[Journal Nature] Nature -.. June.14.2012

THIS WEEK WORLD VIEW Policy-makers WEIGHT LOSS A true measure BLUE DANUBE The cultural EDITORIALS must engage with the reality of the mass of extinct flow of the river of geoengineering p.159 beasts p.160 40,000 years ago p.161 Reply to all Scientists discussing their work through written media, including e-mail, should be aware that they could at any time be asked to reveal their conversations. ou are commanded to produce … any and all documents, on science, by forcing researchers to avoid topics that could become data, and/or communications.” Towards the end of last year, subjects of litigation. Is the institute right? It is hard to judge the scale   “Ythose orders appeared in a subpoena that landed at the Woods of the potential damage the decision could cause. Even well before the Hole Oceanographic Institution in Massachusetts. The energy firm BP subpoena, some researchers declined to study the spill, in part because demanded that Woods Hole produce e-mails and other documents of the legal risk, so the decision may not make related to its research on the 2010 Deepwater Horizon oil spill in the “It is hard to much difference on that front. Researchers Gulf of Mexico. Woods Hole fought the sweeping request, but a US judge the scale who work in other contentious fields, such district court has now forced researchers at the institute to surrender of the potential as animal experimentation, are not gener- thousands of e-mails. That decision has disturbing implications for damage the ally scared off their work, even by threats of science in the United States, although the situation is perhaps not as decision could physical harm. dire as some have warned. cause.” The decision on the Woods Hole e-mails The demand for the e-mails emerged from a huge lawsuit, in which should nonetheless serve as a warning. BP is being sued by the US government and others affected by the oil Researchers who choose to study topics that have multiple and con- spill. As part of that suit, the company faces fines of up to US$4,300 flicting implications for powerful special interests must go in with per barrel of oil spilled, which could amount to more than $17 billion their eyes open and be aware of the risks. Not only have Woods Hole if the court sides with government estimates for the size of the spill. BP researchers had to surrender their e-mails, they have also spent hun- argues that these estimates — much higher than the company’s own dreds of hours complying with the subpoena. And the case has drained — rely heavily on research conducted by Woods Hole. And it claims considerable funds from the non-profit institution through lawyers’ that aspects of the work involve “puzzling, apparently arbitrary, sus- fees and lost staff time. piciously offsetting, and highly significant decisions by Woods Hole The decision provides yet another reminder that scientists should researchers”. not regard e-mails as being private. Whether by theft or by court Woods Hole is not a party to the lawsuit, but it did have a contract order, such communications can be taken away. Think before you with the government during the first month of the spill to measure press Send. ■ how much oil and gas was spewing from the broken well. After that, researchers from the institute worked to refine their analyses and publish papers on the spill in academic journals. One Woods Hole ANNOUNCEMENT scientist also participated in a governmental panel asked to estimate the size of the spill. Calling Nordic To defend itself in court, BP contends that it needs more than just the raw data collected by Woods Hole and a description of the methods mentors used by its researchers. Woods Hole turned over much of the data and analysis tools to BP on its original request, but it fought against sur- rendering confidential academic communications, arguing that those very year, Nature awards prizes to senior researchers in the have been protected in the past by courts, which have recognized the Enatural sciences for sustained and outstanding scientific importance of ‘scholastic privilege’. Indeed, the judge who ruled over mentoring of young researchers. There are two prizes, each Woods Hole’s arguments recognized the principle of scholastic privi- worth €10,000 (US$12,500): one for lifetime achievement, one lege regarding confidentiality, but only up to a point. She found that for mid-career achievement. BP had a compelling need for the Woods Hole e-mails and other com- The competitions are organized on a country or regional munications for the period before the government-led group issued basis. We shall give this year’s accolades to researchers who live its report in March last year. The e-mails handed to BP could be made in the Nordic countries: Sweden, Norway, Denmark, Finland, public if the case goes to trial. Iceland and Greenland. But the judge did not allow BP access to communications after that Nominations are now open, with a deadline of Monday time, when the Woods Hole researchers were preparing academic pub- 13 August. Each applicant should be nominated by five people lications. “If BP gains access to the analysis documents for these article who have been mentored by her or him over different periods. [sic], that could hamper future research efforts,” she said. The forms for nominations, and other essential details about The decision pleased neither BP nor Woods Hole. BP appealed, the competition, including the list of judges, can be found at seeking all the documents it requested, but was unsuccessful. Woods go.nature.com/bxzc9y. Hole contends that surrendering the e-mails will have a chilling effect 1 4 JUNE 2012 | V O L 486 | N A TURE | 1 5 7 © 2012 Macmillan Publishers Limited. All rights reserved

WORLD VIEW A personal take on events Researchers can’t regulate climate engineering alone Political interests, not scientists or inventors, will be the biggest influence on technologies to counter climate change, says Jason Blackstock. cientists are developing geoengineering technologies. But geopolitical calculations. We scientists know this. We have consulted whether these methods eventually succeed in countering climate with civil society, the private sector and government officials through Schange, and whether they will be embraced by the wider popula- the 2010 Asilomar Conference in California — which worked on pol- tion, concerns more than scientists alone. That is why, in the wake of icy recommendations for geoengineering — and the ongoing Solar the cancellation last month of the Stratospheric Particle Injection for Radiation Management Governance Initiative launched by the Royal Climate Engineering (SPICE) field trial and the attendant publicity, it Society in London. Both have indicated the need for action beyond is important that the correct lessons are drawn by scientists, funders, geoengineering researchers. But if assembling these groups has not yet regulators and politicians alike. generated the necessary ‘practical actions’, then what will? In an Editorial about SPICE, this publication pointed out that geo- Geoengineering researchers can experiment with ways to translate engineers must “grasp the nettle of regulation and oversight” (see guidelines into a practical regulatory framework, beginning with a vol- Nature 485, 415; 2012). It added that community-proposed guidelines untary registry of ongoing and planned research. But responsibility also such as the Oxford Principles need practical implementation frame- rests with funders. More research is needed to ensure that we understand works to make an impact. Both issues do demand the abilities and limits of solar-geoengineering urgent attention, but there is a more important technology before it is deployed in political des- consideration: something that geoengineers com- peration. It would be a tragedy if the negative pub- ing together to “draft detailed, practical actions”, GEOENGINEERING licity around SPICE scared funds away from this as the Editorial recommended, simply cannot WILL work. Funders can also help to establish norms address. Geoengineering will alter the geopolitics of international cooperation. First steps would of climate change and this cannot be ignored by ALTER THE include creating incentives for collaboration on climate policy-makers. research, and sharing lessons on how to respon- SPICE turned the focus of the geoengineering GEOPOLITICS sibly oversee and monitor controversial projects. debate onto patenting and concerns that personal Ultimately, climate policy-makers need to or corporate ownership could take precedence OF CLIMATE CHANGE get involved. Current international institutions over global public interest. But patents are far are simply not prepared for geoengineering. from the biggest issue for techniques such as solar AND THIS Discussing solar geoengineering at the United geoengineering (blocking the Sun’s radiation, as Nations climate talks now would only disrupt investigated by the SPICE project). CANNOT BE progress towards the already ambitious goal of The cost of injecting enough aerosols into the agreeing a global mitigation and adaptation strat- stratosphere to counter the warming projected for IGNORED. egy by 2015. And the Convention on Biological even high-emission scenarios is estimated to be Diversity, the only international body yet to only about US$1 billion per year. That amounts tackle the issue of solar geoengineering directly, to less than $0.01 per year to compensate for each has neither the mandate nor sufficient political tonne of carbon dioxide emitted. And most of the necessary technology clout to broker a geopolitical agreement. exists already, such as high-altitude aircraft (of which only a couple of Climate negotiators and political leaders need to develop strate- dozen would be needed). Inventors of solar-geoengineering methods gies to fill the governance gap. They also need to consider the signals might try to charge large sums to license patents on their ideas, but this that domestic funding of geoengineering research sends about future will not create a lucrative new industry for large corporations. climate-policy intentions. Failure to come to grips with these issues That said, existing industries, especially agriculture and energy, will could lead to problems if events such as geoengineering field experi- have a strong interest in whether and when solar geoengineering is ments outpace political preparations. used, given that these methods could have sweeping effects on climate, Greater political engagement may be uncomfortable for climate both desirable and undesirable. But industry influence will occur scientists. Climate science has fought hard to resist agendas that force much more through political lobbying than through patent ownership. particular research or conclusions. But such agendas — both corpo- At present, the power in climate negotiations is squarely in the hands rate and national — do influence climate policy, and geoengineering of the major carbon-emitting nations. Technically, a coalition of vulner- technologies could magnify that influence. Politics can’t be avoided, able nations — say, low-lying island states threat- and ignoring it is dangerous for all of us. ■ ened by rising seas — might be able to muster NATURE.COM $1 billion per year to reverse global warming, Discuss this article Jason Blackstock is a visiting fellow with the Institute for Science, but the potential game-changer when it comes to online at: Innovation and Society at the University of Oxford, UK. geoengineering is not technical assessments, but go.nature.com/ws6bxs e-mail: [email protected] 1 4 JUNE 2012 | V O L 486 | N A TURE | 1 5 9 © 2012 Macmillan Publishers Limited. All rights reserved

Selections from the RESEARCH HIGHLIGHTS scientific literature CULTURE of Bayreuth in Germany developed a synthetic protein Religion as based on a repeating amino- W. SELLERS cuckoldry defence acid pattern found in one of the proteins in lacewing silk. How can patriarchal societies The researchers introduced a be sure that the men who synthetic gene that codes for inherit their fathers’ goods are the protein into Escherichia coli actually their fathers’ sons? bacteria. Religions help men to be more Filaments of the bacteria- confident in their paternity by produced silk proved to be setting standards for female almost as strong as natural sexual behaviour. lacewing silk, except at high Beverly Strassmann at the humidity, and more elastic. University of Michigan in Ann Angew. Chem. Int. Edn. Arbor and her team studied http://dx.doi.org/10.1002/ genetic data from 1,706 father– anie.201200591 (2012) son pairs among the Dogon of Mali. Although many Dogon ZOOLOGY are Christian or Muslim, the adherents of their indigenous Live birth without religion had the lowest rate of a placenta male births due to cuckoldry: 1.3% versus 2.9% for the other Some sharks and rays give faiths. The researchers chalk birth to live young but lack this up to the traditional huts placentas or umbilical cords. where menstruating women So how do their embryos must spend their nights. In a obtain oxygen? society in which women are Taketeru Tomita of the often pregnant or unable to Hokkaido University Museum conceive owing to intensive in Hakodate, Japan, and his breast-feeding, a sojourn in the team used ultrasound to study hut informs a woman’s husband a pregnant manta ray (Manta and his kin that she has become alfredi) to find out. They found fertile again. The family can DINOSAURS that the embryo rhythmically then increase their vigilance raises and lowers its jaw, towards her. Weighing extinct animals pumping uterine fluid into Proc. Natl Acad. Sci. USA its mouth and through holes http://dx.doi.org/10.1073/ behind its eyes called spiracles. pnas.1110442109 (2012) Knowing an extinct animal’s mass is crucial for estimating its After birth, the spiracles shrink physiological traits but the standard technique — in which as the animal becomes able BIOMIMETICS a model of the animal is made and its mass then calculated to force water over its gills by from its density — has been criticized for being too subjective. swimming. Synthetic silk Bill Sellers at the University of Manchester, UK, and his Biol. Lett. http://dx.doi. inspired by insect team laser-scanned the skeletons of 14 large mammals, org/10.1098/rsbl.2012.0288 including the bison and the elephant. The researchers used (2012) The green lacewing (Mallada the scans to mathematically derive ‘convex hulls’ of the bones signata), an insect used in — the minimum volume that encloses a set of points, akin to DRUG DISCOVERY biological pest control, has gift-wrapping a teapot — and converted these volumes into inspired the creation of an estimates of mass. These were then compared to the known Melanoma artificial silk. values. pathway targeted To protect its progeny from The method consistently underestimated true body mass predators, the female lacewing by 21%. Thus, using this method and then adding 21% should A drug that targets the RAS suspends its eggs from the provide more accurate predictions. When the team used signalling cascade — which underside of a leaf using a thin the corrected technique on Giraffatitan brancai, one of the is thought to drive tumour silk stalk of remarkable tensile largest dinosaur skeletons in the world, the beast clocked in at growth in 20% of cancers — strength. To forge a similar 23,200 kilograms, similar to recent volumetric estimates. improves survival in some stalk, Thomas Scheibel and Biol. Lett. http://dx.doi.org/10.1098/rsbl.2012.0263 (2012) patients with advanced Felix Bauer at the University melanoma. 160 | N A TURE | V O L 486 | 14 JUNE 2012 © 2012 Macmillan Publishers Limited. All rights reserved

RESEARCH HIGHLIGHTS THIS WEEK The drug, called trametinib, dated Aurignacian sites in inhibits MEK, a protein that Europe. amplifies cancer-promoting J. Hum. Evol. http://dx.doi. COMMUNITY The most viewed signals. Keith Flaherty at org/10.1016/j.jhevol.2012.03.003 CHOICE papers in science the Massachusetts General (2012) Hospital in Boston and his EVOLUTION team tested trametinib in EXTRASOLAR PLANETS melanoma patients with a Domesticated apes mutated version of a RAS- A new world pathway protein BRAF, is born ✪ HIGHLY READ Selection against aggression seems which is mutated in 50% of on journals.elsevier. to have occurred naturally in some advanced melanoma patients. Astronomers have identified a com/animal-behaviour animals and to have led to traits similar A total of 322 patients were planet in the making. March–May to those seen in domesticated animals. randomly assigned to receive The variable brightness of The bonobo (Pan paniscus) is either trametinib or standard GM Cephei — a 4-million- less aggressive and more sociable than its sister species, the chemotherapy. year-old star 870 parsecs away chimpanzee (Pan troglodytes). Brian Hare at Duke University Twenty-two percent — has been noted for decades. in Durham, North Carolina, and his team propose that of patients responded to But whether that variability is these differences, along with a suite of physical variations — trametinib, which delayed caused by bursts of light from bonobos have smaller childlike heads, plus paler lips and tails, disease progression by the star or by an object in the than chimps — are a linked set of traits that parallel those 3 months longer than disk of dust that surrounds it seen in domesticated animals such as dogs and guineapigs. chemotherapy alone. has been a matter of debate. Bonobos are, the authors argue, a self-domesticated ape. N. Engl. J. Med. http://dx.doi. Wen-Ping Chen at the Selection pressures that might have favoured bonobo self- org/10.1056/nejmoa1203421 National Central University domestication include the acquisition of bigger territories, (2012) in Jhongli, Taiwan, and his reducing competition for food and the emergence of team argue for the latter. Using coalitions of females that enforced the peace. ARCHAEOLOGY telescopes positioned around Domestication, far from being a human invention, may the world, the researchers also occur spontaneously in nature, they say. Cultural monitored GM Cephei from Anim. Behav. 83, 573–585 (2012) wellspring 2009 to 2011 and found that the brightness of the star dipped Certain forms of art and music each year for about a month. and found that the animals might have emerged among The researchers interpret this were leaner, ate less and had ancient humans living in variability as evidence of a improved glucose and fat southern Germany and then young planet: a clump of dust, metabolism compared with SOEST/UNIVERSITY OF HAWAII spread through Europe along roughly the mass of an asteroid, normal mice. The researchers the Danube River. which is orbiting GM Cephei. pinpointed the receptor Gpr17 The Aurignacian culture, Astrophys. J. 751: 118 (2012) as mediating the effects of which is characterized by FoxO1. innovations such as figurative METABOLISM Targeting this pathway could art and musical instruments be a strategy for anti-obesity (mammoth-ivory flute A pathway for drugs, the authors say. an underwater earthquake pictured), originated in feeding control Cell 149, 1314–1326 (2012) occurred off the coast of Europe more than 40,000 years Chile. Filtering the data on ago. However, imprecision The activation of a group of GEOPHYSICS the basis of tsunami models in carbon dating has made neurons in a region of the allowed the researchers to it difficult to determine brain called the hypothalamus Ship GPS could differentiate between choppy precisely where the culture boosts food intake, but what flag tsunamis seas and changes in ocean arose. Thomas Higham at controls this activation has surface height due to a tsunami. the University of Oxford, been unclear. Researchers have Commercial ships on Earth’s The team detected a roughly UK, Nicholas Conard at now identified a receptor in oceans could provide a 10-centimetre rise as the the University of Tübingen, these neurons that is targeted cheap and easy way to track tsunami passed, and estimated Germany, and their team used by a protein called FoxO1 to propagating tsunamis. wave speed and arrival time. improved sample preparation promote feeding. Current warning systems Although data from a single techniques for carbon dating The FoxO1 protein is rely on sparse, expensive ship could be prone to false to study Aurignacian remains involved in regulating the buoys and underwater positives, recruiting thousands from Geißenklösterle cave in signalling of key hormones sensors that track a wave once of ships could overcome this southern Germany’s Swabian that suppress appetite. it has been triggered by an problem, the authors suggest. Jura region. Domenico Accili at Columbia earthquake. James Foster at the Geophys. Res. Lett. http://dx.doi. The analysis revealed that University in New York and University of Hawaii at Manoa org/10.1029/2012GL051367 UNIVERSITY OF TÜBINGEN are about 42,500 years old. mouse hypothalamic neurons examined Global Positioning For the latest research published by in Honolulu and his team his team deleted FoxO1 from the artefacts at Geißenklösterle (2012) NATURE.COM This pre-dates other recently System (GPS) data from a research vessel (pictured) that Nature visit: was heading from Hawaii to www.nature.com/latestresearch Guam in February 2010 when 1 4 JUNE 2012 | V O L 486 | N A TURE | 1 6 1 © 2012 Macmillan Publishers Limited. All rights reserved

SEVEN DAYS The news in brief POLICY Nuclear restarts Two of Japan’s shuttered J. FREUND/NATUREPL.COM nuclear reactors may soon reopen, having received a safety thumbs-up from a scientific panel appointed by regional government. The reactors, at the Ohi plant in Fukui prefecture, had already passed safety tests in January. But public protests (and some nuclear analysts) opposed their restart. On 8 June, Prime Minister Yoshihiko Noda appeared on public television asking for his nation’s support to reopen the nuclear reactors, and on 10 June, a 12-member scientific panel appointed by the Fukui prefecture’s Great Barrier Reef protection row governor reported that the Ohi plant could be operated safely. State and federal governments in Australia the United Nations Educational, Scientific and X-ray mission axed are clashing over the approval of industrial Cultural Organization (UNESCO) had said that NASA has cancelled a small developments that could damage the Great the reef was threatened by the rapid increase astrophysics mission that Barrier Reef. On 5 June, environment minister in coastal development. UNESCO’s Heritage would have studied the Tony Burke delayed the approvals process Committee is meeting from 24 June to consider polarized X-rays streaming for a multibillion-dollar coalmining project the report’s findings — which stopped short of from black holes and neutron in Queensland, calling the state’s operation recommending a potentially embarrassing ‘in stars. The Gravity and Extreme “shambolic”. Three days earlier, a report from danger’ designation. Magnetism Small Explorer (GEMS) had been selected for funding in 2009 and ethically acceptable, if proven summit in Brazil. Only in the side had garnered 49.2% of was scheduled to launch in safe and effective by additional areas of stopping ozone-layer the vote, just 63,000 behind 2014, but was estimated to research currently under way, depletion, removing lead in those rejecting the idea — be running 20–30% over its and if conducted as clinical fuel, improving access to water but hundreds of thousands US$119-million budget by the trials. The UK government and marine pollution research of postal votes are yet to be time it was axed on 7 June. See begins a public consultation has there been any major counted. See go.nature.com/ go.nature.com/bit1rn for more. in September, a first step to advance in line with promised yck8eu for more. legalizing the process. See objectives, the report says. Altering embryos go.nature.com/fpn5bo RESEARCH Reproductive procedures that for more. Cancer fund would spare children from An attempt in California to Piezonuclear row inheriting mitochondrial Environment gloom create a cancer-research fund More than 1,000 scientists diseases received approval from Only four of the 90 most from the proceeds of tobacco have signed an Internet appeal an influential UK bioethics important internationally taxes looked to have been to Italy’s research ministry body on 12 June. The technique agreed environmental narrowly defeated, but was requesting that the National involves transferring genetic goals have seen “significant still too close to call, after a Institute for Meteorological material from an egg cell progress”, the United Nations state vote on the measure on Research (INRiM) in Turin containing faulty mitochondria Environment Programme 5 June. Proposition 29 would withdraw its intention to study to an egg from another woman warned on 6 June. Its fifth add a US$1 tax to every pack ‘piezonuclear reactions’, nuclear that has been stripped of its Global Environment Outlook of cigarettes and generate fission that can supposedly nucleus (see Nature 481, 419; is the UN’s main status report around $735 million by be induced by mechanical 2012). The London-based on the health of the world’s 2013–14 for cancer research, stress such as compression of Nuffield Council on Bioethics ecosystems, and was released smoking prevention and crystals. Alberto Carpinteri, found that these procedures are two weeks ahead of the Rio+20 smoking cessation. The ‘yes’ a prominent proponent of 162 | N A TURE | V O L 486 | 14 JUNE 2012 © 2012 Macmillan Publishers Limited. All rights reserved

SEVEN DAYS THIS WEEK S. CASTILLO/AP the controversial idea, was a Sandia-owned laptop on a COMING UP trip to China. Sandia said that appointed president of INRiM Huang had been fired in April last August, and introduced the theme into the institute’s his facility did not have access 2012–14 research plan, which for violating procedures, and 2022 JUNE was published on 29 February. to classified national-security Rio de Janeiro, Brazil, On 6 June, parliamentarians information. hosts this year’s also asked the research minister biggest environmental about INRiM’s use of public Heartland fallout meeting, the United funds. The Pacific Institute in Nations Conference Oakland, California, has on Sustainable Thawed brains reinstated Peter Gleick as its Development — About 150 brains donated for The Martian Chronicles and president. Gleick had taken 20 years after the same research — including more Fahrenheit 451, among other a leave of absence after his city hosted the original than 50 from people with works, died on 5 June aged embarrassing admission UN Earth Summit. autism — may no longer be 91. Bradbury’s works tapped that he had lied to obtain www.earthsummit2012.org fit for study after a freezer both scientific wonder and the internal budget documents malfunction at the Harvard unease about technological from the Heartland Institute, 21 JUNE Brain Tissue Resource change, exploring how a libertarian think tank in The Royal Society in Center at McLean Hospital science and technology shape Chicago, Illinois, that aims to London launches a in Belmont, Massachusetts. human identity. His stories combat climate science. In a report on how best After the refrigeration system anticipated flat-screen TVs, 6 June statement, the Pacific to open up access to and two independent alarms personal stereos and the Institute accepted Gleick’s modern research’s vast all failed, an investigator ‘butterfly effect’ of chaos apology, and said that an volumes of data. discovered the calamity on theory — but, in an oft- independent investigation go.nature.com/1yiefm 31 May. On 11 June, staff repeated remark, he said that had confirmed his account at Autism Speaks, a non- he tried not to predict the of events. See go.nature.com/ profit organization based in future, but to prevent it. cjnqqa for more. the winners of each prize to New York City that leads a be announced in October; programme to distribute brain Stealing secrets FUNDING last year’s prizes amounted to samples to autism researchers, A nanotechnology researcher 10 million kroner apiece. It alerted the families of donors to who until recently worked at Nobel thrift is the first time the prize has the situation. An investigation Sandia National Laboratories This year’s Nobel prize been cut in nominal value into the freezer breakdown is in Albuquerque, New recipients will split a pot of since 1949. See go.nature. to be completed by the end of Mexico, has pleaded not money 20% smaller than that com/1sml4p for more. June. See go.nature.com/fu14vi guilty to embezzling and shared by last year’s laureates. for more. passing research information In response to sluggish Telescope funding to institutions in China. financial markets, which The European Southern PEOPLE Jianyu Huang was charged have eaten into the capital Observatory (ESO) on 5 June with five counts of that supports the prize, the announced on 11 June that Sci-fi writer dies federal-programme fraud Nobel Committee said on its member states have given Ray Bradbury (pictured), from 2009, as well as falsely 11 June that it would divide approval to start building the the acclaimed author of telling a counterintelligence up 8 million Swedish kroner €1.1-billion (US$1.4-billion) the science-fiction classics officer that he would not take (US$1.1 million) between European Extremely Large Telescope, although not everyone has committed their budget contributions. At a SOURCE: PLOS ONE The open-access journal PLoS RISE OF OPEN ACCESS council meeting in Garching, TREND WATCH Germany, six member states The journal PLoS ONE expects to publish more than 2,000 research articles this month. voted for the programme ONE has swiftly expanded since its launch in late 2006 to become 2,000 and four backed it pending confirmation of support by the world’s largest journal; it national ministries; four has already published more 1,500 others are yet to agree to than 9,000 articles this year (see support the project, which is chart). Its growth has encouraged planned for Cerro Armazones the launch of an innovative Research papers published per month 1,000 in Chile’s Atacama Desert. open-access journal, PeerJ, However, almost one-third which announced its business of the telescope’s funding model on 12 June. But instead 500 is scheduled to come from of charging authors per article, Brazil, which has not yet a one-off membership fee will ratified its ESO membership. give them the rights to publish 0 peer-reviewed articles in PeerJ for 2007 2008 2009 2010 2011 NATURE.COM life. See page 166 for more. For daily news updates see: www.nature.com/news 1 4 JUNE 2012 | V O L 486 | N A TURE | 1 6 3 © 2012 Macmillan Publishers Limited. All rights reserved

NEWS IN FOCUS GENETICS Hungarian company ASTRONOMY Medium-sized FUNDING A mess in Texas as PROFILE How Adrian Owen slammed for certifying telescopes face early cancer grant roils state detects awareness in ‘racial purity’ p.167 retirement p.168 funding body p.169 500,000 people in 80 villages over 14 sites. vegetative patients p.178 KENYA MILLENNIUM VILLAGES PROJECT last month , the project claimed a significant In a paper published online in The Lancet 1 milestone. It reported that after three years of interventions, child mortality was decreas- ing three times faster in the project’s villages than in the host nations in general. But the analysis was criticized for underestimating nationwide improvements in child mortality, and over estimating those in the Millennium 2 Villages . The paper’s lead author, Paul Pro- nyk, later accepted that this claim had put the Millennium Village mortality reduction “in 3 an excessively positive light” , and retracted it. Pronyk then resigned as director of Monitoring and Evaluation at Columbia University’s Center for Global Health and Economic Development. The MVP’s founder, Jeffrey Sachs, head of the Earth Institute at Columbia and a co-author of the partially retracted paper, says that the MVP research teams were too autonomous, and he regrets not having brought in external advisers earlier. “I don’t want such mistakes to Health interventions may have reduced child death in African villages, but it isn’t clear by how much. occur again,” he says. Sachs has now created a faculty committee to oversee MVP research GLOBAL HEALTH and increase interactions with outside research- ers; he will co-chair the committee, along with Poverty project Cheryl Palm, a scientist at the Earth Institute’s tropical agriculture programme. An external advisory board called the Inter- national Scientific Expert Advisory Group will opens to scrutiny oversee how the MVP assesses the impact of its work. The panel is still being assembled, but will be chaired by Robert Black, head of the department of international health at Panel set to reshape evaluation of Millennium Villages Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. Black says that research after partial retraction of health claims. Sachs has given him a remit “to open the study to more scrutiny, to be more transparent, to be very explicit about what are the expected BY DECLAN BUTLER York, is simultaneously applying a raft of aid outcomes of the study, and to be sure that eval- interventions — from bed nets for malaria uation is as well done, as rigorously, as possi- he Millennium Villages Project (MVP) control to fertilizers — to help impoverished ble”. Black also wants to respond to criticisms aims to chart a course out of poverty for villages to meet the United Nations’ eight Mil- by giving external researchers access to as Tthe most deprived people in Africa. But lennium Development Goals (MDGs), includ- much of the MVP data as he can, as well as to after being forced to partially retract the find- ing reducing hunger, extreme poverty and the detailed information on the project’s costs, so ings of a paper that included the claim that its burden of major diseases, and increasing levels that outsiders can have greater confidence in interventions had slashed child mortality, the of primary education. The first Millennium the project’s results and cost–benefit analyses. project is revamping its oversight to make its Villages were launched It is too soon to say what sort of recommen- science more robust and determine whether in Ethiopia and Kenya NATURE.COM dations the external panel will make on the its approach works. in 2004 and 2005, and To read about how MVP’s future research in the study villages. But The MVP, a joint venture between Colum- the project now oper- Africa is building given that the project is already almost seven bia University and the non-profit organi- ates in 10 African coun- science capacity: years into its planned ten-year pilot phase, the zation Millennium Promise, both in New tries, reaching about nature.com/africa scope for change is limited, says Black. “It is 1 4 JUNE 2012 | V O L 486 | N A TURE | 1 6 5 © 2012 Macmillan Publishers Limited. All rights reserved

NEWS IN FOCUS impossible to completely redesign the study, by one-third more than that in matched com- covering 30,000 people in Ghana. “A massive though many of us would have designed it dif- parison villages over the course of the study. effort is needed to raise millions of people in ferently,” he says. “The whole study should have been retracted,” Africa out of poverty. Millennium Villages Michael Clemens, a migration and develop- he says, adding that he has submitted a new represent one approach, and they could make ment researcher at the Center for Global letter to The Lancet to this effect. a major contribution,” the department notes. Development, an independent research insti- Black says that whether the MVP ultimately “Such an opportunity should not be missed tution in Washington DC, is unimpressed with proves a success or failure, it will still provide use- merely for want of evidence. But nor should the creation of the advisory panel, and argues ful information, so it is important to improve its scaled-up resources be committed to a model that the MVP needs rigorous and transpar- evaluation mechanisms. “I don’t think it should without assessing whether it is indeed a cost- ent evaluation from completely independent be dismissed because it has flaws,” he says. effective approach.” ■ 4 groups. Clemens, who co-authored a letter to The UK government’s Department for Inter- The Lancet that led to the partial retraction of national Development last year launched its 1. Pronyk, P. M. et al. Lancet 379, 2179–2188 (2012). 2. Gilbert, N. Nature 485, 158–159 (2012). the MVP’s findings, believes that the paper still own £3.8-million (US$5.9-million) independ- 3. Pronyk, P. Lancet 379, 1946 (2012). has problems — in particular, a claim that the ent evaluation to accompany an £11.5-million 4. Bump, J. B., Clemens, M. A., Demombynes, G. & child mortality rate in Millennium Villages fell ten-year grant to create Millennium Villages Haddad, L. Lancet 379, 1945 (2012). RESEARCH Journal offers flat fee for ‘all you can publish’ Latest venture is part of an explosion of ideas for open-access publishing. BY RICHARD VAN NOORDEN interesting period for the next few years,” says Group’s Scientific Reports. It marks a distinc- Binfield. tion from selective open-access journals such cience-publishing ventures continually Binfield hopes PeerJ’s growth will resemble as the forthcoming eLife, which plans to pub- battle for market space, yet most operate that of PLoS ONE, which went from publishing lish only high-impact work. To avoid running Son one of only two basic business models. some 1,000 articles in its first full year (2007) out of peer reviewers, every PeerJ member is Either subscribers pay for access, or authors to its current 2,000 articles a month. “PLoS required each year to review at least one paper pay for each publication — often thousands of ONE is publishing so many articles that it is or participate in post-publication peer review. dollars — with access being free. But in what stretching the boundaries of what is a journal Untangling user fees from the publica- publishing experts say is a radical experiment, — instead, it’s becoming a large, peer-reviewed tion of individual articles is a significant an open-access venture called PeerJ, which repository of research articles. We’re setting innovation — but other radical ideas are formally announced its launch on 12 June, is ourselves up for exploring that future,” says in the pipeline. In high-energy physics, for 3 carving out a fresh niche. It is asking its authors Binfield. But he adds that PeerJ will not need example, a consortium called SCOAP , for only a one-off fee to secure a lifetime mem- PLoS ONE’s volume of papers to be viable. which includes funding agencies and librar- bership that will allow them to publish free, Whereas PLoS ies, is planning to pay publishers for all the peer-reviewed research papers. ONE charges $1,350 “I thought — costs of publication, so that articles can Relying on a custom-built, open-source per paper, PeerJ wow — if the be free to access and authors will not be 3 platform to streamline its publication process, users pay $299 for people I’m charged directly. On 1 June, the SCOAP PeerJ aims to drive down the costs of research unlimited open- hearing about initiative said that it had sent out tenders to publishing, say its founders: Peter Binfield, who access publications are working publishers to bid for these contracts, with until recently was publisher of the world’s larg- and submissions, or there — that’s the services expected to start in January 2014. est journal, PLoS ONE, and Jason Hoyt, who a smaller fee ($199 sign of something Other ideas under discussion include jour- previously worked at the research-paper-shar- or $99) for a limited happening.” nals that charge for submissions rather than for ing site Mendeley. Their involvement is a major number per year. (All publications; direct government funding for all reason for the buzz around PeerJ. “I thought authors on multi-author papers must be mem- publications; and research funders setting up — wow — if the people I’m hearing about bers, although papers with 13 or more authors their own publication infrastructure (much as are working there — that’s the sign of some- need only 12 paying members.) The journal, some do with biology databases), says Cam- thing happening. It makes it less crazy,” says which received undisclosed start-up support eron Neylon, recently appointed director of John Wilbanks, an advocate of open access and from the venture-capital fund O’Reilly Alpha- advocacy at the Public Library of Science in a senior fellow at the Ewing Marion Kauffman TechVentures in San Francisco, California, will San Francisco, which publishes PLoS ONE. Foundation in Kansas City, Missouri. be accepting articles from August. No one knows what will work. But many say PeerJ is just one of a flurry of experiments, Despite the low publication cost, PeerJ’s that the experiments now under way will help encouraged in part by the gathering momen- founders promise that, as with PLoS ONE, to reveal the true costs of sustainably publish- tum of open access, that might shape the articles will be peer reviewed for scientific ing articles and research data. “PeerJ is part future of research publishing. “We are seeing validity — but not for importance or impact. of the assertion that this can be done cheaper a Cambrian explosion of experiments with Other open-access journals have also adopted — and for that alone it will be interesting to new publishing models. It’s going to be an this policy, including Nature Publishing watch,” says Neylon. ■ 166 | N A TURE | V O L 486 | 14 JUNE 2012 | C O RRECTED O NLINE 1 3 JUNE 2012 © 2012 Macmillan Publishers Limited. All rights reserved

The rise of the right: Hungary’s Jobbik party rallies supporters in Budapest. GENETICS Genome test slammed for assessing ‘racial purity’ Hungarian far-right politician certified as ‘free of Jewish and Roma’ genes. BY ALISON ABBOTT The ETT’s secretary, József Mandl, chair of for further consultation. It argues that the com- medical chemistry at the Semmelweis Uni- pany “rejects all forms of discrimination, so it fficials in Hungary united this week versity in Budapest, says that the certificate has no right to judge the purpose for which an T. KOVACS, MTI/AP to condemn ongoing ethnic violence is “professionally wrong, ethically unaccepta- individual will use his or her test result, and so Oand anti-Semitic attacks, including an ble — and illegal”. The council discussed the for ethical reasons it could not have refused to assault on the former Chief Rabbi on 5 June. issue on 7 June and concluded that the genetic carry out the test”. But a cause for further soul-searching has test violates the 2008 Law on Genetics, which The certificate first appeared on a right- emerged: a scientific scandal recalling discred- allows such testing only for health purposes. wing website, which described the intention ited notions of racial purity. “The council’s stand is important,” says behind the gene test as “noble”, although it Hungary’s Medical Research Council (ETT), Lydia Gall, an Eastern Europe and Balkans questioned the science. After the news blog which advises the government on health pol- researcher at civil-rights group Human Rights Petőfi utca republished the certificate on icy, has asked public prosecutors to investigate Watch, who is based in Amsterdam. In Hun- 14 May, the Hungarian Society of Human a genetic-diagnostic company that certified gary, “there have been many violent crimes Genetics issued a statement condemning that a member of parliament did not have against Roma and acts of anti-Semitism in the the test. István Raskó, director of the Insti- Roma or Jewish heritage. past few years”, she says. Politicians who try to tute of Genetics of the Hungarian Academy The MP in question is a member of the far- use genetic tests to prove they are ‘pure’ Hun- of Sciences in Szeged, and the society’s vice- right Jobbik party, which won 17% of the votes garian fan the flames of racial hatred, she adds. president, says that it is impossible to deduce in the general election of April 2010. He appar- Nagy Gén scanned 18 positions in the MP’s origins from genetic variations at a few places ently requested the certificate from the firm genome for variants that it says are charac- in the genome. “This test is complete nonsense Nagy Gén Diagnostic and Research, which teristic of Roma and Jewish ethnic groups; and the affair is very harmful to the profession rents office space at the prestigious Eötvös its report concludes that Roma and Jewish of clinical genetics,” he says. Loránd University in Budapest. The company ancestry can be ruled out. The certificate adds: Nagy Gén’s rental contract with Eötvös produced the document in September 2010, a “For an interpretation of the test result and for Loránd University ended this month, says few weeks before local elections. genetic consultation relating to the family-tree György Fábri, a university spokesman. “The The certificate — with the MP’s name blacked research, please contact us as soon as conveni- university is not commenting publicly on the out — emerged on the web last month and was ent.” affair because it is not our business — our seized on by the Hungarian media. One of Nagy Nagy Gén did not respond to e-mail and researchers had no contact with the com- Gén’s financial partners, Tibor Benedek — a telephone requests from Nature for comment. pany.” In a written statement he added that three-time Olympic water-polo gold medal- But a statement on its website claims that news- the university “fully rejects” the abuse of list and a member of a prominent Jewish fam- papers had reported the story “incompletely” scientific results to promote discrimination ily — immediately pulled out of the company. and points to the certificate’s recommendation or hatred. ■ 1 4 JUNE 2012 | V O L 486 | N A TURE | 1 6 7 © 2012 Macmillan Publishers Limited. All rights reserved

NEWS IN FOCUS One collaboration, the Dark Energy Survey, will install a 570-mega pixel camera on the 4-metre Blanco telescope in Chile. By taking pictures of hundreds of millions of galaxies, it could reveal tiny distortions in their shape ROYAL OBSERVATORY, EDINBURGH/SPL that would betray the effect of dark energy. Another group, called BigBOSS, plans to investigate dark energy by looking for patterns in the distribution of 20 million galaxies using an instrument installed at the 4-metre Mayall telescope in Arizona (see Nature 481, 10–11; 2012). “The highest-impact science right now are these things where you want to put in more than 100 nights a year,” says NOAO director David Silva. In Europe, one productive niche has been the search for planets outside the Solar System. An instrument at the ESO’s 3.6-metre telescope at La Silla in Chile has already discovered more exoplanets than any other ground-based search. And in April, the University of Geneva in Switzerland installed a near-clone of that instrument in the Northern Hemisphere, at Italy’s 3.6-metre National Galileo Telescope in The United Kingdom Infra-Red Telescope is setting records for scientific publications. the Canary Islands. A third emerging use for these telescopes ASTRONOMY is to obtain spectra of millions of stars in the Milky Way, to try to understand their chem- Stellar UK scope istry and their wanderings through space. This would allow astronomers to reconstruct a detailed history of the Galaxy’s formation. A spectrograph specialized for this purpose faces closure is already being built for the 3.9-metre Anglo- Australian Telescope in Australia, and the ESO is considering one for its 3.6-metre New Tech- nology Telescope in Chile. But Drew says that it is sometimes difficult Specialize or die is the mantra for medium-sized instruments. to convince disparate user groups to coalesce around a coordinated scientific campaign. And, BY ERIC HAND European Southern Observatory (ESO), which especially in Europe, multinational ownership is planning a 40-metre giant. “Once again, the makes it difficult for telescope operators to erched near the 4,200-metre summit UK is leading the way,” Davis adds archly. change course. “Structures in Europe are oddly of Mauna Kea in Hawaii, the United But survival strategies are coming to light. complex,” she says. “They get in the way a bit.” PKingdom Infra-Red Telescope (UKIRT) Chief among them is that, rather than using Moreover, UKIRT itself is proof that a dedi- enjoys one of the finest sites in all of astronomy. 4-metre telescopes as general-purpose obser- cated speciality campaign does not guarantee It was among the world’s largest telescopes vatories, with time being divided among hun- survival. In 2005, for example, its operators when it opened more than 30 years ago, and dreds of astronomers, they should be dedicated invested in a wide-field camera that allowed it its enviable record of publications shows no to specific problems requiring large collabora- to survey galaxies across the sky. Patrick Roche, signs of slowing. Yet on 30 May, the UK Sci- tions, long campaigns and custom-built instru- an astronomer at the University of Oxford, UK, ence and Technology Facilities Council (STFC) ments. “We’ve become much more like particle and chair of UKIRT’s oversight board, says announced that it will close the 3.8-metre physics, oriented towards doing specific things that in the first four months of this year, more tele scope in 2013, unless a buyer can be found. in big teams,” says Janet Drew, an astronomer at than 70 papers have been published contain- UKIRT’s closure could be the first of many, the University of Hertfordshire in Hatfield, UK, ing UKIRT data. That puts UKIRT on course say concerned astronomers. Just as 1- and who chaired a committee planning the future to being the most scientifically productive 2-metre telescopes began to be mothballed in of Europe’s 2–4-metre telescopes. telescope in the world — outstripping any of the 1990s to free up funding for a new class of In the United States, for example, the Depart- the 8-metre-class instruments. 8–10-metre instruments, more than a dozen ment of Energy is hoping to fund the devel- The telescope’s board, which has protested 4-metre telescopes around the world could opment of instruments that will allow two against the closure decision, claimed that the face a similar fate as astronomers prepare for ageing, 4-metre-class telescopes belonging facility could be kept open a year longer for the arrival of 30-metre behemoths (see Nature to the National Optical Astronomy Observa- a mere £100,000 (US$155,000). And Davis 479, 18–19; 2011). tory (NOAO) to engage thinks that he might be able to find an institu- “Is this a sign of things to come? It may be,” in a quest to under- NATURE.COM tion willing to take on the costs, although he says Gary Davis, director of the Joint Astronomy stand dark energy, the Read more about hasn’t quite settled on the best way to advertise Centre in Hawaii, which operates UKIRT. The mysterious force that is 30-metre a 34-year-old telescope with a fine 3.8-metre cash-strapped STFC decided to sacrifice UKIRT speeding up the expan- telescopes at: mirror. to preserve its membership commitment to the sion of the Universe. go.nature.com/tlvntb “eBay?” he wonders. “I don’t know.” ■ 168 | N A TURE | V O L 486 | 14 JUNE 2012 © 2012 Macmillan Publishers Limited. All rights reserved

IN FOCUS NEWS FUNDING Grant review opens up Texas-sized rift Big money and big ambitions roil state’s research efforts. BY MEREDITH WADMAN scientists since 2007, when its citizens voted overwhelmingly to establish the CPRIT and hen Ronald DePinho took the authorized $3 billion in bond issues to support helm at the MD Anderson Can- its efforts. The money — $300 million a year Wcer Center in Houston, Texas, last for ten years — began flowing in 2010. Since September, he wasn’t shy about his ambitions. then, CPRIT has funded 387 grants worth a He is on a “Moon shot” quest, he said, with total of $671 million — most of them to aca- the aim of making huge gains against five can- demic research institutions (see ‘Mapping the cers in the next decade, partly by attacking a millions’). Roughly 17% of the CPRIT’s funds void in cancer drug development. Wasting have gone to commercialization, helping Texas no time, DePinho launched a drug-discovery companies to develop cancer diagnostics and centre, the Institute for Applied Cancer Sci- treatments. Before the IACS award, all grant ence (IACS), where his wife, Lynda Chin, was applications were subject to both commercial appointed chief scientist. The effort gained and scientific review. momentum in March, when an IACS research Then, in Sep- F. CARTER SMITH team led by Chin won most of a US$20-million tember, as DePinho and Chin arrived in commercialization grant from the taxpayer- funded Cancer Prevention and Research Insti- tute of Texas (CPRIT), based in Austin. Houston from the Dana-Farber Cancer But within weeks the funding coup had Institute in Boston, turned into a media firestorm — one that has Massachusetts, the led to harsh criticism of the CPRIT’s decision- CPRIT unveiled a dif- making process and exposed tensions within ferent species of com- the community the institute serves. The affair mercial grant. Called led the CPRIT to announce on 6 June that it “The reality is: an ‘incubator’ grant, plans to re-review the award it had made to we applied, our its aim was to provide Chin, this time on its scientific merits. The proposal was expert technical and original review had considered only its com- reviewed and it business assistance to merical potential. And this week the embattled got funded.” Texas-based transla- institute has advertised for its first compliance Ronald DePinho tional research pro- officer — whose job it will be to ensure that the jects and start-ups. institute’s internal policies and procedures for The IACS team seized on the opportunity with grant-making are followed. a six-and-a-half-page proposal and submitted “Hindsight is twenty–twenty,” says the its application on 11 March. By 29 March, an CPRIT’s executive director William Gimson. annually renewable grant worth $18 million “We want to hold ourselves to a higher stand- per year to the IACS and $2 million to Rice ard. So we are willing to come back and say: ‘If University in Houston had been approved by these questions have been raised, let’s have a the CPRIT’s Commercialization Review Coun- scientific and a commercial review’.” cil and signed off by the institute’s governing The controversy became public with the rev- Oversight Committee. The grant named Chin elation on 8 May that the CPRIT’s chief scien- as principal investigator. tific officer, Nobel laureate Alfred Gilman, was On 24 April, after seeing a copy of the grant resigning. Gilman, it emerged, was incensed by proposal, Gilman wrote to the CPRIT’s Sci- the speedy awarding of the IACS grant with- entific Review Council, which is chaired by out a scientific review and by the simultane- Nobel laureate Phillip Sharp at the Massachu- ous shelving of seven research awards worth setts Institute of Technology in Cambridge, $39 million that the institute’s scientific review- complaining about the award. In Gilman’s ers had recommended for funding. If the situa- view, the proposal was a “back door” submis- tion was not fixed, and quickly, Gilman warned sion, amounting to no more than “a vague in an e-mail to top managers obtained under organizational plan” “You would be shocked Texas public-records law, “cancer patients will to see it,” he wrote. lose; the citizens of Texas will be deceived; the After Gilman resigned, Gimson received a integrity of science in Texas will be soiled”. blistering missive from the eight members of The state has been the envy of cancer the scientific council. The institute’s failure 1 4 JUNE 2012 | V O L 486 | N A TURE | 1 6 9 © 2012 Macmillan Publishers Limited. All rights reserved

IN FOCUS NEWS to include them in reviewing the IACS award “calls into question our roles and the MAPPING THE MILLIONS University of Texas integrity of the review program in general”, A handful of institutions have received more than MD Anderson Cancer Center SOURCE: CPRIT $126 million they wrote. “This by-pass is inherently unfair US$10 million in research funds from the Cancer + $18 million incubator award Prevention and Research Institute of Texas. to every scientist in Texas who participates in the CPRIT program … These scientists have University of Texas Baylor College of Medicine $66 million played by the rules.” Southwestern Medical Center at Dallas Methodist Hospital Both Chin and DePinho have repeatedly $118 million Methodist Hospital Resear insisted that they, too, played by the rules. Research Institutech Institute $25 million $25 million DePinho, who asked the CPRIT if it wanted University of Texas TEXAS to re-review the grant after the controversy Health Science Center University of Texas Health at San Antonio Science Center at Houston erupted, says that he is certain that the award $13 million $16 million will stand on its own merits and notes that Rice University CPRIT officials encouraged the MD Ander- UNITED $16 million son team to try for the award. “The reality S TAT E S University of Statewide Clinical Trials + $2 million incubator award is: we applied, our proposal was reviewed Texas at Austin Network of Texas and it got funded,” he says, adding that the $31 million $25 million team’s submission “was done in a way that was totally consistent with the CPRIT’s guidelines”. MD Anderson provost Raymond DuBois and concern about the precise pathway by which some scientists who are connected with the Kenneth Shine, the University of Texas System the grant was submitted,” says Shine. DePinho CPRIT award process and that some of the vice-chancellor for health affairs, to whom acknowledges that the application should not Oversight Committee members were unhappy DePinho reports, say that they agree. have been submitted directly to the CPRIT. that so many grants were flowing to the Uni- Yet CPRIT correspondence suggests that The Houston Chronicle has also raised versity of Texas Southwestern Medical Center some in authority at the institute worked behind questions about potential conflicts of interest at Dallas, where Gilman is based. Gilman the scenes to make sure that the MD Ander- among some of the application’s commercial wrote to CPRIT executives that the most meri- son team qualified for the grant. For instance, reviewers. The CPRIT repudiates this, noting torious proposals were being funded, irrespec- the minutes of an that those with connections to DePinho or Rice tive of geography, adding: “We have assembled University recused themselves from voting on the best from outside the state to evaluate our internal telephone HKSTRATEGIES conference sent on the relevant parts of the award. programs. If we do not accept their advice we Nonetheless, appearances can be problem- are arrogant and foolish.” 4 January to Robert Ulrich, chairman of the commercializa- atic, says Paul Root Wolpe, director of the Gilman’s e-mails suggest that he was increas- Center for Ethics at Emory University in ingly at odds with the Oversight Committee, tion council, and Jerry Atlanta, Georgia. “An absolutely unassailable which consists mainly of political appoin- Cobbs, CPRIT’s chief process is desirable,” he opines. “Greater pains tees. In his letter of resignation, he wrote that commercialization should have been taken to avoid any appear- he wanted stay until October, which would, officer, includes an ance of favouritism.” among other things, allow him to monitor a action item for Cobbs DePinho did not improve perceptions when, crucial 26 July meeting of the committee, when to “change some “The integrity of on 18 May, he was a guest on a national cable the seven grants sidelined in March, including wording” to the incu- science in Texas television show that offers investment tips. five to the University of Texas Southwestern bator grant request will be soiled.” When asked which cancer drug companies Medical Center worth a total of nearly $26 mil- for applications, “to Alfred Gilman would make good buys, he touted AVEO lion, will again come up for approval. Gimson broaden the scope to Oncology of Cambridge, mentioning that he will also seek the committee’s approval to include incubators that would serve earlier- had helped to found the company but not that review the MD Anderson grant and oth- stage programs, such as Lynda Chin’s endeavor.” he owns 542,000 shares in it. DePinho later ers like it using a merged committee — half The compliance office of the University of apologized for his comments in an article in commercialization experts and half scientific Texas System, of which MD Anderson is a the weekly newsletter The Cancer Letter. Shine reviewers — and to require from MD Ander- part, is investigating why the incubator grant says that a conflict-monitoring committee for son a level of scientific detail not present in its application was submitted directly from Chin’s the University of Texas System is examining original proposal. team without first being reviewed by the MD the incident. “We will be taking a look at that Noting that this is the first of hundreds of Anderson provost. The provost normally episode and what it has to teach us.” CPRIT grants to have raised questions, Gim- reviews all grant applications going out of the The controversy has also exposed some of son says: “From my perspective we have had institution, looking, in part, for financial con- the competing agendas within CPRIT. E-mails a stellar record. My insistence will be that we flicts, or appearances of them. “I do have some show that DePinho’s ambitious style has irked continue to have that stellar record.” ■ TOP STORY NEWS VIDEO EDELMANN/SPL MORE Fetal ● NASA scientists raise awareness of Giant reef M. MEUR/STOCKTREK IMAGES/CORBIS budget cuts with cupcakes go.nature. fish defend genome ONLINE com/b95na3 deduced territory from outbreak in Africa go.nature.com/eitejb headbutts parental ● Vaccines used to control cholera with DNA go.nature. ● Vitamin D fails diabetes test go.nature. go.nature.com/ com/zsylkq com/onhrfn baelyu 1 4 JUNE 2012 | V O L 486 | N A TURE | 1 7 1 © 2012 Macmillan Publishers Limited. All rights reserved

NEWS IN FOCUS PHYSICS Tabletop X-rays light up Compact device promises to open window on chemical reactions in the lab. BY KATHERINE BOURZAC and must then fly his students halfway across with a wavelength of 0.8 nanometres. Around the country to do the work. these wavelengths, many of the chemical ele- he pressurized, cylindrical chamber The tabletop sources rely on a technique ments used in magnets and superconductors fits in the palm of Margaret Murnane’s called high-harmonic generation, in which absorb a characteristic band of light. Kapteyn Thand. Yet out of one end of the device laser light is passed through a medium that says that this could be used by chemists to dis- comes an X-ray beam that packs almost as converts it to light of shorter wavelengths and cern the spin states of nickel atoms that make much punch as the light generated by massive higher frequencies. Shine a ruby laser into up the bits of information in magnetic com- particle accelerators. a quartz crystal, for example, and a beam of puter hard drives, for example. Murnane and Henry Kapteyn, both physicists ultraviolet light comes out — albeit dimmer, The tabletop systems have already surpassed at JILA in Boulder, Colorado, a joint institute of but still focused like a laser beam. the larger light-source facilities in terms of the University of Colorado and the laser pulse speed. Murnane and US National Institute of Standards Kapteyn’s device produces very and Technology, have reported the fast pulses, as short as 2.5 atto- −18 first tabletop source of ultra-short, seconds (10 seconds) — faster –12 laser-like pulses of low energy, or than the picosecond (10 ) pulses ‘soft’, X-rays. The light, capable of of synchrotrons and the femto- probing the structure and dynamics second (10 –15 ) pulses of free- of molecules, was previously avail- electron lasers. That timescale is T. POPMINTCHEV & B. BAXLEY/JILA/UNIV. COLORADO able only at large, billion-dollar even quicker than the making and national facilities such as syn- breaking of chemical bonds. “At chrotrons or free-electron lasers, this timescale, we can start using where competition for use of the these light sources to address ques- equipment is fierce. But the report tions where we have no idea what by Murnane, Kapteyn and their the answers will be,” says Ferenc colleagues, published in the 8 June Krausz, a physicist at the Max issue of Science (T. Popmintchev et Planck Institute for Quantum al. Science 336, 1287–1291; 2012), Optics in Garching, Germany, suggests that the devices might and co-founder of Femtolasers, a soon lie within the grasp of a uni- company that sells ultrafast light versity laboratory budget. “For us, sources. it’s incredible that we can do this Light produced by these at all in a tabletop system,” says sources is much less intense than Murnane. “Three years ago, people that at the big national facilities, would have said ‘only large facilities however. That’s one reason why can do that’.” physicist Emma Springate, who Murnane and Kapteyn, a hus- runs Artemis, part of the Central band-and-wife team who also Laser Facility at the Science and head the Boulder-based company Technology Facilities Council’s KMLabs, already sell a similar tab- Chemical bonds can be probed with fast, laser-like X-ray pulses (illustrated). Rutherford Appleton Laboratory letop source of extreme-ultraviolet near Didcot, UK, wants access to light. Murnane thinks that a future soft X-ray Murnane and Kapteyn have pushed high- both technologies. Artemis already has one of source should cost about US$1 million, and harmonic generation to its limits, with a sys- KMLabs’ ultrafast extreme-ultraviolet sources, hopes that its relatively low cost and small tem that uses an infrared laser as the source which it combines with access to a synchro- size will open up X-ray studies for materials and pressurized helium gas as the medium. tron source. “The synchrotron gives you a scientists, biologists and others. The beams The laser creates a strong electric field, which static, really clear high-resolution picture, and generated by the device could, for instance, draws electrons away from the helium atoms, the ultrafast source gives you a slightly fuzzy help materials scientists to make better solar allowing the electrons to absorb energy from movie,” Springate says. materials by tracking the paths of electrons the electric field. When they slam back in to Tabletop X-ray sources could still be through solar cells, and might allow chemists the helium atoms, they release that absorbed several years away, Murnane says, but she to trace the ultrafast dynamics of photo- energy as shorter-wavelength photons — but hopes that they will one day be as common in synthesis and catalysis. “This is something only about one photon comes out for every labs as electron microscopes are. Shpyrko, for people have been waiting for for a very long 5,000 infrared photons that are put in. one, is looking forward to that day. Waiting to time,” says Oleg Shpyrko, a physicist at the Uni- The result is light at wavelengths almost as get an experiment accepted at a national facil- versity of California, San Diego. Shpyrko often short as those delivered by synchrotrons. By ity, he explains, can feel like waiting for a space waits months to get his experiments accepted increasing the pressure in the gas — something shuttle to launch. “If you have one of these in at the Advanced Photon Source, a synchrotron theorists thought might defocus the light beam your own lab, you can dream up an experi- at Argonne National Laboratory in Illinois, — Murnane and Kapteyn can produce light ment and try it tomorrow,” he says. ■ 172 | N A TURE | V O L 486 | 14 JUNE 2012 © 2012 Macmillan Publishers Limited. All rights reserved

NEWS FEATURE Samples crushed between two diamonds can be probed with lasers. HARD PRESSED 174 | N A TURE | V O L 486 | 14 JUNE 2012 © 2012 Macmillan Publishers Limited. All rights reserved

FEATURE NEWS TWO PHYSICISTS under a couple of research groups.” whether Eremets and Troyan are among them. 1 In their experiments , the Mainz physicists On 26 June, the main figures in this SAY THEY HAVE controvery will gather in Biddeford, Maine, started with pairs of brilliant-cut diamonds. FORCED HYDROGEN during a Gordon Research Conference on They trimmed each of the diamonds’ points high-pressure science. The result could be a into a flat surface, or culet, 20–30 micrometres TO BECOME AN meeting of minds — or a display of fireworks. across, then aligned the diamonds with those “This is a very intense field,” says Jeanloz. truncated tips almost touching, on either side EXOTIC METAL High-pressure scientists have been trying — of a piece of metal foil pierced with a culet- and failing — to make metallic hydrogen ever sized hole that would enclose a minuscule THOUGHT TO since theorists first predicted its existence in experimental chamber. 1935 (ref. 3). Anyone claiming success can EXIST ONLY IN THE expect an all-out critique from rival groups — THROUGH A GEM DARKLY HEARTS OF GIANT especially considering what is at stake. For each experiment, Eremets and Troyan loaded hydrogen gas into the hole, and started Not only would making metallic hydrogen in PLANETS. NOW the laboratory allow researchers to do planetary tightening a set of screws that forced the dia- science at the bench — gas-giant planets such as monds closer together. As the culets bit into the THEY MUST FACE Jupiter, or the even larger ones being discovered foil at the rim of the hole, the metal deformed around distant stars, are thought to have huge around them to form a seal trapping the hydro- THEIR CRITICS. amounts of the stuff in their interiors — but it gen. And as the force exerted by the screws was could point the way towards an entirely new focused down onto the culets, the pressure in world of high-pressure phenomena. the chamber began to skyrocket. “Hydrogen is the simplest atom, the simplest This is where high-pressure experiments molecule and perhaps the most complicated often go awry. Although the anvil’s diamond elemental solid,” says Arthur Ruoff, a high-pres- jaws are made of one of the hardest materials BY IVAN AMATO sure physicist at Cornell University in Ithaca, known, superpressured hydrogen routinely New York. In 1968, Cornell physicist Neil Ash- infiltrates them, making them brittle and ikhail Eremets and Ivan Troyan croft predicted that solid metallic hydrogen causing the gems to crack like cheap plastic 4 work only with the very best, gem- might be a superconductor . In 2004, calcula- cups. This also spoils the gemstones’ trans- 5 quality diamonds. Nothing else can tions by Ashcroft and others suggested that, parency, stopping the physicists from seeing Mhandle the stresses involved — not under certain combinations of pressure and what is happening in the chamber. Eremets when the two physicists make a habit of forcing temperature, hydrogen atoms would rearrange and Troyan addressed that problem by apply- the diamonds’ tips together until the pressure themselves into a new kind of quantum liquid ing semi-transparent coatings to protect their between them reaches levels normally found with attributes of both superconductors, which diamonds from the infiltration of hydrogen. at the centre of the Earth. conduct electricity without resistance, and But even so, they went through about 100 pairs Eremets and Troyan, both at the Max Planck superfluids, which flow without resistance. of diamonds as they worked out the bugs of Institute for Chemistry in Mainz, Germany, are their apparatus and ran trials and controls. not alone in this strange pursuit. Their appara- BRIGHT FUTURE When the pressure inside their anvils tus, known as a diamond anvil cell, is a stand- Such exotic behaviours become particularly reached 200 billion pascals (200 GPa), or about ard fixture in high-pressure research labs. But interesting if some of these phases of hydrogen 2 million times Earth’s atmospheric pressure at they have provoked widespread agitation in turn out to be metastable. This would mean sea level, the two Mainz physicists saw spec- their research community by claiming to have that the phases could retain their high-pressure troscopic signs that the diatomic hydrogen crushed hydrogen in their cells until it gave up forms for an indefinite period once external molecules had begun to interact in a way that being a diatomic gas, and instead became a forces are removed, much as diamonds formed signalled that they were becoming a solid. shiny, presumably monatomic, solid that con- by high temperatures and pressures deep inside At 220 GPa, the sample chamber became ducted electricity like a metal. Earth remain diamonds even after they reach dark, another sign that hydrogen had appar- The arguments over this alleged discov- the surface, instead of immediately reverting to ently assumed a condensed phase. Eremets and ery — one of the most sought-after results in carbon’s more stable form, graphite. Nellis and Troyan found that laser pulses fired through high-pressure research — have been raging others have imagined a host of applications for the transparent diamond triggered small flows ever since Eremets and Troyan published their metastable metallic hydrogen, ranging from of electrons that they could detect by means 1 results last November . “We could just read super-lightweight structural materials that of copper and gold electrodes deposited on the their paper and say it was wrong,” declares would allow entire cities floating on the sea to culet surfaces — behaviour characteristic of condensed-matter physicist William Nellis, be built, to rocket fuel that packs nearly four semiconducting materials, in which electrons an associate of Harvard University’s physics times as much propellant power per kilogram need a small energy kick to flick them out of department in Cambridge, Massachusetts, as the liquid hydrogen used in the most power- orbit around atoms and into a conductive flow. 2 6 and one of the team’s most vocal challengers . ful rockets today . At 240 GPa, Eremets and Troyan recorded But others, such as Raymond Jeanloz, a First, however, comes the reality check. small currents even without the laser shots, planetary scientist and high-pressure-materi- Diamond anvil cells can use only vanishingly an indication that room-temperature thermal als researcher at the University of California, small sample sizes. (The volume of Eremets and vibrations alone could nudge the electrons into Berkeley, are keeping an open mind. Whether Troyan’s hydrogen samples was about 160 cubic a conductive mood. Eremets and Troyan are eventually proved right micrometres — somewhat smaller than an And at about 270 GPa, the researchers saw or wrong about metallic hydrogen, Jeanloz average human cell.) High-pressure experi- their samples’ electrical resistance suddenly says, “what I feel is beautiful about their work is ments are fraught with the potential for error. drop by several orders of magnitude, just BEN SMITH that they did a bazillion different experiments And even the most experienced researchers run as their spectroscopy was showing that the at these extreme conditions. They lit a fire the risk of fooling themselves. The question is hydrogen’s molecular vibrations were slowing 1 4 JUNE 2012 | V O L 486 | N A TURE | 1 7 5 © 2012 Macmillan Publishers Limited. All rights reserved

Mikhail Eremets (left) and Ivan Troyan stand by the apparatus they used to create what they believe to be metallic hydrogen. down and morphing in ways suggestive of by equally strong reflectivity at infrared wave- that the hydrogen had become metallic. But a phase transition — and the samples were lengths. Eremets and Troyan were not able to Eremets and Troyan also plan to attempt more becoming shiny like a metal. get good infrared data on their samples. But thorough and extensive electrical measure- CARSTEN COSTARD “It is hard to sit on data like these,” says Hemley says that in his own experiments with ments, which could prove conclusive. Eremets. He and Troyan are convinced that hydrogen at similar pressures, “we see it trans- Looking back, Eremets admits that he and their findings are at least consistent with hav- mitting” in the infrared. Moreover, in a paper Troyan probably should have been more cir- 7 ing made metallic hydrogen. published in April , Hemley and his colleagues cumspect in their paper — conveying the But others are not so sure. Sceptics note that report signs that hydrogen squeezed up to message that they might have made metallic pitfalls are everywhere in experiments such as 360 GPa holds on to its diatomic character and hydrogen, rather than claiming more strongly these. If an experimenter peers through the fails to morph into a monatomic metal. Adding that they had done so, as they did in their abstract and their concluding paragraphs. “OUR MEASUREMENTS ARE NOT PERFECT, BUT METALLIC Meanwhile, the race for metallic hydrogen continues, as other high-pressure research HYDROGEN REMAINS A VIABLE INTERPRETATION.” groups pursue their own experiments. Jeanloz points out that many members of this com- diamonds and sees the sample begin to darken, to the complexity of the situation, some theo- munity, himself included, have mingled over 8 for example, that may mean that it is becom- rists suggested that, if squeezed enough, even the years as collaborators, postdocs, supervi- ing a solid — or that the hydrogen is reacting intact hydrogen molecules might develop a new sors and mentors, only to go on to become each with the foil or other impurities to form metal and crowded bonding pattern that could have other’s staunchest critics and rivals, unlikely hydrides. If odd electrical signals start coming metallic properties. to let the slightest chink in an argument in from the culet electrodes, they may indicate Eremets and Troyan are standing their go unchallenged. What emerges from this the formation of a new phase of hydrogen — or ground. “Our measurements are not perfect,” dynamic, say Jeanloz and others, is a creative that the diamond jaws are deforming, causing Eremets concedes, but he insists that “metal- tension that could eventually force those who the electrodes to short out or emit spurious sig- lic hydrogen remains a viable interpretation”. claim to have produced metallic hydrogen to 9 nals. Eremets says that he and Troyan are well He points to a paper published in March by do enough experiments, with enough controls, aware of such pitfalls, and did their best to avoid Eugene Gregoryanz, a physicist at the Uni- to compile enough lines of evidence to con- them. Nonetheless, says Ruoff, “I don’t know versity of Edinburgh, UK, and his colleagues. vince even the pickiest of critics. Until then, anybody who thinks their claim is valid”. “They observe a new phase, the same Raman the trophy seems to be up for grabs. ■ One fact that troubles Ruoff and other crit- spectra and a darkening of the sample” at ics is that the resistance rises as the sample’s around 220 GPa, says Eremets. Clearly, he Ivan Amato is a freelance writer based in temperature drops. This is contrary to nor- argues, something is happening at that point Silver Spring, Maryland. mal metallic behaviour, in which the resist- — although Gregoryanz and his colleagues ance goes down as the temperature does. But attributed the changes to formation, not of 1. Eremets, M. I. & Troyan, I. A. Nature Mater. 10, 927–931 (2011). when reviewers of the paper raised that issue, metallic hydrogen, but of a previously unseen, 2. Nellis, W. J., Ruoff, A. L. & Silvera, I. F. Preprint at says Eremets, he successfully argued that the graphene-like phase of molecular hydrogen. http://arxiv.org/abs/1201.0407 (2012). upward trend is consistent with that seen in a In an effort to clarify the situation, Eremets 3. Wigner, E. & Huntington, H. B. J. Chem. Phys. 3, 764–770 (1935). disordered metal, in which the atomic struc- and Troyan travelled to Villigen in Switzerland 4. Ashcroft, N. W. Phys. Rev. Lett. 21, 1748–1749 ture is more like that of a glass than a crystal. in late April, to gather infrared spectra using the (1968). Russell Hemley, a high-pressure-materi- synchrotron light source at the Paul Scherrer 5. Babaev, E., Sudbø, A. & Ashcroft, N. W. Nature 431, als researcher at the Carnegie Institution of Institute there. The data could reveal vibrations 666-668 (2004). 6. Silvera, I. F. & Cole, J. W. J. Phys. Conf. Ser. 215, Washington in Washington DC, is sceptical of in the lattice structures of high-pressure hydro- 012194 (2010). Eremets and Troyan’s claims for another reason: gen samples that would help theoreticians to 7. Zha, C.-S., Liu, Z. & Hemley, R. J. Phys. Rev. Lett. 108, if the hydrogen really becomes metallic, then identify specific structures of any solid phases 146402 (2012). 8. Labet, V., Gonzalez-Morelos, P., Hoffmann, R. & the shininess that the Mainz team reports at that might be present, Eremets says. Such struc- Ashcroft, N. W. J. Chem. Phys. 136, 074501 (2012). optical wavelengths ought to be accompanied tural information would not, by itself, prove 9. Howie, R. T. et al. Phys. Rev. Lett. 108, 125501 (2012). 176 | N A TURE | V O L 486 | 14 JUNE 2012 © 2012 Macmillan Publishers Limited. All rights reserved

THE MIND READER 178 | N A TURE | V O L 486 | 14 JUNE 2012 © 2012 Macmillan Publishers Limited. All rights reserved

FEATURE NEWS Adrian Owen has found a way to use brain scans to communicate with people previously written off as unreachable. Now, he is fighting to take his methods to the clinic. BY DAVID CYRANOSKI drian Owen still gets animated when he talks about patient 23. The had put her in a coma — a condition that generally persists for two to four patient was only 24 years old when his life was devastated by a car weeks, after which patients die, recover fully or, in rare cases, slip into Aaccident. Alive but unresponsive, he had been languishing in what a vegetative or a minimally conscious state — a more recently defined neurologists refer to as a vegetative state for five years, when Owen, a neuro- category characterized by intermittent hints of conscious activity. scientist then at the University of Cambridge, UK, and his colleagues at Months after her infection cleared, Bainbridge was diagnosed as the University of Liège in Belgium, put him into a functional magnetic being in a vegetative state. Owen had been using positron-emission resonance imaging (fMRI) machine and started asking him questions. tomography in healthy people to show that a part of the brain called the Incredibly, he provided answers. A change in blood flow to certain fusiform face area (FFA) is activated when people see a familiar face. parts of the man’s injured brain convinced Owen that patient 23 was When the team showed Bainbridge familiar faces and scanned her brain, conscious and able to communicate. It was the first time that anyone had “it lit up like a Christmas tree, especially the FFA”, says Owen. “That was exchanged information with someone in a vegetative state. the beginning of everything.” Bainbridge was found to have significant 3 Patients in these states have emerged from a coma and seem awake. brain function and responded well to rehabilitation . In 2010, still in a Some parts of their brains function, and they may be able to grind their wheelchair but otherwise active, she wrote to thank Owen for the brain teeth, grimace or make random eye movements. They also have sleep– scan. “It scares me to think of what might have happened to me if I had wake cycles. But they show no awareness of their surroundings, and not had mine,” she wrote. “It was like magic, it found me.” doctors have assumed that the parts of the brain needed for cognition, Owen moved from visual to auditory tests — “up the cognition ladder, perception, memory and intention are fundamentally damaged. They from basic sound perception, to speech perception and then to speech are usually written off as lost. comprehension”. For example, he presented people in a vegetative state 1 Owen’s discovery , reported in 2010, caused a media furore. Medical with phrases containing words that sound the same but have two mean- ethicist Joseph Fins and neurologist Nicholas Schiff, both at Weill Cor- ings, such as “The dates and pears are in the bowl”. The ambiguity forces nell Medical College in New York, called it a “potential game changer the brain to work harder and shows up in characteristic fMRI patterns 2 for clinical practice” . The University of Western Ontario in London, in healthy people — if, that is, they are comprehending the words. One Canada, soon lured Owen away from Cambridge with Can$20 million of Owen’s patients, a 30-year-old man who had been incapacitated by 4 (US$19.5 million) in funding to make the techniques more reliable, a stroke, showed the same pattern . But not everyone was convinced cheaper, more accurate and more portable — all of which Owen consid- that these signs pointed to comprehension. “Every time I would go to a ers essential if he is to help some of the hundreds of thousands of people neurologist or anaesthesiologist and say, ‘he’s perceiving speech’, they’d worldwide in vegetative states. “It’s hard to open up a channel of commu- ask ‘but is he conscious?’.” Owen realized that he needed a different nication with a patient and then not be able to follow up immediately with experiment to persuade the sceptics. a tool for them and their families to be able to do this routinely,” he says. Many researchers disagree with Owen’s contention that these ANYONE FOR TENNIS? individuals are conscious. But Owen takes a practical approach to apply- It was June 2006. Wimbledon was on, and in a headline-stealing study, ing the technology, hoping that it will identify patients who might respond Owen took fMRI scans of a 23-year-old woman in a vegetative state to rehabilitation, direct the dosing of analgesics and even explore some while he asked her to imagine playing tennis and walking through the patients’ feelings and desires. “Eventually we will be able to provide some- rooms of her house. When healthy, conscious adults imagine playing thing that will be beneficial to patients and their families,” he says. tennis, they consistently show activation in a region of the motor cortex Still, he shies away from asking patients the toughest question of all — called the supplementary motor area, and when they think about navi- whether they wish life support to be ended — saying that it is too early gating through a house, they generate activity in the parahippocampal to think about such applications. “The consequences of asking are very gyrus, right in the centre of the brain. The woman, who had been unre- complicated, and we need to be absolutely sure that we know what to do sponsive for five months after a traffic accident, had strikingly similar with the answers before we go down this road,” he warns. brain activation patterns to healthy volunteers who were imagining these activities, proving, in Owen’s mind, that she was conscious. The 5 LOST AND FOUND result, published in a one-page article in Science , evoked wonder and With short, reddish hair and beard, Owen is a polished speaker who is disbelief. “I got two types of e-mail. People either said ‘this is great’ or not afraid of publicity. His home page is a billboard of links to his televi- ‘how could you possibly say this woman is conscious?’,” Owen says. sion and radio appearances. He lectures to scientific and lay audiences Other researchers contended that the response was not a sign of with confidence and a touch of defensiveness. consciousness, but something involuntary, like a knee-jerk reflex. Daniel Owen traces the roots of his experiments to the late 1990s, when he Greenberg, a psychologist at the University of California, Los Angeles, was asked to write a review of clinical applications for technologies such suggested in a letter to Science that “the brain activity was unconsciously as fMRI. He says that he had a “weird crisis of confidence”. Neuroimag- triggered by the last word of the instructions, which always referred to 6 ing had confirmed a lot of what was known from brain mapping studies, the item to be imagined” . But Owen went on to bolster his case. Working with neurologist he says, but it was not doing anything new. “We would just tweak a psych and neuroscientist Steven Laureys from the University of Liège, Owen test and see what happens,” says Owen. As for real clinical applications: JOHN HRYNIUK “I realized there weren’t any. We all realized that.” showed that of 54 patients in a vegetative or minimally conscious state, 1 Owen wanted to find one. He and his colleagues got their chance in five responded in the same way as the first woman . Four of them were in a vegetative state. After refining their methods, the researchers asked 1997, with a 26-year-old patient named Kate Bainbridge. A viral infection 1 4 JUNE 2012 | V O L 486 | N A TURE | 1 7 9 © 2012 Macmillan Publishers Limited. All rights reserved

NEWS FEATURE patient 23 to use that capability to answer yes-or-no questions: imagine the research team can ask up to 200 questions in 30 minutes. “From a playing tennis for yes, navigating the house for no. They then asked about single trial you’re not going to say, ‘that person is saying yes’, but if they things that the technicians scoring the brain scans couldn’t possibly know. get 175 of 190 right when tested, it’s pretty clear.” Is your father’s name Thomas? No. Is your father’s name Alexander? Now, using an EEG, Owen is planning to study 25 people in a vegetative Yes. Do you have any brothers? Yes. Do you have any sisters? No. The state every year. He will have the help of a new ‘EEGeep’, a jeep equipped experiment is no easy feat for the patient. Owen’s protocol demands with experimental equipment that will allow the researchers to travel patients maintain focus for 30 seconds then rest for 30 seconds, with around to test patients who cannot be transported to Western Ontario. lots of repetition. One goal is to identify other brain systems, such as smell or taste, that In front of a computer screen showing the fMRI data, Owen traces a might be intact and usable for communication. Imagining sucking a blue line indicating activity in the supplementary motor area — a ‘yes’ — lemon, for example, can produce a pH-level change in the mouth and a 8 as it rises during the ‘answer’ period. It dives during the rest periods. A recognizable brain signal . Owen has shown that registering jokes pro- 9 red line — indicating activity in the parahippocampal gyrus — represents vokes a characteristic response in healthy people and plans to try it on the ‘no’. The lines are sharp and clear, and Owen, who has a taste for puns, patients in a vegetative state. He hopes that he can use these tests to find calls the implication “a no-brainer”. “You don’t need to be a functional- some level of responsiveness in patients who cannot produce the tennis imaging expert to appreciate what this person is and navigation patterns of activity because of their telling you,” he says. The patient answered five of “IT WAS LIKE MAGIC. level of brain damage. 1 six questions correctly . There was no discernible The studies will also explore whether these Russell Poldrack, a neuroimaging expert at the THE BRAIN SCAN FOUND ME.” depth. Owen thinks that some people in a vegeta- signal for the sixth. patients have the capacity for greater intellectual University of Texas at Austin, calls Owen’s meth- tive state will eventually be able to express hopes ods ingenious. “When I want to give someone examples in which fMRI and desires, perhaps like French magazine editor Jean-Dominique has told us something we really didn’t know before, I use these,” he says. Bauby, who dictated his memoirs by repeatedly winking one eye. “I But Parashkev Nachev, a clinical neuroscientist at Imperial College don’t see a reason why they could not have a similar richness of thought, London, criticizes the work for “assuming that consciousness is a binary although undoubtedly some will not,” Owen says. phenomenon”. Many patients, such as those having certain types of epi- His techniques could also radically change treatment. Owen is already leptic seizures, exhibit limited responsiveness without being conscious. asking patients whether they feel pain. The answers will be useful in dos- Nachev says that more data are needed to indicate where in the con- ing pain killers, and similar tests could even be used in intensive-care tinuum of cognitive abilities people in vegetative states fall. units to guide rehabilitation resources, says Loretta Norton, a graduate Owen agrees that consciousness is not an “on-or-off thing”. He sees student who is undertaking a study for this purpose. But she recognizes it as an “emergent property” of many “modules” of the brain working that this will be controversial. together. Enough of these modules are at work in his exercise, he says, for responsive patients to qualify as being conscious. A person needs long- DECISION TIME term memory to know what tennis is, short-term memory to remember Owen’s methods raise more difficult dilemmas. One is whether they the question or command and intention to give an answer. Ultimately, should influence a family’s or clinician’s decision to end a life. If a patient Owen is not concerned with pinpointing a threshold of consciousness or answers questions and demonstrates some form of consciousness, he with providing a comprehensive definition for it. He takes a “know it if or she moves from the ‘possibly allowed to die’ category to the ‘not gen- you see it” approach. Responding to commands and questions — com- erally allowed to die’ category, says Owens. Nachev says that claiming munication — is an undeniably conscious activity, in his view. “In the consciousness for these patients puts families in an awkward position. end if they say they have no reason to believe the patient is conscious, I Some will be given hope and solace that their relative is still ‘in there say ‘fine, but I have no reason to believe you are either’,” he says. somewhere’. Others will be burdened by the prospect of keeping them alive on the basis of what might be ambiguous signs of communication. TO THE CLINIC Even more ethically fraught is whether the question should be put Currently, there are tens of thousands of people in a vegetative state in to the patients themselves. Fins and Schiff question whether patients the United States alone. Owen reckons that up to 20% of them are capa- would ever be able to show that they can understand the complexities ble of communicating; they just don’t have a way to do so. “What we’re of that question in the way that is normally demanded of, for example, seeing here is a population of totally locked-in patients,” Owen says. patients giving informed consent. Owen now wants to put his technique into the hands of clinicians and Owen hopes one day to ask patients that most difficult of questions, family members. So far, the technology has done little. The first woman but says that new ethical and legal frameworks will be needed. And it will in the tennis study died last year, and patient 23, for logistic and financial be many years, he says, “before one could be sure that the patient retained reasons, was assessed only once. Even if a person in a vegetative state is the necessary cognitive and emotional capacity to make such a complex ‘found’, there is no guarantee that he or she will later be able to return a decision”. So far, he has stayed away from the issue. “It might be a little normal life. Owen nevertheless insists that “clarifying” a patient’s state reassuring if the answer was ‘no’ but you can’t presuppose that.” A ‘yes’ of consciousness helps families to deal with the tragedy. “They want to would be upsetting, confusing and controversial. know what the diagnosis really is so that they can move on and deal with For now, Owen is hoping to use the technology to find other respond- that. Doubt and uncertainty are always bad things.” ers like Kate Bainbridge — who Owen now describes as a “motivational Two years ago, Owen was awarded a 7-year Can$10-million Canada force”. “Otherwise,” he says, “what’s the point?” ■ Excellence Research Chair and another $10 million from the University of Western Ontario. He is pressing forward with the help of three new David Cyranoski is Nature’s Asia-Pacific correspondent. faculty members and a troop of postdocs and graduate students. 1. Monti, M. M. et al. N. Engl. J. Med. 362, 579–589 (2010). An early goal of the programme was to repeat the fMRI findings using 2. Fins, J. J. & Schiff, N. D. Hastings Center Report 40, 21–23 (2010). 7 an electroencephalogram (EEG) . An EEG lacks fMRI’s precision, and 3. Menon, D. K. et al. Lancet 352, 200 (1998). 4. Owen, A. M. et al. Neuropsychol. Rehabil. 15, 290–30 (2005). it cannot look as deeply into the brain, so the regions active in the ten- 5. Owen, A. M. et al. Science 313, 1402 (2006). nis study were “off the menu”, says Owen. But other tasks — imagining 6. Greenberg, D. L. Science 315, 1221 (2007). wiggling a finger or toe — produce signals that, through repetition, 7. Cruse, D. et al. Lancet 378, 2088–2094 (2011). 8. Wilhelm, B., Jordan, M. & Birbaumer, N. Neurology 67, 534–535 (2006). become clear. An EEG is also cheap, relatively portable and fast (with 9. Bekinschtein, T. A., Davis, M. H., Rodd, J. M. & Owen, A. M. J. Neurosci. 31, milliseconds of lag compared with 8 seconds for fMRI), meaning that 9665–9671 (2011). 180 | N A TURE | V O L 486 | 14 JUNE 2012 © 2012 Macmillan Publishers Limited. All rights reserved

COMMENT CLIMATE CHANGE Uncertainty PUBLIC HEALTH Why India INNOVATION Building ENVIRONMENT Strengthen in models needs careful cannot afford to flush and better toilets is an urgent t p policies around Brazil’s explanation p.183 forget p.185 technology challenge p.186 86 f forestry code p.191 CHANDRA X-RAY OBSERVATORY CENTER The Milky Way as a combined image of near-infrared (yellow), infrared (red) and X-ray (blue and violet) data collected by NASA’s ‘Great Observatories’. A midlife crisis for X-ray astronomy As the field celebrates its 50th birthday, Martin Elvis asks how to keep this unique window into the Universe open. n 18 June 1962, an 8-metre rocket has opened up such exotica as black holes surprises: a strong source of X-rays in the carried three small X-ray detectors and dark matter to detailed investigation. It constellation Scorpius and a bright back- Oto the edge of space. They spent has provided a unique window into ‘extreme’ ground of X-rays from all over the sky. The just under 6 minutes above the altitude of places of the Universe, where gas can be researchers were lucky. Had they looked when 80 kilo metres, high enough for kiloelec- 1,000–10,000 times hotter than the surface Sco X-1, as this first source was dubbed, was tronvolt-energy X-rays from space to reach of the Sun. The question now is whether that below the horizon, they would have det ected them through the thinned atmosphere. The progress will continue. only the bright background noise. Interest result of this brief flight by physicist Riccardo In the 1960s, X-rays were known to be in cosmic X-rays might have withered. Giacconi and his colleagues revolutionized produced by the Sun — that had been discov- Many teams rushed to follow up in astronomers’ view of what the Universe ered in 1948. But the Sun’s weak X-ray output the subsequent years. X-ray astronomy contains. made it seem futile to try to detect any other papers often dominated the pages of For 50 years, X-ray astronomy has star this way. Giacconi justified his flight by Astrophysical Journal Letters. One impor tant burgeoned. The field has grown a billion telling the US Air Force that he was looking discovery was that the brightness of these times more sensitive — a feat that took opti- for X-rays from the Moon, but he hoped to cosmic X-ray sources often changed within cal astronomy 400 years to achieve — and find more. Fortunately, the Universe delivered seconds. Because nothing can change its 1 4 JUNE 2012 | V O L 486 | N A TURE | 1 8 1 © 2012 Macmillan Publishers Limited. All rights reserved

COMMENT output faster than light can travel across it, the summed emissions of millions of active can have more modest price tags of around this meant that the objects must be tiny — galaxies (most of the rest comes from fainter, $200 million. In the next few years, several just light seconds across. Creating so much star-forming galaxies). Chandra and XMM such missions will be launched — one in energy from such a small volume required have also delimited the extent of dark matter’s pursuit of higher-energy rays (NuSTAR, some not-yet recognized energy source. This interaction with itself, determined properties part of NASA’s Explorer class), one as an turned out to be gravity: the accretion of gas of dark energy and showed that as much as updated ROSAT (Germany’s eROSITA) and falling down the deep gravitational well of a one-fourth of the energy of a supernova goes one with relatively high spectral resolution compact star converts potential energy into into accelerating protons, solving the mystery (Japan’s ASTRO-H). But none of these even millions of degrees of heat. of the origin of high-energy cosmic rays. approaches Chandra’s spatial resolution. The next big step was the development of Fifty years on, the founding mysteries of Since 2010, some ideas for achieving orbiting X-ray instruments, which allowed X-ray astronomy have been solved. But our more powerful missions on a tight budget for exposure times of days rather than min- understanding of more complex questions have emerged, including combining the fine utes. NASA’s 1970 Uhuru mission, led by is still primitive. In my own sub-field alone, imaging of Chandra with a light-gathering Giacconi, was the first in a small fleet of these. we don’t yet know why active galaxies emit surface 30 times more powerful. This would Uhuru and its successors detected hundreds of X-rays, where the massive black holes at their require the development of mirrors that can X-ray sources 1,000–10,000 times fainter than centres come from or how a massive black be actively corrected to ensure a sharp image, Sco X-1. hole accelerates which seems feasible. But such a project But it was the cosmic X-ray background “Prospects for matter in bulk to would cost at least $2 billion. Prospects for that set the real programme for X-ray astro- a set of ‘Greater speeds more than a set of ‘Greater Observatories’ that span the nomy for the next 40 years. Was it caused by Observatories’ 90% that of light in electro magnetic spectrum look bleak. hot gas pervading intergalactic space, or by that span the a tight beam that millions of faint and distant sources blending electromagnetic can extend over A PROFITABLE SOLUTION together? Early detectors could not answer spectrum look millions of light The only viable solution is to lower the cost this question, because they had to collect bleak.” years. of getting equipment into orbit. Launch X-rays from a large chunk of the sky to detect At the same costs have held steady at some $10,000 per a signal; discrete sources that might make up time, X-ray astronomy has the power to test kilogram of payload for more than 50 years. the background produced no more than one two bases of twentieth-century physics — Spacecraft must have ingenious designs to X-ray per square centimetre of detector each general relativity and quantum chromody- keep their masses low, which makes the cost day. To see with greater precision, research- namics (which describes interactions of the of building and launching high: $100,000 or ers needed more sensitive telescopes, which ‘strong force’ between quarks and gluons) more per kilogram of craft. Overall mission they built from nested cylindrical mirrors. — in the extreme conditions around black costs could plummet if launch costs were to The first such imaging X-ray telescope holes and neutron stars. decline. — NASA’s 1978 Einstein Observatory, led But for astronomers to answer these ques- The best — perhaps only — way to lower by Giacconi — detected radiation 100-fold tions, X-ray astronomy must become even launch costs is to allow private enterprises fainter than any of its predecessors. It found more sensitive, by collecting more photons to profit from space ventures. Profit is the that 20% of the cosmic X-ray background with larger mirrors while maintaining the counterweight to caution, and competition came from active galactic nuclei, later under- fine resolution seen with Chandra. The US will drive down costs. Several companies stood to host supermassive black holes in 2010 decadal survey for astronomy ranked have already developed operational launch- their centres. a larger-area X-ray mission fourth among ers for government payloads, including major space missions, but that is low enough, Orbital Sciences Corporation of Dulles, Vir- LEAPS AND BOUNDS given the restricted US science budget, to put ginia, whose Pegasus rocket was, as Nature By 1987 — the twenty-fifth anniversary of a new X-ray observatory on the back burner went to press, scheduled to launch NuSTAR the discovery of Sco X-1 — X-ray astronomy for at least a decade. Each space observatory, on 13 June, and SpaceX of Hawthorne, Cali- had become 10 million times more sensitive. be it optical, infrared or X-ray, now costs fornia, which last month launched the first The next generation of X-ray telescopes more than US$2 billion. The worldwide private mission to resupply the International came in the early 1990s. Notable among space astronomy budget of about $5 billion Space Station. them was Germany’s ROSAT, which sur- a year is not enough to sustain a comprehen- Ultimately, a healthy market that spurs veyed the whole sky, cataloguing 100,000 sive programme. lower costs will require customers other X-ray sources and, by going tenfold fainter NASA’s current ‘Great Observatories’ — than the government, such as those seek- still than Einstein, resolving some 60% of Hubble, Chandra and Spitzer — span the ing minable resources more plentiful in the cosmic X-ray background that had an infrared to X-ray bands. They will prob- space than on Earth. One new company, energy lower than 2 kiloelectronvolts (keV). ably have just one successor: the James Planetary Resources of Bellevue, Wash- The current era was ushered in by the Webb Space Telescope (JWST), which ington, announced in April its aim to mine launch of two large X-ray observatories in was designed to study cosmology and gal- asteroids. 1999: NASA’s Chandra and the European axy evolution in the distant Universe, and Such profit-seeking could decrease launch Space Agency’s XMM-Newton. XMM has a so works primarily in the infrared. Over costs by more than an order of magnitude, large collecting area, but Chandra — with the rest of the spectrum, astronomers will such that fuel costs dominate the overall an angular resolution ten times better than be blind. A US successor to Chandra is price. Then, and only then, will new gen- anything previous — was revolutionary. unlikely until 2030. By then, the JWST erations of greater observatories, in X-rays Giacconi received the Nobel prize in 2002, will probably be dead, preventing cross- and across the electromagnetic spectrum, perhaps stimulated by the outpouring of fertilization of ideas become affordable for scientists. ■ results from Chandra, which he had been among different NATURE.COM instrumental in getting started. wavelengths. For more on the Martin Elvis is at the Harvard-Smithsonian Chandra has resolved the cosmic X-ray Ingenious, but more benefits of private Center for Astrophysics, Cambridge, background at all energies up to 7 keV. specialized, missions space enterprises: Massachusetts 02138, USA. More than 90% of the background is due to in X-ray astronomy go.nature.com/4288nl e-mail: [email protected] 182 | N A TURE | V O L 486 | 14 JUNE 2012 © 2012 Macmillan Publishers Limited. All rights reserved

COMMENT Another layer of uncertainty comes from D. PIGNATELLI/BLOOMBERG VIA GETTY how the global climate models are weighted. For example, in the most recent IPCC assess- ment, released in 2007, the economic sce- narios were input into more than 20 general circulation models. Every model has its own design and parameterizations of key pro- cesses, such as how to include the effects of clouds; and every model and its output was assumed to be equally valid, even though some perform better than others in certain ways when tested against historic records. The differences between the models will be exacerbated in the 2013 IPCC assessment, because many, but not all, of the models have improved spatial resolution. The outputs from the circulation models are then often used to drive detailed regional climate models to predict local environ- mental variations. Such regional models have huge uncertainties, thanks largely to the fact that precipitation is highly variable over small scales of time and space. This leads to a large range of potential futures, some of which contradict others. For exam- ple, detailed hydrological modelling of the Water levels in the Mekong Basin could rise or fall with climate change — models cannot say which. Mekong River Basin using climate model input from the UK Met Office’s HadCM3 Climate models model projects changes in annual river dis- charge that range from a decrease of 5.4% to an increase of 4.5% (ref. 2). Changes in predicted monthly discharge are even more at their limit? dramatic, ranging from a fall of 16% to a rise of 55%. Advising policymakers becomes extremely difficult when models cannot pre- dict even whether a river catchment system Estimates of climate-change impacts will get less, will have more or less water. Projected regional changes are then used rather than more, certain. But this should not excuse as a basis for ‘impact models’ that estimate inaction, say Mark Maslin and Patrick Austin. the effect on the quality of human life. But these effects often depend more on the rela- tive resilience of a given society than on the or the fifth major assessment of climate very nature, models cannot capture all the magnitude of environmental change. Even science by the Intergovernmental factors involved in a natural system, and the most advanced socioeconomic models, FPanel on Climate Change (IPCC), due those that they do capture are often incom- which look at the monetary costs arising both to be released next year, climate scientists pletely understood. Science historian Naomi in market and non-market sectors, often fail face a serious public-image problem. The Oreskes of the University of California, San to account adequately for major aspects of 3 climate models they are now working with, Diego, and her colleagues have argued con- human suffering that are hard to quantify . which make use of significant improvements vincingly that this makes climate models 1 in our understanding of complex climate impossible to truly verify or validate . STRUGGLE WITH EXTREMES processes, are likely to produce wider rather The more-concrete, less-philosophical A key debate has emerged between scientists than smaller ranges of uncertainty in their problems can be illustrated by following about how well models can predict extreme predictions. To the public and to policy- the path of cascading uncertainties that are climates. On the optimistic side, Tim Lenton makers, this will look as though the scientific building up in the models used today. of the University of Exeter, UK, has argued understanding of climate change is becom- One of the first inputs into any climate that, with more research, models will help ing less, rather than more, clear. model is the expected accumulation of to provide an early warning system of cli- Scientists need to decide how to explain greenhouse gases and aerosols in the matic tipping points such as the melting of this effect. Above all, the public and policy- atmosphere by the end of the century. These the Greenland ice sheet, the dieback of the makers need to be made to understand that projections are based on economic mod- Amazon rainforest and the shift of the West 4 climate models may have reached their limit. els that predict global fossil-fuel use over African monsoon . By contrast, Paul Valdes They must stop waiting for further certainty 100 years given broad assumptions about of Bristol University, UK, argues that climate or persuasion, and simply act. how green the global economy will become. models are too stable, built to ‘not fail’ rather 5 Why do models have a limited capabil- The economic collapse of 2008 showed dra- than to simulate abrupt climate change . ity to predict the future? First of all, they matically, and to our cost, how difficult it is When the current IPCC models were tested are not reality. This is perhaps an obvious to predict changes in the economy. And eco- against four major past climate changes, he point, but it is regularly ignored. By their nomic unpredictability is just the beginning. notes, two were unable to even get the basic 1 4 JUNE 2012 | V O L 486 | N A TURE | 1 8 3 © 2012 Macmillan Publishers Limited. All rights reserved

COMMENT climate before the shift correct and the other two had to be fed parameters up to ten times PREDICTION STABILITY greater than would be realistic to produce Estimates of climate sensitivity — the rise in global temperature caused by a doubling of atmospheric the abrupt shift. carbon dioxide levels — have remained fairly steady for decades. The climate models, or ‘climate simula- 7 tors’ as some groups are now referring to From theory From models (number of models) them, being used in the IPCC’s fifth assess- 6 From palaeoclimate records ment make fewer assumptions than those Published best estimate from the last assessment, and can quantify Published potential range 5 the uncertainty of the complex factors they include more accurately. Many of them contain interactive carbon cycles, better 4 1 representations of aerosols and atmospheric Temperature change (ºC) 1 17 chemistry and a small improvement in spa- 3 1 15 18 18 tial resolution. 4 1 Yet embracing more-complex processes 1 11 1 means adding in ‘known unknowns’, such 2 as the rate at which ice falls through clouds, or the rate at which different types of land 1 cover and the oceans absorb carbon diox- ide. Preliminary analyses show that the new 0 models produce a larger spread for the pre- 1890 1900 1940 1950 1960 1970 1980 1990 2000 2010 dicted average rise in global temperature. References for data supplied in Supplementary information. Details can be found at go.nature.com/8dzwxv. Additional uncertainty may come to light as these models continue to be put through their paces. Dan Rowlands of the University date by which things will happen, rather than are”, or, “we need to wait for public opinion of Oxford, UK, and his colleagues have run onto whether they will happen at all. A recent to be behind action”. The former will never one complex model through thousands of study, for example, showed that the politically occur, because modelling can never provide simulations, rather than the handful of runs expedient 2 °C limit will be reached between that level of certainty. The latter is a sleight that can usually be managed with available 2040 and 2100, depending on our emission of hand. Politicians often take action without 8 computing time. Although their average pathway and the model used . This ‘when’ public support, from wars to bank bailouts, results matched well with IPCC projections, not ‘if’ approach is powerful. taxation to health-care reforms. more extreme results, including warming of In the face of scientific uncertainty, vari- Greater knowledge and improved models 6 up to 4 °C by 2050, seemed just as likely . As ous philosophies for decision-making have will always be desirable, but they are not a computing power becomes more accessible, arisen. But perhaps the best approach is to panacea for political and public reticence that ‘hidden’ uncertainty will become even ensure that policies include ‘win–win’ strat- to action on climate change. Despite the more obvious. egies. Supporting a huge increase in renew- uncertainty, the weight of scientific evi- able energy would reduce emissions and dence is enough to tell us what we need to STABLE AND CONFIDENT help to provide energy security by reduc- know. We need governments to go ahead None of this means that climate models are ing reliance on imported oil, coal and gas. and act, as both the United Kingdom and useless. The present models are clearly able Reduced defor- Mexico have done in making national laws to reproduce natural climate variability over “The biggest estation and refor- that contain carbon reduction targets of the past 150 years, and have provided an obstacle is the estation should 80% and 50%, respectively, by 2050. We do essential test of the theoretical link between unwillingness draw-down CO 2 not need to demand impossible levels of cer- CO 2 and global temperatures. Their vision of politicians to from the atmos- tainty from models to work towards a better, of the future has in some ways been incred- act in the long- phere and help to safer future. ■ ibly stable. For example, the predicted rise in term interests of retain biodiversity, global temperature for a doubling of CO 2 in society.” stabilize soils and Mark Maslin and Patrick Austin are with the atmosphere hasn’t changed much in more provide livelihoods the Environment Institute and Department than 20 years (see ‘Prediction stability’). for local people through carbon credits. of Geography, University College London, This message of stability and confidence Measures that lessen car use will increase Pearson Building, Gower Street, London, is often lost on the public: when Andreas walking and cycling, which in turn reduces WC1E 6BT. Schmittner of Oregon State University in obesity and heart attacks. No one can object e-mail: [email protected] Corvallis published a value for the climate’s to creating a better world, even if we turn out 1. Oreskes, N., Shrader-Frechette, K. & Belitz, K. sensitivity to a doubling of CO 2 that was to be extremely lucky and the scale of climate Science 263, 641–646 (1994). 7 on the low side of previous estimates , the change is at the low end of all projections. 2. Kingston, D. G., Thompson, J. R. & Kite, G. Hydrol. media declared that “climate sensitivity was The biggest obstacle is the unwillingness Earth Syst. Sci. 15, 1459–1471 (2011). 3. Stern, N. The Economics of Climate Change: The overestimated”. This was despite some sig- of politicians to act in the long-term inter- Stern Review 692 (Cambridge Univ. Press, 2007). nificant criticisms of the study and the fact ests of society. Politicians use public opin- 4. Lenton, T. M. Nature Clim. Change 1, 201–209 that the findings still fell within the range of ion and scientific uncertainty as excuses for (2011). those in all the IPCC reports. This is a sad inaction. They used to say “we need to wait 5. Valdes, P. Nature Geosci. 4, 414–416 (2011). 6. Rowlands, D. J. et al. Nature Geosci. 5, 256–260 indicator of the headlines we might expect until scientists prove that mankind is caus- (2012). in the wake of the next IPCC report. ing climate change”. That hurdle has, argu- 7. Schmittner, A. et al. Science 334, 1385–1388 One approach to tackling the public- ably, passed, so now they have moved on to (2011). 8. Joshi, M., Hawkins, E., Sutton, R., Lowe, J. & perception problem is to subtly rephrase the “we need to wait until scientists can tell us Frame, D. Nature Clim. Change 1, 407–412 conclusions, placing the uncertainty on the exactly what will happen and what the costs (2011). 184 | N A TURE | V O L 486 | 14 JUNE 2012 © 2012 Macmillan Publishers Limited. All rights reserved

COMMENT Sanitation for all Water pollution from sewage is causing great damage to India. The nation needs to complete its waste systems and reinvent toilet technologies, says Sunita Narain. anitation is a much-sanitized word. City planners worry more about supplying eventually disappear: one day, everywhere It hides the horror of disease and the water to their citizens than about the waste will have flush toilets, sewers and treatment Scrippling indignity that people have water generated. Yet the effluent inevitably plants. But in reality, Indian cities are way to endure when they do not have access to goes into streams, lakes and rivers, or seeps behind: they are growing so fast that their a toilet. It also hides the technology divide into the ground to contaminate drinking infrastructure cannot catch up. This cycle for human excreta, which favours the rich water. Nitrate levels in groundwater across must be broken. in its collection, conveyance and disposal. India exceed 45 milligrams per litre — a sure 3 The only solution is a complete sanitation sign of sewage contamination . THINK OUTSIDE THE BOX system — toilets that are connected to a Governments must demand change in how waste-removal and treatment system. But water and waste are managed. They must conventional technology does not work INDIA’S SANITATION DIVIDE cut the length of the pipeline, by investing in everywhere, or for all. City dwellers are more likely than people in rural local water supplies such as lakes and ponds areas to have fushing toilets, but only one-third Rapidly-modernizing India is drowning of those toilets are connected to underground and using water more efficiently. They must in its own excreta. According to the World sewers; the rest go to septic tanks. invest more in sewage systems, even before Health Organization, more than 600 million URBAN RURAL they invest in water supply. Water accounts Indians practise open defecation — making Flush or 19.4% and tariffs must reflect the full cost of supply up 60% of the 1.1 billion people who do so pour toilet and of waste collection and treatment. 72.6% 1 worldwide . But even as toilets get built, the The challenge for science is to look 11.3% challenge of managing excreta grows. beyond the modern engineering mindset. More than 87% of people in India’s cities We know that current technologies, which (compared with 33% in rural areas) now use large amounts of clean water to transport 2 have access to a toilet . But leaking and Pit or small amounts of excreta through expensive service incomplete sewage systems contaminate latrine pipes to costly treatment plants, are unwork- are unwork-are unwork- rivers and lakes, causing diseases such as 8.8% able and unaffordable in much of the world. cholera. Around 97 million Indians do not No latrine Yet toilets and sewage disposal are among have access to clean drinking water, putting within the least researched technologies. premises 2 the nation second only to China . Similar 18.6% 69.3% New technologies and new thinking are problems afflict other developing countries. urgently needed for use across diverse eco- The challenge for India is to come up with systems. Open drains might become planted ways of dealing with excreta that are afforda- Leaked sewage leads to a deadly and waterways, with the vegetation cleansing the ble and sustainable. The first step is to match costly spiral. As surface or groundwater water. Or microbes might be used to decom- investment in waste-water systems with that gets contaminated, the city must source pose and de-pathogenize effluent. Sewage for water supply. Innovative and affordable clean water from farther afield. The cost of must be treated as a resource — turned into toilets must be designed and accessible to pumping water rises — it now accounts for water for drinking, irrigation or industry. everyone. Only if all waste is treated can 30–50% of the price of supplying water. The Cities must leapfrog within the sanitation pollution be controlled. cost of building and maintaining pipelines trajectory — go straight from no toilets to increases. And if the network is not main- hygienic toilets for all that do not cost the THE SEWAGE SPIRAL tained, water is lost — 30–50% of the water Earth. Only then can the challenge be met. ■ Emerging countries such as India are follow- leaks. The nation therefore has less clean ing a sanitation trajectory, gradually upgrad- water to supply and needs to pay more to Sunita Narain is director general of the ing facilities from no toilets to sophisticated get it to the people. It cannot provide these Centre for Science and Environment in New systems (see ‘India’s sanitation divide’). By services for everyone, and it chooses the rich. Delhi and author of Excreta Matters: How 2011, just 20% of urban Indians had no toilet As the water system degrades, the rich move Urban India is Soaking up Water, Polluting 2 or used a public latrine . But most of those to bottled water. The poor get sick. Rivers and Drowning in its Own Waste with toilets had them connected to septic The over-burdened water utility then (State of India’s Environment, Centre for tanks or flowing into open drains. Only the has no money to invest in sewage facilities. Science and Environment, 2012). top end — one-third of urban households Most Indian cities do not have underground e-mail: [email protected] and 2% of rural — had toilets that were con- — had toilets that were con-had toilets that were con- systems, and those that do, have old pipes 1. WHO/UNICEF Progress on Drinking Water and nected to underground sewage networks, that are in disrepair. There are few treat- Sanitation (WHO/UNICEF, 2012). and not all of those reached treatment plants. ment plants. Officially, the country has the 2. Office of the Registrar General and Census 4 Progress along the trajectory is slow capacity to treat 30% of its waste water .But Commissioner Census of India 2011 because the technology for collecting and in practice only 20% is processed: not all (Government of India, 2012). 3. Kamyotra, J. S. Water quality and waste water disposing of excreta was invented in the plants function and the pipes leak. The final management vision 2012–17 (Central Pollution water- and money-rich industrialized world. blow comes when the treated waste water of Control Board, 2011). It is capital-intensive, favouring the rich over the minority gets mixed with the untreated 4. CPCB Status of Water Supply, Wastewater Generation and Treatment in Class-I cities and the poor. And it is resource intensive, using sewage of the majority. Class-II towns of India (Central Pollution Control huge quantities of water. Most believe that the sanitation divide will Board, 2009). 1 4 JUNE 2012 | V O L 486 | N A TURE | 1 8 5 © 2012 Macmillan Publishers Limited. All rights reserved

COMMENT BOOKS & ARTS P. MORGAN following pages through the work of Peter Morgan in Zimbabwe, Ralf Otterpohl and his team in Germany, Shunmuga Parama- sivan in India, and Ed Harrington and his colleagues in California. In compost-based ecosanitation, excreta is reframed as a resource: fertilizer. Much of the research on this has focused on upping nutri- ent levels and finding faster, more effective ways of removing heavy metals and patho- gens such as viruses. Meanwhile, research- based, ecological processing of waste water is vastly improving water-based systems, bring- ing them closer to the ecosanitation ideal. Environmental sustainability is only part of ecosanitation, however. Defecation is as culture-laden as other behaviours, so the designs must also be socially sustainable — tailored to local customs and strictures, whether in Malawi or Manhattan. The developed world may think it has cracked the problem, but trouble is gurgling away underground. ‘Flush and forget’ sani- tation systems constitute one of the more bizarre hangovers from the Victorian age. In older toilets, up to 25 litres of drinking water go down the pan per flush, although ‘low- flow’ toilet designs are coming into their own and, in 1995, the US federal government set a 7-litre-per-flush limit. Aside from wasted water, the faeces-laden ‘black water’ from flush toilets is not always treated. Many older US and UK sewage sys- tems, for instance, mix toilet waste water with storm water in so-called combined sewage outflows, which can overflow after heavy rain. The US Environmental Protection Agency estimated in a 2004 report to Con- gress that 850 billion gallons of untreated water were entering US waterways every year. An ‘eco’ toilet such as Peter Morgan’s Blair VIP, which traps disease-carrying flies, can transform lives. Sewage sludge — the semi-solid mush left after wastewater treatment in sewage works ECODESIGN — can be as problematic. Although it can contain significant traces of pharmaceuticals The bottom line and heavy metals even after treatment, it is widely used in the West as a soil conditioner and fertilizer on cropland, with uncertain effects on human health. If architecture is ‘design for living’, one of its greatest In the packed cities and scattered villages of the developing world, the challenge is challenges is how to live with the masses of waste we even more daunting. Thousands of children excrete. Four pioneers in green sanitation design outline die every day from a lack of basic sanitation or clean water. Open defecation contami- solutions to a dilemma too often shunted down the pan. nates soils with the eggs and larvae of soil- borne intestinal worms, or helminths, as well as other pathogens. More than one billion very year, on average, each of us excretes have hidden sanitation issues of their own. people are infected with these helminths, 50 litres of faeces, rife with pathogens There is no single design solution to sani- which cause, among other problems, weak- Eand heavy metals. Multiplied by Earth’s tation. But there are universal principles for ness and malnutrition. population of 7 billion — and rising — that systematically and safely detoxifying human So a toilet can be transformative. A clean constitutes not so much an elephant in the excreta, without contaminating, wasting environment means better health — and that, room as a herd of mammoths. Sustainable or even using water. Ecological sanitation in turn, is a springboard to development. As solutions are urgently needed, particularly design — which is focused on sustainability governments debate the finer points of global for the 2.6 billion people who lack adequate through reuse and recycling — offers work- development challenges at Rio+20 next week, sanitation and the 1.1 billion practising open able solutions that are gaining footholds they might find it worth asking why sanitation defecation. Rich countries, meanwhile, often around the world, as Nature explores on the falls to the bottom of most policy agendas. ■ 186 | N A TURE | V O L 486 | 14 JUNE 2012 © 2012 Macmillan Publishers Limited. All rights reserved

BOOKS & ARTS COMMENT PETER MORGAN from the unventilated toilets and only these have been built in Malawi and about 70,000 in Ethiopia. 146 from the ventilated toilets (P. R. Mor- gan Cent. Afr. J. Med. 23, 1–4; 1977). A fam- The Fossa Alterna is another variation: Inspired by ant ily BVIP will last 10–15 years, and once it is two shallow pits are dug and used alternately, abandoned, the superstructure materials can swapping at annual intervals. By the time turrets and the be recycled. The excreta gradually dries, and one pit has filled, the compost in the other flight paths of flies can be used as compost. will be mature and ready for use. The BVIP is now the backbone of Perhaps working in an area for which Zimbabwe’s sanitation programme, with I have not received formal training has Environmental scientist and designer half a million family toilets built so far, and given me freedom of expression in observ- of the Blair VIP toilet, Harare is widespread in other African countries. A ing, exploring and researching. I had to multicompartment unit was designed for use instinct and plain logic. And it pays to “The designer knows he has reached perfec- schools. More recently, I have drawn up a adapt natural principles honed over millions tion, not when there is no longer anything to cheaper, upgradeable family unit, which can of years. add, but when there is no longer anything to be built in stages — allowing them to ascend take away.” I recalled this anonymous quote the ‘sanitation ladder’. when, as a young biologist in Rhodesia (now I devised other toilets to speed up the RALF OTTERPOHL Zimbabwe) in the 1970s, I was working for composting process. The Arborloo is an the health ministry’s Blair Research Labo- unlined pit 1 metre deep, which is fitted with Boosting compost ratory — named after former health secre- a circular brick or concrete rim and a sani- tary Dyson Blair. Blair had persuaded me to tary slab. As it fills, soil, ash and leaves are with biochar and change fields, from schistosomiasis control added to accelerate composting and control bacteria to technological solutions for public health, flies and odour. After a year, the toilet super- and tasked me with designing new toilet structure is moved to a new pit, and a tree is systems for use in rural areas. planted in a layer of soil on top of the old pit, Environmental engineer and director, Open defecation was then common, to provide shade, fuel or fruit. Thousands of Institute of Wastewater Management and the existing pit toilets bred blowflies of and Water Protection, Hamburg University of Technology, Germany the genus Chrysomyia, as well as other fly SOURCE: P. MORGAN species that carry enteric disease. In a survey AIR TRAFFIC CONTROL With my team in Hamburg, I have studied The Blair toilet uses a vent to trap fies, conducted between March 1974 and April preventing them from spreading disease. 1975, we counted more than 20,000 flies resource-oriented sanitation — in which The vent also draws out odours from the pit, emerging from a single pit toilet. was drawn towards this path having started It had long seemed to me that simplicity making the toilet interior almost odour free. waste is seen as reusable — for 15 years. I Flies outside are attracted to the could be related to elegance of design. My the odour from the vent pipe out mathematically modelling mass flows at first innovation, called the Blair toilet after large-scale wastewater treatment plants — a Dyson (and later dubbed the Blair ventilated Wind fow process I found frustratingly inefficient. improved pit, or BVIP toilet), is simple: a In 2010, I began to focus on a practice pit, lined with bricks for stability; a con- originating in Brazilian Amazonia more crete sanitary slab with one hole for squat- A fy screen prevents fies from than 1,000 years ago that could, paradoxi- ting, and another fitted with a vent pipe entering and leaving the pit cally, kick-start a modern revolution in stretching from the slab to above roof level; composting sanitation. The pre-Colum- and a spiral superstructure that obviates bian Indians created ‘black’ soils known the need for a door but guarantees semi- in Portuguese as terra preta. Found in darkness (see ‘Air traffic control’). patches throughout the Amazon, they The design harnesses natural prin- are composed of charcoal (biochar), ciples. The turrets of ant nests — the Vent pipe composted excreta and other bio-waste. most elegant of nature’s chimneys — They are absorptive and high in nitrogen, inspired the vent. The natural behaviour phosphorus, potassium and calcium. At of flies, which are attracted by odour and Hamburg, we are adapting this mixture for light, determined the other design features. use in ecosanitation systems. When air passes over the top of the vent, Airfow Systems using terra preta technology suction draws more air through the can help to solve two problems that squatting hole into the pit, then sends plague many developing countries: the odours up through the vent. Some Vent Entrance poor soils and a lack of sanitation. flies are drawn to those odours; oth- The technology offers the efficient Squat ers, entering the pit through the squat Concrete hole creation of well-structured, humus- hole, are drawn to the light from the slab rich compost, which is important for bottom of the vent. Either way, the flies food security, resistance to soil ero- are trapped and die, because the vent Pit sion, water retention in soil and the is fitted with a non-corrodable screen, growth of local agricultural econo- usually made of aluminium. mies. And it is cost-effective. A basic The concept is simple and it works. terra preta sanitation toilet costs about Flies from pit are From October to December 1975, weekly drawn towards the US$50, inputs are cheap, and it is not counts of fly output were taken from two light of the vent hooked up to sewage systems. Blair toilets and two unventilated pit toi- Terra preta sanitation is a three-step lets: a total of 13,953 flies were trapped process. First, lactic-acid bacteria are 1 4 JUNE 2012 | V O L 486 | N A TURE | 1 8 7 © 2012 Macmillan Publishers Limited. All rights reserved

COMMENT BOOKS & ARTS There is a social side to sustainable sanitation: safe and attractive toilet blocks are being built for girls at schools in India, raising attendance levels. toilets, which use little water and counter collection, mixed with at least five parts added after each defecation: the anaerobic WHEREVER THE NEED fermentation sanitizes and deodorizes. We water. India’s serious faecal pollution problem (see For urban settings we are designing a have used cultures ranging from sauerkraut page 185). new family toilet flushed with very small liquor to strains scientifically selected not The challenges we are up against are con- to produce gas, such as Lactobacillus plan- practise open defecation daily, polluting with a bottle or through a nozzle attached to tarum, Lactobacillus casei and Pediococcus amounts of water, sprayed either manually siderable. More than 626 million Indians acidilactici. At the same time, a waste-sugar sink pipes. This toilet mixes faeces and urine. groundwater and creating ideal breeding source such as molasses or vegetable scraps Because moisture impedes composting and conditions for disease. Meanwhile, urban is added as bacterial feed. This process con- the high nitrogen content must be compen- India’s pace of growth is incredible — by tinues while the excreta collect and for at sated for with a carbon source, half a kilo- 2030, estimates suggest that some 575 mil- least another week after collection ceases. gram of woody waste must be added later at lion people will be living in cities. One in Second, about 50 grams of powdered the composting site. This unit has a tank big four of the country’s city dwellers (93 mil- charcoal — preferably ‘clean’, from wood-gas enough for at least a week’s worth of waste. lion) lives in slums. stoves — is added with each bacterial appli- The treated waste can then be collected and But the social side of sustainability is cation to absorb odour and bind nutrients. made into terra preta at a professional com- as important as the environmental. Inad- This biochar also creates microporous space munal composting site. equate or no sanitation facilities in schools for the lactic-acid bacteria to inoculate the Our research shows that these toilet sys- mean that once girls reach puberty they faeces and lower their pH value. tems and variations on the basic terra preta stay at home when they are menstruating, Finally, earthworms (vermiculture) com- processes could work even in densely popu- disrupting their studies. And women tend post the collected and treated material aero- lated cities — a revolution indeed. to excrete when it is dark because they are bically, further sanitizing the mixture over a seeking privacy — but that makes them period of three months to a year. The result- vulnerable to attack, or even rape. So our ing compost is safe for use with non-food SHUNMUGA PARAMASIVAN designs factor in safety and ease of use for ‘industrial’ crops or forest trees. Two years girls and women. of further processing creates compost that Creating social The girls’ school sanitary blocks we have can be used on food crops. designed in Cuddalore, Tamil Nadu, have an Terra preta sanitation systems can be inclusivity for exclusive wash room with a washing facility, modified to suit rural or urban sites, but girls and women napkin vending machine and an incinerator. it must be possible to seal collection and They are painted in brilliant colours, fully transport receptacles for the fermentation enclosed and imaginatively laid out so that to work. Rural versions can be simple bucket Country director, Wherever the Need, they are enjoyable to use. We educate the toilets fitted with a urine diversion, so that Pondicherry, India girls with a software programme underlin- faeces drop into one bucket and urine is ing the need for toilets, personal hygiene, piped into another. Urine can be lacto-fer- Since 2007, I’ve helped to design and install and maintenance and management of the mented separately with the bacterial mix for toilets across India that tackle specific facility. Pupils play their part by helping to a month or more to avoid nitrogen losses environmental and social challenges — clean the toilets. and odours, then used as fertilizer, pref- including those relating to women, schools School sanitation is a large part of our erably on non-food crops. Alternatively, and slums. All are environmentally sus- focus, especially in rural villages. Although the urine can be used immediately after tainable urine-diversion dry (composting) the older generation uses entrenched 188 | N A TURE | V O L 486 | 14 JUNE 2012 © 2012 Macmillan Publishers Limited. All rights reserved

BOOKS & ARTS COMMENT methods of toileting, it is easier to convince children to use new ways. They then become WATER MANAGEMENT WETLANDS STYLE agents of change for their families and By carefully selecting plants that are suited to the local environment and can INTERFACE MEDIA communities. support particular bacterial communities, wetland cells provide an attractive In 2008, we installed 150 toilets in the way to treat and reuse all of a building’s waste water on site. slums of Cuddalore, which presented dif- ferent issues. Family toilets with dedicated compartments to serve women and chil- dren are essential, but space was so limited we opted for mobile toilets. Two hundred families used the first unit; the second, rede- signed to resemble a Portaloo, serves 280 Vertical-fow wetlands families. We developed new single mobile Tidal-fow wetlands ecosanitation units serving 15 to 20 fami- lies when the community asked for them. Mobile urinals were deployed in the most congested places, such as the hospital and harbour. Both human compost and urine as a fer- tilizer are in high demand from farmers and Wherever the Need is now storing and treating both for eventual sale. The proceeds are paying for the logistics involved in this operation. Next we hope to replicate the Recirculation tank operation in Chennai. ED HARRINGTON Primary tank Building a coastal Black water from toilets and grey water from sinks and showers is directed to the primary tank for filtration. wetland in the Water is pumped to tidal-fow wetland cells, which are repeatedly filled and drained to create multiple tidal cycles each day, speeding up natural water-treatment processes. heart of a city Vertical-fow wetland cells provide a final level of treatment, removing any remaining organic material and excess nitrogen. General manager, San Francisco Public The treated water is disinfected with ultraviolet light and trace amounts of chlorine, Utilities Commission, California, and and is ready for reuse in toilet fushing. former chair of the Water Utility Climate Alliance. design (LEED) platinum certification from periodically to the municipal sewage sys- From the earliest planning stages, in 2009, the US Green Building Council in Washing- tem. From the tanks, the water is pumped for the new 13-storey headquarters of the ton DC, contains a sustainable, integrated into tidal-flow wetland ‘cells’, set next to the San Francisco Public Utilities Commission, water-management system that will serve pavement and in the lobby, and disinfected I knew the building would need to demon- more than 1,000 staff and visitors daily. using ultraviolet light and trace amounts of strate the commission’s ambitious sustain- The Living Machine system treats all waste chlorine. ability goals — we needed to ‘walk the talk’. water in the building for reuse in flushing The cells are filled with gravel, bacteria Water reuse was a central concern, but toilets (see ‘Water management wetlands and flowering grasses and plants — includ- we quickly discovered that many decen- style’). Rainwater is harvested from the ing Japanese sweet flag (Acorus gramineus) tralized water-reuse technologies were too roof and the child-care centre’s play area and western bleeding heart (Dicentra for- energy-intensive for our building’s energy for landscape irrigation. By treating and mosa). The plants were chosen for their root budget. My team proposed that we pursue reusing all waste water on site in a self-con- structure, which supports the establish- ecological sanitation methods inspired by tained system, we avoid discharging usable ment of treatment bacteria, and for resil- wetlands, and challenge ourselves to defy water. iency in San Francisco’s climate and urban conventional wisdom that the space such Our system reduces total water use by environment. methods demand is too big for dense urban about 65%, saving 3 million litres of drink- The cells mimic the ecology and natu- areas. ing water per year. We anticipate eventually ral water-treatment processes of coastal In our low-energy solution, wastewater producing a surplus of 2.6 million litres of wetlands, and are alternately flooded and treatment, which is usually buried in the treated water for non-potable uses such as drained to create multiple tidal cycles per basement, is visible — in the atrium and toilet flushing or park irrigation nearby. day, speeding up the natural water-treatment from the pavements where thousands walk The process begins and ends with low- processes by increasing the influx of oxygen. every day. And we’ve done it in one of the flow toilets. After flushing, black water from The system is responsible for recycling some highest-density neighbourhoods in one the toilets is combined with grey water, from 19,000 litres of water per weekday, but all of the highest-density cities in the United the sinks and showers, in plumbing pipes. people see is lush, vibrant plantings. It is a States. The mixed waste water is then directed to blend of function and aesthetics, as well as The building, which is expected to receive tanks beneath the pavement for filtration; a demonstration of the ecological sanitation a leadership in energy and environmental filtered solids such as faeces are pumped processes at work. ■ 1 4 JUNE 2012 | V O L 486 | N A TURE | 1 8 9 © 2012 Macmillan Publishers Limited. All rights reserved

COMMENT BOOKS & ARTS OUP PAKISTAN Is Orangi a model for other cities? As an outgrowth of the process of building sanitation communally, residents became community activists and got involved in OPP- supported health, education, housing and micro-credit programmes. The architects and technicians who helped to initiate the project now run it, and have expanded it to cities and settlements all over Pakistan, often in collabo- ration with local governments and planning agencies. The OPP’s philosophy has had a major impact on the attitudes of professionals, academic institutions, government officials and international non-governmental organi- zations and agencies working in Pakistan. What other urban problems are you tackling? In 1992, a square metre of land on the periph- ery of Karachi cost 1.7 times the daily wage. Today, it is 40 times. Many cannot afford that, so housing is getting denser. In the inner city, The underground sewage system that residents installed in Orangi has vastly improved public health. the density is more than 4,000 people per hec- tare [compared with less than 150 in London]. Q&A Arif Hasan Although water supply and electricity provi- sion have increased hugely in Karachi over the past 20 years, the sharing of toilets and kitch- Architect of change ens has risen, along with the number of peo- ple per room. You can’t live a comfortable life at such densities unless they are planned for. Urban campaigner and architect Arif Hasan has been central to a sanitary revolution, transforming Orangi, Karachi, from informal settlement to thriving community. Using his What are your solutions? technical know-how, residents built a sewage system, sparking vast social change. Now chair of With colleagues, I have developed design Pakistan’s urbanization task force, he discusses incorporating sustainable design into poor cities. guidelines and incremental development pro- cesses to accommodate high densities in an environmentally friendly, affordable way. We hypothetically redesigned four different Kara- How did you help? What challenges did OUP PAKISTAN Orangi face when you I proposed cheap, simple, local solutions: chi communities with computer modelling. concrete-curing methods, casting cheap Three redesigns showed that densities even arrived? In 1980, the lanes of Orangi, a katchi abadi steel-shuttering manhole covers in situ, higher than those prescribed by the Karachi Building Control Authority were workable. site-appropriate tools such as manual com- or informal settlement pactors, and surveys and maps. I also devel- housing a million oped rules of thumb for gradients, manhole What other challenges does Karachi face? people, were running and pipe sizes, survey procedures and Many natural drainage channels and water with waste water and inexpensive one-chamber septic tanks. bodies have been filled in to make way for sewage, and infant mortality was 128 in These designs and methods, which chal- elite coastal housing and new informal settle- 1,000. The conditions stymied development: lenged conventional engineering standards, ments upstream. So all of Karachi now floods. school attendance was down and trade dif- have stood the test of time. They also But other environmental issues are arising ficult to establish. The psychological effects, reduced costs by more than 40%. because of the new paradigm of Karachi as too, were severe, sapping the will for change. a ‘world-class city’, fuelled by direct foreign The lanes couldn’t be used as public space How did sanitation transform public health? investment. New infrastructure caters to the and quarrels over sanitation issues were fre- By 2000, some 85% of Orangi had self-laid, corporate sector, and its architectural style quent. The wastewater also damaged house self-financed sewer lines. The lanes are imitates the West. There is a new dependence foundations and triggered unhealthy rising clean: children play in them, women sit and on air conditioning despite local expertise in damp. talk. Health indicators have improved, and creating buildings comfortable without it. by 1993 infant mortality had fallen to 37 in How did you become involved? 1,000. How has architecture in Karachi changed? That year, the social scientist Akhtar When I began my practice in 1968, an archi- Hameed Khan set up the Orangi Pilot Pro- What are the social and economic changes? tect designed for the state, or for the rich. ject [OPP] to understand local problems and Literacy rates there are now among the Today, clients vary hugely. This new archi- develop models to overcome the constraints highest in Pakistan. Socially and economi- tectural world belongs to women, who make governments face in upgrading informal cally, Orangi is much more connected to up 92% of the architecture and planning stu- settle ments. Khan encouraged people to the rest of Karachi in diverse ways. Many dents at the University of Karachi. In many build and pay for their own underground people are white-collar workers; a substan- ways, the role of the architect is immense sewage system, at a cost of around US$30 a tial minority are professionals; women and compared to before. ■ household. A year later, he needed an archi- entrepreneurs work in and service formal- tect. That was me. sector industry. INTERVIEW BY ANNA PETHERICK 190 | N A TURE | V O L 486 | 14 JUNE 2012 © 2012 Macmillan Publishers Limited. All rights reserved

Correspondence Don’t forget health Bianca Brijnath Monash law, which has created barriers assessment, institutional in sustainability talks University, Australia. to drug access in low-income interaction and social–ecological [email protected] countries. innovation will enable us to Many wealthy nations are Anthony J. McMichael, Colin Instead of implementing an work more effectively towards confronting the health and D. Butler National Centre for aspect of US foreign policy that is planetary stewardship. welfare implications of high Epidemiology and Population intended to protect US economic Victor Galaz* Stockholm unemployment, political Health, Australian National interests, the GRC should Resilience Centre, Stockholm instability and eroding social University, Australia. promote scientific research University, Sweden. victor.galaz@ security. Such crises are part of in low-income countries. stockholmresilience.su.se our failure to move sustainability Apart from implying that they *On behalf of 4 co-authors (for a beyond rhetoric — a fact not US policy should not will discuss the expansion of full list, see go.nature.com/uct6dd). adequately recognized by the shape collaborations open-access publishing in these Group of Eight (G8) community. countries, GRC members seem The Rio+20 meeting in Brazil The aims of the Global to have paid little attention to Combat the effects of next week must accept that Research Council (GRC) this issue. Forest Code changes sustainable development and the to improve international Bridget Pratt, Bebe Loff health of populations depend on scientific collaboration (Nature Monash University, Australia. On 25 May, Brazil’s President each other. 485, 427; 2012) have been [email protected] Dilma Rousseff endorsed Peak global health may enthusiastically endorsed by revisions to the country’s Forest already be here. Low- and John Holdren, director of the Code. Thanks partly to an middle-income populations White House Office of Science Planetary boundaries appeal from the international endure a double burden and Technology Policy, and concept is valuable scientific community and non- from communicable and Subra Suresh, head of the US governmental organizations, non-communicable diseases, National Science Foundation As researchers studying the together with a petition of while health inequity and (see go.nature.com/rbiykb). We concept of setting environmental more than 2 million signatures, undernutrition persist. Social disagree with their statement boundaries for planetary Rousseff also vetoed some of the and ecological factors such as that “good science anywhere well-being (J. Rockström et al. code’s provisions. But more is climate change, energy and food in the world is good for science Ecol. Soc. 14, 32; 2009), we needed. insecurity, counterfeit drugs, — and good for people — disagree with Simon Lewis’s The revised code will continue antimicrobial and insecticide everywhere in the world”. suggestion that there are flaws to protect forests in crucial resistance and poverty all The agreed GRC standards in these proposals (Nature 485, locations, such as along rivers, on undermine health in our for merit-based peer review will 417; 2012). hilltops and in coastal wetlands, interconnected world. improve research quality through Lewis contends that the as well as a specified percentage Many development specialists collaborations between high- and concept’s focus is too narrow, that of those on private property (see suggest that health has had middle-income countries, which it doesn’t distinguish between go.nature.com/fzxmj5). There its opportunity through the have strong research systems. ‘boundaries’ and ‘thresholds’ and will be no amnesty for offenders United Nations’ Millennium But the guidelines are unlikely that it should clarify the influence who illegally logged forests in Development Goals, and that the to boost science capacity in low- of scale on different problems. the past. strategic imperative must shift to income countries. These are misunderstandings. I believe, however, that policies agriculture or energy. But these Holdren and Suresh point Planetary boundaries are not to reduce deforestation and foster are only two legs of the stool: out that US researchers could fixed ‘supply limits’, but are set sustainable development need health remains the third. lose global funding if other within a safety margin around to be strengthened to counter When sustainability becomes governments do not review US complex thresholds that are any potentially adverse effects of a reality, it will reduce many risks proposals on their merit, and intertwined at regional and the new Forest Code. Payments to health. For example, clean that the country’s economic global scales. Ecosystem changes for ecosystem services must energy will eliminate the need interests could be harmed caused by nitrogen pollution, be increased — for example, to clear forests and use crops if colleagues do not respect for example, are driven by to expand the important work for biofuel, so people will be confidentiality and intellectual global trade and cannot be of the Forest Conservation better fed. Improved agricultural property. Subsequently, the uncoupled from climate change Allowance Programme (Bolsa practices will reduce exposure to heads of publicly funded and alterations in land use. Also, Floresta) in the Amazon. the animal-to-human infections science agencies from 47 investment in new phosphorus Ranching, agriculture and other that are associated with land countries agreed on the GRC’s technologies can address the economic activities should be clearing. A green revolution Statement of Principles for problems of both pollution and confined to existing deforested will protect biodiversity by Scientific Merit Review. stock control. areas. Environmental laws need producing more food on land It therefore seems that the It is a mistake to see the setting stricter enforcement, and regular that is already cleared. Better GRC standards are transposing of environmental boundaries as a monitoring of forest areas is a economic, educational and social concern about intellectual call for multilateral negotiations priority. opportunities in rural areas will property to the arena of peer around static limits. They Alison G. Nazareno Federal slow migration and alleviate the review. This is reminiscent are instead a bid to reform University of Santa Catarina, pressure on overloaded urban of the linking of intellectual- environmental governance Florianópolis, Brazil. health resources. property rights with world trade at multiple scales. Scientific [email protected] 1 4 JUNE 2012 | V O L 486 | N A TURE | 1 9 1 © 2012 Macmillan Publishers Limited. All rights reserved

NEWS & VIEWS MICROBIOLOGY Learning about who we are Microbial inhabitants outnumber our body’s own cells by about ten to one. These residents have become the subject of intensive research, which is beginning to elucidate their roles in health and disease. See Articles p.207 & p.215 DAVID A. RELMAN used to infer the genetic relationships between Anterior nares organisms. The researchers also surveyed the 3 he dawn of the twenty-first century has 900 Buccal genomes of the microbes in 681 of the samples 30,000 mucosa seen the emergence of a major theme in 800 using a shotgun sequencing approach, which Tbiomedical research: the molecular and Supragingival 70,000 generates random sequences (reads) from a genetic basis of what it is to be human. Sur- plaque complex pool of DNA molecules. The reads 1,300 prisingly, it turns out that we owe much of our 20,000 are then assembled on the basis of overlap- biology and our individuality to the microbes ping sequence similarity, allowing researchers that live on and in our bodies — a realization Faeces to identify genes and to predict the functions that promises to radically alter the princi- (distal gut) of the proteins that they encode. ples and practice of medicine, public health 4,000 Posterior The investigators mapped their reads to 800,000 fornix and basic science. It is therefore appropriate 300 all available microbial and viral genome that ever more research is focused on these 10,000 sequences to assess community composition microbes and their genes, which together — the different types of microbes and their 1 are known as the human microbiome . In relative abundance — at the various body sites. this issue, the Human Microbiome Project The researchers also determined the whole- 2,3 Consortium publishes the most exten- genome sequences of about 800 bacterial sive catalogue yet of organisms and genes strains isolated from humans (from a planned pertaining to our microbiomes. total of 3,000); these sequences have been The first observations of indigenous human placed in public databases and can be used as microbiota were published more than 300 years reference genomes for comparative purposes. 2,3 ago, soon after the invention of the micro- The consortium authors conclude that they scope. Today’s view of the microbial world has Figure 1 | Variation in diversity. Researchers of have identified the majority of the common the Human Microbiome Project are studying the been radically improved by DNA-sequencing microbial inhabitants of the human body, using microbial taxa and their genes present in these technology. In the wake of the Human Genome samples taken from 242 healthy adults at 15 (for 242 healthy humans. 1,4 Project, calls were issued for enhanced efforts males) or 18 (for females) body sites — from the One of the great strengths of the HMP is to be made to characterize the ‘second human skin (four sites), mouth and throat (nine sites), that samples were collected simultaneously genome’ — the human microbiome. At the vagina (three sites), nostrils and faeces (to represent from multiple body habitats of the same indi- 2 end of 2007, the US National Institutes of the distal gastrointestinal tract). Huttenhower et al. 2 viduals. This allowed Huttenhower et al. to 3 Health (NIH) launched the Human Micro- and Methé et al. have estimated the number of discover that taxonomic and genetic diver- biome Project (HMP) and, in early 2008, the microbial species and their genes in these samples, sity were greatest in tooth and stool samples, European Commission and China initiated and found substantial variation in microbial inter mediate in skin samples and on the inside the Meta genomics of the Human Intestinal community composition at different body surface of the cheek, and lowest in vaginal sam- Tract (MetaHIT) project. Other countries habitats. The two groups used different counting ples 2,3,7 (Fig. 1). The researchers report that methodologies, and their numbers vary accordingly, have begun similar ventures, motivated in such that exact figures are not available. However, each habitat is characterized by a small num- part by an interest in better defining their crude estimations of number of microbial species ber of highly abundant ‘signature’ taxa, but that 3 biological heritage. (red) and number of microbial genes (blue) are the relative representation of taxa and genes 2 Two studies, by Huttenhower et  al. shown for examples of: sites containing high species in each habitat varies considerably between 3 (page 207) and Methé et al. (page 215), diversity, such as the gastrointestinal tract and teeth individuals. In most samples, high-abundance 5,6 together with 15 other papers that are (supragingival plaque); sites with intermediate taxa are accompanied by low-abundance taxa being published simultaneously elsewhere, diversity, such as the inside of the cheek (buccal from the same genus, suggesting that within- comprise the first reports of the HMP Con- mucosa) and nostrils (anterior nares); and sites with community niche specialization occurs. sortium research groups. The primary data, lower diversity, such as the vaginal posterior fornix. These findings confirm those of an earlier The authors also found substantial variation in both 8 3 as described by Methé and colleagues , the diversity and the composition of the microbial study , which demonstrated that body habitat were derived from samples collected from communities at different sites within the same accounts for much of the variation in bacte- 242 healthy adults in the United States, at 15 general body region. rial community composition. Although there (for males) or 18 (for females) body sites — is clear evidence for individuality in people’s from the skin, nose, mouth, throat, vagina and The consortium researchers obtained the microbiome compositions, the limited tem- faeces (to represent the distal gastro intestinal nucleotide sequence of the small-subunit ribo- poral scope of the HMP data set prevents a tract). Each person was sampled up to three somal RNA — a molecule found in all cellular robust analysis of how these communities times over 22 months, generating a total of life — from microorganisms in 5,177 of these change over time. 9 3 11,174 samples. samples . These sequences are commonly As shown previously for faecal samples , 194 | N A TURE | V O L 486 | 14 JUNE 2012 © 2012 Macmillan Publishers Limited. All rights reserved

NEWS & VIEWS RESEARCH 2 the relative abundance of microbial genes As Huttenhower and colleagues suggest , the David A. Relman is in the Departments associated with certain physiological path- fact that some of the microbiome’s functions of Medicine and of Microbiology and ways varied less between samples from the are likely to be performed by rare community Immunology, Stanford University, Stanford, same habitat than did the relative abundance members or to involve genes that are expressed California 94305, USA, and at the Veterans of taxa. This suggests that there is functional at low levels will further complicate attempts to Affairs Palo Alto Health Care System, redundancy between microbial community decipher their influence. Palo Alto, California. members. The prevalence of low-abundance Despite the valuable initial findings from e-mail: [email protected] genes varied the most between habitats, and the HMP and other projects, multiple lines of 1. Lederberg, J. Science 288, 287–293 (2000). Huttenhower and colleagues speculate that the enquiry remain. Which factors are responsible 2. The Human Microbiome Project Consortium functions of these genes correspond to body- for the day-to-day or longer-term variation in Nature 486, 207–214 (2012). niche-specific activities. Interestingly, the the composition and functions of a person’s 3. The Human Microbiome Project Consortium Nature 486, 215–221 (2012). researchers also found evidence of taxonomic microbiome? To what degree are such fac- 4. Relman, D. A. & Falkow, S. Trends Microbiol. 9, co-variation across sites in an individual, tors intrinsic to the microorganisms, related 206–208 (2001). such as between the communities of the skin to the host, or, indeed, stochastic? Which 5. www.ploscollections.org/hmp 2 and the saliva . One possible explanation mechanisms regulate bacterial colonization or 6. Segata, N. et al. Nature Methods http://dx.doi. org/10.1038/nmeth.2066 (2012). for this is that interactions between com- invasion of the human microbiome, how does 7. Li, K., Bihan, M., Yooseph, S. & Methé, B. A. PLoS munity members are subject to selection the microbiome respond to disturbance, and ONE 7, e32118 (2012). pressure by host-specific, and host-wide, to what degree does this response involve the 8. Costello, E. K. et al. Science 326, 1694–1697 environmental factors. propagation of surviving organisms versus new (2009). 9. Turnbaugh, P. J. et al. Nature 457, 480–484 Studying the human microbiome has so colonization from outside? What is the basis of (2009). far been a lesson in humility. Although the resilience in the human microbiome, and can it 10. Qin, J. et al. Nature 464, 59–65 (2010). 10 HMP and the MetaHIT project are revealing be predicted and restored? Such questions sug- 11. Yatsunenko, T. et al. Nature 486, 222–227 (2012). vast amounts of previously uncharacterized gest that the work of Methé et al., Huttenhower 12. Costello, E. K., Stagaman, K., Dethlefsen, L., microbial diversity within our ‘home turf’, the et al. and the numerous others studying the Bohannan, B. J. M. & Relman D. A. Science 336, functions of these communities remain largely human microbiome is only just beginning. ■ 1255–1262 (2012). 3 unknown. Moreover, Methé et al. report that only 57% of the non-redundant gene families identified by the HMP and MetaHIT research- QUANTUM PHYSICS ers were detected by both groups, with 34% of the gene families being detected only in the HMP data and 10% only by the MetaHIT Majorana modes project. This raises questions about the representativeness of the people in the two pro- jects. In both cases, samples were taken from materialize adults in developed nations who have relatively similar lifestyles and, in the case of the HMP, without inflammatory disease. Another recent Elusive theoretical fantasies known as Majorana modes have been observed in a 11 report reveals that populations living in less- hybrid semiconductor–superconductor system. These emergent exotica open up developed regions of the world have markedly promising prospects for quantum computation. different microbiomes from those living in the United States. It is also important to consider the defini- FRANK WILCZEK atomic nuclei are what we get to work with. tion of health. The most common cause for Furthermore, the basic interactions among exclusion of people from the HMP was chronic he condensed-matter physics com- those ingredients are known to high accuracy: gum disease, a condition that is increasingly munity has been galvanized by the Maxwell’s electrodynamic and Schrödinger’s regarded as ‘normal’ in developed countries. Tapparent experimental discovery of quantum equations rule. So how, within that 1 Furthermore, the prevalence of overweight Majorana modes, reported by Mourik et al. familiar and reliable framework, can new and and obese individuals continues to rise in many in a paper published in Science. These entities, exotic ‘particles’ arise? 2 populations around the world, the chronic use whose existence had been predicted theo- Phonons are the original examples of quasi- 5 of prescription drugs is becoming more com- retically, could become major components in particles. They were introduced conceptu- mon, urbanization is increasing, and our natu- quantum engineering. Specifically, they might ally by Albert Einstein in 1907. Two years ral environment is changing in unexpected provide the basic elements — the qubits — for previously, he had proposed the idea that 3,4 ways. Future studies of the human microbiome a quantum computer . light has particle-like properties, being cre- should accommodate such factors, which are Over the past few decades, physicists have ated and transmitted in discrete units, namely likely to influence our microbial inhabitants. discovered that particle-like excitations called photons. Generalizing that intuition, he sug- Many areas of human-microbiome research quasiparticles, found in condensed-matter sys- gested that the vibrations of solids come in warrant further investigation, but viruses and tems, can have strange, fascinating and pos- discrete packets, which we now call phonons. small non-bacterial organisms such as fungi sibly useful properties, including fractional Einstein used this notion to explain an other- deserve special attention, as do questions electric charge and unconventional quantum wise mysterious deficit of vibrational motion regarding the functions of the microbiome. We statistics. Majorana modes are a major addi- in diamond at low temperatures. Einstein’s are essentially blind to many of the services that tion to this universe of exotica. work pre-dated the modern understanding our microbial ecosystems provide — and on To set the context and avoid misunderstand- of solids (for example, the atomic nucleus was 12 which our health depends — and investi- ing, a brief reflection on the fundamental discovered only in 1911), but its central con- gators desperately need new approaches for nature of quasiparticles is in order. The ele- cepts endure. ‘Holes’ are another crucial kind 6 studying interactions between members of the mentary building blocks of material systems of quasiparticle . As their name suggests, holes microbial community and their human hosts. are not negotiable; electrons, photons and represent the absence of an electron where 1 4 JUNE 2012 | V O L 486 | N A TURE | 1 9 5 © 2012 Macmillan Publishers Limited. All rights reserved

RESEARCH NEWS & VIEWS one would normally be expected. They come is convenient to have a word for the concept in discrete, localized units and move as if they ‘quasiparticle that supports Majorana modes’, 13 are particles. and I have suggested ‘mode-icule’. To describe Those two classic examples are good illus- the quantum state of a mode-icule, we must trations of noteworthy peculiarities of quasi- specify a two-component wavefunction, just particles. Phonons, although they arise from as we do for a (spin-ful) electron. the correlated motion of atomic nuclei, are Building on previous theoretical designs 14,15 50 Years Ago particle-like objects that in no way resemble for detecting Majorana modes, Mourik et al. 1 atomic nuclei. Holes, despite their origin in studied the electrical properties of indium the correlated motion of electrons, have very antimonide nanowires lying atop a substrate With the increasing use of different properties from electrons; indeed, made of a conventional superconducting irrigation in horticulture and they have the opposite electric charge. Quasi- mater ial. Indium antimonide is a semiconduc- agriculture and the developing particles transcend the elementary units tor that displays a strong quantum interaction interest in the effects of from which they are built. They are emergent called spin–orbit coupling: the motion of the evapotranspiration, it is frequently objects, embodying recognizable — that is, electrons in the material is strongly coupled necessary to locate the level of a reproducible and long-lived — organizations to their spin. Interaction with the substrate’s shallow water-table. This can be of energy within structured materials. electrons induces superconductivity in the done inexpensively and effectively, Different materials can support different wire’s electrons as well, through a phenom- using a small-diameter observation kinds of quasiparticles. Of course, each mater- enon known as the proximity effect. Mourik well and an electric probe … ial’s quasiparticles depend on the structure of et al. observed that, in such a hybrid semicon- Twelve observation wells and a the material and exist only within that mater- ductor–superconductor device, electrons can probe … have been satisfactorily ial. Modern physicists can exploit their broad tunnel into and out of the wire with no change used by me, in soils ranging from understanding of matter to design mater ials in energy, at an energy independent of applied fine clay to coarse gravel, for a whose quasiparticles will have interesting or voltage. This shows, quite directly, that there period of eighteen months, in useful properties. Transistors, the building are unusual quantum states, associated with connexion with investigations blocks of modern electronics, are an outstand- the ends of the wire, which have the properties of the water-table in the Thames ing, but by no means singular, success story. predicted for Majorana ‘spins’. The sensitivity flood-plain. It is almost certain, They orchestrate the motion of electrons and of the strength of this tunnelling to the magni- however, that, if necessary, these holes to amplify and switch electronic signals. tude and direction of applied magnetic fields instruments would give trouble- Majorana modes add a striking new vari- also matches theoretical expectations for the 7 free service for a much longer ation to the quasiparticle theme . Appearing states associated with Majorana modes. 8 period. as solutions to equations of a type invented The analogy of Majorana modes to spin From Nature 16 June 1962 by Ettore Majorana in 1937, Majorana modes proves inadequate when we come to describe represent forms of excitation predicted — and systems of several identical mode-icules. Cru- now observed — to be available to a few very cially, the emergent ‘Majorana’ states attached 100 Years Ago special and specific kinds of quasiparticles. to separate mode-icules, unlike ordinary spins, They were discovered as mathematical pos- are not entirely independent. On the contrary, 9 sibilities within quantum field theory , and those emergent states are, unavoidably, highly A Reuter message from New York were also found in theoretical models of pos- entangled. As a result, the quantum state of n reports that a steamer arrived sible exotic superconductors and of a particu- 2n mode-icules is described by a 2 -dimen- 10 at Seward (Alaska) on Sunday lar form of the quantum Hall effect , which sional wavefunction, whereas 2n independ- 2n 16 covered with volcanic dust from occurs in two-dimensional electron systems ent spins would require 2 dimensions . an eruption at Katmai, in the held at low temperatures and subjected to This constraint arises because mode-icules 17 Aleutian Islands. It is stated by strong magnetic fields. are entities called non-Abelian anyons , and those on board that a steady In a brilliant paper, Alexei Kitaev then so have unconventional quantum statistics — 2 stream of volcanic fragments and showed how Majorana modes could arise at as opposed to fermions (such as electrons) or ash followed a terrific explosion, the ends of superconducting wires. His reason- bosons (such as photons). spreading over the countryside. ing was (relatively) simple and transparent, The wavefunction’s dimensionality, The sun was obscured. Although and is at the heart of most subsequent propos- although drastically reduced by entanglement, the vessel was seventy miles als for the realization of Majorana modes — remains exponentially large in n. Interchange distant, at four o’clock on Thursday including those that underlie the experiments of mode-icules is accompanied by the com- afternoon complete darkness set in of Mourik et al. and of other researchers 11,12 plicated, but perfectly predictable, evolution and ash fell in a thick layer on the who have also reported evidence of the phe- of their wavefunctions in a complex math- decks. It is estimated that volcanic nomenon in different but related systems. ematical region known as Hilbert space. This ash covers three hundred square To become acquainted with Majorana evolution of wavefunctions in Hilbert space miles of fertile country. According modes, it may be helpful to draw on their anal- embodies the elegant principles of Clifford 7,18 to a telegram from Seattle ogy to a more familiar property possessed by algebra . (Washington State) the volcanic many particles and quasiparticles — their spin. Theorists have developed ingenious and disturbance is rendering wireless For example, an electron at a given position ambitious proposals for exploiting mode- telegraphic communication with can be in either of two states, with spin ‘up’ or icules, with their controllable entanglement, 3,4 Kadiak, Rospberry, and Afognac, ‘down’. Spin provides new dynamic options to enable quantum computation . Until three of the most important for particles that have it; that is, the possibil- recently, their visions have been, at best, islands of south-western Alaska, ity of spin-dependent interactions, including loosely tethered to laboratory reality. To do impossible. interactions that change the spin’s direction. useful computations, we will need to create From Nature 13 June 1912 Majorana modes generate, for quasiparticles many mode-icules, and to develop the abil- that support them, a kind of emergent spin. It ity to move their ‘spins’ around one another. 196 | N A TURE | V O L 486 | 14 JUNE 2012 © 2012 Macmillan Publishers Limited. All rights reserved

NEWS & VIEWS RESEARCH Arrays of superconducting wires of the type & Das Sarma, S. Rev. Mod. Phys. 80, 1083–1159 1 developed by Mourik and colleagues could (2008). 5. Einstein, A. Ann. Phys. 22, 180–190 (1907). each support mode-icules at their ends. By 6. Shockley, W. Electrons and Holes in Semiconductors linking them together, and applying suitable With Application to Transistor Electronics (Van electromagnetic fields, it ought to be possible Nostrand Reinhold, 1950). to substantiate the theorists’ dreams. Much dif- 7. Wilczek, F. Nature Phys. 5, 614–618 (2009). 8. Majorana, E. Nuovo Cimento 5, 171–184 (1937). ficult terrain separates proof of mode-icules’ 9. Jackiw, R. & Rossi, P. Nucl. Phys. B 190, 681–691 existence from the promised land of complex, (1981). scalable mode-icule circuits, but a beachhead 10. Read, N. & Green, D. Phys. Rev. B 61, 10267–10297 (2000). has been established. ■ 11. Williams, J. R. et al. Preprint at http://arxiv.org/ abs/1202.2323 (2012). Frank Wilczek is at the Center for Theoretical 12. Deng, M. T. et al. Preprint at http://arxiv.org/ abs/1204.4130 (2012). Physics, Department of Physics, Massachusetts 13. Ghaemi, P. & Wilczek, F. Physica Scripta T146, Institute of Technology, Cambridge, 014019 (2012). Massachusetts 02139, USA. 14. Sau, J. D., Lutchyn, R. M., Tewari, S. & Das Sarma, S. Phys. Rev. Lett. 104, 040502 (2010). e-mail: [email protected] 15. Oreg, Y., Refael, G. & von Oppen, F. Phys. Rev. Lett. 105, 177002 (2010). 1. Mourik, V. et al. Science 336, 1003–1007 (2012). 16. Nayak, C. & Wilczek, F. Nucl. Phys. B 479, 529–553 2. Kitaev, A. Preprint at http://arxiv.org/abs/cond- (1996). mat/0010440 (2000). 17. Moore, G. & Read, N. Nucl. Phys. B 360, 362–396 3. Kitaev, A. Ann. Phys. 321, 2–111 (2006). (1991). 4. Nayak, C., Simon, S. H., Stern, A., Freedman, M. 18. Ivanov, D. A. Phys. Rev. Lett. 86, 268–271 (2001). MICROSCOPY Reconstructing the third dimension An approach to microscopy has been developed that can be used to determine, from a single imaging angle, both the position of a specimen’s individual atoms in the plane of observation and the atoms’ vertical position. See Letter p.243 DILANO SALDIN using only the objects’ observed positions in the sky. 1 n this issue (page 243) , Van Dyck and Chen The problem of calculating the distance report an electron-microscopy technique of an object from the plane of observation Ithat draws on an analogy with the method (the image plane) also exists in other fields of used in astronomy for determining distances research. One such field is electron micros- to galaxies. The technique allows high- copy. Because an electron microscope pro- resolution, three-dimensional information duces a two-dimensional image of a sample, to be obtained about a sample using only one the lateral positions of the sample’s atoms can viewing direction. be observed directly to high precision. How- A central observation in astronomy is that ever, as with most images recorded on two- distant galaxies are moving away from us, and dimensional media, including conventional from each other, with a speed that is propor- cameras, the vertical positions (heights) of the tional to their distance from Earth. In other specimen’s constituents in the direction per- words, the farther away they are, the faster they pendicular to the image plane are not easily are moving. Because the speeds of galaxies can found. be measured from the Doppler effect, which One way to determine these heights involves shifts the galaxies’ light to the red end of the tomographic electron microscopy, in which a electromagnetic spectrum, their distances can three-dimensional image is reconstructed be determined using the constant of propor- from projected two-dimensional images tionality between speed and distance, known obtained from a range of viewing direc- 2 as the Hubble constant . This central obser- tions. But for imaging at atomic resolution, vation, called Hubble’s law, is crucial evidence this method would require the sample to be for the now accepted view that the Universe mechanically tilted with sub-ångström pre- originated in a Big Bang, as a tiny, unimagina- cision over a large angular range, a feat that bly dense entity that has been expanding ever has not yet been achieved. Moreover, a typical since. What’s more, it provides astronomers electron microscope records only the inten- with a neat way of determining the distances to sity of the electron wave that is scattered by objects, which would otherwise be impossible the sample. The wave’s phase provides much 1 4 JUNE 2012 | V O L 486 | N A TURE | 1 9 7 © 2012 Macmillan Publishers Limited. All rights reserved

RESEARCH NEWS & VIEWS of the important structural information about 1. Van Dyck, D. & Chen, F.-R. Nature 486, 243–246 4. Hsieh, W.-K., Chen, F.-R., Kai, J.-J. & Kirkland, A. I. the sample, but the phase at different image (2012). Ultramicroscopy 98, 99–114 (2004). points is not ordinarily recorded on an electron 2. Hubble, E. Proc. Natl Acad. Sci. USA 15, 168–173 5. Lehmann, M. & Lichte, H. Microsc. Microanal. 8, (1929). 447–466 (2002). micrograph. However, it can be found using a 3. Coene, W. M. J., Thust, A., Op de Beeck, M. & 6. Gabor, D. Nature 161, 777–778 (1948). 3,4 process known as focal series reconstruction , Van Dyck, D. Ultramicroscopy 64, 109–135 (1996). 7. Saldin, D. K. Surf. Rev. Lett. 4, 441–457 (1997). or by creating interference between the scat- tered wave and a known (unscattered) refer- ence wave, as is done in an imaging technique PLANT IMMUNOLOGY 5 called electron holography . Van Dyck and Chen suggest that it is pos- sible to calculate the heights of atoms from A life or death switch the image plane using only one viewing direc- tion, if this phase can also be determined. The authors point out that the phase speed — the The identification of two receptors for salicylic acid reveals how the hormone rate at which the phase changes with scattering controls cell death and survival during plant immune responses, in tissues close angle — near the image of a particular atom to and distant from the site of infection. See Letter p.228 is approximately proportional to the height of that atom. This approximate proportional- ity then allows the height to be determined, ANDREA A. GUST & THORSTEN NÜRNBERGER both cell death at the site of infection, and in rough analogy to Hubble’s law. However, cell survival and immune activation in it should be noted that the proportionality is mmunity to microbial infection is an non-infected tissues. strictly valid only in the vicinity of the atom’s inherent feature of multicellular organisms. In plants, effector-triggered immunity (ETI) projected position in the image plane, and that IIn plants, immune responses are activated is often accompanied by programmed cell its value is approximate because of aberrations when cellular receptors recognize microbial death (PCD) at the infection site. In addition to in the microscope’s lenses. Therefore, the local proteins (effectors) that betray the invader to participating in local immune responses, PCD 1,2 and approximate constant of proportionality the plant’s surveillance system . This activa- triggers long-lasting immunity against a broad allows only the height of that particular atom tion requires the plant hormone salicylic acid, spectrum of microbes throughout the plant — 3 to be measured. which is produced on microbial attack . But a protective mechanism referred to as systemic 3 In applications of holography that have how plants detect the hormone, and how it acquired resistance . Salicylic acid participates captured the public’s imagination, a ghostly performs its immunity-associated functions, in these immune responses by controlling the three-dimensional image of a macroscopic has remained unclear. On page 228 of this movement of a protein called NPR1 (non- 4 object is reconstructed from the information issue, Fu et al. report the identification of expresser of pathogenesis-related genes 1) 5 given by a two-dimensional interference pat- two salicylic acid receptors in the model plant from the cell cytoplasm to the nucleus . Once tern (the hologram) of two laser beams. In this Arabidopsis thaliana, and provide a fascinat- in the nucleus, NPR1 regulates the expres- 6 form of imaging, which was first proposed by ing explanation of how the hormone controls sion of plant defence genes. Because mutant the physicist Dennis Gabor to image micro- scopic objects using electron waves instead of light beams, the macroscopic object may be regarded as an ensemble of point scatterers, and the fact that fringes in the interference pat- tern overlap is no obstacle to correctly recon- structing the spatial positions of these point scatterers. In this technique, the three-dimen- sional nature of the image automatically gives information about the third dimension. This Infected area Non-infected area 7 is also the basis of atomic-source holography , which has been used, for example, to deter- mine the positions (including the heights) of atoms adsorbed on a surface. NPR3 NPR1 NPR4 NPR1 Van Dyck and Chen propose that knowl- edge about the third dimension can instead be Salicylic acid obtained by first reconstructing the normally Programmed cell death Cell survival invisible phase of the electron wave, and then exploiting the analogy with Hubble’s law. They demonstrate their technique for atoms in a sys- Local immunity Systemic immunity tem composed of two layers of graphene — a one-atom-thick, honeycomb-like lattice of carbon. But for the proposed technique to be Figure 1 | Salicylic acid-mediated control of plant cell death and survival. On microbial infection, more generally applicable, it will be necessary to levels of the plant hormone salicylic acid increase, with its concentration decreasing gradually with 4 extend the algorithm to reconstruct truly three- increasing distance from the site of infection. Fu et al. show that at high salicylic acid concentrations — typically found in infected areas of the plant — the receptor NPR3, which binds salicylic acid with dimensional objects, as Gabor envisaged. ■ low affinity, mediates degradation of the cell-death suppressor NPR1 (left panel), thereby favouring programmed cell death and local effector-triggered immunity. However, at the lower salicylic acid Dilano Saldin is in the Department of concentrations typically found in cells distant from the infection site, salicylic acid cannot bind to the Physics, University of Wisconsin-Milwaukee, low-affinity receptor NPR3, so cell death is blocked. In these cells, salicylic acid instead binds to the high- Milwaukee, Wisconsin 53211, USA. affinity receptor NPR4 (right panel), blocking degradation of NPR1, and thereby favouring cell survival e-mail: [email protected] and the expression of genes associated with systemic immunity. 198 | N A TURE | V O L 486 | 14 JUNE 2012 © 2012 Macmillan Publishers Limited. All rights reserved

NEWS & VIEWS RESEARCH plants that are insensitive to salicylic acid and levels to increase systemically as well as locally, such as auxin, gibberellic acid and jasmonic 10 plants that lack NPR1 exhibit similar immune with its concentration decreasing gradually acid . However, NPR3 and NPR4 are the first 6 defects, NPR1 was previously proposed to be with increasing distance from the infection plant-hormone sensors for which differences 8 4 a salicylic acid receptor. However, Fu et al. did site . In cells farther away from the infected in binding affinity have been shown to medi- not detect any physical interaction between area, salicylic acid levels are likely to drop ate differential control of plant responses. salicylic acid and NPR1, suggesting that NPR1 below the concentration required for NPR3- Because most plant hormones regulate does not serve this receptor function. mediated NPR1 degradation and, thus, PCD. multiple aspects of plant life, it is certainly What, then, could be the bona fide salicylic Fu and colleagues propose that, in these cells, possible that other plant hormone receptors acid receptor mediating local and systemic salicylic acid binds instead to the higher- use a comparable mode of action. Consistent 11 immune activation in plants? The research affinity receptor NPR4, which inhibits NPR4- with this idea is the recent identification of group presenting the current paper has previ- mediated NPR1 degradation and thereby auxin hormone-binding proteins that have 7 ously shown that the proper functioning of facilitates NPR1 accumulation, cell survival different ligand affinities, suggesting that NPR1 requires that the protein is broken down and subsequent salicylic acid-dependent gene plants also have means for differential sensing 1 by cellular protein-degradation machinery expression (Fig. 1). Consistent with this model, of auxin . ■ called the proteasome. So Fu and colleagues the authors showed that NPR1 levels are lowest hypothesized that adaptor proteins that link in cells undergoing PCD and highest in cells Andrea A. Gust and Thorsten Nürnberger NPR1 to the proteasome might be receptors surrounding PCD lesions. are in the Centre of Plant Molecular Biology, for salicylic acid. Two members of the NPR Several mutant plants that exhibit runaway Department of Plant Biochemistry, University 9 protein family, NPR3 and NPR4, exhibit a pro- PCD have been identified , and the question of of Tübingen, D-72076 Tübingen, Germany. tein-domain structure that is characteristic of how plants control PCD has been a major area e-mails: [email protected]; such adaptor proteins, leading the authors to of research. Fu and colleagues’ findings provide [email protected] surmise that these proteins could be the protea- compelling evidence that salicylic acid acts as 1. Dodds, P. N. & Rathjen, J. P. Nature Rev. Genet. 11, some adaptors that mediate NPR1 degradation. an immune signal to determine cell fate in plant 539–548 (2010). To validate this assumption, the researchers immunity. Studies investigating plant proteins 2. Jones, J. D. & Dangl, J. L. Nature 444, 323–329 demonstrated that NPR1 is degraded by the associated with abnormal PCD should now (2006). 3. Spoel, S. H. & Dong, X. Nature Rev. Immunol. 12, proteasome in wild-type A. thaliana plants, but examine whether these proteins might con- 89–100 (2012). not in plants in which the genes for NPR3 and tribute to the functionality of NPR3 or NPR4. 4. Fu, Z. Q. et al. Nature 486, 228–232 (2012). NPR4 have both been knocked out. Salicylic acid is the only major plant hor- 5. Mou, Z., Fan, W. & Dong, X. Cell 113, 935–944 (2003). Fu and colleagues used in vitro protein–pro- mone for which the receptor has remained 6. Cao, H., Glazebrook, J., Clarke, J. D., Volko, S. & tein interaction studies to assess the effect of elusive. Fu and colleagues’ demonstration that Dong, X. Cell 88, 57–63 (1997). salicylic acid on the formation of protein com- the two salicylic acid receptors control dis- 7. Spoel, S. H. et al. Cell 137, 860–872 (2009). plexes between NPR1 and NPR3 or NPR4. tinct defence strategies by de-repressing local 8. Enyedi, A. J., Yalpani, N., Silverman, P. & Raskin, I. Proc. Natl Acad. Sci. USA 89, 2480–2484 (1992). The authors found, surprisingly, that salicylic cell death and immunity at the infection site 9. Lam, E. Nature Rev. Mol. Cell Biol. 5, 305–315 acid promotes NPR1–NPR3 interaction, but in one case, and systemic immunity remote (2004). disrupts formation of the NPR1–NPR4 com- from the infection site in the other, is remi- 10. Robert-Seilaniantz, A., Grant, M. & Jones, J. D. Annu. Rev. Phytopathol. 49, 317–343 (2011). plex. Thus it seems that salicylic acid interacts niscent of the de-repression of physiological 11. Calderón Villalobos, L. I. et al. Nature Chem. Biol. 8, physically with NPR3 and NPR4 in a recep- programs enacted by other plant hormones, 477–485 (2012). tor-like manner, but that this inter action has opposing effects on the adaptor proteins’ inter- actions with NPR1. The authors also found ASTRONOMY that although NPR3 and NPR4 both bind to salicylic acid, NPR4 binds with greater affin- ity than does NPR3. Hence, Arabidopsis plants An infant giant contain two salicylic acid receptors, NPR3 and NPR4, which differ in their affinity for the hor- mone and in their roles in NPR1 degradation, Spectroscopic measurements of a galaxy that shines brightly at submillimetre with NPR3 mediating NPR1 breakdown only wavelengths place it in the middle of a nascent galaxy cluster at a scant in the presence of salicylic acid and NPR4 one billion years after the Big Bang. See Letter p.233 only in its absence. What are the biological consequences of NPR3- or NPR4-mediated degradation of ALBERTO D. BOLATTO resulting discovery of a class of luminous NPR1? Fu and colleagues found that both yet elusive galaxies. On page 233 of this 1 local PCD and local ETI responses to bacterial s in many scientific fields, but perhaps issue, Walter et al. describe an analysis that infection were compromised in plants lacking more than in most, advances in tech- advances our understanding of this family of the genes encoding both NPR3 and NPR4. The Anology frequently drive progress in galaxies and closes a chapter on the story of impairment of PCD, combined with the fact astronomy. The deployment of a new instru- their origins. that NPR1 accumulates in the mutant plants ment or a capability can afford a completely Early on, images taken with SCUBA (because it cannot be degraded) suggests that different view of the Universe, opening a revealed a population of galaxies that shine NPR1 suppresses PCD in wild-type plants. window onto an aspect of reality that was pre- brightly at submillimetre wavelengths, prosai- Because salicylic acid levels are highest at viously unsuspected or only theorized. One cally named submillimetre galaxies (SMGs). 8 infection sites , Fu et al. propose that binding such advance occurred in the late 1990s with One of the first deep SCUBA images to 2 of the hormone to the lower-affinity recep- the advent of large-format submillimetre- uncover SMGs was obtained in 1998 through tor NPR3 mediates NPR1 degradation and wave cameras — particularly SCUBA, the observations of the Hubble Deep Field (Fig. 1), de-repression of PCD and ETI in infected Sub millimetre Common-User Bolometer which is perhaps the most emblematic patch cells (Fig. 1). Array mounted on the James Clerk Maxwell of sky observed by the Hubble Space Tele- However, infection causes salicylic acid Telescope in Mauna Kea, Hawaii — and the scope. Surprisingly, SMGs were very faint, or 1 4 JUNE 2012 | V O L 486 | N A TURE | 1 9 9 © 2012 Macmillan Publishers Limited. All rights reserved

RESEARCH NEWS & VIEWS even invisible, in optical images of dust relative to gas in HDF 850.1 is this and other fields. Moreover, the similar to that found in the Milky REF. 2 SCUBA data provided no spectro- Way. Dust is predominantly com- scopic information, and thus no posed of heavy elements (elements direct knowledge of the objects’ other than hydrogen and helium), distance or redshift, which are nec- most of which originate from stel- essary to establish most of a galaxy’s lar explosions known as superno- properties. What were these myste- vae, which are caused by the death rious submillimetre sources? of massive stars. The unexpectedly The poster child for this ques- high abundance of dust relative to tion is HDF 850.1, the brightest gas at this early cosmic epoch indi- SMG in the Hubble Deep Field. cates that heavy-element enrich- Walter and colleagues determine ment of the interstellar medium the galaxy’s redshift, providing an of HDF 850.1 proceeded at an important piece of the SMG puzzle. extremely fast pace. The mecha- Analyses of the galaxies present in nism responsible for creating this optical images at positions coinci- much dust so quickly is not entirely dent, within errors, with those of understood. SCUBA sources suggested from the A remarkable finding is that outset that these sources are located HDF 850.1 is not alone. It is sitting at cosmological distances from in the middle of a clear ‘overdensity’ Earth, corresponding to a time of sources that also includes a rare when the Universe was a fraction quasar (an active galactic nucleus of its present age. The analyses also powered by a supermassive black indicated that SMGs are tremen- hole). Twelve other sources have dously powerful systems — with been identified within a redshift energy outputs of the order of Figure 1 | Structure in the infant Universe. The brightest source in this interval of about 0.03 from the submillimetre-wavelength image of the Hubble Deep Field, obtained using 12 2,3 10 times that of the Sun . Such the SCUBA camera , is a galaxy called HDF 850.1. Walter and colleagues’ galaxy’s location. This interval cor- 2 luminosities imply that, if they are spectroscopic observations indicate that this object is at the centre of a responds to a local depth in the sky 1 powered mostly by star forma- nascent galaxy cluster at redshift 5.183. White and yellow denote bright of about 2.5 megaparsecs (8 mil- tion, SMGs are forming stars at sources; red represents fainter sources. The circle’s diameter is about lion light years), which is also the rates several hundred times that 200 arcseconds (one-tenth of a full Moon). approximate extent of the structure of our Milky Way. Yet dust hides in the sky. This overdensity is one of 5 these starbursts from optical observations, associated with two rotational transitions two spectroscopically verified candidate pro- which could therefore be missing an impor- of the carbon monoxide (CO) molecule to toclusters at such high redshift, and thus repre- tant fraction of the star-formation activity unambiguously determine the redshift. The sents one of the earliest structures known in the 3 occurring in the early Universe . method has recently become feasible thanks Universe — occurring after the epoch at which Although there are indirect indications of to the increasing information-transmission relic radiation from the Big Bang, known as how far away SMGs are located, spectroscopy speed and computing power of (sub)milli- the cosmic microwave background radia- of these sources — and so direct measurement metre-wave interferometric spectrographs, tion, emerged. This discovery lends further of their redshifts — has remained difficult. which can provide instantaneous spectra support to the idea that the most luminous One successful indirect technique relies on spanning tens of gigahertz. Determination SMGs are signposts for rare overdensities in the correlation between an object’s radio and of redshifts at millimetre and submillimetre the overall structure of the Universe. Such far-infrared luminosities, and uses radio wavelengths is a powerful tool, and will be used extremely overdense regions are thought interferometers to pinpoint its precise sky increasingly for the study of the early Universe to have evolved into present-day massive coordinates. Measurement of the source’s red- with new advanced observatories, particularly clusters, and the brightest SMGs in these shift then requires long-exposure spectroscopy the Atacama Large Millimetre Array in Chile’s regions probably became today’s giant ellip- of its optical counterparts using the largest Atacama Desert. tical galaxies at the centres of the clusters’ 6 optical telescopes. The results from studies The authors’ spectroscopic analysis also potential well . The conclusion of the story based on this indirect method indicate that revealed a spectral line associated with ionized for HDF 850.1, then, is that this SMG is most SMGs exist at redshifts of about 1.5–3, carbon. This detection not only confirms the nothing less than an infant giant undergoing around the peak of star-formation activity in SMG redshift, but also supports the idea that a growth spurt. ■ 4 the Universe . Because of the built-in obser- the radiation previously detected by SCUBA vational selection effects of this technique, the stems from a monstrous starburst producing Alberto D. Bolatto is in the Department question of how many SMGs lie at redshifts stars 800 times faster than the present-day of Astronomy, University of Maryland, beyond 3 is still open. SMGs could shine in the Milky Way. Yet the source is completely invis- College Park, Maryland 20742, USA. submillimetre range at much greater distances ible in the deepest optical images, in which e-mail: [email protected] than in the radio range, and so this approach the radiation from young stars is not detected might fail to detect distant SMGs. because of obscuration by dust present in the 1. Walter, F. et al. Nature 486, 233–236 (2012). 2. Hughes, D. H. et al. Nature 394, 241–247 In their study, Walter and collaborators source. This obscuring dust absorbs ultraviolet (1998). used the IRAM Plateau de Bure Interferom- and optical light and re-emits it at far-infrared 3. Blain, A. W., Smail, I., Ivison, R. J. & Kneib, J.-P. eter near Montmaur, France, to obtain direct wavelengths, which are subsequently ‘red- Mon. Not. R. Astron. Soc. 302, 632–648 (1999). spectro scopic measurements of HDF 850.1, shifted’ (stretched) by the expansion of the 4. Chapman, S. C., Blain, A. W., Smail, I. & Ivison, R. J. Astrophys. J. 622, 772–796 (2005). pinpointing its redshift at 5.183 — a scant Universe and so fall in the submillimetre band 5. Capak, P. L. et al. Nature 470, 233–235 (2011). 1.1 billion years after the Big Bang. The tech- observed by SCUBA. 6. Tacconi, L. J. et al. Astrophys. J. 680, 246–262 nique relies on detecting the spectral lines The authors find that the abundance of (2008). 200 | N A TURE | V O L 486 | 14 JUNE 2012 © 2012 Macmillan Publishers Limited. All rights reserved

ARTICLE doi:10.1038/nature11204 Visualizing heavy fermions emerging in a quantum critical Kondo lattice 1 1 2 2 1 3 Pegor Aynajian *, Eduardo H. da Silva Neto *, Andra ´s Gyenis , Ryan E. Baumbach , J. D. Thompson , Zachary Fisk , Eric D. Bauer 2 & Ali Yazdani 1 In solids containing elements with f orbitals, the interaction between f-electron spins and those of itinerant electrons leads to the development of low-energy fermionic excitations with a heavy effective mass. These excitations are fundamental to the appearance of unconventional superconductivity and non-Fermi-liquid behaviour observed in actinide- and lanthanide-based compounds. Here we use spectroscopic mapping with the scanning tunnelling microscope to detect the emergence of heavy excitations with lowering of temperature in a prototypical family of cerium-based heavy-fermion compounds.Wedemonstratethe sensitivity ofthe tunnellingprocessto thecompositenature oftheseheavyquasiparticles, which arises from quantum entanglement of itinerant conduction and f electrons. Scattering and interference of the composite quasiparticles is used to resolve their energy–momentum structure and to extract their mass enhancement, which develops with decreasing temperature. The lifetime of the emergent heavy quasiparticles reveals signatures of enhanced scattering and their spectral lineshape shows evidence of energy–temperature scaling. These findings demonstrate that proximity to a quantum critical point results in critical damping of the emergent heavy excitation of our Kondo lattice system. Localized abc Itinerant A local magnetic moment occurs when a strongly interacting quantum state, such as an atomic d or f orbital, cannot be doubly CeRhln 5 1 occupied owing to strong on-site Coulomb repulsion . In the presence of a dilute concentration of such magnetic moments in a metal, spin- Temperature NFL flip scattering of conduction electrons from these local moments AFM CeColn 5 HFL results in their collective magnetic screening below a characteristic 2 temperature called the Kondo temperature, T K (Fig. 1a) . In materials SC QCP where local moments are arranged in a dense periodic array, the Tuning parameter so-called Kondo lattice, the deconfinementof localizedorbitalsthrough de f 100 1.3 2.5 their hybridization with the conduction electrons results in composite spd band 6 h f band low-energy excitations with a heavy effective mass (Fig. 1b). Tuning the HF bands ~2Q 2 50 1.1 hybridization between f orbitals and itinerant electrons can destabilize 2Q the heavy Fermi-liquid state towards an antiferromagnetically ordered Normalized conductance 0.9 Normalized conductance 1.5 3–8 ground state at a quantum critical point (QCP) . In proximity to such Energy (meV) 0 6 h a quantum phase transition—between itinerancy and localization of f 0.7 1 electrons—many heavy-fermion systems exhibit unconventional –50 Strong 9 superconductivity at low temperatures (Fig. 1c) . coupling to 0.5 Strong coupling 0.5 spd electrons to f electrons Thermodynamic and transport studies have long provided evidence –100 0 1 –100 –50 0 50 100 –100 –50 0 50 100 for heavy quasiparticles, their unconventional superconductivity and k (//a,0) Energy (meV) Energy (meV) non-Fermi-liquid behaviour in a variety of material systems 9–14 . Figure 1 | Tunnelling into a Kondo lattice. a,b,Schematicrepresentationsofa However, the emergence of a coherent band of heavy quasiparticles near single-impurityKondoeffect (a)andaKondolattice(b),illustratingthe screening theFermienergyinaKondolatticesystemisstillnotwellunderstood 14–17 . (hybridization) of the local moments (red arrows) by the itinerant conduction Part of the challenge has been the inability of spectroscopic measure- electrons (green arrows). c, Schematic phase diagram of heavy-fermion systems ments to probe thedevelopment of heavy quasiparticles with lowering of where the electronic ground state can be tuned from antiferromagnetism (AFM) temperature and to characterize their properties with high energy reso- with localized f moments to a heavy Fermi liquid (HFL) with itinerant f electrons. lution. Such precise measurements of heavy-fermion formation are not At low temperatures, superconductivity (SC) sets in near the quantum critical onlyrequiredforunderstandingthenatureoftheseelectronicexcitations point (QCP) from a non-Fermi liquid (NFL). Insets show cartoon pictures of the 18 close to quantum phase transitions , but are also critical to identifying spin fluctuations in the different phases. d, Bare electronic bands (dashed lines; spd and f ) and hybridized heavy-fermion bands (HF; solid lines) displaying a the source of unconventional superconductivity near such transitions. direct (2v) and an indirect (D h ) hybridization gap. e, Tunnelling spectrum computed from the hybridized band structure in d for a tunnelling ratio t f / Composite heavy-fermion excitations t c 520.025, showing sensitivity to the direct hybridization gap (2v). f,Similar The emergence of composite heavy fermions in a Kondo lattice can be spectra computed with t f /t c 520.37, showing sensitivity to the indirect gap (D h ). considered as a result of the hybridization of two electronic bands: one See Supplementary Information section I for details of the model. 1 2 3 Joseph Henry Laboratories and Department of Physics, Princeton University, Princeton, New Jersey 08544, USA. Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA. Department of Physics and Astronomy, University of California, Irvine, California 92697, USA. *These authors contributed equally to this work. 1 4 JU NE 20 12 | V O L 486 | N A TU RE | 2 01 ©2012 Macmillan Publishers Limited. All rights reserved

RESEARCH ARTICLE dispersing band due to conduction electrons and one weakly dispers- Figure 2 shows STM images of a single crystal of CeCoIn 5 that has ing band originating from localized f electrons (dashed lines in been cleaved in situ in our variable temperature ultrahigh-vacuum Fig. 1d). This hybridization generates low-energy quasiparticles that STM. In this family of compounds, the cleaving process results in the are a mixture of conduction electrons and f electrons with a modified exposure of multiple surfaces terminated with different chemical band structure characterized by the so-called direct (2v) and indirect compositions. The crystal symmetry necessarily requires multiple (D h ) hybridization gaps, as shown in Fig. 1d 17,19 . Various theoretical surfaces for cleaved samples, as no two equivalent consecutive layers approaches, including several numerical studies, reproduce the generic occur within the unit cell. Therefore breaking of any single chemical composite band structure shown in Fig. 1d 20–24 . Recent theoretical bond will result in different layer terminations on the two sides of the modelling has also shown that tunnelling spectroscopy can be a cleaved sample. Experiments on many cleaved samples have revealed powerful probe of this composite nature of heavy fermions 25–28 . three different surfaces, two of which are atomically ordered (termed ˚ Depending on the relative tunnelling amplitudes to the light conduction surfaces A and B in Fig. 2a, b) with a periodicity of ,4.6 A corres- (t c )ortotheheavyf-like(t f )componentsofthecompositequasiparticles, ponding to the lattice constant of the bulk crystal structure, whereas and due to their interference, tunnelling spectroscopy can be sensitive to the third surface (termed surface C, Fig. 2b) is reconstructed. different features of the hybridized band structure. Figure 1d–f shows Comparison of the relative heights of the sub-unit-cell steps between examples of model calculations (see Supplementary Information section the different layers (Fig. 2c, d) to the crystal structure determined I) illustrating the sensitivity of the spectra to predominant tunnelling to from scattering experiments 41 suggests that exposed surfaces A, B the light (Fig. 1e) or heavy (Fig. 1f) electronic states. and C correspond to the Ce–In, Co and In 2 layers, respectively. Recent advances in the application of scanning tunnelling micro- Experiments on CeCo(In 0.9985 Hg 0.0015 ) 5 and CeRhIn 5 reveal similar scopy (STM) to heavy fermions are providing a new approach to results, where cleaving exposes the corresponding multiple layers in examining the correlated electrons in these systems with high energy those compounds (see Supplementary Information section II). Hg and spatial resolutions. STM and point-contact experiments on defects in CeCoIn 5 at this concentration have negligible influence heavy-fermion compounds have shown evidence for hybridization on its thermodynamic and transport properties and are introduced of the conduction electrons with the f orbitals and have been used for the scattering experiments described below . 42 to probe the so-called hidden order phase transition involving heavy f electrons in URu 2 Si 2 (refs 29–32). Sudden onset of the hidden order Signatures of hybridization and composite excitations phase seems to give rise to strong modification of the band structure in Spectroscopic measurements of CeCoIn 5 show the sensitivity of the URu 2 Si 2 as detected by STM measurements 30,31 . However, these tunnelling process to the composite nature of the hybridized heavy- changes are correlated with the phase transition into the hidden order fermion states. Tunnelling spectra on surface A (identified as the at 17.5 K rather than being the generic physics of heavy Fermi liquids Ce–In layer) of CeCo(In 0.9985 Hg 0.0015 ) 5 show that on cooling the that should appear at higher temperatures and evolve smoothly sample dramatic changes develop in the spectra in an asymmetric with lowering of temperature. Direct experimental observation of fashion about the Fermi energy (Fig. 3a). (The same behaviour is also the gradual formation of heavy quasiparticles with decreasing tem- observed in CeCoIn 5 ; see Supplementary Information section III.) perature and evidence of their composite nature, which is ubiquitous to all heavy fermions, as well as examination of their properties in a Surface A b Surface B Surface C proximity to QCPs, have remained out of the reach of STM and other 5 0.5 4 spectroscopic measurements. pm pm pm CeMIn 5 as a model heavy-fermion system –5 –0.5 –4 To provide a controlled study of the emergence of heavy-fermion excitations within a Kondo lattice system that can be tuned close to a QCP, we carried out studies on the CeMIn 5 (with M 5 Co, Rh) material system. These so-called 115 compounds (the chemical formula could be written Ce 1 M 1 In 5 ) offer the possibility of tuning 25 Å 50 Å the interaction between the f orbitals of Ce and the itinerant spd conduction electrons using isovalent substitutions at the transition c d Ce-In metal site within the same tetragonal crystal structure. Consequently, In the ground state of this system can be tuned (in stoichiometric com- A Co 2 pounds) between antiferromagnetism, as in CeRhIn 5 (Ne ´el temper- C A ature T N 5 3.5 K), to superconductivity, as observed in CeCoIn 5 0 A (superconducting transition temperature T c 5 2.3 K) and CeIrIn 5 3.0 2.34 9 (T c 5 0.4 K) . Previous studies indicate that CeCoIn 5 is very close to B 2.5 C 1.44 a QCP 33–36 , whereas CeRhIn 5 can be tuned close to this transition with Å 5.0 B 1.1 application of pressure 7,37 . These experiments confirm that super- 3.5 3.78 conductivity in the 115 system emerges at low temperatures close to 7.5 0 100 200 A 300 a QCP from heavy low-energy excitations that developed at high Å temperature 7,9,36 . More specifically, transport studies show a drop in Figure 2 | STM topographies on CeCoIn 5 .a, Constant current topographic the electrical resistivity of CeCoIn 5 around 50 K (which has been image (1200 mV, 200pA) showing an atomically ordered surface (termed ˚ interpreted as evidence for the development of a coherent heavy surface A) with a lattice constant of ,4.6A. b, Topographic image (2200mV, quasiparticle band) followed by a T-linear resistivity at lower temper- 200pA) showing two consecutive layers: a distinct atomically ordered surface ˚ 38 ature (above T c ) — a behaviour that has been associated with the (termed surface B, lattice constant ,4.6A, dark blue) and a reconstructed proximity to the QCP. Quantum oscillations and thermodynamic surface (termed surface C, light blue). Insets in a and b show magnified images ˚ 2 (453 45 A ) of the three different surfaces. c, Constant current topographic measurements find a heavy electron effective mass (10–50 m 0 , where image (2150 mV, 365pA) displaying all three surfaces (the derivative of the m 0 is the bare electron mass) for CeCoIn 5 , whereas in the same tem- topography is shown to enhance contrast). d, A line section through the perature range the f electrons in CeRhIn 5 are effectively decoupled different surfaces (solid line in c) showing the relative step heights (left) from the conduction electrons 39,40 . compared to the bulk crystal structure (right). 2 0 2| N A T U R E |V O L 4 8 6 |1 4J U N E2 0 1 2 ©2012 Macmillan Publishers Limited. All rights reserved

ARTICLE RESEARCH ac ordered surfaces of CeCo(In 0.9985 Hg 0.0015 ) 5 . Following recent theoretical efforts 26,27 , we compute spectroscopic properties of a Normalized conductance 0.8 70 K 0.8 18.9 meV spd-like electrons hybridizes with a narrow band of f-like electrons 1 1 model band structure in which a single hole-like itinerant band of (see Supplementary Information section I for details of the model). CeCo(In 0.9985 Hg 0.0015 ) 5 The results of our calculations (Fig. 3c, d) are sensitive to the ratio of 60 K 16.8 meV tunnelling (t f /t c ) into the heavy f states to tunnelling into the light 50 K 14.7 meV 40 K conduction band—a behaviour that explains the differences between 30 K 12.6 meV 20 K 10.5 meV the tunnelling processes on the different cleaved surfaces (Fig. 3a, b). CeRhIn 5 8.4 meV 20 K Although naively one would expect that tunnelling to the heavy 0.6 0.6 –60 –30 0 30 60 –60 –30 0 30 60 excitations would be more pronounced on the Ce–In layer, recent bd first principles calculations show that the amplitude of the hybridiza- 1.2 1.2 tionofthe f states withthe out-of-plane spd electrons canberemarkably Normalized conductance CeCo(In 0.9985 Hg 0.0015 ) 5 1 18.9 meV electrons . larger than the amplitude of the hybridization with the in-plane spd 21 Visualizing quasiparticle mass enhancement To directly probe the energy–momentum structure of heavy 16.8 meV 40 K 68 K 14.7 meV 20 K 50 K troscopic mapping with the STM that enables us to visualize the 10.5 meV 0.8 60 K 30 K 0.8 12.6 meV quasiparticles in the 115 material systems, we have carried out spec- CeRhIn 5 8.4 meV scattering and interference of these quasiparticle excitations from 20 K impurities or structural defects. Elastic scattering of quasiparticles –60 –30 0 30 60 –60 –30 0 30 60 Bias (meV) Energy (meV) from these imperfections gives rise to standing waves in the conduc- tance maps at wavelengths corresponding to 2p/q, where q 5 k f 2 k i Figure 3 | Composite nature of heavy-fermion excitations. a Averaged is the momentum transfer between initial (k i ) and final (k f ) states at tunnelling spectra (2150 mV, 200pA) measured on surface A of CeCo(In 0.9985 Hg 0.0015 ) 5 for different temperatures (T, in K; solid lines) and on the same energy. We expect that those q with the strongest intensity the corresponding surface A of CeRhIn 5 at 20 K (dashed line). b, Averaged connect regions of high density of states on the contours of constant tunnelling spectra (2150 mV, 200pA) measured on surface B of energy, and hence provide energy–momentum information about CeCo(In 0.9985 Hg 0.0015 ) 5 for different temperatures (T, in K; solid lines) and on the quasiparticle excitations. We characterize the scattering q using corresponding surface B of CeRhIn 5 at 20 K (dashed line). c, d, Tunnelling discrete Fourier transforms (DFTs) of STM conductance maps spectra computed for t f /t c 520.01 (c) and t f /t c 520.20 (d) for selected values measured at different energies. The presence of Hg substitutions in of c f (in meV; solid lines). See Supplementary Information section I for details CeCo(In 0.9985 Hg 0.0015 ) 5 provides a sufficient number of scattering of the model. centres to enhance signal to noise ratio for such quasiparticle interference (QPI) measurements. The redistribution of the spectra observed on this surface is consistent Figure 4a shows examples of energy-resolved STM conductance with a tunnelling process that is dominated by coupling to the light maps on surface A of CeCo(In 0.9985 Hg 0.0015 ) 5 measured at 20 K; the conduction electrons and displays signatures of the direct hybridiza- maps display signatures of scattering and interference of quasiparticles tion gap (2v) experienced by this component of the heavy-fermion from defects and step edges. These conductance maps show clear excitations (for example, see Fig. 1d, e). In contrast to these observa- changes of the wavelength of the modulations as a function of energy. Perhaps the most noticeable are the changes around each random tions, similar measurements on the corresponding surface of CeRhIn 5 show spectra that are featureless in the same temperature range defect (see Supplementary Information section II for the correspond- (Fig. 3a, dashed line) and are consistent with the more localized nature ing STM image showing the location of the Hg defects). Figure 4b of the Ce f orbitals in CeRhIn 5 as compared to CeCoIn 5 . The hybrid- shows DFTs of such maps; sharp non-dispersive Bragg peaks (at the ization gap structure in CeCoIn 5 is also centred above the chemical corners,(62p/a,0),(0,62p/a))correspondingtotheatomiclatticeare potential (8 meV, see Fig. 3a), which makes access difficult for angle- seen, as well as other features (concentric square-like shapes) that resolved photoemission experiments 43–45 —the typical technique used rapidly disperse with energy, collapse (Fig. 4b; 0 meV) and then dis- for probing electronic band structure in solids. appear (Fig. 4b; 9 meV) near the Fermi energy. We have carried out The composite nature of the heavy-fermion excitations manifests such measurements both at low temperatures(20 K, Fig. 4b), where the itself by displaying different spectroscopic characteristics for tunnelling spectrum shows signatures of hybridization between conduction elec- into the different atomic layers. Figure 3b shows spectra measured on trons and f orbitals, and at high temperatures (70K, Fig. 4c), where surface B (identified as Co) of CeCo(In 0.9985 Hg 0.0015 ) 5 that look very such features are considerably weakened (for example, Fig. 4c; 2 meV, differentfromthosemeasuredonsurfaceA(Fig.3a).Inthetemperature 10 meV). As a control experiment, we have also carried out the same range where spectra on surface A (Fig. 3a) develop a depletion of measurements on the corresponding surface of CeRhIn 5 (Fig. 4d), for spectralweightneartheFermienergy,surfaceBshowsasharpenhance- which signatures of heavy electron behaviour are absent (for example, ment of spectral weight within the same energy window (Fig. 3b). With Fig. 3a) in the same temperature window (20 K). Although further lowering of temperature, the enhanced tunnelling on surface B understanding details of the QPI in Fig. 4 requires detailed modelling evolvesintoa double-peakstructure.Asa controlexperiment,measure- of the band structure of the 115 compounds, the square-like patterns ments on the corresponding surface in CeRhIn 5 , once again, display observed in the data correspond to scattering wavevectors that can be no sharp features in the same temperature and energy windows identified from the calculated local-density approximation (LDA) (Fig. 3b, dashed line). The spectroscopic features of surface B of band structure (see Supplementary Information section V). 46 CeCo(In 0.9985 Hg 0.0015 ) 5 display the characteristic signatures of We find that analysing the features of the energy-resolved DFT dominant tunnelling to the f component of the heavy quasiparticles, maps provides direct evidence formass enhancement of quasiparticles, which reside near the Fermi energy and are expected to display the in unison with related signatures in the tunnelling spectra. Figure 5a indirect hybridization gap (D h ; see Fig. 1d, f). and b shows line sections of the DFT maps plotted along two high- Modelling the tunnelling to composite heavy excitations can repro- symmetry directions (the thick white lines in Fig. 4b) as a function of duce our spectroscopic measurements on the two different atomically energy for CeCo(In 0.9985 Hg 0.0015 ) 5 at 20 K, and in Fig. 5c we show their 1 4 JU NE 20 12 | V OL 486 | N A T U R E | 203 ©2012 Macmillan Publishers Limited. 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RESEARCH ARTICLE CeCo(In Hg ) CeRhIn 0.9985 0.0015 5 5 abc 60 abcd m*/m o 10 60 CeCo(In 0.9985 Hg 0.0015 ) 5 PSD 60 T = 20 K T = 20 K T = 70 K T = 20 K Energy (meV) 40 0 0.4 0.5 –20 0 0 –70 meV –70 meV 2//a,0 –60 meV –50 meV 20 1 40 30 20 q (2π/a,0) –20 0,2//a –40 –40 –30 –38 meV –38 meV –37 meV –35 meV –60 T = 20 K –60 T = 20 K T = 20 K –60 0.15 0.25 0.35 0.45 0.55 0.65 0.25 0.35 0.45 0.55 0.65 0.6 0.8 1.0 de f PSD CeCo(In 0.9985 Hg 0.0015 ) 5 60 40 40 Energy (meV) –20 0 –20 0 0 0 meV 0 meV 2 meV 0 meV 20 20 30 –40 –40 –30 T = 70 K T = 70 K T = 70 K –60 –60 –60 0.15 0.25 0.35 0.45 0.55 0.65 0.25 0.35 0.45 0.55 0.65 0.6 0.8 1.0 9 meV 9 meV 10 meV 5 meV ghi PSD 60 60 CeRhIn 5 60 Energy (meV) 40 0 20 0 30 40 20 0 53 meV 53 meV 53 meV 55 meV –20 –20 –40 –40 –30 –60 T = 20 K –60 T = 20 K T = 20 K –60 0.15 0.25 0.35 0.45 0.55 0.65 0.25 0.35 0.45 0.55 0.65 0.6 0.8 1.0 q (2π/a,0) q (π/a, π/a) Norm. cond. Normalized conductance PSD PSD PSD Figure 5 | Visualizing quasiparticle mass enhancement. a, b, Energy– Figure 4 | Spectroscopic mapping of quasiparticle interference (QPI). a, b, Real space (a) and corresponding DFT (b) of conductance maps momentum structure of the QPI bands extracted from line sections (solid white (2200mV, 1.6 nA) at selected energies (top left of each panel) measured on lines in Fig. 4b) along the atomic direction (2p/a,0) (a) and along the zone surface A of CeCo(In 0.9985 Hg 0.0015 ) 5 at 20 K. c, d, Similar DFTs for diagonal (p/a, p/a)(b) in CeCo(In 0.9985 Hg 0.0015 ) 5 at 20 K. The solid red line CeCo(In 0.9985 Hg 0.0015 ) 5 at 70 K (2150 mV, 1.5nA; c) andon thecorresponding represents a fourth-order polynomial fit to the data. Inset in a shows the surface A for CeRhIn 5 at 20 K (2200mV, 3.0nA; d) at selected energies. effective mass m*/m 0 as a function of momenta obtained from the curvature 2 21 2 2 Arrows indicate the position of the Bragg peaks at (2p/a, 0) and (0, 2p/a). All (J B (d E/dq ) ) of the outer band (solid red line in a). c, Average spectrum DFTs were four-fold symmetrized (due to the four-fold crystal symmetry) to on surface A of CeCo(In 0.9985 Hg 0.0015 ) 5 at 20 K, reflecting the suppression of enhance resolution (see Supplementary Information section IV). The intensity scattering in the QPI bands. Similar measurements performed in is represented on a linear scale. PSD, power spectrum density. CeCo(In 0.9985 Hg 0.0015 ) 5 at 70 K (d–f) and in CeRhIn 5 at 20 K (g–i). The intensity is represented on a linear scale. corresponding spatially averaged spectrum. The square-like regions of enhanced quasiparticle scattering in Fig. 4b appear in the line sections Signatures of quantum criticality of Fig. 5a, b as energy-dependent bands of scattering, which become Theabilitytotunnelthroughthefcomponentoftheheavyquasiparticles strongly energy dependent near the Fermi energy. Clearly the scatter- on surface B of CeCo(In 0.9985 Hg 0.0015 ) 5 provides an opportunity to ing of the quasiparticle excitations in the energy window near the probe the lifetime of the heavy quasiparticles as a function of temper- direct hybridization gap has a flatter energy–momentum structure ature in a system that is close to a QCP. The narrow dispersion of the f than that at energies away from the gap. This is a direct signature of band results in a direct connection between the experimentally the quasiparticles acquiring heavy effective mass at low energies near measured width of the peak in the density of states near the Fermi the Fermi energy. Detailed analysis of one of the QPI bands estimates energy (Fig. 3b) and the lifetime of the heavy quasiparticles. Analysis the mass enhancement near theFermi energyto beabout 30m 0 (Fig.5a of this width measured at different temperatures is displayed in Fig. 6a inset), a value which is close to that seen in quantum oscillation studies (see Supplementary Information section VI), and shows a strong of CeCoIn 5 (refs 39, 40). Our model calculation, which describes the temperature dependence with a finite intercept (,3.5 meV) in the spectroscopic lineshapes on the different surfaces, can also be limit of zero temperature. The finite width at zero temperature can be extended to reproduce the signatures of mass enhancement in the understood as a consequence of a small but finite dispersion of the f QPI data (see Supplementary Information section I). band as well as a finite probability of tunnelling into the spd electrons (see Supplementary Information section I). However, the large linear ContrastinglowtemperatureQPIpatternsonCeCo(In 0.9985 Hg 0.0015 ) 5 to measurements on the same compound at high temperatures (70 K, slope in Fig. 6a (that is, larger than 3/2 k B T,where k B is Boltzmann’s Fig. 5d, e), where the hybridization gap is weak (Fig. 5f), or to measure- constant and T is temperature) indicates that the lifetime of the f ments on CeRhIn 5 (20 K, Fig. 5g, h), where signatures of a hybridiza- electrons, as opposed to thermal broadening, is strongly influencing tion gap are absent in the tunnelling spectra (Fig. 5i), confirms that the spectra and its temperature dependence. Consistent with this the development of this gap results in apparent splitting of the bands observation, we also find that to capture the temperature evolution and is responsible for both the scattering and the heavy effective of the spectra in Fig. 3b, we have to use rather large values of scattering mass in the QPI measurements. Furthermore, these measurements rate (inverse lifetime) of the f component of the heavy quasiparticles, show that the underlying band structure responsible for the scattering c f 5 B/t f (where B is Planck’s constant h divided by 2p and t f is the wavevectors away from the Fermi energy is relatively similar between lifetime of the quasiparticles), in our model calculations (Fig. 3d). CeCo(In 0.9985 Hg 0.0015 ) 5 and CeRhIn 5 . Only when f electrons of the A T-linear scattering rate (or inverse lifetime) for the heavy Kondo lattice begin to strongly hybridize with conduction electrons quasiparticles is consistent with the expectation that CeCoIn 5 is close and modify the band structure within a relatively narrow energy to a QCP, because for systems tuned close to such transitions, window (30 meV) do we see signatures of heavy-fermion excitations temperature is the only relevant energy scale available to determine in QPI measurements, signalling a transition from a small to a large the quasiparticle lifetime, resulting in B/t f / k B T (refs 18, 47). Fermi surface (see Supplementary Information section V). However, a more precise signature of a QCP would be the observation 2 0 4| N A T U R E |V O L 4 8 6 |1 4J U N E 2 0 1 2 ©2012 Macmillan Publishers Limited. All rights reserved

ARTICLE RESEARCH a 30 heavy-fermion systems near QCPs 3,5,49,50 . However, here we show for the first time that the signatures of scaling and critical phenomena FWHM Thermally deconvoluted appear in the spectroscopic properties of the quasiparticle excitations. FWHM 3/2 k T B Conclusion and outlook FWHM (meV) 20 The experimental results and the model calculations presented here provide a comprehensive picture of how heavy-fermion excitations in the 115 Ce-based Kondo lattice systems emerge with lowering of 10 temperature or as a result of chemical tuning of the interaction between the Ce f electrons and the conduction electrons. The changes in the scattering properties of the quasiparticles directly signal the flattening of their energy–momentum structure and the emergence of heavy quasiparticles near the Fermi energy. Such changes are also 0 consistent with the predicted evolution from a small to a large Fermi 0 20 40 60 Temperature (K) surface as the localized f electrons hybridize with the conduction electrons. The sensitivity of the tunnelling to the surface termination b 0.45 20 K and the successful modelling of these data provide direct spectro- 30 K scopic evidence of the composite nature of heavy fermions and offer 40 K a unique method to disentangle their components. 50 K 0.4 Our experiments also demonstrate that the emergent heavy 60 K quasiparticles in our system are strongly scattered and show signatures (dI/dV) s (k B T 0.53 ) 0.35 0.35 of scaling associated with critical damping of excitations in proximity to a QCP. Like many other heavy-fermion systems, thermodynamic and transport studies of the 115 systems have shown evidence of D 0.55 quantum criticality, but such signatures have not been previously 0.3 isolated in an electron spectroscopy measurement, as described here. Such spectroscopic signatures are direct evidence for the breakdown of coherent fermionic excitations approaching a QCP. Future 0.75 0.6 1 1.4 E extension of our measurements to lower temperatures could probe 0.25 –3 –2 –1 0 1 2 3 the interplay between quantum fluctuations and the appearance of E/k T superconductivity, an issue which continues to be one of the most B debated in condensed matter physics. Figure 6 | Signatures of quantum criticality. a, Full width at half maximum (FWHM) of the heavy quasiparticle peak (red squares) as a function of METHODS SUMMARY temperature extracted from a Gaussian fit to the sharp lineshape of the spectra of Fig. 3b after a smooth background subtraction (see Supplementary The single crystals of CeCoIn 5 , CeCo(In 0.9985 Hg 0.0015 ) 5 and CeRhIn 5 used for this Information section VI). Blue squares represent the thermally deconvoluted study were grown from excess indium at Los Alamos National Laboratory. Small, FWHM corresponding to the intrinsic width in the absence of thermal flat crystals were oriented along the crystallographic axes and cut into sizes 3 broadening. The green line represents 3/2k B T. Error bars, 1 s.d. b, Energy– suitable for STM measurements (,2 3 2 3 0.2 mm ). The samples were cleaved temperature scaling of the different spectra of Fig. 3b, after the removal of a on a surface perpendicular to the c axis in ultrahigh vacuum (UHV) and trans- temperature independent background (see Supplementary Information ferred in situ to the microscope head. Differential conductance (dI/dV) measure- sections VI and VII), within a narrow energy window near the Fermi energy. ments were performed using standard lock-in techniques. Approximately ten Key shows temperature T in K. Inset shows the ‘goodness of the collapse’ different samples of CeCoIn 5 , CeCo(In 0.9985 Hg 0.0015 ) 5 and CeRhIn 5 were success- (colour scale) as a function of the critical exponents a and b. fully cleaved and studied, and the spectroscopic data collected were reproducible on the corresponding identical exposed surfaces of the different samples. Spectra measured at different locations on each surface showed negligible variations. The of energy–temperature scaling of experimental quantities near such spectra presented here (in the main paper) are averaged over approximately 200 transitions. In fact, recent theoretical work suggests that the instability individual spectra measured over an area of at least 100 A ˚ 3 100 A ˚ . The spectro- of the Fermi surface near a QCP should result in scaling properties of scopic lineshapes showed negligible variations as the tip height was varied (vari- the single-particle excitation that can be directly probed in measure- ation of the tunnelling current by two orders of magnitude). ments of the tunnelling density of states . To test this hypothesis, we 48 examine the lineshape of the tunnelling spectra on surface B of Received 21 December 2011; accepted 30 April 2012. CeCo(In 0.9985 Hg 0.0015 ) 5 near the chemical potential at different 1. Anderson,P.W.Localizedmagneticstatesinmetals.Phys.Rev.124,41–53(1961). temperatures, and attempt to scale the data (Fig. 3b) by plotting 2. Shiba, H&. Kuramoto, Y. (eds) Kondo effect — 40 years after the discovery. J. Phys. b a (dI/dV) S (k B T ) as a function of E/(k B T) . (Here (dI/dV) S is the Soc. Jpn 74, 1–238 (2005). background-subtracted spectra of Fig. 3b (see Supplementary Informa- 3. Schroder, A. et al. 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Supplementary Information is linked to the online version of the paper at Phys. Rev. Lett. 103, 206402 (2009). www.nature.com/nature. 27. Figgins, J. & Morr, D. K. Differential conductance and quantum interference in Acknowledgements We acknowledge discussions with P. W. Anderson, E. Abrahams, Kondo systems. Phys. Rev. Lett. 104, 187202 (2010). 28. Wo ¨lfle, P., Dubi, Y. & Balatsky, A. V. Tunneling into clean heavy fermion P. Coleman, N. Curro, D. Pines, D. Morr, T. Senthil, S. Sachdev, M. Vojta, C. Varma and C. V. Parker. Work at Princeton University was primarily supported by a grant from the compounds: origin of the Fano line shape. Phys. Rev. Lett. 105, 246401 (2010). 29. Park,W.K.,Sarrao, J.L.,Thompson,J.D.& Greene, L.H.Andreevreflection inheavy- DOEOffice of Basic Energy Sciences (DE-FG02-07ER46419). Theinstrumentation and fermion superconductors and order parameter symmetry in CeCoIn 5 . Phys. Rev. infrastructure at the Princeton Nanoscale Microscopy Laboratory are also supported Lett. 100, 177001 (2008). by grants from the NSF-DMR1104612 and NSF-MRSEC programmes through the 30. Aynajian, P. et al. Visualizing the formation of the Kondo lattice and the hidden Princeton Center for Complex Materials (DMR-0819860), and the W.M. Keck order in URu 2 Si 2 . Proc. Natl Acad. Sci. USA 107, 10383–10388 (2010). foundation aswellastheEricand Linda Schmidt TransformativefundatPrinceton. P.A. 31. Schmidt,A.R. etal.Imaging the Fano latticeto ‘hidden order’ transition inURu 2 Si 2 . acknowledges postdoctoral fellowship support through the Princeton Center for Nature 465, 570–576 (2010). Complex Materials funded by the NSF-MRSEC programme. Work at Los Alamos 32. Ernst, S. et al. Emerging local Kondo screening and spatial coherence in the heavy- National Laboratory was performed under the auspices of the US Department of fermion metal YbRh 2 Si 2 . Nature 474, 362–366 (2011). Energy, Office of Basic Energy Sciences, Division of Materials Science and Engineering. 33. Sidorov, V.A.etal. Superconductivityandquantumcriticality inCeCoIn 5 . Phys.Rev. Z.F. acknowledges support from NSF-DMR-0801253. Lett. 89, 157004 (2002). Author Contributions P.A., E.H.d.S.N. and A.G. performed the STM measurements. P.A. 34. Paglione, J. et al. Field-induced quantum critical point in CeCoIn 5 . Phys. Rev. Lett. and E.H.d.S.N. analysed the data. E.H.d.S.N. and P.A. performed the theoretical 91, 246405 (2003). calculations. R.E.B., J.D.T., Z.F. and E.D.B. synthesized and characterized the materials. 35. Paglione, J., Sayles, T. A., Ho, P. C., Jeffries, J. R. & Maple, M. B. Incoherent non- A.Y., P.A. and E.H.d.S.N. wrote the manuscript. All authors commented on the Fermi-liquid scattering in a Kondo lattice. Nature Phys. 3, 703–706 (2007). manuscript. 36. Urbano, R. R. et al. Interacting antiferromagnetic droplets in quantum critical CeCoIn 5 . Phys. Rev. Lett. 99, 146402 (2007). Author Information Reprints and permissions information is available at 37. Hegger, H. et al. Pressure-induced superconductivity in quasi-2D CeRhIn 5 . Phys. www.nature.com/reprints. The authors declare no competing financial interests. Rev. Lett. 84, 4986–4989 (2000). Readers are welcome to comment on the online version of this article at 38. Petrovic, C. et al. Heavy-fermion superconductivity in CeCoIn 5 at 2.3 K. J. Phys. www.nature.com/nature. Correspondence and requests for materials should be Condens. Matter 13, 337–342 (2001). addressed to A.Y. ([email protected]). 2 0 6| N A T U R E |V O L 4 8 6 |1 4J U N E 2 0 1 2 ©2012 Macmillan Publishers Limited. All rights reserved

ARTICLE doi:10.1038/nature11234 Structure, function and diversity of the healthy human microbiome The Human Microbiome Project Consortium* Studies of the human microbiome have revealed that even healthy individuals differ remarkably in the microbes that occupy habitats such as the gut, skin and vagina. Much of this diversity remains unexplained, although diet, environment, host genetics and early microbial exposure have all been implicated. Accordingly, to characterize the ecology of human-associated microbial communities, the Human Microbiome Project has analysed the largest cohort and set of distinct, clinically relevant body habitats so far. We found the diversity and abundance of each habitat’s signature microbes to vary widely even among healthy subjects, with strong niche specialization both within and among individuals. The project encountered an estimated 81–99% of the genera, enzyme families and community configurations occupied by the healthy Western microbiome. Metagenomic carriage of metabolic pathways was stable among individuals despite variation in community structure, and ethnic/racial background proved to be one of the strongest associations of both pathways and microbes with clinical metadata. These results thus delineate the range of structural and functional configurations normal in the microbial communities of a healthy population, enabling future characterization of the epidemiology, ecology and translational applications of the human microbiome. A total of 4,788 specimens from 242 screened and phenotyped adults 1 involving microbiome samples collected from healthy volunteers at (129 males, 113 females) were available for this study, representing the two distinct geographic locations in the United States, we have defined majority of the target Human Microbiome Project (HMP) cohort of themicrobial communitiesat each body habitat, encountering 81–99% 300 individuals. Adult subjects lacking evidence of disease were of predicted genera and saturating the range of overall community recruited based on a lengthy list of exclusion criteria; we will refer configurations (Fig. 1, Supplementary Fig. 1 and Supplementary to them here as ‘healthy’, as defined by the consortium clinical Table 1; see also Fig. 4). Oral and stool communities were especially sampling criteria (K. Aagaard et al., manuscript submitted). diverse in terms of community membership, expanding prior observa- 5 Women were sampled at 18 body habitats, men at 15 (excluding three tions , and vaginal sites harboured particularly simple communities vaginal sites), distributed among fivemajor bodyareas.Ninespecimens (Fig. 1a). This study established that these patterns of alpha diversity were collected from the oral cavity and oropharynx: saliva; buccal (within samples) differed markedly from comparisons between mucosa (cheek), keratinized gingiva (gums), palate, tonsils, throat samples from the same habitat among subjects (beta diversity, andtonguesofttissues,andsupra-andsubgingivaldentalplaque(tooth Fig. 1b). For example, the saliva had among the highest median alpha biofilm above and below the gum). Four skin specimens were collected diversities of operationaltaxonomic units (OTUs, roughly species level from the two retroauricular creases (behind each ear) and the two classification, see http://hmpdacc.org/HMQCP), but one of the lowest antecubital fossae (inner elbows), and one specimen for the anterior beta diversities—so although each individual’s saliva was ecologically nares (nostrils). A self-collected stool specimen represented the micro- rich, members of thepopulationshared similar organisms. Conversely, biota of the lower gastrointestinal tract, and three vaginal specimens the antecubital fossae (skin) had the highest beta diversity but were were collected from the vaginal introitus, midpoint and posterior intermediateinalphadiversity.Thevaginahadthelowestalphadiversity, fornix. To evaluate within-subject stability of the microbiome, 131 with quite low beta diversity at the genus level but very high among individuals in these data were sampled at an additional time point OTUs due to the presence of distinct Lactobacillus spp. (Fig. 1b). The (mean 219 days and s.d. 69 days after firstsampling, range35–404 days). primary patterns of variation in community structure followed the After quality control, these specimens were used for 16S rRNA gene major body habitat groups (oral, skin, gut and vaginal), defining as a analysis via 454 pyrosequencing (abbreviated henceforth as 16S profil- resultthecompleterangeofpopulation-widebetween-subjectvariation ing, mean 5,408 and s.d. 4,605 filtered sequences per sample); to assess in human microbiome habitats (Fig. 1c). Within-subject variation over function, 681 samples were sequenced using paired-end Illumina time was consistently lower than between-subject variation, both in shotgun metagenomic reads (mean 2.9gigabases (Gb) and s.d. 2.1 Gb organismal composition and in metabolic function (Fig. 1d). The 1 per sample) . More details on data generation are provided in related uniqueness of each individual’s microbial community thus seems to 1 HMP publications and in Supplementary Methods. bestableover time(relativetothe population asa whole), which may be another feature of the human microbiome specifically associated with Microbial diversity of healthy humans health. The diversity of microbes within a given body habitat can be defined as No taxa were observed to be universally present among all body the number and abundance distribution of distinct types of organisms, habitats and individuals at the sequencing depth employed here, which has been linked to several human diseases: low diversity in the unlike several pathways (Fig. 2 and Supplementary Fig. 2, see below), 2,3 gut to obesity and inflammatoryboweldisease , for example, and high although several clades demonstrated broad prevalence and relatively 4 6,7 diversity in the vagina to bacterial vaginosis . For this large study abundant carriage patterns . Instead, as suggested by individually *Lists of participants and their affiliations appear at the end of the paper. 14 JUN E 2012 | V OL 486 | N A T U R E | 207 ©2012 Macmillan Publishers Limited. All rights reserved

RESEARCH ARTICLE a Within-sample alpha diversity c Phylotypes (16S) Gastrointestinal OTUs (16S) 4 Reference genomes (WGS) log 2 (relative alpha diversity) 2 0 PC2 (4.4%) Urogenital Oral Metabolic modules (WGS) Gene index (WGS) Skin –2 –4 Nasal b Between-sample beta diversity d 5 PC1 (13%) 0.6 Technical replicates (16S) Between visits (16S) Between visits (WGS) 4 3 Between subjects (16S) Between subjects (WGS) 0.4 log 2 (relative beta diversity) 0.2 log 2 (relative diversity) 2 1 0 0.0 –0.2 –2 –0.4 –1 –3 –0.6 –4 Urogenital Skin Nasal Gastrointestinal Oral Throat Stool Saliva Anterior nares L antecubital fossa R antecubital fossa L retroauricular crease R retroauricular crease Buccal mucosa Keratinized gingiva Hard palate Palatine tonsils Tongue dorsum Subgingival plaque Supragingival plaque Mid-vagina Posterior fornix Vaginal introitus Figure 1 | Diversity of the human microbiome is concordant among alpha- and beta-diversity are not directly comparable, changes in structure measures, unique to each individual, and strongly determined by microbial among communities (a) occupy a wider dynamic range than do changes within habitat. a, Alpha diversity within subjects by body habitat, grouped by area, as communities among individuals (b). c, Principal coordinates plot showing measured using the relative inverse Simpson index of genus-level phylotypes variation among samples demonstrates that primary clustering is by body area, (cyan), 16S rRNA gene OTUs (blue), shotgun metagenomic reads matched to with the oral, gastrointestinal, skin and urogenital habitats separate; the nares reference genomes (orange), functional modules (dark orange), and enzyme habitat bridges oral and skin habitats. d, Repeated samples from the same families (yellow). The mouth generally shows high within-subject diversity and subject (blue) are more similar than microbiomes from different subjects (red). the vagina low diversity, with other habitats intermediate; variation among Technical replicates (grey) are in turn more similar; these patterns are individuals often exceeds variation among body habitats. b, Bray–Curtis beta consistent for all body habitats and for both phylogenetic and metabolic 1 diversity among subjects by body habitat, colours as for a. Skin differs most community composition. See previously described sample counts for all between subjects, with oral habitats and vaginal genera more stable. Although comparisons. focused studies 2,3,5,8,9 , each body habitat in almost every subject was Allergy and Infectious Diseases) class A–C pathogens above 0.1% characterized by one or a few signature taxa making up the plurality of abundance (aside from Staphylococcus aureus and Escherichia coli) the community (Fig. 3). Signature clades at the genus level formed on from the healthy microbiome, but the near-ubiquity and broad dis- 12 average anywhere from 17% to 84% of their respective body habitats, tribution of opportunistic ‘pathogens’ as defined by PATRIC . completely absent in some communities (0% at this level of detection) Canonical pathogens including Vibrio cholerae, Mycobacterium and representing the entire population (100%) in others. Notably, less avium, Campylobacter jejuni and Salmonella enterica were not dominant taxa were also highly personalized, both among individuals detected at this level of sensitivity. Helicobacter pylori was found in and body habitats; in the oral cavity, for example, most habitats are only two stool samples, both at ,0.01%, and E. coli was present at dominated by Streptococcus, but these are followed in abundance by .0.1% abundance in 15% of stool microbiomes (.0% abundance in Haemophilus in the buccal mucosa, Actinomyces in the supragingival 61%). Similar species-level observations were obtained for a small plaque, and Prevotella in the immediately adjacent (but low oxygen) subset of stool samples with 454 pyrosequencing metagenomics data 10 subgingival plaque . using PhylOTU 13,14 . In total 56 of 327 PATRIC pathogens were Additional taxonomic detail of the human microbiome was pro- detected in the healthy microbiome (at .1% prevalence of .0.1% vided by identifying unique marker sequences in metagenomic data 11 abundance, Supplementary Table 2), all opportunistic and, strikingly, (Fig. 3a) to complement 16S profiling (Fig. 3b). These two profiles typically prevalent both among hosts and habitats. The latter is in were typically in close agreement (Supplementary Fig. 3), with the contrast to many of the most abundant signature taxa, which were former in some cases offering more specific information on members usually more habitat-specific and variable among hosts (Fig. 3a, b). of signature genera differentially present within habitats (for example, This overall absence of particularly detrimental microbes supports the vaginal Prevotella amnii and gut Prevotella copri) or among indivi- hypothesis that even given this cohort’s high diversity, the microbiota duals (for example, vaginal Lactobacillus spp.) One application of this tend to occupy a range of configurations in health distinct from many specificity was to confirm the absence of NIAID (National Institute of of the disease perturbations studied to date 3,15 . 2 0 8| N A T U R E |V O L 4 8 6 |1 4J U N E 2 0 1 2 ©2012 Macmillan Publishers Limited. All rights reserved

ARTICLE RESEARCH a Phyla Firmicutes Actinobacteria Bacteroidetes Proteobacteria Fusobacteria Tenericutes Spirochaetes Cyanobacteria Verrucomicrobia TM7 b Metabolic pathways Central carbohydrate metabolism Cofactor and vitamin biosynthesis Oligosaccharide and polyol transport system Purine metabolism ATP synthesis Phosphate and amino acid transport system Aminoacyl tRNA Pyrimidine metabolism Ribosome Aromatic amino acid metabolism Anterior nares RC Buccal mucosa Supragingival plaque Tongue dorsum Stool Posterior fornix Figure 2 | Carriage of microbial taxa varies while metabolic pathways retroauricular crease. A plurality of most communities’ memberships consists remain stable within a healthy population. a, b, Vertical bars represent of a single dominant phylum (and often genus; see Supplementary Fig. 2), but microbiome samples by body habitat in the seven locations with both shotgun this is universal neither to all body habitats nor to all individuals. Conversely, and 16S data; bars indicate relative abundances colored by microbial phyla most metabolic pathways are evenly distributed and prevalent across both from binned OTUs (a) and metabolic modules (b). Legend indicates most individuals and body habitats. abundant phyla/pathways by average within one or more body habitats; RC, Mean non-zero abundance (size) and population prevalence (intensity) of microbial clades ab Abundant genera (16S data) Abundant species (metagenomic data) Lactobacillus Lactobacillus crispatus Propionibacterium Propionibacterium acnes Streptococcus mitis Streptococcus Lactobacillus iners Bacteroides Lactobacillus gasseri Corynebacterium Prevotella amnii Staphylococcus Lactobacillus jensenii Moraxella Prevotella copri Haemophilus Corynebacterium kroppenstedtii Prevotella Corynebacterium accolens Anterior nares Buccal mucosa Supragingival plaque Veillonella Anterior nares Retroauricular crease Hard palate Throat Tongue dorsum Supragingival plaque Posterior fornix Stool Stool Saliva Mid-vagina Posterior fornix Buccal mucosa Tongue dorsum Vaginal introitus Antecubital fossa Keratinized gingiva Subgingival plaque Retroauricular crease Prevalence (%) 0 100 Actinobacteria|Actinobacteria 100% Bacteroidetes|Bacteroidia Firmicutes|Bacilli 0% Firmicutes|Negativicutes Beta-diversity added by sampled microbial communities Proteobacteria|Gammaproteobacteria Abundance Enzyme classes (metagenomic data) OTUs (16S data) c Abundant PATRIC ‘pathogens’ (metagenomic data) d e 0.5 Subgingival plaque Anterior nares Propionibacterium acnes 0.3 Anterior nares Saliva Attached keratinized gingiva Right antecubital fossa Streptococcus mitis Right retroauricular crease 0.4 Supragingival plaque Left antecubital fossa Palatine tonsils Corynebacterium matruchotii Left retroauricular crease Stool Right retroauricular crease Buccal mucosa Staphylococcus aureus Posterior fornix Tongue dorsum Left retroauricular crease Staphylococcus epidermidis 0.2 Stool 0.3 Throat Vaginal introitus Hard palate Mid-vagina Bifidobacterium dentium Diversity (Bray–Curtis) Supragingival plaque Diversity (weighted UniFrac) Buccal mucosa Posterior fornix Tongue dorsum Alistipes putredinis Bacteroides vulgatus 0.2 Gardnerella vaginalis 0.1 Rothia mucilaginosa 0.1 Stool 0.0 0.0 0 20 40 60 80 100 0 50 100 150 200 250 300 Anterior nares Posterior fornix Buccal mucosa Tongue dorsum Samples Samples Supragingival plaque Retroauricular crease Figure 3 | Abundant taxa in the human microbiome that have been and sequencing depths of the HMP have well defined the microbiome at all metagenomically and taxonomically well defined in the HMP population. assayed body sites, as assessed by saturation of added community metabolic a–c, Prevalence (intensity, colour denoting phylum/class)and abundancewhen configurations (rarefaction of minimum Bray–Curtis beta-diversity of present (size) of clades in the healthy microbiome. The most abundant metagenomic enzyme class abundances to nearest neighbour, inter-quartile metagenomically-identified species (a), 16S-identified genera (b) and range over 100 samples) (d) and phylogenetic configurations (minimum 16S 12 PATRIC pathogens (metagenomic) (c) are shown. d, e, The population size OTU weighted UniFrac distance to nearest neighbour) (e). 14 JUN E 2 012 | V O L 486 | N A T U R E | 209 ©2012 Macmillan Publishers Limited. All rights reserved

RESEARCH ARTICLE Carriage of specific microbes for example differentially eliminating S. mitis carriage of the V-type Inter-individual variation in the microbiome proved to be specific, ATPase or choline binding proteins cbp6 and cbp12 among subsets of functionally relevant and personalized. One example of this is illu- the host population (Fig. 4d). These losses were easily observable by strated by the Streptococcus spp. of the oral cavity. The genus dominates comparison to reference isolate genomes, and these initial findings 16 the oropharynx , with different species abundant within each sampled indicate that microbial strain- and host-specific gene gains and body habitat (see http://hmpdacc.org/HMSMCP) and, even at the polymorphisms may be similarly ubiquitous. species level, marked differences in carriage within each habitat among Other examples of functionally relevant inter-individual variation individuals (Fig. 4a). As the ratio of pan- to core-genomes is high in at the species and strain levels occurred throughout the microbiome. 17 many human-associated microbes , this variation in abundance could In the gut, Bacteroides fragilis has been shown to prime T-cell 18 be due to selective pressures acting on pathways differentially present responses in animal models via the capsular polysaccharide A , among Streptococcus species or strains (Fig. 4b). Indeed, we observed and in the HMP stool samples this taxon was carried at a level of at extensive strain-level genomic variation within microbial species in least 0.1% in 16% of samples (over 1% abundance in 3%). Bacteroides this population, enriched for host-specific structural variants around thetaiotaomicron has been studied for its effect on host gastrointestinal 19 genomic islands (Fig. 4c). Even with respect to the single Streptococcus metabolism andwaslikewisecommonat46%prevalence.Ontheskin, mitis strain B6, gene losses associated with these events were common, S. aureus, of particular interest as the cause of methicillin-resistant M00280: PTS system, glucitol/sorbitol-specifc II cpnt M00283: PTS system, ascorbate-specifc II cpnt M00270: PTS system, trehalose-specifc II cpnt a b M00274: PTS system, mannitol-specifc II cpnt M00269: PTS system, sucrose-specifc II cpnt 00265: PTS system, glucose-specifc II cpnt Average relative Other M00277: PTS system, N-acetylgalactosamine−specifc II cpnt Streptococcus abundance Relative Streptococcus species abundance (%) 40 S. thermophilus M00159: V-type ATPase, prokaryotes M00279: PTS system, galactitol-specifc II cpnt 60 S. sanguinis S. gordonii S. mitis 50 S. oralis S. mitis S. peroris S. vestibularis S. australis 30 S. infantis S. thermophilus LMD9 S. salivarius 20 S. suis 05ZYH33 S. parasanguinis S. sanguinis SK36 S. pyogenes SF370 S. pneumoniae TIGR4 10 S. mutans UA159 S. mitis B6 S. gordonii Challis 0 127 tongue dorsum samples V CH c Streptococcus mitis B6 1 log(RPKM) 0 –1 Genomic islands 1 500 1000 1500 2000 kb d log(RPKM) –2 –1 0 0.5 1 V-type H + ATPase subunits Choline-binding proteins Streptococcus mitis 127 tongue dorsum samples Figure 4 | Microbial carriage varies between subjects down to the species c, Comparative genomic coverage for the single Streptococcus mitis B6 strain. and strain level. Metagenomic reads from 127 tongue samples spanning 90 Grey dots are median reads per kilobase per million reads (RPKM) for 1-kb subjects were processed with MetaPhlAn to determine relative abundances for windows, grey bars are the 25th to 75th percentiles across all samples, red line each species. a, Relativeabundances of 11 distinct Streptococcus spp. In addition the LOWESS-smoothed average. Red bars at the bottom highlight predicted 27 to variation in broader clades (see Fig. 2), individual species within a single genomic islands . Large, discrete, and highly variable islands are commonly 1 habitat demonstrate a wide range of compositional variation. Inset illustrates under-represented. d, Two islands are highlighted, V (V-type H ATPase average tongue sample composition. b, Metabolic modules present/absent subunits I, K, E, C, F, A and B) and CH (choline-binding proteins cbp6 and 24 (grey/white) in KEGG reference genomes of tongue streptococci denote cbp12), indicating functional cohesion of strain-specific gene loss within selected areas of strain-specific functional differentiation. cpnt, component. individual human hosts. 21 0 | NA TUR E | V O L 4 86 | 1 4 J U N E 2 0 1 2 ©2012 Macmillan Publishers Limited. All rights reserved

ARTICLE RESEARCH S. aureus (MRSA) infections, had 29% nasal and 4% skin carriage global standard deviations 5 0.0023 with s.d. 5 0.0033) secretion sys- rates, roughly as expected . Close phylogenetic relatives such as tems, indicating a high degree of host–microbe and microbe–microbe 20 Staphylococcus epidermidis (itself considered commensal) were, in interactions in the healthy human microbiota. This high variability contrast, universal on the skin and present in 93% of nares samples, was particularly present in the oral cavity; for phosphate, mono- and and at the opposite extreme Pseudomonas aeruginosa (a representative di-saccharide, and amino acid transport in the mucosa; and also for Gram-negative skin pathogen) was completely absent from both body lipopolysaccharide biosynthesis and spermidine/putrescine synthesis habitats(0%atthislevelofdetection).Theseandthedataabovesuggest and transport on the plaque and tongue (http://hmpdacc.org/ that the carriage pattern of some species in the human microbiome HMMRC). The stability and high metagenomic abundance of this may be analogous to genetic traits, where recessive alleles of modest housekeeping ‘core’ contrasts with the greater variability and lower risk are maintained in a population. In the case of the human micro- abundance of niche-specific functionality in rare but consistently biome, high-risk pathogens remain absent, whereas species that pose a present pathways; for example, spermidine biosynthesis, methionine modest degree of risk also seem to be stably maintained in this degradation and hydrogen sulphide production, all examples highly ecological niche. prevalent in gastrointestinal body sites (non-zero in .92% of Finally, microorganisms within and among body habitats exhibited samples) but at very low abundance (median relative abundance relationships suggestive of driving physical factors such as oxygen, , 0.0052). This ‘long tail’ of low-abundance genes and pathways also moisture and pH, host immunological factors, and microbial inter- probably encodes much of the uncharacterized biomolecular function 21 actions such as mutualism or competition (Supplementary Fig. 4). and metabolism of these metagenomes, the expression levels of which Both overall community similarity and microbial co-occurrence and remain to be explored in future metatranscriptomic studies. co-exclusion across the human microbiome grouped the 18 body Protein families showed diversity and prevalence trends similar to habitats together into four clusters corresponding to the five target those of full pathways, ranging from maxima of only ,16,000 unique body areas (Supplementary Fig. 4a, b). There was little distinction families per community in the vagina to almost 400,000 in the oral among different vaginal sites, with Lactobacillus spp. dominating all cavity (Fig. 1a, b; http://hmpdacc.org/HMGI). A remarkable fraction three and correlating in abundance. However, Lactobacillus varied of these families were indeed functionally uncharacterized, including inversely with the Actinobacteria and Bacteroidetes (see Supplemen- those detected by read mapping, with a minimum in the oral cavity 9 tary Fig. 4c and Figs 2 and 3), as also observed in a previous cohort . (mean 58% s.d. 6.8%) and maximum in the nares (mean 77% s.d. Gut microbiota relationships primarily comprised inverse associa- 11%). Likewise, many genes annotated from assemblies could not tions with the Bacteroides, which ranged from dominant in some be assigned a metabolic function, with a minimum in the vagina subjects to a minority in others who carried a greater diversity of (mean 78% s.d. 3.4%) and maximum in the gut (mean 86% s.d. Firmicutes. A similar progression was evident in the skin communities, 0.9%). The latter range did not differ substantially by body habitat dominated by one of Staphylococcus (phylum Firmicutes), and is in close agreement with previous comprehensive gene catalogues 3 Propionibacterium,or Corynebacterium (both phylum Actinobacteria), of the gut metagenome . Taken together with the microbial variation with a continuum of oral organisms (for example, Streptococcus) appear- observed above throughout the human microbiome, functional vari- ing in nares communities (Supplementary Fig. 4c). These observations ation among individuals might indicate pathways of particular import- suggest that microbial community structure in these individuals ance in maintaining community structure in the face of personalized may sometimes occupy discrete configurations and under other immune, environmental or dietary exposures among these subjects. circumstances vary continuously, a topic addressed in more detail by Determining the functions of uncharacterized core and variable protein several HMP investigations (ref. 6 and unpublished results). An families will be especially essential in understanding role of the micro- individual’s location within such configurations is indicativeof current biota in health and disease. microbial carriage (including pathogens) and of the community’s ability to resist future pathogen acquisition or dysbiosis; it may thus Correlations with host phenotype prove to be associated with disease susceptibility or other phenotypic We finally examined relationships associating both clades and characteristics. metabolism in the microbiota with host properties such as age, gender, body mass index (BMI), and other available clinical metadata Microbiome metabolism and function (Fig. 5 and Supplementary Table 3). Using a sparse multivariate As the first study to include both marker gene and metagenomic data model, 960 microbial, enzymatic or pathway abundances were sig- across body habitats from a large human population, we additionally nificantly associated with one or more of 15 subject phenotype and assessed the ecology of microbial metabolic and functional pathways sample metadata features. A wide variety of taxa, gene families and in these communities. We reconstructed the relative abundances of metabolic pathways were differentially distributed with subject 22 pathways in community metagenomes , which were much more ethnicity at every body habitat (Fig. 5a), representing the phenotype constant and evenly diverse than were organismal abundances with the greatest number (266 at false discovery rate (FDR) q , 0.2) of (Fig. 2b, see also Fig. 1), confirming this as an ecological property of total associations with the microbiome. Vaginal pH has also been 2 the entire human microbiome . We were likewise able to determine observed to correlate with microbiome composition , and we detected 9 for the first time that taxonomic and functional alpha diversity across in this population both the expected reduction in Lactobacillus at high microbial communities significantly correlate (Spearman of inverse pH and a corresponding increase in metabolic diversity (Fig. 5b). Simpson’s r 5 0.60, P 5 3.6 3 10 267 , n 5 661), the latter within a Intriguingly, and not previously observed, subject age was most asso- more proscribed range of community configurations (Supplemen- ciated with a collection of highly differential metagenomically tary Fig. 5). encoded pathways on the skin (Fig. 5c), as well as shifts in skin clades 24 Unlike microbial taxa, several pathways were ubiquitous among including retroauricular Firmicutes (P 5 1.0 3 10 , q 5 0.033). The individuals and body habitats. The most abundant of these ‘core’ examples of associations with ethnicity and vaginal pH are among the pathways include the ribosome and translational machinery, nucleo- strongest associations with the microbiome, however, and most cor- tide charging and ATP synthesis, and glycolysis, and reflect the basics relates (for example, with subject BMI, Fig. 5d) are more representa- of host-associated microbial life. Also in contrast to taxa, few path- tively modest. This lower degree of correlation held for most available ways were highly variable among subjects within any body habitat; biometrics (gender, temperature, blood pressure, etc.), with even the exceptions included the Sec (orally, pathway relative abundance most significant associations possessing generally low effect sizes and s.d. 5 0.0052; total mean of oral standard deviations 5 0.0011 with considerable unexplained variance. We conclude that most variation s.d. 5 0.0016) and Tat (globally, pathway s.d. 5 0.0055; mean of in the human microbiome is not well explained by these phenotypic 14 JU NE 201 2 | V O L 486 | N A T URE | 2 1 1 ©2012 Macmillan Publishers Limited. All rights reserved

RESEARCH ARTICLE a M00028: ornithine biosynthesis, glutamate => ornithine (tongue dorsum) M00026: histidine biosynthesis, PRPP => histidine (tongue dorsum) Proteobacteria|Gammaproteobacteria|Enterobacteriales|Enterobacteriaceae|Klebsiella (anterior nares) Norm. rel. abundance Proteobacteria|Gammaproteobacteria|Pseudomonadales (antecubital fossa) Mexican Black Asian Race/ethnicity Puerto Rican White b M00222: Phosphate transport system, Actinobacteria, posterior fornix mid-vagina 3.5 4.0 4.5 3.5 4.0 4.5 5.0 Vaginal pH (posterior fornix) c M00012: Glyoxylate cycle, Firmicutes, retroauricular crease retroauricular crease 20 25 30 35 20 25 30 35 40 Age d M00004: Pentose phosphate pathway, tongue dorsum Pseudomonadaceae, throat 20 25 30 20 25 30 BMI Figure 5 | Microbial community membership and function correlates with indicating best simple linear fit. Race/ethnicity and vaginal pH are particularly host phenotype and sample metadata. a–d, The pathway and clade strong associations; age and BMI are more representative of typically modest abundances most significantly associated (all FDR q , 0.2) using a multivariate phenotypic associations (Supplementary Table 3), suggesting that variation in linear model with subject race or ethnicity (a), vaginal posterior fornix pH the healthy microbiota may correspond to other host or environmental factors. (b), subject age (c) and BMI (d). Scatter plots of samples are shown with lines metadata, and other potentially important factors such as short- and variabilityinthehumanmicrobiometoaskhowandwhythesemicrobial long-term diet, daily cycles, founder effects such as mode of delivery, communities vary so extensively. and host genetics should be considered in future analyses. Many details remain for further work to fill in, building on this reference study. How do early colonization and lifelong change vary Conclusions among body habitats? Do epidemiological patterns of transmission of beneficial or harmless microbes mirror patterns of transmission of This extensive sampling of the human microbiome across many sub- jects and body habitats provides an initial characterization of the pathogens? Which co-occurrences among microbes reflect shared normal microbiota of healthy adults in a Western population. The response to the environment, as opposed to competitive or mutualistic large sample size and consistent sampling of many sites from the same interactions? How large a role does host immunity or genetics play in individuals allows for the first time an understanding of the relationships shaping patterns of diversity, and how do the patterns observed in this among microbes, and between the microbiome and clinical parameters, NorthAmericanpopulationcomparetothosearoundtheworld?Future that underpin the basis for individual variation—variation that may studies building on the gene and organism catalogues established by the ultimately be critical for understanding microbiome-based disorders. Human Microbiome Project, including increasingly detailed investi- gations of metatranscriptomes and metaproteomes, will help to unravel Clinical studies of the microbiome will be able to leverage the resulting extensive catalogues of taxa, pathways and genes , although they must these open questions and allow us to more fully understand the links 1 between the human microbiome, health and disease. also still include carefully matched internal controls. The uniqueness of each individual’s microbiome even in this reference population argues METHODS SUMMARY for future studies to consider prospective within-subjects designs where Microbiome samples were collected from up to 18 body sites at one or two time possible. The HMP’s unique combination of organismal and functional points from 242 individuals clinically screened for absence of disease (K. Aagaard data across body habitats, encompassing both 16S and metagenomic et al., manuscript submitted). Samples were subjected to 16S ribosomal RNA gene profiling, together with detailed characterization of each subject, has pyrosequencing (454 Life Sciences), and a subset were shotgun-sequenced for allowed us and subsequent studies to move beyond the observation of metagenomics using the Illumina GAIIx platform . 16S data processing and 1 2 1 2 | NA TUR E | V OL 48 6 | 14 JUN E 2 01 2 ©2012 Macmillan Publishers Limited. All rights reserved

ARTICLE RESEARCH 23 diversity estimates were performed using QIIME , and metagenomic data were International Human Microbiome Consortium, particularly the investigators of the 22 11 taxonomically profiled using MetaPhlAn , metabolically profiled by HUMAnN , MetaHIT project, for advancing human microbiome research. Data repository and assembled for gene annotation and clustering into a unique catalogue . 1 management was provided by the National Center for Biotechnology Information and the Intramural Research Program of the NIH National Library of Medicine. We 12 Potential pathogens were identified using the PATRIC database , isolate reference appreciate the participation of the individuals from the Saint Louis, Missouri, and 24 genome annotations drawn from KEGG , and reference genome mapping per- Houston, Texas areas who made this study possible. This research was supported in 25 formed by BWA to a reduced set of genomes to which short reads could be part by National Institutes of Health grants U54HG004969 to B.W.B.; U54HG003273 matched . Microbial associationswereassessed bysimilaritymeasuresaccounting to R.A.G.; U54HG004973 to R.A.G., S.K.H. and J.F.P.; U54HG003067 to E.S.Lander; 26 21 for compositionality , and phenotypic association testing was performed in R. All U54AI084844 to K.E.N.; N01AI30071 to R.L.Strausberg; U54HG004968 to G.M.W.; U01HG004866 to O.R.W.; U54HG003079 to R.K.W.; R01HG005969 to C.H.; data and additional protocol details are available at http://hmpdacc.org. Full R01HG004872 to R.K.; R01HG004885 to M.P.; R01HG005975 to P.D.S.; methods accompany this paper in the Supplementary Information. R01HG004908 to Y.Y.; R01HG004900 to M.K.Cho and P. Sankar; R01HG005171 to D.E.H.; R01HG004853 to A.L.M.; R01HG004856 to R.R.; R01HG004877 to R.R.S. and Received 2 November 2011; accepted 16 May 2012. R.F.; R01HG005172 to P. Spicer.; R01HG004857 to M.P.; R01HG004906 to T.M.S.; R21HG005811 to E.A.V.; M.J.B. was supported by UH2AR057506; G.A.B. was 1. The HumanMicrobiomeProjectConsortium. Aframeworkforhuman microbiome supported by UH2AI083263 and UH3AI083263 (G.A.B., C. N. Cornelissen, L. K. Eaves research. Nature http://dx.doi.org/10.1038/nature11209 (this issue). and J. F. Strauss); S.M.H. was supported by UH3DK083993 (V. B. Young, E. B. Chang, 2. Turnbaugh, P. J. et al. A core gut microbiome in obese and lean twins. Nature 457, F. Meyer, T. M. S., M. L. Sogin, J. M. Tiedje); K.P.R. was supported by UH2DK083990 (J. 480–484 (2009). V.); J.A.S. and H.H.K. were supported by UH2AR057504 and UH3AR057504 (J.A.S.); 3. Qin, J. et al. A human gut microbial gene catalogue established by metagenomic DP2OD001500 to K.M.A.; N01HG62088 to the Coriell Institute for Medical Research; sequencing. Nature 464, 59–65 (2010). U01DE016937 to F.E.D.; S.K.H. was supported by RC1DE0202098 and 4. Fredricks, D. N., Fiedler, T. L. & Marrazzo, J. M. Molecular identification of R01DE021574 (S.K.H. and H. Li); J.I. was supported by R21CA139193 (J.I. and bacteria associated with bacterial vaginosis. N. Engl. J. Med. 353, 1899–1911 D. S. Michaud); K.P.L. was supported by P30DE020751 (D. J. Smith); Army Research (2005). Office grant W911NF-11-1-0473 to C.H.; National Science Foundation grants NSF 5. Costello, E. K. et al. Bacterial community variation in human body habitats across DBI-1053486 to C.H. and NSF IIS-0812111 to M.P.; The Office of Science of the US space and time. Science 326, 1694–1697 (2009). Department of Energy under Contract No. DE-AC02-05CH11231 for P.S. C.; LANL 6. Huse, S., Ye, Y., Zhou, Y. & Fodor, A. A core human microbiome as viewed through Laboratory-Directed Research and Development grant 20100034DR and the US 16s rRNA sequences clusters. PLoS ONE http://dx.doi.org/10.1371/ Defense Threat Reduction Agency grants B104153I and B084531I to P.S.C.; Research journal.pone.0034242 (14 June 2012). Foundation - Flanders (FWO) grant to K.F. and J.Raes; R.K. is an HHMI Early Career 7. Li, K., Bihan, M., Yooseph, S. & Methe, B. A. Analyses of the microbial diversity Scientist; Gordon& Betty MooreFoundationfunding and institutionalfunding fromthe across the human microbiome. PLoS ONE http://dx.doi.org/10.1371/ J. David Gladstone Institutes to K.S.P.; A.M.S. was supported by fellowships provided by journal.pone.0032118 (14 June 2012). the Rackham Graduate School and the NIH Molecular Mechanisms in Microbial 8. Grice, E. A. et al. Topographical and temporal diversity of the human skin Pathogenesis Training Grant T32AI007528; a Crohn’s and Colitis Foundation of microbiome. Science 324, 1190–1192 (2009). Canada Grant in Aid of Research to E.A.V.; 2010 IBM Faculty Award to K.C.W.; analysis 9. Ravel, J. et al. 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Acknowledgements The Consortium would like to thank our external scientific Readers are welcome to comment on the online version of this article at advisory board: R. Blumberg, J. Davies, R. Holt, P. Ossorio, F. Ouellette, G. Schoolnik and www.nature.com/nature. Correspondence and requests for materials should be A. Williamson. We would also like to thank our collaborators throughout the addressed to C.H. ([email protected]). 14 JU NE 201 2 | V O L 486 | N A T UR E | 2 1 3 ©2012 Macmillan Publishers Limited. All rights reserved