News

31 October 2007Funded by the Wellcome Trust, UK and US researchers are to conduct what is said to be the largest genome-wide association (GWA) study to date for Alzheimer Disease (AD), looking at DNA samples from a total of 14,000 people; 6,000 ‘cases’ with late-onset AD and 8,000 healthy ‘controls’. Project lead Professor Julie Williams of Cardiff University commented: "Alzheimer's is a genetically-complicated story involving many genes, so we need large sample sizes to make sure any genetic links that we find are not mere coincidence… We need to build a complete picture of the different pathways that lead to the disease" (see press release).

The Alzheimer’s Society estimates that number of people in the UK with dementia will exceed one million by 2025; AD is the most common form of dementia (see Facts about dementia).

31 October 2007Scientists at the Beijing Genomics Institute (BGI) in China have announced that they have completed the first complete diploid genome sequence of a Chinese individual (see press release). This comes within months of the first two individual genomes to be sequenced, that of James Watson, Nobel Laureate and co-discoverer of the double helix structure of DNA (see previous news article), and Craig Venter, maverick scientist who lead the private bid to sequence the human genome (see previous news article). It is the first non-Caucasian genome to be sequenced in its entirety, although it has not yet been published in a peer-reviewed journal for international scientific use.

The project was undertaken by BGI’s Shenzhen branch, also known as Shenzhen Huada, a non-profit research organization funded primarily by local governments in partnership with several companies. The institute plans to sequence 99 more Chinese genomes as part of a 100-person project to map DNA polymorphisms in the Chinese population, and is offering wealthy Chinese the opportunity to have their own genome completely sequenced and analyzed for $1.3 million. Another project to sequence the panda genome is also underway at the institute.

30 October 2007The Council of Europe unveiled new guidelines regarding mail order and over-the-counter genetic tests at a conference in Paris at the beginning of October (reported by the Royal Society of Chemistry). The guidelines stipulate that diagnostic, predictive, ‘healthy carrier’ and pharmacogenetic tests should only be used under medical supervision. The move comes at a time when private genetic testing is not only commercially available but also heavily advertised in the US and represents an attempt to circumvent potential ethical quandaries relating to genetic testing, not least the perceived low public understanding of the complex relationship between genes and diseases.

Speaking about private genetic tests, Dr Ron Zimmern, director of the PHG Foundation, was recently quoted on BBC News as saying, “I think it is certainly too early to start offering the test both directly to the public or indeed through a physician. My main problem is that clinical studies that try to see what the predictive value of these tests is at the individual level just have not been done."

The European protocol will require that genetic tests meet generally accepted criteria of scientific and clinical validity. Legislators will scrutinise the text over the next few months before Ministers are asked to approve it, making it available for national ratifications. However, it is unclear how many states will choose to accept the complete, legally binding protocol.

29 October 2007A new report on the increasing health problem of overweight and obesity in the UK has been launched; the report from the UK Government group Foresight, Tackling obesities: future choices, is the product of a two year study by a large group of experts to produce a ‘long-term vision of a sustainable response to obesity in the UK over the next 40 years’ (see Foresight project website). Looking at the causes and predicted progression of obesity, the report predicts that 60% of men and 40% of women in the UK population will be obese by 2050, with the annual cost based on increased morbidity reaching £46 billion. It is proposed that an effective response to this trend towards widespread obesity, rather than being focused solely on individuals, will require cross-cutting societal approaches to increase activity levels and decrease consumption of high-calorie foods in the population as a whole. The role of individual genetic factors in determining resistance or predispostion towards obesity must also be taken into consideration.

The report also considers emerging areas of research such as the field of nutrigenomics (‘the science of personalised nutrition’), and their potential applications in the struggle to reduce levels of obesity, although Dr Siân Astley of the European Nutrigenomics Organisation (NuGO) has reportedly said that nutrigenomics has: "potential to underpin more-targeted more-specific public healthcare advice and perhaps in the future, when we have a better understanding of which if any genes are most important, maybe individualised advice via nutrigenetics and genetic testing" whilst cautioning that the influences of genetics on obesity are multiple, and intimately associated with environmental and behavioural factors (see FoodNavigator report).The UK government has reportedly announced the intention to work at the ‘environmental and organisational level’ to combat the obesity epidemic [Hitchen L (2007) BMJ 335(7624):789].

28 October 2007The Human Genome Epidemiology Network (HuGENet™), which is an international collaborative venture to investigate the role of human genome variation in population health, has launched a new resource for genome epidemiologists (see HuGE news). HuGE Navigator is a searchable and continuously updated knowledge base of human gene-disease associations; it also includes information on gene-gene and gene- environment interactions, population prevalence of genetic variants, and the evaluation of genetic tests. The new HuGE Navigator replaces older database search tools as well as offering additional functions for researchers.

25 October 2007Researchers presented work at the recent American Society for Reproductive Medicine conference on the use of RNA interference (RNAi) as a contraceptive tool (see BBC news). There is general interest in producing alternatives to the contraceptive pill as novel forms of birth control, particularly because the hormonal-based pills have unwanted side-effects in some women, and are contraindicated in others, such as those at increased risk of deep-vein thrombosis.

The new method is based on using RNA complementary to that produced to allow expression of a gene active in egg cells just prior to ovulation; blocking expression of the gene is said to prevent the formation of the egg cell’s outer membrane, to which sperm cells must bind in order to allow conception. However, thus far the technique has only been developed in mice, and trials in humans are a very long way off. Moreover, it is not yet known what the side-effects of this application of RNAi might be.

23 October 2007The National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH), announced recently that is to expand two of its ongoing initiatives. One of these is intended to broaden knowledge of the human genome by, for example, identifying individual genes, their location and how they are regulated. The other addresses the ethical, legal and social questions associated with the acceptance and use genetic research in medicine and public health.

 

Genes themselves, which are the protein-coding component of DNA, make up only around 1.5% of the human genome. It appears likely that many non-coding regions of the genome also have important functions in health and disease affecting, for example, gene expression, but relatively little is known about the locations of these functional elements or how they work.

 

In 2003 NHGRI initiated the initial phases of the ENCyclopedia Of DNA Elements (ENCODE) project in which a worldwide consortium of scientists developed and tested a range of computational and informational techniques to identify the functional elements in human DNA. Together they developed a suite of approaches, focusing efforts on ~1% (30mB) of the human genome.

 

The ENCODE project has now been extended with the announcement of grants totalling more than $80 million to 16 centres over the next four years. The new funding will build on the pilot studies, providing an accurate 'annotation' of the whole human genome and expanding knowledge of human genes. Dr Francis Collins, NHGRI director, said: "The ENCODE pilot produced findings that are reshaping many long-held views about our genome. ENCODE's effort to survey the entire genome will uncover even more exciting surprises, providing us with a more complete picture of the biological roots of human health and disease" (see press release).

 

Central to the goal of safely and effectively moving discoveries into the clinic is understanding the ethical, legal and social implications of this type of research. To address this NHGRI is adding two new centres to the Centers for Excellence in Ethical, Legal and Social Implications Research Initiative (see press release). Grants totalling over $12 million will be awarded to the University of North Carolina-Chapel Hill and the University of Pennsylvania in Philadelphia who will focus on issues that relate to the applications and uses of genomic research, technologies and information. Teams at each centre include experts in bioethics, law, behavioural and social sciences, clinical research, theology, public policy, and genetic and genomic research.

The Center for Genomics and Society (University of North Carolina) will examine the impacts of discoveries from large-scale genomic research for individuals, families and populations, focusing on the implications for specific racial, ethnic or other socially defined groups. The University of Pennsylvania's Penn Center for ELSI Research will concentrate on the ethical, legal, and social factors associated with genetic testing, with the overall goal of developing tools to educate consumers, professionals, policy makers and insurers, helping them to understand genomic studies and how they might be applied. This research will contribute to the translation of genomic research findings into clinical and public health practice.

23 October 2007The second instalment of the human HapMap has been published in Nature by a team of over 200 international scientists [The International HapMap Consortium (2007), Nature 449: 851-862].  The International HapMap is “a multi-country effort to identify and catalogue genetic similarities and differences in human beings”. The project takes its name from the term haplotype, which refers to a set of closely linked alleles that are often inherited together due to physical proximity on the chromosome. The human haplotype map describes the variation seen in 270 individuals from America, Japan, China and West Africa, providing a key resource for biomedical researchers.

The International HapMap consortium was launched in 2002 and since the publication of the first phase in 2005 (see previous news story), with around a million single nucleotide polymorphisms (SNPs), the data have been extensively used in genome-wide studies of disease association; a search for ‘HapMap’ brings up over 350 citations in PubMed. The new, more thorough, high resolution version, HapMap2, contains over 3.1 million SNPs with a density of around one per kilobase. Over 32,000 recombination hotspots have been identified, accounting for around 60% of recombination events of the human genome but only 6% of the sequence. The new version also contains more diversity between individuals than was originally expected, consistent with recent literature describing huge structural variation in the genome (see previous news story).

An indication of how genome-wide association studies will be extended with HapMap2 is presented in the same issue of Nature [Sabeti et al. (2007) Nature 449: 913-918]. Three examples of population-specific selection based on geographical location are identified, involving genes linked to Lassa virus in West Africa, skin pigmentation in Europe and hair follicle development in Asia.

Comment: Whilst the relevance of the HapMap project to human health was initially unclear when the first phase was published, there is now little doubt that it provides an invaluable tool to researchers trying to understand the genetic basis of disease susceptibility. The higher resolution HapMap2 characterises human genetic variation much more extensively than the original, tripling of the number of genetic markers included, significantly increasing its utility for detection of rare disease determinants. This may be critical for understanding the effect of genome variations on public health.

22 October 2007The European Patent Office (EPO) has rejected an appeal by US company Myriad Genetics and the University of Utah, and upheld an earlier decision  to revoke some claims of patent EP705902 relating to the BRCA1 gene and its applications (see press release). Myriad was originally granted the patent in 2001, later transferring it to the University of Utah Research Foundation whilst retaining exclusive licensing rights; the patent claims the isolated BRCA1 gene, the BRCA1 protein, and possible therapeutic applications and diagnostic kits based on the gene.

There was widespread objection to the extent of this claim among European researchers, since it granted an effective monopoly to Myriad which they believed unjustified; six bodies filed objections, leading to a decision by the EPO in 2005 to substantially amend the patent, retaining only the claims relating to a specific nucleic acid probe and vectors containing gene sequences. The EPO has now rejected an appeal by Myriad and the University of Utah, and amended the patent, meaning that European laboratories retain the right to perform diagnostic tests for mutations in the BRCA1 gene sequence, which are associated with increased susceptibility to breast and ovarian cancer.

The EPO has yet to examine the appeals made by Myriad Genetics and the University of Utah against decisions to revoke patent EP699754 in 2004 (see previous news) and amend EP705903 in 2005 (see previous news); both of these patents also relate to the BRCA1 gene.

20 October 2007A new trial of prospective gene therapy to treat the genetic disease Duchenne muscular dystrophy (DMD) is about to begin in London. DMD is inherited in an X-linked recessive pattern, meaning that it affects predominantly males, around 1 in every 3500 live male births. The inherited mutation prevents the production of dystrophin protein, which leads to progressive muscle wasting beginning in early childhood. Affected children gradually lose mobility; the condition becomes increasingly serious as the wasting affects heart and respiratory function, leading to premature death by the early twenties.

There is as yet no effective treatment for the condition.It is hoped that by delivering a specially targeted genetic ‘patch’ in the form of antisense oligonucleotides, production of some functional dystrophin will be possible, and disease progression could be slowed. Animal trials of the drug have proved highly successful. Professor Francesco Muntoni of Imperial College London said: "Maybe this will not be a complete cure, but it could definitely buy a lot of time for these children" (see BBC news).

Funding for the trial was awarded by the  Department of Health in 2004, as part of the £50 million allocated in the 2003 Genetics White Paper (see previous news).

18 October 2007A UK consortium is to undertake a genome-wide association study to identify genes that are associated with osteoarthritis (see press release). The 2-year arcOGEN project involves eight UK centres and has received £2.2 million in funding from the Arthritis Research Campaign (arc).

According to arc, osteoarthritis affects about 8 million people in the UK making it the most common joint disease in the UK. Potentially it can affect any joint, causing severe pain and stiffness as the cartilage at the ends of bones wears away, and no treatments are currently available. Osteoarthritis of the knee and hip is the main cause of mobility problems in the elderly, with joint replacement the only option for many as the disease progresses.

The disease often runs in families. This indicates that it is likely to have a considerable genetic component, although lifestyle factors such as obesity are also known to have a role. It appears likely that several (possibly many) genes act together to increase a person's susceptibility, with each individual gene having a relatively small effect. In order to identify gene variants that predispose to the disease, this large study will scan the genomes of 8000 affected individuals, comparing the results with existing data from 6000 healthy volunteers.

The results of the study will be made freely available and are expected to provide a resource that will help identify many of the biological pathways that are involved disease development and progression. As such, the results are likely to be of considerable interest to pharmaceutical companies who could use the data to develop potential therapeutics. Ultimately, it might lead to new drugs to either prevent disease onset or delay its progression. arc also expresses the hope that the study will lead to additional breakthroughs such as genetic tests to predict who is likely to develop osteoarthritis and how severely they will be affected - the intention being that this information is used to offer treatment or life-style advice on how to reduce the risk.

16 October 2007The UK media has widely reported on the disapproving reaction of scientists to the news that a private US company is to market a service to harvest and store stem cells from excess IVF embryos. Company StemLifeLine, which revealed the new service at the American Society for Reproductive Medicine conference in the US this week, markets itself to parents with the slogan "Think of our service as an investment for the future". It offers parents having in vitro fertilization (IVF) treatment the option to pay to store stem cells from embryos that are not implanted, which could potentially be used in the future to treat disease in their children.

However, stem cell scientists have condemned the service as exploitation, saying that the £8,500 charge is unfairly preying on the fears of parents, and saying that the claim that stem cell lines created "may one day" help create therapies for living children who prove to be good immunological matches for the tissue created from the embryonic siblings is not justified. UK stem cell expert Professor Stephen Minger of King's College London commented: "My worry is that this is a commercial service that is being promoted to companies when the science is really not there to justify it” (see BBC news).

This service goes a step further than current commercial stem-cell banking initiatives, which offer to store cord blood from the umbilicus of newborn babies as a potential source of immunologically identical stem cells, which could be used for some future treatments of that newborn. Such companies operate in the UK, although their services have been criticized (see previous news). The Human Fertilisation and Embryology Authority (HFEA), which regulates the use of embryos created by IVF, has reportedly said that a service using frozen embryos would be unlikely to gain approval in the UK, since licensing requires that the proposed application is both necessary and desirable. The UK already has a national stem cell bank maintained for research purposes, and a public cord blood bank.

16 October 2007The second parasitic genome to be elucidated in recent weeks (see previous news story) has been reported in the journal Science [Morrison, HG. (2007) Science 317, 1921-6]. 

The unicellular intestinal parasite Giardia lamblia (also known as G. intestinalis and G. duodenalis) occurs worldwide. Transmitted via animal and human faeces, it is recognised as a major cause of diarrhoea in humans and is one of the most common causes of waterborne disease both in the USA as well as less affluent nations. However despite the major health risks associated with Giardia, the basic biology of this parasite is not well understood.

In addition to the major health burden associated with this organism, Giardia intrigues scientists for another reason: taxonomists consider that it occupies a position very close to the transition between eukaryote and prokaryote phylogenies and so is a valuable model from which to gain basic insights into genetic adaptations that led to the formation of eukaryotic cells.

As stated by the authors, ‘This genome sequence will not only be valuable for investigatingthe evolution of eukaryotes, but will also be applied to thesearch for new therapeutics for this parasite’.

Comment: Several existing drugs are available for treating giardiasis. However, since these must be given repeatedly to combat recurring infection from contaminated water, improving access to clean drinking water is likely to have a more direct impact on the incidence of this disease in many parts of the world. 

12 October 2007Three multinational pharmaceutical companies have entered into a partnership with the UK government to develop human embryonic stem cells for use in toxicity testing (reported in Reuters). Stem Cells for Safer Medicine (SC4SM), a non-profit British company to be headed by Philip Wright, science director at the Association of the British Pharmaceutical Industry, will be the first major public-private collaboration in stem cell research. Drug giants GlaxoSmithKline, AstraZeneca and Roche have each contributed £0.1 million to help fund the first year's work, whilst the British government is contributing £0.75 million; other drug companies are expected to join soon.

 

Within its 5 year programme, the consortium will focus on converting stem cells into specific differentiated cell lines for toxicity testing; it will not directly investigate the therapeutic use of stem cells to treat disease. This type of research falls under the broad heading of “animal-on-a-chip” technology, and could significantly reduce the need for animal testing by providing alternatives for evaluating drug toxicity. Reduction in live animal testing is desirable on practical and commercial grounds as well as ethical grounds. Around 10% of the 3 million animals used for testing in the UK in 2006 were used for toxicity testing by the pharmaceutical industry (see Statistics of Scientific Procedures on Living Animals Great Britain 2006) and the number is likely to increase dramatically as a result of the recent European Union legislation regarding the regulation of chemicals (REACH).

 

More than 90% of new drugs entering into clinical trials fail to get to market, either due to lack of effectiveness or adverse side-effects not predicted during pre-clinical development. SC4SM will initially focus on producing liver cells (hepatocytes) from stem cells, as unexpected liver toxicity is the biggest single reason why new drugs fail during clinical trials. In the longer term, the consortium will investigate differentiating stem cells into various other cell types including heart cells (cardiomyocytes).

11 October 2007The National Institutes of Health (NIH) is making a vast collection of genetic and clinical data freely available to researchers. Called the SNP Health Association Resource (SHARe), it will allow researchers to access extensive phenotype and genotype information from several of the large cohort studies that are funded by the National Heart, Lung, and Blood Institute (NHLBI). The intention is to use the SHARes to identify genes that are involved in disorders such as cardiovascular and lung disease, as well as conditions such as osteoporosis and diabetes.

 

The first SHARe to be launched will enable researchers access to data from the The Framingham Heart Study (FHS). Designed to identify common risk factors for cardiovascular disease, the FHS started in 1948 with the recruitment of 5,209 men and women from Framingham, Massachusetts, and now includes comprehensive data from three generations of the same families, much of which has been collected repeatedly in the original and offspring cohorts. Over the years, careful monitoring of the FHS population has helped to identify major risk factors, such as hypertension and high blood cholesterol as well as lifestyle factors. More latterly, it has expanded to study genetic determinants of cardiovascular disease with several large-scale genotyping projects in the past decade.

 

The FHS SHARe includes genotype information in over 9,300 subjects from three generations of more than 900 families. This includes data on 550,000 single nucleotide polymorphisms (SNPs) that have been determined recently, as well as SNP and microsatellite genotyping conducted previously. Linked to this is a phenotypic database of information from all three generations plus an array of biomarkers, disease imaging measures, disease outcomes and ancillary studies.

 

To protect confidentiality, the database is stripped of information that might identify individual participants, all of whom have consented to genetic research and to allowing their data to be shared. Furthermore, investigators must meet certain requirements before gaining access to the full dataset.

 

NHLBI Director Elizabeth G. Nabel commented: "As one of the most comprehensive studies ever undertaken, the Framingham Heart Study will play a vital role in laying the foundation for this vast dataset to help researchers link genes and disease" (see press release).

10 October 2007Government plans to review legislation on assisted human reproduction and embryo research are one step closer with publication on 8 October 2007 of the Government’s response to the Parliamentary Scrutiny Committee’s report on the Human Tissue and Embryos (Draft) Bill. The principal recommendations in the draft Bill published on 17 May 2007 (see previous news) included updating the legislation on assisted human reproduction to take account of societal changes, redefining the scope of permissible research to take account of scientific advances and also restructuring of the regulatory framework to license the use of tissue and embryos. This response document indicates which of the Committee’s recommendations are likely to be included in a revised Bill to be introduced next Parliamentary session. As previously drafted, the Bill devolved power to the regulator to enable it to licence research involving a list of inter-species embryos defined in the Bill. The revised Bill will contain an extended list to include ‘true hybrids’ created from mixing animal and human embryos, enabling comprehensive scrutiny of this issue when the Bill is reviewed by Parliament. The revised Bill will also remove the current restriction preventing researchers from altering the genetic structure of a cell while it forms part of an embryo, provided that researchers can justify the use of embryos as part of their research.

Another proposal in the draft Bill was the merger of two existing regulatory authorities (the Human Fertilisation and Embryology Authority (HFEA) and the Human Tissue Authority (HTA)) to form a single regulatory authority (RATE). This proposal has now been dropped in response to what the Joint Committee described as ‘overwhelming and convincing evidence’ but opportunities will be taken to streamline the administration of the two authorities.

The Government has also accepted the Committee’s recommendations that HLA compatible siblings could be selected to treat serious as opposed to life-threatening conditions using any histocompatible tissue. This brings these proposals in line with current HFEA policy. The response document rules out more comprehensive review of the Human Tissue Act, proposals by the Joint Committee to bring all human-animal research within the remit of the HFEA, and proposals to acknowledge a child’s donor conceived status on their birth certificates. The change in Governmental policy evidenced by the response document is to be welcomed as a proportionate response that takes account of the divergent stakeholders and the sensitivities involved.

9 October 2007In Italy, a Sardinian court has ruled that gynaecologist Giovanni Monni must provide pre-implantation genetic diagnosis (PGD) for a couple who are beta-thalassaemia carriers, the BMJ has reported [Turone F (2007) BMJ 335, 687]. Beta-thalassaemia is an autosomal recessive genetic disorder caused by mutation in the beta-globin gene; individuals who inherit two faulty copies of the gene suffer from severe (and potentially fatal) transfusion-dependent anaemia. Carrier frequency for defective beta-globin genes in the Sardinian population is high, at around 10%.

Dr Monni supported the couple’s request for PGD, but was prevented from doing so by Italy’s restrictive legislation on aspects of in vitro fertilisation (see previous news), which does not permit the procedure. The court’s decision followed an earlier hearing by a constitutional court, where it was ruled that the ban on PGD was part of health ministry defined guidelines, as opposed to law, and thus not a violation of the constitutional right to health.

The couple in question had reportedly already travelled to Turkey for PGD and are expecting a baby, but have said they will have the embryos created in Italy implanted to establish another pregnancy as soon as possible, if they are shown by PGD to be free from beta-thalassaemia.

8 October 2007Americans Mario R. Capecchi (University of Utah; Howard Hughes Medical Institute) and Oliver Smithies (University of North Carolina) along with their British collaborator Martin J. Evans (Cardiff University) share the Nobel Prize in Physiology or Medicine 2007 “for their discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells" (see Nobelprize.org).

 

The trio developed a technique known as gene targeting which enabled them to introduce specific genetic modifications into mice through the use of embryonic stem cells. The basic technique involves introducing a targeted DNA fragment into mouse embryonic stem cells by a process called homologous recombination. These modified cells are then injected into an early mouse embryo (blastocyst) which is implanted into a female mouse. The resulting offspring are genetic chimeras which can subsequently be mated to normal mice to produce genetically modified offspring, often known as ‘knockout’ mice. Further development of this versatile technique has resulted in so-called ‘knock-in’ technology which also be used to replace an existing gene with another, or to introduce specific mutations.

 

The Nobel committee said that “their discoveries led to the creation of an immensely powerful technology … now being applied to virtually all areas of biomedicine – from basic research to the development of new therapies.” Since the production of the first knock-out mouse in the late 1980’s, gene targeting has become enormously widespread. Sequencing of both the human and mouse genomes in the early part of this century revealed that 99% of mouse genes have homologues in human, and in 2005, the National Institutes for Health (NIH) instigated the Knockout Mouse Project to generate a comprehensive source of mouse embryonic stem cells containing every possible gene knockout. Although gene targeting is not without its technical limitations and ethical difficulties, knockout mice have become an indispensible tool in biomedical research by providing experimental models of development and disease.

8 October 2007Last month the US National Institutes of Health (NIH) published its plan to implement an Executive Order from President Bush to explore methods to expand the number of approved pluripotent stem cell lines ‘without creating a human embryo for research purposes or destroying, discarding, or subjecting to harm a human embryo or fetus’ (see press release).

Under the plan, NIH intends to change the name of its ‘Human Embryonic Stem Cell Registry’ to the ‘Human Pluripotent Stem Cell Registry’. It will also prioritise the development of funding opportunities for research on human pluripotent stem cells derived from non-embryonic sources, such as somatic cells, and cells from amniotic fluid.

The plan also calls for an assessment of possible alternative sources of stem cells including , so-called, ‘dead’ embryos (which are created during IVF but stop dividing and so are unsuitable for implantation), altered nuclear transfer (ANT), single cell embryo biopsy (in which a single cell is removed from a pre-implantation embryo), and reprogramming (dedifferentiation) of somatic cells.

Although many of these alternative approaches show promise they are, as yet, unproven. To address this issue, NIH intends to undertake a comprehensive analysis of the research that it funds in these areas, convening a state-of-the-science workshop to identify the outstanding scientific questions and to ensure that all its research using these techniques is consistent with the Executive Order as well as with existing federal law and policy. Also planned is a symposium to explore the current state of basic and clinical research into pluripotent stem cell biology with the aim of helping to prioritize research according to clinical potential.

Despite surveys suggesting that a majority of Americans support expanded stem-cell research, President Bush has personally and repeatedly blocked government-approved legislation to increase state funding for studies using embryonic stem cells (see previous news). Developing techniques that do not harm human embryos should bypass ethical objections to this type of research, although it is by no means certain that these unproven methodologies will prove successful.

Meanwhile, Democrat presidential candidate Senator Hillary Rodham Clinton has recently said that, if elected, she would issue an Executive Order rescinding President Bush's restrictions on federal funding for embryonic stem cell research (see AP news). She has also said that she favours a return to ‘evidence-based decision-making’ and would prevent political appointees from altering or removing scientific conclusions from government research without legitimate reason.

5 October 2007The US Department of Health and Human Services (HSS) has published what it terms a ‘reconnoitring’ report entitled Personalized Health Care: Opportunities, Pathways, Resources. Produced as part of a HSS priority initiative on personalized health care, it presents a long-range plan for achieving individualized treatment for patients based on the ability to predict individual susceptibility to disease and to target medicines more precisely and safely. The ultimate goal is to allow patients and their doctors to make better, safer health choices based on knowledge of an individual’s genetic profile in addition to other clinical and personal factors. The report articulates how ongoing work from programmes coordinated by HSS (such as the National Institutes of Health, the Centers for Disease Control and Prevention, and the National Cancer Institute), and elsewhere, are likely to come together in the future to offer the prospect of ‘the right treatment, at the right time’ for each individual patient. The report also looks ahead to a point where developments could allow early detection and monitoring of diseases basked on molecular biomarkers, and even individualized tools for preventing disease.

The report emphasises that in order to develop clinically useful products it is essential that advances in biomedical sciences (including systems biology, bioengineering, genomics, proteomics, epigenetics, nanotechnology, cellular and tissue engineering, bioimaging, computational methods and advances in information technologies, especially health information technology) be integrated fully with insights from population sciences, humanities and social sciences. Only such comprehensive integration will result in appropriate regulatory structures that support development of safe, effective interventions that are accepted and trusted by the medical community, patients and the public in general. The importance of electronic health information in gathering patient data to support clinical care and develop new or more appropriately targeted new interventions is underlined, with the observation that advances in medicine require both scientific knowledge and evidence, and appropriate technology ‘to make complex information useful’.

Early examples of personalized health care are cited, such as anti-cancer drugs like Herceptin tailored to specific genetic features of the tumour, or BRCA mutation testing for inherited susceptibility to breast and ovarian cancer. The report implies that, inevitably, such examples will become increasingly common until the whole practice of medicine is shifted from something of an art, to a precise science where treatment is dictated by detection and analysis of multiple and complex biomarkers, this data simultaneously providing a platform for further biomedical research and assessment and refinement of interventions. This new ‘smart’ approach is heralded as the dawn of a new era in which not only will treatments be more effective and more economic, but also patients will become increasingly in control of their own health care based around genetic testing and therapy, managing their own ‘health portfolios’ in consultation with medical advisers

Barriers to progress are also considered, including the rate of scientific advances which is said to outstrip the ‘ability of clinicians and providers to remain up-to-date on the latest medical information’; hampering the adoption of new approaches ‘such as the incorporation of genetic testing practices in routine clinical decision-making’. It is not clear what form of genetic testing they consider to be clinically useful but currently underused due to ignorance on the part of health practitioners, though the report does concede a need ‘to ensure that medical genetic test information is both clinically and analytically valid’.

The sheer scale and complexity of the information on molecular pathways and interactions involved in health and disease, and the effects of genetic and environmental factors on these networks, is alluded to but never made explicit. The report does call for further research in various areas – outlining current research initiatives - but does not go into detail about the necessity for revolutionary breakthroughs in computing that would be necessary to record, handle and analyse the vast mass of data from such research.

HHS Secretary Mike Leavitt commented:  “Personalized health care means knowing what works, knowing why it works, knowing who it works for, and applying that knowledge for patients. These goals may sound elementary, but a generation of effort lies ahead of us in achieving them” (see press release). Whilst the earliest examples of personalised medicine are already with us, realising the full potential of the field as envisioned by the report may be rather more than a generation ahead.

4 October 2007A new guide on genetic conditions for primary care clinicians in Australia has been launched. Genetics in Family Medicine: The Australian Handbook for General Practitioners was reportedly developed in response to demand for support on genetics from GPs by the Genetics Education in Medicine Consortium; both GPs and geneticists were consulted in order to make the resource as relevant and useful as possible, and production was overseen by a national expert advisory group. The handbook covers family history, testing and pregnancy, genetic services and testing and genetic conditions including familial cancer, fragile X and other causes of developmental delay, cardiovascular conditions and clotting and bleeding conditions.

Australian Minister for Health and Ageing Tony Abbott said: "Genetic medicine is a constantly evolving field and this handbook, produced by Biotechnology Australia, addresses key genetic issues such as cancer in the family, cardiovascular conditions, diabetes and many inherited conditions…[it] will help GPs provide information on genetic conditions to patients and make appropriate referrals" (see press release).

Copies of the handbook, which is intended to act as the ‘gold standard’ for genetics information for GPs and other health professionals, will be released at the 50th annual conference of the Royal Australian College of General Practitioners in Sydney on 7 October, and made available online at www.gpgenetics.edu.au.

2 October 2007Seven major pharmaceutical companies have joined with academic centres, the US Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products (EMEA)  to form a new group, the International Serious Adverse Events Consortium (SAEC). The SAEC will work together to seek genetic markers that can predict which individuals are at risk of serious side-effects from a given drug or drug class (see press release).

The group intends to begin with studies to identify genetic markers associated with two forms of adverse effect that can result from the use of multiple different drugs, drug-related liver toxicity and a drug-related skin reaction known as Stevens-Johnson Syndrome (SJS), which can in extreme cases be fatal. These side-effects are very rare, such that no single company has enough pharmacogenetic data to identify common genetic factors in affected trial subjects.

Research will be performed by academic centres and external contractors, but funded by the companies (Pfizer, Abbott, GlaxoSmithKline, Johnson & Johnson, Roche, Sanofi-Aventis and Wyeth, each contributing around $1 million annually). The projects will rely on DNA samples from European research consortia Diligen and Eudragene, taken from individuals affected by the adverse drug events (ADEs) in question, which will be used for genome-wide searches of around one million genetic markers to identify any that are associated with the ADEs. It is intended that results will be made publicly available, so that any company could develop pharmacogenetic tests based on the results.

The benefit to the major pharma companies may be the potential to get effective drugs approved for use in restricted populations, if by excluding individuals who are genetically predisposed to extreme drug reactions from receiving the drugs, they are able to demonstrate acceptable efficacy and safety in clinical trials. Pfizer representative Duncan McHale reportedly said: “We have to remove drugs that are clearly offering patients benefits because a handful are getting these severe adverse reactions” (see Pharmalot news). However, pharmacogenetic tests to identify at-risk individuals are often not economically viable, even if suitable genetic markers are identified; most companies would prefer to develop drugs that affect different pathways in the body and do not risk serious ADEs in any recipients.

1 October 2007Postmortem tests on a patient who died during a gene therapy trial for active inflammatory arthritis have found no evidence that she was killed directly by the gene therapy, a US National Institutes of Health committee has been told. However, as reported by the Washington Post, many questions remain and further tests are needed to see if the trial contributed to the death, possibly because of immune suppression.

The trial, which has been halted (see previous news), used a recombinant adeno-associated virus (rAAV) vector to deliver DNA encoding a soluble form of the TNF alpha receptor, which is an immunosuppressant. As part of the trial the rAAV was injected directly into an affected joint in patients who continued to take their usual treatment of anti-TNF alpha (another immunosuppressant).

The committee heard that the patient’s symptoms started on the day of injection and she died three weeks later as a result of massive fungal infection.

A spokeswoman for Targeted Genetics Corp, who is developing the treatment, said the company was gratified by several of the test results. However, some of the committee voiced concerns about how the patient was enrolled to the trial. In particular, they noted that many patients overestimate the likelihood that a Phase I clinical trial, which is designed to assess safety, will help them, and that this is even more likely to occur when they are recruited by their personal physician, as happened in this case. The patient also signed up for the trial immediately rather than taking time to consider, which is also less than ideal, and, although not prohibited, there was no mention in the informed consent document that her doctor was paid to enlist  patients.

The committee will meet again in December, when they hope to conclude whether gene therapy played a role in this death.

1 October 2007A UK couple has received approval from the Human Fertilisation and Embryology Authority (HFEA) to have their IVF embryos screened or early onset Alzheimer’s disease (EOAD).

 

Alzheimer’s disease is characterised by adult-onset progressive dementia. The majority of cases are thought to involve a number of different genetic and environmental factors and only become apparent once a person reaches their seventies and eighties. In contrast, EOAD is a rare dominant genetic condition that can manifest from the age of 35.

 

The couple involved have a strong family history of EOAD; the man’s mother and two uncles died prematurely from the condition. Although the man in question does not know himself whether he carries the disease mutation, the couple do not wish to run the risk of passing it onto their child. The Bridge Centre in London has been granted a licence to screen embryos to ensure that the specific chromosome that could carry the disease mutation is not passed on to the child. 

 

In determining whether embryo screening would be appropriate for EOAD, the HFEA looked at eight factors including the degree of suffering and the speed of degeneration associated with the condition. Although EOAD is an adult-onset disorder, the decision to allow PGD in this instance is less controversial than for some previous decisions where the conditions show reduced penetrance (see previous news), or cause non-progressive and non-life threatening symptoms (see previous news).

 

26 October 2007US researchers have developed a blood test that measures levels of proteins associated with cell signalling, indicating whether people have the condition, or are likely to develop Alzheimer’s disease (AD) in the next few years [Ray S et al. (2007) Nat Med. Oct 14 (Epub ahead of print); doi:10.1038/nm1653], published in the journal Nature Medicine.

In seeking molecular biomarkers of disease, they reasoned that the levels of cell signalling molecules in the blood plasma might be altered as part of the disease process. Microarray analysis of the expression levels of 120 proteins in blood from cases (patients with AD) and controls (without AD), identified nineteen proteins that showed significantly different expression profiles in the two groups. Mathematical analysis produced a predictive model based on the levels of eighteen of these proteins, which was tested using samples from people with symptoms of dementia ranging from mild cognitive impairment to severe AD, and found to be consistent with previous clinical diagnosis in 89% of cases. Importantly, the test was found to perform with 81% accuracy when used to analyse blood samples taken from a group of 47 patients 2-6 years previously, and compared with current clinical status.

The eighteen proteins on which testing was based were found to be involved in two independent regulatory networks, one involving tumor necrosis factor alpha and monocyte-colony stimulating factor, and the other involving epidermal growth factor; these pathways are involved in inflammation, haematopoiesis (blood cell production) and apoptosis (programmed cell death). The authors conclude that these protein expression levels, which they dub the ‘cellular communicome’ may be a valuable target for therapeutic intervention as well as diagnostic testing, and further suggest that similar gene expression signatures may exist for other diseases of the central nervous system (CNS).

Comment: According to the Alzheimer’s Society, over 700,000 people in the UK have dementia of which Alzheimer’s Disease is thought to account for around half. A proteomic blood test for AD would be beneficial because it is often difficult to distinguish the condition from other forms of dementia and currently a definitive diagnosis can only be achieved post-mortem. Dr Susanne Sorensen of the Alzheimer's Society told the BBC: "Early diagnosis is essential if we are ever to develop treatments that can change the course or halt the progression of dementia rather than just treat the symptoms" (see BBC news). Similar excitement also surrounds Pittsburgh compound B, a molecular diagnostic that binds to amyloid plaques present in the brains of AD patients and is detectable using a PET scanner. However, the specificity and clinical validity of this compound is currently unclear.

Using a test to predict which individuals are likely to develop AD in coming years could be controversial; although it would probably be used only in patients already affected by mild forms of dementia and could therefore help to direct the most appropriate form of early treatment, current UK policy only permits the use of drug treatment in patients where the disease has reached moderately severe levels. In particular, the widespread implementation of a diagnostic test may be hindered by the current lack of treatments to cure AD or significantly halt progression in the early stages of the disease.

Further analysis with much larger samples will be required to verify how accurate the new test really is, but it nevertheless presents a promising area of research for both diagnostics and therapeutics for AD.

25 October 2007Three papers in a recent issue of Nature Methods describe the use of DNA microarrays as a highly efficient and cost-effective method for capture and amplification of thousands of DNA sequences simultaneously [Okou DT et al. (2007) Nature Methods. doi: 10.1038/nmeth1109, Porreca GJ et al. (2007) Nature Methods. doi: 10.1038/nmeth1110 and Albert TJ et al. (2007) Nature Methods. doi: 10.1038/nmeth1111].

 

Since its development in the early 1980’s, polymerase chain reaction (PCR) has been the dominant technology for amplification of specific DNA sequences. This ‘front-end’ step permits selective enrichment of discrete regions that can be sequenced in an individual read and then pieced together by a computer based on overlapping regions. However, PCR is limited to amplifying short pieces of DNA, has limited performance in repetitive regions of sequence and it does not multiplex easily for the purposes of analysing large genomes.

 

With a new generation of sequencing technologies (see Shendure J  et al. (2004) Nat Rev Genet. 5: 335-344 for a review) poised to reduce DNA sequencing costs and time requirements (see previous news), a major bottleneck is currently isolation of the target DNA to be sequenced. The research described in Nature Methods goes a long way to solving this problem. The new methods involve sonication of genomic DNA followed by hybridisation of the fragments to a custom designed high-density microarray, allowing for the capture of thousands of large DNA regions. The selected target DNA is then amplified using PCR technology ready for sequencing.

 

A senior author on one of the papers, Dr Richard Gibbs, director of Baylor College of Medicine’s Human Genome Sequencing Centre, said “this new technology will replace PCR for many purposes… if the aim is to sequence a whole genome for everybody, this is a huge step in that direction” (quoted in News-Medical.net).

 

Comment: This development is another step on the way towards faster, cheaper sequencing methods which are integral to future genomics research and the realisation of personalised medicine. So far, however, the methods have been trialled on exons (coding regions) which comprise only around 1% of the entire human genome. Although this methodology significantly reduces the amount of DNA that needs to be sequenced, the other 99% of the sequence, erroneously named ‘junk’ DNA in the past, is also a significant source of variation which may be critical to controlling gene expression and alternative splicing of gene products. Future developments in this technology will therefore rely upon even greater multiplexing.

15 October 2007Research carried out in the Netherlands has shown that earlier detection of clinically relevant cervical lesions can be achieved by the use of a genetic test for human papillomavirus [Bulkmans NWJ et al. Lancet (2007), doi: 10.1016/S0140-6736(07)61450-0].

 

The human papillomavirus (HPV) is a group of viruses that includes more than 100 different strains, more than 30 of which are sexually transmitted. Most people who become infected with HPV will not have any symptoms and will clear the infection on their own. However, certain high risk HPVs are the major cause of cervical cancer and may also play a role in a number of other cancers.

 

Unlike many cancers, cervical cancer can be detected and prevented prior to progression into full blown cancer. According to Cancer Research UK (CRUK) statistics, around 2,700 women are diagnosed with cervical cancer annually (1% of all cancer cases) with over 1,000 deaths from the disease. Although cervical cancer was once the leading cause of cancer death for women, incidence and mortality have declined significantly since screening of adult women aged 25-64 every 3-5 years started. The standard smear test, also known as Pap test after its inventor Georgios Papanikolaou, is a cytological test in which a sample of cervical cells is taken and then examined under a microscope for pre-cancerous changes. The sensitivity of the Pap test is relatively low and is compensated by a regular screening programme.

 

DNA testing for high risk HPV has a higher sensitivity than cytological testing for detecting cervical lesions, albeit with a slightly lower specificity. Therefore, significantly fewer false negatives would be reported using the genetic test, accompanied by a slight concomitant increase in the number of false positives. As a result, a combined cytological and HPV test is approved for use in screening of women aged 30 and over by the US Food and Drug Administration (FDA).

 

The Population Based Screening Study Amsterdam (POBASCAM) cohort study compares the outcome of around 17,000 women tested with just the Pap test versus the HPV DNA test. Each woman was followed for at least 6.5 years to cover the full period of two screening rounds plus possible repeat calls at 6 and 18 months. The DNA test identified 14 high risk types of HPV using multiplex PCR and detected 70% more lesions in the first round of screening. Significantly, the 5 year cumulative risk of lesions per woman screened decreased from 0.8% using the Pap test alone, to 0.2% using the HPV test alone and 0.1% using both tests. Based on these results, the researchers suggest that the current recommended maximum screening interval of 5 years be extended by at least a year, which could significantly reduce the number of lifetime screening tests. Clinical trials assessing the long-term effect of HPV DNA testing are on-going, and a full cost-effectiveness analysis is needed to determine whether the use of this additional test, with a slightly increased false positive rate, is offset by a reduction in the number of screening tests and the overall incidence of cervical cancer.

 

5 October 2007Most of the genetic difference between individuals is normally ascribed to variations in single bases – so-called single nucleotide polymorphisms (SNPs). However, research published in the journal Science suggests that structural variations in the DNA are much more common than previously assumed [Korbel JO et al. (2007) Science doi: 10.1126/science.1149504].

 

Researchers at Yale University developed a new technique in order to examine structural variation between two women of differing ethnic origins. The approach, known as paired-end mapping, involves breaking up genomic material into pieces of around 3 kilobases in length which are then analysing using a high throughput, rapid sequencing method developed by 454 Life

Sciences. Using this technique, the two 6 billion base-pair diploid genomes were sequenced several times over, revealing over 1,000 structural variations spread throughout the genome including indels (insertions and deletions) as well as inversions (a type of chromosomal rearrangement). Although the majority of rearrangements identified were small, less than 10 kilobases, some were over a 100 kilobases in size, potentially encompassing hundreds of genes. This work is supported by similar findings in Craig Venter’s diploid genome sequence (see previous news), where structural variations represented 74% of the variant bases between chromosomal copies.

 

Comment: This research could have a huge impact on genome-wide association studies searching for genetic determinants of disease, which have traditionally focused on point mutations (SNPs). However, exactly how structural variation between individual genomes can be incorporated into genetic epidemiological studies is unclear and may require substantial changes to the way genetic data are both collected and analysed.

3 October 2007Scientists in Singapore have developed a hand-held device for the rapid detection of H5N1 bird flu from a simple throat swab. This highly pathogenic virus is now well established in Southeast Asia with sporadic human infections leading to significant morbidity and mortality. World Health Organisation (WHO) containment plans to prevent a local outbreak leading to a global disaster rely upon timely diagnosis, quarantine and administration of antiviral drugs. There is therefore a desperate need in the field for a low-cost, user-friendly method for decentralised testing.

 

The operation of the microfluidic device is described in the journal Nature Genetics [Pipper J, et al. (2007) Nature Medicine doi: 10.1038/nm1634]. A droplet from a throat swab is placed inside the device onto a layer of mineral oil containing superparamagnetic particles. A permanent magnet is used to manipulate the droplet and perform standard tasks such as mixing, splitting and merging the sample. This allows multiple steps – viral cell lysis, RNA isolation, purification and concentration – to be carried out sequentially within the device. Even more remarkably, identification by ultrafast real time reverse transcription PCR is also performed inside the device using a miniaturised thermocycler. Although the efficiency of the PCR is only 93% compared with around 100% for bench-top PCR, the reduction to a hundredth of the normal reaction volume means that the cost is significantly lower. The authors estimate that each reaction is 2,000-5,000% cheaper than standard than a standard test. And due to the short diffusion distances and fast heat transfer typical in a microsystem, the entire test is completed in 28 minutes, compared with the typical 4 hour wait for a bench-top test.

 

This test could help contain an outbreak much more easily than other available laboratory tests for H5N1 and it is thought that this strategy could be easily adapted for other infectious diseases.

 

Comment: Although only currently at the prototype stage, this device is the first diagnostic platform of its kind. Providing that it can be shown to have high clinical specificity and sensitivity, point-of-care devices such as this for the rapid detection and identification of pathogens offer huge potential benefits to countries who can afford high tech public health surveillance. In the event that the H5N1 virus mutates and becomes more contagious to humans, this device could prove critical in preventing an epidemic by allowing fast diagnosis, isolation and treatment of infected persons.

3 October 2007Uninformed consent? Nat Med. 2007 13(9):999. Editorial calling for updated regulations for obtaining informed consent from clinical trials subjects in the US, in particular making clear whether or not they are likely to benefit from the intervention, in addition to the risks of participation (PubMed).

Will genomics widen or help heal the schism between medicine and public health? Khoury MJ, Gwinn M, Burke W, Bowen S, Zimmern R (2007) Am J Prev Med. 33(4):310-7. Special article / review arguing that genomics, whilst having the potential to push clinical and public health medicine further apart, should rather be integrated into health care via strong partnerships between the disciplines, to maximise the population health benefits (PubMed).

Medicine. The future of personal genomics. McGuire AL, Cho MK, McGuire SE, Caulfield T (2007) Science 317(5845):1687. Policy forum piece on the potential applications of genomics in medicine during this current period of transition from specific diagnostic genetic tests to assays for genetic variants of individually mild and poorly understood effect. The authors call for clinical practice guidelines, since ‘only clinically meaningful genomic test results should be integrated into medical decision-making’ (PubMed).

Integrating physical and genetic maps: from genomes to interaction networks. Beyer A, Bandyopadhyay S, Ideker T (2007) Nat Rev Genet. 8(9):699-710. Review of approaches to building maps and networks of complex biological interactions (PubMed).

Translation matters: protein synthesis defects in inherited disease. Scheper GC, van der Knaap MS, Proud CG (2007) Nat Rev Genet. 8(9):711-23. Review of genetic diseases caused by mutations that affect mRNA translation, and the possible role of such mutations in more common forms of disease (PubMed).

Epigenetics: Perceptive enzymes. Ferguson-Smith AC, Greally JM (2007) Nature 449: 148-149.News and Views article on new research into how DNA methyltransferases are capable of a high degree of sequence specificity (PubMed).

Life as we know it. Nature 2007 449(7158): 1.Editorial emphasising the importance of studying and comparing the genomes of different species, rather than solely focusing on the human genome (PubMed).

Genomics. DNA duplications and deletions help determine health. Cohen J. (2007) Science 317(5843):1315-7. News focus article reviewing the role of genome copy number variations (CNVs) in human health ad disease (PubMed).

Animal-human hybrid-embryo research. Lancet 2007 370(9591):909. Editorial on the HFEA decision to allow the creation of human-animal hybrid embryos for stem cell research, praising the consultative process (PubMed).

Asthma Genetics: From Linear to Multifactorial Approaches. Guerra S, Martinez FD (2007) Annu Rev Med. Sep 10; [Epub ahead of print]. Review of recent advances in asthma geneticscalling for a new dynamic disease model, in which variance in genetic and environmental factors are linked with phenotypic traits (PubMed).

Genetics of Alzheimer's disease. A rapidly evolving field. Serretti A, Olgiati P, De Ronchi D (2007) J Alzheimers Dis 12(1):73-92. Review underlining the importance of understanding gene-environment interactions in order to predict the risk of disease (PubMed).

Recent advances in genetic analysis of multiple sclerosis: genetic associations and therapeutic implications. Niino M, Fukazawa T, Kikuchi S, Sasaki H (2007) Expert Rev Neurother. 7(9):1175-88. Review looking at progress in (and prospects for) research into the genetic and pharmacogenetic factors that affect MS and its treatment (PubMed).

Screening for familial hypercholesterolaemia. Calonge N, Guirguis-Blake J. (2007) BMJ 335(7620):573-4. Editorial saying that universal screening as proposed by Wald et al. in the same issue of the journal is not justified by current evidence (PubMed). See also previous news.

Mechanisms of Disease: the genetic basis of coronary heart disease. Kullo IJ, Ding K (2007) Nat Clin Pract Cardiovasc Med. 4(10):558-69. Review of current knowledge about genetic factors affecting heart disease risk, and future challenges in extracting useful information from genomic studies (PubMed).

The Declaration of Helsinki. Goodyear MD, Krleza-Jeric K, Lemmens T (2007) BMJ 335(7621):624-5. Editorial looking at the development, current status and value of this key declaration in research ethics (PubMed).

The long and winding road. Nature 2007 449(7161):377. Editorial calling for German researchers to continue debate on the use of human embryonic stem cells in research, despite claims that adult stem cells will be an adequate alternative, in the run up to a review of national stem cell laws (PubMed).

Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins. Wang W (2007) Nat Rev Genet. 8(10):735-48. Review on current understanding of the FA protein network and its role in the response to DNA damage (PubMed)

Splicing in disease: disruption of the splicing code and the decoding machinery. Wang GS, Cooper TA (2007) Nat Rev Genet. 8(10):749-61. Review looking at the role of mutations and polymorphisms that disrupt normal splicing in disease and disease susceptibility (PubMed).

Gene conversion: mechanisms, evolution and human disease. Chen JM, Cooper DN, Chuzhanova N, Ferec C, Patrinos GP (2007) Nat Rev Genet. 8(10):762-75. Review on the mechanisms and implications of gene conversion, including known associations with human genetic disease (PubMed).

Renal abnormalities and their developmental origin. Schedl A (2007) Nat Rev Genet. 8(10):791-802. Review looking at genetic defects in kidney and urinary tract development and function (PubMed).

How geneticists can help reporters to get their story right. Condit CM (2007) Nat Rev Genet. 8(10):815-20. Science and society perspectives piece on the role of the media in communicating scientific advances, and how geneticists can minimize inaccurate and inappropriate coverage of their research results, such as genetic determinism (PubMed).

Nature Reviews this month has a new MicroRNA collection of key reviews from 2004-7, all of which are freely available until the end of March 2008

How do we monitor the impact of genomics on population health? Online seminarprovided by the US CDC National Office of Public Health Genomics and National Center for Chronic Disease Prevention and Health Promotion (presentation).

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