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24 February 2004The charity Cancer Research UK (CRUK) has been granted a European patent on the breast cancer gene BRCA2, discovered in 1995 by Professor Mike Stratton and his team during CRUK funded research at the Institute of Cancer Research (ICR) in London. The European patent is held by Cancer Research Technology Limited, the commercial subsidiary of Cancer Research UK, and covers all forms of sequencing of the gene or testing for damaged and inactive variants. In a move welcomed by researchers across Europe, the charity will in principle permit free use of the patent (by not imposing fees for licenses to use the gene) by European public laboratories, as in the UK where it already held the UK patent. Previously, although Cancer Research Technology held the UK patent for the BRCA2 gene, the US-based company Myriad Genetics (which owns US patents on both the BRCA1 and BRCA2 genes) had been granted a European patent on BRCA2. Objections to this patent, applied for just a few hours in advance of the publication of the discovery of BRCA2 by the ICR in the journal Nature [Wooster R et al. (1995], have been fierce. The primary concern has been that Myriad, which has an effective monopoly over BRCA testing in the US, might exercise legal rights as patent holder to impede the use of better and cheaper testing by public laboratories in Europe.
In a press release Professor Alex Markham, Chief Executive of Cancer Research UK, commented: "BRCA2 plays a central role in the inheritance of some important forms of cancer and we're delighted to have secured the patent for the gene in Europe…If the BRCA patents had been owned entirely by private companies, it would have made research into the inheritance of cancer far more expensive and made it costly for doctors to provide genetic services for those with a strong family history”.
3 February 2004The European Commission’s Joint Research Centre has published a report detailing the prospects for commercial and research activities in the field of human tissue engineering. In 'Human tissue-engineered products - Today's markets and future prospects', the authors state that while these emerging activities have great potential in for health care, they are not currently adequately covered by existing legislation. In addition, current differences in regulations are preventing the exploitation of this research in Europe. New regulations could harmonise the current regulatory framework to allow growth in this still-young industry.
At the present, products being commercialised include simple tissues such as skin, cartilage and bone. However, engineered tissues may be able to be used in the treatment of cardiovascular or neurodegenerative diseases and new products, such as tissue-engineered heart valves, are now being developed. In the future, proponents hope that larger organs, such as livers and hearts, can be created, thus countering the shortage of donor organs. But in order to fully exploit this new industry, the Commission has decided that new regulations are needed. They would differ from the current draft directive on human tissues and cells, as they would cover the marketing of tissue-engineered products in order to promote a common European market. The Commission has not indicated a time-scale for consideration of this initiative.
17 February 2004A team of scientists from Duke University in the US have revealed evidence indicating that stem cell transplants from umbilical cord blood cells can successfully replace damaged tissue in target organs. Stem cells derived from umbilical cord blood have been successfully used to treat children with rare genetic diseases (resulting in heart, brain and liver defects) for several years, but without evidence that the stem cells were directly responsible.
However, heart tissue from a child who received a successful stem cell transplant but later died from an infection has been used to demonstrate the presence of heart muscle cells of donor origin. The boy suffered from Sanfilippo Syndrome B, a rare metabolic genetic disease that arises due to the absence of a key enzyme needed to break down complex sugars. As sugars accumulate in vital organs such as the liver, heart and brain, cells become damaged and die. The boy had been treated with stem cells from the cord blood of a baby girl; by using differential staining of X and Y chromosomes, researchers were able to identify the origin of each heart muscle cell. A small number of female heart cells were identified among the male heart cells. Presenting their findings to the International Association of Bone Marrow Transplantation Research meeting in Orlando this week, the researchers proposed that even the presence of a few heart cells derived from healthy donor stem cells can provide sufficient levels of enzyme to restore function to the damaged tissue.
Private companies in the UK are already offering a service for collection and storage of cord blood from newborn babies for a fee of around £1000, but there are concerns about inappropriate marketing of these services to prospective parents. Banking of stem cells from umbilical cord blood has been undertaken by NHS facilities within the National Blood Service since 1996, primarily for research and development purposes; there is no routine collection and storage (see the Royal College of Obstetricians and Gynaecologists Scientific Advisory Committee report). Currently, there is some provision for donation of umbilical cord blood to public stem cell banks, with a view to providing a resource for matching stem cells for people who develop diseases requiring transplants. This is viewed as an ethically acceptable alternative to private stem cell banks, which store cells for the sole future use of their donor. Some transplant centres may provide collection and storage of cord blood in families with known genetic diseases.
26 February 2004The report, "Securing Good Health for the Whole Population", by government adviser Derek Wanless was published this week. It follows the earlier 2002 report “Securing Our Future Health: Taking A Long-Term View”, which assessed the resources required for long-term provision of health services, and instead focuses on measures needed to improve public health. For the purposes of this review, public health was defined as “the science and art of preventing disease, prolonging life and promoting health through the organised efforts and informed choices of society, organisations, public and private, communities and individuals”. The report refers to a changing climate for public health in the UK, with growing concern among the public about issues such as smoking, diet and obesity making the potential for public engagement in health promotion and disease prevention greater. Mr Wanless noted that: “Achieving the goal of a population 'fully engaged' in improving health, to avoid becoming sick rather than treating sickness, is a major prize for the whole community”, but warned that although the ultimate responsibility for health lay with individuals, the government needed to provide a suitable framework for success.
The report also cites the increasingly important role of genetics in public health, as understanding of genetic predisposition to disease, the effect of gene-environment interactions in health and disease and the genetics underlying disease processes increases. Knowledge of genetics and individual risk factors is predicted to have a prominent role in future moves towards individualized health care and disease prevention. The call for more active support to enable people to make better decisions about their own health and welfare, including the need for provision of adequate information and the wider implications of particular behaviours, is of particular relevance to public health genetics. It is envisaged in the report that primary care trusts will bear the bulk of the workload in developing this ‘self-care’ approach, and that this will require improvements in resources for areas including information systems, risk assessment and monitoring and education and advisory services.
Health secretary John Reid has announced that a White Paper on Public Health will be produced later in the year.
1 February 2004Health economists from the University of East Anglia have argued in The Lancet [Raithatha, N. and Smith, R.D. (2004) Lancet 363, 395-396] that insurers should have access to the results of genetic tests so that they can fairly determine insurance premiums. The authors contend that genetic tests, when compared to a standard predictive medical test, such as a blood cholesterol test, can “pose no new ethical issues.” If a similar diagnosis can be made from either test, then there is no reason to withhold the information from the genetic test. Indeed, withholding genetic test information can give an unfair advantage to an individual being tested while disadvantaging the insurer, which the authors consider unethical. As for the argument that individuals will be reluctant to take a genetic test if the results must be disclosed, the authors argue that if an individual’s condition can be improved through diagnosis and treatment, then the genetic test is no different from any other indicative test. The benefits will outweigh any distress caused by the test.
Opponents believe the potential disclosure of genetic test results might add to the anxiety already felt by discovering one has a disease. They also claim that there is no evidence to show that people are attempting to cheat the insurance industry by not disclosing genetic test information. For the moment, no resolution on this issue can take place, as there is a moratorium until 2006 restricting insurers from requesting genetic test information. The Genetics and Insurance Committee (GAIC), which oversees this issue, has only approved one test for consideration in determining insurance premiums, that is the test for Huntington’s Disease and only for insurance policies over £500,000. However, in their latest report (see newsletter item January 2004), GAIC has stated that they will be looking at an additional 17 genetic tests to see if these can, in the future, be considered by insurers.
12 February 2004As expected, the Italian Parliament has passed strict legislation regulating artificial reproductive technologies (ARTs) (see newsletter article December 2003). The law prevents research using human embryos, embryo freezing, gamete donation and surrogacy. It also limits doctors to treating ‘stable heterosexual couples who live together and are of childbearing age’ and who have been proven ‘clinically infertile’. Single women and same-sex couples cannot take advantage of ARTs. The law also bans pre-implantation genetic diagnosis and prenatal screening for genetic disorders.
In addition, there will be new rules for the processes involved in ARTs. No more than three eggs can be fertilised at any one time and any and all eggs fertilised must be implanted together into the woman’s uterus. Unwanted existing stored IVF embryos will be offered for use; the embryo storage facilities will eventually be closed. Doctors breaking the rules face the possibility of heavy fines and jail sentences.
Opponents claim that the law is too restrictive and some of its provisions may prove to be harmful to women’s health, while supporters say it will prevent the past practice of foreigners coming to Italy for treatments not available in their own countries. The law still needs to be signed by the President before it comes into force.
26 February 2004The National Institute of Clinical Excellence (NICE) has released its first set of NHS guidelines outlining the treatments that should be made available to people with fertility problems. Key recommendations include that six cycles of intra-uterine insemination (IUI) should be offered to couples with unexplained fertility problems, slightly abnormal sperm count, or mild endometriosis, and that 3 cycles of stimulated IVF should be offered to couples with have an identified cause of their fertility problems or unexplained fertility of at least 3 years, and where the woman is aged between 23-39. The guidelines propose that a maximum of two embryos should be transferred during any one IVF cycle, to balance the chance of a live birth and the risk of multiple pregnancy and its consequences.
In a press release, NICE Chief Executive Andrew Dillon said: “A consistent approach by the NHS to the treatment of fertility problems is long overdue. This national guidance sets clear standards by outlining which types of treatment offer couples the best chance of conceiving”, although he also noted that implementation of the guidance would take time. The Department of Health confirmed that it would be looking for Primary Care Trusts to offer all women aged 23-39 who meet the NICE clinical criteria a minimum of one full cycle of IVF from April 2005, with priority for treatment being given to couples who do not already have a child living with them (see press release). Welcoming the NICE guidelines, Health Secretary John Reid also said that in the longer term he would expect the NHS to make progress towards full implementation of the guidance.
20 February 2004A new £1.5 pilot scheme to assess genetic risk and provide counselling for concerned individuals has been launched by Macmillan Cancer Relief and the Department of Health. The scheme will be aimed at those who believe they have a genetic risk for cancer and want advice on whether they need genetic testing. The four pilot studies will focus on people affected by breast, bowel and ovarian cancer. If people are worried about a potential family history of cancer, they can seek support from GPs, local cancer experts and specialised genetics services. If the risk is confirmed, genetic testing can be carried out. In cases where a higher risk is ruled out, specialists will be able to reassure people that no further action is necessary. As many people overestimate their risk of cancer, counselling can provide the support people need to allay their fears.
This initiative acts on one of the Department of Health’s pledges made in the Genetics White Paper. Pilot schemes will take place in southeast London (Lambeth and Southwark), southwest London, Bradford and Middlesbrough. Some of the projects will examine how genetics services can be improved for ethnic minorities and those from deprived areas. An evaluation of these studies is planned and the information gained will be used to develop future cancer services.
13 February 2004A group of scientists in South Korea have created human embryos by cloning, and extracted stem cells from the embryos for research purposes; the team says that the embryonic stem cells are to be used to investigate potential means of treating disorders such as diabetes, Alzheimer’s and Parkinson’s disease. Published on-line by Science journal’s Science Express site, this is the first report of human cloning and embryo growth to such an advanced stage of development. A total of 242 eggs were taken from 16 different women, and clones produced by inserting the genetic material from the nucleus of a somatic cell into an egg from the same woman. 30 cloned embryos were grown to the 100-cell blastocyst stage. A blastocyst is is the most highly developed form of embryo that can be cultured outside the body, an embryo that has been growing for at least five days, comprising 30-200 cells of two distinct types: the stem cells that give rise to the foetus and cells which form the placenta if the embryo is implanted in a uterus. A stem cell line was successfully established from one of the cloned embryos, and the stem cells are reported to have shown the ability to differentiate into diverse specialised cell types.
Professor Woo Suk Hwang, one of the lead researchers of the Seoul National University team, is quoted as having said: "Because these cells carry the nuclear genome of the individual, after differentiation they could be expected to be transplanted without immune rejection for treatment of degenerative disorders…Our approach opens the door for the use of these specially developed cells in transplantation medicine" (see BBC report). However, years of intensive research will be required before therapeutic stem cell transplantation could become a practical reality. The researchers are now investigating methods of directing which tissues are formed from the stem cells.The group have emphasised that they have no intention of seeking to produce babies from cloned embryos, but the report will nevertheless revive controversy over human cloning, whether for reproductive or non-reproductive purposes.
26 February 2004The National Institute of Clinical Excellence (NICE) has released its first set of NHS guidelines outlining the treatments that should be made available to people with fertility problems. Key recommendations include that six cycles of intra-uterine insemination (IUI) should be offered to couples with unexplained fertility problems, slightly abnormal sperm count, or mild endometriosis, and that 3 cycles of stimulated IVF should be offered to couples with have an identified cause of their fertility problems or unexplained fertility of at least 3 years, and where the woman is aged between 23-39. The guidelines propose that a maximum of two embryos should be transferred during any one IVF cycle, to balance the chance of a live birth and the risk of multiple pregnancy and its consequences.
In a press release, NICE Chief Executive Andrew Dillon said: “A consistent approach by the NHS to the treatment of fertility problems is long overdue. This national guidance sets clear standards by outlining which types of treatment offer couples the best chance of conceiving”, although he also noted that implementation of the guidance would take time. The Department of Health confirmed that it would be looking for Primary Care Trusts to offer all women aged 23-39 who meet the NICE clinical criteria a minimum of one full cycle of IVF from April 2005, with priority for treatment being given to couples who do not already have a child living with them (see press release). Welcoming the NICE guidelines, Health Secretary John Reid also said that in the longer term he would expect the NHS to make progress towards full implementation of the guidance.
10 February 2004Cardiovascular diseases such as coronary heart disease (CHD), myocardial infarction (MI) and stroke represent the leading causes of mortality and morbidity in the developed world. Although many of the clinical features associated with such diseases have been determined, the contribution of genetic factors to the aetiology of these diseases remains uncertain. Advances in molecular techniques have allowed the identification of several gene variants that may modify the risk of MI, although the findings sometimes result in a relatively modest alteration to risk. In addition, genome-wide scans of families with MI have identified genomic regions which may contain gene(s) associated with the disease, however, the specific gene location(s) have yet to be determined.
The findings of a study in Nature Genetics (08/02/04) have begun to receive media coverage in both America (New York Post, CNN and USA Today), Australia (The Melbourne Age) and the UK (BioNews). The research, performed by Helgadottir and colleagues and sponsored by the Icelandic company deCODE genetics, identified two variants in the ALOX5AP gene, encoding the arachinodate 5-lipoxygenase-activating protein (FLAP), which the researchers suggest may increase the risk of myocardial infarction or stroke [Helgadottir, A., et al. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nature Genetics (online)].
The researchers claim to have identified a variant of ALOX5AP (HapA) carried by 29% of myocardial infarction (MI) patients in Iceland, which is associated with an 80% increase in risk of MI. Carriers of HapA may also be at a 67% increase in the risk of stroke. Although HapA was present in a British population, the study failed to detect any association with MI risk. However, a second ALOX5AP variant (HapB) was shown to be associated with increased risk of MI among British MI patients, although this association did not reach the same level of statistical significance as among Icelanders.
The ALOX5AP gene product, FLAP, which has been implicated as playing a role in regulating the production of substances that trigger inflammation, for example leukotrienes which are potent vasoconstrictors of coronary arteries. It is proposed that increased FLAP activity may lead to the accumulation of leukotrienes on fatty deposits on the arterial wall. The subsequent breakdown of these deposits by the immune system may then result in the development of blood clots and an increased risk of MI. Helgadottir and colleagues showed an increase in the release of the leukotriene LTB4 from cells taken from Icelandic MI survivors who possessed the HapA variant compared to those without the variant. However, the small numbers on which this assumption is based, together with supplementary data published online indicating that the increase was also observed among males who did not carry the HapA gene variant, require this association to be interpreted with caution. Indeed, the researchers do acknowledge that this finding may be explained by additional ALOX5AP variants not included in their analyses, or by variation in another gene(s) involved in the regulation of the inflammatory response.
Comment: The researchers present the identification of two ALOX5AP genetic variants, HapA and HapB, that appear to be associated with increased risks of MI in Icelandic and British MI patients, respectively. The study utilised a genome-wide scanning approach to identify potential genomic regions that may be associated with MI which resulted in scores that were slightly below those which are accepted as providing strong evidence for linkage (i.e. greater than 3). Therefore, although the region on chromosome 13q12-13 may contain loci that are associated with MI, it is possible that such an association may have arisen by chance. Cases of MI are clearly defined, although no exclusion criteria are provided for the Icelandic control population and confidence intervals are not provided for the statistical analyses. The polygenic nature of cardiovascular disease, coupled with the proven influence of both environmental and social factors in disease development, complicates the identification of causal genetic variants. Therefore, these findings will require validation in independent studies before any definitive conclusions may be drawn as to the clinical application of these results.
17 February 2004A Belgian study into the inheritance of telomere length published in The Lancet this week proposes that ageing may be an X-linked trait. Telomeres, specialised DNA sequences at the end of chromosomes, act as ‘caps’ to protect and stabilise the chromosome ends during replication. Human telomeres comprise tandem repeats of the sequence TTAGGG, and the overall telomere length (typically 15,000 base pairs at birth) decreases during every cycle of cellular replication, losing 25-200 base pairs per cell division. Eventually, once its telomeres have become critically short, the cell becomes senescent, and eventually dies. Previous research has suggested that telomere shortening and cellular senescence may be directly linked to the ageing process, and that shorter telomeres are associated with increased incidence of disease and risk of mortality. Twin studies have indicated that telomere length may be inherited. This study [Nawrot TS et al. (2004) Lancet 363, 507-510] reports findings on the inheritance of telomere length.
The length of a terminal fragment of chromosomal DNA from white blood cells was determined for subjects from families, including 128 parents and 199 offspring. A normal distribution of telomere length was observed, with age having the most significant influence on length, although a smaller effect was noted for gender (men tending to have shorter telomeres than women of the same age) and for smoking, with a shorter sex and age adjusted terminal fragment length observed for smokers than for non-smokers. Correlations based on relationship were examined both with and without adjustment for gender, age and smoking status. In both cases, strong and significant correlations were observed between telomere length in father-daughter, mother-son and mother-daughter pairs, but not father-son (or spouse-spouse) pairs. The authors propose that the most plausible explanation for this correlation is an X-linked mechanism of inheritance for telomere length, and suggest candidate genes on the X-chromosome that may account for this.
Comment: This study provides sufficient evidence to warrant further investigation into the nature of inheritance of telomere length, which may also shed light on genetic factors that influence telomere length and ageing. A better understanding of the mechanisms that underlie the ageing process is potentially of enormous value to medicine with respect to age related diseases and conditions, and also to cancer. For example, telomerase (an enzyme that replaces the TTAGGG repeats lost during cell division and allows indefinite cellular reproduction without ageing) is absent from normal somatic (non-reproductive) cells but found in around 90% of human cancers.