News

31 March 2009 There have been several developments in the US recently in the controversial area of open access publishing of scientific research. On 11 March, the public access policy of the US National Institutes of Health (NIH ) was made permanent. First adopted in January 2008, this policy was previously subject to annual renewal. It states that all NIH-funded researchers must submit an electronic version of their peer-reviewed manuscripts to the National Library of Medicine’s PubMed Central (PMC), making them freely available to all no later than 12 months after publication. On 18 March, the Massachusetts Institute of Technology (MIT) adopted the policy that all faculty members’ publications will be available for free on the web (see MIT news article ). This follows the adoption of a similar policy by the Faculty of Arts and Sciences at Harvard University last year (see press release ). Unlike the NIH policy, neither institution grants a period of ownership to the publishers, but claims the right to freely disseminate the work of their faculty immediately.

These developments are controversial because they threaten the traditional model of scientific publishing, and the whole financial basis of the academic publishing industry. As more and more research is read online rather than in print journals, mandatory free online access to both all publicly-funded research, and to that produced by the nation’s most important academic institutions, would appear to leave little room for publishers to generate income.

In a bid to overturn the NIH policy, US Representative John Conyers has introduced a Bill into Congress, the Fair Copyright in Research Works Act H.R.801, which would rescind the right of Federal agencies to require the transfer or waiver of copyright for research that they have funded. Rep. Conyers has been debating his position with Professor Larry Lessig – co-founder of Change Congress, a group that campaigns against special interest groups influencing Congress – in the popular liberal weblog and news site The Huffington Post. Lessig accuses Conyers of opposing the public’s right to access research that they have effectively already paid for and has suggested that Conyer’s position is influenced by financial contributions from the publishing industry. Conyers responds that he does not oppose open access, but is concerned that the loss of journals’ copyright undermines the source that funds the peer-review process – which is crucial for quality control of scientific publications – and will ultimately damage science (see also previous news ).

Scientists are effectively caught in the middle of this debate, conflicted by their reliance on both funders and publishers in order to sustain their careers. Scientists wish to see their work as widely disseminated and read as possible, but are motivated to publish in recognised high impact journals in order both to enhance their scientific standing, and to secure future funding; since a recognised publication track record is a key factor in attracting funding. Many major journals have adopted some level of open access over the past few years, typically allowing free access a year after initial publication, whilst the PLoS initiative has led to a range of highly regarded online open access journals that charge authors to publish, rather than readers to access articles. Many smaller niche journals however fear that they may not be able to operate profitably under either of these models.

In the UK, both the MRC and the Wellcome Trust now have open access policies for the research they fund, requiring that electronic copies of papers be deposited in PubMed Central or UK PMC within six months of publication. Whereas in the US the open access policy for publicly funded research is written into law, and is a mandatory condition of the grant award, in the UK the means of enforcing compliance unclear, and many MRC and Wellcome Trust funded researchers continue to publish in journals that do not support open access.

Scientific publishing is currently undergoing a revolution, and the move towards open access has the clear benefit of removing financial barriers to accessing scientific knowledge, putting disparately-resourced institutions and countries on a more equal footing and facilitating the performance of studies such as meta-analysis or literature reviews. It is vital for the credibility of science, however, that the standards of peer review are not eroded in the process. It remains to be seen whether the outcome of this revolution will be a new uniform online-only publishing landscape, or a patchwork of traditional and alternative approaches.

27 March 2009 The Times newspaper has reported that some UK National Health Service (NHS) hospitals are refusing to permit private collections of umbilical cord blood at birth. Cord blood is a source of stem cells with the potential to be used for the treatment of serious diseases; both public and commercial stem cell banks store samples of cord blood for these purposes. However, public cord blood banks provide samples for the treatment of unrelated individuals; commercial companies may reserve each samples for the sole use of the original donor, although the Virgin Health Bank is a commercial bank that also requires an altruistic donation of a sample from each collection to a public resource. Of note, although cord blood retained for potential future use by the new baby would be a perfect tissue match, the probability of it being needed is extremely small. An individual receiving cord blood from a public resource would not receive a perfect tissue match – but, given a significantly large pool of available samples, it should be possible to identify a sample that will provide a satisfactory tissue match for transplantation purposes.

In 2008, the UK Human Tissue Authority (HTA) announced new regulations governing the collection of umbilical cord blood requiring that in hospital maternity units must be licensed to perform collections; licensing requires that hospitals meet certain minimum standards of procedure both for harvesting the cells and for maintaining care of the mother, as well as paying several thousand pounds (see previous news). Commercial banks now provide a licensed healthcare professional to perform the harvesting procedure.

The Times newspaper has reported that King’s College hospital in London and Watford General hospital in Hertfordshire have banned the collection of stem cells at birth for private (individual) storage, whilst permitting collections for donation to the public NHS Cord Blood Bank or Anthony Nolan Trust cord blood bank. Other hospitals such as the University College London hospital are reported to ban any personal collections of stem cells, including for donation to public banks (see Times report). Individuals who wish to store cord blood for private use – including those with strong personal reasons for doing so, such as the woman featured in the article, whose sister died from a rare blood disorder – may need to pay not only for private collection of the cord blood, but also to give birth in a private hospital that would permit this, which would be substantially more expensive. This could be seen as widening still further the inequity of healthcare services available to the majority of citizens and the few with significant personal wealth.

This is a particular issue in the UK, with a national public healthcare system. In countries where insurance-based medical care is prevalent, commercial cord blood banking is already booming, notably in Asia and the US. This month the merger of two cord blood banks Biocell and Cellsense to create Australia’s largest private cord blood bank, Australian Stem Cell Healthcare Pty Ltd, was announced, making it possible for parents have cord blood collected after giving birth in any hospital in Australia. Biocell chief executive Professor Mark Kirkland also commented that “…the size of Australian Stem Cell HealthCare Pty Ltd gives us the power to lobby government and private health funds in order to make storage of cord blood stem cells an affordable and essential service for all Australians, which is in line with international endeavours" (see NineMSN news report). Whilst donors retain ownership of the samples, the companies are reportedly involved in collaborative research into stem cell therapeutics (see LifeScientist news article).

Meanwhile in the US, new legislation has been introduced that would provide tax advantages for families paying for cord-blood banking (see press release). The Family Cord Blood Banking Act would amend the Internal Revenue Code to add cord blood banking services as a qualified medical expense, allowing individuals to pay for it via flexible health savings or reimbursement systems, or to include it with other tax-deductible medical expenses (see press release).

24 March 2009 The European Organisation for Rare Diseases, EURORDIS, is a patient-driven alliance of patient organisations and individuals active in the field of rare diseases, many of which are genetic disorders. The organisation has been conducting a series of surveys as part of the Eurordis Survey Programme, which aims to contribute to the establishment of guidelines and standards for the management of rare diseases throughout Europe. Summaries of the findings from two of these surveys have been published in a book - The Voice of 12,000 Patients (reported by the Lancet).

The Eurordis Survey Programme has conducted three surveys since 2003, aimed at gathering patient views on the diagnosis and access to health services for 18 rare diseases across 22 European countries. The first survey – EurodisCare1– was designed to measure the differences between European countries on rare disease care, focusing on diagnosis, treatment, level of knowledge and need and provision of services for rare diseases. EurodisCare2 was launched to identify the main causes that lead to delays in diagnosis and subsequent treatments and their preventable consequences. The final survey, EurodisCare3, was carried out in order to gather patient perspectives that would inform recommendations for the creation and development of National Centres of Expertise and a European Reference Network that would address the unmet needs of patients. The findings of these surveys reflect the challenges faced by patients in a quantitative way, such as the number of misdiagnosed patients (40%) and the number of patients who reported waiting between 5 and 30 years from the appearance of the first symptoms to receiving the correct diagnosis (25%). It is hoped that the book will be of benefit to stakeholders as well as patients and contribute to “shaping patient-centred public health policies” (see The Voice of 12,000 Patients).

Diagnosis of rare diseases is often difficult due to their broad diversity and spectrum of symptoms. Recently, the US based National Centre for Genome Resources (NCGR) and Beyond Batten Disease Foundation have announced a partnership in order to develop a multiplex screening test for over 75 rare diseases (see press release). It is still undecided yet what platform will be used for testing, i.e. microarray or next-generation sequencing. However, the Foundation is hoping that this screening test will help eradicate Batten disease.

Rare diseases are those with low prevalence (affecting fewer than one in 2000 individuals) and are often characterised by chronic, degenerating conditions. Approximately 80% of these diseases have an identified genetic origin; others can be a result of infections or environmental influences. However, these diseases are often difficult to diagnose due to the diversity of disorders and this can lead to inaccuracies in the management of patients. In addition, due to the rarity of these conditions, specialist services for their care can be lacking. Endeavours like the Eurordis survey are important in gathering patient views in order to understand gaps in health service provision which can inform improvements care.

21 March 2009

The Framingham Heart Study is a well-known health research project initiated in 1948 in the town of Framingham, Massachusetts, and supported by the US National Heart, Lung, and Blood Institute. The study recruited a large group of healthy middle-aged participants who were followed over the coming years to look at the incidence of cardiovascular disease (CVD), with the aim of identifying key factors involved in CVD. The recruitment and follow-up of large cohorts of people over time is now a well-established form of research (for example, projects linked to the UK Biobank initiative), but the ongoing Framingham Heart Study was among the first of its kind. Now, the Framingham study is to embark on a new project to identify biomarkers for CVD that could be measured via blood tests via a public-private partnership with company BG Medicine, in collaboration with Boston University School of Medicine and School of Public Health.

The project is called the Systems Approach to Biomarker Research in Cardiovascular Disease (SABRe CVD), and will use BG Medicine’s technology for the detection and validation of molecular biomarkers, and linked changes in gene expression. Around 1000 blood biomarkers will be studied, and levels correlated heart disease, metabolic syndrome and other risk factors in around 7000 study participants. Data from the project will be made available to other researchers via the Database for Genotype and Phenotype.

NHLBI Director Elizabeth Nabel said: "Imagine having a simple blood test to tell us if a patient is at high risk for a heart attack or stroke - we could do so much more to prevent or delay these often debilitating and deadly diseases" (see press release). However, previous work has suggested that the additional predictive value of biomarkers for CVD on top of well-established risk factors and markers such as blood pressure and blood cholesterol levels is likely to be limited, so that this research, while valuable, may not have as great an impact on public health initiatives as suggested. Data from this sort of study can also be very difficult to interpret when attempting to decide whether or not they justify an alteration in policy.

18 March 2009Genetic testing company 23andMe has announced plans to collect DNA samples from 10,000 people with Parkinson’s disease as the basis for a new genome-wide association research project to identify genetic variants associated with increased risk of developing the disease, disease progression, or with individual responses to current Parkinson’s medication. The project will be carried out in conjunction with two non-profit US research groups, the Parkinson’s Institute and the Michael J. Fox Foundation, and only patients registered with these groups will be able to participate, although the project could be extended to non-US Parkinson’s charities. DNA and lifestyle data will be compared with control information from normal paying customers of 23andMe who choose to participate.

Participants will receive a kit to take and submit saliva samples for DNA extraction, and to complete an Internet-based survey with information about their disease and treatment history, along with lifestyle information that could be relevant in identification of environmental factors involved in the disease. They will receive information about their own genetic variants in the same way that paying customers would, as well as information on any discoveries arising from the project, becoming part of what the company is styling the 23andMe Parkinson’s Community. 23andMe founderAnn Wojcicki said: “We’re very frustrated with the pace of research discoveries and we felt one way to accelerate it would be to empower individuals and form communities and self-create a research cohort...We also believe we are really democratizing research in a new way” (see Bloomberg news report).

Google co-founder Sergey Brin, who is married to Ann Wojcicki, is providing financial backing for the project; he reportedly has variant of the LRRK2 gene previously associated with an increased risk of developing the disorder, which also affects his mother, and the couple have a child who has reportedly been tested for the LRRK2 gene variant. Ms Wojcicki commented: “We are highly motivated about this disease because of Sergey, but also potentially because of our child” (see Times news report). The financial subsidy means that Parkinson’s patients who choose to participate in the project will be charged US$25 for the full genotyping service, which normally costs US$399.

Experts have expressed some reservations about the value of the project, depending on how well it is designed and carried out; there are concerns that the recruitment process for both patients and controls could be subject to particular bias. The (admittedly small) fee required for participation is also controversial. The company says that the use of the internet “significantly increases the efficiency and reduces the cost of recruiting participants and conducting research” (see press release), although participation in this sort of medical research project is usually free.

17 March 2009The US Secretary’s Advisory Committee on Genetics, Health and Society (SACGHS) has released a draft report on gene patents and their impact on patient access to genetic tests for public comment (see GenomeWeb report). The report was drafted together with Duke University’s Centre for Genome Ethics and contains findings on how gene patents affect clinical and patient access to genetic tests, as well as suggested policy options for consideration by the public. In conducting this inquiry, the Committee has narrowed its scope to “genetic tests that rely on analysis of nucleic acid molecules to determine human genotype, whether used for diagnostic, predictive or other clinical purposes” (see press release). This means that patent claims in relation to genetic tests that infer genotype based on analysis of other biomarkers (e.g. biochemical assays for proteins) were not included.

Information on the impact of gene patents on patient and clinical access to genetic tests was gathered through conducting literature reviews, expert consultations, exploring international perspectives and gathering public views. They examined eight-comment-gene case studies of ten diseases to see how gene patents influence pricing, access to and availability of genetic tests, new innovations and research related to genes, and other areas. They also considered the effects of gene patents on translational research, as patient access could also be influenced by how new tests are developed and integrated into clinical practice. The findings indicated that although there was little consistent evidence to indicate either positive or negative influence of gene patents on patient access to genetic tests, there were several issues of concern which could create barriers in the future, as the number and complexity of genetic tests increase. One of these concerns is that multiplex testing and whole genome sequencing may be hindered by patenting of genes.

As a result, the Committee has suggested a number of policy options such as developing a set of principles and guidance documents to engage stakeholders in a discussion of issues related to patenting and licensing strategies, and adoption of practices by Federal regulators that would allow increased transparency of intellectual property rights in order to allow uniform assessment and monitoring of the landscape. In addition, they also propose policy developments to allow more data on gene patenting and licensing to be gathered, and studies of the implementation of Federal intellectual property laws, as information in respect to these (especially in relation to DNA-based interventions) was found to be lacking.

SACGHS is hoping to receive input on its preliminary findings contained in the report and the policy options from the public prior to developing specific recommendations for the Secretary of Health and Human Services (HHS).

16 March 2009How extensively should governments be able to share personal data without consent for the public good? This question has vexed many of those involved in medical research who have sought more effective means of carrying out large scale research studies without the need to take consent from every patient. Issues arising from the use of personal data for medical research were the subject of a review by the Academy of Medical Sciences in 2006, and it was widely acknowledged that the complex legal and regulatory framework arising from statute and case law, created widespread uncertainty about the limits to legitimate sharing. These concerns, coupled with some gross lapses in security which caused major losses of data, caused the Government to commission a report from Richard Thomas, (Information Commissioner) and Dr Mark Walport (Director of the Wellcome Trust) last year. Their subsequent Data Sharing report (published in July 2008) contained robust criticisms of the current position arguing that 'the law and its framework lack clarity, responsiveness and bite' and set out a series of recommendations for improving systems for data sharing which were broadly accepted by the government.

One of these recommendations, namely that a fast track procedure should be established 'where there is a genuine case for removing or modifying an existing legal barrier to data sharing' formed the basis of data sharing clauses in the Coroners and Justice Bill which has just completed its committee stage in the House of Commons. However, the scope and breadth of those clauses have been roundly condemned as being disproportionately wide in scope, and even that they would allow government to ride roughshod over the protections contained in existing national legislation (such as the Data Protection Act) or even the Human Rights Act itself, particularly if the clauses were used to deliver large scale policy initiatives such as the National DNA database or the National Identity Register. Moreover, critics argued, the safeguards contained in the draft legislation, namely that the Office of the Information Commissioner could police any applications and determine whether they were 'necessary and proportionate' were inadequate to quell worries that these provisions might cause evaporation of public confidence. Indeed these fears were compounded by the fact that the safeguard mechanism of issuing assessment notices by the Office of the Information Commissioner was limited to the public sector and not private and voluntary sectors.

Significantly Sir Mark Walport, a joint author to the review which had initiated these reforms stated in a written Memorandum to the Committee scrutinising the Bill that 'the drafting goes wider than the precisely defined circumstances' defined in our Recommendation’. The Office of the Information Commissioner also argued that 'the Bill's information-sharing provisions are too wide, and its safeguards too weak'.

For medical research charities, it was ironic that the most trenchant critics of these provisions in the Bill (such as Liberty) used the example of sharing medical records without consent as one of the abuses which were likely to flow from these provisions, whilst the Thomas and Walport Data Sharing Review had made a set of separate recommendations which addressed the difficulties of secondary research, which have not been taken forward by Government. On 3rd March, a group of UK medical organisations including the British Medical Association, the Royal College of GPs, the Royal College of Surgeons, the Royal College of Nursing, the Faculty of Public Health, the Academy of Medical Royal Colleges, the Medical Defence Union, and the Medical Protection Society wrote to Justice Secretary Jack Straw to protest about clauses in the Coroners and Justice Bill that would allow ministers to ’remove or modify any legal barrier to data sharing‘ (see Economist report).

Although clause 152 was intended to balance the public interest against the privacy of individuals, doctors were concerned that it would violate patient confidentiality, and others feared that it could allow the government to disclose personal data to third parties. This provision will now be dropped from the Bill, and a modified version introduced in the future; a spokesman for Jack Straw said: "Jack recognised the strength of feeling and he recognised that the clause was drafted in a way that was too wide, and so needed to be looked at again” (see Telegraph report).

Meanwhile, UK medical charities the British Heart Foundation, the Wellcome Trust, and CancerResearch UK have called for more public participation in discussions about the use of patient data. They warned that increasing levels of regulation are necessitating the devotion of disproportionate resources to gaining consent and access to medical data, with diminishing returns in terms of recruitment of suitable subjects for clinical trials, stifling medical research. Wellcome Trust Director Mark Walport said: "The big challenge is in gaining public confidenceabout access to electronic patient records. There has to besome form of partnership to help that debate and move it forward” (see BMJ news report), adding that it was important for the public to understand the integral role of health care providers in clinical research. A previous PHG Foundation consultation response to the 2008 Data Sharing Review made similar points.

Moving to a global perspective on data-sharing, Nature recently reported on plans to develop a non-profit, open-access research platform called Sage with a view to creating comprehensive biological databases for scientific research, to support the development of more predictive disease models.The scientists from Rosetta Inpharmatics say that their long term vision is of an open-access platform for “research scientists, clinicians and maybe even patients” to access data and to contribute their own information and findings to further extend and improve the database along the lines of Wikipedia (see Nature news report).

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12 March 2009

The ‘Guidelines and Guidance’ section of PLoS Medicine, an open-access journal, was launched with the goal of encouraging the highest possible standards in medical research and reporting. Articles that raise awareness of emerging and novel methodological approaches, provide community consensus standards for reporting or carrying out particular types of research, and provide easily digestible guides on conducting commonly used statistical methods or methodological techniques are published in this section. These include articles such as STROBE [Von Elm et al. (2007) PLoS Med 4(10):e296 ; Vandenbroucke et al. (2007) PLoS Med 2007 4(10):e297] and STREGA [Little et al. (2009) PLoS Med 6(2):e22] (see also previous news).

A new guidelines and guidance paper published last week by PLoS Medicine on systematic reviews of genetic association studies aims to describe the important components of the methodology for undertaking a systematic review. The increase in published literature on gene-disease associations has led to an increase in efforts to collate and synthesise this epidemiological evidence. Many systematic reviews and/or meta-analyses are published and are often not explicit in outlining the methods used or even how included studies were identified. The principal aim of a well-conducted systematic review (and meta-analysis) of genetic association studies should be to reliably establish the presence and magnitude of a gene-disease association. Systematic reviews are designed as rigorous research studies, with predefined methods and allow the objective appraisal, critique and synthesis of relevant study data. This is a marked difference from traditional (narrative) reviews which are generally subjective, rarely state how studies were included or assessed for quality, and often support and reinforce the author’s view.

In this paper [Sagoo et al. (2009) PLoS Med 6(3):e1000028 doi:10.1371], the authors (who include PHG Foundation funded staff) outline the general process involved in a systematic review including the need for minimising bias, as well as highlighting some of the issues encountered in the human genome epidemiology field. The search process for eligible articles is described, and a non-statistical overview of meta-analysis presented, along with summary points that highlight the key methodological points for a systematic review of genetic association studies.

The guidance is derived primarily from the Human Genome Epidemiology Network (HuGENet) HuGE Review Handbook, updated to reflect developments in technology and methodology.

10 March 2009 US President Barack Obama has, as expected,  signed an executive order lifting the effective ban on federal funding for embryonic stem cell research and promised to "vigorously support" new research (see BBC news report), although he also made it clear that only research meeting strict ethical guidelines would be allowed. This excluded any sort of research into human reproductive (as opposed to therapeutic) cloning, of which he said: "It is dangerous, profoundly wrong, and has no place in our society, or any society". Previous legislation put in place by the Bush administration prevented scientists in the US from using government funding on work utilising stem cells created after 2001 (see previous news).  It is still uncertain at to how long it will take for these changes to be put in place, as precise guidelines on how embryonic stem cells can be used will need to be drafted.

This news comes at a time when President Obama has also created an unprecedented amount of funding for science and technology as part of a stimulus bill to boost the US economy [Mervis, J 2009, Science 323(5919):1274-5]. In addition to providing funds for basic research, this package also includes funding for research into the comparative effectiveness of treatments and it is hoped that some of this funding could go towards developing guidelines on the use of embryonic stem cells for research. The importance of sustaining science and technology was also echoed to some degree in the UK by Prime Minister Gordon Brown who announced that the science and technology budget would not suffer under the current economic climate; however, further government funding for R&D was not offered (see Times report).

4 March 2009A team of researchers has sequenced and analysed the genomes of all 99 known strains of the virus that causes the common cold, the human rhinovirus (HRV). This group of viruses are highly infectious, and adults typically suffer with between 2-4 colds each year, with higher numbers of infections among children (see press release). Prior to the study [Palmenberg AC et al. (2009) Science Feb 12, Epub ahead of print] published in the journal Science, only a few strains of HRV had been sequenced. The research has shown for the first time that it is not uncommon to be infected by two or more strains of the virus at the same time, and – in contrast to the results of earlier studies – that gene transfer and recombination between these is likely to be the mechanism leading to the development of new strains.

While this new knowledge of the genetics of the virus offers the possibility of new effective therapies, it also suggests that a preventative vaccine is unlikely at this stage, since the reshuffling of genes would constantly generate new strains that the immune system would not be able to recognise as the same infection. One of the study authors Dr Stephen Liggett has however speculated in interviews that it should be possible to develop medicines able to stop a cold in its tracks, based upon the specific genetic characteristics of a patient’s infection. Famously, there is currently no cure for the common cold.

Despite this possibility, it is not necessarily the case that such therapies will become available: since a cold is more an inconvenience than a serious health threat for most people, it is questionable whether patients would be inclined to pay for new medicines, and therefore whether pharmaceutical companies would think it worth the huge expense to develop them. However, in addition to causing the common cold, HRV plays a role in other more debilitating infections such as bronchitis, sinusitis, pneumonia and in particular the onset of asthma and the triggering of attacks, which could provide greater impetus for the development of effective medicines.

The study also constructed a ‘family tree’ of the HRV genomes, and the authors conclude from apparent gaps that there are likely to be many more strains of HRV awaiting discovery. They suggest that a wider collection of samples from patients may help to locate these strains, and that full sequencing of their genomes combined with more detailed cross-referencing across all genomic regions may yet lead to the identification of a common target for a vaccine in the future.

2 March 2009

25 March 2009All screening programmes cause some harm; the question is whether they also have benefits that outweigh these harms. To date, the UK National Screening Committee (NSC) has decided that there is insufficient evidence to support a national screening programme for prostate cancer, the most common cancer in men, which according to Cancer Research UK affects around 35,000 men annually in the UK. (This contrasts with the US, where most men over the age of 50 years have been screened for prostate cancer.) One of the problems is that the majority of cases of prostate cancer are benign rather than being clinically significant, and the individual is not benefitted by treatment. Although the prostate-specific antigen (PSA) blood test is available for the detection of early prostate cancer, it does not adequately distinguish between clinical significant and benign cases (see previous news), leading to unnecessary biopsies and treatments. Therefore, data from large studies are needed to determine the effect of PSA testing prostate cancer mortality.

Preliminary results from two large prostate-cancer screening trials, published back-to-back in the New England Journal of Medicine, will contribute significantly to this debate. Both studies used a randomised design, in which the participants were randomly assigned either to a screening group and given regular screening tests, or a control group who were just monitored; the incidence and mortality rate from prostate cancer was then compared between the two groups.

The first, an American study with 76,693 men aged 55-74, found that the “the rate of prostate cancer was very low and did not differ significantly between the two study groups”, i.e. those who received annual PSA screening and those who did not [Andriole GL et al. (2009) NEJM 360: 1310-1319]. In fact, after 7 years, 50 deaths were attributed to prostate cancer in the screening group, compared with 44 in the control group.

The second, a European study with 162,243 men aged 55-69, was more positive and found that “PSA-based screening reduced the death from prostate cancer by 20%, but was associated with a high risk of overdiagnosis” [Schröder FH et al. (2009) NEJM 360:1320-1328]. After 9 years, 214 deaths were attributed to prostate cancer in the screening group, compared with 326 deaths in the control group. Whilst, on the surface, this result sounds very encouraging, the authors note that this means that 1,410 men would need to be screened, and an additional 48 cases treated, to prevent one death from prostate cancer. Given the numerous risks associated with screening – including misdiagnosis, false alarms, anxiety, and the treatment of early disease which would not otherwise have become a problem – it is unclear whether a 20% reduction in mortality is a large enough benefit to justify these harms.

Comment: Although both trials diagnosed more cases of prostate cancer in the screening group, only one trial found a reduction in prostate cancer mortality as a result of screening. The differing findings from these two large studies are almost certainly due to differences in trial design, including differing age ranges and regularity of screening. Importantly, the European study had a lower PSA threshold for biopsy than the American, and hence the test had a higher sensitivity resulting in a higher diagnosis rate (which may account for the observed mortality benefits), and lower specificity leading to overdiagnosis and increased harms assocaited with screening.

Therefore, far from ending the controversy in this area, these studies will no doubt fuel the continuing debate. The benefits of PSA screening still remain unclear. Moreover, neither trial quantified the harms associated with screening, which included infection, bleeding and urinary difficulties following diagnostic testing, and infection, incontinence and impotence following treatment. The accompanying editorial notes that “serial PSA testing has at best a modest effect on prostate cancer mortality during the first decade of follow-up”, but that this potential benefit “comes at the cost of substantial overdiaganosis and overtreatment” [Barry MJ (2009) NEJM 360: 1351-1354]. Future data from these and other ongoing trials may shed more light on this area. Additionally, given the large number of common genetic variants that have been shown to be associated with prostate cancer (see previous news), genetic profiling or gene expression testing might improve the predictive ability of the test in future (see previous news). However, regardless of the test used, it is important to remember that the key question is not whether screening is effective, but whether it does more good than harm.

11 March 2009A new report details the induction of pluripotency in cells derived from human skin cells without the use of viral vectors. Induced pluripotent stem (iPS) cells were first produced in 2007 (see previous news) and were hailed as a potential source of therapeutic stem cells that would not provoke the ethical concerns raised by the use of human embryonic stem (HES) cells; however, the technique used to achieve this cellular reprogramming required the use of viral vectors to introduce genes. This was cause for concern because the use of viruses for therapeutic purposes is known to carry a risk of viral-induced tumour formation, as observed in rare cases for gene therapy (see previous news) and more recently for stem-cell transplantation (see previous news).

The new technique was developed by teams at the University of Edinburgh, UK and the University of Toronto, Canada and published in Nature. It delivers the key genes required to achieve pluripotency in differentiated cells (c-Myc, Klf4, Oct4 and Sox2) via the introduction of a vector comprising short peptide (amino acid) sequences linked to the genetic coding sequences, which directs expression of the attached genes [Kaji K et al. (2009) Nature Mar 1, Epub ahead of print]. The copies of these genes in the genoms of differentiated (specialised) cells are inactive or silenced. Analysis showed that a single copy of the vector was inserted to a specific site within the genome of target human or mouse to permit stable gene expression with minimal modification of the target cell genome. The process was found to be efficient with good expression of the inserted genes, and functional pluripotency demonstrated using in vitro differentiation.

Perhaps more impressively, the researchers were able to subsequently remove the non-viral vector and the genes it carried from target mouse cells using a transposase enzyme without affecting the newly induced pluripotent state of the cells. Active expression of the previously silent, endogenous pluripotency genes was sustained in the absence of the vector over multiple cell passages (ongoing cycles of in vitro growth), suggesting that the system allowed complete removal of the vector and external genes without disturbing the induced pluripotent state of the target cells.

The authors suggest that, while further work is required to optimize the system, it is a method that could provide an efficient means of generating iPS cells for therapeutic stem cell treatments, drug screening and the creation of in vitro models of disease for research purposes. Study leader Dr Keisuke Kaji commented: "It is a step towards the practical use of reprogrammed cells in medicine, perhaps even eliminating the need for human embryos as a source of stem cells" (see BBC news report).

Comment: By both eliminating the need for virus-derived vector sequences to induce pluripotency of human cells, and further demonstrating the potential to remove the vector and genes without disrupting the induced pluripotent state of the target cells, this work represents a major step forward in therapeutic medicine.The next key step would be to demonstrate effective removal of the vector and maintenance of pluripotency in human cells. A number of crucial stages would still remain, notably maintaining stable pluripotency and then reliably inducing the cells to re-differentiate as required for therapeutic purposes. However, this method could permit the creation of a greatly superior source of therapeutic stem cells, greatly reducing the risk of pathogenic processes linked to the inappropriate expression of viral or other externally-derived genes.

9 March 2009Scientists at Johns Hopkins have used ‘personalised genome’ sequencing on an individual patient to locate a susceptibility gene to pancreatic cancer [Jones S et al (2009) Science DOI: 10.1126/science.1171202]. Published in Science Express, this represents the first time that a genome-wide sequencing technique has been used clinically for diagnosis of an inherited disorder caused by mutation in a single gene.

 

In this case, the sister of the patient also had pancreatic cancer, suggesting the disease was familial. Using standard linkage techniques of genetic analysis, data from a very large family would normally be required to find the causal mutation, which was not possible in this case. Researchers therefore used complete exomic sequencing to determine the sequence of all the coding regions of the genome (approximately 1% of the complete sequence, accounting for around 20,000 genes). Over 15,000 germline variants were found relative to the human reference sequence, most of which were irrelevant to the sequence of the protein product itself. However, only three genes contained coding errors in both alleles, including PALB2, which encodes a tumour suppressor protein that binds with the product of the BRCA2 gene and has previously been linked with breast cancer. The single base mutation found in this study causes a coding error resulting in an abnormally short version of the protein, which prevents it from working with BRCA2 to repair damaged DNA effectively. The team then scanned the PALB2 gene in 96 other individuals with pancreatic cancer, each of whom had at least one relative with the cancer, and found that three of them also had errors coding errors in this gene.

 

Comment: This approach could be used to identify inherited alterations that cause or predispose people to numerous other inherited diseases. Importantly, unlike classical approaches to gene discovery, this method is unbiased to particular genes and does not require large family studies. Whilst there continues to be considerable debate about the value of personal genome sequencing, numerous commentators have proposed that this type of approach will eventually be used routinely to scan for disease-related genes. However, although the cost of sequencing is likely to reduce dramatically in the next 5 years (from $150,000 in this study), as next generation sequencing technologies continue to develop, fears over accuracy and clinical utility will still remain. Since genetic differences between individuals and the reference sequence are very commonplace, it can be extremely difficult to interpret such findings and determine which changes are actually pathogenic.

6 March 2009Type 1 diabetes (T1D) is a young-onset (before the age of 40) form of diabetes that affects an estimated 300,000 people in the UK alone, including 20,000 children under the age of 15. An autoimmune process causes progressive destruction of insulin-producing beta-cells in the pancreas, and a concomitant inability to control blood glucose levels. This form of diabetes, which accounts for 5-15% of all diabetes cases (see Diabetes UK website), would be fatal without multiple daily injections of insulin, in addition to careful dietary control. Susceptibility to this form of diabetes is known to have a significant genetic element, but is presumed to also involve important environmental factors.

Researchers at the University of Cambridge have identified new genetic variants associated with a reduced risk of developing T1D. The genome-wide association study (GWA) published in Science identifies four variants in the IFIH1 (MDA5) gene, which encodes an enzyme involved in the induction of immune responses to the RNA of picornaviruses [Nejentsev S et al. (2009) Science DOI: 10.1126/science.1167728 (Epub ahead of print)]. The IFIH1 protein detects the presence of viral RNA in the cellular cytoplasm and triggers activation of key signaling pathways to induce an interferon-beta mediated antiviral immune response. The variants associated with reduced risk of T1D are suggested to reduce the normal functionality of the IFIH1 protein.

The authors note that infection with enteroviruses (a picornavirus sub-group of small RNA genome viruses) is more common among newly diagnosed T1D patients and pre-diabetic subjects than in the general population, and speculate that normal IFIH1-mediated immune activation caused by enterovirus infection may stimulate the autoimmune response against pancreatic beta cells. IFIH1 mutations that disrupt this mechanism may therefore confer a protective effect against the disease. Senior author Professor John Todd commented: "We have been able to pin-point one particular gene among a long list of candidates. Now we and others can begin to study the biology of IFIH1 in the context of type 1 diabetes knowing that it is part of the cause of the disease" (see press release).

Another recent study to be published in Diabetologia supports the proposed link between T1D and enterovirus infection. It reports the detection of enteroviruses in pancreatic tissue from about 60% of 72 paediatric patients with T1D, but very few of the samples of tissue from 50 children without the disease (see press release). This research also found that 40% of adults with type 2 diabetesshowed signs of enteroviral infection of their pancreatic beta cells, compared with only 13 percent of non-diabetic (control) adults of the same age. The authors propose that vaccination against enteroviral infection in childhood could reduce the incidence of both common forms of diabetes.

Comment: This latest research provides a prime example of how genetic and environmental factors may interact to cause disease, as well as a demonstration of how highly-powered GWAs can provide vital insight into the genetic basis of disease, and of pathological mechanisms, opening up prospects for improved prevention and development of novel therapeutics. The proposal that anti-enteroviral vaccines might be important prevention is perhaps somewhat premature, however, since there are approaching 100 different strains of enterovirus, and it is not yet known which may be associated with diabetes.

2 March 2009

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