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2 December 2004

The Human Fertilisation and Embryology Authority (HFEA) has announced the formation of the Horizon Scanning Expert Panel (HHSEP) (see press release). This is part of the HFEA’s newly launched horizon scanning programme to inform policy development and decision making; the HFEA policy team will monitor scientific literature and identify emerging issues and the panel will provide expert assessment of new scientific developments and identify key areas for further scrutiny. The HHSEP includes experts in stem cell and assisted reproductive technologies, cloning techniques, developmental genetics and cryopreservation. HFEA policy development and consultation for the coming year includes analysis of stakeholder feedback on the use of preimplantation genetic diagnosis (PGD) to detect genetic susceptibility to disease and work on the implementation of the European Union tissue directive, as well as projects directly related to sperm, egg and embryo donation and use. HFEA Chair Suzi Leather commented: “The HFEA’s role is to protect the public interest by making sure that regulation keeps pace with scientific developments…Our horizon scanning work will…strengthen the decisions we make by providing a broader scientific picture on which we can explore the ethical and regulatory implications”.

The UK HHSEP members will be:

Professor Twink Allen (University of Cambridge)
Professor Peter Andrews (University of Sheffield)
Professor Keith Campbell (University of Nottingham)
Dr David Edgar (University of Liverpool)
Professor Martin Evans (Cardiff University)
Professor Stephen Hillier (Centre for Reproductive Biology, Edinburgh)
Professor Martin Johnson (University of Cambridge)
Professor Henry Leese (University of York)
Dr Maureen Wood (Aberdeen Fertility Clinic)

International members of the panel are:

Dr Jacques Cohen (Institute Reproductive Medicine and Science of Saint Barnabas, USA)
Professor Alan DeCherney (UCLA, USA)
Dr Christopher De Jonge (University of Minnesota, USA)
Professor Paul Devroey (Centre for Reproductive Medicine, Belgium)
Professor Hans Evers (Academic Hospital Maastricht, Netherlands)
Professor Gab Kovacs (Monash IVF, Australia)
Dr Norio Nakatsuji (Kyoto Univeristy, Japan)
Professor Andre Van Steirteghem (University Hospital Brussels, Belgium)
Professor Alan Trounson (Monash University, Australia).

2 December 2004Health Secretary John Reid has announced the dissolution of the NHS University (NHSU), as part of the timetable of changes intended to cut back "Arm's Length Bodies" (see July newsletter). A new NHS Institute for Learning, Skills and Innovation will take over the role of both the NHSU and NHS Modernisation Agency, with total staffing levels falling from 1500 to 300. The university was set up in autumn 2003 for the purpose of teaching individuals entering or returning to healthcare employment, as well as current NHS staff. Commenting on the move, John Reid said: "This is a vital step in the NHS's long-term programme of reform to improve efficiency and reduce bureaucracy", whilst NHSU chair Barbara Stephens said: "NHSU has been fully operational for only a year, and the reasons for setting it up, the objectives it set itself and the ways of working it espoused still hold and are still important. The board hopes that these will be carried forward into the new organisation" (see BBC news report). The new NHS Genetics Education and Development Centre in Birmingham, which was set up earlier this year to educate NHS staff about genetics and the role it plays in modern healthcare and which is affliated to the NHSU, has been funded for £1.8 million over the next three years; there is no information to suggest that it will be directly affected by the replacement of the NHSU by the new NHS Institute.

10 December 2004The German health insurance company Kaufmännische Krankenkasse (KKH) has reportedly offered free testing for hereditary haemochromatosis to its customers, of whom 4000 took the test and a further 2000 declined [BMJ 2004; 329, 1364]. Haemochromatosis is an autosomal recessive condition; some individuals who are homozygous for mutations in the HFE gene will develop clinical haemochromatosis, characterized by inappropriately high levels of iron in the blood that, if untreated, can eventually lead to fatal liver or heart failure. However, penetrance of the disease is highly variable; many homozygotes show no clinical disease. The mutations associated with hereditary haemochromatosis are very common; around 10% of Caucasian populations carry a copy.

Results of the genetic test were not divulged to the company, but it was reported that a total of 67 individuals were told that they were ‘at high risk’ of the disease, on the basis that they were found to be homozygous for mutations in the HFE gene. The assertion was that these individuals could avoid developing serious disease by undergoing preventative treatment (regular blood-letting). A company spokesman said that the estimated cost of treating someone with late-stage haemochromatosis was around €100 000, compared with a cost of about €14 per genetic test. However, this overlooked the fact that many individuals considered to be at high risk would never develop the disease anyway. The testing also identified around 500 heterozygous carriers of haemochromatosis mutation, many of whom reportedly regretted taking the test.

The German government is in the process of drawing up a draft bill on gene testing to establish new regulations, expected to become law in 2006. These will protect individuals from having to disclose the results of any genetic tests to employers or to life insurance companies, for insurance of less than €250 000. It will also become compulsory to offer counselling for all people offered genetic tests.

2 December 2004Plans to implement a long-term study of 100,000 American children from conception to adulthood, in order to examine multiple environmental exposures and link them in cause-effect relationships with multiple outcomes, have been revealed. The National Children’s Study aims to recruit pregnant women, couples planning pregnancy and women of child-bearing age but not planning a pregnancy, so that children’s exposures from as early as pre-pregnancy and early pregnancy can be captured and examined in the context of their genetic makeup. Sampling would begin with blood samples from mothers before and during pregnancy.

Led by the US Department of Health and Human Services and the US Environmental Protection Agency (EPA), and based at the National Institute of Child Health and Human Development, a total of 96 study locations across the US have been announced; children will be followed over 21 years and examined for a range of factors from family genetics, social and behavioural environment, and chemical exposures linked to the physical environment. It is hoped that the project will provide valuable information on how genes and the environment interact to cause disease, and reveal the underlying causes of some disorders. The genetics protocol for the study will be developed by Dr Cynthia Moore of the CDC, looking at issues such as which genetic information to gather; data collection, processing, and storage; and the ethical, legal, and social implications of acquiring genetic information. The study received $50 million for the four year planning stage that has brought it up to the current position, and now requires Congress to approve on-going funding, estimated at a total of $2.7 billion. Supporters have stressed the potential financial gains of improved health among the population.

3 December 2004Recently, two procedures for creating ‘ethical embryos,’ embryos that could be used in research without controversy, have been proposed. According to the BBC, researchers at the University of Wales in Cardiff have created a technique to cause eggs to start dividing but be unable to become an embryo or a fetus. They inject the egg with the protein in sperm, PLC-zeta, that triggers the normal fertilisation process and causes an egg to start dividing. However, in this case the division will only proceed to the multi-cell blatocyst stage where embryonic stem cells (ES cells) can be removed. But because the egg only has the DNA from the mother, the ‘parthenogenetic embryo’ cannot develop further.

Dr William Hurlbut, an American scientist who is opposed to embryo research, has proposed another method. He espouses a technique he has called ‘altered nuclear transfer.’ In this process, the DNA is removed from an egg. Donor DNA is then inserted into the egg, the egg is stimulated to begin division and a new blastocyst is formed. However, before the DNA is injected, it is mutated to prevent the formation of the trophectoderm or placental wall. Without this, Hurlbut claims, the cells cannot become an embryo and eventually a fetus. A ball of cells will form and from this ES cells can be harvested but the cells will eventually die. According to a BioNews report, for Hurlbut “…this means 'the embryo is forming', but 'unless it forms itself properly, it is not an embryo.'”

Both methods are being advocated as means to bypass the controversies around the destruction of human embryos for the sake of research. Now that President Bush has been returned to office, US researchers are seeking ways around the federal ban on creating new ES cell lines for research purposes. But can a cell mass not be an embryo, satisfying opponents of ES cell research? Whether either of these methods will be considerable ethically acceptable or ultimately workable remains to be seen. The Cardiff group have shown that their method can be done and have recommended that it might be used for couples who are undergoing intracytoplasmic sperm injection treatment (ICSI). In ICSI a single sperm is injected into an egg to fertilise it. Sometimes this is not successful if the PLC-zeta in the sperm is defective; adding PLC-zeta could help the process to be more successful. Hurlbut’s method, on the other hand, has not been proven scientifically, although there are plans by researchers to try it in mice. However, it does have support from conservative religious leaders in the US. More work is needed on both procedures to prove their effectiveness in producing embryonic stem cells and to ascertain the quality of those stem cells if they are to be used in subsequent research or treatment.

2 December 2004Health Secretary John Reid has announced the dissolution of the NHS University (NHSU), as part of the timetable of changes intended to cut back "Arm's Length Bodies" (see July newsletter). A new NHS Institute for Learning, Skills and Innovation will take over the role of both the NHSU and NHS Modernisation Agency, with total staffing levels falling from 1500 to 300. The university was set up in autumn 2003 for the purpose of teaching individuals entering or returning to healthcare employment, as well as current NHS staff. Commenting on the move, John Reid said: "This is a vital step in the NHS's long-term programme of reform to improve efficiency and reduce bureaucracy", whilst NHSU chair Barbara Stephens said: "NHSU has been fully operational for only a year, and the reasons for setting it up, the objectives it set itself and the ways of working it espoused still hold and are still important. The board hopes that these will be carried forward into the new organisation" (see BBC news report). The new NHS Genetics Education and Development Centre in Birmingham, which was set up earlier this year to educate NHS staff about genetics and the role it plays in modern healthcare and which is affliated to the NHSU, has been funded for £1.8 million over the next three years; there is no information to suggest that it will be directly affected by the replacement of the NHSU by the new NHS Institute.

2 December 2004Plans to implement a long-term study of 100,000 American children from conception to adulthood, in order to examine multiple environmental exposures and link them in cause-effect relationships with multiple outcomes, have been revealed. The National Children’s Study aims to recruit pregnant women, couples planning pregnancy and women of child-bearing age but not planning a pregnancy, so that children’s exposures from as early as pre-pregnancy and early pregnancy can be captured and examined in the context of their genetic makeup. Sampling would begin with blood samples from mothers before and during pregnancy.

Led by the US Department of Health and Human Services and the US Environmental Protection Agency (EPA), and based at the National Institute of Child Health and Human Development, a total of 96 study locations across the US have been announced; children will be followed over 21 years and examined for a range of factors from family genetics, social and behavioural environment, and chemical exposures linked to the physical environment. It is hoped that the project will provide valuable information on how genes and the environment interact to cause disease, and reveal the underlying causes of some disorders. The genetics protocol for the study will be developed by Dr Cynthia Moore of the CDC, looking at issues such as which genetic information to gather; data collection, processing, and storage; and the ethical, legal, and social implications of acquiring genetic information. The study received $50 million for the four year planning stage that has brought it up to the current position, and now requires Congress to approve on-going funding, estimated at a total of $2.7 billion. Supporters have stressed the potential financial gains of improved health among the population.

20 December 2004A study published in the current edition of Science reports the discovery that a gene called Olig 1 is essential for the repair of myelin in diseases of the central nervous system (CNS) such as multiple sclerosis (MS), which affects around 85,000 people in the UK and 2.5 million worldwide. Myelin is a fatty substance that surrounds and effectively insulates nerves cells in the brain and spinal cord and allows rapid transmission of nervous impulses from brain to muscle. When the myelin sheath becomes damaged, as in MS and other forms of demyelinating disease, neural transmission is impaired with debilitating results, such as difficulty in walking, impaired vision, bladder and bowel dysfunction and altered cognitive function (eg. defective memory). MS typically begins as a series of attacks interspersed with complete or partial remissions when damaged nerves become recovered with myelin. Eventually the ongoing repair process seems to break down and over time the disease tends to follow a progressively worsening course. Researchers from the Centre for Brain Repair and the School of Veterinary Medicine at the University of Cambridge and the Dana-Farber Institute at Harvard University have found that the Olig1 gene controls a process that can restore myelination of nerve fibres [Arnett HA et al. (2004) Science 306, 2111-2115].

Olig1 and Olig2 are closely related transcription factors (proteins that bind to DNA in the cell nucleus and regulate expression of particular genes) present in mature oligodendrocytes, nerve cells that produce myelin in the CNS. To investigate the functions of these genes, the researchers used antibodies against the Olig proteins to identify their location in oligodendrocytes in mice at different stages of CNS development. Olig2 was localised to the cell nucleus throughout, as expected for a transcription factor, whereas the Olig1 proteins became progressively located in the cytoplasm as the cells matured into myelin producing oligodendrocytes. This differential localization of Olig1 and Olig2 was also seen in the adult human brain.

Next, using rodent models of induced myelin injury and regeneration, it was found that Olig1 proteins were present in the nucleus of cells in remyelinating lesions. Post-mortem adult brain tissue from MS patients showed that Olig1 was present in the cytoplasm of cells in normal, healthy areas of white matter, but largely in the nucleus of cells at the edges of damaged areas where remyelination would be expected to occur. This finding was therefore taken to be consistent with movement of Olig1 to the cell nucleus as part of the myelin repair process in MS patients. The researchers also looked at mice in which the Olig1 and Olig2 genes were absent. Olig2–/– mice die at birth because oligodendrocytes and motor neurones do not develop properly, but analysis of Olig1–/– mice showed that they develop normal, fully myelinated brains and spinal cords with no apparent phenotypic abnormality. However, it was found that these mice were not able to regenerate myelin following induced white matter injury and demyelination, suggesting that Olig1 expression was essential for oligodendrocyte mediated repair of the adult CNS.

The authors conclude that Olig1 function is critical during remyelination. In a BBC news report, author Dr Charles Stiles of the Harvard's Dana-Farber Institute speculated that during the later, progressive stages of MS "Perhaps the signal that calls Olig 1 into service becomes weaker”. It is suggested that further investigation and improved understanding of the role of Olig1 in remyelination may allow the development of therapeutic interventions to promote ongoing neural repair in MS patients.

Comment: The causes of MS and similar demyelinating diseases remain unclear, with the prospects of a cure remote. However, there is hope that it may be possible to treat the disease by promoting the natural processes of neural repair; this paper represents an important step towards such a goal, although it is only the beginning and further research is certainly required, particularly into what happens to Olig1 function as disease progresses.

2 December 2004It is known that disease-associated genetic variants are more prevalent in some ethnic populations than others (for example, pathogenic mutations associated with cystic fibrosis in the CTFR gene are most common in Caucasians of northern European ancestry; beta-thalassaemia is most common in individuals of Mediterranean, Asian and Far Eastern ancestry). However, if such mutations are present in any individual, they almost invariably cause disease. The position with respect for common complex diseases (such as diabetes and cardiovascular disease) is much less clear; in this instance, multiple genetic variants may influence predisposition towards disease and also response to treatments. Identifying key genetic polymorphisms involved in complex diseases is a major research area. In the midst of this, there is on-going debate about the existence of racial differences in genetic associations with disease susceptibility and drug response; specifically, whether the effect of a given genetic variant is different when present in individuals of different racial backgrounds. This is an important question to address in the development of genetic medicine, since it potentially makes it much more difficult to assess disease risk and drug response.

A new study in Nature Genetics attempts to address this question by comparing the genetic effects of 43 validated gene-disease associations across different populations; these 43 meta-analyses were selected to satisfy certain criteria, including using data from at least two 'racial' or 'ethnic' groups and having significant results overall or for at least one ethnic group [Ioannidis JPA, Ntzani EE and Trikalinos TA (2004). Nature Genetics 36, 1312-1318]. The authors note the difficulty (and general inconsistency) in defining such groups, and opted to focus on major, distinct groups, primarily European, East Asian and African populations.

The frequencies of the genetic markers of interest in control populations varied between studies, as did the magnitude of observed effect of the markers. Racial group-specific frequencies of the genetic markers of interest also showed considerable variation between studies; significant heterogeneity was found in 25 of the 43 meta-analyses (58%), calculated using the I-measure, a statistical tool that gives an indication of whether observed heterogeneity is likely to be significant, or merely a chance finding. Next, the researchers looked at a statistical measure of the increased risk associated with a genetic variant, known as the odds ratio, for different racial groups in each study. They found that race-specific odds ratios were consistent in 32 of the 43 selected studies, in that variants that were associated with increased risk in one group had a similar effect in other groups. Although some estimated odds ratios in the other studies showed opposing directions (associated with increased risk in one group but decreased risk in another), in all of the 15 studies that showed significant risk association in two different racial groups, the effects were in the same direction. Significant heterogeneity in the effects of the genetic variants of interest was observed between different racial groups in only 6 of the 43 meta-analyses (14%).

The authors emphasise that, whilst racial group-specific frequencies of genetic variants showed significant heterogeneity in 58% of the studies, racial group-specific effects showed significant heterogeneity in only 14% of the studies, concluding that their data are “compatible with the hypothesis that genetic effects are consistent across traditionally defined 'racial' groups”. However, they do caution that, due to the limitations of the available data used in their study, it is impossible to exclude the possibility of racial differences, nor to conclude that race-specific genetic effects are exactly the same. Consistent effects of given genetic variants across different ethnic or racial groups lends weight to evidence that individuals from such groups are genetically highly similar; the authors stress that it is “implausible” to expect that all genetic polymorphisms will have highly similar effects in individuals from anywhere in the world, but note that in most cases differences in the genetic effects of disease-associated variants between racial are likely to be very small.

Comment: A News and Views article accompanying the research letter [Goldstein DB and Hirschhorn JN (2004). Nature Genetics 36, 1243 – 1244] notes the many limitations of such a study, notably the lack of clear evidence to support the reportedly validated gene-disease associations, and also inconsistency in factors such as sample sizes and the defined population groups between meta-analyses. These authors nevertheless conclude that the work by Ioannidis et al. is “probably the best that can be done currently”. The study’s conclusion that gene variants probably have broadly similar effects in different populations, if confirmed, has potentially important medical implications. Notably, information about genetic variants associated with disease risk or drug response obtained from a given population could be applied to other populations, hastening the advent of ‘personalised medicine’ for all individuals, irrespective of their ethnic background. This strengthens the claims of those who assert that racial or ethnic characteristics are a poor marker of genetic make-up and should not be used to stratify drug development (see November newsletter item).

10 December 2004Oxford University spin-out company G-Nostics has launched a novel genetic test that can reportedly help smokers who wish to give up, by identifying individuals most likely to respond well to nicotine replacement therapies (NRTs). The Nico-Test™, which costs £95, uses a finger prick blood sample to test for a genetic variant which the company says is associated with an increased probability of nicotine addiction, and is present in around 35% of individuals. These people are thought to be more likely to succeed in giving up smoking if they use NRTs, whereas those without the so-called ‘addictive gene’ are thought to be better off without such treatments. The test is also used to give a ‘metabolic profile’ indicating an individual’s rate of nicotine clearance, which can be used to calculate the appropriate dose of NRT. The genetic test results are analysed in conjunction with a lifestyle questionnaire by the company, and a personalised treatment programme is offered.

The gene in question may be the dopamine D2 receptor (DRD2) gene; a paper published by lead scientist Dr Rob Walton and colleagues earlier this year reported a link between a common polymorphism (32806 C/T) in this gene and the efficacy of nicotine patches in smoking cessation among women, but not men [Yudkin P et al. (2004) BMJ 328, 989-990]. Other genes with variants that have been linked with the ability to give up smoking include the human forms of 5HTT-LPR (serotonin transport protein) and CYP2A6 (cytochrome P450). A BBC news report says that the test could theoretically be used to check whether children have the gene variant and are at risk of becoming addicted to nicotine in the future (although anyone who smokes is at risk of addiction). Dr Walton commented: "I think many people would like to know whether their children have the gene or not…there are lots of ethical issues that need to be sorted out before we could offer anything like that". G-Nostics has also said that it would plan to incorporate any further genetic variants found to be associated with nicotine addiction into future tests to improve specificity. Anti-smoking groups have expressed reservations about the test.

3 December 2004Recently, two procedures for creating ‘ethical embryos,’ embryos that could be used in research without controversy, have been proposed. According to the BBC, researchers at the University of Wales in Cardiff have created a technique to cause eggs to start dividing but be unable to become an embryo or a fetus. They inject the egg with the protein in sperm, PLC-zeta, that triggers the normal fertilisation process and causes an egg to start dividing. However, in this case the division will only proceed to the multi-cell blatocyst stage where embryonic stem cells (ES cells) can be removed. But because the egg only has the DNA from the mother, the ‘parthenogenetic embryo’ cannot develop further.

Dr William Hurlbut, an American scientist who is opposed to embryo research, has proposed another method. He espouses a technique he has called ‘altered nuclear transfer.’ In this process, the DNA is removed from an egg. Donor DNA is then inserted into the egg, the egg is stimulated to begin division and a new blastocyst is formed. However, before the DNA is injected, it is mutated to prevent the formation of the trophectoderm or placental wall. Without this, Hurlbut claims, the cells cannot become an embryo and eventually a fetus. A ball of cells will form and from this ES cells can be harvested but the cells will eventually die. According to a BioNews report, for Hurlbut “…this means 'the embryo is forming', but 'unless it forms itself properly, it is not an embryo.'”

Both methods are being advocated as means to bypass the controversies around the destruction of human embryos for the sake of research. Now that President Bush has been returned to office, US researchers are seeking ways around the federal ban on creating new ES cell lines for research purposes. But can a cell mass not be an embryo, satisfying opponents of ES cell research? Whether either of these methods will be considerable ethically acceptable or ultimately workable remains to be seen. The Cardiff group have shown that their method can be done and have recommended that it might be used for couples who are undergoing intracytoplasmic sperm injection treatment (ICSI). In ICSI a single sperm is injected into an egg to fertilise it. Sometimes this is not successful if the PLC-zeta in the sperm is defective; adding PLC-zeta could help the process to be more successful. Hurlbut’s method, on the other hand, has not been proven scientifically, although there are plans by researchers to try it in mice. However, it does have support from conservative religious leaders in the US. More work is needed on both procedures to prove their effectiveness in producing embryonic stem cells and to ascertain the quality of those stem cells if they are to be used in subsequent research or treatment. -

17 December 2004Doctors at the Institute of Child Health (ICH) in London have reported the successful treatment of several children with severe combined immunodeficiency (SCID) using gene therapy. SCID is a rare X-linked genetic disorder that prevents immune system function, leaving children so vulnerable to life-threatening infections that they have to live in ‘bubbles’ to protect them from infection. The disorder can be treated effectively with a bone marrow or stem cell transplant, but this procedure relies on the availability of a suitable donor, and on the child being strong enough to undergo the transplant. The disease was therefore one of the earliest candidates for gene therapy approaches. A report to be published in the next edition of The Lancet details the treatment of four boys, although the researchers that a total of seven such boys have now received gene therapy for X-SCID (see press release). Functional copies of the defective gene were introduced via a leukaemia viral vector to stem cells from the patients’ own bone marrow, leading to the restoration of near-normal levels of immune function. Dr Bobby Gaspar, one of the UK researchers, said: "We hope this paves the way for developing gene therapies for other genetic disorders", citing the examples of other forms of inherited immunodeficiency or sickle cell anaemia.

Previously, concerns have been raised about this form of gene therapy when two out of eleven children treated for X-SCID with this form of gene therapy at the Necker Hospital in Paris developed identical forms of leukaemia (see journal club article). Commenting on this latest publication, Dr Marina Cavazzana-Calvo of the Necker Hospital said: "This paper is very important. It shows that this approach is highly reproducible…The safety issue is always a concern, but we hope that it will be limited" (see BBC news report). As yet there have been no further cases of leukaemia among children in the Paris or London gene therapy trials.