Hot off the presses! Apr 15 Nature

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Latest Articles Include:

• Testing time for gene patents
  - Nature 464(7291):957 (2010)
  A surprising US court decision highlights the need to modernize gene-patenting practices if patients are to benefit from advances in genetic research.
• Winners take all
  - Nature 464(7291):957 (2010)
  Scientific competition is lacking in Japan, and efforts to increase it are not always best focused.
• Welcome Nature Communications
  - Nature 464(7291):958 (2010)
  Since the launch of Nature Genetics in 1992, the number of Nature research journals has grown to 16 — the most recent, Nature Chemistry, was launched a year ago. This month sees the launch of the seventeenth: Nature Communications. All of the previous Nature research journals have focused on a particular discipline or community of research interests. Their aim is to publish the most original and scientifically impact-making research appropriate to those particular audiences. Their high ranking in the citation league tables would suggest that this goal is generally being fulfilled. Nature Communications differs in being multidisciplinary. It aims not to compete with the established Nature journals, but to publish rigorous and comprehensive papers that represent advances of significance to specialists within each field. In addition, it welcomes submissions in fields that are not represented by a dedicated Nature research journal — for example, developmental biology, plant science, microbiology, ecology and evolution, palaeontology, astronomy and high-energy physics (see http://go.nature.com/xJzuY5). Readers will find in the launch issue papers on topics including classical and quantum correlations under decoherence; a candidate gene for mechanoreception in Drosophila sensory cilia; a strategy to obtain sequence-regulated vinyl copolymers using metal-catalysed step-growth radical polymerization; how a ritualized vibratory signal evolved from locomotion in territorial caterpillars; and more besides. Like all Nature journals, it is editorially independent. It is also the first Nature research journal to be funded in hybrid fashion: by both subscriptions and optional authors' fees that allow instant free access to their published papers. (It is our publishers' policy to keep subscription rates of hybrid journals under review to reflect the volume of content that is behind the subscription firewall.) Furthermore, it is the first Nature journal to be launched entirely without a print edition: its content is available only online. Nature welcomes this distinctive new sibling publication — this time, serving the whole research community.
• Animal behaviour: Behind enemy lines
  - Nature 464(7291):960 (2010)
  
• Pathology: Bent out of shape
  - Nature 464(7291):960 (2010)
  
• Nanotechnology: Down the tube
  - Nature 464(7291):960 (2010)
  
• Planetary science: Venus vents
  - Nature 464(7291):960 (2010)
  
• Neuroscience: Stressing memory
  - Nature 464(7291):960 (2010)
  
• Physics: Monopoles on demand
  - Nature 464(7291):960 (2010)
  
• Oceanography: Early bloomers
  - Nature 464(7291):961 (2010)
  
• Behavioural genetics: South bee-ch diet
  - Nature 464(7291):961 (2010)
  
• Seismology: On shaky ground
  - Nature 464(7291):961 (2010)
  
• Astrophysics: The odd couple
  - Nature 464(7291):961 (2010)
  
• Journal club
  - Nature 464(7291):961 (2010)
  
• News briefing: 15 April 2010
  - Nature 464(7291):962 (2010)
  The week in science. This article is best viewed as a PDF. Research|Business|Events|Policy|Funding watch|The week ahead|Number crunch|Sound bites Four and a half years after a launch failure saw its first incarnation splash into the Arctic Ocean, the European Space Agency's ice-measuring CryoSat-2 has successfully made it into orbit. Launched from the Baikonur Cosmodrome in Kazakhstan on 8 April, the space probe will monitor variations in the extent and thickness of polar ice. The information it provides about the behaviour of coastal glaciers that drain thinning ice sheets will be key to better predictions of future sea-level rise (see also Nature 464, 658; 2010). After examining some 400 studies published since 2005, the US Institute of Medicine said in a report released on 9 April that a complex of symptoms including joint pain and fatigue, popularly known as Gulf War syndrome, is associated (but not necessarily causally) with service in the Gulf War. The 12 authors called for further research refining the diagnosis and developing treatments for Gulf War syndrome — which it dubs "multisymptom illness". Of nearly 700,000 US personnel who were deployed to the Gulf region, more than 250,000 suffer from persistent, unexplained symptoms. The deepest underwater hydrothermal vents ever found have been spotted by a robot exploring waters off the Cayman Islands in the Caribbean. The black smokers are 5 kilometres down in the Cayman Trough, more than 900 metres deeper than previously known. The vents consist of spires of copper and iron ores erupting superheated water from the sea floor, at temperatures hot enough to melt lead. Scientists from the University of Southampton, UK, who are leading the Cayman expedition on the research ship RRS James Cook, announced the find on 11 April. A new superheavy element with atomic number 117 has been synthesized at Russia's Joint Institute for Nuclear Research in Dubna, an international team of researchers announced on 6 April (Y. T. Oganessian et al. Phys. Rev. Lett. 104, 142502; 2010). Six atoms of 'ununseptium' (the element's temporary name) were made by smashing calcium-48 into a berkelium-249 target that was made at Oak Ridge National Laboratory, Tennessee. The US wind-energy industry installed more than 10 gigawatts (GW) of new wind-power-generating capacity in 2009, bringing the total capacity (all onshore) to some 35 GW — about 1.8% of the country's electricity generation. Texas has installed the largest capacity (9.4 GW), whereas Iowa is the state most reliant on wind energy: its 3.7 GW generated 14.2% of its electricity last year. The figures come from a report released on 8 April by the American Wind Energy Association, an industry group based in Washington DC. An inadequate transmission grid threatens further expansion of the industry, the report said. Two large producers of scientific software, Accelrys and Symyx Technologies, will merge, the firms announced on 5 April. Symyx, headquartered in Santa Clara, California, produces electronic laboratory notebooks and chemical informatics software. Accelrys, headquartered in San Diego, California, offers modelling and simulation software. The combined firm will be based in San Diego. R. BECK/AFP/GETTY A rally in defence of scientists who use animals in research drew between 300 and 400 supporters at the campus of the University of California, Los Angeles (UCLA) on 8 April. Organized by the group Pro-Test for Science — founded by UCLA neuroscientist David Jentsch — it follows a similar rally in 2009. Since Pro-Test has begun confronting anti-research protesters on campus and organizing dialogue with peaceful groups who oppose animal research, animal-rights activists have stepped down attacks on UCLA researchers, Jentsch says. "They still come to my house and scream obscenities at me. But the most important objective has been achieved, which is that nothing has been burned or blown up." See go.nature.com/54MVKO for more. The council of the UK's Royal Institution successfully fought off a coup attempt this week. Members of the UK's oldest scientific research organization, founded in 1799, overwhelmingly rejected proposals put to a special general meeting that the entire governing council, bar the president, be removed. The move was sparked by a group of members lamenting the removal in January of former director Susan Greenfield, a high-profile neuroscientist at the University of Oxford, and the multimillion pound funding shortfall that prompted the redundancy. Nuclear-weapons research could benefit from the US Nuclear Posture Review. The policy, unveiled on 6 April ahead of both an agreement signed with Russia on 8 April to reduce nuclear stockpiles and a nuclear-security summit in Washington DC this week, tempers the threat of nuclear attacks against other countries and repeats that no new nuclear weapons will be built. But it may also boost basic research at national-security laboratories. See page 965 for more. At the latest round of United Nations climate talks last week in Bonn, Germany, delegates from 175 nations failed to break the impasse in international climate diplomacy. Delegates agreed to hold two additional meetings before the next UN climate summit in late autumn in Cancun, Mexico. Even so, prospects are "slim" that a new climate agreement can be reached by the end of the year, Yvo de Boer, head of the UN's Framework Convention on Climate Change, told the meeting on 11 April. Demissie Habte The Ethiopian Academy of Sciences (EAS) was launched on 10 April in Addis Ababa. A growing number of African countries — most recently, Zambia, Mauritius and Mozambique — are establishing such organizations to promote research quality and offer scientific advice. The EAS starts with 50 fellows from both the natural and social sciences; its elected president is Demissie Habte (pictured right), former dean of medical research at Addis Ababa University. Its funding structure is not yet clear, but the founders hope the government will support the body. See go.nature.com/K6tBzV for more. A US government report has found "significant weaknesses" in the inspection of domestic food facilities by the Food and Drug Administration (FDA). The agency has also failed to take adequate regulatory action against some facilities, said the report, released on 6 April by the Office of Inspector General for the Department of Health and Human Services, the FDA's parent agency. Legislation that would boost the FDA's food-safety inspection powers has stalled in the Senate. The FDA says it had already addressed many of the issues in the report, which covered 2004–07. A call for more research funding for the US National Institutes of Health (NIH) in Bethesda, Maryland, shows how much the agency has relied on the national stimulus package to boost its spending power. The Federation of American Societies for Experimental Biology (FASEB) — an advocacy group based in Bethesda that represents 23 biomedical societies — has published trends summarizing how the NIH's budget has been falling in real terms since 2004, taking into account the rate of inflation for biomedical-research costs (see chart). SOURCE: FASEB The stimulus bonanza brought the NIH's budget up to US$36.4 billion in 2010 (above that of 2004, in real terms). US President Barack Obama's 2011 budget request (see Nature 463, 594–595; 2010) boosted the agency's basic budget by $1 billion to about $32 billion — an increase of 3.2%. But with no stimulus, that represents a 14.3% decrease from the 2010 purchasing power of the NIH. FASEB calculates that the total number of research-project grants that the NIH will be able to support may drop from 39,579 in 2010 to 35,202 next year. The federation also expressed concern that the NIH's assumption used for that calculation — a 1.4% rise in average research-grant costs — is too low. Fearing the looming cliff of the post-stimulus sag, the group recommends that Congress appropriate $37 billion for the agency in 2011. Studying the genomes of individual cancer types is a hot topic at the American Association for Cancer Research's 101st annual meeting, in Washington DC. → go.nature.com/IDRmCV The World People's Conference on Climate Change and the Rights of Mother Earth is held in Cochabamba, Bolivia. The country's president, Evo Morales, announced the summit, which expects thousands of attendees, after the failure of talks in Copenhagen. → http://pwccc.wordpress.com New ways of measuring biological diversity — and of conserving it — will be discussed at the Royal Society in London. → go.nature.com/eqb5BD Barcelona, Spain, hosts the first ever European Energy Conference — an interdisciplinary meeting focused on energy technology research. → www.e2c-2010.org Source: American Association of University Professors survey, 12 April Raja Ram Chhatkuli, director general of Nepal's survey department, confirms that China and Nepal have agreed to disagree over Mount Everest's exact height. Source: Reuters There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Lab-animal battle reaches truce
  - Nature 464(7291):964 (2010)
  Biomedical scientists say revised European directive on animal welfare averts feared disaster for research. A minimum cage size for research animals is one factor addressed in proposed EU legislation.G. ROBERTSON/EYEVINE After more than a decade of pitched battles between research advocates and animal-rights campaigners, European Union (EU) legislators have finally agreed on a new legal framework to regulate the use of animals in research. A closed-door meeting between representatives of the European Commission, the European Parliament and the European Council (respectively, the EU's executive and two legis­lative bodies) reached a compromise on a directive covering the protection of animals used for scientific purposes (86/609/EEC) on 7 April. The directive must still be ratified by the parliament and council, but this is likely to happen without further debate by July. Previous drafts of the directive had seemed set to severely hamper European biomedical research, by placing significant restrictions on invasive studies using primates, for example (see Nature 456, 281–282; 2008). But the final directive has largely diffused scientists' concerns. Basic research using primates will now be allowed, for example, and animals will not have to be destroyed immediately after research procedures that cause "moderate" discomfort, as previous forms of the directive had decreed. Instead, the animals can be used in other procedures. At the same time, the draft addresses concerns about animal welfare by introducing minimum cage sizes and other measures. "It is a political document, a compromise text," says Stefan Treue, director of the German Primate Centre in Göttingen. "But it could have been worse and we can live with it." "The compromise that has been reached is something we can live with." "The compromise that has been reached is something we can live with," agrees Kirsty Reid of the Brussels-based animal-welfare lobby group Eurogroup for Animals, adding that she still regrets the many exemptions to bans on several types of research. The legislation was designed to update 1986 rules for protecting research animals and to harmonize regulations across the EU. Political discussions began in 1998, and in 2002 the European Parliament mandated the commission to write a draft also taking into account the EU's new commitment to the reduction, replacement and refinement of animal tests. The commission draft that eventually emerged in November 2008 alarmed both academic researchers and the pharmaceutical industry by proposing extreme restrictions on research and increasing bureaucratic demands on researchers. For example, it banned research on non-human primates unless it was directly applicable to the treatment of "life-threatening or debilitating human conditions", thus blocking basic research, particularly on the brain. Its scope was so broad that it forbade the scientific use of hens' eggs, essential for vaccine production. And in insisting that animals be destroyed after an experiment causing mild discomfort, it would have dramatically increased the number of animals used in research. "That draft was a big wake-up call to the scientific community, which didn't lobby enough at the right time," says Simon Festing, chief executive of the London-based research lobby group Understanding Animal Research. Instead, he claims, the commission was exposed to the emotionally powerful influence of the well-organized animal-welfare and anti-vivisection lobby. But in 2009, research organizations swung into action to persuade parliament to be more sympathetic to their point of view. In its first parliamentary reading in May 2009, most of the controversial restrictions in the draft directive had been removed (see Nature 459, 139; 2009). But the new parliament added a clause of its own, requiring sharing of data generated on animals. Drug-development companies pointed out that this would be difficult for them to comply with, given that much of this information is proprietary intellectual property. The battle continued through 2009 as the amended draft was discussed by the European Council, which comprises representatives of the EU's 27 member states, many of which considered it too liberal towards researchers. After a new parliament was elected last June, the animal-welfare lobby pounced on new members, convincing many to argue for further restrictions, says Julian Böcker, parliamentary assistant to directive rapporteur Elisabeth Jeggle. "I'd like to be able to convey just how hard we had to fight to maintain research-friendliness in the directive," says Böcker. Endangered experiments The outcome is less than perfect, but at least animal research will be possible, says an administrator at the DFG, Germany's largest grant-giving agency. The directive does ban some forms of research — those involving great apes or causing extreme and prolonged pain. But researchers can appeal for an exemption, on grounds of clinical urgency, through a special committee to be set up in Brussels. The final draft of the directive also allows experiments on endangered species, such as the barn owl (Tyto alba), which is bred in captivity specifically for auditory research. Pro­cedures for project applications and evaluations are more streamlined than in earlier drafts, and the bureaucratic burden should not increase for researchers from countries in which rules are already strict, such as Britain, Germany and France. Mandatory sharing of animal-research data has also been dropped. But some scientists are still worried that problems could arise when the loosely worded directive is translated into more tightly worded national laws, which will have to specify, for example, which types of experiment are considered to cause "long-lasting, severe pain". Others maintain that an outright ban on some types of studies clashes with Europe's constitutional duty to carry out research, as enshrined in the Lisbon Treaty, adopted in December 2009. And physiologist Rainer Nobiling of the University of Heidelberg in Germany worries that restrictions on the use of non-human primates might encourage more testing of experimental therapies in humans, against the Nuremberg code of research ethics. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• US nuclear policy could boost basic research
  - Nature 464(7291):965 (2010)
  National laboratories to see funding increases. The National Ignition Facility is part of the US push to modernize its nuclear infrastructure.LLNL US President Barack Obama's nuclear-weapons policy represents a delicate compromise that could limit research on new warheads but bolster the workforce of scientists at the national security laboratories. The balancing act came into sharp focus in the 2010 Nuclear Posture Review (NPR), publicly released last week. The policy downplays the role of nuclear weapons in US foreign policy and formally abandons efforts to build new warheads. But the language contains loopholes that could allow most nuclear-weapons design work at the laboratories, Los Alamos and Sandia in New Mexico, and Lawrence Livermore in California, to continue unfettered. The NPR also emphasizes the need to modernize nuclear infrastructure (see 'Laser-fusion showdown') and maintain and expand scientific expertise at the weapons labs. The National Nuclear Security Administration, which manages the nuclear-weapons programme, employs thousands of scientists and engineers at these labs and draws recruits from fields such as astrophysics. The document follows up the president's fiscal 2011 budget, which would boost weapons and non-proliferation spending by more than 13%, to US$11.2 billion. Many experts see the administration's moves as an effort to please the leadership at the weapons labs. "The administration needs to work with the lab directors very closely to make sure they are happy," says Stephen Young, a nuclear expert with the Union of Concerned Scientists in Washington DC. Obama will need their support as he tries to finally win Senate approval of the 1996 Comprehensive Nuclear-Test-Ban Treaty outlawing all nuclear testing. "The large budget increases for the labs are a principal demonstration of that fact," says Young. Obama unveiled his international agenda on nuclear security and non-proliferation a year ago in Prague, recommitting the United States "to seek the peace and security of a world without nuclear weapons". On 8 April, two days after releasing the NPR, Obama signed a new arms-reduction treaty with Russia, reducing the cap on deployed weapons from 2,200 to 1,550 per country over the next seven years. He followed that up earlier this week by hosting a two-day summit in Washington DC to discuss broader nuclear-security issues. William Press, a physicist who is on the president's science advisory board and who formerly served as deputy director for science and technology at the Los Alamos lab, supports the general thrust of the new weapons policy but regrets that the NPR doesn't make clear what kind of work will be allowed at the labs. For example, although modifying nuclear components in a weapon would require authorization from the president and Congress, Press says that one loophole would allow the labs to build weapons that are in many respects 'new' by mixing and matching components that have been tested in the past. Although this may satisfy lab directors who are concerned about maintaining the skills of weapons designers, Press is worried about these loopholes and says that they deserve broader discussion. Nonetheless, Press supports the additional funding for nuclear-weapons research. "The labs have been starved in a way that is not healthy," he says. The extra money, he adds, will benefit the full suite of US scientific work — from climate and materials sciences to all manner of computational and simulation expertise — that underpins the nuclear programme and provides it with new talent. William Rees, who manages non-proliferation programmes as principal associate director for Global Security at Los Alamos National Laboratory, says that the lab needs to ensure a broad scientific base as an entry point for new recruits. Initially, these researchers might start work at the lab in its non-weapons programmes, such as projects in studying greenhouse-gas emissions and seismology. Some of those may then move into the weapons programme. Rees says there are no guarantees that Congress will agree to the budget boost or that those numbers will be sustained in future years. He adds, however, that "we are cautiously optimistic". This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Japan rolls out elite science funds
  - Nature 464(7291):966 (2010)
  FIRST scheme targets large grants to world-leading researchers. Akira Tonomura has received ¥5 billion to build his dream microscope.D. CYRANOSKI Physicist Akira Tonomura struggled for seven years to raise funding for his dream project: developing a microscope able to image three-dimensional arrays of atoms in unprecedented detail. Last March, with little hope of finding this financial support, he even considered retiring from his research fellowship at the Hitachi Advanced Research Laboratory in Hatoyama, Japan. Then, last month, the Japanese government awarded him ¥5 billion (US$53.6 million) — the biggest grant for an individual research project in the country's history. Tonomura has already set to work on creating his ultra-high-voltage holographic electron microscope, which will measure the phase of electrons scattering off a sample, rather than their intensity, as in conventional electron microscopes. These phase measurements can produce an image with much higher resolution. Tonomura was one of 30 scientists to win a grant from the ¥100-billion Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST). The awards, announced on 9 March after a rollercoaster six months that saw the programme cut drastically, mark a major shift in the landscape of Japanese science funding. At between ¥1.8 billion and 5 billion per project, many of the grants are more than double the size of the largest from the Japan Science and Technology Agency, which until now offered the country's most presti­gious and generous funding awards. And unlike conventional grants in Japan, FIRST awards give researchers the freedom to spend their grant money at any time during the grant's four-year period. Funding shift In general, FIRST's 30 grants are targeted towards areas in which Japan is already a world leader, such as microscopy, stem-cell research and electronics. Tonomura, one of only two scientists to receive the largest possible FIRST grant of ¥5 billion, pioneered electron holography in the 1960s. The other big winnner is Kyoto University's Shinya Yamanaka, who wowed the world of stem-cell research in 2006 with his group's creation of induced pluri­potent stem cells. Click to enlarge. The awards also mark the latest chapter in Japan's effort to spend a greater proportion of its overall research budget on competitive grants (see 'Getting competitive'), a process that seems to be putting bigger chunks of money into the hands of fewer scientists. It is not yet clear how this shift is affecting the scientific community, says Atsushi Sunami, a science-policy expert at the National Graduate Institute for Policy Studies in Tokyo. However, many scientists in Japan have been privately critical of the heavy concentration of funds, which they believe could be better spent on a larger number of smaller, focused research projects. Part of the motivation for the shift in funding was the perception that other countries were benefiting from greater investment in competitive grants. Earlier efforts to direct funding into large competitive grants included a centres of excellence programme rolled out in 2002 (see Nature 419, 547; 2002) and the World Premier International Research Centers that were created in 2007 (see Nature 447, 362–363; 2007). At the same time, organizational reforms in 2004 saw basic operating budgets for universities and research institutes pared down by 1% per year. At the University of Tokyo, for example, these operating budgets accounted for 46% of total income in 2004; this shrank to 40% by 2009. However, that decrease was balanced by a growth in competitive funding over the same period, upping its contribution to the university's income from 30% to 35%. That proportion is sure to grow: the university has won funding for five FIRST projects, bringing in an extra ¥17.6 billion. Scientists at the university are wasting no time. Although his FIRST funding cheque had yet to arrive, Yoshinori Tokura held a retreat on 30 March for core members of his ¥3.1-billion study on correlated electrons. The group hopes that controlling the interactions between electrons — based on characteristics such as charge and spin — could help to develop materials useful for energy-efficient electronics, high-temperature superconductors and new types of battery. Meanwhile, Shizuo Akira of Osaka University has already started spending his ¥2.5-billion FIRST grant, which he says will give him the freedom to "do some gambling" at the frontiers of immunology. Akira — the most cited scientist in the world in 2005–06 and 2006–07, according to academic data-provider Thomson Scientific — hopes to create a comprehensive picture of the immunological mechanisms involved in eliminating pathogens and cancer cells, and to then try to control those mechanisms. He has already hired postdocs and technicians, and has ordered a two-photon microscope, an electron microscope, mass-spectrometry equipment and DNA-sequencing machines. Not so bold Despite the air of excitement that the awards have generated, some scientists point out that the FIRST grants were supposed to be bigger, and the projects bolder. In June 2009, the Council for Science and Technology Policy under the then-ruling Liberal Democratic Party announced that FIRST would distribute ¥270 billion. Council members had already selected the 30 recipients before the Democratic Party of Japan came to power. "I want to create a history-making instrument." The new government promised to re-evaluate all large spending programmes (see Nature 461, 854–855; 2009), eventually slashing the budget and capping the largest projects at ¥5 billion. Some scientists had hoped to get considerably more: Yamanaka, for example, originally applied for ¥15 billion. All of the grantees then had to reapply for their funding with scaled-back projects. "Every strategic research plan was shrunk and every brave enterprise was cut," says Tokura. Yamanaka, for example, has dropped plans to carry out preclinical trials with induced pluripotent stem cells for diabetes and other diseases. Tonomura, meanwhile, says that his FIRST grant will still leave him ¥2 billion short of what his project requires, an amount he hopes to persuade Hitachi to chip in. But with the money he already has in hand, he has no immediate plans to retire: "I want to create a history-making instrument," he says. There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Stem-cell funding in sight
  - Nature 464(7291):967 (2010)
  Most popular cell lines close to approval for US federal funding. Two of the most widely used embryonic stem (ES) cell lines could be just weeks away from being eligible for US federal funding. The lines, which were approved under the administration of former president George W. Bush, have spent months in limbo pending the go-ahead from the current administration of President Barack Obama. Researchers' frustrations are boiling over at the amount of time lost because of the delays. "The stem-cell community has really been jerked around," says Julie Baker, an associate professor of genetics at Stanford University, California. The two key cell lines — known as H9 and H7 — that Baker and others are desperate to see approved were derived more than a decade ago and are owned by the WiCell Research Institute in Madison, Wisconsin. According to a stem-cell registry maintained by the University of Massachusetts Medical School in Worcester, H9 has led to 551 publications, and H7 has been used in 133 reports — an order of magnitude more than any of the other 19 Bush-era lines, with the exception of another heavily used WiCell line called H1, which was approved for federal funding in January. Under guidelines announced in July 2009 by the US National Institutes of Health (NIH) in Bethesda, Maryland, ES cell lines must meet extensive informed-consent conditions before research using the cells can be funded. Whereas the NIH has approved 51 ES cell lines for federal funding since December 2009, H1 is the only Bush-era line to win the agency's approval so far. "The H7 [and] H9 submission is still in draft and has not been submitted to the NIH," says NIH spokesman John Burklow, adding that the agency has contacted all of the Bush-era line holders and offered technical assistance in preparing their submissions. "The NIH does recognize that these lines are important to many NIH-funded researchers now and in the future." Erik Forsberg, executive director of WiCell, says that he expects approval "in the next month or so" for four outstanding WiCell lines, including H7 and H9. "We are extraordinarily close to getting all the documents that we anticipate are needed for approval," he says. But scientists are still concerned that there could be further hitches. "With the Obama administration, we thought things were going to get better, and this is almost worse," says Baker. "If they don't approve these lines, we have to go backwards." It's crucial that the lines held by WiCell are approved, adds Joseph Itskovitz-Eldor, a stem-cell expert at the Technion-Israel Institute of Technology in Haifa, who helped to derive the four H-lines held by WiCell using donated Israeli embryos. "They are being used so widely. To switch to other cell lines is going to be time-consuming and costly." Gathering the paperwork needed for the NIH application has been slowed by translation requirements (the original documents are in Hebrew) and other problems. One donating couple had not been informed that the lines could be used commercially and that they would not benefit financially — requirements that are spelled out in the NIH guidelines. Itskovitz-Eldor e-mailed patient re-consent forms, and institutional review board approvals for them, to WiCell on 8 April. "At this point, we have completed our part. But I am sure that more documents will be needed. The whole process may take some weeks or maybe more," he says. ADVERTISEMENT The hoped-for approval can't come soon enough for Baker, who almost exclusively uses H9 in her lab. "The one that's really easy to produce in the lab, which grows well, is H9. That's why all the publications use it," she says. In early March, Baker submitted an NIH grant application to use H9 to examine how ES cells use cell signalling to form endoderm, which gives rise to many internal tissues. If H9 is not approved soon, she plans to write to reviewers and suggest that she switch to using H1. But that would require extra work to extrapolate data she has already generated in "extremely expensive" H9 experiments to H1. Even if the four outstanding WiCell lines are approved, that still leaves 16 Bush-era lines unapproved. "Obama made his announcement over a year ago and right now there is only one of the [formerly approved] lines on the federal registry," says Tim Kamp, the director of the Stem Cell and Regenerative Medicine Center at the University of Wisconsin–Madison. "Is it going to take another two months? Another year? We just don't know." There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• What it will take to feed the world
  - Nature 464(7291):969 (2010)
  Nature talks to the chief executive of France's national agricultural institute. HAMILTON/REA Marion Guillou is the chief executive of France's National Institute for Agricultural Research, Europe's largest agricultural-research agency. She talks to Declan Butler about how researchers are trying to meet the challenge of feeding a world population that is estimated to grow to 9 billion people by 2050. The conference showed that agricultural researchers are mobilized and recognize themselves as a global community. At the same time, there is strong tension between the CGIAR [Consultative Group on International Agricultural Research] international research centres and the global agricultural research community. The centres tend to be too closed to those outside, and there is pressure to open them up to national and other agricultural research bodies. Developing countries at the conference also sent a strong message about the return in strength of family farms; that making these more productive is key to both alleviating poverty and meeting local and global food demand. It's a new political message: count on and help small farms. The international focus has long been on large-scale industrial farming, so this changes quite a few things. The themes of research for smallholdings are very different from those of large-scale farming, involving, for example, concepts such as crop rotation, complements of animals and plants, and the use of animal waste as fertilizer, so the research questions are not the same. The first priority is to fight loss and waste. We lose as much as 30 to 35% of the world's food output. That gives us a large margin of manoeuvre to increase the food available. We are doing research with food processors and distributors to explore solutions. We certainly won't be able solve the problem, but we can improve it. Diet will also be a major determinant in our capacity to nourish the world [animal products require considerably more energy and land than plants]. We need to ensure food availability of 3,000 kilocalories a day per person, of which only 500 kilocalories is from animal products — we are not trying to transform everyone into vegetarians. This provides a healthy and satisfying diet, but is far from a typical Western diet. If we continue the current dietary regime typical of OECD [Organisation for Economic Co-operation and Development] countries, and if many other countries follow us on this trajectory, we will not have the same results in terms of food availability as we would with a more moderate diet worldwide. One really big research area is studying the volatility of prices. It is the main problem. Remember the food riots in several countries in 2008? We are still trying to understand what happened, but much of it was because of financial speculation. We already have enough food to feed everyone on the planet at 3,000 kilocalories per day, but it is a question of price. We need research to find out which economic tools are available to stabilize prices at the international level, and to ensure, for example, adequate available reserves of cereal. We need to propose economic solutions, and regulation of markets of agricultural foodstuffs to avoid the yo-yo whereby prices can go so high that people do not have access to food. We also have to guarantee minimum prices if farming is to remain viable. It's clear that genetic progress in the past in France and other rich countries accounted for much of the increase in production, so genetics is far from passé; it's still the number-one technique for increasing yields, for example. For Africa to improve its yields, we clearly need new genetically selected varieties, engineered by either genetic modification or classic breeding techniques. For me, GMOs are not a magic bullet, but we should not refuse them a priori. It's critical to look at GMOs on a case-by-case basis. The first generation of genetically modified organisms on the market is not the one that will solve Africa's problems, although one crop, a Chinese GMO cotton that is resistant to bollworm, has proved extremely useful to the population, because it avoids the spraying of dangerous pesticides — the risk–benefit equation is clearly in favour of its use. ADVERTISEMENT We are now at a stage where we have years of extensive research results on the ecological, economic and health aspects of many GMOs. There are GMOs for which the assessment is undisputedly positive, but there are others — in particular some crops engineered to be resistant to this or that herbicide — for which this is not so. For example, some GMOs result in increased use of herbicides, which can lead to concentration of these chemicals in the environment and negative effects. The results are mixed — that's why it is important not to speak of GMOs in general, but case-by-case. Pest resistance is a really promising and important application for genetic selection because there are a lot of health problems in developing countries that have been linked to the spraying of pesticides. We need to continue to innovate and reinvest, in particular to increase yields. This isn't happening in rich countries, but worldwide budgets are on the increase — largely in emerging economies such as China, India and Brazil. China is heavily involved in training and technology transfer to Africa, and in Europe we should be trying to offer Africans an alternative; we have the scientific capacity. It would be a pity if we were to leave all collaborations in the hands of the Chinese. This is a translated and edited version of an interview conducted in French. There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Pentagon turns to 'softer' sciences
  - Nature 464(7291):970 (2010)
  US defence research to focus more on biology, cybersecurity and social sciences to help win conflicts. Zachary Lemnios is overseeing the research shake-up.M. A. BURGESS, US NAVY By highlighting the limits of traditional military technology, the drawn-out conflicts in Iraq and Afghanistan have spurred the US defence department to shake up its US$12-billion science and technology research programme. The defence research and engineering office, headquartered at the Pentagon in Washington DC, is overseeing a budget shift away from applied research that supports weapons and into areas such as biology, computer science and the social sciences. All of these have "a potential for being game-changers" on the battlefield, says Zachary Lemnios, the defence department's chief technology officer and director of defence research and engineering. Lemnios, who is nearing the end of his first year as research director, recently testified before Congress for the first time since he was confirmed for his position, and answered questions from Nature about his scientific priorities. He says that the new emphasis will have reverberations outside the Pentagon, noting that US universities will receive more than half of the $1.8 billion that the defence department will spend on basic research in the current fiscal year. "Basic research funding not only leads to the next generation of technology but, just as importantly, supports a pipeline of researchers and graduate students," he says. Among the areas that are fast becoming a priority for the Pentagon is synthetic biology, which seeks to build new organisms or re-engineer existing ones to perform specific functions. Lemnios says that the Pentagon is interested in understanding "how organisms sense and respond to stimuli — such as chemicals, ions and metals, or electrical, magnetic, optical and mechanical impulses — at a genetic level". That knowledge, he says, could help researchers to design "living sentinels" that can monitor the presence of explosives or chemical pollutants. "We can also develop tools that will allow us to detect adversarial uses of synthetic biology," he says. According to Lemnios, the Office of Naval Research in Arlington, Virginia, is looking at how to biosynthesize targeted antibiotics that work by sensing and attacking specific pathogens. President Barack Obama's proposed budget for next year would also provide $20 million to the Defense Advanced Research Projects Agency (DARPA), another research arm of the Pentagon, to fund work in synthetic biology. As potential adversaries of the United States strengthen their abilities to attack computer networks, cybersecurity is another growing priority in the defence department's research portfolio, says Lemnios. He and the director of the Intelligence Advanced Research Projects Activity, Lisa Porter, last summer launched a joint study to look at where cybersecurity research dollars could be best spent. The results are feeding into a proposal to Congress for a new $200-million research and technology programme in cybersecurity. As part of that programme, Lemnios told a House of Representatives panel on 23 March, his office will sponsor research to "harden key network components; increase the military's ability to fight and survive during cyber attacks; disrupt nation-state level attack planning and execution; measure the state of cybersecurity; and explore and exploit new ideals in cyberwarfare". The unconventional wars now being fought by the US military have also bolstered interest in the social sciences. With the military trying to stave off a growing insurgency in Afghanistan, the Pentagon now believes that understanding cultural dynamics is at least as important as weapons. Consequently, Lemnios is ramping up funding in social-science projects, including a model developed by Los Alamos National Laboratory in New Mexico to simulate the opium trade in Afghanistan and analyse the effectiveness of efforts to combat it. The office is also supporting a project at the University of Chicago, Illinois, to model and predict potential conflicts. "New funding programmes like this are out there, while money for basic social science has gone away." Not all social scientists welcome the Pentagon's support, particularly if they are not happy with the direction that the military pushes the research. "There's something that happens when social science enters into this militarized model; all the rough edges, no matter how complicated, are smoothed, and the models themselves become pretty simplistic," says David Price, a cultural anthropologist at Saint Martin's University in Lacey, Washington state. "I worry in general what's happening to social science; new funding programmes like this are out there, while money for basic social science has gone away." In the 1960s and 1970s, the office now headed by Lemnios held immense power in the Pentagon, but in recent decades it has had more of an advisory role. "They controlled no budget; that was my experience with them," says Subrata Ghoshroy, a research associate in the Program in Science, Technology, and Society at the Massachusetts Institute of Technology in Cambridge, Massachusetts, and a former congressional staff member. "It was an organization without any teeth." ADVERTISEMENT But the office has gained renewed stature in recent years, and Lemnios now has a role in evaluating the Pentagon's weapons. That means ensuring that the technology in new weapons is mature enough for combat, and speeding the development of new technologies, notes Guy Ben-Ari, a fellow at the Washington-based Center for Strategic and International Studies. For a country that has troops fighting in Afghanistan and Iraq, focusing on moving science from the lab to the battlefield quickly is critical, says Ben-Ari. "They're getting shot at today." There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Panel to take broad view of bioethics
  - Nature 464(7291):971 (2010)
  President Obama appoints commission to advise on stem cells, clinical trials and more. Lonnie Ali, an advocate of Parkinson's disease research, has been appointed to the Presidential Commission for the Study of Bioethical Issues.M. BUCKNER/GETTY US President Barack Obama last week announced the full membership of his bioethics advisory council, unveiling a more diverse body and one that is likely to have a greater impact on policy than its predecessor. In the past decade, ethical questions in science have made headlines on issues such as the patenting of human genes, financial conflicts of interest in biomedical research and risk assessments related to environmental exposure to chemicals. These issues were largely ignored by the bioethics commission established by former president George W. Bush, which maintained a relatively narrow focus on stem cells, cloning and abortion. But all fall within the remit of the new Presidential Commission for the Study of Bioethical Issues, as outlined by the executive order which established it in November 2009. Obama had already broken with the past by not appointing a bioethicist to chair the commission, instead selecting Amy Gutmann, a political scientist at the University of Pennsylvania in Philadelphia (see Nature 462, 553; 2009). The 12-person panel unveiled on 7 April includes six scientists and two lawyers and has a wide range of expertise and viewpoints. Unlike the previous 18-member commission, Obama's panel features only two bioethicists. The diversity and qualifications of the new panellists means that "this group has tremendous power and potential," says Patrick Taylor, chief counsel for Research Affairs at Children's Hospital Boston in Massachusetts, adding that the committee's diversity makes it hard to predict how much influence the views of individual members will have on its reports. Obama's panel reports to the Secretary of Health and Human Services and includes three members from government agencies, who would have been ineligible for previous panels. In February 1998, bioethicist Ezekiel Emanuel had to leave former president Bill Clinton's bioethics panel on his appointment as chair of the bioethics department at the National Institutes of Health (NIH) in Bethesda, Maryland. The current commission, however, includes Christine Grady, an expert in human subjects research who is currently the acting bioethics chief at the NIH. George Annas, a bioethicist at Boston University in Massachusetts, fears that the government employees could wield "effective veto power". But bioethicist Thomas Murray of the Hastings Center in Garrison, New York, who served on the commission with Emanuel in the 1990s, thinks that the links may empower the committee: "Individuals placed in government could be in a better position to ensure that the commission's reports get some traction." There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Big science: The cancer genome challenge
  - Nature 464(7291):972 (2010)
  Databases could soon be flooded with genome sequences from 25,000 tumours. Heidi Ledford looks at the obstacles researchers face as they search for meaning in the data. Download a pdf of this story. When it was first discovered, in 2006, in a study of 35 colorectal cancers1, the mutation in the gene IDH1 seemed to have little consequence. It appeared in only one of the tumours sampled, and later analyses of some 300 more have revealed no additional mutations in the gene. The mutation changed only one letter of IDH1, which encodes isocitrate dehydrogenase, a lowly housekeeping enzyme involved in metabolism. And there were plenty of other mutations to study in the 13,000 genes sequenced from each sample. "Nobody would have expected IDH1 to be important in cancer," says Victor Velculescu, a researcher at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland, who had contributed to the study. But as efforts to sequence tumour DNA expanded, the IDH1 mutation surfaced again: in 12% of samples of a type of brain cancer called glioblastoma multiforme2, then in 8% of acute myeloid leukaemia samples3. Structural studies showed that the mutation changed the activity of isocitrate dehydrogenase, causing a cancer-promoting metabolite to accumulate in cells4. And at least one pharmaceutical company — Agios Pharmaceuticals in Cambridge, Massachusetts — is already hunting for a drug to stop the process. Four years after the initial discovery, ask a researcher in the field why cancer genome projects are worthwhile, and many will probably bring up the IDH1 mutation, the inconspicuous needle pulled from a veritable haystack of cancer-associated mutations thanks to high-powered genome sequencing. In the past two years, labs around the world have teamed up to sequence the DNA from thousands of tumours along with healthy cells from the same individuals. Roughly 75 cancer genomes have been sequenced to some extent and published; researchers expect to have several hundred completed sequences by the end of the year. Click to enlarge.ADAPTED FROM M. R. STRATTON, P. J. CAMPBELL & P. A. FUTREAL The efforts are certainly creating bigger haystacks. Comparing the gene sequence of any tumour to that of a normal cell reveals dozens of single-letter changes, or point mutations, along with repeated, deleted, swapped or inverted sequences (see 'Genomes at a glance'). "The difficulty," says Bert Vogelstein, a cancer researcher at the Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins, "is going to be figuring out how to use the information to help people rather than to just catalogue lots and lots of mutations". No matter how similar they might look clinically, most tumours seem to differ genetically. This stymies efforts to distinguish the mutations that cause and accelerate cancers — the drivers — from the accidental by-products of a cancer's growth and thwarted DNA-repair mechanisms — the passengers. Researchers can look for mutations that pop up again and again, or they can identify key pathways that are mutated at different points. But the projec! ts are providing more questions than answers. "Once you take the few obvious mutations at the top of the list, how do you make sense of the rest of them?" asks Will Parsons, a paediatric oncologist at Baylor College of Medicine in Houston, Texas. "How do you decide which are worthy of follow up and functional analysis? That's going to be the hard part." Drivers wanted Click to enlarge. Because cancer is a disease so intimately associated with genetic mutation, many thought it would be amenable to genomic exploration through initiatives based on the collaborative model of the Human Genome Project. The International Cancer Genome Consortium (ICGC), formed in 2008, is coordinating efforts to sequence 500 tumours from each of 50 cancers. Together, these projects will cost in the order of US$1 billion. Eleven countries have already signed on to cover more than 20 cancers (see map). The ICGC includes two older, large-scale projects: the Cancer Genome Project, at the Wellcome Trust Sanger Institute near Cambridge, UK, and the US National Institutes of Health's Cancer Genome Atlas (TCGA). The Cancer Genome Project has churned out more than 100 partial genomes and roughly 15 whole genomes in various stages of completion, and intends to tackle 2,000–3,000 more over the next 5–7 years. TCGA, meanwhile, wrapped up a three-year, three-cancer pilot project last year! , then launched a full-scale endeavour to sequence up to 500 tumours from each of more than 20 cancers over the next five years. Although the groups collaborate, TCGA has not yet been able to fully join the ICGC owing to differences in privacy regulations governing access to genome data. For now, members of both consortia are sequencing a subset of tumour samples from each cancer type — around 100 — and will follow this by sequencing promising areas in the remaining 400. That's useful, says Joe Gray, a cancer researcher at Lawrence Berkeley National Laboratory in California, but it's just a start. "In the early days, I thought that doing a few hundred tumours would probably be sufficient," he says. "Even at the level of 1,000 samples, I think we're probably not going to have the statistics we want." "Even at the level of 1,000 samples, I think we're probably not going to have the statistics we want." What bigger numbers could provide is more driver mutations like the one in IDH1. These could, researchers argue, provide the clearest route to developing new cancer therapies. Many scientists have looked for mutations that occur repeatedly in a given type of tumour. "If there are lots and lots of abnormalities of a particular gene, the most likely explanation is often that those mutations have been selected for by the cancers and therefore they are cancer-causing," says Michael Stratton, who co-directs the Cancer Genome Project. This approach has worked well in some cancers. For example, with a frequency of 12%, it is clear that the IDH1 mutation is a driver in glioblastoma. Such searches should be fruitful for cancers that have fewer mutations overall. The full genome sequence of acute myeloid leukaemia cells yielded just ten mutations in protein-coding genes, eight of which had not previously been linked with cancer5. Other cancers have proved more challenging. IDH1 was overlooked at first, on the basis of the colorectal cancer data alone. It was not until the search was expanded to other cancers that its importance was revealed. Moreover, some mutations shown to be drivers haven't turned up as often as expected. "It's very clear, now that all the genes have been sequenced in this many tumours, you have drivers that are mutated at very low frequency, in less than 1% of the cancers," says Vogelstein. To find these low-frequency drivers, researchers are sampling heavily — sequencing 500 samples per cancer should reveal mutations that are present in as few as 3% of the tumours. Although they may not contribute to the majority of tumours, they may still have important biological lessons, says Stratton. "We need to know about these to understand the overall genomic landscape of cancer." Another popular approach has been to look for mutations that cluster in a pathway, a group of genes that work together to carry out a specific process, even if the mutations strike it at different points. In an analysis of 24 pancreatic cancers6, for instance, Vogelstein and his colleagues identified 12 signalling pathways that had been altered. Nevertheless, Vogelstein cautions that this approach is not easy to pursue. Many pathways overlap, and their boundaries are unclear. And because many have been defined using data from different animals or cell types, they do not always match what's found in a specific human tissue. "When you layer on top of that the fact that the cancer cell is not wired the same as a normal cell, that raises even further difficulties," says Vogelstein. How much is enough? Click to enlarge. Separating drivers from passengers will become even more difficult as researchers move towards sequencing entire tumour genomes. To date, only a fraction of the existing cancer genomes are complete sequences. To keep costs low, most have covered only the exome, the 1.5% of the genome that directly codes for protein and is therefore the easiest to interpret. Assigning importance to a mutation found in the murky non-protein-coding depths of the genome will be more challenging, especially given that scientists don't yet know what function — if any — most of these regions usually serve. The vast majority of mutations fall here. The full genome sequence of a lung cancer cell line, for example, yielded 22,910 point mutations, only 134 of which were in protein-coding regions (see graphic, right)7. Nevertheless, finding them is worth the cost and effort, argues Stratton. "It could be that none of those mutations pertain to the causation of cancer," he says. "But it equally could! be that some do. We'll never find out unless we systematically investigate." Not everyone agrees. Some researchers argue that the costs of cancer-genome projects currently outweigh the benefits. Prices are poised to drop dramatically in the next few years as a new generation of sequencing machines comes online, says Ari Melnick, a cancer researcher at Weill Cornell Medical College in New York. "Why not wait for that?" he asks. In the meantime there are lower-hanging fruit to pick, says Stephen Elledge, a geneticist at Harvard Medical School in Boston, Massachusetts. Mutations that affect how many copies of a gene are found in a genome, he argues, are cheaper to assess and provide a more intuitive insight into biological processes. "If you delete something, you can turn a pathway off very efficiently," he says. "And if you amplify something, you can increase flow through the pathway. Making point mutations in genes to activate them is a little dicier." Changes in gene copy number can be detected using fast, relatively inexpensive array-based technologies, but sequencing can provide a higher-resolution snapshot of these regions, says Elaine Mardis, a sequencing specialist at Washington University in St Louis, Missouri. Sequencing can enable researchers to map the boundaries of insertions and duplications with more precision and to catch tiny duplications or deletions that might have gone undetected by an array. Mardis, along with her colleague Richard Wilson and others, used sequencing to detect overlapping deletions in a breast cancer that had spread to other parts of the body (see page 999)8. The deletions spanned the region containing CTNNA1, a gene thought to suppress the spread, or metastasis, of cancer. Meanwhile, cancer genomics is spreading out from under the large, centralized projects. For example, a $65-million, three-year paediatric-cancer genome project headed by researchers at St Jude Children's Research Hospital in Memphis, Tennessee, and Washington University aims to sequence 600 tumours. And more small projects seem poised to pop up. "Pretty much any cancer centre with any interest in the genomics of cancer is now buying these sequencers and using them," says Sam Aparicio, a cancer researcher at the University of British Columbia in Vancouver, Canada. ADVERTISEMENT Part of the reason that cancer-genome proponents don't want to wait for sequencing costs to drop is that the real work starts after the sequencing is over. As Velculescu puts it, "Ultimately it's going to take good old-fashioned biology and experimental analyses to really determine what these mutations are doing." With this in mind, the US National Cancer Institute established two 2-year projects in September last year to develop high-throughput methods to test how the mutations identified by the TCGA pilot project affect cell function. The two centres — one at the Dana-Farber Cancer Center in Boston, and another at Cold Spring Harbor Laboratory in New York — aim to systematize the way that researchers pull other needles like the IDH1 mutation from the cancer-genomes haystack and make sense of them. The Boston team will systematically amplify and reduce the expression of genes of interest in cell cultures, and the Cold Spring Harbor centre will study cancer-associated mu! tations using tumours transplanted into mice. "It's going to take good old-fashioned biology to really determine what these mutations are doing." In addition, large-scale projects are being run in parallel with the cancer-sequencing consortia to assess the effects of deleting each gene in the mouse genome, enabling researchers to learn more about the normal function of genes that are mutated in cancer. Sequencing is all very well, researchers have realized, but it won't be enough. "Some people say statistics should get us all the drivers that are worthwhile," says Lynda Chin, an investigator with TCGA at Harvard Medical School. "I don't agree with that. At the end of the day, we need these functional studies to prioritize the list of potential cancer-relevant candidates." * References * Sjöblom, T.et al. Science314, 268-274 (2006). * Parsons, D. W.et al. Science321, 1807-1812 (2008). * Mardis, E. R.et al. N. Engl. J. Med.361, 1058-1066 (2009). * Dang, L.et al. Nature462, 739-744 (2009). * Ley, T. J.et al. Nature456, 66-72 (2008). * Jones, S.et al. Science321, 1801-1806 (2008). * Pleasance, E. D.et al. Nature463, 184-190 (2010). * Ding, L.et al. Nature464, 999-1005 (2010). There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Moment of reckoning
  - Nature 464(7291):975 (2010)
  Tough choices lie ahead in UK research policy, and they need to be debated openly in the general election campaign, says Colin Macilwain. Science issues are set to receive a wider airing than usual in the British general election campaign, which, after running on slow-burn all winter, officially kicked off last week. With the country facing an estimated £166-billion (US$250-billion) fiscal deficit this year and its biggest sector — financial services — in intensive care, politicians are looking to science, technology and innovation as a possible path to an export-led economic recovery. But rhetorical differences aside, the laissez-faire approach of the three main parties is basically the same: spend on science and engineering in the universities, leave industry well alone and hope that innovation will flourish. No one has had the time or inclination to formulate anything more radical, despite nagging suspicions that this approach is not equal to Britain's daunting competitiveness challenges. This is unfortunate in a country that, whatever its other woes, remains a major power in many scientific disciplines. Voters need to know what the parties' real research priorities will be when, as many economists forecast, public spending falls by 10% or more over the next four years. The electorate — especially that portion of it about to be thrown out of work by these spending cuts — should be asking how well research spending will serve its needs. Most of all, the parties need to explain how, after 30 years of spurning the kind of industrial policies pursued by France and Germany, Britain can achieve export-led growth. Record to defend Encouraged by the example set by Barack Obama in his campaign for the US presidency, the ruling Labour Party is portraying the opposition Conservative Party as anti-science, alleging with some justification that they are likely to make large cuts to science and university funding. But Labour will struggle to put this argument across. They are cutting science too — £600 million in 'efficiency savings' have already been requested from the universities — and it is they, not the Conservatives, who have a 13-year record to defend. Part of this record is outstanding. In a move personally orchestrated by Prime Minister Gordon Brown when he was chancellor of the exchequer, the Labour government has doubled the annual university research budget to £6 billion over the past decade. Other aspects of Labour's record are less impressive. Industrial research spending has stagnated, and government laboratories, in everything from agriculture to defence, have been scaled back or closed. Labour has also done little to shift research priorities towards meeting social goals — in housing, health and transport, for example — as opposed to commercial ones. It has consulted endlessly with business interests, but seldom stooped to listen to its main groups of supporters, the liberal-minded middle classes and the shrunken industrial working class, who might benefit from a different set of research priorities. And it largely missed the opportunities that arose after the bovine spongiform encephalopathy (BSE) outbreaks and the public's rejection of genetically modified food to develop more advanced approaches to public consultation. Paul Drayson, the biotechnology entrepreneur who has served as Labour's science minister since 2008, says that he has sought to break down elitism in science and to welcome a broad range of voices, on issues such as stem cells and nanotechnology. He even says, in response to the charge that Labour only heeds the Confederation of British Industry (CBI), that Labour is listening to the trade unions. However, only last month, the government began a crucial, early consultation on future research priorities that will include the Royal Society and the CBI, yet exclude the unions, local authorities, and environmental groups. "British scientists have never had it so good, and they know it." The Conservative Party, which, according to the bookmakers, remains likely to form the next government, is doing its best to avoid firm commitments that might limit its future room for manoeuvre. Its clearest position is that more attention should be paid to teaching at universities. Party leader David Cameron — perhaps fearing unfavourable comparisons with Brown's impressive Oxford lecture on science (see http://go.nature.com/6rNuES) — dropped plans to devote a speech to the topic last summer. Cameron instead commissioned a report on innovation from James Dyson, the inventor of stylized vacuum cleaners. Last month, Cameron welcomed its findings — without promising to implement them. These included more focused research-and-development tax credits and more sponsorships for science and engineering students. Deciding vote The most progressive noises in the campaign so far have come from the Liberal Democrats, led by Nick Clegg, whose ambition is to hold the balance of power after the election. Their science spokesman, Evan Harris, has called for the government to adopt the Royal Society's recommendations on the treatment of independent scientific advice. He also wants reform of the libel laws to protect free scientific discussion in light of the case of Simon Singh, a science writer whose legal battle with chiropractors has become a cause célèbre for liberals and rationalists. The Royal Society sought to lay the ground for the consideration of science issues ahead of the 6 May election by publishing a report, The Scientific Century, on 9 March. The authors hoped that it might replicate the influence of Rising Above the Gathering Storm, a similar report published by the US National Academy of Sciences in 2007, which presaged $21 billion of additional science spending by the US Congress. Britain won't have the money for that kind of thing — science instead faces a severe funding crunch. A series of three live, televised debates will now take place between the three party leaders for the first time and will, at the media's insistence, come to dominate the campaign. The embattled prime minister should use these to advertise some of his under-exposed knowledge of and compassion for science, and challenge anticipated Conservative spending cuts. Until the September 2008 financial crisis, Brown's campaign message to Britain would have echoed that of Conservative prime minister and one-time publisher of this journal, Harold Macmillan in 1957: "You've never had it so good." Scientists haven't, and they know it. But no government can now save them from the austerity ahead. Colin Macilwain is based in the United Kingdom. e-mail: cfmworldview@gmail.com There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Questioning how different societies respond to crises
  - Nature 464(7291):977 (2010)
  In his Review of our book Questioning Collapse (Nature 463, 880–881; 2010), Jared Diamond alleges that it contains factual errors, which he uses to justify his devaluation of our emphasis on human resilience. In doing so, he shores up what we contend are his simplistic theses regarding societal 'collapse'.
• Students caught up in legal impasse at Mexican institute
  - Nature 464(7291):977 (2010)
  As graduate students from the nanoscience and nanotechnology group of the Institute for Scientific and Technological Research of San Luis Potosí (IPICYT), we wish to update you on events affecting us since the departure of Humberto and Mauricio Terrones (Nature464, 148–149; 2010).We have no wish to discredit the authorities of our institute, but we are concerned about the way in which they are handling our situation.
• Weighing up the case for telescope site on La Palma
  - Nature 464(7291):977 (2010)
  The European Southern Observatory (ESO) Council will soon decide where to install the European Extremely Large Telescope (E-ELT). The currently recommended site is Armazones, a sierra near Paranal in Chile (Nature464, 146; 2010).
• Let parents decide
  - Nature 464(7291):978 (2010)
  Twenty years on from the first pregnancies after preimplantation genetic diagnosis, Alan Handyside argues that informed prospective parents are largely good guides to the use of the thriving technology.
• Beyond the image of the tragic genius
  - Nature 464(7291):980 (2010)
  Our stereotypical view of mathematicians shifted during the Romantic era from worldly scholar to tortured soul, explains Jascha Hoffman.
• Calibrating the scales of suffering
  - Nature 464(7291):981 (2010)
  Biologist Victoria Braithwaite found herself in the media spotlight in 2003 after publishing research findings suggesting that fish feel pain. After injecting the faces of trout with bee venom and vinegar, anatomical and physiological studies revealed nerve endings called nociceptors, which respond to noxious stimulation.
• Books in brief
  - Nature 464(7291):982 (2010)
  To what extent are we in control of our actions? Not as much as we think, says neuroscientist Eliezer Sternberg in My Brain Made Me Do It (Prometheus Books, 2010).
• Artificial reefs to buffer New York
  - Nature 464(7291):982 (2010)
  Within the next 40 years, projected sea-level rises of up to a third of a metre threaten coastal cities, including New York. By 2100, rising sea levels could inundate 21% of Lower Manhattan at high tide and warmer ocean temperatures could bring more frequent hurricanes, accompanied by storm surges 7 metres high.
• Q&A: John Sims on mathematical art
  - Nature 464(7291):983 (2010)
  While pursuing his doctorate in dynamical systems, John Sims was drawn to explore the connections between mathematics and art. Now curating a year-long series of maths–art shows at the Bowery Poetry Club in New York City, the conceptual artist explains the cultural significance of maths.
• Complex networks: The fragility of interdependency
  - Nature 464(7291):984 (2010)
  A study of failures in interconnected networks highlights the vulnerability of tightly coupled infrastructures and shows the need to consider mutually dependent network properties in designing resilient systems.
• Genomics: Lessons in complexity from yeast
  - Nature 464(7291):985 (2010)
  A challenge in biology is to understand complex traits, which are influenced by many genetic variants. Studies in yeast provide the prospect of analysing such genetic variation in detail in other organisms, including humans.
• 50 & 100 years ago
  - Nature 464(7291):986 (2010)
  In form, texture and structure chondrules are not like any spheroidal bodies observed in terrestrial rocks, and their origin has been argued by investigators for more than a century ... These hypotheses are often linked with the generally accepted belief that these meteorites are fragments of a disrupted body of asteroidal or planetary dimensions. I would suggest an alternative hypothesis, that the structure of chondritic meteorites is the result of reaction and recrystallization of pre-existing material essentially in the solid state, and that many ... have always been independent and individual objects ... The texture and structure of the chondritic meteorites is quite remarkable if they have originated in any body with a considerable gravitational field.
• Single-molecule analysis: A ribosome in action
  - Nature 464(7291):987 (2010)
  The manufacture of proteins by ribosomes involves complex interactions of diverse nucleic-acid and protein ligands. Single-molecule studies allow us, for the first time, to follow the synthesis of full-length proteins in real time.
• Information science: Guaranteed randomness
  - Nature 464(7291):988 (2010)
  You have received a device that is claimed to produce random numbers, but you don't trust it. Can you check it without opening it? In some cases, you can, thanks to the bizarre nature of quantum physics.
• Cancer: Genomics of metastasis
  - Nature 464(7291):989 (2010)
  Cancer cells that invade other parts of the body do so by accumulating genomic aberrations. Analysis of the genomic differences between primary and metastatic tumours should aid the understanding of this process.
• Vision: Fisheye views
  - Nature 464(7291):990 (2010)
  Abstract
• Behavioural ecology: Ways to raise tadpoles
  - Nature 464(7291):990 (2010)
  To reduce parental care, just add water — that's the conclusion of an intriguing investigation into the extent of the motherly and fatherly devotion that different species of frog extend to their offspring.
• Obituary: Leena Peltonen-Palotie (1952–2010)
  - Nature 464(7291):992 (2010)
  A visionary in medical genetics.
• International network of cancer genome projects
  - Nature 464(7291):993 (2010)
  The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
• Genome remodelling in a basal-like breast cancer metastasis and xenograft
  - Nature 464(7291):999 (2010)
  Massively parallel DNA sequencing technologies provide an unprecedented ability to screen entire genomes for genetic changes associated with tumour progression. Here we describe the genomic analyses of four DNA samples from an African-American patient with basal-like breast cancer: peripheral blood, the primary tumour, a brain metastasis and a xenograft derived from the primary tumour. The metastasis contained two de novo mutations and a large deletion not present in the primary tumour, and was significantly enriched for 20 shared mutations. The xenograft retained all primary tumour mutations and displayed a mutation enrichment pattern that resembled the metastasis. Two overlapping large deletions, encompassing CTNNA1, were present in all three tumour samples. The differential mutation frequencies and structural variation patterns in metastasis and xenograft compared with the primary tumour indicate that secondary tumours may arise from a minority of cells within the p! rimary tumour.
• Molecular basis of infrared detection by snakes
  Gracheva EO Ingolia NT Kelly YM Cordero-Morales JF Hollopeter G Chesler AT Sánchez EE Perez JC Weissman JS Julius D - Nature 464(7291):1006 (2010)
  Snakes possess a unique sensory system for detecting infrared radiation, enabling them to generate a 'thermal image' of predators or prey. Infrared signals are initially received by the pit organ, a highly specialized facial structure that is innervated by nerve fibres of the somatosensory system. How this organ detects and transduces infrared signals into nerve impulses is not known. Here we use an unbiased transcriptional profiling approach to identify TRPA1 channels as infrared receptors on sensory nerve fibres that innervate the pit organ. TRPA1 orthologues from pit-bearing snakes (vipers, pythons and boas) are the most heat-sensitive vertebrate ion channels thus far identified, consistent with their role as primary transducers of infrared stimuli. Thus, snakes detect infrared signals through a mechanism involving radiant heating of the pit organ, rather than photochemical transduction. These findings illustrate the broad evolutionary tuning of transient recept! or potential (TRP) channels as thermosensors in the vertebrate nervous system.
• Real-time tRNA transit on single translating ribosomes at codon resolution
  - Nature 464(7291):1012 (2010)
  Translation by the ribosome occurs by a complex mechanism involving the coordinated interaction of multiple nucleic acid and protein ligands. Here we use zero-mode waveguides (ZMWs) and sophisticated detection instrumentation to allow real-time observation of translation at physiologically relevant micromolar ligand concentrations. Translation at each codon is monitored by stable binding of transfer RNAs (tRNAs)—labelled with distinct fluorophores—to translating ribosomes, which allows direct detection of the identity of tRNA molecules bound to the ribosome and therefore the underlying messenger RNA (mRNA) sequence. We observe the transit of tRNAs on single translating ribosomes and determine the number of tRNA molecules simultaneously bound to the ribosome, at each codon of an mRNA molecule. Our results show that ribosomes are only briefly occupied by two tRNA molecules and that release of deacylated tRNA from the exit (E) site is uncoupled from binding of aminoac! yl-tRNA site (A-site) tRNA and occurs rapidly after translocation. The methods outlined here have broad application to the study of mRNA sequences, and the mechanism and regulation of translation.
• An image of an exoplanet separated by two diffraction beamwidths from a star
  - Nature 464(7291):1018 (2010)
  Three exoplanets around the star HR 8799 have recently been discovered by means of differential imaging with large telescopes1. Bright scattered starlight limits high-contrast imaging to large angular offsets, currently of the order of ten diffraction beamwidths, 10λ/D, of the star (where λ is the wavelength and D is the aperture diameter1, 2, 3, 4, 5). Imaging faint planets at smaller angles calls for reducing the starlight and associated photon and speckle noise before detection, while efficiently transmitting nearby planet light. To carry out initial demonstrations of reduced-angle high-contrast coronagraphy, we installed a vortex coronagraph6, 7, 8, 9 capable of reaching small angles behind a small, well-corrected telescope subaperture that provides low levels of scattered starlight10, 11. Here we report the detection of all three HR 8799 planets with the resultant small-aperture (1.5 m) system, for which only 2λ/D separate the innermost planet from the st! ar, with a final noise level within a factor of two of that given by photon statistics. Similar well-corrected small-angle coronagraphs should thus be able to detect exoplanets located even closer to their host stars with larger ground-based telescopes12, 13, 14, 15, and also allow a reduction in the size of potential space telescopes aimed at the imaging of very faint terrestrial planets.
• Random numbers certified by Bell's theorem
  - Nature 464(7291):1021 (2010)
  Randomness is a fundamental feature of nature and a valuable resource for applications ranging from cryptography and gambling to numerical simulation of physical and biological systems. Random numbers, however, are difficult to characterize mathematically1, and their generation must rely on an unpredictable physical process2, 3, 4, 5, 6. Inaccuracies in the theoretical modelling of such processes or failures of the devices, possibly due to adversarial attacks, limit the reliability of random number generators in ways that are difficult to control and detect. Here, inspired by earlier work on non-locality-based7, 8, 9 and device-independent10, 11, 12, 13, 14 quantum information processing, we show that the non-local correlations of entangled quantum particles can be used to certify the presence of genuine randomness. It is thereby possible to design a cryptographically secure random number generator that does not require any assumption about the internal working of the ! device. Such a strong form of randomness generation is impossible classically and possible in quantum systems only if certified by a Bell inequality violation15. We carry out a proof-of-concept demonstration of this proposal in a system of two entangled atoms separated by approximately one metre. The observed Bell inequality violation, featuring near perfect detection efficiency, guarantees that 42 new random numbers are generated with 99 per cent confidence. Our results lay the groundwork for future device-independent quantum information experiments and for addressing fundamental issues raised by the intrinsic randomness of quantum theory.
• Catastrophic cascade of failures in interdependent networks
  - Nature 464(7291):1025 (2010)
  Complex networks have been studied intensively for a decade, but research still focuses on the limited case of a single, non-interacting network1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14. Modern systems are coupled together15, 16, 17, 18, 19 and therefore should be modelled as interdependent networks. A fundamental property of interdependent networks is that failure of nodes in one network may lead to failure of dependent nodes in other networks. This may happen recursively and can lead to a cascade of failures. In fact, a failure of a very small fraction of nodes in one network may lead to the complete fragmentation of a system of several interdependent networks. A dramatic real-world example of a cascade of failures ('concurrent malfunction') is the electrical blackout that affected much of Italy on 28 September 2003: the shutdown of power stations directly led to the failure of nodes in the Internet communication network, which in turn caused further breakdow! n of power stations20. Here we develop a framework for understanding the robustness of interacting networks subject to such cascading failures. We present exact analytical solutions for the critical fraction of nodes that, on removal, will lead to a failure cascade and to a complete fragmentation of two interdependent networks. Surprisingly, a broader degree distribution increases the vulnerability of interdependent networks to random failure, which is opposite to how a single network behaves. Our findings highlight the need to consider interdependent network properties in designing robust networks.
• Phosphate oxygen isotopic evidence for a temperate and biologically active Archaean ocean
  - Nature 464(7291):1029 (2010)
  Oxygen and silicon isotope compositions of cherts1, 2, 3 and studies of protein evolution4 have been interpreted to reflect ocean temperatures of 55–85 °C during the early Palaeoarchaean era (~3.5 billion years ago). A recent study combining oxygen and hydrogen isotope compositions of cherts, however, makes a case for Archaean ocean temperatures being no greater than 40 °C (ref. 5). Ocean temperature can also be assessed using the oxygen isotope composition of phosphate. Recent studies show that 18O:16O ratios of dissolved inorganic phosphate (δ18OP) reflect ambient seawater temperature as well as biological processing that dominates marine phosphorus cycling at low temperature6, 7. All forms of life require and concentrate phosphorus, and as a result of biological processing, modern marine phosphates have δ18OP values typically between 19–26‰ (VSMOW)7, 8, highly evolved from presumed source values of ~6–8‰ that are characteristic of apatite in igne! ous rocks9, 10 and meteorites11. Here we report oxygen isotope compositions of phosphates in sediments from the 3.2–3.5-billion-year-old Barberton Greenstone Belt in South Africa. We find that δ18OP values range from 9.3‰ to 19.9‰ and include the highest values reported for Archaean rocks. The temperatures calculated from our highest δ18OP values and assuming equilibrium with sea water with δ18O = 0‰ (ref. 12) range from 26 °C to 35 °C. The higher δ18OP values are similar to those of modern marine phosphate and suggest a well-developed phosphorus cycle and evolved biologic activity on the Archaean Earth.
• Périgord black truffle genome uncovers evolutionary origins and mechanisms of symbiosis
  Martin F Kohler A Murat C Balestrini R Coutinho PM Jaillon O Montanini B Morin E Noel B Percudani R Porcel B Rubini A Amicucci A Amselem J Anthouard V Arcioni S Artiguenave F Aury JM Ballario P Bolchi A Brenna A Brun A Buée M Cantarel B Chevalier G Couloux A Da Silva C Denoeud F Duplessis S Ghignone S Hilselberger B Iotti M Marçais B Mello A Miranda M Pacioni G Quesneville H Riccioni C Ruotolo R Splivallo R Stocchi V Tisserant E Viscomi AR Zambonelli A Zampieri E Henrissat B Lebrun MH Paolocci F Bonfante P Ottonello S Wincker P - Nature 464(7291):1033 (2010)
  The Périgord black truffle (Tuber melanosporum Vittad.) and the Piedmont white truffle dominate today's truffle market1, 2. The hypogeous fruiting body of T. melanosporum is a gastronomic delicacy produced by an ectomycorrhizal symbiont3 endemic to calcareous soils in southern Europe. The worldwide demand for this truffle has fuelled intense efforts at cultivation. Identification of processes that condition and trigger fruit body and symbiosis formation, ultimately leading to efficient crop production, will be facilitated by a thorough analysis of truffle genomic traits. In the ectomycorrhizal Laccaria bicolor, the expansion of gene families may have acted as a 'symbiosis toolbox'4. This feature may however reflect evolution of this particular taxon and not a general trait shared by all ectomycorrhizal species5. To get a better understanding of the biology and evolution of the ectomycorrhizal symbiosis, we report here the sequence of the haploid genome of T. mel! anosporum, which at ~125 megabases is the largest and most complex fungal genome sequenced so far. This expansion results from a proliferation of transposable elements accounting for ~58% of the genome. In contrast, this genome only contains ~7,500 protein-coding genes with very rare multigene families. It lacks large sets of carbohydrate cleaving enzymes, but a few of them involved in degradation of plant cell walls are induced in symbiotic tissues. The latter feature and the upregulation of genes encoding for lipases and multicopper oxidases suggest that T. melanosporum degrades its host cell walls during colonization. Symbiosis induces an increased expression of carbohydrate and amino acid transporters in both L. bicolor and T. melanosporum, but the comparison of genomic traits in the two ectomycorrhizal fungi showed that genetic predispositions for symbiosis—'the symbiosis toolbox'—evolved along different ways in ascomycetes and basidiomycetes.
• Dissection of genetically complex traits with extremely large pools of yeast segregants
  - Nature 464(7291):1039 (2010)
  Most heritable traits, including many human diseases1, are caused by multiple loci. Studies in both humans and model organisms, such as yeast, have failed to detect a large fraction of the loci that underlie such complex traits2, 3. A lack of statistical power to identify multiple loci with small effects is undoubtedly one of the primary reasons for this problem. We have developed a method in yeast that allows the use of much larger sample sizes than previously possible and hence permits the detection of multiple loci with small effects. The method involves generating very large numbers of progeny from a cross between two Saccharomyces cerevisiae strains and then phenotyping and genotyping pools of these offspring. We applied the method to 17 chemical resistance traits and mitochondrial function, and identified loci for each of these phenotypes. We show that the level of genetic complexity underlying these quantitative traits is highly variable, with some traits influe! nced by one major locus and others by at least 20 loci. Our results provide an empirical demonstration of the genetic complexity of a number of traits and show that it is possible to identify many of the underlying factors using straightforward techniques. Our method should have broad applications in yeast and can be extended to other organisms.
• APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex
  - Nature 464(7291):1043 (2010)
  Hereditary hypotrichosis simplex is a rare autosomal dominant form of hair loss characterized by hair follicle miniaturization1, 2. Using genetic linkage analysis, we mapped a new locus for the disease to chromosome 18p11.22, and identified a mutation (Leu9Arg) in the adenomatosis polyposis down-regulated 1 (APCDD1) gene in three families. We show that APCDD1 is a membrane-bound glycoprotein that is abundantly expressed in human hair follicles, and can interact in vitro with WNT3A and LRP5—two essential components of Wnt signalling. Functional studies show that APCDD1 inhibits Wnt signalling in a cell-autonomous manner and functions upstream of β-catenin. Moreover, APCDD1 represses activation of Wnt reporters and target genes, and inhibits the biological effects of Wnt signalling during both the generation of neurons from progenitors in the developing chick nervous system, and axis specification in Xenopus laevis embryos. The mutation Leu9Arg is located in the signa! l peptide of APCDD1, and perturbs its translational processing from the endoplasmic reticulum to the plasma membrane. APCDD1(L9R) probably functions in a dominant-negative manner to inhibit the stability and membrane localization of the wild-type protein. These findings describe a novel inhibitor of the Wnt signalling pathway with an essential role in human hair growth. As APCDD1 is expressed in a broad repertoire of cell types3, our findings indicate that APCDD1 may regulate a diversity of biological processes controlled by Wnt signalling.
• Functional genomic screen for modulators of ciliogenesis and cilium length
  - Nature 464(7291):1048 (2010)
  Primary cilia are evolutionarily conserved cellular organelles that organize diverse signalling pathways1, 2. Defects in the formation or function of primary cilia are associated with a spectrum of human diseases and developmental abnormalities3. Genetic screens in model organisms have discovered core machineries of cilium assembly and maintenance4. However, regulatory molecules that coordinate the biogenesis of primary cilia with other cellular processes, including cytoskeletal organization, vesicle trafficking and cell–cell adhesion, remain to be identified. Here we report the results of a functional genomic screen using RNA interference (RNAi) to identify human genes involved in ciliogenesis control. The screen identified 36 positive and 13 negative ciliogenesis modulators, which include molecules involved in actin dynamics and vesicle trafficking. Further investigation demonstrated that blocking actin assembly facilitates ciliogenesis by stabilizing the pericentr! osomal preciliary compartment (PPC), a previously uncharacterized compact vesiculotubular structure storing transmembrane proteins destined for cilia during the early phase of ciliogenesis. The PPC was labelled by recycling endosome markers. Moreover, knockdown of modulators that are involved in the endocytic recycling pathway affected the formation of the PPC as well as ciliogenesis. Our results uncover a critical regulatory step that couples actin dynamics and endocytic recycling with ciliogenesis, and also provides potential target molecules for future study.
• Therapeutic antibody targeting of individual Notch receptors
  - Nature 464(7291):1052 (2010)
  The four receptors of the Notch family are widely expressed transmembrane proteins that function as key conduits through which mammalian cells communicate to regulate cell fate and growth1, 2. Ligand binding triggers a conformational change in the receptor negative regulatory region (NRR) that enables ADAM protease cleavage3, 4 at a juxtamembrane site that otherwise lies buried within the quiescent NRR5, 6. Subsequent intramembrane proteolysis catalysed by the γ-secretase complex liberates the intracellular domain (ICD) to initiate the downstream Notch transcriptional program. Aberrant signalling through each receptor has been linked to numerous diseases, particularly cancer7, making the Notch pathway a compelling target for new drugs. Although γ-secretase inhibitors (GSIs) have progressed into the clinic8, GSIs fail to distinguish individual Notch receptors, inhibit other signalling pathways9 and cause intestinal toxicity10, attributed to dual inhibition of Notch1 a! nd 2 (ref. 11). To elucidate the discrete functions of Notch1 and Notch2 and develop clinically relevant inhibitors that reduce intestinal toxicity, we used phage display technology to generate highly specialized antibodies that specifically antagonize each receptor paralogue and yet cross-react with the human and mouse sequences, enabling the discrimination of Notch1 versus Notch2 function in human patients and rodent models. Our co-crystal structure shows that the inhibitory mechanism relies on stabilizing NRR quiescence. Selective blocking of Notch1 inhibits tumour growth in pre-clinical models through two mechanisms: inhibition of cancer cell growth and deregulation of angiogenesis. Whereas inhibition of Notch1 plus Notch2 causes severe intestinal toxicity, inhibition of either receptor alone reduces or avoids this effect, demonstrating a clear advantage over pan-Notch inhibitors. Our studies emphasize the value of paralogue-specific antagonists in dissecting the contri! butions of distinct Notch receptors to differentiation and dis! ease and reveal the therapeutic promise in targeting Notch1 and Notch2 independently.
• Chemoprevention of colorectal cancer by targeting APC-deficient cells for apoptosis
  Zhang L Ren X Alt E Bai X Huang S Xu Z Lynch PM Moyer MP Wen XF Wu X - Nature 464(7291):1058 (2010)
  Cancer chemoprevention uses natural, synthetic, or biological substances to reverse, suppress, or prevent either the initial phase of carcinogenesis or the progression of neoplastic cells to cancer1. It holds promise for overcoming problems associated with the treatment of late-stage cancers. However, the broad application of chemoprevention is compromised at present by limited effectiveness and potential toxicity. To overcome these challenges, here we developed a new chemoprevention approach that specifically targets premalignant tumour cells for apoptosis. We show that a deficiency in the adenomatous polyposis coli (APC) gene and subsequent activation of β-catenin lead to the repression of cellular caspase-8 inhibitor c-FLIP (also known as CFLAR) expression through activation of c-Myc, and that all-trans-retinyl acetate (RAc) independently upregulates tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptors and suppresses decoy receptors. Thu! s, the combination of TRAIL and RAc induces apoptosis in APC-deficient premalignant cells without affecting normal cells in vitro. In addition, we show that short-term and non-continuous TRAIL and RAc treatment induce apoptosis specifically in intestinal polyps, strongly inhibit tumour growth, and prolong survival in multiple intestinal neoplasms C57BL/6J-ApcMin/J (ApcMin) mice. With our approach, we further demonstrate that TRAIL and RAc induce significant cell death in human colon polyps, providing a potentially selective approach for colorectal cancer chemoprevention by targeting APC-deficient cells for apoptosis.
• Migrastatin analogues target fascin to block tumour metastasis
  - Nature 464(7291):1062 (2010)
  Tumour metastasis is the primary cause of death of cancer patients. Development of new therapeutics preventing tumour metastasis is urgently needed. Migrastatin is a natural product secreted by Streptomyces1, 2, and synthesized migrastatin analogues such as macroketone are potent inhibitors of metastatic tumour cell migration, invasion and metastasis3, 4, 5, 6. Here we show that these migrastatin analogues target the actin-bundling protein fascin to inhibit its activity. X-ray crystal structural studies reveal that migrastatin analogues bind to one of the actin-binding sites on fascin. Our data demonstrate that actin cytoskeletal proteins such as fascin can be explored as new molecular targets for cancer treatment, in a similar manner to the microtubule protein tubulin.
• Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles
  Davis ME Zuckerman JE Choi CH Seligson D Tolcher A Alabi CA Yen Y Heidel JD Ribas A - Nature 464(7291):1067 (2010)
  Therapeutics that are designed to engage RNA interference (RNAi) pathways have the potential to provide new, major ways of imparting therapy to patients1, 2. Long, double-stranded RNAs were first shown to mediate RNAi in Caenorhabditis elegans3, and the potential use of RNAi for human therapy has been demonstrated by the finding that small interfering RNAs (siRNAs; approximately 21-base-pair double-stranded RNA) can elicit RNAi in mammalian cells without producing an interferon response4. We are at present conducting the first in-human phase I clinical trial involving the systemic administration of siRNA to patients with solid cancers using a targeted, nanoparticle delivery system. Here we provide evidence of inducing an RNAi mechanism of action in a human from the delivered siRNA. Tumour biopsies from melanoma patients obtained after treatment show the presence of intracellularly localized nanoparticles in amounts that correlate with dose levels of the nanoparticles a! dministered (this is, to our knowledge, a first for systemically delivered nanoparticles of any kind). Furthermore, a reduction was found in both the specific messenger RNA (M2 subunit of ribonucleotide reductase (RRM2)) and the protein (RRM2) levels when compared to pre-dosing tissue. Most notably, we detect the presence of an mRNA fragment that demonstrates that siRNA-mediated mRNA cleavage occurs specifically at the site predicted for an RNAi mechanism from a patient who received the highest dose of the nanoparticles. Together, these data demonstrate that siRNA administered systemically to a human can produce a specific gene inhibition (reduction in mRNA and protein) by an RNAi mechanism of action.
• Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis
  - Nature 464(7291):1071 (2010)
  Large intervening non-coding RNAs (lincRNAs) are pervasively transcribed in the genome1, 2, 3 yet their potential involvement in human disease is not well understood4, 5. Recent studies of dosage compensation, imprinting, and homeotic gene expression suggest that individual lincRNAs can function as the interface between DNA and specific chromatin remodelling activities6, 7, 8. Here we show that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression. The lincRNA termed HOTAIR is increased in expression in primary breast tumours and metastases, and HOTAIR expression level in primary tumours is a powerful predictor of eventual metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells induced genome-wide re-targeting of Polycomb repressive complex 2 (PRC2) to an occupancy pattern more resembling embryonic fibroblasts, leading to altered histone H3 lysine 27 methylation, gene expression, and increased cancer invasiv! eness and metastasis in a manner dependent on PRC2. Conversely, loss of HOTAIR can inhibit cancer invasiveness, particularly in cells that possess excessive PRC2 activity. These findings indicate that lincRNAs have active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.
• Fructose 1,6-bisphosphate aldolase/phosphatase may be an ancestral gluconeogenic enzyme
  Say RF Fuchs G - Nature 464(7291):1077 (2010)
  Most archaeal groups and deeply branching bacterial lineages harbour thermophilic organisms with a chemolithoautotrophic metabolism. They live at high temperatures in volcanic habitats at the expense of inorganic substances, often under anoxic conditions1. These autotrophic organisms use diverse carbon dioxide fixation mechanisms generating acetyl-coenzyme A, from which gluconeogenesis must start2, 3, 4. Here we show that virtually all archaeal groups as well as the deeply branching bacterial lineages contain a bifunctional fructose 1,6-bisphosphate (FBP) aldolase/phosphatase with both FBP aldolase and FBP phosphatase activity. This enzyme is missing in most other Bacteria and in Eukaryota, and is heat-stabile even in mesophilic marine Crenarchaeota. Its bifunctionality ensures that heat-labile triosephosphates are quickly removed and trapped in stabile fructose 6-phosphate, rendering gluconeogenesis unidirectional. We propose that this highly conserved, heat-stabile a! nd bifunctional FBP aldolase/phosphatase represents the pace-making ancestral gluconeogenic enzyme, and that in evolution gluconeogenesis preceded glycolysis5.
• CpG islands influence chromatin structure via the CpG-binding protein Cfp1
  - Nature 464(7291):1082 (2010)
  CpG islands (CGIs) are prominent in the mammalian genome owing to their GC-rich base composition and high density of CpG dinucleotides1, 2. Most human gene promoters are embedded within CGIs that lack DNA methylation and coincide with sites of histone H3 lysine 4 trimethylation (H3K4me3), irrespective of transcriptional activity3, 4. In spite of these intriguing correlations, the functional significance of non-methylated CGI sequences with respect to chromatin structure and transcription is unknown. By performing a search for proteins that are common to all CGIs, here we show high enrichment for Cfp1, which selectively binds to non-methylated CpGs in vitro5, 6. Chromatin immunoprecipitation of a mono-allelically methylated CGI confirmed that Cfp1 specifically associates with non-methylated CpG sites in vivo. High throughput sequencing of Cfp1-bound chromatin identified a notable concordance with non-methylated CGIs and sites of H3K4me3 in the mouse brain. Levels of H3K! 4me3 at CGIs were markedly reduced in Cfp1-depleted cells, consistent with the finding that Cfp1 associates with the H3K4 methyltransferase Setd1 (refs 7, 8). To test whether non-methylated CpG-dense sequences are sufficient to establish domains of H3K4me3, we analysed artificial CpG clusters that were integrated into the mouse genome. Despite the absence of promoters, the insertions recruited Cfp1 and created new peaks of H3K4me3. The data indicate that a primary function of non-methylated CGIs is to genetically influence the local chromatin modification state by interaction with Cfp1 and perhaps other CpG-binding proteins.
• The frozen hive of her mind
  - Nature 464(7291):1094 (2010)
  A familiar face.