Stem Cell News

News articles are provided by the PHG Foundation.

Zinc-fingers are small DNA-binding proteins that mediate DNA-protein interactions within cells, playing an important role in regulation of DNA expression. Zinc-finger nucleases (ZFNs) are synthetic enzymes that combine zinc-finger peptide domains (which target the protein to attach to specific DNA sequences) and a nuclease domain that will cut double-stranded DNA at the point where the protein is bound. Importantly, ZFNs can be used to create specific genomic modifications via these sequence-specific DNA breaks, encouraging the insertion of new DNA sequences or targeting the region for inactivation or repair via normal cellular mechanisms.

Research teams from six different US and German institutions, all members of the international Zinc Finger Consortium, have now published a new and efficient method for producing ZFNs in the journal Molecular Cell. The new technique, which they have dubbed OPEN (for Oligomerized Pool Engineering) is significantly more efficient than current methods, as well as being much easier and faster to perform [Maeder ML et al. (2008) Mol. Cell 31, 294-301, doi:10.1016/j.molcel.2008.06.016]. Target DNA sequences are used to select ZFNs from an archive of collections (or ‘pools’) of different zinc fingers. The method was used to produce ZFNs that were able to introduce modifications at sites in three different human genes (VEGF-A, HoxB13, and CFTR; mutations in the latter are associated with cystic fibrosis) within human cells, as well as a plant gene and an isolated human EGFP ‘reporter’ gene, with efficiencies ranging from 1%–50%. However, the paper reports that the desired genetic modifications were not introduced at some sites for which ZFNs were produced. It is suggested that this may have been the result of the state of the DNA at a target site (for example, active/unwound or inactive/supercoiled) or the stability of the ZFNs in the cell.

The researchers are now working to create more ‘pools’ of different ZFNs. Crucially, they are making them publicly available via non profit-making distributors for a modest charge, so that other researchers will be able to create special targeted zinc finger nucleases by the new method. Previously, methods for constructing ZFNs have been hugely labour-intensive, and the primary commercial provider has made them available only for selected academic collaborative projects; although they reportedly plan to offer a service to produce custom-made ZFNs, the expected charges will be very high (see Science news).

It is hoped that the availability of this novel method will facilitate all sorts of genome-based research, including the development of gene therapies directed against the mutations that cause single-gene diseases such as cystic fibrosis; the research was supported by the Cystic Fibrosis Foundation, among other bodies.Senior author J. Keith Joung of the Massachusetts General Hospital in Boston commented: “Our method will enable academic researchers to rapidly create high quality ZFNs for genes of interest and will stimulate use of this technology in biological research and potentially gene therapy” (see press release).

Comment: Research news is often dominated by discoveries or achievements, but new and effective methods can have the greatest impact of all if they facilitate rapid progress in many different areas of research simultaneously, as this latest technique may do for genomic research.

The prevalence of a specific infectious disease typically varies in different populations; much of this variation may result from differing social and economic factors, but genetic factors that influence susceptibility and resistance to the infectious agent can also play a significant role, and are of obvious relevance to public health. For example, it has been known for a long time that cellular receptors play a role in viral entry, and that mutations in such receptors can confer increased resistance to infection by HIV-1. HIV-1 enters a type of white blood cell via interactions with the CCR5 surface receptor; around 1% of Caucasians are homozygous for a specific deletion in the CCR5 gene, which confers a significant degree of resistance to HIV-1 infection.

New research has implicated the red blood cell (RBC) surface Duffy antigen receptor for chemokines (DARC) in susceptibility to HIV-1 (see BBC news). DARC is the RBC receptor for Plasmodium vivax, one of the four most common species that causes human malaria. Individuals who lack a functional DARC (with a DARC −46C/C genotype) including over 90% of West Africans, are resistant to infection by P. vivax; it is thought that the very high population prevalence of this genotype in areas where P. vivax malaria is endemic is the result of a selective evolutionary advantage.

A paper published in Cell Host and Microbe from researchers at University College London and the University of Texas has reported that DARC is also a receptor for HIV-1 attachment and entry to RBCs, which influences blood plasma levels of chemokines (molecular mediators of the immune response) that suppress HIV-1 and promote inflammatory responses. The researchers also report that the DARC-negative genotype is associated with 40% increase in risk of HIV-1 infection among African Americans [He W et al. (2008) Cell Host Microbe. 4(1):52-62], allowing for the influence of different environmental factors, and propose that, based on the prevalence of this genotype in sub-Saharan African populations, it could account for 11% of all HIV-1 cases. However, the DARC-negative genotype is also associated with slower disease progression. The authors conclude that DARC influences HIV/AIDS susceptibility by mediating infection of red blood cells by HIV-1 and immune responses to the virus.

Comment: The processes by which HIV-1 is able to infect different types of human cell and to evade human immune responses are many and complex, and this research merely adds one more piece of evidence to the body of knowledge in this area; it does not represent a breakthrough that could lead to an effective vaccine or curative therapeutic. The epidemiological work should be repeated in native African populations to determine a more accurate assessment of the impact of the DARC-negative genotype on infection rates and disease progression. However, the paper marks the “first genetic risk factor for HIV found only in people of African descent, and sheds light on the differences in genetic makeup that play a crucial role in susceptibility to HIV and AIDS” (see press release), helping to explain at least some of the observed variation in prevalence rates between different populations.

Regenerative medicine has continued to feature in the headlines recently. The European Science Foundation has announced plans to strengthen the research base in this area, which they define as “the development of stem cell therapies to restore lost, damaged, or ageing cells and tissues in the human body” (see press release). The new REMEDIC initiative, a five-year a research networking programme intended to facilitate information exchange and collaborative research, is supported by organisations from several European countries including Germany, Spain, Switzerland, Austria and the Netherlands. The Canadian government has announced funding of more than $100 million for the Canadian Cancer Stem Cell Consortium (see CBC news), which is to join with the California Institute for Regenerative Medicine (CRIM) in the US for a project on the role of cancer stem cells in disease development (see press release). CRIM has also announced a collaborative partnership with the Australian state of Victoria (see press release).

Stem cell researchers in California have called for a relaxation in state legislation to permit financial compensation for women who donate eggs for the creation of human embryonic stem (HES) cell lines (see Nature news). In some US states, it is legal for women to receive payment for donating eggs (ooctyes) for fertility treatments, but not for research purposes, making it difficult for researchers to recruit donors and, they say, stifling the progress of research. In the UK, women may donate eggs for fertility treatment or research in exchange for limited financial compensation (see previous news), or in exchange for a reduction in the price of their own fertility treatment (see previous news).

Meanwhile, a new publication in the journal Cell Stem Cell has claimed that countries with less restrictive regulatory regimes account for a disproportionately high level of scientific publications [Levine AD (2008) Cell Stem Cell2(6): 521-4], supporting concerns cited by many prominent US researchers that without easing of current legislation such as current restrictions on the use of federal funding for stem cell research (see previous news), the country will lag behind in this area of medicine. Countries dubbed ‘overperforming’ in stem cell publications were Singapore, the UK, Israel, China and Australia, whilst ‘underperformers’ included the US, Japan, France and Switzerland (see Nature news). The author concludes that the most highly performing countries had generally permissive policy environments for HES cell research, whilst those lagging behind were characterised by “protracted policy debates and ongoing uncertainty, regardless of their current policy environment”.

Within the UK, there is debate about the regulatory remit of relevant statutory authorities, with the HTA, HFEA and MHRA issuing a position statement on the use of human embryonic stem cells for human application. The potential for more general debate is evidenced by the discussion and media exposure surrounding the passage of the Human Fertilisation and Embryology Bill through Parliament (see previous news), but surveys of public attitudes have suggested that up to 79% of respondents were broadly in favour of the use of human embryos for medical research (see Times article).

Whether the public have a reasonable expectation of how long it might take for major benefits from such research to be realised is less clear, since progress is always publicised. For example, a triumph cancer ‘cure’ from therapeutic cloning has been hailed (see BBC news) following the publication of a paper in the New England Journal of Medicine detailing remission of a malignant melanoma (skin cancer) for a two-year period. Using immune cells produced by the patient’s body, US researchers created CD4 T-lymphocytes directed against a tumour-specific protein, cloned them and produced a massively expanded population of identical cells, which were then reintroduced to the patient [Hunder NN et al. (2008) N Engl J Med. 358(25):2698-703]. Although not all of the tumour cells were producing the corresponding protein, the patient’s immune system was apparently able to respond effectively against all the tumour cells.

This study is published in a respected peer-reviewed journal and does not make misleading claims, but concerns have arisen from the growing phenomenon of unproved ‘stem cell treatments’ being offered via private clinics and commercial websites. The International Society for Stem Cell Research is reportedly developing guidelines to condemn the use of stem cell treatments outside clinical studies (within which stem cell use is subject to regulation including research ethics approval)..These guidelines are intended to protect the safety of patients and combat misleading claims made about stem cell therapies (see Reuters news).

Health minister Lord Darzi has released his report on and strategy for the NHS in England, the NHS Next Stage Review, which is based around delivering quality of care; quality is defined as “clinically effective, personal and safe” (see report summary). It is suggested that that NHS funding for hospitals, GP practices and other bodies will depend on how well they are deemed to have provided accessible, high quality care by patients, although how this will be measured is not decided. This includes increased emphasis on improving health and preventing disease, including implementation of all recommendations from national expert committees for screening programmes.

The Human Fertilisation and Embryology Bill received considerable media and Parliamentary coverage in May as members of the House of Commons spent two days debating its most contentious clauses on which they had been given a free vote. Gordon Brown briefed Labour members of Parliament in advance by letter which set out utilitarian arguments in favour of the proposed legislation, suggesting that Britain’s ongoing support for stem cells was ‘not only in our own interest, but also the global interest’. Despite speculation that a government defeat might be imminent, in a debate on 19 May there was support for the legislation with many MP’s justifying these advances on the basis of their potential for developing effective treatments in the future. The majority of MP’s supported clauses to allow the creation of human admixed embryos within a tightly regulated research environment.

They also supported the selection of embryos which could be used to treat siblings affected by a serious genetic condition, (so called ‘saviour siblings’). In responses to questions about the scope of this clause, the Minister of State for Health, Dawn Primarolo acknowledged that the Human Fertilisation and Embryology Authority (HFEA) had licensed more than 80 conditions for pre-implantation genetic diagnosis including Huntington’s disease, muscular dystrophy and cystic fibrosis and that the selection of diseases which could qualify as ‘serious’ and utilise the techniques described in the Bill was a matter for the HFEA’s ethics committee. In the same debate, Dawn Primarolo also signalled the prospect of further regulation concerning the use of stem cell lines for treatment rather than research, acknowledging that the regulatory oversight by the HFEA ‘finishes once a stem cell line is derived’. Interim guidance has been published by the Human Tissue Authority.

The House of Commons also supported changes to the Human Fertilisation and Embryology Act 1990 to require clinicians to consider the need of any child born as a result of assisted reproduction to have supportive parenting (which replaces an explicit requirement to consider the need for a father). The Bill was also used as a vehicle to debate the ethics of abortion. One contentious area was the extent to which the time limit for certain types of abortion (excluding those carried out on grounds of fetal disability) should be reduced from the current limit of 24 weeks. It was argued that care of premature babies had improved and some evidence suggested that babies born at 22 or 23 weeks had improved viability. After considerable debate, MP’s voted for existing time limits to be retained.

In subsequent committee debates in the House of Commons, the Bill has been further amended to set out the basis for using cells from those lacking capacity (either as children or adults) or where the donor can no longer be identified or has died. These amendments are in line with the legislative framework laid down by the Mental Capacity Act 2005 and the Human Tissue Act 2004. With the House of Commons committee stage due to be completed by 17 June, one might expect the Bill to receive Royal Assent before Parliament breaks for the summer recess (22 July) although no dates have yet been published.

The University of Cambridge Institute for Manufacturing has released a new white paper, based on the Cambridge Service Science, Management and Engineering Symposium held in July 2007. Sponsored by IBM and BAE Systems, this meeting was attended by leading academics and business leaders from a range of different sectors. The new report, Succeeding through Service Innovation, looks at key service systems including healthcare that are crucial to the modern economy, and underlines the current paucity of funding for service innovation from governments, businesses and universities. Service innovation refers to developments that improve service delivery via changes in the way that technology, people, organisations and information work

The report notes that although relevant expertise does exist, it tends to be distributed across separate disciplines, and calls instead for a systematic and interdisciplinary approach to services innovation. Professor Mike Gregory, Head of the Institute for Manufacturing (IfM) and co-author of the report commented: “…there are enormous opportunities for companies and economies that are able to integrate science, technology, production and service” (see press release).

Recommendations include that:

Comment: Although the scope of this paper extends far beyond just healthcare systems, it is interesting that the emphasis on ‘bridging the gaps’ and building multidisciplinary collaborative models of research and delivery echo the approaches advocated by the PHG Foundation.

The report refers to ‘T-shaped professionals’, defined as individuals who are “deep problem solvers in their home discipline but also capable of interacting with and understanding specialists from a wide range of disciplines and functional areas”. This is a very apt description of many of the Foundation staff; experts from various disciplines, they also possess much wider experience and understanding of other relevant fields, allowing them to act as effective knowledge brokers. Public health genomics seeks to integrate knowledge from genetic and molecular science along with other relevant disciplines, in order to drive translation of this science into improved population health.

It seems that the underlying processes required for the effective transfer of knowledge from different sources into improved services (referred to in the report as the “fundamental challenges in integrating various strands of knowledge”) are shared across different types of service.

To learn more about how the Foundation works to bridge the knowledge gap in healthcare, by working with expert partners and stakeholders, see our What we do pages.

On 30 April 2008, the UK Human Tissue Authority (HTA) announced the release of regulations that will, for the first time, govern the collection of umbilical cord blood at birth. As stem cells present in cord blood can potentially be used to treat serious diseases such as leukaemia, there is an increasing trend among parents to collect and store the blood for use in the event that the child requires future medical treatment. Various companies will store the blood in a cord blood bank, which acts as an ‘insurance policy’ by securing a source of stem cells that is tissue-matched to the child (see previous news). The practice has raised some concerns, including the potential for commercial exploitation of parents in light of the very low risk that future disease will actually transpire. Commercial services might also divert efforts away from public sector banks such as the NHS Cord Blood Bank.

The new rules, which will take effect from 5th July 2008, emanate from the European Union Tissue and Cells Directive, which was implemented in the UK on 5 July 2007 by the Regulations on Human Tissue (Quality and Safety for Human Application) under the Human Tissue Act. The rules are intended to ensure safety and traceability by requiring that only specially trained individuals may harvest the cord blood, using approved procedures, in hospital maternity units that meet essential standards. An HTA license will require the unit to demonstrate not only that cord blood will be harvested in the proper manner, by qualified staff, but also that procedures are in place to prevent medical attention being drawn away from mother or child during the collection (see BBC news). HTA Chief Executive Adrian McNeil commented: “We are introducing this regulation to make sure that the best quality samples are taken in the safest way…The Human Tissue Authority is one of the frontrunners in Europe for implementing this legislation, which puts patients’ safety at the heart of the process” (see press release).

The Virgin Health Bank, which - unlike most commercial cord blood storage facilities - requires donors to make a portion of each blood sample publicly available (see previous news). has objected to the move, saying: “We already know that there is a critical shortage of cord blood units and there is little incentive for NHS Maternity units to apply for these licenses which may result in further constraint on the availability of cord bloods for lifesaving transplants” (see press release). Notably, procurement centres that do not already hold a suitable HTA licence will probably be charged a licence fee: 2007/8 HTA fees are £7600 for new applications, and £1000 for additional licences for the same centre (see HTA licence fees).

An EU funded project to design a tool for diagnosis and monitoring of coeliac disease is underway (see news source). The collaborative project named CD-MEDICS ('Coeliac disease management monitoring diagnosis using biosensors and integrated chip systems') will be an interdisciplinary venture aimed at developing a lab-on-chip device which can be used at the point-of-care to screen blood samples for genes which make people more susceptible to developing coeliac disease as well as auto-antibodies which can indicate disease status.

Coeliac disease is an autoimmune disease, also known as gluten intolerance, for which the treatment is strict adherence to a gluten free diet. Although it is estimated to affect around 1% of the population, it is thought to be significantly under diagnosed as the disease may present at anytime in a person’s life and can be difficult to diagnose due to a wide range of associated symptoms and their similarity to symptoms of other diseases. It is a polyfactorial disease, although there is a heritable component and genetic factors have been identified which contribute to increased risk of disease. However, it is not always the case that people possessing susceptibility genes will develop the disease. Absolute diagnosis requires antibody screening and a small bowel biopsy.

This device will form an efficient way to identify at risk individuals and monitor them, as early detection and treatment can help reduce the adverse effects of the disease. It may also negate the need for invasive diagnosis and will allow monitoring of patients who already have the disease in order to ensure that they are complying with a gluten free diet.

Whilst point-of-care tests for coeliac disease are already available, they usually only measure the antibodies associated with the disease. It is hoped that the addition of a genetic test to this panel will help to identify pre-symptomatic high risk individuals, although the clinical utility of this approach is currently unclear.

The programme involving various institutions in 10 countries will be sponsored for four years under the seventh framework programme (FP7). It is hoped that the technologies developed under this programme could be applied to other health conditions such as diabetes and rheumatoid arthritis.

In recent weeks, the health department of New York State has issued letters warning companies which offer direct-to-consumer tests that they require a permit in order to carry out gene scans (see news source). Public health law in New York State prohibits clinical laboratories from providing direct-to-consumer tests without the intervention of a medical professional, unless the tests have been approved by the FDA for direct, over-the-counter sale to consumers (see guidance on Direct Access Testing). In California, health regulators are investigating companies that offer genetic tests without the presence of a physician (see news source). The need for an adequate framework to regulate genetic tests and companies that offer them direct-to-consumer is becoming an increasingly important issue.

A number of US organisations have called for policies to regulate genetic tests, especially those that are available direct-to-consumer. The American College of Medical Genetics has released a policy statement outlining five minimum requirements for genetic testing protocols. This follows a statement on direct-to-consumer genetic testing released by the American Society for Human Genetics containing similar recommendations, and a report from the UK Human Genetics Commission on the availability, marketing and regulation of genetic tests supplied directly to the public (see previous news story), both published in December 2007. The US Genetics and Public Policy Center has also recently called for tighter regulation of genetic tests in an article published in Science (see press release).

These organisations call for greater transparency in the evidence in support of genetic tests so that physicians and the public can make an informed choice. They also recommend health professionals to be involved in ordering and interpreting tests and a greater oversight of laboratories and companies that provide them.

In the last month there have been several new moves form the US intended to accelerate the pace of change in pharmacogenomics, the study of genetic influences on drug responses. The National Institutes of Health (NIH) has sought input from scientists, the pharmaceutical sector and other on challenges and barriers to pharmacogenomics research, on behalf of the Trans-NIH Pharmacogenomics Working Group, with a view “to highlight opportunities, reveal gaps, and aid in identifying specific, achievable goals that will advance the field” (see Request for Information).

Scientists from the NIH Pharmacogenetics Research Network have joined with Japanese scientists from the Centre for Genomic Medicine (part of the RIKEN Yokohama Institute) to sign a letter of intent for the creation of a new Global Alliance for Pharmacogenomics. The aim is to co-ordinate ongoing research efforts to identify genetic factors that influence responses to drugs, with initial projects including investigation of warfarin and selected drugs for breast and pancreatic cancers, as well as exploring genetic factors that affect drug-induced long QT syndrome.Yusuke Nakamura, director of the Center for Genomic Medicine said: "By bringing together our resources, we will advance the understanding of how changes in DNA affect our responses to medicines. Thus we can begin to realize the promise of personalized medicine" (see press release).

Meanwhile, in a move intended to harmonize pharmacogenomic definitions and guidance with Japan and the EU, the US Food and Drug Agency (FDA) has issued a new industry guideline for comment. E15 Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding Categories defines a genomic biomarker as a measurable DNA or RNA characteristic that is an indicator of normal biologic or pathogenic processes or a response to therapeutic or other interventions, and also notes that certain principles in the document may also be applicable to proteomics and metabalomics (see FDA news).

Our inheritance, our future, the 2003 White Paper on genetics, set out the UK Government’s first explicit policy commitments in the field of human genetics. Significant investment was announced in a range of areas including clinical genetic testing, pharmacogenetics research, service development, and education and training of health professionals. The Genetics Knowledge Parks programme aimed to look ahead to the scientific and policy developments that would be needed to bring genetics advances into mainstream health care and public health.

Five years on, the Department of Health has reviewed progress on the White Paper’s commitments. Some important achievements are highlighted, notably the development of a system for evidence-based evaluation of clinical DNA tests through the auspices of the UK Genetic Testing Network, the setting up of the National Genetics Education and Development Centre, and some improvement in the speed and capacity of clinical genetic testing services. The progress of White Paper-funded research projects in pharmacogenetics, service development and gene therapy is also described.

So far, so good, but the report, while acknowledging ‘future challenges and opportunities’ in a general way, fails to offer any real commitment or strategy, on the part of Government, to tackle these challenges. It is clear that five years is far too short a time for significant benefits from investment in genetics to have been realised. Genomics research is generating a flood of new information about associations between genetic variants and common diseases. What is needed is a rational approach, with realistic resources, for identifying and evaluating clinical applications of this information, and for steering health services through the process of change management that will be needed if validated new tests and interventions are to be successfully implemented.   

Amendments proposed last year in a review of the 1990 Human Fertilisation and Embryology Act contain a new provision in relation to fertility treatment that has offended members of the deaf community and raises important questions about government policies on embryo selection and serious disability. The controversy is centered on a new licensing condition proposed in clause 14(4) of the Human Fertilisation and Embryology Bill that would prohibit the selection of a ‘disabled’ embryo when a normal one is available. Embryos known to have a genetic abnormality (including a gender-related abnormality) that places them at ‘significant risk’ of ‘serious disability or illness’ are not to be preferred over those that are not known to have the abnormality. The same prohibition extends to the preference of persons with a genetic condition who might act as donors of gametes or embryos. The express intention of the clause, indicated in both the explanatory notes and proceedings in the House of Lords, was to prevent situations similar to those reported elsewhere in which deliberate attempts had been made to produce a deaf child through positive selection of embryos or donors.

The ensuing legal and ethical debate is far from theoretical for the deaf couple who wish to share their experience with a deaf child rather than a hearing one. Tomato Lichy and his partner Paula Garfield view their deafness as membership in a linguistic minority, rather than a serious disability, and attempts to prevent them from choosing a deaf child as discrimination violating their rights to equality and privacy. This view is opposed by members of the medical community, who have serious concerns about permitting the deliberate selection of deaf babies. Professor Peter Braude, director of the Assisted Conception Unit at Guy’s and St Thomas’ Hospital in London is quoted as saying that “This is the same as taking a normal child and deliberately making it deaf so that it can fit in with a community. I don’t see how that can be acceptable” (see Telegraph article). Neither is it a view that is accepted by some of those who campaign on behalf of the unhearing. The Royal National Institute for Deaf People (RNID) does not support the choice of deaf embryos over those who would not be born with hearing problems. Chief executive Jackie Ballard says that “No one should be forced into having genetic testing if they don't want it. But if they do, we would want the embryos without the gene to be implanted” (see BBC news).


Nevertheless, the outcry and media coverage has elicited a response from the Department of Health, which has reportedly agreed to drop any reference to deafness as a serious medical condition. The concession does not extend to removal of the general prohibition against preference of embryos with genetic conditions, but it could pave the way for a challenge in the House of Commons later this year as to whether deafness should be classed as a serious medical condition for the purposes of the Bill. If successful, amendment of the Bill might permit parents undergoing IVF treatment to choose an embryo that will develop into a deaf child.

14 Conditions of licences for treatment

(1)        Section 13 of the 1990 Act (conditions of licences for treatment) is amended in accordance with subsections (2) to (4).

…

(4)        After subsection (7) insert:

(8)       Subsections (9) and (10) apply in determining any of the following:

(a)      the persons who are to provide gametes for use in pursuance of the licence in a case where consent is required under paragraph 5 of Schedule 3 for the use in question;

(b)     the woman from whom an embryo is to be taken for use in pursuance of the licence, in a case where her consent is required under paragraph 7 of Schedule 3 for the use of the embryo;

(c)      which of two or more embryos to place in a woman.

(9)            Persons or embryos that are known to have a gene, chromosome or mitochondrion abnormality involving a significant risk that a person with the abnormality will have or develop—

(a)      a serious physical or mental disability,

(b)      a serious illness, or

(c)      any other serious medical condition,

must not be preferred to those that are not known to have such an abnormality.”

Clause 14(4) of the Bill (above) effectively means that a person with a genetic condition, at significant risk of serious illness or disability, may not donate eggs or sperm for IVF treatment if there is an existing donor without such a condition. It also means that an embryo with a genetic abnormality posing a significant risk of serious illness or disability must not be implanted if there is one available that does not, or is not known to, have the abnormality.

The case raises a number of legal and social questions about perceptions of disability and the parameters of reproductive choice. The ‘medical model’ of disability employed in the Act has been blamed by supporters of the deaf community for undervaluing people with genetic conditions, their contributions to society, and – in the case of the deaf couple – their unique language and culture. It is true that the choice PGD offers to parents is one based on purely medical criteria – while each embryo is equally valuable in human terms. It is also true that the objective of PGD is to provide families with a means of choosing to avoid hardships associated with serious physical limitations - and that parents are not obliged to have their embryos diagnosed prior to implantation. At the point at which the in vitro fertilization has taken place and diagnosis obtained, however, a crucial decision must be made. The decision is not about whether an unhearing child would be better off with hearing. It is about which of the embryos, each legitimate offspring of a couple, will be nurtured and raised, and which will perish. The decision involves an element of discretion that the government is apparently not content to leave entirely to the parents, and which the parents might justifiably consider their personal prerogative.

The legislation currently places some controls on the use of PGD, limiting the genetic characteristics that may be tested for, and thus the information upon which the selection is to be based. These parameters are not presently in question, but within them there is an issue over the right to make the actual selection. The legislation and the goal of medical intervention by PGD are based on a presumption, reiterated in clause 14(4), that the interests of the public are best served by avoidance of genetic abnormality and physical impairment, and propose to prevent any other result. The values that suffuse this presumption are a cause of concern for Tomato and Paula, who argue that their preferences should not be legislated and that the government should not be arbiters of their family life. 

Various arguments are being flung about in the debate as to the right of disabled parents to choose children like themselves. The right to privacy in such intimate matters, the right to family life and the right to equality as well as non-discrimination are being hailed. The public interests against which such individual rights must be balanced, apart from overarching public health questions and economic considerations, are not self-evident. There is unlikely to be a floodgates problem of people seeking to use PGD in this way. Still, the government may be committed in principle to a prohibition of deliberate preference of disabilities, and refocus the debate on whether deafness is outside of the scope of ‘serious disability’ or ‘serious medical condition’. The absence of definitions in the Bill is perhaps by design, providing a degree of flexibility to permit interpretative application in individual cases. Where however ambiguity is informed by a contextual understanding of the intention of the legislators - in this case the accompanying explanation that deafness was being targeted – the legislative interpretation must take it into account. By removing this reference the notes should have less (prejudicial) relevance for the interpretation of ‘serious disability’ in the context of individual PGD assessments involving deafness.

Given the current limitations of the treatment - the prevalence of IVF births is just 1% and PGD has a low success rate and high cost - one has to question the need for any change in the level of regulatory scrutiny regarding preferences in the selection process. While Tomato and Paula remain the exception to the rule, the case-by-case method for addressing such decisions may continue to be the most appropriate way of handling them.

New technologies that have a potential to impact on health services are in constant development, and adequate Health Technology Assessment (HTA) systems are needed in order to make evidence-based decisions on the benefits of new clinical tools. A recent report published by the European Observatory on Health Systems and Policies has identified areas which could lead to improvements in HTA systems; Ensuring value for money in health care: The role of health technology assessment in the European Union is based upon a review of HTA organisations and processes across Europe.

The authors concluded that improvements to HTA could be made through a number of mechanisms such as increased transparency and stakeholder involvement, assessment of existing technologies as well as new ones, assessing the timing of evaluations so that decisions can be made quicker and more effectively and the implementation of a system which allows re-evaluation of products based upon new information on clinical and health economics. Some of these recommendations are similar to those published in a report by the House of Commons Health Committee following an inquiry into NICE, the National Institute for Health and Clinical Excellence (see also NICE’s response).

Comment: The importance of the assessment of new biomedical tools and interventions is strongly supported by the PHG Foundation; one of the key strategic objectives is to promote the development of systems and policies for the proper evaluation of new technologies that arise from biomedical research, and many of our projects relate to evaluation of this kind; for example, see our work streams on the Evaluation and regulation of genetic tests and Promoting genetics in mainstream medicine.

Prompt and effective translation of emerging technologies into health service practice requires key steps of evaluation, assessment, appraisal and implementation following on from ‘bench to bedside’ research; the PHG Foundation suggests that in the UK, these stages are not optimally handled, with the Health Technology Assessment (HTA) scheme limited to evaluation and assessment, and not directly linked with policy development (see Genomic Medicine consultation response). Our aim as practitioners of public health genomics is to bridge the current gap between assessment/evaluation and clinical implementation, a gap which creates unnecessary delay at translating potentially valuable new technologies into clinical practice and better health.

In 1995 the House of Commons Select Committee on Science and Technology published Human Genetics: the Science and its Consequences, a report which showed for the first that UK politicians were becoming aware of new developments in genetics and their potential impact on health care. Publication of the report was followed, during the second half of the 1990s, by the establishment of the first Government advisory committees devoted to aspects of genetics policy.

More than a decade later, the Human Genome Project is complete and the Commons Science and Technology Committee is defunct, but its counterpart in the House of Lords has appointed a sub-committee to carry out an inquiry into Genomic Medicine, aiming to “provide an assessment of genome technologies and their actual and potential impact on clinical practice in the post-genome era”. The initial consultation stage of the inquiry, which has just closed, asked for evidence on issues ranging from the state of the science to how effectively it is being translated into new clinical tests and interventions, whether the existing regulatory framework is appropriate, and whether ethical, legal and social considerations are being adequately addressed.

In its response to the call for evidence, the PHG Foundation emphasises that, although genomic science is in a robust state, progress is much slower in evaluating the clinical and public health relevance of these scientific advances. There is insufficient recognition of, or resources for, the final stage of translation, which is not a research activity but a process of change management that includes knowledge integration and synthesis, knowledge brokering, stakeholder dialogue and consensus-building, clinical and public policy development, service review and reorganisation, education and training. These activities form the core of the work of public health genomics.

The PHG Foundation calls for a regulatory and policy regime that avoids ‘genetic exceptionalism’, instead treating DNA as one among several types of biomarker that may be used in the diagnosis of disease or estimation of disease risk. It points out that, in the context of common disease, the concept of ‘individualised medicine’ may be misleading. Advances in genomics are unlikely to lead to an ability to provide an individual with a precise, personalised prediction of drug response or disease risk. Rather, genomics will refine our ability to place that person within a band or segment of the population characterised by a particular array of diagnostic features or a particular average disease risk. This process does not differ in principle from the current practice of population stratification based on phenotypic features such as blood pressure or cholesterol levels.

Finally, the Foundation predicts that new service models and professional roles will need to be defined as genetics becomes integrated into mainstream medical practice, and routine genetic aspects of care are devolved to appropriately trained health professionals in other specialties.

The next phase of the House of Lords’ inquiry will be a series of public meetings and oral evidence sessions. The Committee expects to publish its final report, with the accompanying evidence, towards the end of 2008.

South Africa’s first Centre for Proteomic and Genomic Research (CPGR) has been officially opened (see news article). Based within the Institute of Infectious Disease and Molecular Medicine at the University of Cape Town, the centre houses a number of genomic and proteomic technology platforms which will be used to provide support and solutions to scientific communities both in industry and academia. The centre is also engaged in a number of research activities relating to both human and plant sciences such as identification of diagnostic markers for diseases like malaria and leukaemia, understanding the correlation between human genetic variation and drug response and the search for markers of pathogen resistance in maize.

Founded in 2006 through a grant provided by South Africa’s Department of Science and Technology, CPGR will contribute significantly to biotechnology in South Africa thereby helping to tackle many health problems faced by the country, as well as being a source of information about genomics for the public at large. It is hoped that public engagement and education about genomics and proteomics will assist in establishing adequate regulatory and evaluation systems for genomic and proteomic technologies (see keynote address by Minister Mangena).

There have been several recent international developments in stem cell regulation. On Friday 11 April, the Bundestag (lower house) of the German Parliament voted 346-228 to ease current legal restrictions on human embryonic stem (HES) cell research (see BBC news). Previously, German researchers have only been able to use HES cells harvested before January 2002, but now they will be free to use cells created up to May 2007. Germany has in general adopted a conservative approach towards controversial lines of medical research, but this latest move reflects concerns that their international scientific reputation could suffer if research is hindered by excessive regulatory burden.

Meanwhile, the UK National Stem Cell Network, which last week hosted its inaugural Annual Science Meeting in Edinburgh, has warned that the current status of the UK as a world leader in stem cell research will be in jeopardy in the absence of an increase in research funding in excess of £100 million. Professor Roger Pedersen said that the UK was at risk of being eclipsed by Germany and the US, both of which are investing heavily in this area (see Times Higher article).

A survey of public opinion on controversial work using human-animal hybrid embryos in the UK (see previous news) has suggested that 50% of respondents were in favour of the work, and of proposed legal amendments to facilitate such research (see The Times article)., A legal challenge has howeverbeen mounted by the UK Christian Legal Centre (CLC) against the decision of the Human Fertilisation and Embryology Authority (HFEA) to licence such research (see press release), on grounds that the 1990 Human Fertilisation and Embryology Act does not permit the creation of human-animal embryos. The 1990 Act has yet to besuperseded by amendments proposed by the Human Fertilisation and Embryology Bill, which are currently before Parliament.

In the US, a stem cell research advisory panel to the Food and Drug Administration (FDA) has been meeting recently to consider appropriate safeguards for potential use in clinical trials regarding new stem cell therapies on human subjects (see WebMD news). It is not clear whether these will be more rigorous than those applied to normal drug trials.

The Australian Capital Territories (ACT) legislative assembly is the latest Australian government body to lift its prohibition on human therapeutic cloning and pass the Human Cloning and Embryo Research Amendment Act 2008 (see press release). The state governments of Victoria (see previous news), Queensland (see ABC news), New South Wales (see previous news) and Western Australia (see ABC news) passed similar legislation last year, following the decision of the Australian federal government to lift its prohibition on cloning of embryos for stem cell research in December 2006 (see previous news). Reproductive cloning remains banned by federal, state and territorial law across Australia.

The UK Prime Minister Gordon Brown has announced a compromise whereby Labour Members of Parliament (MPs) will be permitted a free ‘conscience’ vote on selected elements on the Human Fertilisation and Embryology Bill currently before Parliament (see previous news); however, they are expected to support the Bill as a whole and not block its progress (see Ananova news).

Following this decision, and with less than a month until the Bill is scheduled to reach the House of Commons, UK scientists announced that they had successfully created the first human-animal hybrid embryos (see BBC news). It has been stressed that results are only preliminary findings, and have yet to be subject to the normal peer-review process, but the researchers reported the successful creation of embryos from the fusion of bovine egg cells from which the genetic material had been removed with human genetic material, to create embryos that were (in genetic terms) 99.9 per cent human and 0.1 per cent cow. The embryos survived for three days in the laboratory, but it is hoped that this period can be extended to at least six days for optimal research conditions; the legal limit is fourteen days. Professor John Burn, Head of the Institute of Human Genetics at Newcastle University where the work was carried out commented: “Cells grown using animal eggs cannot be used to treat patients on safety grounds but they will help bring nearer the day when new stem cell therapies are available” (see press release).

Work involving the creation of hybrid embryos is regulated by the UK Human Fertilisation and Embryology Authority (HFEA), which earlier this year granted licensed centres at Newcastle University and King's College London to create human admixed embryos as sources of embryonic stem cells for medical research purposes (see previous news).

108 UK academic professors (including scientists, lawyers, philosophers and theologians) have written to the Times newspaper calling for the Prime minister Gordon Brown to allow Members of Parliament (MPs) a free vote in the House of Commons on the Human Fertilisation and Embryology Bill. Proposed amendments to this legislation will be voted on, and the writers have said that ‘conscience voting’ (ie. not dictated by the political party, but left to the individual consciences of the MPs) should be maintained for bioethical issues such as this, despite the fact that they themselves did not share a common position on the proposals.Presently, MPs have been given permission to abstain from voting, but not to vote according to their own preferences; MPs have also been calling for a free vote (see BBC news).

Earlier the same week, forty cross-party MPs wrote to the Telegraph newspaper to express dismay at the decision of the Human Fertilisation and Embryology Authority to grant licences to conduct research with hybrids before the debate on the Human Fertilisation and Embryology Bill (see previous news).

The US Genetics and Public Policy Center has made a new internet resource available; the International Law Search facility allows users to search a database of laws in 16 countries related to human cloning, human genetic modification, and reproductive genetic modification. The database contains information derived from a 2004 survey of laws on prenatal genetic testing and preimplantation genetic diagnosis (PGD) by Bartha M. Knoppers and Rosario M. Isasi of the University of Montreal, Canada [Hum Reprod. 2004 19(12):2695-701], but is reportedly to be updated soon.

The UK Human Fertilisation and Embryology Authority (HFEA) has issued one-year licences permitting the creation of chimeric human-animal embryos for research purposes to two centres at King's College London and Newcastle University (see press release). Both centres wish to create embryonic stem cells for medical research purposes; creating hybrids by using enucleated animal egg cells fused with a human cell nucleus provides a better source of (near) human embryos than using surplus embryos from in vitro fertilization treatment.

The HFEA postponed a decision on these applications in order to carry out a public consultation exercise on the issue (see previous news), but in September 2007 they concluded that there was there was no fundamental barrier to such cytoplasmic hybrid research as it was ‘in principle, necessary and desirable in both scientific and ethical terms’ (see previous news) and the public were ‘at ease’ with the concept. However, opponents of such research contend that it is both ethically unacceptable, and also unnecessary in the light of alternative approaches to the creation of human stem cells.

The US Agency for Healthcare Research and Quality (AHRQ) has released a new report sponsored by the Center for Disease Control (CDC) on the use of gene expression profiling of breast tumour samples as a guide to prognosis and treatment. The report, Impact of Gene Expression Profiling Tests on Breast Cancer Outcomes, looked at three commercially available gene expression assays in order to determine whether there was sufficient evidence to support their claims of improved prognostic accuracy, treatment choice and health outcomes in women with early-stage breast cancer.

The assays examined were Genomics Health’s Oncotype DX™, Agendia’s MammaPrint® and AviaraDX’s H/I™ test, and they were assessed for their analytic and clinical validity, clinical utility and impact on healthcare (including costs), and any associated harms. Relatively little evidence was identified for any of the assays, but the authors of the report found that the Oncotype DX did enhance standard prognostic indices “in a clinically meaningful manner” but evidence of clinical utility was not found for the other two tests. Assessments of the cost-effectiveness of the assays were inconclusive.

Overall, the conclusion was that further study was required to provide reliable evidence on the use of all three forms of test, although the Oncotype DX was “furthest along the validation pathway”. Of note, Food and Drugs Agency (FDA) guidance on applications for In Vitro Diagnostic Multivariate Index Asseys (IVDMIAs) such as the gene expression profiling kits requires evidence of analytical and clinical validity for the test (see previous news), but not of clinical utility.

Following scrutiny by the Joint Committee of both Houses of Parliament over the summer, the re-named Human Fertilisation and Embryology Bill was introduced into the House of Lords in early November. Previous plans to merge the regulation of tissue and embryos and form a single regulatory authority, RATE, have now been scrapped and the significant reforms introduced by the Bill include extending the regulatory scope of the Human Fertilisation and Embryology Authority to cover all human embryos created outside the body. Thus inter-species embryos may be created for research, provided that such use is justified as being necessary and desirable, that the proposed use is licensed and appropriate safeguards adopted (such that embryos cannot be retained beyond 14 days of development or allowed to continue developing in either a woman or animal). The Bill imposes a statutory ban on sex selection for non-medical reasons and codifies the basis for screening and selecting embryos both for treatment and research. This is significant given technological advances which enable fetal sex to be identified in the first trimester using non-invasive techniques.

Since the Bill will take effect by amending the Human Fertilisation and Embryology Act 1990 (HFEA), there was substantive debate at second reading concerning proposed amendments to existing abortion law (since the HFEA amends the Abortion Act 1967). This is relevant because the House of Commons Science and Technology Committee recently considered whether the extent of technological change since 1990 warranted changes to the time limits for, and reform of the process of termination of pregnancy, the majority report concluding that there is a strong case for reform. Other widely debated areas at second reading concerned the removal of the ‘need for a father’ provisions from existing legislation. There was also questioning of the need for regulatory reform of embryo research, particularly interspecies hybrids (so to facilitate the production of stem cells) given recent reports of research which bypass the need for embryonic cells by reprogramming adult somatic cells to convert to stem cells.

All these topics were revisited in the more structured committee stage debates. Amongst the topics covered were the regulation of cell lines by the Bill; the regulation of human/animal hybrids and difficulties around framing a workable definition of interspecies embryo; the extent to which saviour siblings can and should be created to treat serious disease in a sibling and the extent to which this is ethically justifiable; whether cells or embryos from a child not able to give consent can be used for research, and mandatory counselling for prospective parents of donor conceived/IVF children.

Significantly the Government agreed to reconsider the definition of animal/human hybrids and the regulation of cell lines. An updated version of the Bill is likely to be published in advance of the Lord’s Report debate on 15 January 2008.

The UK Human Fertilisation and Embryology Authority (HFEA) has granted a licence to University College Hospital in London, permitting pre-implantation genetic diagnosis (PGD) for familial hypercholesterolaemia (FH), an inherited condition typified by very high levels of low-density lipoprotein (LDL) cholesterol and early onset cardiovascular disease (see HFEA statement).

The most severe form of FH is caused by the presence of two copies of disease-associated variants of the LDL-R (LDL receptor) gene; homozygotes for this variant have very serious disease that can be fatal in childhood or early adulthood. However, PGD could also identify embryos that are heterozygous (have only one copy of) a disease-associated variant; this generally causes a milder form of FH, which is treatable with drugs and an appropriate dietary regimen, and which is thought to affect as many as one in every 500 individuals in the UK. However, the HFEA has restricted the licence to selection against embryos with the homozygous, more serious form of the condition only.

Presumably this means that only embryos identified with two copies of the disease-linked genetic variant may be disposed of, and no distinction may be made between embryos that are entirely free from the FH-linked variant (and would be disease-free), and those that are heterozygous for the disease variant and would be affected by the milder form of FH. Some would suggest that it is unethical to fail to select the healthiest embryos to implant (as part of the in vitro fertilisation process); others have expressed concern at the possibility of screening out embryos that will not be affected by a serious form of disease.

The couple on whose behalf the licence application has been made are both heterozygous carriers with mild FH, who have a homozygous daughter with severe FH, as well an unaffected son. They are quoted as saying: “We had no idea that we both carried a gene for high cholesterol until the double gene was expressed in our first child. We are very lucky that our child has responded so well to the very high-dose drug regime. We have been led to understand that other children with the same double gene may not be so lucky” (see Times report).

The Human Genetics Commission (HGC) has published More Genes Direct: A report on developments in the availability, marketing and regulation of genetic tests supplied direct to the public. This document builds upon the recommendations made in an earlier report Genes Direct which was published in 2003, the year after regulations implementing the In Vitro Diagnostic (IVD) Directive into UK law were enacted. These recommendations include developing an independent system of pre-market review to ensure that genetic tests offered direct to the public satisfy requirements for clinical validity and clinical utility, supported by a code of practice and appropriate educational initiatives.

At the time of the publication of Genes Direct, the HGC acknowledged that few genetic tests were being offered to the public. That situation has now changed. More Genes Direct (Appendix A) lists a range of tests that are currently offered ‘direct-to-public’ (via a non-medical intermediary) and ‘direct-to-consumer’ (without an intermediary between consumer and test provider). It also draws upon a meeting organised by the HGC in 2007 to make a series of consolidated recommendations. The HGC reiterates its call for a proportionate response, which falls short of an outright ban upon direct genetic tests (unlike other jurisdictions such as Switzerland and France, which have introduced statutory prohibition), concluding that most genetic tests that provide predictive health information should not be offered as direct genetic tests. However, it suggests that a pre-requisite for allowing such tests is to introduce a new offence of misuse of genetic information.

The HGC also presses for review of the classification system, which currently deems most genetic tests to be ‘low risk’, and for an alternative regulatory mechanism to be considered for lifestyle tests that currently fall outside the IVD directive. Because of the information that they are likely to yield, the HGC recommends that certain tests should only be made available via a health professional. For this category of tests, direct to public advertising should be restricted. Multiple stakeholders should be encouraged to develop a code of practice that takes account of guidance from the OECD and relevant international standards.

Comment: A proportionate regulatory approach, which takes account of both the seriousness and complexity of the information that a genetic test may yield, offers a pragmatic solution to the regulation of this complex area. However some commentators have questioned whether a methodology that builds upon genetic exceptionalism and additional regulation is the most effective strategy and that a better use of existing regulatory structures might suffice.

Advisors to the UN have called for an urgent international prohibition on the reproductive cloning of humans. In the UK, as in more than 50 other countries, national law forbids the cloning of humans for the purposes of reproduction. In a report issued on 10th November 2007, the United Nations University’s Institute of Advanced Studies (UNU-IAS) says that the proposed ban is intended to prevent "unscrupulous scientists" from taking their research activities to countries that impose no legislative barriers to it.

Previous attempts at international agreement in favour of a total ban on human cloning have failed, despite a common belief that a legal prohibition on reproductive cloning was desirable. The absence of consensus was attributable in part to the complex and controversial questions surrounding cloning for therapeutic research purposes, a matter that is permitted in the UK (subject to strict regulation via the Human Fertilisation and Embryology Authority (HFEA)) but remains illegal in many other countries. As a result, in 2005 the UN issued a non-binding