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17 October 2003The UK research councils are having discussions with the UK government about creating an ethical code of conduct for scientists working with pathogens and chemicals that could possibly be used in creating terrorist weapons [Pincock (2003) Lancet 362, 1634]. It has been suggested that if researchers sign up to such an ethical code, they would be more aware of their responsibility not to misuse such potentially dangerous research tools. Groups such as the Wellcome Trust agree that a code could be beneficial but warn against legislating against research. A self-regulatory code is preferred to a legislative intervention that might inhibit worthwhile research. Discussions are at an early stage and will continue between the councils and the Foreign and Commonwealth Office, the government office taking the lead on this issue.

12 October 2003The Human Fertilisation and Embryology Authority (HFEA) announced today its recommendations to the Government on gender selection (see press release). These were produced as the result of a review process lasting for a year, which took into consideration both expert opinion and research on factors related to sex selection including scientific and ethical issues. An HFEA public consultation also formed part of the review input, and found that 80% of people in the UK did not want sex selection techniques to be made available for non-medical reasons. The HFEA report proposes that current policy, which permits sex selection only where it is necessary to avoid the birth of children with serious sex-linked disorders, should continue.

The report further recommends that sex selection involving a technique known as sperm sorting should be regulated; at present this form of gender selection is not regulated in the UK, but the HFEA public consultation found ‘overwhelming support’ for the introduction of regulation. Sperm sorting refers to techniques used to selectively separate male sperm and female sperm (that is, sperm carrying a Y chromosome which would create a male embryo on fertilisation, and those carrying an X chromosome which would create a female embryo) prior to artificial insemination or in vitro fertilisation (IVF). Sperm sorting has variable efficacy, although it does not at any stage involve the creation or loss of human embryos, making it an ethically preferable alternative to pre-implantation genetic diagnosis (PGD) for some individuals. PGD is already regulated by the HFEA and its use for sex selection is currently confined to avoiding sex-linked genetic diseases such as Duchenne Muscular Dystrophy. Sex selection by means of abortion is illegal in the UK.

Commenting on the recommendations, HFEA Chair Suzi Leather said: “The HFEA has to balance the potential benefit of any technique against the potential harm. We are not persuaded that the likely benefits of permitting sex selection for social reasons are strong enough to outweigh the possible harm that might be done.” -

14 October 2003The National Human Genome Research Institute (NHGRI) in the US has announced a novel initiative to identify the regions of the human genome essential for biological function (see press release). The ENCODE project (ENCyclopedia Of DNA Elements) aims to bring together international researchers from government, industry and academia to study functional elements within the human genome. An initial three-year pilot study will evaluate high-throughput methods to locate and analyse all the functional elements within selected regions of DNA, amounting to approximately 1% of the genome. The long-term aim is to extend this effort to cover the entire genome, establishing a database of the information generated, which is to be made publicly available. The project also intends to compare genomic sequences from humans and a range of animals in order to identify evolutionarily conserved regions, which are more likely to contain sequences with important biological functions.

In the same week, German-based company Epigenomics AG and the Wellcome Trust Sanger Institute (Hinxton, UK) have announced an agreement to fund and initiate the Human Epigenome Project (HEP), following a pilot study funded by the EU; see press release. The aim of the five-year project is to map DNA methylation sites in the human genome; methylation is a crucial mechanism for regulating gene expression. DNA methylation is essential for the normal development and function of our bodies, and altered patterns of methylation are thought to be important in cancer and other diseases, and in the ageing process. The HEP is intended to increase current understanding of gene regulation in health and disease. The collaboration combines high-throughput methylation analysis by Epigenomics with sequencing by the Sanger Institute; data generated will be combined with the human genome sequence and publicly released.

28 October 2003Following approval by the cabinet in July 2003, the Spanish government has formally ruled this month that surplus frozen embryos from in vitro fertilization (IVF) programmes may be used for research purposes, to provide stem cell lines [see report by Bosch X (2003) Lancet 362, 1385]. The number of frozen embryos currently stored in Spanish clinics may be as high as 200,000. A national centre is to be established to maintain a registry of embryos stored in IVF centres and to create a bank of stem cell lines created from embryos. The centre will oversee research using these cell lines, including ethical issues. The creation of embryos for research purposes is not permitted, and parental consent will be required for the use of embryos from fertilization programmes. This is in line with an EU ruling from earlier this year, which restricted funding to research using surplus embryos created for fertility treatment only.

This ruling changes previous Spanish law on assisted reproduction in place since 1988, which forbade research on human embryos and stipulated that surplus embryos must be stored by clinics for up to 5 years. The new law requires that future embryos created by IVF remain in frozen storage for the full fertile period of the mother’s life, and also places limits on the number of eggs that may be fertilised per cycle and the number of embryos transferred per procedure to three in each case. These measures are intended to minimise the number of surplus embryos in storage and to reduce the incidence of multiple-pregnancies following IVF.

7 October 2003A working group of the General Assembly of the United Nations appears to have reached an impasse in attempts to reach international agreement on a treaty to ban reproductive cloning (see report from Reuters new agency). The problem is that a group of nations led by Costa Rica, and including the United States, wants the ban to include so-called “therapeutic cloning”, also known as somatic cell nuclear replacement, a technique that some scientists think has promise as a means of producing embryonic stem cells genetically matched to those of a patient needing treatment. Other nations, including the UK, want the ban to be limited to reproductive cloning. Therapeutic cloning research is currently legal in the UK, subject to licence by the Human Fertilisation and Embryology Authority. The UN General Assembly’s legal committee is now charged with trying to decide how to proceed, but it seems unlikely that the deadlock can be resolved. Meanwhile the UK’s Royal Society has issued a statement supporting a complete ban on reproductive cloning but favouring the continuation of research on the use of cloning techniques for therapeutic purposes. The statement has been endorsed by a total of around 60 national and regional academies of science worldwide.

17 October 2003After seven years’ negotiation, the United States Senate has unanimously passed The Genetic Information Nondiscrimination Act 2003. This Act, which must also be passed by the House of Representatives before it becomes law, prohibits the use of genetic information by insurers or employers. “Genetic information” is defined as information concerning genetic tests on an individual or his/her family members, or information about the occurrence of a disease or disorder in a family member, that is used to predict disease risk in an asymptomatic person. Information about a person’s age or sex, and information derived from laboratory tests or physical examinations used to check a person’s current health status or diagnose disease (for example the result of a cholesterol test) are explicitly excluded from the definition. These sorts of tests are also excluded from the definition of a “genetic test”, which in the context of the Act means “the analysis of human DNA, RNA, chromosomes, proteins and metabolites, that detect genotypes, mutations, or chromosomal changes”.

Companies offering health insurance will not be able to use genetic information about an applicant, whether the person is applying individually for insurance cover or as part of a group scheme. Nor will insurers be permitted to ask whether a person has requested or received genetic services.

Employers, employment agencies and labour organisations (i.e. trades unions) will be prohibited from asking for or using genetic information in decisions about recruitment (or membership in the case of labour organisations), employment conditions and privileges, or promotion and dismissal. There is an exception to this prohibition: an employer can use a selection criterion that might tend to exclude people on genetic grounds if they can show that the criterion is directly related to the specific job and “consistent with business necessity”. “Genetic monitoring” in the workplace – that is checking to see if employees have sustained any genetic damage as a result of their work environment – is allowed under the Act but only if it is mandated by law, if the employer gives due notice and the employee consents.

President Bush has indicated that his administration supports the enactment of Federal legislation on genetic non-discrimination.

6 October 2003A group in Finland have published the first report of a link between a specific gene and developmental dyslexia [Taipale M. et al. (2003) PNAS 100, 11553-11558]. Dyslexia, literally meaning ‘difficulty with words’, is characterised by difficulties in learning to read and write, despite adequate intelligence and education of sufferers. It is the most common childhood onset learning disorder; severe forms of dyslexia affect around 4% of the UK population, with up to 6% affected to a lesser degree. Dyslexia has a neurological basis; areas of the brain that process information related to language are altered in affected individuals. Dyslexia is known to have a familial (inherited) component, and evidence suggests that it is a complex genetic disorder, involving multiple genes. Multiple loci on different chromosomes have previously been linked to dyslexia, but Taipale and colleagues are the first group to propose a specific gene candidate: DYX1C1 on chromosome 15 encodes a novel protein of unknown function found in certain areas of the brain. They suggest that this gene and the corresponding protein DYX1C1 provide a starting point for further research.

Comment: Although undoubtedly many genes are involved in dyslexia and a comprehensive understanding of the genetic basis of the disorder is a long way off, this report is nevertheless an important milestone. A commentary in the same issue of PNAS [Grigorenko E. L. (2003) PNAS 100, 11190-11192] heralds it as the “beginning of a new stage of research into genetic pathways of dyslexia”. The author notes, however, a number of caveats with regard to the DYX1C1 gene, not only the need for independent replication of results, but also the issue of co-morbidity: there are many different child-onset learning disorders, and more than one of these may occur in the same child. Genes such as DYX1C1 may therefore prove to influence broader mechanisms of learning rather than specific pathways related only to dyslexia.

23 October 2003The finished DNA sequence and accompanying analysis of human chromosome 6 has been published in today’s edition of Nature. It is the seventh chromosome to be fully sequenced and annotated to date, and the largest, representing nearly 6% of the human genome. The paper from the Wellcome Trust Sanger Institute, Cambridge [Mungall AJ et al. (2003) Nature 425, 805-811] reports the identification of 1577 genes, including many of medical importance. The MHC (major histocompatibility complex) region on the chromosome was sequenced some years ago, because of its critical role in immunity and disease, but many genes outside this region have also been associated with diseases including schizophrenia, cancer and heart disease. The Sanger team used genome sequences now available for a number of other species (mouse, rat, zebrafish and two species of pufferfish, Fugu and Tetraodon) to perform comparative sequence analysis in order to improve the accuracy of gene identification. The full analysis is available from the vertebrate genome annotation (VEGA) database.

16 October 2003A study of long-lived Ashkenazi Jewish men and women to investigate biological and genetic factors associated with unusual longevity has reported an association with significantly increased sizes of high and low-density lipoproteins [Barzilai, N. et al. (2003) JAMA 290, 2030-2040]. Previous studies have suggested that there is a genetic basis for exceptional longevity. Long-lived individuals (aged between 95 and 107, with a mean age of 98.2 years) and their offspring were found to have significantly larger high and low-density lipoprotein (HDL and LDL) particle sizes than controls, independent of total blood lipoprotein levels. This phenotype was associated with a lower prevalence of hypertension, CVD and metabolic syndrome in offspring compared with controls (matched for age and body mass index), and with an increased frequency of homozygosity for an allelic variant of the cholesteryl ester transfer protein (CETP) gene. Cholesteryl ester transfer protein is involved in regulation of levels and sizes of HDLs and LDLs. Whether the size of lipoproteins has a direct functional influence on survival has not been determined, but the authors propose that lipoprotein particle size may well have a causal effect, since smaller lipoproteins are associated with the development of CVD. They cite the reduced incidence of CVD in offspring (which was found to correlate with larger lipoprotein size) as further support for a link between lipoprotein sizes and age-related disease.

Comment: Identifying biological markers and genes that contribute to a prolonged lifespan is relevant to the study of ageing and mechanisms that protect people from common diseases. It is worth noting that the offspring of long-lived individuals will not necessarily prove to be long-lived themselves, but their inclusion in the study is important because it allowed comparison with an age and BMI matched control group (not feasible for the extremely old study participants).

21 October 2003A recent publication in Molecular Brain Research suggests that genes may exert a direct effect on the male/female sexual differentiation of the brain. Sexual differentiation of the brain is classically considered to arise due to hormonal influences during embryogenesis directing different neural development in the two sexes. Researchers from the University of California, Los Angeles (UCLA) compared gene expression patterns in the brains of male and female embryonic mice, at a stage prior to the formation of sexual organs or the influence of hormones (oestrogen and testosterone) on development. A selection of genes expressed at different levels in the brains of male and female mice were identified. The actual function of these genes has yet to be determined, but the researchers propose that they trigger key differences in the development and function of male and female brains and may contribute to sexual identity (see report from Reuters new agency).

1 October 2003Stroke is the most common cause of severe disability and the third most common cause of death in the UK, accounting for over 8% of all deaths in men and 13% of all deaths in women. It therefore represents a major health burden. Ischemic stroke, caused by blockage of a cerebral artery, is the predominant form of the disease. Besides known environmental factors such as hypertension, atherosclerosis, smoking and diabetes that may predispose an individual to suffering a stroke, the disease also has a genetic component; family history of stroke is known to be an independent risk factor for developing the disease.

In the October edition of Nature Genetics, an association between the gene encoding phosphodiesterase 4D (PDE4D) and ischemic stroke is reported [Gretarsdottir, S. et al. (2003) Nature Genetics 35, 131-138]. PDE4D is a complex gene with multiple different isoforms (functional variants with different N-terminal regulatory domains). Gretarsdottir and colleagues found that relative expression patterns of the PDE4D isoforms correlated with the incidence of stroke. They report a disease-associated haplotype (set of closely linked genetic markers) for the PDE4D gene, carried as a single copy by around 16% of the general population and present as a double copy in less than 1%. The paper reports that the PDE4D gene is most strongly associated with forms of stroke related to atherosclerosis, and propose that the PDE4D enzyme is involved in the pathogenesis of stroke, suggesting that inhibition of PDE4D could reduce the risk of stroke in individuals with a genetic predisposition towards the disease.

Comment: This is the first reported association between a specific gene and the risk of stroke, which now joins a small group of multifactorial diseases (including diabetes and Alzheimer’s disease) with known genetic contributions. Although the increased risk apparently conferred by the variant PDE4D haplotype is low (less than two-fold for heterozygotes and less than four-fold for homozygotes), this study creates a potential opportunity for novel therapeutics; phosphodiesterase inhibitors have already been proven as successful drugs, such as sildenafil (Viagra) for the treatment of erectile dysfunction. Further discovery of genes involved in susceptibility to stroke might contribute both to treatment and to genetic testing for increased risk of the disease.

20 October 2003An article in Science [Hacein-Bey-Abina et al. (2003) Science 302, 415-419] reports on an investigation into the cause of T-cell leukaemia in two out of ten patients who received retrovirus-mediated gene therapy for X-linked severe combined immunodeficiency (SCID-X1); the therapy successfully corrected the SCID in nine of the ten cases. Nearly three years on, the two youngest patients (aged one and three months at the time of treatment) have developed a form of leukaemia triggered by integration of the gene therapy retrovirus vector near to the promoter region of the LMO2 proto-oncogene. It has previously been considered that the risk of insertional oncogenesis (cancerous changes caused by insertion of a retrovirus near to a gene that regulates cell growth) in gene therapy is small, so the report of it occurring in two out of ten patients is a serious one. The fact that insertion of the retrovirus has occurred in exactly the same position of the chromosome in both cases is also alarming, as it contradicts the common view that insertional events would be not only rare but also random in nature.

A commentary accompanying the report [Williams DA and Baum C (2003) Science 302, 400-401] notes that whilst all gene therapy techniques involving integration of new DNA to the patient’s chromosomes carry a risk of insertional oncogenesis, the disease SCID is fatal if untreated, and that gene therapy offers the highest rates of correction with lower rates of side-effects than bone marrow transplantation, which is the only alternative therapy (and which requires an appropriate donor). It is therefore important to keep in mind the context of fatal disease in which these adverse treatment reactions have occurred. The very young age of the patients, the presence of immune deficiency when treatment was initiated and the precise nature of gene therapy for the particular disease probably all contributed to the development of leukaemia.

Comment: Although this report underlines the importance of a cautious approach to gene therapy trials, it need not represent a barrier to realising the potential clinical benefits of the technology. It will be necessary to minimise the risks of adverse effects such as oncogenesis by developing safer gene vectors, and by considering the particular risks posed by each individual disease and selecting vectors accordingly, but this is not the end of the road for gene therapy.