In the news

A new report suggests that the majority of people living with rare diseases in the UK are unable to access suitable medical expertise to help explain and manage their conditions.

Rare diseases – many of which are primarily genetic conditions – are those that affect fewer than one in 2000 people. However, collectively these diseases are not rare, affecting one person in 17 at some point in their lives in the UK, for example, and many are very serious medical disorders (see previous news).

Launched on global Rare Disease Day (28 February 2011), Improving Lives, Optimising Resources, the new report from Rare Disease UK (RDUK) highlights an alarming lack of medical professionals who understand rare conditions, long delays in diagnosis, and an absence of systems to allow people to access adequate medical and psychological information and support.

The report sets out recommendations for a national strategy to address these problems and make the most effective use of health service resources in delivering improved diagnosis, care and treatment, and research into rare diseases, drawing on resources from academia, industry, patient groups and medical research charities. The proposals include:

• revision of the current newborn screening programme (see previous news)
• establishment of a reliable online information portal
• development of personalized care plans for patients with rare diseases

Referring to the recommendations of the report, RDUK Chair Alastair Kent commented: “Many of the actions proposed can be taken now with little alteration of existing practices, immeasurably improving the quality of life of millions of people. We must act now”.

This is an important example of how co-ordinated action and systems to allow information sharing and equitable access to services can deliver significant health improvements; it is to be hoped that the UK National Health Service will consider the report very carefully. 

Dr Hilary Burton, Director of PHG Foundation, who chaired the Working Group on Research for the Report, also noted the importance of strengthening research programmes on rare diseases, which is much more difficult when patients are few in number and widely dispersed. There is a need to support collaborations, develop rare disease registries and streamline the systems for research and development approval and implementation.  

Nature News reports on the issue of overly-restrictive commercial licensing holding up research into cures for rare diseases.

They give the example of a French researcher unable to use a mouse model with a tagged version of the gene implicated in Rett syndrome, developed by Novartis in the US, because of licensing restrictions – even though Novartis researchers are no longer using the model themselves. Despite years of attempts, no Rett syndrome researcher has been able to obtain access.

The scientists who developed the model have reportedly said that they would like to grant access, but are unable to do so under the terms of the licence. Outside labs have now stepped in to remake the mouse model; Adrian Bird of the Wellcome Trust Centre for Cell Biology in Edinburgh says that his lab has re-engineered the mutated mice and will distribute them once the breeding population is large enough.

Legal restrictions have long been one of the issues preventing the free sharing of information and materials between researchers, but there are indications that the situation is becoming worse. A 2007 study on this topic found that requests by academics for research materials from other labs were being turned down almost twice as frequently as had been the case late 1990’s. A study from this year found that competitive environments decrease the likelihood of sharing, as does awareness of legal restrictions and the norms of the culture in which the researchers are working.

Research into rare diseases is big business - witness sector leader Genzyme’s recent sale to Sanofi-Aventis in a deal reported to be worth over $20 billion – and a company’s value in this area is dependent upon the range and strength of the licenses that it holds, but when this intellectual property inhibits the development of therapies it becomes morally problematic. It is not clear what the answer to this issue is - without intellectual property rights commercial laboratories wouldn’t have the incentive to develop therapeutic tools in the first place - but it seems evident that it shouldn’t be the patients who suffer the consequences.

Leading UK biomedical research charity the Wellcome Trust has published a portfolio review reflecting on progress and challenges in human genetics.

The Wellcome Trust spent £740 million on human genetics research between 1990 and 2009, the period covered by the new review, including a major contribution to the Human Genome Project via the Wellcome Trust Sanger Institute and to genetic epidemiological studies via the Wellcome Trust Case Control Consortium (see previous news).

The review identifies key challenges for future research into human genetics and disease, such as the importance of high quality genetic epidemiology, monogenic and infectious disease studies, investigation of genetic links to phenotype including epigenetic factors, and ethical and social implications. It also calls for:

• Potential engagement with private genomics companies - including providers of personal genomics services - to explore possibilities for research based on their data.
• Involvement of clinicians (including pathologists) in research; establishment of a central UK pathology laboratory is proposed to be beneficial.
• Development of governance frameworks to support open access to genomic data.
• Strategic global partnerships to support the transfer of useful genomic technologies to improve health in emerging economies.

Some of these latter areas beyond basic research represent possible new directions for the Wellcome Trust, and fit closely with the aims and practice of public health genomics, including efforts to promote equitable access to the benefits of genomics for health around the world.

Doctors in the US have used whole genome sequencing (WGS) to direct the treatment of a pancreatic cancer patient. 

Clinicians at the Mayo Clinic worked with the company TGen to sequence and compare the normal and tumour cell genomes from the patient using WGS technologies. Identification of key mutations in the cancer cells reportedly allowed them to select a therapy specifically directed against them, although no details are given (said to be ‘included in an upcoming scientific paper’).

Although this particular report is not very informative, we are certain to see more and more examples of the use of WGS in clinical settings (as opposed to research studies), to improve characterisation of rare genetic causes of disease, and the specific genetic nature of individual tumours. In many cases this may allow doctors to choose treatments that are more likely to be effective. The feasibility of clinical applications will depend on a range of key issues – currently the subject of a PHG Foundation project - including cost and logistics. 

Federal funding for the US Office of Public Health Genomics (OPHG) has been dramatically cut from more than $11 million to under $1 million per year. 

The predecessor of the OPHG was established by the Centers for Disease Control (CDC) under the auspices of Dr Muin Khoury in 1997– the same year that Dr Ron Zimmern founded the PHG Foundation’s UK predecessor body, the Public Health Genetics Unit. As OPHG Director, Dr Khoury has built up an admirable operation and made enormous progress in championing and driving forward the application of genomics for population health. The restructured organisation will still work to address ‘issues relevant to genomics in health policy and practice’, providing expertise in public heath genomics, the evaluation and implementation of emerging genomic applications. However, the scale of their operations will necessarily be reduced.

Ron Zimmern, whilst appreciating the need for restrictions in public funding in the US as elsewhere in the world, has criticised the scale of the OPHG budget reduction (see commentary), suggesting that the CDC has ‘failed to comprehend the strategic importance of genomic science for the health of individuals and populations’ and of the ongoing need to build infrastructure to allow the rapid translation of genomic innovations into health services.

 To receive our monthly round-up by email please register here (also gives you access to our Resources section).

Go to monthly round-up

The US National Human Genome Research Institute (NHGRI) has released a strategic plan for the next decade that sets out ‘the path towards an era of genomic medicine’.

Published to coincide with the tenth anniversary of release of the first draft human genome sequence, the paper is titled Charting a course for genomic medicine from base pairs to bedside. It says that the last decade has heralded great progress in understanding the structure and biology of genomes, whilst the next decade must focus on understanding the biology of disease, improving the effectiveness of healthcare, and ‘advancing the science of medicine’. This latter area is defined as distinct from the practice of medicine, ie. heathcare delivery; genomic discoveries are anticipated to lead to improved diagnostics, therapeutics and clinical decision-making tools, as well as ‘an evidence-based approach for demonstrating clinical efficacy’.

The inevitable delay in clinical translation due to the requirement to demonstrate efficacy is also noted, along with the need to engage with regulatory processes and for ongoing health professional and public education and awareness of the potential and limitations of genomic information. The essential requirement for multi-disciplinary input to the ongoing analysis of societal impacts of genomic research and medicine is also noted, along with a range of issues requiring attention ranging from regulation of genetic testing, pharmacogenomics and genomic therapeutics to ethical and philosophical considerations.

Many practical challenges are also highlighted, most notably the need for computational innovation to meet the demands for data capture, analysis, integration and visualisation that are rapidly becoming the rate determining step in genomic medicine as sequencing methods become ever faster. There is also a corresponding need for improved technological infrastructure, and increased professional capacity in bioinformatics and computational genomics.

Other promising prospects for the future include the development of novel therapeutics based on improved understanding of disease pathology and classification, and the increasing use of stratified medicine – using genomic information to define sub-populations in whom therapeutics are expected to produce more beneficial results for targeted clinical trials and treatments.

Overall, the paper sets an optimistic but very realistic tone, referring to the ‘staggering challenges’ ahead and the need ‘to balance ambition with reality’ – in contrast with the grandiose claims at the beginning of the human genome project, when it was hoped that the monumental achievement of deciphering the genome would herald an immediate switch to the new era of genomic medicine. We have the same goal as before – a future where medicine is underpinned by a profound understanding of the basis of genomics in health and disease. It’s just that we can see that the road ahead is longer and more winding.

Interestingly, although the paper refers only to ‘medicine’ and not ‘public health’, many of the domains discussed are very firmly within the compass of applications at the population, as well as individual, level – diagnostics, prognostics and decision-making tools, for example. Over time, the concept of ‘public health genomics’ may become redundant as genomics is embedded firmly within all forms of preventative and therapeutic medicine. 

A new collaboration between four international consortia concerned with Alzheimer's disease (AD) genetics has been announced.

The International Genomics of Alzheimer's Project (IGAP) aims to completely understand the role inheritance plays in AD. To achieve this goal, IGAP will work to identify all the genes that contribute to the risk of developing this disease.The IGAP collaboration will enable investigators to compare combined genetic data from more than 20,000 people with AD with about 20,000 healthy elderly subjects. The subjects for these studies come from different AD research project locations across Europe, the UK, the US, and Canada. IGAP expects to present its first findings at the Alzheimer's Association International Conference on Alzheimer's Disease (AAICAD) in July 2011.

International collaboration and the sharing of genetic data on this scale is a significant step forward in understanding and combating this tragic disease. A new report from Alzheimer's Research UK calls for increased support from government and charitable sources for research, noting that ‘for every UK scientist working on dementia, six work on cancer’.

Kyoto University and associated Japanese company iPS Academia have announced an agreement with US company iPierian to share a worldwide ‘pool’ of patents relating to induced pluripotent stem cell (iPSC) technologies.

Academic researchers will be able to use the technologies without payment, whilst companies will have to negotiate licensing fees, the reported aim being "to bring iPSC technology to patients with intractable diseases as soon as possible". Patent pooling for stem cell technologies to boost the development of medical applications was recently recommended by an international group (see previous news). However, this is a very small pool, relating to three parties only; other holders of iPSC patents are not involved, and could even raise legal objections to any other users if they feel their own intellectual property rights are being infringed. 

Considered a potentially more ethically acceptable alternative to human embryonic stem (HES) cells, iPS cells are the subject of intensive research efforts. A new method for comparing them with ‘gold standard’ HES cells based on genomic profiles has just reported a high level of equivalence, though some researchers are less confident that iPS cells will perform as well. 

The Chinese Academy of Sciences (CAS) has released broad plans for the future of scientific research that emphasise the importance of translation.

Innovation 2020 is the fruit of the CAS Knowledge Innovation Programme (KIP) and sets out key areas for project funding including public health and regenerative medicine. There are also plans to create new science parks in Bejing, Shanghai and Guangdong province with a special focus on driving the translation of basic research into products, including in biomedicine, and to employ more than 5000 top scientists by 2020.

Productivity is never a problem for Chinese science, but these new plans to actively foster creativity, innovation and the application of science in creating beneficial outputs are an exciting development, and could mark a move towards the creation of important new biomedical tools.

A consortium of European DNA sequencing centres have established the new GEUVADIS (Genetic European Variation in Disease) initiative.

GEUVADIS aims to build a strong European framework to study the genetics of disease and to implement genomics responsibly in the clinical setting, by defining technological and ethical standards, and promote multidisciplinary training in genomics. Next-generation DNA sequencing technologies are increasingly affordable and fast; however, storage and interpretation of the vast amounts of data produced, and its use in diagnosis and treatment, is complex. The goal of the GEUVADIS project is to develop standards in quality control, storage and access of sequence data; biological and medical interpretation; and the ethical aspects of sequence variation analysis.

Described as "a strong European framework that can be used to dissect the genetics of disease and to implement genomics responsibly in the medical setting", this project is a sensible step towards creating shared standards and methods that will facilitate data sharing in genomic research and medical applications.

China has pledged US$300 million (around £190 million) for a new institute in Beijing to contribute to the Human Variome Project (HVP).

The HVP (see previous news) is an international collaborative initiative linking researchers and clinicians in an effort to drive the collection and sharing of human genetic and clinical data, to understand the effect of genetic variation on disease. Now the Chinese Government has made the largest single financial contribution to the project since it was launched in 2006. HVP Scientific Director Professor Richard Cotton commented: “China has shown the world that not only do they recognise genetic disease as a serious global health issue, but that they are serious about addressing it”. 

Besides representing another clear signal that China takes genetics very seriously as a determinant of individual and population health, this move is also a great boost for the HVP, since it will provide large quantities of valuable new data about genetic diversity within Chinese populations. Relative to their total number (1.4 billion), these groups have previously been rather under-represented in genetic and epidemiological research.

A study published in Neurology has provided further evidence that the phenomenon of sleepwalking can have a genetic basis.

The study set out to determine the inheritance of sleepwalking across four generations of a family of extreme sufferers, and to identify the chromosomal region responsible. Nine sleepwalkers and thirteen unaffected family members were interviewed and DNA samples collected and analysed.

The results indicated that the family’s sleepwalking was inherited as an autosomal dominant disorder with reduced penetrance, meaning that inheriting a single copy of the gene responsible can be enough to cause the condition, but that it will not always cause it to appear; perhaps due to lifestyle factors or interaction with other genes. A linkage study of this type is not able to pinpoint the specific gene concerned, but was able to narrow it down to a region on chromosome 20 containing around 28 genes.  

Sleepwalking is a widespread phenomenon, particularly during childhood, and can potentially put sufferers in dangerous situations. It had previously been known that the condition was heritable, but it had not been linked to a particular chromosome or region. Since this study is a small-scale one within a family of particularly severe sleepwalkers though, it doesn’t necessarily follow that the genomic region identified here is responsible for the condition in those with less severe or variant forms of the disorder. The researchers themselves point out that since other studies have shown different inheritance patterns, it is likely that sleepwalking has a number of genetic causes. Further studies will be required to determine how widely applicable these findings are, and also to identify the specific genes involved and the underlying mechanism before this work can point to possible therapies.

Get ready for the flood of fetal gene screening.

Greely HT. Nature. 2011 Jan 20;469(7330):289-91.

Bring on the biomarkers.

Poste G. Nature. 2011 Jan 13;469(7329):156-7

Common disease: are causative alleles common or rare?

Shields R (2011) PLoS Biol 9(1): e1001009. doi:10.1371/journal.pbio.1001009

New life for the HFEA?

Dyer C. BMJ. 2011 Jan 25;342:d439

Synthetic associations created by rare variants do not explain most GWAS results.

Wray NR, Purcell SM, Visscher PM (2011) PLoS Biol 9(1): e1000579. doi:10.1371/journal.pbio.1000579

Synthetic associations are unlikely to account for many common disease genome-wide association signals.

Anderson CA et al. (2011) PLoS Biol 9(1): e1000580. doi:10.1371/journal.pbio.1000580

The importance of synthetic associations will only be resolved empirically.

Goldstein DB (2011) PLoS Biol 9(1): e1001008. doi:10.1371/journal.pbio.1001008

RNA sequencing: advances, challenges and opportunities.

Ozsolak F, Milos PM. Nat Rev Genet. 2011 Feb;12(2):87-98.

Diagnosis and management of hereditary haemochromatosis.

Bokhoven MA, Deursen CT, Swinkels DW. BMJ. 2011 Jan 19;342:c7251.

New year, new science.

Van Noorden R, Ledford H, Mann A. Nature. 2011 Jan 6;469(7328):12.

Behavioural neuroscience: a gene for impulsivity.

http://www.nature.com/nature/journal/v468/n7327/full/4681049a.html

Synthetic biology: Division of logic labour.

Li B, You L. Nature. 2011 Jan 13;469(7329):171-2. 

Access to clinical trial data.

Chan AW. BMJ. 2011 Jan 12;342:d80. doi: 10.1136/bmj.d80. 

Research practice and participant preferences: the growing gulf.

Trinidad SB et al. Science. 2011 Jan 21;331(6015):287-8.

Human gene patents and genetic testing in Europe: a reappraisal

N Hawkins (2010) 7:3SCRIPTed 453.

Bad decisions for global health

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60066-4/fulltext

Systems biology and red cells.

Weatherall DJ. N Engl J Med. 2011 Jan 27;364(4):376-7.

PARP and cancer- if it's broke, don't fix it.

Carey LA, Sharpless NE. N Engl J Med. 2011 Jan 20;364(3):277-9.

read more ...