News

27 April 2010A native American tribe, the Havasupai Indians, have been in the news recently following a payment from Arizona State University in compensation for the use of blood samples for genetic research. In addition to the out-of-court settlement of US$700,000 and return of the blood samples, the university is reportedly to provide additional assistance to the tribe such as scholarships. This decision was the result of legal actions brought by tribe members after it came to their attention that DNA samples provided for a specific research project in the 1990s had subsequently been used for a range of other studies, without the permission of the original subjects.

 

In fact, the original consent obtained had been quite broad, referring to research into causes of ‘behavioral/medical disorders’, but the study participants had been convinced particularly by the prospect of research into diseases of immediate relevance to their tribe, such as type 2 diabetes, which is unusually prevalent. They were displeased to discover that a much broader range of articles had been published based on studies of the DNA samples, including discussion of issues such as racial origins (see New York Times report).

 

Although no misconduct has been proven on the part of the researchers, the university had reportedly already spent US$1.7 million on legal costs and were no doubt disinclined to spend more. However, the move is potentially significant from a legal perspective since it recognises a lack of fully informed consent with respect to the scope of research conducted with donated samples as misuse (see the Genomics Law Report for more discussion of the legal implications of this case).

 

Comment: Whilst it seems very plausible that the Havasupai Indians who donated blood samples for research should have been angered and distressed on discovering uses to which they did not feel they had given consent, sympathies must also lie with the researchers. Suitable protection of research participants is crucial, but not to the point that research is stifled – and fears of legal action of this type could have just that effect; the original lawsuit reportedly sought US$75 million in damages (see Nature blog) – that is, damages of approaching US$2 million for each claimant, which is clearly ridiculous.

 

Robust consent procedures that allow for effective use of patient samples for different forms of research are essential; robust responses to claims of misuse may be more difficult to achieve in an increasingly litigious society.

26 April 2010Switzerland has announced a major new three-year programme of research in stem cells and regenerative medicine. The aim of the NRP 63 programme, which is to receive CHF 10 million (£3.6 million; €4.2 million) from the Swiss National Fund, is to ‘better understand how stem cells work’ and lay ‘solid groundwork for future medical applications’. The twelve projects within the programme will be based at academic institutions and include research on adult human stem cells and embryonic and adult stem cells from other organisms. There is no reference to the more controversial human embryonic stem cell research.

The Vatican, which governs the Roman Catholic Church, is reportedly also to support research into adult intestinal stem cells as potential medical treatments for disease in the US. Ethically opposed to the use of embryonic stem cells because it involves the destruction of human embryos, the Catholic Church is apparently seeking to boost awareness of its official support for somatic stem cell research with support and, it is suggested, funding (see MSNBC news report).

23 April 2010Last month the Health Secretary Andy Burnham announced that the Academy of Medical Sciences (AMS) has been commissioned to produce a review of the current regulatory and governance framework for medical research in the UK, which AMS president Professor Sir John Bell described as ‘stifling’ and working group chair Sir Michael Rawlins as ‘unnecessarily complex and burdensome’ (see AMS response).

This move follows a report published by the AMS earlier this year challenging the Government to act promptly in making the most of opportunities offered by medical research to improve health, and calling for a proportionate regulatory framework (see previous news).

The review will focus on research involving humans, human tissue and data, and will include epidemiological research and experimental medicine, as well as conventional clinical trials. The AMS is calling for evidence to inform the current review from all relevant stakeholders by 1st June 2010.

22 April 2010The Nuffield Council on Bioethics, which examines ethical issues in biology and medicine, has launched a new consultation on the use of human organs, tissues and cells for use in medical treatment and research. They are looking particularly at how society should respond to increasing demand; whether people should be encouraged or incentivised to donate; issues of consent in different circumstances; and how much control donors might expect to exercise over the use of donated tissues.

 

A background paper on the issue considers the uses of ‘human bodily material’ for different forms of treatment, to create new humans via fertility treatments, and for directed donation (that is, to known recipients such as relatives) or non-directed donation (for unknown recipients). With respect to research, distinctions are drawn between immediate, specific uses and long-term, unknown applications, and between non-commercial and commercial uses.

 

The closing date for consultation responses is 13th July 2010.

22 April 2010The prevalence of certain childhood diseases such as asthma, eczema and cancers has seen a worldwide increase in recent decades. However, the underlying cause of this increase is as yet unknown, and could be due to genetic and/or environmental factors. The NewGeneris project was launched in 2006 to investigate the effects of prenatal and early-life exposure to genotoxic chemicals (chemicals causing damage to genetic material) present in food and the environment in the development of childhood cancers and immune disorders.  The project is coordinated by Maastricht University and consists of 25 partners from 16 European countries, who will contribute data on prenatal exposures and biomarkers. Information on biomarkers will be gained from samples of maternal and umbilical cord blood collected from groups of mother-child pairs and stored in biobanks in different European regions. This allows the researchers to analyse a birth mega-cohort with subjects coming from regions with a wide diversity of environmental conditions and dietary and lifestyle habits. The project is approaching its target to gather gene-rate data from around 1000 mothers and their infants (see Cordis news).

Along with collecting biological samples, the project also collects information on the dietary exposures of the mother, father and child using questionnaires. It is also involved in experimental studies to identify and validate new biomarkers. In addition, the project is also assessing the effects of certain chemicals on sperm, transplacental transport and metabolism. It is hoped that an understanding of in utero exposures to chemicals as a result of maternal diet will lead to identification of health risks for newborn children and inform appropriate policy decisions on food and environmental safety.

Comment: The impact of maternal health on child health has been well documented in relation to conditions such as neural tube defects (see previous news) and smoking (see previous news). However, conclusive evidence between environmental exposure to certain chemicals and risk of childhood diseases has been lacking for other childhood illnesses. Ventures such as NewGeneris could help improve our understanding of environmental risk factors thereby allowing for policy development in this area. This may be particularly relevant in low and middle-income countries where environmental factors may contribute to the burden of congenital anomalies (see previous news). The PHG Foundation is working to enable individual low and middle-income countries and regions to deliver better care and help reduce the prevalence and impact of birth defects, by producing tools to help them to assess local health needs and develop simple, cost-effective health services (see our work).

19 April 2010

A family has received full-genome sequencing for non-medical reasons for the first time from the company Illumina. The West family – parents and two children aged 14 and 17 – had their genomes sequenced in the hope that the information would benefit their health in terms of predicting disease risk and drug responses, and also contribute to research into medical genetics. Of note, the family only submitted one adult genome sequence to the GenBank public database, to protect their privacy; the teenage children may choose to submit their own genome sequences when they are adults (see press release). 

Refuting concerns about full genome sequencing of minors, father John West – former CEO of genomic technology company Solexa, which was acquired by Illumina in 2007 – said: “A few years from now I think it will be ethically improper if you don’t have your children sequenced. What kind of parent are you if you don’t give your children a small amount of money to find out things that can help their health?” (see Times news report). The reported cost of sequencing was a total of US$200,000 / £130,000, but prices are predicted to fall rapidly in the next few years due to rapid developments in sequencing technologies. 

The major concern about genetic analysis of minors for non-medical purposes – that is, for all purposes that do not involve a medical decision – is that there is a small possibility that information would be revealed that the child might later wish it had not known about. The most glaring example is non-paternity (discovering that a presumed father is not genetically their father – this being a surprisingly common phenomenon) but it might also be carrier status for a genetic disease, or genetic predisposition towards a common disease. Many experts believe that where genome sequencing does not provide immediate health benefits, the risks mean that it would be better to wait until adulthood before testing.

 

Alison Hall of the PHG Foundation commented: “Until the balance of benefits and risks are clearer, the starting point should be to approach with caution, and on a case-by-case basis. In this case, the family seem to have been aware of the potential risks involved.” As genomic sequencing becomes more accessible, there is clearly a need for prompt consideration of related issues, including the testing of minors. The PHG Foundation is therefore developing a major new programme of work to consider the implications of DNA sequencing for individuals and society. Staff are also currently involved with an expert group that is reviewing current UK professional guidance on the genetic testing of minors.

17 April 2010Libel action against science writer Simon Singh (see previous news) has been dropped by the British Chiropractic Association. The move follows a successful appeal that would have allowed him to use the defence of fair comment against the charges; the BCA has subsequently announced that it was dropping charges against him ‘to avoid further legal costs being incurred by either side’ – possibly also because their chances of winning were substantially diminished and the action incurring major opposition from the science, medicine and media communities.

 

Although this is a technical victory for Dr Singh, who has spent more than £200,000 of his own money defending himself against the libel suit, said: “It still staggers me that the British Chiropractic Association and half the chiropractors in the UK were making unsubstantiated claims. It still baffles me that the BCA then dared to sue me for libel and put me through two years of hell before I was vindicated.  And it still makes me angry that our libel laws not only tolerate but also encourage such ludicrous libel suits” (see Libel Reform news). He noted that the effect was to stifle legitimate scientific inquiry and debate, to the detriment of the wider public (see BBC news).

15 April 2010The Global Ethics Observatory (GEObs) is a system of databases with worldwide coverage in bioethics and other areas of applied ethics in science and technology accessible via the UN Educational, Scientific and Cultural Organization (UNESCO) website. It is designed to serve as a resource hub of ethics activities around the world and advance ethics activities by assisting those interested in identifying experts, establishing ethics committees, constructing informed policies in the area of ethics, and designing ethics teaching curricula. As part of this initiative UNESCO has also launched Regional Documentation and Information Centres (RDIC) whose broad aims are to collect and disseminate information within particular regions and collaborate with GEObs. The first such centre was established in Lithuania in 2004 and followed by a second centre in Kenya in 2007. Last month a third centre was officially launched in Egypt to serve the Arab region (reported by SciDev Net).

The centre will be based at the Academy of Scientific Research and Technology (ARST) in Cairo, and will be managed by regional and local committees of experts from UNESCO and Arab countries. Along with assisting the development of ethics databases and establishing ethics committees in the region, it would also promote setting ethics standards and running workshops, seminars and developing university curriculum related to ethics.

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6 April 2010The UK science writer Simon Singh, whose dispute with the British Chiropractic Association (BCA) highlighted the absurdity of English libel laws when used to defend scientific criticism (see previous news) has won a victory in the Royal Courts of Justice in London. The Court of Appeal ruled that his published statements about the BCA and their claims about the efficacy of chiropractic treatments were an honest expression of opinion, as opposed to factual assertions as decided in a previous court ruling (see Nature News). This means that his statements can be defended as fair comment as opposed to libel, and will not require that he produce evidence to support these comments in order to defend the case.

 

The judges noted that the legal case brought by the BCA against Dr Singh "almost certainly had a chilling effect on public debate which might otherwise have assisted potential patients to make informed choice" (see judgement)

 

Speaking on behalf of the Coalition for Libel Reform, Tracey Brown commented: "We are delighted with the judges' ruling but it does not go far enough…There is a cardiologist currently being sued by a device manufacturer, we have researchers who have been unable to publish their critique of lie detector technology because of threats of libel action. A major science journal is also currently being sued and our academics are being told to pull down blogs. We urgently need a public interest defence so that we can all be sure of our rights as publishers, writers, authors and academics" (see Guardian article).

4 April 2010According to a Nature News report, a new law in Turkey will prevent the creation of any form of genetically modified organism, and will necessitate approval from a new Biosafety Council for any application involving the use of any form of transgenic organism or genetic manipulation – including basic and applied biomedical research.

 

The move was intended to restrict the use of genetically modified plants, with the new approval body existing within the ministry of agriculture – but could cause massive disruption for medical research, with lengthy bureaucratic delays between application and approval. For more details, see [Nature 2010 Feb 25;463(7284):1000].

5 April 2010Regenerative medicine is a fast-moving interdisciplinary field, combining stem cell therapeutics and tissue engineering with a range of other techniques to repair or replace cells, tissues or organs damaged by accident or disease. Simpler forms of tissue for transplantation grown from a patient’s own cells, such as skin, are already commercially available, but more complex organs are much harder to produce. Success depends on the highly precise manipulation of stem cells to specialise into different types of cells that comprise an organ, in combination with tissue engineering approaches to ensure that an appropriate tissue scaffold for the organ is present.

 

Now, the first transplant of a windpipe created by tissue-engineered stem cells into a ten-year old child has been successfully performed in the UK (see BBC news). The third and most ambitious procedure of this type created a longer tissue windpipe than that created for the two previous adult recipients – but in all cases, much of the new organ was grown from stem cells belonging to the patient, making the risk of immune rejection much lower than for a normal donor transplant.

 

The bone marrow-derived stem cells from the patient were used to colonise (or ‘seed’) a donor organ from which most of the functional cells had been removed to leave the structural collagen framework. The stem cells are expected to specialise into tracheal cells over time following the transplant. If successful, it is hoped that the same technique can be used more widely for similar procedures and for other organs such as oesophageal transplants.

 

The child’s own trachea was non-functional. Previous recipients of similar organs were both adult women from Spain and Italy, but in these cases the stem cells were grown on the tracheal scaffold for some days in the laboratory before transplantation (see BBC news).

 

Meanwhile, tissue engineering using stem cells is flourishing for a whole range of other medical applications. One recent report focuses on a new technique to grow bones from stem cells – in specific shapes suitable for transplantation (see New York Times).

30 April 2010A new paper in the Lancet provides the first example of a full-genome sequence of a healthy individual being combined with a broad clinical analysis [Ashley EA et al. Lancet (2010) 375: 1525-35]. Although the genome sequence was published last year (see previous news), the “comprehensive” clinical work-up is new.

 

Unlike the previous examples of clinical whole genome sequencing, which involved families with specific rare genetic disorders (see previous news), the focus of this study is a healthy man with a family history of vascular disease and early sudden (presumed cardiac) death. In addition, rather than focusing on a single condition, or even a single type of condition, this study tries to extract as much clinically relevant information as possible from the genome relating to any kind of disease predisposition. Researchers used so-called third generation (single molecule) sequencing technology for sequencing the entire genome; in addition, a subset of single nucleotide polymorphisms (SNPs) were independently validated using a standard SNP-array and some variants were confirmed using traditional Sanger sequencing. Various online databases were used to screen for variants of clinical relevance, and the findings include information about genetic susceptibility to common complex diseases, pharmacogenetic information that could inform drug choice and dose, and information about variants in genes associated with inherited cardiac conditions that can predispose to sudden cardiac death.

 

Comment: This is an exemplar of the sort of approach that will become increasingly feasible in the future as the costs of genome sequencing continue to fall. The authors state that “an important benefit of sequencing compared with DNA chip-based methods of genotyping is the identification of rare or novel variants”. While true, this benefit is actually a double-edged sword: almost by definition, it will often be extremely difficult to determine the effect of rare and novel variants on the phenotype. Even where a novel variant is present in a gene of known function, which has been linked to a Mendelian disease, the effect of that specific variant upon either the encoded protein, the individual’s physiology, or their overall phenotype may still be impossible to determine. Hence, deriving clinically actionable information may often not be possible.

 

The analysis of common variants and their implications for increased genetic risk to a range of common complex diseases is certainly admirable for the clarity and transparent manner in which the information is displayed. However, there are serious concerns about the validity (and utility) of using these common variants to predict disease risk in an individual (see, for example, previous news); in addition, questions remain over the long-term effectiveness of using genetic information to motivate behaviour change.

 

The paper highlights a range of issues that require urgent consideration as full-genome sequencing moves towards reality in medical practice. Evaluation of clinical utility – distinguishing between genuinely useful and irrelevant, misleading or even harmful genetic information – will be crucial, taking into account the complexity of combining genetic data with other clinical and risk information such as family history, markers of current health and lifestyle or environmental factors. Dealing with ‘incidental’ or unintended findings will also be critical, and determining how far the duty of care extends, both within and between overlapping clinical specialties, may dictate the boundaries for medical negligence. Prompt action is needed to consider how health services should be preparing for the onset of whole genome-sequencing as a clinical tool, including such areas as the development of the necessary bioinformatic and IT systems, consideration of the wider ethical, societal and regulatory issues related to the more extensive use and storage of personal genomic information, and development of a health professional workforce with the necessary knowledge and skills to capitalise upon the benefits of next generation whole genome sequencing technologies (see Guardian news article).

20 April 2010The FTO gene is known to be associated with the risk of increased body mass index (BMI) and obesity (see previous news); obesity is a serious public health problem. The aim of research into the genetic basis of disease is to understand how conditions arise, and to identify the best opportunities for prevention and treatment.

 

The FTO gene encodes a DNA / RNA demethylase enzyme that preferentially binds to 3-methylthymidine (3-meT) residues in single-stranded DNA or 3-methyluracil (3-meU) residues in single-stranded RNA. FTO is known to be involved in the regulation of energy homeostasis and body metabolism Now, scientists have generated a high resolution crystal structure of the FTO protein bound to a 3-meT [Han Z et al. (2010) Nature doi:10.1038/nature08921].

 

The structure (combined with biochemical assays) reveals that the protein has two main domains separated by a fold, and that interaction between these two regions is crucial for the enzymatic activity of FTO. It also shows the region of the protein crucial for selective binding of substrate residues in DNA. The potential application of these findings is that it may allow the design of new drugs to inhibit the FTO protein – by blocking ability to bind to DNA / RNA or interfering with enzymatic function – that could serve as effective new anti-obesity treatments.

Comment: This research from China provides only a starting point for rational drug design, but is nevertheless a promising development following relatively quickly after the identification of the FTO gene as a significant player in obesity. In the UK recently there has been criticism of government attitudes to obesity  and their effects on the medical profession; National Obesity Forum chair Dr David Haslam reportedly praised recent initiatives to prevent and reduce obesity levels by encouraging healthier lifestyles, but that too few resources were available for the treatment of those who were already obese, such as drugs or surgery [White C. BMJ (2010) 340:c1716. doi: 10.1136/bmj.c1716]

19 April 2010Overall tobacco smoking is estimated to be responsible for approximately 29% of all cancer deaths and up to 90% of lung cancer deaths in the UK (see Cancer Research UK). However, despite the fact that smoking is a very strong risk factor for lung cancer, the majority of smokers never develop this specific disease; genetic factors (along with other environmental factors) are presumed to be involved in overall susceptibility. On the basis of the concept that genomic changes in airway epithelial cells reflect damage due to smoking, US researchers have developed a genomic approach for identifying smokers at the highest risk of developing lung cancer  [Gustafson AM et al. Sci Transl Med. 2010 Apr 7;2(26):26ra25].

 

 

In order to explore the patterns of pathway deregulation, the investigators examined oncogenic pathways in apparently normal epithelial cells from the upper bronchial airway by looking at gene expression patterns in 60 current and former smokers with lung cancer and 69 current and former smokers without lung cancer. They found that genes involved in the phosphatidylinositol 3-kinase (P13K) signaling pathway were significantly up-regulated in lung cancer patients relative to patients without lung cancer (although there was no evidence for a copy number change in the P13K gene itself). The gene expression findings were further validated using biochemical tests on airway epithelium of a cohort of smokers with clinical suspicion of lung cancer, and a significantly higher P13K activity was found in smokers who were ultimately diagnosed with cancer. Similarly, increased P13K pathway activation was observed in normal airways of smokers with pre-cancerous lesions. Since activation of the pathway occurred in normal airway epithelium distal to the location of the tumour, the authors concluded that the PI3K pathway was altered early in lung cancer development.

 

The researchers also found that P13K pathway gene expression activity was decreased in the airway of high-risk smokers (those with pre-cancerous lesions at risk of progression to lung cancer) following treatment with the chemopreventative agent myo-inositol. This agent also inhibited the P13K pathway in vitro. They concluded that deregulation of the P13K pathway in the bronchial airway epithelium of smokers is an early, measurable, and reversible event in the development of lung cancer, and that genomic profiling of these relatively accessible airway cells (which may be sampled using a non-invasive procedure such as bronchoscopy) could provide early warning of cancer development and allow intervention to prevent it.

 

Comment: Previous research has revealed the potential value of gene expression profiling for precise diagnosis and prognosis in forms of cancer, and this is an area of extensive research (see previous news). This study provides an interesting demonstration of how genomic data might also prove valuable in prediction and prevention of another major cancer type. Whether the specific agent used will be effective in preventing cancer is another question that must await further results.

15 April 2010A new paper in Nature reports on the use of an approach termed pronuclear transfer to prevent transmission of mitochondrial disease. Genetic forms of mitochondrial disease, whilst rare, can have devastating consequences, so there is considerable interest in finding ways to prevent them in affected families. Work last year used a technique called metaphase II spindle transfer to combine monkey egg cells with healthy mitochondria (from which the nucleus had been removed) with the nucleus from a monkey carrying mitochondrial mutations. The resultant egg cells, when fertilised, gave rise to apparently healthy baby monkeys that were the genetic offspring of the diseased mother – but with normal mitochondria (see previous news).

The latest research uses a different approach, pronuclear transfer – using human zygotes produced by in vitro fertilisation (IVF) rather than egg cells [Craven L. et al. (2010) doi:10.1038/nature08958]. Pronuclei are the bodies containing genetic material derived from the sperm and egg cells that are present in the zygote following fertilisation, but before the two fuse to form a single nucleus. The researchers created zygotes using egg cells from women with mitochondrial mutations and healthy sperm cells, then transferred either one or two pronuclei from the zygotes into another zygote from a healthy mother (ie. with mitochondria that did not contain mutations) from which the pronuclei had been removed. The resultant zygotes were grown to the blastocyst stage (70-100 cell embryos, day 5-6 after fertilisation). The proportion of zygotes reaching this stage was around 8% - half that of artificially created zygotes that had not been manipulated.

The researchers also looked at the proportion of donor (ie. mutated) mitochondrial DNA (mtDNA) in embryos grown following pronuclear transfer and found it quite variable; one contained no donor mtDNA at all, the ideal scenario, but others showed levels ranging from 2- 40%. Refinement of the pronuclear transfer technique to minimise the amount of celullar material transferred along with the pronuclei reduced this to below 2%.

The authors conclude that the technique, along with the previously published alternative approach, has the potential to be used to ‘treat’ (rather, prevent or ameliorate) human mtDNA disease, and weight the relative advantages and disadvantages of each. They are careful to note that this sort of genetic manipulation is only appropriate for use in families affected by serious forms of disease that ‘can affect multiple family members with catastrophic consequences’, as per the example of a woman with seven affected children, of which six died shortly after birth and the seventh has very serious medical problems (see BBC news report).

Comment: Calls for further investment in this line of research seem justified, given the severity of the conditions it is intended to prevent. However, there are two areas that will continue to require scrutiny. The first is the safety of the procedure; the researchers themselves point out that artificial manipulation of embryos can result in abnormal development. The second is bioethical concerns; generic issues relating to any form of cloning, and specifics relating to this particular technique – which involves the creation and manipulation of multiple zygotes, as opposed to unfertilised egg cells.

13 April 2010 Chronic kidney disease is a common disorder, affecting around 1 in 10 adults, resulting in progressive loss of kidney function. The condition is associated with increasing age, and is increasing in prevalence partly due to the ageing population in many countries. Despite this growing global health burden, only a limited number of inherited monogenic kidney disorders (e.g. polycystic kidney disease) have been identified, accounting for a small proportion of chronic kidney disease. Two large research collaborations have recently published studies in Nature Genetics identifying several new common genetic variants associated with kidney function and chronic kidney disease.

The first paper reports a genome-wide association (GWA) study and a replication study to identify genetic loci associated with serum creatinine levels, a common measure of kidney disease [Chambers et al. (2010) Nat Genet 11 April; doi:10.1038/ng.566]. The data from nine individual studies involving almost 24,000 participants of European descent were combined using a meta-analysis and five positions (on chromosomes 2, 4, 6, 17 and 19) were associated with creatinine levels; only the locus on chromosome 4 had been previously reported. The strongest SNP from each of the four novel loci was then analysed in a further 16,500 Europeans. All four SNPs showed association with creatinine levels (but not with other factors known to mimic links to creatinine) and also with one or both of two alternative measures of kidney function and with chronic kidney disease, so they are good candidates for genuine genetic variants linked to kidney function.

The second study also used a two-stage design to identify association with two measures of kidney function and chronic kidney disease [Kottgen et al. (2010) Nat Genet 11 April; doi:10.1038/ng.568]. The first stage involved a GWA meta-analysis of 20 studies involving 67,000 participants of European descendent, which identified 28 loci, only five of them previously reported. The strongest SNP at each of the 23 novel loci were analysed in a further 23,000 individuals of European ancestry; sixteen still showed significant association. A meta-analysis of both stages of the study suggested that a total of twenty of these novel genetic variants showed significant association with kidney function; thirteen are thought to affect renal function and disease, and seven to relate to creatinine metabolism.

Comment: These very large and well-conducted studies involving more than 100,000 people have identified several strong candidate genes likely to be involved in renal development and function. However, the authors estimate that these variants still only account for a small proportion of variation in kidney function. The studies are also wholly within European populations, but kidney failure is more common among those of South Asian and African Caribbean descent. It will be interesting to see whether the genetic architecture underlying this disease is the same is differing populations.

12 April 2010A recent paper argues that the mechanisms traditionally employed to protect the identity of participants in medical research are 'increasingly untenable in genomics' [Heeney C et al. (2010) Public Health Genomics; Epub ahead of print]. Existing methods have focused upon the data source: customary safeguards include making data unidentifiable or by only disclosing those data where identifiable variables have been removed or the data aggregated. Threats to privacy and confidentiality should take account of the prevailing data environment: in many contexts, there is a plethora of other available datasets which may be used for the purposes of reidentification of an individual, ranging from publically accessible data sets of genomic sequence data to supermarket loyalty schemes. Moreover, it is not sufficient to consider the range of ways in which data may be extracted or inferred. To be effective, data sharing policy must consider the perspective of a 'data intruder' namely 'someone with a motivation to investigate the attributes or identity of a data subject, and who uses available information for reidentification of individuals'. 

These concerns are not merely theoretical: in 2008, a description of the analysis of 3 datasets to identify an individual in the data [Homer N et al. (2008) PLoS Genet. 4(8):e1000167] resulted in the Wellcome Trust and the NIH withdrawing open web access to genomic datasets (see previous news). Heeney et al. describe this episode and go on to chronicle the potential for genetic discrimination which may arise as a result of identifiable genomic information becoming available, particularly in the context of insurance and employment. The integration of genomic data from forensic and biomedical datasets is an especial cause of concern, particularly if combined with computational techniques such as redlining (a process used to exclude access to goods and services to selected subgroups) and inference.

The authors argue that there is now a need to develop a more sustainable response to concerns over privacy and confidentiality, which is unlikely to be satisfied by the strategy of withdrawing genomic datasets from the public domain. Instead Heeney et al. offer recommendations for privacy protection that include restricting access to genomic data to legitimate academic researchers; engaging in privacy risk assessments that take account of all the resources available to potential data intruders in the data environment; refining the promises of confidentiality that are made to participants in research so that assurances about data protection are both robust and realistic; and that these initiatives are 'supported by appropriate legislative and governance responses, at a higher policy level, and by ensuring fair access to employment and healthcare'. A failure to address these challenges, they propose, could result in widespread loss of public trust and a decline in willingness to take part in research.

Comment:  Although the paper concentrates upon the challenges for genomics research, the threat to privacy and confidentiality within the context of providing health care services is likely to become increasingly pressing as genetic and genomic technologies are rolled out more widely. As financial pressures build, it seems that more may be at stake both in terms of insurers and employers wishing to exclude those who are likely to become costly claimants in the future: and also because the exhortation for governments to provide fair access to healthcare might become increasingly difficult to satisfy.

8 April 2010

Following the initiation of the Human Genome Project in 1990, a first draft of the human genome sequence was released nearly ten years on. Various journals have decided to commemorate the tenth anniversary of this achievement by publishing articles and discussion from eminent researchers and commentators in the field, debating the importance of human genetics and genomics. What is perhaps most notable about this plethora of riveting reviews is the undercurrent of uncertainty, which flows beneath the surface of the plaudits, over the value of genomics research for medicine and health.

A special issue of the journal Nature includes several excellent overviews of the underlying complexity revealed by modern biological research, the race to sequence the first human genome, and the recent explosion in the amount of sequence data. Perspectives from leaders of both the public and private sequencing efforts in the US reveal much about the progress – both actual and expected – towards the much lauded goal of personalised medicine. Venter, now head of the J. Craig Venter Institute, predicts that personal genomic data will soon become a “commodity” due to enormous increases in sequencing capacity, but accepts that there “is still some way to go before [genomics] can have a significant impact on medicine and health” [Venter, JC. Nature (2010) 464:676-7]. Part of this challenge, he believes, will be accurately cataloguing phenotypes rather than genotypes. Collins, now Director of the NIH, remains positive about the future of genomics in medicine, and helpfully lists “five major lessons that could be gleaned from this first decade of the genomic era” [Collins, F. Nature (2010) 464:674-5]:

free and open access to human genome data is crucial for progress;

the public and private sectors should continue to invest in developing new genomic technologies;

the success of personalised medicine will depend upon large studies to identify genetic and environmental risk factors;

public-private partnerships will be needed to develop targeted therapeutics; and

good policy decisions are needed with regard to issues such as protecting personal privacy and education of heath professionals and the public.

The BMJ also contains two opposing responses to the question “Is modern genetics a blind alley?”, one from a practicing GP [Le Fanu,J.BMJ (2010) 340:c1156] and the other from a distinguished genetics researcher [Weatherhall, DJ. BMJ (2010) 340:c1088]. Despite a passionate and compelling defence of genetics from the Oxford Regius Professor Emeritus, it is nonetheless revealing that, from the perspective of a practicing primary care physician, “the influence [of genetics] on everyday medical practice remains scarcely detectable” and it remains a small component of disease.

Comment: There is no doubt that enormous advances have been made over the last decade in our understanding of human biology and disease, which have been catalysed by the human genome project. The sequence of the human genome itself has provided a glut of information, which will no doubt inform the future development of new diagnostic and therapeutic strategies. So why is there so much debate?

Part of the underlying problem is the slow and difficult process of translating scientific knowledge into clinical practice and improvements for health. Translational research involves much more than basic science, proof-of-principle or 'bench-to-bedside' studies. It also requires clinical evaluation, evidence synthesis, analysis and dissemination of knowledge, as well as policy and service development. The benefits of genomics research are emerging, but given the pace of technological advance, it is essential that these final phases of the translation process are recognised and adequately funded.

7 April 2010Newborn screening involves the testing of blood samples from newborn babies for various different rare genetic disorders. In some cases, early identification can allow interventions to prevent or ameliorate disease; other potential benefits of early, pre-symptomatic diagnosis include avoiding the need for extensive medical investigations later in life and allowing prompt genetic counselling for families (including advice about the risk of recurrence in future children).

Technological developments have led to the possibility of screening for many rare disorders. However, prior to their inclusion in a newborn screening programme, careful consideration of the risks and benefits of screening must be undertaken. In the US, a wide panel of disorders are included in newborn screening programmes: 29 conditions are deemed mandatory and another 25 secondary conditions have been recommended for inclusion in screening (see previous news). However, expanded newborn screening has raised some concerns and a white paper published by the President’s Council of Bioethics discusses some of the ethical implications of newborn screening in the US (see previous news).

Evaluating rare conditions nominated for population-based newborn screening is made difficult by the scarcity of data, such as those from large-scale population screening studies and randomised clinical trials. In a recent issue of Genetics in Medicine dedicated to newborn screening, two articles describe the US approach to evaluating evidence in screening for rare conditions. Perrin et al. describe some of the challenges in the evidence review for rare diseases and the adaptation of standard evidence review processes to screening for rare diseases [Perrin et al. (2010) Genet Med 12 (3):131-134]. Calonge et al. describe the framework by which the US Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children evaluates conditions to be included in newborn screening programmes [Calonge et al. (2010) Genet Med 12(3):153-159]. The approach taken by the Committee involved the formation of an Evidence Work Group to review all the published evidence as well as unpublished data from experts relating to a particular disorder. The report it produces highlights the key findings, and indicates where key data are missing. This review is then evaluated by the Committee in three broad areas relating to the condition, the screening and diagnostic test, and the treatment. Recommendations are made based on the systematic evidence review and additional information that may be available from other sources.

Comment: With rapidly developing techniques for high-throughput analysis such as tandem mass spectroscopy (MS/MS), it has become increasingly feasible to test for multiple genetic diseases. However, the inherent difficulties of studying the epidemiology of conditions that are extremely heterogeneous and also very rare, in addition to the differing considerations of what constitutes the benefit of screening (see previous news) make assessment of what to include in a newborn screening panel a difficult decision. The PHG Foundation is currently undertaking a literature-based systematic review of the evidence to support expanded newborn screening for five conditions in the UK.

1 April 2010 The failure of genome-wide association studies (GWAS) to uncover common genetic variants which confer a substantial risk to common disease has raised the question of where the so-called ‘missing heritability’ may lie. Rather than being due to single nucleotide polymorphisms (SNPs), it has been widely suggested that copy number variants (CNVs) might explain a large proportion of genetic susceptibility to common disease (see previous news).

However, this hypothesis has now been largely disproven by the Wellcome Trust Case Control Consortium [Craddock N, et al. Nature (2010) 464:713-20]. In the first GWAS of CNVs, researchers used an array-based approach to evaluate over 10,000 CNVs in 3,000 controls and around 2,000 cases of eight diseases: bipolar disorder, breast cancer, coronary artery disease, Crohn’s disease, hypertension, rheumatoid arthritis, type 1 diabetes and type 2 diabetes. Although several known susceptibility loci that had previously been detected through SNP association studies were confirmed – such as the involvement of the human leukocyte antigen system in all three autoimmune diseases – no convincing new associations of any of the diseases with common CNVs were found. The authors therefore concluded that “common CNVs typable on current platforms are unlikely to have a major role in the genetic basis of common diseases… [and are] unlikely to account for a substantial proportion of the ‘missing heritability’ for these diseases.”

Comment: While some people will no doubt be surprised or even disappointed in this result, the technical and interpretive challenges overcome in the study should not be overlooked, and may set a new standard of statistical rigor in genome-wide analyses. It is likely that researchers will now turn their attention towards other targets in their search to find solve the case of the missing heritability [Maher B. Nature (2009) 456:18-21], such as rare genetic variants and epigenetic markers. However, it is possible that the discrepancy between the theoretical heritability of complex diseases (which is generally based on family and twin studies) and the extent to which genetic variants cause these diseases is actually an artefact. Not only could the heritability estimates themselves be an over-estimate, due to the importance of a shared environment, but also interactions (gene-gene and gene-environment) which are excluded from the standard models could account for a substantial proportion of the heritability.

More discussion on this and other key developments in human genomics can be found in the same issue of Nature, which contains a special series of commentaries and reviews celebrating the tenth anniversary of the publication of the draft human genome sequence – see The Human Genome at Ten.

2 April 2010Personal genome sequencing: current approaches and challenges

Snyder M, Du J, Gerstein M. Genes Dev. 2010 Mar 1;24(5):423-31.

 

Individual Genomes on the Horizon

Lifton RP. N Engl J Med. 2010 Mar 10

 

The pursuit of genome-wide association studies: where are we now?

Ku CS, Loy EY, Pawitan Y, Chia KS. J Hum Genet. 2010 Mar 19. [Epub ahead of print]

 

The future of psychiatric research: genomes and neural circuits

Akil H et al. Science. 2010 Mar 26;327(5973):1580-1.

 

Genome-wide association studies in pharmacogenomics

Daly AK. Nat Rev Genet. 2010 Apr;11(4):241-6.

 

The genetics of prion diseases

Mastrianni JA.  Genet Med. 2010 Mar 3. [Epub ahead of print]

 

Repeat expansion disease: progress and puzzles in disease pathogenesis

La Spada AR, Taylor JP. Nat Rev Genet. 2010 Feb 23;11(4):247-258.

 

Chromatin structure and the inheritance of epigenetic information

Margueron R, Reinberg D. Nat Rev Genet. 2010 Apr;11(4):285-96.

 

Unlocking the pathogenesis of celiac disease

Plenge RM. Nat Genet. 2010 Apr;42(4):281-2.

 

Epigenetic marks identify functional elements

Morse RH. Nat Genet. 2010 Apr;42(4):282-4.

 

Protective hemoglobinopathies and Plasmodium falciparum transmission

Pasvol G. Nat Genet. 2010 Apr;42(4):284-5.

 

Chinese bioscience: The sequence factory

Cyranoski D. Nature. 2010 Mar 4;464(7285):22-4.

 

Ameliorating amyotrophic lateral sclerosis

Rowland LP. N Engl J Med. 2010 Mar 11;362(10):953-4

 

The March volume of the Annual Review of Public Health has a whole section on the public health significance of genomics and eco-genetics, including:

Genome-wide association studies and beyond

Witte JS. Annu Rev Public Health. 2010 Apr 21;31:9-20 4 p following 20.

 

Nutrigenetics / Nutrigenomics

Simopoulos AP. Annu Rev Public Health. 2010 Apr 21;31:53-68.

 

The behavioral response to personalized genetic information

McBride CM, Koehly LM, Sanderson SC, Kaphingst KA. Annu Rev Public Health. 2010 Apr 21;31:89-103.

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