In the news

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

In the news

News story   |   By Dr Philippa Brice   |   Published 5 May 2005

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.

News story   |   By Dr Philippa Brice   |   Published 23 May 2005

At 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.

News story   |   By Dr Ireena Dutta   |   Published 19 May 2005

The 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

The Initiative forms part of the Government’s continuing commitment to science and technology in the UK, and builds on the strategy outlined in the Science and Innovation Investment Framework published last year.

News story   |   By Dr Ireena Dutta   |   Published 26 May 2005

A 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:

  • “Proof of concept” studies designed to explore pathophysiology, gain early evidence that an intervention has an effect and/or investigate mechanism of action. 
  • Early evaluation of novel diagnostic methodologies 
  • The characterisation of intermediate phenotypes or surrogate markers of disease progression or response to treatment 
  • Investigation of new technologies and technology assessment
Expressions of interest should be submitted by the 17th June 2005, and further details of the call can be found at the MRC website.
Keywords : uk

News story   |   By Dr Ireena Dutta   |   Published 20 May 2005

A 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."
Keywords : asia

News story   |   Published 19 May 2005

The 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.

News story   |   By Dr Ireena Dutta   |   Published 27 May 2005

The 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”.
Keywords : USStem CellsGovernment

News story   |   By Dr Philippa Brice   |   Published 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.
Keywords : uk

News story   |   Published 25 May 2005

The 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.
Keywords : Stem CellsGovernment

News story   |   Published 17 May 2005

The 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.

News story   |   Published 13 May 2005

The 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:

  • MGT is offered both publicly and privately, usually close to clinical genetic services
  • Most tests are ‘home-grown’; few laboratories rely on commercial test kits
  • The total number of specimens processed rose from 874,608 in 2000 to 1,401,536 in 2002
  • Most referrals come from clinical geneticists and physicians; in three countries patients could request their own tests
  • All OECD countries have measures to control the costs of genetic test services
  • Availability of tests varies greatly across the OECD countries
  • Disease prevalence does not seem to affect test availability
  • Reports from laboratories are generally of high quality, but financial and organisational barriers can hinder quality improvement

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.

News story   |   By Dr Philippa Brice   |   Published 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 to give is of dubious nature". Some scientists have suggested that it is unnecessary to actually sequence and analyse participants’ DNA - an expensive process - to study how they react to health-related genetic information (see ScienceNow report).

News story   |   By Dr Philippa Brice   |   Published 12 May 2005
The international ENCyclopedia Of DNA Elements (ENCODE) project, established in 2003 with the aim of identifying all the functional elements in the human genome sequence, held its Gene Prediction Workshop at the Wellcome Trust Sanger Institute in Cambridge last week. This workshop was the culmination of a competition called EGASP to develop improved gene prediction software for genome sequence analysis. Automated methods for gene prediction are important in genomic research, since the standard experimental procedures to identify and annotate gene sequences are expensive and laborious, but their accuracy is generally limited. A total of eighteen teams were challenged to use their programs to predict gene positions in selected areas of the genome; the ENCODE team used normal analytical methods to determine the actual genes in the same regions. Although no one program was superior to the rest, the combined predictions of the various software packages for the genome regions in question identified 70% of the genes identified by the ENCODE researchers [Abbot A (2005) Nature 435, 134]. They also predicted the existence of hundreds of genes not identified by the normal analysis, some of which will be investigated further and may represent some novel genes.

News story   |   Published 11 May 2005

The European Commission has published for consideration a draft framework to regulate advanced therapy medicinal products. 'Human Tissue Engineering and Beyond: Proposal for a Community Regulatory Framework on Advanced Therapies' will be open for comments until 20 June 2005. A consultation paper explains the background and legislative strategy chosen for regulating these products. The Commission has twice previously consulted on a framework to regulate human tissue engineered products (hTEPs) (see the DG Enterprise Advanced Therapies website), but the proposed Regulation has now been broadened to include gene therapy and somatic cell therapy products as well.

The finalised Regulation will lay down rules for the authorisation, supervision and pharmacovigilance of these products. Any Regulation will be directly enforceable and binding in all Member States, unlike a European Directive which enables Members States to create or amend existing national law, as appropriate, in order to implement its provisions. The Commission decided on a Regulation, rather than a Directive, in order to “establish legal certainty” in this emerging field. While products for gene and somatic cell therapy have been regulated as medicinal products, hTEPs do not currently fall under any legislative framework. Without a harmonised framework for these products, the Commission believes that this legal uncertainty “…impair[s] the free movement of human tissue engineered products in the Community, and hinder[s] patients’ access to these innovative therapies.” A “single, integrated and tailored framework” with the flexibility to keep pace with the fast-changing future is seen as necessary in order to ensure access to therapies and to “…foster the competitiveness of European undertakings operating in this field.”

Products made with cells or tissues from animals are excluded from the proposed Regulation. As for ethical aspects of using human tissue and cells, it is proposed that decisions regarding the use or non-use of human cells such as germ cells or embryonic stem cells will be left to the Member States.
Keywords : euRegulatory Framework

News story   |   By Dr Philippa Brice   |   Published 13 May 2005
The Centre for Arab Genomic Studies (CAGS) in Dubai (United Arab Emirates, UAE) was established to characterize and prevent genetic disorders in the region; genetic diseases represent a significant public health problem in the Arab world, due in part to social factors such as relatively high rates of consanguinity and parity (number of children born to each woman). CAGS recently initiated a project to establish a comprehensive Catalogue of Transmission Genetics in Arabs (CTGA), to “enlighten the scientific community and the public on the occurrence of inherited disorders in Arabs and to suggest future investigation strategies”. A model of the CTGA database for the UAE has proved successful and led to calls for an international collaboration along similar lines, to further research into genetic disease in Arab communities and, ultimately, develop patient treatment programmes. The project is also intended to improve public and professional education on genetic diseases and diagnosis, and will address potential ethical, legal, and social issues associated with the implementation of genetic screening and diagnosis services.

News story   |   Published 4 May 2005

A committee of experts set up by two of US National Academies’ constituent members, the Institute of Medicine and the National Research Council, have announced the release of a report, “Guidelines for Human Embryonic Stem Cell Research” [Holden C et al, Science (2005) 308, 611]. It includes guidelines that are “…intended to enhance the integrity of privately funded human embryonic stem cell research by encouraging responsible practices.” The report notes that there is a perception that some aspects of hESC research are unregulated. There are rules for all types of research that is funded by the US federal government, as well as other requirements that would apply to hESC research, but no federal regulations designed specifically for this type of work. As the Washington Post notes, the rules that were imposed by President Bush in 2001 focus on which cells can be used in research but little about what can be done with them [Weiss R, Post 27/04/05]. With the increase of private money becoming available for hESC research, as a way of avoiding the restrictions on federally funded research, the hESC research community has recognised the need for a set of voluntary guidelines [Holden C, Science (2004) 306, 586].

The guidelines cover all derivations of hESC lines and all research using hESCs from donated unused embryos from IVF treatments, embryos made specifically for research using IVF and somatic cell nuclear transfer. They do not cover non-human stem cells. The report lists three categories of research applications: accepted research, research that needs additional review before it is permitted, and research that should not be permitted. Into this last category falls the culturing of embryos for longer than 14 days or until the formation of the primitive streak, whichever occurs first; introducing human stem cells into nonhuman primate blastocysts or introducing any embryonic stem cells into human blastocysts; or allowing any animal into which hESCs have been placed to breed. All other types of research will be considered.

The report recommends a dual system of oversight of the research. Decisions on whether research should take place would be devolved to the level of the institution conducting the research. All institutions that conduct hESC research should create and host an Embryonic Stem Cell Research Oversight (ESCRO) committee, which would be responsible for reviewing hESC research proposals. It should include both lay and expert members. ESCRO committees would not replace institution review boards (IRBs), the US equivalent of research ethics committees, but would “…provide an additional level of review and scrutiny warranted by the complex issues raised…” by this research. At a national level, the report recommends the creation of a body to review the guidelines periodically to see if they are adequate and are taking into account new advances in the field. The national body would not interfere in decisions on individual research proposals. Other recommendations include ensuring the ethical procurement of donor oocytes and embryos; that informed consent procedures are in place; that no fees are paid for donations for research purposes, except for payment of direct expenses as a result of a procedure; and that uniform tracking procedures are put in place for the distribution of cells. In order to ensure that researchers and institutions follow these guidelines, the report recommends that ESCROs, IRBs, funding bodies and journal publishers should require evidence of compliance.

Research articles

Research article   |   By Dr Philippa Brice   |   Published 5 May 2005

Hereditary Nonpolyposis Colorectal Cancer (HNPCC) is the most common form of familial colorectal cancer and accounts for 1-3% of all colorectal tumours. It is diagnosed following established guidelines, the most recent version being the Revised Bethesda Guidelines for HNPCC (Lynch Syndrome) and Microsatellite Instability [Umar A et al. (2004) J Natl Cancer Inst 96, 261-268]. These guidelines update the original Bethesda Guidelines of 1997 on testing individuals with apparent HNPCC for microsatellite instability, or MSI. This is a genetic feature of tumours that have lost DNA mismatch repair (MMR) activity, mostly due to mutations in the MSH2 or MLH1 genes, although additional genes can also be involved. Such mutations generally cause abnormal MSH2 or MLH1 protein expression, which can be detected by immunostaining.

The purpose of testing for HNPCC is to identify individuals in whom colorectal cancer has arisen due to inherited, strongly disease-predisposing mutations. A diagnosis of HNPCC has implications for the individual’s family, who may then elect to be tested for the presence of the familial mutation and, if found to be carriers, opt for increased levels of medical surveillance or preventative treatments. A new study published in the Journal of the American Medical Association reports on the efficacy of the revised Bethesda Guidelines as a testing strategy for the detection of MSH2/MLH1 gene carriers. The guidelines cover two types of test. Since MSI is present in more than 90% of HNPCC associated cancers, MSI testing to identify the presence of abnormal microsatellite sequences in colorectal tumour samples is a useful method for identifying patients in whom genetic testing for HNPCC is appropriate. However, immunostaining for abnormal MSH2 or MLH1 protein expression is also useful; some tumours with MSH2 or MLH1 mutations do not display MSI.

In this multi-centre Spanish study, researchers compared the performance of both methods, as well as the selection of patients based on the Bethesda Guidelines, for identifying carriers of MSH2 or MLH1 germline mutations [Pinol V et al. (2005) JAMA 293, 1986-94]. They looked at data from a total of 1222 patients with newly diagnosed colorectal cancer between 2000 and 2001. Patients were tested for both MSI and absent protein expression detected by immunostaining; all those who were found to have positive results for either test were then tested for germline MSH2/MLH1 mutations. In all, 287 patients (23.5%) fulfilled the revised Bethesda guidelines for MSI testing, and of these 91 had a mismatch repair deficiency, with tumors exhibiting either microsatellite instability (n = 83) and/or loss of protein expression (n = 81). Germline testing identified 11 mutations in either MSH2 or MLH1 genes. Statistical analysis was used to evaluate the performance of screening strategies based on microsatellite instability testing and/or protein immunostaining, either directly or through previous selection of patients according to the revised Bethesda guidelines. A cost-minimization analysis was also performed to establish the most efficient strategy, using set costs of €100 (US $130), €200 (US $260) and €2400 (US $3120) for microsatellite instability testing, MSH2/MLH1 immunostaining and MSH2/MLH1 genetic testing, respectively.

The revised Bethesda guidelines were found to be the most discriminating set of clinical parameters for identifying patients at risk of HNPCC. Clinical selection of patients according to these guidelines followed by either MSI analysis or protein immunostaining was found to be more cost-effective than any of these approaches performed directly, with estimated costs per mutation detected of €11989 or €10644 for MSI or immunostaining respectively, compared with €32140 and €37956 for the use of these techniques without pre-selection of patients according to the Bethesda criteria. Both microsatellite instability testing and immunostaining were found to be highly accurate strategies for the identification of MSH2/MLH1 gene carriers, and equivalent in terms of cost-effectiveness. Given that immunostaining is “more available than DNA analysis in a clinical setting”, the authors propose that the use of this technique rather than MSI testing may help to identify a larger proportion of patients with HNPCC.

Comment: Other reports have found MSI testing and immunostaining to be equally effective approaches for HNPCC mutation screening, but some have found MSI superior. This study focused only on mutations in the two most common HNPCC associated genes, and not other genes (MSH3, MSH6, PMS1 and PMS2). However, as observed in an article accompanying the research report, including antibodies against the corresponding proteins in immunohistochemical analyses could further increase diagnostic efficacy [Vasen HF and Boland CR (2005) JAMA 293, 2028-30]. Ideally, a more comprehensive study should be performed to determine whether one method is genuinely better than the other. However, the key question for these researchers was the performance of the Bethesda guidelines and they were clearly found to be effective, irrespective of the testing method used. This provides a strong validation of the guidelines and means that clinicians should apply them to all cases of colorectal cancer, and have access to at least one screening method, in order to maximise the detection of HNPCC.
Keywords : colo_cancerjournal

Research article   |   By Dr Alison Stewart   |   Published 12 May 2005

HFE-associated hereditary haemochromatosis (HFE-HHC) is a disorder that causes inappropriately high levels of iron absorption and tissue storage. Almost all individuals of Northern European origin with clinical haemochromatosis are homozygotes or compound heterozygotes for mutations in the HFE gene. Around 11% of Europeans carry one or more mutant HFE allele(s). These individuals are at an increased risk of developing raised levels of serum ferritin (an iron storage protein) and of liver disease, cardiomyopathy, diabetes, arthritis, impotence, and chronic fatigue, with symptoms generally developing in late middle age. Pathology can be avoided by regular phlebotomy (blood-letting) to prevent excessive accumulation of iron in the bloodstream and tissues. In some respects, hereditary haemochromatosis represents an ideal condition for screening programmes to improve public health: homozygous carriers are common and easily identifiable by genetic testing, and the condition has a straightforward intervention to prevent disease, whereas treatment initiated after the onset of symptoms has a poor success rate. However, the penetrance of clinical disease is known to be low (one report suggests as low as 1%), and identification of homozygotes does not predict who would go on to develop clinical disease in later life. There are also concerns over the personal and societal implications of genetic testing in terms of possible anxiety and discrimination with respect to insurance and employment.

An early online publication in The Lancet reports an Australian study of workplace-based genetic screening of asymptomatic individuals for HFE-HHC, the HaemScreen programme [Delatycki MB et al. (2005) Lancet, doi:10.1016/S0140-6736(05)63012-7]. Participants completed questionnaires before testing that included sociodemographic details, symptoms and medical conditions potentially related to hereditary haemochromatosis, and questions to assess perception of health and levels of anxiety. A total of 11307 individuals with an average age of 37 were tested; a total of 51 (0.5%) were found to be homozygous for the C282Y mutation (four of whom had prior knowledge of their genetic status) and 1338 (12%) heterozygous. There were no significant differences between the normal, heterozygous and homozygous groups with respect to age, gender, medical conditions or symptoms other than tiredness, which was found to be significantly higher among homozygotes.

42 C282Y homozygotes and 158 age and sex-matched controls completed follow-up questionnaires one month after testing. Anxiety and health perception scores were essentially unchanged for both groups. A new measure of ‘impact of event’ was also assessed, with mean scores significantly higher (ie. the testing considered more intrusive) for the homozygous participants than controls. However, 98% of the homozygous group and 95% of the control group said that they were pleased to have had the test, although interestingly, only 80% of the control group could actually remember their test result (compared with 98% of the C282Y homozygotes). Among the 47 newly identified homozygotes, 46 agreed to clinical follow-up and management; 30 had raised serum ferritin levels and were referred for phlebotomy to reduce this. Four subjects had liver biopsies, and two were found to have advanced pre-cirrhotic liver fibrosis.

The authors conclude that genetic screening for HFE-HHC did not cause anxiety among participants, and led to high levels of compliance in preventative therapy among newly identified C282Y homozygotes. They also note that, although their study was not intended to assess penetrance of the C282Y mutation, two individuals (representing over 4% of the homozygous group) were found to have advanced pre-cirrhotic liver fibrosis. Moreover, levels of fatigue were generally raised among the C282Y homozygotes. They therefore propose that, should screening for HFE-HHC prove to be cost-effective, it should be implemented, on the grounds that the risks are outweighed by the health benefits.

Comment: A notable aspect of this study is that the Australian insurance industry had previously agreed that asymptomatic homozygous individuals would not be discriminated against [Delatycki M et al. (2002) Lancet 359, 1433]. A commentary on the study by a Canadian author notes that, in his experience, insurers generally request further information following positive genetic testing for haemochromatosis, but only discriminate against individuals with cirrhosis or diabetes [Adams PC (2005) Lancet, doi:10.1016/S0140-6736(05)66384-2]. This paper suggests that genetic screening programmes need not cause anxiety among participants, and can lead to high degrees of compliance with preventative interventions among newly identified homozygous individuals (presumably aided by the HaemScreen educational oral or video presentation provided prior to testing). However, although this evidence would support moves towards establishing routine screening for the condition, it does not attempt to assess whether the actual (as opposed to presumed) health benefits of screening and preventative interventions justify the practice.

Research article   |   By Dr Philippa Brice   |   Published 18 May 2005

About 5% of breast cancers occur in individuals with a strong hereditary predisposition to the disease, mostly due to inherited mutations in the BRCA1 and BRCA2 breast cancer susceptibility genes. Women with either of these mutations have an approximately 80% chance of developing breast cancer by the age of 70 (compared with a general population risk of 11%); the disease typically develops at a much younger age than sporadic breast cancer. For asymptomatic women considered to be at a high risk of familial breast cancer, based on their family history and in some cases genetic testing, clinical management in the UK is based on either annual screening by mammography, or prophylactic mastectomy. As younger women (under the age of 50) have generally much denser breast tissue, mammography is less effective at early tumour detection than in older women; cancers in BRCA1 mutation carriers also tend to develop very rapidly. A high proportion of high-risk individuals therefore opt for the removal of both breasts to prevent cancer.

A new study by the Institute of Cancer Research published in The Lancet has revealed evidence compared the performance of standard mammography with that of magnetic resonance imaging as a surveillance approach for women at a high genetic risk of breast cancer [MARIBS study group (2005) Lancet doi:10.1016/S0140-6736(05)66481-1]. Contrast enhanced breast magnetic resonance imaging (CE MRI) has high sensitivity for cancer detection, even in dense breasts. The researchers reasoned that, if superior to mammography, the relatively high cost of MRI could be justified among young women with strong genetic susceptibility to breast cancer, because of their high lifetime risk of developing the disease.

The MARIBS (Magnetic Resonance Imaging Breast Screening) study set out to compare the diagnostic accuracy of annual CE MRI with X-ray mammography in young women with a high genetic risk of breast cancer. Individuals aged 35–49 years who fulfilled UK high-risk breast cancer criteria for yearly mammography screening from age 35 or younger were recruited between 1997 and 2004 from 22 UK centres. Women with previous breast cancers, who developed cancer during the study, or who were found on genetic testing not to carry BRCA1, BRCA2, or TP53 mutations were excluded from the study. The 649 women in the study had annual mammography and CE MRI examinations, where possible on the same day, and by different operators who did not know the results of the other form of screening. The mammography and CE MRI scores for each woman were compared with her true cancer status.

Screening with CE MRI to detect breast tumours was found to show an overall sensitivity of 77% compared with 40% for mammography, although the latter had consistently slightly better specificity (around 93% compared with 81% for CE MRI). Combining both forms of screening increased overall sensitivity of breast cancer detection (94%), but with some loss of specificity. MRI showed the greatest increase in sensitivity over mammography among women who were BRCA1 mutation carriers or first-degree relatives of a BRCA1 mutation carrier, detecting 92% of tumours compared with just 23% by mammography. This group has the highest absolute risk of breast cancer in the age-range studied, and the researchers conclude that: “CE MRI screening might be particularly productive in this group”. Among women with BRCA2 mutations or no identified mutations, CE MRI was not found to perform significantly better than mammography (58% detection rate compared with 50%), although these groups had fewer cancers overall. The relatively low sensitivity of mammography is attributed to underlying biological factors in the young high-risk group of women compared with normal screening groups, including the probable higher density of breast tissue and higher proportion of rapidly developing tumours, particularly in BRCA1 mutation carriers.

The authors conclude that their results, combined with evidence from other studies, suggest that CE MRI screening would be most beneficial for BRCA1 mutation carriers; the most effective screening strategy for the high-risk group as a whole would be a combination of CE MRI and mammography. They note that a comprehensive assessment of the benefits of MRI for women at high risk of breast cancer should include an estimation of the effect on mortality.

Comment: These results provide evidence of an improved screening strategy for women at high genetic risk of breast cancer. Early detection of tumours is important to minimise surgical intervention and maximise survival prospects. The paper reports that a parallel psychological study will investigate the features of both MRI and mammography screening that women find difficult to accept and how they may cause anxiety, and a full cost-effectiveness analysis linked to this screening study will also be published. One of the study authors, Dr Ros Eeles, said: "We might finally now have an alternative to prophylactic mastectomy for women at high risk of breast cancer", noting that this approach would require around 1000 MRI scans a year in the UK (see BBC news report). Experts stressed that mammograms are an effective technique for screening the general population, but there have been calls for the National Institute for Health and Clinical Excellence (NICE) to review its guidance on the use of MRI for breast scans for women at high genetic risk of breast cancer.

For more information on genetic susceptibility to breast and ovarian cancer, see the disease profile section.

Research article   |   By Dr Philippa Brice   |   Published 15 May 2005

Hereditary non-polyposis colorectal cancer (HNPCC) or Lynch Syndrome is caused by mutations in DNA mismatch repair (MMR) genes. The genes MLH1, MSH2, MSH3, MSH6, PMS1 and PMS2 have all been implicated in this inherited propensity towards colorectal cancer, although mutations in MSH2 or MLH1 are the most common. Diagnosis of HNPCC is based on clinical criteria; the original Amsterdam criteria were subsequently modified, and followed by the less stringent Bethesda criteria, which are intended to identify colorectal cancer patients for whom molecular genetic testing is appropriate (see Accuracy of Revised Bethesda Guidelines for HNPCC diagnosis journal club, below).

Due to the high cost of testing for mutations in the MMR genes, pre-screening to identify the highest risk patients is desirable. A paper in the New England Journal of Medicine compares the two current techniques of pre-screening, testing for microsatellite instability (MSI) and immunohistochemical analysis of colorectal tumour samples [Hampel H et al. (2005) N Engl J Med. 352, 1851-1860]. A total of 1066 newly diagnosed colorectal cancer patients took part in the study; 208 were found to have MSI, and of these, 23 individuals were found to have Lynch Syndrome. Five of the 23 did not meet the Amsterdam or Bethesda criteria for the diagnosis of HNPCC. MSI testing and immunohistochemical analysis were concluded to perform equally well, on the basis that each method failed to identify two individuals with germline MMR mutations. However, the sensitivity and specificity of the two methods were not determined; it was too expensive to test all the samples by each screening method and genotyping.

The authors conclude that molecular screening methods for Lynch Syndrome are required to identify the maximum possible number of affected individuals. Given the performance of the screening techniques, they propose that immunohistochemical analysis could replace MSI testing without adversely affecting testing, and with the advantage that it can be performed in general pathology laboratories, saving time and money.

Comment: This study reinforces the conclusions of Pinol et al. (below) that immunostaining for abnormal MSH2 or MLH1 protein expression is a valid and probably preferable alternative to MSI testing of colorectal tumours in HNPCC screening. However, their suggestion that molecular screening of all colorectal cancer patients in this manner is justifiable, on the basis of the identification of additional Lynch syndrome patients (and prognostic implications of positive results for either form of test), is open to question. Although molecular screening costs much less than full genetic testing for the MMR mutations, it is nevertheless an expensive strategy, and whether it is truly cost-effective should be evaluated.