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Using fibroblast cells from an SMA1 patient and his unaffected mother, they generated induced pluripotent stem cells (iPS cells) using vectors based on lentiviruses to introduce the necessary genes OCT4, SOX2, NANOG and LIN28. Both wild-type and SMA cell-lines were established, and showed normal replication and growth. Analysis of RNA from the original fibroblast and iPS cells showed that intact (full-length) SMN1 transcripts were present in both forms of wild-type cells, but neither the original nor the induced pluripotent SMA cells.
23 December 2008
The gold standard for mutation screening for many years has been amplification of target sequences by polymerase chain reaction (PCR) followed by Sanger sequencing. However, when it comes to conditions where the mutation may be in one of several genes or polygenic conditions where a number of different genes may be involved (e.g. breast cancer), gathering results by this technique can often be labour intensive and time consuming as numerous different genes have to be sequenced. Although a number of parallel sequencing techniques have been developed, along with “front-end” methods to amplify a subset of genes (see previous news), these procedures are still too expensive and complex to be applied in a routine diagnostic or screening setting.
22 December 2008
The European Court of Human Rights (ECHR) has ruled that the retention of fingerprint information, cellular material and DNA profile of two British men in the National DNA database is in violation of Article 8 of the European Convention on Human Rights (see BBC news). The men had appealed for their data to be removed as they had not been convicted of any crime, and approached the European Court of Human Rights after their cases were rejected by the House of Lords. In their judgement, the ECHR was "struck by the blanket and indiscriminate nature of the power of retention in England and Wales’’. In particular, the Court singled out the fact that the existing regime takes no account of age of the subject (contrary to the UN Convention on the Rights of the Child 1989, which asserts the right of every child to be treated with dignity and worth). This was one of the grounds on which the Nuffield Council on Bioethics reached their critical assessment of the existing system (see previous news). The ECHR finding against the UK Government was also on the basis that the system failed to discriminate on the basis of the seriousness of the crime or the likelihood of reoffending as do comparative systems elsewhere in Europe. The Court also noted that the Government had failed to justify continuing with the existing system by describing the number of convictions that would have been lost had the current system not been in place.
The ruling was welcomed by the Nuffield Council on Bioethics, who in their 2007 report The Forensic Use of Bioinformation: ethical issues (see previous news) cautioned against the storage of such information when the alleged offences are minor, or individuals are not ultimately charged or convicted (see press release). The case highlights the sensitivity of retaining DNA samples and data rather than fingerprints, and both the case and the report by the Nuffield Council draw distinctions between the ethical issues raised by the storage of fingerprint data, digitised DNA profiles and biological samples. The ECHR noted that the latter two categories have a stronger potential for future use of personal information than fingerprint information, and are capable of being used "as a means of identifying genetic relationships between individuals" and as such "their retention interferes with the right to the private life of the individuals concerned".
19 December 2008
New publications have shed light on some of the genetic factors involved in obesity, (defined as a body mass index or BMI greater than 30 kg/m2). Two papers in Nature Genetics report the association of specific genetic variants with obesity. The first presents the results of a genome-wide association (GWA) study with more than 300,000 single nucleotide polymorphisms (SNPs) typed in around 31,000 individuals. Most of these were Icelandic, along with around 3,000 Dutch, 2,000 European Americans and 1,000 African American subjects; results were combined with previously published results in over 5,500 Danish individuals. A total of 29 genetic variants in 11 chromosomal regions were found to be significantly associated with obesity, including previously identified variants close to or in the FTO, MC4R, BDNF and SH2B1 genes, and variants at seven loci not previously connected with obesity [Thorleifsson G et al. Nat. Genet. 2008 14 December | doi:10.1038/ng.274].
16 December 2008
Screening newborns for certain inherited conditions is undertaken in most countries to provide a means of early identification and treatment of conditions such as phenylketonuria (PKU) and sickle cell anaemia. With the emergence of new high-throughput technologies such as tandem mass spectrometry (MS/MS), the number of conditions that can potentially be screened for has increased and is likely to expand further as genomic technologies develop. MS/MS allows for the detection and quantitation of over 20 different metabolites simultaneously, following simple sample preparation, thereby allowing screening for a number of inherited metabolic disorders to be carried out. In the US, the American College of Medical Genetics (ACMG) has recommended screening to be undertaken for a “core” panel of 29 conditions (see previous news) and 25 secondary conditions. In the UK, newborn screening has not expanded to such and extent and MS/MS is only offered for the detection of phenylketonuria (PKU) and Medium Chain Acyl CoA Dehydrogenase Deficiency (MCADD). A health and technology assessment carried out in 2004 concluded that although it could be used for screening a number of other inherited metabolic disorders, lack of evidence about the incidence of these conditions as well as the impact of screening on management of the conditions precluded their inclusion in the newborn screening programme (see previous news).
Screening for a wide panel of disorders, especially when many of them are extremely rare, not fully understood and as yet untreatable raises a number of ethical, legal and social issues (see previous news). This month the President’s Council of Bioethics in the US has released a white paper on expanded newborn screening with the aim to “foster public awareness of the practice, the ethical principles that have guided it until now, and the ethical problems posed by its current and future expansion”. In their report: The Changing Moral Focus of Newborn Screening: An Ethical Analysis by the President's Council on Bioethics, the council examine the ethical implications of offering screening for a wide range of conditions, especially when in many cases there are no treatments available for the detected conditions. Their report concludes that screening for untreatable conditions may do more harm than good and this may be “accentuated once new DNA technologies make it possible to expand screening to target additional diseases and to detect disease susceptibility as well”. As a result they recommend that screening should only be offered for conditions that meet the traditional Wilson-Jungner screening criteria. The report acknowledges that expanded newborn screening can contribute to biomedical knowledge of rare diseases; however, they recommend that where screening is possible for untreatable conditions, this should be offered through pilot studies, so that evidence about the benefits of screening can be gathered. In addition, informed consent should be gained from parents prior to this undertaking.
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11 December 2008UK campaign groups the Christian Legal Centre (CLC) and Comment on Reproductive Ethics (CORE) have lost their bid against the Human Fertilisation and Embryology Authority (HFEA). They sought leave from the High Court to bring a test case application for judicial review over the HFEA’s approval in principle of the use of animal eggs in the creation of cytoplasmic hybrid embryos for stem cell research (see previous news), and its subsequent decisions to grant licences to researchers Newcastle University and King's College London allowing them to create cytoplasmic hybrid embryos for stem cell research (see previous news).
9 December 2008Currently, prenatal diagnosis of recessive autosomal diseases is only possible through invasive testing, such as amniocentesis and chorionic villus sampling, which carries around a 1% risk of miscarriage. However, a new technique developed by Dennis Lo’s laboratory in Hong Kong – based on the presence of cell-free fragments of fetal DNA present in the maternal bloodstream during pregnancy – has raised the possibility that such diseases could potentially be prenatally diagnosed non-invasively [Lun et al (2008) PNAS 105: 19920-19925].
9 December 2008Plans to roll out cascade screening for familial hypercholesterolaemia (FH) in Wales have been announced (see BBC news). FH is a common genetic disorder, inherited in an autosomal dominant manner and with an estimated frequency of around 1 in 500 of the UK population (more than 100,000 people).The vast majority of these individuals are currently undiagnosed. The screening programme will test family members of individuals diagnosed as having FH. Early identification of the condition, characterized by significantly raised cholesterol levels, allows preventative interventions - such as diet and lifestyle modifications, and the use of drugs such as statins - to reduce the risk of premature coronary artery disease.
5 December 2008
Patients diagnosed with early stage colon cancer (stage I and II) are usually considered to be cured after surgical removal of the tumour. However, in about 20% of patients, the disease can recur and it is important to identify these patients in order to improve their care. It may soon become possible to predict disease recurrence of colon cancer and individualise therapy through examination of the genomic signature of individual tumours (see press release). Researchers from the Duke Institute of Genome Science and Policy in the US have developed a model based on examining the gene expression pattern of tumour cells, to predict the risk of recurrence in early stage colon cancer patients. In addition, this model may also be useful in predicting the response of tumours to various chemotherapy agents, thereby allowing targeted follow-up strategies or therapy to be employed.
In their study, Garman et al. retrieved gene expression data from 52 samples representing clinical stage I and II disease from a publicly available database, and correlated the patterns of gene expression with information on tumour recurrence in order to develop a prognostic model [Garman et al. (2008) PNAS 105(49):19431-19436]. The model they developed was based on examination of the expression pattern of 50 genes and was 90% accurate in predicting risk of recurrence in this initial data set. The model was further validated by examining its predictive power using two independent date sets consisting of 55 and 73 tumours and was able to correctly classify 69.1% of patients in the first cohort and almost all patients in the second. Following on from the identification of those at high-risk of recurrence, the researchers went on to investigate therapeutic strategies for this group. They used colon cancer cell lines to investigate the relationship between the high-risk gene expression phenotype and sensitivity to therapeutic agents, and demonstrated a correlation between the two; furthermore, treatment with certain agents was able to reverse the profile of a tumour from high risk to low risk. However, this was only demonstrated under laboratory conditions using cell lines and clinical trials would need to be undertaken in order to validate the observed effects.