In the news

A new report from the European Science Foundation (ESF) has called for the creation of an EU-wide network of RNA research laboratories to maximise progress towards new therapeutics. 

ESF is an independent NGO that promotes collaborative research. Their new report RNA World: a new frontier in biomedical research features the increasing realisation of the pivotal role RNA plays in the regulation of gene expression via RNA interference (RNAi).
The report proposes a ‘virtual institute’ of linked, locally-funded multidisciplinary RNA research centres across Europe. It also sets out a 5-10 year vision of the field of RNA research in general and clinical applications, and identified priority areas for research, including studies of RNA transport, structure, splicing and interactions with proteins; epigenetics; development of bioinformatics capacity; creation of an RNA expression atlas; the role of RNA in bacterial infections; and development and delivery of RNA therapeutics. 

Whilst it may seem unhelpful to call for moves to be funded by individual countries and centres at a time when most budgets are under pressure, the ESF report is right to highlight the likely importance of RNA in genomic medicine of the future.

The charity Cancer Research UK (CRUK) has teamed with the Government’s Technology Strategy Board (TSB) to drive the use of stratified cancer medicine in the UK.

The TSB, which supports economically beneficial technological developments including in the area of healthcare, has said it will invest up to £50 million in a new Stratified Medicines Innovation Platform for the development of stratified medicine in the UK, including genetic analysis of tumours to inform treatment and care and the development of pharmacogenetic tests to predict responses to current or emerging drugs. 

CRUK’s parallel programme seeks to harness the benefits of genomic medicine to improve cancer diagnosis and management. It will work with selected NHS hospitals and laboratories, and companies Pfizer and Life Technologies, to improve genetic testing services and collect genetic data from patients with certain tumour types linked to information on outcomes to inform research. The aim is to expand the use of genetic analysis of tumours to inform patient care, including prognosis and treatment choices, and to drive the development of new drugs targeted to different tumour types and sub-types. 

The first babies have been born following the use of a technique called array comparative genomic hybridization (arrayCGH) as a genetic screen prior to in vitro fertilization (IVF). 

ArrayCGH is already being used for various forms of medical analysis such as diagnosis of genetic causes of learning disability; it uses DNA microarrays. More recently, the technique has been used to screen embryos (see previous news) and egg cells (oocytes) as part of the IVF process, to increase the chances of successful pregnancy. As many as two out of three embryos implanted into a woman’s womb may fail to yield a pregnancy due to chromosome abnormalities. 

The birth of twin girls in Germany and a boy in Italy have now been announced as the first from a pan-European pilot study, conducted by the European Society of Human Reproduction and Embryology (ESHRE). The study was a ‘proof-of-principle’ assessment of the utility of this screening method in increasing live birth rates following IVF treatment. A large-scale international clinical trial is expected to start in 2011. ArrayCGH oocyte screening is likely to be most useful where the rate of chromosomal abnormality is higher than average, such as in older women or those with a history of unsuccessful IVF. It may also be of particular importance in countries such as Germany where genetic analysis is permissible for egg cells but not embryos.

Proponents of UK science are becoming more vocal in the face of proposed Government plans to cap immigration and to cut funding for scientific research.

Concerns have been expressed about the prospect of a brain drain, with the best researchers potentially moving abroad if more funding is forthcoming for their projects in different countries. At the same time, a group of Nobel laureates have written an open letter to the Times newspaper protesting at Government plans to cap immigration to the UK as potentially damaging to the UK’s current pre-eminence in scientific research; they note that if premier league footballers can be granted exemptions from the normal visa process, why not star scientists too?   Professor Mike Stratton of the famous Wellcome Trust Sanger Institute has warned that if implemented, the measures would mean the loss of most of their experts from outside the European Economic Area (EEA) and seriously jeopardise the progress of key research projects.

The UK Science is Vital campaign (see previous news) has held a mass protest march in London to demonstrate against proposed funding cuts in science and engineering. 

The official announcement from the UK Government on the future of quangos has confirmed the rumoured abolition of a total of 192 public bodies, with a further 118 to be merged.  

These include as rumoured (see previous news) the Human Genetics Commission (HGC), Gene Therapy Advisory Committee (GTAC) and Genetics and Insurance Committee (GAIC), along with the Human Fertilisation and Embryology Authority (HFEA) and Human Tissue Authority (HTA) as announced in July 2010 (see previous news). The recommendation is that the HGC should be reconstituted as a Department of Health committee of experts, whilst the functions of the HFEA and HTA and various health related committees should transfer to regulatory bodies, including a proposed new research regulator. 

The effect of these changes is likely to hinge significantly on the nature and remit of regulatory functions as devolved between existing and new regulators. It is not clear that financial savings will be made in the short term, though the Government says the moves will increase transparency and accountability. However, the capacity of public bodies to examine issues relating to genetics and medicine will certainly be reduced.

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The US National Institutes of Health’s Roadmap Epigenomics Project has begun its first major release of data, Nature News reports.

The project aims to map and annotate the human epigenome, and to identify which particular epigenetic states – changes in the regulation of gene activity that are not dependent on DNA sequence - contribute to disease. The work is being carried out by a consortium of US research institutions that have divided the work of mapping four major forms of epigenetic gene regulation - DNA methylation, histone modifications, chromatin accessibility and RNA transcription - within three tissue types: stem cells, developing tissue, and adult tissues and cells.

The newly-published data maps hundreds of epigenetic changes in dozens of tissue types, and marks a significant milestone in the project, which is due to run for a further five years. The usefulness of the project in tackling disease has not gone unquestioned though; some are unconvinced by an approach that generates enormous amounts of data without reference to specific biological questions. However, the next phase of the project, and the bulk of its budget, provides grants to individual researchers who will use the data to investigate specific diseases.

The first clinical trial to use potentially therapeutic human embryonic stem (HES) cells in human subjects has begun in the US.

Patients with recent spinal cord injuries will receive injections of HES cells that have been ‘programmed’ to form new nerve cells. This procedure, from a company called Geron, has shown some success in animal models but has not previously been tested in humans. The main purpose of this first stage trial is to assess safety. The US Food and Drug Administration (FDA) licensed the trial, and Geron announced today that they have recruited their first patient. However, it will probably be some years before it is possible to determine how safe and effective the treatment is.

This trial follows soon after the news that the UK General Medical Council (GMC) has struck off a doctor for giving multiple sclerosis patients wholly unproven stem cell treatments, and further for using stem cells from a source not approved for use in humans. It must be highly frustrating for researchers in regenerative medicine working to create genuine treatments to see the promise of their work tarnished in public perception by proponents who may wildly exaggerate the degree or timescale of potential benefits, or even exploit vulnerable patients.

Meanwhile, as the legal wrangling over federal funding for HES cell research (see previous news) continues in the US, a new poll has shown that a majority of Americans support such research. This refers specifically to the use of surplus embryos left after in vitro fertilisation procedures for medical research, as opposed to commercial production of a therapeutic product, which might attract a slightly different view.

Sources: BBC news, The Telegraph, US News Health

The Nuffield Council on Bioethics has released a new report on personalised healthcare, calling for more action from the UK Government to help people use online health information and services safely and effectively.

The new report was informed by a major external consultation about issues including whether direct-to-consumer services such as genetic testing or body imaging were scientifically sound and if greater regulation was required (see PHG Foundation response). The working party behind the report sought to weigh up the benefits of information and personal freedom against potential harms

They report finds that online health services are convenient, they could ‘mislead, confuse or create unnecessary anxiety’ for users, and called for action to ensure that people were aware of the limitations – for example, of DNA profiling to accurately predict disease risk. One of the report authors noted: “People should be aware that other than prompting obvious healthy lifestyle choices…the tests are unlikely to inform them of any specific disease risks that can be significantly changed by their behaviour”.

Calls are made for more regulation, including the necessity for to provide evidence in support of their claims about tests and services, and an accreditation scheme for online health record providers. This would set standards for use, storage and confidentiality of personal information. One sensible measure proposed is that websites offering health information and advice should ‘state where the information originates and what it is based upon, who wrote it, and how the author or organisation is funded’, and make advertisements clearly distinguishable from other information.

However, increased regulation as suggested may prove impractical while the UK Government is actively reducing the number of regulators and oversight bodies, to make savings and improve efficiency. Meanwhile, a cautious approach for users remains advisable; whilst they are relatively unlikely to be harmed by the services on offer, the expenses may well outweigh the health benefits.

The Genomes Unzipped project (see previous news) is releasing personal genetic data from contributors – researchers and other genomics experts and commentators, who have had their genome scanned by personal genomics companies. 

They have chosen to make their genetic data publicly available, in an attempt to provoke useful discussion about the use and limitations of genomic information and to address common fears and concerns. The view at Genomes Unzipped is also that sharing data is a public benefit, necessary to further scientific and medical research, and that the benefits outweigh the potential personal harms.   Ultimately, they aim to publish whole personal genome sequences, along with a custom browser to let others make sense of their own genome data, and build an online community of interested individuals.  Meanwhile, in addition to blogging about genomics more widely, contributors will analyse and discuss their own results and reactions, and invite other experts to comment.

Dr Caroline Wright of the PHG Foundation, one of the Genomes Unzipped team, said that having her genome analysed had been “interesting, educational and worthwhile…But it hasn’t really been useful for my health”. She expects this experience to be quite common: “we shouldn’t expect to find hidden treasures in everyone’s genomes, nor skeletons in the cupboard”.  

The Structural Genomics Consortium (SGC) has just announced the release of its 1000th high-resolution protein structure.

The Consortium was formed in 2004 as an international non-for-profit partnership to determine the three-dimensional structures of medically relevant proteins. All research results are made available to the public domain without restriction on use and protein structures are deposited in the Protein Data Bank (PDB). The SGC's 180 scientists are based at the Universities of Oxford (UK) and Toronto (Canada) and Karolinska Institutet, Stockholm.

The 1000th structure, JmjD2C, belongs to a class of proteins involved in epigenetic signalling. It is known to play an important role in the maintenance of self renewal in stem cells and in cancer. Scientists believe that a better understanding of epigenetics will lead to discovery of novel treatments for a wide range of diseases.

The SGC adopted a systematic approach to solving of relevant protein structures by targeting entire protein families such as protein kinases, as well as potential drug target classes. In 2009, the SGC contributed nearly a third of all new human protein structures deposited in the Protein Data Bank (PDB), and a similar fraction of protein structures from pathogenic protozoa. Since its formation, the SGC has identified the key protein structures involved in all aspects of cellular function and linked them to diseases such as cancer, inflammation, diabetes, neurological disorders and infection.

Information generated by the Consortium provides a structural framework for the rational chemical design of new or improved drugs that can inhibit or enhance protein function. It proves to be a highly valuable resource to the entire biomedical research community and its research output is expected to have a great impact on human health.

Sources: Wellcome Trust press release, Structural Genomics Consortium

The US Secretary's Advisory Committee on Genetics, Health, and Society (SACGHS) of the National Institute of Health (NIH) has held its final meeting before closure.

Established more than ten years ago to advise the Secretary of Health and Human Services, SACGHS examined a wide range of topics relating to the use of genetic and genomic technologies for health, and their medical, social, ethical, legal and economic implications. The US Government reportedly considers that the body has now ‘fulfilled its mandate’.

The final meeting considered the implications of affordable whole-genome sequencing, noting that the current ‘$10,000 genome’ actually carries an additional ‘$100,000 interpretation’ price tag. The cost of data analysis and interpretation massively outweigh the expense of actual sequencing at present, as well as taking much longer to perform, and this is likely to be the key barrier to clinical implementation.

Other issues raised included what to do about incidental (that is, unexpected) findings of serious, minor or unknown health significance, the need for potentially lengthy consent procedures, and the challenges of  evaluating clinical validity and utility of sequencing data, providing workforce education and training, and addressing medical insurance and reimbursement issues.

The termination of SACGHS precludes a full investigation of the wide-ranging issues arising from the technological developments in DNA sequencing, but the PHG Foundation is already engaged in a programme to examine them in depth, with a particular focus on the implications for health care and society in the UK.

Sources: SACGHS meeting webcast, SACGHS website

 A new UK campaign has been launched to prevent ‘destructive levels of cuts to science funding’ amid widespread reductions in public spending.

The Science is Vital campaign has already attracted nearly 16,000 signatories from scientists and other supporters of scientific endeavour for their petition to the UK Government, calling for protected investment in science and engineering as a crucial element for future global competitive excellence and economic growth. Indeed, it is suggested that intellectual capital in these areas should form a major part of national economic outputs. Supporters of the campaign are also encouraged to join a protest rally in London and to lobby Parliament.

Clearly, scientists and engineers have a vested interest in preventing possible cuts to any sources of research funding; however, the argument that science is a crucial element for future economic growth is a sound one. This is not to say that money should not be spent wisely and to the best effect in science and technology, as in everything else, but in general there is a genuine danger that the UK’s current global pre-eminence could rapidly diminish – without an obvious replacement in economic output.

Sources: Science is Vital, Guardian news

The US National Institutes of Health (NIH) has announced that it is to scale-up its controversial National Children's Study with the opening of 30 new study locations in addition to the existing seven.

The goal of the study is to monitor the effects of the environment on the health of more than 100,000 children from before birth until age 21 in order to improve understanding of the role of these factors in disease.

At the study locations pregnant women, and those likely to become pregnant, will be asked to commit to a 21-year project that involves questionnaires, home visits from researchers, and the collection of samples ranging from blood and urine to house dust and parental toenail clippings. The study’s 28 proposed hypotheses aim to investigate such questions as whether prenatal infections are a risk factor for autism and the effect of low-level pesticide exposure on cognitive skills.

There has been controversy amongst politicians over both the study’s cost and design, which the NIH addressed with the removal of both the study director and the director of the National Institute of Child Health and Human Development (NICHD) last year. The acting director of the NICHD at the time, Susan Shurin, stated that some of the 28 hypotheses will likely be dropped in order to keep within budget.

Sources: Nature Blog, Nature News

Along with Brazil, China and the EU, India is often predicted to become a ‘science superpower’ at some point in the 21st century. This is because India currently fulfills key criteria with its large population, huge gross domestic product and strong economic growth. However, it also faces many serious challenges such as significant poverty and social inequality. Though sustained economic growth over more than a decade has helped India to become a leader in knowledge-based industries, it is yet to become a major force in global science, possibly due in part to inadequate investment by the government and industry,

Recently, to inspire the scientific community of India to strengthen science, the Prime Minister Dr Manmohan Singh (a graduate of both Cambridge and Oxford universities), released a vision document, India as a Global Leader in Science, prepared by the Scientific Advisory Council (see Science news). The document envisages India becoming a major scientific player in 20 years, on the condition that the right kind of structural and administrative reforms are made, and a favourable environment is created for carrying out such work in India.

With the recent economic boom in India, it is suggested that it would be feasible to provide the appropriate support for science and research by the large community of talented young Indian people. Though there are already well established institutions in India, educational reforms would be required and bureaucracy must be minimised to encourage creativity and quality, and create a congenial environment for science to proliferate.

The development of science in India (Indic civilisation) dates back to the origin of the Rig Veda, (1700–1100 BC) leading to milestones in mathematics, astronomy, cosmology and medicine. However, India has systematically failed to capitalise on basic research findings, as exemplified by the ‘Raman effect’ which was used by other countries to develop the Raman scanners. Now, this new effort by the Indian government to help India to contribute significantly to the world of science faces numerous challenges such as increasing scientific publications, claiming more intellectual property, training scientists and increasing science spending. Nevertheless this is a decisive step by the Indian government indicating their ambition to take India to a new level of excellence in science and technology. 

The 2010 Nobel Prize for Medicine has been awarded to Professor Robert Edwards for his work developing the technique in vitro fertilisation or IVF (see press release), which has reportedly led to the birth of around four million children conceived by this technique.

Not only has IVF made it possible for many previously childless couples to have biological children of their own, it has also allowed the subsequent development and application of preimplantation genetic diagnosis (PGD), allowing families affected by serious genetic diseases to have healthy children. The technique is also increasingly used in developed countries where the trend among women to delay childbearing into their thirties and forties means that natural fertility levels are lower and assisted conception is more likely to be needed, although the process is also less likely to be successful among older women.

New developments in the area include the advent of chromosomal egg screening (see previous news) and embryo screening for a range of genetic conditions (see previous news).

Although initially highly controversial, IVF is widely accepted in many countries today, although how far it should be publically funded as a health ‘need’ is sometimes the subject of debate.  Interestingly, many of the current ethical arguments surrounding human embryonic stem cell research centre on the creation and destruction of human embryos in vitro (i.e. in the laboratory), even for medical research or application; IVF typically involves the same process, since a number of embryos are created and a smaller number implanted; supernumerary ones are frequently destroyed or donated for stem cell research (see previous news). Whether public acceptance of stem cell therapeutics will increase over time as the benefits become more tangible and commonplace in medical practice remains to be seen.

Professor Edwards’ work on IVF was shared with gynaecological surgeon Dr Patrick Steptoe, but as the latter died many years ago he does not share the Nobel Prize, which cannot be awarded posthumously; similarly, Dr Rosalind Franklin did not share the Nobel Prize awarded to Francis Crick, James Watson and Maurice Wilkins in 1962 for the discovery of the structure of DNA (see Wikipedia).

Ultra high-throughput DNA sequencing strategies are already being used to study human genomes. The potential usefulness of such data for clinical practice is of great interest, and is the subject of a current PHG Foundation project. Early examples of how whole-genome sequencing (WGS) can be used for diagnosis and choice of therapy were recently presented at the Personal Genomes conference at Cold Spring Harbor Laboratory.

The case of a female patient with acute promyelocytic leukemia (APL) was presented. Most APL patients have a chromosomal translocation resulting in the fusion of the PML and RARA genes and production of  a PML-RARA fusion protein, which can be effectively targeted by a specific drug ATRA (all–trans retinoic acid).

Normal analysis of the patient in question did not reveal the presence of the translocation, so she was not treated with ATRA. However, rapid sequence analysis and comparison of tumour and control (skin) samples from this patient revealed a novel chromosomal change creating a PML-RARA fusion protein. The patient was then given treatment with ATRA, with good results; there are plans to sequence the genomes of other atypical cancer patients in the future.

Another centre presented the case of a man with a rare tumour, an adenocarcinoma of the tongue, for which no established treatment protocol existed [Jones SJ et al. (2010) Genome Biol. 11(8):R82.]. The genomes of the tumour and normal DNA from this patient were sequenced, and researchers then compared key genomic features of the cancer (such as somatic mutations, and copy number alterations, and gene expression data), with drug target information from the DrugBank database. They found that several genes encoding proteins targeted by a specific class of drugs were either amplified or highly expressed in the tumour. The patient was treated with these drugs and showed a good response.

Examples were also presented of the use of WGS in other types of serious disease to inform treatment, such as exome-sequencing of a child with a severe form of inflammatory bowel syndrome.

Despite the promise of these approaches, doctors were quick to point out that no therapy was selected based solely on the findings of genome sequencing, but the additional information was of value in some cases where standard diagnosis or treatment had not been successful. It is also important to note that, whilst the cost of whole genome sequencing continues to plummet, the analysis and interpretation of the data it produces to inform clinical management is a complex matter.

Despite amazing progress in the analysis of the genome, the role of as much as 95 percent of human DNA is still unclear; the genes or coding regions represent only a very small proportion of the total sequence. Some of the rest specifies the production of long non-coding RNA (ncRNA). Now a new study recently published in Cell sheds new light on the distribution of nc-RNA molecules, and suggests a potential role in the regulation of gene expression.

The researchers mapped the ncRNA sites within the genome using GENCODE, a database that annotates the human genome with currently available scientific evidence. They found 3,000 ncRNA sites within the genome and estimated that there could be a total of 10 to 12,000 such sequences in human DNA. Interestingly, this is comparable with about 20,000 genes known to encode proteins [Ørom UA et al. (2010) Cell 143(1):46-58].

The ncRNA sites were mostly in close proximity to genes critical for cell development and differentiation, and the long ncRNAs themselves were found to be present in a variety of cell types.  Depletion of a number of ncRNAs led to decreased expression of their neighbouring protein-coding genes, revealing a possible role for ncRNAs in regulating gene expression, acting as gene enhancer elements - short regions of DNA that can promote gene transcription. The concept of gene enhancers has been known for decades but there has been no consensus how they might work; improved understanding may reveal new therapeutic avenues for conditions such as cancer.

The results of this study add to the ever-growing body of evidence that the classic ‘central dogma’ of molecular biology is incomplete. This original dogma set out a unidirectional flow of information from DNA transcribed into RNA, then translated into proteins. In recent years, however, studies have shown that a significant portion of transcribed RNA molecules are not translated into proteins, but play various regulatory roles in the cell. 

Researchers set out to investigate possible genetic causes of otherwise unexplained male fertility problems by examining the NR5A1 gene, known to be involved in sexual development, in a group of men with unexplained low sperm counts seeking fertility treatment.

Of 315 men, seven were found to have mutations in NR5A1, whereas none of the control men (370 with at least two children and a further 359 with normal sperm counts) had any changes in the gene. 

Four of the men with NR5A1 mutations had altered levels of sex hormones and one had a minor structural abnormality of the testes. Functional studies showed that the mutations caused altered function of the NR5A1 protein, which regulates the expression of other genes.

The authors concluded that mutations in the NR5A1 gene account for approximately 4% of cases of unexplained male fertility, and propose that careful clinical investigation is necessary for men who do not produce sperm normally.

Comment: This is a useful contribution to the currently very limited knowledge about genetic factors underlying male fertility, although the authors' conclusion that 4% of all cases are caused by mutations in this specific gene seems rather sweeping, despite the absence of any mutations in the control population, given the relatively small sample size and the limited data available for comparison.

A similar study of women with fertility problems would be of interest, since the same gene is reportedly involved in female sexual development.

Sources: Bashamboo A et al. Am J Hum Genet. DOI: 10.1016/j.ajhg.2010.09.009, BBC news 

Preparing for a consumer-driven genomic age. Evans JP, Dale DC, Fomous C. N Engl J Med. 2010 Sep 16;363(12):1099-103.

Risks of Presymptomatic Direct-to-Consumer Genetic Testing.
Annes JP, Giovanni MA, Murray MF. N Engl J Med. 2010 Sep 16;363(12):1100-1.

Personalized investigation.
Dolgin E. Nat Med. 2010 Sep;16(9):953-5.

Ten years of genetics and genomics: what have we achieved and where are we heading?
Heard E et al. Nat Rev Genet. 2010 Oct;11(10):723-33.

Exclusion of genetic information from the medical record: ethical and medical dilemmas.
Klitzman R. JAMA. 2010 Sep 8;304(10):1120-1.

Screening student athletes for sickle cell trait - a social and clinical experiment.
Bonham VL, Dover GJ, Brody LC. N Engl J Med. 2010 Sep 9;363(11):997-9.

Advances in understanding cancer genomes through second-generation sequencing.
Meyerson M, Gabriel S, Getz G. Nat Rev Genet. 2010 Oct;11(10):685-96.

A question of benefit. Newborn screening
Nat Genet. 2010 Oct;42(10):811.

Infectious diseases not immune to genome-wide association.
de Bakker PI, Telenti A. Nat Genet. 2010 Sep;42(9):731-2.

Copy number variation in Parkinson's disease.
Toft M, Ross OA. Genome Med. 2010 Sep 6;2(9):62.

Global noncommunicable diseases - where worlds meet.
Narayan KM, Ali MK, Koplan JP. N Engl J Med. 2010 Sep 23;363(13):1196-8

Patent fixes for Europe.
Van Pottelsberghe de la Potterie B. Nature. 2010 Sep 23;467(7314):395.

Genetics: Exposing a DUX Tale
Mahadevan MS. Science 2010 Sep 24;329(5999):1607-1608.

GWAS identifies a common breast cancer risk allele among BRCA1 carriers.
Kraft P, Haiman CA. Nat Genet. 2010 Oct;42(10):819-20.

Gene therapy: Targeting β-thalassaemia.
Persons DA. Nature. 2010 Sep 16;467(7313):277-8.

Genomics: The long and the short of it.
Shadan S. Nature 2010 Sept 30;467:539.

Translating cancer research into targeted therapeutics.
De Bono JS, Ashworth A. Nature 2010 Sept 30;467:543-549.

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