Hot off the presses! Mar 25 Nature

The Mar 25 issue of the Nature is now up on Pubget (About Nature): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Tough love
  - Nature 464(7288):465 (2010)
  A British research council's 'blacklisting' rule is a radical, unpopular but courageous effort to address a crisis in the peer-review system.
• Buyer beware
  - Nature 464(7288):465 (2010)
  Lack of US regulation is allowing dubious dietary supplements to be sold as life-enhancing elixirs.
• Content rules
  - Nature 464(7288):466 (2010)
  Nature's new online commenting facility opens up the entire magazine for discussion.
• Biology: A jewel's true colours
  - Nature 464(7288):468 (2010)
  
• Regenerative biology: Pregnancy boosts repair
  - Nature 464(7288):468 (2010)
  
• Chemistry: Water splitting
  - Nature 464(7288):468 (2010)
  
• Imaging: A view to a kill
  - Nature 464(7288):468 (2010)
  
• Evolutionary biology: Lend a helping claw
  - Nature 464(7288):468 (2010)
  
• Geoscience: Marine malaise
  - Nature 464(7288):469 (2010)
  
• Genetics: Cross out crossovers
  - Nature 464(7288):469 (2010)
  
• Neuroscience: Live-action brain cells
  - Nature 464(7288):469 (2010)
  
• Atmospheric science: Paparazzi pollution
  - Nature 464(7288):469 (2010)
  
• Journal club
  - Nature 464(7288):469 (2010)
  
• News briefing: 25 March 2010
  - Nature 464(7288):470 (2010)
  The week in science. This article is best viewed as a PDF Policy|Research|Events|People|Business|Business watch|The week ahead|Number crunch|News maker Britain has launched a national space agency, intended to coordinate the country's civilian space activities and develop a long-term strategy for the sector. Previously, space funding for technology, instruments and subscriptions to international bodies — such as the European Space Agency — came from separate grant-giving agencies and various government departments. At the 23 March launch, science minister Paul Drayson also announced an international space innovation centre, to be based at Harwell, near Didcot, which will be supported by £40 million (US$60 million) from government and industry. The US National Institutes of Health (NIH) announced last week that it would establish a public online database to store information on genetic tests voluntarily submitted by manufacturers. The Genetic Testing Registry aims to help people to access information — including validity and availability data — on the more than 1,600 genetic tests now offered commercially. It will be developed by the NIH's National Center for Biotechnology Information in Bethesda, Maryland, by 2011. Europe continues to lag well behind Japan and is no longer catching up with the United States, according to a 2009 innovation scoreboard released by the European Commission on 18 March. The report, based on data from 2007 and 2008, highlights four key issues for Europe to improve: business spending on research and development, number of researchers, public–private linkage and international patenting. China continues to gain on Europe. Last year's innovation scoreboard (see Nature 457, 523; 2009) told a similar tale. Disgruntled members of the cash-stricken Royal Institution of Great Britain want to oust the venerable body's council. Last week they announced that a meeting will be held on 12 April for members to vote on whether to replace the institution's board of trustees, which in January forced out director Susan Greenfield (see Nature 463, 140; 2010). The council responded that the proposed changes to the governance "would cause profound harm". It also noted that other members, including prominent chemists, had signed a motion in support of the council. The Science Council of Japan has for the first time outlined its country's future large-scale research projects and facilities, estimating for each the budget and degree of international collaboration required. The council, which represents 840,000 scientists, posted a lengthy 'master plan' on its website on 17 March. It covers 43 projects, including proposed telescopes and satellites, as well as materials science, particle physics and biological-science facilities. The council's unprecedented evaluation was published in part to gain public understanding of basic research in the wake of a tussle over Japan's science budgets late last year (see Nature 462, 557; 2009). The University of Copenhagen has received Denmark's largest ever private donation for research. The Novo Nordisk Foundation announced on 22 March that it would hand over 885 million kroner (US$161 million) to create a centre for research into human metabolism. The centre, to open in October, will focus on diseases such as type 2 diabetes and other obesity-related illnesses. In a report published on 18 March, the World Health Organization released more data on the incidence of multidrug-resistant tuberculosis (TB) — but admitted that major gaps in monitoring prevent understanding of whether the disease is spreading. Based on data from 2008, the report puts the total incidence of the disease at about 3.6% of all TB cases, similar to previous estimates. No reliable information on proportions of drug-resistant TB is available from around 41% of the world's countries. South Korea last week chose Terra Nova Bay as the site for its first research base on mainland Antarctica. A survey earlier this year by the country's first icebreaker research ship, Araon, found that the site was more accessible and had better weather than another option, Cape Burks. The 100-billion-won (US$88-million) base, to be completed by 2014, will be used to study global warming. The country has had another base on nearby King George Island since 1988. England's top research universities have gained a greater proportion of public research funds than last year. Last week's 2010–11 allocation of £1.6 billion (US$2.4 billion) saw the five best research universities win 39.2% of the funds available for science subjects, up from 38.2% the previous year. Research funds, which are distributed to universities by the Higher Education Funding Council for England, have grown by 2% in cash terms from last year, but total hand-outs (including teaching) dropped by 1.6%. See go.nature.com/Vsisfy for more. T. GENTILE/REUTERS In a victory for politics and business over conservation science, a proposal to ban international trade in Atlantic bluefin tuna was roundly rejected last week at a meeting of the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) in Doha, Qatar. Thanks to vigorous overfishing, stocks of bluefin tuna have plummeted by an estimated 82.4% in the West Atlantic between 1970 and 2007, and both the European Union and the United States have backed a ban to save the species. The CITES meeting also rejected a proposed ban on polar-bear trade, and voted against trade restrictions on some Mediterranean corals. See go.nature.com/4l4ZfS for more. Renowned pharmacologist James Black died on 22 March, aged 85. A pioneer of many areas of drug discovery, he shared the 1988 Nobel Prize in Physiology or Medicine. He transformed the treatment of heart disease with work on receptor-selective drugs, developing the first β-blocking drug, propranolol, in the 1960s. In the 1970s, he helped develop the peptic-ulcer treatment cimetidine, which blocks a type of histamine receptor. He was knighted in 1981. Israeli drug-maker Teva Pharmaceuticals Industries announced on 18 March that it would acquire ratiopharm, Germany's second biggest generic pharmaceuticals producer, for €3.6 billion (US$4.9 billion). The move sees Teva, which is based in Jerusalem, expand its reach in Europe. The merger will create Europe's largest generic drugmaker, with total revenue of $16.2 billion for 2009. The European Space Agency has chosen Thales Alenia Space (a Franco-Italian joint venture) and German group OHB to build Europe's next six weather satellites. The Meteosat Third Generation system, whose first spacecraft may launch in 2016, will significantly upgrade weather monitoring. Ten sites in Scottish waters have been leased to companies hoping to build up to 1.2 gigawatts of wave and tidal power by 2020 — about the same power as that provided by two nuclear plants. The schemes, announced on 16 March, mark the world's first commercial leasing round for marine energy. Installation of the projects will cost around £4 billion (US$6 billion). Click for larger image China will become the world's third largest market for pharmaceuticals by 2011, behind the United States and Japan. But most global drug companies are not yet tapping the full potential of emerging markets. The analysis comes from Pharmerging shake-up, a report released on 16 March by IMS Health, a market-intelligence company in Norwalk, Connecticut. The report focuses on 17 countries that IMS identifies as fast-growing markets — including China, Brazil, Russia and India. These markets are expected to account for 15.5% of global sales in 2009, but the world's largest drug companies derive on average only 9.4% of their sales there, and only 0.9% from China (see chart). "This reflects a continued focus on the premium section of the market rather than the typically larger branded generics segment," says the report. Multinational firms have been expanding research work in China, however. And, "as China shifts emphasis from traditional Chinese medicine to Western medicine, the multinationals are likely to gain," says Greg Scott, founder of ChinaBio, a consulting firm in Shanghai. Four-fifths of grants from a Chinese drug-discovery programme in 2008, for example, were used in Western-style drug development, he estimates. The International Energy Agency releases data on the costs of generating electricity by a variety of fuels and technologies — its first such report for five years. → go.nature.com/knH18f Progress on climate-change policy and the global Millennium Development Goals are among issues on the agenda of the 'State of the Planet 2010' conference, which will link up delegates in Beijing, London, Nairobi, New Delhi and New York. → www.stateoftheplanet.org The Global Conference on Agricultural Research for Development is held in Montpellier, France. It hopes to reshape agricultural research to better benefit the world's poorest people. → go.nature.com/BH1nrz — Number of computers dumped every year. — Number predicted by 2030. Most of these will come from developing regions. See go.nature.com/DvNxnc Source: Yu, J. et al. Environ. Sci. Technol. doi:10.1021/es903350q (2010). F. ROBERTS/NEWSCOM Grigory Perelman The reclusive Russian mathematician has won — but may not collect — the US$1-million Millennium Prize awarded on 18 March by the Clay Mathematics Institute in Cambridge, Massachusetts, for solving the Poincaré conjecture. He turned down a Fields Medal for the achievement in 2006. 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.
• Fossil finger points to new human species
  - Nature 464(7288):472 (2010)
  DNA analysis reveals lost relative from 40,000 years ago. In the summer of 2008, Russian researchers dug up a sliver of human finger bone from an isolated Siberian cave. The team stored it away for later testing, assuming that the nondescript fragment came from one of the Neanderthals who left a welter of tools in the cave between 30,000 and 48,000 years ago. Nothing about the bone shard seemed extraordinary. A finger bone found in Denisova Cave in Siberia could add a branch to the human family tree.B. VIOLA Its genetic material told another story. When German researchers extracted and sequenced DNA from the fossil, they found that it did not match that of Neanderthals — or of modern humans, which were also living nearby at the time. The genetic data, published online in Nature1, reveal that the bone may belong to a previously unrecognized, extinct human species that migrated out of Africa long before our known relatives. "This really surpassed our hopes," says Svante Pääbo, senior author on the international study and director of evolutionary genetics at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. "I almost could not believe it. It sounded too fantastic to be true." Researchers not involved in the work applauded the findings but cautioned against drawing too many conclusions from a single study. "With the data in hand, you cannot claim the discovery of a new species," says Eske Willerslev, an evolutionary biologist and director of the Centre for GeoGenetics at the University of Copenhagen. "I almost could not believe it. It sounded too fantastic to be true." If further work does support the initial conclusions, the discovery would mark the first time that an extinct human relative had been identified by DNA analysis. It would also suggest that ice-age humans were more diverse than had been thought. Since the late nineteenth century, researchers have known that two species of Homo — Neanderthals and modern humans — coexisted during the later part of the last ice age. In 2003, a third species, Homo floresiensis, was discovered on the island of Flores in Indonesia, but there has been no sign of this tiny 'hobbit' elsewhere. The relative identified in Siberia, however, raises the possibility that several Homo species ranged across Europe and Asia, overlapping with the direct ancestors of modern people. The Siberian site in the Altai Mountains, called Denisova Cave, was already known as a rich source of Mousterian and Levallois artefacts, two styles of tool attributed to Neanderthals. For more than a decade, Russian scientists from the Institute of Archaeology and Ethnology in Novosibirsk have been searching for the toolmakers' bones. They discovered several bone specimens, handling each potentially important new find with gloves to prevent contamination with modern human DNA. The bones' own DNA could then be extracted and analysed. When the finger bone was discovered, "we didn't pay special attention to it", says archaeologist Michael Shunkov of the Novosibirsk institute. But Pääbo had established a relationship with the Russian team years before to gather material for genetic testing from ice-age humans. After obtaining the bone, the German team extracted the bone's genetic material and sequenced its mitochondrial DNA (mtDNA) — the most abundant kind of DNA and the best bet for getting an undegraded sequence from ancient tissue. After re-reading the mtDNA sequences an average of 156 times each to ensure accuracy, the researchers compared them with the mtDNA genomes of 54 modern humans, a 30,000-year-old modern human found in Russia and six Neanderthals. The Denisova Cave DNA fell into a class of its own. Although a Neanderthal mtDNA genome differs from that of Homo sapiens at 202 nucleotide positions on average, the Denisova Cave sample differed at an average of 385 positions. The differences imply that the Siberian ancestor branched off from the human family tree a million years ago, well before the split between modern humans and Neanderthals. If so, the proposed species must have left Africa in a previously unknown migration, between that of Homo erectus 1.9 million years ago and that of the Neanderthal ancestor Homo heidelbergensis, 300,000 to 500,000 years ago. Study author Johannes Krause, also at the Max Planck Institute in Leipzig, says that the researchers are now generating nuclear DNA sequences from the bone with the hope of sequencing its entire genome. If they are successful, it would be the oldest human genome sequenced, eclipsing that of the 4,000-year-old Eskimo from Greenland that Willerslev and his colleagues reported last month2. A complete genome might also enable the researchers to give the proposed new species a formal name. They had originally planned to do so on the basis of the mtDNA genome. But they opted to wait until more bones are found — or until the DNA gives a clearer picture of its relationship to modern humans and Neanderthals. Willerslev emphasizes that, on its own, the mtDNA evidence does not verify that the Siberian find represents a new species because mtDNA is inherited only from the mother. It is possible that some modern humans or Neanderthals living in Siberia 40,000 years ago had unusual mtDNA, which may have come from earlier interbreeding among H. erectus, Neanderthals, archaic modern humans or another, unknown species of Homo. Only probes of the nuclear DNA will properly define the position of the Siberian relative in the human family tree. ADVERTISEMENT Anthropologists also want to see more-refined dating of the sediments and a better description of the finger bone itself. "I haven't seen a picture of the bone, and would like to," says Owen Lovejoy, an anthropologist at Kent State University in Ohio. "The stratigraphic age for the bone is 30,000 to 48,000 years old, but the mtDNA age could be as old as H. erectus," says Lovejoy. "That doesn't tell us much about human evolution unless it truly represents a surviving ancient species." The cave has yielded few clues about the culture of the Siberian hominin, although a fragment of a polished bracelet with a drilled hole was found earlier in the same layer that yielded the bone3. Pääbo suspects that other human ancestors — and new mysteries — may emerge as geneticists grind up more ancient bones for sequencing. "It is fascinating that molecular studies make a contribution in palaeontology where there is little or no morphology preserved," he says. "It is clear we stand just in the beginning of many fascinating developments." * References * Krause, J.et al. Naturedoi:10.1038/nature08976 (2010). * Rasmussen, M.et al. Nature463, 757-762 (2010). * Derevianko, A. , Shunkov, M. & Volkov, P.Archaeol. Ethnol. Anthropol. Eurasia34, 13-25 (2008). 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.
• Teams set for first taste of Antarctic lakes
  - Nature 464(7288):472 (2010)
  Samples could reveal unique life forms from beneath the ice. Click for larger image The pitch-black lakes hidden beneath Antarctica's ice sheet will finally start to release their secrets next year. At a meeting last week, scientists from Russia, the United Kingdom and the United States described their plans to explore the planet's last uncharted ecosystems by drilling into three very different examples of these subglacial lakes. Over the past 40 years, radar imagery has revealed around 150 freshwater lakes of various sizes and ages beneath the massive Antarctic ice sheet. Some have been isolated from the outside world for millions of years, raising the possibility that they hold unique life forms. The dark, nutrient-deprived environment of the lakes could resemble conditions on Jupiter's moon Europa, which is assumed to hold a large ocean beneath its frozen surface. Scientists have longed to draw samples from the lakes, but technical problems and environmental concerns have slowed their progress. Now, the Russian team expects to reach its quarry, Lake Vostok, by February 2011. The Americans and British will follow several years later with forays into lakes with different hydrological and geological characteristics (see graphic). "Over the next few years we'll be able to explore a continental-scale ecosystem that has never before been sampled," says Robin Bell, a senior researcher at Columbia University's Lamont-Doherty Earth Observatory in Palisades, New York. "This is a madly exciting endeavour." Lake Vostok is the best known and largest of the subglacial lakes, measuring roughly the size of Lake Ontario. Buried beneath almost 4,000 metres of ice in eastern Antarctica, the lake is thought to be 35 million years old and could host ancient microbial life. "It's like going fishing in the Everglades, in the Rocky Mountains and in Northern Canada." Russian drillers had planned to penetrate the lake in the 2008–09 Antarctic field season, but their drill got stuck 80 metres above the lake surface. All technical problems have been resolved during the past field season, says Valery Lukin, director of the Russian Antarctic programme, who spoke at the meeting, held by the American Geophysical Union in Baltimore, Maryland. Some researchers worry that a Russian success could come at the cost of biological and chemical contamination of the pristine waters. "Let's hope they don't spoil the lake," says Robert Bindschadler, a glaciologist at NASA's Goddard Space Flight Center in Greenbelt, Maryland. Lukin says that his country's team has come up with plans to safeguard Lake Vostok. The team will cut through the ice using a heated drill, with non-toxic silicone oil serving as the lubricating fluid. It will also explore the lake in stages; at first it will only suck up a water sample before allowing the bottom of the hole to refreeze. Plans for lowering instruments into the lake to explore the bottom sediment will be postponed until an extra environmental assessment has been completed. The Antarctic Treaty's committee for environmental protection is expected to approve the Russian plans in October, although there is no official requirement for the team to wait until then. "The Russians are trying very hard to do it right, and that means a lot," says Bell. At the meeting, US and British researchers described their longer-term plans for exploring subglacial lakes on the opposite side of the pole. Lake Ellsworth, a relatively small lake in western Antarctica, is the target for researchers from the British Antarctic Survey. And over the next two field seasons, US researchers will conduct radar surveys from the surface to study Lake Whillans near Antarctica's Ross Ice Shelf, says Ross Powell, a geologist at Northern Illinois University in DeKalb. The US$20-million Whillans Ice Stream Subglacial Access Research Drilling (WISSARD) project, which Powell oversees, plans to drill into the lake during the 2012–13 field season. Lake Whillans has a subsurface connection with the ocean beneath the ice shelf, making it more dynamic than isolated lakes such as Vostok. "We know that the lake surface is constantly falling and rising, and we assume the lake is occasionally draining and refilling completely," says Powell. ADVERTISEMENT The ebb and flow of lakes such as Whillans are thought to influence the movement of the overlying ice sheet. The WISSARD team will study processes at the interface of ice and water that affect the movement. With so many drilling projects, "it's like going fishing in the Everglades, in the Rocky Mountains and in Northern Canada", says Bell. "The catch will be very different and we're going to learn a lot." 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.
• Fixing a grant system in crisis
  - Nature 464(7288):474 (2010)
  Facing a flood of applications from researchers, a UK funding agency is taking drastic steps. The United Kingdom's physical-sciences funding council is struggling to find scientists to peer review the 5,000 grant applications it receives every year.M. FERMARIELLO/SPL Like every scientist, Philip Moriarty has experienced the pain of a failed research application. But the e-mail that he received on 21 January from the UK Engineering and Physical Sciences Research Council (EPSRC) was a far more personal rejection. Moriarty, a physicist at the University of Nottingham, had been identified as a "repeatedly unsuccessful" applicant, said the e-mail, which was copied to his university's research office. Under a new EPSRC policy that comes into full effect on 1 April, he is now in a year-long 'cooling-off' period, limiting him to making only one funding bid to the council in that time. Previously, there was no limit — in principle — to the number of applications that scientists could make. "The thing that really hacks me off is the unfairness of the scheme," says Moriarty, who in 2008 was awarded an EPSRC 5-year, £1.5-million (US$2.3-million) leadership grant designed to fortify "talented researchers". "There is no evidence at all to suggest that peer-review panel rankings are sufficiently robust to be used in the way the EPSRC has introduced," he says. Moriarty is one of around 140 researchers whose applications the agency — Britain's main funding body for physical sciences — will start to ration next week. Although some scientists are not troubled by the policy, others have tagged it "blacklisting" and "draconian". "No one is supportive of this crazy scheme," says Amalia Patanè, a physicist also at the University of Nottingham who has been told — along with 450 other scientists — that one more rejected application could put her on the cooling-off list too. Click for larger image The step by the EPSRC, which plans to spend £815 million on research and training in the 2009–10 fiscal year, is just one of a series of measures designed to relieve pressure on an overloaded system. Although 43% of applications to the council were funded in 2000, by 2008 that proportion had dropped to 26% (see 'Poor odds'). At the same time, the council has faced an increasingly difficult challenge finding peer reviewers to look at the roughly 5,000 proposals it receives annually. In addition to imposing the new rule, the EPSRC has already begun refusing uninvited resubmissions of failed proposals. For the moment, the policies seem to be working: the agency has received around 35% fewer applications than this time last year, says Clive Hayter, the council's associate director for research. Click for larger image With submission rates on the rise and grant success rates plummeting around the world (see 'A common problem'), other funding agencies in the United States, Europe and Asia are taking note of the EPSRC's approach. Most say that they face similar pressures — and that if the situation got worse they would be willing to consider similar drastic steps. "These rules are more sensible than I would have feared," says one official at the US National Science Foundation who asked not to be named. Although he had initially thought that the EPSRC's move was too drastic, he now says that "I could see this being proposed and discussed here". Three strikes and you're out The EPSRC is caught between a flat budget (adjusted for inflation) and the rising demands of researchers. The number of applications has remained constant since 2000, but the agency has been pushing to award fewer, larger grants. As a result, success rates have plummeted. Last year, some of the council's panels — which rank research proposals that have already been peer reviewed — awarded funds to fewer than 15% of applications. A 2006 report by Research Councils UK, the umbrella body for the seven UK research councils, assessed the efficiency and value for money of peer review (see www.rcuk.ac.uk/research/peer/efficiencypr.htm). The report found that such low success rates at the EPSRC have "significantly degraded" the system, says Hayter. Scientists were avoiding submitting high-risk proposals for fear of almost certain rejection, hoping instead that safe, incremental research would be more likely to be funded in a system that was increasingly seen as a lottery. Overall, this damages the quality of the science produced by the researchers that the council funds, says David Delpy, chief executive of the EPSRC. "It's a burden on the community," adds Hayter. "Our goal is to ask the community at large to change its behaviour." To push that change, the agency announced in 2009 that scientists would be immediately barred from applying for grants for one year if they met two conditions: that they were principal investigators on at least three proposals that fell in the bottom half of panel rankings over a two-year period; and that their overall success rate was below 25%. This 'three strikes and you're out' rule set off a storm of protest, and was subsequently delayed and softened to the current policy of one submission per year (see Nature 459, 20; 2009). "Poor scientists being blacklisted doesn't bother me," says Mike Glazer, a physicist at the University of Oxford. The problem, he says, is that the system doesn't just exclude scientists who keep submitting bad proposals — it can also exclude promising scientists hit by a run of bad luck in their applications. Tom Welton, head of chemistry at Imperial College London, adds that "when you do something that affects somebody's career, you'd better be sure you're doing it right". "When you do something that affects somebody's career, you'd better be sure you're doing it right." Many researchers that Nature asked to comment on the scheme did not want to be named. But some worry that the exclusion will create a stigma that could particularly damage younger researchers — especially because their identities are disclosed to their institutions. "It isn't about naming and shaming," responds Hayter. He argues that if an institution is going to help researchers change their submission behaviour, then it has to know who they are. Hayter, who signs each letter to the targeted researchers, hopes that the rules will be only temporary. If the community can learn to send in fewer applications and the EPSRC can sustain success rates of 30–40%, "I think we'll be willing to relax our measures", he says. Measured response Granting agencies in other countries face similar challenges. Applicants to the US National Institutes of Health (NIH) in Bethesda, Maryland, had a success rate of just 22% in 2008, and a recent flood of pitches for stimulus funding hasn't helped to improve that number, says Sally Rockey, the NIH's acting director of extramural research. The Japan Society for the Promotion of Science (JSPS), a funding body affiliated with the Japanese education ministry, has a success rate of around 25% for its Grants-in-Aid for Scientific Research, the bread-and-butter funding stream for the country's scientific community. The DFG, Germany's main research agency, has a success rate of 47%, but it is under less pressure because scientists in Germany can receive more of their funding directly from their universities, compared with their colleagues in the United Kingdom or the United States. In trying to address the problem, these agencies have taken a more egalitarian approach than the UK council. In Japan, for example, a stagnant budget and increasing number of grant applications have led funding bodies to decrease the size of individual grants. But Ichiro Kanazawa, president of the Science Council of Japan, which acts as an advisory body to the government, worries that this trend is compromising scientists' ability to do the research they promise in their applications. In the United States and Germany, funding agencies have cut down the length of proposals in the hope that shorter applications will reduce the workload of grant officers and peer reviewers. The DFG announced last month that it would drastically restrict the number of publications that researchers can list in their grant applications (see Nature 463, 1009; 2010). But requiring shorter grant requests could actually make it easier for scientists to bombard the agency with applications, says Rockey. Neither Rockey nor other officials contacted by Nature felt that they had a good solution to the problem. So for now, they would rather watch the EPSRC experiment than implement tougher measures themselves. Rockey says that the NIH had considered allowing reviewers to reject a proposal without the possibility of resubmission, but the research community revolted. Many feared the stigma that such a policy would create, especially in the US biomedical community, where researchers' careers can depend on the number of grants they pull in. In Japan, granting bodies are becoming increasingly desperate to deal with growing pressure on their grant systems, but "we have no concrete measures and are unlikely to come up with any that could overcome criticism", says Hiroshi Takahashi, a programme director at the Japan Science and Technology Agency in Tokyo, which is affiliated with the education ministry and handles larger grants than the JSPS. ADVERTISEMENT Despite fears that UK scientists would stage mass protests over the more stringent grant procedures, as they did after last year's tougher proposal, most UK researchers now seem resigned to taking part in the funding experiment. "The only thing we can do is let it play out — and evaluate any unintended consequences," says Welton. A few, however, have simply opted out of the system. Martin McCoustra, a chemical physicist at Heriot-Watt University in Edinburgh, who also received a blacklisting e-mail, says that he will turn down any requests from the EPSRC to review proposals. For other scientists, the EPSRC's policy has permanently soured their relationship with the agency. As Tom Simpson, a chemist at the University of Bristol and a fellow of the Britain's Royal Society, says: "While having some sympathy with the situation that the EPSRC finds itself in, I really believe that it is treating the community in the shittiest way conceivable." 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.
• China boosts African research links
  - Nature 464(7288):477 (2010)
  Expanded programme of academic collaboration promised. Is Africa benefiting from Chinese expertise?O. Asselin/New York Times/Eyevine Next week, representatives of dozens of African countries will gather in Beijing to firm up a broad programme of economic and scientific partnerships with China. It is the latest evidence that China's efforts to strengthen ties with Africa are increasingly focused on science and technology. The Forum on China–Africa Cooperation (FOCAC) — which includes 49 African countries — will launch clean-energy projects, agricultural initiatives and training programmes. It will also see the inauguration of the China–Africa joint research and exchange programme, which aims to set up research collaborations and academic visits between the partners. China's government has not disclosed what it will spend on these plans, and its past efforts to boost African science have had mixed results. Many Western powers and some Africans are also wary of Chinese aid. "Its real intentions are well known: to elbow out all foreign companies and gain access to Africa's resources at cheap prices," said George Ayittey, a native of Ghana and an economist at American University in Washington DC, in an online debate in February sponsored by The Economist. Chinese politicians counter that their goal is mutual benefit, and point to the tangible improvements that their partnership has already brought to African nations. According to China, an 'eight-step commitment' that was begun in 2006 has since given training to 15,000 professionals, including scientists. China has also started construction on 26 hospitals and completed 30 centres for the prevention and treatment of malaria, which offer drugs based on artemisinin, derived from a herb used in Chinese traditional medicine. At FOCAC's fourth ministerial meeting, held in the Egyptian city of Sharm el-Sheikh in November 2009, China's Premier Wen Jiabao laid out a much more ambitious set of cooperative measures for the next three years (see 'Bold plans for Africa'). A planned network of agricultural technology centres will receive three years of financial and technical support to develop technologies relating to rice, fisheries or biomass, for example. Those that succeed in developing commercial products will get another five years of support from China. This mixture of aid and investment is a hybrid that explicitly tries to foster new business, says Deborah Brautigam, an international-development scholar at American University. "The Chinese government is hoping there will be a commercially oriented operation that would profit both sides." Promises, promises The goal of next week's meeting is to turn these promises into reality by fleshing out the details of how and when to implement each part of the proposed plan. "The track record of the Chinese government fulfilling its pledges towards Africa is strong, so I would anticipate the new pledges will be fulfilled," says Jing Gu, a researcher at the non-profit Institute of Development Studies in Brighton, UK. But some scientists in Africa say that past efforts have not been as successful as China claims. "China's visibility is very high in trade and business but quite low in science and technology," says Kazhila Chinsembu, a molecular biologist at the University of Namibia in Windhoek. Chris Whiteley, a enzymologist at Rhodes University in Grahamstown, South Africa, says that he has had a series of frustrating collaborations with Chinese researchers, and was unaware of FOCAC's efforts. Although his collaborations produced several research articles, Whiteley says that he often had to pay for his own trips despite being told that there would be funding available. "In my mind there are a lot of verbal promises but not much action," he says, adding that he is hopeful that new FOCAC commitments will improve the situation. Other researchers argue that China's efforts aren't always tailored to Africa's needs. For example, China already sponsors long-term training programmes for African students, who move to China for several years, taking language courses while they study science in Chinese. Students see the experience as a good career move, but once they return to Africa, "the calibre of such scientists is very low", says Chinsembu, noting that the students struggle to assimilate scientific concepts in a foreign language. "Most cannot pass local examinations here in African universities." ADVERTISEMENT Another problem, Chisenmbu says, is that once scientists return from China they are given no funding or equipment to put their training to work. "It is like the umbilical cord has been cut off," he says. He says that with more support, his university, which carries out research on traditional medicine, could benefit from China's experience. "I wish we could do more," he says. Kenneth King, an African-studies specialist at the University of Edinburgh, UK, says that FOCAC's programme of short courses for African professionals is larger than that of any other nation except perhaps Japan. He estimates that science and technology subjects account for more than 60% of the courses under the eight-step commitment, and applauds the fact that they are conducted in English or French. King questions, however, how much good the short courses, which only run for one to two months, can achieve. "Is this form of short-term training exactly what African countries wanted?" he asks. "It is difficult to 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.
• Turkish law could cripple bioscience
  - Nature 464(7288):478 (2010)
  Research involving transgenic organisms may be strangled by red tape. In most countries, molecular biologists can place an order for a particular genetic strain of fly and be working on it within weeks. The same is true in Turkey — for now. But under a new law approved by the Turkish parliament on 18 March, scientists' access to these laboratory staples could face delays of up to a year, or even be denied. The legislation was intended to control the use of genetically modified plants in agriculture, in response to popular mistrust of the technology. But it extends to all transgenic organisms, with no exceptions made for those used in research — the law was formulated without consulting molecular biologists on the implications (see Nature 463, 1000; 2010). "It is hard to see how we will be able to do any experiments at all." After the law comes into effect, in around six months, scientists will have to apply to a new Biosafety Council within the agriculture ministry for approval to import individual strains of any transgenic organism, or to conduct any experiment involving genetic manipulation. Up to 105 days are allowed for each decision, but scientists fear that the system will quickly become clogged up, causing huge delays. The law also bans the breeding of genetically modified plants and animals. "I am scared," says fly geneticist Arzu Çelik at Boğaziçi University in Istanbul. Three years ago, Çelik won a prestigious European Molecular Biology Organization Installation Grant, which allows young scientists to return to their home country and set up an independent lab there. "We don't know what will happen — according to the law, we won't be able to make the simplest genetic construct," she says. "It is hard to see how we will be able to do any experiments at all," adds cancer researcher Mehmet Öztürk of Bilkent University in Ankara, whose research uses knockout mice, in which specific genes are silenced. Creating the mice requires breeding over several generations. ADVERTISEMENT Some are nursing the forlorn hope that Turkey's president will hear scientists' pro­tests and exercise his constitutional right to return the bill to parliament for reconsideration, or that regulations govern­ing how the law is applied will soften the impact for research. Given that the law is at odds with Turkey's aim of strengthening its biomedical research base, others speculate that it will not be rigorously enforced for researchers. But that assumption could be risky, says plant geneticist Selim Çetiner at Istanbul's Sabanci University, not least because the new law mandates up to 12 years' imprisonment for non-compliance. 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 health bill promises changes for biomedical researchers
  - Nature 464(7288):479 (2010)
  Translational work set to receive a boost. Barack Obama applauds the health reform bill.P. Souza/CNP/Newscom The historic health-care bill that passed the US House of Representatives on 21 March includes several lesser-known provisions that will significantly affect biomedical researchers, teaching hospitals and the biotechnology industry. The final legislation, which is expected to become law, would establish a new competitive grant programme at the National Institutes of Health (NIH). Called the Cures Acceleration Network (CAN), this provision was written into the law by Senator Arlen Specter (Democrat, Pennsylvania). It will authorize as much as US$500 million annually for speeding the translation of basic discoveries into treatments, through individual awards of up to $15 million per year. The CAN would be separate from an already existing NIH programme called Clinical and Translational Science Awards, which has a budget of roughly $483 million in 2010. The CAN programme comes without the guarantee of new money, and how it will be funded remains unclear. Advocates for basic research are worried that if Congress does not increase the NIH budget, funding might be pulled from its flagship, investigator-initiated R01 awards. "There has already been a long slide or stagnation in the funding of the gold standard: the R01," says Mark Lively, president of the Federation of American Societies for Experimental Biology in Bethesda, Maryland. "We would be concerned that any mandate that would require the NIH to move money to the CAN could very well come at the cost of losing still more R01s." Another provision in the bill will expose relationships between physician researchers and the medical industry. From 2013, companies will have to report to the Department of Health and Human Services every payment in cash, stock or kind of more than $10 they make to physicians and to teaching hospitals, in gifts, entertainment, and for services such as consulting and public speaking. The department will post the payments in a publicly accessible database. Companies that produce biologics — complicated and expensive protein-based drugs — do well out of the legislation. The new law will effectively guarantee 12 years of exclusive market access for makers of brand-name biologics before generic competitors can produce 'biosimilars', which mimic the original molecules. This provision is part of language that establishes a regulatory path by which makers of biosimilars can win marketing approval from the Food and Drug Administration (FDA). The European Union opened just such a regulatory path in 2005; the European Medicines Agency has since approved 14 such drugs. When Congress considered similar biologics legislation in 2008, the Congressional Budget Office estimated that its provisions for FDA approval of biosimilars would save about $25 billion over ten years by driving down prices of biologic drugs. ADVERTISEMENT Jim Greenwood, the president and chief executive of the Biotechnology Industry Organization, a lobby group based in Washington DC, said that the law "will lead to new and improved treatments, cures and cost-savings for patients, while driving job growth in our industry". But Kathleen Jaeger, president of the Generic Pharmaceutical Association, also based in Washington DC, lamented the pathway's "excessive and unprecedented market exclusivity protections for the brand industry". Generics makers and their congressional allies had sought to limit brand-name exclusivity to six years. 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.
• Correction
  - Nature 464(7288):479 (2010)
  The News story 'Science survives Canadian budget' (Nature 464, 153; 2010) gave the wrong affiliation for Paul Dufour: he is head of the science-policy consultancy Paulicyworks based in Gatineau, Quebec. 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.
• Ageing: Much ado about ageing
  - Nature 464(7288):480 (2010)
  Questions about a laboratory assay are making Sirtris, a high-profile biotechnology company, the talking point of the ageing field. Heidi Ledford investigates. Download a PDF of this story Konrad Howitz wasn't looking for a fountain of youth. As director of biochemistry at BIOMOL International in Plymouth Meeting, Pennsylvania, Howitz wanted to add new molecular assays to the company's catalogue. A protein called a sirtuin had recently been shown to lengthen lifespan in yeast1, and Howitz was developing methods to measure the activity of one of its mammalian forms, called SIRT1. But when Howitz and his team stumbled on the discovery that a compound called resveratrol seemed to activate SIRT1, they quickly realized the implications. Resveratrol was rumoured to be the ingredient in red wine that kept the French healthy. In 2003, Howitz shared his findings with David Sinclair, a molecular biologist at Harvard Medical School in Boston, Massachusetts, who had studied sirtuins extensively. Sinclair immediately saw commercial potential for resveratrol as a human anti-ageing drug. Fearing corporate espionage, Sinclair code-named the compound 'R'. A year later, 'R' became the centrepiece of Sirtris, a company Sinclair co-founded in Cambridge, Massachusetts. Four years after that, Sirtris became a biotechnology success story when London-based pharmaceutical giant GlaxoSmithKline (GSK) purchased it for US$720 million. Yet behind the scenes, researchers have been voicing concerns about some of the research that forms the basis for the company. Most recently, questions have resurfaced2 over whether the interpretation of Howitz's original SIRT1 assay3 was flawed. It is a technical debate with big implications, not just for Sirtris but also for the rapidly expanding research community that is now studying sirtuins. Some researchers are questioning whether resveratrol, and other compounds like it that Sirtris is now testing in clinical trials, really does activate sirtuins. Until the mechanism is clear, they are cautious about pursuing drugs that might have unanticipated biological targets and effects. "It is an exciting time in the ageing field," says Brian Kennedy, a molecular biologist at the University of Washington in Seattle. "But this issue has had a polarizing effect. It needs to be resolved." Helped in no small part by Sirtris's public-relations efforts, sirtuins have been trumpeted in the press as the key to boosting human lifespan. The compounds have a compelling biological narrative: Sinclair and others have proposed that resveratrol and other SIRT1 activators imitate the effects of 'caloric restriction', a drastic reduction in calories that lengthens lifespan in some animals. Compounds that activate sirtuins might therefore have all the benefits of caloric restriction without the starvation. Seeing the light Those were the exciting implications when, in 2003, Howitz, Sinclair and their colleagues showed that sirtuin activators could extend yeast lifespan by 70%. Their paper, published in Nature3, also showed results from Howitz's assay. The sirtuins are members of a class of enzyme called deacetylases, which strip acetyl groups from proteins. To measure this activity, Howitz designed an acetylated protein fragment bearing a chemical tag. When activated, SIRT1 deacetylated this peptide substrate and the tag started to fluoresce. The greater the activity of SIRT1, the greater the fluorescence — and in the paper, resveratrol and other chemicals thought to activate SIRT1 generated a mighty glow. Doubts about the assay first surfaced publicly two years later. Two papers4,5 showed that resveratrol boosted the activity of SIRT1 only when its peptide substrate contained the fluorescent tag: no tag, no activity (see graph). The papers caused a stir in the field, but failed to register among investors or the public. "The sirtuin stuff has just sort of been a runaway train," says Kennedy, who was lead author on one of the papers4. "We might have caused the train to wobble a little, but it kept barrelling down the tracks." Click for larger image The assay controversy wasn't the only stone on the tracks. Some labs have been unable to consistently reproduce Sinclair's life-extending results in model organisms such as fruitflies and nematodes6, and debate has simmered over whether SIRT1 activation truly mimics caloric restriction. For Sirtris, however, the arguments have little practical bearing — the company hopes to market its drugs as a way to stave off diabetes and other diseases associated with ageing, rather than a way to extend lives. And by 2006, Sinclair and his colleagues had shown that resveratrol improved the health of mice fed extremely high-fat diets7. Then, in a high-profile Nature paper published at the end of 2007, Sirtris unveiled a set of compounds that its researchers said were 1,000 times more potent than resveratrol8. In April the following year, GSK announced that it planned to purchase the tiny biotech for $22.50 per share, nearly double its $12 trading price. In the paper, the team used mass spectrometry instead of the fluorescence assay to show that resveratrol and the more potent newcomers activated SIRT1, allaying some researchers' concerns. "A lot of people read 'mass spec', considered that a different assay, and moved on," says Joseph Baur, a molecular biologist at the University of Pennsylvania in Philadelphia and a former member of Sinclair's lab. Yet closer inspection showed that the peptides used in the mass spec experiments still carried a fluorescent tag, hinting that this assay, too, worked only when the tag was present. "That should have thrown up a red flag to one of the reviewers, but apparently it did not," says Ronen Marmorstein, a structural biologist at the Wistar Institute in Philadelphia, Pennsylvania. Sinclair says that they used peptides originally prepared with a fluorescence screen in mind. When they switched to mass spectrometry, they simply used the substrates they had on hand. The debate blew up again this year when a team led by Pfizer researchers in Groton, Connecticut, published a paper in the Journal of Biological Chemistry2. The group claimed that several of the new Sirtris compounds did not activate SIRT1 without the fluorescent tag. Worse, they presented evidence that the compounds were inhibiting a slew of other proteins — and some of the mice taking high doses of the drugs died. The paper concluded that the Sirtris compounds and resveratrol were pharmacological dead-ends owing to "their highly promiscuous profiles". Biotech blogs have been abuzz about Sirtris ever since. What did GSK know about these problems before it bought the company? Do the drugs work as claimed? Do they confer metabolic benefits at all? Most researchers seem to agree with Sirtris that the SIRT1-activating compounds do have beneficial effects in mice. Rafael de Cabo at the National Institute on Aging in Baltimore, Maryland, and a co-author on the 2006 Nature paper, says that he has safely tested one of the compounds, SRT1720, in more than 1,000 mice, some of which received the compound for two years. At least three other groups have published data showing that SRT1720 is beneficial and non-toxic in mice9,10,11. But the debate about how the compounds act rages on. Some interpret the Pfizer results to mean that the assay had yielded an artefact, and the compounds, resveratrol included, may not act on SIRT1 at all. "If this drug is just binding to this fluorigenic group, then why would it really talk to SIRT1 in vivo?" asks Kennedy. Instead, the compounds might be acting directly on the tag, and they could be bestowing beneficial health effects by acting on other, unknown, targets. "The sirtuin stuff has just sort of been a runaway train." Sinclair, Howitz and their colleagues at Sirtris acknowledge that the assay does not work with some substrates in the absence of a fluorescent tag. But they stand by their argument that the drugs are acting on SIRT1, saying that when the peptide is attached to the fluorophore, it mimics a natural SIRT1 substrate found in the cell. "To my mind, these results are structural clues," says Howitz, who says that the biochemical data in the Pfizer group's paper are solid. Howitz, whose company is now called ENZO Life Sciences, says that the assay was still worthwhile because it yielded drug candidates that are looking promising in follow-up work. If the assay was useless, Sinclair points out, then it would have been highly unlikely to have repeatedly identified compounds that all identically improve the health of mice. "What's going on? These compounds just happen to hit random targets in the cell and most targets just happen to lower blood sugar, increase endurance and boost mitochondrial function?" asks Sinclair. "I wish finding drugs was that easy." In fact, several companies, including GSK, dropped their pursuit of SIRT1 activators after the results of their high-throughput fluorescence screens failed to stand up to closer scrutiny. A former GSK employee says that the firm's internal hunt for SIRT1 activators was killed well before the Sirtris deal. The same fate met putative SIRT1 activators fished out of a screen at Elixir Pharmaceuticals, a company founded two years before Sirtris, says chief scientific officer Peter DiStefano. Whereas Sirtris's fortunes soared, Elixir is now down to five employees at its office in Cambridge, Massachusetts. The same fate might have met Sirtris's programme, says Baur, but for the compelling animal data from Sinclair's lab and from the company itself. Ad Rawcliffe, head of worldwide business development at GSK, said in a statement that the company was aware of the controversies surrounding the fluorescence-based assays before it purchased Sirtris. GSK fully evaluated those risks, he says, and remained "confident that the consistency of the activity in cell-based and animal studies is driven through a SIRT1-dependent mechanism". Not everyone shares that confidence, but few are willing to dismiss sirtuin activators until they see the outcomes of Sirtris's clinical trials. These include phase IIa trials against type 2 diabetes, inflammation and cardiovascular disease. Meanwhile, the field is intent on working out exactly how resveratrol and these compounds act, something that is likely to be important for drug development, says Marmorstein. "If something goes wrong with the compound, you can't modify it based on an understanding of sirtuin function if you don't know that is the target." ADVERTISEMENT Several academic labs hope to tackle the assay question head on. Anthony Sauve, an enzymologist at Weill Cornell Medical School in New York and a member of Sirtris's scientific advisory board, is considering treating cells with SIRT1 activators to look for 'native' substrates that are deacetylated by SIRT1. And biologist Leonard Guarente from the Massachusetts Institute of Technology in Cambridge, whom Sinclair calls the "grandfather" of the sirtuin field and who is co-chair of Sirtris's scientific advisory board, says he is so anxious to have the matter resolved that his lab may begin a hunt for other proteins that may be required to activate SIRT1 alongside resveratrol. At Sirtris, the labs are just as intent on clarifying how the drugs work, says company president George Vlasuk. "I care what the mechanism is," he says. "I think everybody cares what the mechanism is." * References * Kaeberlein, M. , McVey, M. & Guarente, L.Genes Dev.13, 2570-2580 (1999). * Pacholec, M.et al. J. Biol. Chem.285, 8340-8351 (2010). * Howitz, K. T.et al. Nature425, 191-196 (2003). * Kaeberlein, M.et al. J. Biol. Chem.280, 17038-17045 (2005). * Borra, M. T. , Smith, B. C. & Denu, J. M.J. Biol. Chem.280, 17187-17195 (2005). * Bass, T. M. , Weinkove, D. , Houthoofd, K. , Gems, D. & Partridge, L.Mech. Age. Develop.128, 546-552 (2007). * Baur, J. A.et al. Nature444, 337-342 (2006). * Milne, J. C.et al. Nature450, 712-716 (2007). * Liu, Y.et al. Nature456, 269-273 (2008). * Feige, J. N.et al. Cell Metab.8, 347-358 (2008). * Yamazaki, Y.et al. Am. J. Physiol. Endocrinol. Metab.297, E1179-E1186 (2009). 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.
• Physics: The Large Human Collider
  - Nature 464(7288):482 (2010)
  Social scientists have embedded themselves at CERN to study the world's biggest research collaboration. Zeeya Merali reports on a 10,000-person physics project. Download a PDF of this story. "I am here to watch you." So began anthropologist Arpita Roy when introducing herself in 2007 to a roomful of particle physicists. At the time, those scientists were racing to finish work on the world's biggest machine, the Large Hadron Collider (LHC) at CERN, Europe's high-energy physics laboratory near Geneva, Switzerland. The LHC carries the hopes of generations of physicists, who have designed it to reach energies never before achieved in a collider and — possibly — to produce a zoo of particles new to science. But the LHC is also a huge human experiment, bringing together an unprecedented number of scientists. So in recent years, sociologists, anthropologists, historians and philosophers have been visiting CERN to see just how these densely packed physicists collide, ricochet and sometimes explode. "The LHC allows a unique sociological study of how an experiment develops in real time: how scientists form opinions, make technical decisions and circulate knowledge in such a big project," says Arianna Borrelli, a particle physicist and philosopher of physics at the University of Wuppertal in Germany. Sergio Bertolucci, CERN's research director, is acutely aware of the importance of cohesive collaboration. "This is an incredible social experiment," he says, noting that roughly 10,000 physicists around the world are taking part in the LHC experiments and 2,250 of them are employed at CERN. Just reflecting on the size of the collaboration he co-manages makes Bertolucci's head ache. "Imagine the organization needed when 3,000 people all want to know in advance if they can go home for Christmas," he says. Managers at CERN have endured a series of headaches since the LHC powered up in September 2008. A little more than a week after the collider came online, a faulty electrical coupling caused an explosion that brought the project to a halt for 14 months. That setback demoralized the scientists at CERN, particularly the graduate students, who worried about the fate of their degrees, says Roy. A graduate student herself, from the University of California, Berkeley, Roy has been camped out at CERN on and off for three years to observe the "language, taboos and rituals of this exotic community". The collider restarted in November 2009 and should gather two years of data before it shuts down for a year of scheduled upgrades in 2012. Next month, the LHC is expected to achieve record energies of 7 teraelectronvolts. The collider will reach such an extreme by accelerating two beams of protons to nearly the speed of light and then sending them in opposite directions around a 27-kilometre underground track. The beams cross each other at four spots along the ring, and it is here that the real science happens, within giant detectors surrounding each collision zone. The two biggest particle detectors, A Toroidal LHC Apparatus (ATLAS) and the Compact Muon Solenoid (CMS) experiment, are the size of apartment buildings and each boasts a team of nearly 3,000 people. Population explosion Each generation of collider has brought a jump in the size of the experimental collaborations (see graph, below), a trend that provides ample opportunities for researchers interested in human interactions. Karin Knorr Cetina, a sociologist at the University of Constance in Germany, is one of the few social scientists to have witnessed this growth directly over multiple generations. She has been studying CERN's collaborations for almost 30 years. Click for a larger version.SOURCE: CERN; FERMILAB When Knorr Cetina first arrived, physicists there were working on a smaller collider and their detector teams were less than one-tenth the size of today's. "In those days 100 people in a team was considered huge," she says. Knorr Cetina says she was met with friendly bemusement by particle physicists, who were helpful, but thought of a sociologist "as a poor cousin of real scientists". That attitude continues today, says Roy. "What can you say? Physicists are professionally contemptuous," she says. Social scientists say they earn the trust of the physicists at CERN by immersing themselves in the culture, just as they would with any other population. Knorr Cetina used this approach to unravel the politics of peacekeeping among the thousands of scientists at the lab. When she first started, she says, "I expected the same lines of command we know from other complex organizations — industry or government". But she didn't find that hierarchy at CERN. Although there are spokespeople who hold positions of authority in the collaboration, there is no top-down decision-making because there are so many highly specialized teams working on different parts of the detector. Knorr Cetina says that at CERN, "the industrial model cannot work. One human simply cannot make technical decisions on such a large scale. CERN's unconventional structure stems in part from its history and philosophy. The lab was established on the Swiss–Franco border in 1954 to unite a Europe that had been fractured by war. "It's a place for global collaboration, where science exists beyond the politics of nationality," says Bertolucci. But within the lab, the idealism runs into the tensions of conducting actual research. "The paradox is that science is not democratic; we don't determine who is right by a vote or the majority decision." "It's a cognitive bubble that you can't escape — that you don't want to escape." If not an industry or a democracy, what is the structure? Knorr Cetina says that CERN functions as a commune, where particle physicists gladly leave their homes and give up their individuality to work for the greater whole. The communal lifestyle is encouraged by the fact that the laboratory stands on its own international territory. "Even the Swiss police cannot come in and grab us," says Bertolucci. It has its own restaurants, post office, bank and other facilities. "You can live forever within CERN, without ever needing to visit nearby Geneva," says Knorr Cetina. "It's a cognitive bubble that you can't escape — that you don't want to escape." Bertolucci says that this immersion is essential to CERN's success as a global enterprise. "People coming here from around the world don't feel like they are visiting someone else's country, they feel they are coming home." "The laboratory does feel like a commune with so many people coming from around the world to work towards a collective goal," says Kevin Black, a postdoc with the ATLAS collaboration. Sacrificing identity Around the CERN campus, the atmosphere is welcoming, and its two restaurants live up to their reputation for offering some of the best food of any physics canteen in the world. But it takes more than comfort and the promise of discovering new particles to persuade thousands of physicists to join the commune. Knorr Cetina points to the organizational structure of the collaborations as a factor that leads physicists to sacrifice their identity to the LHC. As a window into that structure, she describes the evolution of the LHC's largest experimental collaboration, the ATLAS team, which she has studied since its formation in the late 1980s from the remnants of older groups at CERN. ATLAS will be looking for, among other things, the elusive Higgs particle, hypothesized to give other elementary particles their mass. During the 'birth stage' of the ATLAS collaboration, LHC management had to choose between various proposals for detector designs offered by rival groups at different universities and institutes. It might seem that the most obvious and efficient strategy would be for a committee of experts to a make a decision about which technology to use. However, the ATLAS group did not take that path, says Knorr Cetina. Instead, the birth stage was a laborious process in which competing groups were repeatedly sent back to retest their designs, until they all agreed on a single plan. In this way, they avoided alienating groups and losing the manpower needed to build the detector. "It's an interesting strategy to get groups to accept losing out, yet remain committed to the collaboration," says Knorr Cetina. This prolonged process inevitably delayed construction. Physicists at the lab laugh that there are still brochures at CERN that advertise "the start-up of the LHC coming in 2000" — a deadline that was missed by almost a decade. Such delays were no doubt frustrating for physicists but, at least in some cases, they were the necessary cost of keeping the collaboration together, says Knorr Cetina. Albert de Roeck, deputy spokesman for the CMS experiment, notes other practical reasons behind the strategy. "Spokespersons are considered to be the 'bosses' of the experiment, but we actually have no means of enforcing tyrannical decisions," he says. In industry, if people don't agree with you and refuse to carry out their tasks, they can be fired, but the same is not true in the LHC collaborations, he says. "On our experiments, physicists are often employed by universities, not by us." John Krige, a historian at the Georgia Institute of Technology in Atlanta who studied the collaboration structure at CERN before the formation of ATLAS, agrees that there is no simple top-down decision-making at the laboratory. However, he notes that the word "commune" implies that there is little rivalry between the members of the collaboration. By contrast, he says, the collaboration thrives on healthy "organized competition" between subgroups working to build different components for the detector quickly and effectively. Like a giant commune, members of the ATLAS collaboration work, eat and party together.C. MARCELLONI/CERN Now that the collider is running, there are other policies within the collaborations that reinforce the communal over the individual, essentially divorcing physicists from ownership of their research, says Knorr Cetina. All papers containing experimental results must list the name of every member of the thousands-strong collaborations alphabetically by country, giving little hint of the real originators of the work. "This could never happen in biology, where the most intense disputes are about publishing, and reputations are established by your publications," says Knorr Cetina, who has also studied the lab life of molecular biologists. "So much of the narrative of science is about the genius of the individual — even the Nobel can only be shared by three people," says Maria Ong, a sociologist at TERC, an education research collaborative in Cambridge, Massachusetts. "The LHC is an amazing anti-example of that." Who can review? Collective authorship opens up questions about the construction of knowledge in particle physics, says Peter Galison, a historian at Harvard University in Cambridge, Massachusetts. In February, the CMS collaboration published its first paper based on an analysis of LHC data that showed that a larger than expected number of exotic particles, known as mesons, were produced during the first collisions (CMS Collaboration J. High Energy Phys. doi:10.1007/JHEP02(2010)041; 2010). The paper includes 15 pages of author names, totalling between 2,200 and 2,300 people (the collaboration leaders are unsure of the exact number). "Can it be said that any one person truly understands all the knowledge that it contains?" says Galison. And who, he asks, can externally review the papers produced? "You reach a stage where the only people qualified to truly review the work are within the collaboration," Galison says. "The only people qualified to truly review the work are within the collaboration." De Roeck says that the size of particle-physics collaborations does inevitably affect peer review. The CMS paper went through months of rigorous checks and revisions during its internal review process; by contrast, it passed through external peer review by the Journal of High Energy Physics in just four days. "External peer review for publication in journals is becoming less important because it is far less stringent than our internal peer-review process," he says. Although the collaboration's strength comes from stressing the communal good, recent developments may strain the system. A rising number of particle physicists are turning to the individualistic pursuit of blogging. Although most posts are not controversial, the Fermi National Accelerator Laboratory (Fermilab) in Batavia, Illinois, has had to deal with cases in which physicists broke ranks and leaked information before their collaborations were ready to release it. James Gillies, CERN spokesman, says that the European laboratory has no desire to censor blogs, but it does provide strict guidelines about when it is appropriate to discuss results. Even with these guidelines in place, the blogging phenomenon at CERN — and its possible tension with official lines of communication — is something that will be closely followed by Borrelli as part of a team of more than 20 historians, philosophers and sociologists — "a huge collaboration in the humanities," Borrelli jokes — that will begin investigating the LHC this year, with funding by the German Research Foundation (DFG). "This will be a real-time study of how knowledge circulates in such a big project," says Borrelli. She is particularly interested in the immediacy of publication in the physics community via the online repository arXiv.org, where a hundred or so non-peer-reviewed high-energy physics preprints are deposited every day and are openly accessible. "How do physicists select papers and orient themselves given this onslaught of information?" she asks. Social scientists are looking beyond the professional lives of the scientists to assess how the collective collaborations affect the physicists on a personal level. Knorr Cetina says that many particle physicists are plagued by nightmares in which their actions cause the project to fail. "These are the nightmares of those who perceive themselves as a link in a chain, not as an individual," she says. Abnormal stress Knorr Cetina argues that the anxiety displayed by particle physicists is heightened beyond the usual career stress because they strongly identify with the detector (K. Knorr Cetina Interdiscipl. Sci. Rev. 32, 361–375; 2007). "This is an object that they built with their hands, but they describe it as a friend," says Knorr Cetina. When reporting their nightmares, physicists described being shaken by the imagined loss of the detector as though it was the death of a beloved family member — something not routinely seen in other experimental scientists. ADVERTISEMENT De Roeck agrees that physicists at the LHC are under extreme pressure. Each experiment is made up of subgroups who oversee different components of the experiment and no subgroup wants to be the weakest link that lets thousands of other people down. But he cautions against making too much of the relationship between experimenter and detector. "I wouldn't go so far as to say that physicists have some psychological problem where they start mistaking the detector for a friend and talking to it," he says with a laugh. Ultimately, it is the ever-growing detectors that are to blame for the increasing size of collaborations in particle physics. The invention of the bubble chamber for tracking the path of particles in the 1950s required groups of 10 physicists — at the time thought to be a large collaboration. Physicists are already making plans for the next generation of particle accelerators. But these may provide little new territory for social scientists to explore. "There won't be another step up in collaboration size to 25,000 physicists," says Galison. "We're hitting the limits of people in high-energy physics." 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.
• Industry in academia: ethical frameworks would clarify links
  - Nature 464(7288):486 (2010)
  The appointment of William Chin, from the drug giant Eli Lilly, as executive dean for research at Harvard Medical School should be judged by the extent to which he can supplant his allegiance to industry and promote the university's mission of social good. Academia cannot be a "pristine bubble" striving to be "untainted and uninformed" by industry, as some critics may have implied (Nature 463, 999–1000; 2010
• Industry in academia: transparency alone is not enough
  - Nature 464(7288):486 (2010)
  I disagree with your Editorial supporting ties between drug companies and academia (Nature 463, 999–1000; 2010) — particularly the appointments of a top Eli Lilly executive as executive dean for research at Harvard Medical School and Genentech's head of product development as chancellor of the University of California at San Francisco.
• Structural changes to aid science in developing countries
  - Nature 464(7288):486 (2010)
  I am quoted in a News story as saying that I wouldn't work in a developing nation again, after having been forced to leave my laboratory at the federal Institute for Scientific and Technological Research of San Luis Potosí in Mexico (Nature464, 148–149; 2010). Because I have many valued friends and collaborators in developing countries, I would like to clarify this statement, in case it should cause offence.
• European routes to reinventing Internet technology
  - Nature 464(7288):486 (2010)
  Your News Feature about reinventing Internet technology is timely (Nature463, 602–604; 2010). Complementary initiatives to the US projects are under way in Europe.
• Issues raised by use of ethnic-group names in genome study
  - Nature 464(7288):487 (2010)
  I question the ethnic labels used by Stephan Schuster and colleagues in their paper 'Complete Khoisan and Bantu genomes from southern Africa' (Nature 463, 943–947; 2010) and in the public database where they deposited the sequences.
• Issues raised by use of ethnic-group names in genome study: Schuster and colleagues reply
  - Nature 464(7288):487 (2010)
  The naming conventions associated with indigenous hunter-gatherers of southern Africa are given in a historical, social and participant-driven context in the Supplementary Information to our paper (S. C. Schuster et al. Nature 463, 943–947; 2010
• Questions over the scientific basis of epigenome project
  - Nature 464(7288):487 (2010)
  We were astonished to see two sentences in your Editorial on the International Human Epigenome Consortium (Nature 463, 587; 2010) that seem to disregard principles of gene regulation and of evolutionary and developmental biology that have been established during the past 50 years.
• Let's make science metrics more scientific
  - Nature 464(7288):488 (2010)
  To capture the essence of good science, stakeholders must combine forces to create an open, sound and consistent system for measuring all the activities that make up academic productivity, says Julia Lane.
• How do morals change?
  - Nature 464(7288):490 (2010)
  Emotions such as empathy and disgust might be at the root of morality, but psychologists should also study the roles of deliberation and debate in how our opinions shift over time, argues Paul Bloom.
• Exposing the longevity business
  - Nature 464(7288):491 (2010)
  From caloric restriction to red-grape skins, the anti-ageing industry goes beyond scientific results to market treatments to those who hope to cheat death, cautions S. Jay Olshansky.
• Learning from history's trials
  - Nature 464(7288):492 (2010)
  Natural Experiments of History is a short book packed with huge ideas. Its collected essays advocate how controlled experiments can be applied to the messy realities of human history, politics, culture, economics and the environment.
• Matisse's methods revealed
  - Nature 464(7288):493 (2010)
  In 1913 the French artist Henri Matisse embarked on a period of restless experimentation, eschewing the rich colours and sinuous lines of his earlier works for a more abstract, geometric approach to painting, dominated by blacks and greys. He reworked his paintings again and again, scraping at the paint as if it were plaster and carving it like wax.
• Evidence for RNA origins
  - Nature 464(7288):494 (2010)
  The RNA-world hypothesis proposes that today's DNA-based life forms evolved from earlier ones that were based on much simpler RNA molecules. Although no such RNA-based organism, or ribocyte, has yet been found, biochemist Michael Yarus marshals the theoretical considerations and lab experiments that lend support to this notion for the origin of life.
• Books in brief
  - Nature 464(7288):494 (2010)
  As global natural resources dwindle and Earth warms, the Arctic is set to become a geopolitical stage. In The Future History of the Arctic (PublicAffairs, 2010), Charles Emmerson, a writer and global-risk specialist, explains how the region's oil and mineral wealth is being eyed by surrounding nations.
• Plant science: The hidden cost of transpiration
  - Nature 464(7288):495 (2010)
  Theoretical analyses reveal how plant investment in the architecture of leaf veins can be shuffled for different conditions, minimizing the construction costs associated with supplying water to leaves.
• Materials science: Reconfigurable colloids
  - Nature 464(7288):496 (2010)
  Colloid particles that form bonds to each other at specific orientations might self-assemble into all sorts of useful materials. The key — and the lock — to such binding has been discovered.
• Surface science: Liquid marbles
  - Nature 464(7288):497 (2010)
  Abstract
• Developmental biology: Plumbing the heart
  - Nature 464(7288):498 (2010)
  Ever since Leonardo da Vinci sketched the heart vessels in his anatomical notebook in the late fifteenth century, the origin of the coronary vasculature has been in question. We might just have come upon the answer.
• 50 & 100 years ago
  - Nature 464(7288):499 (2010)
  A recent report from British Glues and Chemicals, Ltd., reflects the increasing interest in leaf protein; the Chayen impulse process, introduced a few years ago by this firm for the disintegration and extraction of bones and animal fats, has now been applied to a variety of other materials, including oilseeds, such as groundnuts, and grasses.
• Carbon cycle: A warm response by soils
  - Nature 464(7288):499 (2010)
  The flux of carbon from soils to the atmosphere has apparently increased with climate warming. But does this reflect a net loss of carbon to the atmosphere that could exacerbate climate change?
• Biogeochemistry: NO connection with methane
  - Nature 464(7288):500 (2010)
  Microorganisms that grow by oxidizing methane come in two basic types, aerobic and anaerobic. Now we have something in between that generates its own supply of molecular oxygen by metabolizing nitric oxide.
• Obituary: William E. Gordon (1918–2010)
  - Nature 464(7288):502 (2010)
  Builder of the world's largest radar/radio telescope.
• Ageing
  - Nature 464(7288):503 (2010)
  The nematode Caenorhabditis elegans ages and dies in a few weeks, but humans can live for 100 years or more. Assuming that the ancestor we share with nematodes aged rapidly, this means that over evolutionary time mutations have increased lifespan more than 2,000-fold. Which genes can extend lifespan? Can we augment their activities and live even longer? After centuries of wistful poetry and wild imagination, we are now getting answers, often unexpected ones, to these fundamental questions.
• The genetics of ageing
  - Nature 464(7288):504 (2010)
  The nematode Caenorhabditis elegans ages and dies in a few weeks, but humans can live for 100 years or more. Assuming that the ancestor we share with nematodes aged rapidly, this means that over evolutionary time mutations have increased lifespan more than 2,000-fold. Which genes can extend lifespan? Can we augment their activities and live even longer? After centuries of wistful poetry and wild imagination, we are now getting answers, often unexpected ones, to these fundamental questions.
• Lessons on longevity from budding yeast
  - Nature 464(7288):513 (2010)
  The past decade has seen fundamental advances in our understanding of the ageing process and raised optimism that interventions to slow ageing may be on the horizon. Studies of budding yeast have made immense contributions to this progress. Yeast longevity factors have now been shown to modulate ageing in invertebrate and mammalian models, and studies of yeast have resulted in some of the best candidates for anti-ageing drugs currently in development. The first interventions to slow human ageing may spring from the humble yeast.
• Linking functional decline of telomeres, mitochondria and stem cells during ageing
  - Nature 464(7288):520 (2010)
  The study of human genetic disorders and mutant mouse models has provided evidence that genome maintenance mechanisms, DNA damage signalling and metabolic regulation cooperate to drive the ageing process. In particular, age-associated telomere damage, diminution of telomere 'capping' function and associated p53 activation have emerged as prime instigators of a functional decline of tissue stem cells and of mitochondrial dysfunction that adversely affect renewal and bioenergetic support in diverse tissues. Constructing a model of how telomeres, stem cells and mitochondria interact with key molecules governing genome integrity, 'stemness' and metabolism provides a framework for how diverse factors contribute to ageing and age-related disorders.
• Neural mechanisms of ageing and cognitive decline
  - Nature 464(7288):529 (2010)
  During the past century, treatments for the diseases of youth and middle age have helped raise life expectancy significantly. However, cognitive decline has emerged as one of the greatest health threats of old age, with nearly 50% of adults over the age of 85 afflicted with Alzheimer's disease. Developing therapeutic interventions for such conditions demands a greater understanding of the processes underlying normal and pathological brain ageing. Recent advances in the biology of ageing in model organisms, together with molecular and systems-level studies of the brain, are beginning to shed light on these mechanisms and their potential roles in cognitive decline.
• Biodemography of human ageing
  - Nature 464(7288):536 (2010)
  Human senescence has been delayed by a decade. This finding, documented in 1994 and bolstered since, is a fundamental discovery about the biology of human ageing, and one with profound implications for individuals, society and the economy. Remarkably, the rate of deterioration with age seems to be constant across individuals and over time: it seems that death is being delayed because people are reaching old age in better health. Research by demographers, epidemiologists and other biomedical researchers suggests that further progress is likely to be made in advancing the frontier of survival — and healthy survival — to even greater ages.
• Nitrite-driven anaerobic methane oxidation by oxygenic bacteria
  - Nature 464(7288):543 (2010)
  Only three biological pathways are known to produce oxygen: photosynthesis, chlorate respiration and the detoxification of reactive oxygen species. Here we present evidence for a fourth pathway, possibly of considerable geochemical and evolutionary importance. The pathway was discovered after metagenomic sequencing of an enrichment culture that couples anaerobic oxidation of methane with the reduction of nitrite to dinitrogen. The complete genome of the dominant bacterium, named 'Candidatus Methylomirabilis oxyfera', was assembled. This apparently anaerobic, denitrifying bacterium encoded, transcribed and expressed the well-established aerobic pathway for methane oxidation, whereas it lacked known genes for dinitrogen production. Subsequent isotopic labelling indicated that 'M. oxyfera' bypassed the denitrification intermediate nitrous oxide by the conversion of two nitric oxide molecules to dinitrogen and oxygen, which was used to oxidize methane. These result! s extend our understanding of hydrocarbon degradation under anoxic conditions and explain the biochemical mechanism of a poorly understood freshwater methane sink. Because nitrogen oxides were already present on early Earth, our finding opens up the possibility that oxygen was available to microbial metabolism before the evolution of oxygenic photosynthesis.
• Coronary arteries form by developmental reprogramming of venous cells
  - Nature 464(7288):549 (2010)
  Coronary artery disease is the leading cause of death worldwide. Determining the coronary artery developmental program could aid understanding of the disease and lead to new treatments, but many aspects of the process, including their developmental origin, remain obscure. Here we show, using histological and clonal analysis in mice and cardiac organ culture, that coronary vessels arise from angiogenic sprouts of the sinus venosus—the vein that returns blood to the embryonic heart. Sprouting venous endothelial cells dedifferentiate as they migrate over and invade the myocardium. Invading cells differentiate into arteries and capillaries; cells on the surface redifferentiate into veins. These results show that some differentiated venous cells retain developmental plasticity, and indicate that position-specific cardiac signals trigger their dedifferentiation and conversion into coronary arteries, capillaries and veins. Understanding this new reprogramming process and id! entifying the endogenous signals should suggest more natural ways of engineering coronary bypass grafts and revascularizing the heart.
• Neurogenic radial glia in the outer subventricular zone of human neocortex
  Hansen DV Lui JH Parker PR Kriegstein AR - Nature 464(7288):554 (2010)
  Neurons in the developing rodent cortex are generated from radial glial cells that function as neural stem cells. These epithelial cells line the cerebral ventricles and generate intermediate progenitor cells that migrate into the subventricular zone (SVZ) and proliferate to increase neuronal number. The developing human SVZ has a massively expanded outer region (OSVZ) thought to contribute to cortical size and complexity. However, OSVZ progenitor cell types and their contribution to neurogenesis are not well understood. Here we show that large numbers of radial glia-like cells and intermediate progenitor cells populate the human OSVZ. We find that OSVZ radial glia-like cells have a long basal process but, surprisingly, are non-epithelial as they lack contact with the ventricular surface. Using real-time imaging and clonal analysis, we demonstrate that these cells can undergo proliferative divisions and self-renewing asymmetric divisions to generate neuronal progenitor! cells that can proliferate further. We also show that inhibition of Notch signalling in OSVZ progenitor cells induces their neuronal differentiation. The establishment of non-ventricular radial glia-like cells may have been a critical evolutionary advance underlying increased cortical size and complexity in the human brain.
• Escape of about five per cent of Lyman-α photons from high-redshift star-forming galaxies
  - Nature 464(7288):562 (2010)
  The Lyman-α (Lyα) emission line is the primary observational signature of star-forming galaxies at the highest redshifts1, and has enabled the compilation of large samples of galaxies with which to study cosmic evolution2, 3, 4, 5. The resonant nature of the line, however, means that Lyα photons scatter in the neutral interstellar medium of their host galaxies, and their sensitivity to absorption by interstellar dust may therefore be greatly enhanced. This implies that the Lyα luminosity may be significantly reduced, or even completely suppressed. Hitherto, no unbiased empirical test of the escaping fraction (fesc) of Lyα photons has been performed at high redshifts. Here we report that the average fesc from star-forming galaxies at redshift z = 2.2 is just 5 per cent by performing a blind narrowband survey in Lyα and Hα. This implies that numerous conclusions based on Lyα-selected samples will require upwards revision by an order of magnitude and we provide a ! benchmark for this revision. We demonstrate that almost 90 per cent of star-forming galaxies emit insufficient Lyα to be detected by standard selection criteria2, 3, 4, 5. Both samples show an anti-correlation of fesc with dust content, and we show that Lyα- and Hα-selection recovers populations that differ substantially in dust content and fesc.
• Anomalous structure in the single particle spectrum of the fractional quantum Hall effect
  - Nature 464(7288):566 (2010)
  The two-dimensional electron system is a powerful laboratory for investigating the physics of interacting particles. Application of a large magnetic field produces massively degenerate quantum levels known as Landau levels; within a Landau level the kinetic energy of the electrons is suppressed, and electron–electron interactions set the only energy scale1. Coulomb interactions break the degeneracy of the Landau levels and can cause the electrons to order into complex ground states. Here we observe, in the high energy single particle spectrum of this system, salient and unexpected structure that extends across a wide range of Landau level filling fractions. The structure appears only when the two-dimensional electron system is cooled to very low temperatures, indicating that it arises from delicate ground state correlations. We characterize this structure by its evolution with changing electron density and applied magnetic field, and present two possible models for u! nderstanding these observations. Some of the energies of the features agree qualitatively with what might be expected for composite fermions, which have proven effective for interpreting other experiments in this regime. At the same time, a simple model with electrons localized on ordered lattice sites also generates structure similar to that observed in the experiment. Neither of these models alone is sufficient to explain the observations across the entire range of densities measured. The discovery of this unexpected prominent structure in the single particle spectrum of an otherwise thoroughly studied system suggests that there exist core features of the two-dimensional electron system that have yet to be understood.
• Atom-by-atom structural and chemical analysis by annular dark-field electron microscopy
  - Nature 464(7288):571 (2010)
  Direct imaging and chemical identification of all the atoms in a material with unknown three-dimensional structure would constitute a very powerful general analysis tool. Transmission electron microscopy should in principle be able to fulfil this role, as many scientists including Feynman realized early on1. It images matter with electrons that scatter strongly from individual atoms and whose wavelengths are about 50 times smaller than an atom. Recently the technique has advanced greatly owing to the introduction of aberration-corrected optics2, 3, 4, 5, 6, 7, 8. However, neither electron microscopy nor any other experimental technique has yet been able to resolve and identify all the atoms in a non-periodic material consisting of several atomic species. Here we show that annular dark-field imaging in an aberration-corrected scanning transmission electron microscope optimized for low voltage operation can resolve and identify the chemical type of every atom in monolaye! r hexagonal boron nitride that contains substitutional defects. Three types of atomic substitutions were found and identified: carbon substituting for boron, carbon substituting for nitrogen, and oxygen substituting for nitrogen. The substitutions caused in-plane distortions in the boron nitride monolayer of about 0.1 Å magnitude, which were directly resolved, and verified by density functional theory calculations. The results demonstrate that atom-by-atom structural and chemical analysis of all radiation-damage-resistant atoms present in, and on top of, ultra-thin sheets has now become possible.
• Lock and key colloids
  - Nature 464(7288):575 (2010)
  New functional materials can in principle be created using colloids that self-assemble into a desired structure by means of a programmable recognition and binding scheme. This idea has been explored by attaching 'programmed' DNA strands to nanometre-1, 2, 3 and micrometre-4, 5 sized particles and then using DNA hybridization to direct the placement of the particles in the final assembly. Here we demonstrate an alternative recognition mechanism for directing the assembly of composite structures, based on particles with complementary shapes. Our system, which uses Fischer's lock-and-key principle6, employs colloidal spheres as keys and monodisperse colloidal particles with a spherical cavity as locks that bind spontaneously and reversibly via the depletion interaction. The lock-and-key binding is specific because it is controlled by how closely the size of a spherical colloidal key particle matches the radius of the spherical cavity of the lock particle. The streng! th of the binding can be further tuned by adjusting the solution composition or temperature. The composite assemblies have the unique feature of having flexible bonds, allowing us to produce flexible dimeric, trimeric and tetrameric colloidal molecules as well as more complex colloidal polymers. We expect that this lock-and-key recognition mechanism will find wider use as a means of programming and directing colloidal self-assembly.
• Temperature-associated increases in the global soil respiration record
  - Nature 464(7288):579 (2010)
  Soil respiration, RS, the flux of microbially and plant-respired carbon dioxide (CO2) from the soil surface to the atmosphere, is the second-largest terrestrial carbon flux1, 2, 3. However, the dynamics of RS are not well understood and the global flux remains poorly constrained4, 5. Ecosystem warming experiments6, 7, modelling analyses8, 9 and fundamental biokinetics10 all suggest that RS should change with climate. This has been difficult to confirm observationally because of the high spatial variability of RS, inaccessibility of the soil medium and the inability of remote-sensing instruments to measure RS on large scales. Despite these constraints, it may be possible to discern climate-driven changes in regional or global RS values in the extant four-decade record of RS chamber measurements. Here we construct a database of worldwide RS observations matched with high-resolution historical climate data and find a previously unknown temporal trend in the RS record afte! r accounting for mean annual climate, leaf area, nitrogen deposition and changes in CO2 measurement technique. We find that the air temperature anomaly (the deviation from the 1961–1990 mean) is significantly and positively correlated with changes in RS. We estimate that the global RS in 2008 (that is, the flux integrated over the Earth's land surface over 2008) was 98 ± 12 Pg C and that it increased by 0.1 Pg C yr-1 between 1989 and 2008, implying a global RS response to air temperature (Q10) of 1.5. An increasing global RS value does not necessarily constitute a positive feedback to the atmosphere, as it could be driven by higher carbon inputs to soil rather than by mobilization of stored older carbon. The available data are, however, consistent with an acceleration of the terrestrial carbon cycle in response to global climate change.
• A computational model of teeth and the developmental origins of morphological variation
  Salazar-Ciudad I Jernvall J - Nature 464(7288):583 (2010)
  The relationship between the genotype and the phenotype, or the genotype–phenotype map, is generally approached with the tools of multivariate quantitative genetics and morphometrics1, 2, 3, 4. Whereas studies of development5, 6, 7 and mathematical models of development4, 8, 9, 10, 11, 12 may offer new insights into the genotype–phenotype map, the challenge is to make them useful at the level of microevolution. Here we report a computational model of mammalian tooth development that combines parameters of genetic and cellular interactions to produce a three-dimensional tooth from a simple tooth primordia. We systematically tinkered with each of the model parameters to generate phenotypic variation and used geometric morphometric analyses to identify, or developmentally ordinate, parameters best explaining population-level variation of real teeth. To model the full range of developmentally possible morphologies, we used a population sample of ringed seals (Phoca his! pida ladogensis)13. Seal dentitions show a high degree of variation, typically linked to the lack of exact occlusion13, 14, 15, 16. Our model suggests that despite the complexity of development and teeth, there may be a simple basis for dental variation. Changes in single parameters regulating signalling during cusp development may explain shape variation among individuals, whereas a parameter regulating epithelial growth may explain serial, tooth-to-tooth variation along the jaw. Our study provides a step towards integrating the genotype, development and the phenotype.
• Whole-genome resequencing reveals loci under selection during chicken domestication
  Rubin CJ Zody MC Eriksson J Meadows JR Sherwood E Webster MT Jiang L Ingman M Sharpe T Ka S Hallböök F Besnier F Carlborg O Bed'hom B Tixier-Boichard M Jensen P Siegel P Lindblad-Toh K Andersson L - Nature 464(7288):587 (2010)
  Domestic animals are excellent models for genetic studies of phenotypic evolution1, 2, 3. They have evolved genetic adaptations to a new environment, the farm, and have been subjected to strong human-driven selection leading to remarkable phenotypic changes in morphology, physiology and behaviour. Identifying the genetic changes underlying these developments provides new insight into general mechanisms by which genetic variation shapes phenotypic diversity. Here we describe the use of massively parallel sequencing to identify selective sweeps of favourable alleles and candidate mutations that have had a prominent role in the domestication of chickens (Gallus gallus domesticus) and their subsequent specialization into broiler (meat-producing) and layer (egg-producing) chickens. We have generated 44.5-fold coverage of the chicken genome using pools of genomic DNA representing eight different populations of domestic chickens as well as red jungle fowl (Gallus gallus), the! major wild ancestor4. We report more than 7,000,000 single nucleotide polymorphisms, almost 1,300 deletions and a number of putative selective sweeps. One of the most striking selective sweeps found in all domestic chickens occurred at the locus for thyroid stimulating hormone receptor (TSHR), which has a pivotal role in metabolic regulation and photoperiod control of reproduction in vertebrates. Several of the selective sweeps detected in broilers overlapped genes associated with growth, appetite and metabolic regulation. We found little evidence that selection for loss-of-function mutations had a prominent role in chicken domestication, but we detected two deletions in coding sequences that we suggest are functionally important. This study has direct application to animal breeding and enhances the importance of the domestic chicken as a model organism for biomedical research.
• The dynamic genome of Hydra
  Chapman JA Kirkness EF Simakov O Hampson SE Mitros T Weinmaier T Rattei T Balasubramanian PG Borman J Busam D Disbennett K Pfannkoch C Sumin N Sutton GG Viswanathan LD Walenz B Goodstein DM Hellsten U Kawashima T Prochnik SE Putnam NH Shu S Blumberg B Dana CE Gee L Kibler DF Law L Lindgens D Martinez DE Peng J Wigge PA Bertulat B Guder C Nakamura Y Ozbek S Watanabe H Khalturin K Hemmrich G Franke A Augustin R Fraune S Hayakawa E Hayakawa S Hirose M Hwang JS Ikeo K Nishimiya-Fujisawa C Ogura A Takahashi T Steinmetz PR Zhang X Aufschnaiter R Eder MK Gorny AK Salvenmoser W Heimberg AM Wheeler BM Peterson KJ Böttger A Tischler P Wolf A Gojobori T Remington KA Strausberg RL Venter JC Technau U Hobmayer B Bosch TC Holstein TW Fujisawa T Bode HR David CN Rokhsar DS Steele RE - Nature 464(7288):592 (2010)
  The freshwater cnidarian Hydra was first described in 17021 and has been the object of study for 300 years. Experimental studies of Hydra between 1736 and 1744 culminated in the discovery of asexual reproduction of an animal by budding, the first description of regeneration in an animal, and successful transplantation of tissue between animals2. Today, Hydra is an important model for studies of axial patterning3, stem cell biology4 and regeneration5. Here we report the genome of Hydra magnipapillata and compare it to the genomes of the anthozoan Nematostella vectensis6 and other animals. The Hydra genome has been shaped by bursts of transposable element expansion, horizontal gene transfer, trans-splicing, and simplification of gene structure and gene content that parallel simplification of the Hydra life cycle. We also report the sequence of the genome of a novel bacterium stably associated with H. magnipapillata. Comparisons of the Hydra genome to the genomes of other! animals shed light on the evolution of epithelia, contractile tissues, developmentally regulated transcription factors, the Spemann–Mangold organizer, pluripotency genes and the neuromuscular junction.
• Analysis of Drosophila TRPA1 reveals an ancient origin for human chemical nociception
  Kang K Pulver SR Panzano VC Chang EC Griffith LC Theobald DL Garrity PA - Nature 464(7288):597 (2010)
  Chemical nociception, the detection of tissue-damaging chemicals, is important for animal survival and causes human pain and inflammation, but its evolutionary origins are largely unknown. Reactive electrophiles are a class of noxious compounds humans find pungent and irritating, such as allyl isothiocyanate (in wasabi) and acrolein (in cigarette smoke)1, 2, 3. Diverse animals, from insects to humans, find reactive electrophiles aversive1, 2, 3, but whether this reflects conservation of an ancient sensory modality has been unclear. Here we identify the molecular basis of reactive electrophile detection in flies. We demonstrate that Drosophila TRPA1 (Transient receptor potential A1), the Drosophila melanogaster orthologue of the human irritant sensor, acts in gustatory chemosensors to inhibit reactive electrophile ingestion. We show that fly and mosquito TRPA1 orthologues are molecular sensors of electrophiles, using a mechanism conserved with vertebrate TRPA1s. Phyloge! netic analyses indicate that invertebrate and vertebrate TRPA1s share a common ancestor that possessed critical characteristics required for electrophile detection. These findings support emergence of TRPA1-based electrophile detection in a common bilaterian ancestor, with widespread conservation throughout vertebrate and invertebrate evolution. Such conservation contrasts with the evolutionary divergence of canonical olfactory and gustatory receptors and may relate to electrophile toxicity. We propose that human pain perception relies on an ancient chemical sensor conserved across ~500 million years of animal evolution.
• Primary contribution to zebrafish heart regeneration by gata4+ cardiomyocytes
  - Nature 464(7288):601 (2010)
  Recent studies indicate that mammals, including humans, maintain some capacity to renew cardiomyocytes throughout postnatal life1, 2. Yet, there is little or no significant cardiac muscle regeneration after an injury such as acute myocardial infarction3. By contrast, zebrafish efficiently regenerate lost cardiac muscle, providing a model for understanding how natural heart regeneration may be blocked or enhanced4, 5. In the absence of lineage-tracing technology applicable to adult zebrafish, the cellular origins of newly regenerated cardiac muscle have remained unclear. Using new genetic fate-mapping approaches, here we identify a population of cardiomyocytes that become activated after resection of the ventricular apex and contribute prominently to cardiac muscle regeneration. Through the use of a transgenic reporter strain, we found that cardiomyocytes throughout the subepicardial ventricular layer trigger expression of the embryonic cardiogenesis gene gata4 within a! week of trauma, before expression localizes to proliferating cardiomyocytes surrounding and within the injury site. Cre-recombinase-based lineage-tracing of cells expressing gata4 before evident regeneration, or of cells expressing the contractile gene cmlc2 before injury, each labelled most cardiac muscle in the ensuing regenerate. By optical voltage mapping of surface myocardium in whole ventricles, we found that electrical conduction is re-established between existing and regenerated cardiomyocytes between 2 and 4 weeks post-injury. After injury and prolonged fibroblast growth factor receptor inhibition to arrest cardiac regeneration and enable scar formation, experimental release of the signalling block led to gata4 expression and morphological improvement of the injured ventricular wall without loss of scar tissue. Our results indicate that electrically coupled cardiac muscle regenerates after resection injury, primarily through activation and expansion of cardiomyocy! te populations. These findings have implications for promoting! regeneration of the injured human heart.
• Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation
  - Nature 464(7288):606 (2010)
  Although mammalian hearts show almost no ability to regenerate, there is a growing initiative to determine whether existing cardiomyocytes or progenitor cells can be coaxed into eliciting a regenerative response. In contrast to mammals, several non-mammalian vertebrate species are able to regenerate their hearts1, 2, 3, including the zebrafish4, 5, which can fully regenerate its heart after amputation of up to 20% of the ventricle. To address directly the source of newly formed cardiomyocytes during zebrafish heart regeneration, we first established a genetic strategy to trace the lineage of cardiomyocytes in the adult fish, on the basis of the Cre/lox system widely used in the mouse6. Here we use this system to show that regenerated heart muscle cells are derived from the proliferation of differentiated cardiomyocytes. Furthermore, we show that proliferating cardiomyocytes undergo limited dedifferentiation characterized by the disassembly of their sarcomeric structure! , detachment from one another and the expression of regulators of cell-cycle progression. Specifically, we show that the gene product of polo-like kinase 1 (plk1) is an essential component of cardiomyocyte proliferation during heart regeneration. Our data provide the first direct evidence for the source of proliferating cardiomyocytes during zebrafish heart regeneration and indicate that stem or progenitor cells are not significantly involved in this process.
• Heteroplasmic mitochondrial DNA mutations in normal and tumour cells
  He Y Wu J Dressman DC Iacobuzio-Donahue C Markowitz SD Velculescu VE Diaz Jr LA Kinzler KW Vogelstein B Papadopoulos N - Nature 464(7288):610 (2010)
  The presence of hundreds of copies of mitochondrial DNA (mtDNA) in each human cell poses a challenge for the complete characterization of mtDNA genomes by conventional sequencing technologies1. Here we describe digital sequencing of mtDNA genomes with the use of massively parallel sequencing-by-synthesis approaches. Although the mtDNA of human cells is considered to be homogeneous, we found widespread heterogeneity (heteroplasmy) in the mtDNA of normal human cells. Moreover, the frequency of heteroplasmic variants varied considerably between different tissues in the same individual. In addition to the variants identified in normal tissues, cancer cells harboured further homoplasmic and heteroplasmic mutations that could also be detected in patient plasma. These studies provide insights into the nature and variability of mtDNA sequences and have implications for mitochondrial processes during embryogenesis, cancer biomarker development and forensic analysis. In particul! ar, they demonstrate that individual humans are characterized by a complex mixture of related mitochondrial genotypes rather than a single genotype.
• Haploid plants produced by centromere-mediated genome elimination
  - Nature 464(7288):615 (2010)
  Production of haploid plants that inherit chromosomes from only one parent can greatly accelerate plant breeding1, 2, 3. Haploids generated from a heterozygous individual and converted to diploid create instant homozygous lines, bypassing generations of inbreeding. Two methods are generally used to produce haploids. First, cultured gametophyte cells may be regenerated into haploid plants4, but many species and genotypes are recalcitrant to this process2, 5. Second, haploids can be induced from rare interspecific crosses, in which one parental genome is eliminated after fertilization6, 7, 8, 9, 10, 11. The molecular basis for genome elimination is not understood, but one theory posits that centromeres from the two parent species interact unequally with the mitotic spindle, causing selective chromosome loss12, 13, 14. Here we show that haploid Arabidopsis thaliana plants can be easily generated through seeds by manipulating a single centromere protein, the centromere-spe! cific histone CENH3 (called CENP-A in human). When cenh3 null mutants expressing altered CENH3 proteins are crossed to wild type, chromosomes from the mutant are eliminated, producing haploid progeny. Haploids are spontaneously converted into fertile diploids through meiotic non-reduction, allowing their genotype to be perpetuated. Maternal and paternal haploids can be generated through reciprocal crosses. We have also exploited centromere-mediated genome elimination to convert a natural tetraploid Arabidopsis into a diploid, reducing its ploidy to simplify breeding. As CENH3 is universal in eukaryotes, our method may be extended to produce haploids in any plant species.
• Transcriptional control of preadipocyte determination by Zfp423
  Gupta RK Arany Z Seale P Mepani RJ Ye L Conroe HM Roby YA Kulaga H Reed RR Spiegelman BM - Nature 464(7288):619 (2010)
  The worldwide epidemic of obesity has increased the urgency to develop a deeper understanding of physiological systems related to energy balance and energy storage, including the mechanisms controlling the development of fat cells (adipocytes). The differentiation of committed preadipocytes to adipocytes is controlled by PPARγ and several other transcription factors1, but the molecular basis for preadipocyte determination is not understood. Using a new method for the quantitative analysis of transcriptional components, we identified the zinc-finger protein Zfp423 as a factor enriched in preadipose versus non-preadipose fibroblasts. Ectopic expression of Zfp423 in non-adipogenic NIH 3T3 fibroblasts robustly activates expression of Pparg in undifferentiated cells and permits cells to undergo adipocyte differentiation under permissive conditions. Short hairpin RNA (shRNA)-mediated reduction of Zfp423 expression in 3T3-L1 cells blunts preadipocyte Pparg expression and d! iminishes the ability of these cells to differentiate. Furthermore, both brown and white adipocyte differentiation is markedly impaired in Zfp423-deficient mouse embryos. Zfp423 regulates Pparg expression, in part, through amplification of the BMP signalling pathway, an effect dependent on the SMAD-binding capacity of Zfp423. This study identifies Zfp423 as a transcriptional regulator of preadipocyte determination.
• Transcription-independent ARF regulation in oncogenic stress-mediated p53 responses
  Chen D Shan J Zhu WG Qin J Gu W - Nature 464(7288):624 (2010)
  The tumour suppressor ARF is specifically required for p53 activation under oncogenic stress1, 2, 3, 4, 5, 6. Recent studies showed that p53 activation mediated by ARF, but not that induced by DNA damage, acts as a major protection against tumorigenesis in vivo under certain biological settings7, 8, suggesting that the ARF–p53 axis has more fundamental functions in tumour suppression than originally thought. Because ARF is a very stable protein in most human cell lines, it has been widely assumed that ARF induction is mediated mainly at the transcriptional level and that activation of the ARF–p53 pathway by oncogenes is a much slower and largely irreversible process by comparison with p53 activation after DNA damage. Here we report that ARF is very unstable in normal human cells but that its degradation is inhibited in cancerous cells. Through biochemical purification, we identified a specific ubiquitin ligase for ARF and named it ULF. ULF interacts with ARF both i! n vitro and in vivo and promotes the lysine-independent ubiquitylation and degradation of ARF. ULF knockdown stabilizes ARF in normal human cells, triggering ARF-dependent, p53-mediated growth arrest. Moreover, nucleophosmin (NPM) and c-Myc, both of which are commonly overexpressed in cancer cells, are capable of abrogating ULF-mediated ARF ubiquitylation through distinct mechanisms, and thereby promote ARF stabilization in cancer cells. These findings reveal the dynamic feature of the ARF–p53 pathway and suggest that transcription-independent mechanisms are critically involved in ARF regulation during responses to oncogenic stress.
• Control of female gamete formation by a small RNA pathway in Arabidopsis
  Olmedo-Monfil V Durán-Figueroa N Arteaga-Vázquez M Demesa-Arévalo E Autran D Grimanelli D Slotkin RK Martienssen RA Vielle-Calzada JP - Nature 464(7288):628 (2010)
  In the ovules of most sexual flowering plants female gametogenesis is initiated from a single surviving gametic cell, the functional megaspore, formed after meiosis of the somatically derived megaspore mother cell (MMC)1, 2. Because some mutants and certain sexual species exhibit more than one MMC2, 3, 4, and many others are able to form gametes without meiosis (by apomixis)5, it has been suggested that somatic cells in the ovule are competent to respond to a local signal likely to have an important function in determination6. Here we show that the Arabidopsis protein ARGONAUTE 9 (AGO9) controls female gamete formation by restricting the specification of gametophyte precursors in a dosage-dependent, non-cell-autonomous manner. Mutations in AGO9 lead to the differentiation of multiple gametic cells that are able to initiate gametogenesis. The AGO9 protein is not expressed in the gamete lineage; instead, it is expressed in cytoplasmic foci of somatic companion cells. Mut! ations in SUPPRESSOR OF GENE SILENCING 3 and RNA-DEPENDENT RNA POLYMERASE 6 exhibit an identical defect to ago9 mutants, indicating that the movement of small RNA (sRNAs) silencing out of somatic companion cells is necessary for controlling the specification of gametic cells. AGO9 preferentially interacts with 24-nucleotide sRNAs derived from transposable elements (TEs), and its activity is necessary to silence TEs in female gametes and their accessory cells. Our results show that AGO9-dependent sRNA silencing is crucial to specify cell fate in the Arabidopsis ovule, and that epigenetic reprogramming in companion cells is necessary for sRNA–dependent silencing in plant gametes.
• The drained world
  - Nature 464(7288):640 (2010)
  Deep thoughts.