In the news

The National Human Genome Research Institute (NHGRI) has issued a press release announcing the release of the first draft version of the chimpanzee (Pan troglodytes) genome sequence to the publicly accessible NIH database, GenBank. NHGRI teams from the US Broad Institute (Massachusetts Institute of Technology and Harvard University), and the Genome Sequencing Center in Washington assembled the genome sequence and have also produced an alignment with the human sequence. An international team of scientists, led by NHGRI researchers, are performing comparative analyses of the two genomes, expected to yield important functional insights due to the similarity between the two species. Chimps are genetically the most closely related species to humans, and the chimp and human genomes differ by only about 1.2%. These sequence differences must account for the major differences in physiology and disease susceptibility and pathology observed for the two species. It is hoped that comparative analysis of the genomes will allow the identification of key human genes relevant to disease and evolution.

The Department of Health (DoH) has announced an invitation to tender to conduct evaluations of the service development projects arising from the White Paper, ‘Our Inheritance, Our Future: Realising the potential of genetics in the NHS’. To fulfil its commitments under this initiative, the DoH has commissioned pilot projects in the areas of familial cancer and familial hypercholesterolaemia, bringing genetics into mainstream services, building capacity in primary care and introducing GPs with special interest to genetics. It is now also seeking external evaluation projects to run in parallel with them. Proposed evaluation projects should have the aim of learning from and within the commissioned projects, looking specifically at questions related to service commissioning, education and training, research and development and internal (DoH) governance. Projects are expected last approximately 2-3 years. The deadline for application submission is 12 February 2004. Further information and an application form can be found at www.doh.gov.uk/genetics/eval_of_nhs_invitationtotender.htm.

It seems that the European Directive “setting standards of quality and safety for the donation, procurement, testing, processing, storage, distribution and preservation of human tissues and cells” is nearing the end of its tortured progress through the EU’s decision-making process. As we have reported in previous Newsletter items (see items in March and June), the draft Directive had been subject to attempts by some members of the Parliament to use it to ban embryonic stem cell research and tissue transplants involving material derived from embryonic stem cells. This ban, had it succeeded, would have been binding on all member states. However the Council of Ministers and the Parliament have now reached agreement on a text that excludes these contentious provisions; the amended text was adopted by the Parliament on 16 December and is expected to be approved by the Council. (The text adopted by the Council in July 2003 and referred to Parliament can be found here, and the amendments that were finally adopted by Parliament are set out here.) The UK is likely to adopt the legislation early in 2004 and it would come into force in 2005.

The Council did accept some of Parliament’s amendments to the Directive, including a ban on direct payment for tissue donations (apart from reasonable compensation for expenses and inconvenience), and adoption of traceability requirements that will mean records will have to be kept for at least 30 years after clinical use of the tissue. Tissue recipients will not be told the identity of the donor, though member states can relax this requirement in the case of donated gametes.

All establishments involved in cell or tissue therapy will be placed on a register and will have to show that they adhere to strict criteria for quality control, professional training and record-keeping.

The Human Fertilisation and Embryology Authority (HFEA) recently announced its decision to contact all licensed fertility clinics and inform them to cease egg-giving schemes (see press release). Egg giving refers to the practice whereby all the eggs from a woman’s first cycle of ovarian stimulation and egg retrieval are donated to another woman; the donor patient then receives a second cycle of IVF treatment (retaining the eggs produced for herself) at reduced cost. The HFEA initiated a review of egg-giving in July 2003. The basis of its decision is the increased risk necessitated by additional treatment cycles, in particular the risk of ovarian hyperstimulation syndrome (OHSS), a complication arising from around 1% of procedures. HFEA chair Suzi Leather commented: “…the HFEA cannot allow clinics to offer a treatment where a woman, for no other reason than financial inducement, subjects herself to an unnecessary and possibly risky procedure”. The announcement does not affect the more common practice of egg-sharing, in which some of the eggs produced from a cycle of IVF treatment are donated to another woman and the rest retained for the use of the donor woman, again in exchange for a reduction in treatment cost.

The long awaited Human Tissue Bill was published by ministers yesterday almost five years after the first internal inquiry into organ retention at Alder Hey Children’s Hospital in Liverpool. The eventual publication of reports in 2000 concerning Alder Hey (the Redfern report) and Bristol Royal Infirmary (the Kennedy report) suggested that many institutions had stores of tissue samples for which consent had never been obtained. This fuelled a stream of revelations from hospitals around the country confirming that thousands of hearts, brains and other body parts had been retained without permission. The scale and scope of the retention was reinforced by a census of retained body parts carried out by the Chief Medical Officer in 2000.

Despite pledges of immediate action by the Chief Medical Officer there has been a delay of nearly 3 years in publishing a revised Bill for a number of reasons. Extensive consultation by the Department of Health and by the Retained Organs Commission (the organisation set up to oversee the return of tissue samples to bereaved families) and various professional bodies has meant that the resulting legislation has had to be seen to be balancing the rights and expectations of individuals and the considerations of research, education, training, pathology and public health surveillance to the population as a whole. The situation was compounded by the reckless inefficiency of some hospitals in returning bodies and organs to parents, so that in some cases parents had to endure second or third funerals, years after the death of their child. The simultaneous scandal revealed in the Shipman reports published this year and a report by Dr Jeremy Metters, the HM Inspector of Anatomy which showed that retention was on an even larger scale than had previously been thought, meant that the resulting Bill is a much more comprehensive review of legislation than was at first envisaged.

The resulting Bill establishes a new body – the Human Tissue Authority – which will replace the Retained Organs Commission, due to close on 31st March 2004. The Authority will have oversight of the use of human tissue for a widely drafted series of purposes including anatomical examination, education and training relating to human health and research, research and transplantation. As such it will subsume HM Inspectorate of Anatomy and ULTRA. Any person carrying out any of the activities specified in the act must be licensed and there are strict guidelines and procedures governing the use of tissue to be used for donation or research purposes.

The legislation provides for consent from the donor him or herself or from a hierarchy of family members to be the basis of the keeping or use of tissues and cells. It also establishes an offence of analysis of DNA without consent as envisaged in the recent Genetics White Paper. -

The Italian Senate has agreed a new law strictly limiting the conduct of assisted reproduction technologies (ARTs). Under the law, which still needs to be approved by the lower house of parliament, only heterosexual couples will have access to ARTs; same sex couples and single women will be denied access. Only three embryos will be fertilised at one time and, even if they are defective, must all be implanted simultaneously in the woman’s womb. If there is not a successful pregnancy, the woman will have to undergo the IVF treatment from the beginning. Couples must be deemed ‘clinically infertile’ to qualify for treatment.

Research involving embryos, pre-implantation genetic diagnosis and prenatal screening for genetic diseases will be banned under the law. Violations for being found to be involved in cloning activities will be punished with a one million Euro fine, a prison term and the loss of one’s career. There will also be fines for those providing ART outside of the law. Existing IVF embryos will be stored for some period for the use of the couples that created them and leftover embryos will be donated. At some point all storage facilities will be closed.

Opponents of the law have expressed their outrage. They feel it is too restrictive and may cause a woman’s life to be put at risk. Many leading Italian researchers, including Nobel laureate Rita Levi-Montalcini, have expressed their feelings in a public statement. “Some of these bans, such as that of the preimplantation diagnosis with the obligations of transferring all the formed embryos in the womb, are astonishing from a scientific point of view and disgusting from a moral point of view.” Some fear this will be disastrous for Italian research. There is little expectation, however, that these views will be considered. The lower house of the Italian parliament is not expected to change any of the wording when they consider the law.

The Joint Committee on Medical Genetics (JCMG) has released a consultation document, Consent and Confidentiality in Medical Genetics: guidance on genetic testing and sharing genetic information. The JCMG, comprising representatives from the Royal College of Physicians, Royal College of Pathologists and British Society for Human Genetics, has written the report for genetics professionals to clarify the issues of consent and confidentiality in clinical practice. The report takes into account current legislation as well as the results of a questionnaire study conducted in genetics units around the UK to discover current practice, as well as areas of concern. Four areas are explored: general aspects of consent as applied to genetics, the sharing of information to other family members and between professionals, genetic investigations including those performed on stored material, and the Data Protection Act and the processing of medical genetic information. For each, the general principles are discussed and appropriate documents are referenced. Responses to the report are welcome; the closing date is 9 January 2004.

The Council of Ministers could not reach a decision on funding for research using human embryonic stem (ES) cells. Ministers met on 3 December, after agreeing last week to delay their decision; however, no compromise could be reached and the meeting was adjourned. This was the last opportunity to reach a decision before a moratorium on funding expires on 31 December.

Deep division between countries has led to this lack of agreement. Countries such as Germany, Austria and Italy strongly disagree with EU money being spent on ES research, especially as this research is illegal is some EU countries. Other countries, such as Britain, where some types of ES research are legal, have supported having EU funds made available. In order to reach a compromise, the European Commission, Parliament and Council have made proposals and counter-proposals, trying to take into account these different positions. Originally, the Commission, in 2002, had supported funding ES cell research through its sixth-framework funding programme. But, after the European Parliament called for heavy restrictions on the research, it was agreed to impose the current moratorium that prohibits funding on research using already stored ES cell lines, and continue the discussions. The European Commission next proposed a moratorium on funding any research that used ES cell lines created after June 2002. The European Parliament rejected this but narrowly voted to support funding for research on new cell lines. However, the final decision on a funding position rested with the Council of Ministers.

Ultimately, they were not able to reach an agreement on the issue and the current moratorium will therefore expire. A final compromise was introduced to allow the use of ES cells from ‘left-over’ IVF embryos created before 3 December 2003, however it was not accepted. Countries such as Britain, the Netherlands, Greece, Sweden and Finland, fear that imposing a cut-off date will inhibit research.

After the moratorium expires on 31 December, funding will be considered on a case-by-case basis. It is not known whether the Irish government, which will take over the EU presidency from Italy on 1 January 2004, will reopen the issue.

The Queen’s speech has included Ministers’ plans to introduce a Human Tissue Bill in this session of Parliament. The new bill will include tighter rules on organ retention as well as a new agency responsible for regulating activities related to post mortems, transplants, and the retention of tissue and organs. It will also include measures to ensure that doctors have the consent of relatives before tissue or organs are retained. In the wake of the scandals at Alder Hey Hospital and Bristol Royal Infirmary, the government has been working to reassure the public that organs will no longer be kept without the full knowledge and consent of the parties involved. The Department of Health had consulted on the issues late last year in ‘Human Bodies, Human Choices.’ The families who have been fighting for legislation are pleased it will soon finally be in place.

Men are flocking to respond to an advertisement placed by an Australian reproductive medicine clinic for a free two-week trip to Sydney in exchange for donating their sperm. The ad, placed in a University of Calgary student publication, offers return airfare, accommodation and expenses to men aged 18-40 in exchange for their sperm. Local donation rates have fallen and proposed changes in the law in New South Wales appear to be to blame. The new law would require those donating to disclose their identify, whereas previously they could remain anonymous. Donors will be identified in confidential records and will have their identity given to offspring who have reached the age of 18. However, donors will have no legal responsibilities for the child.

While the ad was placed in Canada, men from all over the world have responded. Calgary was chosen because the Australian clinic has contacts there to screen applicants. However, getting accepted will not be easy. Volunteers must agree to attend two counselling sessions, pass a battery of medical tests and give up every other day of their trip to donate sperm. Regardless of the hurdles though, based on the response so far, it appears that there will be no lack of those willing to sign up.

The United Nations will revisit the issue of a treaty banning human cloning in one year, rather than the two years that had been previously agreed. This decision was reached after supporters of a total ban attempted to force more debate on the issue by opposing the time delay when it came up for final vote this past week. In November, the delay was agreed after no decision could be reach between competing resolutions, the first supporting a ban on both reproductive and therapeutic cloning and the second banning human reproductive cloning only (see October newsletter). Now, total ban supporters have stepped back from trying to force a decision at this time. As a compromise, deliberations will resume on the text of a treaty sometime next year rather than in 2005. However, it is unclear whether any consensus will ever be reached. The UK stands firm in its support of the potential benefits of treatments using cloned early embryo cells. The US, on the other hand, has reaffirmed its support for the total ban on cloning. Advocates on both sides agree a compromise between these positions is unlikely

Lawmakers in the US have approved language added to an appropriations bill to ban patenting of human organisms while not interfering with stem cell research. Once approved, the amendment will codify into US national policy, for the first time, a position on human patenting. The ban will cover genetically engineered human embryos, fetuses, and human beings, but will not affect patents on genes, cells, tissue and other biological products as well as process patents.

The approved language is a clarification of an earlier amendment that would have simply banned patents on ‘human organisms.’ Critics claimed that the term ‘organism’ could be broadly interpreted to include a ban on products derived from embryos, such as embryonic stem cells. They feared that the inability to secure patents could reduce their appeal to the commercial sector and thus stifle research investment. New language was added to make clear that the ban would not inhibit stem cell research.

The fight has been intense. Supporters of stem cell research have claimed that this legislation is part of a process, directed by conservative members, aimed at giving embryos human rights, according to the Washington Post. Conservatives claimed, in turn, that the industry wants to have the option to patent embryos, an ‘offensive and unacceptable level of commodification of human life.’ Now an agreement has been reached that seems to satisfy both parties. The bill is waiting for Congressional approval and will then go to the President for his signature.

Hereditary hemochromatosis (HHC) is a recessive genetic disorder in which inappropriately high levels of iron are absorbed in the gut, causing excessive iron storage in organs such as the liver. Without treatment, hepatic cirrhosis and other serious conditions including diabetes, cardiomyopathy and arthritis may occur from the age of around 40 onwards. Routine venesection (blood-letting) to maintain appropriate serum iron levels is a simple yet effective means by which to prevent these complications.The majority of people with hereditary haemochromatosis are homozygous for the C282Y mutation in the HFE (haemochromatosis) gene. In the UK, C282Y homozygotes comprise over 90% of affected individuals, and 1 in 150 of the general population; the disease shows relatively low penetrance, and many homozygotes never develop clinical symptoms. Early diagnosis and pre-symptomatic treatment can prevent all potential complications of hemochromatosis, but there is no way of identifying which individuals with the mutation are likely to develop symptoms. Population screening for HHC has been proposed in the UK, due to the high prevalence of the mutant allele coupled with the low cost and high efficacy of early diagnosis and treatment compared with that for late stage diagnosis. However, opponents cite the low penetrance and unpredictablity of the clinical genotype as arguments against population based screening.

A publication in the Lancet reports on an assessment of the uptake of screening by first-degree relatives of two groups, C282Y homozygotes identified by genetic screening of blood donors, and patients presenting clinically with haemochromatosis [McCune et al., 2003, Lancet 362, 1897-98]. They found that whilst 53% of relatives of haemochromatosis patients had previously been screened, only 24% of the relatives of non-symptomatic blood donors had been tested. The authors conclude that the absence of a relative affected by clinically apparent haemochromatosis apparently reduced motivation for relatives to avail themselves of screening, despite the provision of information about the disease and the risk to family members. They note that: “the possibility of a muted response from high-risk family members has not been considered in the debate about population screening”.

Following interview, 99% of relatives of the non-symptomatic C282Y homozygotes opted to be tested for the mutation, leading to the identification of 25 C282Y homozygotes of which ten showed raised serum iron levels. All previously untested relatives of the clinical proband C282Y homozygotes asked to be tested, and 34 were found to be C282Y homozygotes; 20 of these had raised serum iron levels. The authors note that the original uptake of screening by the relatives of clinical cases, whilst substantially higher than that by the relatives of blood donors, is nevertheless unsatisfactory, and point to the success of their proactive approach to offering counselling and testing in raising uptake. They conclude that previous calculations that have claimed screening for HHCis cost effective have assumed a much greater rate of uptake by relatives than was observed in this study. Although a proactive approach can substantially improve uptake, this has associated cost implications that would need to be taken into account in any calculation of cost-benefit. Moreover, given the relatively low uptake of screening among even relatives of individuals diagnosed with clinical haemochromatosis, the probable degree of compliance in population screening programmes (and hence their efficacy) is called into question.

Comment: This study makes an important contribution to the debate over optimal strategies for HHC population screening. Clearly, there is scope for considerable improvement of uptake in the context of cascade (familial) screening of the relatives of clinical patients, and it seems that active recruitment, counselling and the provision of detailed information can facilitate such an improvement. Although an approach such as this is obviously desirable, it would necessitate a substantial input of resources. However, the economic implications of undiagnosed C282Y homozygotes who may go on to develop clinical disease must also be taken into consideration.

Researchers in the US have identified a gene involved in a familial form of cardiovascular disease. A specific mutation in the MEF2A gene was shown to have a direct causal effect on the incidence of coronary artery disease (CAD) and heart attacks in a single large family with a history of CAD. Multiple risk factors for CAD and myocardial infarction (heart attack) have been identified, including obesity, hypertension and hypercholesterolemia, smoking and diabetes. Family history of the disease is also a known risk factor, but no specific associated genes have previously been identified, although chromosomal susceptibility loci have been reported from genetic studies. A paper in the latest edition of Science reports on genome-wide linkage analysis of thirteen members of a single family with an autosomal dominant pattern of CAD [Wang, L. et al. (2003) Science 302, 1578-1581]. Significant disease linkage was found with a locus on chromosome 15, a region that included a candidate causative gene, MEF2A, which encodes a transcription factor. Systematic DNA sequence analysis of the gene from each of the family members identified a specific 21 base-pair deletion in all affected individuals. This deletion was absent in unaffected members of the same family, and in over 100 control individuals with no evidence of CAD, suggesting that the deletion was the cause of CAD in the study family.

The seven amino acid deletion was found to prevent normal nuclear localisation of MEF2A, and to reduce the transcriptional activity of the protein to a third of wild-type levels. MEF2A is thought to play an important role in vascular endothelial cell development and function; the mutation may result in an abnormal vascular endothelium, which in turn could increase susceptibility to the formation of atherosclerotic plaques and hence to cardiovascular disease. Three additional large families with a history of CAD and MI were not found to show any genetic linkage between disease and the locus on chromosome 15, nor were any MEF2A mutations identified in 50 patients with non-familial cases of CAD and mycocardial infarction. The authors therefore propose that MEF2A mutations may be a rare cause of the disease, although large-scale association studies will be required to determine the actual prevalence of such mutations in general cardiovascular disease patient populations. They also suggest that the MEF2A signalling pathway and other genes regulating endothelial development and function may prove to be involved in the pathogenesis of CVD.

Comment: These results may prove to be highly significant to understanding genetic factors that underlie cardiovascular disease and the pathogenic process; however, they may also prove to have little or no relevance to the majority of familial or sporadic cases, as the gene deletion in question may be specific to the study family. Further studies will be required to determine whether MEF2A or additional genes related to vascular endothelial function are important for CVD in general.

A report published by researchers from the California-based company Celera Diagnostics and Cornell University in the latest edition of Science compares equivalent chimpanzee, human and mouse genes [Clark et al. (2003) Science 302, 1960-1963]. The chimpanzee and human genomes share over 99% sequence identity, so regions of variation between these two genomes can help to identify biologically important species differences. More than 7500 chimpanzee gene sequences were aligned with the orthologous human sequences in order to identify genetic differences. These alignments were then compared with the corresponding murine sequences, in order to identify evolutionary changes that occurred since the human and chimp ancestral lineages diverged more than five million years ago.

Evolutionary genetic changes (resulting from processes of natural selection) were defined as those showing significantly more rapid alteration than would be expected from normal rates of random mutation alone; over 1500 genes were classified as showing evidence of this ‘accelerated evolution’. In humans, these included genes involved in smell, sensory perception, hearing and digestion; in chimps, genes for skeletal structure. The authors postulate that differences in life-style between chimps and humans may have created divergent positive selection pressures on these genes; for instance, it is suggested that development of hearing acuity may have been necessary for humans for the comprehension of complex spoken language. Of note, genes known to underlie human Mendelian genetic disorders also showed accelerated evolution in the human lineage (as defined by those present in the Online Mendelian Inheritance in Man (OMIM) catalogue of genes associated with genetic disease). Human genes that have diverged from the common ancestral human and chimp genome may therefore represent a valuable resource for identifying novel disease associated genes. Interestingly, the gene showing the most marked degree of positive selection in humans is that for tectorin-alpha, a component of the inner ear membrane; mutations in the TECTA gene are associated with dominant and recessive familial forms of hearing loss.

Comment: This publication represents an initial attempt to use comparative genomic analysis to identify the genetic basis of the differences between humans and our closest relatives, chimpanzees. Comparison of the human and chimp genes with a more closely related genome than the mouse (for example, that of another great ape species) might lead to the identification of more key genes that distinguish humans from chimps, but as yet no other great ape genomes have been sequenced. Previous studies have also suggested that the major differences between the two species relate to altered gene regulation as opposed to variations in genes themselves.