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Three new reports published in the latest edition of Nature Methods agree that the use of microarrays can yield more reproducible results than previous analyses have suggested, provided that standardized protocols and data processing are used. Microarrays are platforms that allow the simultaneous analysis of expression from thousands of genes, allowing researchers to identify patterns of gene expression that are associated with specific tissues and diseases. They are already being used in clinical trials for use in determining the prognosis and hence treatment options for breast cancer patients.
A study led by the US National Institute of Environmental Health Sciences (NIEHS) funded Toxicogenomics Research Consortium, comprising seven different centres, to assess the causes of variation between gene expression experiments and different microarray platforms has been running since 2001.These researchers report that using a standardized process led to more consistent results, and that using commercially manufactured microarrays made results more reproducible [Bammler T et al. (2004) Nat Methods 2, 351-356]. Dr Brenda Weis, one of the authors of the report, commented: "So far, gene expression data have been very useful in understanding diseases and biological processes…But if we standardize protocols the knowledge we gain from microarray studies can be used to improve clinical practice", adding: "If microarrays are to be used effectively in the clinic to diagnose patients and design patient-tailored therapies, they will need to be like any other clinical tests; they will need to be standardized" (see NIH press release).
A further two studies lend weight to these conclusions. One compared gene expression between two microarray platforms and using different experimental treatments, and concluded that biological treatment had a far greater overall impact on measured gene expression than the use of different platforms [Larkin JE et al. (2005) Nat Methods 2, 337-344]. The second compared microarray analysis data from ten different laboratories generated using identical RNA samples on three different platforms. This group found that different labs using the same RNA and the same microarray platform could produce significantly divergent data; but that the “best-performing” laboratories produced fairly consistent results [Irizarry RA et al. (2005) Nat Methods 2, 345-350]. Taken together, these results are encouraging endorsements of the potential value of microarrays in harnessing genomic information for clinical benefit.23 May 2005At the Sixth International Symposium on Preimplantation Genetic Diagnosis held in London last week, society president Dr Yury Verlinksy called for all embryos created by IVF to be checked for genetic abnormalities prior to implantation in the womb. Dr Verlinksy, of the Reproductive Genetics Institute in Chicago, presented results on the outcomes of pregnancies in 709 women who had IVF, reporting that the use of PGD increased the chance of a live birth from 11% to about 80%, due to fewer miscarriages and better foetal implantation rates. He commented that "40-70% of all embryos are somewhat abnormal and this is human nature" , and therefore proposed that all IVF embryos should be checked in order to maximise the success rate of the procedure, saying that the additional expense of PGD could be justified by the reduced need for further cycles of IVF.
He also said that couples undergoing IVF should be allowed to select the sex of the embryo to be implanted, and was supported in this assertion by IVF pioneer Professor Robert Edwards, who commented: "We need politicians to realise how far PGD has come, and it has to be paid for by the health service". However, critics condemned these proposals as unethical; a spokesman from pro-life charity LIFE said: "Just because something is scientifically possible it does not mean we should do it…My fear is that scientists are deriving this without recourse to ethics and public opinion" (see BBC news report). The Department of Health reportedly said the safety, clinical effectiveness and relative health benefits of PGD would need to be assessed before any decision about widespread provision could be made.19 May 2005The Government has revealed details of the composition and remit of the UK Stem Cell Initiative (UKSCI) first announced in the Chancellor’s Budget speech earlier in the year. The UKSCI will undertake a high-level review in order to formulate a ten-year vision for stem cell research in the UK. This will involve public and private sector stakeholders, and aims to create a platform for coordinated research funding from both these sources.
The Initiative is chaired by Professor Sir John Pattison, former head of research and development at the Department of Health. Its membership includes the heads of the MRC, BBSRC and Wellcome Trust as well as executives from the companies Stem Cell Sciences and Smith and Nephew. It also includes representatives from the newly established UK Stem Cell Foundation formed by Professor Sir Chris Evans. The UKSCI’s specific goals will be to:
To develop a ten-year vision for UK stem cell research, which seeks to make the UK the most scientifically and commercially productive location for this activity over the coming decade, and which commands the support of public and private research funders, practitioners and commercial partners.
To present a costed plan to Government and business for implementation over 2006-2015, to inform future public spending reviews and private sector investment planning.
To identify options for better coordinating and leading UK stem cell research and commercial translation in the coming years.
To report back to Government (DTI, Department of Health, HM Treasury) by Pre-Budget Report 2005
26 May 2005A new funding programme for experimental medicine has been announced by the UK Clinical Research Collaboration (UKCRC). The UKCRC is made up of a number of commercial, governmental and research organisations and aims to improve the environment for clinical research in the UK. As part of this goal it has allocated £74million to support experimental medicine and the translation of scientific research into clinical application. The Medical Research Council, the Wolfson Foundation, the Wellcome Trust, the Department of Health and the Scottish Executive Health Department are acting together as partners in the UKCRC to provide these funds.
Almost half of the available funds have been allocated to the establishment of new clinical research facilities that will enable universities and hospital trusts to work together on patient-focused research. A further £5million will be dedicated to the development of new treatments in clinical settings.
As part of the package, the MRC is also committing £15million for experimental medicine research, and has issued a call for proposals in this area. The proposals should involve human participants either from the outset or at some stage of the study, and should also seek to translate the research into clinical practice in the short to medium term. It is specifically seeking to fund collaborative research between basic and clinical scientists and industry with an emphasis on:
Expressions of interest should be submitted by the 17th June 2005, and further details of the call can be found at the MRC website.
20 May 2005A team of South Korean scientists have developed the first human stem cell lines derived from specific patients. The team, which was led by Professor Woo Suk Hwang, was also the first in the world to create human embryos by cloning in 2004 (see previous newsletter item). Unlike the announcement of the cloning of the first human embryo in the UK, made by researchers in Newcastle, this discovery has been published in a prominent scientific journal.
Publishing a summary of their results in Science Express, the researchers described the creation of eleven human embryonic stem cell lines by somatic cell nuclear transfer. Nuclear material was obtained from the skin cells of patients with various diseases or injury, and injected into donated oocytes from which the nuclei had been removed. The cell lines that were developed were reported to be pluripotent, chromosomally normal, and genetically identical to the original patient, even if they had been grown on genetically-unrelated human feeder cells. Comparison of the Major Histocompatibility Complex (MHC) of each of the lines with the original patient from which the nuclear material was taken demonstrated that they were also immunologcally compatible. This indicated that these cells could eventually be used in transplantation, to replace damaged tissues, without the risk of rejection. However the authors also highlight that additional studies are required to investigate the genetic stability of these lines over time and how to sustain them without the need for animal-derived components in the culture media. Further research is also need to develop appropriate methods for directing the differentiation of these cell lines into specific types of tissue or cells with particular functions that would be both clinically safe and useful for patients.
The safety issues surrounding the therapeutic use of stem cells have also recently been raised in a publication by a number of leading researchers in the field. Writing in the British Medical Journal the authors, including Dr Stephen Minger of King’s College London, state that the premature and unregulated implementation of stem cell therapy using poorly sourced cell lines could put patients at risk of contracting viral or prion diseases. This situation should be avoided in Europe with the implementation of the EU directive on cells and tissue, which will impose stringent quality standards on all clinics and laboratories but many countries still do not have relevant legislation governing this particular field.
However despite the complex technical and clinical issues that still need to be addressed it is clear that the scientific advances made by the Korean team have moved forward the possibility of using stem cell-based therapies as treatments for a range of conditions such as Parkinson’s disease, heart disease and diabetes. Commenting on the breakthrough to BBC News, Professor Roger Pedersen, of the Cambridge Stem Cell Institute, said “The work provided ample evidence for the feasibility of replacing the genome of a human egg with that of an adult body cell”. Professor Ian Wilmut of the Roslin Institute added, "These new observations make a very significant and important step forward toward the use of cells from cloned human embryos for research and therapy."19 May 2005The Department of Health has published its second edition of its Research Governance Framework for Health and Social Care (RGF). The RGF, first published in 2001, has been revised to take into account of a number of important pieces of legislation in the healthcare field: the Human Tissue Act 2004 (which will come into force in 2006), the Mental Capacity Act 2005 (which comes into force in 2007), section 45 of the Health and Social Care (Community Health and Standards) Act 2003 and the Medicines for Human Use (Clinical Trials) Regulations 2004, which implements the EU Clinical Trials Directive into UK law.
For example, as part of the Clinical Trials Regulations, responsibilities for the ‘partners’ in the research trial, the sponsor, research funders, the chief investigator, the organisation hosting the research, etc., have been clarified. In addition, the requirements for ethics review of proposed research projects have changed. While the Clinical Trials Regulations only apply to trials of investigational medicinal products involving human subjects, many of these requirements have been included in the RGF and therefore are applicable to all research “…concerned with the protection and promotion of public health, research undertaken in or by the Department of Health, its non-Departmental Public Bodies, and the NHS, and research undertaken by or within social care agencies.”
Research governance arrangements came into existence in response to the report of a panel, chaired by Prof Rod Griffiths, convened to look into complaints about clinical research that took place at the North Staffordshire Hospital in the 1990s. The 'Griffiths Report' recommended that some form of governmental oversight of research should be put into place to reassure patients about the quality of the research projects in which they were agreeing to participate. “Patients need to know who is responsible for what, and that responsibilities are being monitored regularly – not just when things go wrong,” the report stated. The RGF states that, “The dignity, rights, safety and well-being of participants must be the primary consideration in any research study.” Therefore, this framework gives guidance to researchers on how they must conduct their studies so as to fall within existing law, guidance and the RGF. While there is debate as to whether research governance is a help or a hindrance to researchers (for both perspectives, see for example the articles and letters published in the British Medical Journal, 31 July and 11 September 2004, vol 329), the Government sees it as an important step in ensuring public confidence in research, which is necessary if Britain is to continue to be a major force in medicines research, development and innovation.27 May 2005The body that advises the President of the United States on ethical issues surrounding biomedical research has published a report on stem cell biology and alternatives to the use embryonic cell lines. The President’s Council on Bioethics was created by President Bush in 2001 and is made up of leading academics in the fields of law, ethics, policy and medicine from a number of US universities. The Council has been investigating methods of producing stem cells that are pluripotent and genetically stable but do not involve the creation or destruction of human embryos. They specifically evaluated the scientific and ethical strengths and weaknesses of four approaches involving obtaining stem cells from four sources: dead early stage embryos; living embryos by non-destructive biopsy; bioengineered embryo-like artefacts; and reprogrammed adult somatic cells.
The report entitled, Alternative Sources of Pluripotent Stem Cells, was unable to conclude which, if any, of these particular approaches would provide a viable alternative to the use of embryos for the derivation of pluripotent stem cell lines mainly due to the lack of scientific and technical evidence. However, it did form preliminary conclusions on the approaches in terms of their ethical acceptability. It found that the derivation of cells from dead embryos was “ethically acceptable for basic investigation in humans, provided that stringent guidelines…are strictly observed”. The extraction of material from living embryos was found to be ethically unacceptable, and it concluded that, “we should not impose risks on living embryos destined to become children for the sake of getting stem cells for research”. The derivation of cells from engineered biological artefacts was not found to be ethically acceptable at this time, although further research in animal models may change this view. Obtaining cells from adult somatic cells was also ethically acceptable to the Council. The report conceded that some Council members might have felt that the “quest for alternative sources of stem cells is misguided” and that existing methods utilising embryos should continue to be used. But it also endorsed the four alternative options as “worthy of further public discussion” and called for further research in the area.
The composition of the Council has proved to be controversial following the departure from it last year of some members supportive of embryonic stem cell research. Critics of the Council have accused it of pursuing a neoconservative political agenda that is aligned to the Bush administration, rather than reflecting a range of bioethical viewpoints but its Chair Leon Kass has maintained that the Council is “easily the most intellectually and ethically diverse of the bioethics commissions to date”, and that “no one who has attended any of our meetings or read the transcripts can believe that we do anything but serious and careful work, without regard to ideology, partisan politics or religious beliefs”.20 May 2005 In a paper submitted to the journal Reproductive and BioMedicine Online (but not yet peer reviewed or accepted for publication), a team of scientists from the Newcastle Fertility Centre at Life and Newcastle University led by Professor Alison Murdoch report the creation of human blastocysts following heterologous nuclear transfer of DNA from human embryonic stem cells into a human oocyte. A total of 36 oocytes from 11 women were used; three clones survived for three days and one for five days. The researchers said that the speed with which oocytes were collected and manipulated was a key factor in the survival of the clones; those that survived in culture had been created within an hour of oocyte harvesting, and within 15 minutes for the one that survived for five days.
The Human Fertilisation and Embryology Authority (HFEA) granted a therapeutic cloning licence to the Newcastle team in August 2004 (see newsletter item), for the purpose of increasing knowledge about the development of embryos as the foundation for further development in the treatment of serious disease.25 May 2005The US House of Representatives, by 238 to 194, has passed a bill that would repeal the current restrictions on federal funding for human embryonic stem cell (hESC) research, according to the Washington Post [25 May 2005]. However, it will still need approval by the US Senate and the President, who has already stated he will not sign the bill into law. The Stem Cell Research Enhancement Act of 2005 [H.R.810.EH], would allow researchers to apply for federal money to remove hESCs from surplus embryos from in vitro fertilisation treatments, with the consent of the donor couple and without financial inducements to donate.
Currently, US researchers can only use federal money to conduct hESC research on stem cell lines that existed on 9 August 2001, the date President Bush announced an executive order limiting federal funding of hESC research. Critics of the current policy argue that limiting research to ‘approved’ stem cell lines, many of which are contaminated by animal products and therefore cannot be used in human experiments, is seriously hindering medical research in the country. They argue that the United States must be active in this research, in order to develop treatments for illnesses such as Parkinson’s disease and cardiac disorders, as well as to maintain a competitive position for US universities and companies involved in this field. However, many in Congress oppose the bill and a relaxation in the federal policy, such as Congressman Henry J Hyde, a Republican from Illinois, who believes that if it passes, “…taxpayers’ dollars are going to be spent for the killing of innocent human life.”
This vote does not signal the end of the process of attempting to change the current regulatory position in the US. The US Senate has yet to vote on their version of the bill, although indications show that that vote will take place soon. If both the House and the Senate agree a version of the bill, it will go to the President, who has said he will veto the measure, his first veto since taking office. The House of Representatives does not currently have the necessary votes, two-thirds of their membership, to override a veto. The fact that a large number of Republicans joined their Democratic counterparts to pass this bill does show that there is a shift in attitude in favour of hESC research, but researchers may need to continue to rely on private funding, which avoids the federal restrictions, for the time-being.
In addition to the hESC bill, the House also passed the Stem Cell Therapeutic and Research Act of 2005 [H.R.2520.EH], which authorises federal money to be spent on the collection and banking of unused umbilical cord blood, from which foetal stem cells could be sourced for research purposes. This much less controversial bill passed easily, 430-1. This bill will also need to progress through the Senate and then to the President for signature, but it should face much less opposition.However, hESC researchers have noted that foetal stem cells have only been shown to differentiate into a limited number of cell types, unlike hESCs which can change into any cell type, and therefore the therapeutic applications may be limited.17 May 2005The UK Biobank Ethics and Governance Council has a new website. The Council, founded in 2004, monitors the ethics and governance of the UK Biobank project. The Council is independent of the project and was appointed by UK Biobank’s funders, the Wellcome Trust and the Medical Research Council. Prof Alistair V. Campbell, from the University of Bristol, chairs the Council.
The aim of the UK Biobank project is to better understand how genetic and environmental factors impact our health. Volunteers aged 45-69 will donate blood and urine samples, complete a questionnaire on their lifestyle and have measurements taken. The participants will then be followed over the years, with additional information about their health and lifestyle collected. The data collected will form a resource for researchers to use in research studies designed with the aim to improve the prevention, diagnosis and treatment of illness as well as to promote good health. A Phase 1 pilot study received research ethics approval in February 2005, with the first volunteers being recruited in Nottingham. The main project is expected to begin in 2006.
Any studies conducted under the auspices of UK Biobank must adhere to the principles laid out in the Ethics and Governance Framework (EGF) and the Council’s remit includes this oversight role. The Council can also recommend changes to the EGF necessary to keep it up-to-date with current developments in the science or ethics. The Council will not approve research applications; this will be done by the UK Biobank Board of Directors. The Council will instead keep the use of the project data under review as an “independent guardian.” The Council, as the EGF states, will not “…speak ‘on behalf of’ UK Biobank…” but rather will “…speak ‘about’ UK Biobank.” The Council will, in case there is a need to liquidate the UK Biobank resources, approve any transfer to third parties. Agendas and reports from Council meetings are available on the website, as are biographies of the Council members and press releases on the Council’s activities.13 May 2005The Organisation for Economic Co-operation and Development (OECD) has published its survey, 'Quality Assurance and Proficiency Testing for Molecular Genetic Testing: survey of 18 OECD member countries'. The OECD states that it recognises that preventative medicine can profoundly contribute to the improvement of public health, “…provided governments implement the appropriate regulatory and legal frameworks to retain the confidence of the public.” Specifically, genetic tests can be successfully integrated into clinical practice if governments could ensure the quality of those tests. The OECD undertook to survey 18 member countries (see list below) for the availability and extent of their molecular genetic testing (MGT) services, the quality assurance policies used in their laboratories, their policies for handling samples and genetic data, and policies for cross border transport of specimens. Responses were received from 827 Laboratory Directors. Dr Rob Elles, Head of the Manchester National Genetics Reference Laboratory, chaired the expert group for the project. Some of the conclusions drawn from the data were:
The report sees accreditation as a major factor in ensuring quality. They recommend that standards of accreditation across countries should be harmonised and mutual recognition of standards for proficiency testing and external quality assessment should be facilitated. Minimum standards for professional competence need to be identified and formal training should be developed and encouraged. As genetic testing is taking place internationally, the report recommends greater access to national and international networks testing for rare diseases. In addition, the ways in which countries measure the clinical validity and utility of genetic tests need to be explored if tests are to cross national borders. However, the transportation of samples across borders raising security and privacy issues and these should be considered at an international level. The report does recognise the need to balance the needs of privacy for individuals with the needs of the public, such as equal access to genetic tests, the ability of researchers to conduct public health research and the ability to exchange information for medical care. They suggest that international guidelines are needed to address the long-term storage of samples for medical care and privacy and security issues, especially for samples crossing borders.
Countries surveyed were: Austria, Belgium, Canada, the Czech Republic, Finland, France, Germany, Ireland, Italy, Japan, Norway, Portugal, Spain, Sweden, Switzerland, Turkey, the United Kingdom and the United States.19 May 2005 The National Human Genome Research Institute (NHGRI) has announced plans for a new study to look at how people react to learning their genetic risk factors for diseases. The clinENCODE project will involve sequencing sections of DNA from 400 healthy volunteers and analysing it for polymorphisms associated with predisposition towards certain diseases. Participants, who will also be extensively tested for other indicators of health such as blood pressure and white blood cell counts, will be informed of these results and their reactions to the health-related genetic information studied. It is considered important to learn more about how people will respond to this sort of ‘personalised medicine'. Information on genetic susceptibility to certain conditions may be considered beneficial in terms of informing individuals and in some cases allowing them to make preventative lifestyle changes. However, there are also concerns that people may become unduly worried about their health, fear discrimination from insurers or employers, or adopt a fatalistic approach and neglect their health, on the basis of genetic test results.
The project is not universally welcomed; one of the organisers of the Biology of Genomes meeting at which the clinENCODE project was announced, Kelly Frazer of Perlegen Sciences, reportedly said: "There are so many genes whose function and link to disease is unknown that the information we are going