In the news

The Medical Research Council (MRC) has published its Delivery Plan for 2006-08, which outlines its projected spending and priority research areas. It has identified two key areas of work over the next decade. These are to increase understanding of fundamental cell processes in normal and diseased states and to then translate these results into actual healthcare, products and services.

With this in mind the MRC’s strategy for improving the translation of basic research into clinical benefit includes measures such as:

• Increased support for experimental medicine, including patient and volunteer studies based on the latest basic knowledge.
• Raised funding for clinical trials and other population level studies, for example on interactions between environment, behaviour, and predisposition to disease.
• Promotion of translational research approaches; where there is a vigorous exchange of ideas, methods, people, and priorities between basic and clinical sciences.

MRC funding for clinical and public health research will also rise from £127million in 2004/05 to £162million a year by 2007/08. As well as research funding the MRC are also committed to increasing resources and capacity in this field. Awards for the establishment of new translational medicine centres will be made later in the year, as well as initiatives to increase numbers of clinical training fellows, and provide increased training opportunities in biostatistics and health economics. There will also be increased support for the health informatics tools and infrastructure needed for the analysis of complex clinical data. The MRC has also recently launched a Population and Health Sciences Research Network, which will act to facilitate translational research. Additionally, proposals for the establishment of Centres in Population Health Sciences Research will be explored. These activities relating to health and population sciences will be coordinated with the MRC’s strategic goals in other areas such as infectious diseases, biomarkers and regenerative medicine.

The MRC currently receives around £500million a year from the Department of Trade and Industry, but following an announcement in the last budget this will eventually change to a joint MRC and NHS research budget of around £1billion (see previous newsletter item). The MRC describes this latest delivery plan as containing ‘a significant reprioritisation of MRC spending, with increased funds for clinical and public health research and training’ which it hopes will ultimately result in a ‘a major impact on diseases of significant health burden’.

The entire MRC delivery plan report can be found on the MRC website.

The Joint Committee on Medical Genetics has published a report, Consent and confidentiality in genetic practice: guidance on genetic testing and sharing genetic information. The Joint Committee, whose parent bodies are the Royal College of Physicians, the British Society of Human Genetics and the Royal College of Pathologists, has said the report “…is a response to requests from genetics professionals for clarification of issues of consent and confidentiality in clinical practice, particularly with regard to the requirements of the Data Protection Act 1998 and the Human Tissue Act 2004.” The draft report was made available for consultation in 2003, but its publication was delayed until 2006 in order to take into account issues arising from the Human Tissue Act 2004 and the Human Tissue (Scotland) Bill.

The report provides information, advice and guidance on the general aspects of consent in medical genetic practice, the giving and sharing of genetic information, genetic investigations on stored samples or archival pathological material, consent and DNA analysis under the Human Tissue Act 2004, and the Data Protection Act 1998 and the processing of medical genetic information. It also contains detailed flowcharts summarising the recommendations for clinical practice. Specifically, the flowcharts cover requesting information and samples during a genetic consultation, sharing and disclosing genetic information and consent for genetic analysis of stored samples or archival pathological material.

The Joint committee recognises that the report will not answer all questions. However, Dr John Crolla, Chairman of the Joint Committee, in his cover letter to the report, notes that they hope “…it will provide a framework which in time will lead to a consistency of approach in this difficult area for all of the UK’s clinical and laboratory genetics services and in those other areas of medicine and pathology for which genetic technology and information is becoming an increasingly important feature of clinical practice.” As the contents of the report are time-sensitive, with the implementation of the Human Tissue Act 2004 scheduled for September 2006 and the Human Tissue (Scotland) Act 2006 receiving Royal Assent, the aim is to revisit and revise the guidance after two years.

The US Secretary’s Advisory Committee on Genetics, Health and Society (SACGHS) is seeking public comment on its draft Report on Large Population Studies. SACGHS, an advisory committee to the US Department of Health and Human Services, launched a task force in 2004 to consider whether the US should undertake a large population project to study genes, environments, their interactions and common diseases. Such a project would seek to create a resource for research into the relationship between genes, the environment and common disease. However, there is a diversity of expert opinion as to the wisdom of embarking on this project. Some experts argue that a disease-specific resource would be more beneficial; others advocate creating a more general data and tissue resource that could lend itself to a variety of research projects. There are also concerns that the large amount of funding needed for this kind of population study would impact negatively on funding for other areas of research. In their report SACGHS presents its findings and its preliminary conclusions regarding the development of a large population research project and seeks additional comment.

SACGHS notes in their report that the proposed project raises multiple policy issues. Because of the large number of participants that will be need to be recruited, it will have a direct impact on the public; it will require a large investment of public resources and therefore needs to prove its relative value to science, society and the Nation; and the information derived from the project will raise ethical, legal, social and public policy concerns. SACGHS emphasises the need for public consultation and engagement throughout the project if it goes ahead. It recommends that the public needs to agree that the project should happen, the public should have input into its design and procedures, the public should provide feedback as to their experiences and concerns as the project progresses, and results from the project should be disseminated to and discussed with the public.

SACGHS also highlights many other issues that need to be considered. Clear definitions and parameters for what information is to be collected need to be developed, included ways of unobtrusively collecting environmental information. The subject selection must fair and subpopulations must be chosen for recruitment. Also clear intellectual property policies must be created to cover any discoveries made. Consultations should be held with the international community and the private sector to explore possible collaborations. SACGHS has recommended that an independent standing committee be appointed for the duration of the project to seek comment and report ongoing progress, consisting of members with expertise in the relevant sciences, medicine, law, ethics, and patient and community advocacy.

SACGHS is enthusiastic about the project “…because of its potential to generate significant health benefits.” However, it has recognised that these and many other issues need to be discussed before a decision is taken to go forward with the project. SACGHS welcomes all comments on its draft report from the national and international community. The consultation will close on 31 July 2006.

Suspected victims in public health emergencies in the US, such as a flu pandemic or bio-terrorist attack, may have experimental tests run on blood or tissue samples without their consent, according to an interim federal rule published on 7 June 2006 (see news report). In emergency situations, health care workers at US public health laboratories will be able to test samples from victims to identify the chemical, biological, radiological or nuclear agent involved with the normal requirements for obtaining informed consent waived in these situations.

The US Food and Drug Administration (FDA) has issued this rule due to concerns regarding a possible bio-terrorist attack or pandemic. To protect the public’s health and well being, the dangerous agent must be identified as quickly as possible. The conundrum in this particular situation is that the in vitro diagnostic tests that a laboratory would need to use might may not have yet been approved for clinical use, as many diagnostic tests for potential emergencies, such as Avian flu, are still in pre-clinical stages of development. But using an experimental test is considered ‘research,’ according to federal regulations on the protection of human subjects in research, and requires the informed consent of the person whose sample is being testing. This kind of research also requires approval from an authorised Institutional Review Board (the US equivalent of a research ethics committee). The FDA is concerned that, during a public health emergency, the delay caused by the time needed to seek and obtain informed consent from the victim might jeopardise not only their health, but also the health of others who may have been exposed to the dangerous agent. The victim may have left hospital and not be readily contactable, or the victim may be incapable, due to illness or other reasons, of giving informed consent and their legal representative might not be able to be contacted. The FDA notes in their justification of the rule that “The absence of this exception [waiving informed consent] was an impediment to the most efficient and effective public health response to the SARS outbreak,” and they do not want this to be the case in some future emergency.

Privacy activists say the waiver is unnecessary and there is a possible of it being abused. The public health laboratories conducting the testing will decide what constitutes a life-threatening public health emergency and critics fear that the laboratories will begin to use this power in non-emergency situations. This may be because, unlike other research trials, people whose samples are tested using one of these new in vitro diagnostic tests will not have the right to ask that their data be withdrawn from the research. The FDA justify this by stating “…it is critical that FDA obtain and have available for review all data on the investigational in vitro diagnostic device’s use in order to determine whether it is safe and effective.” One could possibly imagine a laboratory broadening the definition of a public health emergency in order to obtain sufficient samples to test the efficacy of a diagnostic test, without having to go through the rigours of a normal research study. But it is debatable whether this would provide sufficient incentive to abuse the waiver. Another possible concern is that, as in normal clinical practice, the results of the test would be sent to the person’s health care provider and possibly to public health authorities. People may not be happy with their personal medical data being distributed in this way without their informed consent. The FDA has considered safeguards. Included in the requirements for using this waiver are that, before the test is conducted, both the investigator (e.g. director of the clinical laboratory) and a physician “…who is not otherwise participating in the clinical investigation…” agree that the test is necessary. In addition, the appropriate Institutional Review Board must be notified within five days after the test has been used.

The new law regulating the removal, storage and use of human material in England and Wales - the Human Tissue Act 2004 – also recognises that there may be a public interest in research in these circumstances. After the Act is implemented on 1 September 2006, the High Court is empowered to grant deemed consent to the removal, storage and use of tissue and cells from the living and the dead in certain prescribed circumstances. However, the regulations detailing these circumstances are yet to be made. Explanatory notes to the Act suggest that ‘this power would be exercised only in rare and unusual cases where the research would be in the overwhelming public interest, for example, where a person has died of an unknown virus which has the potential to spread among the general population’. The Ebola virus was mentioned as an exemplar when this clause was debated in Parliament. Other provisions in the Act allowing material from the living to be used for public health monitoring without consent are confined to using population-based or epidemiological techniques to study established diseases and could not be used in circumstances of bio-terrorist attack.

While the US federal rule came into effect on the day it was published, as the FDA felt it important to have it in place as soon as possible, the public can still submit written or electronic comments stating their views. The deadline is 7 August 2007 (address information is provided as part of the interim rule.)

(Alison Hall also contributed to this article)

The Royal College of Obstetricians and Gynaecologists (RCOG) has updated its advice on umbilical cord blood banking and storage. RCOG had published advice for obstetricians, midwives and other healthcare practitioners on these issues in 2001, but new legislation, such as the Human Tissue Act and the EU Tissue and Cells Directive, have introduced changes. In addition, more women have been asking whether they should store their baby’s cord blood after birth. In light of these changing circumstances, the RCOG felt it was timely to update their advice.

RCOG has confirmed their opinion that there is no compelling reason for low risk families to bank their baby’s umbilical cord blood. Transplanting haemopoietic stem cells from umbilical cord blood is often a viable alternative to a bone marrow transplant. Currently, families at a high risk, for example of passing a genetic condition to their child, can bank cord blood for the future use of a family member at an established public sector cord blood bank, such as the NHS Cord Blood Bank or the Anthony Nolan Trust. These public banks also will take donations not directed for use by a particular family and provide material for transplants as required. But increasingly private companies have approached families to bank their baby’s cord blood ‘just in case’ there is a need in the future. Companies market their services in GP surgeries, antenatal clinics and directly to the public and people are uncertain whether or not to take advantage of this service. The RCOG notes that “the interest generated by the potential of [umbilical cord blood], and parental guilt for not storing their child’s stem cells, is a potent driver to commercial storage.” In response, the RCOG has recommended that only families at high-risk consider storing cord blood, as there is little evidence that low-risk families will ultimately benefit from the practice.

The RCOG also recommends that each Trust and hospital develop its own policy regarding prenatal requests for cord blood storage. The process of collecting the cord blood can have an impact on how the birth is managed and Trusts and hospitals need to ensure the family is aware of the institution’s policy. Finally, the RCOG advises that the NHS consider improving the funding for the collection and banking of unrelated cord blood and directed donations for families with genetic disorders, “…in order to provide a broad coverage and equitable access for those in need of the benefits that stem cell transplantation can achieve now, and those that may be available in the future.”

Progress continues on finalising the plans for the European seventh framework programme (FP7) (see press release). The European Parliament, in its first reading on FP7, agreed a budget of over €50 billion for research and development for 2007-2013. Also, the EP has followed the lead of the European Commission, voting to allow funding for both embryonic and adult stem cell research under FP7. Embryonic stem cell research will to continue to be reviewed for funding on a case-by-case basis, as is being done currently under FP6. Decisions would be based on the scientific proposal submitted and the legal framework of the Member State applying for the funding. Projects using embryonic stem cells would be subject to strict licensing and controls, based on the legal requirements of the Member State. Human reproductive cloning, therapeutic cloning such as by somatic cell nuclear transfer, and genetic modification of humans will be banned. The vote was close, with 284 votes in favour, 249 against and 32 abstentions.

This decision follows the advice given by the Industry, Research and Energy Committee (ITRE) of the European Parliament (see news story). According to Science and Research Commissioner Janez Potoènik (see press release), an unpublished Eurobarometer on biotechnology has shown that 55% of Europeans approved of conducting embryonic stem cell research under current government regulations. Only 17% would require some extra conditions to be imposed, while 9% would not approve it under any circumstances and 15% were undecided.

The charity Breakthrough Breast Cancer has released a warning that delays for genetic test results are so long that women at risk of familial breast cancer are opting for mastectomies rather than wait two years for test results (see news). Familial breast cancer represents up to 5% of all cases; women with the disease-associated BRCA gene mutations have up to an 85% lifetime risk of developing breast cancer, and up to 40% of ovarian cancer.

A survey by the charity found that 55% of the 27 genetic counsellors interviewed had seen patients who had their breasts removed whilst awaiting results from genetic screening for mutations associated with familial breast and ovarian cancer. 59% of the genetic counsellors also had patients who decided to go private because they had waited so long for NHS test results. Of the women with family histories of the disease and experience of the genetic screening process interviewed, 70% said that the wait made them worry about their own health or the health of their relatives (see report, Testing Times – Waiting for Genetic Test Results).

Breakthrough Breast Cancer chief executive Jeremy Hughes criticised the length of the waiting times, commenting: "That some [women] then feel compelled to make crucial healthcare decisions out of fear of developing breast cancer while waiting for their test results is appalling" (see Telegraph report).

The Government's Genetics White Paper of June 2003 pledged to reduce genetic test result waiting times to a maximum of eight weeks for diagnostic testing (identification of a mutation in a woman with breast cancer) and two weeks for predictive testing (identification of the same mutation in currently healthy relatives) by 2006. However, screening the BRCA1 and BRCA2 genes for mutations associated with hereditary breast cancer predisposition is a labour-intensive and time consuming process, and the backlog for testing is so great that some patients are still waiting for years to receive their results. Average waiting time is currently six months, with wide variation across the country.

A Department of Health spokesman said that the Government understood that long waits for the results of genetic tests can cause distress to patients, and it was for this reason that the White Paper has pledged funds to help modernise NHS genetic laboratories and enhance capacity, adding: "The laboratories are now working very hard to get their new equipment and working practices up to speed in order to meet these standards" (see ITV report).

Guy’s and St Thomas’ NHS Foundation Trust have launched a new development in pre-implantation genetic diagnosis (PGD). Pre-implantation genetic haplotyping (PGH) involves screening embryos conceived by in vitro fertilisation (IVF) for the presence of familial disease haplotypes, as opposed to specific mutations. Researchers presented the novel technique to delegates at the European Society of Human Reproduction and Embryology annual meeting in Prague this week. It has already been in use at the Guy’s and St Thomas’ Centre for Preimplantation Genetic Diagnosis for three months for cystic fibrosis, with a total of five healthy pregnancies thus far, but the team expect to be able to offer the service to more than 100 families a year.

The new and faster technique effectively increases the number of couples from families affected by severe genetic disease for whom selection of unaffected embryos prior to implantation will be possible. As for PGD, a single cell is removed from each early embryo; DNA is extracted and amplified (replicated) before being used for DNA fingerprinting. Whilst PGD relies on the identification of the presence or absence of a specific disease-associated mutation in the embryos, PGH can be used where the precise mutation is not known or cannot be identified. Instead, the technique scans for the presence of a broader genetic ‘signature’, or haplotype, associated with the familial disease gene region (see press release). For example, PGD for cystic fibrosis can only be used to test for the single most common causative mutation, but PGH can be used for couples that carry less common variants that also cause the disease.

Diagnosing genetic disorders in embryos is a complex process, and hitherto it has only been possible to identify the presence of a relatively small number of conditions in embryos, but with the use of PGH it should be possible to extend embryo screening to many more families affected by severe disorders caused by defects in a single gene. For couples that are carriers of X-linked disorders such as Duchenne muscular dystrophy (where female children are not affected by the disease, but half of all male children are) it will now be possible to identify unaffected male embryos; hitherto, it was not possible to identify affected embryos, and PGD could only be used to select for female embryos.

Team member Alison Lashwood, a consultant nurse in genetics, commented: “Preimplantation genetic haplotyping has revolutionised the service we can now offer…We are thrilled to have developed this technology as it opens up new possibilities to a number of couples who are at risk of conceiving a child with a serious genetic disorder” (see press release ).

A new international network has been launched that aims to bring together all those interested in the translation of advances in genomic science and technologies into benefits for population health. The network, officially launched on 6 June at the 4th International Conference on DNA Sampling: Genomics and Public Health in Montreal, Canada, is called GraPH-Int, standing for Genome-based Research and Population Health International Network. “Int” also signifies that the network is interdisciplinary and integrated.

The idea for GraPH-Int stems from a multidisciplinary workshop held last year in Bellagio, Italy (see workshop report). The workshop participants decided that the time was right to build on burgeoning efforts in several countries to establish the new discipline of public health genomics. The initial goals of GraPH-Int include providing an international forum for dialogue and collaboration; supporting the development of an international knowledge base for public health genomics; encouraging communication and engagement with the public and other stakeholders; and informing public policy; and promoting education and training.

The Public Health Agency of Canada hosts an administrative hub and website for the network, with a secretariat based at the Centre de Recherche en Droit Public at the University of Montreal. The GraPH-Int website (www.graphint.org) will act as a portal to organisations and activities in public health genomics around the world, and provide information about GraPH-Int’s working groups. Initial working groups have been established on topics including education and training; facilitating integration within the ‘ELSI’ community and between ELSI researchers and others; and defining the research needs of public health genomics. A News and Views section of the website is also being developed.

Speaking at the launch of GRaPH-Int, David Butler-Jones, Chief Public Health Officer of Canada, welcomed the network and endorsed its aim of using new knowledge and interventions deriving from genomics research to benefit the health of populations.

The Industry, Research and Energy Committee (ITRE) of the European Parliament has suggested a compromise position on funding for stem cell research under the draft European 7th Framework Programme (FP7) (see press release). In their report, ITRE has recommended that funding should not be made available for research aimed at human cloning, heritable modifications of the human genome or the production of human embryos solely for the purpose of obtaining stem cells, including by means of somatic cell nuclear transfer. However, they have recommended that other research on the use of human stem cells be funded “…depending both on the contents of the scientific proposals and the legal framework of the Member State(s) involved.” This would include research using both adult and embryonic stem cells, but only if Member States place strict controls on that research. Any application for funding “…must include details of the licensing and control measures that will be taken by the competent authorities of the Member States.” ITRE has also recommended that these provisions be reviewed in the second phase of FP7 (the programme lasts from 2007-2013) in response to the changing nature of this scientific field.

It is unclear whether this compromise position will be upheld or be subject to further debate. Funding was a controversial issue for the FP6 programme (see December 2003). When an agreement could not be reached, it was decided that each application under FP6 would be considered on a case-by-case basis. There is still a strong aversion by many in Parliament to embryonic stem cell research. The Legal Affairs Committee voted against giving any funding under FP7 to research involving human embryos or human embryonic stem cells (see press release). The Committee on Women’s Rights and Gender Equality, in their opinion submitted to ITRE, stated that no FP7 funding should be provided to any research that requires an embryo to be destroyed. 

These amendments have been sent to the European Parliament for discussion at their next sitting, tentatively scheduled for 13 June, with a vote tentatively scheduled for 15 June.

A report entitled Human Rights, Privacy and Medical Research has recently been published by John Gillott and the Genetics Interest Group. This is the first part of a study examining the impact of privacy rights on the regulation of medical research and clinical practice, with particular emphasis on the implications for human genetics. This first report is concerned with UK policy on tissue and data, and a second will examine the impact of privacy rights on human reproduction.

The report explores how human rights, particularly privacy rights comprised in the Human Rights Act 1998 and in relevant case law, impact upon research and clinical practice. Its starting point is the Human Tissue Act 2004 – the author demonstrates by textual study and legal analysis that the Government’s promotion of patient-centred consent-based practice is sometimes inconsistent with promoting research and clinical practice that may be in the public interest. The report goes on to analyse the philosophical basis for privacy based arguments, (noting that this may impact upon the ideology of other regulators), and then compares recent legislative developments on tissue with the legislation regulating the processing of data.

In the context of data, the report concludes that there is a failure to balance the right to individual privacy on the one hand, and the public interest in research and the health needs of other individuals on the other, compounded by privacy-centric guidance from some regulatory bodies. The report suggests that ‘the right to privacy is extensive, but also extensively qualified’ and argues that the effect of recent judgements is to suggest that recent developments in tissue law and in the interpretation of data laws unduly emphasise the right to privacy. The report advocates a less privacy-centric treatment and one that reflects the courts emphasis on a necessary and proportionate approach.

It concludes by challenging research and genetics communities to ‘make the case for the value of research and to explain the means as well as the ends of research to a wider audience’ and urges them not to be cowed by government rhetoric that suggests that researchers are not to be trusted and that research ‘is an optional frill in evidence-based care’. A report published today by the UK Evaluation Forum has taken this forward by advocating a number of strategies for improving the knowledge and perception of medical research, including promoting an evidence base for demonstrating the impact of research and improved use of evaluation tools. In this respect, Human Rights, Privacy and Medical Research adds textual and intellectual weight to the growing momentum for comprehensive reform initiated by the Academy of Medical Sciences earlier this year.

Embryonic stem (ES) cells possess the property of pluripotency, and are thus able to develop into any specialised cell of the body. Once cells differentiate they are committed to a particular developmental pathway and are no longer pluripotent. However differentiated cells can be returned to a pluripotent state in vitro, via the transfer of their nucleus into an enucleated oocyte or by fusion with a pluripotent stem cell.

A new publication by Silva et al., investigates the molecular mechanism by which pluripotency arises following cell fusion. The authors focus on the role of Nanog, a homeodomain protein expressed in the early embryo and which has the capacity to sustain pluripotency in ES cells. The role of Nanog was investigated using cell fusions between mouse neural stem (NS) cells and mouse ES cells that had been modified to overexpress Nanog. The NS cells contained a gene cassette containing Oct4-GFPirespac (O4G), allowing the expression of green fluorescent protein (GFP) under the control of an Oct4 regulatory element that is only active in pluripotent and germline cells. Expression of GFP in these cells can therefore be used as an indicator for the acquisition of pluripotency. Polyethylene glycol (PEG) was used to induce fusion between the NS-O4G cells and the Nanog-overexpressing RHN ES cell line, which also expressed the red fluorescent protein dsRed2. The authors found that two hundred times more hybrid colonies expressing both green and red fluorescence were formed from the RHN x NS-O4G fusions than from fusions between NS-O4G and RH ES cells, an ES cell line that did not overexpress Nanog. A number of different NS cell lines were used to confirm that this difference was due to the presence of Nanog rather than atypical behaviour by the NS-O4G cell line. The increased hybrid colony number effect was also seen when a different ES cell line that also contained the Nanog gene cassette was used to fuse with the NS-O4G cells. The effect was removed when the Nanog gene cassette was excised from the ES cell line using Cre recombinase before fusion.

The hybrid colonies that were produced from the RHN x NS-O4G fusions resembled ES cells morphologically, and were only supported on ES and not NS medium, leading the authors to conclude that cell reprogramming was a unidirectional process that either resulted in an ES cell phenotype or in a non-viable cell state. Epigenetic analysis of the hybrids revealed that the histone marks which characterise the inactive X chromosome of XX somatic cells had been removed, and epigenetic modifications characteristic of ES cells had been introduced. The authors also investigated if the ES x NS hybrid cells were able to differentiate into non-neural cell lines. The Nanog gene cassette was excised allowing the hybrids to differentiate into embryoid bodies. These were then analysed for the expression of the early mesoderm marker T-brachyury and endoderm marker, Gata4. These genes were not detected in the NS cells or undifferentiated hybrids but were up-regulated during embryoid body differentiation. The embryoid bodies were allowed to outgrow and most plate wells were found to contain beating cells which expressed the myogenic marker alpha-actinin. This indicates that the hybrid genome had been reprogrammed to possess an ES cell identity and had the ability for multilineage differentiation. However, when NS-O4G cells were transfected with a Nanog expression vector to create a cell line that stably overexpressed Nanog at a level similar to ES cells, these cells did not show a phenotypic change and retained normal expression of NS cell markers. This indicates that Nanog alone is not sufficient to institute pluripotency.

Experiments to determine if the effect of Nanog was specifically dependent on the particular characteristics of NS cells was also investigated by fusing the RH and RHN ES cell lines to other cell types including mouse fibroblasts and thymocytes. The yield of hybrid colonies produced was found to be an order of magnitude higher in the RHN, compared to the RH fusions. However, significantly fewer hybrid colonies were observed from the fibroblast and thymocyte fusions than were seen when NS cells were used. This indicates that the somatic cell partner and its developmental state may be a key factor in ES phenotype conversion.

Comment:

This paper illustrates the crucial role that Nanog plays in creating and maintaining the state of pluripotency. It offers a potential future strategy for converting somatic cells into a pluripotent state, without using nuclear transfer or cell fusion. However, a number of questions still need to be addressed before this could be possible. It is apparent that Nanog does not act alone, as simply increasing Nanog expression within NS cells did not result in pluripotency. Therefore the components of the ES cell that contribute to the action of Nanog following cell fusion need to be identified. The authors suggest that Nanog may act as a ‘master transcriptional organiser’ that instills pluripotency by triggering a hierarchy of gene expression, it may also act by coordinating the activity of chromatin re-modelling factors, or it might undertake both these activities. Fully identifying the mode of action of Nanog and the proteins that it interacts with it will be necessary to understand how pluripotency arises, and determining if a viable experimental alternative to nuclear transfer will actually be possible.

Nanog promotes transfer of pluripotency after cell fusion J. Silva, I. Chambers, S. Pollard and A. Smith (2006) Nature 441 997-1001.

Down's Syndrome is usually caused by trisomy of chromosome 21, when non-disjunction during meiosis results in three copies of chromosome 21 being present during development rather than the normal two. The increase in gene dosage from the presence of the extra chromosome results in the features of Down's Syndrome. These include cognitive impairment, skeletal and cardiovascular defects and an increased risk of disorders such as leukaemia. Only a small proportion of the genes on chromosome 21 are thought to be involved in Down's Syndrome and these are located on the q arm of the chromosome in the Down's Syndrome critical region (DSCR). But until now is has remained unclear as to how an increase in gene dosage causes the range of phenotypic effects seen in Down's Syndrome.

Arron et al., have recently suggested a mechanism by which some of the features of the syndrome may arise, by studying mouse models. The nuclear factor of activated T cells (NFAT) signalling pathway is a critical regulator of vertebrate development and organogenesis. The pathway is modulated by calcineurin, which dephosphorylates NFAT transcription factors after Ca2+ entry into the cell and leads to their forming NFAT transcription complexes in the nucleus. Arron et al., noted that mice in which genes of the NFAT signalling pathway had been knocked-out, displayed embryonic bone development resulting in facial characteristics similar to those seen in human Down's Syndrome. The NFAT mutant mice also showed increased social interaction, decreased muscular strength and decreased anxiety-related behaviour. The authors then went on to examine the human DSCR for genes that might inhibit NFAT function. They identified Dscr1, which encodes an inhibitor of calcineurin and NFAT signalling, and Dyrk1a which encodes a serine/threonine kinase. DYRK1A primes substrates for phosphorylation by glycogen synthase kinase 3(GSK3). GSK3 phosphorylates NFAT proteins in the nucleus which causes their inactivation and export. The authors studied the activity of these proteins in cortical neurons and found that DYRK1A and DSCR1 act synergistically to block NFAT-dependent transcription that is normally mediated by fibroblast growth factor 8 (FGF-8). They also found that DYRK1A synergises with GSK3 to facilitate the phosphorylation of NFAT proteins, leading to their export from the nucleus and a reduction in transcriptional activity. The effect of increasing Dscr1 and Dyrk1a gene dosage was studied by creating transgenic mice which overexpressed these genes during embryonic development. Overexpression of DYRK1A alone at 2-3 fold above endogenous levels, resulted in vascular defects and blocked heart valve development, and overexpression of both genes caused failure of heart valve elongation.

The authors also used mathematical modelling to predict the effects of NFAT signalling and its disruption in different tissues, and then used mouse models to validate them. Their mathematical simulation predicted that chromosome 21 trisomy would produce a disproportionate reduction in NFAT activity resulting in a milder version of the defects observed in the NFATc mutant mice. This was based on the assumption that the promoters of target genes would require a threshold level of NFAT complexes and therefore would not be transcribed when increased levels of DSCR1 and DYRK1A inhibited NFAT pathway activity. An examination of DYRK1A levels in two mouse Down's Syndrome models showed no overall increase in expression levels in the whole head, but an increase in the cortical neurons was detected. Similarly a study of tissues from human foetuses with Down's Syndrome found hyperphosphorylated forms of NFAT in the brain and heart (consistent with DSCR1 and DYRK1A overexpression), but not in the spleen or muscle. This indicates that it is probably only during brief developmental periods and under certain conditions that an increased dosage of Dscr1 and Dyrk1a results in reduced NFAT transcriptional activity leading to Down's Syndrome.

NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21 JR Arron et al., (2006) Nature 441, 595-600

Comment: The authors of this paper appear to have identified a key pathway through which many of the defects of Down's Syndrome arise. It is already known that certain post-developmental conditions seen in Down's Syndrome such as leukaemia and early onset Alzheimer's disease are caused by the triplication of specific genes, but the disruption of the NFAT pathway, via DSCR1 and DYRK1A, may explain the defects seen in cardiac, muscle and other tissue development. However, as the authors acknowledge they have only studied a limited number of tissues, at specific developmental stages. In order to fully confirm their findings trisomic tissues from developmental periods that correspond to the time of key NFAT pathway activity will have to be studied. This research does not currently offer any immediate therapeutic benefits to those with Down's Syndrome, or for it's diagnosis. It does however go some way towards explaining how the range of features that this syndrome can include, may arise.

Genetic defects in the human glycome. Freeze HH (2006) Nat Rev Genet. 7(7), 537-51. Review of genetic diseases arising from defects in the genes involved with glycan biosynthesis pathways (PubMed).

Designed DNA molecules: principles and applications of molecular nanotechnology. Condon A (2006) Nat Rev Genet. 7(7), 565-75. Review on the potential applications of DNA structures in nanotechnology, for example in therapeutic and diagnostic applications (PubMed).

First among equals: competition between genetically identical cells. Khare A and Shaulsky G (2006) Nat Rev Genet. 7(7), 577-84. Opinion article proposing that competition between genetically identical cells could improve the fitness of a multicellular organism by directing fitter cells to the germ line or by eliminating unfit cells, and that competition between genetically identical or very similar individuals could have selective advantages at societal levels (PubMed).

Alternative splicing and RNA selection pressure - evolutionary consequences for eukaryotic genomes. Xing Y and Lee C (2006) Nat Rev Genet. 7(7), 499-509. Review of the contribution of alternative splicing to modern genome composition, and of constraints on alternative splicing that may have medical implications (PubMed).

Newborn Screening: Towards a uniform screening panel and system. Special supplementary edition of Genetics in Medicine on findings of American College of Medical Genetics Newborn Screening Expert Group. See Executive Summary, Watson MS, Mann MY, Lloyd-Puryear MA and Rinaldo P (2006) Genet Med. 28(5 Suppl), 1S-11S (PubMed).

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Social, Political, and Epistemological Aspects of Genetics and Genomics. Lock M, Cox S and d'Agincourt-Canning L (2006) Community Genet 9, 137-141. Introduction to special issue on Genomics, Genetics and Society: Bridging the Disciplinary Divides, based on a conference held in Toronto in 2004 (PubMed).

Down’s Syndrome: Critical genes in a critical region. Epstein CJ (2006) Nature 441, 582-583. News and views article on the NFAT signalling pathway in Down Syndrome (PubMed).See also journal club article.

Single-cell genomics. Hutchison CA 3rd and Venter JC (2006) Nat Biotechnol. 24(6), 657-8. News and views piece on a novel method for amplifying DNA for genome sequencing from single bacterial cells (PubMed).

RISC control for gene therapy. Qasim W and Thrasher AJ (2006) Nat Biotechnol. 24(6), 661-2. News and Views article on the use of microRNA to reduce transgene expression following administration of gene therapy (PubMed).

The germ of pluripotency. Kanatsu-Shinohara M and Shinohara T (2006) Nat Biotechnol. 24(6), 663-4. News and Views article on the pluripotent potential of spermatogonial stem cells from the adult testis, in comparison with embryonic stem cells (PubMed).

Osteoclasts eat stem cells out of house and home. Purton LE and Scadden DT (2006) Nat Med.12(6), 610-1. News and views piece on the role of osteoclast cells in stem cell mobilization and haematopoiesis (PubMed).

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