From artificial intelligence to natural pattern formation, Alan Turing’s creativity lives on PAGE455 : STAGE GET WITH THE INDUSTRIAL vouasano Tse CRAFT PROGRAMS RELATIONS 08> How actors stir Computer codes and the European PhD programme | | ll the emotions publication process breaks new ground ll PAGE 465 PAGE 485 PAGESST 7700281085095)R&D Systems Tools for Cell Biology Research™ Development Endocrinology Glycobiology immunoLOGICAL | Neuroscience Infitratin of tumors by regulatory T (reg) cls suppresses ant-tumor immune responses and Proteases promotes tumor growth, Asa result, mechanisms ta inhibit Tg el effeentition expansion, recruitment and function re being widely explored, With over 25 years of experince developing Signal Transduction and manufacturing immunolog-rlated research reagents, R&D Systems the lagi choice for products you can trust. 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WV y a | “CX OT III RESEARCH™Antibodies and Related Reagents for Signal Transduction Research Gene qe yonte brat ‘pice ‘amar re crane C2 TA peas MAPK aaa PE | (oot) paket 5 Sec> Bxrceere: eae Ma 8 sey arene ons matanees pf mc oe mare OMFS? evan tas ee wow celsigaleom A ae The Highest Quality MAPK Antibodies e from C Unparalleled product quality, validation, and technical support Over 30 thoroughly validated MAPK Antibos Call Signaling Technology (CST™) offers the , h la i extensive in-house validation in a wide range widest range of phospho and total protein of applications means that optimization is not loft MAPK antibodies. These reagents are the most up to you, the user. thoroughly validated, widely used, and highly cited MAPK antibodies available. CST™ phospho and total protein MAPK s available antibodies offer unsurpassed speci sen: ity, and performance. ity, = Technical support is provided by scientists ‘who produce the products and know them best fg WINNER! Life Science Industry Awards” Best Antibodies :: Best Breakthrough Products for Cancer Research for quality products you can trust... www.cellsignal.com Fa Cell Signaling das tors! 47 86.CEL 5 rsrsceleigescom | Faxadrng 1-97 86725 | Tae spyr ole -97-STE-TECH EH) spoons cam | nui incl conCONTENTS 23 February 2012 / Vol 482 / Issue No 7386 etn EDITORIAL 440 Turing at 100 chance to meta unique mind WORLD VIEW 441, The man behind the machi Andrew Hodges ‘What happened to Turing's reputation FEATURES 455 Legacy of a universal mind, "Nature tours Turing’s many facets 456 Brain ina box (Ona quest to model the human brain COMMENT 459 The dawn of computing George Dyson ‘Turing paved the way to computers. dy Pot/Turing amiy/NPLIKing's College Pema NEWS IN FOCUS EDITORIALS 447 BIOSECURITY 499 PUBLICATION Flu papers warrant full publication ‘Summit declares benefits exceed risks ‘WHO favours full publication of flu work 448 EPIDEMIOLOGY Children’s study copes with cutbacks 40 CLIMATE 449 oeTHics Over the line Editor's career move sparks backlash Dishonesty i not suited to scientists 450 FUNDING RESEARCH HIGHLIGHTS The top seven NIH grant recipients 442. SELECTIONS FROM THE SCIENTIFIC LITERATURE Immunity beats ime / Stem-cell heart therapy /A lizard meets its match / "New route to fluorine compounds SEVEN DAYS | 444, THE NEWSIN BRIEF | Anirals spared from testing / Fracking doesn't contaminate groundwater / Greek artefacts stolen / Nanotech frm presents frst data / Nobel virologist dies 453. HIGH-ENERGY PHYSICS Tevatron plundered for parts, 453. PALAEOBOTANY Viable plant created from Ice-Age seeds Out) 557 EDUCATION Outside the box Industria PhDs make sense 559 TURNING POINT Christopher Wilson on California biotech [NATUREJOBS ADVERTISING FEATURE Spotiight on post-grad opportunities 461 Life's code script ‘Sydney Brenner "Turing machine’ in every cell 462 Isthe brain a good model for machine intelligence? Rodiey Brooks, Demis Hassabis, Dennis Bray & Amnon Shashua Should computers mimic neurons? 464 Pattern formation slohn Reinitz “Turing instabilities’ pervade nature 485 The incomputable reality Bany Cooper ‘The Universe beyond the limits of computation 9 | TURING AT 100 Aloo al psc | nature ve tuing | COMMENT | poons 2 ants 466 NEUROSCIENCE Powerful acts Giovanni Frazzetto 467 BOOKS IN BRIEF 468 INFECTIOUS DISEASE Chronicles ofa killer virus Robin Weiss | 469 08a The eternal optimist The down-to-Earth | | ambitions ofspace- fight entrepreneur Peter Diamancis CORRESPONDENCE 470. Prepare for next flu pandemic / Biosecurity priorities / Questionable Use of chimps in research / The case against sugar / Managing the Australian bush FUTURES 562 Ghostin the machine Grace TangBreak free from routine sample prep. Go from boring to bold. The Samplicity™ Filtration System takes sample prep in a flexible, new direction. This vacuum-powered system filters one sample or eight, of Virtually any viscosity or composition, into HPLC vals in seconds with minimal manual effort \With the Samplicty filtration system and Millex Samplicity™ fters, [Merck Millipore has transformed multi-sample filtration forever. Discover how at www. millipore.com/GoBold Merck Millipore is a division of " MERCK Merc Migr, he M mak Semple Sample ae tears of Merck KGBA Darmstadt, Germany. ©2012 0 Mire Corporation, leis MAUSA lights eservesNEW ONLINE 473. Papers published this week at nature.com NEWS & VIEWS 474 CELL BIOLOGY Collagen secretion explained Ubiquitination of vesicle coats allows packaging of large proteins David J Stephens See ARTICLE R495 475 ASTROPHYSICS First results from Planck observatory ‘Studying dust in distant galaxies ‘and gas in galaxy clusters, Uros Sefik 476 FLUID MECHANICS Mist opportunities Therules of fibre wetting Rosamund Daw SEELETTER F510 ATT MATERIALS SCIENCE Cell environments programmed with light Controlled attachment of cells to hydrogels, Matthias PLutott 478 QUANTUM COMPUTING ‘A topological route to error correction Reducing the sensitivity of quantum ‘computing to errors James D Franson SEE ARTICLE P89 4480 STRUCTURAL BIOLOGY Muscarinic receptors become crystal clear Structures of two muscarinic PHYSICS Fault lines Topological eror correction in quantum computing, PRBE 4 CONTENTS 23 February 2012 / Vol 482 / Issue No 7386 i vs acetylcholine receptors Rebecca L Kow& Neil M Nathanson SEELETTERS P.547 & P.552 CANCER GENETICS Evolution after tumour spread Primary and metastatic ‘medulloblastoma features divergent mutations Steven CCiiford see LETTER P52 (CLIMATE CHANGE Shrinking glaciers under scrutiny ‘Measuring the mass-oss rate of Blaciers using satellite gravity data Jonathan Bamber see LETTER pia PERSPECTIVE 485 COMPUTING SCIENCE The case for ‘open computer programs DCInce, L Hatton & J Graham-Cumming 481 492 ARTICLES 409. PHYSICS Experimental demonstration of topological error correction XC Yaoetal. sceNavRa7s (CELL BIOLOGY Ubiquitin-dependent regulation of COPII coat size and function Luinetal. seenav rare STRUCTURAL BIOLOGY Structural basis of highly conserved ribosome recycling in eukaryotes and archaea T Becker et a LETTERS 507 ASTRONOMY Abrupt acceleration of ‘cold’ ultrarelativistic wind from the Crab pulsar FA haronia, S V Bogovalov &D Khangulyan FLUID MECHANICS Wetting of flexible fibre arrays CDuprat $Protéve, A ¥ Beebe GHAStone See NAV P4768 (CLIMATE SCIENCE Recent contributions of glaciers and ice caps to sea level rise Tacob, J Way WT Peter &S Swenson SEE NAV e482 NEURODEGENERATION The microRNA rmiR-34 modulates ageing and rneurodegeneration in Drosophila Nlivetal 510 524 STEM CELLS Maintenance of muscle ‘stem-cell quiescence by microRNA-489 TH Cheung etal CANCER Clonal select genetic divergence of metastatic ‘medulloblastoma XWuetal See Nav Past CANCER DCC constrains tumour progression via its dependence receptor activity M Castts eta CANCER Deleted in colorectal carcinoma suppresses metastasis in p53-deficient ‘mammary tumours P Krimpentor.J-¥ Song, N Proot, JZevenhoven, J Jonkers & A Bers STRUCTURAL BIOLOGY The same pocket in menin binds both MLL and JUND but has opposite effects on transcription J Huang etal. STRUCTURAL BIOLOGY Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist K Hoga etal See wav Paso STRUCTURAL BIOLOGY Structure and dynamics of the M3 muscarinic acetylcholine receptor ACKruseetal, see nav p90 529 54 538 582 CLIMATE GRACE notes Gravity data from the GRACE satelite used to map sea-level trends, PAGESIAnature 23 February 2012 / Vol 482 / Issue No. 7386 EDITORIAL LONDON, MUNICH, WASHINGTON, NEWYORK, [BOSTON, PARIS, SAN FRANCISCO, TOKYO DRAM Pip Capo cine eon: Wes coe oe Cheermanane canon: hopes ‘hs wen/sewsaties Aon At Davi Adan, any Bhstachann, Geo rum Dela Bute Enon alouy ra Check Hayden, Dal Cressey, Did Opane, Natasha iba Ee Han Hed ests Core ak, ronan ior Ema Wai chard Moray Bran Ovens Helen Pearson, Mar Peplon age Sar! eich han Semenak Que Sater Je Tle Ror Yon Nocae, Weed Wada, Miche Wliop coma Sera Abul Jae her Rossin Cater Borsa Kar ‘ison Cah cy Og Sr Sara ori NATURE PEAS veo Ay Rue Er Olson, eth Carte toda ews AKO MENS: So! Sha, Lopes ro ‘eran on Cou, Trguy Chou, Rasrnand Dw Ale xl, gl apes. Jos Fike, erry Gee atk Goyer Noah Gry, Mare Trae Roel Maple, ‘cron Howe, Cauca Lup, Barbara Marte Are Micron lane Mésingr sens Nath Ls age. NashraSkope Cle Thora oth Yanbu, Let enema ra ‘is chou Wt Sti Revews/PessrctWEs: Us Wee CAMS: Coe Pus, ‘rer Ral Teor ATURE: oye ar UTE: Hoy Cow SUE: Het ‘5 Mean, Ty Sty SUeEDTERS: Coin Slo Seren eos, Nels ‘Baiey Ae Blew Neos ange ee Flanagan Pel cer aneh Gray ah Loon, ‘Arma Yue Oza Father Pry Dav Pricey Reok Dan Wee Asta Yerk cour ny Henderson Lsnor Dawson Boing On ley Sioa re, Stan Gry Simon Grob, Hae Mayhow, aes cus Em Ova, Nee Song Rober Sula. Rover Tarr Chres Wes ARTAND SIN Ky Burs Kn Vly Fn Maine tein, rar esta, Pal oes, ss Keys es ew NkSpena: Care Wes Mak eos sua boon Mae, eye Use Sate ‘je PSs OE: ath Francs Nada Maman sa Bauer Raha Tin one \Woton Abst: Pa! 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The smeTHIS WEEK CUMATE Dishonesty isa weapon notsuited to scientistsn440 EDITORIALS | WORLD VEW How Alan Turing | GOINGBOWN Madagascan managed to go from_zeroto | jungle harbours smallest heropaat lizard pad Flu papers warrant full publication Although more debate is needed, the benefits of publishing sensitive data outweigh the risks that have so far been made public. « 10 one should presume to know all the ways in which N flues virco be misused, and the movatons foro cabunthe consequences cd because Theeitemny continence nigh hannailonesieeae See Japoand member olen eons custo nation ita peas undef at of caine Theearlow-potaity are ein coldinsaduces en cckonay HSN seins Setnnmes htscensneto cua in nae Themightet ce Ser nif aren aa aeseree rate inion selon? fart rationale provided by Paul Keim, acing chal ofthe anata Scoes Ano Bese fo Biuecerty NSABB) a Coe ee eit Nase ee Nae at 36 17 Sol) shoe the NSADBS retrumcatin tht recent wok on te ‘cht inrammal fart seanofslan HSN i caer chal at bepubehed infu The work wasconducted in ferrets — generally considered the best animal models for human. tere ad sone etan HEN arco haves ener pote ocvole ne ansible forms iano ncing Pete an Pad besa thought The waksecporcdin wo papes tan bantye pbb aN and Scone Lea a eau ec tian peiC be expr gaberel the Wl as Onpantation WHO) headguarso Geneve Samnd to cients ce gencarconfuyton) And ucletar the wetng th sve opening que prec only rationale that attendees had received, Meee eat haat US porerment the NSABBis the only Meo ofioreacnaieseallrantgvermen dear then inndngtncgene an ary genes) owen Friant Tye GASB planes to anisrat ist acy a er utan che inpaaeand paca pasion ook eta acaig atc WHO. spun Tieihe MEADE bedyempooced only tomerevonmen duo petienion nino Ronsrand sanyo parsismats eabiog cee reir coclieing puree tarbarepabc heath Su acencbenftbia that migh ao ete asecury rk Se megeretatethe pcty tats jureal wea ret paper eerie Ls ofpaeaiog ued te bencte Naue eee eee re aUenatnen neoealetes teammate Sitheatalpaperantmot of hesdvcrsevomsended pues coon arate paper suet any Na our fans econsscadaone hee ssn nde sai pblcton on Dosey round Hee rr jatthepapen gens the NSABD\ opinion both Nature and Science decided to investigate another option: to pub- lisha redacted version omitting key methods and data, But acondition ‘of such an approach was that a method should exist for distributing a full version to those in need of the results for public-health reasons ‘and those capable of pursuing the science. Both journals accordingly prepared full and redacted versions. ‘Those at the WHO meeting, under conditions of strict security, examined both versions ofthe two papers. It had already been said in blogs and news coverage that, because the “Thereis methods used are not novel and because one already a of the papers had been presented at an open substantial ‘meeting, redaction wouldbe pointless. Asone immediate ‘WHO participant said: “It was only when fa risk to humans.” _ seenboth versions that [realized how ineffec: tive redaction would be” What was also con. cluded was thata system for distributing the full paper only to selected individuals would be impossible to setup on any relevant timescale, ‘But what also became clear, partly from unpublished data, was that notonly does the mammalian transmissibility threat seem greater than. previously thought, but also that current avian viruses have some of the ‘mutationsidentified in the new work. In other words there isalready a substantial immediate risk to humans. The meeting aso concluded that the new data are of value for surveillance, and that the results should be built on to explore the mechanisms underlying transmissibility and the high fatality rate observed in humans infected by HSN Given the inadequacy of redaction, and the immediate risks to global public health the biosecurity objections expressed above seem too gen- eral and hypothetical to justify obstructing publication and further research. Moreover, with regard to the NSABB’ recommendations and the recommendations of the WHO meeting (see go.nature.com/ ky2skc), neither of the discussions that preceded them were suficiently inclusive ofthe security, societal and research interests at stake. Therefore, further discussion is essential. That must include review ‘of the safety regimes (lab equipment, buildings and practices) in which future work should be conducted. The two laboratories in which the latest research originated are categorized as ‘BSL-3 enhanced! (see ‘Nature 480, 421-422; 2011), classification that, although rigorous in these cases, is not well defined in general. The Public Health Agency ‘of Canada has deemed the highest level of BSL-4to be required (see page 447). Safety-standards committees in the United States and Europe are currently assessing required safety levels, and may report within afew weeks, ‘As was agreed by the journalsand the lead authors at the meeting, publication ofthe papers must wait at least for the outcome of those discussions, There may yet be regulatory or legal obstacles to publica tion, or biosecurity or biosafety risks sufficient to outweigh the health risks. Otherwise itis Nature's view that the papers should ultimately be published in full.Turing at 100 This year marks the centenary of the birth of Alan Turing. He deserves your attention. London Olympics kicks off. So it seems apt that, in a special issue this week, Nature invites its readers to embrace and «celebrate a superb marathon runner — who also happened to be one ‘ofthe brightest minds ofall ime. Alan Turing, computer pioneer, wartime code-breaker and poly: ‘math, was born in London on 23 June 1912, But for injury, he would probably have joined the British Olympic team for the London games ‘of 1948, (His personal best marathon time of 2 hours and 46 min- ‘utes was barely 11 minutes behind the gold medallist that year) Yet, 100 yearsand one month after hisbirt, when the Olympics will return, to the city, no official celebration of the connection is planned. An ‘opportunity to bring an intellectual giant — and science itself — to the attention of the international public willbe missed. ‘Taring’s marathon time gives us an objective quantification of his physical excellence. His scientific genius and legacy, however, are much more difficult to measure — as his biographer, Andrew Hodges, a mathematician atthe University of Oxford, UK, points out ‘on page 441, Still, setting asicee quarrels over his role in the develop- ‘ment of the computer the scientific world should stand together and relish the wonderful diversity of universal mind. (See the special section starting on page 455 and wewnature.com/turing for more.) The scope of Turing’sachievementsisextraordinary: Mathematicians vill honourthe man who cracked David Hilbert’s Enscheidungsproblem ‘or iecision problem, and cryptographers and historians will remember hhimas the man who broke Nazi Germany’ Enigma code and helped toshorten the Second World Wat. Engineers will hail the founder of ‘the digital age and artificial intelligence. Biologists will pay homage to the theoretician of morphogenesis, and physicists will raise a glass to C= the summer, many minds will turn to sport as the Over the line Dishonesty, however tempting, is the wrong way to tackle climate sceptics. this publication urged researchers to acknowledge that they are involved in a street fight over the communication of climate Science. So would it now be hypocritical to condemn Peter Gleick for fighting dirty? Gleick, a hydroclimatologist and president of the Pacific Institute for Studies in Development, Environment and Secu: rity in Oakland, California, admitted in a statement on news website The Huffington Post on 20 February that he had duped the Heart- land Institute, a right-wing think tank based in Chicago, Iinois, into handing over documents that detailed its financial support for cli- ‘mate sceptics. Gleick had passed these documents on to the website DeSmogBlog.com, which made them public on 14 February, Gleick’ deception — using an e-mail address set up in someone ‘elses name to request the documents from Heartland — is certainly in line with some of the tactics used to undermine climate science. ‘When in November 2009 a hacker distributed thousands of e-mails stolen from climate researchers at the University of East Anglia in Norwich, UK, Heartland was prominent among those who criticized not the hacker, but the scientists who wrote the messages. However, ys much-quoted Editorial in March 2010 (Nature 464, 141;2010),, the pioneer of nonlinear dynamics. Philosophers, meanwhile, arelikely to continue to frown over his one-liners on the limits of reason and intuition: “Ifa machine is expected to be infalibe, it cannot also be intelligent” he said in a 1947 alkto the London Mathematical Society Turing demonstrated a terrific ability to combine first-hand experi ‘mentation, keen observation, rigorous theory and practical application. ismultiisciplinary approach alone makes him ofinterest to this jour nal, yet questions still arise on whether the “Turing’smind best papers in pure mathematics, computer was truly his science and artificial intelligence should be own, and this published in Nature. We certainly thinkso, contributed to 0,100, dothe researchers invited todecode the tragedy of Turingslegacyin series of Commentartile, his life.” starting on page 459. They are thought: provoking piecesin thei own right, but, more importantly, we hope that they will entice readers to seek out Turing’ original work (see, for example, B.J. Copeland (ed,) The Essential Turing; Clarendon, 2004). His papers are models of accessibility and clarity despite their extreme conceptual depth and intellectual rigour, Even his throwaway comments — about symmetry in physics versus biology. randomness in intelligence, learning in unorganized machines, ‘or emotions in extrasensory perception, for example — are gems, ‘Turing’ mind was truly his own, and this contributed tothe trag, edy ofhis life. Turing was persecuted by the British authorities for his homosexuality, and used cyanide to take his own life, aged 41 ‘That 2012 will see numerousevents commemorating Turing world wide (see, for example, www:turingeentenary.cu) is almost entirely doven to volunteers, who have received litle or no official help. This is instarkcontrastto the World Yea of Physics in 2005, when the German state helped to promote the centenary of Albert Einsten's‘miracle year, in which he published his four groundbreaking papers. ‘What could 2012, the Alan Turing year, be named? Nature suggests, “The Year of intelligence: Ofthe finest types of intelligence — human, artificial and military — Turingis perhaps the only person to have made a world-changing contribution toa three. Use this special issue, and the res of 2012, to discover and make up your own mind about thisextraordinary man. Gleick, as he has admitted, crossed an important line when he acted in such a duplicitous way: It was foolish action fora scientist, espe cially one who regularly engages with the public and critics. Society ghtly ooks to scientists for fairness and impartiality. Dishonesty, whatever its form and motivation, isa stain on the individual and the profession. Gleick does deserve credit for coming clean — but, it must be said, he did so only after he was publicly accused on the Internet of being involved. ‘The original accusation, incidentally, was more serious: that Gleick had deliberately forged a Heartland Institute memo that brought together, with suspicious convenience, the most incriminating sections ofthe other climate documents, which seem to have been presented to the Heartland board meeting in January He denies doing so, and says thathe received the memo, in which heisnamed and which Heartland sayshas been faked, separately from an anonymous source. Thee-mail chicanery, he says, was an attempt to check whether it was genuine. Inhisstatement on Monday, Gleick aid: “My judgment was blinded by my frustration with the ongoing efforts — often anonymous, well funded, and coordinated — to attackclimate science and scientists and prevent this debate and by the lack f transparency ofthe organizations involved. Nevertheless I deeply regret my own actions inthis case” ‘On 24 January, Gleick had published another article in The Huff ington Post, entitled ‘Climate Change: Sifting SNATURECOM —— ‘Truth From Lies in a Complex World: As he Tocommentonine, now knows, the best way for scientists to help clickonEdtorialsat: people find this truth is through open and fauaturecon/shangy honest debate. mSeay EPITUMICS Cre ‘www.epitomics.com/ RabMAbs = Better AKT Antibodies CIN High quality antibodies to Akt and related proteins ( ) © Validated in WB, IHC, IF, IP and FACS © Over 7000 antibodies and counting [At Epitomics, we provide a wide range of high quality antibodies to Akt and related proteins. Using our patented Rabbit Monoclonal Antibody (RabMAD") technology, we have developed a collection of high qualty Akt specific antibodies. Each Akt specific RabMAb offers superior antigen recognition of the rabbit immune system and the specificity of a monocional antibody. [AktT Phospho (pT450) Akt! 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Featured articles include: Bone marrow and the control of immunity Ende Zhao, Huanbin Xu, Lin Wang, llona Kryczek, Ke Wu, Yu Hu, Guobin Wang and Weiping Zou Targeting and utilizing primary tumors as live vaccines: changing strategies Xuanming Yang, Eric D Mortenson and Yang-Xin Fu Optimal cutture conditions for the generation of natural killer cellinduced dendritic cells for eancer Immunotherapy Je-Jung Lee et al Antiy6 TCR antibody-expanded y6 T cells: a better choice for the adoptive immunotherapy of lymphoid malignancies Jianhua Zhou, Ning Kang, Lianxian Cui, Denian Ba and Wei He To access the Special Issue and Web Focus on Cancer Immunology visit: www.nature.com/CMI/focus/cancer_immunology/ www.nature.com/emi nature publishing group &eA The man behind the machine Alan Turing is famous for many reasons. Andrew Hodges delves into why Turing’s achievements took so long to be recognized. also for his 1952 conviction for having gay sex (legal in Brit- ain until 1967) and his suicide two years later. Former Prime Minister Gordon Brown issued an apology to Turing in 2008, and a ‘campaign for ‘pardon’ was rebuffed earlier this month. ‘Must you bea great igure to merta ‘pardon’ for being gay? Ifso, how {great Isit enough to break the Enigma ciphers used by Nazi Germany inthe Second World War? Or do you need to invent the computer as wel, with artificial intelligence asa bonus? Is that great enough? “Taring’ reputation has gone from zero to hero, but defining what he achieved is not simple. Isit correct to credit Turing with the computer? Tohistorians who focus on the engineering of early machines, Tur isan also-ran. Today's scientists know the maxim ‘publish or perish and Turing just did not publish enough about computers. He quickly became perishable goods. His major published papers on computability (in 1936) and artificial intelligence (in 1950) are some ofthe most cited inthe scientific literature, but they leave a yawning gap. His extensive com: puter plans of 1946, 1947 and 1948 were left as "unpublished reports. He never put into scientific journals the simple claim that he had worked out how to turn his 1936 “universal machine" into the practical electronic computer of 1945. Turing missed those first opportunities to explain the theory and strategy of programming, and instead {got trapped inthe technicalities of primitive stor age mechanisms He could have caught up after 1949, had he used his time at the University of Manchester, UK, to write a definitive account ofthe theory ‘and practice of computing Instead, he founded a new field in math- ‘ematical biology and left other people to record the landscape of com- puters. They painted him out oft. The first book on computers to be published in Britain, aster than Thought (Pitman, 1953), offered this derisive definition of Turing’ theoretical contribution “Turing machine. In 1936 Dr. Turing wrote a paper on the design and limitations of computing machines. Fr this reason they are some- times known by his name. The umlautisan unearned and undesirable addition, due, presumably, to an impression that anything so incom: prehensible must be Teutonic.” ‘Thata book on computers should describe the theory of comput- ing as incomprehensible neatly illustrates the climate Turing had to endure, He did makea brief contribution to the book, buried in chap- ter 26, in which he summarized computability and the universal machine, However his low. key account never conveyed that these central concepts were his own, or that he had planned the computer revolution AAs Tigi ein he news for hisplaein science bat ANYONE LOOKING INTO HIS STORY AFTER HIS DEATH WOULD SEE DARK HINTS THAT HE HAD BEEN PERSONA NON GRATA. TURING AT 100 ‘legacy that spans science: nature com/ tut ‘The 1955 Royal Society's obituary of Turing, written by mathematician Max Newman, did him few favours when it claimed that computer designers were unaware of Turing’ 1936 work. The ‘Turing machines soon made a comeback, but Turing’ image had become that ofa pure mathematical logician, unrelated to practi cality. It did not help that anyone looking into his story after his death would see dark hints that he had been persona non gratain an ‘unmentionable manner — possibly excusable fora remote theorist, from Cambridge University but totally inappropriate forthe founder ofa mega-industr. Yet the mid-1970s revealed Turing to have heen highly practical: the chief scientific figure at code-breaking headquarters Bletchley Park, and in charge of methods and state-of-the-art machines for beating the German navy. Now it was clear why he had emerged as a computer builder in 1945 — he had gained experience he could never reveal By the 1970s, there was also more room for his vision of computation. Software for “every known process’, as he foresaw in 1946, was on the way. Turing’ vision of mind and machine, which drew from his personal consciousness and experience, also became more acceptable ‘When in 1977 started to investigate Turing life, | found that his code-breaking was the hidden bridge between the 1936 theory and the “univer sal practical computing machine” he described inhis unpublished 1948 work, ‘On the question of individual reputation, in that 1948 report he wrote: “The isolated man does not develop any intellectual power. Itis necessary for him to be immersed in an envi- He may then perhaps do litle research of his own and ‘makea very few discoveries... the search for new techniques must be regarded as carried out by the human community asa whole, rather than by individuals” Science slike that, and he effaced himself in that spirit. But he wasa star nonetheless. ‘What would Turing have thought of the campaign for his‘pardon’? When arrested, he was unrepentant and told police he expected a “Royal Commission to legalize it’ Sixty years later, British law has ‘aught up, not for him as a special ease, but as a matter of princi ple. That practical action speaks louder than symbolic words, and is truer tohis vision, see the question not as whether the government should have pardoned Turing, but how on Earth Turing could ever have pardoned the government. ronment Andrew Hodges isa mathematician atthe University of Oxford, UK, and author of Alan “Turing: the Enigma, e-mail: andrewhodges@wadh.ox.ac.ukRESEARCH HIGHLIGHTS Le POPHYSICS Claustrophobic DNA in tug of war Whena long thin polymer such as DNA is forced into.a confined space — saya small ‘membrane channel — itoses some ofits freedom, and hence its entropy. Regaining that ‘entropy isa powerful driving force for escape. Chia-Fu Chouat the Academia Sinica in Taipei and his colleagues used an electri pulse to forcea single DNA molecule toextend from ‘one microchannel to another ‘through a restrictive gap just nnanometres high. When the clectrc field was turned off, tug-of-war lasting from seconds to minutes occurred as both ends ofthe DNA tried to pull outof the nanometze-sized space. Eventually, one side won and the DNA retracted ‘The forces acting on the DNA depended only on the height ofthe confined passage between channels, and not nits length or the length of DNA passing through it. This understanding ‘could aid applications from ‘molecular filters to nanopore transporters, the authors say. ‘Nano Lett htp://dx.dol ‘org/10.1021/n12045292 (2012) Pe TELL SICNALLING Sideways activation Elucidation ofa cell receptors crystal structure has revealed ‘unique lateral docking mechanism, report Hugh Rosen of the Seri Institute in La Jolla, California, and his colleagues. G protein-coupled receptors (GPCRS) are Selections from the Ree eects Soo Lilliputian lizards come to light The forests of northern Madagascar harbour a dwarf chameleon thats the smallest lizard in the world in terms of total length. Adult males ‘of the diminutive Brookesia micra reach length ofless than 24 millimetres. B. micra and three other tiny lizard species ‘were discovered in the regions rainforests and dy forests, Miguel Vences at the Technical University of Braunschweig in Germany and his ‘group analysed tail length and head width, male ‘genital morphology and gene sequences to place cach species within the chameleon taxonomy. Alloccupy a small, discrete geographical range, and probably evolved some 10 million to 20 million years ago, the authors suggest. PLoS ONE 7, 081314 (2012) —Connecicutand hiscoleagues _earsago), when ce activity in analgorthm to prioritize ~vihichblocksa lasofgene- constructed a phylogeny of The Southern Ocean thought tiutations found in medial regulating RNA fragments these notothenioid shes tohave increased. The authors genomesequencingforfarther called microRNAs isactive (sample pictured) and suggest that the appearance fnvestigation inthe tem calls that form correlated ttoboth the ofthisnew polar habitat, Science 35, 823-828 2012) a mouses immune eystera appearanceofthe poteinsand combined wit the pre-existing carlyinliyetisabsent fom changesin global ciate ffeze proteins spurred the adult bone marrow. Marrow Contrary tothe perception ‘evolution of notothenioids Cellengineeedtocxpressa__thatheappearanceof Pre Nal Acad. Si USA Zombie star Gosely elated gene, Linz, and antfreezr protein was the ft/s. doverg/10.1078/ transplantedinto adult mice crucalfatordrivingevolution, pas 1115169109 2012) rising form fetal-like immune cells. they found that the most_ Whena star suddenly Because the fetal-like species-rich lineages diversified ONATURE.COM brightened in 1961, many immune cell areknown to atleast 10 milion earsafer_Frthelatestresearchpublishedby assumed thad diedina beeffectiveagunst some theproteing appearance. Tis Rates: supernova —butitseems pathogens cancersandother _outofevolution happened ‘icineSYN See Flu work freed Two studies that created ferret-transmissible strains ofthe highly pathogenic avian HBNI influenza A Virus should be published in full, meeting of 22 experts convened by the World Health Organization in Geneva, Switzerland, concluded on ebruary. Last December, the US government and the US National Science Advisory Board fr Biosecurity had asked that the research be censored. See pages 439 and 447 for more Anhigh-profle water and ‘climate scientist acknowledged (0n 20 February that he had dishonestly acquired internal budget documents from the Heartland Institute a libertarian think tankin chicago, linois, that aims tocombat climate science. Peter Gleick, president of the Pacific Institute in Oakland, California, released the documents o environmental ‘website DeSmogBlog. Heartland has not disputed the authenticity of most of the papers, but saysthata strategy ‘memo — which Gleick says he received anonymously — is fake, See go.nature.com/vLzrb and page 440 for more. Animal testing Tensofmillionsofanimals have been saved from use in chemical safety test, after Europe’ chemical regulator gave the go-ahead toastreamlined method for checking substances’ effects on animals reproductive systems. ‘Toxicologistshavebeen concerned that up to 54 million animals could be required for extra tests mandated by the European Unions ‘weeping 2007 chemicals legislation — with most ofthe The struggle against soot ‘An international coalition has launched a modest fund to curb emissions of methane, black carbon (soot) and other short-lived climate-affecting, pollutants (see Nature 481, 245-246; 2012). The United States, Canada, Sweden, Mexico, Bangladesh and Ghana founded the programme, which was unveiled in Washington DC on 16 inerease down to reproductive- toxicity tests that have tobe lone in two generations of animals. But on 15 February the European Chemical Agency, based in Helsinki, approved test that uses only. ‘one generation, See go.nature. com/optaux for more. AIDS budget cut Health advocates sadist week that they were dismayed Byplanned cuts to the US administrations global AIDS programe, Aconding othe Kaiser Family Foundation, healthpalicy analysts headquartered in Menlo Park, Califonia, President Barack Obama’ 203 budget request wouldcut 13% {USS543 milion) fom the US state department’ support for HIV work, although it would add 27% ($350 million) to the Global Fund to Fight AIDS, ‘Tuberculosis and Malaria, See go.nature.com/redhh for Iran concern Iran has responded to tightened trade sanctions by claiming that ithas made technical advances in its naclear programme, including building anev generation of centrifuges to enable faster enrichment of uranium, Diplomats from the United States and Europe dismissed the pronouncements on 15 February as political bluster As Nature went to press inspectors from the February. With initial funding of USS15 million, itwillaim to support projects such as cleaning up inefficient biomass stoves, brick kilns (pictured, in Kabul) diesel vehicles and coke ovens; and reducing gas leakage from rice paddies, landfills, ‘wastewater systems and oil and gas extraction. See go.nature.com/nu3ak5 for more. International Atomic Energy Agency in Vienna were visiting Tehran to discuss Iran's nuclear programme for the second timein three weeks. Drug trials rap On 14 February; three senior Democrats in the US House of Representatives questioned the National lsttutes of Health and the Food and Drug Administration over their apparent failure to enforce the public reporting of clinical trial results. Under a 2007 act, sponsors must report the results of trials of already. approved drugs and devices on clinicaltils.gov within a year of completion —orbe fined. Astudy (A. P.Prayle et al. Br. Med. J344, 47373; 2012)published in January found that results of only 22% of 738, trials completed in 2009 were reported in time. Fracking risks There site or no evidence that fracking — pumping high-pressure fluids into shale to force out natural gas — has contaminated groundwater, accordingto a university-funded report (ee go.nature.com/sopiwm) from researchers assembled by the Energy Institute at the University of Texas at Austin ‘The report, released on 16 February at the meeting of the American Association for the Advancement of Science in Vancouver, Canada, found thatharm ascribed to the controversial technique could usually be traced to above- ‘ground chemical spills or problems common to al ol and gas drilling operations, such as casing failures. Dioxin health risk "The US Environmental Protection Agency has released long-delayed assessment of the health rsks of dioxins — ‘work thathastaken more than twodecades to produce. In line with its 2010 draft report, theagency recommends safe consumption limitfor the ‘chemicals that is well below that proposed by the World Health Organization. Butit a A study ofthe careers of nearly 3,000 tenure-track science and engineering assistant professors in 14 US universities suggests that men and women are retained and promoted at about the same rate, spending a median time of 10. years at their first university But in mathematics, women leave significantly sooner than ‘men (see chart). A problem lies in hiring: only 27% of incoming academics are women, the authors point out. See gonature, com/nn23z1 for more, also says that current exposure to dioxins “does not pose a significant health risk’ See ‘gonature.com/dh3ary for a TS Greek robbery Greece's economic suffering has been compounded ‘ofthisyear and plansto sell by desecration ofits ‘aminiaturized, disposable archaeological heritage, with sequencer (pictured) forless the robbery of77 artelacts than US$900, Se gonature. from the Museum of the com/evpele for more. History of the Olympic Games in Olympia on 17 February. Culture minister Pavlos Geroulanos offered to resign Nobel laureate dies afterthe theft, which ministry Virologist Renato Dulbecco, officials said included a who shared the 1975 Nobel 3,300-year-oldgoldrringanda Prize in Physiology or 2:400-year-old oil jar Medicine, died on 19 February, aged 97. Dulbecco won the MTT Nobel for workin the 1950s and 60s showing that some Nanoporesequencer —yirusesinsert their genesinto ‘Oxford Nanopore the genomes of the cells they Technologie UK fem infects and that these changes thatpromisestistechnology anager cancer Born in could theoretically sequence a Italy, Dulbecco also worked in. human genome in 15 minutes, the United States and Britain. impresed scents withthe From 1988 to 1982 he was fimtpublicpreentaionofiis president ofthe Salk nsute dataon 17 February at the for Biological Stdiesin AdeancesinGenome Biology San Diego, alfori. and Technology meeting in Marco sland Florida. The MIT head resigns technology sents bases The rst femal president of inrelimey measuring theMassachusets Institute electrical conductivity asa of Technology (MIT) in DNA strands fed through ‘Cambridge has announced ‘biological nanopore. The that she wil eign the Companyexpectstostrtseling, post after sevenyearsin ismuchinetnthesecondhall Charge Susan Hockfield a RETAINING SCIENCE TALENT en and women hired by US scence and engnaering acute are retained at sbout the same rate ~ excptin matnomatie 100 > tte une) é Semele su Br Male mathemati) i = Female mateatis 8 50 : 23 5 e-snss oo © 6 © % » | 5 | seven oays ISIE 26-29 FEBRUARY Jn Washington DC, scientists and policy- ‘makers discuss research and political efforts con biodefence and 27 FEB-2 MARCH. Graphene, solar- energy technology and hot topicsat this year's ‘American Physical Society meeting in Boston, Massachusetts uaatue.com/GmTekh neuroscientist, has headed MIT since 2004; she previously spent two decadesat Yale University in New Haven, Connecticut, including time asprovost. On 16 February she said that she would step down whena successor was appointed, to pave the way for anew fund-raisingeffort Italy research head Italy multiisciplinary National Research Council (CNR), which runs more than 100 institutes and research centres, fnallyhasa new president. Itshould nowbe able to implement 2009 Jaw intended to make the country’s research system more transparent and meritocratic (see Nature 476, 386; 2011) ‘Te reform has dragged oon because outgoing CNR president Francesco Profumo, appointed ast August, declined to resign the postafter becoming national research ‘minister last November. On 18 February; after Profumo was finally pressed into resignation, Luigi Nicolai, a chemical engineer whois alsoa member of parliament, was appointed aspresident ofthe CNR. ‘NATURE.COM Fordaily news updates see wow atrecom/newsIBMS5) BoneKEy BoneKEy Knowledge Environment The premier online global network for bone health professionals ae BoneKEy BoneKEy Knowledge Environment Ape eon tai Pag Sorat roan Emtcrnrihes incl ond ratologia charm ‘iene ch onsres wrayer Boneky Reports | Boneky Genates | Archive | Community | Fer Authors ‘About BonekEy Knowledge Environment | recorder cet Spldamislogy, ptogenstemectanans ak Soe engpyscane ton sna he wore = Sor Sein manger ‘Sciatest at repeued rs robot coment hese met ees Bae Sccutyond bw intertta Sone end Mine! ‘Scewae eemee ‘Sponsors: ea aoe eee ee eet Lt AMGEN BoneKEy Knowledge Environment provides ‘extensive coverage of bone diseases and the clinical care of such diseases through: ‘High-quality opinion and analysis News & Commentaries Meeting Reports - - Webinars ‘Web Portals: BoneKEy Genetics and Adhering to the highest standards of publication inthe scientific BoneKEy Oncology varmamog 2012 ee enn Soar oe eet ‘= Multimedia article templates to rigorous peer review, copyediting and production procedur ‘= BoneKEy Community Rey nature publishing group eNEWSIN FOCUS Bioethicist signs on with controversial stem-cell company 9448 Uperading the biosafety level for studi NIH’stopgrant recipients will face extra scrutiny p480 ‘on mutant avian influenza could puta stranglehold onthe work. Tevatron p43 Flu meeting opts for openness Controversial virus studies should be published and oversight of such work strengthened, conference concludes. BY DECLAN BUTLER fler weeks of debate, two controversial papers describing forms of the HSN1 avian influenza virus capable of sitting between mammals should be published in fall. That was the unexpected ‘outcome of a meeting convened last week in Geneva, Switzerland, by the World Health Organization (WHO), which also promised to createa more rigorous oversight system for such research, The decision goes against a recommenda. tion from the US National Science Advisory Board for Biosecurity (NSABB), which the US government has adopted as its official pos! tion. In December 2011, the board said that experimental details ofthe two studies should Vultures circle over the corpse of the sizingup science’sdebtto Alan ‘Turing pass D3 be redacted from any publications, because of ‘concerns that the information could be used in a bioterror attack. The board also feared that publishing the details would prompt more laboratories to work on the viruses, making an accidental release more likely The studies, which created forms of HSN1 that can spread between ferrets through air borne transmission, are likely to be published ina few months. The 22 experts at the meet- ing, mainly flu researchers, believe that the delay is needed to explain the benefits of the work to the public, and allay concerns about its safety. Meanwhile, a 60-day moratorium on similar research willbe extended untila system. is putin place to review levels of biosafety and biosecurity. To that end, the WHO intends to e international discussions among regu Iatorsand other bodies in the next few months. The two researchers at the centre of the controversy say that they are pleased with the outcome. “I was pleasantly surprised by the fact that there were unanimous decisions about most issues, and strong consensus on the others” says Ron Fouchier, a flu virologist at Erasmus Medical Center in Rotterdam, the Netherlands, whose study has been accepted by the journal Science. Yoshihiro Kawaoka of the University of Wisconsin-Madison, lead researcher on the other study, adds that the meeting allowed him and Fouchier to explain their work, including the potential benefits for surveillance of emerging flu strains (Nature 481, 417~418; 2012) and for vaccine prepa ration (Nature 482, 142-143; 2012). “We presented why we did these experiments, what we did, what data we obtained, what these data contribute to public health and to the scien tific field, and why we think the results should be shared” says Kawaoka, whose paper has been accepted by Nature. He adds that data he and Fouchier presented on the evolution of HSN1 in the wild clarified the threat from he virus, although he would not be drawn on the detail, citing confidentiality Microbiologist Paul Keim, who chairs the NSABB and attended the meeting, did not respond to Nature's request for an interview, butis reportedly “disappointed” by the recom: ‘mendation to publish the papers. Nature and Sciencelast year agreed in principle Formore, see Nature's mutant fu special: to redact the papers, on the condition that theCS 1 Focus US government would develop a mechanism to disseminate the full papers to researchers and health officials on a need-to-know basis. But meeting participants concluded that this ‘was impractical, and thatthe potential public- health benefits of the work outweighed any risk of publishing the papers in full, BIOSAFETY FIRST Many flu researchers have already seen the Papers, so there was little to be gained by restricting their dissemination, says Richard Ebright,a molecular biologist and biodefence expert at Rutgers University in Piscataway, New Jersey. Itis much more urgent, he says, toputin place strict biosafety, biosecurity and oversight provisions for such research. David Fidler, an expert in international and national security law at Indiana University in Bloomington, points out that the meet ing hasn't actually broken the publication deadlock, because Keim and representatives, ofthe US government still do not agree with publishing the studies in full. "Most of the ‘meeting’ participants appear to have rejected the US position” says Fidler, “but [have] agreed. tothe extended moratorium and publication delay a the hope that the US government will nge its mind” Participants agreed that the mutant viruses should remain in their two containment facil tios — rated at ‘BSL-3 enhanced, the second: highest evel ofbiosafety —and that both should be reviewed before any work restarts. Didier Houssin, president of the French Evaluation ‘Agency for Research and Higher Education, says that the biosafety review of the work must consider whether studies of this kind should be conducted only in labs with the highest biosafety rating of BSL-4, a restriction imposed this month by Canada. Houssin, who attended the meeting, notes that imposing such a restric: tion globally would curtail similar work because there are justafew dozen BSL-4 labs worldwide. ‘The safety level of BSL-3 labs is very variable, ch he says, and so any facilities working on st viruses would need tobe rigorously assessed Fidler and other experts note that the ‘meeting did not address the overall risks and benefits ofthe work, or how similar research might be overseen in future. Keiji Fukuda, WHO Assistant Director-General for Health Security and Environment, explains that later meetings will deal with these topics and will have wider participation. “Meanwhile, the meeting agreed that it was “critical” forthe WHO to form a communica tions plan over the next few months to increase public awareness and understanding of the {importance ofthe flu work, and to alleviate public anxieties. But Peter Sandman, a risk communications consultant in Princeton, New Jersey advises against any attempt by the WHO to"educae” the public outofits concerns. Asa strategy he say, it “is thoroughly discredited because itdoesit work” msEFEDTORNL RAD Gro pains for rowing children’s study Door-to-door recruitment abandoned for US project. BY MEREDITH WADMAN proposed 15% budget cutis making A for a troubled adolescence at the National Children’ Study (NCS), an ambitious US government project that aims tochart biological, environmental and social influences on the health of 100,000 American children from before birth to age 21 years. The study’s managers at the National Institute of Child Health and Human Devel ‘opment (NICHD) in Bethesda, Maryland, say that they can cope with the White House’ budget proposal, released on 13 February. ‘This would cut funding for the programme bby US$28 million, to $165 million in 2013 (see ‘Bel tightening’). But their plan to save money, by recruiting study participants through health-care providers rather than by door-to-door recruitment is worrying some ofthe study's scientists, who already fe! shut out from its planning, In 2010, a year after it started, the N pilot phase had to expand from seven sites 10 37 ater recruitment rates fll well short ‘of expectations. As the pilot winds down recruitment this year, ithas enrolled only 4,000 subjects. The study. which could be used to probe the roots of conditions such as asthma, autism and diabetes, must therefore accelerate recruitment sharply after its main armlaunchesin2013. NICHD director Alan Guttmacher says that there was “understandable angst” among, study-site directors the day the budget was ‘made public. But NCS managers see room. BELT TIGHTENING Facing a proposed 155 cu the US National Childrens Stay seling cheaper ways to ‘ecru fs chor of more than 100,000 een, 200: study phase 1 impiomentation fe Request 0 USS ion) 2003 2005 2007 2009 2011 2013, for savings, estimating that $30 million was spent on recruitment in 2011 alone. Although door-to-door recruitment is con- sidered a gold standaed in epidemiology, study managers believe that subjects can be recruited much more cheaply through health-care-providers' offices, where pilot- study data show that recruiters are much more likely to find eligible women who are pregnant or trying to become pregnant. The household recruitment has another down- side, says Guttmacher: "It would take so long it would compromise the study” A “scien- tifically compelling” study with a budget of $165 million is stil possible, he says According to one of the study’s principal investigators (Pls), however, money isalready too tight. “The idea that there arecost savings tobe madehereis absolutely absurd’ says the researcher, who contends that many Pls have yet to receive funding for their data- manage- ‘ment systems that was promised by NICHD _managers last October. Some are coping by diverting funds from other parts ofthe study; others have simply stopped entering data for study subjects, The study’s managers say that the Pls have been adequately funded, Some Pls ate also worried that recruitment athealth-care-providers offices would bias the study and render ts findings inapplicable to the wider population, They point toa 2008 Institute of Medicine report that called the household-based sampling approach one of the study's main strengths And some scientists complain that they trad no inpat into the decision to change the recruiting strategy, which many failed to hear about even after the budget was announced, “Wedont have any full,thorough discussion ‘of this” says Nigel Paneth, a paediatrician at ‘Michigan State University in East Lansing who isPlat the NCS site in Wayne County. “What this study needs is full scientific input, not Bureaucratic Planning Central” Guttmacher notes that government officials cannot talk about White House budget proposals before they are released, But with many congressional districts hosting study centres, the programme has proved resilient. The administration of former president George W. Bush repeat edly tried to cancel it, but Congress always restored full funding.Bioethicist Glenn McGee's new job raised questions of conflict of interest atthe journal he founded. Editor’s move sparks backlash Bioethicists are forced to consider their purpose as leading practitioner joins controversial stem-cell company. BY DAVID CYRANOSKI jhe field of bioethics is embroiled in a period of soul-searching, sparked by startling career move by one of its biggest names ‘Glenn McGee is the editor-in-chief of the American Journal of Bioethics (AJOB), the most cited bioethics journal, which he founded in 1999, Since December 2011, he has also been president for ethies and strategic initiatives at CellTex Th controversial company involved in providing customers with unproven stem-cell therapies A Cell ex press release says that “Dr McGee responsibilities wll include ensuring that al of the firms work, centered on adult stem eels, ‘will meet the highest ethical standards ofthe medical and scientific communities. Although McGee has said he will leave the journal on 1 March, many bioethicists have criticized him, the journal’ editorial board and its publisher, London-based Tay- lor and Francis, They argue that in holding both posts, McGee has a conflict of interest between his responsibilities to the journal ipeutics in Houston, Texas, a and his new employer's desire to promote the clinical application of stem-cell treatments that are not approved by the US Food and Dra Imagine if the Editor of the New England Journal of Medicine took ajob as Vice Presi dent at Merck, and the Mass Medical Society asked him to stay on as Editor, opining that the conflicts of interest would be manageable ‘One might rightly wonder, ‘What are these people smoking?” says John Lantos, director of the Childrens Mercy Bioethics Center in Kansas City, Missouri, and a past president of the American Society for Bioethics and Humanities. More broadly, bioethicists are questioning whether it can ever be acceptable to work for companies, which, they argue, may be using the appointment to present a veneer of ethical pro bity. The episode brings to ahead concerns that have emerged among bioethicists over the past decade, says Insoo Hyun, a stem-cell bioethicist at Case Western Reserve University in C land, Ohio, “Ita perfect storm,’ he says. McGee isa leading voice on one side of the debate, arguing that bioethics must have prac tical relevance. For the past three years he has been chair ofbioethies at the non-profit Center weocus [EY for Practical Bioethicsin Kansas City, where he na course for those who might goon to chair hospital ethics committees or serve as ethical 8 to corporations. But during McGee's tenures editor-in-chief of the AJOB, four editors are known to have resigned from the editorial board because advis of differences in opinion over how the jour: nal handles conflicts of inte ‘month, including Lantos, who wrote on his blog that he will no longer work withthe jour nal because of Meee’ simultaneous employ mentat theAJOB and Ce over the lack ofa clear conflit-of-interest po icyat the AJOB. In response to Nature's ques: tions about the situation, Taylor and Francis, responded that it “is geateful for Dr McGee’ editorship of AJOB” and “supportive of Glenn's decision to step down’ (On 17 February, McGee announced that he is merely acting in an advisory capacity atthe st. Two left this Nex, and frustration, journal until l March, when its new editors: in-chief take over. They are David Magnus, director of the Center for Biomedical Fthicsat Stanford University, California, and Summer Johnson McGee, director of graduate studies at the Center for Practical Bioethics and the journal's current executive editor. She is also Glenn McGee’ wife. Responding to questions from Nature, Sum- ‘met Johnson McGee says thatthe journal has a conflict-of interest policy that requires edi tors to withdravr from reviewing a manuscript if they perceive a conflict. She cals allegations thather appointment results from her relation: ship with her husband “baseless and sexist” ‘David Magnus and I were hired by our pub: lisher, not by my husband.” Magnus says that atleast a dozen editorial board members have supported his and Summer Johnson McGee’ appointments, Two even indicated that Glenn McGee should have been able to retain an advisory or editorial role. Other bioethicists’ blogs and Twitter feeds about the episode have expressed concer Leigh Turner of the Uni versity of Minnesota ‘Mainstream bioethicsis no longer speaking truth topower.” board of the A/OB to resign for allowing the situation to persist. And many say that McGee's move illustrates a broader problem. “Mainstream bioethics is no longer speaking truth to power” complains Jan Helge Solbakk atthe University of Oslo, “Instead ithas become the handmaiden of the medico-industrial com plex, nd of bioscience and technology’ So how should companies get their adv on bivethies? Magnus never takes cash from industry for advising or speaking — “I'ma hardass about that” — but he believes that bioethicists can work for industry as long as they give up their academic positions, includ ing posts on journal editorial boards.LEY "Focus > Working for a respected company may be acceptable to some bioethicists but McGee’ new employer comes with a {great deal of baggage. Cell Tex, which was founded last year and as yet has no website, licenses stem-cell technology from Seoul. based RNI Bio. The South Korean com- pany has made a business out of taking fat cells from people, processing them in a way that the cenchymal stem cells, and then reinjecting them in an effort to treat conditions such asspinal cord injury. McGee already had a connection with RNL Bio, In 2010, two patients died fol lowing injections of RNLS cells. McGee, working for stem-cell lobby group the International Cellular Medicine Society, based in Salem, Oregon, helped to conduct an investigation into the company. This concluded that only one of the two cases say increases the number of mes was likely to be related tothe injections, and because the patient understood the risk the company was not culpable, Jin Han Hong, the then president of RNLS US subsidiary, admitted in 2010 that there was no clinical-trial evidence proving that these treatments are effective (Nature 468, 485; 2010). As treatment with RNLS. is not approved in the United States or South Korea, for the procedures the company sends patients to China or Japan, where regulations are less strictly enforced, Using RNLS methods, CellTex. is banking stem cells that have gone on to be used in a number of patients, including Rick Perry, governor of Texas (Nature 477, 377-378; 2011). CellTex says that it does not conduct medical procedures itself When Nature contacted McGee to put the criticisms to him, he directed us to pre: vious statements indicating that he wants to put CellTex on firmer ethical ground by having it conduct clinical trials that meet standards set by the International Society for Stem Cell Research, based in Deerfield, inois, which represents most mainstream stem-cell researchers around the world. Hyun warns that working directly for business can be fraught with danger, how ever good a bioethicist’s intentions. In 2005, he helped to craft the informed con- sent procedure for egg donations used in a cloning procedure by disgraced Korean stem-cell scientist Woo Suk Hwang, Follow ing Hwang’ claim, later proved fraudulent thathehad cloned human embryos andlhar- vested stem cell from them, itemerged that he had ignored the consent procedure for egg donations (Nature 438, 536-537; 2005), leading to embarrassment for Hyun, “know first hand how difficult itis to separate conflict of interest the role of bioethicist” says Hyun. “I know you need tonot be toa chummy with enter: prises tryin d ahead in stem cells?”'= stem ce tomaintain to sp Researchers who, ike Vadim Backman, top $1.5 milion in NIH grants wl face an extra layer af review. Extra scrutiny for ‘grandee grantees’ Ananalysis by Nature reveals who holds the most grants from the US National Institutes of Health. BY ERIC HAND ‘adim Backman no longer relies on cof fee to get him through the 100-hour weeks he puts in at his biomedical ‘engineering laboratory at Northwestern Uni- versity in Evanston, Illinois. Since giving up caffeine, he drops to the floor and does press ups whenever he needs to clear his head. It certainly takes an alert mind to supervise 20 students, collaborate on clinical trials at Shospitals worldwide, and manage 7 grants ‘wortha total of more than USS3 million from the US National Institutes of Health (NIH) in Bethesda, Maryland. At 38, Backman is already a biomedical superstar. He is developing an imaging tech: nology that could detect abnormal structures in cells during the earliest stages of cancer And a Nature analysis has identified him as ‘one of seven scientists whom the NTH sup- ports with the most grants (see Seven lucky seven). That puts him near the top of alarger group of NIH- supported researchers who will soon be targeted for extra scrutiny beyond the peer-review process Asiit released its 2013 budget proposal last week, the agency said that researchers who control more than $1.5 million in grants will undergo an extra layer of review from exter nal advisers before further grants are approved. The decision comes as the agency tries to scrape money together for new grants in order to raise itscurrent grant success rate of 18%, historic low, But the countermeasure — poten: tially penalizing applicants on the basis of their previous success — is also histori. The basic rule for giving out grants at the NIE has always been simple: to fund the best science. A retreat from pure meritocracy is “shocking’, says Howard Garrison, director ‘of public affairs atthe Federation of Ameri- can Societies for Experimental Biology in Bethesda, Maryland. "Its huge sea change” Nevertheless, Garrison supports the new rule because he is concerned about the vast number of researchers who are struggling to win, or hold, just one grantNearly 1,500 principal investigators (PIs) — about 5% of those who held grantsin 2011 — come in above the $1.5-million threshold and would besubjectto the review. A'$750,000 threshold for similar layer of extra review has bbeen in place since the 1990s at one NIH inst tute, the Nationa Institute of General Medical Sciences, and has worked well, ays the insti- tutes former director Jeremy Berg, now atthe University of Pittsburgh in Pennsyivania, ‘SHOPPING AROUND sally Rockey, the NIH deputy director for ‘extramural research, says the agency isnt con- sidering hard cap based on the number of {grants per scientist, norextra review for those ‘with many grants. She points out that a cap based on numbers of grants would have to be draconian to spread grants to a significantly greater numberof researchers. An analsisshe presented on her blog in October 2011 found that setting a maximum of two grants per I would increase the grant success rate by just 2%. In 2008, two NIH advisory panels tasked with reforming the peer-review process for grants recommended that Pls spend at least 20% of their time on any given grant — a de facto cap of five grants per researcher. “Although most of the recommendations were ultimately adopted, the 20% rule was not Berg, ‘who was on one ofthe advisory panels, says, he would still supporta review threshold — although nota hard cap — fora certain num- ber of grants, “You look at people with more than a certain number of grants and ask, ‘Is this good investment for the NIH?” he say. ‘There are concerns, he adds, that Pls could gain multiple grants by presenting similar ‘experiments to different NTH institutes. ‘Berghastried tomeasure the output oflabo- ratories of different sizes, and found that the richest are not necessarily the most produc- tive (see Nature 468, 356-357; 2010). “There are some people who are definitely capable of running bigger operations while maintaining tremendous productivity per dollar’ he says “There are other people who are very well funded and arerit so productive” INFOCUS: [ Eo ‘Those questions are especially important for the ery top grant winners, whom Nature iden. tified on the basis of ‘esearch project grants, an NIH-defined category composed mostly of the R01 grants that provide bread-and-butter support to most Pls John Tainer, a structural biologist at the Scripps Research Institute in La Jolla, Califor nia, feels that the new rule will only farther entrench a bias against those with multiple grants, and worries that it could restrict inno- ‘ation by the elite. With 7 grants worth a com- bined sum of more than $5 million, itis hard to feel sorry for Tainer. Butearlier this month, helost a competitive renewal for a grant that hie has held since 1985, to study the hair-like pilion the surface of bacteria that make them sticky and contribute to their pathogenicity Because he relies on grants to pay the salaries of 18 lab members, as well as his own, this rejection could mean lay-off Tainer suspects thatthe decision “reflects the act that Ihave other projects: But, he con- tinues, “The science hasnit changed. What YO te dome naw ie peoplewithmmore rer than what maraber of The Tost ofthe grants and ask, grant will extend ‘Isthisagood beyond hisown ab, heads. “Forthe next decade, people will be publishing parts of things that I had done better. The cost to the NIH will be higher. If you're leader and you have momentum and technology, the impact of taking that away and having other people do itata different level is destructive” Backman also dislikes the idea of capping, the number of grants that an individual can ‘win, but is more relaxed about the proposed $1,5-million threshold review. He is sympa- theticto the plight of young researchers casting. about for their first grant — he was in the same position justa few years ago — but says that the ‘competition for established researchers must be based purely on the strength of their ideas. “Tlike the idea of meritocracy” he says. ‘SEVEN LUCKY SEVEN Seven NIH supported researchers are principal investigators on seven research project grant each. Nome Granttotal Institution Research Ronald Davis 36986908 Stanford University Genomics John Tainer 35069800 Scripps Researchinsttute Structural biology Anjana Rao $3512571 _LaJoliainttute for Alergy Signalling and gene exoression Elmmunology ‘George Koob $3365229 Scripps Revearch Institute Neurobiclgy of diction Vadim Backman $354,165 Northwestern University Blophotonics Pier Pandit $2929857 eth rae! Deaconess Tumorigenesis Medical Center “Pietro Sanna $2,114.278 __Sctiope Research Institute Neurobiology ofadction Fiscal 2011 ont data were used. rant tata refec actional shares of mult grants Analysis exudes grants made to bre resoe conte. Grant supplemtsare muda ort orginal pan ah tan ea coprte mar Pare rie rs ee about this important k The Energy for the Future Peete ea) ane chic odes lee aoe ine and tell us what you think Which area of the energy dustry will advance the most in the next 10 years? 40% lal espondents hough ht the solr rd flrs he most potenbl technological progres, The wind, iil ‘nd nur indus eoch cored bot 118.0 the wes, hough Asa ond Asalio respondents ried meat os 0 lor acond most effective as a solution to the energy challenge? {1% of bal responders om mond alemcive energy ashe mos elave pal, whe neticingrnewcle on {at} ond carbon oes 144) were oko Stony sported inthe recive Gicttlon nar of repos poled chet conelng errgy tomompten ond ining aston ose re port Sep we canta sey ene aaa eidPriya Professorships & Lectureships We are seeking individuals with We provide a fast-paced, collegiate and outstanding scientific credentials and supportive environment where Principal Dundes is situntnd in spectacular ‘excting plans for ground-breaking Investigators can thrive through access Scottish landscape, framed by the 84 research to become part of our thriving _to state-of-the-art technologies and ed eave riee be sie oot ate ‘mut-discipiinary research community. collaborative opportunities in a single ‘mountains, The city has a dynamic, Principal investigator postions at lecturer integrated complex. international outlook and a worldwide to prcfosesral eve! We avananig reputation as a crucible for pioneering fe ‘Apply online at: sciences research. + Biological Chemistry & Drug Discovery jttp://Jobs.lifesci.dundee.ac.uk and + Cell and Developmental Biology find out more about our research, our The Collegeof Lite Sciences is home to + Gell Signaling & Immunology exceptional facies, and what ls tke to preeminent researchers fom around the Bioinformatics, Biophysies, ie ndooku nan world working atthe cuting-edge, across” Computational & Mathematical Biology disciplines and consistently producing» Molecular Medicine The University of Dundee is committed highly-cited papers in thee ec. * Molecular Microbiology to equal opportunites and welcomes * Piant Sciences applications trom all sections of the + Protein Phosphorylation & community Ubiauityiation gn Royal Botanic Garden Edinburgh DIRECTOR OF SCIENCE As a world-class plant biodiversity research institute with a long history in scientific exploration, horticulture and education, the Royal Botanic Garden Edinburh has internationally important collections of living and preserved plants, modern laboratories and an extensive botanical library. With four gardens across Scotland, our mission is “exploring and explaining plants for a better future”. RBGE is a Non-Departmental Public Body largely funded by the Scottish Government. We are seeking a dynamic and well-qualified Director of Science to join the senior team reporting direct to and working closely with the Regius Keeper. He or she will lead the 75 people in our Science Division and contribute to developing and implementing strategies and policies across the organisation. This is an opportunity to make a difference in an ‘organisation that contributes to tackling the challenges of the biodiversity crisis and climate change and is committed to engaging with people in wider society to inspire them about plants and the environment. The Director of Science will also be responsible for promoting our science nationally and internationally and further enhancing our links with universities and other research institutions. He or she will have a strong focus on increasing income from research grants and scientific consultancy and will maintain an active and innovative personal programme of research in an appropriate field. Applicants must be of high standing in scientific research, with an international reputation for leadership in their field. A PhD in a subject central to our scientific mission is essential, as is a strong track record in research evidenced by high quality research publications and the award of research grants. ‘They must also be able to demonstrate a successful record of scientific leadership, including the management of people and financial resources. Excellent interpersonal skills will be required, including the ability to articulate and communicate our science to Ministers, Scottish Government research committees, leaders of our partner institutions, the wider scientific community, and to the wider public. ‘To apply send your CV and a covering letter stating your motivation in applying and describing the skills and experience you would bring to the role to Gillian Oddie in our HR team (g.oddie@rbge.org.uk) by 16th March 2012, Interviews are expected to take place in the week commencing 26th March. To advertise here please contact — US tel, 1 800 989 7718, naturgjobsanatureny.com or Furope/ROW fel, “44 20 7843 4961, naturcjubsamnature comDTS inrocus EIS Physicists raid Tevatron for parts Fermilab icon plundered amid tight budgets and shifting scientific aims BY EUGENIE SAMUEL REICH stories high, chock full of particle detectors, power supplies, electronics and photo- ‘multiplier tubes, all layered lke a giant onion around acylindrical magnet. During 26 years ‘of operation atthe Fermi National Accelerator Laboratory in Batavia, Illinois, this behemoth, the Collider Detector at Fermilab (CDP), helped to find the top quark and chased the Higgs boson, But since the lab flagship parti le collider, the Tevatron, was switched off in September 2011, the detector hasbeen surplus stock — and itis now slowly being cannibal ized for parts. When the Tevatron closed, Fermilab announced that the CDF would become an ‘educational display. Along with its companion experiment, DO, the detector was supposed to form the centrepiece ofa tour through simu: lated control rooms and decommissioned accelerator tunnels, But tight budgets for ‘experimental particle physicists — combined with their tendency to tinker and recycle pushing the outcome in a different direction, atleast for the CDE. “Some parts are worth pennies, but inthis, budgetary climate, even pennies are worth sav ing” says Rob Roser, who until recently was co-spokesman for the CDF and has now him: selfbeen recycled into a new position as head of scientific computing at Fermilab. ‘Recycling equipment is as old as science itself” says Jonathan Lewis, the Fermilab scientist in charge of decommissioning the l isa 4,000-tonne edifice that stands three ‘The CDF, ono ofthe Tevatron’ two detectors, i slowly surrendering its parts to other experiments. CANNIBALIZING THE TEVATRON Parts atthe Tevtron and its two main experiments Teratron 300m CDE And thriftisin fashion. With most of the action in particle physics taking place at the Large Hadron Collider near Geneva in Swit zerland, US researchers were preparing for hard times even before US President Barack Obama released his 2013 budget request on 13 Febru ary (see Nature 482, 283-285; 012). Although the Office of Science at the Department of Energy (DOE) got a 2.4% funding boost, the budget cut Fermilab’ allotment by 5% and DOE funding for high-energy physicsby 1.8%. Looking for savings, Bogdan Wojtsek- hhowski, who leads three experimentsto probe nuclear structure with an electron beam at the DOF's Jefferson Lab in Newport News, Virginia, convinced Fermilab to send him 600 photomultiplier tubes, which capture the light ‘emitted as particles streak through detector materials. Buying them new would have cost $600,000, ‘The recycling reflects not only parsimony, but also a programmatic shif in US particle physics. With the shutdown ofthe Tevatron, researchers moved from the energy frontier, where physics is tested with particle collisions atthe highest energies, to the intensity frontier, where the highest numbers of particles are collided. The {ate of the CDF parts mirrors this switch, Some power supplies are going to Mu2e,an intensity-frontier experiment at Fermilab to 1 COF and, ere being "he wake ofthe calider osure in September 201 0 look for the rare conversion of muons to elee- trons. Amplifier chips are going to g-2, another intensity-frontier experiment at Fermilab to measure a key magnetic parameter of the muon. Some scintillation materials, which emit light along the path of charged particles pass- ing through them, are destined for the Long. Baseline Neutrino Experiment, which plansto send neutrinos 1,300 kilometres from Fermilab tothe Homestake Mine in Lead, South Dakota Although most of the donations involve small items that would not stop the CDF from goingon display, the most ambitious recycling Fequest so far would see it gutted. A proposed experiment called ORKA, which would search for a predicted, but as yet unobserved, rare decay of kaon particle, needs a massive sole noid magnet like the one at the CDF’s heart. ORKA has yet to be funded by the DOE, but the Physics Advisory Committee at Fermilab approved its scientific goals in December 2011 Robert Tschirhart, co-spokesman for ORKA, saysthat adapting the magnet from the CDF by replacing some ofits present detectors with a kaon detector may cost several million dollars, That would still be about half the cost ofbuyinga new magnet. Lab management will make adecision about whether ORKA can eviscerate the CDF in abou 6 months time.RNY 'Nrocus Wild flower blooms again after 30,000 years on ice Fruits hoarded by ancient ground squirrels give new life to prehistoric plants. BY SHARON LEVY [Aprohistoric plant resurrected frm frozen issue inside a bell pepper — gives rise toand holds the seeds. The tissue produced shoots when it ‘was cultivated in vitro, and the scientists used these to propagate more plants. They are the oldest living multicellular organisms on Earth, second generation of fertile plants. During 3 propagation, the ancient form of the wild flower produced more buds but was slower to put out roots than modern S. stenophylla, which is found along the banks ofthe Kolyma. This suggests that the original has a distinct phenotype, adapted to the extreme environ- of the Ice Age “Tm excited that someone has finally suc ceeded in doing this” says Grant Zazula of the Yukon Palaeontology Program in White: horse, Canada, who has investigated previous claims of ancient seed germination. “There is 1 good chance that extinct plant species could now be brought back to life from permafrost preserved seeds” Although some members of the mam. moth steppe ecosystem survive, no place on arth currently holds the same combination of grasses, sedge and wild flowers that have been found in the mummified guts of ce Age ‘mammoths or in the frozen hoards of squirrels (B.Y. Gaglioti etal. Quatern. Res.76,373-382; 2011). Zazula speculates that living plant tissue from much earlier — hundreds of thousands cof yearsago — might also be revived, revealing evolutionary change over a longer timescale, and helping scientists to understand the lost ecology of periods such as the Ice Age. @ CLARIFICATION The tablein the News story ‘Obama shoots for science increase’ (Nature 482, 283-285; 2012) was und the make-up of the Food and Drug Administration's budget Obama's request leaves the government's input nearly flat, but arse in user fees from § andhiscolleaguestook sample of placental theteam says Industry would it te agency’ vera 2013 F tisueftomsstenoyla fats Theplantpla-_Theplants ave already blossomed to pro- | budge to $446 milion 4 cona—anexampleofwhchisthewhitemater duce etl seeds, which were grown Into a 1) rH | a i @e0nArobot | Tourette csr in NewYork fan Tuts ° MORE Could kilcaneer | schol confounds experts ates | biti te cel sotng | Aa | Yervomesome © ONLINE © themeutend | @citzen scene goesexteme. | sts around delivering a ‘ev natore.com/T¢haal | and how cells : deadly payload. | @ Kilogram conundrum on the road to sense pain, : faaanconha | resoldtonnteecnliie | ‘hase trLEGACY OF AUNIVERSAL MIND rom the day he was born — Fister ate itn ‘Turing seemed destined to solitude, misun- derstanding and persecution see page 41). As hiscentenary year opens, Natureailshimasone of thetop scientific minds ofall time (see page ‘40). This special issue sweeps through Tarings innumerable achievements, taking us from his ‘most famous roles — wartime code-breakerand founder of computer science (seepage 459) —to hislesser known interests ofbotany, neural nets, unorganized machines, quantum physics and, wel ghosts (ee page 562) Everyone sees different Turing. A molecu- larbiologist might surprise youby saying that ‘Turing’ most important paper is his 1936 work on the “Turing machine’ because of its rel evance to DNA-based cellular operations (see page 461). A biophyscist could instead point tohis 1952 workon the formation of biological patterns — the first simulation of nonlinear dynamics ever to be pub: ‘QNATURECOM lished (see page 464). Formoreon Beneath it all, Turing “uring, se: was driven by the dream of taturecam/twing reviving — possibly in the By TANGUY CHOUARD form of a computer program — the soul of Christopher Morcom, perhaps his only true friend, who died abruptly ‘when they were both teenagers. [want to “build brain’ he said. So does electrophysiologist Henry Markram (see page 456). But itis still a ‘matter of debate whether machine intelligence shoul faithfully simulate neuronal circuitry, or just emulate brain function using whatever expedient (see page 462). Even when Turing was kept busy by wartime code-breaking and the practical implementa tion ofhis universal computer, he never forgot that e had, in 1936 discovered somethingeven bigger: the incomputable world. Contempo: rary physics hast even started to work out the implications ofthat discovery (see page 465). Itis typical of Turing’s brilliance and play fulness that even as he gave so many fields the tools thatallowed them toblossom, he planted ‘ concept that pushes science as we know it — physical reality and Newtonian causality — towards the abyss. ‘Tanguy Chouard, a biology editor at Nature, swasthe consulting editor for this special issue.RAIN N ABOX Henry Markram wants €1 billion to model the entire human brain. ics don’t think he should get it. BY M. MITCHELL WALOROP y | TURING AT 100 | Alegacy that spans science: | twastit quite the lynching that Henry Markram had expected. But the barrage of sceptical com: ments from his fellow neuroscientists — “It's = crap! sid one — defintely made the day fel like a tribunal. z Officially, the Swiss Academy of ‘meetingin Bern on 20 january was an overview of large-scale computer modelling in neuro- science. Unofficially, it was neuroscientists first real chance to get answers about Markram’s controversial proposal for the Human Brain Project (HBP) — an effort to builda supercomputer simu lation that integrates everything known about the human brain, from the structures of ion channels in neural cell membranes up to mechanisms behind conscious decision-making, Markram, a South-African-born brain electrophysiologist whojoined the Swiss Federal Institute of Technology in Lausanne (EPFL) a decade ago, may oon see his ambition fulfilled. The project is one of ix finalists vying to win €1 billion (USS1.3 billion) as one ofthe European Union's twonew decade-long Flagship initiatives, Brain researchers are generating 60,000 papers per year” said Markram as he explained the concept in Bern. “They're all beauti ful, fantastic studies — butall focused on their one little corner: this ‘molecule, this brain region, this function, this map” The HBP would integrate these discoveries, he sid, and create models to explore how neural citcuts are organized, and how they give rise to behaviour and cognition —among the deepest mysteries in neuroscience. Ultimately, said Markram, the HBP would even help researchers to grapple with disorders such as Alzheimer’s disease, “Ifwe dont have an integrated view, we wor't understand these diseases” he declared. As the response at the meeting made clear, however, there is deep tunease about Markram’s vision, Many neuroscientists think it isl conceived, not least because Markramsidiosyncraticapproach to brainsimulation strikes them as grotesquely cumbersome and over-detailed. ‘They see the HBP as overhyped, thanks to breathless media reports about what it will accomplish. And they're not at al sure that they can trust Markram to run a project thats truly open to other ideas, “We need variance in neuroscience” declared Rodney Douglas, co-director ofthe Institute for Neuroinformatics (INT), a joint initiative ‘ofthe University of Zurich and the Swiss Federal Institute of Technology in Zarich (ETH Zurich). Given how litle is known about the brain, he said, “weneed as many different people express ing as many different ideas as possible” — a versity that would be threatened if so much scarce neuroscience research money were to be diverted into single endeavour. Markram was undeterred. Right now, he argued, neuroscientists have no plan for achieving a comprehensive understanding of the brain. “So thisis the plan,’he said. “Build unifying models” MARKRAM’S BIG IDEA Markram has been on a quest for unity since atleast 1980, when he began undergraduate studies at the University of Cape Town in South Africa. He abandoned his first field of study, psychiatry, when he decided that it was mainly about putting peple into diagnostic pigeonholes and medicating them accordingly. “This was never goingt.o tell us how the brain worked,” he recalled in Ber. His search for a new direction led Markram to the laboratory of Douglas, then a young neuroscientist at Cape Town. Markram was ‘enthralled. "Isai, "That it! For the rest of my life, Tm going to dig into the brain and understand how it works, down to the smallest detail we can possibly find?” "That enthusiasm carried Markram toa PhD at the Weizmann Institute of Science in Rehovot, Israel; to postdoctoral tints at the US National Institutes of Health in Bethesda, Maryland, and at the Max Planck Inst- tute for Medical Research in Heidelberg, Germany; and, in 1995, to a faculty postion at Weizmann. He earned a formidable reputation as an experimenter, notably demonstrating spike-timing dependent plasticity — in which the strength ofneural connections changes according to when impulsesarrive and leave (H. Markram etal Science 275,213-215; 1997) By the mid-1990s, individual discoveries were leaving him dissatisfied, realized I could be doing this for the next 25,30 years of my career, and {twas still not going to help me understand how the brain works” he said To do better, he reasoned, neuroscientists would have to pool their discoveries systematically. Every experiment at least tacitly involves model, whether itis the molecular structure ofan ion channel or the dynamics of a cortical circuit. With computers, Markram realized, you could encodeall of those models explicitly and get them to work together. That would help researchers to find the gaps and contradictions in their knowledge and identify the experiments needed to resolve them. “Markramisinsight wasnt original: scientists have been devising math ‘ematical models of neural activity since the early twentieth century, and using computes for the task since the 1950s (see page 462). But hisambi tion was vast. Instead of modelling each neuron as say, apoint-like node inalarger neural network, he proposed to model them in ll their multi- branching detail — down to their myriad ion channels (see ‘Building brain), And instead of modelling ust the neural circuits involved in, says the sense of smell he wanted to model everything, “from the genetic level, the molecularlevel, the neurons and synapses, howe microcircuts are formed, macrocircuits, mesocircuits brain areas — until we get to under- stand how to link these levels all the way up to behaviour and cognition’ ‘The computer power required to run such a grand unified theory of the brain would be roughly an exaflop, or 10" operations per sec ‘ond — hopeless inthe 1990s. But Markram was undaunted: available computer power doubles roughly every 18 months, which meant that exaseale computers could be available by the 2020s (see ‘Far to go) “IT WILL BE LOTS OF EINSTEINS COMING TOGETHER T0 BUILD ABRAIN.” FeaTure [GY And in the meantime, he argued, neuroscientists ought to be getting ready for them, Markrams ambitions fit perfectly with those of Patrick Aebischer, a neuroscientist who became president ofthe EPFL in 2000 and wanted to make the university a powerhouse in both computation and biomedical research. Markram was one of his first recruits, in 2002. “Henry gave uusan excuse to buy a Blue Gene,’ says Aebischer, referring toa then- new IBM supercomputer optimized for large-scale simulations. One ‘was installed atthe EPFL in 2005, allowing, Markram to launch the Blue Brain Project: his first experiment in integrative neuroscience and, in retrospect, prototype for the HBP. Part ofthe project has been a demonstra tion of what a unifying model might mean, says Markram, who started with a data set ‘on the rat cortex that he and his students. had been accumulating since the 1990s. It included results from some 20,000 experi ‘ments in many labs, hesays — “data on about every cell type that we had come across, the morphology, the reconstruction in three dimensions, the electrical properties, the synaptic communication, where the synapses are located, the way the synapses behave, even genetic data about what genesare expressed” By the end of 2005, his team had integrated all the relevant portions ‘of this data set into a single-neuron model. By 2008, the researchers had linked about 10,000 such models into a simulation of a tube-shaped. jece of cortex known asa cortical column. Now, usinga more advanced version of Blue Gene, they have simulated 100 interconnected columns. TThe effort has yielded some discoveries, says Markram, such as the as-yet unpublished statistical distribution of synapsesin a column, But its real achievement hasbeen to prove that unifying models can, as promised, serveas repositories for data on cortical structure and function. Indeed, _most of the team’ efforts have gone into creating “the huge ecosystem of | infrastructure and software" required to make Blue Brain useful to every neuroscientist, says Markram. This includes automatic tools for turning data into simulations, and informatie tools such as http//channelpedia net —auser-editable website that automatically collates structural data BUILDING A BRAIN The Biue rai simulation —a protetype forthe Human Brain Project Constructs smulted section of corte am the bltom up staring om ‘NeocoRTICAL COLUMN SIMULATED NEURON (10000 neurons) ton channels Invesen mol fFecitar units Y 50 eyinseal tho'wons and, "060 connections Sap snares a esc perneuron pass yo BenaFEATURE | FARTO GO The Blue Brain Project has stadlly increase the scale fs cortical simubtions through the uso of eating adge supercar ulars and eversrereasig memary resources But the fulscalesmulaton cae or inthe proposed Huan Ban Project (ec) would rue resources roughly 100000 mes age ti © a Exo ‘conrica, MESOCIRCUIT @ ar 204 ‘comPtere fa g a as RAIN Been Ziman » e 2 100. ae 3 mee ‘10.600 neurons) © op. NEURON. MODEL @ 10 2 20 10% 108 102 10% 104 10% 101 107 1018 ‘onion channels from publications in the PubMed database, and currently incorporates some 180,000 abstracts ‘The ultimate goal was always to integrate data across the entice brain, says Markram. The opportunity to approach that scale finaly arose in December 2009, when the European Union announced that it was pre: pared to pour some €1 billion into each of two high-risk, but potentially transformational, Flagship projects. Markram, who had been part of the 27-memberadvisory group that endorsed the initiative, lost no time in ‘organizing his own entry. And in May 2011, the HBP was named as one ofsix candidates that would receive seed money and prepare full-scale proposal, due in May 2012. Ifthe HBP is selected, one of the key goals will be to make it highly collaborative and Internet-accessible, open to researchers from around the world, says Markram, adding that the project consortium already comprises some 150 principal investigators and 70 institutions in 22 countries. “It will be lots of Einsteins coming together to build a brain,’ he says, each bringing his or her own ideas and expertise. ‘orrom To TOP ‘The description of he HBP asan open user facility sparked interest and ‘enthusiasm at the Bern meeting, But much more vocal were Markra sxistence> other machine by executing an encoded description of it. Thus, he foresaw the concept of software Finally, Turing answered Hilbert’s conundrum. He identified a question that could not be answered by any machine ina finite number of steps: willa given encoded description come to a halt or run forever ‘when executed by the universal computing machine? The answer to the Entscheidung: sproblem was, therefore, no. “You can build an organ which can do anything that can be done” explained von ‘Neumann, paraphrasing Turing, ina lec: ture in 1949, "but you cannotbuild an organ which tells you whether it can be done”. Sensing the limits of deterministic machines, ‘Turing began to explore non-deterministic compatation by ‘oracle’ machines. These proceed step-by-step, but occasionally make "unpredictable leaps by consulting “a kind of oracleasit were”. (CODE BREAKING Having completed his PhD, Turing returned to England in July 1938. The outbreakof the ‘Second World War soon sparked demand for his ideas, and he was sequestered at the Gov: ‘emment Code & Cypher School at Bletch- ley Park. There, Turing and his colleagues, including his mentor, topologist Maxwell “Max’ Newman, deciphered enemy commu nications, including messages encrypted by the German Enigma machine — a Turing machine with an internal mechanism that shifted through 10” possible configurations to scramble the input text. Starting with a set of electromechanical devices called bombes, each of which could emulate 36 suspected Enigma configurations ata time, the researchers at Bletchley Park, assisted by engineer Thomas Flowers at the General Post Office Research Station in Dol lis Hill, London, developed a machinecalled Colossus —a sophisticated electronic digi- tal computer. A 1,500-vacuum-tubeinternal :memory provided Colossus with a program- ‘able state of mind that searched for clues in coded sequences scanned from punched paper tape. Colossus was swiftly improved and duplicated, producing a second generation ‘of 2,00-tube machines that influenced the outcome ofthe war and the development of ‘modern computers although Britains Off- cial Secrets Act kept the details embargoed for more than 30 years. When the war ended, the push for more powerful computers shifted from cryptanalysis to the design of nuclear ‘weapons, and the United States, which had declassified its wartime computer, the ENIAC (Electronic Numerical Integrator and Com pater), in February 1946, assumed the lead, At the Institute for Advanced Study in Princeton, and with funding from the US Army, the Office of Naval Research and the US Atomic Energy Commission, von Neumann set out to build an electronic version of Turing’s universal computing machine, He wanted a Taring machine with a memory that was accessible atthe speed of light, and he decided to build it him: self. The US government wanted to know ‘whether a hydrogen bomb was feasible, so ‘von Neumann promised ita machine, with 5 kilobytes of storage, that could run the required hydrodynamic codes. The com puter’ design was made publi that copies could be freely duplicated — and commer- 0.5—(W) =0.605 40.023. This confirmed the presence of genuine eight-photon entanglement. @ (lH) HI? -Ivyqvl Experimental topological error correction Given such acluster state, topological error correction is implemented using a series of single-qubit measurements and classical correction operations. Inthe laboratory, operations are performed on state |) (equation (3)), which differs from |G,) in Fig. 2a by the Hadamard, operation H®®, Therefore, the correlation to be protected in equation (1), (&X<), corresponds to (524) in the experiment; similarly, each ‘(K.X) in equation (2) corresponds to (2,2). Furthermore, X errorsare simulated instead of Z errors. Figure 4 | Experimental results for the created eight-photon cluster state, a, Measured eightfold coincidence in the {/H),|V} basis. b, The expectation values fr different witness measurement settings. The measurement settings Fe Ay = (HH) 2°— | VXV 8°), XX Ay = (HH) [XV 6 Y,¥qand B= MP*(|HYH| ©? — VXVI%)o, with #0... 5. The In the experiment, the noisy quantum channels on polarization 4ubits are simulated by one HWP positioned between two QWPs, ‘which are set at 90° relative to the horizontal. By randomly setting the HWP axis to be oriented at 0 with respect to the horizontal direction, the noisy quantum channel can be simulated with abit-ip ertor probability of p= sin“(20), We first study the casein which only a single Xerror occurs on one ofthe six photons (1.6). The syndrome correlations are measured (Fig. 5) For comparison, in Fig. 4c we plot the correlations without any simulated error. This comparison, together with Table 1, makes it possible to locate precisely the physical qubit undergoing an X error We then consider the case in which all six photons are simulta neously subject to a random X ertor with equal probability 0< p< 1 and study the rate of errors, (ZZ) = —1 forthe topological quantum correlation (Z sodium pyruvate, x ‘non-essential aminoacid, mM P-mercaptoethanol and 1,000 U mal "leukaemia inhibitory factor (Millpore), and grown on gelatin-coated culture plates. Doxyeycine inducible 2931 Trex Flag-BTB stable cell lies were made withthe lpn T-REx 293 Call Line system (Invitrogen) and maintained with blasticidin and hydromyein B For screening, two siRNA oligonucleotides were designed against 40 mouse ubiquitin Higases (Qiagen). sIRNA oligonucleotides (10 pmo) and Lipofectamine 2000 were pre-incubated ina gelain-coated 96wel plate. D3 mouse ES cll were Sseeded.at 15,000 cells per wellon top ofthe siRNA miatue,and the morphology of S cell colonies was examined by bright field microscopy 48h aftr transfection, ‘To identify CULS-KLHLI2 substrates, doxyeyeline-inducible 239T cll ines expressing Fag-KLHLI2 or Flag-KLHLS were induced for 48h. Cleared lysate was subjected toanti-lag M2 affinity gel (Sigma), and precipitation were cuted with 3%Flag peptide (Sigma). Concentrated eluates were analysed by SDS- PAGE, and specific hands wer identified by mas spectrometry analysis bythe Vincent - Coates Poteomics(Mass Spectrometry Laboratory. For in vitro ubiquitylation reactions, CUL3/RBXI purified from 19 cals was ‘conjugated to NEDDS using recombinant APPBPI-UBA3, UBC12 (also known 4s UBE2M) and NEDDS. KLHLI2 putified from Escherichia coli and SECSIA~ ‘SECIS complexes from Si cells were added together with energy mix, El, UBCHSC (also known as UBE2D3) and ubiquitin an incubated at 30°C for th For confocal microscopy, calls fixed in paraformaldehyde and permeabilized with Triton X-100 were incubated with primary antibodies for 2h and Alexa labeled secondary antibodies (Invitrogen) for Uh. Pictures were taken on Zss [M510 and 710 confocal microscopes and analysed with LSM image browser and Imari 3D imaging processing software. Images were processed for contrast ‘enhancement to remove noise. Full Methods anc any associated references are availabe nthe online version of the paper at wwn.raturecom/nature. Received 3 August 2011; accepted 3 January 2012. 1. Letnger 8, Transmembrane collagen receptors. Annu Re. Cell Dev Bit 27, 265-250 2011) 2. Wicastrem S.A, Radovanac,K & FsslerR. Genetic analyses integrin signaling Cold Spring Hark Perspect Sel 10 1101 esnperspest 005116 20. December 2010), 3. Caswell PT, Vacrew,S & Norman. J.C Integrins: masters an slaves of endocytic transport Nature Re. Mol Ce iol 10, 843-853 (2003) 4. Stephens Leta Delton of beta 1 integrin n mice results in nner cell mass falureand permplantaton thay, Genes De 9, 1883-1898 (1995), 5. Chen, SS Fitzgerald W, Zimmerberg J Kleinman, H.K.& Margolis, Cela and cal-eiracelar mab interecons regu embyone stem cell ‘iterntiaton Stem Cale 25, 583-56) (2007). 6, Lang, MR, Lapierre, LA Frotecher MGoldenvingJR.& Knapik EW. Secretory COP ect componeni Sac238 ie azantal or rant chondoete maturation Nature Genet 38, 1198-1203 2006). 7. Toney, K etal Etcent coupling of Ser23-Sec24 to Sec3-Sec31 drives, CCOPI-dependent collagen secretion ard sextant for normal eranofacial ‘evelopment J Cel Sa. 121, 3025-3034 (2008). 8 Sarmah, Seal Sec240-cependent anspor of extracellular mata proteins raquied tor brash haletal morphegeress. PLoS ONE 5, €10367 2010). 9. Onis. Inoaya K, Takano ¥& Kodo A sec24dencadnga component COP sesso fr vrtobra formation, reveled by te analyss ofthe medaka mtant, '0i, De. io 342, 85-35 (2010), 10, Boyadev S.A eta Cran-lentcul-sutural dysplasias cause by a SEC23A mulation eading fo abnormal endoplasmicratculurete-olgrtfcking Nate Genet 38, 11921197 (2006) 11. Fromme, etal Thegeneicbssis ofa craniofacial sae provides insight ito ‘COPI cat assembly, Dev. Call 13, 623-634 (2007). 12, Jensen D.& Schelman R COPilmedates vesicle frmationata glance. J Calis yaa T-4 2010), 500 | NATURE | VOL 482 | 23 FEBRUARY 2012 13, Stage SM. ta Structural basis or cargo regulation of CPI costassembly. Cell 154,474-454 (2008), 14, Fath, Mania JD, 8.x & Goldberg. Structure and organization of coat rotons inthe COFI cage Ce 128, 1325-1336 (2007) 18, Fromme, J.C. & Schokman,. COPiRi. However, formally we ean explain the pulsed VHE ‘emission even for c= 1. In this case the acceleration should occur closer to the pulsar (Ry. 0 1/0") to compensate for the reduction in ‘the wind's kinetic energy. But inthis case, the inverse-Compton ‘y-ray radiation is expected to have quite different spectral and temporal features The above estimates ofthe location of wind’s acceleration siteandits Lorentz factor are quite robust, but they are obtained under the assumption that the transformation of the Poynting flux proceeds very quickly, at a specific radius between Ry and Ry 2 Ry with ARR = 1. This is not an obvious assumption, but is instead a ‘working hypothesis thatthe wind acceleration takes place in a narrow zone atthe radius Ry ~ 30R,, We cannot priori exclude the possibility Figure 2| Complex comprising the pulsar ‘magnetosphere the ultrarcativstic wind and the pulsar wind nebula. Dense electron ¢~)-positon (e*)plasma produced in the pulsar magnetosphere by pair creation processes initiates an electron Positron wind a the ligt eylinder, which has radius R, = 10°m. Initially, the rotational energy lost by the pulsar, Ege % 10" Js, i released ‘mainly inthe frm of electromagnetic energy (Poynting flux) and the wind's Lorent factor therefore cannot be very large. Atadistance yy the Poynting fx is converted tothe kinetic energy of bulk motion (green zone), leading to an increase in the balk-motion Lorent Factor toa least” T= 108. The termination ofthe wind by a standing reverse shock at Rs, 3% 10m boosts the energy ofthe electrons to 10! eV and randomizes ther pitch angles. The radiative Cooling ofthese electrons through the synchrotron and inverse-Compton processes results in an extended non-thermal source” theCrab nebula, Teemination shock Non thermal nebula