are also mentioned. The text of the report is supplemented by Boxes giving examples of different types of tests, what they cost and how they are viewed by health professionals in the relevant field. The striking thing about the discussion is that genetic tests are mentioned only as examples of some of the different types of tests. To be sure, one column of the report does deal with the issue of whether there is anything exceptional about genetic tests, but leaves one with the clear impression that the answer is “not really” (with only one exception: the implications of tests for single-gene conditions for other family members). Perhaps the main value of the controversy about genetic tests is that it has served to highlight deficiencies in the regulation of all medical tests made available directly to consumers. 

17 April 2003The Wellcome Trust has launched a new website, “The Human Genome”. Subtitled “The human genome and what it means for society”, the site is pitched somewhere between the very simplified level of most sites for lay users, and the advanced level appropriate for professionals and researchers in the field. The site has four main themes: in the genome, genes and body, tackling disease, and genetics and society. Within each theme, articles on key topics are supplemented by news items from a variety of sources (including several selected from the PHGU website), more detailed feature articles, and background information, offering a layered approach so that the user can choose the depth to which he or she would like to explore the topic. Parallel strands of the site called Interactive Centre, Technology Centre and Around the Web offer, variously, some fancy web wizardry allowing the user to “browse” selected chromosomes and their genes; concise explanations of key technologies including PCR, SNP chips and mass spectrometry; and a round-up of web-based “news and views related to the human genome”. The site is information-rich, well written and well designed, though there is as yet no search feature and it is not clear how the information will be structured and archived – and pruned? - as the site grows.  

15 April 2003The UK is required to implement the European Directive on Good Clinical Practice in Clinical Trials 2001/20/EC, and is preparing to do so by means of the Medicines for Human Use (Clinical Trials) Regulations 2003 (currently in draft form). Part of the EU Directive requires that, if a clinical trial involves participants who are unable to give consent (for example, because they are unconscious), consent must be obtained from a legal representative acting on the patient’s behalf. The Department of Health has issued draft guidance on how this aspect of the Regulations would be implemented in practice, and is seeking comments on this guidance. The guidance explains the requirements both in emergency and non-emergency situations. In non-emergency situations, a personal legal representative of the patient (normally a close relative or other person in a position to know the patient’s likely views) would usually decide whether to consent on behalf of the patient. If no such person can be found, a person such as the clinician in charge of the patient’s care may act as the patient’s “professional legal representative” provided they are not themselves directly involved in the trial. A professional legal representative would also need to provide consent on the patient’s behalf in emergency situations where it was not possible to identify a personal legal representative in time. In all cases, a patient’s legal representative is required to act in good faith in a way they consider to be in the patient’s best interests and, where it is possible to know the patient’s likely wishes, in accordance with those wishes. The guidance stresses the importance of training and full provision of information for people who are likely to be in the position of needing to act as a professional legal representative for a particular trial. Comments on the draft guidance should be sent to the Department of Health Clinical Ethics Branch by 16 May 2003.

A separate consultation on the Regulations themselves is being carried out by the Medicines Control Agency. This more detailed consultation covers all aspects of clinical trial conduct that are affected by the implementation of the EU Directive, including standards of good clinical practice, the role of ethics committees, clinical trials authorisation, consent procedures, pharmacovigilance, appeal procedures and proposals for fees charged by the bodies involved in assessing, authorising and monitoring clinical trials. Provisions of the Directive that involve changes to current UK legislation are highlighted. Responses to this consultation are also due by 16 May. 

29 April 2003The anti-coagulant drug warfarin is well known as a treatment for venous thromboembolism. A recent paper reports the results of a study designed to determine whether treatment with lower doses of warfarin over an extended period could successfully prevent thromboembolism in patients who had already experienced a thromboembolic event [Ridker, PM et al (2003) N Engl J Med 348, 1425-1434 (Abstract)]. Half of a group of about 500 such patients were given placebo treatment and half were treated with low-dose warfarin. After follow-up for 4.3 years, 37 of the 253 placebo-treated patients and 14 of the 255 warfarin-treated patients had experienced a further thromboembolism, giving a calculated risk reduction of 64% due to warfarin treatment. Neither the risk of recurrent thromboembolism, nor the degree of risk reduction by low-dose warfarin, was affected by mutation status for the thrombophilic mutations prothrombin G20210A or factor V Leiden, or by a family history of venous thromboembolism. Long-term warfarin treatment did not appear to lead to an increased risk of major haemorrhage or stroke.

Comment: It is often suggested that people who experience a thromboembolic event should be offered genetic testing for thrombophilic mutations. The results of this study lend support to those who question the clinical value of testing in this setting, as knowledge of the patient’s mutation status does not significantly affect either the risk of a further event or clinical management.  

2 April 2003Obesity is generally a polygenic condition, arising from the effects of a variety of genetic factors (mostly unidentified, so far) interacting with the environment. In recent years, however, some largely monogenic forms of obesity have been identified that are associated with mutations in genes that encode components of biochemical pathways involved in the control of appetite and eating behaviour. The melanocortin 4 receptor (MC4R) protein is one of these components, and mutations in the MC4R gene have been found by some research groups in about 4-5% of severely obese people. Two recent papers in the New England Journal of Medicine provide further insight into the relationship between MC4R mutations and obesity. Farooqi et al report that 5.8% of 500 unrelated people with severe, childhood-onset obesity had mutations in the MC4R gene that were not found in unaffected control subjects [Farooqi, IS et al (2003) N Engl J Med 348, 1085-1095]. Functional analysis confirmed that the mutant receptor proteins were inactive or only partially active. Relatives of mutation carriers were genotyped in order to study the segregation of mutant alleles with obesity. In some families, obesity was very strongly associated with the presence of a single MC4R mutation, whereas in other families ascertained through a homozygous proband (all of whom were of Indo-European origin), homozygotes were more severely affected than heterozygotes. The authors suggest that the penetrance of MC4R mutations may vary in different ethnic groups. As well as increased body fat, MC4R mutation carriers had increased lean body mass, higher blood insulin levels and showed over-eating behaviour; the severity of these characteristics could be correlated with the severity of the effect of the MC4R mutation(s) on