NGeee peeeeses i CT a ) Inet Gantt panes eens Deter Baty Seas and Rapradutbityovera Wide ange of Concentration ‘Standard crv plat of 10 tons fron 2004 downto 029 toa ANA or ghtrepiates ofan ARF tage gene 191.5% 0/) Bilan” HSYBR® Geen CGATPCR Sep Master Mic devez tenpate at ~25 Ct attr wih ghee ‘aesatite lane eaneentins us. and canada 800-424:5424 x8 ‘europe 00800-7000-7000 ata Patria Our complote quantitative PCR portfolio features products that include sample preparation, cONA synthesis. OPCA amplification and detection, and powerful date analysis software to meet today’s research needs as well as tomorow’ future applications. Couple our Mx" line of high performance teal-time QPCR systems with our next generation Brilliant I QPCR reagents and there's no need to look any further than Stratagene for your OPCR reseaich needs. + Brilliant? I reagents improved reproducit jasigned for earlier Ct detection, ind dynamic range + Four- or five-color Mx” QPCR systems with powerful MxPro” QPCR Software + Complete OPCR portfolio of instruments, reagents, and support Visit www stratagene.com/MxOPCR for more information about our Biiliant® Il OPCR reagents or Mx" OPCR systems — and find a biliant connectioneee peeeeses i CT a ) Inet Gantt panes eens Deter Baty Seas and Rapradutbityovera Wide ange of Concentration ‘Standard crv plat of 10 tons fron 2004 downto 029 toa ANA or ghtrepiates ofan ARF tage gene 191.5% 0/) Bilan” HSYBR® Geen CGATPCR Sep Master Mic devez tenpate at ~25 Ct attr wih ghee ‘aesatite lane eaneentins us. and canada 800-424:5424 x8 ‘europe 00800-7000-7000 ata Patria Our complote quantitative PCR portfolio features products that include sample preparation, cONA synthesis. OPCA amplification and detection, and powerful date analysis software to meet today’s research needs as well as tomorow’ future applications. Couple our Mx" line of high performance teal-time QPCR systems with our next generation Brilliant I QPCR reagents and there's no need to look any further than Stratagene for your OPCR reseaich needs. + Brilliant? I reagents improved reproducit jasigned for earlier Ct detection, ind dynamic range + Four- or five-color Mx” QPCR systems with powerful MxPro” QPCR Software + Complete OPCR portfolio of instruments, reagents, and support Visit www stratagene.com/MxOPCR for more information about our Biiliant® Il OPCR reagents or Mx" OPCR systems — and find a biliant connectionSee What You’ve Been Missing PrimeFect™ Primary Cell Transfection Reagents fection efficier And with Clonetics' information go to!GE Healthcare OPURE Expertise Want to purify even the most challenging proteins and gain the edge in your research? Want to purify even the most challenging proteins and gain the edge in your research? \Well now you con, PURE Expertise i the distillation of $0 years of chromatography experience ~ available online. Smply put it’s everything you need to gain the best resultsin protein purification Register for the live webinar event “Overcoming Purification Challenges with Difficult Proteins" at www. gelifesciences.com/ar-CPwebinar www gelifesciences.com/pure EOE: ie Ehenening Proteins imagination at work ear te sere aseateenccowery Sia sre the Coren mseVolume 317, Issue 5844 COVER DEPARTMENTS Supercomputer simulation ef the Slementary 1463. Seence Ontne environment which the vary ist stars 165 THs Waae in Scerce foumed, 100 mien years afte the Big Bana 1371 Eater” Choice Thefllamens, about 9000 lchtyears In 1474 Comact Science length, ate characteristic of a medal universe 1077 Random Samples {in which the dark matter consists of 1479 Newsmakers fast-moving elementary partces, 1367 New Products Seepage a7 1568 Sesnce Gres ‘mage Liang Gao ond Tom Teun, Institute for Computational Cosmology, cS EDITORIAL es 1869 Ante Partnership bya Kjos NEWS OF THE WEEK LETTERS Beyond Einstein Should Stat With Derk Energy 1480 ‘Why Do Tean-tuthored Papers Get Cited More? 1496 robe, Saye Pana TA. ederas BA Bertey 8 Buckley KB. Wray Selous Feat Cubs on acest Satelite Data——«1481 Response 5. Mich, 8. Jones. Uzh Ate Gne eran Gea eng Ray 1483 ‘or ue n Dang Toren ‘SCIENCESCOPE 1483 . Scien Say Ebola Has Pushed Weston Gorilas 1464 BOOKS ET Al. te the Brie Fins into Limbs Evolution, Development, and 1502 Tropical Disease Follows Mosquitoes o farope 1485 “ansormation & K Hall Ed, reviewed by A.C. Love Reports lame Animal Heath Lb in 1486 Sia ome rth fame ang foe omncinn < AGES foctand-ou'h Whodurit Sonam ia Lapses in Bisa Spare Concarn 1487 POLICY FORUM The Lit of Consensus 1508 ‘MM Oppenheimer, B.C. O'Neill, M. Webster S. Agrawaia PERSPECTIVES Square Dancing Antibodies 1507 DR Boren and A Wilson New Players in anandent Cycle 1508 Bthomcrp Cultural Modeting in 1509 65, Subramanian Sizing Up the Uncutivted Majority 1510 AMM Koypers rom Dares tL NEWS FOCUS {pom Dainessteisbt et Is neat Timing Kay to Mantal Meath? 1488 ve Report an alm Oi Pantatons Come Gear? 1491 Research in Japan: Big Winners, Big Bpectations 1499 Hunt for Dengue Vaccine Heats Up asthe 1494 1502 Disease Burden Grows ww scioncomag.crg SCIENCE VOL317 14SEPTEMBER 2007QIAGEN Sample & Assay Technologies Wepest i 2 a ae _ a | m/l i. DNA RNA Protein Sample & Assay Sample & Assay Sample & Asscy Technologies Technologies Technologies Molecular RNAi Automated s .. * Assay Sample & Assay Diagnostics Teddies sainaoges Sample & Assay Technologies 00 QIAGEN” Sample & Assay TechnologiesScience SCIENCE EXPRESS PLANT SCIENCE FKF2 and GIGANTEA Complex Formation Is Required for Day-Length Measurement in Arabidopsis M. Sama, D.A, Nusinow, S.A Koy, J Imaizumi Flowering wiggered ery when xh ight and enough ofa patty preteln are anaialein the aftuncon, conditions only satisfied during lange days of spring. TOL 26iscierce 1146994 GeocHenisTRY ‘Mass-Dependent and -Independent Fractionation of, Hg Isotopes by Photoreductin in Aquatic Systems B.A. Bergquist and}. O. Blum Te od isatpes of merry ar octnated na mas independent maser ding phetoreduton proving atiacer of mercuty species and reains though food webs. CONTENTS q MEDICINE Coactivation of Receptor Tyrosine Kinases Affects the Response of Tumor Cells te Targeted Therapies LM, Sicmmet eta In glblestora cancer alls, cups that wok by ining reeptr tyrosine kinases are mare powerful corbinaton than when adnistred as sng agent. 10.1126iscierce-1148050 OL 26iscience-1142946 TECHNICAL COMMENT ABSTRACTS BREVIA CANCER DEVELOPMENTAL BIOLOGY ‘Comment on “The Consensus Coding Sequences of 1500 Production of Trout Offspring from 1517 Human Breast and Colorectal Cancers” WF Forest and G. Covet 9 Sequences of Human Breast and Colorectal Cancers” G. Get etal Comment on “The Consensus Coding Sequences of Human Breast and Colorectal Cancers" ALE Pubin and P. Green Response to Comments on “The Consensus Coding Sequences of Human Breast and Colorectal Cancers” 6. Parmigiani etal REVIEW Complexity of Coupled Human and Natural Systems 1512 Ltivetal ww scioncomag.crg SCIENCE Obey, S. Shika, M, Konno, ¥. Takeuchi, G. Yoshiaki “ansplantation of wout spermatogonia to nenter stele salon recta male and fomale als that pode tout opr, 2 method that ay bel revive eatin specie RESEARCH ARTICLES ‘COMPUTER SCIENCE Checkers Solved J. Schaefer etal. ‘Asai of upto 200 computes running ince 1989 has censored the 5X 10® posible pestons or checers, showing thet perfect lay aways ea toa cau IMwUNoLogy “TUR3 Deficiency in Patients with Harpes simplex Encephalitis So% Zheng etal. ‘an orate irvure meptrin tumor select protec against sererinfcon ofthe cetal nous sto by herpes simpler ius L REPORTS ASTROPHYSICS Lighting the Universe with Filaments LGaoandt Theme ‘na madol ofthe oaly univrsowith wm eck mato the ire a focmin tne flamerts not clumps ths, the tar dsibton may 118 1522 1827 rove dikaraterconoat, => Pesce 1802 PHysics Phase-Coherent Transport in Graphene 1530 Quantum siliards Faliao eal. raphene act 36 aquanum bila tbl, the edges of ubich scatter the mavefuncenscf elecvonsandhoes, producing Intrieronco fics hat doped a tho shoot earety. CONTENTS censinued >> VOL317 14 SEPTEMBER 2007 1459IU Meld With MISSION*® siRNA - It's About Design! Sigma and Rosetta Inpharmatics, 2 recognized leader in Bioinformatics, have partnered ‘0 bring you the best siRNA design to improve your RNA results, Current studies suggest that the rules used to design gene-specific siRNAs have a direct effect on how wall your siRNA will perform in a aiven RNAI experiment. Using an RNA designed with a bestin-less algorithm saves time and money, enabling you to focus on downstream applications, not up-front siRNA design work. Better siRNA Design The MISSION siRNA Druggable Genome Libraries designed with Rosetta algorithm provide: Effient knockdown for low abundance messege Improved target specificy Flexible gene family sets, pre-arrayed for a range of applications ‘Optimum produts from highest quality, experienced manufacturing Freedom to operate for research use The MISSION siRNA Performance Guarantee Sigma quatantees that 2 out of 3 SRNA duplexes per target gene will achieve knockdown efficiencies of greater than or equal to 759% For more information on MISSION siRNA Druggable Genome Libraries, please visit us on the Web at ee Our innovation, Your Research ROSETTA Shaping the Future of Lite SesnesScience REPORTS CONTINUED. GEOCHEMISTRY Eally Archaean Microorganisms Preferred Elemental 1534 Sulfur, No: Sulfate 2 Phalippot etal Data rom malipl ltr icolopes imply hat 3S-biion-yaarold rmicrbeson Earth ere nt sulfate reducers as had been suspected, but instead metabolized eernetal sls APPLIEDPHYSICS Curret-incuced Magnetization Snitching witha 1537 Spin-Polarized Scanning Tunneling Microscope 5 reuse etal The spin-polarimd cuont rom 2 pat ascanning turetng microscope can itch, maripulate, and ead out the magntizaon ‘nsoval sland af about 100 von ars CONTENTS i MOLECULAR BIOLOGY Functional Architecture and Evolution of 1387 “ansciptional Elements That Drive Gene Cooxpression CD. Brown, 0.5. Tohason, A Sidon ‘The regulatory region of smultansoudy expressed muscle genes sre unexpectedly diverse within asa quit specie, yet each 8 ‘olutnaryconswed ameng specs. EcoLocy ‘Mutual Feedbacks Maintain Both Geneticand 1561 Species Diversity in a Plant Community RA Lankou and’. ¥ Strauss Inblack mustard alllechericas, which nit the erowth of other spies, are more adapive in verse coments an als influence community composion. icroBiotoGy socioLocy Quantitative Imaging of Nitrogen Fixation by 1563 Global Pattem Formation and EthnigCutturel 1540 Ingividval Bacteria Within Animal Cells Vielence ‘ALi, R Meter, ¥ Bar-Yom ‘Amedabsed on principle of phase-roparation predicts region cf violence when poked othe ditibution of ethnic rosin the ‘oxmer Yagesawa ae inca EVOLUTION Crystal Structure of an Ancient Provein: Evolution 1544 by Conformational Epistasis EA. Onlund, JT Bridgham, M. R.Redinbo,} W. Thornton Te stucur of» 450-milion yao certo cept, reurected Computational and biochercaly.sipess how mecernhoirmne receptors sled AComman Fold Mediates Vertebrate Defense 1548 and Bacterial Attack Ch Rosado eal Structure of CBa-MACPF Reveals Mecharismef 1552 Membrane Artack in Complement immune Defence MA Hodders,D.X. Beringer, P. Gros [Adonai tua hae by amarvnalandofonce peta and ‘bacterial tocprotein suggests thal the ivnune proteins disrupt ‘membres by fring pore IMMUNOLOGY Antinflammatory Activity of Human 1g 1584 [Antibodies by Dynamic Fab Aim Exchange ‘ML van der Neut Kojfchoten etal. neat the wo armsof.atype of antibody i oten replaced, lowing bing toto diferent aaigons and reixieg ‘oisinking andimmune responses. CP Lechene, ¥Lujen, G McMahon, D. L. Distel Mapping of ara bot0eof nitrogen shows that ymbict hace nth gill shipwouns fx ategen and varerittonkiagen-poor tissues of the host, >> Peso scenes. ped eens et i embod AVAAAS SS wy scioncemag.crg CONTENTS corsinued >> SCIENCE VOL317 14SEPTEMBER 2007 1461Gene Transfer | Electroporation .. for Better Results Use the Gene Pulser Moe!” electroporation system to quickly optimize conattions for dewering molecules efficiently ino mammalian cells — especialy ito prinary and difclt-c-transfect cells, ‘This high-throughput system uses disposable 12-, 24-, and 96-wvell plates and can be used for transfecting siRINA, plesmid DNA, and other molecules directly into the nucleus. ‘Optimize Your Research Tima ® Use 2 preset optimization protocol or a gradient protocol to decrease programming time ® Process an entire multivell platoin 2 minutes or less ‘Optimize Your Reading Timo * Take advantage of Bio-Rac's extensive Ebrary of electroprotocols Optimize Your Resources * Use fewer cals and less sample — siRNA or DNA — by defining clectroporation parameters: ‘Optimize Your Experimental Conditions ® Program up to 24 eteciroporation protocols, with replicates, on a: ‘Optimize Your Bench Space «= Pertorm high-throughput screening and standard laboratory-scale experiments ‘Quality for an electroporation butter sample oniine, or submit your optimization protocol fora tree git. To learn more, go to www.bio-rad.com/ad/ MXcell Toth loca cls ofc, vit wamblo m.cem/eontact Inthe US. cat fae 120 EIOAD THEO DI-ET ‘ai ut on the Woot tecoverbieradioom, BIO-RADSCIENCENOW surscienceron.org Dsl Grey Whales Far From Recovered? Genetic analysis ovals population fit wall below itshistarc igh, Born to Run Long Distance Stamina sretching mutation widespread in ome groups of people, Dwindling Days for Arctic ke New projections suggest eratr and greater annual mls ES COVERAGE rout GF Brain, nitric oxide synthase, SCIENCE'SSTKE Ywwsthe,org SIGNAL IRAISDUCTION KNOWLEDGE ENVIRONMENT PERSPECTIVE: Dialog Between LKBI and AMPK— Alot Topic atthe Cellular Pole Foret ord a, Blow UB1 appearsto be a novel ls of tumor suppressor that ass an energy sensing are! poly cheat, PERSPECTIVE: B-Actin—A Regulator of NOS:3 ¥.Su, D. Kondrikow E. 8. Block Bractn regulates the activty onic ove synthase ype 2 eet and ince though #590, Your first choice for investment funds SCIENCE CAREERS usclencecaraatsorg CAH RESDUR GLOBAL: Should | Doa Ph.D.2 Poin ‘Whether or at to do a Ph.D. is 2 decision many stadents nly underake, US: Opportunities —the Most importane Venture Capitalist Fiske Urele Sam maybe the key venture capitalist. halp tart your science-based copay. US: A New Tech Newus in Silicon Valley A. Fasehos The Bio-ifo-Neno Research apd Development site wil doresearch and ain sets. US: From the Archives—Facing Life's Challenges sa Foreign Scientist X Huong Postdoc Kiyan Huang overcame mary obsaces when sho fist arivedas a sudenttiom China, SCIENCEPODCAST Dowload the 14 Seplebe Science cca ef art catng a taal ont, creado cos ok re mera het et Sar founato, end are ha ‘ feces speeae AL WS SCIENCE ONLINE FEATURE THE GONZO SCENTIST Check out the frst installment (including an audi slideshow) in 3 series of reports ‘onthe connections between scence, culture, and the ats. sor serena orp ctgonsacetst Separcteindvidea sttutional subscriptions to these products may be required erful tet ocess. ww scioncomac.crg SCIENCE VOL317 14SEPTEMBER 2007ANo-Win Solution for Checkers Computer scientists have traditionally used games such as chessas test cases for research in artificial intelligence. Les challenging games that have a small search space can be con pletely solved with computers by examining every possible set of maves from a given starting position, Chess hasan immense search space that would requie the fastast computers ecns to salve, but other games provide tough but feast bie challenges. Schaeffer otal (p.1828, pub lished online 19 July; ee the 20 July news story bby Cho) report their solution ofthe game of checkers. black moves fist, and the apponents execute perfect play the game ends in adran. The analysis bagan in 1989 and required dozens of compat fora complete solution Strings of Stars Gravy caused the eststars ht formed in he catty urivers to clase in overly dense ‘regions. These regions were seeded by clumps of dark meter panicles that nether low or intra wih ight excep aravitatonaly. Most rmodting ofthe rst srs has ued eo" dak meter, bits possible that the dark matt: was nar” it nas made ol more anegetic fundamental partes. In computer simaktions thatinlude warm dat mater, Gao and Theune {9.1527 see he cover andthe Perspective by Brom) show that the faster mations ofthe ‘vam dak matter erased very smal density Stucures, and ite sabe elorgeted ges duds formed instead that ragmente to prouce stings a star. the patern of he fist Ce ee eo] << Switching Magnetism on the Spot eae cue eed ener ior ones eerie eel red this way are limited by re ey information that was already stored. The use of spin-polarized current to locally contro and read out the magnetization is expected to over ‘come such problems, but the underlying mechanisms involved in spin: polarized magnetization switching remain unclear. Krause et al. (p. 1837) show that spin-polarized current from a scanning tunneling microscope tip can be used to both manipulate and read out the mag netization in small islands of iron atoms. The magnetization switching in the island is dominated by a spin-torque effect exerted by the spin- polarized current, whereas the Oersted field (magnetic field arising probe. The bit densities that can be achi ate toe ncemag.crg SCIENCE eee ent stars may tellus about the dark matter content of the universe. Graphene Billiards ith ts stv band scr and mechan cal tabi gephene slated sheets of srrtte) hesbeen predic to ahibi a num ber o exotic anspor propa. Howes, he tenspat of cars mend the ito pet (vee fe leone bands meet manent spec that gest to mary ol he predic perer (6.1830) tema sued warspr prop ert eran Fis ropon devia cies of inhi he tes cut be tail Gris the graphene have alae her oxen Meteaues tanger Sepend on gece. effect the wave fncions of ects ened telesca erie as ey ere scared tm the edge ete gapene See whichis quant coeet ilar x Pass the Sulfur, Please Carer and sultr top signatures provide the main evidence forte identification of the cots Iie on Eth. Dataisin the signatures of the several sul sotopes cannon beused to track metabolism. nas previous suggested thata large fraioration in the "S versus 2% vousi7 has remained contoversal, Mino etal ~A \sotopes implies that sulfateedcing bacteria rere present in rocks dated to about 3.5 bilbon years ago. Philippot eta. (p. 1534; see the Pesspective by Thamdup, making Use of "5 data, show these rocks record the presence of joiganisms that metabolized and disproportion ated elemental sulfur. Several such organisms are present nea the base ofthe phylogenetic Human Interactions Humans have continuously interacted with nate ral sjstems. Livet al. (p. 1513) review the int cate rature ofthe organizational, spatial, and temporal couplings of human and natu- ral systems. Case studies on diferent continents suggest that couplings have evolved from directo more indirect Ineractons, fom a¢jacent to more estant linkages fom local 1 global scales, and from simple to complex pattems and processes, An appreciation of such intr ations should help inthe development of effective policies for ecological and sociveconomic sutanatiliy. Humans not only interact with nature but with one another in groups. tim et ol (p. 1540) have adapted concepts of phase separation fiir in Chemistry and pysics to study patterns in gl populations that can help predict and petzps prevent conflicts. They posit that violence arses 2 boundaries between regions that ae na suffi= Cienty well defined. Armadel based on spatial distnibutions of ethne groups gave good pret tions about regions of violence in the former Yugoslavia and in India, 14 SEPTEMBER 2007 1465Contned fo gage 1465 Tailor-Made Toll-Like Receptor Laboratory based immunology has revealed much about the cole of innate immune receptors frm ‘nse to mammals, but to what extent do such receptors protect humans from infections? Zhang etal. (1822) report a primary human immunodeficiency that points toa dedicated rote fra Tll-tke receptor {TLR in protection irom infection with a single specific virus, without any apparent influence ‘on ather pathogens. Herpes simples virus (HSV) causes encephalitis in children carrying a mutant allele of TLR, which normally regulates the antiviral interferon response to virus nucle acd inthe ‘central nervous system and in dendritic cell ofthe immune system, Naintenance of TUS inthe inate armory of humans may have been driven by viral infection. These results suggest that other similarly narow host-pathogen interactions may have also co-evahed. Functional Evolution of Proteins “he dec identficaton of protein evolution mechanisms requites comparing pci trough evolu- tionary time. The sequence ofthe 450-milion-yea-oié ancestor of vertebrate mieralacortceid (MR) and glucocerticod (GR) was previcesly determines by phylogenetic analyss, and the ancestor nas shown to have MR-tke hormone specify. Ortlund et al (. 2544, published online 16 August see the 17 August newsstaxy by Service) use structural, functional and phylogenetic analysisto deter imine how specific mutations resulted in achange from Mike to GR hormore specificity. They find evidence for epittic interactions nhere a substitution change the conformation at anather site. Substiusions that he! no immediate fueron effec, but affected stability tallow subsequent {urctionl switching mutations, played an important ele in GR evolution. An Airy Meal “he tation of atmospheric aitogen into ammonia thats essential te human raion and global ecoysersis per forme by eedivng bacers and by symbionts in plant oot ‘nodules. Lechene eta. (p.1563; se the Perspective by Kuypers using mul-sotope imaging mass spectrometry with the stable istope of ™N, measred nitrogen fraton by symbiotic ace, They raced the ublzation af fied trogen, inthis ase by animal rater than ty part host els Doubling Up Antibody Specificity The lg and ea halesthat make up arecls bth ay arable regen athe ands hat Coniar fo fo ehh dveseantgar-brin est te nbd mae Inmuoagka dopa dates tha singe Bical geeraes antes of one cefed spect ach kee at Hes deni yeti heavy ight chan conbleaton) tere area cass aed awn a5 immunoglobulin G4 {IgG4) has been suspected of breaking this rule, Van der Neut Kolfschoten et al, i. 154; see te Pesci by Baron aed Wee) now povided: ences tal gc ar sap Thuy oat ola tes cS nga peo eSog Wu foe Got teh dal peck Forbermore,narmodelol dese hates n css, by aes, Theboselsigespecily Unde losaf be eliy io coselnt)worelledbeetehing das Regulatory Motifs in Making Muscle During metazoan development, multiple genes are co-expressed so that interacting gene prod- ucts can be produced in the same place and time. Brown etal (1557) examined how genes ‘thot function together ate coordinately expressed by dissecting cis-tegulatory elements in 19 ‘co-regulated Clona genes that encode components af a muscle multiprotein complex. Assays defined the cis regulator elements through mutational analyses, and mutant-construct gene expression in muscle cl's was quantified to estimate the activity ofeach regulatory mati. A B comparison barween the divergent species C. intestinalis and C. scvignyi revealed that moti § arrangements dfer widely among co-requlated genes within a species but orthologous mats E are evolutionary conserved Ri ee ocd for Biotechnology ea eat “MI Microarrays Inc Mis cx the forefront of development and commercalization of rucleie acid and protein microarray technologios. M offers researchers validated gone expression products and custom content manufacturing services. ~ speclzing nthe manuscture ‘of research and diagnostic use OEM products, eaurirg comprehensive validation services and decumertaton ~ ieroarrays Inc will locate to the HudsonAlipha Institute Fall 2007 HUDSONALPHA wwscioncemag.crg SCIENCE VOL317 14SEPTEMBER 2007 1467‘Anita Jonesica profes sor inthe Department of Computer Seance at the Univesity of Vina, Charlottes, VA, ne chakedtheNatenal eaderics commer that produced the rept Polar kebreekering hanging Worl: Assessment of US. ees An Icy Partnership KNOWLEDGE OF THE WORLD'S POLAR REGIONS—ANTARCTICA AND THE ARCTIC—IS OF intemational interes for economic, environmental, territorial, and security wasens. Studying these environments hasbeen a cooperativeactivity among countries for half century Icebreaker ships lave played a critical ole. Unfortunaiey, ihe US. icebreaking capability has deterioratcd sastantially. Of the worlds roughly 50 high-capability iccbreakers (at least 10,000 horsepower and capable of steaming steadily through ice 4 to 8 feet thick), Russia possesses 15. Canada ‘operates six. The US. govemment owns three, two of which ate atthe end of their 35-year service lives. This not only threatens U.S. access to these egions but also jeopardizes the ability ‘ofthe US. research communiy to condctsolo and international research missions. A long-lived, suuccessfulpartnership between the polar research community and the US. Coast Guard (USCG), ‘which operates the government icebreakers, has been built over decades, ‘That partnership is unhealthy now and should be revitalized. ‘Many nations have benefited ftom the know edge gained from research inboth polarregions, Forexample, we have adeeper understanding ofthe ‘molecular mechanisms that anamals use to cope with freezing conditions, ‘the mansport of onzanie pollutanss to polar food webs, and the influence of the polar regions on the deep ocean “vonveyer bet” Eight nations (Canadh, Denmark, Finland, Iceland, Norway, Sweden, the Russian Federation, andthe United States) have nd and population inthe Artic, Their interests are not only scientific but also encompass ‘security, aw enforcement, environmental, and econcmic matters. With 1" inereasedretreatof the summer ice margin, human activity especially that ralated to resource exploitation, is likely to increase, The Russians (only) have made a territorial claim to about half ofthe scabed under the Arctic ‘Ocean. Other nations are considering their response to the Russian flag recently planted atthe North Pole Increased human ativity inthe Aretie nocessarily requires an increased presence in ice-bound ‘waters. The US. has combined USCG Arctic patos for maritime and environmental safery and ‘maritime law enforcement with research cruises. Building or contracting for separate ships for the two missions is less cost-effective, particularly for the research community. Past history ‘Shows thatthe missionsand objectives ofthe research cemmunity and the SCG are compare ‘even complementary. These can be simultancously served by’ an icebreaker following a course ‘titable for research by 30 to SO scientists aboard, ‘The facture in the USCG/scientfic community partnership comes from the Coast Guards inability to fund replacements for the aging icebreakcer ships. Surprisingly, the L.S. Office of Management and Budge: (wth congressional concurrence) transferred the budgst For operating iccbreakers to the National Science Foundation (NSE), mgjor funder of polar research. Asa result, science agency is currently making decisions that affect the safety and training of a nltary force, risking NSF’ repuiation and posing potential physical dangers tothe crew. Until the fleets recent deterioration, the USCG ieebreaker ships made.an annual break-in to McMurdo Station in Antarctica, so that tanker and earyo ships could provision rescarch activity. In recent ‘years, NSF has contracted for ships from cther nations to do the annul break-in, but those ships have not ahvays performed without incident In 2004, Congressasked the National Academiesto invest gate what icebreaking capability the United tates needs andhowbesttoacquire and operate that capability. Our committee reaffirmed the value and efficacy ofthe USCGiresearch community partnership and recommended placing the aging icebreakers with new ships, designed with research community involvement. Modem, ‘technology, particularly for hull design, propulsion, and electronics, candelivervessesto support ‘needs in the Arctic and Antarctic without increasing the current number of ships The Coast ‘Guard should be fanded to buildand operate the new ships. Researchers should pay the modest incremental costs incurred by their presence on a crise, as in the past. This would revitalize the ‘decades-old icy partnership that benefits not only US. interests but also the world community of polar researchers Anita K. Jones wwscioncemag.crg SCIENCE VOL317 14SEPTEMBER 2097Appuiee prysics Sending Plasmons Round a Bend The orders-of-magnitude size dilference between optical fibers and nanometer-scale elector cir- city presents a substantial compatibility gap bbetneen the fastlong-distance optical signal communications offered by photonics and the comerience f small-scale integrated miroelec- twonics. Surface plasmens ae hybrid excitations 1 ight and packets of electrons confined tothe interfacial region of ametal and a dielectric, and they affr the potential to fill that gap. Honeve, plasmons ae dspessive and tend to leak away because of scattering and radiation Losses, gi Ing tse tothe general preblem of efficiently 4uding the plasmon ound the two-dimen sional plane to desired sits. Steinberger er af have fabricated surface plasmon waveguides by lithographicaly paterning tracks of stcon diox- ‘de deposited ona gold fim. They demonstrate the ability to guide plasmons around 2 90° bend, showing hat there isa tradectf between bend ‘edius and propegation length forthe optimal transmission ofthe plasmons through the wave guide. The sults should help shrink the icom= patibility cop yet further. — ISO ‘Appl. Phys. Let. 92, 81111 2007. Mobile Electron Carriers Miceobes that have rot yet been cultured under laboratory conditions are, not surprisingly, rather mote dificult to work with than these that wy scioncomag.crg, [-Dhite)zeln oleae EDITED BY GILBERT CHIN AND JAKE YESTON svocnemistey Peptides to Sway Iron Levels Ferritin proteins are best known for storing iron within their cores, but ferritin also release iron when itis needed, such as uring hemoglo- bin synthesis or when iron is lst through hemorrhage. Although the release proces is driven by the reduction af Fe" and uptake by Fe* Ghelators or chaperones, changes in the gated pore ofthe protein, such as motations of conserved pore residues affect the rate of iton release, and in vitro, millimolar concentrations of urea can unfold pore helices ang increase the release rate, Liu et al. searched 2 combinatorial peptide library of ferritn-binding peptides and identi- fied a single heptamer that accelerated iran release threefold, and when combined with Desferal, an iron chelator ia therapeutic use, led to an ightfold increase. Another heptapeptie was identified that decreased iron release, possibly by binding across the pore, Potential applications include treatment of iron overload of timiting unwanted effects of ion release, such as consumption of cellular reductants. — PDS |.Bot Chem. 282, 10:107a96c.700153200 (2007. have, suchas the perenial wrkhorses Escherichia and Soccharomyces. Nevertheless, recent forays into soit and marine commutes have hinted ata wealth of untapped pharmaceu- tical and biechemical expertise, and technolag Cal aivancesin extracting and sequencing genomic DNA of unpurified (and in mary eases, unseen) organisms have begun to bring those microbial sil within reach, ‘MuBmano e af. have analyzed a single ‘Beggictoa filament oughly 30 um wide end 1 ‘en long) of almost 1000 cellby whale- genome amplification and pyrolphosphate) sequencing. They have been able to assemble enough sequence to cover approximately} ofthe IeM gence a esti mated by the recovery ‘of single-copy marker ‘genes and amincacy RNA synthetases. The callecton of sulfur, nitogen and oxygen metabolizing enzymes, albet stil incomplete, provides genetic evidence fr the elevatortike lifestyle ofthis bacterium, which cycles vertically asitharvests energy from the oxidation of ul- fidic deposits. tthe relatively orygen-rich sur- face of marine sediments, electrons fom elemen- tal culur are donated to oxygen, yielding slite; in deeper, anoxicregions of he sediment nitrate is recuted as the acceptor of electrons trom hydragen sulfide. Beygiataa are energetic hoard- Beggiatoa filament. SCIENCE VOL317 rs fiat, accumulating it in vacuolesin cor- ‘centrations a high 250.5 tothe cismay of competing éenitniying bacteria. — GIC PLoS Bol. 5, «230 2007) Oxygen on Demand Inthe desion of xii sus ota ol lexae wounds ere etc iting foes the s- ability of the oxygen necessary for vascularization and healing oc Tosi slow cnygen ition, Hain eo have explored the possibility of cratrgamateral hat can generate onygen in Sh Sodium pereatbanate nas ied th oO aie cay) (PGA) insolation, ands wee sltioncast aed stony ried to prevent re ora tion of ois namo envonmert steady onyoenprodtton was observed for 24 hours and then gradual sowed and enced ate 7 Fount. PLGAFIME were placed under dorsal skin sin mice nd then abserved over perc of Lael Tho contin ing sodium percarbonate hited a significant deen lap rersis oe the fest 3 drs, slong sss thse damage ard ester mechani stengh. However, here wes no bene fitafeca mec in compan wth uneteg Pins. The autor ae setingtexond the anygen release tine, ether thaugh encapsl- Centeudon pe 1472 14 SEPTEMBER 2007 1471tion ofthe socium percarbonate or through the use of diferent cxygen- generating chemical components. — MSL oratrts 28,4626 (200 Breaking Two Rings Polyesters have traditionally been prepared by condensation of monomers bearing acid of ester groups: The chain grows by formation of O-C bonds with concomitant loss of water or alcohol Choosing a cyclic monomer can eliminate fr mation of these smallemolecule by-products, 2s chain growth proceeds by ring-opening, but this approach offers limited functional diversity along the polymer backbone. Jeske eta have developed a zinc catalyst that links epoxies to ‘ic anhydrides through alternating ring» opening steps and thereby introduces backbone substituents ranging from methyl and cyclohexyl to vinyl moieties by apoending them to the strained three-membered rings. cyano group tn the giiminate ligand coordinated to zinc proved key to catalyst stability under the reac- tion conditions. esystem achieved number average molecular weights exceeding 10! and low potyatspersities (1.110 1.5). —ISY 1A, Ce. So, 129, 1010210077568 (com www.stke.org Pressure From Above ‘recent interdiscptinary tren is the use of o> nomic tansactions, which yield @ quantitative expression of preferences, in experimental studs of human social behavior. Inthe arerymmous one Shot dictator game, a ptson i alloted the task of ‘aking any pert oral ofa sum of money, withthe remainder given to a second person who i neither seen nor encountered again. Sta and Norenza- yan engaged 75 residents ages 17 to 82) of Var cauver and offered them the opportunity of play- ing this game after having completed one of th porsible srambled sentence tests, Acres the three group, the moda choice was to take ether the entre amcunt cr enly hal oft, Within each of the two groups noohze been imglicty primes ith concent of region orf civic justice, 11 out of 25 people ceded hall ofthe money, a5 com pared to 100825 abscorcingwith eveything in the neural prime condition. Furthermare, bath |ypes of pro-social priming evoked sigriicantty teeter expressions of generosity (than the neutral Prime) by theists. Linking institutional systems of ‘moray to other-tegarding behavior by individu aslends support tothe proposal thatthe develop ‘ment of sacal nar erabled the increase of aroup size in cu human ancestors. —GIC ‘Pryhol. Si, 28,803 (2007, << Knitting a Ravelled Sleave For an activity in which we spend a thie of our ives, much about seep ‘remains enigmatic. Foltenyi eta. investigated the role of epidermal growth factor receptor (EGFR) signaling in regulating sleep in Drosopbia. inthe fly, the aaivaton of EGFR ligands such as Spite depends on te transmembrane protein Star and on Rhombod fay (Rho) proteases. Using fies in which Rho ard Star expression could be conditionally induced they showed that overexpression led to transiert increase in both the duration and number of sleep episode, which was folloned by 2 decrease aré then 2 return to normal. The overexpression of Rho ang Star also led to an increase in phospterylation of extracellular signal-regulated kinase (ERK, a target of EGFR signaling) that paralleled the temporal pattern ofinciezsedsleep, andthe increase in ERK phosphor ation was greatestin the tritaerabrum. Moreover, several ines of as in which Rho activity in neurons projecting rom the pars intercerebralis (PL, arecion analogous to the vertebrate hypothalamus) tothe teitecerebrum was inhibited with RNA interference showed decreased sleo. This decrease involved brief sleep episodes in conjunction with en increase in the numberof times that sleep was atempted-—potentialy ly model of insomnia, The authors pro te thatthe prociction of EGFR ig- and by Pl neurons leads to ERK activa- tion in triteatebrum neuron, thereby promatirg sleep, — EMA ‘ot. Newesc. 30, 1160 2007) SF TD, th ad The Pi, median bundle, and titocerebrum Cee ret rs wwaciencemag.org SCIENCE VOL317 PIPETMAN Co: eG ee esc Ameer CN tn ee too eet eerste easy 14 SEPTEMBER 2007 14731474 Science elects a 82 ‘ateman Hows, 8238 le Road Canorige,URCE2 110 es 0085-781 Be retirees taunts SSeteans’ Sceeaace SS Sa Seiogaaas Siorcirsats Ferrera sehen ema Pamerd erect ‘receseane sn mviton he ate probe utersnding Specimen nf ctor ae tee srr er ieee tad clay etre Se fae 120 and 1210 thes sary 207 be or ces ‘rovicenansg npfatrornbsoneshint Ace Nesey Buran, Cle nn ‘east keer ‘cream, Cong nero bed Cheon Hine Feiss ves et for Savio ey Ne {yf rh fst tana ermal tmnt ome oh ‘Sri ery es: monn maar Do (Grea pi, age ey ern ate Sa, {fn ton Sun Wie, Sn When eee sis Sey {Gtr it tare Pata sete name ‘Slt utes arrays hale ‘sen ear tt oem as oan Ret eer fst tty ore Lt fer oman ‘arm leat eta Poy Shimer, we war ‘Sear hin pre Caen Dae Corn Data na eer sh aera hen nuit eR oer ate Lyne oman nents tripe en an ak Dae eee ors habe an er te Gratien Ee tae Gy nes como Ra rol eh meat ieee cern eene SE Sa cone ane Creche tne mere rate SSS Aiee Pet Sree eerste SEwesevieecns incense ionamin ed ee Seems mean Sige ieemoniintyoetas Secu patigsaeng ts Seren SRS Cuca sheen onan ena shone eterna Seca erect Scere ear ee Ivesiataninveenstenment BOE TEA a FEES omemn simon ferme srs Ouro nenserheden Apreamemesnanns Saltese sen Nace me Imscans ae we aryl Cony bo he peereeri enn aereeee seebhnceiicne ceminee Sape arsscrion crane mare Sam ee mee oa Setters See ieee ne Serene some a sencan at igri as Rises ee ‘eid: 202-326-6523; amas co ™ milan at me Ftc ery mean amt sawcener moe seein etme tain inf Dons, an ttn na AG ce en they tut Homa, ar tye Sa MVAAAS oe Saneese esa Seat Riese EERE = eee ane Ser eal i ERE yer, ene RS son Sueeo? Baer 14 SEPTEMBER 2007 VOL317 SCIENCE wraurscioncemsg.org,¥ Down in the Swamp “the Ever Glades [scl are now suitable ony for the haunt of naxaus vermin or the resort of Desilent reps.” That was the verdict of an 11848 report to Congress that recommended raining the vast Florida netand. I'sone ofthe jewels tucked anay in the Everalades Diitel Library, created by Rerida International University in Mier The archive contains more than 400 articles, maps, photos, and other materials about south Florida history and envionment. Offerings range from plant censuses ané rainfall analyses to recorded interviews with Marjory Storeman Douglas (1890-1998, the writer who gava- nize efforts to preserve the Everglades. n this 11908 phot agit in Miami poses on a stuffed alligatx. >> vis idaeduledl Psyching Out the Fruit Fly Fruit fl brains are usetul for studying genes implicated in neurological scr such as ‘Alaheimer’s ané Parkinson's disease. > Getting at ther, honever, requites messy dissections ‘that can damage tis sue. Now, a new tech= wurm.sciencemag.o1g jr For Health nique may offer a hands-off peek into the miniature mind of Drosophita, ‘team led by Leeann McGurk ofthe Meical Research Coundl's Human Genetics Unit in Edinburgh, U.K. takes lies bred with genetic ‘martes that make the newous systems fluoresce (blue in phot) and blezhes their exoskeleton, ‘making the bacies translucent. Optical projection tomography reveals the 30 siuctute cf the organs and allows researchers o virtually sic the flies" bins on any axis, the authors report cnline on 5 September in PloS One, The procedie may one day be automate, collaberaor Liam Keegan sys, and-—tuth better tesaluton andlongerlived fuorescence—could make hand dissection of Frat Ry brains 2 thing ofthe pas = ~ Farming Good The worldwide agricultural evolue tion that began about 20,000 yeats ago had its downside: Many researchers have found that early farmers were notas healthy a5, their hunter-oatherer ancestors (Scieace, 9 June 2006, p. 1448). But anew study of teeth from Nile Valley farmers offers the Fist comprehensive evidence—ttom date spanning some 10,000 years—thet the farming fe was better for health ia the long run Bear Facts Why does a bear rl Teeth from an early Neolithic farm woman show enamel loss. in the woods? This giant grzaly bear VI EDITED BY CONSTANCE HOLDEN Childhood exposure to stress from disease or bad nutrition has a lasting eect onthe formar tion of tooth enamel. So anthropologist Anne Sterling of Duke Univesity in Durham, North Carolina, an lay Stock of the University of Cambrigge in the U.K. studied the teeth of 242 individuals who lived in the He Valley between 13,000 and 1500 8.C., They found that 70% of the Badari people, early farmers ‘ho ived between 5000 and 4000 B.C, showed signs af enamel los, compared to only 399% of hunter-gatherer fom the same area 2 few thousand years earlier. But once food Stocks became mace reliable, health improved markedly: Orly 33% of people whe lived from 11900 0 3100 B.C, had lost enamel. And by 2000 B.C. the incidence nas down to 21%, the authors reported onine 4 September inte ‘American Journal of Phycol Anthropology. Anthropelogist lak Larsen of Ohio State University in Columbus calls the study “especially inter sting” because it shows that health improved with the cise of urbanization and the Egyptian state Healso says itbolsers the notion thet hunter- gatherers were initially pushed ito farming by population pressures or climate changes. from the forests of British Columbia had his ree-rubbing habits scrutinized as pat of a project to gett the bottam of the question. it seers that bears engage in scent merking, rubbing, bitieg, and scratching the same tees over many seasons. Once a bear has “anointed” a tree, others follow suit—in fact, stepping in the same tracks. To leam more, Owen Nevin, now at the University of ‘Cumbria in Wales, setup comerasin fourbear rubbing trees ‘and recorded 52 beat events on spring nights in 2008 and 2006. t's mainly adult males that doit, Nevin reported this week at a British Ecological Society meeting in Glasgow, UK Hesays the evidence suggest that dominant males use tne marking to warn off or override the scent af competi- tors for bath terttory anc females. It's an unusually thorough experiment, says Barrie Gilbert, who was Nevin’s graduate adviser at Utah State University, Logan. But there are stil ft of unknowns— such ashy bears choose the trees they do. SCIENCE VOL3I7_ 14 SEPTEMBER 2007 1477INTE SNs EDITED BY YUDHIJIT BHATIACKARIEE WELL-COMNECTED. Most people owning phone that doesn’t work with their family's TEMebile service plan would cither switch providers or getadifferent phone. Not George Hotz, who spentthe summer after his high school graduation from Bergen County Academics in New Jersey finding a way to unlock his iPhone from the device's sole serv- ice provider, AT&T. Hotz posted his solution, which involves altering the phone's circuit board and uploading unique programs, on his bloz 23 August before heading off last week to begin classes zt the Rochester Insitute of Technology in New York stat, ‘The rewired iPhone isn’t Hotz’ first technolo May, he was atop finisher inthe 2007 fel In Engineering Fair fora spiming computer di 3D images. Hotz reports that he traded one unlocked plone for mon anda “sweet Nissan 3502,” which lists new starting at $2 the phone in his pockets working fine. gical triumph: In national Seience and. lay capable of creating POLITICS JUMPING IN .. Bill Foster Gigh? spent 22 yearsas an experimental physics at Ferm National Accelerator Laboratory in Batavia, Ilinois. Now he wants to set up shop inthe U.S. Congress. He's tunning forthe seat being vacated by the former House Speaker, Ilinois Republican Dennis Haste, whois tiring net year ‘ADemocrat and afellow of the American Physical Soci, the 51-year-old Foster says Congress needs more meres with a scentifc badharound. “Almost every issue we face has a technica edge,” he sys. To get good poi, youneed clear goals, a good technical under & standing, anda firm grasp of economics.” § Fostrsays he would push for more research & nto biofuels, articpation in international i cfforts to fight climate change, and a renewed Gora tip fortis page? F-mapeoplag@azacorg emphasis on nuear nanpraieaton. ‘Observers say Fostors deep pockets shoul serve him well in his campaign As teanagers, he and his y brother Fred started a AY company that now makes most of the theater fighting in the United states "e's a serous candi cate because he has vomed to spend at least 51 milion of his jaan money,” says Eric Krol, politcal writer forthe local Daly Herald. But although Foster may outspend his two Democratic rivals, Republican businessman jin Oberweis plans'o spend $2.5 milion on his campaign, and, Kol nots, the districts “still one of the more Republican pats of thin.” BOWING OUT. Peter Aare, the Nobalstin Chemisty who dreamed of becoming a sena- tor has decided after dipping into Minnesota’s palitis thatthe waters are too chilly fr hin. [Agre, 58, took leave from his ob as vice chancellor for science at Duke University in Durham, North Carolin, to see if he could stir up enough enthusiasm—and cash—for a run nest year against the incumbent senater, Republican Nonm Coleman (Science, 25 May, p.2122). To his dismay, says Age, an outspoken tib= eval, the main obstace mas not conservative oppasiion but an inability to impress the Democratic Party, nhose help he needed "There's a huge priority on how much money you can ais; .. [party leaders] were looking for at least $10 million,” He says having two rich Democrats alady inthe fialé—comedian |ALFranken and attorney Michael Ciresi—also puta damper on his plans. Three Q’s >> 8 § & 5 g E ror nearly a decode, Bernat Soria Escoms, 36 has boca trying to _ turmembryonic stem cells into invalneproducing cells for treating 3 diabetes, most recently at his lab at the Andalusian Center for & Molecular Biology and Regeneative Medicine in Seville. Span. In £ July, Spain's President Jose Luis Rodriguez Zapatero appointed him £ to jointhe Cabinet as minister of health and consume afairs, The 5 5 3 i 2 b 5 ‘ministry, based in Madrid also controls much of Spain’ $2 billion biomedical rsearch budget Q:You have said you were surprised by the job offer. Was ita hard decision? ‘Yes, but ifyou say no, you can never again criticize the government, Q: Do you miss your lab? ‘The Council of Ministers meeting ends at noon on Friday, andi then wunnscioncemag.org SCIENCE take the fast train to Seville. 1 am in the lab Friday afternoon and evening and on Saturday. Ifthe minister of culture goes to exhibitions and the theater [t0stay current inthe arts}, can 200 the lab, 0: When will stem cell research have a measur able impact on doctors and patients in Spain? Very soon, if you consider stem cells as a broad concept including adult stem cells. In the coming weeks, Iwill announce a program for clinical research fon cell therapies for 12 diseases, including complications from diabetes, eardiopathy, multiple sclerosis, amyotrophic lateral ele rosis, and muscular dysteophy. For embryonic stem cells, we are still at the level of baste research, VOL3I7 14 SEPTEMBER 2007 14791480 SPACE PHYSICS O eres Beyond Einstein Should Start With Dark Energy Probe, Says Panel Dark energy is a subtle force believed to be responsible for accelerating the uni- verse’s expansion, Last week, it also proved irresistible to panel of US. physi- cists and astronomers asked to sct priori- ties for an ambitious set of modestly priced missions to tackle the most exciting cosmological questions of the era. Its omic year asked the National Academie National Rescarch Council (NRC) for advice on deciding which missions should ct off the ground first, starting in 2009, The council's 220-page report, issued 6 September, gives top billing to the dark nergy effort, followed by the Laser Inter- ferometer Space Antenna (LISA), a three TO Oey ieee eee nr eeeett ees Prensa eee In the spotlight. Anen report ranks the proposed missions under NASA's Beyord Einstein program ané offers cos estimates ignicanty higher than those om project teams. report recommends that NASA and the Department of Energy (DOE) begin work next year on a $I-billion-plus Joint Dark Eneigy Mission (IDEM), while saying hat plans for four other space physics spacecraft should be delayed—some indefinitely, given the pressure on NASA's science budget. Four years ago, cosmologists came up with five distinet projects to examine black holes, gravitational waves, dark matter, the carly inflation of the universe and dark energy as part of what NASA labeled its Beyond Einstein program Faced with tight budgets and prompted by congressional concerns, the agency last 14 SEPTEMBER 2007 VOL317 satellite mission designed to detect gravi- tational waves, The rest of the projects, says the report, will have to wait their turn, Making a queue for these missions is critical given the limited funding for new science initiatives at NASA. The NRC panel, led by Charles Kennel, an atmos pheric scientist and physicist at the Univer sity of California, San Diego, also broke new ground by developing independent ‘cost estimates for missions that are not yet in NASA’ pipeline—aad by concluding that each project team had seriously unde estimated the cost of building and operating the spacecratt. It said Constellation-X, an advanced x-ray telescope, for example, SCIENCE Pat) rin) ‘would cost $3 billion rather than $2.1 bil- lion, And with a program budget expected to rise from only $37 million in 2009 to 5211 million in 2012, Beyond Einstein seems incapable of supporting more than fone mission in the near future. “Our task was to address a mission which could fit into a] budget wedge opening up in 2009, Kennel explained to reporters, IDEMS sucess was due to both its sei- centitic appeal and the maturity of nology, panel members said. DOE's prom- ise of up to $400 million didn’t hurt, Saul Perlmutter, a DOE Lawrence Berkeley National Laboratory physicist and co-prineipal investigator on one of the three different proposed versions of the project, says that JDEM could be launched by 2015 and thatthe project has benefited from $40 million from DOE during the past 3 years. LISA, estimated 10 cost 52.75 billion rather than $2 billion, is another project counting on outside fund- ing, with the European Space Agency (ESA) offering to foot $600 million of the bill Kennel says the panel found LISA “an enchanting and technologically exciting ission” but suggested that NASA make ‘no further plans until after the Pathfinder spacecraft, an ESA/NASA mission that will fest LISA technologies, flies in late 2009. “We felt that inthe Long term, LISA will be the Beyond Einstein flagship,” Kennel ‘noted, “But it will aot be ready in 2009 In contrast, the NRC panel recom- ‘menaled kicking Constellation-X out ofthe Beyond Einstein tent because its contribu tons o Science are likely to extend beyond the scope of the initiative. “Beyond Einstein is not the sole justification [for Constellation-X] or its primary benefit to the science community,” the report con: cludes. Another mark against itis a price tag that is comparable to one of NASA's major observatories, and $900 million above the previous projection Bringing up the rear are the Black Hole Finder Probe and Inflation Probe, a rank= ing that didn’t surprise backers of those two projects. “The competition was intense,” says Harvard University astro- physicist Jonathan Grindlay, principal investigator on one of the two black-hole projects. The committee found a number of problems with the probe, which is wraurscioncemsg.org,Ter ermnenn eta) Preis designed to find black holes of all sizes, including the difficulty in pinpointing low= luminosity black holes, questions about whether it could accurately determine ‘growth rate of black holes, and uncertainty in identifying the galaxies in which they reside. It also gave a cost that’s roughly double the initial S1 billion estin Grindlay disputes the new price tag, which U.S. NATIONAL SECURITY he calls “way out of Line,” and adds that the committee ignored recent findings on high- redshift gamma-ray bursts that are beacons for blackhole creation, Other researchers give the NRC panel high marks for weighing the science that could be done before considering schedules and cost. “There were so many good ideas, they had a tough choice.” says Bradley ‘Schaefer, an astrophysicist at Louisiana State University in Baton Rouge. NASA officials were also pleased with the results. “We'te happy with what they've accom= plished” says Jon Morse, NASA astro physics chief, emphasizing the importance ‘of afiscaly realistic plan, “We need t0 con tain irrational exuberan ANDREW LAWLER, Scientists Fear Curbs on Access to Satellite Data For more than 3 decades, U.S. seience agen= cies have used images taken by the nation’s spy satellites to study everything from erupt- ing volcanoes to the migration of marine _mammals. Now, anew plan to expand the use ofthe satellites for homeland security and! aw enforcement has left some officials worried that science will ser Last month’s announcement by the Department of Homeland Security (DHS) that ie was seting up a new Nasional Appli sions Office (NAO) this fall to widen the use of spy-satellite imagery has sparked protests fiom civil liberties advocates. They worry that federal, state, and local authorities will seck high-feselution, real-time images to monitor activities of US. citizens inthe same ‘way that the satellites help track terrorist actttes overseas, But officals at federal cence agencies are concerned for a different reason: They suspect that the new arrange ‘ment could mean fewer chances toinvestigate scientific questions or cause delays that undermine the value of the information. The satellites are operated by defense agencies and used mainly forreconnaissance overseas. Federal scientists can ask for per mission to see specific images—as well as request that specific images to be taken ~ by applying to the Civil Applications Comnmit- ‘tec (CAC), Recammendations from the com mittee, which is headed by the director of the U.S. Geological Survey (USGS) and includes officials from more than a dozen agencies, are reviewed by the National Geospatial-lntelligence Ageney (NGA), which oversees military and intelligence mapping efforts. Last year, CAC forwarded about SU such requests Researchers have used the program to weunnscioncemag.org, access images of phenomena such as the ‘movement of glaciers in Yakutat Bay in Alaska, forest fires in Montana, and Mount Pinatubo in the Philippines. “IF cerned that a volcano is about to erupt, we fobeable tw gerthe data now.” says ‘The big picture. Spy-satelite images have helped scientists study forests and other phenomana James Devine, an adviser to USGS director and CAC chair Mark Myers, Under the new plan, CAC will report to [NAO in parallel with nwo new working groups that will serve homeland security and law enforcement. NAO will take requests from all three working groups and pass them on to NGA, essentially adding a layer of bureau cracy. SomeCAC members fear that scientific SCIENCE VOL317 requests will end up at the bottom of the queue, far behind requests such as aerial mages of vehicles atthe U.S. Mexico border. ‘Science officials are also concerned th ‘agreements over privacy could lead Congres to decide that only intelligence agencies ‘can use the data, ‘Some legislators have expressed similar apprehen- sions. Ina 16 August letter to DHS Secretary Michael (Chertof, Representative Edward Markey (D-MA) asked the agency to describe how it plans “to ensure that vital scientific activites arevot eroded” asthe program expands “to include omeland security objectives.” DHS officials say those fears we unfounded. Speaking to Science at a House hearing last week on the new office, (Charles Allen, DHSchiefinel ligence officer, said that the sei program is goingto We are going to work hard for all four customers, including science agencies.” ‘CAC members sy they won't know ifscience is being served until they learn more about the new offic “The people in charge have been a group of scientists representing their respective agencies” says another CAC member who requested anonymity. “With the pr ‘moving toward some sort of a domest veillance mission, can the science continue as before? I don’ know.” YupwyT BHATTACHARIEE 14 SEPTEMBER 2007GENOMICS Extra entynies. Hada dit dries gene copying, A Little Gene Xeroxing Goes a Long Way Researchers studying the evolution of starch digestion have uncovered evidence of a surprising adaptation: Rather than relying on mutations ina particular gene to help us digest roots and tubers better, the human genome simply made more copies of the gene in question, The finding is one of the strongest examples yet of evolution affecting gene copy number in humans and sheds light on how our diet split us apart from other primates. An enzyme called salivary amylase encoded by the AMY! gene—helps humans digest starchy food. Ina typical evolutionary scenario, natural selection would favor ran- dom mutations in AMY? that caused it to churn out more of the enzyme ora more effective version of it in people who ate a high-stareh dice ‘Buta study published online 9 September in Nature Geneties contcnals that something else happened. Nathaniel Dominy, an evolu- tionary anthropologist at the University of California, Senta Cruz, and George Perry at Arizona State University in Tempe analyzed AMY! in high-starch caters such as Ameri cans of European descent, Japanese, and Hadza from Tanzania, hunter-githerers who cat many reots and tubers, as well as groups that eat lite starch, such a she Biaka ofthe Central African Republic and the Mbuti from Congo, both rainforest hunter. gatherers, sand Tanzamia’s Datog and Siberia’s Yakut pastoralists. In all the researchers studied ‘amples from more than 200 people. wwurnsscioncomsg.org ‘The team found that rather than having mutations that boosted AMYI's activity, the high-starch eaters had extra copies of the gene, On average, the high-siarch caters had seven copies of the gene, whereas the low-starch populations had only five. “I you have a gene that’s working well, why not just copy it over and over again?” asks Dominy. “Why wait for evolution to just roll the dice?” For a broader evolutionary perspective, the researchers looked at 15 chimpanzees, which eat litte starch, All had only wo copiesof AMY7, And an analysisof the gene ‘rom bonobos, the chimp's closest relative, found that it had mutations that may prevent AMY! from functioning altogether. “I was, very excited to see this,” says Gregory Laden, a biological anthropologist at the University of Minnesota, Twin Citi, who contends that eating starcherich roots and tubers played a key role in differentiating ‘humans from other apes. Ait Narki, who studies human origins at the University of California, San Diego, says the report also suggests that humans ‘may have had access to starchy foods before the advent of agriculture, as is commonly thought, Even populations with low-starch Jiets had extra AMY! copies, he notes: ‘This would imply that first there were some rounds of duplication of the gene in preagricultural humans, and then that went further in agricultural humans: oncom SCIENCE VOL317 Still Waiting for Cybrids Despite provisional kay fom British regule- tos Scie who wart to se arial eggsas part ofa proceso produce paientspectic embryonic stam (5) clés wil hae to wata bit longer forte expete green Boh. Two UK «xoups hve apliedt that coun Human Feriiszion and embryology thor (FEA) tot nudes taser techniques that noid camrbine human cellnueli and animal oocytes toceate socalled bids. The technique, which US. and Chinese scents have tried swt tite success, might allow researchers to make ptint-pecic ES ce without wna human occyts, wich ae dificult to obtain. tea yeriongcevien HEA id ast eck that saw no fundamertal reason to pre- Hibithe technique hat it plas to make a dedsion in Novernber after additonal study. Stephen Minger of Kings College Londen, who submited his pplication in vember 2006, sayshetssattied with the Bich egultary cess. ee he fact tha this esene i tightly equated thnk eve come outthe thar end with 3 huge ameurtof suppor” from thepubic ——GRETCHEN vocet Stem Cell Funding Plans German scientists hoping for a relaxation of the strc ans governing hurnan embryonic stern (ES) cells wont be geting eny help from ‘education and research minister Anette Schavan. This fal, the German parliament is expected to dabate the county's current stem cell reguéations, which make ita crime to werk with human €5 clis derived after 1 January 2002. This week, Schavan said she would rot Support iting the cutoff dete, although she id not rte out shifting itt allow nork with more recently derived cals At the sare time, Schavan enncunced $6.85 milion in new funding for research into methods that wouls produce pluripotent cell-cell that cen become nearly all the bodys ell types— without using human embryos. She saysher geal is tomake £5 cells “superfuous.” As Germany continues to tread cutusly, Californias speeding toward its goal of becoming the nori's stem cell mecca. On 10 September, the Eli and EcytheL.Broae Faundation announced a $20 million donation to the Univesity of Calfrnia tos Angeles, for faculty development, equipment, and facilities atts stem cel institute, now renamed after the cones, Last yea, the faundation gave 525 milion to the Univesity of Southern Cali- fornia in tos Angeles fr the same purse. “GRETCHEN VOGEL AND ‘CONSTANCE HOLDEN 16 SEPTEMBER 2007| NEWS OF THE WEEK 1484 CONSERVATION Scientists Say Ebola Has Pushed Western Gorillas to the Brink The combined threat of the Ebola virus and poaching have pushed westem gorillas, imto the “critically endangered” category in the latest international ranking of species threatened with extinction Although estimates suggest that tens of thousands of the animals still live in west- central Afi, the new Red List from the World Conservation Union (IUCN) moves, the species into its highest alert category, in large patt because of fears that contin ing Ebola outbreaks could swifily wipe out stil-significant gorilla populations, ‘The list released on 12 Sept ember, highlights the western gorilla as well as dozens of other species for which new data indi- cate an increased risk of extinction, The “critically endan= gored” category is usually ap- plied when just a few hundred individuals survive in the wild, ‘But researchers say that western gorillas, despite their relatively large numbers, are in serious trouble. An ongoing series of Ebola outbreaks has killed up to 90% of the animals in some regions (Science, 8 Decembe 2006, p. 1522), and the use of vaccines to stem the disease faces daunting challenges, e rapid evelopment of logging reads has opened up vast new regions to ppoachingancl the bushe-meat trade. Although the other species in the Gorifla emus, the eastern gorilla, is far less numerous than the western gorilla, IUCN ranks the former one level lower at “endangered” because itis out- side the current area of Ebola outbreaks. As for western gorillas, there may be as many as 30,000 left in their cur rent range, which stretches across Gabon, Equatorial Guinea, and parts of Cameroon, the Central African Republic, and the Republic of the Congo. There are two subspecies, the more common western lowland gorilla and the extremely rare Cross River gorilla, of which fewer than 200 probably remain It is unusual for disease to be cited as a reason for reclassification, says wildlife 14 SEPTEMBER 2007 VOL317 ‘At sk The theat for the d Scions to call western gorilas critically endangereé. disease specialist Richard Kock of the Zoological Society of London, who ‘co-chairs the IUCN Veterinary Specialist Group. But even if the new status has come sooner than expected, the change is war- ranted, says Kenneth Cameron, a field vet- crinarian with the Wildlife Conservation Society in Brazzaville, Republic of the Congo. “Is this jumping the gun a bit? Some would argue that iti.” he says. "But itis inevitable that this species is going to tend up on a critically endang simply a matter of when” red list. 1's IUCN experts found that the western ‘gorilla population has declined by 60% in the past20 to 25 years and estimated that in the past 15 years Ebola has killed one-third ‘ofthe animals living in protected areas such as national parks. Those numbers are only the roughest of estimates, Kock says. The current gorilla range “is a huge place. I$ Bloody impossible to know what's ‘on in the remote forest regions, he sys Conservationists say they hope the new status will help pressure governments and ng SCIENCE jeadly Ebola vius and poaching have prompted international donors to increase efforts to protect gorillas and thet habitat. They also Say they hope it will lead to more funding forth search foran Ebola vaccine What is certain is that western gorilla habitat willbe under severe pressure inthe next’ years, Cameron says. Plans are under tray in the Republic of the Congo to improve the road and rail connections between Brazzaville and Ouesso, the largest iowa inthe north, Both projets wil cut through prime gorils haba, making it casier for hunters to reach and for bush meat be sipped back to city markets, While public awareness campaigns and increased antioceching efforts might hep ratigate presure ftom hamers, sciewats are struggling to blunt the impact of Ebola, The virus can pass fom ape to ape, ‘0 regions with higher popula: tion densities are especially at risk, “It appears to at like a bushfire” Cameron sys. “You geta lightning strike some- these, and it starts to barn” Althoughadmitingit'a ong shor, some researchers hope a vaccine campaign could at leat fave enough animals preserve fhe species, Areas alfa dozen vaccine candidates have pro- tected mice or monkeys inthe lab from the Ebola viras, Bat Finding a way to deliver a va cine safely to wild animal sno bral challenge Few believe that vaccine- laden darts could reach enough sores to stem the spread ofthe disease. Petsr Walsh ofthe Max Planck insite for Evolutionary Antnropelegy in Leipzig, Ge many, 8 working witha vaccine company to develop possible baitthacouldcerry amoral yac= cine. The bait must Kop the vac Give van the ot, humid cone ditions ofthe fort, atict great apes, an be safe for other an mals who might find it first, Walsh says that before the end of the year, he and hs col Icagues plan to begin testing darting and ova bait eatgie, without incorporating 8 § saesine, inthe Republic ofthe Congo. S “This isnot just about Ebola” Walsh saya. “All apes are under increased disease threat, especially fiom humanrintroduced diseases, Vaccines are going to be an § increasing pat of conservation... This is © not going to be wasted time or money” onercuewvocet § wraurscioncemsg.org,EPIDEMIOLOGY Tropical Disease Follows Mosquitoes to Europe For years, medical enomologiss have wore rie that the astonishing ascent ofthe Asian ‘iger mosquito (Aedes afopicrus) might bring nt omy nasty bites but also new pb- licheath surprises. Meral,themosquo isa inom yetor for more than 20 viral diseases. “They were right, This summer, the mos 1 which has become firmly exablished in southern Europe, has infected almost 200 people in Italy with ehikungunys, a painful viral disease ts the first lenown example of eikenguanya transmission outside the trope ies and i's making scientists swonder whether. albopicrus has the potential to ouch off much larger outbreaks in Europe and the United States. CChikungunya is rarely fetal but can cause severe fevers, headaches, fatigue, nausea, and muscle and join pains. People started falling ill in Casiglione di Cervia and Castiglione di Ravenna two villages sepa- rated by a riverin the provinee of Raventna—in early July says Antonio Cassone ofthe Isiito Superiore di Sanita (ISS). nations! government Isbin Rome, But most patints’ symptoms were mild and resembled those of other diseases Such asthe Toscana vnss, so heath officials didn't notice fora while. Samples reached 18S on 27 August, and te virus was ident the next ds Epidemiological detective work suggests chatthe index patient was aman who tveled :o.one ofthe villages and became sick ther, after having been infeed in India soon 4 and sequencing ofthe virus are under way to § contirm that theory, Cassone says. One 2 patent, an 83-year man with severe § cxistingmeial problems has died §_ Chikungunya sickened more th § snird ofthe almost 800,000 inhabitants of E La Réunion, a French island in the Indian # Ocean in20s and 2006 Scene, 24 Fetmary § 200 p 08S) Inia saad an expe 2 & e g boatbreak in 2006 with more than 1.25 million cases, although some believe the real toll is ‘much higher. Several European countries had seca “imported” cases of chikungunya lately, but Local transmission in Europe has never been observed before. “It's fascinat- ing,” says entomologist Paul Reiter of the Pasteur Institute in Paris, wwurnsscioncomsg.org A daytime biter, A. albopicis originated in Southeast Asia and has made impressive strides across the globe in the past 2 decades. It was first found in the United ‘States in secondhand tires imported from Asia in Houston, Texas, in 1985; today, it has spread to more than 20 southern and easter states. In Furope, the mosquito has appeared in Mediterranean countries from Greece to Spain and as far north as the x stowaway. Aedes Netherlands, Its eggs often hitch ride with plants shipped in water containers, such as the popular Lucky bamboo. Wstoo early to tell whether chikunguaya now has a permanent foothold in Europe. New cases have slowed toa trickle, says Cassone, in part because the mosquito pop- ulation is dwindling temperatures drop. A cenitical question is whether infected mos- quitoes can survive the winter or pass onthe virus to their offspring via their eggs, says Reiter. "Ii they can, we might see a np-roaring cridemie next year.” he says. Even if they can't, any newly imported case could kick off'an outbreak in the future There are no drugs or vaccines against chikungunya, but the outbreak at La Réu- nion triggered renewed interest in an old ‘vaccine candidate developed inthe 1980s by aUS. Army lab in Fort Detrick, Maryland, Scientists at three French government insti- tutions are now working on that vaccine, and new clinical trials might begin before the tend of 2008, says epidemiologist Antoine lahat, who chaired a French taskforce on chikungunya last year -MaRTIN ENSERINK SCIENCE VOL317 The Full Taleyarkhan Itlooks as though bubble fusion researcher Resi Taleyarthan of Purdue University in West Lafayette, Indiana wll go under the micro Scope after al. ast week, Purdue officals anounced that an internal panel has con= cluded that allegations of research mis- conduct warant a full investigation. The atest inquiry wes prompted by & request from the Office cf Naval Research (ON, wich ebed fund some of Taleyarkan's work, and fllons congressional criticism of Purdue's handling of te alleged misconcua, The decision reverses previous inquiry by the urivesiy that recommended against 2 full investigation Science, 16 February, . 921), Purdue expects ta begin te irvest sation once it hears back rom ONR officials. “ROBERT. SERVICE Show Me the Data any gone hunters who tram the entice Fhuman gerome for disease genes wil soon be asked to share their data, Stating 25 January, recipients of rants rom the National Inst- tutes of Heath (NIH) for “aenomewide associ ation stuies" wil be “strongly encouraged” to submit their datasets stripped of identifiers to central database. The sharing wil allow findings tobe valid ted in many populations cience, 11. May p- 820). NIM ell give researchers wo submit data sets yeat to publish beforeotherscanuse the data in their onn publications Privacy protec tions woul prevent nonresearches from using the Freedom of Infrmation Act to obtain (genetic and clinical data on an indvigua, MIM Concluded. One acecemic says she hopes NIH wil poll cuthaw institutional review boares should comply wh the policy. JOCELYH KAISER Florida Bound? Germany's Max Planck Institute (MP is 2 big step close to opening it fst research center inthe United States. his week, county com> rmissiorers in Palm Beech, Frid, urani- ‘mously supported the idea of sling $86.9 mil- liom in bonds as pat of 2 $281.8 milion incen= tive package to lure the institute, the tate bikin ts share, MPI il ull 2 $000-m= bioimaging research facility onthe campus Florida Alantc Univesity in Jupiter, nest door tonenly arrived Scripps lonida. ‘ve spent about 10 seconds corsidering this," ays Commissioner Jeff Koons. “{he] said, ‘Go do it!" MP officials called the vote “an impor tant steppingstone.” -ROBERT & SERVICE 14 SEPTEMBER 2007 1485| NEWS OF THE WEEK 1486 BIOSECURITY Reports Blame Animal Health Lab In Foot-and-Mouth Whodunit Neglected, leaky pipes and England’ record- setting wet summer likely combined to cause the country’s recent outbreak of foot-and- mouth disease (FMD), according 10 180 reports issued lst week. The virus responsi- be probbly escaped flea company, Meri that grew vast amounts of it for vaccine production, the studies say. Yet the reports assign most ofthe Blame forthe outbreak 10 the Institute for Animal Health LAH), go cermin lab atthe same sit in Pirbrigh that owned the aging network of underground ‘wastewater ppesandas avare that itneeded ‘maintenance, IAH breached bioseeurty in other naysas nell. therepors found. “The findings are ablow tothe reputation oF AHI, world xenownedFMDresearch center, says Andrew Mathieson, an environmental hal expert a he University ofthe West of Englandin Bristol But they should also serve asamore general waming. “My worry i What about the many othe esearch etablish- ments of the same ge!” he sys Rapid government action helped contain the FMD outbreak, first confirmed on 3 Augus,tojustiwo farms in Suey (Science 10 Aus, p, 722), Stil the National Fam. ers" Union puts the accident’s economic impact at more than $100 million, and some politicians have called fr resignations atthe Deparment for Environment, Food and Rural Affairs (Defi), which oversees biosafety at ‘Merial Large-scale FMD vacire poducton Disinfection of wastenater wth cite acld [st sep) a an xiweat TAH siatsialeFuD experiments Uncen sanage newer AH and also finds some 65% ofits work. Genomic comparisons of the outbreak virus to strains from Merial and LAH can’t pinpoint from which ofthe two labs the virus ‘seaped, according to the reports, one led by the U.K.’s Health and Safety Executive (HSE), 2 government agency, and the other by ‘molecular epidemiologist Brian Spratt of Imperial College London, Still, the pancls say, its much more likely thatthe virus came fom Merial, which grew it in two 6C00ite- vats shortly before the accident, producing a million times more virus than LAH used in its small-scale experiments. But how did it escape? The reports con- clude that air leaks, contamination from solid waste, and foul play by terorists or dis _gruntled employees are unlikely. Instead, both Focus their suspicions on the site’s ‘wastewater system. A.tworstep chemical strategy is used at Pirbright to prevent FMD from escaping in liquid waste, Both Merial and 1AH first treat ‘wastewater a their own buildings with adis- infectant such as eiric acid. Then, a complex system of pipes takes the water to a shared effluent treatment plant, managed by !AH, where caustic soda is used to raise the pH 0 12 and kill off any remaining virus during @ |-hour holding period, Finally the liquid is released into the sewer ‘Although the fist treatment step proba- Ltosenes Recipe for an outbreak. The scoped fect and-mouth disease virus (ted) probably erginated a vaccine smanlactuer Mei wo repr sy, but he Insitute for Animal Heath os the laky drainage system that precumably lt the vrs 08 ina the cal. Tucks may hve then cave close toa farm, 14 SEPTEMBER 2007 VOL317 SCIENCE bly killed off almost any leftover virus at IAH, it likely didn't inactivate the larger amounts in Merial’s wastewater. The second treatment step would normally take care of that, but the nerwork of pipes, pumps, and ‘manholes Leading to it suffered from leaks dducto eracks, tree roots, and other problems. The reports hypothesize that live virus seeped into the soil as a result, especially because July $ excessive rainfall may have caused the drainsto overflow. As it happened. construction crews were sigging holes around the leaks atthe time, and heavy trucks—without proper IAH over- sight—drove through the presumably vinu laden mud, Some of these vehicles ater took a road that went very close to the fist infected farm. From there the farmer may have caried the virus to his herd, IAH, apart ofthe UK. Biotechnology and Biological Sciences Research Council (BBSRC), owns the antiquated drainage sys- tem, the HSE report says. It was also aware of some of the networks problems. In fact, JAH, Defia, BBSRC, and Merial hac debated an ‘upgrade since 2003; the problem was money. ‘As to Merials discharge of virus into its ‘wastewater, HSE says this wasn’t a breach of biosecurity, because Defra had approved the procedure used in the fist disinfection stsp ‘But ina statement, |AH pointed its finger at ‘Merial, suggesting thatthe company should have taken better care to inactivate any virus, ‘Strangely, the Spraz repor says, [AH didn't seem to know that Merial might rclease active virus into the system; biosafety officers from the lab andl the company hardly ever talked. Both panels question the wisdom of chemically inactivating wastewater alto- scther. Indeed. most modem labs use thermal Inactivation that is, pressure-cooking at 121°C—t0 destroy any pathogens, says Lee Thompson, a biosafety officer atthe Univer- Sity of Texas Medical Branch in Galveston, Sill the second step, using caustic soda, “is very effective against FMD.” Thompson ssiys—but underground pipes that cannot be Inspected “are abig problem.” Defia says will adopt a range of recom ‘mendations to fix problems at Pirbrigt, such askeeping better track of vistors and making sure biosafety officers communicate. Merial has agreed not to grow live virus until U.K. authorities give tthe green light. JAH, which was constructed in 1924, is due to be almost completely rebuilt by 2012, although some funding issues remain. Defra has also asked Health and Safety Commission chair Bill Callaghan to review the regulatory framework for animal pathogens, He is due ‘oreparthy December. -MARTINENSERINK wraurscioncemsg.org,BIODEFENSE RESEARCH Lapses in Biosafety Spark Concern ‘An apparent breakdown inbiosafety a Texas A&M Univensty (TAMU) in College Station is prompting serutiny of the expansive USS. biodefense research progtam and the assurance that federal inspections keep researchers following the rules, Last week, the Centers for Disease Control and Preven- tion (CDC) in Atlanta, Georgi, described a dlozen safety lapses at TAMU, from unre- Ported exposure to pathogens to inadequate protective gear. TAMU'S research on select agents, pathoyens that are considered poten- til bioweapons eon old until st complies with the regulations. But ina twist, CDC may have indicted itl along with TAMU, Toward the end ofa 2L-page report, it nox that it had inspected TAMU as recently a8 February and found nothing ther than minor problems, sach as ‘aration in how staf racked lb inventory ‘fer prodding by an independent wiistle- blower, hovever, CDC inpectors retumed 10 ‘TAMU in July and uncovered the violations described in ast week’ report, many from before the February inspection. Bios bbioweapons experts say the charges are among the most damning that they can recall, They include three missing vials of Brucella bacteria, unau- thorized employees working with select agents; a faculty member performing @ recombinant DNA experiment without the rcessary CDC approval; concerns about disposal of animals used in select-agent 2 expsriments; and three unreported cases oF individuals exposed to the bacterium Coxiella burnetii, which causes Q fever, & B sreatable but infectious disease. “There weunnscioncemag.org, was no evidence that a coordinated response or biosafety assessment was per~ formed as a result” of these exposures, notes the CDC report. The report “reflects about as badly on CDE as it does on Texas A&M,” says Edward Hammond, director of the Sun- shine Project in Austin, Texas, a bio- weapons watchdog group. Last spring Hammond's repeated demand for TAMU documents under a sate openerecords law revealed that in April 2006, an employee vwas diagnosed with brucellosis, an animal disease. TAMU did not report the infection toCDC until after it came to light (Science, 20 April, p. 353). Inspectors initially missed the “train wreck of a select-agent program.” says Hammond, CDC has "got some explaining todo.” The agency declined to comment. “There's nothing I can add.” said CDC spokesperson Von Roebuck, when asked whether the agency would speak tits File ure to detect the major safety viola- sions in its February inspection of TAMU. One possibieexpl- nation, says Ronald Atlas, 2 microbio- logist at the Univers sity of Louisville in Kentucky, is that normally, “the in- spections ate of the le fciiy”andexip- ment, not an in-depth look at lab proce- SCIENCE Exposed. Brucela bacteria infected 3 researcher, but the case went unreported fora yer. NEWS OF THE WEEK i Under fire. Texas ABM University was faulted for lapses nts oversight of pathogen reseaich des. Many ofthe TAMU violations, however, ‘eoncern access to pathogens ant Tab practices The problems CDC citedare serious but probably not unique, according to scien tists both inside and cutside TAMU, “Ifyou were to apply an equivalent level of serutiny at other institutions, I think you ‘would find issues of concern,” says TAMU, microbiologist Vernon Tesh, one of four lab leaders singled out for safety lapses in CDC's report. “You always have to have safety in mind” he added. “Having said that, accidents happen.” In a press confer- tence last week, TAMU's interim president Eddie Davis said that other “institutions under that same level of review would probably have findings that would be reportable to the CDC." Since the CDC's July inspection, the uni- versity’ vice president of research and over- seer of biosafety compliance, Richard Ewing, has resigned from his position and returned tothe mathematics department (Science, 17 August, p. 879), Another biosafety offic cial, Brent Matton, also left his post. Davis declined to assign esponsibility forthe lapses orsay whether any employees would face ds ciplinary action. He praised Ewing for having “been very loyal and competent.” (CDC has passed its report up the ranks is parent agency, the Department of Health and Human Services, whose inspector general’s office will consider whether to levy fines of up to $500,000 for each of the 12 violations. The Government Accountability Office, Congress’ inve: tigative arm, is looking beyond TAMU, examining risks associated with the grow- ing number of high-level biosafety labs. The House Committee on Energy and Commerce plans to hold 2 hearing on the subject in carly October. Meanwhile, scientists wonder what effect the TAMU findings will have. “Biosafety is man- dated by the public, orthey’re not going to let us do this research,” says Atlas. “This looks bad for all of us,” says Philip Hauek, a josafety professional in New York City. Abiding by the ‘guidelines isessental, he says. But “poople yet blasé, I hate to say it. After a while as micro- biologisis, you're like, ‘This thing never bit me.” ~JeMnaFER cOULIN VOL3I7_ 14 SEPTEMBER 20071488 NEWSE EVERY YEAR, AFTER THE COLORS OF ‘autumn faded fom the trees and left barren branches to herald the winter, Herbert Kern would fee! his mental skies darken. As the days shortened, the middle-aged materials researcher would retrcat from almost all, social interaction, The routine was so familiar t Kern's colleagues at Bell Labs in Murray Hill, New Jersey, that they would not expect much work from him during those winter months in the 1970s, The seasonality of Kern's depression was reflected in the pocket notebooks in which he kept a log of his life, “During the ros ofthe year, I could fill anotebook every 2 weeks; in the winer, it would take months,” recalls Kern, Neither the few approved antidepressants of te time nor lithium injections did arything to help. ‘Then, in the late "70s, Kem learned about research in animals showing that melatonin, hormone regulated by the light-dark eycle of day and night, plays a role in controlling seasonal behaviots such as mating. Wonder Ing ifthe hormone had sornething to do with his conditien, he got in touch with psychia- tuistand melatonin specialist Aired Lewy at the National Institute of Mental Health (NIMH) in Bethesda, Maryland, who was wrapping up a study demonstrating that cexposire to bight light during the night sup pressed nightie secretion of tae hormone in normal humans. When Kern sank into 14 SEPTEMBER 2007 VOL317 depression the following winter —in Decem= ber 1980—Lewy’s team exposed him toa fw hours of light in the dark mornings and evenings, trying to match the amount of nat ural light ofa spring day. After a few days of the treatment“! bewan to be bubbly ayain.” says Kem, who later continued the regimen athome, “It worked like magic: Kem’s case, and 3 years of follow-up work, led researchers to identity winter depression asa psychiatric illness that subse quently came to be known as seasonal affec tive disorder. SAD has since been shown to afflict millions of people, primarily in the northern lariudes, and a recent analysis by the American Psychiatric Association (APA) in Arlington, Virginia, provided a strong cendorsement for ight therapy asa treatment And yet it’s not settied how light, er other imverventions that target the eitcadian clock, helps people with SAD. SAD provides the strongest evidence to date of a link between the biological clock —the body's 24-hour timekeeper and mental health, a proof of principle that circadian hythmsthat are out of sync could underlie some mood disorders. But there is increasing evidence that circadian distur- bbances are involved in other common men: tal ailments such as bipolar disorder and more ebscure ones such as @ syndrome in which people compulsively estat night. In Light therapy and other in target the body's biological clock treat depression and other mood Is Internal Timi y to Mental Healt recent years, psychiatrists working with small groups of patients have shown that correcting abnormal circadian rhythms through exposurs to light, melatonin pills, of even sleep deprivation —can help treat some of these disorders and can also benefit patients with neurodegenerative illnesses suchas Al¢heimer’s, Some drug companies are even taking heed. “The circadian model is clearly beginning to bear fruit,” says David Avery. a psychiatrist atthe Universit ‘of Washington School of Medicine in Seat the. “It is lopicaly geiting extended beyond SAD and should lead to better treatments for a number of psychiatric disorders The fog about light ‘When Kem contacted Lewy at NIMH. sci- cntists already knew that all mammals have ‘amaster clock in the brain suprachiasmatic nucleus, which regulates the waxing and waning concentration of numerous hor- ‘mones and proteins in the body over an approximately 24-hour cycle. They also knew that the rhythns of many ofthese body chemicals including melatonin, secreted by the pineal gland during darkness—were synchronized to the light-dark cycle of the environment. Intreating Kern with light, the NIMH researchers—led by Lewy and his senior colleague, Thomas Wehr simp! ted the! SCIENCE vawscioncomsg.org sler dawn and later dusk of |spring, hoping that by tion of melatonin secretion, they'd lift Kern ‘out of his depression, Although it worked —and has since proven effective in teating many ether cases ‘of SAD Wehr and Lewy formed different ‘opinions about light therapy’s mechanism, Wehr grew convinced thatthe antidepressant effect was a result ofthe artificially length- cened daytime, which led to less melatonin scoretion and presumably had downstream effects leading to an improvement in the patient's mood. Lewy instead came to believe thatthe effect was due to the resetting ofthe patient Scircadian clock, not the overall du tion of melatonin production. In most SAD patients, he argited, the depression was the result of circadian clocks being out of sync ‘with respect to the sleep-wake eyele, like a chronic form of jet lag. The theory has become known as the phase-shift hypothesis, Last year, researchers led by Lewy—who has been at Oregon Health and Science Uni: versity in Portland since 1981 presented thestrongestevidenos to date for this theory. Rather than using bright lights o reset the c= cadian clock, Lewy and his col- leagues gave SAD patients mela- tonin pills. (The body's melatonin thythm is tightly coupled to rhythms of ether hormones such as cortisol and serotonin, and researchers have established that administering melatonin isa way to shift all of those rhythms en bloc. People normally stat secret ing melatonin a couple of hours before bedtime to prime the body forsleep, so administering thehor- ‘mone in the afternoon should advance a patient’ circadian clock relative to his sleep-wake eyel. If given in the moming, it should hhave the opposite effet, By making patients stick to their regular sleep times, the researchers ensured that their sleep-wake cycle remained constant throughout the study. After 3 weeks, they found that SAD patients whose circadian clocks normally lagged behind their sleep~ wake cycle did better when they received afterioon melatonin and worse when they ‘were given the hormone ia the morning, The treatments had the opposite effects om those whose cycles were shifted the other way. Lewy points ou thatthe treatments increased the duration of melatonin production, yet patients improved when their cycles were ‘brought ino sync. “IF Tom [Weby] was right, wuwscioncemag.org SCIENCE VOL317 ‘these people should have gotten worse,” he says. Lewy notes that the melatonin results are consistent with previous studies showing ‘that morning light is significantly better at treating SAD than evening light (whieh eor- sonds to there being a higher proportion of phase-delzyed rather than phase-advanced individuals among SAD patient), Wehr, who retired from NIMH in 2003 and is now a practicing psychiatrist in Bethesda, Maryland, remains unconvinced, He points to animal studies showing that ‘morning light brings about a quicker end to melatonin secretion without really affecting the hormones onset rime in the evening. 1's possible, he angues, that afternoon melatonin led Lewy'spatients to stop sereting the hor- mone a lot earlier than normal the following morning, in effect shortening the length of their melatonin production. To settle the question, Wehr says, researchers would need 10 keep a continuous track of the patients* 24-hour melatcnin profile. Chronobiological Mood Disorder ‘SLEEP Out of syne. Some researchers believe that misalignments between certain circadian hychms and the leep-aake cyle maybe a driver of merea nesses Leay’s hypothesis does not rule out the possibility that additional mechanisms are involved in light’s antidepressant action, Some studies have shown, for example, that exposure to sunlight ean increase brain levels, of serotonin—a neurotransmitter associated with well-being and Lewy says it's possible that serotonin is related to circadian align- ment. To get a full mechanistic account ofthe clock’ role in mental healt, researchers still ried to understand what cellular events are triggered when out-of-syne rhythms are snapped back into phase with each other, and NEWSFOCUS L by the same token, what happens inthe brain ‘when rhythms go avry-—as they do even in Incalthy individuals who are jet-lagged. Beyond SAD ‘A better understanding of these mechanisms could shed light ondisorders beyond SAD, for abnormal circadian rhythms are tuming out to bbe a factor ina number of other mental ill- nesses. Two years ago, in Chronobiology JIntermaticnal, Vishovajt Nimgaonkar and his colleagues at the University of Pittsburgh Medical Center in Pennsylvania reported that among 75 patien’s with bipolardisorder,inter- nal biological clocks —asmeaswedby a ques- tionnaire probing activity and sleep pat tems—tended to be disturbed in comparison tothose of aset of normal individuals. And in two ongoing studies, researchers led by Anna Wirz-Justice of the Centre for CChronobiology at the Psychiatric Univer Clinic in Basel, Switzerland, are findin sian ic ten to jents and in patients wit ‘Vordeline personality dsnder (Che preliminary results from the studies were presented at the ‘annual meeting of the Society for Light Treatment and Biological Rhythms in Copenhagen, Den- ‘mark, in June.) Also this summer, ata meciing on biological clocks and rhythms at Cold Spring Harbor Laboratory in New York state, psychiatrist Nami Goel of the University of Pennsylvania reported that many 24-hour hor onal rhythms in patients with night eating syndrome were either ‘advanced or delayed with respect tothe sleep-wake cycle. ‘Some tescarchers suspect that defects in the gears of the body's biological clock, caused by ‘genetic mutations, will be shown to play a role in mental health problems. They point to studies such as one reported last year by Colleen MeChung and her colleagues at the University of Texas Southwestern Medical (Center in Dallas. The researchers created mice ‘missing the Clock gene—which encodes a key protein in the machinery ofthe eiteadian system—and found thatthe animals showed ‘manic behaviors, becoming hyperactive and keener to take risks. Expressing the CLOCK. protein in the animals’ midbrains restored behavior of the mutant mice to normal, McClung and her colleagues further reported, inthe 1D April issucof the Proceedings of the National Academy of Sciences this year. 14 SEPTEMBER 2007 1489| NEWSFOCUS 1490 If disrupted circadian shythms contribute to mental illnesses other than SAD, those coniltions coul also benefit from light ther- apy. Indoed, researchers have begun testing thisidea in small groups patien', and they say the results look promising. ‘Nearly 200 people with Aisheimer’s dis- case, spread across 10 homes forthe elders, are now helping researchers test whether ight therapy can alleviate some symproms ofthe fatal neurodegencrative disease—-one of which is disturbed sleep-wake rrythms Psychiatrist Eus J. W. yan Someren of the Netherlands Insitute for Newroscienoein Ams. terdam and his colegues have installed bright light Fixtures in the leungesof six ofthe homes; athe remaining ses they inal similar bu fever lishtso set up the lighting equivalent of 1 placebo, Van Someren says thet the unpub- lished preliminary resus, base on more than 4 yer of data, show tha bright ight improved Dispeting gto works inpatients with seasonal affective disorder. the sleep-wake chythms of patents. He aims the data aso show that itslowed their cognitive decline, hinting that the disturbed cic thytms were partial cause Light and melatonin are not the only inter- ventions that researchers are using in their attempts to treat mental disorders by tinkering ‘withthe cincadian clock. Francesco Benedet a psychiatrist atthe San Raffaele Scientific Institute in Milan, Italy, has spent the last decade studying the antidepressant effects of total sleep deprivation —a strategy discovered by chance in the 1960s when German clini cians observed significant improvement in a depressed patient who had spent the night biking. Although how the technique works is poy understood psychianists routinely use sleep deprivation to produce a rapid emotional lift in deeply depressed patients, including ‘hesehospitalized after a failed suicide ater. Benodetti and others have shown that this ‘dramatic effect, which invariably vanishes afiera day, can besustained for several weeks by using light therapy to shift the patient's sleep-wake cycle in the days that follow. The idea again is to bring the circadian rhythms back in alignment. The researchers have reported in a study published in The Jounal ‘of Clinical Pavehiatry in 2005, that combin- ing light therapy with inital sleep deprivation can effectively treat bipolar patients, In a more recent study involving 55 bipolar paticns, presented atthe Cold Spring Harbor meeting by University of California, Irvine, Psychiatrist Joseph Wu, those who received a treatment package including antidepressant | A Psychiatrist ltred Lewy wants to understand why ight therapy (eng setup, ebove medication, light therapy, and sleep-wake adjustment following total sleep deprivation did significantly better than those who only received medication Witch healers? Such studies seem to be making an impres- jon on the broader psychiatric community 1n2005,agroupset upby APAto examine the efficacy of light therapy concluded from a meta-analysis of published literature that the treatment significantly reduced depression symptoms in SAD, as well as in other mood disorders. The group, led by psychiatrist Robert Golden, now at the University of isconsin School of Medicine and Public Health in Madison, declared in April 200 in TheAmerican Journal of Pyychiaury tit “the effects of light therapy are comparable to those found in many antidepressant pharima- cotherapy trials.” However, the authors lamented the relatively small number of tude ics that met their criteria for the analysis only 20out ofa total of 173 that were initially identified —and they noted that “additional randomized controlled trials with appropri- atenumbers of subjects are needed” Until even a few years ago, “people looked atusas if we were some kind of strange witeh Irealers” says Benedetti, who began combi ing lie therapy with sleep deprivatien inthe 1980s. Stil, with recent data showing th drugs do not significarely help up t0 40% of patients with mood disorders, he says, “there is a growing interest in chronobiological methods of treatment” Unfortunately, proponents of such methods say nding has been hard to come by, in part because of the perception that effective ami- depressants are available, Michael Terman, psychiatrist at Columbia University recalls ‘at one grant application ted dev by the ‘National Institutes of Health contained this ‘comment: “Why do we need anew antidepres sant modality when we already know that drugs work’! The proposed work, a random- ized trial testing light therapy in pregnant women with depression, is now being funded by the Swiss National Science Foundation, “The pharma-driven mode! is so sirong that itis dificult 0 wn support for sudying anything that does not involve drugs,” says Wire Justice. ‘Nonetheless, the F rch pharma company Servier haspatented amclatoninagonist called ‘agomelatine that is now undergoing clinical trials in Europe and in the United States as a treatment for depression Merck hasalso setup ‘a research group to look into the circadian basis of mood and sleep disorders in hopes of developingmore effective drugs."A- therapi 2, it would be far easier to pop a pill than carry around a fluorescent bulb, ‘Anthony Gotier, amember ofthe group. Kern, who is now practically blind from macular degeneration, would welcome a pill substitute, He says that light therapy became less and less effective for him over the years as. his eyesighe faded, “Now I can hardly see, and allhal! has broken loose""he says with surpris- ing cheer in his voice. “I have had perieds of depression lasing over a year, and highs lst- ‘ng as long. I thnk my clock is just running freely wihautany conta by the environmen’ | don't know when I'm going to fee! what.” ‘“YUDHIJIT BHATTACHARJEE 14 SEPTEMBER 2007 VOL317 SCIENCE yaw scioncemag.orgBumper crop. Oil palm fut bunches rrr es pene ECOLOGY Can Palm Oil Plantations Come Clean? Under fire for their poor environmental record, makers of the world’s top vegetable oil are turning to scientists for advice on how to make their industry sustainable TELUK INTAN, MALAYSIR—A canary-yellow ‘machine lumbers onto a fallow oi palin fcld and, with a er of its moto, rps intoapile of fionds and shavings of dead turks. As pantae tion operators and scientists observe the mulching process, ther guide, Cheriachange! Mathews, senior manager at United Plenta- sions’ Jendarata Estate, warns tha the group hhas been inflated. “We have a journalist with us "he says.“ wanthim and all of you o know thattnothing here—neehing—is wasted” ‘Mathews has good reason tobe concerned about the take-home message, With prices soaring, palm oil, Malaysia's number-one crop, has recently surpassed soybean as the top-selling v n the world. Oil squecced from palm fruit bunches isan inere~ dient in myriad produecs, from ice eream to soap. and it is being touted as a biofuel that can stem reliance on fossil fuels, But the industry has been taking a mulching in the press. Environmental groups haye accused planttions of zing foress to plantthe hicra- ‘ive crop and slaughtering orangutans that pil- fer and cat the fut. Hoping to turn over a new fiond, the oil palm industry is now endeavoring to demon: strate its sustainably I faces an uphill ate AA just-completed review by three dazen aca ddemics details species declines pinned on the oil palm, a native of West Africa that has become a dominant feature of Southeast landseape. It is an “unavoidable fact wawscioncomag.org SCIENCE VOL317 ‘thatthe replacement of diverse wppical forest with an exotic monoculture significantly impacts biodiversity.” states the Biodiversity ‘and Oit Palin Briefing Document. Wewill be presented at gathering in November ofthe Roundtable on Sustainable Palm Oil (RSPO), inwhich industry officials, scientists, and other parties are hammering out a voluntary certification scheme for minimizing harm 0 the environment. ‘Scientists and like-minded industry inside cers hoping toctrb destructive growth may get help from the market. Rising palm oll prices are strangling demand for palm asa biofvel Eddgare Kerkwijk, managing director of the BioX Group, a renewableeererey company in Singapore, told the International Palm Oil Congress in Kuala Lumpur late lest month, ‘That’ bitter news for companies in Southeast Asia that have been raving to ramp upeapacity toprocess palm into biodiesel. With erude palm oil now topping $700 per ton, “we believe that palm oil is not a long-term bioe Fuel,” Kerkwiik said The industry, nevertheless, is riding high Accordingtto the Food and Agriculture Orga- nization ofthe United Nations (FAO), global palm oil production last year was 37 million tons, 85% from Indonesia and Malaysia, Palm cil yields—2.8 tons per hectare, on average oil, ac higher: ye seven times those of soybean ding to FAO, Aiming for even elds, the Asiatic Centre for Genome NEWSFOCUS L Technology in Kuala Lumpur and Synthetic Genomics, 2 company in Rockville, Mary- land, founded by J. Craig Venter, in July announced apartnershipto sequence and ana- |yze the oil palm genome Higher yields are vital to an industry look ing clean upits act Seen fromthe air pen sular Malaysia isa patchwork of settlements and plantations interspersed with forest; in 2003. te peninsula hod! more than half of th ‘country’s 3.7 million hectares of oil palm, Malaysian officials maintain tha plantations are new allowed to expand only onto existing agricultural fields or degraded land, Indonesia isa different try. There, renegade plantations fuel expansion through timber sales. “At the state level, there are no clear limits on plantae tion growih,"says Reza Azmi, director of Wild Asia, a company in Kuala Lumpur that is advising plantations in both countris on how ‘olimit thai environmental footprint. SPO was formed $ years ago to turn the positive environmental record of outfits such ‘8s United Planationsinto competitive an tage through the certification of “sustainable palm oil” To bolster this effort, a network of researchers drew on wealth of data 10 assess the impact of plantations on biodiversity. An advanced draft ofthe document pro- vided to Science paints a grim picture. The authors, led by Emily Ftzherbert ofthe Zoo- logical Society of London, summarize rescarch documenting shifts in biodiversity in and around plantations. In Sumatra, for exam pleless than 10% ofbirds andmammnals found in primary forests live in plantations, and more than 75% of bat species were lst in Thailand, Al birdspecies were foundinplanations,com- pared to 108 species in nearby sepicalforews "Plantations need to accept that ol palm is not compatible with biodiversity” says report author Mathew Stucbig of Qucen Mary, Unie versity of London, U.K. “Environmental groups and scientists need to work with, not ‘agains, the industry to help them minimize ¢hisimpact” The document delivers a clear bottom line to RSPO: “The most immediate and important action needed to prevent further biodiversity loss isto ensure that oil palm expansion does not contribute to deforesta- tion.” The report also highlights how pro= active management can reduce species losses, for example by salvaging native stands inside plantations. Wild Asia is work ing with plantations on plans to link frag~ ‘ments into “natural corridors” and set aside ‘SO of every 2000 hectares for forestregener- ation. “Two yearsago” says Azmi, “this cussion would never have happened” RICHARD STONE 14 SEPTEMBER 2007 1491RESEARCH IN JAPAN Big Winners, Big Expectations Five groups have been awarded decade-long grants in a drive to win global attention ‘and draw international talent TOKYO—imminologist Shizio Akira i indis- Pulably atthe wp of is field. For2 years run= ning the Osaka University professor hasbeen ‘Thomson Sciemific's “Hottest Researcher” the most highly cited papers in his field, But Osaka has not won recognition asa leading world center for immunclogy kira fears the university may even ger of falling behind, Advancin technology “makes it very difficult for a sin- igle laboratory” to create an international buzz he says: “What's needed is o accumu late. research team and get a big grant” He has just gotten a very big eran’; Japan hopes the international buzz will grew. Akita’s center is one of five selected to receive in the neighborhood of $12 million per year for LO years under a World Premier Intemational Research Center Initiative sponsored by Japan's Ministry of Education. The grants, ‘which mus: be supplemented by the hest insti tutions, are intended to take the winners to a new level of global prominence through gen- erous discretionary finding and support For internationalizing research, Akira hopes to ture leading Jopanese and foreign immunolo- its to Osaka and in particular, push into the nascent field ofn vivo imaging ofthe cell-cell interactions that define immune response. ‘The grant program isn audacious bet by Finance, which is out 0 ‘make at least this handful of centers widely wawscioncomag.org SCIENCE VOL317 recognized as the Massachusetts Institute of Technology's Media Lab or the U.K. Labo- ratory of Molecalar Biology in Cambri “It's a visionary program.” says Matthew Mason, director ofthe Robotics Institute at Carnegie Mellon University in Pittsburgh, Pennsylvania, Mason was one of sx foreign scientists on an internetionel panel that reviewed [3 short-listed applications, The ‘objective was to “pick groups already atthe peak [of ther field} and give them suppor: 10 make them globally visible.” says Hivoshi Lkukawa, who is heading development ofthe program forthe Ministry of Eduestion Tohoku University in Sendai, for example proposed cresting anatom-molecule-materials center around its Institute for Materials Research, which is already one of the worlds mext prolific material science proups. Yos ori Yamamoto, slate to direct the new center, says they hope fo take their werk on bulk a _materials to anew levelby adding theoristsand ‘computational scientists. The University of ‘Tokyo is partly building on the breakthrough studies of neutrinos done at its Sup. Kamiokande Neutrino Observxory with ance Institute forthe Physics and Mathematics of| the Universe. Hitoshi Murayama, atheorsical physicist at the University of California, Berkeley, says they will bring together expe mental cbservations, theory, and new mats. _matical approaches “to try © understand such Objective To understand and cnteal chemical and physical processes at the cedar sale Te promote the development of new materials, particulary bulk lass a study basic questions about the origin, 5000 peptides) teases (> 2000 peprides) Contact us now: JPT Peptide Technologies GmbH poptideejpt.com | www.jpt.com shosphatases (> 2000 phospho peptides) Discover your Biomarker Map antibody epitopes Mep immuno-dominant regions Choose your technology format Pepstar™ «High Density (HD) Microarrays son glass sides Pepspot™ * Medium Density (MD) Artays on cellulose membranes in microplates New: Random Compilation Arrays Unbiased peptides complied as set of individual single peptides Profile patient samples systematically for antibody signatu + Infectious diseases Allergies & autoimmune diseases = Cancer and any known proteome ‘Accelerate developing vaccines Accass now: Complete proteome-spanning peptide arrays Fast & highly flexible _ {9| TTERS through false buzz about the song, a process that could be created in scientific circles ‘hrough self-promotion. However, Salzanik et al, (2) demonstrate thet this effect works only ‘ona song-by-song basis. When average effects are examined, average popularity and average quality are Fighly correlated, Our measures of average citations taken over large numbers of papers would then appear to be a reasonable ‘measure of scenic influence. ‘More generally, we avoided the term “quality” and used the broader constructs of “impact” and “influence” to construc the ‘meaning ofa paper citation ate. A paper that ishigh “quality” by some standard (functional contribution, breadth of application, timeless- ress, elegance, etc) will ypically have little impactifitis not cited. ‘Our analysis focuses on impact at the paper level, Buckley is interested in the impact of individualauthors, Heattemptstoinferindivid- ual impact from our paper-level analysis, but this inference is not possible without knowl edge of the amount of time each author con- tributes per paper. His implicit assumption is ‘hat a paper with N authors requires N times as much colleciveeffortasa soloauthored paper. A more unexceptionable assumption may be ‘that multiauthored papers require less effort per person, which would explain the prevalent observation that people who tend to write in teams tend to write more papers. With higher rates of publication, team authorship may be assceiated not just with more citations, but more citations per unit of author's time. Nevertheless, assessment of the impact of indi- vidual authors requires data on time inputs, an important direction for future work, Wray provides a possible interpretation for why scientists work in teams. As we noted in our paper there are many possiblemechanisms behind the universal structural shift toward teams in science, and we look forward to future work that assesses and disentangles potential sresan mucaTy, [BENJAWIN F. JONES, BRIAN UzZI"* 'Nerthneiem Inittate 99 Crsplesity (HCO, North: ester Unversity, Coast, 160208, USA. logy ‘Schoolof Management, Herweser ives, anton ILe0200.usa Reterences 1. | lace A Gineeo, er eo. Sto, 7742008) 2 ALL Sant eva. Selec 31, 658 EC, Coral Reefs Still in Danger from Tourism Head ASA DIVER SINCE 2985 WITH OVER 500 DIVE hhowrs logged on tropical reefs and now a coral reef conservationist working directly withthe ‘marine tourism sector, [have to wonder if ‘Norman Karin i talking about the same dive community [now (‘A diver’ perspective on conil damage,” Letters, 13 July, p. 196), Tm not about to pretend that recreational use and overuse ranks ate change, coastal development, and unsustainable and destructive fishing practices as the mest sig- nificant global threatsto coral health. AndI've hhad the honor to dive with stellar dive busie nesses who ac ambassadors for sustainability. But to suggest that the dive community as a whole has had some sort of collective epiphany around sustainable behavior and best practices is just uninformed. ‘According to a 2002 report (/), marine tourism is a major factor contributing to reef” decline at no-take Marine Protected Areas (MPAs) in Hawai. In 2003, between 28,000 and 100,000 people per year visited jus. four Biomarker Discovery WEBINAR : Brought to youby the Science Business Office Eng M. Ton, M.D. Sena Reser stats Michael Snyder, Ph.D. "le Uses Paul Pred, Ph.D. lover copoition Moderator: ‘Sean Sanders, Ph.D. Commer eter Scene Discovery of Antibody Biomarkers for Cancer and Autoimmune Disease Participating Experts: Join our panel of experts to: » Leam about the promise of auto: artibodes as biomarkers for Cancer and autoimmune disease. » Obtain insight into how to advance your biomarker discovery research using proteomics approaches. » Hear about successful application of protein arrays to biomarker discovery in ovatian cancer. RECORDED aN on June 20, EL] To viewon demand, goto www.sciencemag.org/webinar Science BYAAAS ‘Webinar sponsored by Invitrogen 1498 14 SEPTEMBER 2007 VOL317 SCIENCE yaw scioncemag.org1500 AAAS Tiave Come explore the ave with AAAS this vear. You will discover excellent itincraries and leaders, and congenial goupsof likeminded travelers who sharea love of learning and discovery Sea of Cortez Docember 10-17, 2007 Vonage to Baa Caloris anal the sent Cortez on be Explore Mewso's Galpagos th fesinatng wildemess land and shundint sealife. $2820 air Costa Riea December 23- January 1,208 Enjoy an introduction over the Anolis tothe natural wealth of Costa Ricafrom tropical rainforests toaclivevoleanoes, monkeys, sloths, maeaws & more! 82699 alr Discover Chile from Santiagotothe ‘ukisPatagonan fords an, legendary Eastoriskand! Onb AD VScorpios I explore Pats including Puerto Aa Casiro & Quitraco Fjord, ieee. Rr ag Sane iene Soeee rete ertte Taj Mahal including hiree premiere Undiscovered West Africa February 13-23, 2008 Explorethe teases of Senegal and'The Gambia, on board the. Bt passenger yacht Callisto. See Dakar, Goree Island World Iteritage Site& more! From $5,995 ~air Himalayan Kingdom of Nepal March 23,2008 Discover the fascia catural heritage of Nepal. the spectacular imalayar andtigers ithe tra! Explore Katana, Pokhace more! Gall for irip brochures © the Expedition Calendar (800) 252-4910 Cupertino, California 95014 tinail: W8inbosbetchurtexpedtons.com Ontho ies wvrotchertespediirs. com 14 SEPTEMBER 2007 AL LETTERS sites, with diving and snorkeling being the ‘most popular marine recreation activity (2) “Tourism numbers haveinereased steadily over the years. In 1999, tiny Honolua Bay on Maui averaged 250 tourists per day and up to 700 pper day during peak season (3). This volume thas certainly increased, Research also shows that 45% of certified SCUBA divers who visit dive sites break coral colonies. Most of this damage appears w be from fin kicks (4), Finally, Karin points to Bonaire Marine Park as evidence of diver awareness. I agree that Bonaire is spectacular and a mode! that should be emulated and exported worldwide. Bur to hold up the wellfunded, relatively ffl cent, politically table, and uncorrupt Nether- lands Antilles as somehow representative of ‘most coral ref destinations and MPA systems is disingenuous, Most MPAs are not reaching their conservation goals. Crushing poverty and TECHNICAL COMMENT ABSTRACTS Comment on “The Consensus Coding Sequences of Human Breast and Colorectal Cancers” William F Forrest and Guy Cavet Siétor eto Research Mle 13 Ocebe 2006, p. 258) ‘ed data fr cancer genome eseavencing tery (ones wih elevated mutation ates Ther analysis used ore probbites wren it shoul have used Paes oe the nypotiese ty intndec te ts. Reimpereatng thei analy method wi exact yates rel far fewer genes with mutton rates at achieve absta| Sapien Fille at nw sereomag eroeciemonu/317S8141 15008 Comment ow “The Consensus Coding Sequences of Human Breast and Colorectal Cancers” Gad Gets, Holger Hafling il P. Mesiro, Todd R Golub, Matthew Meyerson, Robert Tipshirani, Eric 5, Lander ‘ble eto Rowan At, 13 Oca 2006, . 268) repetednaady 20 novel cancer geessaidtohavea 90% ppobabilty of bene ole in colon or brest ance. Hone ter analsraes wo asta crces, Wher these concensar alesse fen gees wh erica ‘seated matin rates remain though te Bologeal meheclegyn ble et. und, ror apie ede 2 achieve aac pow Full wi atweusdereamay oy chconva 7584 35008 Comment ow “The Consensus Coding Sequences of Human Breast and Colorectal Cancers” ‘Alan F. Rubin and Phil Green Sietkcn eto Reseach Ate, 13 Occ 2006, 258) Teporec many new gees with an apparent sgn fant ‘competing resource use often derail the best ‘conservation efforts, Denial or special pleading todisplace turism’ contibution and resporsi= bility certainly doesn thelp. FICK MACPHERSON Freqram Decor, rl Ree! Mince CORA, 417 Mere omer Stet, Site 265, San Fanescs, Ch A104 USA. References 2 Oren, RAW este caret cst the Utes Ses Pel Asa {US Deparisee of commerce Nanna Ocean nd Ape Adahistaten Navona cae Serve Pots venga on uses ar stu stare Baca. Faedh. ML 203. 4. Ek toes, Setnet sank Nok acon Cor Scere cara eaters tn Mc ay ‘UC, Stes See anceps aed ‘ual eases nr liine case 4. HALL wees CL Hobe BL Cons 120, a8 (ann, excess of mutations in breast and colorectal cance Reanaysis of tht date mth rare opr ate sata methods and beckground mutation rat esumptons reveal that few fan ofthese genes hesitant ee ats tain as, Fullte at ena scencomagarkcbontntll9175084) 3500 RESPONSE TO COMMENTS ON “The Con- sensus Coding Sequences of Human Breast and Colorectal Cancers” Giovanni Parmigiani, Jimmy Lin, Simvina M. Boca, Tobias Sjislom, Sian Jones, Laura D. Wood, D. Williame Parsons, Thoma: Barber, Phittip Bucthaults, Sanford D. Markowitz, Ben Ho Park, Kurtis E. Bachman, Nickolas Papadopoulos, Bert Vogelstein, Kenneth W. Kingler, Vitor €, Volculescu Forest and Cau, Gazeta ard Rubin and Geen dese Aare eftatstical methods to ana the mutational tha pbladedn blo va Howe the conesons Se nace becaue he at zed on analy ta do ot ly tee into acceu the enperimertl eign snc cher ical features of or stedy. When thes fads ae incr porated, thes methods provide estimates sim to those me reparted and support the orden that lage rub of genes ave mtated at tes peter tan the pas Senger mutation ate Full tat waesciencemag orlegVcntet L317) s944/15004 Mee Onn err cree eee nt mee ern erent To VOL 317. SCIENCE unwrsciencemag.org1502 EVOLUTION Putting the Pieces Together ‘Alan C. Love hecompletion of ajie- faw puzzle brings te Eee rmendous saiisf however, afew missing pieces lead 10 considerable frustration Having the intended picture of puzzle on the container con- [aaa tributes to the satisfaction (or the frustration). But what about a puae where theres no mas. ter picture to guide the recon struction? Hew do you know if you have all the pieces? And what ifthe con ‘ours of some piazes are unclear, making it df= ficult 10 see how they fit together? Such isthe New view. Thoth rseae (cent), from the Devonian ofthe Canadian ‘tic isa transitional species ‘bemcen lbo-finned fish ner right) and tevapods (upper Ltt. let of biologists attempting 1 explain key evo Iutionary wanstions inthe history of ie Fins into Linas isn exploration of along standing evolutionary puzzle associated with the origin of tetrapods and the vertebrate inva- sion of land, Brian Hall has assembled 2 stel- lar array of contribuors fiom various fields {he sven nha DapainastPateaphy, Unvrsty staimeess Wersipl, SSA, USk Erma tinea 14 SEPTEMBER 2007 VOL317 ett id by Brinn Halt Ed eee ie Peter Peas Ser iety that represent the pieces maces sary fora solution. Thevolume is handsomely execuied and also timely, Itcollectsa diverse body of recent research on fins and limbs emerging from evolutionary developmental biology (evo-dev), Functional morphology, and paleontol- ‘ogy, all of which hav formedour conceptionof what the fin-Limb transition looked like, Instead of a lobe-finned fish hauling itself up onto the sand, we havea much differ- ent image of the evolutionary transformation Line ((), Recent papers that could not be incorpo- ratedin the volume have revealed rew transi- tional fossils (2) and continued to augment our understanding of the molecular genetic, mechanisms of limb development (3) ‘The volume firs par, Evolution, provides historical background an the fio-to-imbpuzale and paired appendage locomotion, as well as a phylogenetic context informed by pale omtlogy. The origin ofthe autopodium (hand! feot)—encapsulated in Halls pithy slogan SCIENCE “fins minus fin ays plus digits equal limbs" is analyzed fiom an evo-devo perspective. In the second par, Development, an overview of fin and limb ontogeny is followed by trest- ments of chondrogenesis, osteogenesis, apop= tosis, joint formation, postnatal growth, and regeneration. The third part, Transformation, addressesthe subsequent fatcoftetmpod limbs, ‘ncludhng the appendicular skeleton of amphi ians, digit and limb reduction in repilians, ‘mammalian limb diversity, and skeletal adap- tations for flight, digging, and swimming. ‘These later chapters are not picoes ofthe puz- z2le themselves 2s much as investigations of other evolutionary transitions of tetrapod appendages relevant to understanding how the different pieces fit together when explaining the origin of movations “Although the lengths of the contributions vary substantially, the more interesing varia- tion les inthe styles they exhibit: anatomical, functional morphological, and molecular genetic. Very few chapters bring these consid- ‘rations together, ndeventhe contrast among cognate entries is sisiking. Chondrogenesis ‘and osteogenesis in fins aretreated in terms of histology, whereas the entry on limbs grants priority to molecular genetics. The influence ‘of mode! organisms (zebrafish, chicken, and mouse) chosen for different scientific puzzles (uch as isolating key processes underlying hhow an organism develops from embryo to adult), i also apparent, My favorite was the last chapter, by Matthew Vickaryous and Wendy Olson, on the curiesty of sesemoids and ossielesin the appendicula skeleton. The combination of a topic neatly uniouched by other contnbutors and an explicit blending of the different styles makes ita gem, Specialists will no doube question particu lar interpretations within individual chapters, but the book's significance lis in the over- arching outlook on the fins-into-limbs puzzle. Attacking the thomy empirical and concep tual questions that compose this problem requires multiple disciplinary approaches, cach with specialized concerts and methods. ‘Sometimes this introduces petential commu ation difficulties e-., the developmental ‘mesamere” of vertebrate mesoderm and anatomical "mesomeres” in pectoral fins), and the substantial differences in terminology are on full display. But do we have all the disciplinary piewes tothe puzzle? The volume lacks discussions from evolutionary genetics and (paleo)ecology, which encourages a com paint that evolution plays second fiddle to ‘comparative development in it, Some might disagree with claims about the evolutionary process suchas patterns of genetic regulatory clements pointing “to changes in a region- wraurscioncemsg.org,specific regulatory sequence as being the ‘mechanism for evolutionary change.” As the editor acknowledges. this book is focused on skeletal elements, which is his area of exper- tise (4). Thus, musculature, inmervation, vascu lature, and other features are relegated to the ‘background although some of these missing pieces can be found elsewhere (5) Knowing how the pieces fit together is a more diffcul: question, Thecontributors make litte effort to integrate the research fiom dif- ferent appreaches, One author notes tha “the challenge is to continually synthesize knowl- ‘edge gained from multiple perspectvesinto an ‘ever more refined understanding.” In some 2 this synthesizing is studiously avoided, and at other points, there is inadvertent stum- bling over borrowed concepss. (An exception 's Gunter Wagner and Hans Larsson’ discus sion of evolutionary novelties, with its explicit fusion of anatomy, phylogeny, development, and evolution.) But this not the fault ofthe ‘editor or contributors Is sympromatie of the complex siructure of biological knowledge. Multidiseiplinary research on evolutionary problems may be essential, bu tbe nature ofits composition and functioning remains clusive, Fins into Limbs serves as a necessary ref= erence anda worthy guide to future research on this and other evolutionary transitions. It tells us what we know, what we don't know, and what we'd really like to know: Thus it BOOKS era L points us inthe direction of which pieses are required to solve the puzzle and reminds us of the pressing need to figure out how they all fit together. Referonces 1. JACatk Gang cert Ihe Onpnendévtstenct Tapa (ngana us rs, ligt M02. eee stor Sece 3027582003. 2, Net at £6 Duele A als, ae 4, Youiz06 3, MC Das #.0.0she,NH Shin (oon. 4, Dl, Boe and Caria Deleent ord Felton Set Boy ears 500 Dag, 2005. 5, Rye Abaia | Morphol 268, 5042000, Ch THE GONZO SCIENTIST A Summer Camp for Grown-Ups ‘er las oreo copes baa po |e pehsmee crn oe aor oor iinet be se Sao fern berte re meaperat sires nectar Cas Ty nl noma wo stutesps nits sar ries car, a seaman te Dic Unenty pi wo rime Ve ears ney tr Srv Eran Urry bag itr Bt he et of Clo ol gabe” oi aetna tage i seh acy ners ot al sant) nb pene et df ieee serving uth eer Rr Dn ab i Srl ntact septs 1 srt pes lpg cans mye sevsa theo hte hse no sista ents grgpnonter ns Cadel sare ae age rg wawsciencemsg.org SCIENCE mini-lecture on the anthropic principle did than we ere. Our own “A air uccawesonteaete WOO almost certainly doesn't exist. ‘Shmuley deployed 2 fighting style perfected by “Rowdy” Roddy Piper, the eee ea eet aah answers, | change the questions!” And that's just whet the rabbi did. His Pe let eestearars teeters Bates oem teases es intel re Of course, the real show is always afterward, when the fight spills out Jou nowsanon at ofthe rng. \e SR Ye pnd out more and tow our imei reporter ne o jung of space tourism, eco-nariars, robots, pandemics, and even belly dancing, we vite you to tar to the fist installment of the Gonzo Scientist, an approximately monthly adventure chronicled at wn. sciencemag.orgiegivcontentfull317/5844/1495b. W.labicene LL VOL317 14 SEPTEMBER 2007CLIMATE CHANGE The Limits of Consensus Michaet Oppenheimer” Brian C. O'Neill Mort Webster* Sherdul Agraw he Intergovernmental Panel on Clie I ate Change (IPCC) has just deliv- ced its Fourth Assessment Report (ARA) since 1990, The IPCC was a bold innovation when it was established, and. its accomplishments are singular (7, 2). It ‘was the conclusion in the IPCC First Assessment Report that the world is likely to see “a rate of increase of global mean temperature during the next century... that is greater than scen ever the past 10,000 ‘years” (3) that proved influential in eatalyz- ing the negotiation of the United Nations Framework Convention on Climate Change. ‘The conclusions of the Second Assessment with regard to the human influence on climate (4) marked a paradigm shift in the policy debate that contributed to the negoti- ation of the Kyoto Protocol. IPCC conclu sions from the Third, and now the Fourth, assessments have further solidified consen- sus behind the role of humans in changing the earths climate The emphasis on consensus in IPCC reports, however, has put the spotlight on expected outcomes, which then become anchored via numerical estimates in the minds of policy-makers. With the credibility ofthe science of climate change established, itis now equally important that policy-makers understand the more extreme possibilities that consensus may exclude or downplay (5). For example, the Working Group L (WGD “Summary for Policymakers" (SPM) ‘of AR4 anticipates a rise in sea level of ‘erween 18 and 59 em by the year 2100 (4), “model-based range” composed largely of thermal expansion of oceans, melting of nonpolar glaciers, and the gradual response ofiice sheets. The range doesnot include the eral nation Wikan Sec! of Public and internatena Aas, Prnctan Unversity, rican, USA. “Depa tment of Georoacer Pancten Unies, Pinson USA international natu fori Syeme nee Linenbuig, farina. aon Inte frlntenst na Stuer. oan Users, Provence, B, USA lo Progiom on the Science and Pokey ef Global Change, Maisensets Ista of Teehrelagy, Cmbgg, IN. Usk “Oigenzzben for Econom Cooperation’ 340 Davelopat (05D, Par ance. “aaioslcorepondene Ena eihati@prinetonalu The von presen tpape athe oth aes ant cesar hove he nseutane thoy a Bid oth. wwurnsscioncomsg.org potential for increasing contributions from rapid dynamic processes in the Greenland and West Antarctic ice sheets (WAIS), which have already had a significant effect onsea levelover the past ISyears and.could eventually raise sea level by many mete Lacking such processes, models cannot fully explain observations of recent sea- level rise, and accordingly, projections based on sch models may seriously under- state potential future increases, Although the ARS SPM recognizes the possibility of a pe Not captured by icesheet models Top) The Larsen B ice shell along the Artarctic Peninsula on 31 January 2002. (Bottom) A Large section has cisinte- arated, 5 Merch 2002. laces tend the collapsed Section ofthe Ke shel subsequent accolerated ther Alischarge inte the ocean, apparent because of the loss of butressng by the ice shal. Nether rapido! lapsenar butresing ar captured by ceshet mod ls, and both could subsantialy affect the rate of Future sea-level ise 3 ager ice shelves tothe south In West amaetica wae (2). SCIENCE VOL317 The establishment of consensus by the IPCC is rnolonger as critical to govemments asa full exploration of uncertainty, larger ice-sheet contribution, its main quantitative results indicate the opposite: Uncertainty in sea-level rise is sraller, and its upper bound is lower, for the 2Istcen- tury than was indicated in the Third As- Report (7). On the related ques level rise beyond the 2ist cen- tury, whereas the Third Assessment’s SPM. provided a numerical estimate of a poten- tial contribution from WAIS, the AR4 WGI ‘SPM doesn't mention WAIS at all. This ‘omission presumably reflects. lack of con- sensus arising from the inadequacy of ice- sheet models for WAIS made so apparent by recent observations. Nevertheless, alternatives to model-based approaches, such as empirical analysis and expert elicitation, were available for explor- ing uncertainty in 2lst-contury (8)and lon, term sea-level rise (9), respectively. Such information certainly would have been useful to policy-makers, particularly for WAIS, which cont I by about 5m, tion of se enough ice to raise sea le citing aside or minimizing the impor- tance of key structural uncertainties in underlying processes is a frequent outcome fof the drive for consensus (5, 0), For exams pie, ranges of projected warming and atmo- spheric composition in AR4 include an amplifying effect of interactions between climate and the carbon cycle. However, the estimated uncertainty in this effect is based largely on models that omit a number of poorly understood processes (/7), such as feedbacks on carbon contained in perma frost; changes in marine ecosystem struc- ture; and responses to land-use history nutrient limitation, and air-pollution effects These models also share similar assump- tions about the temperature sensitivity of carbon fluxes from soils based on experi- ‘mental results that cannot be reliably scaled to the ecosystem level (/2). A fuller ac- counting of uncertainty would be more appropriate ‘Similarly, the narrowing of uncertainty (relative to previous assessments) associated ‘with potential changes in the meridional overturning circulation relics.on agreement across models, but the structural uncertain in all the models means th be known than suggested by the numerical estimates (13). 16 SEPTEMBER 2007Br 1506 LICYFORUM Like models of physical processes, con- clusions drawn on the basisof socioecanomic models may also be subject to premature con sensus, Estimates of the costs of mitigating emissions come primarily from models that omit endogenous technical change, « poorly understood process, This omission could cause a significant bias, not only in mi tion costs, but also in the stringency of near- ‘erm mitigation that may be justified for a aiven damage function or stabilization tar- get (14-10). Similarly the conventional use of the range of emissions described by the IPCC Special Reporton Emissions Scenarios (SRES) marker scenarios as a key determi: rant of uncertainty in projecting climate cchange, sea-level rise, impacts, and mitiga- tion costs may be misguided. The SRES sco- narios were intended to be representative of scenarios available in the literature at the time they were produced, with no explicit goal of spanning the full range of uncer- tainty. The SRES assessment made no antemp: to judge whether emissions path- ‘waytsoutsidethe range itcovers could plausi- bly oceur. In fact, pathways outside that ange ‘ere known at the time, and more have been developed since the publication, of SRES (17). To be sure, the underlying IPCC chapters do detail the limitations and uncertainties associated with such conclusions. But the caveats are often cryptic or lost entirely inthe highly influential SPMs. This inevitably leads to an anchoring by both policy-makers and scientists around any numerical estimates, ‘hat are reported in these summaries, Ignoring the implications of structural uncertainty in models of key aspects of the climate system is reminiscent of the way assessments trcated the uncertainty in ozone ‘hotochemical moxkls. Projections of ozone depletion wore made fom 1974 onward based on improved understanding of gas- phase chemistry (78). Knowledge of stato spheric chemistry was then transformed by ‘he report in 1985 of lange, seasonal Antarctic depletion (the “czonchole”); the validation in 1987 ofits cxiginin talogen phowochemisiry, and subsequent identification of depletion at the mid-latitudes and in the Arctic (9, 20). Various heterogeneous chemical reactions, discounted by most researchers years before and absent from nearly all made! simulations (21), were shown to be the missing photo- chemical processes required t0 explain ‘observed depletion. Their potential implica tions were of concem to some scientists (22), bu this structural uncersainty was generally downplayed in assessments until the ozone hole was reported, 14 SEPTEMBER 2007 VOL317 Avoiding Premature Consensus ‘The IPCC has made progress over four assessment eycles in its treatment of uncer ‘ainties, However, thisprogress is limited and uneven across its Working Groups, Several \dditional modifications to the current prac- could reduce the risk of ignoring or underemphasizing critical uncertainties, First, given the anchoring that inevitably occurs around numeri the basis for quantitative uncertainty estimates pro- vided must be broadened to give observa- tional, paleoclimatic, or theorstical evi- dence of poorly understood phenomena comparable weight with evidence from numerical modeling. In areas in which modeling evidence 1s sparse or lacking, IPCC sometimes provides no uncertainty ‘estimate at all, In other aress, models are used thet have quantitatively similar struc tures, leading to artificially high confidence in projections (e.g, in the sea-level, ocean- circulation, and carbon-eycle examples above). One possible improvement would be for the IPCC to fully include judgments from expert elicitations (23), as Working Group II as sometimes done, Beyond this, increased transparency, including @ thor- ‘ough narrative report an the range of views ‘expressed by pane! members, emphasizing areas of disagreement that arose during the assessment, would provide a more robust ‘evaluation of risk (24), It would be critical to include this information not only in the aptess, but in the summaries for policy makers as well, Second, [PCC should revise its procedure for expert review to guard against overconfi- dence External reviewers should ferret out differences between chapters or author sub- ‘groups, and a special team of authors could be instructed t examine the treatment of unlikely bur plausible processes, perhaps ina separate cchaprer. Imegration of risk assessment aenoss Working Groups in advance of dratiing ofthe ‘Synthesis Report would highlight internal dis- ‘cussions and disagreements. At the end of an assessment cycle, a small external team of ‘ombudsmen should review key problematic issucs (ofa scientific nature) that may have ‘emerged from the report and should recom- mend modifications of approaches for han- dling these areas in subsequent repors. Third, IPCC could also formalize a process of continuous review ofits structure and procedures, A useful example is pro= vided by the history of IPCC emissions sce aario development, which included a series ‘oF reviews for production ofthe SA99, 1892, ‘and SRES scanatios (25), Fourth, and perhaps most important, SCIENCE national govemments now need t confont a sore fundamental question of how often they need comprchensive assessments of climate change. Addressing the special risks entailed in particular aspects ofthe climate sytem, like the ice sheets or carbon eycte, might be beitor approached by increasing the number of con- css, highly focus sper ial pcs dat canbe compleredrelatvely quickly by smaller groups, pethaps even by compesing teams of exper. Atthis juncture, fll assessments emphasizing Consens, which are a ajor dain on partie pants anda deflection fom research, may not bbenseddmerethan once po: decade References and Notas 1, Sigil Ci Chnge 29,6298, 2 N.Orses Sine 306 1686 2900. 3. CC Sumy er poleymaes. in ScenapcAsesmort at Chrgy pe of ering Gap LC Seat, Gano, 1080) 4 9S erpteyma inci change 19%6:Ineseance Cee Change ICE Seana Geo, 3995, NG Pat Pid Da a4 1 099), IRC Sumnay pokey, Change 200 Te ye Sime Bo ont tone inting Gasp totheFaut Assan pet oe Itgoanmertd Pare on Cac eng © Sen al (abridge Un Pest, Nero, 2007 2. HC Summa ex pteymaes, Coat Change 2DMisThe yal Scie Br) 1 Weigh o, fe Conve Ute Pea, Cambie, 2000 8 S Rabe Sie 315,368 (207) 9. DG-Waghan JR Spape, i,Chge $2, 652002, 10, ML Opperteine, 8. © ONAL Wee paper pe- fete stb Cece on ling nde Ging tenses rte pled yer ‘nas Cnr, ust, 1092008, AL iraltogtent al}. 19.337 00, 12 JM Mle, Sconce 28 2372 200, 1B, K Dll ol Ce Change 2,25 O07, 1A Civcou 5 Svsd eae Erg Eee. 23, 21199). SE al Ratu Eregy Eon 27,19 (208) 16. R Gens 6 va Zan, Resor Ena Eon. 25, 2 Goon, 17, Mester alm Enon. 36,3889 2002) 1B E Pason Fraetng tie iene Loe Sece and Saag (dre Un Pres, took, 2003. 19, ardor Oana, apr fhe Iierabanal ioe Wen Pae 2080 ape 1 Geb Oxo Rech sedate Pj, Hod earls Oana, Genera, 1968 20 Wald Weeordegal Oganeaton Serf Aesmert Ose Dalton 1991 apa 25, dst Cave Fave lar ving jet A lee gant, Gove, 2990- 21, Wald hts Ogmiton Reaper Ore 1985 Rpt 26 Gl res Rasach aon Pre asi gai, Gene, 2000, 22, FS Aolig AS 7, 360909, 24. Giron Heir Uncotai AGuie te Dacog ih Unctainyn Gunnin Rikon Poe ees (Cantrige Un Pres, Conbdge 190, 24, KPa Gb. Emo. Carge3? 97 2007 25, he 960 wana ere pede UFC ‘canet Rept Te S92 canoer nar shee the 1892 Supplement Apert tothe CC Aes 26, Tames | Slade 8 Rap comple, rage Avaric shes 20, pated 2302 Natal Son and leat tr, aie wraurscioncemsg.org,IMMUNOLOGY Square-Dancing Antibodies Dennis R. Burton end lan A. Wilson antibodies are among nature's most Aris miei ec {¥-shaped molecules can recognize essentially any antigen by the variable tips of the Fab (fragment antigen binding) arms, ‘whereas the Fe (Fragment erystallizabe) stem ecognizes effector molecules thathelp elmi- rate antigen (sce the figure). The two Fab aamsareidzntcal, allowing antibodies to bind bivalently to repeating zn gens on, for exzane ple, microbial pathozens or tumor cells. This, arrangement enhances the affin- ity of antibody for antigen and allows antibodies to cross-link. sn molecules under certain 3. Mdentity of the Fab mms is expected because an ant- boily isa tetramer of two ident- cal dimers. However, on page 1554 in this issue (7), van der Neut Kolfschoten er al. show that one type of antibody can exchange dimer pariers, generating a hybrid antibody that contains ‘wo different Fab arms. Although this newly formed antibody can only bind mono lentiy, even toa repeating antigen, itis capa- ble of cross-linking two different antigens, The consequences of such hybrid antibody formation are very interesting, but with some potentially scrious ramifications, Theantibody molecule that exchanges Fab arms is human immunoglobulin Ga (IgG), the predominant antibody in the serum, consists of four subelasses in humans. The eas abundant subclass is IgA, which is pres cnt in serum ata concertration of about 0. t0 05 mg/ml (2). The 126 sibclasses differ most in their Feegions and laG4 notably hasan Fe ‘hat interacts poorly with effector systems of the immune response, such as complement and Fe receptors expressed by certain white blood cells. This property has made 1gG4 a favorite for therapeutic applications in which amsibody is required to bind to a target, but not trigger effector activities. Previously, it was noted that sera from donors making Ig antibodies toboth house ddustmite and grass pollencan cross-link these ey ae 1. Burton icin he Deprenents of lnmunelogy 20d Molecular any, and A Wson inte Depzmert of Molecular Blog ae The tangs site fer Chena Biclgy, The Soipos Research Insitate 10550 Hort Torey Pres Rat. La Ja, CR82037, USK Ematt Dutonasernnsedy, wkend eo, wurm.sciencemag.o1g Ansbody structure Upton fm dude two antigens, whereas sera ftom donors that make antibodies to one antigen alone cannot (2), Further, whereas most IgG molecules pre~ cipitate antigens when mixed inthe right pro Portions, 1gG4 antibodies do not (4). Some interesting hypotheses (5) were advanced to interpret these data, but this new study con- vincingly explains the behavior of IgC4. In Particular, ation of a reducing agent, such as reduced glutathione, promotesexchange of Fab arms in vitro for both polyclonal and ‘monoclonal xGtantibodics and, portant ly thisexchange ices Sf 1964 a‘ 1964 ¥ ry vy ve Ditorert calle 2 thea wth rode diferent pose ie constantly changing 3m. Partners in a ‘Therapy wih new antibody 1964 perce formed Antibody therapies need to take account of 2 subclass of immunoglobulin G that can swap subunits in vivo, How then does this exchange of Fab arms ‘occur between IgG molecules? Dimenzation ‘of IgG heavy chains is thougly w be driven by the pairing ofthe third constant domain (C ofeach heavy chain. Tispairingisusualysta- bilized further by intcrheavy chain disulfide bridges some distance away in the hinge region In]gG4,thchingeregionhastheamino acid sequence Cys-Pro-Ser-Cys, compared to (Cys-Pro-Pro-Cys in IgG |, and this diflerenc haa been linked toa tendency of lzG4 to form novel intachain disulFides ithe hinge region rather than the standard interchain heavy chain disulfide bonds (6-8) Surprisinaly perhaps, the present work suggests that these hinge dif= ferongos are not primarily responsible for the ne ¥ ¥ xX ¥ ¥ Amex ange may ater tec! berate St Top! The Y-shaped structure ofan 19G molecule is composed of two identical heaw (1 chains and two ideal ight WL) chains, resting in two ential antigen-binding sites 3 ho tips of the. However an HL unit of one lgG4 melecle can exchange wth that of anther 1G to produces hybrid mol cal with iflerest antigen species. Because the Feparts of two G4 molecules are Henicl their Fab arms are effectively tapped. (Bottom) The exchange of Fab arms betwen 1968 molecules © eyramic. An ‘nity homogeneous 1g6t antibod, when adminxered to a human, will begin snapping arms, Partners exchange conse, a this “dance” progresses. An insightful application ofthis Fab arm. ‘exchange is illustrated in amonkey mode! of the human autoimmune disease myasthenia gravis. The disease presents as muscle w: ness associated with autoantibodies to acetylcholine receptors (ACHR) expressed onmuscle cells. van der Neut Kolfschoten et al, show that a human IgGI_ antibody to ACHR isolated from a patient with myasthe~ nia gravis induces disease symptoms in ‘monkeys presumably by crosslinking ACHR. molecules. However, a human IgG4 anti- body with identical binding properties to ACHR as the [gGI antibody docs not cause disease. Furthermore, the lgG4 antibody protects ayainst IyGl-mediaied discase likely by displacing Lg nding monavalently to ACHR SCIENCE VOL317 exchange of Fab arms but, instead, implicates the G3 domains. Sequence diffrence in the C,,3 domain of IgG and IgG1 are limited to four residues: most notably, an aginine at psition 409 at the interface between C3 domains in [gG4 is replaced bya sine in IgGl, and this may be crucial for Fab arm exchange. Although this appears to be a rather conservative mutation ainine-o-hsine substitutions can have large eff on pretein-proein interactions in other systems (9,10). Cleary, further mutegenesis studies are warranted addressthispossbily What are the ramifications of Fab arm exchange for anibody-mediated immu nity? IgG4 is produced particulary in response to high doses of protein antigen, and there has heen controversy over the abl. 14 SEPTEMBER 2007 15071508 i PERSPECTIVES ity of G4 to dampen IgE responses when the antigen is an allergen and also whether this dampening effect has clinical uility (5, 11). Any effects are likely due to competition between IgE and IgG4 to bindantigen, but this, should now be ecnsidered inthe light of the findings of van der Neur Kolfschoten eal. Several leG4 molecules ae in clinical use or in clinical trials. In some instances, the hinge region of lgG4 hus already been “Siabi- lized” by mutation to the IgGl Cys-Pro-Pro- (Cys sequence, and itis probable that Fab sam. exchange has been reduced orevenabrogated. nother instances, a wildhtype IgG4 molecule may have been used, andthe possibility that Fabarm exchange could contribute to adverse effects in IgG4 therapy (12, 13) should be ‘explored immediately References 1. Alvan cu NeatRolscoten et, Scene 317, 3858 (aan. 2. Ne let nds nd nel pec offre Subd Sak, ar Best 188) vl 19. Mschusaeet cl, mola 976931199) 1S ve 2 an Suen Aloe Irma 337, 3366 1990, 5. RC palbese. 1 Shaun nso 105 92002 5 Shuma Gj. Pet, A.. Gate, CAs, ‘et iral.38,1.@00D, 7, Sgt, ll rear. 30,505 993 Wel. Mada 0 Mert T Wee, 9. 5 Ghadaer i lB 245, 261.0995, An Fella, j mmunt 178 S7I0;007. AL MalgeadefDveaas, J Akegy Cin muro, 95 43299. 12, G Surtaratngu etl e355, 1018 (ec, 18, BHA Deastes, KL THe ec 553 369(205). sa 12cm 124005 GEOCHEMISTRY New Players in an Ancient Cycle Bo Thamdrup rooaniams sucht anbace M: se rfc, and ethane joc ucice can be taced Bask to 7 lion yar ago onthe bs of chemical biomarkers microti an sable toes ar bck ining ieee mri metabo resis a pizza ‘hich no pees ae ing. On pe 1534 ofthis sue, Picea (0) resent anew pie: orp eva foal dpreger onto «itl explred mei ross inn33-len yearcld marin coos "The geoegal ero vale mur ox topes olds ial er bout Ears io. Siiatevsping bce and archaea fn matne sediments favor oer Sf hel The autora the RerdlcCeee or Eat Eon, Insite of iio, Unset Sethen Denar, 5250 Odense, Denmark Ema txeplogy ce + tis. 9, s 550 t The sulfur cycle at North Pole according to (2). Atmospheric reactions of sultur gasses induce 2 mass-inéependent fractionation with postive 25 «anomalies (A"5) in elemental sufur (5%) and negative enomalies in sulfuric ci 50). Sullur ane sulfate are deposited ina shalom, slfate-sich basin 14 SEPTEMBER 2007 VOL317 SCIENCE reduction of sulfate, yielding “S-depleted hydrogen sulfide; this signal can be traced back 2.5 wo 2.7 billion years. Sulfate reducers, only diseriminate the isotopes at sulfate con- ‘centrations above ~1 millimelar. The isotope signal thus documents asulfite-rich ecean (2), “The absence of this isotopic signal befare billion years ago (3) could mean that sul- fat levels were low or that sulfate reduction had not ye: evolved. In sapport of the former ‘explanation, Shen ef al. (4) have reported evi- dence that sulfite reducers existed 3.5 billion years ago. The authors found S-depleted sul- Fideassociated with abarium sulfate bed from North Pole, Western Ausra The results of Shen eral (are one ofthe two oldest reported datings of @ specific ‘energy metabolism. More recently, methano- _genesis was dated to the same age (3). Carbon ‘sctope analysis has provided evidence for UUtrviokt tint 1,50, a3s<0 + # ‘sotope data from Australia provide evidence for the existence of bacteria that used lementalsultur in metabolic processes about 3.5 billion years ago, biological carbon fixationby 3.8billion years ago (6), but carbon fixation may be linked to different types of energy metabolism, Philippot cr ai. have now repeated the sulfur Isotope analyses from North Pole with new samples, finding slightly more “S-depleted sulfide than the previous study. They also extended the analysis to §'S, which gives information about the sulfur source. The results show thatthe simplest explaration is, not always the right one, For elements with several stable iso- topes such as sulfur, isotopic fractionation Jn aqueous processes—including enzy- matic ones—depends closely on the mass differences between the isotopes; for example, the fiactionation between #8 and. 53 jg O.S1S times that between *S and °S. (). tn contrast 10 this mass-dependent fractionation, atmospheric photochemical 2 N04 fe ee fp aes scfoplted pte Fes, a5 >0 Sue sspopationte ‘nsew Elemental slats isproprtionated by microbes, wih masé-dependent fractionation into °"S-depleted hydregen sulfide and "S-enriched sultate Hydrogen sulfide precipitates a "depleted pyrite on te surlace ofthe Gus, whereas the sllae i duces no thelarge sutace pool. unwnscioncemag.orgreactions may result in mass-independent fractionation, seen as deviations from the fixed mass-dependent ratios. Sulfur species from sediments older than 2.5 billion years exhibit large mass- independent fractionations, which are not found in younger sediments. This indicates thatthe early sulfur eyele was influenced strongly by atmospheric reactions (7). ‘These reactions likely involved photolysis of voleanogenie HS and SO, by ultraviolet radiation, leading to the deposition of elo- ‘mental sulfur with a positive "5 anomaly and sulfate with a negative ¥S anomaly (see the figure) (8). Ifthe *S-depleted sulfur in pyn North Pole were produced by sulfate reduc. tion, it should carry the samme slightly nega tive ®S anomaly as the sulfate from which it formed, Instcad the pyrite carries the posi tive 'S anomaly predicted for atmospheri- COMPUTER SCIENCE cally generated clemental sulfur, Only one inown abot or blological elementals fur tramaformation generates a substantial MS depletion a fow temperature: the bacte- tal dsproportionation reaction 48° 4HLO—> 3HS + $0," 421 Justthree pure baci cultures tha grow by sulfur disproportionation are known (9, {0p These bacteria are the masters of simple rgani lif, For example, Deslicapsa sifoesigens needs only water, sll, CO and morgane muren's for grown (Df otixins energy fom the hydrolysis of cle- mental lf, thioslfate, or sulfite sd fos anacrebicallyas long te concetr ton of H,$prodicedis kept low (7), "The sii eavirormental fequlrerens of kon salir dproprtonaing baci an ano ewironment colde than ~40°C with near neutral pH and low hydrogen sulfide con-_ centrations (9) may help clay dives Cultural Modeling in Real Time ¥.8. Subramanian S Sisiressey eres and og consogawos of he actions in201- US cmmanies we tale ib sere epee “hens ate deals with local tihesmen “og to prevent the eseape of bin ‘Yovute ¥ pe ‘Social networks Laden, even though reports indicate that they had excellent intelligence on where he was. The ay afterthe United Nations approved a resolution calling ‘or the deplayment of 17,300 peacekeepers ‘to Sudan, the Sudanese government launched ‘a major offensive in Darfur. In December 2006, an unexpectedly large group of protest- crs in Kyrgyzstan marched against the deci sion by their government to enter 2 debt- relief program under the auspices of the World Bank, Accurate forecasts depend critically upon the ability to build behavioral models of the people and groups involved, Social scientists {ie ator ee Compt Seance Onpartnetane the Uniorsty of Maryond Intute for kénced Compas Suche, Urey Hayand, Callge Pak, MD 20742, USK Ena ngs und as wwurnsscioncomsg.org Building 2 real-time sociocultural most bac timely, ‘eloaet eat have traditionally constructed cross-cultural models by conducting either insperson or ventten surveys (/),0F living with such groups (2), and then hypothesizing and test lations in collected data by means of various statistical models (3). None ofthese strategies will work in countries riddied with conflict ke Iraq and Sudan today, Old surveys are ely to be outdated, Questionnaites and sur- vey respondents may be influenced by the imate under which the survey is taken, In con flict situations, data must be gathered with real-time methods. However, building behav- jeval models in real time is particularly di cule (see the figure). Computational social models may offer SCIENCE VOL317 mT > Lean “eteining coeitone” \ \ at gathered from mary sources i sited for elevantinlrmation. Modeling scfiware takes this information to extract “determinant conitions” or svations that cou lead t possible bersot a group, The models can forecast ico actions are refine those forecasts nth feebac fom uses PERSPECTIVES q interpretations of the North Pole paleoemiron- -ment(/2, 13) However, caution needed with such conjectures: This group of bacteria has received so litle attention that other species ‘with different environmental preferences may have escaped the microbiologiss' notice. References 1 BPMppotet a, Scene 37,1834 2000, 2K Stabe ta, Sone, 27722002) 3. DLE Gand Rate 396, 45003950 4 Shas BBO. Cal, Rt 20,77 2009, 5 Ueno, Metre 440,516 (2006. 6. Slo, None 333,313 2988, 1. [famatarh Si M Thenen, Sr 29,756 200) 8. [fr Ang Ea an Lt 233, 1200, 9 Kner W esd 8. Tp, oat Enon irate 6, 19 0950, 10, AY.Obseboa CA Fond BML bo, Gomiceick J. 39,u7 ann. 2, 0-E Cl 8. thandbup Since 266, 1072 898, Bid | Dany, Solinewcegy 37,207 190. roazerdenescen? Computer models ate being developed that «an help policy-makers predict the behavior of political, economic, and social groups. Dovelop forcast: —, ~~ ——< > Provide feedback <—— of men: the best solution in cases where conventional data gathering is not possible. Tools such as The Resource Description Framework Extractor (FREX) (4) use socio-cultural political-economic-religious (SCPER) vari= ables provided by social scientists in conjunc- tion with ocher data sources (¢., surveys), if available, and automatically extract relevant data from news sources, blogs, newsgroups, and wikis i.e. collaboratively written infor- ‘mation sharing sites) Othereffors such asthe KEDS project (5) extract variables from spe cific news sources, The SCPER variables can include financial activites, violent event information, of political relationships. The souce data can be automatically analyzed to 14 SEPTEMBER 2007i PERSPECTIVES 1510 recognize spikes in such activities, providing “early warnings” of potential confliets. Un- like past methods, these methods do not require previous knowledge of the groups being investigated. Past behavioral models [e., to forecast turmoil in Indonesia (6)] were painstak- ingly built by hand. Building behavioral ‘models in real-time trom such data is achal- that is only now being addressed by software development, ‘Systems such as the Cultural Reasoning Architecture (CARA) (4) can be used to study the Janjaweed in Sudan (a militia of Arab descent engagedin the systematic useof mass rape and violent attacks against Muslims of noneArab descent in the Darfur region), Data may include parameters that indicate increases or decreases in these actions. In another example, the probability of suicide attacks by the Lebanese Shite group Hez- bollah when they are not engaged in rocket attacks and car bombings depends upon ‘whether Hezbollah was using education and propaganda as a major part of their strategy. When they were, the probability of suicide attacks was around 47%, but when they were not, the probability shot up t0 80% This is one example of a rule automatically discovered by the CARA architecture (4) with the MICROBIOLOGY “Minorities at Risk data set (7). The nurnber of possible determining conditions is enor- mous, and a human analyst could easily miss ‘an interesting hypothesis. Moreover, because programs like REX provide a flood of data (45,000 pages per day), sophisticated alzo- rithms are needed. Classification algorithms (3) to demify conditions that neatly separate desirable situations from undesirable ones (eg, violent actions versus more acceptable forms of negotiation) offer an excellent start- ing poin, slthough sabsamtal scaling to huge data setsisrequired. ‘We can use these methods to model tenor groups, political parties, US. allies, compa ries, oF regulatory bodies. The final step isto forecast how members ofthe modeled group may act once a st of determining conditions has been found. Even if we study just 1000, actions, thercare 2" possible sets of actions that a group might take at just the next time point. This corresponds to about 10° possi- ble setsofuctions. Current ystems such asthe stochastic modeling agents inthe CARA (4) architecture can estimate the k most probable sets of action the opponent might take in a few minutes when 10°” sets of actions are imolved, The ability to access realtime infor- mation on these topics, to rapid'y analyze the le actions that interested partis might Sizing Up the Uncultivated Majority Marcel M.M. Kuypers cupling the identity of microbes with their activity in the environment re- mains an important gap in our bility to explore microbial ecology, The develop- ment oF techniques to quanti the metabolic activity of single microbial cells has beenespe- ly challenging, mostly due to their small Microbiologists are therefore excited about a new high-resolution imaging method. called multi-isotope imaging mass spectro metry (MIMS) or nanoSIMS, which can help decipher what individual microbes re “doing” in the envirenment, On page 1563 ofthis issue (J), Lechene and colleagues apply MIMS to idemtify a symbiotic relationship between a nitrogen-fixing bacterium and an animal host. The techniques poised to reveal the meta bolic diversity ofthe planet's microorganisms, ‘he author at Be Man Plane atte for Marne ‘cotily, Cebusstsse 1, 0-28359 Bremen Germany, Emalrmkiypesgncrireren 14 SEPTEMBER 2007 VOL317 SCIENCE 99% of which has cluded cultivation (2). MIMS can determine the chemical, radio- isotopic, and stable-isotopic composition of biological material down to the submicrome- ter level 3-6), By exposing microbial com= _munities to substrates that have boca labeled ‘with stable isotopes, MIMS-based imaging allows visualization of metabolic activity in single cells. Moreover, nutrient uptake rates and faxes can be quantified. Lechencer al, used MIMS te quantify nitro- ‘gen (N,) fixation by individual bacteria that inhabit the gills of the shipworm Lyradus edicellaws. L. pedicellans sa wood-eating ‘marine bivalve with ile nitrogen in is dict and _must therefore rely on other nitrogen sources (), Previous studies reported N, fixation for intact shipworms, as wells forpureculturesof bacterial symbionts isolated from shipwerm. gills (7,8), but neither the site of fixation nor whether the fixed nitrogen is supplied to the ‘host cold be determined. Lechene etal. grew engage in, and to determine how best (c.g. ‘with methods of game theory) to respond, will provide a key tactical advantage to organ tions that are entering foreign cultures with goals ay diverse as stopping terrorism or improving corporate profits. References 1. AC eae fae Khoon Ean anébonk of adsl nd Orgel 5 Caloy scach Mesos, 5 Rage. (Eadel New Yo, 2002p. 236261. 2 D Etat fore ian Centos of teAtan iad Uni. Calta fe, ete, 2002) 2, RSet in Goneterel Heo fx hcraina Cue Restston nd erie, Tap (aver, bore, 2008 9. 61-18 4 We Sabramarln eta EEE ne S22, 2 (Goan. 5. PShod Simp, 0. Genes aber oreere te hte Seti Cnicenceon etna Wan Seat: Cnt Recacha Ub Con Reid ana Pees Upp, Swede, 8 ard 9 Jute 2001. 6 [sont AP 5.0m, Bad, apt peared tthe easton cles fcc ert, Wont, 7 221 Mar 200 >. Valet ¥ Asal Cs, A Pa Mice The se of alee by Epo Oceans he Hidde fst Ronchi ato Gavin er he Siu Taaise crd Repro, Colece Pak MD, 2007 matt utedupuslatoes ‘eseunbietvene7o2S when pk 0. Lane EE erst St Man, "a0 99, 0.2126 1140006 ‘Are imaging technique allows the metabolic activity of single microbial cells tobe (quanttie in environmental samples shipwormsinseavater containing nitrogen sas enriched inthe rare stable isorope "'N and used MIMS to measure "N incorporation in sym bions and shipworm tissue (se the figure) The incorporation of #'N was determined by comparing the quantitative mass images of 22CHN™ and BCEN — produced by Bomband- ment of tissue with a essium ion beam—to measure the increase in BN/N ratios relative to the natura abundance ratio (0.00367), ‘Transmission elton microscopy ofthe same shipsom gil issue wasusedt identify bacto- ria and host cells. The combined data provide the first rect evidence for in situ fixation by bacterial symbionts and demonsirat that this nitrogen is wed by te shipworm bos Untilthe work of Leshens ea, it had not been pessible to quantify the incorporation of nitrogen by individual N,-ficing microorgn- imsorto map the fatcof fie nirogenin the microbial environment. Other methods cur- rently used either do not provide single-cell unwnscioncemag.orgy Baceroeyt containing acer Gem aypmern ‘De baci in gil ie ilrogen forthe shperm? gown in tt, ‘Anew window on microbial activity. The incorporation of 2 stable isotope Ina a miced population of cells (animal cells and bacteria) is determined by comparing two quantitative mass images (#CHN" and resolution of, like micro-auteradiograply, require that microorganisms be fed radioac- tive labeled substrates). The uptake of rod labeled isotopes ditectly Tinks individual microbial cells o their activity in the environ- tment, However, because this approach requires radioactivity its use is imited to el 8 mens that awe a radioisotope with a suitable halflife 1 day: for example, #C and?) and exchides the study of other slements such as § niogen. MIMS, on the other hand, can be used to measure the disibutin of ary stable isotopeas wellas any raiosstope witha su able hal-ife, Hence, the approach used by Lechone era holds great promise for study ing symbiont-hos ieractions and microbial activity inthe environment. Combining MIMS with Muoressence in sin hybridization (FS 1) is an even more ASTRONOMY Volker Bromm hat isthe nature ofthe dark matier that is believed to dominate the sictire of the universe at larg seals? How did the cosmic dark ages end ‘when the fist stars lit up the universe again a few hundred million years after the Big Bang? These questions might be intimately related, (On page 1327 ofthis sue, Gan and Theuns (1) presentnumerical simulatins of cosmological ‘sructure formation in the early universe. Their simulations demonstrate how sensitively the formation ofthe first stars depended on the Aesciled properies of the sill mysterious dark matter. The macrophysics of eanly star forma tion might thus hold important lessons forthe microphysics of exotic elementary particles. i i 5 ' : i : 2 i i 8 i i ‘he ahr in he Deparment of Aono, Univer Teas, Rusty 178/12, Sk. Ema tromaaea Hutcaceds wwurnsscioncomsg.org Ces bear 2 : J + : F ep mires \ othe obtained by powerful technique for identifying and char- ‘acterizing single microbial cells. FISH uses ‘luorescent labeled probes that are specific to the organism of interest and that bind :0 the intracellular 16S ribosomal RNA (2), Replacing fluorescent probes with isotopi- cally labeled (stable or radioactive) or halo- ‘genated probes wouldallow individual cells to be ciectly identified (by probe Hybrid zation to targets) by MIMS (0) The hybridization procedure is essentially identical to that used. ‘or FISH, and the same probes canbe applied ‘By combining this probing technique with isotope labeling of subsite, one ean assess the metabolic activity of cells and simultane ously identity their phylogenetic characteris» ties during a single MIMS scan. This ap- proach links the identity of microbial ells to ‘heir in situ activity. MIMS is uly ai From Darkness to Light According t9 the standard model (2), tar formation in the early universe was very dif rent fom the present, Stars today form in giant clouds of molecular gas and dust embed dod in the disks of large galaxies like our Milky Way, whereas the first stars emerged inside “minihalos,” agglomerates of primor- dial gas and dark matter with a eral mass of a zillion times that ofthe Sun, ‘Another difference arises from the initial absence of elements other than the hydrogen and helium that were synthesized in the Big Bang. Gas clouds today can efficiently cool via radiation emitted by atoms, molecules, or dust grains that contain heavy elements Because the primordial gas lacked those coolants, it remained comparatively hot. For _gravity to overwhelm the higher thermal prese sure, the mass of te frst stars must have boon, langer as well. Numerical simulations have led SCIENCE VOL317 PERSPECTIV acer HN for hat stipe smutisotope imaging mas spectemety (IAIN). Te increasein NAM ratios relate tothe natural abundance aio can then be measured to ently the fae breakthrough, whose application is only just beginning to yield information once corisid= ered inaccessible. References, 1 Chueh Ltn, Mali D.L Ot Scene 31,1563 200. 59,13 0995) 3. Lota PL Webee ML Langa, 0. hen 56 ower ace, 3948 200) 4, Worse a, Sence346, 14000007, 5. RPopct ol SWE) 1, 354007. 6 Cethnee a il 5, 2002000, ve [Lak Sere 487, £52 079, Ball, Dre, Scone 22, or ibaa. JO. Neaed . Wagret 1€ Maral e203, Gaon. 10, MLL Mapes 8.8 Jerse Evie. iobok 9 61200, [Asupercomputer simulation shows that matter in the early universe might have formed dense Filaments before collapsing into the fist sas, most researchers to believe that the frst stars \were predominantly very massive, typically a FR hundred solar masses ‘The emergence ofthe frststarsfundamen- tally changed the early universe at the end of the covmic dark ages (3), Owing to their high mass, these stars were copious producers of savy chemical elements that were rapidly dispersed by supernova explosions. They also produced many ultraviolet photons that were energetic enough o ionize hydrogen, the most abundant element in the universe. Thus began the extended process of what cosmologists call “reionization” (see the figure), which transformed the universe from 2 completely cold and dark neutral state into the fully tone ized medium of today. Observations of the polarization in the eosmic microwave bac ‘ground (CMB), due tothe scattering of CMB. Photons off free electrons, place constraints 16 SEPTEMBER 2007 JES q 15111512 Cosmic renaissance. This supercompster simulation shows a primordalstarf 100solar masses, formed inside a dark matter minihale and surounded by a bubble of ionizing radiation (light blue). The bubble is embeded inthe stl neutral cosmic gas (neblike structure in shades of purple and yellow. This frame depics the nal sep in he process of cosmic reonzatien. ‘on the onset of reionization. Measurements ‘made with the Wilkinson Microwave Aniso- sropy Probe(WMAP) indicate that about 10% of the total signal was likely produced by the First stars (4). ‘Our picture of how the first stars formed and ow they affected the evolution ofthe cos. amos assumes that dark matter is made up of ‘weakly interacting massive particles (WIMPs) Such particles are predicted by several theories but are as yet undetected because they interact with normal matter only via gravity and the weak nuclear interaction. A plausible WIMP candidate is the “neutralino,” the lightest “superpartn ymamettcal the- Supersymmetry postulstes that for every known particle there i a Superfan, thus effectively doubling the z00 of elemen- “arypartiles, Mos of these superparticle that were produced briefly after the Big Bang are le and have decayed, The lightest of ther, however, could not decey into any other particle and thas would exis today The neutralino is expected to be rather massive, having toughly the mass of hur ded protons, and so it would move compara ively slowly (it would be “cold”), Such cold dark matter (CDM) particles preserve any density perturbations from the very eatly uni- 14 SEPTEMBER 2007 verse, Tosee this, considerthe opposi ‘which the dark matter woud be “hot! to very light particles, Streaming and such hot dark matter could not be wapped in small density condensations, The fist sructures to form the universe would then be larg sive systems, whereas in CDM mod scale structures would survive and would be the first emerge CDM models predict thatthe first stars formed in dark mater minitsles. In turn, the evolution of the primordial gas falling into ields stars with roughly a 1a of the Sun, Gao and this CDM-based hhandred times the Thouns are now ch standard view. They which the dark matter is slightly less cold, termed “warm dark matter" (WDM), WDM ree with CDM models on large but they lead to drastically different predictions for the small scales that ane relo- vant for the formation of the first stars. In the WDM scenario investigated by Gao and pours, there are ao minihlos that could host the formation ofthe firs stars instead the pri ld collapse firs ino massive mtary structures. The completely difer- story experienced by the star-forming vou 317 08 would likely result in stars with a different distribution of masses, po sibly skewed toward somewhat le The simulations pre the massive sta sented he formation ofthe actual stars, render ing any conclisions about the precice stellarmasses tentativ How do we docide betwoen the CDM and WDM models? One way is to compare the predicted strength of the CMB polarization signal wit the WMAP measurement (6). Ifthe sup: pression of small-scale features in WDM mov duce enough scenarios canbe ‘arnot yet resolv sis too severe t0 prox cided, A comple tocmpirically probe the mess and mass disaibution of the first stars is to hunt locally for fossils of the dark ages, low-mass stars in our mentary state Milky Way that contain only a tiny amount of heavy elements. Th would carry the imprint of the first stars that produced those elements with an abundance pattern that sens tively depends on mass (7, 5). Again, the simulations are not yet detailed ‘enough to make predictions with the required degree of precision, but the game iscleariy onnow This new frontier of connections between particle physics and the first stars offers intriguing possibilities. If dark matter particles could decay, orf they were concen= w occur, then heating of the primordial gas ‘would result, with the potential to modify sar formation (9, 10}, Cosmology has a huge stake in the scarch for possible dark ‘mater candidates soon to be carried out tthe Large Hadron Collider at CERN. 40 that annihilation reactions could References and Notes DN Spree Ash Sup er 70.377 Ginga Manoel re, Pye ap. 27 195 1998 ‘Aeeephys 594 12902). 7. 18ers, 8 Ont Ar 48,521 09). A Feb LL Jesen ¥ rom Ml ot Aton 9. E Rnmort MMi A Fer, Mon. Na A Aten fey Aton Ato SCIENCE inwsciencomas.org71 Complexity of Coupled Human and Natural Systems Jianguo Liu,”* Thomas Dietz. stephen R. Carpenter,? Marina Alberti,* Carl Fotke,5* Emilio Moran,” Alice W. Pell," Petar Deadman,’ Timothy Kratz,” Jane Lubchenco,’” Elinor Ostrom ® Zhiyun Ouyang,” William Provenche,}* Chaves L. Redman, Stephen H. Schneider, william W. Taylor’ Integrated stuies of coupled human and natural systems reveal new and complex patterns and processes not evident when studied by social or natural scientists separately Synthesis of sx case studies from around the world shows that couplings between human and natural systems vary across space, time, and organizational units. They also exhibit nontinear dynamics with threshold, teciprocal feedback loops, time lag, resilience, heterogeneity, and suipt s, Furthermore, past ‘couplings have legacy effets on present conditions and Future possiblities ‘upd human and natural ystems ae in tegrated systems in which people intert ‘with natural components. Although many ‘sues have examined humansture interactions (5), the complexity of coupled systems has net been nel understood 6,7). The lack of progres is largely ducto the tudticnal separation of eologi- px feedback loops. For example, local residents in Woiong use forests as fuelwood for cooking ad heating As forests near households were de> pleted duet fuelwood collection (76), local wes- ‘don fad to collet fuchvood from areas far away (/7) Because these forests are bamboo forests (bit for the endangered giant pasa) sid the bamboo in the foros 6 the staple food for the panda, fuclvcod collection has led 10 substantial deterioration in forests and_ panda habitat (16) To prevent fiber degradation and restore panda habitat, dhe Chinese government began implement three major conservation polices several years ago, which help both local residents and panda habital In Kenya, local residents convert forests into cropland inksn- sively cultivate land withoutsupplyng additoral ‘uteri, in sone eases for mor than 100 yeas, Soil degradation with the resulting decreases in crop yields and greater food insecurity hastens conversion of remaining forss to agdculture. Similarly in Altamira, 255,739 hectwes (ha) of forests had been convened into pasture and cropland as of 2003. As scl quality declines, fonilzers must be applied, crops are shifed to hese with lower autent ecuirements, or more forests are converted into cropland (here wore still 136,913 ka of forested area in 2003), Feedhack besween human and natural 9S tems in the agricultural and tourism sectors of developed countries in many ways similar to fondback in developing counties. For example, local poopie (76,000 in 2005) in Viatenriket be efit rom ecosystem services that are the result oF Jong-tam hunan management ofthe agricultural landscape. In Wisconsin, esosystam ccnitions act tourisn, which she mainstay ofthe econ ‘omy, but evoraric development and ecosystem «exploitation from tourism often degrade the qual- itos that atact tourists, ‘The ecological and socioeconomic pattems sd processes in urban coupled systems ae die ferent from those in rural areas. They are me- dlisted by factors such as the urban form, built infrastusturo, and locaton and consumption pret ferences of heterageneous heusshods and busi- ness For example, in Puget Sound, 3 distinctive spatial leterogencty can be observed across an tutan (0 rural grdient in relation to diverse development pattems (18). Land-cover changes {influence biophysical processes (eg, w2ter par fication) and scam biotic integrity (15). Furor: nce, changes in lad cover due to development in tum aff land valucand real estate markets, as evidenced by ves of realestate having up 10 8 6.5% premium associated with forest cover (19). 14 SEPTEMBER 2007 15131514 Dynamics of lurman-nature systoms are in fluenced by many fotos, including government polices and contextual Facts in which local processes ore shaped by largerscale and ulti- mately global-scale processes (20). Beth markets and governance can cause decisions mde in one ‘lacs to affect people and ecosystems far away. For instance, economic opportunities in cities attacted many Tocal residents fom Wolong -WoFK in ete inthe past several years, dhs re- ducing fuelwood collection and coasunytion. ‘Compared with the migrant workers in cities from Woloag, however, more than a thousand times more tourists from around dhe world in creased the demand for fuelcod through con- suming local products, whose production may ‘require fuelwood and elt. Nonlinearity and Thresholds ‘Numerous relationships in coupled systems ore ‘nonlinear. {a Wiscorsin, for instance, allen toes that provide critical fish habitat in lakes and swam dsically decrease when housing den- sity exoeeds about seven houses per kilometer of shoreiine (Fig. 2). Bind richness in the Puget ‘Sound landscape with single-family housing and fragments of native forest increases nonlinearly ih forest cover and peaks when 50 60% of te land is frestod (Fig 3) (2 Thresholds (iansiton poins between ar- fat sats (22)} ae common fom of noalin- catty In Vane, an iatentonalpatsipatory procs mobilzadsskeolden yng the gran ‘work fora shift from conventional management 10 adaptive co-management (23). Cultralvahaes and cavzonmentl concems prompted eal sake- holds to build new knowsdee, develop ne vison and oa and cet ne soil natok The west ofthese community acivites was a few and more suiable govemance system of sdepiveco-mmagenent othe andcape. System bohaviow shit from one ste to an- ‘oer overtime (empora threshold’) and eros space Spatial resol). tami depicts ater- poral resold. wheres Wolong demnstates a sot theshold, Deforestation rs Alenia atch during he ist 5 07 year ofsetdement and then doers rapidly, fn Wolong, 2s the ds- tance between locations of households and fael- vod collection sites snereases. pond habitat decries, reahing a minimum af a distance of anprosinstely 1890 m (7), When the distance ‘etcen houssholds ard fuehvood supplies is sal the total are for faehvood collection is Northern Highland Lake District (Wisconsin) (© Centerec on Vias County Wsconsin. USA. 9 5,300 kr {9 65,00 parmenontresidan's (2000) {@ 7,600 lakes ard socond growth ost (Tourism end fret products ‘9 Wisconsin Dopartvent of Natura Roscurces, lake asscciatens tnt! government Central Puget Sound Region (Puget Sound) © Seatio, Wachington, USA 16281 km? ssnall and thus panda habitat is better potted, ‘When the distance is large 1800 m), fuelwood collection is scatered throughout a larze region snd affected areas can recover riatvely Quickly. ‘Whcn the distances approximately 1800un, local residents’ fuehvond demand is mist by cuting ‘mest available toes and causes more habitat lass un. Surprises When complexity is not understood, poople may be suprise 2 the outcomes of humane nature couplings. For example, smelt (Osnarus ‘moras was initially intrxkacal to Wisconsin 8 a prey species for game fish such a5 walleye (censeedion vireun), but stick ate juvenile walleyes leading to los of walleye poplztions. In Puget Sound. growth management policy hs caused urban dersity to intensity inside the turban growth bourdary while unintentionally faciiting sprawl outside the urban growth boundary. ‘Conservation policies can also generate un intended porverse results. In. Wolong, for ia- stance, high-quality panda habit degraded faster aller the area was established asa reserve than before the reserves creation (24). To prevent Kristianstads Vattenrike (Vaitenvike!) county gverninent, Area near Altamira (Altamira) Para, Bast L057 kn Kenyan Highlands (Kenya) @ Enbu Dstt in Eastorn Province: Veiga Oitiet in Wostem Province, Kenya 728 ko in Emu, 589k" nViiga © 278,198 peoplein Embu, 496,883 pecule in Vinaa (1999) ‘© Hichlands attade +1500 mas! {© Manty agreiture, seme oftiarm ampioymant © Preuireal and nano governments 1 Scania county, south Sweden @ 1.100 km 1 76.000 poopie (2005) © Gomiurban wetland end acuta landocapes © Agricuture and well-developed tourist fad servico dusty @ Dverstycflocal groups, eco-museum, ‘municipal and ccunty govenmenis, Wolong Nature Reserve (Wolong) @ SicuanPresince, souwestern Chin 9 2.000 ue {@ 4.500 poop (2008) 8 Bamboo forest. gant parces, and 6,000 cthor annals and plant seces (9 Marly aycutue, sme otttarm empeymen ‘Wolng Nature Reserve Adrinisration, ovine andnatanal governments Fig. 1. Map highlighting major attibutes ofthe sx coupled human and natura systoms Cocation; spatial extent; population size and ecological, economic, and administrative attributed. To save space, short names within the parentheses represent the coupled systems. See table 1 for more detailed descriptions. 14 SEPTEMBER 2007 VOL317. SCIENCE wxwscioncemsg.org_; . : a |. i Seal ils, eal ° % 9.9%, of FS" Bote «© 3 te i House dealt (r20288/km) United States. modified from (38), with permission} further degradation a natural forest conservation program was inuoduced in 2001 for local es- dents to monitor legal harvesting. Unexpocted- ly. a large ruber of ew ousaholds formed in 2001 because many households decided to split iewo smaller ones to more effectively capture subsidies (20 to 25% of the average bouschold income) given to ousohalds part of the pro ‘gram. The houschold proliferation and reduction in household size (numberof people ina house- ‘hoid) increased demand for fusivood and land for house construction (25), Some eccsystems can only be sustcinod ‘Hough husran maragerent practoes, whereas ‘many conservation efforts provide such burnan interference. For example, the wetland ste under the Ramsar Convention (an intemationl testy for the conservation and sustainable use of wot lands) in Vatteniket was set aside For conserva ton purposes but the wetland became overgrown vwhen giving was Hed. This unintended con- sequence led to an understanding of grazing as ‘essential to mainisining this wetland system (23). Legacy Effects and Time Lags Legacy flees are empacts of prio human-nature couplings on later conditions. Among the sites, legacies vary in duration from decades to ‘centres. The shortest legacy is im Altamira, a froniigr area whore the land tenure system im- posed by the government in 1970 sill shapes the present spatial patem of land-oover change, human population distribution, and human Activities. The longest legacy isin Vatenrkot, ‘where the landscape es been affected by human actions such as using wet grasslands over Ihundreds of years ‘Legacy durations in the other sites fall sompwshervin between, In Wolong, curent forest wwscioncomag.org. 2. Therelationship between fish hatitat ogs per hlameten and house densty in the Northen Highland Lake District of Wisconsin, types in areas at lower ceva ‘ons (1200 9 3000 m) are shaped by forest harvesting thre wo nine decades ago, iro duction of a keystone species fen resinicture fish population for decades or longer, as has been demonstrated in the Wis: consin study area which stated fish stocking in the 1930s. Long-term (up 10 100 years) ‘continous cutvaton in Kenya thas decreased crop yields, wath ‘most of the degradation oecur- fing during the first 15 to 20 years afler conversion from fest w agriculture. In Puget © Sound, landscape pattens ae influenced byinfastucuarebuilt decades or even a centr ao The ecological and socio. seonomis impeets of human nature couplings: may. nat be immediately observable oF pre- dictale because of time gs between the human-noture interactions and the appearance of ecological and sociossonomic consequences. In Kenya, there isa ime delay between investment in soil improvement and. aiereases in income. In Vaitearket, the city of Kristianstad stopped taking i drinking water from the Helged River in the 1940s because untrated industial and Ihowschold sewage had accumu: lated. several docades caster Disturbances to groundwater ‘quality can take « Tong time © appear “downstream” because ‘groundwater movement be: tween adjacent lakes can tke ‘centuries. In Puget Sound, 220: logical effcats of the Growth Management Act adopted in the State of Washington in 1990 could not have been ob serve in es than 8 years 2). “The length of lags abuts. ble to a single cause may vary {or different indicators; con- versely, diferent causes may hecome apparent exer dlleent time periods forthe same indi ‘ator. The former can be seen in ‘Altamira, whore changes in erp Prices quickly affet plning of annuals but effcis on planting (ce abandonment) of percanials (such as cocoa and black pepper often are delayed. As tothe liter station, changes in the price of clewcity {quickly alfect pads habiat in Wolong because ‘of sharp changes in ficlwood demand, but spacing of bins within households has a much slower effect (27). Enorgy for cooking is needed iy and Dctuatons in the price for clocicty may quickly force local resents to use more SCIENCE VOL 317 oo REVIE! fuelwood (dus destroying, Forests and. panda Ibitat, whoreas it takes a longer time for chil- dren to establish new houscholds that increase demand for energy, Resilience Coupled systems have different degrees of resilience the capability 0 retain similar sic- tures and functioning after disturbances for continuous development (10, 28,29). Resience can be afleeted by many factors. In Wong, for example, lager arezs with fistgrowing. Woe species are more resilient to fuelwood collection than are smaller areas with slower-growing toes. In Konya, remittnces from relatives employedin tuan areas minimize food insecurity duc crop fares caused by croughis and poor soil erty, Human intervention also plays a key role in ‘maintaining resilience. For instance, in Vatenri- et, sustaining the reslience ofthe wetland land- scape requires grazing by cal and incentives to smaks grazing economically vile, Parally be- cause of the asions of environmentalist, Puget Sound is still home to one ofthe lst intact old growth foress in dhe United States despite rapid tubanizaion. In Wisconsin, social-coological resilience comes from the good cendition of ‘many ecosystems: the intention of Native Amee- ‘cans to manage their landsand lakes sustainably the mosaic of tba, private, and state onnership: and innovations in exosystem management by various stakeholders (tbal governments of Native Americans, lake associations, formal Large forest oz os 05 os Proportion of forest within 1 ka? vo 12 FFig, 3. Change in avian richness with progressively more forest, less human setiement) in the humar-influenced landscape in Central Puget Sound regen of Nashngton, United States. (modified fiom @D, with peaission] research organizations, and nongovernment organizations) (/2), Heterogeneity ‘Human-sature couplings vary across space, time, snd organizational units. The seciosconomic ditferenees anvong. people in Wisconsin lead to diferent choices and behaviors, which in tam result in very diferent ecological outcomes than 14 SEPTEMBER 2007 1515Bex 1516 NEW ‘one would find were everyone to have the sme preferences for ecosystem services, In Altamira, different setlement cohorts follow similar wajcc- teres of lad use, but the magnitude of changes in important yaiables ike rates of deforestation ‘varies as product of exogenous and endogenous factors (2 local, gional, and global political economy) (30), For the Kenyan highlands, itis common to find families with soils of diffrent ‘quality and a 2 resol, difirent erp yields Coupled human-raturi! systems are not state; they change overtime. Although the fur ‘man population sizes have increased in all six study sits over the past several decals, the resuitant ecological impacts have differed, n the Kenya study area, human population size has doubled over te past 30 years, causing & marked ‘edtion in Zam size. Smaller funn size has led to growing mize durng both miny seasons 10 ‘meet family demand, but this practice has accelerated the rite of soil degretation and in- ‘teased poverty. An increase in reereatonal land use in Wisconsin led «9 a 4.5-fold increase housing density (Irom 3.7 to 172 unitska) from 1940 v0 2000, For Puget Sound, besween 1991 and 1999 land area covered by dovelop- ‘ment increased by 620 km? GI.5% increase) ‘while forest cover doclined by 714 ka (10.3% decline (269) Temporal changes tke place not ‘only side a coupled system, but also Soros its ‘boundaries. In Wolong. aapidyinereasing num- ber of domestic and foreign tourists have made the system much mow tightly coupled the ‘ational and global economy, Spatial variation exist nal coupled systems. Forexample, more fielwoodis collaied in areas ‘of Wolong with exsy access and lite enforce- ‘ment than in forested areas with more challenging topography or stot enforcement. In ‘Vattenrikel, habitats and management practices, local stewardship associations, secial ntworks, and mulilevel institutions vary ares the ane scope (JT), Landscape heterogeneity of Puget ‘Sound increases with the dewree of urbanization, Dut differs substantially within the region Acpending on urban land-use patterns, intkar stucture, and spatial disibuton of activities (18). In Wisconsin, poople have preferentially setled around lowerelevation lakes, which tend to have riverine inputs, low w moderats dis- solved organic earbon, low wo moderat: nutrients, and reavely diverse sport sh cramunites (31). In Altamira, fertile soils permit eutivation of ‘cea and sugar cane, whereas on poorer soils ‘psture and manioe cultivation are morecemmen. Conclusion and Outlook Ress such as those reviewed here benefit fm and help advance the integration of ecological ad socal sciences, The approaches used andthe 14 SEPTEMBER 2007 VOL317_ SCIENCE results from these stds can be appliod to many. ‘other coupled systems at local, national, and ‘ekbal lvels For instance, the finding that the ‘number of households increased faster than the human population size in Wolong over the past thee decades has led to the discovery that this tread is global and is particularly profound in the 76 counties wth biodiversity hotspxs (25). ‘The Lake Futures Project (32) in Wisconsin was A protoype used to develop apprcaches foe the llennium Ecosystem Assessment scenarios 3) ‘Compesison ofthese studies provides impor: tant insight into diverse complex characteristics that cannot be obsorved in a single sty. The ‘ypes of supries found in the case stcies dif, although all ef ther orginated from the iiwer- actions between bun and natural systens All six studies have demonstrated legacy ef, but legacy durations varied from decades 9 ecntu- Fie. Bocause of the independent nau of these studies, information from one study is not neces available in or tansferable u other studies, To increase the extent of generalizing from eas studies, fume research cn coupled systems mst inchide not only seperate site- specific stuies but also coordinated, long-em ‘comparative projects seross multiple sits to cap- ture 2 fll spectrum of variations (14, 34, 35). Furthermore, all the studs in this review foeus fon inteeetions within the system, rather than interactions among diferent ccupledsysiers. AS ‘skbalzation intensifiss, there are more intrac- tions amomg even geographically distant sysems and cross scales (36, 37) Thus, itis critical to rave beyond the existing approaches for study ing coupled systems, to develop more compre ‘hensive portolos, alto bu an intematinat network for interdsciplinary research spanning local, epional, national, and lobal ves. References and Notee 1. G Pe Mash lan end etre lira rs Hard (nw. Cambrge 1850 2 PM. Wiese A Boney chew, Mele Scie 277, 484 0997) 2, Noforal ecarh nck Ctr Coon ory (Maat Racery fe, Washington, OC 199) 1, MLL The jo Mel hg te Fc othe uth Uns of Ohag Pres, age, 950) 5. BIL Tar at The Earth Tefomed by unas ‘An: Gobal ant hepa Crane ne Bspee er te Pat 200 Years Came Us, Pat, mbps, UE, 1990) 6. Sh Seid Raney, Pe Cooltin of Cte tnd fe Gio Cub ants San Fanaa, O, 1980) 1. Fetes, Citing, Ca, fe, Aanigetrg Soc Ecogal Stars ulin Rasen for Compe aed Ohnge Cami Un. rs Cmte, Ut 2003) ors, Ta, Sc. 12,2 990) 5A Lin, age Cami onplny onde CGmmone are Bost, mb 90 a LMcundesen .§, Wain £65, Racy Undesterdig barslamatns in Hunan aed Neve sors (stand Pes Masnto, 0,200 sete € Foe Fling, Emian Corser 34, 240 (econ, EIR Capes el, Boxee $7,209 (2007, [liver al i eo andthe Cenc derek: Fblintig owe and Coa Saree to Re Sensing and GS Fs VMs RRs 5. Wah, de ort Acer Publihes, Basten MA 2003, pp zat tee Er aan, € Osten, Sei the Foust and he Tees man Enirnmnt trans oF Estas INI Pes, Conia, 2005). ML Nba a te dan an. 0, 345 2007 iver a Corser, B 3, 1300 199), 2 2. a a me NR ben ttl Futur en te pani 14 US. rvsemet Pay pte, ae Uh free ewes 2008p. 7 Potion fle, 1 hat Ee Soc 9, 2 (200 1 vera, Sore 292 000 1.6 Oa Co, GL ae 2, 9900 1 Aes tat 205 lntcape Berna Matingon Sis CED Crp, Wa 2309, WG 3, ag, Bear Gena Bd on. Ahan X Maye fo Se 92,3 oo, {fae Gob Emon Cage 6, 29 8. 5.0. Maca el Metogrmnare Bg Bore Sone 45, B09. fg, Ket 8 1 aon, og fom Spams of kr elena led Pe, Ue 208) Me ae Fats Pi paki Poteee avten te m10, 7G ER apenw, € Foe, he bt 2,209 toa! |. nor, e895, 2179 es. eng et oh Eten Change 36, 28200, 8 sae Feo 4, 24 090) IN pope Me tk yd te Sart ‘ncaa conan ono and geo, Row We heard vi er ee ‘pian ebro eter ssc We lvoe} te fo ping et rf 3 ‘et ar nme cobtoratn md totes et Cts dat lc and nae te SSF Dynan of Capes Ror ad Han Sper as Meth erp ae Lag Tem Eigen ty i at rnc 2 Sco Ames, hae ral See, Fecal i, Mion a Unt enn ‘git pment Seton, Rha Cr Chan Setar, nest Osta: Poiserna. scones ib) Se Rach Supperting Ontne Materat ronson a ere 7 SONAS12/003 Taal ww sciencemsg ors,i Production of Trout Offspring from Triploid Salmon Parents Tomoyuki Olatsu.? Shinya Shikina,* Megumi Kanno, Yutaka Takeuchi? Goro Yoshiaki? spovis has declined marked, and several species have become exinct or endanger Because cryopresenation of fish eggs is dificult. duc to ther lags size ad high ft content, we investigated the potential of surogate broodstock Aexhnologicvas anew method of genetic resource preservation for fish, Sumogatebroodstock teche noeiesimolvethetrasplantationof primera gemcells PGC) (/) oF spermatogonia 2) from 4 target fish species ino a related species for ‘which raring techniques are well developed. In doing s,therecipient species can produce sperm and eggs of the tet species (3). Funthemnore, ‘because PGC'sand spermatogonia are suicsnly ‘smal foreryopreservation, animalscan be gener= ated via the taneplanaion of thawed PGCs or spermatogonia into recipients, even ithe wrzet species bocomies extinct. In price work, We dem- fonstatd that most spermaiozca proxhiced by Xenogencic recipients ae of recipient crigin; few donorderived sperniatazoa are produced (4). Inada, the production of viable donor- dexived exes in nenogene recipients hus not yet ‘been cbse in any animal species to date. The present study thersfore otiempted 9 produce ‘only donor-derived sperm and eges by trans- I nn recent decades, the number of stlmonid planting spermaogonis ints sterile xenogereie recipient In this study, spermatogonia of puawinGfe (ovhere Grp represents green fluorescent protein) hemizygous (prass-Gip-)and dominant orange ‘colored mutant hatrozygous (OR wild type (HT) adult rainbow trout Oncorivnchues mykiss) were intrpertoncally microinjected intonesly hated enbyos of tiple eile masu samen (O. maou), Hybrids ofthese two species donot sunve, His: tological examination showed that, whereas the tess of 2-Vear-old tipo salmon in the contr 210up (no tansplanttion) were immature and con- tained mostly spermatogonia, ees of reipients pared noma (Fig 1A). Ten ofthe 29 mae tip- loid salmon recipients produced mile Offipring produced with mil from these 10 recipients and wild-type wout eggs developed nonnaly (fig. $1 ang ebleS1). Five F, prgeny were collected trom eh of the 10 rexipizts(n 5D) fo spies d= termination using eaidom arppied polyromic DNA (RAPD) analysis All $0 specimens exhib> ited the same DNA fingereint patems as rairbow trou ig $2) indicating that mae plod salmon ‘ipionts produce only donor derived tout. “The ovarics of four ofthe cht female revip- jens conttned vitelogenic oneytes et 17 months Fig. 1. Development of donor-derived germ calls and F1 offspring generated fom surrogate parents (a) Homatorytin and eosin H8E)-staned secon of testes from an intact tilt salmon top) and a ‘triploid salmon reccient that received spermatogonial trnsplertation (bottom). Scale bars inicate 20, um. (B! Doce colony derived from doncr out spermatogonia in the ovary o tipo salmon recipient at 117 months after ransplantation (bottom) and ovaries of ntact triploid salman op) a the ame age asthe ‘eipient insets Fluorescent viens. Scale bas, Sm. (€ Lateral view of orerge-colared offspring (nse), witha highly magnified image of a frame. Gfp was expressed in PGC (asters. 1D) Trt juverts at 6 months olé generated from surogate triploid salmon parent. wwuscioncomag.org SCIENCE VOL 317 post transplantation (Fig, 1B), Allvitellognic 00- ‘ytes exhbited donorspeifc green fluorescence. ‘Ovaries oF inet tploid salmon ofthe same age sontined no vitelogsnic eocytes (Fig, 1B). When respionts reached 2 10 3 years af ag, 5 ofthe 50 female tplod salmon recipients ovulaed eges (table $2) that were then fertize with mit har- vested from the male trplow salmon recipien’s Although development rac ofthe ofring var- jad from ope female broodstock to the next, the hatching rae eachod 89.5% (able $2), The ae ios of orange-colored tout to wild-ypetwoutand of praso-Cjot) 10 prusa-Gj-) were beth about 3:1 sn the F, generation (Fig. IC snd tble $3). These findings show Mendelian inheritance of LORDIVT ad pcsa-Ghp, implying ha the Fy gen- craton was produced tom donorderived spem sid eggs. Resulting Fry also developed nomnaly (ig. ID), Restriction fiagment length polymee- phism (RFLP) analysis of mitochondeial DNA fevealed that all F fish specimens examined (r= 18) carried tux mitochondia (fig. $3). Thus, female triploid salmon rxipicns that received rut spermtogonia predced only donorderived tut cags. In addition, RAPD alysis of total DNA showed thatthe DNA fingerpining etter ofthe F, generation was the same a that of tout (Sg, $3)- Purther, dh: Fy generation was fertile and could reduce normal F, wout. Werhereforeestbishod a surrogate brcodstock cchnique for salmonids in ‘which spemnatogonis can be tranplaed ino ster- ie wiploid xenogeneic rospients produce anest _geveratio consisting ently of denarerved fish. ‘Wealso confined that rout spermatogonia fozen ina cryomecium had a high sssocited survival rate (454%), Thus, by tersplanting eryopreservad spermatogonia into sterile xenogeneic eipiens, itis possible to genarote individuals of an endan™ gered, and pettps extinct, species. Roferonces and note Wine esa, Tabu, el eer 6 ua fo, Teds, Si. au Ftc Yoni roe Na Hod SA 208 295 08). buss at. Ryd Dev 52, 685 2000, 5. rs toys supported by he nds Fema Recor en Progen en he Met Egy sn Instat Tema Dealopnert Crna REDD. supporting figs S103 Table Ste $8 etree 24M 2007, aceted 26 Wy 2007 Sounassdercesi4se25 ine Materiad “eparaertl Mare Biocenes Too Uivesty afMarne Scent ar echo 3-7 tan, Anak ago 108- 23477, apn, “SdutonOreved esearth fr Soence and Techrolagy (SOR) lz Sence and Teel Aen) Sand, Cyd Too 102.0075.) ‘To whow coreponlerce sould be adlesed Ema seagiaipas arp 14 SEPTEMBER 2007 15171518 Checkers Is Solved Jonathan Schaeffer,” Neil Burch, Yngvi Bjdrnsson,t Akihiro Kishimoto,t ‘Martin Maller, Robert Lake, Paul Lu, Stave Sutphen ‘The game of checkers has roughly 500 bilin bilion possible postions (5 x 10%. the task of solving the game, determining the final resut in a game with ne mistakes made by citer player is ‘auming. Since 1988, almost continuously, zens of computers have been working on Solving checkers, applying state-of the-art artifical intelligence techniques tothe p ing process. This paper announces that checkers fs new solve: Perfect play by both sides leads toa dia. This i the most challenging popular game tobe solved to date, roughly one milion times as complex as Connect Fou. Artificial intelligence technology has been used to generate strong heuristic based ‘game playing programs, such as Deep Blue for chess. Solving 2 game takes this tothe next level by replacing the heuristics with perfection. ‘hesimyatu ofa cheseplaying progr in 1980 (2), atc inte gence researchers have developed programs capableat challenging and defeating the stonget human players in the ‘word, Supethuran-stergth programs ext for pope games such as chess (Doop Frit: (2), checker [Chinook (3), Othello (Logistello @), and Serbbie [Maven (5), Honever strong thes progeans ar, they a not pect Psion inpliss solving a sane dotemining the ial result (game-heorctic valu) when acter player sakes mistake, Thr are toe levels of sang 4 game (0). For th lovest level. ulawwably felved th perioplay rel, but nota stegy for achioving that vale, is own fe in Hox the ist player wins, but for large bara Sizes the winning strategy isnot krown (7) For weakly solved games, Bath the rst ne a stategy for achiving it rom the str of tho games aro known fee. in Go Moku the fst payer wins and a prog can demonsiate the win (6). Sonal Solve gates have the result compte fr all possible posionsthatean ase inthe game 8, ‘Awat CO) Checkers « 8 draughts) is a popular game enjoyed by millions of people workwid. with ‘many annual tumariens anda sens of competitions that determine the vrldcharmpcn. “Thor are numerous vant ofthe game played around the world. The game that is popular in Nori America and the (ormer) Betish Come sexsvelth has pases (checkers) moving fore ward one sq diagonally, kines moving forvard or backward ene square diagonally, and 4 forebcapure mle (see supporting onine material (SOM) tet) S ince Claude Shannon's semiral paper on Departmen of Comping Silence. Uivesy of Abe, fomorton, Alber 66 28, Canada im conegonterce sould be adds, Ema jonaiande bere ART dar Cope ol Conn Scene Rin Univerty Rho, Kran (53D, eli Presa adds: Darton of Mela Acnecr, Fue Unirerty, Hakedse, 1262 Noredarsaroco Holadte Wolk, 04855, oan. 14 SEPTEMBER 2007 VOL317_ SCIENCE ‘The effort to solve checkers began in 1989, ‘and the computations needed to achieve that result have been running almost continuously since dhen, Atibe peak in 1992, mere than 200, processors were devoted to the problem sina: neously. The end result © one of the longest, rnxning computations complete to date ‘With this paper, we announce tht checkers thas boon weakly solved. From the stating po- sition Fg. 1 tp) we havea computational prot that checkers adraw, The proof consists of an ‘explicit strategy that never lses—the program ‘ean achieve at east draw aguinst any opponent, playing either the black or white pices. That ‘checkers isa draw isnot a surprise; grandmaster players have conjectured this fr decades, “The chackors res pues the boundary of “tfc intelligence (AD. In the early days oF AT research, the easiest path achieving high performance was believed to be emulating the ‘human appreach, This was faaght with ciiul- 'y, expecially the problems: of capturing and ‘encoding hunan knowledge, Humanlike stale egies are not necessarily the best computational stiatevies. Pethaps the biggest centibution of applying AL technology to developing game- playing programs was the realization that a search.iniensive ("peue-free") approach could produce high-quality performance using minimal _applieation- are wins and all scores <1 are lasses Ie den proves the est given this as- sumption, Once complete, is increased to =A, and the process is repeated. Eventually aches the valuvof a win andtheproofis complete. This iterative approach concentrates the elfor on forming dhe outline of the proof with low vals of and then fleshing out the details with the est of the computation ‘One complication the grph history inter: scion (GH1) problem. Is pesible wo reach the same postion though two diferent sequences of ‘moves. This means that some draws depend on the moves played leading to the duplicated position, In stindard scarch aigorims, GHI ‘muy cause some pottions (0 be incomeclly infeed as draws Pat of this research project, was to develop an improved algorithm for addressing the GHI problem (19). Correctness. Given # cemputtion that has run ors korg on many processors, an important ww sciencemsg ors,‘question to ask is “Are the results comet” Early fon in tho computation, we realized tht there wore many potential sources of errors, including algorthm bugs and data tarsmission emors. Great cate has been taken to eliminate any pose sibility of ewor by verifying all computation results and doing consistency checks. As well, some of the computations have been indepen- dently verified (SOM text) ven if un ror h tions, it ikely does not change the final result. Assunre a pesiton dat is 40 ply away’ fer the ‘stat is ingore. The probability that this er roncous result cam propagate up 40 ply and change the value for the game of chockers is vanishingly small (20). Results, Our approach to solving the game was fo detemine the game-thoorctic result by doing the least amount of wore, In tournament checkers, the stardord stuting postion (Fig. 1, top) is considered “boring.” $0 the fint three moves (ply) ofa game arctndomly chosen at the stat. The checkers proof coasted of solving 19 three move openings, leading to a determination of the stating positions value: acros. Athough there are roughly 300 thrae-mve openings, more than 100 are duplicates (move transpositions) The rest can be proven (9 be irelevant by an alpharbota seach, Table 2 shows the results forthe 19/epenings solved to detemnine the perfeckpay result for checkers, (Other openings have been solved but are not included her.) After an opening was proven, postprocessing program pruned the oe to climinate all the computations that were net pst of the smallest proof tre. In hindsight, the pruned work was unnecessary but i was not 30 atte time when it was assigned for evaletion. Figure 3 shows the proof tree forthe first 3 ply ‘The leftmost move sequence in Fig. 3 is as follows: Black moves from 09 to 13 (represented using the standard checkers notation 09-13), White replies with 22-17, and then Black moves 13.22. The resulting poston lnas been searched and shown tobeadraw (openingline | inFig.3) ‘That means the postion aller 22-17 isalsoa dean, given that there is only one legal move asilable (13-22) anditisa proven draw, What ithe value fof the position afler Black moves 09-13? To determine this, ll posible moyes for White have to be considered. The move 22-17 guarantees White atleast a dra (at most a daw for Black). But it is possble that this positon is a win for White (and a loss for Block). The remaining moves QI-7, 22-18, 23-18, 23-19, 24-19, and 24.20; opening lines 2 to 7 in Fig. 3) ore all shown 1 be atleast draw for Black. Hence, White prefers the move 22-17 (po worse than any ‘other move). Thus, 093 lead to a draw CWhite will move 22-17 in response) Given that 08-13 is a draw, it mains to “demorsirate thatthe other opening moves cannot win for Black, Note that sore openings have a prover result, whereas for others only the partial result that was necessny for the proof was ‘computed, The number of openings is small bocause the freed-capiue rule was exploited. ‘Opening lines 13 10 19 in Fig. 3 are needed to prove that the opening 12-16 & not a win. Ac tually, one opening would have sufficed (12-16, 23.19, and 16:23). However, human analysts ‘consider this ine to be a wan for Black, and the preliminary analysis agreed. Hence, the seven ‘openings beginning with the moves 12-16 and 24.19 were proven instead, This led tothe Least. amount of computing. There is aneodotl evidence thatthe proof ioe 'S cone. Main lines of play were manually ‘compared to human analysis (74), with no errs found in the computer's reals (unimportant eros wore found in the human analy), “The proof tree shows the perfect ines of play needed to achieve a draw. Irone side makes a losing mistake, the proof toe may not necessary show how w wi. This addtional information is not necessary for proving tbe draw result. “The stored proof tree is only 10” pasion. Saving the entire proof tree, rom the start ofthe game 90 that every line ends in an endgame database position, would require many tens of fi) “i ‘20 By ee iy fa-ripenlass a) ‘3 Bel joo) F 5a. aaa cfc coe oa eo 0 [29 [29 | = | 20 | 0 29 | 20) 20 |e0)|29| 20) Joo) <0] eo]| oo|| «0 | ao 1236 56 7 be WHR HOT DD 3. The first three moves of the checkers proof tree. Move sequences are indicated using the notation from Fig. 38, with the from-square and to-squae of the move separated by a hyphen, The result ofeach po loss; <=D, loss or dram; and >=D, draw or win). considered; the restare cutoff, as indicated by the move because of the forced-capture rule, wwscioncomag.org. tion is given for Black, the first player to move (=D, a proven craw; =L, a proven ‘In some postions, only one move needs to be rotated "T” Some positions have ony one legal SCIENCE VOL 317 RESEARCH ARTICLES i terabytes, sours tha nero not avilable instead, only the tp of the proof te, the infomation rites by the manage. is sowed ndisk. When a ser ques the poo ithe end ‘of a line of play in the proof is reached, then the tolver is veel to como tte ne nny the deta, This stntly roses the seeage reds athe costo ecempacng ahi? per cach) The longest ine nalyred was 154 py. The positon atthe ond ofthis lie was anaiyzed by the slr, and that analysis may have gone Boor mare ply deep. Ai the ond of tis anaes ina databane poston which cou be the esl of several hundred ply of analysis. This vides seppoting évdeacs of tre difficaly St eheckers for compas and humans. How mich computation was dape inthe roof? Roughly speaking there are 10” polions fn the sored prof (ec, cick representing & search of 10” positions (relatively small because ‘of the extensive disk operations), Hence, 10"* isa tod balck esimate of the fd search ‘ft. ‘Should we be impressed with “only” 10!* computdone? At ont extems, checks could te sclved using storagebid endgame dat esos forthe corps sears pace, Ths would rote 5% 1 data cots. Even an excellt Cemression algo might only ee is 0 10 byics, impractical with today’s technology. This aso makes i unlikely tat checkers will soon be story sched ‘an alterative would be 10 use only computing ie, build a sah tse using the Sipe lgorihm, Consider he lowing i reusonbly cptmiste esumptons: number of moves 10 consider eign noneapae posi fins, game hts 70 ply, ll apts are ofa single pce (23 cagtue moves). and the alps beta stam door the lest posible wok. The assumptions result in a search tree of 8°? ¥7 states, The perfect alpha-beta search will ‘halve the exponent, leading to a search of roxighly 8°10". This wouldtake morethana lifetime to search, given current technology. Concusion, Wht ' the sionfc sig cence of this rel? The catty esac was devoted wo developing Chink and Gomonstat ine spothumn play in checkers 9 milestone ftjredatsdihe Dep Blue sccessin chess The projcthas bon a maiage of rescach in A and Perils computing. wth contrition med in bath ofthe rca. This esc as bac wid by abininfennatis cmpany, walsime aco of ‘very le date set for uo paral arch i relevent frsolving a gore ti or biological ‘ommptstions “The choskerscomrataton pushes the bound ary of wht con be acieved by earch itenve alaorths.Iprovides comping evidence oF the poner of imvtd-knowledgespyronhes to artificial intelligence. Deep search implicitly tcovers nowinge.Furthenne, sth al fthms ae wll psd wo take advaniag ofthe 14 SEPTEMBER 2007 1521i RES| 1522 EARCH ARTICLES increase in onchip parallelism that multicore computing will son offer. Scarch-inensive approaches to AL will pisy an inercasinely important gol in te evoltion of the Feld. With checkers finished, the obvious question is whother chess is solvable. Checkers has roughly the square mot of the number of Positions in chess (somenhere in the 10" to 10° range). Given the effort recited to solve checkers, chess will remain unsolved fer a long time, barring the invention of new technology. The disk-fipping game of Othello is the next ‘popular game thats kay to be solved, butt will require Considerably more resourss than were ‘needed 10 s0WNe checkers (7), Notes Mo. 256 (850), Seta em 2: Suellen Abd eng eas, New % 4 MB, EE te Sst) 14,22 9) 5. 0 Shope, hes Ut Masi, Mantice, Nahr (202 thes, Unrest of Unb, Maat, Nahata (9. 7. vane ek Uti, van ie, tt 34,277 0m. 8. Rome, H Bal. EE Compete 34, 26 2003. 9. Kage Haken, SoA 297,308 (979, 10, Oink es tenth po lone eh 1. b's met fur Pograre poner. si-wempeataten), BR Giserie, TW Zit Stn 99) 1. | Shlr ea “Seeg Chere” (wma? 20545 1, R Ferman Base Checks tome da ont bosch, 5 ones 108 WT" pipogs roi ste hcervnge pet) 1b | Shuler a al nde In Cmte Cana, bn den Ha Ke, Hee, a lay, Dee Netter SED) po. 185-240, 7. D Kath, 8 Meare Aw Ile, 293 091). AB A hig thes Usveiy Tog, psn 292) 8, Aina Mey in Pocetngr ft rer Natl Crees on feat grec AIP, Menlo Poe Ch, 2008 9p. 64-4, 20, del thes, Une Masa, Msi, Needs 9991 21 The sgpe of Gnde’'s otal Seres and Cneiecng Resch Cure MER, Abe's Ifomases Cie ol Rs Eee (EDRO, and the CanaiaFandton fr asain rey ‘ppraited. Noveres pepe ce ah ork, inci MB, lbenn, 3. Gard, 8 aight, Supporting Ontine Materat omen eget 84879002 otarte sa titer figs Ste 86 Rares 20 Jpn 2007 apd 6 dy 2607 ‘btd one 19 ay 207 so uzsesmet107 inde tie lomaton sen cin th pape TLR3 Deficiency in Patients with Herpes Simplex Encephalitis ‘Shen-Ying Zhang,!?* Galle Elain,* Pedro Romero,’ David Sega Emmanuelle Jouangyy,'** Sophie Ugoini* Asma Smani .* Vanessa Sancho-Shimizu,’* Lazaro Lorenzo, ‘Anne Puel,** Capucine Picard,**" ariane Chapgiet,*? Sabine Plancoulaine,"* ‘Matthias Titeux,* Céline Cognet,* Horst von Bernuth, Cheng-tung Ku! ‘Atmanda Casrouge,*? Xin-Kin Zhang," Luis Barreco,”* Joshua Leonard," Claire Hamilton, >? Luis Quintana: Muri Pierre Lebon,”* Bénédicte Héron, Louis Vallée,’ Alain Hovnanian. ** Flore Rozenberg.” Eric Vivier,“ Frédéric Geissmann, Laurent Abel," Jean-Laurent Casanova®#>*¢ ‘Marc Tardieu, ** Some Tol and Tolblite receptors (TLR) provide immunity to experimental infections in animal ‘models, but their contribution to host defense in natural ecosystems is unknown. We report a dominantenegative 1123 allele in otherwise heal childcen with Herpes simplex virus 1 (HSV-2) ‘encephalitis, TLR3 is expressed in the certral nervous system (CNS), where i is required to ‘control HSV-1, which spreads from the epithelium to the CNS via canal nerves, TR Is also ‘expressed in epithelial and dendritic els, which apparently use TLR3-independent pathways to prevent futher dissemination of HSV-1 and to provide resistance to other pathogens in ‘TLR3-ceficient patients. Human TLR3 appears to be redundant in host defense to mest microbes ‘but s vital for natural immunity to HSV-1 inthe CNS, which suggests that neurotropic viruses have ‘contributed to the evolutionary maintenance of TLR. he cenubution of Tell and Talsike re- ‘epiors to immunity has been sted ex tensvely in the post davate, Toll-dticient Drosophila were shown to bo auscepible to ex- perimental inftions with certin fing in 199% (D),and & Toll-like oeeptor 4 (TLR) null rta- ‘ion in mice resistant 1 lippolysacaide (LPS) ‘but susveptble to certain Gram-negative bacte- sia was identified in 1998 (2) Mice deficient for individual TLRs have since been ganeated and shown to have diverse infectious pheno- types, trom suseeptbily to resistance, depending ‘on the TLR-pathogen combination (3). How fever, it remains unclear whether TLRS ply ‘nonredundant roles beneficial or detrimental: in natural, as oppesed 10 experiment, infections. This biolggical question is important, because 14 SEPTEMBER 2007 VOL317_ SCIENCE natural selection acts on 2 given species in the sting of natural (rather than experimental) coo- systems. The burnin model is pniclirly Sait able ee snalyses of the relevance of genes such as those of TLRS to hos. defense in natural coo systems (#). Novertholes although many studios have suggested that TLR genes are involved in human infectious diseases, this has not been un ambiguously demoneraed (5). in purtcular, no prinary immanedeticieney involving TLRS has bon identified. The dower of nerd fern | neqpor associated kinase4 (RAK) deficicncy in ‘ilren with bacteria) disease implicated fae man TLRS, interukir-1 receptors (ILARS), o both in host dense (6,7. However, the nar range of infections docurnented in such patients indicates thot IRAK-4- dependent, TLR-medited inmmuniy & redundant for protective immunity mest member, In particular, RAK doiciant patents are not susceptible t9 herpes simplex vies | (HSV-1) encephalitis (HSE) In HSE, HSY¢L infects epi cells in the ral are nasa mucosa and. progresses (0 the conta nervous system (CNS) via the tigcmina or olfictry nerves (8). A genetic ology of HSE was found in yo chiken who lacked functional UNC-93B , an eoplasmic reeulum prctein requied for TLR3, TLR, TLRS, and TLRO signaling GO, Boh UNCS3B~ and RAK-4-deicent patents ful to signal dcugh TLR, TLRS, and TLRS, but unlike IRAK-+-eficient patients (7). UNC-93B defisient patonts dsp impaiad TLR3cependant interfere (FN) and 3 production (9). Moreover, HSV-1 is a doublo- seared DNA virus with doublestrandad RNA (GSRNA) intemmedites (I), an TLRS recog- “var Gee of con Dose WA Naor te UaSree del Ree Meava (NSERN USSU Fay hr ate 705 Fone “Unray Pe ew Deane Fare Tt, Fonte “ronencie tt ft ces te Sere fa J Hon San 8 {ony Uenty,Surghe Zoe7s Ohne ‘Moseeconey fmt ree Maro 1328 Wane ‘Dpater ft teresa, MSGR UTE. hc Hea Ft 0s freee aby oan el By. WER US cr Heo, Pte 7308, ance ag ae tr Cone Re Laser an Uses) Hoe lava 05, ‘Scetand. “Eelvent Inne fragt att Ce atte, Nao hae ef Heath ets MO 292 SA "er fr te St ot Imupseeces neler Hapa, Pars SUS, Fave "RS Ses nest) Tue Pa Sb Toast sa ae ete Natal Pele rte ci Fae tt a 15038 Fea Cccnnsaiciner de Pn Hil Uwe Fat Fe Dexa, Fath 75018 Farce Pada Meo, tresses yl Pas B02 Fane. “eat Newby Unnesy Hoga Le S903) Face. “Fede Mev 9, betve Hog Unheay Fay Sud renin ere Sern Fae “Pes Henacgy nnn, Nee Hse Pas 705, ace “To whan coregondrce should be adtesnd mai Gutongnadetie ww sciencemsg ors,sass GSRNA (12). Fly, TLR is expres in CNS resident cals (15-15) and peripboal nerves (16). Clletvey, these observations suzsst ak ined TLRS depen induction of FN 6 aed i might be involved in HSE. ‘A heteonyoeus TLRS mutation in two eil- dren with HSE. We investigated two unrated French chidren (P) and P2) with HSE (SOM Test, note 2). UNC-IBB deficioncy was ex- cluded on genetic and irmunotogicalgrouns (fig. SI, Ao D). Leukocytes and fibroblasts fiom PY and P2 harbored the sare hterazyeous substiuton (C1) in TLRS at mcleoide poston 1660 (166027) (Fig. 1, A and B). ‘Tho (vo kindred represent independent mus tional events beanie the (wo P5545 mutations ‘wore in dif TAS haplenypes. The rat. tion ads the replacement of a prcline P) bya serine (S) at residue S84 (PSSHS) (Fig. IC). PS54S has nt previously boon dosenbed (07,18) ane no ound in any ofthe S81 tunrated hey individuals exanined (3162 ronson), teuding 241 Furnes, Res ide PSS4 of TLRS is conserved inthe 18 an smal species sted (Fig. 1D). The extracel, ligand-binding domain of TLR3 conuins 23 contiguous lecinovich repeats (LRRS) forming 2 lars honeshoe shaped sino Fg 1E) (19) Fig. 1. Heterozygous A TUR 5515. muation jin two unrelated chi den with HSE (Fam. ‘iy pets, wih alle segressten inthe 0 famibe tte tenn =] PSS4 anchor the TLR3spacific insertion of residues 544 to 54 in LRRZO (Fig, 1E) (19, 20, This region is thought 10 be otc for dsRNA binding to TLR3 (20) and TLR muitimerza- tion (19), Thee relatives of Pl and to of P2 were also heterozygous for the mutation (Fig 1A), They were HSV-I seropositive but had not sured fom HSE, which suggests that the SS4S TLR3 mutation confi an autosomal dominant predisgasiion 1 HSE with incom plete clinical penetrnce. Impaired responsiveness of fibroblasts to poly(:O stimulation. We derived derma fibro blastic cll ines, which selectively express TLR3 (©), fom patient and controls. The TLR3 ago nis. polyinosinepolyetidlic acid (poly:O, Which mimes dsRNA (/2), induced IEN-B, 2, and IL-6 in a dose- and time-dependent mane ner in all control fiboblasts but-not in the ‘TLR3 deicont flbosarcoma P21 cll ine (SOM ‘Text, not 1) (Fig. 2A and fg. S2A). Primary and simian virus 40 (SV40)-transformed fibro- blasts from PI and P2 displayed only a resid- ual response at high concentrations of poly and lac Gime pots (Fig. 2A). 11-6 induct was le impaired. The induction of IFN-B and -AimRNA production by poly(:C) was marked ly weaker in PI fibroblasts (fig, S2B). Both black, are heterceygous for the mutation, The other family: members . heterozygous forthe mu tution are indicted by bold vertical tines. (8) Heteraryopus 166027 D. mutation in the patients. “he sequence ofthe pay: merase chain reaction roduc of genic DNA from leukogres of 2 ‘conte (O one PLP i shonn. The mucation was confimed in genomic Sa fel eue DNA and cDNA from — Musmuseae leukocytes and fibro Smhyicus myie bast. (0 Shumate mp- Scorer" resentation of TRS gene ‘con nme stvucure. Human TE has fhe exons (Roman fnumerald encoding @ protein (chown in gray) ‘composed ofa leader sequence 1), an LAR domain, a transmembrane (Td) domain, and a Tolintsleuki-1 receptor (IR) domain. The varicus LRR moti, the N-terminal cap, and the Cterminal cap ofthe L&R domain are separated by dotted vertical lines, and the two LRRS with an insertion are indicated by asters. The CA66OCST mutation reals in a protine (P) to serine () subsiution at amino acié positon 534 (P5S49) i LRR20. (D) LRRZO of TLRS in humans and the corresponding region in the other 17 wwscioncomag.org. amis SCIENCE VOL 317 14 SEPTEMBER 2007 RESEARCH ARTICLES i veer fictr kappa B (NF-xB) (Fig. 2B) and TEN regulatory faeoe3 (RF-3) (Fig. 2C) ac. faton were impaired in response t© pelyfLC) jn the patons’ Thmbless, which responded sommally (© tumor nasosisfaxtor-a (TNF) fd IL-8 (Fig. 2B and fig, SC). NFB ex sential modulator (NEMO) deficient robles (SOM Text, oe 1) did nat spend 0 paielC), ILIB, or TNF-o (Fig, 2B), and UNC-93D- deficient fhrabests (9) il not respand Wo poly EC) (Fig. 2C). Finally, all ested relives cenrying the TLRS mutton, but none of the relates witout this mutuion, esplayed in sid responses t polyLC) (fg. $2D). The cosegropation of genotype and fbreblastc phenotype sugges tht hecragosty forthe DPSSAS TLRS alle confers akosomal dominant Iyporesponsivenss to poly: C) in fibroblasts Dominantnegative effec of the P554S TAR} alee in Fibroblasts. TLR3 multineies ‘upon binding &SRNA, and sever TLRS rae tos ar dominant negative (20-22), which sug- sts th the P8348 mutation may be damian segative. TERS mRNA is produced in noeral quanties (Fig. 2D) in dhe patents cbs (Fg, S20), and the wildtype (WT) and PSS4S TLRS mRNAs were exaly abundant (i. $2F). Stable tensfecton of P21 cals with C-seniral Species studied, with the insertion incated. The amino acds conserved in the insertion in all these species are shaded in gray. (E) Tao views of the hhuman TLRS eciccomain (ECD) surface, HS39 and NS41 deft), implicated in ligand binding, and P554 (ight are shown in magenta, “Ins” refers to the ight residues from W546 to 6553 inthe TIR3-specife insertion 543 to 554 ofthe LR820, and is shawn in dark gray. Glycan s shown in yellow, and the (terminus ofthe TLR3 ECD is atthe bottom. 1523i RESEARCH ARTICLES Ahemagulutnin (HA)-agged WT 7LR3, but not with PSSIS TLAS, restora the cell sponse to poly(:O), 6 measured by IFN-B (fig. 2G) and IFN, production (Fig 2E}. Both WTand PSS4S, TLR3 mRNAs wore detoted (Fig. 2F), The PSSS TERS protda had a lower molecular ‘weight than the WT, as shown by Westem blot ting with two antibodies that specifically recog- size the TLR3 N-crminal ectodomnin, bat not ‘wih an untbedy to Caemin-egged HA (Fig. 2G), Upon transent transfection of contol fibro- bliss with various raion of mock voor and SHS TLRS allele, he nsponse to poly iC) de- creased as the proportion of P5548 TLR} allele increased (fig. S2H)- Moreover, cool fibroblasts sobly uanstected with the PSS4S TLR} die lost their silty w respond wo poly(EC) (Fig. 2H). ‘These servations wee cxtendad toF2.|rxiicnt cals SOM Text note 3), The PSS4S TLRS protein is us Cterminally uncated, loss-offuncton for poly(:C) responsiveness and dominant negaive in dara iboblets and tho fibrosarvorna P2 cell ling, at lest fer IFN indetion. ‘Impaired IFW-cependent control of viruses in TUR3-deficient fibroblasts. UNC-93B ‘deficient fibroblasts prochace lite [FN-B snd =). upon vin stimulation, resulting in high levels of viral replication and cell death (9) We therefore infocted TLR3-heterozysous fibroblasts with HSV41 and another neurorpie vir, vescutar ‘somatits vis (VSV) highly cytopathic virus and potenc TEN indvcer in. human Srcblass. JEN and 2 production affer infection with SV and HSV-1 was markedly weaker in fibro blast fom the pation than in those fram con wos (Fig. 3, A and B), Six hours afer VSV infection, vial replication rates were higher in Pl cecls—as in Stu-l-deficiet (23) and UNC93B deficient (9) celis—than in conuels (Fig, 30) ‘Call sunival was also maskedly lower for the putts than he cools nd inlaw a foe UNC-93B. and Stat doficient els ater 24 hours of VSV and 96 hours of HSV infoton (Fig. 3D), Teament with IFN oF ENS com plzmented the phenotype of TLRS and UNC S3R dices, bat no Skiel-deficen, cols Fig. 3, Cand E) ina dosecpendent manner (fg. 83). NA. 80 paral complemented the phenotype, albeit less efctively thon IPN TENS (Fig. 38), Oo rss thus demonstrat causa rlaceship betwen heerozyzesiy oe fe P5448 TLRS maton, impaired TLRS sige talirg,dhnomaly weak IFN-a and & predus fon, eae vil replicon and highs levels of fibroblast al death upon il nftion Inpaied response to poly stimulation in (MODS, WK, and COB T cals Movocste-drived dendrie cls (MDC) (24 fom PI ad dhe tid sting of P2 63-P2), bath Hetezyzous foe 465°TLR3 mutation, sponded more weekly dan Fig. 2. Impated response to pol{kC) of fibroblasts and ddominant-negative effect ofthe TH P5545 allele in ibecblasts (A) IFN-B, and IL-6 production in Sv40-tansformed fibro. blasts (SV40 fbreblass) from a contol (C), PA, P2, and a UNC: 938-defcient (UNC-938.") patient upon simulation with vatcus doses of poly) for 12 of 28 hous. () NF-xB-DNA™ binding activity of nuclear extracts from the SV40 fibroblasts of 4 contil (0, PA, P2, and a NENO-

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