Stem Cell News

News articles are provided by the PHG Foundation.

The UK Human Tissue Authority (HTA) has issued an official warning that unlawful collections of umbilical cord blood have been taking place in the UK, and that such instances ‘may compromise safety and quality standards’ (see press release).

Cord blood banking is growing in popularity in the UK; last year some 15,000 collections were made of which around one quarter were for public, charitable or research recipients (see BBC news) such as to the NHS Cord Blood Bank, whilst the remainder were via commercial providers who charge £1000-2000 for collection and storage of the samples. Whilst stem cells from cord blood can currently be used for treatment for a few serious diseases such as leukaemia, private companies typically market their services to parents on the basis that stem cells will be the key to successful treatment of a whole range of diseases in the near future.

Banking has been regulated in the UK by the HTA since 2008 (see previous news); collections may only be made under an HTA licence, requiring suitably trained staff. This is to ensure not only the quality, safety and traceability of the sample obtained, but also to ensure that collection procedures do not divert key medical attention from either the mother or baby, which has caused concern in the past (see previous news). 

Now the HTA is contacting more than 150 organisations to warn them about the dangers of unlawful cord blood collection, whether by parents themselves or by unlicensed medical staff. They are also urging parents who wish to chose cord blood banking (for example, via a commercial provider) to make sure that arrangements for proper collection are made well in advance, to avoid midwives or other unlicensed medical professionals being put under pressure by parents to make illegal collections.

The CDC National Office for Public Health Genomics (NOPHG) in the US has announced plans to create a new Knowledge  Synthesis Center for the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) initiative. EGAPP produces periodic reviews which summarise the available evidence for validity and clinical utility of selected genomic tests and other applications (see previous news for examples). This sort of information is potentially very helpful for policy-makers and health professionals trying to determine whether or not a given test is useful or not.

The new project, a collaboration between the CDC and National Institutes for Health (NIH), will provide funding for a dedicated centre to ‘conduct, update, and publish systematic evidence reviews to address selected questions for the evaluation of a set of health-related genomic tests’ (see announcement). This will include production of topic briefs on the use of selected genomic applications for improving health and preventing disease, and related issues, to form part of an online knowledge silo for EGAPP, and research into improved methodology for performing systematic reviews of published evidence.

A total of around $1.5 million funding over three years is available to create and run the new centre, and applications are being are sought.

The Joint NIH-FDA Leadership Council will concentrate on important public health issues, and seek to integrate regulatory considerations into biomedical research planning. The programme will combine work in translational and regulatory science including efforts not only to develop new clinical tools, but also means to assess the safety and efficacy of these tools. This sort of approach can be very important in making sure that innovation is used appropriately and to the best effect to improve health; for example, the PHG Foundation is currently working with other experts to develop quality standards to allow a fair evaluation and comparison of different disease risk prediction models.

It is expected that the new US partnership will have a particular impact on the development of genetic and pharmacogenetic tests for clinical application, as well as drugs for rare diseases (many of which are genetic in origin) and stem cell therapeutics. Sharon Terry, president and CEO of the Genetic Alliance, said: "The exercise of understanding how to endow discovery science with regulatory sufficiency, and retool the regulatory system to be flexible, iterative, and adaptive, will yield great fruit," (see GenomeWeb news).

The official definition of human embryonic stem (HES) cells in US National Institutes of Health (NIH) guidelines is to be broadened from those ‘derived from the inner cell mass of blastocyst stage human embryo’ (ie. from embryos that have reached the blastocyst stage at four or five days old, 70-100 cells), to include also those derived from earlier stage embryos.

Dr Lana Skirboll, director of the Office of Science Policy of the NIH, reportedly said: "We are making what I think is a relatively small technical change to the definition of human embryonic stem cells…This changes none of the ethical requirements in the guidelines" (see Reuters news). This move was prompted by an application from a commercial source to list cell lines derived from eight-cell stage embryos, and will make some commercial and academic research programmes potentially eligible for government funding.

Derivation of HES cells from a cell taken from an eight-cell stage embryo could possibly allow implantation and normal development of the remaining seven-cell embryo. This is what happens in pre-implantation prenatal diagnosis (PGD); one cell is removed for genetic analysis and, if healthy, the seven-cell embryo is implanted and can grow into a normal fetus.

A new facility called BIOFAB (International Open Facility Advancing Biotechnology) has been established with funding from the US National Science Foundation (NSF), the Lawrence Berkeley National Laboratory (LBNL) and the BioBricks Foundation (BBF). BIOFAB intends to create standardised DNA parts that will be made freely available to academic and commercial groups seeking to use synthetic biology to create organisms for different purposes (see press release).

The ‘parts’ will be crucial genetic control elements, initially from the laboratory bacterial strain E. coli, which will be characterised and standardised with a view to creating standard elements that can be used to create de novo biological systems. The hope is that these will substantially decrease the time and cost of developing new synthetic organisms, which have all sorts of potential applications such as the production of biofuels, drugs and other therapeutics.

BIOFAB will use resources such as the BioBrick Public Agreement, a proposed legal framework to support the free exchange and use of standardised biological components; it will also include research into ethical issues such as safety and security. Common concerns about bioengineering include issues relating to the deliberate design of dangerous new biological weapons, and wider worries about the inadvertent creation of organisms with other detrimental effects on nature.

The Academy of Medical Sciences (AMS) has published a new report challenging the next government of the UK to make medical science a central tenet and make the most of the opportunities for health offered by advances in the field (see press release).

Reaping the rewards: a vision for UK medical science, which notes the abundance and world-leading excellence of biomedical research in the UK and the unique opportunities for medical research via the National Health Service (NHS), says that the UK has an ‘unparalleled competitive advantage’ for commercial medical research that could ‘improve the health of the population both here and abroad’.

However, it warns competitors such as the US, China, Singapore and Canada are actively growing their own medical research sectors and that the UK is losing out as clinical trials and research move to other countries. The report sets out seven key challenges that the AMS says must be addressed over the next five years to reverse this trend and capitalise on public sector investment in medical research:

Broadly, the report calls for a more coordinated approach to research across the public, private and third sectors; a ‘proportionate, risk-based regulatory framework’, incentives for excellence and innovation, and the need for medical science to ‘underpin cost-effective international development measures that enable poorer countries to address their health needs’. As such it notes that health research should be central to UK foreign policy.

The new study published in PLoS ONE has linked epigenetic changes with cardiomyopathy, a form of heart disease characterised by weakening of the heart or a change in muscle structure that diminishes the ability of the heart to function effectively. There are three main forms of cardiomyopathy – dilated, where the heart becomes enlarged and weakened; hypertrophic, where the heart muscle becomes thickened, forcing the heart to work harder to pump blood out of the heart; and restrictive, where the heart muscle becomes stiff and hence unable to properly fill with blood (for more information, see The Cardiomyopathy Association).   

Differences in DNA methylation are currently understood to be involved in the control of gene expression, which may in turn contribute to complex disease susceptibility or progression. Strong links have already been found between differential methylation and cancer, and there are efforts underway to examine the link with other complex diseases such as schizophrenia, diabetes and inflammatory bowel disease.

Researchers in Cambridge have found differences in DNA methylation in hearts from a small number of people with end-stage cardiomyopathy who were undergoing heart transplantation and the healthy hearts of age-matched victims of road traffic accidents [Movassagh M et al. (2010) PLoS ONE 5(1): e8564, doi:10.1371/journal.pone.0008564].The differential methylation correlated with differences in gene expression patterns between the heart failure and control groups.

They conclude that differential DNA methylation, along with other epigenetic mechanisms, may influence the development of heart failure in response to environmental factors, including dietary influences, effectively representing a ‘missing link’ between genetic and environmental causes of heart failure. The researchers also comment that, although certain genes are known to play an important role in heart failure, sometimes mutations are not found in those genes and thus it may be methylation rather than mutation that leads to disease. 

Comment: This is small study, but provides very interesting insight into a possible role for epigenetic changes in heart failure. The researchers now hope to identify ‘hotspots’ in the genome to help identify those people at greater risk of developing heart disease, and in particular those people at greatest risk of developing heart disease rapidly. This would allow treatments to be targeted to those at greatest risk, and also enable closer monitoring of those at higher risk, to help prevent and delay heart failure.

Cancer cell genomes are known to contain a variety of structural rearrangements that are thought to play a role in the development of cancer. The involvement of structural changes in driving tumour formation has long been recognised, at scales ranging from whole chromosome translocations (such as the Philadelphia translocation associated with chronic myelogenous leukemia), down to much smaller-scale rearrangements. However, much remains unknown about the nature and role of these changes in driving cancer.

Now, a new paper reports high resolution mapping of the chromosome rearrangements in human breast cancer cells. In all, 24 different breast cancers were examined for the number, position and nature of these structural changes [Stephens PJ et al. (2009) Nature 462(7276):1005-10]. Most rearrangements occurred within chromosomes (as opposed to between different chromosomes) and the most common type were tandem duplications; the authors propose that this may due to a specific (unknown) defect in DNA maintenance in breast cancer cells that generates - or fails to correct - this type of rearrangement.

The researchers also observed correlation between the chromosomal rearrangements and different sub-types of breast cancer; for example, oestrogen- and progesterone-receptor negative, basal-like tumours typically had many tandem duplications, whereas oestrogen-receptor positive luminal type tumours had fewer rearrangements and mostly within repeat regions of the genome.

In many cases rearrangements affected genes and resulted in altered or novel gene products, but none of these were recurrent, suggesting that many different, individually rare mutations may be active in breast cancer cells. However, the authors themselves note that much larger numbers of tumours need to be studied before conclusions may be drawn.

Comment: The observation that breast cancer cell genomes, even from a small sample, show a higher diversity and number of structural rearrangements than expected suggests the need for major new research into how different genomic changes are involved in cancer. It will be interesting to see how far genomic features mirror other characteristics by which tumours are classified into these sub-classes; it may also help to identify key targets for new therapeutics common to some tumour sub-groups, improving prospects for more personalised treatment of breast cancer.

The website brings together information on consent including the HTA Code of practice on Consent, frequently asked questions, a glossary, policy information on non-consensual DNA analysis (and how to apply for this via the HTA), and two flowcharts on Consent and the use of DNA and Qualifying consent.

The Medical Research Council (MRC) also provides an online Data and Tissues Tool Kit, developed in conjunction with the HTA and other relevant bodies, that offers help and guidance on legislative requirements and good practice with respect to the use of human tissue and personal information for healthcare research in the UK (see previous news).

With respect to broader health research, the UK Clinical Research Collaboration (UKCRC) recently released a new booklet on the changing regulatory and governance environment for clinical research, outlining new measures intedned to reduce bureaucracy and streamline research. The UKCRC is a partnership of stakeholders including academia, industry, funders, regulators, patients and the NHS established to redesign the clinical research environment with a view to improving national health and wealth.

The Health Services Research Network has also recently produced a briefing document describing changes in the research governance landscape.

For a given project, the Tool Kit offers graphical representations of regulatory routes, key regulatory questions and milestones, with detailed information about required steps and contacts for each stage.

The resource was developed by the Department of Health and the Medical Resaerch Council with the support of key regulatory bodies including the Gene Therapy Advisory Committee (GTAC), the Human Fertilisation and Embryology Authority (HFEA), the Human Tissue Authority (HTA) and the Medicines and Healthcare Products Regulatory Agency (MHRA), as well as other groups. It will be updated every three months.

Professor Brendon Noble of the MRC Centre for Regenerative Medicine in Edinburgh commented: “This will be an important tool in therapy development planning. It will also act as a focus for discussion over key issues and roadblocks to the development of cell based therapies” (see press release).

In the US, regulators have approved thirteen new lines of human embryonic stem (HES) cells for use by federally-funded researchers, with many more new lines expected to be approved soon if they are found to meet ethical requirements (see BBC news). The current NIH Guidelines for Human Stem Cell Research were established this year after President Barack Obama moved to ease previously strict regulation put in place by the previous administration (see previous news). The National Institutes of Health (NIH) may establish a central repositary for the storage and distribution of approved HES cell lines in the face of demand for new lines.

Work using stem cells derived from alternative sources also continues, and US researchers recently announced promising results - researchers rarely announce results that are not in some way promising - from trials to treat damaged corneas in mice using human umbilical cord stem cells (see BBC news). It is hoped that regenerative medicine using stem cells could eventually help address a serious shortage of organs (including corneas) available for transplantation.

In Italy, scientists have lost a legal appeal against proposals from the health ministry for stem-cell biology funding that specifically exclude HES cells, despite the fact that the use of HES cells is not prohibited (see Nature news). However, the stem cell research community in India will welcome news that construction of a major new Institute for Stem Cell Biology and Regenerative Medicine (inStem) in Bangalore has begun (see Science news) following government approval in July (see Indian Express news).

The ‘Manchester Manifesto’ is a new document from a group convened to consider the current system of ownership and management of science and innovation. Produced by a group led by John Sulston of the Institute for Science, Ethics and Innovation at the University of Manchester and Joseph Stiglitz of the Brooks World Poverty Institute, the brief document identifies the key goal of science as being to ‘serve the public good by generating knowledge to meet human needs and purposes’. Of note, thirty of the fifty signatories are from the University of Manchester.

Unsurprisingly, given their predominantly academic backgrounds, the group concludes that pure (basic) scientific research is ‘clearly in the public interest, since curiosity expands knowledge’ but also note that technical innovation provides additional economic benefits to society. The group asserts that current models of management and commercialisation of science and technology – including the system of patenting scientific inventions, and of intellectual property and licensing relating to patents – restrict public access to the benefits of research. The manifesto states that restrictions imposed by current systems are ‘contrary to the needs of scientific inquiry and are inimical to openness and transparency’, adding that effects are most severe on public, not-for-profit, small and developing country enterprises.

It calls for urgent consideration of alternative new models – claiming that modification of the current intellectual property system would have only limited impact – and states that regulation of frameworks for innovation should seek to promote and balance factors including public benefit, trust between stakeholders, and addressing local and global welfare and resource inequities.

Comment: This brief new document, besides being a clear plea for continued investment in basic research (possibly in reaction to new UK emphasis on translational research and the adoption and diffuusion of new technologies and products) raises some interesting issues with respect to the inequities related to scientific commercialisation.

Some of the principles and concerns are very valid. For example, there is ongoing opposition to patenting of human gene sequences and criticism of their negative impact of patient access to affordable genetic tests; in a current US lawsuit the Association for Molecular Pathology is contesting the legality of existing patents for the BRCA1 and BRCA2 genes held by Myriad Genetics and the University of Utah Research Foundation as contrary to prohibitions on patenting ‘products of nature’ [Lenzer J (2009) BMJ 339, doi: 10.1136/bmj.b4899]

The stated aim of the manifesto to ‘build a better future for humanity’ is likewise a compelling one. Certainly, the PHG Foundation believes that health is an essential prerequisite for human development and is concerned with making the health benefits of science available to vulnerable populations based on need (see About us).

However, the manifesto wholly fails to recognise the critical role of the commercial sector in funding and conducting applied research, and the necessity of some form of system to protect intellectual property in order to retain sufficient economic imperatives for companies to continue their heavy investment in research and innovation. Critical responses to the document, such as the assertion that it is ‘ill-informed and misleading’ are therefore unsurprising.

When the House of Lords published their Report on Genomic Medicine in July 2009, they argued that the pace of change requires a new strategic phase for genomics in health services. By contrast, the Government response published on December 14th largely rehearses past achievements and attempts to make current processes fit future needs without acknowledging the scale and complexity of what will be required.

The Government response explicitly rejects the publication of a new Government White paper on genomic medicine, which formed one of the central recommendations of the House of Lords Genomic Medicine Report. Whilst there is a commitment to establish a cross-departmental Human Genomics Strategy Group (HGSG) which will have responsibility for developing a vision for genomics in the NHS, including limited workforce and bioinformatics planning, in the main the response from Government seems disappointingly lacking in substance.

The Government, for example, does not recognise that current structures and mechanisms to commission and provide genetic testing for single gene disorders are inadequate. Even our present knowledge and capabilities in single gene disorders are not reflected in equitable practice across the UK and there is no doubt that this gap will widen significantly in the next few years. The expectation that commissioning in genomics within mainstream medicine will somehow be improved through World Class Commissioning without setting out in any way how this will be driven, is complacent.

As a further example, as knowledge of genomics and complex disorders gains pace, the response on bioinformatics shows that the Government does not appear to understand the need to start putting infrastructure in place now if the NHS is going to respond adequately to the genomic revolution even though the actual benefits may be some time coming. The Government agreed to 'carefully consider' recommendations about a new Bioinformatics Institute but again does not seem to have recognised the urgency of the need nor the magnitude of the task if we are to develop the necessary capacity and capability to support the integration of genomics information into practice.

It is not our intention at present to provide a detailed commentary on the Government response. Both the original Report and the Government response require and deserve more detailed thought. To that end the PHG Foundation is undertaking a series of consultations with key stakeholders in conjunction with Cambridge University Centre for Science and Policy - a process that will result in a detailed response to the House of Lords Report in late Spring 2010.

The UK National Health Service (NHS) has launched a consultation on a proposed pilot scheme to speed up access to new therapeutics for patients with rare diseases. Normally, novel treatments must be thoroughly evaluated and approved according to strict criteria by the National Institute for Health and Clinical Excellence (NICE), the body that produces guidance on treatments and interventions for the NHS. In some cases – and particularly in the case of rare diseases that individually affect only relatively small numbers of people – it may not be possible to generate adequate data for the rigorous demonstration of cost-effectiveness required by NICE (and hence for NHS funding of the treatment) – for example, because the smaller numbers of patients make demonstration of efficacy slow even where novel therapeutics may actually offer significant benefit in terms of patient outcomes.

Many genetic diseases fall into the category of rare diseases, although in fact collectively their public health impact (and the burden they place upon health services) is significant, so that moves towards a ‘one size does not fit all’ system that can respond more flexibly to different requirements to assess needs and costs for less common conditions are highly desirable.

The new ‘Innovation Pass’ scheme, announced earlier this year by the UK Government as part of the new Office for Life Sciences (OLS) Blueprint (see Central Office of Information news) will allow selected new therapeutics to be made available via the NHS from 2010/2011 for three years. It is hoped that this will simultaneously allow patient access and generate data that could support subsequent full NICE appraisal, with priority to be given to areas of the greatest patient need. 

The Department of Health is now running a consultation for stakeholders to comment on the plans. The consultation notes that the Innovation Pass, currently intended to focus on treatments, could also be extended to include medical technologies and diagnostics, and specifically queries whether this is advisable. This might, for example, include new genetic tests.

The consultation closes on 8th February 2010.

The cancer biobanking organisation onCore UK was established with a stated mission to inform, coordinate and develop cancer biobanking to enable research towards the discovery and development of new interventions against cancer. This involved two key roles: promotion of cancer biobanking, and serving as an active national cancer biobank resource.

Following a decision made earlier this year, onCore UK will no longer undertake the latter role. In a public statement explaining the decision, onCore UK says that ‘a standardised national approach has been difficult to achieve’ for biosample collection and that ‘the needs for biobanking can be effectively fulfilled by local biobank activity’. Instead, the organisation will focus solely on the promotion of cancer biobanking in the research and health service communities, subject to Charity Commission approval since onCore is a charitable body.

OnCore is funded by the Department of Health (England), the Medical Research Council and Cancer Research UK. It is not clear to what extent this strategic decision to cease biobanking may have been influenced by a harsher economic climate; the statement that biobanking needs can be effectively met by local biobanks seems somewhat at odds with the founding principles, which set out to provide high-quality cancer tissue samples to support large-scale research studies on the basis that individual biobanks and collections did not allow this. 

Now, onCore must dispose of the tissue samples currently held in the biobank facility and is seeking to distribute them to ensure that they can benefit medical research. It is advertising the availability of a collection of 300,000 human tissue samples from various parts of the body and including all major diseases, as well as healthy tissue samples, collected over much of the twentieth century up to 1978. Applications are invited from bona fide researchers for ethically approved research purposes (see website for details). Fees will be charged ‘to allow onCore UK to recover some of the costs of storing the collection’.

The independent UK government advisory body the Human Genetics Commission (HGC) has released a new report on the controversial National DNA database. Nothing to hide, nothing to fear? calls for the police DNA database, the largest of its kind in the world, to be established in law through new primary legislation that explicitly defines the permitted and prohibited uses of the DNA records. The report also calls for much clearer regulation of the database, including an independent oversight body, strengthening of the National DNA Database Ethics Group, and an independent appeals procedure for people who are not charged with or convicted of any crime to have their DNA removed.

It is proposed that a Royal Commission is also set up ‘to give focus to, and to learn from, the public debate, and to ensure that its outcomes will be taken forward and reflected in future legislation’. Recent public consultation revealed widespread concerns about the National DNA database (see previous news), and the new report itself discusses anecdotal evidence that the police are encouraged to detain members of the public for the primary purpose of taking DNA samples for the database. There are additional concerns relating to unfair discrimination in this respect, with a disproportionate number of young black men having their DNA profiles recorded (see Times article). Interestingly, the report specifically recommends that the police themselves should be required to submit their own DNA samples to the database as a condition of employment.

Other recommendations include collaborative work with European centres to standardise markers (to facilitate cross-border crime investigation) and research to determine the true ‘forensic utility’ of the database – that is, just how effective it actually is in combating crime. HGC Chair Professor Jonathan Montgomery said: "…there has been a steady 'function creep', allowing more and more people’s DNA to be kept, but it is not clear that this is matched by an improvement in securing convictions.  There needs to be a regular review of the positive value we get from the database" (see press release). Another concern voiced in the report is the issue of ‘function creep’ – making gradual new uses of the database without sufficient debate, with the contentious example of behavioural genetics cited – and ‘function leap’, the application of the database for completely new purposes such as biometric identity cards or linkage to electronic health records.

Comment: The HGC report is in some respects ill-timed, coming so soon after a recent Government climb-down from plans to allow continued retention of DNA samples from unconvicted people (see previous news). However, there is still an urgent need to address the current problems with the database and the HGC proposals are sensible, offering clarity for the police whilst addressing public worries about civil liberty, discrimination and wider concerns about how the use of genomic information might expand in the future.

The OECD state that these guidelines are intended to be “evolutionary” and relevant scientific and societal developments will lead to their review. Accordingly they state a need to review these Recommendations and Guidelines five years after its adoption in the first instance and periodically thereafter.

The new Science and Technology Committee of the UK House of Commons has launched a Bioengineering Inquiry, with a specific focus on ‘how the UK can maintain a globally competitive position in emerging and existing bioengineering research fields’. The specific areas of interest are synthetic biology, stem cells and genetic modification (GM), and in each of these areas the inquiry will consider issues of research, translation and regulation.

The relatively permissive regulatory regime for stem cell research in the UK has allowed it to prosper as a centre of international excellence, but even before the recent changes in the US and Japan relaxing restrictions on research involving human embryonic stem cells (see previous news), there were concerns that the UK could lag behind other global players. In contrast with the UK’s track record in stem cell research, research into many forms of genetic modification suffered significant setbacks following a media-led public backlash against so-called ‘Frankenstein foods’ (see also BBC news feature from 2008). Interest in synthetic biology has been growing in recent years (see previous news).

Written submissions are invited by 4th December 2009.

A study published last week in Nature Neuroscience has described for the first time a mechanism by which stressful events in infancy can alter gene expression in later life Murgatroyd et al. (2009) 8 Nov epub ahead of print.

The research examined epigenetic changes in mice that had been exposed to stress by being separated from their mothers for three hours a day for the first ten days of their lives. It was already known that this causes alterations in hormone levels and the stress responses of the mice that persist in later life. It was also already known that environmental signals in general can cause epigenetic changes to the genome that alter gene expression, and that these changes are often effected by methylation of DNA. Some previous studies have suggested that this form of altered gene regulation may be a factor in some psychiatric disorders.

This study focused on the expression of two regulatory hormones; arginine vasopressin (AVP) and corticotropin-releasing hormone (CRH), both of which are linked to mood and cognitive behaviours. The researchers found that early life stress in the mice caused a surge in stress-associated hormones, altering the methylation of a regulator of the Avp gene resulting in persistent increased expression of AVP and consequent changes in behaviour, such as deficits in memory and a reduced ability to cope with stress. They also found that these behaviours were mostly reversible by the subsequent use of antagonists to block the mice’s AVP receptors. The authors speculate that the behaviours were likely not entirely reversed because other regulators or genes that they had not targeted were also involved.

Comment: Whilst this study is significant in that it is the first to elucidate a mechanism by which stress can alter gene expression, caution must always be exercised when seeking to extrapolate the results of animal studies to humans. It does however seem highly plausible that environmental stresses in humans could cause similar changes to the epigenome; indeed several studies have suggested such effects, such as the thrifty phenotype observed in the children of mothers who have experienced poor nutrition.

There is an established correlation between childhood neglect and psychiatric illness in humans, and this study suggest the possibility that this may not be a purely psychological effect, but may also be influenced by fundamental changes to the expression of some genes. If this proves to be the case, it could open up research into entirely new approaches to the treatment of psychiatric disorders such as depression.

Now researchers have treated haematopoietic stem cells (blood cell precursors) from two seven-year old ALD patients with an HIV-1 derived lentivirus vector carrying the normal ABCD1 gene [Cartier N et al. (2009) Science. 326(5954):818-23]. The patients had aggressive chemotherapy to suppress normal bone marrow production of haematopoietic stem cells followed by administration of the treated stem cells. Since these stem cells were derived from the patients’ own cells, there was no risk of immune rejection as there would be with imperfectly matched donor cells.

Blood cell analysis suggested that around 15% of the reconstituted blood cells in the patients contained normal, healthy copies of the ABCD1 gene. Brain scans and tests of cognitive function showed a halt in disease progression after 14–16 months that has persisted for a further 12 months. There have been no signs of cancer; the major risk from gene therapy (especially using virus-derived vectors) is of insertional mutagenesis where the vector inserts into a place in the recipient cell’s genome that drives the formation of a tumour (see previous news). Analysis of the sites of vector insertion to date reportedly did not show any signs that the vectors were inserting in any one particular site ie. that there was any preferential replication of cells carrying the insert in a particular position, which might be a precursor of cancer formation.

Comment: This was a very small trial; while promising, it is still early days, and it is possible that over time the therapeutic effect of the gene therapy could deteriorate, or leukaemia develop in either of the two patients. However, without this treatment, the outlook for these two boys (for whom no matched bone marrow donor was available) was extremely bleak; for the moment, at least, they have been cured. Further trials with patients in similar positions are certainly warranted  - and no doubt eagerly sought by the patients’ families.

The study is expected to take 12-18 months and will consider scientific, ethical, social, regulatory and safety aspects of the creation and use of non-human animals and embryos incorporating human material, including public perceptions of such research. Professor Martin Bobrow CBE, who is to lead the multi-disciplinary expert group who are undertaking the study, reportedly said: "We are trying to work out what is reasonable" (see Associated Press news).

The study is supported by the Home Office, the Medical Research Council and the Wellcome Trust (see responses to study launch). The AMS says the final report will serve to ‘reinforce the UK’s lead in developing policy and legislation in challenging areas of medical science that is recognised world-wide’. More information is available from their website.

A new national biobanking initiative is to be established after the Dutch government awarded €22.5m funding for the Biobanking and Biomolecular Resources Infrastructure Netherlands (BBMRI-NL), a network including several academic and other research bodies. The initiative is intended to integrate and enrich existing clinical data and samples to make them more accessible for researchers. Professor Gertjan van Ommen of Leiden University Medical Centre said: “The existing materials are often of high value and quality but underused because of fragmentation” (see eHealthEurope news).

Once established, the initiative will presumably link in with larger networks that seek to connect European biobanks, particularly the European BBMRI, Biobanking and Biomolecular Resources Research Infrastructure (see previous news) or the EuroBiobank. The Netherlands is also reportedly competing with Austria and Luxembourg to host the BBMRI itself, which will enjoy special legal status and tax benefits (see EurActive news). Luxembourg is partnering with the US Translational Genomics Research Institute to form the Integrated Biobank Luxembourg (IBBL), a biomedical hub focusing on diagnostic biomarkers. 

Meanwhile in the US, the Kaiser Permanente biobank (see previous news) is partnering with the University of California, San Francisco (UCSF) to collate and analyse genetic and clinical data from 100,000 older Americans, with an average age of 65 (see Technology Review article). The National Institutes of Health (NIH) awarded $24.8 million over two years for this new study into the genetic and environmental factors influencing health and ageing. Richard Hodes, director of the National Institute on Aging (NIA) which was behind the grant said: “We are very excited about the opportunity to develop this extraordinary database in an older population, to facilitate studies of gene-environment interaction as determinants of health, disease, and longevity” (see press release).

One of the concerns expressed when the Human Tissue Act was enacted in the UK in 2004 was that the legislation would have a stultifying effect on research. The Human Tissue Authority has commissioned some research to test the veracity of this claim and assess the effect of the legislation on researchers working with human tissue. The research carried out by Opinion Leader consisted of a questionnaire survey of 295 members of the research community supplemented by ten in depth interviews with a range of stakeholders (together with a literature review and stakeholder meeting).

The results, published in September 2009 in a report - The Impact of legislation and Human Tissue Authority regulation on research suggested that respondents found it difficult to distinguish between the effects of the Human Tissue legislation and Human Tissue Regulation generally (including research ethics and research and development (R&D) governance). Moreover, the respondents were often sharply divided in their opinions. Those appointed as designated individuals pursuant to the Human Tissue Act licensing regime were less likely to be negative about the impact of the legislation, but pathologists and those working in the NHS were more likely to be negative. Indeed the majority of those questioned (59%) believed that the Human Tissue legislation and subsequent regulation by the Human Tissue Authority had a negative impact on research. 68% of respondents believed that the legislation resulted in samples being more difficult to get hold of, and 61%, that potentially valuable samples were being disposed of.

On a positive note, 70% of all respondents agreed that the legislation and HT regulation had helped to ensure that informed consent is given by donors, and more participants agreed than disagreed that the combined effect of the HT legislation and regulation had resulted in increased public confidence in what happens to donated tissue.

Comment: It is unsurprising that those with a positive attitude to governance generally were more likely to be positive about the HT Act particularly as pathology was one of the sectors most critical of the legislation as it passed through Parliament. The complexity of governance in this area is confirmed by the findings of a survey of pathologists and pathology carried out by onCoreUK, in collaboration with the Pathological Society, in response to the National Cancer Research Institute Task Force on the role of pathology in cancer research. This also highlighted the need for guidance to be consolidated into an accessible, authoritative and consistent multi-regulator resource. As a result of these findings, the Medical Research Council has announced that their excellent Data and Tissues Tool Kit is to be strengthened by providing links to guidance from relevant regulatory and governance bodies, and more widely disseminated via a range of stakeholders to provide an authoritative resource in this area.

Mitochondrial disorders are a group of diseases, many very serious, caused by mutations in mitochondrial genes (see previous news). Together they have an estimated prevalence of around 1 in 5,000, and can affect multiple organs. Their clinical presentation is highly variable, and the underlying mutations may lie in one of hundreds of mitchondrial genes, most of which lie within the main genome in the cell nucleus, but a small number of which (thirteen) form the small separate mitochondrial genome.

Diagnosis of a mitchondrial disorders is therefore very difficult, but prompt and accurate diagnosis is important to allow effective treatment to minimise the potentially life-threatening disease progression. At the same time, some mutations associated with mitochondrial diseases also appear to be common in the general population; the penetrance of such mutations is also very variable, further complicating the clinical picture.

Now US researchers have used a combination of next-generation sequencing (see previous news) and microarray technology to create a new screening technique to identify mitchondrial mutations. Publishing in the open access journal Genome Medicine, they report the use of this technique to screen for variations in all the mitochondrial genes and a total of 362 nuclear genes previously associated with mitochondrial function or disease [Vasta V et al. (2009) Genome Med. 1(10):100].

The screen was tested on three DNA samples, two from previously characterised patients with known mitochondrial disorders and one control sample from the HapMap resource (see previous news). Both known mutations were correctly identified by the screen. In addition, the researchers reported detection of up to 336 further variants for each DNA sample, of which 90-94% were recorded in existing SNP databases and 6-10% were novel. One of these new variants was thought to be potentially harmful.

The authors propose that their molecular diagnostic tool “will increase the capacity for early and rapid identification of mitochondrial disorders” and potentially also help in the ongoing investigation of mutations associated with the conditions. They note that as more information is recorded about genetic variants associated with mitchondrial disease, there will be decreasing requirements for investigation of potentially harmful new mutations identified by screening.

Comment: The authors themselves acknowledge that the new screening technique requires considerable further development – three patient samples being on the small side even for a proof-of-concept study – but are right to assert that further analysis of mitochondrial mutations (which could be facilitated by methods such as their own) is likely to help expand understanding of this group of serious genetic disorders.

The Melanoma Genetics Consortium (GenoMEL), an international network coordinated by the University of Leeds' Cancer Research UK Centre, brings together researchers investigating the genetics of familial melanoma.

Melanoma is a form of malignant tumour arising from melanocyte cells, which are primarily found in the skin. The lifetime risk of developing malignant melanoma is around 1 in 91 for men and 1 in 77 for women in the UK (CancerHelp UK), although in Australia, where fair-skinned Caucasian populations are exposed to much higher levels of sunlight, it is much higher at 29.2 (Melanoma Patients Australia). Incidence is also rising in Europe and the US.

Although environmental factors play a key role in melanoma risk, genetic influences are also important. The GenoMEL consortium works to identify genetic susceptibility factors for melanoma, look at gene-environment interactions, determine what genetic variants mean in terms of individual risk of melanoma and develop materials for patients and health care professionals aimed at assessing and reducing risk.

Now the GenoMEL programme is set to expand to develop translational melanoma genetics research in Europe, with new partners in Eastern Europe, Australia, the US, and Israel (see GenomeWeb news article), and to widen gene-environment research to look at the effects of genetic factors and sun exposure in different latitudes. The link between family history and melanoma appears to differ significantly between countries (for example, ranging from 1% in a UK study to 11% in an Australian one, according to the GenoMEL website), which may be the result of gene-environment interactions. 

Meanwhile, preliminary results from a very small clinical trial have indicated that a new drug may offer promise as a treatment for some melanomas. The PLX4302 drug, which targets melanoma cells with mutations in the BRAF gene, reportedly reduced tumour size in more than half of the 22 patients (see Australian news article). Larger trials are expected to follow.

Whilst we often refer to the genome as if it were a simple linear sequence of DNA, in reality, it is folded up and squeezed into the nucleus of a cell. In humans, not only must all 46 chromosomes – six billion base-pairs, stretching over two meters in length – fit into a nucleus that may be only 0.01 millimetres across, but every gene that might be required by the cell must be accessible for transcription. That demands not only condensation, but also three-dimensional structural organisation within the nucleus.

A new method known as Hi-C has provided a snapshot of the folded state of the genome inside a cell nucleus, by combining molecular biology techniques with next generation sequencing [Lieberman-Aiden, E. et al. Science (2009) 326:289-93]. By chemically cross-linking and labelling DNA inside the cell, and then purifying and sequencing the sheared fragments, it was possible to reconstruct a three-dimensional map of the nucleus to determine which parts of the genome sequence were close to each other. This revealed that clear ‘chromosome territories’ were evident, with sequence proximity generally being a good predictor of physical proximity. Interestingly, the small gene-dense chromosomes (16, 17, 19, 20, 21 and 22) were co-localised in the centre of the nucleus and were found to preferentially interact with each other. Within chromosomes, two regions were discernable – one gene-rich region with an open structure, and one densely packed area.

This spatial compartmentalisation results in a self-organised DNA globule, which fills the nucleus without becoming entangled. The authors speculate that this knot-free structure ‘enables maximally dense packing while preserving the ability to easily fold and unfold any genomic locus”.

Comment: Understanding the architecture of the nucleus could provide invaluable insights into gene activity in an active cell. The long range interactions between genetic sequences may allow specific loci to act as either enhancers or inhibitors for the expression of particular genes. Such three-dimensional organisation may therefore explain many of the somewhat counterintuitive results from genome-wide association studies (GWAS), where non-coding regions of the genome known as gene deserts have been associated with disease.

Earlier this year, the US Secretary's Advisory Committee on Genetics, Health and Society (SACGHS) released a draft report on gene patents and their impact on patient access to genetic tests for public consultation (see previous news). Following on from this, the final version of the draft report from the Task Force on Gene Patents and Licensing Practices was discussed at a SACGHS meeting last week. 

The group concluded that ‘Patents do not serve as powerful incentive to conduct genetics research, to disclose genetic discoveries, or to invest in the development of genetic tests’ and that their benefits in the area of genetic testing are therefore limited (see presentation). They also noted that patient access to genetic tests, whilst not in general affected adversely by patents, had in some cases been restricted (especially for poorer patients) when offered exclusively by a single or limited number of providers. This is typified by the exclusive US patent to the BRCA1 and BRCA2 genes held by Myriad Genetics, the subject of a legal challenge in May this year (see previous news). 

Meanwhile, the Task Force on Gene Patents and Licensing Practices proposed that the Secretary of Health and Human Services (HHS) should discourage simple association patent claims – that is, those claiming a basic gene sequence, as opposed to applications relating to that sequence – because they ‘represent basic laws of nature that cannot be invented around’. Other suggestions included that the HHS should establish an advisory board to assess the public health impact of gene patenting and licensing practices, and that stakeholders should work together to develop consensus policies in this area, including steps to ensure patient access. The final report is expected by the end of the year.

The SACGHS meeting also considered the Genetic Information Nondiscrimination Act (see previous news), ethical issues associated with genomic data sharing, genetics education and training, and ditrect-to-consumer genetic testing. Presentations are available from the meeting website.

Comment: The proposed measures, if enacted, would effectively mean that individuals or organisations could perform research or offer tests relating to patented genes without licensing agreements from the patent holders. This could mean a substantial loss of revenue for the patent-holders, who might otherwise enjoy exclusive rights to such applications and charge fees to others who wanted to use them. In practice, many gene patent holders do not attempt to enforce their legal entitlements. Of note, the proposed exemption for those engaged in research already exists in the UK, where it is widely considered to be a beneficial measure, but this is quite different from provision of tests. 

The patenting of basic gene sequences is highly contentious – and possibly increasingly redundant in the light of the increasing ease and low cost of whole genome sequencing; efforts to ensure reasonable patient access to genetic tests are also desirable, However, care may nevertheless be needed to ensure that the commercial sector retains sufficient financial incentives to continue research and development of genetic tests and related applications.

Speaking at the recent World Stem Cell Summit, president of the International Society for Stem Cell Research (ISSCR) Irving Weissman reportedly announced that the creation of a new committee to regulate companies offering unproven stem cell therapies (see Nature news blog). The panel of lawyers, ethicists, stem cell scientists and representatives from the US Food and Drug Administration (FDA) have been discussing a web-based registry of companies that fail to comply with proposed measures to demonstrate credibility.

These measures, also set out in a recent publication in the journal Cell Stem Cell [Weissman I (2009) Cell Stem Cell. 5(2):151-3], would be citation of peer-reviewed literature supporting the therapy in question is theoretically possible; demonstration of institutional review board oversight of the treatment; and approval from the FDA or other equivalent national regulatory body.

The committee expects to produce a preliminary report by the end of the year, and formal guidelines early in 2010.

The US National Heart, Lung, and Blood Institute (NHLBI) has announced $64 million funding for a large-scale DNA sequencing and molecular profiling project that will use samples from several major population studies for research into the basis of heart, lung, and blood diseases (see GenomeWeb news article).

The project, which will run for two years, will analyse genomic data from existing cohorts with well-documented phenotypic and clinical data, in the search for genetic factors that contribute to disease, including gene-environment interactions. The conditions that will be investigated include heart attack, stroke, diabetes, obesity, asthma, chronic pulmonary disease, hypertension, and pre-cancerous blood disorders.

The funding includes $25 million each to two genome sequencing centres at the University of Washington and the Broad Institute of MIT and Harvard, which have developed their own methods of exome sequencing, as part of the Exome Project – an initiative to develop cost-effective, high-throughput sequencing for all of the protein coding regions (exons) in the human genome, funded and run jointly by the NHLBI and the National Human Genome Research Institute (NHGRI).  

This news follows the recent allocation of more than $1 billion for applied genomics research by the US Government (see press release), including $175 million for The Cancer Genome Atlas (TCGA) project, which seeks to map and understand the genetic basis of cancer (see previous news). This sum will be boosted by an additional $100 million from the NHGRI and National Cancer Institute (NCI), and will be used over two years for the collection and analysis of in excess of 20,000 tissue samples from more than 20 cancers. The project aims to produce comprehensive maps of the genomic changes in ten of these cancers, with sequencing and characterisation of at least 100 tumours of up to fifteen additional cancer types.

The Charter was created in collaboration with a working group of scientists, patients, ethicists and public representatives. It sets out five principles for the advancement of stem cell science: responsible science, protection of citizens, intellectual freedom, transparency, and integrity.

Canadian Stem Cell Foundation President and CEO James Price commented that everyone had a vested interest in developing stem cell medicine, saying of the Charter: “It's something that everyone, whether they are doctors, scientists, policy makers or the general public, can get behind. It unifies us in support of this vital area of research" (see Medical News Today article).

This effort to boost public support for this area of research may be considered a necessary counter to concerns about the ethics of those areas of stem cell research that use or stem cell lines derived originally from embryos, although there are prospects for producing therapeutic stem cells without the use of embryonic material (see previous news). At the same time, public expectations of stem cell medicine are often very high, with frustration that the marvellous cures promised by scientists have yet to materialise in the clinic, and an expanding market for unproven treatments (see previous news).

Comment: The website introduction features a video of scientists saying that “right now there’s a way to cure disease…generate organs…prevent heart attacks…let bodies heal themselves…it’s called a stem cell, and it can do all that…not in a hundred years, or in fifty…but in ten”. Will these assertions be borne out? Hopefully there will indeed be some effective therapeutics in this projected timescale, but it is unlikely that the science can deliver on all these ambitious promises in so short a time. Researchers must walk a tightrope between convincing potential funders and those who influence them of the potential importance of this area of research for medicine, and over-hyping the short-term benefits.