News

28 September 2007The Nuffield Council on Bioethics last week released its most recent Report entitled The forensic use of bioinformation: ethical issues. Following its public consultation on the subject last year (see previous news), the Council deals with the central questions of police powers in Britain to obtain biological evidence, to retain it, and to search databases (primarily the UK National DNA Database) for various purposes. The Report is confined to the discrete issues of fingerprinting and DNA in the context of criminal justice as a means of addressing current controversies about the proper balance between police powers and individual rights to liberty, autonomy and privacy.

The Council concludes that while the need to fight crime justifies the use of biological evidence, effective governance and regulation are essential. Importantly, it asserts that ‘the establishment of a population-wide forensic DNA database cannot be justified at the current time’, on the basis that the costs, both economic and in terms of intrusion to privacy, outweigh the potential benefits. It finds, however, that the authority to take and retain fingerprints and biological samples without consent is warranted where individuals are arrested on suspicion of involvement of serious violent or sexual offences. Where the alleged offences are minor, or individuals are not ultimately charged or convicted, the Council cautions against taking and storing of DNA without consent. Further, it recommends that samples of DNA provided in such circumstances be removable from the national database upon request, and that DNA from children should not be retained without good reason.

As with any genetic information, it is noted that the full extent and implications of the information provided by DNA samples are not well understood by all audiences. The Report recommends that legal professionals and juries should receive more guidance to assist their understanding of the meaning of DNA evidence, and that the police should not routinely seek ‘ethnic inferences’ from DNA analysis.

Finally, the Council makes a strong recommendation in favour of the institution of a statutory basis for the regulation of forensic databases and retained biological samples. The regulatory framework should, it suggests, delegate specific powers for the oversight of research and requests for access to an appropriate independent body or official.

28 September 2007The UK’s Human Genetics Commission, which advises the Government on scientific advances in genetics, and in particular on their ethical, legal and social implications, has published its response to the Discrimination Law Review’s consultation on proposals for a Single Equality Bill for Great Britain (see previous news article). In its response the HGC calls for comprehensive legal protection against ‘discrimination on any genetic grounds’ – a recommendation that goes far beyond the question asked in the consultation document, which refers only to the “discrimination on the grounds of genetic predisposition to disease”.

The HGC rejects the Discrimination Law Review’s suggestion that there is little evidence of a current problem, presenting an Appendix listing anecdotal reports of alleged ‘genetic discrimination’ in the UK and elsewhere. The examples presented cover a broad range of situations including prejudice against people with diagnosed genetic conditions, inappropriate applications of DNA tests, unjustified use of family history information, and social stigmatisation of families affected by highly penetrant genetic disease. The HGC notes that clinicians report that people are reluctant to take DNA tests that may be important for their health, because of fears that test results may be used to their disadvantage by third parties such as employers or insurance companies. Genetics researchers also encounter the twin difficulties of extremely burdensome regulation to protect research participants’ privacy and autonomy, while at the same time being unable to foresee all possible future uses of DNA sequence data or to guarantee its complete security; the suggestion is that legislation to outlaw genetic discrimination would remove both of these problems. The HGC believes that “opportunities for genetic discrimination will increase” as knowledge and technology advance, justifying pre-emptive legislation.

Any legislation outlawing ‘genetic discrimination’ or ‘discrimination on any genetic grounds’ would have to define the term ‘genetic’. Unfortunately, the HGC’s response is completely silent on this key question. Its discussion covers far more than just DNA-based information, ranging through family history (which integrates both genetic and shared environmental effects), highly penetrant diseases that are predominantly diagnosed by phenotypic features, and weakly penetrant DNA polymorphisms that interact with environmental factors to affect susceptibility to common disease. The only logical conclusion from the HGC’s suggestions is that the proposed legislation should apply to any human trait with a genetic component – in other words to all human characteristics and all ways of measuring or detecting them. It is difficult to see how such a law could be drafted or could operate. Rather than calling for legislation, a more effective approach would be to lobby for resources for the thorough evaluation and appropriate use of all biomedical tests (DNA-based or otherwise), and to champion a more rational and modern understanding of genetics. These arguments are developed more fully in the PHG Foundation’s response to the Discrimination Law Review’s consultation.

26 September 2007BBC News Online has reported the launch of a gene expression test that could improve the accuracy of the diagnosis of prostate cancer. Currently, a blood test is available that detects raised levels of a protein called prostate serum antigen (PSA); men with a high PSA score may be offered a prostate biopsy to determine whether cancerous cells are present in the prostate. The problem is that the PSA test has relatively poor specificity and positive predictive value, limiting its clinical value. For every 100 men with elevated blood levels of PSA, only about 30 subsequently have a positive biopsy. Management of these patients is then difficult, as they may have to undergo repeated painful and distressing biopsies despite never developing the disease.

A company called Gen-Probe has developed a more accurate, non-invasive test based on measuring expression levels of a gene called PCA3 in a urine sample. The PCA3 gene is over-expressed in about 95% of prostate cancers. The Progensa PCA3 test reportedly has substantially better specificity and positive predictive values than the PSA test but, at £200 per test compared with £10 for the PSA test, is unlikely to be adopted for routine use in the NHS. A Horizon Scanning Technology Briefing Paper produced by the National Horizon Scanning Centre at the University of Birmingham in December 2006 summarises the characteristics of the PCA3 test and suggests that it may prove useful in men who have raised PSA levels but a negative prostate biopsy (thus potentially sparing them repeated biopsies) or in men with slightly raised PSA levels or other clinical symptoms that suggest the possibility of prostate cancer.  

26 September 2007In the last few months, multiple genome-wide association (GWA) studies have been published showing the basis of genetic susceptibility to numerous rare chronic diseases, including multiple sclerosis [International Multiple Sclerosis Consortium (2007), NEJM 357(9);851-862], sporadic amyotrophic lateral sclerosis [Dunckley T et al. (2007) NEJM 357(8): 775-788], Crohn’s disease [Raelson JV et al. PNAS (2007) 104(37): 14747-14752], rheumatoid arthritis [Plenge RM et al. NEJM (2007) 357(12):1199-1209] and restless legs syndrome [Winkelmann J  et al. (2007) Nat Genet 39(8): 1000-1006].

Over the same time period, GWA studies were also published on more common diseases including cardiovascular disease, several cancers and both type 1 and 2 diabetes. Indeed, an entire supplementary issue of the open access journal BMC Medical Genetics was dedicated to genome-wide scans in the Framingham heart study. With advances in sequencing technologies and the increasing availability of fast and accurate sequencing machines, we can expect to see a rising number GWA studies uncovering ever more subtle genetic effects. As the sheer volume of data from GWA studies increases, databases are being set up to provide a public repository for all types of data describing the interaction between genotype and phenotype. Already in existence is the Genotype and Phenotype (dbGaP) database run by the National Centre for Biotechnology Information (NCBI) in the United States, inside which data from a number of reports including the Framingham heart study is already housed. A new initiative to create a European Genotype Archive (EGA) is also currently underway at the European Bioinformatics Institute (EBI) in the UK.

Amongst studies of diverse populations and seemingly unconnected diseases, some common themes are starting to emerge. For example, the association between autoimmune diseases and the major histocompatibility complex (the human leukocyte antigen system), which plays an integral role in the immune system, is now well established for multiple disorders. An increasing number of autoimmune diseases are also associated with variants in one or more of the interleukin receptors, which are activated by cytokines released by white blood cells as a means of communication. The identification of genetic similarities that underpin susceptibility to different but related disorders underlines the power of genome-wide association studies to identify low penetrance, causal variants of complex disease.

However, such associations can be difficult to demonstrate due to the low penetrance and often low prevalence of most causal genetic variants associated with complex diseases. The effect of any given allele is generally very small and can only be verified through huge datasets, independent studies and robust meta-analyses. For example, a small but significant association between the interleukin-7 receptor and multiple sclerosis has been confirmed through the combined data from three independent studies involving over 17,000 subjects. [The International Multiple Sclerosis Consortium (2007), NEJM 357(9);851-862; Gregory SG et al (2007), Nature Genetics 39(9): 1083-1091; Lundmark F et al (2007) Nature Genetics 39(9): 1108-1113].

But even when statistical significance can be proven from extensive and repeated GWA studies, predicting individual risk from population data is complicated. The complex, non-linear nature of gene-gene and gene-environment interactions, as well as the small contributory effect of each individual allele, means that single gene associations will rarely provide the whole picture. However, although the increased risk associated with each locus may be small, knowledge of multiple risk alleles throughout the genome should ultimately allow the identification of individuals who have a significantly increased risk of certain diseases. It remains to be seen whether population stratification by global genetic risk for specific diseases will eventually allow us to target interventions at those who will benefit the most.

25 September 2007Just a month after the label for the blood-thinning drug warfarin was updated to explain that genetic variation in specific genes influences how patients respond to the drug (see previous news article), the US Food and Drug Agency (FDA) has approved the first genetic test for warfarin sensitivity.

Warfarin is the most widely used anti-coagulant medication in the world, prescribed to over 2 million people a year to prevent blood clots, heart attacks and strokes. Patients can display markedly different responses to the drug, so doses vary enormously between individuals. Achieving the correct dose is critical, as patients who receive too high a dose are at risk of severe bleeding, whilst those who receive too low a dose may remain at risk of life-threatening blood clots.

The Nanosphere Verigene Metabolism Nucleic Acids Test detects particular variations in two genes, CYP2C9 and VKORC1, which are involved in the metabolism and mechanism of action of warfarin respectively. Specific variants of these genes are identified from a patient sample by hybridization to sequence specific probes (oligonucleotides) attached to a microarray. These are subsequently detected using the Verigene System which measures light scattering from gold nanospheres tethered to another complementary oligonucleotide. Depending upon the genotype, patients can then divided into slow, fast or normal warfarin metabolisers and their doses adjusted accordingly.

FDA states that it cleared the test based on a broad range of published literature together with the results of a study, conducted by the manufacturer, on hundreds of DNA samples. ‘In a three site study, the test was accurate in all cases where the test yielded a result, although 8% of the tests could not identify which genetic variants were present.’ Although the Nanosphere test is not intended as a stand-alone tool to determine optimum drug dosage but to be used alongside clinical evaluation and other tools to determine the best treatment for patients, this approval underlines the FDA’s ongoing commitment to personalised medicine.

24 September 2007The BBC has reported that a new type of DNA testing “may help prove if people have had their health damaged by exposure to chemicals” (see BBC news). The technique, known as msds1™, involves exposure of DNA samples from a healthy control to the chemicals in question. A distinctive pattern of gene expression, based on which genes or are up-regulated or down-regulated in response to the chemical of interest, is produced and compared with the gene expression profile of the subject under investigation. Certain ‘molecular signatures’ of exposure to specific chemicals or toxins are used to exclude or prove past exposure to the substance or substances of interest. In some cases proteomic profiling (looking at patterns of protein production, as opposed to gene expression) may also be used. The tests have been developed using multiple control individuals of different gender and ethnicity.

The company that developed the test in association with the University of Illinois, The Cytokine Institute, says that this microarray-based technology can: “determine how human cells and their individual DNA respond when exposed to a chemical and its metabolites. By analyzing gene expression and how 36,000 parameters of an individual’s DNA are affected by specific chemical exposures—such as benzene or asbestos—this technology can determine with 99.9% certainty if a person was injuriously exposed to a particular toxin, thereby offering an impartial methodology for providing scientifically-based evidence” (see press release).

The technology is being marketed for use in employee compensation claims for health problems allegedly caused by chemical exposure in the workplace.  It has reportedly been endorsed by the American Bar Association (see Insurance Times article) and admitted as evidence, for both prosecution and defence, in more than twenty legal cases.

Assuming that it is sufficiently rigorous in its ability to discern whether or not cells have been exposed to particular environmental toxins, the test could be a useful evidentiary tool with which to demonstrate chemical exposure and support assertions regarding the potential impact of this exposure on the claimant.  As a health and safety measure, it might also be used to monitor chemicals in the workplace in a manner similar to the current monitoring of employees who handle radioactive substances.  However, in spite of its potential admissibility for certain purposes, the test does not provide conclusive evidence of the timeframe within which the exposure occurred, or that the molecular change correlated with the exposure was a causative factor in the complainant’s health problem.

This test provides an example of one of the wider potential applications of emerging genomic technologies, although it appears to have been developed using cells taken from healthy controls that were subsequently exposed to particular chemicals; the gene expression profiles were then compared with those from test subjects. It is questionable whether experimental exposure of isolated cells is truly comparable with past exposure of cells in the context of a human body, in terms of the resulting gene expression profiles. Ultimately, though, with greater understanding of the highly elaborate interactions in the human body in health and disease, at systemic, cellular and molecular levels, such tests could be used for a range of purposes, including monitoring disease processes and therapeutic effects.

21 September 2007In a rapid response to the previously reported publication by Wald et al proposing population screening of children for FH, familial hypercholesterolaemia (see previous news), Humphries and Hadfield, whilst agreeing that it is desirable to “find more patients with this life- threatening but treatable disorder”, have affirmed some of the potential problems of such an approach, including cost-efficacy and consent [Humphries SE, Hadfield G (2007) BMJ September 14]. They report the results of their recent pilot of cascade testing, funded by the Department of Health, which found that cascade testing was feasible, desirable, cost-effective and acceptable to patients and clinicians. Recommendations based on this pilot are said to be that implementation would require:

• development of a suitable infrastructure to link lipid clinics
• establishment of specialist services for children with FH
• improved awareness of FH in primary care
• DNA testing to underpin the diagnosis of FH in index cases and relatives

Humphries and Hadfield also point out that the National Institute for Health and Clinical Excellence (NICE) are in the process of developing clinical guidelines for the identification and management of patients with FH, due for publication in August 2008.

While they do not dismiss the idea of screening babies, they propose rather that cascade testing from the estimated 15,000 FH patients already attending lipid clinics should be the starting point for increased detection of cases. They also caution that they found the overlap in cholesterol levels between individuals with and without FH to be much greater than that used in the model of Wald et al., which could mean a high rate of false-negative or false-positive results, depending on the cut-off values selected.

21 September 2007The call by UK Health Secretary Alan Johnson for a review of the consent procedures required for organ donation (see BBC news, 20th September) is intriguing as the Human Tissue Authority (HTA), the organisation responsible for regulating organ donation, rejected any review of the law in this area at their public meeting on 6 September 2007 on the basis that consent for organ donation had been thoroughly debated by Parliament when the Human Tissue Bill was scrutinised by Parliament in 2004. Indeed the HTA press release commenting on similar proposals made by the Chief Medical Officer in July pointed to a possible detrimental effect on other areas regulated by the Act stating that ‘the HTA believes that a system of presumed consent for organ transplantation might undermine current provisions in the HT Act for fully informed consent for other purposes, such as body donation for medical science or removal of tissue at autopsies’.

The availability of organs for transplantation is contingent both upon the timing of the removal of organs as well as the consent processes which support donation, and it is part of the statutory remit of the HTA to issue codes of practice relating to various regulatory functions, including a code on the definition of death. The sensitivity of this task is perhaps reflected by the fact that despite assistance from the Academy of Medical Royal Colleges, a final form of the code remains to be published. Recent reports from California of criminal proceedings brought against a transplantation surgeon on the basis of hastening death to procure organs for transplantation, highlights the difficulties of formulating policy in this area.

All this suggests that the procurement of organs for transplantation should not be viewed in isolation. Public trust in the medical profession was severely shaken by the succession of scandals which prompted the implementation of the Human Tissue Act. Indeed the integrated approach to consent which was established by the Act, was commended as a means of rebuilding public trust and as proof of a transition from outdated paternalistic models of medical care. For this reason, any prospective review of the consent model to be used in transplantation should consider not only the advantages and disadvantages of whether everyone in England should be put on the organ donor register unless they opt out, but also the effect such legislation would have on other areas regulated by the Act. The use of human material for research is crucial in developing better health care and effective treatments. If the Government finds a utilitarian approach persuasive in the context of saving the lives of those dying from organ failure, perhaps they should also consider revisiting other areas of the Human Tissue Act where using tissue to save lives is also in the public interest.

19 September 2007The UK Department of Health has joined with UK Biobank in inviting National Health Service (NHS) patients to join the project. Biobank is currently recruiting people aged 40-69 (see previous news) for an initial health assessment and blood and urine sample donation, after which there will be long-term follow-up of their health outcomes. The project is seeking to recruit half a million people from the UK, and to create a unique data resource for researchers to identify key gene-environment interactions that affect health and disease. Professor Sally Davies, Director General of Research and Development at the Department of Health said: "An important part of the Department of Health's work is to stand behind research aimed at tackling important health problems and improving NHS care. Because of its potential for future generations, the government is glad to join with the Wellcome Trust, the Medical Research Council, and others in supporting UK Biobank” (see GovNet news).

A new (and unrelated) tissue bank has recently been established; OnCore UK is a tissue bank which will store blood and tissue samples donated by NHS cancer patients, for use by suitably approved medical research scientists. Chief executive Brian Clark said: "Many patients want to do something to support research into their disease and to help others in the future…OnCore UK can help people with cancer do this by providing them with an accessible and ethically approved way of donating samples and data” (see BBC news). Donors will have to provide informed consent, and although samples will be linked to personal health data, donor anonymity will be maintained.

14 September 2007Scientific publishers in the US are campaigning against calls for publicly funded research to be made freely available to all. The Association of American Publishers has started a new initiative, The Partnership for Research Integrity in Science and Medicine - the PRISM Coalition – whose stated aim is “to educate policy makers and the American people about the risks posed by government intervention in scholarly publishing”.

PRISM is opposed to the open access policy advocated by the National Institutes of Health (NIH), which requires that NIH-funded research be made available via PubMed Central within 12 months of publication. The House of Representatives has passed this in its new budget, while it is under consideration in the Senate.

PRISM argues that the open access approach is damaging to scientific integrity and in particular to the peer review process, and that it amounts to government censorship of science.

Open access supporters dismiss these claims as ridiculous, pointing out that peer review is based almost completely on the voluntary free labour of the research community, and that neither open access journals nor policies alter the process of publication or peer review.

Early reactions to PRISM have been strong, with several commentators calling for a boycott of the association or for academics to resign from editorial boards of journals published by supporters of PRISM. The Association of Research Libraries has issued a briefing which specifically rebuts the claims made by PRISM.

13 September 2007Women aged 21-35 attending the Newcastle Fertility Centre (NFC) in the north of England are to be offered reduced price in vitro fertilisation (IVF) treatment in exchange for donating some of their oocytes (eggs) for research (see BBC news). Women who agree to donate half of the eggs harvested as part of the IVF process will receive a £1500 reduction in the price of their treatment. Researchers from the North East England Stem Cell Institute will use the donated oocytes to generate human embryonic stem cells, which will then be used for medical research.

The Human Fertilisation and Embryology Authority (HFEA) granted a temporary licence to the North East England Stem Cell Institute last year giving them permission to approach women requesting ‘altruistic egg donation’ (see previous news), and followed this with public consultation leading to a decision earlier this year that women should be allowed to donate their eggs for research if they wanted to (see previous news). This decision required that safeguards to prevent possible coercion of women donors be put in place, and did not permit payment of donors, although expenses of up to £250 were permissible.

NFC Head of Department Professor Alison Murdoch pointed out that egg sharing conferred no additional physical risk to the women and said: “We expect this to open the door to some infertile women who may now find it less difficult to meet the cost of IVF” (see NFC website news). However, others have expressed concern that women donors are being exploited, because women who are unable to access NHS treatment or to afford the full cost of private IVF treatment may be more likely to donate than women who can access NHS treatment, or to pay for IVF.

13 September 2007The US National Institutes of Health (NIH) has announced a new policy for the sharing of data derived from genome-wide association (GWA) studies. Starting in January 2008, all researchers who receive NIH funding to conduct GWAs will have to submit their data to a central database.

These large-scale studies are used to identify associations between particular genetic variations and the presence of a phenotype or disease. NIH considers that sharing the information from many studies in one central repository is likely to increase the potential for developing new approaches to the prevention and treatment of disease, as well as maximising public investment. As stated, ‘the goal of the policy is to advance science for the benefit of the public’.

Plans for the database have been developed taking into account the views of both patients and researchers, who raised issues about whether it might be possible to use the data collected for non-research purposes. The effects on researchers’ ability to publish and derive patents from the data were also a concern.

In light of this the database deliberately does not include information that could be used to identify individuals. Investigators are also encouraged to obtain special confidentiality agreements to prevent any information being used for non-scientific research (such as law enforcement, and by employers and insurance companies). In addition, scientists have exclusive publication rights for 12 months on the data they gather, and are encouraged to develop commercial applications such as diagnostic tests and therapeutics.

The policy has been formulated in line with current standards in scientific and ethical issues, but NIH expects to revise the policy as these areas develop further. 

12 September 2007A US television advertisement for familial breast cancer testing has attracted criticism from oncologists and geneticists, who say that advertising a specialised genetic test to the general population could cause anxiety among women for whom the test is not actually appropriate. Director of cancer genetic counselling at the Yale Cancer Center Ellen T. Matloff said: “It really preys on the fears of our society, and one of those fears is getting breast cancer” (see New York Times article). Inherited mutations in the BRCA1 or BRCA2 genes can confer a lifetime breast cancer risk of up to 85%, and an ovarian cancer risk of up to around 40%; however, only a small proportion of breast cancer cases in a population arise in women with a BRCA mutation. Normally, only women considered to have an increased risk of carrying a mutation based on their family history (such as several affected relatives, and/or early onset cases in relatives) are referred for genetic counselling and the option of genetic testing.

The advertisement is sponsored by BRCA 1/2 mutation test provider Myriad Genetics, and urges women with relatives who have had breast cancer to consider testing (which costs in excess of $3000). The company has reportedly defended the promotional campaign, which carries the slogan “Be ready against cancer”, as necessary to boost public awareness of familial breast and ovarian cancer, and prompt women with possible concerns to discuss them with their health care provider. However, some fear it is the beginning of an era in which companies will aggressively market genetic tests to the public; already, private genetic testing services offered via the internet (some with highly questionable clinical utility) are on the increase. Others are concerned at the possible impact on primary care practitioners and genetics services if large numbers of women are prompted by the campaign to query their risk, and/or request genetic testing.

The attorney general of US state Connecticut has ordered an investigation of the claims made by Myriad in the advertisement. However, Myriad president Gregory Critchfield has said: “The purpose of the BRACAnalysis public awareness campaign is to save lives" by identifying BRCA mutation carriers (see press release). He added that: "We are committed to working with healthcare providers around the country to provide useful resources for them to offer hereditary risk assessment, counseling and genetic testing to their patients". However, the key issue is what proportion of the women prompted to ask about genetic testing will be at genuinely increased risk of having a mutation, and whether direct advertising of this genetic test is appropriate.

11 September 2007A UK scientist has developed a computer-based programme that compares 3D facial scans of a patient with those of specific genetic disorders, with a view to speeding up diagnosis. Many genetic syndromes are associated with dysmorphology, including characteristic facial features, which can help clinical geneticists to identify the actual genetic disorder. However, many genetic abnormalities are extremely rare, so that it is difficult for clinicians to associate a particular set of facial anomalies with a likely genetic abnormality.

The software is based on surface modelling techniques developed at UCL, and was developed using multiple facial scans of patients with specific genetic conditions, as well as controls, to produce composite images characteristic of each disorder. Analysis of a subject’s face with the programme can identify significant similarities to the catalogued genetic conditions. Describing his work at the BA Festival of Science in York, UCL Institute of Child Health researcher Professor Peter Hammond reported a 90% success rate thus far when using the programme to diagnose “over 30 conditions with an underlying genetic abnormality” including Cornelia de Lange, Fragile X, Noonan, Smith-Magenis and Velocardiofacial syndromes (see press release). In the future, Professor Hammond is reportedly hoping to compile facial data from individuals of different sexes and ethnic backgrounds with specific genetic disorders.

The software can potentially speed diagnosis by identifying the type of genetic abnormality that may be present in a patient, so that clinical geneticists have a lead to investigate via standard genetic analysis; it is hoped that this sort of tool could avoid inappropriate (and costly) genetic investigations. It could also add to the increasing movement towards international databases such as DECIPHER, which record rare and novel genetic abnormalities linked with phenotypic information from the patients so that clinical geneticists can share information that may help in diagnosis and/or clinical management of individuals with chromosomal abnormalities.

11 September 2007On the 5th of September the Human Fertilisation and Embryology Authority (HFEA) approved in principle the use of animal eggs in the creation of cytoplasmic hybrid embryos for stem cell research. Contrary to press headlines implying blanket support for true animal-human hybrids and chimeras, the decision pertained solely to research involving hybrid embryos cloned by cytoplasmic nuclear replacement (CNR) – the insertion of human nuclear material into an enucleated cow or rabbit egg. Unlike true hybrids, which obtain 50% of their genetic material from each parent, more than 99% of the DNA in cytoplasmic hybrids comes from the donated human nucleus, the remaining tiny fraction being extra-nuclear animal DNA.

Despite the presence of mitochondrial animal DNA, a cytoplasmic hybrid, which contains a complete human genome, is considered to be a ‘live human embryo’ within the remit of the Authority under section 1 of the Human Fertilisation and Embryology Act. All embryo research requires a licence, and last week’s decision was prompted by two 2006 applications which sought to resolve difficulties associated with obtaining human eggs for research by using animal eggs. The HFEA decision did not address the outstanding licensing applications, but decisions are expected in November.

Following a comprehensive consultation on the subject, the HFEA decided that there was no fundamental reason to prevent cytoplasmic hybrid research which is, ‘in principle, necessary and desirable in both scientific and ethical terms’.  It acknowledged that public opinion is finely divided and that people are generally opposed to this research unless it is tightly regulated and it is likely to lead to scientific or medical advancements. Those opposed to human embryo research argue that it is no less unethical to create partly human embryos solely to harvest their stem cells, while others express concern about the potential for gestation of grotesque inter-species hybrids. The British Medical Association and major science funders, the Medical Research Council and the Wellcome Trust pressed for a favourable ruling.

The HFEA underscores that applications must be approached with caution and careful scrutiny.  Individual research teams undertaking projects involving the creation of cytoplasmic hybrid embryos are required to demonstrate, to the satisfaction of an HFEA licence committee, that their proposed research is necessary, desirable, and meets the HFEA standards for embryo research.  Importantly, embryos must be destroyed within 14 days, and are under no circumstances to be transferred to a woman.

The Authority rejected the notion of making a decision on broader hybrid and chimera research without an adequate evidence base, but will continue to monitor the potential for this wider research and any emerging evidence through its ‘horizon scanning’ programme.

For more details, see HFEA meeting documentation, and further information about the consultation.

27 September 2007Type 1 Gaucher Disease (GD) is an autosomal recessive condition caused by mutations in the glucocerebrosidase gene. Symptoms are highly variable but may include anaemia, enlarged spleen, frequent infections, bleeding or bruising, and bone disease. Some individuals have symptomatic disease during early childhood, while others may remain asymptomatic throughout life. Enzyme replacement therapy is an effective treatment for affected individuals but is extremely expensive. The carrier frequency for GD is about 6% in Ashkenazi Jews compared to 0.7-0.8% in non-Jewish populations, and the condition has therefore been included in carrier screening programmes available to Ashkenazi Jews in Israel and some other countries.

Writing in the journal JAMA, Zuckerman et al have analysed the outcomes of carrier screening for GD in Israel between 1996 and 2003 [Zuckerman S et al (2007) JAMA 298, 1281-90 (abstract)]. They report that, during this time, 10 Israeli genetic centres screened nearly 29,000 individuals who reported Ashkenazi Jewish descent, identifying 82 carrier couples for Type 1 GD. On the basis of the mutations detected, 70 of these couples were informed that they were at risk of having asymptomatic or mildly affected offspring, and 12 that their offspring would be at moderate risk. In subsequent pregnancies for these couples, there was 76% uptake of prenatal diagnosis, leading to pregnancy termination for 67% of fetuses predicted to be moderately affected and 15% predicted to be asymptomatic or mildly affected. Although information and counselling was available to all couples, not all had access to a clinician expert in GD; in those who did, there were substantially fewer terminations. The discovery of carrier status in parents also had implications for older children born before the screening programme began; although none of these children were symptomatic, some were subsequently tested and found to be homozygous for Type 1 GD mutations.

Comment: The aim of carrier screening is to provide information and choice to couples who are at risk of transmitting severe genetic conditions to their children. Most professional organisations have recommended against population carrier screening for Type 1 GD because of its low penetrance, clinical variability and poor genotype-phenotype correlation, but have fallen short of calling for existing programmes to be stopped, arguing that couples should have the right to decide whether they wish to participate. Zuckerman and colleagues’ paper provides valuable evidence about how couples react to such programmes. Their findings suggest that, rather than empowering couples, screening places them in the position of having to make serious reproductive decisions on the basis of very poor information. The time for careful consideration of the benefits and harms of screening programmes is clearly before they are introduced, not after.

25 September 2007The genome sequence of the roundworm Brugia malayi, the causative agent of lymphatic filariasis (also referred to as elephantiasis) has been completed by a collaborative US and UK research team, and is reported in the journal Science [Ghedin E (2007) Science 317(5845):1756-60]. Present primarily in the developing world, B. malayi infects more than 130 million people, causing significant morbidity; chronic infection with the parasite can cause severe and disabling swelling of the legs.

The authors say that the genome sequence, along with the predicted repertoire of proteins it encodes, provides a valuable opportunity for rational drug design, by identifying and exploiting key interactions between the parasite, its human and vector hosts (mosquitoes) and its endosymbiotic (internal) bacterium, Wolbachia. The genome sequence of this bacterium, which is present in all B. malayi roundworms, has already been reported [Foster JM et al. (2004) Int J Parasitol. 234(6):733-46].

Drugs that are effective against lymphatic filariasis are already available, but generally not accessible to those who need them most, despite relatively low costs; this makes the need for a vaccine against the disease more acute, and this latest research could facilitate that process. However, others suggest that it would be feasible to eradicate the disease entirely by 2020, if existing antifilarial drugs were provided to those that require them, and propose that genome-based research is unlikely to yield clinically useful products within this timescale (see BBC news report).

20 September 2007It has been suggested that, in the future, it may be possible to use ‘genomic profiling’ – that is, the simultaneous testing of many different gene variants – for the prediction of common diseases such a coronary heart disease or Type 2 diabetes. Continuing their careful theoretical analysis of genomic profiling, Janssens et al have analysed the clinical validity (that is, the ability to predict disease) for a variety of simulated genomic profiles that included 40 independent gene variants, tested on a hypothetical population of 1 million people in whom the average risk for the disease was set at 10% [Janssens AC et al. (2007) Genet Med. 9(8):528-35]. Using a parameter called the area under the receiver-operating characteristic curve as a measure of the discriminative accuracy of each profile (that is, its ability to distinguish those who will from those who won’t get the disease), they looked at the effect of varying the odds ratios for the genetic variants from 1.1-2.0, and varying the population frequency of the higher-risk gene variant from 1% to 50%.

Their results show that the feasibility of using genomic profiling to predict disease depends both on the odds ratio of the variants and on their population frequency, but that the frequency is particularly crucial for variants with odds ratios in the range typical for variants associated with common disease (1.1-2.0). The discriminative accuracy of a profile was low, even for variants with odds ratios between 1.5 and 2.0, if their population frequency was low (a few per cent). Only when the population frequency rose above about 30% was adequate discriminative accuracy achieved for variants with odds ratios in this range.

Janssens et al also analysed a real example in which the variants used in the profile had different odds ratios as well as different population frequencies. They found that a profile using five known variants associated with Type 2 diabetes, with odds ratios from 1.10 to 1.51 and frequencies from 6% to 78%, had poor discriminative accuracy.

Comment: This study underlines the importance of avoiding the premature use of ‘predictive’ tests based on one or a few weak susceptibility genes. Odds ratios of 1.5-2.0 are very impressive in epidemiological terms, but they only translate to a test with high discriminative accuracy if the variants that have these odds ratios are also present at high frequency in the population.

It is clear that the evaluation of genomic profiling for the prediction of common disease – or even for identifying population subsets that are at increased risk – will be an extremely complex process that will have to be carried out separately for each proposed profile. Adding even further complexity, the effects of gene-gene and gene-environment interactions will also eventually have to be taken into account.

18 September 2007Familial hypercholesterolaemia is a highly penetrant, autosomal dominant condition that affects about 1 in 500 people. Affected individuals have very high blood cholesterol levels and are at greatly increased risk of coronary heart disease by the time they reach middle age. It is thought that at least 75% of affected individuals are currently undiagnosed in the UK. As treatment with lipid-lowering drugs (statins) is highly effective in controlling the condition, various population-screening strategies have been proposed in recent years to detect index cases.

In an advance online publication in the BMJ Wald et al, using the results of a meta-analysis of data on total cholesterol levels in affected and unaffected individuals in different age groups, suggest that population screening of children aged 1-9 years would detect 88%, 94% and 96% of affected children for false positive rates of 0.1%, 0.5% and 1% respectively [Wald DS et al (2007) BMJ advance online publication doi:10.1136/bmj.39300.616076.55]. Detection rates would be significantly lower in newborns or in individuals over 10 years of age. Affected children would need to be re-contacted when they were older, at an appropriate time to begin statin treatment.

Wald et al point out that screening in young children, which they suggest could be carried out during a GP visit for routine childhood vaccinations, would also have the effect of screening the parents, as the parent with the higher cholesterol level would be an obligate carrier of the condition. They suggest that the population screening programme would not have to be maintained indefinitely, as within about 30 years virtually all affected families would have been identified and it would only be necessary to test the children in those families.

Comment: The suggestion that there should be a universal childhood screening programme for familial hypercholesterolaemia is likely to be controversial. On the one hand, there are clear benefits in identifying affected individuals in time for them to take advantage of potentially life-saving prophylactic treatment. On the other hand, many people may be uneasy at the prospect of screening young children when treatment will not be initiated until early adulthood. Issues of consent and autonomy also arise, and additional problems may be encountered in the parental-screening part of the programme, for example non-paternity (which Wald et al calculate will affect about 1 in 25000 men) or refusal of consent by one or both parents. The cost and cost-effectiveness of the proposed programme would also need to be assessed.

18 September 2007The next important step towards personalised genomics has been taken with the recent publication in the open access journal PLoS Biology of the first complete genetic sequence of a single individual person [Levy S et al. PLoS Biol (2007). 5 (10): e254 doi:10.1371/journal.pbio.0050254]. This diploid human genome, named HuRef by the researchers from the J. Craig Venter Institute in Maryland, USA, is the complete DNA sequence of one individual Caucasian man – Dr J. Craig Venter himself – and the research coincides with the publication of Dr Venter’s autobiography, “A Life Decoded”.

Dr Venter and his privately owned company Celera Genomics were important players in the race to decode the first human genome, along with the Human Genome Sequencing Consortium,a publicly funded team lead by the Wellcome Trust Sanger Institute in Cambridge, UK. First published in draft form in 2001, the reference human genome sequence is a composite haploid reference genome using just half the DNA contained in a normal cell taken from a number of different (anonymous) individuals. In contrast, HuRef is a diploid genome using the entire DNA contained in a normal cell from just one (named) individual.

Comparison of HuRef with the current reference sequence from the Sanger Institute (NCBI 36) identified 4.1 million DNA variants. These variants include single nucleotide polymorphisms (SNPs), insertion/deletion events, block substitutions, duplications and copy number variations. Moreover, HuRef also reveals that the level of genetic variation within a single human genome is much higher than previously believed. Notably, 44% of Dr Venter’s genes differ between the maternally and paternally derived chromosomes, suggesting a minimum of 0.5% difference between two haploid genomes. This work therefore implies that two individuals share around 99.5% of their DNA, highlighting the importance of environmental and epigenetic effects in affecting individual variations in health.

Comment: Completion of the first diploid human genome sequence is an important milestone in genomic research; new understanding of the high level of variation between the two copies of each chromosome may affect the interpretation of genome-wide association studies and related research.

6 September 2007Huntington's disease (HD) is relatively rare among monogenic disorders, in that it has a penetrance of virtually 100%, ie. every individual who carries a copy of the mutant gene, will go on to develop the disease. The serious nature of the disease and the implications of genetic testing for the presence of disease-associated mutations, combined with the adult onset of symptoms in affected individuals, has in the past argued against predictive genetic testing among the under eighteens. A new study by an Australian group, published in the American Journal of Medical Genetics, reports on the findings from interviews with eight young individuals aged between 17 and 25 about their experiences of genetic testing for HD [Duncan RE et al. (2007). Am J Med Genet Part A 143A: 1984–1989].

When asked about their life prior to genetic testing, the participants reported a range of risk-taking behaviours and a general assumption that they would in the future prove to be mutation carriers, although all were aware the probability of this was 50%. All of the participants went on to have genetic testing, and two of the eight proved to be carriers. Interestingly, both carriers and non-carriers reported reduced levels of anxiety and a sense of being able to ‘move forward’ and get on with their lives following testing, although two of the non-carriers reported difficulties in adjusting to the realization that, contrary to their expectations, they would not go on to develop HD.

Comment: The authors note the similarity of their results and those of earlier researchers, who had not restricted their analysis to younger individuals; they also acknowledge the significant limitations of their very small study. However, the work adds an interesting perspective to the debate about appropriate ages for genetic testing for serious disease; perhaps most notably, “Not one of the young people interviewed regretted undergoing predictive testing”. They observe that genetic testing among younger people may actually alleviate existing harms, whereby the fear or assumption of carrier status presents an effective barrier to the normal progression into independent adult life. This finding would certainly suggest that testing of competent younger people below the legal age of majority for HD and other diseases may indeed be appropriate in some cases.

5 September 2007Genetic testing services, including paternity and some health-related tests, are becoming increasingly available to the general public via the internet and other direct-to-consumer routes. Providers claim this increases the privacy and convenience of testing but, as with other types of genetic tests, limited regulation applies to their use.

One group of tests offered over-the-counter are nutrigenomic tests, which combine testing for multiple common genetic variants (such as those linked in some way to heart disease or osteoporosis) with information on diet and lifestyle, and on the basis of these results suggest a diet supposedly tailored to promote health and reduce the risk of disease in the individual. A report by the US Government Accountability Office last year raised concerns that such tests might mislead consumers by, for example, making unsound or ambiguous predictions about health risks, and making unwarranted recommendations to purchase unnecessary dietary supplements (see previous news story).

It is also feared that people may be following the dietary regimes ‘prescribed’ by such tests without proper medical advice; although many manufacturers advise that consumers discuss test results with their doctors, it is uncertain how many people follow this advice. This issue is addressed in a new paper analyzing the results of two 2006 US surveys on direct-to-consumer nutrigenomic tests [Goddard KA et al. (2007) Genet Med. 9(8): 510-7].

In a survey of the general public, 14% of the 5250 respondents were aware of nutrigenomic tests and 0.6% had used them. These figures showed that awareness of nutrigenomic tests was on a par with that of pharmacogenetic tests (despite the fact that there is far more scientific evidence to support the use of selected forms of pharmacogenetic testing), and lower than awareness of other forms of genetic testing such as disease risk prediction, diagnosis or screening (30-50%). A significantly higher proportion of the 1225 clinicians interviewed in a second study reported awareness of nutrigenomic tests (44%), although almost half (41%) had never had a patient ask about such tests, and most (74%) had never discussed nutrigenomic test results with a patient.

The authors report that “the vast majority” of individuals who reported awareness of direct-to-consumer nutrigenomic tests had not used them, but note with some concern that the media was the primary source of information for both consumers and clinicians. They therefore call for more prominent educational initiatives from professional and government bodies in this area, if only to emphasise the current lack of evidence to support nutrigenomic testing. It is suggested that awareness of this form of testing is likely to rise in the future as advertising increases, and that appropriate policies and education should be developed.

Looking further ahead to a time when genuinely beneficial and validated forms of nutrigenomic testing might become available, the authors also express concern that direct-to-consumer testing might increase health disparities, because of their finding that younger, wealthier and better educated individuals had generally higher awareness of (and presumably capacity to pay for) nutrigenomic tests.

Comment: This study provides new data and raises a number of important issues, including the importance of making sure that health professionals are suitably informed about the health benefits (or otherwise) of forms of genomic testing that are becoming increasingly available (and marketed) to the general public.

4 September 2007Research published in the open-access journal BMC Genomics has revealed that some of the damage caused by smoking cannot be undone and persists long after the smoker has kicked the habit [Chari R et al. BMC Genomics (2007) 8:297]. Permanent changes in the expression of certain genes may explain why around half of newly diagnosed lung cancer patients are former smokers.

Whilst there is no doubt that quitting smoking significantly reduces the risk of illnesses such as heart disease, former smokers continue to have an increased risk of lung cancer and other pulmonary ailments relative to those who have never smoked. In order to investigate the molecular mechanism of this prolonged risk, researchers from British Columbia took bronchial epithelial samples from eight current smokers, twelve former smokers (who had stopped smoking between 1 and 32 years ago) and four individuals who had never smoked. The RNA transcripts in each sample were then evaluated using quantitative serial analysis of gene expression (SAGE) to determine each person’s bronchial gene expression profile, or ‘transcriptome’. Select genes from this investigation were further validated using real-time PCR in a second cohort of nine current, seven former and six never smokers.

Although most human cells contain the full genome comprising nearly 25,000 genes, only a small proportion are active in a specific cell at any given time. When something in the environment changes, certain genes will be switched off whilst others are switched on. These changes, which may include epigenetic alterations to the DNA itself, can be transient or permanent and lead to under or over expression of specific gene products.

By comparing differentially expressed genes between the three groups, researchers were able to identify both reversible and irreversible changes in gene expression as a result of smoking. Amongst the 121 genes only influenced by active smoking are those involved in xenobiotic and nucleotide metabolism, as well as airway mucus secretion. Interestingly, over expression of one particular gene encoding a structural component of mucus has also been implicated in a variety of brain tumours, suggesting a potential role in carcinogenesis. Importantly, the expression of a further 124 genes was irreversibly altered by smoking, including genes involved in the cell cycle and DNA repair, which were under expressed in both current and former smokers. These permanent changes may provide a molecular basis for the persistent lung cancer risk despite smoking cessation.

Comment: This research is an important step towards understanding the adverse effects of smoking at the molecular level. Despite the lack of analysis of differential gene expression between former smokers in relation to the number of years since quitting, the overall message is clear: whilst quitting smoking will significantly reduce your disease risk, not starting in the first place is even better.

4 September 2007Obesity and Genetics:  A Public Health Perspective. Online review and commentary provided by the US CDC National Office of Public Health Genomics and National Center for Chronic Disease Prevention and Health Promotion, including presentations and links to journal reviews, available from http://www.cdc.gov/genomics/training/perspectives/obesity.htm

Statistics and medicine: statistical issues in genomewide association studies. Hunter DJ, Kraft P (2007) N Engl J Med. 357(5) 436-439. Perspective article explaining why GWAs provide more valuable data than smaller scale studies, and anticipating the need for more advanced forms of statistical analysis to deal with data on the complex interactions between genetic and environmental factors involved in disease (PubMed).

Network medicine--from obesity to the "diseasome". Barabasi AL (2007) N Engl J Med. 357(4):404-7. Editorial considering current understanding of the factors (from genetic to social) involved in obesity and their interactions, and predicting the emergence of ‘network medicine’ which takes into account all of the networks that influence health and disease (PubMed).

Engineering targeted viral vectors for gene therapy. Waehler R, Russell SJ, Curiel DT (2007) Nat Rev Genet. 8(8):573-87. Review on progress towards clinical application of gene therapies by the use of targeted viral vectors (PubMed).

Mining gene expression profiles: expression signatures as cancer phenotypes. Nevins JR, Potti A (2007) Nat Rev Genet. 8(8):601-9. Review on the performance and applications of gene expression analysis with particular reference to cancer, including current challenges and possible future directions (PubMed).

Share and share alike: deciding how to distribute the scientific and social benefits of genomic data. Foster MW, Sharp RR (2007) Nat Rev Genet. 8(8):633-9. Perspectives piece on data-sharing policies in development by major health research funding agencies, looking at the different issues and stakeholders involved, and calling for the development of policy frameworks to allow the consideration of multiple interests (PubMed).

Copy number variants and genetic traits: closer to the resolution of phenotypic to genotypic variability. Beckmann JS, Estivill X, Antonarakis SE (2007) Nat Rev Genet. 8(8):639-46. Opinion piece on copy number variants and their effects, calling for efforts to identify all CNVs in the human population in order to make sense of variable penetrance, expressivity and underlying factors in genetic disease (PubMed).

Ethics. Identifiability in genomic research. Lowrance WW, Collins FS (2007) Science 317(5838):600-2. Policy forum article on confidentiality and privacy of subjects in genomic research trials, arguing that although these must be protected, there are several options that would allow useful data access for researchers without significant risk of patient identification (PubMed).

New perspectives for the elucidation of genetic disorders. Ropers HH (2007) Am J Hum Genet. 81(2):199-207. Discussion of how large-scale genomewide association studies are yielding results, and calling for renewed research into monogenic diseases as a priority (PubMed).

Who should be sent for genetic testing in hereditary colorectal cancer syndromes? Lynch HT et al. (2007). J Clin Oncol. 25(23):3534-42. Review suggesting guidelines for referral for genetic testing by colorectal surgeons and oncologists based on clinicopathologic features, as well as family history (PubMed).

History, principles, and practice of health and human rights. Gruskin S, Mills EJ, Tarantola D (2007) Lancet 370(9585):449-55. Review on changing views of human rights and health policy, with reference to the HIV epidemic, calling for public health programmes to incorporate consideration of human rights issues (PubMed).

Clinical aspects of hereditary hearing loss. Kochhar A, Hildebrand MS, Smith RJ (2007) Genet Med. 9(7):393-408. Review looking at the genetic factors underlying forms of hereditary deafness, and discussing the clinical management of such patients (PubMed).

Human-subjects research: Trial and error. Ledford H (2007) Nature 448(7153):530-2. Feature article looking at criticism of Institutional Review Boards (IRBs), the ethics committees that oversee research on human subjects in the US, and considering alternatives but noting potential problems, citing the former UK Central Office of Research Ethics Committees as one example (PubMed).

Pulling rank.(2007) Nature 448, 969. Editorial querying why the military personnel should be excluded from the protections that would be conferred by the US Genetic Information Nondiscrimination Act (PubMed).

Unraveling intrinsic genetic factors in type 2 diabetes. Katzov H (2007) Clin Genet72(3):184-5. Commentary on recent publication of genome-wide association study identifying novel risk loci for type 2 diabetes (PubMed). See also:

Genome-wide association studies provide new insights into type 2 diabetes aetiology. Frayling TM (2007) Nat Rev Genet. 8(9):657-62. Progress review combining recent and earlier understanding of genetic factors in type 2 diabetes, their potential implications, and possible future directions for research (PubMed).

New insights into autism from a comprehensive genetic map. Katzov H (2007) Clin Genet 72(3):186-7. Commentary on recently published results on genetic risk factors for autism spectrum disorder from the Autism Genome Project Consortium (PubMed).

Epidemiologist sees flaws in papers on genes and gender. Couzin J (2007) Science 317(5841):1020-1. News article on recent research by respected epidemiologist John Ioannidis, published in JAMA (PubMed).

Publishing genomewide association studies. Drazen JM, Phimister EG (2007) N Engl J Med. 357(5) 496. Editorial on recent and anticipated GWAs, explaining why they are considered an important advance in medical research .

Scanning the genome for coronary risk. Rosenzweig AR (2007) N Engl J Med. 357(5) 497-499. Editorial on insights into potential genetic risk factors for coronary disease and how they may reveal novel mechanisms of disease.

read more ...