Hot off the presses! Sep 03 Nature

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Latest Articles Include:

• Dangerous nuclear whispers
  - Nature 461(7260):11 (2009)
  Voices within the Obama administration threaten to undermine non-proliferation efforts. They should be ignored.
• Cash costs
  - Nature 461(7260):11-12 (2009)
  Massive funding for Pakistan's ailing universities holds many lessons for other developing nations.
• US visa nightmares
  - Nature 461(7260):12 (2009)
  Barriers faced by foreign scientists seeking entry to the United States do more harm than good.
• Microscopy: Seeing the honeycomb
  - Nature 461(7260):14 (2009)
  
• Exoplanets: Explaining the eccentricities
  - Nature 461(7260):14 (2009)
  
• Biology: A colourful past
  - Nature 461(7260):14 (2009)
  
• Immunology: Killer fat
  - Nature 461(7260):14 (2009)
  
• Pain: Deep, deep in your head
  - Nature 461(7260):14 (2009)
  
• Chemistry: Bacterial factories
  - Nature 461(7260):14-15 (2009)
  
• Cancer biology: Cilia's dual role
  - Nature 461(7260):15 (2009)
  
• Genetics: Y-rated
  - Nature 461(7260):15 (2009)
  
• Microbiology: Resistance is futile
  - Nature 461(7260):15 (2009)
  
• Food chemistry: Bee-devilled by corn syrup
  - Nature 461(7260):15 (2009)
  
• Journal club
  - Nature 461(7260):15 (2009)
  
• News briefing: 3 September 2009
  - Nature 461(7260):16-17 (2009)
  The week in science. This article is best viewed as a pdf. Policy|Business|Research|Events|The week ahead|Sound bites|Number crunch The Indian government has approved a for carbon credits and energy-efficiency certificates that it claims could be worth more than 750 billion rupees (US$15 billion) by 2015. The National Mission on Enhanced Energy Efficiency, one of eight proposals in 's climate-change strategy, is projected to reduce the country's energy consumption by 5%; a year, and cut about 100 million tonnes of carbon dioxide every year from its current annual emissions of 3 billion tonnes. In an unexpected announcement on 27 August, 's top legislative body approved a resolution calling for new laws to target energy saving and emissions reductions in the fight against . The surprise move came at the close of a four-day session of the Standing Committee of the National People's Congress. It was not originally on the meeting's agenda and, state media said, shows that measures to tackle climate change are moving closer to the heart of government policy. H1N1 flu will not be ready in the until mid-October, the US Centers for Disease Control and Prevention reiterated last week — despite a call from the President's Council of Advisors on Science and Technology to accelerate vaccine production to mid-September. But Harold Varmus, co-chair of the 21-strong advisory panel, praised the federal government's response to the virus as "truly impressive". 's environment ministry approved a Aus$50-billion (US$42-billion) development of the country's Gorgon fields off northwest Australia. Energy companies Chevron, ExxonMobil and Shell expect to produce 15 million tonnes of liquefied natural gas a year from the project (about 8% of current global trade), much of it destined for China. Conservation groups worry that the facilities could damage the environment of Barrow Island, a local nature reserve. AstraZeneca has announced that its blood-thinning drug candidate ticagrelor (Brilinta) out-performed one of the world's best-selling drugs, clopidogrel (Plavix), in a head-to-head trial. In a study involving more than 18,000 patients, ticagrelor was better at reducing heart attack and stroke deaths than clopidogrel (L. Wallentin et al. N. Engl. J. Med. doi:10.1056/NEJMoa0904327; 2009). Analysts say that the drug would enter a market worth around US$9 billion. Irish drug maker , based in Ardee, has announced plans to buy the prescription-drug business of , based in Cincinnati, Ohio, for US$3.1 billion, all of which will be borrowed. Six banks are fronting $4 billion to bankroll the acquisition, including $1 billion to refinance Warner Chilcott's current debt. The transaction, expected to close by the end of the year, would be the largest leveraged loan for an acquisition in 2009, portending the return of a looser lending environment. Government officials in announced on 31 August that the country has redirected about US$4 billion of its $400-billion sovereign-wealth fund into environmentally friendly companies. The fund invests the country's oil and gas revenues and owns around 1% of global stocks. The change in investment strategy was decided earlier in the year, and includes $1.2 billion for 232 Indian companies. European pharmaceutical companies offer a better bang for the buck than their US counterparts, according to a re-analysis of more than 20 years of data on . A 2006 investigation (H. G. Grabowski and Y. R. Wang Health Aff. 25, 452–460; 2006) of all novel drugs developed worldwide from 1982 to 2003 concluded that the United States was most productive. But when Donald Light, a health researcher at the University of Medicine and Dentistry of New Jersey in Newark, controlled for the size of companies' investment in R&D, he found that, dollar for dollar, Europe brought more new treatments to market (D. W. Light Health Aff. doi:10.1377/hlthaff.28.5.w969; 2009). Chemical reagent company Sigma-Aldrich is to spin off a business that will create genetically modified (GM) rats. Sigma Advanced Genetic Engineering Labs, based in St Louis, Missouri, should start taking orders by October, according to Sigma representatives. Early releases will include knockouts for the genes APOE1, implicated in atherosclerosis and Alzheimer's, and DISC1, associated with schizophrenia. SOURCE: UK HOME OFFICE The market for GM animals is expected to grow by 12% a year over the next 3 years, says Eric Ostertag of Transposagen Biopharmaceuticals, based in Lexington, Kentucky, one of the world's only suppliers of GM rats. But it is dominated by knockout mice; in Britain last year, they outnumbered GM rats by 1.2 million to 6,000 (see chart; figures exclude Northern Ireland). Rats are seen as superior to mice as models for several human diseases, but are harder to manipulate genetically using embryonic stem-cell methods. Sigma-Aldrich uses zinc finger nucleases — a technology licensed from California-based Sangamo Biosciences — to delete specific genes directly in the rat embryo (see A. M. Geurts et al. Science 325, 433; 2009). The firm will launch its first catalogue of animals in October at the Society for Neuroscience meeting in Chicago, Illinois. Click here for a longer version of this story. The US Department of Veterans Affairs has cancelled a five-year, $75-million contract with the to research . The department cited "persistent noncompliance and numerous performance deficiencies" as justification for ending the research contract after two years. The university said it "strongly disagreed" with the department's assessment. A July report from the department's inspectorate had accused the university's Southwestern Medical Center at Dallas of breaking the terms of the contract, failing to send bills on time and unilaterally changing an informed consent form after it had been agreed. Britain's national academy of science, the Royal Society, has released its first report analysing on a global scale. The 1 September report looked favourably on seeding the stratosphere with sulphates to reflect back sunlight, and on filling agricultural land with minerals to absorb carbon dioxide, but cautioned that even preliminary research projects would need international pre-review. For more, see page 19. The global cost of has been grossly underestimated, according to a report released on 27 August by the International Institute for Environment and Development in London. It could be at least 2–3 times more than the 2007 estimate from the United Nations Framework Convention on Climate Change of between $49 billion and $171 billion per year, the study's authors say. For more, see page 24. Prosecutors in Germany have made public their ongoing investigation into academics who may have taken to students. Professors from a number of universities are suspected of accepting payments of €2,000–5,000 (US$2,870–7,175) to supervise PhDs — and to ensure that passes were awarded to students that might not have made the grade. The director of a Cologne-based academic consulting firm that allegedly connected would-be PhDs with bribable professors was jailed last year, along with an unnamed law professor from the University of Hanover. D. KUROKAWA/EPA/CORBIS The Democratic Party of Japan (DPJ) won a landslide election on 30 August, wresting power from the Liberal Democratic Party (LDP), which had ruled almost continuously since 1955. The DPJ, which is led by (pictured), has promised to increase the science budget and replace the country's highest science-policy body, the Council for Science and Technology Policy, with a 'strategy office' that would promote science more actively. It has also called for a cut in greenhouse-gas emissions to more than 25% below 1990 levels by 2020, a much bigger reduction than the LDP's 8% proposal (see Nature 460, 938; 2009). India formally abandoned its first lunar orbiter on 30 August, after scientists at the Indian Space Research Organisation (ISRO) abruptly lost radio contact with the probe. , launched last year to map the Moon, ended its mission 14 months early, but the ISRO said it had met most of its scientific objectives. Meanwhile, 's Lunar Crater Observation and Sensing Satellite (LCROSS) accidentally burned up most of its spare fuel on 22 August. Mission managers say it remains on track to smash into the Moon on 9 October, in the hope of kicking up evidence of ice. R. JENSEN/DPA Ahead of national elections on 27 September, a dispute flared up last week on how Germany will dispose of its nuclear waste. Documents published by a local anti-nuclear group show that in 1983 Helmut Kohl's government altered a scientific report expressing concern over the Gorleben salt dome (pictured) — chosen in the 1970s to become the national long-term waste-storage facility. A moratorium on exploration of the site is due to expire next year. Chancellor Angela Merkel wants to retain Gorleben; but opposition party — and anti-nuclear — environment minister Sigmar Gabriel said it was "dead" and urged research into alternative sites. The 16th Congress of the International Society of Developmental Biologists meets in Edinburgh, UK → http://www.isdb2009.com The US Congress returns from its summer recess. Later this month, the Senate is expected to introduce for discussion its version of a cap-and-trade bill for carbon emissions. Burton Richter, Stanford University, California Speaking on 26 August at IBM's Almaden Institute the Nobel laureate said that today's expensive and short-lived fuel cells must to go back to the R&D lab. (Greentech Media) Annual amount sought by Africa from developed nations to mitigate the effects of climate change. African leaders met in Libya this week to firm up the draft proposal. There are currently no comments.
• Climate-control plans scrutinized
  - Nature 461(7260):19 (2009)
  The Royal Society reviews options for fighting global warming with geoengineering. Geoengineering ideas include using sea salt to brighten clouds.P. Turner/Getty As atmospheric levels of carbon dioxide soar and political efforts to control emissions stagnate, one scientific academy says that it is time to consider radical intervention. On 1 September, the Royal Society, Britain's premier scientific organiz­ation, released its first analysis of a host of controversial methods for intentionally altering Earth's climate. Such approaches, known broadly as geoengineering, could slow or halt climate change by either restricting the amount of sunlight heating Earth's surface or reducing levels of carbon dioxide in the atmosphere. But they could also have disastrous side effects, such as stifling the Asian monsoons or altering the oceans' oxygenation or pH. For these reasons, the society is calling for international regimes to review even preliminary research projects. Further work, it says, must also go into developing rules for how and when geoengineering might be used. Because the science and policy surrounding geoengineering is so complex, any potential scheme would take decades to put into practice, says John Shepherd, an Earth scientist at the University of Southampton, UK, who chaired the report. "These things may help us get out of a fix later in the century," he says. "But we have to do research now." Geoengineering proposals have been around for decades, but most have been dismissed out of hand because they often seem outlandish, costly or downright dangerous. Some researchers see the Royal Society report as the first real indication that geoengineering is being taken seriously. "This is actually quite a big deal," says David Keith, an environmental engineer at the University of Calgary in Alberta, Canada, and one of a dozen authors on the study. The report is "the first major national academy report solely devoted to this topic", he says. Shepherd stresses that the Royal Society wasn't trying to pick winners and losers among possible geoengineering approaches, but the group did weigh in with which concepts they consider the most promising for future study (see 'Thinking big'). Some popular ideas received low marks. The idea that painting roofs white could cool urban areas — proposed among others in a 27 August geoengineering report by the UK Institution of Mechanical Engineers — would produce a near-negligible change in Earth's overall temperature, the Royal Society argued. Also low on the list was using iron to increase carbon-absorbing algal blooms in the ocean. Such algal outbreaks would absorb relatively little carbon, the new study warns, and would consume vast amounts of oxygen, potentially leading to oceanic 'dead zones'. Other ideas were viewed more favourably. Artificial weathering, the acceleration of geological carbon-absorbing processes, was among the most promising ways to capture carbon, according to the panel. Filling agricultural land with carbonate and silicate compounds could turn fields into carbon sponges, absorbing massive amounts of carbon dioxide. And seeding the stratosphere with sulphate aerosols — a process that would increase the atmosphere's reflectivity — could mimic the immediate cooling effects of major volcanic eruptions. The sulphate strategy has the advantage of being a quick way to cool the planet, Shepherd says. But to keep it cool, "you have to keep it going for many decades or possibly centuries", he says. "There is no silver bullet." Dangerous distraction Most of the top-ranked strategies do have potentially catas­trophic side effects. Some models suggest that putting sulphates into the stratosphere could degrade the ozone layer or alter the monsoons — affecting the livelihoods of billions of people. Using silicate or carbonate compounds, meanwhile, could alter the pH of soil or marine ecosystems, depending on how researchers dispose of the material. For these reasons, experiments must undergo stringent ethical review and public discussion, says Michael Oppenheimer, a geoscience and policy researcher at Princeton University in New Jersey who reviewed the study. "Scientists should not take a step in the direction of field experiments until these issues are resolved," he warns. ADVERTISEMENT Panel members acknowledge that the biggest risk from geoengineering may be that it distracts from the main accepted way of stopping climate change: reducing the amount of greenhouse gases being spewed into the atmosphere. "Geoengineering is already being seen as an easy way out," warns Doug Parr, chief scientist of environmental campaigners Greenpeace UK. Shepherd agrees that geoengineering is no substitute for curbing fossil-fuel use and developing alternative energy sources. "In [the panel's] view, the primary focus has to remain on conventional emissions," he says. For now, Shepherd thinks that a modest annual expenditure of around £10 million (US$16 million) should be enough to determine which schemes hold the most promise. "In five to ten years' time," Shepherd predicts, "we'll have an idea whether it's worth spending serious research money on this." There are currently no comments.
• Pandemic flu: from the front lines
  - Nature 461(7260):20-21 (2009)
  Researchers describe the scientific and public-health challenges they face in battling the H1N1 virus. Mexico | Australia | Japan | Argentina | Vietnam | United States | India | Sub-Saharan Africa Click for larger map of influenza fatalities.SOURCE: ECDC Data suggest that Mexico has seen two waves of infection — the first, which peaked in late April, affected the Mexico City area, and the second, broader wave spanned June through August in southern states, including Chiapas, Yucatan and Quintana Roo. To prepare for a potentially larger wave this winter, Mexico is raising public awareness, standardizing timely diagnosis and treatment and reinforcing equipment and management protocols in intensive-care units throughout the country. To improve surveillance, Mexico has accelerated the upgrading of its public-health laboratory network. The national reference laboratory and 28 states will soon have real-time PCR for running diagnostic tests. This builds on a restructuring of Mexico's national surveillance and reporting systems, which started in 2007. As Mexico's strategic reserve of antivirals would cover only 1% of the population for community cases and up to 80,000 hospitalized cases, the nation is implementing a central logistics and delivery system to assure their efficient allocation. The country also expects to have 20 million doses of the H1N1 vaccine available by December. As even this would cover only a fraction of the population, the government will prioritize health-care workers, then individuals at risk of severe disease, such as pregnant women and people with chronic underlying illnesses. Stefano Bertozzi, executive director at the Center for Evaluation Research and Surveys at the National Institute of Public Health in Cuernavaca The timing of the epidemic has differed across the country, which has meant that we needed different public-health measures and messages in individual states. The pandemic virus seems to be outcompeting the seasonal flu viruses. The great majority of flu cases around the country are now pandemic H1N1. One interesting question is whether this pandemic virus will completely replace any of the seasonal flu strains. If it doesn't, that's going to complicate the production of future seasonal flu vaccines, as we will need a vaccine against four strains instead of the current three. The Australian government has ordered 21 million doses of dedicated pandemic virus vaccine, so if we need two doses per person, that covers half the population. There has been a lot of discussion about who should get it first, and when. We are seeing similar patterns of disease severity to those reported worldwide, with most cases being mild. But there have been a significant number of cases with severe disease, not just in the at-risk groups, but also in healthy people. Our indigenous population is being hit harder, and we are seeing disproportionate numbers hospitalized with severe disease. An important message for other countries that have intensive-care facilities is to expect significant pressure on them. There is a need for mechanical ventilators, and we have seen heavy use of scarce extracorporeal membrane oxygenation units. Anne Kelso, director of the World Health Organization Collaborating Centre for Reference and Research on Influenza in Melbourne Japan stopped counting cases on 25 July and launched a new cluster surveillance system that is directly in the hands of the health ministry. Our Infectious Disease Surveillance Center no longer has any disease data feed, making it difficult to analyse epidemiological trends or disease burden. But we have received hundreds of reports through routine sentinel-based surveillance of clusters of disease from many regions and big cities, so there is extensive spread. The demand on public-health services to report and investigate all cluster cases is overwhelming public-health staff and leading to a breakdown in the normal public-health diagnostic service in local laboratories. With the rising numbers of cases we are seeing a corresponding increase in deaths. As elsewhere, it is younger people who are affected with more severe disease requiring hospitalization, but the overall hospitalization rate is no greater than that of human seasonal influenza. Japan has an ageing population with large numbers of people older than 65, many with at-risk underlying health conditions, but so far pandemic H1N1 seems to be largely sparing the elderly. The country's pandemic plan was based almost entirely on a severe pandemic of H5N1 avian influenza, which limited medical consultations to just a few hospitals. The government seems to be relaxed with the low level of epidemic by the less virulent virus since May, and seems to have yet to draw any lessons from the pandemic. As a result, local and regional authorities have now independently started to prepare for the coming flu season. Masato Tashiro, director of the Department of Viral Diseases and Vaccine Control at the National Institute of Infectious Diseases in Tokyo The current epidemiological situation is a generalized spread of the virus throughout the country, although with a marked downward trend in the number of reports of the levels of influenza-like illness. The epidemic started in mid-May in Buenos Aires, and three weeks later spread to the city's larger metropolitan area. Activity peaked on 25 July, with influenza A representing 80% of the circulating respiratory viruses; 65% were H1N1-pandemic confirmed. Very few isolates were H3 and H1 seasonal. Health systems in Argentina were overloaded because of government advice to people to consult a physician on first signs of flu symptoms such as fever or cough. The major challenge at the lab level was in diagnosing the first cases produced by a new, unknown virus. Later, the challenge was for lab capacity to meet demand. Information transmitted to the public was not always clear enough, and the mass media had a negative role, including providing contradictory information and producing fear. Vilma Savy, head of the respiratory virus service at the National Institute for Infectious Diseases in Buenos Aires The first cases in Vietnam were at the end of May, a bit later than in many other parts of Asia, probably because Vietnam does not have a major international airport hub. We are now seeing an increase in disease and a small number of severe cases. Vietnam was a hotspot for H5N1 avian influenza in 2003 and 2004, and the pandemic preparation that resulted from both this and SARS has made a massive difference to the current situation. Prior to avian flu, few hospital staff had community-acquired pneumonia on their radar; attention was concentrated on malaria, dengue fever and tuberculosis. Now clinicians have a much greater awareness of the need to look out for clusters of respiratory illnesses. There has also been greater interaction and collaboration between clinical and other researchers, and between centres across the country. Access to vaccines and drugs remains an important issue. There is a global shortage of vaccines, and the rich countries have bought up all the first stocks. This is a really urgent issue; if we can get this right now, then many of the past issues around sharing of samples, data and general openness on emerging infectious diseases will be helped, maybe resolved. If we get it wrong, we will be back to square one. If ever there was a time for the rich world to reach out and ensure equity of access to drugs and vaccines, it is now. Jeremy Farrar, Vietnam director for the Wellcome Trust Major Overseas Programme, director of Oxford University's Clinical Research Unit in Ho Chi Minh City, and coordinator of the South East Asia Infectious Disease Clinical Research Network US health-care systems have been stretched and have no surge capacity. The system cannot handle this pandemic, even it if remains moderate in severity. The same applies to many of the supplies we get. Ask anybody who has tried to order an N95 respirator recently; there aren't any. We recently surveyed a group of world-class pharmacists to identify the essential drugs needed daily to keep patients from dying. They came up with a list of more than 30 — all generics, and most made offshore, mainly in Asia, and China and India in particular. Nobody is thinking what might happen to US or global supply chains when pandemic flu hits these countries, where the primary workforce are the young, who are most affected by the virus. The United States has a federal programme for vaccine procurement but it is administered at the state level, and the two do not always mesh up. It is still not clear how this vaccine is going to be rolled out, or whether it will be here in time. I worry most that, given current existing public concerns about vaccines, in the autumn we might see mounting public responses and concerns about pandemic-vaccine safety, and people refusing to be vaccinated. Expect the unexpected over the next six months. Michael Osterholm, director of the University of Minnesota's Center for Infectious Disease Research and Policy in Minneapolis The virus is now transmitting in city clusters. Large numbers of people are turning up at designated testing facilities, swamping an already stretched surveillance system, so there is little room for monitoring mutations and reassortment. This should be done. One way would be to bring in academic labs outside of the government testing system, but sharing of clinical materials and trust is low. Deaths have sparked a fair amount of concern and panic. Poor communication of risks by the government and the public-health system is largely to blame. Even if this pandemic remains moderate, the impact in India is likely to be severe, owing to its high population density, low awareness of the pandemic and the propensity of the virus to infect the young (50% of Indians are under 25 years of age). Moreover, there is a high load of other infectious diseases as well as chronic conditions, groups that are at higher risks of severe forms of pandemic H1N1 disease. The health-care infrastructure is poor. Despite this bleak outlook, India has strengths for tackling the virus, including that the government has pandemic plans in hand, and that we have a vibrant generic-pharmaceutical industry as well as a decent capacity for manufacturing vaccines. There is little clarity, however, as to India's vaccine plans, and the regulatory process is archaic, so it is not even clear whether pandemic vaccine could be rapidly approved for use in the country. The government says it has enough Tamiflu for 3 million people. Shahid Jameel, head of the virology group at the International Centre for Genetic Engineering and Biotechnology in New Delhi H1N1 has not yet been reported in Nigeria, or any of the other sub-Saharan African countries with which we collaborate — Niger, Burkina Faso or the Central African Republic, although the Democratic Republic of Congo has one confirmed case. But surveillance is still very poor, and the virus may well often escape detection. International media attention to the pandemic is probably more than it deserves from an African public health point of view. Any diversion of resources from other important programmes needs to be carefully evaluated for long-term cost-benefit and sustainability. Systems for lab surveillance and reporting of respiratory illnesses have improved since H5N1, which has hit nine sub-Saharan African countries since it first spread to the continent in 2006. With international support Nigeria, for example, has set up a central national laboratory for human influenza surveillance in Abuja, as well as several decentralized satellite labs. ADVERTISEMENT There is no culture of testing for respiratory viruses, however, and the effort that went into H5N1 control is losing steam. The H5N1 virus was perceived as a major threat to the poultry industry, whereas the disease burden of pandemic flu seems low. Don't expect much mobilization for a virus where most cases are mild. Claude P. Muller, head of the Institute of Immunology at the WHO Collaborative Center for Reference and Research on Measles Infections in Luxembourg There are currently no comments.
• Keeping genes out of terrorists' hands
  - Nature 461(7260):22 (2009)
  Gene-synthesis industry at odds over how to screen DNA orders. Low standards could mean that hazardous genes get through screening more easily.W. PHILPOTT/REUTERS A standards war is brewing in the gene-synthesis industry. At stake is the way that the industry screens orders for hazardous toxins and genes, such as pieces of deadly viruses and bacteria. Two competing groups of companies are now proposing different sets of screening standards, and the results could be crucial for global biosecurity. "If you have a company that persists with a lower standard, you can drag the industry down to a lower level," says lawyer Stephen Maurer of the University of California, Berkeley, who is studying how the industry is developing responsible practices. "Now we have a standards war that is a race to the bottom." For more than a year a European consortium of companies called the International Association of Synthetic Biology (IASB) based in Heidelberg, Germany, has been drawing up a code of conduct that includes gene-screening standards. Then, at a meeting in San Francisco last month, two of the leading companies — DNA2.0 of Menlo Park, California, and Geneart of Regensburg, Germany — announced that they had formulated a code of conduct that differs in one key respect from the IASB recommendations. Both codes involve an automated step, in which the genes in a customer's order are compared against those from organisms on lists such as the US Centers for Disease Control and Prevention's 'select agents' list. This step uses computer programs such as the US National Center for Biotechnology Information's Basic Local Alignment Search Tool (BLAST), which searches for similarities between gene sequences. But although the IASB standard specifies that a human expert will follow up on possible 'hits' identified in the automated screening step, the DNA2.0/Geneart code ends with the automated screening step. The two firms are now merging their databases of genes of concern. This worries some observers, because it is difficult to translate the list of select-agent organisms into lists of dangerous genes (although a panel convened by the National Academy of Sciences is meeting in Washington DC on 3 September to grapple with this problem). And no one believes that such lists will catch every dangerous gene. For instance, they might not identify genes from harmless organisms that had been modified in some new and deadly way, so many companies use human expertise to review the results. Lowest common denominator But human expertise costs money, and competition is fierce in the gene-synthesis field, with roughly 50 dedicated companies fulfilling some 50,000 gene orders per year. And some observers think that the industry as a whole might now adopt the cheaper DNA 2.0/Geneart standard. That concerns Markus Fischer, a member of the IASB board and a managing director of Entelechon of Regensburg. "The proposal from DNA2.0 and Geneart is a kind of lowest-common-denominator idea," Fischer says. "Simply taking a list of genes, performing a BLAST against them and taking a sort of threshold cut-off and saying everything below that cut-off is not of interest to us is frankly a little bit naive and dangerous." Claes Gustafsson, vice-president of sales and marketing for DNA2.0, counters that human screening is also not perfect. "There's no way to standardize it," he explains. And as for the incomplete nature of databases of select-agent genes, "we're just going to deal with the stuff that we know something about", he says. "How do you deal with the unknown? It's outside the scope of science." "Now we have a standards war that is a race to the bottom." Stephen Maurer University of California, Berkeley He also says that discussions on governance of gene synthesis have been going on among policy experts and governments for many years, with no definitive conclusion. "We decided to standardize everything, make it consistent, and move on," he says. Other companies have not yet decided where they stand on the issue. In November, the IASB will convene a meeting in Cambridge, Massachusetts, to discuss adopting its code of conduct. But already, some companies are intrigued by the DNA2.0/Geneart proposal. "Our intention is to review the [DNA2.0/Geneart] process and seriously consider switching to that," says John Mulligan, founder and chief scientific officer of Blue Heron Biotechnology, a gene-synthesis company in Bothell, Washington. His company might, however, still keep some of its manual scrutiny. "What I see may come out of this is a standardized minimum across the industry with some companies choosing to augment that," he says. Maurer says he hopes that government officials in the United States, the country most concerned about biosecurity, will step in and communicate with industry about its preferred standard. So far, many branches of the government have been involved in working on potential regulations, but none has offered opinions on concrete issues such as screening standards. "I think if the government expressed an opinion, DNA2.0 would blink," Maurer says. "A little bit of effort now would steer them towards the top of existing practice rather than near the bottom." There are currently no comments.
• Stem-cell projects falter
  - Nature 461(7260):23 (2009)
  Ailing economy leaves California struggling to build research labs. California's troubled economy has hit the state's ambitious stem-cell research programme, delaying the construction of facilities and disrupting recruitment. At least three of the dozen groups that received a share of US$271 million in building grants from the California Institute for Regenerative Medicine (CIRM) won't make the construction deadline of the end of 2010. And efforts to recruit stem-cell researchers have stalled at some institutions, because of the delays in setting up lab space and because of university hiring freezes. Online collection At the University of California, Berkeley, administrators had hoped to recruit 15 principal investigators for a new $160-million building, including two floors paid for with $20 million from the CIRM. The building is on track to open in January 2011, "but we have no recruitments under way", says Mark Schlissel, the university's dean of biological sciences. "My real fear is that the University of California system and California will recover slower than the United States." The CIRM was created by a statewide vote in 2004 to pump $3 billion into stem-cell research when President George W. Bush had restricted federal funding for work in the field. The initiative called for spending the money over a decade, so to help keep things on track, when the CIRM handed out building grants in May 2008, it required the projects to be completed within two years. That schedule is now in doubt for some. In San Diego, the delay may stem from a decision by institutions to join forces. The CIRM gave $43 million to the Sanford Consortium for Regenerative Medicine, which is made up of the historically competing Salk Institute for Biological Studies, the Scripps Research Institute, the Burnham Institute and the University of California, San Diego. But because the consortium doesn't have a financial track record, officials say that it couldn't get a cost-effective loan to help finance its $110-million building, and construction stalled. The group is now seeking a University of California guarantee for a $60 million tax-exempt bond to underwrite construction so the facility can open in 2011. However, the university system is also experiencing its worst-ever financial stress (see Nature 460, 441; 2009). Sanford consortium officials also negotiated with their major donor, South Dakota philanthropist Denny Sanford, to provide more money upfront. The group arranged to receive a promised gift from Sanford in a lump sum of $7.25 million now instead of $10 million later. In Novato, the CIRM facility at the Buck Institute for Age Research has also run into delays. The institute was supposed to match $20.5 million provided by the CIRM. But it couldn't raise the money and is now hoping to get the money from economic stimulus funds from the US National Institutes of Health. If that fails, the institute plans to seek a tax-exempt bond. The CIRM has given the institute a deadline of March 2010 to break ground or risk losing its grant. As plans crawl along, university partners are gauging how this might affect recruitment. Lawrence Goldstein, stem-cell research programme director at the University of California, San Diego, says that the roughly 15 stem-cell researchers recruited in recent years are becoming "landlocked". "Our young people need to expand their labs," he says. In Santa Cruz, the University of California regents last month bailed the local campus out with $64 million. That will help to pay for a bioscience building to include a stem-cell research floor partly funded by the CIRM. It, too, is behind schedule. At the University of California, Irvine, administrators called for bids for a new $61-million facility, which involved reusing a plan from an already constructed building. The competition for work was intense and, because it didn't involve new designs, the university ended up getting an extra, incomplete floor added to its building for no extra cost. Peter Donovan, co-director of the campus stem-cell programme, says he'd like to finish the floor and recruit for it too, but can't. "We committed to five stem-cell faculty hires," he says, "but recruitments now are frozen." Nevertheless, the CIRM is pushing ahead to try to lure recruits in the tight fiscal environment. On 20 August its governing board approved $44 million to bring new scientists to the state. There are currently no comments.
• Cost of climate change underestimated
  - Nature 461(7260):24 (2009)
  The global cost of adapting to climate change could be 2–3 times higher than previously thought, says a study published on 27 August. In 2007, the United Nations Framework Convention on Climate Change (UNFCCC). There are currently no comments.
• Budget instructions
  - Nature 461(7260):25 (2009)
  Last month, the administration of US President Barack Obama released the first document that hints at how it intends to shape the science and technology budget for fiscal year 2011. If the administration rigorously applies the principles in the document, federal science agencies may need to alter their focus and procedures. There are currently no comments.
• GM crops: Battlefield
  - Nature 461(7260):27-32 (2009)
  Papers suggesting that biotech crops might harm the environment attract a hail of abuse from other scientists. Emily Waltz asks if the critics fight fair. Download a PDF of this story Emma Rosi-Marshall's trouble started on 9 October 2007, the day her paper was published in Proceedings of the National Academy of Sciences (PNAS). Rosi-Marshall, a stream ecologist at Loyola University Chicago in Illinois, had spent much of the previous two years studying 12 streams in northern Indiana, where rows of maize (corn), most of it genetically engineered to express insecticidal toxins from the bacterium Bacillus thuringiensis (Bt), stretch to the horizon in every direction. Working with colleagues including her former adviser Jennifer Tank at the University of Notre Dame, Indiana, Rosi-Marshall had found that the streams also contain Bt maize, in the form of leaves, stalks, cobs and pollen. In laboratory studies, the researchers saw that caddis-fly larvae — herbivorous stream insects in the order trichoptera — fed only on Bt maize debris grew half as fast as those that ate debris from conventional maize. And caddis flies fed high concentrations of Bt maize pollen died at more than twice the rate of caddis flies fed non-_Bt pollen. The transgenic maize "may have negative effects on the biota of streams in agricultural areas" the group wrote in its paper, stating in the abstract that "widespread planting of Bt _ crops has unexpected ecosystem-scale consequences"1. The backlash started almost immediately. Within two weeks, researchers with vehement objections to the experimental design and conclusions had written to the authors, PNAS and the US National Science Foundation (NSF), Rosi-Marshall's funder. By the end of the month, complaints about the paper had rippled through the research community. By the time Rosi-Marshall attended a National Academy of Sciences (NAS) meeting on genetically modified organisms (GMOs) and wildlife on 5 November 2007, "She looked hammered", says Brian Federici, an insect pathologist at the University of California, Riverside, one of those who commented on her work. "I felt really sorry for her. I don't think she realized what she was getting into." "The response we got — it went through the jugular." Emma Rosi-Marshall No one gets into research on genetically modified (GM) crops looking for a quiet life. Those who develop such crops face the wrath of anti-biotech activists who vandalize field trials and send hate mail. But those who, like Rosi-Marshall and her colleagues, suggest that biotech crops might have harmful environmental effects are learning to expect attacks of a different kind. These strikes are launched from within the scientific community and can sometimes be emotional and personal; heated rhetoric that dismisses papers and can even, as in Rosi-Marshall's case, accuse scientists of misconduct. "The response we got — it went through your jugular," says Rosi-Marshall. Problem papers Behind the attacks are scientists who are determined to prevent papers they deem to have scientific flaws from influencing policy-makers. When a paper comes out in which they see problems, they react quickly, criticize the work in public forums, write rebuttal letters, and send them to policy-makers, funding agencies and journal editors. When it comes to topical science that can have an impact on public opinion, "bad science deserves more criticism that your typical peer-reviewed paper", Federici says. But some scientists say that this activity may be going beyond what is acceptable in scientific discussions, trampling important research questions and stifling debate. "It makes public discussion very difficult," says David Schubert, a cell biologist at the Salk Institute in La Jolla, California, who found himself at the sharp end of an attack after publishing a commentary on GM food2 (see 'Seeds of discontent'). "People who look into safety issues and pollination and contamination issues get seriously harassed." Protesters can brandish science suggesting that genetically modified crops are harmful.P. PAVANI/AFP/GETTY To see the effect that biotech crop research can have on policy — and why some researchers feel that they need to weigh in against such studies as quickly and forcefully as possible — it is instructive to look back to a study3 published in Nature in 1999. In it, John Losey, an entomologist at Cornell University in Ithaca, New York, and his colleagues reported that nearly half of the monarch butterfly caterpillars eating leaves dusted with Bt maize pollen died after four days, compared with none exposed to untransformed pollen. The media and the anti-GMO community erupted. "Gene Spliced Corn Imperils Butterflies" headlined the 20 May 1999 San Francisco Chronicle. Greenpeace activists demonstrated in front of the US Capitol dressed as monarch butterflies, collapsing from 'killer' GM maize. In response, the US Environmental Protection Agency (EPA) told seed companies to submit data about the toxicity of Bt maize pollen in monarch butterflies or lose the right to sell the maize. Scientists dived into the research, using industry and government funding. The effort produced six PNAS papers in 2001 that concluded that the most common types of Bt maize pollen are not toxic to monarch larvae in concentrations the insects would encounter in the fields4. (Losey had used higher concentrations in his lab studies.) "The Losey paper resulted in a lot of good work and brought to a close that particular question," says Alison Power, who studies ecology and evolutionary biology at Cornell University. Yet some scientists were dismayed that a single paper with preliminary data gave so much ammunition to anti-GMO activists and caused an expensive diversion of resources to calm the scare. They did not want it to happen again. Jennifer Tank (left) and Emma Rosi-Marshall study stream ecology.G. LAMBERTI The caddis-fly study was Tank and Rosi-Marshall's debut in GM research. The idea stemmed from a 2002 talk that Tank gave at Michigan State University in East Lansing about nitrogen dynamics in streams. A researcher in the audience asked whether organic debris from fields of transgenic maize drains into streams, and whether it has any effect on stream life. "We've never thought about that," Tank told the questioner. And once the paper was complete, Tank, Rosi-Marshall and their collaborators had little idea of the storm it was about to kick up. "I thought the response would be 'So what? We're going to lose a few trichopterans'," says co-author Todd Royer, an assistant professor at Indiana University in Bloomington. On a Friday after the paper was published, Federici and plant biotechnologist Alan McHughen, also at the University of California, Riverside, met at a campus bar for a beer after work. "[McHughen] was really annoyed," says Federici. "I don't think there's been another case where I've seen him so really ticked off." Federici says he too was annoyed — Rosi-Marshall's study was "bad science", he says, and they feared that activists would use it to forward an anti-GMO agenda. McHughen and Federici wanted to neutralize any effects that Rosi-Marshall's paper might have on policy. The two discussed the key points of a rebuttal letter. McHughen wrote the critique and "circulated it around to people who might be sympathetic", says Federici. The letter listed six grievances with the "sloppy experimental design", and said the publication of the paper had "seriously jeopardized the credibility of PNAS". "How many busy scientists and how much scarce money will we need to divert to calm this new scare?" the researchers wrote. McHughen got ten other scientists' signatures, including Federici's. On 22 October, they sent the letter to the journal and to the NSF. Days later, Klaus Ammann, a retired botanist and professor emeritus at the University of Bern in Switzerland who had signed the McHughen letter, posted it on an online discussion forum5. Critical mass Wayne Parrott, a crop geneticist at the University of Georgia in Athens, also began working on a rebuttal to Rosi-Marshall's paper as soon as he saw it. He said recently that in his opinion: "The work is so bad that an undergrad would have done a better job. I'm convinced the authors knew it had flaws." He e-mailed the authors, the NSF and PNAS two bulleted lists of flaws that he said invalidated the paper. He wrote: "It is risky to extrapolate from lab results to field results, particularly when key factors were not monitored, measured or controlled appropriately." In January 2008, PNAS published a slimmed-down version of this letter6 and the one from McHughen7. Tank and Rosi-Marshall were dismayed by Parrott's e-mail. A few days after receiving it, Tank called James Raich, her contact at the NSF, to talk it over. "I told her to ignore it," says Raich, an ecosystem ecologist at Iowa State University in Ames who worked for the NSF for two years reviewing grant proposals. He told her that letters like these were unusual. But the critiques kept on coming. On 30 November, Monsanto, a maker of Bt maize based in St Louis, Missouri, sent the EPA a six-page critical response8 to the paper, and posted it online. Eric Sachs, director of global scientific affairs at Monsanto, says that regulators ask seed companies to notify them of papers that relate to crop safety, so Monsanto often includes with its notification evaluations of these papers. Four other signatories of the McHughen letter went on to publish scathing opinion articles over the next few months. In a March 2008 article9 criticizing four papers on biotech crops, Ammann joined forces with Henry Miller, a research fellow at the Hoover Institution in Stanford, California, to ask "Is biotechnology a victim of anti-science bias in scientific journals?". They called Rosi-Marshall's conclusions "dubious", and said their use of evidence "arguably amounts to investigator misconduct". And in a July 2008 commentary in Current Science10, Shanthu Shantharam, a visiting research scholar at Princeton University in New Jersey said Rosi-Marshall's "offending" paper "carried a wrong message to farmers and environmentalists", and that anti-biotech crop activists would use the paper to "hamper the progress of science". Rosi-Marshall took the hits hard. "I experienced it in person and in writing," she says. "These are not the kind of tactics we're used to in science." She was a few years out from her PhD, she did not have tenure at Loyola and her first paper in a prominent journal was getting trashed, along with her reputation. "She's young and was getting picked on," says Michelle Marvier, a biologist at Santa Clara University in California who attended the NAS November 2007 meeting. It was at least some comfort to Rosi-Marshall and Tank that e-mails and phone calls of encouragement came pouring in from other scientists. Some of their supporters had observed similar attacks on other biotech crop papers. "The most reassuring thing we learned was that it had happened before and by the exact same people," says Tank. What was it about Rosi-Marshall's paper that prompted such a strong reaction? The wording of the abstract — "widespread planting of Bt crops has unexpected ecosystem-scale consequences" — was a particular point of contention. Her critics say that the data do not support such a definitive conclusion. "They absolutely went too far," says Randy Schekman, editor-in-chief of PNAS. Of the half-a-dozen letters received by the journal, most of them protested at this wording, he says. "Why this would have escaped the attention of the referees beats me." The authors agree that the wording was unfortunate and in retrospect say that the sentence should have articulated the potential for ecosystem-scale consequences within streams, rather than suggesting that such consequences were observed. "This was an oversight," says Rosi-Marshall. "But we did not expect that this sentence would, in light of all of the other statements in our paper, elicit the response it did. We thought the paper would be taken as a whole." The study's methods also came under fire. It is unclear, for example, whether it was the Bt toxin itself affecting the caddis flies, or some other difference between Bt and non- Bt plants. To test this possibility, critics say the caddis flies should have been fed isogenic lines: strains of maize that are genetically identical except for Bt genes. The authors say they chose not to use such lines because their nutritional quality would have differed — Bt maize has higher concentrations of lignin than non- Bt maize, and so is less nutritious. So the authors matched the Bt samples with non- Bt samples that had similar levels of lignin and other nutrients. "To do otherwise would have resulted in a confounded experiment. Pairing the treatment on the basis of isolines might be standard for agronomic studies, but was inappropriate for an ecological feeding study," the authors told Nature in an e-mail. Rosi-Marshall and her colleagues made this point and other responses to their c! ritics in a correspondence11 published online in PNAS the week after McHughen's and Parrott's critiques. It is also unclear how much Bt toxin the caddis flies ate. The authors let the insects eat as much as they wanted, as they would in the wild. Critics argue that the authors should have fed the insects known amounts of the toxin in a method called a dose-response study that is routine in toxicity assessments. "The Rosi-Marshall et al. paper would have benefited from additional toxicological data," says Doug Gurian-Sherman, a senior scientist at the Union of Concerned Scientists in Cambridge, Massachusetts, and a former reviewer for the EPA. But the method the authors used "is a widely accepted method, and is generally adequate for a preliminary study of possible toxicity", he says. Omitted study The paper was also accused of omitting contrary findings. In June 2007, four months before Rosi-Marshall's PNAS paper was published, Jillian Pokelsek, a master's student at Loyola University Chicago working with Rosi-Marshall, presented results from a preliminary field experiment at the annual meeting of the North American Benthological Society in Columbia, South Carolina. The work showed that Bt maize pollen did not influence the growth or mortality of filter-feeding caddis flies. The society posted an abstract12 of the presentation on its website attributing the work to Pokelsek, Rosi-Marshall, Tank, Royer and four other scientists who also authored the PNAS paper. It was not mentioning this study that prompted Miller and Ammann's accusation of misconduct9. The authors defend the omission on the grounds that the data in the meeting presentation were not published or peer-reviewed, and were less reliable than those in the PNAS paper. "Field experiments are inherently difficult to control and have lower statistical power to detect significant differences compared with controlled laboratory experiments, thus we included the more controlled and statistically rigorous lab experiments in our paper," Tank and Rosi-Marshall told Nature. Also, the caddis flies in the student presentation belonged to a different family, with different feeding mechanisms to those in the PNAS study. Miller's response: "I don't want to split hairs," he says. "If you don't do appropriate controls or if you draw conclusions that are erroneous, I think that's misconduct." But Ammann says he has a "bad feeling" about the accusation. "Maybe we should have been more careful with the wording." Scientists who were not involved in the debate over Rosi-Marshall's paper say the results were preliminary and left some questions unanswered, but that overall the data are valuable. "The science is fine as far as I'm concerned," says Arthur Benke, an aquatic ecologist at the University of Alabama in Tuscaloosa, who called the strong language in some of the criticisms "inappropriate". "When bad science is used to justify bad policies, we all lose." Alan McHughen What drives the critics? Financial or professional ties to the biotech industry don't seem to be the impetus. Such ties do exist — like many people researching biotech crops, some have received research grants from industry or have other interactions with it — but in interviews they say that these are not the major driving force. Rather, many of them feel strongly that transgenic crops are safe and beneficial to the environment and society, and that the image and regulation of these crops has been too harsh. Many of the critics have been studying biotech crops since they were developed commercially in the late 1980s, and some were involved with the first regulatory approvals. They have specific ideas about how the risks of these crops should be scientifically assessed. And they worry that papers that fall short of high standards will give anti-GMO activists ammunition to influence policy, just as the monarch-butterfly study did. "When bad science is used to justify bad p! ublic policies, we all lose," says McHughen, who says he is on a "campaign to make academic scientists a little less politically naive and a bit more careful in their scientific work". Miller adds that "agricultural biotech has been so horrendously, unscientifically regulated and so over-regulated and so inhibited over the past 30 years that to have these pseudo-controversies stirred up unnecessarily does a disservice to everyone and everything". Ammann points to the example of golden rice, a variety engineered in the late 1990s to contain more vitamin A. Regulations have delayed the rice's development, he says, although more than 250,000 children a year go blind from vitamin-A deficiency. "We have to get emotional," says Ammann. "I can't agree with the cool scientists' perspective — only dealing with the facts. We live in the real world." In 2006, Ammann formed a rebuttal team called ASK-FORCE to challenge reports about biosafety of GM crops. On one online site, Ammann criticizes 20 reports — none of them positive toward biotech crops — that he considers biased or bad science. In July, he was revising a critique of a paper that appeared in The Lancet ten years ago. "I'm working nearly day and night on these things," says Ammann. The emotional and sometimes harsh quality of some of the attacks strikes some scientists as strange and unlike the constructive criticism to which they are accustomed. Benke points out that none of the criticisms on the caddis-fly paper, for example, called for further study on the insects. "What papers like this do is alert us to possible reasons to look into this more carefully," he says. "No one mentioned this." To try to dismiss the research out of hand ignores how science is supposed to work, adds Power — you make a hypothesis, test it, refine it, test it and refine it again. "You keep doing that until you have an answer that is as close as you're going to get," she says. "I don't understand the resistance to that notion." Arbiters of the truth Some scientists say they are galled by the certainty with which some of the critics state their opinion. "Part of what exasperates me is that they have declared themselves to be the experts in this field, and forcefully present themselves as the ultimate arbiters of truth," says an editor for the Entomological Society of America who asked to remain anonymous. "I personally am in favour of GMOs in general, and think that they are very beneficial for the environment. But I do have problems with the tactics of the large block of scientists who denigrate research by other legitimate scientists in a knee-jerk, partisan, emotional way that is not helpful in advancing knowledge and is outside the ideals of scientific inquiry." "It is critical to assert the right of scientists to question each other's work." Wayne Parrott The critics respond that they are simply pointing out flaws in research, and that this is an important part of the scientific process. "It is neither fair nor accurate to equate pointing out serious deficiencies with experimental design and data interpretation as 'denigration'," Parrott says. "For science to maintain its integrity and move forward, it is critical to assert the right of scientists to question each other's work." McHughen says that he doesn't condone ad hominem attacks. "They are invariably unproductive," he says, and points out these tactics are often used against scientists who don't oppose GM crops. Federici says he finds it inappropriate to call the reactions 'knee-jerk' ones. "Losey and colleagues, and Rosi-Marshall and colleagues at the time of their studies were newcomers to the field. Most of the people who found their studies flawed and protested had extensive experience with Bacillus thuringiensis." He also points out that the critics varied in how strongly they responded to the Rosi-Marshall paper, saying "I don't consider writing a letter to the editor a harsh response." "Young people are not going into this field because they are discouraged by what they see." Ignacio Chapela Ignacio Chapela, a microbial ecologist at the University of California, Berkeley, says that the attacks may be deterring young scientists from pursuing careers in biotech crop research. "I have a very long experience now with young people coming to me to say that they are not going into this field precisely because they are discouraged by what they see," he says. Chapela faced criticism from pro-GMO scientists after publishing a 2001 paper in Nature, in which he reported that native maize varieties in Mexico had been contaminated with transgenic genes13. Following the criticism, Nature decided that "the evidence available is not sufficient to justify the publication of the original paper". At its worst, the behaviour could make for a downward spiral of GM research as a whole, says Don Huber, a emeritus professor of plant pathology at Purdue University in West Lafayette, Indiana. "When scientists become afraid to even ask the questions … that's a serious impediment to our progress," he says. Miller says: "I don't see how criticism of flawed science that verges on misconduct should discourage anybody." Researchers could be invigorated by entering a field with such lively debate. "For some people it might be exciting because you're doing science that is relevant to society," says Power. Pervasive spread Rosi-Marshall's caddis-fly paper did find its way into the anti-GMO rhetoric, although on nowhere near the scale that the monarch butterfly paper did. For example, the London-based Institute of Science in Society, a not-for-profit organization involved in the GM debate, on 30 October 2007 posted its summary of the paper, saying that: "calling a halt to planting Bt corn next to streams … would be in keeping with the evidence [the authors] have provided". Greenpeace included the paper in an April 2008 briefing on Bt maize, citing it as evidence of environmental risk. The impact went further than that. On 9 January 2008, three months after Rosi-Marshall's paper was published, France's watchdog on GM foods ruled that one of Monsanto's types of Bt maize, known as MON810, may have an impact on wildlife. The evidence it cited included Rosi-Marshall's paper. Two days later, the French government announced a ban on cultivating the maize. "[The paper] got to every agency and non-governmental organization that doesn't like the technology and gave them a flag to wave," says Parrott. Not that he considers the effort wasted: "I have no doubt the impact on policy-makers would have been much worse had it not been countered." Nearly two years since the paper was published, the critics' comments are still pointed. "It was just an idiotic experiment," Miller said this July. But Rosi-Marshall and her co-authors stand behind their paper. "We believe our study was scientifically sound," they wrote in an e-mail, "although many questions on the topic remain to be answered. The repeated, and apparently orchestrated, ad hominem and unfounded attacks by a group of genetic engineering proponents has done little to advance our understanding of the potential ecological impacts of transgenic corn." ADVERTISEMENT And Rosi-Marshall's career seems to have survived the furore. In May 2009 she secured tenure at Loyola University Chicago, and in August she moved to the Cary Institute of Ecosystem Studies in Millbrook, New York. There she will study human-dominated ecosystems and will continue to investigate the influence of maize varieties on stream ecosystems. Since the caddis-fly paper, she has co-authored another study on transgenic crops showing that Bt maize debris decomposes in streams at a faster rate than conventional maize14. She says more data produced with the NSF grant are on the way and that the attacks won't deter her from her studies. "It toughened me up a lot," she says. "I'm not going to be intimidated." * References * Rosi-Marshall, E. J.et al. Proc. Natl Acad. Sci. USA104, 16204-16208 (2007). * Schubert, D.Nature Biotechnol.20, 969 (2002). * Losey, J. E. , Rayor, L. S. & Carter, M. E.Nature399, 214 (1999). * Scriber, J. M.Proc. Natl Acad. Sci. USA98, 12328-12330 (2001). * http://pubresreg.org/index.php?option=com_content&task=view&id=64 * Parrott, W.Proc. Natl Acad. Sci. USA105, E10 (2008). * Beachy, R. N. , Federoff, N. V. , Goldberg, R. B. & McHughen, A.Proc. Natl Acad. Sci. USA105, E9 (2008). * Technical Review: Rosi-Marshall et al. 2007. PNAS 104: 16204-16208 (Monsanto, 2007); available at http://www.monsanto.com/pdf/products/caddisflies_review_810.pdf * Miller, H. I. , Morandini, P. & Ammann, K.Trends Biotechnol.26, 122-125 (2008). * Shantharam, S. , Sullia, S. B. & Shivakumara Swamy, G.Curr. Sci.95, 167-168 (2008). * Rosi-Marshall, E. J. , Tank, J. L. , Royer, T. V. & Whiles, M. R.Proc. Natl Acad. Sci. USA105, E11 (2008). * Pokelsek, J. D.et al. Presentation at the North American Benthiological Society Annual meeting, Columbia, South Carolina, 2007. Available at http://www.benthos.org/database/allnabstracts.cfm/db/Columbia2007abstracts/id/370 * Quist, D. & Chapela, I. H.Nature414, 541-543 (2001). * Griffiths, N. A.et al. Ecol. Appl.19, 133-142 (2009). * Beachy, R.et al. Nature Biotechnol.20, 1195-1196 (2002). * Tabashnik, B. E. , Gassmann, A. J. , Crowder, D. W. & Carrière, Y.Nature Biotechnol.26, 199-202 (2008). * Moar, W.et al. Nature Biotechnol.26, 1072-1074 (2008). * övei, G. L. , Andow, D. A. & Arpaia, S.Environ. Entomol.38, 293-306 (2009). * Shelton, A. M.et al. Transgenic Res.18, 317-322 (2009). There are currently no comments.
• Arctic ecology: Tundra's burning
  - Nature 461(7260):34-36 (2009)
  More than 20,000 lightning strikes were recorded on the North Slope of Alaska in 2007. Some struck the vast stretches of lakes; some hit the treeless tundra. There are currently no comments.
• Conservation: a small price for long-term economic well-being
  - Nature 461(7260):37 (2009)
  Public funds should not just be channelled into boosting immediate economic recovery — we must also be prepared to pay a higher 'insurance bill' to safeguard the ecological long-term basis of our economic and social well-being. Increased spending on conservation could help fund a worldwide core network of protected areas of biodiversity.
• Conservation: the world's religions can help
  - Nature 461(7260):37 (2009)
  The world's religions are emerging as a surprising driver of support for conservation of biological diversity.The International Interfaith Investment Group, for example, which is collectively worth more than US$7 trillion, is encouraging religious organizations to change their current investment policies in favour of those that support conservation (http://www.3ignet.org
• Defining numbers in terms of their divisors
  - Nature 461(7260):37 (2009)
  In her informative Book Review of Yoko Ogawa's The Housekeeper and the Professor (Nature 460, 461–462; 2009), Jennifer Rohn nicely illustrates how one false premise will lead to all kinds of misunderstanding.
• Pakistan's reform experiment
  - Nature 461(7260):38-39 (2009)
  In 2002, Pakistan began an ambitious overhaul of its higher-education system. The successes and failures of the experience hold lessons for other countries, say Athar Osama and co-authors.
• Like minds can be small minds
  - Nature 461(7260):40-41 (2009)
  An adviser to US President Barack Obama argues that people's tendency to seek out those with similar views can entrench extreme opinions. But many other forces can fuel outlandish beliefs, says Herbert Gintis.
• Society need not be selfish
  - Nature 461(7260):41 (2009)
  In the 1950s and 1960s, a major topic of research in animal behaviour was aggression. Konrad Lorenz's popular 1966 book, On Aggression, argued that it has an important role in the social life of many animal species, including humans.
• Pop artist displays primitive instincts
  - Nature 461(7260):42 (2009)
  A retrospective of Todd Schorr's huge oil-painted comic-book visions features his garish image of a hunter-gatherer. Is it a deliberate allegory of consumer culture, asks Martin Kemp?
• Astrophysics: Hidden chaos in cosmic order
  - Nature 461(7260):43-44 (2009)
  "Galaxies, like elephants, have long memories," says an influential article from the 1980s. Tapping into these memories has revealed some surprising facts about the history of our neighbouring Andromeda galaxy.
• Cancer: The fat and the furious
  - Nature 461(7260):44-45 (2009)
  Evidence linking metabolic alterations to cancer progression is accumulating. It seems that cancer cells must sustain their energy production and remain well fed to survive detachment from their normal habitat.
• Materials science: Pulsating vesicles
  - Nature 461(7260):45-47 (2009)
  During her travels through Wonderland, Alice finds several ways of growing and shrinking in size. A polymeric vesicle plays the same trick in response to pH, in a process that might one day be useful for drug delivery.
• Structural biology: A channel with a twist
  - Nature 461(7260):47-49 (2009)
  Mechanosensitive channels release tension in cell membranes by opening 'pressure relief' pores. The structure of a partially open channel suggests a gating mechanism and delivers an unexpected architectural twist.
• 50 & 100 years ago
  - Nature 461(7260):48 (2009)
  The Human Response to an Expanding Universe. By Harlow Shapley — [The author of this book] is a world-renowned figure in the fields of astronomy and cosmography... Dr. Shapley begins by attempting an obituary of the anthropocentric view that man is the centre of the cosmos, and continues by interpreting the consequences to man (or rather to certain aspects of rational thinking) of the latest scientific discoveries in the cosmos...Dr. Shapley's displacement of human life from its once supreme position does not make him a pessimist, for he argues cogently that there must be at least a hundred million planets capable of supporting some form of life.
• Nitrogen cycle: Oceans apart
  - Nature 461(7260):49-50 (2009)
  Reactive nitrogen is lost from the oceans as dinitrogen — N2 — produced by microbial metabolism. The latest twist in an ongoing story is that different pathways dominate in two of the oceanic regions concerned.
• Neuroscience: Persistent feedback
  - Nature 461(7260):50-51 (2009)
  How does the brain remember the consequences of our actions? Persistent activity in the prefrontal cortex and basal ganglia may be crucial for learning correct actions through experience.
• Correction
  - Nature 461(7260):51 (2009)
  The News & Views article "Chemical physics: Electronic movies" by Marc Vrakking (Nature 460, 960–961, 2009) stated at the end of the fifth paragraph that "A similar conclusion was recently reached in a study of harmonic generation from nitrogen molecules", and incorrectly cited reference 8 of the article. This should have cited B. K. McFarland et al. Science 322, 1232–1235 (2008)
• Early-warning signals for critical transitions
  - Nature 461(7260):53-59 (2009)
  Complex dynamical systems, ranging from ecosystems to financial markets and the climate, can have tipping points at which a sudden shift to a contrasting dynamical regime may occur. Although predicting such critical points before they are reached is extremely difficult, work in different scientific fields is now suggesting the existence of generic early-warning signals that may indicate for a wide class of systems if a critical threshold is approaching.
• Scaling of BMP gradients in Xenopus embryos
  - Nature 461(7260):E1 (2009)
  Arising from: D. Ben-Zvi et al.Nature 453, 1205–1211 (2008); Francois et al.reply Metazoan organisms can 'scale', that is, maintain similar proportions regardless of size. Ben-Zvi et al.1 use experiments in Xenopus to support a quantitative model that explains morphological scaling as the result of scaling of a gradient of bone morphogenetic protein (BMP) signals. We believe that the evidence for scaling in Xenopus is misinterpreted, and that their model for embryonic patterning disagrees with prior data. The experiments they present supporting their model admit alternative interpretations.
• Reply to Francois et al.
  - Nature 461(7260):E2 (2009)
  Replying to: P. Francois et al.Nature 461, 10.1038/nature08305 (2009) Francois et al.1, commenting on our paper2, argue that (1) scaling does not occur, (2) our model is inconsistent with existing experiments, and (3) our experiments are not conclusive. We disagree.
• Structures of the tRNA export factor in the nuclear and cytosolic states
  - Nature 461(7260):60-65 (2009)
  Transfer RNAs are among the most ubiquitous molecules in cells, central to decoding information from messenger RNAs on translating ribosomes. In eukaryotic cells, tRNAs are actively transported from their site of synthesis in the nucleus to their site of function in the cytosol. This is mediated by a dedicated nucleo-cytoplasmic transport factor of the karyopherin- family (Xpot, also known as Los1 in Saccharomycescerevisiae). Here we report the 3.2 Å resolution structure of Schizosaccharomyces pombe Xpot in complex with tRNA and RanGTP, and the 3.1 Å structure of unbound Xpot, revealing both nuclear and cytosolic snapshots of this transport factor. Xpot undergoes a large conformational change on binding cargo, wrapping around the tRNA and, in particular, binding to the tRNA 5' and 3' ends. The binding mode explains how Xpot can recognize all mature tRNAs in the cell and yet distinguish them from those that have not been properly processed, thus coupling tRNA export t! o quality control.
• The remnants of galaxy formation from a panoramic survey of the region around M31
  - Nature 461(7260):66-69 (2009)
  In hierarchical cosmological models1, galaxies grow in mass through the continual accretion of smaller ones. The tidal disruption of these systems is expected to result in loosely bound stars surrounding the galaxy, at distances that reach 10–100 times the radius of the central disk2, 3. The number, luminosity and morphology of the relics of this process provide significant clues to galaxy formation history4, but obtaining a comprehensive survey of these components is difficult because of their intrinsic faintness and vast extent. Here we report a panoramic survey of the Andromeda galaxy (M31). We detect stars and coherent structures that are almost certainly remnants of dwarf galaxies destroyed by the tidal field of M31. An improved census of their surviving counterparts implies that three-quarters of M31's satellites brighter than Mv = -6 await discovery. The brightest companion, Triangulum (M33), is surrounded by a stellar structure that provides persuasive eviden! ce for a recent encounter with M31. This panorama of galaxy structure directly confirms the basic tenets of the hierarchical galaxy formation model and reveals the shared history of M31 and M33 in the unceasing build-up of galaxies.
• Laser cooling by collisional redistribution of radiation
  - Nature 461(7260):70-73 (2009)
  The general idea that optical radiation may cool matter was put forward 80 years ago1. Doppler cooling of dilute atomic gases is an extremely successful application of this concept2, 3. More recently, anti-Stokes cooling in multilevel systems has been explored4, 5, culminating in the optical refrigeration of solids6, 7, 8, 9. Collisional redistribution of radiation has been proposed10 as a different cooling mechanism for atomic two-level systems, although experimental investigations using moderate-density gases have not reached the cooling regime11. Here we experimentally demonstrate laser cooling of an atomic gas based on collisional redistribution of radiation, using rubidium atoms in argon buffer gas at a pressure of 230 bar. The frequent collisions in the ultradense gas transiently shift a highly red-detuned laser beam (that is, one detuned to a much lower frequency) into resonance, whereas spontaneous decay occurs close to the unperturbed atomic resonance frequenc! y. During each excitation cycle, kinetic energy of order kBT—that is, the thermal energy (kB, Boltzmann's constant; T, temperature)—is extracted from the dense atomic sample. In a proof-of-principle experiment with a thermally non-isolated sample, we demonstrate relative cooling by 66 K. The cooled gas has a density more than ten orders of magnitude greater than the typical values used in Doppler-cooling experiments, and the cooling power reaches 87 mW. Future applications of the technique may include supercooling beyond the homogeneous nucleation temperature12, 13 and optical chillers9.
• From molecular to macroscopic via the rational design of a self-assembled 3D DNA crystal
  - Nature 461(7260):74-77 (2009)
  We live in a macroscopic three-dimensional (3D) world, but our best description of the structure of matter is at the atomic and molecular scale. Understanding the relationship between the two scales requires a bridge from the molecular world to the macroscopic world. Connecting these two domains with atomic precision is a central goal of the natural sciences, but it requires high spatial control of the 3D structure of matter1. The simplest practical route to producing precisely designed 3D macroscopic objects is to form a crystalline arrangement by self-assembly, because such a periodic array has only conceptually simple requirements: a motif that has a robust 3D structure, dominant affinity interactions between parts of the motif when it self-associates, and predictable structures for these affinity interactions. Fulfilling these three criteria to produce a 3D periodic system is not easy, but should readily be achieved with well-structured branched DNA motifs tailed b! y sticky ends2. Complementary sticky ends associate with each other preferentially and assume the well-known B-DNA structure when they do so3; the helically repeating nature of DNA facilitates the construction of a periodic array. It is essential that the directions of propagation associated with the sticky ends do not share the same plane, but extend to form a 3D arrangement of matter. Here we report the crystal structure at 4 Å resolution of a designed, self-assembled, 3D crystal based on the DNA tensegrity triangle4. The data demonstrate clearly that it is possible to design and self-assemble a well-ordered macromolecular 3D crystalline lattice with precise control.
• Denitrification as the dominant nitrogen loss process in the Arabian Sea
  - Nature 461(7260):78-81 (2009)
  Primary production in over half of the world's oceans is limited by fixed nitrogen availability. The main loss term from the fixed nitrogen inventory is the production of dinitrogen gas (N2) by heterotrophic denitrification or the more recently discovered autotrophic process, anaerobic ammonia oxidation (anammox). Oceanic oxygen minimum zones (OMZ) are responsible for about 35% of oceanic N2 production and up to half of that occurs in the Arabian Sea1. Although denitrification was long thought to be the only loss term, it has recently been argued that anammox alone is responsible for fixed nitrogen loss in the OMZs2, 3, 4. Here we measure denitrification and anammox rates and quantify the abundance of denitrifying and anammox bacteria in the OMZ regions of the Eastern Tropical South Pacific and the Arabian Sea. We find that denitrification rather than anammox dominates the N2 loss term in the Arabian Sea, the largest and most intense OMZ in the world ocean. In seven of! eight experiments in the Arabian Sea denitrification is responsible for 87–99% of the total N2 production. The dominance of denitrification is reproducible using two independent isotope incubation methods. In contrast, anammox is dominant in the Eastern Tropical South Pacific OMZ, as detected using one of the isotope incubation methods, as previously reported3, 5. The abundance of denitrifying bacteria always exceeded that of anammox bacteria by up to 7- and 19-fold in the Eastern Tropical South Pacific and Arabian Sea, respectively. Geographic and temporal variability in carbon supply may be responsible for the different contributions of denitrification and anammox in these two OMZs. The large contribution of denitrification to N2 loss in the Arabian Sea indicates the global significance of denitrification to the oceanic nitrogen budget.
• The oldest hand-axes in Europe
  - Nature 461(7260):82-85 (2009)
  Stone tools are durable reminders of the activities, skills and customs of early humans, and have distinctive morphologies that reflect the development of technological skills during the Pleistocene epoch. In Africa, large cutting tools (hand-axes and bifacial chopping tools) became part of Palaeolithic technology during the Early Pleistocene (1.5 Myr ago)1, 2, 3. However, in Europe this change had not been documented until the Middle Pleistocene (<0.5 Myr ago)4, 5. Here we report dates for two western Mediterranean hand-axe sites that are nearly twice the age of the supposed earliest Acheulian in western Europe. Palaeomagnetic analysis of these two sites in southeastern Spain found reverse polarity magnetozones, showing that hand-axes were already in Europe as early as 0.9 Myr ago. This expanded antiquity for European hand-axe culture supports a wide geographic distribution of Palaeolithic bifacial technology outside of Africa during the Early Pleistocene.
• iPS cells produce viable mice through tetraploid complementation
  - Nature 461(7260):86-90 (2009)
  Since the initial description of induced pluripotent stem (iPS) cells created by forced expression of four transcription factors in mouse fibroblasts, the technique has been used to generate embryonic stem (ES)-cell-like pluripotent cells from a variety of cell types in other species, including primates and rat1, 2, 3, 4, 5, 6. It has become a popular means to reprogram somatic genomes into an embryonic-like pluripotent state, and a preferred alternative to somatic-cell nuclear transfer and somatic-cell fusion with ES cells7, 8. However, iPS cell reprogramming remains slow and inefficient. Notably, no live animals have been produced by the most stringent tetraploid complementation assay, indicative of a failure to create fully pluripotent cells. Here we report the generation of several iPS cell lines that are capable of generating viable, fertile live-born progeny by tetraploid complementation. These iPS cells maintain a pluripotent potential that is very close to ES c! ells generated from in vivo or nuclear transfer embryos. We demonstrate the practicality of using iPS cells as useful tools for the characterization of cellular reprogramming and developmental potency, and confirm that iPS cells can attain true pluripotency that is similar to that of ES cells.
• Adult mice generated from induced pluripotent stem cells
  - Nature 461(7260):91-94 (2009)
  Recent landmark experiments have shown that transient overexpression of a small number of transcription factors can reprogram differentiated cells into induced pluripotent stem (iPS) cells that resemble embryonic stem (ES) cells1, 2, 3, 4, 5, 6, 7. These iPS cells hold great promise for medicine because they have the potential to generate patient-specific cell types for cell replacement therapy and produce in vitro models of disease, without requiring embryonic tissues or oocytes8, 9, 10. Although current iPS cell lines resemble ES cells, they have not passed the most stringent test of pluripotency by generating full-term or adult mice in tetraploid complementation assays3, 11, raising questions as to whether they are sufficiently potent to generate all of the cell types in an organism. Whether this difference between iPS and ES cells reflects intrinsic limitations of direct reprogramming is not known. Here we report fertile adult mice derived entirely from iPS cells t! hat we generated by inducible genetic reprogramming of mouse embryonic fibroblasts. Producing adult mice derived entirely from a reprogrammed fibroblast shows that all features of a differentiated cell can be restored to an embryonic level of pluripotency without exposure to unknown ooplasmic factors. Comparing these fully pluripotent iPS cell lines to less developmentally potent lines may reveal molecular markers of different pluripotent states. Furthermore, mice derived entirely from iPS cells will provide a new resource to assess the functional and genomic stability of cells and tissues derived from iPS cells, which is important to validate their utility in cell replacement therapy and research applications.
• Reptilian heart development and the molecular basis of cardiac chamber evolution
  - Nature 461(7260):95-98 (2009)
  The emergence of terrestrial life witnessed the need for more sophisticated circulatory systems. This has evolved in birds, mammals and crocodilians into complete septation of the heart into left and right sides, allowing separate pulmonary and systemic circulatory systems, a key requirement for the evolution of endothermy1, 2, 3. However, the evolution of the amniote heart is poorly understood. Reptilian hearts have been the subject of debate in the context of the evolution of cardiac septation: do they possess a single ventricular chamber or two incompletely septated ventricles4, 5, 6, 7? Here we examine heart development in the red-eared slider turtle, Trachemys scripta elegans (a chelonian), and the green anole, Anolis carolinensis (a squamate), focusing on gene expression in the developing ventricles. Both reptiles initially form a ventricular chamber that homogenously expresses the T-box transcription factor gene Tbx5. In contrast, in birds and mammals, Tbx5 is r! estricted to left ventricle precursors8, 9. In later stages, Tbx5 expression in the turtle (but not anole) heart is gradually restricted to a distinct left ventricle, forming a left–right gradient. This suggests that Tbx5 expression was refined during evolution to pattern the ventricles. In support of this hypothesis, we show that loss of Tbx5 in the mouse ventricle results in a single chamber lacking distinct identity, indicating a requirement for Tbx5 in septation. Importantly, misexpression of Tbx5 throughout the developing myocardium to mimic the reptilian expression pattern also results in a single mispatterned ventricular chamber lacking septation. Thus ventricular septation is established by a steep and correctly positioned Tbx5 gradient. Our findings provide a molecular mechanism for the evolution of the amniote ventricle, and support the concept that altered expression of developmental regulators is a key mechanism of vertebrate evolution.
• Coordination of Rho GTPase activities during cell protrusion
  - Nature 461(7260):99-103 (2009)
  The GTPases Rac1, RhoA and Cdc42 act together to control cytoskeleton dynamics1, 2, 3. Recent biosensor studies have shown that all three GTPases are activated at the front of migrating cells4, 5, 6, 7, and biochemical evidence suggests that they may regulate one another: Cdc42 can activate Rac1 (ref. 8), and Rac1 and RhoA are mutually inhibitory9, 10, 11, 12. However, their spatiotemporal coordination, at the seconds and single-micrometre dimensions typical of individual protrusion events, remains unknown. Here we examine GTPase coordination in mouse embryonic fibroblasts both through simultaneous visualization of two GTPase biosensors and using a 'computational multiplexing' approach capable of defining the relationships between multiple protein activities visualized in separate experiments. We found that RhoA is activated at the cell edge synchronous with edge advancement, whereas Cdc42 and Rac1 are activated 2 m behind the edge with a delay of 40 s. This indicates ! that Rac1 and RhoA operate antagonistically through spatial separation and precise timing, and that RhoA has a role in the initial events of protrusion, whereas Rac1 and Cdc42 activate pathways implicated in reinforcement and stabilization of newly expanded protrusions.
• A genetically encoded photoactivatable Rac controls the motility of living cells
  - Nature 461(7260):104-108 (2009)
  The precise spatio-temporal dynamics of protein activity are often critical in determining cell behaviour, yet for most proteins they remain poorly understood; it remains difficult to manipulate protein activity at precise times and places within living cells. Protein activity has been controlled by light, through protein derivatization with photocleavable moieties1 or using photoreactive small-molecule ligands2. However, this requires use of toxic ultraviolet wavelengths, activation is irreversible, and/or cell loading is accomplished via disruption of the cell membrane (for example, through microinjection). Here we have developed a new approach to produce genetically encoded photoactivatable derivatives of Rac1, a key GTPase regulating actin cytoskeletal dynamics in metazoan cells3, 4. Rac1 mutants were fused to the photoreactive LOV (light oxygen voltage) domain from phototropin5, 6, sterically blocking Rac1 interactions until irradiation unwound a helix linking LOV! to Rac1. Photoactivatable Rac1 (PA-Rac1) could be reversibly and repeatedly activated using 458- or 473-nm light to generate precisely localized cell protrusions and ruffling. Localized Rac activation or inactivation was sufficient to produce cell motility and control the direction of cell movement. Myosin was involved in Rac control of directionality but not in Rac-induced protrusion, whereas PAK was required for Rac-induced protrusion. PA-Rac1 was used to elucidate Rac regulation of RhoA in cell motility. Rac and Rho coordinate cytoskeletal behaviours with seconds and submicrometre precision7, 8. Their mutual regulation remains controversial9, with data indicating that Rac inhibits and/or activates Rho10, 11. Rac was shown to inhibit RhoA in mouse embryonic fibroblasts, with inhibition modulated at protrusions and ruffles. A PA-Rac crystal structure and modelling revealed LOV–Rac interactions that will facilitate extension of this photoactivation approach to other prot! eins.
• Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment
  - Nature 461(7260):109-113 (2009)
  Normal epithelial cells require matrix attachment for survival, and the ability of tumour cells to survive outside their natural extracellular matrix (ECM) niches is dependent on acquisition of anchorage independence1. Although apoptosis is the most rapid mechanism for eliminating cells lacking appropriate ECM attachment2, recent reports suggest that non-apoptotic death processes prevent survival when apoptosis is inhibited in matrix-deprived cells3, 4. Here we demonstrate that detachment of mammary epithelial cells from ECM causes an ATP deficiency owing to the loss of glucose transport. Overexpression of ERBB2 rescues the ATP deficiency by restoring glucose uptake through stabilization of EGFR and phosphatidylinositol-3-OH kinase (PI(3)K) activation, and this rescue is dependent on glucose-stimulated flux through the antioxidant-generating pentose phosphate pathway. Notably, we found that the ATP deficiency could be rescued by antioxidant treatment without rescue of ! glucose uptake. This rescue was found to be dependent on stimulation of fatty acid oxidation, which is inhibited by detachment-induced reactive oxygen species (ROS). The significance of these findings was supported by evidence of an increase in ROS in matrix-deprived cells in the luminal space of mammary acini, and the discovery that antioxidants facilitate the survival of these cells and enhance anchorage-independent colony formation. These results show both the importance of matrix attachment in regulating metabolic activity and an unanticipated mechanism for cell survival in altered matrix environments by antioxidant restoration of ATP generation.
• Direct activation of protein kinases by unanchored polyubiquitin chains
  - Nature 461(7260):114-119 (2009)
  TRAF6 is a ubiquitin ligase that is essential for the activation of NF-B and MAP kinases in several signalling pathways, including those emanating from the interleukin 1 and Toll-like receptors1, 2, 3. TRAF6 functions together with a ubiquitin-conjugating enzyme complex consisting of UBC13 (also known as UBE2N) and UEV1A (UBE2V1) to catalyse Lys 63-linked polyubiquitination, which activates the TAK1 (also known as MAP3K7) kinase complex4, 5. TAK1 in turn phosphorylates and activates IB kinase (IKK), leading to the activation of NF-B. Although several proteins are known to be polyubiquitinated in the IL1R and Toll-like receptor pathways, it is not clear whether ubiquitination of any of these proteins is important for TAK1 or IKK activation. By reconstituting TAK1 activation in vitro using purified proteins, here we show that free Lys 63 polyubiquitin chains, which are not conjugated to any target protein, directly activate TAK1 by binding to the ubiquitin receptor TAB2 ! (also known as MAP3K7IP2). This binding leads to autophosphorylation and activation of TAK1. Furthermore, we found that unanchored polyubiquitin chains synthesized by TRAF6 and UBCH5C (also known as UBE2D3) activate the IKK complex. Disassembly of the polyubiquitin chains by deubiquitination enzymes prevented TAK1 and IKK activation. These results indicate that unanchored polyubiquitin chains directly activate TAK1 and IKK, suggesting a new mechanism of protein kinase regulation.
• Structure of a tetrameric MscL in an expanded intermediate state
  - Nature 461(7260):120-124 (2009)
  The ability of cells to sense and respond to mechanical force underlies diverse processes such as touch and hearing in animals, gravitropism in plants, and bacterial osmoregulation1, 2. In bacteria, mechanosensation is mediated by the mechanosensitive channels of large (MscL), small (MscS), potassium-dependent (MscK) and mini (MscM) conductances. These channels act as 'emergency relief valves' protecting bacteria from lysis upon acute osmotic down-shock3. Among them, MscL has been intensively studied since the original identification and characterization 15 years ago4. MscL is reversibly and directly gated by changes in membrane tension. In the open state, MscL forms a non-selective 3 nS conductance channel which gates at tensions close to the lytic limit of the bacterial membrane. An earlier crystal structure at 3.5 Å resolution of a pentameric MscL from Mycobacterium tuberculosis represents a closed-state or non-conducting conformation5, 6. MscL has a complex gating! behaviour; it exhibits several intermediates between the closed and open states, including one putative non-conductive expanded state and at least three sub-conducting states7. Although our understanding of the closed5, 6 and open8, 9, 10 states of MscL has been increasing, little is known about the structures of the intermediate states despite their importance in elucidating the complete gating process of MscL. Here we present the crystal structure of a carboxy-terminal truncation mutant (95–120) of MscL from Staphylococcus aureus (SaMscL(C26)) at 3.8 Å resolution. Notably, SaMscL(C26) forms a tetrameric channel with both transmembrane helices tilted away from the membrane normal at angles close to that inferred for the open state9, probably corresponding to a non-conductive but partially expanded intermediate state.
• Direct observation of the binding state of the kinesin head to the microtubule
  - Nature 461(7260):125-128 (2009)
  The dimeric motor protein kinesin-1 converts chemical energy from ATP hydrolysis into mechanical work used to transport cargo along microtubules1, 2. Cargo attached to the kinesin stalk moves processively in 8-nm increments3 as its twin motor domains (heads) carry out an asymmetric, 'hand-over-hand' walk4, 5, 6, 7. The extent of individual head interactions with the microtubule during stepping, however, remains controversial4, 8, 9, 10, 11, 12, 13, 14. A major experimental limitation has been the lack of a means to monitor the attachment of an individual head to the microtubule during movement, necessitating indirect approaches. Here we report the development of a single-molecule assay that can directly report head binding in a walking kinesin molecule, and show that only a single head is bound to the microtubule between steps at low ATP concentrations. A bead was linked to one of the two kinesin heads by means of a short DNA tether and used to apply rapidly alternatin! g hindering and assisting loads with an optical trap. The time-dependent difference between forwards and backwards displacements of the bead alternated between two discrete values during stepping, corresponding to those intervals when the linked head adopted a bound or an unbound state. The linked head could only rebind the microtubule once ATP had become bound to its partner head.
• Fine-tuning the Universe
  - Nature 461(7260):134 (2009)
  Touched by the hand of God.