In the news

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We are taking a short break, and will resume with news and updates to the website early in the new year.

The US Supreme Court has this month been considering whether it is legal for a company to hold a patent covering a biomarker test to determine the most appropriate levels of drug to use for treatment.

Prometheus Laboratories’ patent covers a method to determine the most effective dose of thiopurine drugs to treat gastrointestinal disorders, based on metabolite levels in patients’ blood. Both thiopurine drugs and tests to assess metabolite levels were already in existence, but the patents relate to the process for linking the drug dose and metabolite range.

Prometheus are claiming that a similar test from a Mayo Clinic company infringes their patent, whilst Mayo contests that the patent is invalid since the link between metabolite levels and drug action is based on a natural body process. The American Medical Association and others support the Mayo’s suit, arguing that the patent would interfere with normal medical practice by preventing doctors from assessing metabolite levels and adjusting drug dose in any manner.

Comment: The outcome of this case, expected in 2012, could have a major impact on companies developing products in the area of personalised medicine, such as genetic tests to identify individuals likely to need higher or lower doses of drugs. 

The money comes as part of the government’s new Life Sciences Strategy and includes £180 million for a “biomedical catalyst project” to bring biomedical innovations more quickly to market. £130 million has been earmarked for research into stratified medicines, with £60 million targeted at collaborations between academia, industry and clinicians. £75 million will go to expanding the European Bioinformatics Institute in Cambridge, and funding for other initiatives.

As well as cash the strategy aims to open up access to patient data for researchers, with the assumption of patient consent on all anonymised data unless a specific objection has been raised. A code of practice on anonymisation is being drafted by the UK information commissioner.

The proposals also seek to provide patients in advanced stages of disease with access to novel drugs that have completed phase III and, in exceptional cases, phase II trials. The early access scheme also allows companies to set their own prices for such drugs and by-passes the National Institute for Health and Clinical Excellence, as the drugs will not receive central funding.

Three reports were issued to coincide with the speech: a government report, Investing in UK Health and Life Sciences, a report by the Department of Business Innovation and Skills entitled Strategy for UK Life Sciences, and an NHS report on how to accelerate the adoption and diffusion of new ideas. 

The Autism Genetic Resource Exchange has joined forces with the US National Institutes of Health to create what may be the world’s largest multidisciplinary data resource on autism spectrum disorders (ASDs).

The AGRE, which is run by the US charity Autism Speaks (see previous news), has contributed genetic and phenotypic (medical, behavioural and developmental) data from more than 2000 families to the NIH’s National Database for Autism Research. This resource allows researchers to access data from a large number of different databases relating to ASDs with standardised data and analytical tools.

Dr Clara Lajonchere, Vice President of Clinical Programs at Autism Speaks said that the sharing of data would allow “research to proceed faster, more efficiently and cost effectively” and let researchers focus on the science rather than family recruitment and data collection. 

New research from the US Centers for Disease Control and Prevention (CDC) reports that certain genetic variants are not linked to deaths from influenza in children and young adults.

Influenza (flu) is a relatively mild and self-limiting illness in most cases, but can be fatal among vulnerable groups such as the very old, very young or people with compromised immune systems. Occasionally, it may also cause unexpected deaths in apparently healthy children and younger adults, and this is a worrying public health issue.

Writing in Emerging Infectious Diseases, US researchers report analysis of DNA from 105 children and young adults who died from influenza, looking at single-nucleotide polymorphisms (SNPs) in two key genes associated with immune responses to viral infections - tumor necrosis factor (TNF) and mannose-binding lectin 2 (MBL2).

None of the SNPs showed association, refuting the theory that the people who died might have had a genetic vulnerability to the virus via these two genes. However, MBL2 variants in patients who died were apparently linked with co-infection with methicillin-resistant Staphylococcus aureus (MRSA) bacteria.

Comment: This is an example of how host genomics may become an important element of public health research for the control of infectious diseases. In this case, the authors propose that larger-scale genomic research into factors that affect susceptibility to serious complications from common viral infections is appropriate. 

Preliminary results from a trial of viral-based gene therapy for haemophilia have shown that four of the six patients treated were able to stop taking clotting treatments.

Haemophilia B is a rare disease where inherited mutations prevent the production of a crucial component of the blood clotting cascade, factor IX. The only treatment is frequent injections of synthetic factor IX, which is very expensive.

The adeno-associated virus (AAV) based gene therapy vector was used to deliver normal copies of the factor IX gene to the liver cells of patients at different levels. Factor IX production was increased in all patients to between 2 and 12% of normal levels.

Dr Amit Nathwani from University College London commented: "This is the first study that has shown that you can actually achieve stable, long-term, therapeutic level of expression [factor IX production] in subjects with severe haemophilia B, so it's a fantastic start”.

Researchers hope that if the treatment proves safe and effective in longer-term trials, it may allow haemophilia B sufferers to lead more normal lives, managing without factor IX injections except in cases of injury. A similar gene therapy approach is also under investigation for the more common form, haemophilia A, which affects around five times as many people.

Comment: The main problem with gene therapy is to achieve long-term expression of the healthy genes; however, to people used to receiving injections perhaps several times weekly, having ‘booster’ treatments to maintain gene expression might be acceptable, and even cost-effective. The safety of repeat administration would be another concern, of course. 

Researchers have uncovered new evidence of a genetic link between vitamin D deficiency and increased risk of multiple sclerosis (MS).

Multiple sclerosis is a complex and progressive inflammatory disease of the central nervous system typically diagnosed in young adulthood. The disease is known to have genetic and environmental links, and the marked geographical distribution of cases, which increase significantly the further north populations are located, led to vitamin D being investigated as a potential key risk factor. Potential genetic interactions involved in this mechanism have already been identified (see previous news).

Now, scientists from Canada and the UK have identified a rare genetic mutation in 3000 adults with MS and their unaffected parents. A copy of a rare variant of the CYP27B1 gene was present in 35 affected adults, all of whom had inherited it form a parent. This variant was found to be independently associated with an inherited form of vitamin D deficiency.

The researchers say that these findings further strengthen evidence of the importance of vitamin D deficiency in MS and may justify large-scale trials of vitamin D supplementation as a preventative strategy in northern countries such as Scotland with the highest incidence of the disease.

Comment: Although lack of vitamin D is clearly not the sole cause of this complex disease, the evidence provided by genetic studies is proving highly valuable in offering a potential new way of reducing the number of people affected by MS; vitamin D supplementation is a relatively cheap and low-risk intervention that could be implemented at the population level.

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The UK Stem Cell Bank has received the first deposits of clinical-grade human embryonic stem (hES) cells.

Created by a team at King’s College London, these cells were made under especially stringent conditions to meet the requirements for therapeutic use in humans, although they will now be subject to checking to ensure that these standards have been successfully met. This required new approaches to avoid the usual need for animal-derived products for establishing and propagating the cell lines, such as animal enzymes or ‘feeder’ cells.

Cells used for current clinical trials such as for spinal cord repair (see previous news) were originally research-grade products that received exhaustive safety analysis and subsequent approval for use in humans.

Research leader Professor Peter Braude commented: “This first batch of cells is the culmination of nearly ten years of research funded strategically by the Medical Research Council that will keep the UK at the forefront of regenerative medicine”. Other UK research groups reportedly plan to deposit similar cell lines soon.

Comment: These new bespoke clinical-grade cell lines could potentially be used in clinical trials across Europe, potentially speeding transfer of stem cell therapeutics into the clinic, though some have ethical reservations about the medical use of products derived from human embryos. A recent European court ruling blocked patenting of such products on moral grounds (see previous news), a decision that has provoked fury from researchers. This includes public criticism from the Alliance of German Scientific Organizations, which says that the ruling could discredit hES cell research and that regulation should rest with national government. Practice varies considerably across Europe.

A new study published in Genetic Epidemiology has reported that genotyping provides no additional medical benefit over standard predictive information such as medical and family history.

Researchers recruited over 3000 recipients of the Health Compass service from direct-to-consumer (DTC) genetic test provider Navigenics, which provides an estimate of risk for fifteen conditions. Study participants provided self-reported personal medical and family history information, which was used to predict risk, and the two measures of lifetime disease risk were then compared.

For five conditions with ‘relatively high heritability’ the researchers found significant association between the genetic and medical history risk estimates. They concluded that the genetic risk information was as accurate as traditional risk prediction for these conditions, though it did not offer any additional benefit. For the other ten conditions, there may be no such association, or it may be that too few people were included in the analysis to detect such links, since relatively few had family or personal histories of the diseases.

Of note, recent moves to prohibit DTC genetic testing in the US (see previous news) have led Navigenics to switch to marketing services to health care providers and funders instead.

Comment: This study suggests that DTC predictive genetic testing does not offer additional medical benefits compared with traditional risk assessments, unless of course there is no family history information available. However, at the same time it shows that genetic data can have genuine predictive value. Do legal prohibitions of such services protect consumers from dangerous harms, or from wasting their money – or merely restrict their choices with respect to health information?

A report from a large study looking at cancer risk attributable to lifestyle and environmental factors has been recently published by the Centre for Cancer Prevention research team.

The objective of this comprehensive study was to estimate the percentage of cancers in the UK in 2010 resulting from exposure to a number of lifestyle and environmental factors. The researchers looked at the consumption of tobacco, alcohol, meat, fruit and vegetables, fibre and salt as well as weight and level of exercise. Environmental factors were also considered, such as infections, radiation and occupational hazards.

The relative contributions of each factor to the total number of cancers diagnosed in the UK in 2010 were estimated based on high-quality epidemiological studies. The study concluded that nearly half of cancer cases were linked to 14 lifestyle and/or environmental factors.

Comment: The publication of this report is of great interest and importance and will have a positive impact on public health measures and initiatives. Genetic factors, however, also play a crucial role in the onset and progression of cancer and may, as the science progresses, provide a clue as to which members of the population are most at risk from lifestyle factors in common cancers (that is those that are not associated with specific high risk genes such as BRCA1 or BRCA2). Thus while it should not be doubted that lifestyle modifications will be the key strategy in cancer prevention, genetic risk stratification, by identifying those who might derive the greatest benefit from changing life style, could well improve the efficiency and effectiveness of health promotional advice which, to date, has not resulted in the necessary behavioural change. These are at present just assertions, but there is good a priori reason to believe that the ability to predict cancer risk and response to lifestyle change can be yet another arm of stratified medicine research programmes.

The important role of genetic evaluation in tackling the childhood cancer retinoblastoma has been documented by a group of US physicians in the Archives of Ophthalmology..

Retinoblastoma takes two forms – bi-lateral (both eyes are affected), which is usually inherited, and unilateral (one eye is affected), which may or may not be hereditary.  The multidisciplinary team of ophthalmologists, paediatric oncologists, pathologists, geneticist and genetic counsellors tested retinoblastoma patients attending the Texas Children's Cancer Center. The heritable forms of the disease were found in 90% of patients with bilateral retinoblastoma and 17% of those with unilateral retinoblastoma.  Relatives of those with the heritable mutation were identified as ‘at-risk’ and put forward for genetic test. Relatives of patients who did not have the heritable form of the disease did not require further investigation. Of the 46 who went on to be genetically tested, only six were found to have the mutation, requiring follow-up screening by an ophthalmologist.

Using genetic testing to see whether the patient has a heritable retinoblastoma mutation can inform long-term management of affected children and their families, by more effectively targeting screening for retinoblastoma and related tumours to those who need it most. 

The National Human Genome Research Institute (NHGRI) in the US has announced the $416 million funding to boost the uptake of genome sequencing into mainstream medical practice.

The new funding, part of the Large-Scale Genome Sequencing Program, is intended to focus on medical applications; NHGRI Director Eric Green said that it would begin to “move us into genomic medicine".

The Mendelian Disorders Genome Centers programme aims to identify the genetic basis of all Mendelian or monogenic diseases; most of these disorders are individually very rare and the underlying genetic mutation remains unknown for many thousands. Another major programme will be the Clinical Sequencing Exploratory Research Project, which will explore the medical, ethical and social impacts of using genomic sequencing in a clinical setting. Funds will also be used to develop new, accessible computer software to analyse genomic data for clinically relevant information.

Comment: This funding allocation is timely, and shows recognition of some of the very important issues and barriers that must be addressed if whole genome sequencing technologies are to be used by hospitals for direct medical benefits, as outlined in the key PHG Foundation report released this autumn, Next steps in the sequence. Other countries should similarly be considering how they will realise this potential; key issues identified in the UK centred on the urgent need to develop bioinformatics expertise and infrastructure for clinical applications, as well as economic and policy analysis. Will the UK government show similar commitment by allocating appropriate funding to such endeavours? 

A short sighted approach to services for muscular dystrophy is risking lives and costing the UK National Health Service (NHS) up to £31m a year, says a new study.

The audit of 267 unplanned hospital admissions suggests 41% could have been avoided if patients had had prior access to services such as specialist physiotherapy and medical equipment. The research was carried out by neurologist Professor Michael Hanna of University College London Hospitals NHS Trust, and updates 2007 findings, which revealed inadequacies and serious geographical inequities in services for patients with muscular dystrophy across the UK (see previous news).More than 70,000 people in the UK are affected by one of the 60 forms of the condition, the majority of which are inherited, genetic forms. According to the Muscular Dystrophy Campaign, there are only 30 expert care advisers to support these patients. 

Providing fair and consistent access to appropriate, specialised services for patients with disorders such as MD, who may require care from a range of specialities as well as experts to oversee it, is by no means straightforward. Similar problems have been observed for inherited cardiac conditions and other groups of genetic conditions. However, as this latest research reveals, failure to plan and implement such services can have undesirable outcomes, both for patients and for NHS finances.    

The Office of Public Health Genomics (OPHG) of the US Centers for Disease Control and Prevention (CDC) has released a new report outlining priorities for public health genomics over the next five years to 2017.

These recommendations were developed from stakeholder consultation and an expert meeting of the public health genomics community, along with views from the non-profit and for-profit sectors conducted by the US Genetic Alliance. Recommendations for priority actions in the US included:

• Improve public education about genetics and related issues via community engagement
• Continue to work on issues related to evidence development
• Take a bottom-up approach to technology development, with clinical need as the driving force
• Embed genetics into all aspects of healthcare, including national data and health IT standards
• Expand the public health screening programs that utilise genetic information

Comment: A lack of ‘shared understanding and engagement’ on public health genomics among the public health community is noted to be a barrier to effective delivery, with many public health practitioners failing to appreciate the potential relevance of genomics to public health interventions and programmes – in contrast to the wider medical community who have grasped the possible utility of areas such as pharmacogenetics with more enthusiasm. The call to build understanding and collaborations within public health is therefore highly pertinent – and relevant in other countries such as the UK, too.

A pilot trial reported in Science Translational Medicine further underlines the potential benefit of genomic tumour sequencing to inform clinical management.

Samples from a small number of patients with different forms of advanced cancer were examined using whole genome, exome and RNA transcriptome sequencing, in each case revealing abnormalities that suggested specific treatments.

At under US$5,000 per patient and with results delivered in under a month, this was proposed to be financially and practically feasible; the authors also warned that current trials of targeted therapies needed urgent redesign, to allow inclusion of patients with genetic tumour features that indicated they would be likely to respond.

Comment: Although the authors of this report demonstrate neatly how both clinical practice and research in oncology could (and arguably should) incorporate genomic sequencing, it is worth noting that in this study, results were reviewed by a multidisciplinary group of experts. Providing suitable expertise of this nature is likely to prove much more problematic than access to basic sequencing services.

The key barrier to genomic research at present (where analytical expertise is readily available) is handling the huge volumes of data; as genome sequencing is increasingly used in clinical research this is becoming an issue that concerns increasing numbers of researchers. There is increasing interest in cloud computing as a possible solution to capacity issues, but solving the problem of data overload inside and outside the clinic is likely to require innovation in computing, bioinformatics, and more besides.

The UK government has launched the new Health Research Authority (HRA), charged with protecting and promoting the interests of patients and the public in health research.

The HRA has been formed under government plans to streamline health research regulation. It is intended that the HRA will ‘co-operate with others to combine and streamline the current approval system and promote consistent, proportionate standards for compliance and inspection’. The National Research Ethics Service forms a core component of the new authority.

Chief Medical Officer Professor Dame Sally Davies said that the HRA would “provide the continuity and stability of the national research ethics system but will simplify the way regulations governing research are used whilst ensuring the safety of patients and the public is paramount”, as well as enabling more patients to participate in research.

Comment: In the current format, this new body fulfils some but not all of the purposes proposed by the Academy of Medical Sciences in calls for a ‘super-regulator’ of research (see previous news). However, whilst currently a Special Health Authority, the intention is to make the HRA a Non Departmental Public Body, enabling it to assume additional functions; it has been proposed that these could include research regulation activities currently overseen by the Human Fertilization and Embryology Authority (see previous news). 

Scientists have pinpointed two genes that could help spot patients with aggressive prostate cancer.

Accurate prognoses for prostate cancer are difficult as the disease can take quite different courses ranging from very slow-growing and localised to aggressive, rapidly spreading forms. Doctors therefore often take a ‘watchful waiting’ approach with older patients, but current grading systems for assessing prostate tumours such as the Gleason System cannot always predict which tumours may develop quickly into aggressive forms.  Testing prostate tumour tissue for gene expression signatures associated with poor outcomes, the scientists discovered two tumour sub-types that carried a 3.2-fold increased risk of death. The gene signatures were found in 29% of the 281 patients in the study.

Identifying genes whose activity can indicate fast-spreading tumours is a first step towards developing a genetic test to identify patients in whom the cancer is likely to progress rapidly, and who might therefore benefit from more aggressive treatments, including surgery or chemotherapy.

Scientists have identified a gene that leads to a rare, but fatal neurodegenerative disorder.

Kufs disease strikes in middle-age, causing dementia, motor impairment and early death. There is currently no known treatment

The research team in Washington University School of Medicine in St. Louis sequenced the genomes of two related Kuf’s disease patients and a first-degree relative who did not have the disease. Comparing the results they found variations in the DNAJC5 gene were responsible for Kufs disease.

Kufs disease is a very rare disorder, but the authors of the research believe their discovery could have implications for other, more common, forms of dementia.

“What caught our attention is that synaptic dysfunction underlies other forms of dementia,” says first author Bruno Benitez, MD. “We think this Kufs-causing gene may open up a new avenue of research for these kinds of disorders because it may provide new information about dementia in general.”

The research is reported online in the journal PLoS ONE.

DNA theft: your genetic information at risk.

Joh EE. Nat Rev Genet. 2011 Oct 25. doi: 10.1038/nrg3113

Moving toward precision medicine.

Lancet. 2011 Nov 12;378(9804):1678. 

Genomic future beckons for cancer management

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Personalized Cancer Diagnostics

Corless CL. Science 2 December 2011: 1217-1218.

Gene expression profiling in breast cancer: classification, prognostication, and prediction.

Reis-Filho JS, Pusztai L. Lancet. 2011 Nov 19;378(9805):1812-23.

Inherited cardiomyopathies.

Raju H et al. BMJ. 2011 Nov 21;343:d6966. 

Beyond Base Pairs to Bedside: A Population Perspective on How Genomics Can Improve Health.

Khoury MJ et al. Am J Public Health. 2011 Nov 17. [Epub ahead of print]

Therapy for cystic fibrosis - the end of the beginning?

Davis PB. N Engl J Med. 2011 Nov 3;365(18):1734-5.

Non-coding RNAs in human disease.

Esteller M. Nat Rev Genet. 2011 Nov 18;12(12):861-74

On the futility of screening for genes that make you fat.

Veerman JL. PLoS Med. 2011 Nov;8(11):e1001114. 

Detours on the road to personalized medicine: barriers to biomarker validation and implementation.

Fiore LD, D'Avolio LW. JAMA. 2011 Nov 2;306(17):1914-5.

The rugged landscape of drug design.

Nat Genet. 2011 Nov 28;43(12):1165. 

A rare variant in CFH directly links age-related macular degeneration with rare glomerular nephropathies.

Wright AF. Nat Genet. 2011 Nov 28;43(12):1176-7. 

How evidence based is English public health policy?

Katikireddi SV et al. BMJ. 2011 Nov 17;343:d7310. 

The mind's tangled web.

Nature. 2011 Nov 2;479(7371):5. 

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