In the news

  • Newsletter Edition
The PHG Foundation monthly newsletter features news and views about genetics and genetics research, from a public health perspective. The newsletter is written by staff of the PHG Foundation.

In the news

Report of a story in the news   |   By Simon Leese   |   Published 17 December 2010

The advisory board of the US National Institutes of Health (NIH) have voted to create a new centre for translational medicine, with the aim of accelerating the progress of promising therapies from lab to clinic.

The move was catalysed by NIH Director Francis Collins (pictured) - an avid advocate of the importance of translational research - who had urged the NIH board to reach a decision this month in order that the centre would be eligible for funding in the coming financial year. If approved by Congress, money for the new centre could be in place before the end of 2011. Collins described the decision as a “momentous occasion”.

Our view:

The proposed centre would draw together several existing major programmes to create a ‘pipeline’ between basic and clinical research, and has been described as possibly the most significant evolution of the NIH to date. The plan has been enthusiastically greeted by some for its potential to not only speed progression to the clinic, but also to raise the profile of translational medicine and attract the best people to the field. Others however have expressed reservations, suggesting that the bureaucratic restructuring required could actually delay research, and have implied that the decision was rushed through without sufficient discussion. Collins acknowledged such concerns and assured that they would be addressed in order to ensure that there were no “unintended consequences”. He will now take the proposal to the Secretary of the Department of Health and Human Services who must approve it before presenting it to Congress.

Keywords : FundingGovernmentr

Report of a story in the news   |   By Dr Philippa Brice   |   Published 12 December 2010

Government funding for a major new stem cell research initiative in Australia has been announced, whilst an existing centre is set to close.

The Australian Research Council will give $21 million over seven years to establish the new Stem Cells Australia (SCA) initiative as an ‘international hub for stem cell research’. Academic partners are providing a further $11 million for the venture, which will fast-track research efforts and also create a public engagement arm to encourage debate on ‘the ethical, legal and public policy issues associated with stem cell science’ (see statement). SCA will apparently supersede the existing Australian Stem Cell Centre, whose funding will come to an end in 2011. Some experts warn that the total funding for such research is falling drastically, despite the new initiative; they also fear that money is to be devoted primarily to basic research at the expense of translational efforts.

Our view:

A possible refocus on basic stem cell research to the exclusion of the development of clinical interventions is an interesting move from the Australian government, in contrast to the new trend towards clinical trials of stem cell therapeutics (see previous news). Possibly their hope is that the commercial sector will fill this gap; this week Australian company Mesoblast Ltd announced a staggering $2 billion agreement with US company Cephalon to develop adult stem cell therapies.  

Keywords : Stem CellsFunding

News story   |   By Simon Leese   |   Published 8 December 2010

The funders of research in the UK have jointly published a set of principles designed to improve the engagement of the public with all areas of academic research. The Concordat for Engaging the Public with Research aims to embed a culture of public engagement within research institutions, and it outlines four key principles:

  • UK research has a strategic commitment to public engagement
  • Researchers are valued and recognised for public engagement activities
  • Researchers are enabled to participate through training and support
  • Progress will be regularly reviewed
  • Research Councils UK (RCUK) have produced a short film to promote the principles, and The National Coordinating Centre for Public Engagement have translated them into practical guidelines for four types of staff - Senior Managers, Managers of Researchers, Researchers, and Supporters of Researchers - available on the RCUK website.

    The Concordat says that it intends to provide a “single, unambiguous statement of the expectations and responsibilities of research funders in the UK”, and goes on to say that “much is to be gained by using the agreed principles to reconsider institutional policies and practice”.

    However, while clearly calling on research institutions to adopt proactive new policies for public engagement, without an explicit enforcement regime these are likely to only be encouraging sentiments rather than compelling priorities for researchers. The experience of the limited implementation of open access publishing over the last few years (see previous news) suggests that effectively changing the behaviour and priorities of institutions and researchers takes more than the publication of briefings and guidelines. 

    Report of a story in the news   |   By Dr Philippa Brice   |   Published 7 December 2010

    A major new centre for research in cancer genetics has opened in Cardiff.

    The £5 million Cancer Genetics Building, based at the University Hospital of Wales, will house researchers from the Institute of Medical Genetics. Head Professor Julian Sampson said: “The new facilities will help us to translate the discoveries we make in the lab and shape them into new tests and treatments in patients”. The centre will reportedly focus on linking two broad areas of research, into the genetic alterations linked to cancer and their effects on proteins in cancer cells.

    Our view:

    This month the Institute has also launched a new resource for new patients with familial forms of cancer; the Cancer Genetics Storybank website provides stories and perspectives from existing patients from the local cancer genetics service. The NHS National Genetics Education and Development Centre provides a similar online resource, but aimed at health professionals; Telling Stories: Understanding Real Life Genetics includes examples of familial cancers and many other forms of genetic disorder. 

    News story   |   By Simon Leese   |   Published 6 December 2010

    Researchers have constructed genetic ‘control circuits’ that can be programmed to make human cells alter their behaviour in a variety of ways in response to any chosen protein signal.

    The circuits are RNA sequences consisting of an input component (known as an aptamer) which senses and binds to a target protein, and an output component which encodes another protein, such as an enzyme. The output RNA sequence has a stop codon inserted within it that prevents it from being translated into a functioning enzyme; however when the aptamer binds to its target it results in a configuration change that causes the cell’s machinery to remove the stop signal, and the active enzyme is produced.

    The researchers created a version of the circuit with aptamers responsive to high concentrations of beta-catenin and NF-kappaB - both of which can be characteristic of cancerous cells - activating the production of an enzyme conferring sensitivity to the drug ganciclovir, which in turn causes programmed cell death. When the cells were induced to produce increased levels of the target proteins, those containing the circuits were killed when treated with ganciclovir.

    Artificial devices capable of altering cellular networks have been created before, but have been limited to responding to particular transcription factors, and have not been able to respond to varying protein concentrations within the cell. These new circuits are significant because in principle they can be configured to respond to any specified concentration or combination of target proteins with any desired output, making them potentially enormously powerful devices for research, biotechnology, and ultimately the clinic. Therapeutic application will be a long way off yet though; this proof of concept was carried out in cultured human cells where the potential unintended consequences of disrupting cellular pathways do not need to be considered.

    Report of a story in the news   |   By Simon Leese   |   Published 2 December 2010

    The pharmaceutical company Roche has announced that it is to cease research into RNA interference (RNAi) therapies.

    RNAi  is the technique of silencing specific genes by binding complementary RNA sequences to their transcripts before they are translated into proteins, a process that occurs naturally as part of gene regulation in cells. The process was discovered in 1998, and had been thought by many to be one of the strongest prospects for future therapies, offering the possibility of tailored sequences that could switch off disease-causing genes ‘to order’.  However there have been no RNAi therapies available to patients to date; the biggest issue has been the delivery of RNA molecules to their target cells.  

    Our view:

    The announcement, coming after three years and more than $500 million invested in the research, is part of a corporate restructuring that will involve the cutting of around 6% of Roche’s staff worldwide over the next two years. The news has been described as the biggest vote of no confidence in RNAi to date and has resulted in tumbling share prices for specialist RNAi companies such as Alnylam who had already been forced to lay off staff after Novartis elected not to extend its partnership with them earlier this year.  

    Despite this potential setback for the future of RNAi, other big pharma companies remain invested in it; Merck’s programme continues, and CEO of Alnylam John Maraganore says that the three years that Roche spent on the technology is not enough to evaluate it properly, that “It’s like kicking your three-year-old out of the house and telling him to get a job”.

    Report of a story in the news   |   By Dr Philippa Brice   |   Published 1 December 2010

    The US Commission for the Study of Bioethical Issues has concluded that strict regulation of synthetic biology is unnecessary, calling instead for ‘prudent vigilance’. 

    The presidential panel has been tasked with examining the issues surrounding synthetic biology, following the creation of a bacterial cell with a synthetic genome earlier this year (see previous news). After hearing evidence, the panel has reportedly concluded that watchful oversight of the field constitutes a sufficient level of regulation at present, since the possibilities and risks of synthetic biology are not yet fully understood. However, a government group should undertake ongoing risk analysis and identify potential gaps in existing regulation. Other proposals in the report due out later this month include expanded biosafety training for those involved, marking of synthetic organisms to allow tracking, and the creation of a website by a non-profit group ‘for examining biotechnology claims’. 

    Our view:

    The overriding concerns with respect to synthetic biology are that an engineered organism could cause unexpected environmental harm, or even be used as a tool for bioterrorism; however, the impact of such events must to be balanced against the actual risks of them occurring. Given the potential medical and commercial benefits of synthetic biology, the current plans for a positive but careful watching brief, seem sensible, and contrasts interestingly with the highly protectionist approach to genetic information in the US.

    Research articles

    Analysis of a study published in a science journal   |   By Dr Caroline Wright   |   Published 16 December 2010
    Study: Genetic correction of PSA values using sequence variants associated with PSA levels
    By: et al. (49 authors total)
    In: Science Translational Medicine
    What this study set out to do:

    Combine genetic variants with prostate-specific antigen (PSA) testing to improve the performance of prostate cancer screening

    How they went about it:

    A genome-wide association study was performed to locate genetic variants associated with PSA levels, based on data from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. This was followed by an assessment of the improvement in predictive accuracy of PSA testing when combined with either these genetic variants or all prostate cancer susceptibility variants in 415 Icelandic and 1,291 British men with information on biopsy-outcome (i.e. biopsy positive or negative). 


    Variants at six loci were found to be associated with PSA levels, two of which were not also associated with prostate cancer risk. By applying the combined genetic effect of all 23 known PSA and prostate cancer susceptibility variants on the commonly used PSA threshold for biopsy, the test was slightly better able to discriminate between outcomes: the area under the ROC curve (AUC, which varies from 0.5-1.0, where a value of 1.0 indicates a perfect performance) improved from 0.704 to 0.732 in Icelandic men and 0.571 to 0.636 in British men. Applying this genetic correction, 6-7% of Icelandic men would be reclassified with respect to whether they should undergo biopsy.


    The authors propose that a personalised PSA cut-off value, based on genotype, should be used when deciding to perform a prostate biopsy.

    Our view:

    Although there is substantial international variation, PSA screening for prostate cancer is currently not offered systematically in the UK because it is unclear whether the benefits outweigh the harms due to the large number of false positive results (see previous news). This study is an important step towards trying to improve the balance, by using genetic factors in addition to PSA testing to determine whether a man is likely to have prostate cancer and should go on to have further testing. Although the addition of genetic variants associated with prostate cancer did improve the predictive accuracy of PSA testing, the improvement was marginal and the advice for the vast majority of men would be unchanged. As the accompanying perspective points out, “although this study presents an auspicious beginning, on the basis of the AUCs and reclassification analysis, it does not appear that SNP-adjusted PSA values are primed for translation into clinical practice without additional follow-up studies”. Further large population studies are needed to investigate whether using individual genetic factors, in combination with age and other risk factors, to modulate the PSA threshold for biopsy would substantially improve outcomes.  

    Analysis of a study published in a science journal   |   By Dr Gurdeep Sagoo   |   Published 15 December 2010
    Study: Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis.
    By: et al. (22 authors total)
    In: Nature Genetics
    What this study set out to do:

    To identify genetic loci associated with susceptibility to endometriosis.

    How they went about it:

    The researchers performed a genome-wide association study (GWAS) comparing more than 500,000 SNPs in 3,194 patients with endometriosis and 7,060 healthy male and female controls from Australia and the UK. Initial findings were followed up in a replication sample of 2,392 patients and 2,271 controls from the US. The two cohorts were combined in a meta-analysis.


    This study reports an association on chromosome 7p15.2 (rs12700667) located close to genes (NFE2L3, HOXA10, HOXA11) involved in placental and uterine development. The researchers were also able to replicate an association on chromosome 1p36, located near a gene (WNT4) involved in ovarian follicle and reproductive tract development, when combining their data with that of a Japanese GWAS.


    The authors conclude that this new locus on chromosome 7p15.2 is significantly associated with endometriosis risk in European women as well as replicating a previous finding on chromosome 1p36. Both associations were stronger when patients were sub-catergorised into those with moderate to severe disease and both regions contain interesting biologically-plausible candidate genes. 

    Our view:

    This study not only identified a novel association in women of European ancestry but also replicated an association previously identified in a smaller Japanese population study. Both regions contain biologically interesting candidate genes and so further work is needed to try to identify whether these candidate genes are causally involved in the development of endometriosis. The principal association from this study was estimated to account for less than 1% of the 51% heritability attributed to genetic factors and so much work remains to identify additional genetic risk loci as well as how these loci interplay with each other as well as with the environment.

    Analysis of a study published in a science journal   |   By Dr Philippa Brice   |   Published 14 December 2010
    Study: Short Telomeres and Stem Cell Exhaustion Model Duchenne Muscular Dystrophy in mdx/mTR Mice
    By: et al. (11 authors total)
    In: Cell
    What this study set out to do:

    To test the theory that the milder muscular dystrophy phenotype in mice with dystrophin gene mutations compared with humans (for example, with Duchenne muscular dystrophy, DMD) is due to longer telomeres and larger reserves of muscle stem cells. 

    How they went about it:

    Mice with dystrophin mutations (mdx mice) were genetically modified to remove normal telomerase activity and assessed for symptoms of muscular dystrophy. 


    The mice showed a severe phenotype similar to that of human DMD, with serious and progressive loss of muscle function and shortened life-spans. Transplantation of muscle stem cells into these mice alleviated some of these symptoms


    The muscle defect caused by mutations in the dystophin gene in combination with gradual depletion of muscle stem cells over time produces the dystrophic phenotype. The much milder phenotype in mdx mice may be because mice have significantly longer telomeres than humans, giving their muscle stem cells greater ability to regenerate. DMD is not purely a genetic disease, but rather a multi-factorial condition. 

    Our view:

    This study would be of great value merely in creating an improved mouse model to further ongoing research into the devastating disease DMD. However, it also opens a new line of scientific enquiry with respect to the underlying pathogenesis of the disease in humans, and raises the prospect of potential new therapeutic interventions – whether using stem cell treatments, or new approaches to enhance the telomere function or regenerative capacity of patients’ muscle stem cells.

    Analysis of a study published in a science journal   |   By Dr Anna Pokorska-Bocci   |   Published 10 December 2010
    Study: Mutations in MAP3K1 Cause 46,XY Disordersof Sex Development and Implicate a Common SignalTransduction Pathway in Human Testis Determination
    By: et al. (22 authors total)
    In: The American Journal of Human Genetics
    What this study set out to do:

    To examine the genetic basis of disorders of sex determination (DSDs) and in particular to determine whether the disruption of MAP3K1 could be responsible for the DSDs in some patients.  

    How they went about it:

    Two families were recruited with several members affected by DSDs, and additional sporadic cases were also examined. Some of the people participating in the study were women with apparently male karyotypes, and others were males who had abnormal sex development. The MAP3K1 gene from all participants was sequenced; this gene is a member of the MAP kinase signalling pathway and of interest because the mouse equivalent shows strong expression throughout the sex-determining stage of gonad development.


    Affected members of the two families and two of the sporadic cases were found to have an alteration in their MAP3K1 gene. Several variants were identified but none previously reported as a known SNP. The mutations were shown to alter the regulation of the MAP3K1 gene in cultured lymphoblastoid cell lines.


    Mutations in the MAP3K1 gene result in specific human DSDs with abnormal gonadal development. The results of the study suggest that the MAP kinase pathway may be involved in the balance of expression between the various genes involved in directing the undifferentiated gonad to become a testis or an ovary. 

    Our view:

    These findings shed new light on the genetic causes of DSDs, which are often associated with fertility problems and emotional and social stress, and identify a potentially important biological switch in the process of sex determination during development. They could also improve the clinical management of DSDs patients as alterations in MAP3K1 can lead to the development of life-threatening tumors. Removal of the gonads early in life could therefore be an important preventative intervention.  

    Analysis of a study published in a science journal   |   By Dr Caroline Wright   |   Published 9 December 2010
    Study: Maternal plasma DNA sequencing reveals the genome-wide genetic and mutational profile of the fetus
    By: et al. (11 authors total)
    In: Science Translational Medicine
    What this study set out to do:

    Determine the genetic profile of a fetus at risk of inheriting beta-thalassaemia, using cell-free DNA circulating in the maternal blood. 

    How they went about it:

    The mother and father were genotyped using a SNP-array, and deep sequencing was performed on cell-free DNA fragments extracted from maternal plasma using next generation sequencing technology. Following alignment of the plasma DNA against a reference human genome, comparison with parental SNPs was used to determine the proportion and size of fetal DNA in the maternal plasma, to infer maternal and paternal inheritance patterns, and to create a genome-wide profile of the fetus.


    The entire fetal genome was represented in maternal plasma, comprising just over 11% of cell-free DNA (at 12 weeks gestation). The fetus was found to have inherited the paternal beta-thalassaemia mutation but not the maternal one. 


    This proof-of-principle study suggests the feasibility of using genome-wide scanning to construct a fetal genetic map and determine the mutational status of the fetus from maternal plasma. The method could be applied to non-invasive diagnosis of numerous fetal genetic disorders including autosomal recessive conditions that are not currently possible using standard techniques.

    Our view:

    Non-invasive prenatal diagnosis would allow couples at risk of passing on an inherited condition to their child to avoid a 1% risk of miscarriage associated with invasive diagnostic tests such as amniocentesis. This pioneering study is the first to produce a genome-wide profile for the fetus from a maternal blood sample, and describes a methodology that is potentially applicable to non-invasive diagnosis of almost any genetic condition, rather than being limited to specific traits (such as the sex of the fetus) like most previous methods. However, before such a test could be offered in the clinic, a much larger study is required to determine the robustness of the technique, and numerous logistical, economic and ethical issues need to be addressed, including how to deal with unexpected or incidental findings.

    Analysis of a study published in a science journal   |   By Dr Gurdeep Sagoo   |   Published 3 December 2010
    Study: Recommendations for genetic variation data capture in developing countries to ensure a comprehensive worldwide data collection
    By: et al. (14 authors total)
    In: Human Mutation
    What this study set out to do:

    To create recommendations and guidelines that encourage and allow greater participation of developing countries in documenting the human genetic variation observed worldwide.

    How they went about it:

    Building on the Human Variome Project (see previous news), two planning and implementation workshops in 2008 and 2010 allowed participants from both developing and developed countries to discuss the importance of developing world participation. They also documented current work on National/Ethnic Mutation Databases (NEMDBs), and considered how to harmonise and extend data collection in order to maximise utility.


    The following seven guidelines and recommendations were made.

  • Develop procedures to include clinicians and researchers in developing nations, mostly by creating networks among those of common interest.
  • Create international networks from closely related populations to enhance communication, interaction, and initiate research networks between them.
  • Foster communication, interaction, and research networks between developing and developed countries.
  • Ensure that the database management systems that are being used or developed can be utilised by those in a limited resource environment.
  • Provide support to developing countries to build capacity and to fully participate in the collection, analysis and sharing of genetic variation information.
  • Develop a framework to facilitate interactions between the coordinating centre and national, regional and international agencies.
  • Ensure that all ethical, legal, religious, and social issues are thoroughly considered when NEMDBs and/or data capture projects are launched in developing countries.
  • Conclusion:

    Documenting these population and ethnic specific genetic variation data in developing countries can produce real and tangible benefits not only in improving disease understanding and improving health but also in economic benefit (such as increased human capital).

    Our view:

    Whilst inclusion of data from populations in developing countries is important, the value of genomics for such countries is not merely via large-scale research projects, but also in using existing and emerging genomic technologies for immediate public health needs (see recent report on global public health in the genomic era). Several of these recommendations are also implicitly included in the PHG Foundation Framework for action on birth defects project.

    Analysis of a study published in a science journal   |   By Dr Philippa Brice   |   Published 2 December 2010
    Study: Common variants in DGKK are strongly associated with risk of hypospadias
    By: et al. (19 authors total)
    In: Nature Genetics
    What this study set out to do:

    Identify genetic variants associated with risk of the common birth defect hypospadias, malformation of the male urethral opening on the penis. 

    How they went about it:

     A genome-wise association study (GWAS) using SNP microarrays was performed on 436 cases and 494 controls (European descent), and replicated in two additional groups – a Dutch sample of 133 cases and their parents, and a Swedish sample of 266 cases and 402 controls.


    Ten genetic variants were identified as potentially associated with hyposapdias in the first GWAS analysis, and statistically significant association of two of these ten SNPs with risk of hyposapdias was confirmed in the replication analyses. These two SNPs were both located in the DGKK gene on the X- chromosome and appear to more than double the risk of the condition.


    The authors calculated that around one third of hypospadias cases were associated with a single SNP in the DGKK gene; although careful to note that ‘independent population-based studies should be performed to verify the validity of the estimate’, they point out that, if verified, it would be a relatively strong genetic association for a multifactorial disorder, comparable to the APOE4 variant and Alzheimer’s disease risk. 

    Our view:

    Hypospadias is often (though not always) a relatively minor birth defect, correctable by surgery , but it is also a very common abnormality, affecting around 1 in 750 births in Europe, and hence a not insignificant public health issue. Moreover, it can be associated with other birth defects, and so better understanding of the underlying genetics could also shed light on related malformations. Further studies would therefore be a good idea.

    New reviews and commentaries

    Selected new reviews and commentaries, 1 December 2010

    Reviews & commentaries : by Dr Philippa Brice

    Epigenetic epidemiology of common complex disease: prospects for prediction, prevention, and treatment

    Relton CL, Davey Smith G. PLoS Med. 2010 Oct 26;7(10):e1000356


    Translating genomics into improved healthcare

    Hingorani AD, Shah T, Kumari M et al. BMJ. 2010 Nov 5;341:c5945. doi: 10.1136/bmj.c5945


    Antenatal haemoglobinopathy screening

    Shakespeare J. BMJ. 2010 Oct 18;341:c5243. doi: 10.1136/bmj.c5243


    Triggers for genomic rearrangements: insights into genomic, cellular and environmental influences

    Mani RS, Chinnaiyan AM. Nat Rev Genet. 2010 Dec;11(12):819-29.


    New mutations and intellectual function

    Lupski JR. Nat Genet. 2010 Dec;42(12):1036-8.


    FTO gains function

    Stratigopoulos G, Leibel RL. Nat Genet. 2010 Dec;42(12):1038-9.


    Phenomics: the next challenge

    Houle D, Govindaraju DR, Omholt S. Nat Rev Genet. 2010 Dec;11(12):855-66.


    Evolutionary genomics: When abnormality is beneficial

    Berman J. Nature. 2010 Nov 11;468(7321):183-4.


    Mitochondrial genetic diseases

    Falk MJ, Sondheimer N. Curr Opin Pediatr. 2010 Nov 1. [Epub ahead of print]


    Resurrection of a stem-cell funding barrier - Dickey-Wicker in court

    Annas GJ. N Engl J Med. 2010 Oct 28;363(18):1687-9


    Targeting the Basic Defect in Cystic Fibrosis

    Welsh MJ. N Engl J Med. 2010 Nov 18;363(21):2056-2057.


    The case for RNA

    Liu CC, Arkin AP. Science. 2010 Nov 26;330(6008):1185-6. 


    Gamma-Secretase and Human Disease

    Kelleher RJ 3rd, Shen J. Science. 2010 Nov 19;330(6007):1055-6


    Prion-like behavior of amyloid-beta

    Kim J, Holtzman DM. Science. 2010 Nov 12;330(6006):918-9.


    No rest for the bio-wikis

    Callaway E. Nature. 2010 Nov 18;468(7322):359-360.


    Double trouble? To throw cash at science is a mistake

    Sarewitz D. Nature. 2010 Nov 11;468(7321):135

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