Hot off the presses! Aug 27 Nature

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Latest Articles Include:

• The ethics of egg manipulation
  - Nature 460(7259):1057 (2009)
  Cell research reopens the debate on embryo destruction, egg donation and what is natural.
• All the news you need
  - Nature 460(7259):1057 (2009)
  This issue marks an evolution in Nature's news coverage. On page 1062, we are launching News Briefing — a two-page digest of the key events shaping the scientific enterprise in the past week. With coverage encompassing policy decisions, funding announcements, market trends and business deals, News Briefing offers a complete overview of the developments that affect anyone working in science. The section also features a calendar to highlight important events, reports and initiatives occurring in the forthcoming week. Science is inextricably linked with the messy details of politics and commerce, and it is vital for today's researchers to be aware of how political and business decisions can steer their research programmes — and indeed how their research can affect society. Similarly, policy-makers require the perspective that science can provide on the likely outcomes of their decisions. Yet it is all too easy to miss something important in the torrent of news that pours down on us every day. By gathering all of the important events in one place, News Briefing aims to plug that gap. In doing so, it complements Research Highlights, which for the past four years has brought you our editors' selections of the most interesting research results from beyond the pages of Nature. Both sections will guide you to longer analytical pieces and exclusives in the main news section or online at http://www.nature.com/news. Apart from breaking daily news stories, our news website also carries stories from the print edition before they make it onto paper, getting analysis and information to our subscribers as soon as possible. The introduction of News Briefing to our family of daily online coverage and weekly analysis means that Nature now provides a complete overview of the important events shaping our readers' lives. As ever, we would welcome any feedback on the changes, which should be sent to Email: nature@nature.com.
• Human behaviour: Walking in circles
  - Nature 460(7259):1060 (2009)
  
• Physiology: Smooth transitions
  - Nature 460(7259):1060 (2009)
  
• Cancer biology: A nasty cut
  - Nature 460(7259):1060 (2009)
  
• Ecology: Winter warmer
  - Nature 460(7259):1060 (2009)
  
• Model organisms: A new kind of knock out
  - Nature 460(7259):1060 (2009)
  
• Nanotechnology: Origami bridge
  - Nature 460(7259):1060-1061 (2009)
  
• Biology: Following in the wake
  - Nature 460(7259):1061 (2009)
  
• Physics: Trip the light magnetic
  - Nature 460(7259):1061 (2009)
  
• Plant biology: The other garden path
  - Nature 460(7259):1061 (2009)
  
• Geoscience: Ground down
  - Nature 460(7259):1061 (2009)
  
• Journal club
  - Nature 460(7259):1061 (2009)
  
• News briefing
  - Nature 460(7259):1062-1063 (2009)
  This article is best viewed as a pdf. Policy|Events|Business|Facilities|Environment The week ahead|Sound bites|Number crunch Restrictions on human embryonic stem-cell research in were relaxed on 21 August, after updated government guidelines came into effect. But some scientists fear the new rules have come too late to regain lost ground in the field. For more, see page 1068. last week allowed inspectors from the to visit a heavy-water nuclear reactor near the city of Arak, and agreed to changes that will ease monitoring at a uranium-enrichment facility at Natanz. The country last year withdrew access to the 40-megawatt Arak reactor, which is currently under construction and could enter operation as early as 2014. When completed, it will burn uranium fuel, producing electricity and a range of nuclear isotopes, including plutonium. Iran denies that the reactor has a military purpose. The costs of complying with European Union legislation on chemical safety (REACH) are much greater than thought, according to a study released by toxicologists. Industry may have to spend €9.5 billion (US$13.6 billion) on — six times more than expected — and the number of animals used in the tests could rise by 20 times to 54 million. The chemical industry challenged the numbers as worst-case estimates. For more, see pages 1065 and 1080. People infected with the H1N1 swine flu virus who are otherwise healthy should not routinely be given the World Health Organization (WHO) warned last week. Its recommendations are at odds with current practice in many countries, where oseltamivir (Tamiflu) is routinely given out to all those suspected of having contracted H1N1. Although those with "uncomplicated illness" should not get oseltamivir or zanamivir (Relenza), the WHO did recommend giving drugs to those presenting with severe illness, to children under five and to pregnant women (see http://tiny.cc/WHOH1N1). On 20 August, parliament approved laws that require the country to produce 20% of its electricity from renewable sources by 2020 — up from around 8% today. The renewable-energy target is expected to spur billions of dollars of investment in wind, solar and hydroelectric power, although methane waste gas from coal mining was also classified as a renewable-energy source under the bill. The measures were delinked from a broader legislative package, defeated on 12 August, that proposed a cap-and-trade scheme to limit greenhouse-gas emissions from industry (see Nature 458, 554–555; 2009). After almost three-and-a-half years, the trial of stem-cell researcher may be drawing to a close. On 24 August, in a final evidence hearing, prosecutors requested a four-year prison term for Hwang, who is charged with fraud, embezzlement of state funds and violation of the country's bioethics law. His papers claiming that he had created cloned human embryonic stem cells were shown to be fabrications in January 2006. A court decision is expected in mid-October. South Korea's first space rocket (click to enlarge).JUNG YEON-JE/AFP/GETTY IMAGES (see image, right). It may have been watched by millions, but the launch of South Korea's first space rocket on 25 August was only a 'partial success', according to the country's science ministry. The two-stage Naro-1 blasted off from Naro Space Center, some 485 kilometres south of Seoul but, as Nature went to press, it had failed to put its observation satellite into its intended orbit. A second rocket launch from South Korean territory is planned for spring 2010. A US research vessel left Oregon on 22 August for Canadian waters to conduct imaging seafloor structures, after a Canadian court declined to halt the cruise. As Nature went to press, environmental groups seeking to block the use of air guns during the tests (see Nature 460, 939; 2009) were expected to return to court on 25 August to try to divert the RV Marcus Langseth from her mission. Six months after giving it the green light, the US Food and Drug Administration (FDA) halted plans for the world's of a therapy generated from human embryonic stem cells. The product's manufacturer, in Menlo Park, California, had hoped to start human testing of its potential treatment for spinal-cord injury this summer (see Nature 457, 516; 2009). Geron says the hold order came after it submitted additional data from studies testing dose escalation, and from investigations of the product's use for other neurodegenerative diseases. It added that it was working closely with the FDA to review the data. abandoned development of its drug arzoxifene, after results from an advanced clinical trial suggested it did not offer sufficient benefit over currently available treatments. The company, headquartered in Indianapolis, Indiana, had hoped arzoxifene would be a successor to its blockbuster osteoporosis treatment raloxifene (Evista), which will lose its patent protections by 2014. Meanwhile, of Thousand Oaks, California, has received more positive news for its new-mode-of-action osteoporosis treatment, denosumab. The monoclonal antibody gained recommendations from an advisory committee at the Food and Drug Administration on 14 August, and awaits full approval. Despite the economic crisis, countries are still installing solar capacity at a rapid rate, as the cost of solar panels plummeted in the first half of 2009 (see also Nature 460, 677; 2009 ). Prices of photovoltaic panels have dropped by almost 50% since September 2008, says Jenny Chase of New Energy Finance, a London-based global consultancy firm. The glut of cheap panels saw many solar companies reporting reduced revenues in the past financial quarter. SOURCES: BSW, CNE, GSE, SEIA, DRC, METI, NEW ENERGY FINANCE Chase says that Italy, a relative newcomer to solar power, is likely to be the second largest installer of photovoltaics in 2010. And Germany's solar capacity, which far exceeds that of other countries, should continue to increase (see chart). Only Spain is slowing down. Generous feed-in tariffs, which guarantee a set price for each unit of electricity supplied by a solar provider, saw the country install 2.7 gigawatts of solar capacity in 2008; the Spanish government has now capped the amount of solar power eligible for this tariff at 0.5 gigawatts. As the recession continues to bite, venture-capital investment in solar companies has fallen. Analyst Dallas Kachan, managing director of Cleantech Group, headquartered in Brighton, Michigan, says that solar investment sank from a high of US$1.2 billion in the third quarter of 2008 to $115 million in the second quarter of 2009. The University of California, San Diego (UCSD) and the Indian Institute of Technology Kharagpur signed a pact last week to develop allied research, teaching and medical programmes. The agreement also calls for a joint in Kharagpur. India will fund the 300-bed facility, with UCSD collaborating on clinical care and research. Researchers will study drug development, bioengineering and imaging technologies at the two campuses. The chance to test therapies on different populations makes the collaboration particularly attractive for physicians. A nuclear reactor in Petten, that supplies radioactive isotopes for use in medical imaging reopened last week after a month's scheduled maintenance — partly alleviating a global shortage of the isotopes (see Nature 460, 312–313; 2009). But the reactor is due to shut down again next March for six months of repairs. Chalk River, Ontario, reactor — whose closure precipitated the isotope crisis — will not reopen until 2010. Lawrence Deyton Lawrence Deyton (pictured) was appointed to direct the new in Silver Spring, Maryland, part of the Food and Drug Administration (FDA). Deyton, who will start his new job on 14 September, is a physician at George Washington University's School of Medicine and Health Sciences in Washington DC, and a public health officer at the US Department of Veterans Affairs. He has also led research on allergy and infectious diseases at the National Institutes of Health. The FDA won powers to regulate tobacco for the first time in its 103-year history under legislation passed by Congress in June (see Nature 459, 901; 2009). A quarter of fish sampled from 291 streams across the between 1998 and 2005 contained levels of mercury higher than those deemed safe for human consumption, according to a non-peer-reviewed report from the US Geological Survey (USGS). More than two-thirds contained levels exceeding the Environmental Protection Agency's level of concern for the protection of fish-eating mammals, says the USGS. Coal-fired power plants are the main source of mercury reaching US waterways. The European Molecular Biology Organization holds its first annual conference in Amsterdam. → http://www.the-embo-meeting.org The seventh World Congress on Alternatives and Animal Use in the Life Sciences meets in Rome. → http://www.aimgroup.eu/2009/WC7 The World Meteorological Organization hosts the third World Climate Conference in Geneva. → http://www.wmo.int/wcc3 The ten-person presidential panel deliberating NASA's future, chaired by Norman Augustine, is expected to publish its final report. The UK Royal Society will release a report on climate geoengineering options — the first such review from a major scientific academy. Daniel Gutknecht, Swiss Federal Office of Topography The Swiss government last week approved expanding the country's border into Italy, because melting glaciers in the Alps have altered the watershed that marks the border. (AP) The average surface temperature of the world's oceans in June and July 2009 — the warmest measured since records began in 1880. (NOAA) There are currently no comments.
• Chemical-safety costs uncertain
  - Nature 460(7259):1065 (2009)
  Researchers and regulators disagree on how REACH legislation will affect costs and loss of animal lives. Europe's chemical regulator has questioned a study suggesting that industry will have to spend €9.5 billion (US$13.6 billion) — six times more than expected — on toxicity testing over the next decade, to comply with European Union (EU) legislation on chemical safety. The tests would require an estimated 54 million animals — a situation dismissed as a "worst-case scenario" by the European Chemical Industry Council (Cefic), a Brussels-based organization representing the European chemical industry. REACH rules will necessitate tests on millions of animals.P. GOETGHELUCK/SPL The EU's REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) legislation, which came into force in 2007, is the world's most extensive attempt at improving the safe use of chemicals. It requires the registration and submission of toxicity data for all chemicals sold in the EU in quantities of more than one tonne per year by 2018. But a study by Thomas Hartung, former head of the European Centre for the Validation of Alternative Methods (ECVAM) in Ispra, Italy, and Costanza Rovida, a consultant chemist in Varese, Italy, says that Europe lacks enough laboratories to carry out all the tests that the legislation demands. This will render the legislation unfeasible, concludes the study, which will be presented at the World Congress on Alternatives and Animal Use in the Life Sciences in Rome that begins on 30 August. REACH's aim "will not be achieved" using traditional toxicity testing methods, says Hartung, now at Johns Hopkins University in Baltimore, Maryland. "The problem is that REACH will exceed the test capacities in Europe," he says. "This will cause delays in testing, and [regulators] will not get all the data needed to take the decisions that are necessary." Hartung calls for a moratorium on the requirement to test chemicals' effects on reproductive systems in two generations of animals. These two-generation studies account for the lion's share of the increase in costs and test animals, the study says. The Organisation for Economic Co-operation and Development (OECD) is drawing up guidance for an extended one-generation reproductive toxicity test. The aim of this scheme is that tests beyond the first generation would be conducted only if a specific cause for concern arose in the first-generation offspring. The OECD will hold a meeting in October to discuss outstanding technical issues, including what would be considered as a trigger for additional tests. Draft guidelines are expected to be submitted for approval in March 2010. If they get the green light, the guidelines would be published around September 2010, and could then be instituted before testing begins in December 2010. European enlargement In a written response to Nature, the European Chemicals Agency, in Helsinki, which administers the REACH system, disputes many of the figures put forth in the new study. The agency expects slightly more than 9,000 chemicals to be registered under REACH by its 1 December 2010 deadline for substances produced or imported in quantities of more than 1,000 tonnes a year, and 30,000 chemicals by 2018. It says it does not expect the costs and use of laboratory animals to differ significantly from the original estimates, which were based on an expectation that 8,730 chemicals would be registered by the 2010 deadline. Hartung says that his estimates of cost and numbers of animals used are based on an expectation that at least 68,000 chemicals will be registered by 2018, given the growth in the EU's chemical industry over the past 15 years and the addition of 15 more countries to the EU since 1995. Cefic says it does not think that this growth will result in drastically more substances being registered. The council also expects around 30,000 chemicals to be registered by December 2018. "We are convinced that the situation in the article will not be reached because there will be fewer substances to be registered," says Erwin Annys, the council's director of chemicals policy. However, Manfred Liebsch, a toxicologist at the Federal Institute for Risk Assessment in Berlin, says the study's figures are "realistic". "I support the aims of REACH, but if there are delays in testing, it will not be doing its job of providing safety to people and the environment," he says. "Something must be changed." BASF, the chemical company headquartered in Ludwigshafen, Germany, says "it is not able to give valid feedback on the estimated numbers of needed studies and costs yet", because discussions on toxicity data are ongoing. "It's not clear yet if all needed animal tests requested by REACH can be finalized in time," the company says. "It seems there is not enough testing capacity available globally." ADVERTISEMENT "The article gives the impression that the data requirements for REACH can only be fulfilled by additional testing. This is not correct. So it is difficult to say how accurate the conclusions are," says Claudius Griesinger, a neuroscientist and project manager at the ECVAM. "Only practice will show what data are currently available." Hartung calls for increased funding of new toxicology testing methods, saying that alternatives to animals experiments must be found if REACH is to succeed. He says the biggest advances are currently taking place in the United States, in particular the Environmental Protection Agency's ToxCast programme, which is developing ways to forecast the potential toxicity of chemicals using high-throughput screening bioassays developed in the pharmaceutical industry to discover new drugs. page 1080 There are currently no comments.
• China boosts pandemic surveillance
  - Nature 460(7259):1066 (2009)
  But lack of screening could hamper efforts. As temperatures fall, China hopes to keep the expected winter resurgence of H1N1 flu under control.LIU YING/XINHUA NEWS AGENCY/EYEVINE China is stepping up disease surveillance, drug stockpiling and vaccine development as fear of a second wave of pandemic influenza H1N1 intensifies. Chinese vice-premier Li Keqiang described the country's expanded pandemic plan last week in Beijing at a meeting convened by China's health ministry, the World Health Organization (WHO) and the London-based medical journal The Lancet. Experts warn, however, that the lack of systematic screening of patients with severe respiratory conditions, and inadequate health care in the country's rural areas, may stifle the efforts. As of 24 August, mainland China had confirmed 3,103 cases of H1N1 flu, 75% of which were in five provinces. The only reported severe case, identified on 8 August, involves a 17-year-old in Guangdong province who also has Brugada syndrome, a genetic disease with an increased risk of sudden heart failure. The epidemiology of H1N1 flu in China is similar to that elsewhere, says Yu Hongjie, deputy director of the disease control and emergency response office at the Beijing-based Chinese Center for Disease Control and Prevention (CDC). But of the 1.3 billion people in China, 300 million are children, elderly or pregnant, or have chronic diseases or reduced immune function — and are at high risk of developing severe or fatal disease if infected. "This is a daunting challenge and will be a test case for the country's surveillance strategies and health-care system," says Ira Longini, a biostatistician and epidemiologist at the University of Washington in Seattle. "This will be a test case for the country's surveillance strategies and healthcare system." Initially, China focused on screening those entering the country and on monitoring patients with respiratory illness who had visited areas with confirmed H1N1 cases or had been in contact with diagnosed patients. Healthy people in close contact with H1N1 patients were quarantined. "China has been very open from the beginning and has done an excellent job in containing the outbreak," says Keiji Fukuda, the WHO's assistant director-general for health security and environment. But the containment strategy has become inadequate as the virus continues to spread, he says. The emphasis on detection, laboratory confirmation and investigation of all cases, even mild ones, is resource-intensive, leaving little capacity to investigate severe cases and other exceptional events. Since 8 July, China has switched to testing patients with influenza-like illness for H1N1 infection in the 556 'sentinel' hospitals and 411 virology laboratories across the country, says Yu. The government is closely monitoring local outbreaks and unusual disease clusters. Some experts, such as Tomimasa Sunagawa, an epidemiologist at the National Institute of Infectious Diseases in Tokyo, are "curious" about the small number of confirmed and severe cases of H1N1 infection in mainland China — compared with about 6,000 confirmed and 13 severe cases in Japan, and 8,210 confirmed and 31 severe cases in Hong Kong, as of 20 August. Chen Zhu, China's health minister, says that early diagnosis and intervention in mild H1N1 infection may have resulted in the small number of severe cases reported in mainland China. "Although the purpose of surveillance is to follow the trajectory of the pandemic, rather than to pick up every infected individual, identifying severe cases is an important component of influenza surveillance," says Robert Fontaine, a Beijing-based epidemiologist with the US Centers for Disease Control and Prevention who consults for the Chinese CDC. One approach, he says, might be to collect throat swabs from a fraction of the patients with severe respiratory conditions and test them for H1N1. Others fear that it may be hard to monitor H1N1 infection in the rural areas. Since 2005, China has seen 36 human cases of the avian influenza H5N1 virus, with an average of eight days between disease onset and hospitalization — largely because doctors in village and county clinics are unable to make the diagnosis. In addition, doctors in underdeveloped regions may be offering inadequate or dangerous treatments for symptoms related to H1N1 infection; many clinics and hospitals in China, especially in rural areas, use dexamethasone, a potent immunosuppressant, to treat acute fever. "This could be very dangerous for patients with H1N1 infection," Fontaine says. Wang Yu, director of the Chinese CDC, acknowledges these challenges, but says the central government is making every effort to raise pandemic awareness and the standard of diagnosis and treatment by rural doctors. ADVERTISEMENT Meanwhile, China is trying to produce as much H1N1 vaccine as possible. At the Beijing meeting, Liang Xiaofeng, director of the national immunization programme at the Chinese CDC, disclosed preliminary results of vaccine trials involving more than 13,000 healthy volunteers, including the health minister. Preliminary data from nearly 4,000 people suggest that the vaccine is safe and has elicited significant immune responses after the first injection. "The results are encouraging," says Longini. "But it's still very early days." If the findings are confirmed, says Chen, China will produce 65 million doses of vaccine by the end of the year and another 65 million by next spring. There are currently no comments.
• US plans for science outreach to Muslim world
  - Nature 460(7259):1067 (2009)
  White House to send scientists as envoys. The administration of US President Barack Obama is ramping up plans to develop scientific and technological partnerships with Muslim-majority countries. The move follows a June speech by Obama at Cairo University in Egypt, when he promised to appoint regional science envoys, launch a fund to support technological development and open centres of scientific excellence in Africa, the Middle East and southeast Asia. So far, the science-envoy plan is closest to getting off the ground, say White House officials, who see it as part of a broader drive to improve relations with the Islamic world. "This is a key part of the partnerships with Muslim-majority communities." "Polling consistently shows that science and technology is an area where the United States is widely respected for its leadership," says a top administration official, speaking on condition of anonymity. "This is a key part of the comprehensive partnerships we are pursuing with Muslim-majority communities." The effort is being led by the National Security Council and the Office of Science and Technology Policy. The White House plans for leading US scientists to visit a Muslim-majority region for several weeks, to canvass local researchers, community leaders and others for ideas that would shape scientific initiatives. Various US embassies have already identified themes of interest, officials say. Lebanon, for instance, has expressed an interest in technology development focused on the environment, and Bangladesh wants to initiate mentoring programmes for young scientific professionals. The first science envoy is expected to be announced "shortly", according to the administration official. "They [the administration] clearly have the door open for ideas, and we have ideas," says John Boright, director of international affairs at the National Academy of Sciences in Washington DC, an independent advisory group. ADVERTISEMENT Boright was part of a delegation that visited Syria this spring to discuss science and technology exchanges. Syrian researchers told it that their greatest need was for more training for nurses and medical technicians. Setting up a training centre along those lines might be "low-hanging fruit" for the White House to pluck off, Boright says. In the longer term, the White House will need to work within or around science initiatives that are already underway, such as the Masdar eco-city in the United Arab Emirates and the King Abdullah University of Science and Technology, due to open next month in Saudi Arabia. There are currently no comments.
• Fossil protection law comes under fire
  - Nature 460(7259):1067 (2009)
  Palaeontologists aim to clamp down on illegal trade. Fossils found in Chinese rock formations have fuelled a cottage industry in illegal trading of specimens.M. Leong/Redux/eyevine Chinese palaeontologists met government officials in Beijing last week to lobby for strict federal control of fossil specimens. The researchers are working to get changes incorporated into a draft law released in March by the Legislative Office of the State Council, which advises China's leaders, and the Ministry of Land and Resources. As China has experimented with private enterprise, poor farmers have burrowed into hillsides, uncovering fossils from the Cretaceous to the Jurassic that have rewritten the palaeontological literature. With international traders paying tens of thousands of dollars for important finds, provincial officials have fought with the federal government for control over permits to dig and regulate the bounty. Yet many scientists inside and outside China fear that the proposed federal law may foster the rampant trade in illegal fossil specimens. Zhou Zhonghe, director of the Institute of Vertebrate Paleontology and Paleoanthropology in Beijing, and other researchers have proposed several changes. These would include giving the land and resources ministry authority over vertebrate fossil collections, and setting up a national panel of palaeontologists to regulate the collections on a nationwide level. "I think many of our suggestions will be adopted," Zhou says. The law isn't expected to be finalized until early next year. The process is being watched closely by researchers worldwide who collaborate with Chinese palaeontologists. "I am in complete support of the Chinese government and academic institutions trying to clarify the laws to protect their tremendous fossil heritage," says palaeontologist Mark Norell of the American Museum of Natural History in New York. Palaeontologist Gao Keqin, of Peking University, remains deeply concerned. He says that recent versions of the draft law would not prevent provincial officials from blocking research by demanding large sums from scientists. ADVERTISEMENT "The current situation is problematic because local jurisdictions with rightful interests but only a vague understanding of the scientific value of fossils can unilaterally stop legitimate scientific exploration," says James Clark, a palaeontologist at George Washington University in Washington DC. Many provinces built palaeontological museums in the hope of tapping the tourist trade, but fossil smugglers often use them as a front to buy and sell specimens. "Fossils require an institution with staff educated in curation and preservation," says Clark. "But few places in China have these facilities." "I hope the new law will let us protect the fossil heritage," says Zhou. There are currently no comments.
• Japan relaxes human stem-cell rules
  - Nature 460(7259):1068 (2009)
  A long-sought loosening of Japan's guidelines on human embryonic stem-cell research came into effect on 21 August. But some say the new rules are too little, too late for a struggling field that was once a source of national pride. There are currently no comments.
• FDA narrows drug label usage
  - Nature 460(7259):1069 (2009)
  Cancer treatments limited to specific gene variants. The US Food and Drug Administration (FDA) has altered the usage labels on two cancer drugs on the basis of a re-evaluation of clinical data. The agency introduced the change last month after its Oncologic Drugs Advisory Committee (ODAC) recommended that the drugs Erbitux and Vectibix — approved in 2004 and 2006, respectively, for patients with advanced-stage colorectal cancer — should now be prescribed only to individuals with a certain gene variant. To reach the decision, the agency reviewed seven randomized clinical trials, all of which showed that only the 60% or so of patients whose tumours harbour the non-mutated or 'wild-type' form of a gene called K-RAS responded positively to the drugs. Ideally, the FDA would want to do these kinds of genetic-marker tests for patient response in a well-designed, forward-looking experiment, says ODAC consultant Richard Simon, chief of the National Cancer Institute's biometric research branch in Rockville, Maryland. "But cancer biology is very complex, and I think we're going to find that it's not always possible to have [all the answers] figured out beforehand." Erbitux is made by ImClone Systems and marketed by Bristol-Myers Squibb, both based in New York. Vectibix is made by Amgen, headquartered in Thousand Oaks, California. "Obtaining tissues and having them available in the future is critical." Analysts and scientists are split on whether to expect after-the-fact label adjustments for other drugs. "The FDA will certainly become more open to these types of changes over time," says Bruce Booth, a pharmaceutical analyst with Atlas Venture in Boston, Massachusetts. ODAC member Gary Lyman of the Duke Comprehensive Cancer Center in Durham, North Carolina, says that revisiting drug efficacies could become so widespread that the FDA should at least encourage companies to bank tissues from finished trials for unanticipated post-hoc tests. David Reese, Amgen's executive director of oncology, says that some of the retrospective analyses would not have been possible had the company not banked tissues. "Obtaining tissues and having [them] available in the future is really critical," he says. But David Harrington, a statistician at the Dana-Farber Cancer Institute in Boston, Massachusetts, and another ODAC member, says future calls for retrospective analyses will probably be considered on a case-by-case basis. "It was the striking nature of the data that led to the recommendation" to change Erbitux and Vectibix labelling, he says, "and it's unlikely to happen very often in the future". Indeed, many argue that the conditions surrounding the label change were unique and won't set a precedent. The American Society of Clinical Oncology and the National Comprehensive Cancer Network had already recommended that doctors test for K-RAS variants before treatment. Moreover, the drug companies themselves had asked for restricted use after learning about the K-RAS results. In announcing the change, the FDA affirmed that both drugs are "not recommended for the treatment of colorectal cancer with [ K-RAS ] mutations". Doctors are now advised — but not compelled — to test for K-RAS before administering the drugs, notes Stephen Little, chief executive of DxS, a diagnostics company in Manchester, UK, that markets a K-RAS mutation test kit. He says that most drug companies now conduct diagnostic screening during clinical development. ADVERTISEMENT In Europe, Erbitux's label changed more than a year ago to reflect the K-RAS status, and Vectibix won approval only for those patients with non-mutated K-RAS. "Europe has been more inclined to look at retrospective data if otherwise those data are robust and reflect the general population in that trial," says Hagop Youssoufian, senior vice-president of clinical research and development at ImClone in Branchburg, New Jersey. Both drugs are currently being tested for use in combination with chemotherapy; data on this will be presented next month at a joint meeting in Berlin of the European Cancer Organisation and the European Society for Medical Oncology. These tests include two phase III trials, of roughly 1,200 patients each, that show Vectibix in combination with chemotherapy kept tumours in check for significantly longer in cancer patients with wild-type K-RAS, and a similar trial — details of which are not yet public — involving Erbitux. There are currently no comments.
• Canada assumes weighty mantle
  - Nature 460(7259):1070 (2009)
  Instrument to help redefine the kilogram makes a transatlantic move. Ian Robinson might be able to tweak Canada's watt balance to increase its accuracy.NPL In the mission to define the kilogram more sensibly, only two of the instruments known as 'watt balances' have proven good enough to tackle the job. And one of them is currently in pieces, having been sold and shipped from the United Kingdom — the birthplace of this type of device — to Canada. The move has some UK scientists saddened by their loss, and Canadians excited by their gain. It also has metrologists around the world holding their breath. "Taking it all apart, shipping it, putting it back together — the worrisome thing is that something will break," says Richard Steiner, who works with the other top watt balance at the US National Institute for Standards and Technology (NIST) in Gaithersburg, Maryland. "It's very fragile, and a lot of it is pretty old." The Canadian lab expects to receive the package by the end of August. The kilogram is the only unit of measure still defined by a single object — a lump of platinum-iridium held in a vault near Paris. Over time, as atoms accrete or fall off this particular kilogram, its mass changes. Metrologists are thus aiming to redefine the kilogram on the basis of something more stable — such as Planck's constant, the value that quantifies the relationship between the energy and frequency of light, and which can be related to mass through equations of quantum physics and electromagnetism. The best way to pin down the value of Planck's constant is with a precision watt balance. Canada's device, which is about the size of a minivan, contains a metre-long balance beam, with a precisely known mass at one end and a 30-centimetre-wide metal coil in a magnetic field at the other. Running a current through the coil creates an electromagnetic force that balances the gravitational force on the other side. Further measurements are made to eliminate hard-to-measure factors and produce a value for Planck's constant. "If anyone was going to bust it, it had to be me." The watt balance was thought up in 1975 at the National Physical Laboratory (NPL) in Teddington, UK. Ian Robinson, who helped to develop that first instrument and worked with its successor for more than 30 years, disassembled his life's work this summer. More than 500 items, including the 1-tonne magnet, were stowed in some 50 wooden crates to be shipped. Robinson packed the precision coil himself: "If anyone was going to bust it," he says, "it had to be me." NPL research director Kamal Hossain says they decided to discontinue the watt-balance work because they already had some good results from the device and wanted to focus on more practical areas, such as nanometrology. "It was a bit of a surprise when the NPL decided to roll this up," says Alan Steele, head of metrology for the Institute for National Measurement Standards in Ottawa, Ontario. The machine will both stretch the metrological science done in the lab and give Canada an entrée into the kilogram scene. Pursuit of accuracy Another approach to redefining the kilogram involves more accurately calculating the Avogadro constant — the number of atoms or molecules in one mole of a substance — by determining the number of atoms in a near-perfect silicon sphere. Should the watt-balance project win out, national labs with watt balances will have an advantage in measuring exact masses and maintaining mass standards. Watt balances are being built and tested in Switzerland and France, but have not produced published results to prove their precision. Thus far, the NIST watt balance and the one from the NPL do not quite agree on the value of Planck's constant. Although each has an uncertainty of tens of parts in a billion, the difference between the two most recently published values is ten times larger than that. The team working on the silicon-sphere approach, meanwhile, say they have data that are in fairly good agreement with NIST's value for Planck's constant, although these have not yet been published. The goal is to iron out discrepancies in time to redefine the kilogram in 2011. ADVERTISEMENT Steele says his team plans to start reassem­bling the watt balance this October, with Robinson's help. They hope that the Ottawa lab, which is vibration-free and shielded from magnetic interference, will prove an ideal spot for the sensitive instrument. Moving the device should help to create a third, independent, set of data to help pin down Planck's constant, says Steele: "The equipment is so complex, just taking it apart and reassembling it is equivalent to doing a novel experiment." Robinson says he has possibly identified a small flaw in the experiment that he intends to fix once it is reassembled. If that creates agreement with the NIST value, then consensus should be easy. Robinson, whose work was plagued by magnetic interference from a train line near the NPL, agrees that the Canadian lab is a real improvement. Although he says he is sad not to be able to continue his work in Britain, he adds that the important thing is that someone — anyone — will keep it running: "The main thing is that it doesn't get thrown away." There are currently no comments.
• Medicine: Last chance clinic
  - Nature 460(7259):1071-1075 (2009)
  Dunham Aurelius is eager to take his shirt off and show his scars. One, a centimetre wide and roughly 20 long runs up his lower back and is from the placement of a steel rod to straighten his spine at the age of 14. There are currently no comments.
• Robotics: The bot that plays ball
  - Nature 460(7259):1076-1078 (2009)
  Giulio Sandini cannot help smiling as his child reaches out a hand and tries to grasp the red ball that Sandini keeps waving before his eyes. "He is getting really good at it," he says, with the proud tone of any father. There are currently no comments.
• Italy leads the way in supporting African biotechnology
  - Nature 460(7259):1079 (2009)
  In your News story 'African science drops down G8 agenda' (Nature460, 16; 2009), you express concern about the lack of interest that has been shown by the G8 countries in the development of science in Africa. But there are bright spots: for example, a laboratory of international standard recently opened in South Africa as a direct result of G8 discussions, with Italy taking the lead towards its rapid realization.
• Investors likely to venture back as crisis subsides
  - Nature 460(7259):1079 (2009)
  As an investor and an independent adviser to corporate management, I am not convinced by John Browning's arguments that venture funding is unlikely to bounce back, as suggested by his Essay 'The incredible shrinking venture capital' (Nature 460, 459; 2009).Earlier trends indicate that venture-capital funding will probably rebound after the current financial crisis subsides.
• Czech bibliometric system fosters mediocre research
  - Nature 460(7259):1079 (2009)
  Following your News story 'Czech researchers angry over government changes' (Nature460, 157; 2009), we would like to point out that ill-conceived bibliometrics can be used as an excuse for deep cuts in basic research funding and the diversion of funds to 'applied' research.The innovative evaluation system endorsed by the Czech government's research and development council ascribes a certain number of points to every paper, patent, technology and piece of software.
• Non-scientists could still contribute to reform of the ERC
  - Nature 460(7259):1079 (2009)
  The mid-term review of the European Research Council (ERC), the European homologue of the US National Science Foundation, draws attention to some of the council's bureaucratic shortcomings.Towards a World-class Frontier Research Organisation (http://tinyurl.com/noa7ra
• Chemical regulators have overreached
  - Nature 460(7259):1080-1081 (2009)
  The costs — both in animal lives and euros — of the European REACH legislation on chemical testing are escalating. Thomas Hartung and Costanza Rovida argue for a suspension of certain toxicity tests.
• Bridging the gender gap in Indian science
  - Nature 460(7259):1082 (2009)
  A set of biographies reveals the trials and triumphs of India's women researchers, says Asha Gopinathan.
• The many faces of mathematics
  - Nature 460(7259):1083 (2009)
  The question of how one makes a great scientific discovery, or teaches others to do so, is central to two recent books that portray mathematicians. In Mathematicians, Mariana Cook photographs more than 90 living mathematicians, each portrait accompanied by an explanation of how they became interested in their subject.
• Numerical reading
  - Nature 460(7259):1083 (2009)
  In Number Freak (Perigee Books, 2009), Derrick Niederman tells the stories behind the numerals 1 to 200. Each number gets an entry, detailing its significance from ancient myth to mathematical reality.
• Q&A: Science pop songsters
  - Nature 460(7259):1084 (2009)
  The US band They Might Be Giants has played rock to adults for more than two decades — and to children since 2002. Next week it releases the album Here Comes Science, with educational tunes about the elements and evolution. John Linnell, who fronts the band with John Flansburgh, explains why a science-friendly thread runs through their music.
• Stem cells: The promises and perils of p53
  - Nature 460(7259):1085-1086 (2009)
  Five studies show that disabling p53, an essential tumour-suppressor protein, improves the efficiency of stem-cell production. Are these results a 'heads up' that cancer cells and stem cells are disturbingly similar?
• Extrasolar planets: Secrets that only tides will tell
  - Nature 460(7259):1086-1087 (2009)
  Evidence that the most recently discovered extrasolar planet is virtually at the end of its life is a surprise. The odds of that are very low — similar to drawing two consecutive red aces from a well-shuffled deck of cards.
• Developmental biology: Jumping-gene roulette
  - Nature 460(7259):1087-1088 (2009)
  Jumping genes, which make DNA copies of themselves through an RNA middleman, provide a stochastic process for generating brain diversity among humans. The effect of their random insertion, however, is a bit of a gamble.
• Optics: Ultrafast X-ray photography
  - Nature 460(7259):1088-1090 (2009)
  A super-fast, lensless microscope has been developed that works by decoding the diffraction patterns of bright, laser-like flashes of X-rays. This advance should enable ultrafast events at the nanoscale to be recorded.
• 50 & 100 years ago
  - Nature 460(7259):1090 (2009)
  Phoenix Re-born. By Dr. Maurice Burton — For many years anting in birds has held considerable fascination for students of bird behaviour.
• Solid-state physics: An insulator's metallic side
  - Nature 460(7259):1090-1091 (2009)
  Certain insulators have conducting surfaces that arise from subtle chemical properties of the bulk material. The latest experiments suggest that such surfaces may compete with graphene in electronic applications.
• Gamma-ray bursts: Maybe not so old after all
  - Nature 460(7259):1091-1092 (2009)
  The discovery of a short-lived -ray burst at a surprisingly early epoch in the history of the Universe shows how much is still unknown about the evolution of the parent systems of such bursts.
• Developmental and species-divergent globin switching are driven by BCL11A
  Sankaran VG Xu J Ragoczy T Ippolito GC Walkley CR Maika SD Fujiwara Y Ito M Groudine M Bender MA Tucker PW Orkin SH - Nature 460(7259):1093-1097 (2009)
  The contribution of changes in cis-regulatory elements or trans-acting factors to interspecies differences in gene expression is not well understood. The mammalian -globin loci have served as a model for gene regulation during development. Transgenic mice containing the human -globin locus, consisting of the linked embryonic (), fetal () and adult () genes, have been used as a system to investigate the temporal switch from fetal to adult haemoglobin, as occurs in humans. Here we show that the human -globin (HBG) genes in these mice behave as murine embryonic globin genes, revealing a limitation of the model and demonstrating that critical differences in the trans-acting milieu have arisen during mammalian evolution. We show that the expression of BCL11A, a repressor of human -globin expression identified by genome-wide association studies, differs between mouse and human. Developmental silencing of the mouse embryonic globin and human -globin genes fails to occur in mi! ce in the absence of BCL11A. Thus, BCL11A is a critical mediator of species-divergent globin switching. By comparing the ontogeny of -globin gene regulation in mice and humans, we have shown that alterations in the expression of a trans-acting factor constitute a critical driver of gene expression changes during evolution.
• An orbital period of 0.94 days for the hot-Jupiter planet WASP-18b
  - Nature 460(7259):1098-1100 (2009)
  The 'hot Jupiters' that abound in lists of known extrasolar planets are thought to have formed far from their host stars, but migrate inwards through interactions with the proto-planetary disk from which they were born1, 2, or by an alternative mechanism such as planet–planet scattering3. The hot Jupiters closest to their parent stars, at orbital distances of only 0.02 astronomical units, have strong tidal interactions4, 5, and systems such as OGLE-TR-56 have been suggested as tests of tidal dissipation theory6, 7. Here we report the discovery of planet WASP-18b with an orbital period of 0.94 days and a mass of ten Jupiter masses (10 MJup), resulting in a tidal interaction an order of magnitude stronger than that of planet OGLE-TR-56b. Under the assumption that the tidal-dissipation parameter Q of the host star is of the order of 106, as measured for Solar System bodies and binary stars and as often applied to extrasolar planets, WASP-18b will be spiralling inwards o! n a timescale less than a thousandth that of the lifetime of its host star. Therefore either WASP-18 is in a rare, exceptionally short-lived state, or the tidal dissipation in this system (and possibly other hot-Jupiter systems) must be much weaker than in the Solar System.
• A tunable topological insulator in the spin helical Dirac transport regime
  Hsieh D Xia Y Qian D Wray L Dil JH Meier F Osterwalder J Patthey L Checkelsky JG Ong NP Fedorov AV Lin H Bansil A Grauer D Hor YS Cava RJ Hasan MZ - Nature 460(7259):1101-1105 (2009)
  Helical Dirac fermions—charge carriers that behave as massless relativistic particles with an intrinsic angular momentum (spin) locked to its translational momentum—are proposed to be the key to realizing fundamentally new phenomena in condensed matter physics1, 2, 3, 4, 5, 6, 7, 8, 9. Prominent examples include the anomalous quantization of magneto-electric coupling4, 5, 6, half-fermion states that are their own antiparticle7, 8, and charge fractionalization in a Bose–Einstein condensate9, all of which are not possible with conventional Dirac fermions of the graphene variety10. Helical Dirac fermions have so far remained elusive owing to the lack of necessary spin-sensitive measurements and because such fermions are forbidden to exist in conventional materials harbouring relativistic electrons, such as graphene10 or bismuth11. It has recently been proposed that helical Dirac fermions may exist at the edges of certain types of topologically ordered insulators3, 4! , 12—materials with a bulk insulating gap of spin–orbit origin and surface states protected against scattering by time-reversal symmetry—and that their peculiar properties may be accessed provided the insulator is tuned into the so-called topological transport regime3, 4, 5, 6, 7, 8, 9. However, helical Dirac fermions have not been observed in existing topological insulators13, 14, 15, 16, 17, 18. Here we report the realization and characterization of a tunable topological insulator in a bismuth-based class of material by combining spin-imaging and momentum-resolved spectroscopies, bulk charge compensation, Hall transport measurements and surface quantum control. Our results reveal a spin-momentum locked Dirac cone carrying a non-trivial Berry's phase that is nearly 100 per cent spin-polarized, which exhibits a tunable topological fermion density in the vicinity of the Kramers point and can be driven to the long-sought topological spin transport regime. The observed t! opological nodal state is shown to be protected even up to 300! K. Our demonstration of room-temperature topological order and non-trivial spin-texture in stoichiometric Bi2Se3.Mx (Mx indicates surface doping or gating control) paves the way for future graphene-like studies of topological insulators, and applications of the observed spin-polarized edge channels in spintronic and computing technologies possibly at room temperature.
• Topological surface states protected from backscattering by chiral spin texture
  - Nature 460(7259):1106-1109 (2009)
  Topological insulators are a new class of insulators in which a bulk gap for electronic excitations is generated because of the strong spin–orbit coupling1, 2, 3, 4, 5 inherent to these systems. These materials are distinguished from ordinary insulators by the presence of gapless metallic surface states, resembling chiral edge modes in quantum Hall systems, but with unconventional spin textures. A key predicted feature of such spin-textured boundary states is their insensitivity to spin-independent scattering, which is thought to protect them from backscattering and localization. Recently, experimental and theoretical efforts have provided strong evidence for the existence of both two- and three-dimensional classes of such topological insulator materials in semiconductor quantum well structures6, 7, 8 and several bismuth-based compounds9, 10, 11, 12, 13, but so far experiments have not probed the sensitivity of these chiral states to scattering. Here we use scanning ! tunnelling spectroscopy and angle-resolved photoemission spectroscopy to visualize the gapless surface states in the three-dimensional topological insulator Bi1-xSbx, and examine in detail the influence of scattering from disorder caused by random alloying in this compound. We show that, despite strong atomic scale disorder, backscattering between states of opposite momentum and opposite spin is absent. Our observations demonstrate that the chiral nature of these states protects the spin of the carriers. These chiral states are therefore potentially useful for spin-based electronics, in which long spin coherence is critical14, and also for quantum computing applications, where topological protection can enable fault-tolerant information processing15, 16.
• Demonstration of a spaser-based nanolaser
  - Nature 460(7259):1110-1112 (2009)
  One of the most rapidly growing areas of physics and nanotechnology focuses on plasmonic effects on the nanometre scale, with possible applications ranging from sensing and biomedicine to imaging and information technology1, 2. However, the full development of nanoplasmonics is hindered by the lack of devices that can generate coherent plasmonic fields. It has been proposed3 that in the same way as a laser generates stimulated emission of coherent photons, a 'spaser' could generate stimulated emission of surface plasmons (oscillations of free electrons in metallic nanostructures) in resonating metallic nanostructures adjacent to a gain medium. But attempts to realize a spaser face the challenge of absorption loss in metal, which is particularly strong at optical frequencies. The suggestion4, 5, 6 to compensate loss by optical gain in localized and propagating surface plasmons has been implemented recently7, 8, 9, 10 and even allowed the amplification of propagating sur! face plasmons in open paths11. Still, these experiments and the reported enhancement of the stimulated emission of dye molecules in the presence of metallic nanoparticles12, 13, 14 lack the feedback mechanism present in a spaser. Here we show that 44-nm-diameter nanoparticles with a gold core and dye-doped silica shell allow us to completely overcome the loss of localized surface plasmons by gain and realize a spaser. And in accord with the notion that only surface plasmon resonances are capable of squeezing optical frequency oscillations into a nanoscopic cavity to enable a true nanolaser15, 16, 17, 18, we show that outcoupling of surface plasmon oscillations to photonic modes at a wavelength of 531 nm makes our system the smallest nanolaser reported to date—and to our knowledge the first operating at visible wavelengths. We anticipate that now it has been realized experimentally, the spaser will advance our fundamental understanding of nanoplasmonics and the development! of practical applications.
• 2,000-year-long temperature and hydrology reconstructions from the Indo-Pacific warm pool
  - Nature 460(7259):1113-1116 (2009)
  Northern Hemisphere surface temperature reconstructions suggest that the late twentieth century was warmer than any other time during the past 500 years and possibly any time during the past 1,300 years (refs 1, 2). These temperature reconstructions are based largely on terrestrial records from extra-tropical or high-elevation sites; however, global average surface temperature changes closely follow those of the global tropics3, which are 75% ocean. In particular, the tropical Indo-Pacific warm pool (IPWP) represents a major heat reservoir that both influences global atmospheric circulation4 and responds to remote northern high-latitude forcings5, 6. Here we present a decadally resolved continuous sea surface temperature (SST) reconstruction from the IPWP that spans the past two millennia and overlaps the instrumental record, enabling both a direct comparison of proxy data to the instrumental record and an evaluation of past changes in the context of twentieth century ! trends. Our record from the Makassar Strait, Indonesia, exhibits trends that are similar to a recent Northern Hemisphere temperature reconstruction2. Reconstructed SST was, however, within error of modern values from about ad 1000 to ad 1250, towards the end of the Medieval Warm Period. SSTs during the Little Ice Age (approximately ad 1550–1850) were variable, and 0.5 to 1 °C colder than modern values during the coldest intervals. A companion reconstruction of 18O of sea water—a sea surface salinity and hydrology indicator—indicates a tight coupling with the East Asian monsoon system and remote control of IPWP hydrology on centennial–millennial timescales, rather than a dominant influence from local SST variation.
• Surface hydrophobin prevents immune recognition of airborne fungal spores
  - Nature 460(7259):1117-1121 (2009)
  The air we breathe is filled with thousands of fungal spores (conidia) per cubic metre, which in certain composting environments can easily exceed 109 per cubic metre. They originate from more than a hundred fungal species belonging mainly to the genera Cladosporium, Penicillium, Alternaria and Aspergillus1, 2, 3, 4. Although these conidia contain many antigens and allergens5, 6, 7, it is not known why airborne fungal microflora do not activate the host innate immune cells continuously and do not induce detrimental inflammatory responses following their inhalation. Here we show that the surface layer on the dormant conidia masks their recognition by the immune system and hence prevents immune response. To explore this, we used several fungal members of the airborne microflora, including the human opportunistic fungal pathogen Aspergillus fumigatus, in in vitro assays with dendritic cells and alveolar macrophages and in in vivo murine experiments. In A. fumigatus, this ! surface 'rodlet layer' is composed of hydrophobic RodA protein covalently bound to the conidial cell wall through glycosylphosphatidylinositol-remnants. RodA extracted from conidia of A. fumigatus was immunologically inert and did not induce dendritic cell or alveolar macrophage maturation and activation, and failed to activate helper T-cell immune responses in vivo. The removal of this surface 'rodlet/hydrophobin layer' either chemically (using hydrofluoric acid), genetically (rodA mutant) or biologically (germination) resulted in conidial morphotypes inducing immune activation. All these observations show that the hydrophobic rodlet layer on the conidial cell surface immunologically silences airborne moulds.
• EBI2 mediates B cell segregation between the outer and centre follicle
  Pereira JP Kelly LM Xu Y Cyster JG - Nature 460(7259):1122-1126 (2009)
  B cell follicles are specialized microenvironments that support events necessary for humoral immunity1, 2, 3. After antigen encounter, activated B cells initially seek T-cell help at the follicle–T-zone boundary and then move to interfollicular and T-zone distal (outer) regions of the follicle4, 5, 6, 7, 8, 9, 10. Subsequently, some cells move to the follicle centre, become germinal centre B cells and undergo antibody affinity maturation1, 2, 11. Although germinal centres within follicles were described in 1885 (ref. 12), the molecular cues mediating segregation of B cells between the outer and centre follicle have remained undefined. Here we present a role for the orphan G-protein-coupled receptor, Epstein-Barr virus induced molecule-2 (EBI2, also known as GPR183)13, in this process. EBI2 is expressed in mature B cells and increases in expression early after activation, before being downregulated in germinal centre B cells. EBI2 deficiency in mice led to a reduction! in the early antibody response to a T-dependent antigen. EBI2-deficient B cells failed to move to the outer follicle at day 2 of activation, and instead were found in the follicle centre, whereas EBI2 overexpression was sufficient to promote B cell localization to the outer follicle. In mixed bone marrow chimaeras, EBI2-deficient B cells phenocopied germinal centre B cells in preferentially localizing to the follicle centre. When downregulation of EBI2 in wild-type B cells was antagonized, participation in the germinal centre reaction was impaired. These studies identify an important role for EBI2 in promoting B cell localization in the outer follicle, and show that differential expression of this receptor helps position B cells appropriately for mounting T-dependent antibody responses.
• L1 retrotransposition in human neural progenitor cells
  Coufal NG Garcia-Perez JL Peng GE Yeo GW Mu Y Lovci MT Morell M O'Shea KS Moran JV Gage FH - Nature 460(7259):1127-1131 (2009)
  Long interspersed element 1 (LINE-1 or L1) retrotransposons have markedly affected the human genome. L1s must retrotranspose in the germ line or during early development to ensure their evolutionary success, yet the extent to which this process affects somatic cells is poorly understood. We previously demonstrated that engineered human L1s can retrotranspose in adult rat hippocampus progenitor cells in vitro and in the mouse brain in vivo1. Here we demonstrate that neural progenitor cells isolated from human fetal brain and derived from human embryonic stem cells support the retrotransposition of engineered human L1s in vitro. Furthermore, we developed a quantitative multiplex polymerase chain reaction that detected an increase in the copy number of endogenous L1s in the hippocampus, and in several regions of adult human brains, when compared to the copy number of endogenous L1s in heart or liver genomic DNAs from the same donor. These data suggest that de novo L1 retr! otransposition events may occur in the human brain and, in principle, have the potential to contribute to individual somatic mosaicism.
• Suppression of induced pluripotent stem cell generation by the p53–p21 pathway
  - Nature 460(7259):1132-1135 (2009)
  Induced pluripotent stem (iPS) cells can be generated from somatic cells by the introduction of Oct3/4 (also known as Pou5f1), Sox2, Klf4 and c-Myc, in mouse1, 2, 3, 4 and in human5, 6, 7, 8. The efficiency of this process, however, is low9. Pluripotency can be induced without c-Myc, but with even lower efficiency10, 11. A p53 (also known as TP53 in humans and Trp53 in mice) short-interfering RNA (siRNA) was recently shown to promote human iPS cell generation12, but the specificity and mechanisms remain to be determined. Here we report that up to 10% of transduced mouse embryonic fibroblasts lacking p53 became iPS cells, even without the Myc retrovirus. The p53 deletion also promoted the induction of integration-free mouse iPS cells with plasmid transfection. Furthermore, in the p53-null background, iPS cells were generated from terminally differentiated T lymphocytes. The suppression of p53 also increased the efficiency of human iPS cell generation. DNA microarray ana! lyses identified 34 p53-regulated genes that are common in mouse and human fibroblasts. Functional analyses of these genes demonstrate that the p53–p21 pathway serves as a barrier not only in tumorigenicity, but also in iPS cell generation.
• The Ink4/Arf locus is a barrier for iPS cell reprogramming
  - Nature 460(7259):1136-1139 (2009)
  The mechanisms involved in the reprogramming of differentiated cells into induced pluripotent stem (iPS) cells by the three transcription factors Oct4 (also known as Pou5f1), Klf4 and Sox2 remain poorly understood1. The Ink4/Arf locus comprises the Cdkn2a–Cdkn2b genes encoding three potent tumour suppressors, namely p16Ink4a, p19Arf and p15Ink4b, which are basally expressed in differentiated cells and upregulated by aberrant mitogenic signals2, 3, 4. Here we show that the locus is completely silenced in iPS cells, as well as in embryonic stem (ES) cells, acquiring the epigenetic marks of a bivalent chromatin domain, and retaining the ability to be reactivated after differentiation. Cell culture conditions during reprogramming enhance the expression of the Ink4/Arf locus, further highlighting the importance of silencing the locus to allow proliferation and reprogramming. Indeed, the three factors together repress the Ink4/Arf locus soon after their expression and conc! omitant with the appearance of the first molecular markers of 'stemness'. This downregulation also occurs in cells carrying the oncoprotein large-T, which functionally inactivates the pathways regulated by the Ink4/Arf locus, thus indicating that the silencing of the locus is intrinsic to reprogramming and not the result of a selective process. Genetic inhibition of the Ink4/Arf locus has a profound positive effect on the efficiency of iPS cell generation, increasing both the kinetics of reprogramming and the number of emerging iPS cell colonies. In murine cells, Arf, rather than Ink4a, is the main barrier to reprogramming by activation of p53 (encoded by Trp53) and p21 (encoded by Cdkn1a); whereas, in human fibroblasts, INK4a is more important than ARF. Furthermore, organismal ageing upregulates the Ink4/Arf locus2, 5 and, accordingly, reprogramming is less efficient in cells from old organisms, but this defect can be rescued by inhibiting the locus with a short hairpin RN! A. All together, we conclude that the silencing of Ink4/Arf lo! cus is rate-limiting for reprogramming, and its transient inhibition may significantly improve the generation of iPS cells.
• Linking the p53 tumour suppressor pathway to somatic cell reprogramming
  - Nature 460(7259):1140-1144 (2009)
  Reprogramming somatic cells to induced pluripotent stem (iPS) cells has been accomplished by expressing pluripotency factors and oncogenes1, 2, 3, 4, 5, 6, 7, 8, but the low frequency and tendency to induce malignant transformation9 compromise the clinical utility of this powerful approach. We address both issues by investigating the mechanisms limiting reprogramming efficiency in somatic cells. Here we show that reprogramming factors can activate the p53 (also known as Trp53 in mice, TP53 in humans) pathway. Reducing signalling to p53 by expressing a mutated version of one of its negative regulators, by deleting or knocking down p53 or its target gene, p21 (also known as Cdkn1a), or by antagonizing reprogramming-induced apoptosis in mouse fibroblasts increases reprogramming efficiency. Notably, decreasing p53 protein levels enabled fibroblasts to give rise to iPS cells capable of generating germline-transmitting chimaeric mice using only Oct4 (also known as Pou5f1) an! d Sox2. Furthermore, silencing of p53 significantly increased the reprogramming efficiency of human somatic cells. These results provide insights into reprogramming mechanisms and suggest new routes to more efficient reprogramming while minimizing the use of oncogenes.
• Immortalization eliminates a roadblock during cellular reprogramming into iPS cells
  - Nature 460(7259):1145-1148 (2009)
  The overexpression of defined transcription factors in somatic cells results in their reprogramming into induced pluripotent stem (iPS) cells1, 2, 3. The extremely low efficiency and slow kinetics of in vitro reprogramming suggest that further rare events are required to generate iPS cells. The nature and identity of these events, however, remain elusive. We noticed that the reprogramming potential of primary murine fibroblasts into iPS cells decreases after serial passaging and the concomitant onset of senescence. Consistent with the notion that loss of replicative potential provides a barrier for reprogramming, here we show that cells with low endogenous p19Arf (encoded by the Ink4a/Arf locus, also known as Cdkn2a locus) protein levels and immortal fibroblasts deficient in components of the Arf–Trp53 pathway yield iPS cell colonies with up to threefold faster kinetics and at a significantly higher efficiency than wild-type cells, endowing almost every somatic cell ! with the potential to form iPS cells. Notably, the acute genetic ablation of Trp53 (also known as p53) in cellular subpopulations that normally fail to reprogram rescues their ability to produce iPS cells. Our results show that the acquisition of immortality is a crucial and rate-limiting step towards the establishment of a pluripotent state in somatic cells and underscore the similarities between induced pluripotency and tumorigenesis.
• A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity
  - Nature 460(7259):1149-1153 (2009)
  The reprogramming of differentiated cells to pluripotent cells (induced pluripotent stem (iPS) cells) is known to be an inefficient process. We recently reported that cells with short telomeres cannot be reprogrammed to iPS cells despite their normal proliferation rates1, 2, probably reflecting the existence of 'reprogramming barriers' that abort the reprogramming of cells with uncapped telomeres. Here we show that p53 (also known as Trp53 in mice and TP53 in humans) is critically involved in preventing the reprogramming of cells carrying various types of DNA damage, including short telomeres, DNA repair deficiencies, or exogenously inflicted DNA damage. Reprogramming in the presence of pre-existing, but tolerated, DNA damage is aborted by the activation of a DNA damage response and p53-dependent apoptosis. Abrogation of p53 allows efficient reprogramming in the face of DNA damage and the generation of iPS cells carrying persistent DNA damage and chromosomal aberration! s. These observations indicate that during reprogramming cells increase their intolerance to different types of DNA damage and that p53 is critical in preventing the generation of human and mouse pluripotent cells from suboptimal parental cells.
• Initiation of myoblast to brown fat switch by a PRDM16–C/EBP- transcriptional complex
  Kajimura S Seale P Kubota K Lunsford E Frangioni JV Gygi SP Spiegelman BM - Nature 460(7259):1154-1158 (2009)
  Brown adipose cells are specialized to dissipate chemical energy in the form of heat, as a physiological defence against cold and obesity1. PRDM16 (PR domain containing 16) is a 140 kDa zinc finger protein that robustly induces brown fat determination and differentiation2. Recent data suggests that brown fat cells arise in vivo from a Myf5-positive, myoblastic lineage by the action of PRDM16 (ref. 3); however, the molecular mechanisms responsible for this developmental switch is unclear. Here we show that PRDM16 forms a transcriptional complex with the active form of C/EBP- (also known as LAP), acting as a critical molecular unit that controls the cell fate switch from myoblastic precursors to brown fat cells. Forced expression of PRDM16 and C/EBP- is sufficient to induce a fully functional brown fat program in naive fibroblastic cells, including skin fibroblasts from mouse and man. Transplantation of fibroblasts expressing these two factors into mice gives rise to an ! ectopic fat pad with the morphological and biochemical characteristics of brown fat. Like endogenous brown fat, this synthetic brown fat tissue acts as a sink for glucose uptake, as determined by positron emission tomography with fluorodeoxyglucose. These data indicate that the PRDM16–C/EBP- complex initiates brown fat formation from myoblastic precursors, and may provide opportunities for the development of new therapeutics for obesity and type-2 diabetes.
• Riboflavin kinase couples TNF receptor 1 to NADPH oxidase
  Yazdanpanah B Wiegmann K Tchikov V Krut O Pongratz C Schramm M Kleinridders A Wunderlich T Kashkar H Utermöhlen O Brüning JC Schütze S Krönke M - Nature 460(7259):1159-1163 (2009)
  Reactive oxygen species (ROS) produced by NADPH oxidase function as defence and signalling molecules related to innate immunity and various cellular responses1, 2. The activation of NADPH oxidase in response to plasma membrane receptor activation depends on the phosphorylation of cytoplasmic oxidase subunits, their translocation to membranes and the assembly of all NADPH oxidase components3. Tumour necrosis factor (TNF) is a prominent stimulus of ROS production, but the molecular mechanisms by which TNF activates NADPH oxidase are poorly understood. Here we identify riboflavin kinase (RFK, formerly known as flavokinase4) as a previously unrecognized TNF-receptor-1 (TNFR1)-binding protein that physically and functionally couples TNFR1 to NADPH oxidase. In mouse and human cells, RFK binds to both the TNFR1-death domain and to p22phox, the common subunit of NADPH oxidase isoforms. RFK-mediated bridging of TNFR1 and p22phox is a prerequisite for TNF-induced but not for Tol! l-like-receptor-induced ROS production. Exogenous flavin mononucleotide or FAD was able to substitute fully for TNF stimulation of NADPH oxidase in RFK-deficient cells. RFK is rate-limiting in the synthesis of FAD, an essential prosthetic group of NADPH oxidase. The results suggest that TNF, through the activation of RFK, enhances the incorporation of FAD in NADPH oxidase enzymes, a critical step for the assembly and activation of NADPH oxidase.
• Liquid water on Enceladus from observations of ammonia and 40Ar in the plume
  - Nature 460(7259):1164 (2009)
  Nature 460, 487–490 (2009) In this Letter, the address for author J. Westlake was listed incorrectly. The correct address is: Department of Physics and Astronomy, University of Texas at San Antonio, San Antonio, Texas 78249-1644, USA.
• CBP/p300-mediated acetylation of histone H3 on lysine 56
  - Nature 460(7259):1164 (2009)
  Nature 459, 113–117 (2009) In Fig. 4e of this Letter, one band was incorrectly labelled. We thank B. Lüscher for drawing this to our attention. The correctly labelled version of the figure is provided below. As such, the statement that there is "a notable correlation between levels of H3K56 acetylation and ASF1A but not ASF1B in a wide variety of normal and cancerous human tissues" is no longer accurate. However, the main purpose of Fig. 4e is still valid, which was to show by western blotting analysis that the level of H3K56ac is much higher in some tumours as compared to the matching normal tissue. We also note that although the fractionation of the total stained proteins in Figs 1f and 4d did not show obvious differences, the fractionation of histones and tubulin was effective between the supernatant and pellet fractions (see Supplementary Figure). We also omitted to state that the ultraviolet light used in our analysis was 312 nm UVB, which causes 1% of the amount of DNA damage as 254 nm UVC.
• The Gower Street cuckoos
  - Nature 460(7259):1170 (2009)
  It's a growing problem.