In the news

PHGU partner organisation PHGEN (the Public Health Genomics European Network) has launched a new website outlining key activities and updates.

One of the key functions of PHGEN is to help develop and coordinate activities associated with public health genetics among EU Member States (see previous news). As part of this, the first meetings of PHGEN National Task Forces (NTFs) have taken place in Turkey and Italy; NTFs are also being established in other countries. The National Task Forces are intended to establish public health genomics within the public health and healthcare systems in specific countries.

Brief reports from the meetings in Ankara, Turkey (June 2006) and Rome, Italy (July 2006) are available from the PHGEN website. The Turkish meeting concluded that a background policy document should be prepared by the Task Force, in consultation with stakeholders, along with an inventory of people and institutions working in areas related to public health genomics. The Italian Task Force (NTF) decided that it was vital to establish discourse on Public Health Genomics, starting with working groups and courses in the national scientific societies of public health and genetics; they also resolved to produce an overview of regional guidelines that could inform development of national practice guidelines for public health genetics.

The Human Fertilisation and Embryology Authority (HFEA) has issued a license to the North East England Stem Cell Institute in Newcastle to allow researchers to ask women undergoing fertility treatment to donate eggs for research purposes in exchange for having the cost of their treatment reduced (see BBC news report). This will be the first time women have in effect been paid for their IVF eggs. The researchers investigate stem cell therapies for conditions such as Alzheimer’s disease, diabetes and Parkinson’s. Previously they have had permission to ask women to use their extra IVF eggs, if the women had produced 12 or more during treatment, but this strategy had not yielded sufficient eggs for their research needs. They hope that this license will provide more opportunities to collect eggs but they will not be able to start their plans immediately as they now have to apply for and receive funding. The HFEA had previously signalled its willingness to consider egg-sharing schemes (see news story).

As this license is recognised to be controversial, the HFEA has also announced that they will launch a full consultation on issues surrounding the donation of eggs for research purposes in the autumn. The consultation will examine the potential medical risks to women donating solely for research, the consent process, whether this newest scheme will impact the supply of eggs available for treatment, how the regulatory system would work to protect women from possible coercion to donate and whether the way in which the eggs were procured would impact how any successful research results could be used internationally, especially the use of any stem cell lines derived from those eggs.

Some critics question whether this latest license is in conflict with the tradition of altruistic giving and whether women will feel coerced to donate. Proponents say it will help in the goal to produce stem cell therapies to help the ill and disabled. The consultation is expected to be launched in September and last until November.   Any guidance and new regulatory measures resulting from the consultation process will be issued in Spring 2007.

The European Competitiveness (Internal market, Industry and Research) Council has met, in an extraordinary meeting, to debate the proposed Seventh Framework programme (FP7) and, by a majority, has reached an agreement to support the draft FP7 proposal. One of the main issues halting progress of the proposal was whether or not embryonic stem cell research should be funded under FP7. The European Commission and the European Parliament had reached an agreement that FP7 would be funded under, following the same strict rules as had been created for the FP6 programme (see news story). With some clarifications, the Council has now also agreed on that compromise position.

As with FP6, three categories of human embryonic research will be excluded from FP7: research into human cloning, research that would result in the modification of the germ-line (thus making changes hereditable), and the creation of embryos solely for research purposes or for the derivation of stem cells. FP7 will not fund the research step where the embryo is destroyed (the procurement phase), but down-stream research will be considered under strict controls. No activity will be funded that is forbidden in all Member States. Research proposals will only be considered for funding from Member States where the research is legal. All research proposals involving embryonic stem cells must undergo local or national ethics review, scientific review that proves that the use of human embryonic stem cells is necessary, and an ethics review at the European Commission level. Only if the proposal passes all of these reviews will it be presented to the European Commission’s Regulatory Committee for review and possible approval. Each proposal will be considered on a case-by-case basis. According to Commissioner Janez Potoènik, the proposals that have been funded under FP6 would also have been funded under today’s agreement. Nothing substantial has been changed from the FP6 method of working; these debates have served as clarification.

The FP7 proposal now will be returned to the European Parliament for its second reading, tentatively scheduled for November. Commissioners are hopeful that the FP7 proposal will be approved this year so that funding can begin in early 2007. Additionally, Commission Potoènik noted that the European Commission is committed to the creation of a European stem cell registry which could help negate the need to duplicate embryonic stem cell lines.

The US Congress’ attempt to pass legislation to loosen federal restrictions on embryonic stem cell research has failed (see newspaper article). The current law states that researchers can only apply for federal funding to conduct experiments using embryonic stem cell lines created before 9 August 2001. As this field has progressed, researchers have found that those limited number cell lines were inadequate. To compensate, states like California have passed laws to allow state funds to be used for research; other researchers have found private funding in order to bypass the federal restrictions. But in the last year lawmakers, seeing the US fall behind in this field, have moved to revise the federal regulations on stem cell research. In May 2005 the US House of Representatives passed a bill, HR 810, “To amend the Public Health Service Act to provide for human embryonic stem cell research.” (see news story). That bill allows researchers to apply for federal money to conduct research using embryos provided that the embryos were created in the course of fertility treatment, were excess to needs and were scheduled to be destroyed, and that the embryo donors had given their informed consent. It was sent to the US Senate in 2005, but has taken over a year to come to a vote. Senate leaders who support embryo research did garner a sufficient number of votes to pass the measure on 18 July. However, President Bush on 19 July issued his first veto of his presidency and rejected the bill. The House of Representatives rapidly voted 235 to 193 to attempt to override the veto, but did not get the two-thirds majority needed.

President Bush had consistently stated that he would not sign this piece of legislation into law. In a White House ceremony he said it “…crosses a moral boundary that our decent society needs to respect.” He praised women who had ‘adopted’ embryos and brought them to term. Opposing House and Senate leaders argue that most of the approximately 400,000 embryos awaiting destruction will not be adopted by childless couples and should be used for medical research to help sick and disabled rather than being discarded. This issue is expected now to be used by both parties in the upcoming mid-term elections. Public opinion polls show there is wide spread support for embryonic stem cell research and Democrats have predicted that voters will not re-elect those who voted against the bill.

The President has signed into law another measure passed by both the House and Senate. This bill bans the creation of human foetuses for the sole purpose of harvesting their organs. The President is also expected to sign a third bill, which has not as yet reached his desk, that promotes the creation of pluripotent stem cells lines using techniques that will not ‘knowingly’ harm embryos.

OECD seeks comments on draft genetic testing quality assurance guidelines

The Organisation for Economic Co-operation and Development (OECD) is seeking comments on its draft Guidelines for Quality Assurance in Molecular Genetic Testing (see press release). The Guidelines set out principles and best practice for quality assurance in molecular genetic testing for clinical purposes. Specifically, they address diagnostic and carrier testing, as well as genetic testing to predict a person’s response to a drug or course of therapy (i.e. pharmacogenetic testing). The goal of the guidelines is to introduce procedures and best practice to ensure minimum international requirements for QA systems and laboratory practices across OECD countries, to facility mutual recognition of existing national or regional QA frameworks, strengthen international co-operation when testing and test information crosses borders and increase public confidence in the governance of molecular genetic testing.

In 2002 the OECD conducted a survey on the availability and extent of molecular genetic testing in the OECD member countries, as well as the quality assurance practices used in testing laboratories. Eighteen countries participated; a summary report was published in 2005 (see news story). The survey found that there has been a steady growth in molecular genetic testing and many countries had mechanisms in place to reduce risk from inappropriate or inaccurate testing, including licensing, accreditation and certification procedures. However, the OECD has determined that “…these regulatory and oversight procedures have not penetrated diagnostic molecular genetic testing laboratories across OECD countries to a high degree and with any consistency.” Therefore, “[a]s laboratories increasingly provide their services to both national and international customers, there is a need to develop international consensus and best practice to assure consistency in the quality of services available.” The draft Guidelines set out general principles and practices for molecular genetic testing and more specific recommendations for best practice for quality assurance systems, the monitoring of laboratory practices, quality reporting procedures, and the education and training of laboratory personnel.

Comments on the draft Guidelines are encouraged. The consultation is open until 4 September 2006. The OECD Member States will consider all comments during their final negotiations. The final Guidelines are due to be available in Spring 2007.

DH consults on Regulations to implement EU Tissue and Cells Directive

The Department of Health (DH) has opened a public consultation on two sets of draft Regulations that will, when finalised, implement provisions of the EU Tissue and Cells Directive into UK law. The Directive sets out the standards for the quality and safety of the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells. It covers tissues such as bone marrow, umbilical cord blood, sperm, eggs, embryos, bone and heart valves. It excludes blood, blood products and organs, which are covered by other EU legislation. The Directive came into force in April 2004 and was to be fully implemented into UK law by 7 April 2006. Completing this process has been delayed due to the fact that the Directive is dependent on two technical Directives being created by the European Commission. The first of these two technical Directives, Directive 2006/17/EC, covers donation, procurement and testing of human tissue and cells. The second will cover traceability, coding, processing, preservation, storage, distribution and the notification of severe adverse events. It is still being drafted, but it is expected to be published in late summer 2006.

In the UK, the Human Tissue Authority (HTA) and Human Fertilisation and Embryology Authority (HFEA) act as the competent authorities for the EU Tissue and Cells Directive. The HFEA licences and monitors centres that conduct in vitro fertilisation, donor insemination and embryo research. The HTA regulates the removal, storage, use and disposal of human bodies, organs and tissue from the living and deceased (other than gametes and embryos which are covered by the HFEA). There are plans for the HTA and the HFEA to merge to form the Regulatory Authority for Tissue and Embryos in 2008. In the meantime, the HTA and HFEA will implement the provisions in the tissues and cells Directives.

The DH has decided to transpose the three Directives through two sets of Regulations that will amend the Human Tissue Act 2004 and the Human Fertilisation and Embryology (HFE) Act 1990. As the HFE Act already regulates the licensing and storage of human gametes and embryos, the draft Human Fertilisation and Embryology Act 1990 Amendment Regulations 2006 will bring the existing standards for establishments that handle gametes and embryos in line with the requirements of the Directives. For example, the consultation document for this Regulation states that requirements will be set for “…the environmental standards required of premises, use of appropriate equipment and practices, introduction of documented quality control systems and the qualification and experience required of staff.” Establishments that were not previously subject to regulation, such as those that conduct artificial insemination using a couple’s own gametes, will now come under the HFE Act 1990. The draft Human Tissue (Quality and Safety for Human Application) Regulations 2006 include requirements for the licensing of establishments that handle human tissue, other than gametes and embryos. The storage and preservation and import and export (outside the European Economic Area) of tissues and cells for human application constitute activities that will require a license. The European Economic Area currently includes the European Union, the 25 Member States, Norway, Iceland and Liechtenstein.

The consultation is open until 13 October 2006. Information on how to submit responses is available on the DH website.

Alison Hall assisted with this news article.

The Eurobarometer 2005 survey shows that there is widespread public support for medical (red) and industrial (white) biotechnologies, while there is opposition in most European countries to agricultural (green) biotechnologes, such as genetically-modified (GM) food (see news article). The survey, taken approximately every 2-3 years, is based on a representative sample of 25,000, approximately 1,000 people in every Member State. It seeks to paint “a portrait of European citizens” that can be used in policy discussions.

That portrait shows that, in comparison to earlier surveys, European citizens are “more optimistic about technology, more informed and more trusting of the biotechnology system.” The European public is not risk-adverse towards technological innovations that are seen to promise tangible benefits.” There is support for the development of nanotechnologies, pharmacogenetics and gene therapy, as these are seen as “both useful and morally acceptable.” There is also interest in more research into the risks and benefits of stem cell research, provided that there are tight regulations in place. Bio-fuels, bio-plastics and bio-plants for pharmaceuticals are supported. A majority of those surveyed said that they would pay more for a car that runs on bio-fuels. There is general, but not overwhelming, support for the use of genetic data for personal medical diagnosis and of gene banks for research. Equally, there is support for forensic uses of DNA, but most people oppose the use of genetic data by insurers or for governmental reasons such as social security.

The exception to this general level of support for biotechnology is GM food, as a majority of those surveyed see it as “not being useful, as morally unacceptable and as a risk for society.” When comparing European views with those of people in the US and Canada, there are some differences of opinion. Europeans are as optimistic about computers, IT, biotechnology and nanotechnology as those in North America. But Europeans and Canadians have similar views on GM food, while Americans see this technology as beneficial and less risky.

A new international collaborative project is to search for key genetic variants that determine indviduals’ response to infection by HIV, human immunodeficiency virus. Researchers at Duke University in the US will lead a consortium of American, European and Australian scientists, supported by the Center for HIV/AIDS Vaccine Immunology (CHAVI). The EuroCHAVI project will recruit 600 patients from nine cohorts and seek to identify common genes that affect immune responses to HIV using advanced technologies for genetic analysis. By identifying links between certain types of response and specific haplotypes, key genetic variants involved in these responses may be distinguished. This project is an undertaking made possible by the creation of the human haplotype map or HapMap, a catalogue of sets of single nucleotide polymorphisms (SNPs) representing key sites of genetic variation between human individuals.

Individuals exposed to HIV show considerable variation in terms of the immune response mounted against the virus, which affects the timing and progression to AIDS. A minority show a high degree of resistance to infection, and a few genetic variants (such as the CCR5 delta32 mutation) have been identified that confer some measure of innate resistance. By studying the nature of different responses to HIV and the genetic factors underlying this variation, researchers hope to find a way of creating a vaccine that would stimulate appropriate, protective immune responses against the virus. CHAVI also plans to extend the same genetic analyses used in the EuroCHAVI project to a larger, African cohort of HIV-infected patients.

Director of CHAVI's host genetics research core David Goldstein said: "We intend to use natural genetic differences among people to point the way toward the most promising avenues for vaccine development", adding that: "the prospects are very real for getting answers by next year" (see press release). Director of the Duke Institute for Genome Sciences & Policy Huntingdon Willard commented: "Large-scale genome analyses like this are critical for determining the role of the genome in complex diseases such as AIDS…The combination of large population cohorts and state-of-the-art genome technology will allow us to dissect the genetic factors that contribute to disease".

A new paper by members of the Public Health Genetics Unit in Cambridge provides a meta‑analysis of the relative risks of developing colorectal cancer among individuals with a family history of the disease, produced by a systematic review of published literature on familial colorectal cancer risk [Butterworth et al. (2006) Eur J Cancer 42(2), 216-27].

As noted in the previous journal club piece, identification of individuals at high risk of colorectal cancer is important for offering appropriate surveillance measures and preventative interventions, to reduce the risk of developing serious disease. The first stage in locating people with inherited predisposition to colorectal cancer is by their family history, and Butterworth and colleagues found a substantial body of epidemiological data on the links between family history and disease risk in colorectal cancer. Using this information, they calculated pooled estimates of relative risk for different categories of family history, and converted these figures into measures of absolute, lifetime risk using life tables; a commentary in The Lancet proposes that absolute risk is a more easily comprehensible and hence useful concept for most people [Hakama M (2006) Lancet 368(9530), 101-103].

Risk estimates were affected by the age of the individual in question, but in brief, they found that the lifetime risk of colorectal cancer for a 50 year old with at least one affected first-degree relative was 3.4%, rising to 6.9% for those with at least two affected first-degree relatives, compared with a population level lifetime risk of 1.8%. That is, risk almost doubles if a close relative has had colorectal cancer and doubles again if at least two relatives have been affected. The authors note that although this study did not attempt to assess the relative contributions of genetic and shared environmental factors in contributing to familial risk, previous evidence has suggested that as yet unidentified hereditary factors are likely to play a significant role.

Comment: A well-constructed and performed meta-analysis such as that of Butterworth et al. provides a useful estimate of colorectal cancer risk based on family history that is much more reliable and robust than estimates produced by individual studies. This information, which includes risk curves showing an individual’s ten-year, twenty-year or lifetime risk with age, stratified by family history category, is a valuable tool for determining risk and directing clinical management.

Colorectal cancers are the third most common form of cancer (around 35,000 cases annually) and the second leading cause of cancer deaths (around 16,000 cases annually) in the UK. Although most colorectal cancers occur in individuals with no significant family history of the disease, a small proportion of these are familial cancers. Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch Syndrome, is the most common of these, representing 1-5% of all cases. A recent paper in the New England Journal of Medicine presents a new approach to the identification of colorectal cancer patients with HNPCC [Barnetson et al. (2006) NEJM 354(26), 2751-2763]. Finding cases of familial colorectal cancer is important because it allows the identification of affected family members at high risk of the disease; increased levels of surveillance or preventative interventions in this group greatly decrease the mortality rates.

HNPCC is caused by mutations in specific DNA mismatch repair (MMR) genes. Identification of these mutations is a time-consuming and expensive process, and inappropriate for unselected colorectal cancer patients. Instead, specific clinical criteria (the Amsterdam criteria and Bethesda guidelines) are applied to identify those at increased risk, and this stratification, combined with molecular testing techniques, is used to determine which patients should be referred for genetic testing, and which genes should be analysed. Barnetson and colleagues present a new predictive algorithm said to be more effective than the current criteria, which can be used in combination with molecular testing to identify patients who should receive genetic testing for HNPCC. The model was developed using data from a moderate sized cohort of 870 colorectal cancer patients under the age of 55, who were tested for mutations in three key MMR genes. 38 such mutations were identified, representing 4.4% of the cases.

Comment: The new approach to assessing the probability of an underlying familial MMR gene mutation being present in a colorectal cancer patient represents a potentially useful addition to the techniques already in use to identify HNPCC, but there are further complications that need to be considered too, such as the cases caused by rarer mutations in additional genes, and the limitations of genetic testing. However, all moves towards improving the rate of identification of HNPCC are valuable in terms of prevention of further familial cases.

Clarifying the mechanics of DNA strand exchange in meiotic recombination. Neale MJ and Keeney S (2006) Nature 442(7099), 153-8. Review (PubMed).

Gene regulation: a finger on the mark. Becker PB (2006) Nature 442(7098), 31-2. News and views piece on current understanding of how chromatin (DNA packaged with histone proteins in the cells) is involved in the regulation of gene expression (PubMed).

Advances in genetics: what are the benefits for patients? Munnich A (2006) J Med Genet. 43(7), 555-6. Commentary on the current and future impact of technological advances on improving treatment for genetic diseases, particularly monogenic diseases (PubMed)

Oesophageal atresia, tracheo-oesophageal fistula, and the VACTERL association: review of genetics and epidemiology. Shaw-Smith C (2006) J Med Genet. 43(7), 545-54. Review (PubMed).

Family history in colorectal cancer surveillance strategies. Hakama M (2006) Lancet 368(9530), 101-3. Discussion (PubMed). See also corresponding journal club article.

Evolutionary Genetics: Is brain evolution still continuing in modern humans? Stern Rand Woods CG (2006) Eur J Hum Genet. 14(7), 799-800. Commentary on the controversy aroused by recent papers proposing that novel haplotypes of the microcephalin and ASPM genes may be involved in determination of cognitive traits, and that the relatively recent appearance of these haplotypes may mean that the brain is continuing to evolve (PubMed).

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Pink, parkin and the brain. Pallanck L and Greenamyre JT (2006) Nature 441, 1058. News and views piece on mutations in the PINK1 gene and their role in Parkinson’s disease (PubMed).

Mitochondrial disease. Schiapira AHV (2006) Lancet 368, 70-82. Review of recent advances in the understanding of diseases associated with mitochondrial defects, including genotype-phenotype correlations, inheritance and penetrance, and prospects for accurate genetic counselling and the development of novel therapies.

Statistical false positive or true disease pathway? Todd JA (2006) Nat Genet. 38(7), 731-733. Commentary on how new collaborative approaches combined with well-designed epidemiological studies may at last be yielding genuine disease-gene associations (PubMed).

CIMPle origin for promoter hypermethylation in colorectal cancer? Schuebel K, Chen W and Baylin SB (2006) Nat Genet. 38(7), 738-40. News and views article on the role of promoter CpG island DNA methylation in colorectal cancer (PubMed).

GATA1s goes germline. Mundschau G and Crispino J (2006) Nat Genet. 38(7), 741-2. News and views article on a recent study showing that inherited GATA1 mutations cause defects in multiple hematopoietic cell lines (PubMed).

If it's not one thing, it's another. Paulson HL (2006) Nat Genet. 38(7), 743-4. News and views article on new evidence that spinocerebellar ataxia type 8 may be caused via two distinct molecular mechanisms arising from transcription in opposite directions from a CTG/CAG repeat expansion (PubMed).

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