Brendan Maher

Personal genomes: The case of the missing heritability

When scientists opened up the human genome, they expected to find the genetic components of common traits and diseases. But they were nowhere to be seen. Brendan Maher shines a light on six places where the missing loot could be stashed away.

Metrics: Do metrics matter?

Many researchers believe that quantitative metrics determine who gets hired and who gets promoted at their institutions. With an exclusive poll and interviews, Nature probes to what extent metrics are really used that way.

Exome sequencing takes centre stage in cancer profiling

To help battle their way through the stream of data coming in from human gene sequencing, major cancer-genome screening projects such as the International Cancer Genome Consortium (ICGC) seem to be choosing to simplify matters. The ICGC aims eventually to sequence the full genomes of 25,000 tumour samples as well as those of the people from whom the tumours were taken, which would give 50,000 distinct genomes. But in the near term, the project is doing targeted sequencing of just the 1% of the genome known to code for proteins — the ‘exons’ within genes. Sequencing of the ‘exome‘—all the exons in the genome—involves chopping the genome into millions of pieces and capturing and sequencing only selected DNA from exon regions. It differs from transcriptome sequencing by focusing on DNA rather than the expressed RNA in a given cell, and it promises to be vastly cheaper than whole-genome sequencing. It will be a significant focus of the ICGC, which comprises ten projects from nine member countries, says Tom Hudson of the Ontario Institute for Cancer Research in Toronto and a member of the ICGC secretariat. Last week, at the ‘Biology of Genomes’ meeting at Cold Spring Harbor Laboratory in New York state, some cancer researchers questioned whether exome sequencing is the most efficient way forward. They say it could represent a piecemeal half-step, and not provide a full picture of the mutations that lead to cancer. At the conference, Michael Stratton of the Wellcome Trust Sanger Institute in Cambridge, UK, presented early results from a study of 24 breast-cancer samples that analysed more than 2,000 chromosomal rearrangements, including regions in which vast tracts of DNA were duplicated, swapped between chromosomes, inverted or otherwise adulterated. With so many potentially deleterious rearrangements occurring in any given cancer cell, it becomes difficult to distinguish what Stratton calls the “driver” mutations, which spur and maintain cancer development, from “passenger” mutations that are just along for the ride. Drivers might be in the coding regions of the genome, but some will presumably be in regulatory elements and other non-coding BEIJING The Chinese Ministry of Health has implemented regulations on the clinical application of cutting-edge therapies such as stem-cell injections. Stem-cell scientists in China contacted by Nature hope that the rules may help to curtail a growing trade in unproven treatments that attract patients from around the world, risking their health and potentially damaging the reputation of stem-cell research. The new regulations, which came into effect on 1 May, designate all forms of stemcell therapy as ‘category 3’ medical technologies — those deemed “ethically problematic”, “high risk” or “still in need of clinical verification”. The ministry will take direct responsibility for regulating all category-3 procedures, which include gene therapy, surgical treatment of mental disorders or drug addiction, and sex changes. Institutions wishing to offer stem-cell therapies must first demonstrate safety and efficacy in clinical trials; the treatment will then be assessed by a ministry-approved regulator. Institutions failing that process must wait 12 months before reapplying. Although the penalties for not adhering to these rules have not been made explicit, institutions that transgress are likely to face fines or have their permit to practice medicine revoked, says Renzong Qiu, a bioethicist based at the Peking Union Medical College in Beijing. “These regulations will make people understand that the Ministry of Health and many scientists in China are concerned about these unverified procedures,” says Ching-Li Hu, a paediatrician and senior adviser to Shanghai Jiaotong University’s medical school, and a member of the International Bioethics Committee of the United Nations Educational, Scientific and Cultural Organization. Hu and Qiu are members of an expert panel that will deliver recommendations to the ministry later this year on how to implement the regulations effectively.

Malaria: The end of the beginning

After decades of work, a pioneering malaria vaccine may soon reach the final phase of clinical trials. In the first of two features on efforts against malaria, Brendan Maher reports on a vaccine that is far from perfect - but which may provide new direction and save thousands of lives.

Swine flu: One killer virus, three key questions.

As the world mobilizes against the H1N1 flu pandemic, researchers are working to answer pressing questions about the virus. Brendan Maher visited pathologists at the US Centers for Disease Control and Prevention who are looking at how the virus kills, and a New York laboratory that is testing how it spreads. Declan Butler spent time at a French biosafety level-4 facility where researchers are working out the chances that the pandemic virus will reassort with the H5N1 avian flu virus.

Research integrity: Sabotage!

Postdoc Vipul Bhrigu destroyed the experiments of a colleague in order to get ahead. It took a hidden camera to expose a surreptitious and malicious side of science.

Epidemiology: Fear in the dust

Cancer epidemics in Turkey could hold the secret to staving off a public health disaster in North Dakota.

Bird-flu research: The biosecurity oversight

The fight over mutant flu has thrown the spotlight on a little-known government body that oversees dual-use research. Some are asking if it was up to the task.

Malaria vaccine gets shot in the arm from tests.

agency, the CNRS in France, is now vetting not only non-European Union (EU) researchers working on sensitive topics, but also all scientists from Iran regardless of what they work on. Researchers allege that the move exacerbates an already difficult situation in which visa applications are denied based on nationality. A 12 November memo, relayed by the CNRS’s security office from the state national security and industrial espionage services, requires that all projects with Iran go through formal security screening, to identify ones potentially meriting further scrutiny. It translates UN sanctions that call for member states not to provide Iran with technical assistance or training that might be used for the proliferation of weapons of mass destruction, says Joseph Illand, who heads the CNRS security office. It’s the first case Illand can recall of such an explicit country-specific instruction at the CNRS — although similar, if unwritten, restrictions have in practice long been in effect for Iran and other countries considered as security risks. Given the threat of proliferation, such extra scrutiny is normal, he says. The rules expand on those introduced in January 2005, which require extra scrutiny for visits from non-EU scientists whose work relates to an undisclosed list of ‘sensitive’ laboratories or topics. In such cases, the heads of host laboratories must give details of proposed visits, and their opinion of the visitor, to security authorities. For lesssensitive laboratories, lab heads need only declare foreign visitors monthly, whereas no-risk labs must simply maintain an internal register that can be consulted by authorities if needed. In recent years, Iranian researchers have struggled for academic equality and scientific access. In July, for instance, the Netherlands banned Iranians from accessing nuclear laboratories or courses, and the United States has subjected Iranian visa requests to lengthy interagency reviews in the wake of the terrorist attacks of 11 September 2001. Britain last year also introduced tough vetting of non-EU science students. The fact that France is cracking down on Iranian researchers A long-anticipated candidate vaccine for malaria may be more than 50% effective at preventing the disease in African children, say results published this week in The New England Journal of Medicine. The work sets the scene for phase III clinical trials to start within the next few months. The vaccine, called RTS,S, has been in development for more than two decades, and earlier studies had suggested that it was effective at rates of little better than 30%. Yet even modest protection against malaria is deemed a success because of the disease’s deadly and endemic nature. But “there’s something quite important in getting beyond 50%”, says Kevin Marsh, director of the KEMRI–Wellcome research programme in Kilifi, Kenya. “It really strengthens the argument that it will be possible to develop something like a complete vaccine.” Malaria experts are impressed with the latest findings, which were also presented on 8 December at a meeting of the American Society of Tropical Medicine and Hygiene in New Orleans, Louisiana. “Overall, these show good progress with RTS,S,” says Adrian Hill, director of the Jenner Institute in Oxford, UK, who was not directly involved in the work. The results are from phase II trials conducted at three sites in western Africa by the vaccine developer GlaxoSmithKline (GSK) and a wide-ranging team of clinical, academic and non-profit funding partners. The next step will be phase III trials, which scale up the numbers treated. These will be funded largely by the Bill & Melinda Gates Foundation in Seattle, and will involve up to 16,000 children at 10 sites in 7 African countries (see map). In work described in one of the new papers, more than 800 children aged 5 to 17 months in Kenya and Tanzania received either the RTS,S vaccine or a rabies vaccine as a control. After an average follow-up of eight months, only 32 children in the RTS,S group had developed clinical malaria compared with 66 in the control group. That corresponds to roughly 53% efficacy. The trial tested a newer vaccine formulation that uses an adjuvant called AS01 to help stimulate an immune response. AS01 seems to trigger much stronger antibody responses in the body than the previous adjuvant used, but this still doesn’t translate into massive gains in protection against clinical malaria. Marsh, a co-author of the work, calls this disparity puzzling and frustrating, as complicated clinical trials such as these are the only way to get a good idea of efficacy. Part of the problem, Marsh says, is that “no one really knows how RTS,S works”. The other study, conducted in Bagamoyo, Tanzania, was smaller and was mainly concerned with the feasibility and safety of administering RTS,S with other vaccines. A group of 340 infants was given either RTS,S or the hepatitis B vaccine, together with routine vaccines for diphtheria, tetanus, pertussis and

Workplace violence: Caught on campus

lege student: there are selfies of her on a coastal holiday, or smirking mischievously after an experiment in hair colour. But in 2012, Bourque, then a criminology student at Simon Fraser University in British Columbia, told a classmate that she fantasized about killing a homeless person and that she was studying forensics so that she could get away with it. She also talked about killing her family pets and neighbourhood cats. The classmate told a teaching assistant what Bourque had said, and the department chair called campus security. This triggered a formal process called a threat assessment, in which security, university administrators and outside consultants gathered evidence and evaluated Bourque’s recent behaviour. They took the allegation seriously, says Stephen Hart, a forensic psychologist at Simon Fraser who advised on the case. “Often something like this is a cry for help,” he says. But her actions on several occasions suggested that she might pose a threat to other students, so simply referring her to the university’s outpatient mental-health services would not suffice. The team notified the local police, and told Bourque that she would not be CAUGHT ON CAMPUS