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Belgian doctors have announced that an infertile woman has conceived naturally and given birth after having her frozen ovarian tissue re-implanted into her body. Ms Touirat and her daughter, Tamara, are reported as healthy and well. Doctors believe that this is the first birth of its kind. Ms Touirat had become infertile due to chemotherapy treatment. Prior to the treatment, some of her ovarian tissue was removed and frozen; one ovary was left in place. When she was found to be cancer-free, the tissue was re-implanted near the existing ovary, at the ends of her fallopian tubes. Months later she was menstruating and ovulating normally; over a year later she was pregnant.
There is a question as to whether the new implanted ovarian tissue is responsible for the ovulation or whether her original ovary was able to function normally. If the pregnancy is due to the implanted tissue, this success provides hope for many women who are faced with the risk of infertility at a young age. Chemotherapy can cause young women to go through menopause early and loose their chance of producing children. This technique provides another alternative that will allow such women to pursue motherhood once cancer treatment is finished. However, there is a question as to whether healthy women will attempt to use this technique to ‘beat’ menopause and have children at a later age; whether this will raise great enough concern to consider putting rules in place to regulate use is unclear. In addition, new European regulations requiring standards for the storage of tissue in tissue banks might limit the number of clinics able to meet the new standards and thus provide this service to women. Fertility doctors are awaiting further details about this success to judge its impact on their work.
9 September 2004Speaking at the BA Festival of Science in Exeter yesterday, Dr Stephen Minger (Director of the Stem Cell Biology Laboratory, King’s College London) announced that the first human stem cell line with the mutation for cystic fibrosis (CF) had been created (see BBC news report). Cystic fibrosis is the most common life-shortening recessive genetic disorder in the UK, affecting about 1 in 2500 newborns.The King's team, who last year became the first group to grow human embryonic stem cells in the UK, have created a cell line that contains the most common CF mutation, delta-508, derived from an embryo which had been shown by pre-implantation genetic diagnosis to possess the mutation. Noting the limitations of animal models for cystic fibrosis, Dr Minger has commented: “having a human cell line with this genetic defect will be very useful. Researchers will be able to use it to study how the mutation affects cells, screen for new treatments, and also look at gene therapy” (see press release). The research is reportedly under review for publication in a scientific journal. The King’s team is now attempting to derive similar cell lines for other genetic disorders such as Huntingdon’s disease, and to develop human embryonic stem cell-based therapeutics to treat diseases such as Parkinson’s disease and diabetes.
For more information on cystic fibrosis, see the Disease Profiles section.
7 September 2004Researchers in the US have raised questions about the feasibility of keeping data about individuals in genetic databases confidential. Specifically, they are concerned about the ability to identify individuals through their single-nucleotide polymorphism (SNPs) data. SNPs are changes in a person’s DNA sequence that occur in every approximately 3000 base pairs. SNPs are collected to aid researchers in understanding the genetic basis of predisposition to disease as well as healthy bodily functions. Some SNPs can cause individuals to metabolise certain substances in a different way, making them useful in pharmacogenetic research. However, SNPs can also be used to identify people. The authors [Lin, Z et al. (2004) Science 305, 183] state that “If someone has access to individual genetic data and performs matches to public SNP data, a small set of SNPs could lead to successful matching and identification of the individual.” If this did happen any other information in the data record would also be available. The authors estimate that as few as 75 SNPs can identify an anonymous research subject and if that person has any rare SNPs, this number could be further reduced. Even using techniques such as data suppression or disregarding the exact genomic location of SNPs will not increase the confidentiality of the data.
This raises concerns about the ability of genetic databases to protect data about research subjects. Without these databases pharmacogenomic studies may suffer; however proper safeguards must be put into place. The authors believe that, lacking technical methods of protecting confidentiality, the answer lies in policy and regulation. They advocate strict guidelines for genetic databases and changes in US regulations to make it clear who is authorised to use and exchange human genetic data and for what reasons. These changes should “…explicitly protect genetic privacy and set strong penalties for violations.”
However, there are others who question this call for treating genetic information in a special way, as this might hinder medical research. Morris Foster, associate professor of anthropology at the University of Oklahoma, commenting on this issue, [Howard K (2004) Nat Rev Drug Dis 3, 725], stated “Lots of information in medical records could be used to identify individuals.” Bartha Knoppers, professor of law at the Center for Public Law Research at the University of Montreal, also commenting in Nature, believes that the way forward is to ensure that there are data protection officers associated with databases who are properly trained to handle issues of privacy protection.
27 September 2004The Managing Director of an internet-based DNA testing company has been jailed for three years for making up the results for over 150 tests. Simon Mullane ran his firm, High Profile DNA, from Poole, Dorset. He stated in court that he was too overwhelmed with work to send the tests to laboratories in Canada and America, where the tests would be carried out with the results emailed back to him. So he had made up the results himself. Mullane admitted to 16 charges, which equated to a theft of £22,740, involving 118 clients. The harms caused by Mullane’s deception are wide-ranging, as the court heard from the people involved. One victim testified that he had separated from his wife due to the confusion over whether or not he had fathered a child with another woman. Judge Lester Boothman recognised the gravity of the matter when sentencing Mullane to three years in prison, stating, “These offences are so serious that a non-custodial sentence is not justified”.
No statutory controls on paternity testing services are currently in place in the UK. The Department of Health did publish a Code of Practice and Guidance on Genetic Paternity Testing Services in 2001, with the aim to guide organisations engaged in the practice without imposing regulation. However, in the White Paper on genetics, the government asked the Human Genetics Commission (HGC) to consider the area of paternity testing in greater detail. The HGC is currently reviewing the available evidence and will be consulting on the issue later this year.
10 September 2004The UK public interest group GeneWatch, a not-for-profit organisation that monitors developments in genetic technologies, has warned of a major threat to public health if human gene tests are not strictly regulated (see The Guardian news article). They report that one major pharmaceutical company, Roche, has presented draft guidance to the US Food and Drug Administration (FDA) to cover how its new genetic testing business should be regulated. The guidance, now being considered by the FDA, includes a requirement for the analytical validity of the test in question to be demonstrated (that is, the ability of a test to accurately measure the property or characteristic it is intended to measure, such as the presence of a genetic variant) but there is no requirement for scientific or clinical data to support claims of a link between a gene and the risk of future illness.
GeneWatch notes that Roche would stand to profit enormously if the FDA adopted the guidance, as it would allow them (and other companies) to market medicines to healthy people identified by genetic tests as being ‘predisposed’ to future illness – without any evidence to support these claimed links between genes and diseases. Genetic tests in the UK do not at present have to provide any evidence of a causal link between genetic variants and disease; this has not been a problem for single-gene diseases such as cystic fibrosis, but as tests for genes that may be involved in polygenic disorders such as heart disease and diabetes begin to appear, the dangers of unregulated marketing become more apparent. Helen Wallace, deputy director of GeneWatch, commented: "Most claims that genes increase a person’s risk of common conditions, such as heart disease, depression or obesity, later turn out to be wrong. Unregulated genetic testing would mean that we could all be frightened into taking medicines for illnesses that we are never going to get" (see press release). GeneWatch has called for the issue to be considered by the UK Commons select committee on health.
7 September 2004The Human Fertilisation and Embryology Authority (HFEA) has approved its first request for pre-implantation tissue typing since changing its policy on this technology. This will allow the Fletcher family to attempt to create a ‘saviour sibling’ for their son Joshua. The Fletcher family had had their earlier request pre-implantation genetic diagnosis and tissue typing refused. The HFEA had previously ruled that the child to be created should benefit from the procedure – avoiding a genetic disorder – and not be created simply to act as a donor for its sibling. Joshua did not inherit his condition, Diamond Blackfan anaemia (DBA), from his parents and there was no expectation that the new child to be created would be afflicted with DBA. Therefore the new child would not benefit from the procedure; this case did not meet the criteria set by the HFEA. However, the HFEA has now relaxed its rules and will allow tissue typing on its own without the requirement for an accompanying genetic test.
Mohammed Taranissi, the director of the Assisted Reproduction and Gynaecology Centre in London greeted the news enthusiastically. He has pursued the case on behalf of the Fletcher family, believing that every thing should be done in order to save a sick child, and had been considering a legal challenge. Whether this case will prompt more families to request pre-implantation tissue typing will remain to be seen. The HFEA reviews each case on its individual merits.
7 September 2004A patient support group for a rare genetic disorder, pseudoxanthoma elasticum (PXE), has secured patent rights for the gene involved in the disease. PXE, which is thought to affect as many as 1 in 25,000 people, causes calcium to accumulate in connective tissue, causing symptoms that include loss of vision, gastrointestinal bleeding and heart disease. The US Patent and Trademark Office has recognized five co-inventors on a patent for the recently discovered MRP6 (also known as ABCC6) gene, four researchers from the University of Hawaii and the head of the patient support group PXE International, Sharon Terry, who has two children affected by the disorder. This is the first time a non-scientific member of a patient advocacy group has been recognized as a co-inventor on a gene patent, although Ms Terry did in fact work in the laboratory as well as recruiting affected families for research into the genetic cause of the disease. With the consent of the patent holders, the University of Hawaii has granted the lead role in patent prosecution and licensing to PXE International. The patent application on the gene was filed to attempt to ensure that access to any resulting genetic tests would be affordable and widely available (see press release).
Francis Collins, director of the US National Human Genome Research Institute, said that PXE International's involvement in the discovery and exploitation of the gene was “a wonderful example of how parents and lay organisations can play a catalytic role in research on rare diseases”. PXE International has out-licensed diagnostic rights to the US biotech firm Transgenomic, although developing a cheap genetic test will be difficult due to the number of different mutations in the MRP6 gene.
22 September 2004A recent Heath Technology Assessment literature review on psychosocial aspects of genetic screening in pregnant women and neonates [Green JM et al. (2004). HTA 8(33), 1-109] focused on five key areas: knowledge, anxiety and other emotional aspects of screening, factors associated with participation in screening and the consequences of false-positive, false-negative, true-positive and true-negative results. Literature reporting on any antenatal or neonatal screening programmes that included a genetic target condition (chromosomal disorders such as Down’s Syndrome, and the more rare single-gene disorders such as cystic fibrosis and Tay-Sachs disease) and any psychosocial data from parents was included in the review; this amounted to a total of 116 publications. However, because some forms of screening test for more than one condition, some data from non-genetic testing, such as antenatal screening for neural tube defects and neonatal Guthrie bloodspot testing for congenital hypothyroidism, was necessarily included in the review.
The authors found that knowledge levels with respect to genetic testing were generally inadequate, and that significant social and cultural inequalities existed. Educational interventions such as leaflets or videos had some effect, but superficially acquired knowledge was not necessarily retained. It was noted that public understanding of the basic concepts underpinning screening programmes was generally poor, and that informed consent for neonatal screening was an under-researched area. Anxiety levels were not typically raised among women following successful interventions to improve knowledge, although the authors observe that knowledge that improves decision-making is not necessarily the same as that which reduces anxiety. Anxiety levels were raised among women who received screen-positive results (and not necessarily eliminated by subsequent reassuring results), but there was a lack of evidence to support a reassuring effect of screen-negative results; the manner in which carrier screening is offered may affect anxiety levels in such individuals. There is little published work on knowledge or anxiety in the male partners of screening programme participants.
It was concluded that the majority of women hold positive attitudes towards antenatal screening, but that women undergoing screening tended to have more negative attitudes towards fetal abnormality and be more likely to consider termination as the likely option if a fetus is affected. Their perceptions were altered in a number of respects, considering the risks of screen-positive results to be higher and the risks of procedures available following positive results (such as amniocentesis or chorionic villus sampling) to be lower. Up to 30% of women who actually received screen-positive results expressed regret about the decision to undergo screening. The authors note that uptake of neonatal screening has been treated as a ‘given’ and not as a subject for research.
The most urgent policy implications of the results of the HTA review are considered to relate to the inadequacy of current procedures for achieving informed consent, the cost of providing a satisfactory service, and the presently unmet needs of individuals receiving false-positive results and of the partners of women, especially in carrier screening programmes. The authors call for further research in these areas, and also outline issues pertinent to research for future screening programmes, including new conditions (such as haemoglobinopathies), new target groups (such as ethnic minorities) and new forms of testing.
Comment: This timely review raises a number of important questions with respect to screening for genetic conditions. One is the issue of what women need to know in order to make informed decisions about screening; previous assumptions have been based around factors such as understanding procedural matters and risk rather than questions of more interest to participants, such as the implications of having a child affected by the condition in question. The authors call for an approach based on the needs of parents rather than professionals. Another relevant issue is the highly negative perceptions of the term ‘genetic’ with respect to disorders, something that must continue to be taken into account when seeking to improve knowledge and understanding. The importance of information and choice for participants when implementing and monitoring screening programmes is a key message from this report.
27 September 2004The UK Royal Society, a national independent academy of science and technology, has announced plans for an investigation into pharmacogenetics and the prospects for personalized medicine based on genetic profiling (see press release). Pharmacogenetics refers to the study of genetic variation underlying individuals’ differential responses to drugs, in terms of efficacy and toxicity; genes involved in drug metabolism are key determinants of drug response, and common polymorphisms in such genes can have a substantial effect. Personalized or individualized medicine is an extension of pharmacogenetics, the concept of tailoring drug type and dosage to individuals based not only on traditional clinical factors but also on their genetic profiles.
The study aims to 'provide a balanced assessment of the future potential and limitations of this technology' in a report published by Summer 2005.The Society is calling for submissions of evidence from botht he public and private sectors to inform the study, to be carried out by a working group of experts chaired by Sir David Weatherall of the Weatherall Institute for Molecular Medicine, University of Oxford; the deadline for responses is Friday 12 November 2004. The group will review the current status of research in pharmacogenetics, from 'fundamental developments in genetic understanding to clinical applications', the potential impact on areas such as drug development, screening and clinical trials. They will also seek to identify novel ethical legal and social (ELSI) issues related to the field, regulatory concerns, and the potential for pharmacogenetics to address key areas such as adverse drug reactions, drug efficacy and knowledge about the links between genetics and health. Potential constraints on the introduction of pharmacogenetics into the NHS cited include the associated costs of implementation and staff training and the technological barriers to the storage and management of genetic information. Ethical concerns are also noted, including the potential for exclusion of certain population groups from future drug development based on genetic factors.
2 September 2004The US National Human Genome Research Institute (NHGRI) has announced the creation of four Centers of Excellence in Ethical, Legal and Social Implications (ELSI) Research. The centres are being funded through grant monies from NHGRI, the US Department of Energy (DOE), and the US National Institute of Child Health and Human Development (NICHD). Both NHGRI and NICHD are institutes within the National Institutes of Health.
The four centres will be located at Case Western Reserve University, Cleveland, Ohio; Duke University, Durham, North Carolina; Stanford University, Palo Alto, California; and the University of Washington, Seattle, Washington. Each will be funded to do specific work related to ELSI issues. For example, the group at the University of Washington will “…conduct research on the ethical, legal and social factors that influence the translation of genetic information to improved human health.” At Duke, researchers will “…gather and analyze information about the role of publication, data and materials sharing, patenting, database protection and other practices that may affect the flow of information in genomics research.” Each grant will be for five years; multidisciplinary team of experts will make up the project teams. Three additional exploratory grants have been made to investigators who are planning and developing potential new centres.
Funding for ELSI research has long been seen as an integral part of the US Human Genome Project. The NHGRI and the DOE have historically devoted 3%-5% of their genome research budgets to ELSI research. It is envisioned that the research that comes out of these new centres “…will be critical in formulating and implementing effective and equitable health and social policies related to genomic research.”
6 September 2004A recent paper reports on a novel technique for specific amplification of DNA sequences with the potential to produce a significant impact on DNA-based applications, including mutation detection and analysis [Vincent M, Xu Y and Kong H (2004) EMBO Rep. 5, 795-780]. The basis of current technology is the polymerase chain reaction (PCR), a technique that allows the rapid and highly specific amplification of a single DNA sequence to a billion copies using a thermostable bacterial polymerase enzyme. PCR is a pivotal component of modern molecular biology and genetics; its inventor Kary Mullis was awarded a Nobel Prize in recognition of the crucial contribution made by this pioneering technique. One of the main limitations of the technique is the requirement for a PCR machine to create the necessary thermal cycling between optimal temperatures for the three stages of each cycle of the PCR reaction. Each PCR cycle comprises three stages, controlled by temperature: separation of the two strands of the DNA double helix (denaturation) at 90°C, binding of short ‘primer’ DNA sequences to the separated template strands at 55°C, and extension of these primers by the polymerase to create replica DNA molecules, which takes place at 75°C.This thermocycling process is perfomed using a PCR machine, which is expensive and also has a significant power requirement.
However, the new variation on DNA amplification reported by Vincent et al. avoids the need for thermocycling by using a DNA helicase enzyme to unwind the DNA double helix ready for primer binding and extension by a polymerase enzyme at a single reaction temperature of 37°C. This helicase dependent amplification, dubbed HDA, was shown to be capable of over a million-fold amplification of the target sequence; inclusion of an initial 90°C denaturation period improved efficiency of the technique, but was not required. DNA amplification levels at 37°C were lower than those obtainable by PCR, but nevertheless highly promising.
Comment: HDA could represent a useful addition to current research and diagnostic techniques in molecular biology and medicine. Although the potential financial savings are less critical for healthcare in developed countries (PCR-based molecular diagnostics are prohibitively expensive in poorer countries), for certain applications where the superior capabilities of PCR are not required it may effect a considerable financial saving. It also has potential to provide faster results than PCR, which could be of value in terms of more rapid diagnostic tests.
8 September 2004Scientists at the US National Cancer Institute (NCI) have created a database of genes associated with multi-drug resistance in cancer cells. A paper in the journal Cancer Cell details the findings of their research on the expression of ABC transporter genes in 60 different cancer cell lines (the NCI-60 collection, which includes leukaemia, melanoma, ovarian, breast, prostate, lung, renal, and colon cancer cells). ABC (ATP binding cassette) transporters are a family of proteins that regulate transport of substances, including drugs, across cell membranes. There are 48 known human ABC transporters, including a number of multi-drug resistance (MDR) pumps that actively export drugs from cells, making them important factors in drug resistance. The researchers used a phamacogenomic approach, correlating expression of the ABC transporter genes assayed using the real-time polymerase chain reaction (RT-PCR) with patterns of activity of 1,429 candidate anticancer drugs previously tested in the cell lines [Szakács G et al. (2004) Cancer Cell 6, 129-137].
Statistical analyses of the relationships between the 48 genes and 1429 drugs were performed to identify those ABC transporters and their substrates with a possible role in drug resistance of cancer cells. A total of 131 highly inverse correlations were found – that is, examples where expression of a particular ABC transporter gene showed a strong negative association with efficacy of a given drug, suggesting that the transporter could well be involved in export of and resistance to that drug. In some cases, these associations were tested and confirmed by specific investigations, creating cell lines expressing the ABC transporter gene in question and assessing their sensitivity to the drug. The database is proposed to represent a resource for the identification of new ABC transport