) | COVER Giraffes eye a smorgasbord of Acacia at the Mpala Research Certre in Kerya. Large herbivores suchas gaffes are key to maintaining a mutually benefical felationship between ants and Acacia in an East african ecosystem. See page 192. Photo: Amy Wolf NEWS OF THE WEEK Budget Cuts Mean Layoffs at no DOE Labs, End for SLAC Colder HIV Gets By With a Lot of Help From Human Host o> Scene Daggers Are Drawn Over Revived Cosmic Ray-clhmate Link ‘More Climate Wackiness inthe Cretaceous Supergreenhouse? SCIENCESCOPE Panel: EPA Proposal far Ar Pellation Short on Science ‘The importance of Being Eaten Marine Mammals Stl imperiled After Sonar Ruling NEWS FOCUS Gunning for the hy League Enjeers infor Quality Boot Valérie Presse interviews Alter lit 1 Reforns, French Minister Promises More changes ‘American Geophysical Union Neeting eting a QuickRead on the Biggs una arhtes ite Tipping ots Come in from the id Cance’s Bulwark Against Immune Attack: MDS Celis vawescioncomag.org 145 145 106 146 147 148 182 153 184 LETTERS Fighting Algae Response) Tei Lake Not Correcting the CONTENTS Volume 329, Issue $860 DEPARTMENTS 134 Science Ontine 135 This Weee in Scence 137 Editors” Choice 138 Contact Science 139 Random Samples 141 Newsmakers 221 New Products 222 Séiance Careers EDITORIAL 135 ACasefor New institutions by KamaljtS. Bovo, Ganeson Bolochander, ere Peter Roven in Kaneohe Bay J. Goreou 157 Smith etal to Blame for Wuai’s Woes M. Yang eta. Record onthe Data Quality At W.G Rely CORRECTIONS AND CLARIFICATIONS BOOKS & AGuinea Pig's History of Biology The Plants and TAL. 160 Animals Who Taught Us the Facts of ile 1h Endersby, ee Introduction to Perspective D POLICY Ft (Ocean ron Fertization—Woving Forward in a Sea of Uncerta 0. Buesseler PERSPECTIVES ‘AF to Flip the Angiogenic Sitch ened by V.B. Smocovits Quantum Achar Tin Dependent Tonnor, revigwed by 5, Gray 161 ORUM, ity etal 5. Rofii ond. lycen Quo Vadis, specificiy? 164 4H. Schieber and 0.A, Rowley Dicey Assemblies Hane What Tigges Tremor? 168 166 E, Richardson and C, Marone Not So Simple HI. Brouman SCIENCE VOL 319 168 CONTENTS continued >> 11 JANUARY 2008 131J CONTENTS SCIENCE EXPRESS vinoLocy Idertitication of Host Proteins Required for HN Infection Through a Functional Genomic Screen ALL. Brass tal ‘an RNA screen gered 237 new an 38 knonn human pots equi {oc HI infect, including ones seen Gal rosport ane i val integration an ranscrintion, > Mews stay 9 145 Stance GE Generics Widespread Genetic Incompatibility in C elegans Maintained by @alancing Selection HS. Seidel, MV Rockman, L Kruglyok Strong natal selection smatwaining mutt alleles ofa gee in wild populations othe nematode C elegans, deste tei regaiveeffecton fines. Paysics Electronic Liquid Crystal State inthe High-Temperature Superconductor YBa,Cu, V.Hinkov etal. Neutron catering measrerents sugges that ordering of utatingeectrn spins ‘oplains the eu tl phases recertl sce in some coveted elecon stems IO126%cience 1152309 Physics Observation ofthe Spin Hal Effect of Light via Weak Measurements (0. Hosten and & Kinat Displacement oftght at an at-gssinerlace depends ont polaron, showing thot photons have aspin Mal fet comparable to that seen fr elecvons. 1O1126iclerce 1151107 2O1126scence 1152697 TECHNICAL COMMENT ABSTRACTS BREVIA OCEANS ceopivsics Comment on “The Southern Ocean Belgica 159. Widespread iggeing of Nonolcanic emer 173 Response to Aeclian kon Deposten in Cairo PW. Boytand Mackie J.Garnberg ta fl tt ot wm scenery leotnt 32988607582 Alrge Nasa etheuak tiggerd veers along the San Aras Iespence fo Conmmend on The Scidters Goce) ane oe seks outs Calf, shown tats ces Breast Respense to eaian kon Depostion” setsuic te mcictinn oes, ‘M. Cassor et al. i a REPORTS REVIEW ASTRONOMY ecovocy Stele Feedback in Dna tary Formation 4 Climete Change, Deforestation, and the 169 & Hesbeheate sedan tl Mb Counce, Reaneniin Simulsons how atta wnd 396 mater expe tom Chokes supervae athe carta ote of art axes, ap epahing Wo arate. aysics Supercondtng Vortices in CeCe, Toward 7 166 & 132 the Paul-Limitng Field A.D. Bianchi etal The respons of CoCo, ier om thatof ater superconductors and om accepted heer because is sinerconduting sate Bpproaches a quantum crticl pint CHEMISTRY Self-Assombled Water-Soluble Nucic Acid Probe ies or Label-Free RNA Hybridization Assays ¥ Ke S.Lindsoy, ¥. Chang, ¥ Lu, H. Yoo. large DNA scaffolds with rutile os of single-strand overhangs «an capture spec RNA alec for subseeuentbel‘ree Aetection by atari force ioscony. 180 CONTENTS continued >> 11 JANUARY 2008 VOL319. SCIENCE wwrsciencemag.orgREPORTS CONTINUED. cHemsTRY Imaging Nucleophilc Substitution Dyoamics 183 J Aikesch eta. Apcecisety contlled gas shase colisionexperientumels the ‘quantum macraical tas undoing the class ganic comical reaction of CT with CH. >> Perpectveg 168 GEOPHYSICS Tidal Modulation of Nonvolcanic Tremor 186 JL Rubinstein etal Sal trewors and sow ip along the Cascaea subduction one pulse every 124 and 281925 hos, inping that nar ties re cing this acy long weak us >> Pesce. 166; Breviap. 173 PALEOCLIMATE Isotopic Evidence for Glaciation During the 189 Cretaceous Supergreenhouse A.Bornemann etal. ‘Agiacal tal ang aout 200,000 yas nterugte he warm Late Cretaceous climate and preducd ice sheets hall aslageas the mater Antic le Sheet. ons so9/p 138 EcoLocy Breakdown ofan Ant-Plant Mutualism Follows the 192. Loss of Large Herbivores from an rian Savanna CML, Palmer eta. ‘ling mimmaian hebinors oma savanna ecasstem deceased ant colonies on te resdent Acacia tes, leading © attakty betls and unexpected tre moray. MEDICINE Endothelial Progenitor Cells Control the Angiogenic 195 ‘Switch in Mouse Lung Metastasis D.Gao etal, ‘aperments in mice sow that certain bone marta cel promote ‘he develeprent of lang ances by helping blod veses frm wthinthetmos. >> Pesnetie 163 IMMUNOLOGY Dendritic CeltInduced Alemory T Cell Activation in 198 Noniymphoid Tissues Lt Wahine al Imm cls, nrmaly pede in yrpoidomans, can aso be activated in the neous teria response to a ial calege MOLECULAR BIOLOGY DNA Oxidation as Triggered by H3K9me2 202 Demethylation Drives Estrogen-Induced Gene Expression 2B. Perla etal xogenstriggerhistone demethyaton which beta Local DNA dative bust hat guides inal assembly ofthe ranscriton repair comple. CONTENTS L BIOCHEMISTRY Designed Protein-Protein Assocation 206 D. Grueninger eta ‘few charges in he side chains of aio ais at the contact Inceriacs of natal engymes may slice to induce higher-order ligomers. => Aerperne 165, CELL BIOLOGY ‘Membrane Pnosphatidyserine Regulates Surface 210 Charge and Protein Localization T Yeung, GE Giibert J Sh. Sivius, A Kopus, S. Grinstein Aorescentta specific for a negatively charged ie shows thats ighe concanration i endosomes and yosomes tos cationic tens within he cl PSYCHOLOGY The Limits of Counting: Numerical Corition 213 ‘Between Evolution and Culture S.Bellerand A. Bender ‘Svoral Pacicdan languages with few woes for numbers may D2 erivd fem more sophisticated and abstact counting stems rather than being the prcusers IMwuNoLoGy Recognition of @ Ubiquitous Self Antigen by Prostate 215 CCancer-Infitrating CD8* T Lymphocytes PA Savage etal ‘nme, acommon histone prea hat ceats ONAs unaxpecealy etected within pretetumo's by theinvnune ystem, suggesting 2 poten therapeutic approach, 28a 165 & 206 ADVANCING SCENGE, senna YOCtETY absense iiccesectorgunegee us oc coe ee egrcae apap carer ioe to matoageegieas remaeatanereta CONTENTS continued >> wwwescioncemag.org SCIENCE VOL 319 11 JANUARY 2008 133134 N wrwn.sciencemag.org_ Future fuel SCIENCENOW wn sclencenoatorg DALY NES COVERAGE Biofusls on 2 Big Scale Sutcharass produces five tes as much ena) 2s requied to make into a copa fue. Evolution: Read All About tt ‘New booklet airs to bring Darwin's theory to the masses. Third Gene Copy isa Charm ‘Agee tilcted in Donn syndrome may provide cancer prtecten. Receptor clustering atthe newemuscoar junction, SCIENCE SIGNALING ste. THE SIGNAL TANSCUCTON KNOWLEDGE ENVRONNEN PERSPECTIVE: Notch and Integrin Alfinty—A Sticky Situation A Karson Notch-dependon actnation of Ras eversasH-as-medinted suppression of integrin activi, PERSPECTIVE: An Emerging Picture of Synapse Formation — Balance of two Oppesing Pathmays FOn0 Aispersing anda dustring pathuay or aceycnoine receptors Cenvesge onthe postsyraptic protein psy in sett mule. ‘Separete individual or institutional subscriptions to these products mey be required for fulttext access. |SCIENCEPODCAST newly identified host proteins fiwolved in HIV infection, ~ ‘cancer immunotherapy, Quarterly Author Index wnuw.sciencemag.org/feature/date/aindex.dtl Following childhood dreamsto acareet SCIENCE CAREERS un clencecaeers.org CAREER RESOURCES FOR SCLEMISIS Special Feature: Changing Careers, Following Dreams Kravis Moving frnard can ican looking bck at chilshood fascnations chat est engaged your ove for science Finding the Way Back toa First (Career) Love S. Webb [Uke reknding an old romance, the pursuit fan od iterest canbe exciting and rearing, The Accidental Pateontologist E.ouill Nike Tylor’ ascnation wth sauropods led hint 603 PRD. In Person: ACereer Home Run K Wooiner Asctnare deeloper’s hobby in baseball statistics landed him ad wth amajor league baseball tom, Download the 12 January Scfence Podcast to hear about glaciation during the Gietaceous, and more. 11 JANUARY 2008 VOL319. SCIENCE wwwzsciencemag.orgj j ; : a ; ‘ i i : i : : : t tas To ensure a steady supply of oxygen and nutrients, tumors send signals that stimu- late the growth of new blood vessels. Bone marrow-derived cells called endothelial. progenitor cells (EPCS) ate known to be recruited to the tumor-associated growing. vessels, but the presence of these cells at nly very low levels inthe tumor vascuta- ture has made it difficult to assess their funetional contribution. Studying mouse models of lung metastasis, Gao et al. (p. 195; see the Perspective by Rafii and Lydon show that EPCs are critical regulators of the “angiogenic switch” that helps drive the progression of dormant micrometas- tases to lethal metastases, Genetic manipu- lations that blocked EPC mobilization in tumor-bearing mice inhibited angiogene- Si, impaired formation of lung metastases, and increased survival time. Exotic Superconductors in Magnetic Field When a magnetic eld is applied toa supercon ductor, a regular lattice of vortices usally forms in hich each vote is threaded by a single quanti, of magnetic fx. Tis process soften described by the phenomenelogical Ginzburg Landau the ‘yin ters of to lent scales forthe magnetic file acoherenceleneth and a penetiation pth. Bianchi e af. (p. 177) now report ne tron scattering results onthe hear fermion com ound CeCatn, that shaw a complete departure from this model The authors suggest thatthe respanse is caused by spin polation ofthe quasiparticles within te normal state vortex core that arises from the superconducting state being ‘near aquantum ctl poi wowsciencemag.org SCIENCE VOL 319 Chemical Ins and Outs in bimolecular nucleophilic substitution (he Sy2 reaction) an attacking group, usually an anion binds toa carbon center an simuitaneously ‘ects leaving group on te opposite side. This reaction hasbeen understood in broad ters for many decades, but many detais have been obscured by mecium eects ad the lweneroy rate before we go further: “HAO XIN AND DENIS NORMILE \With reporting by Gong Vidong ef China Features in ‘Beting ant Richaré Stone in Shang 11 JANUARY 2008 151a NEWSFOCUS 182 VALERIE PECRESSE INTERVIEW After Initial Reforms, French Minister Promises More Changes Despite fierce protests, France's new higher education and research minister pushed through a major university reform bill. I'm only getting started, she says PARIS—French Higher Education and Research minister Valérie Pecresse has sur- vived her first big political test. In Novem ber and December, students organized occu pations and strikes at almost hall of France’s universities to demand the repeal of the “Pécresse Law” Designed to give univers ties more autonomy and part of French Pi ident Nicolas Sarkozy's plan to revamp the nation’s research, the law had been pre- sented in June and was approved by France's August The protests, fueled by broader discontent about pen- sion changes and salaries, ever tually died down, And Pésresse has already announced other reforms, including a reduce the $0% failure among first-year versity stu dents. Although some say fur- ther shakeups in France’ exe ‘cation system are long overdue, left-leaning researchers” groups are wary ofthe ministers plans to boost project-based funding ana private research, Péeresse, 40, arrived with litle previous experience in research or higher education. A graduate of the elite Ecole Nationale a’ Administration in Paris—the training ‘ground for many French politicians she had a series of jabs in the government of former president Jacques Chirae, In 2002, she was elected to the National Assembly, where she bas focused on family issues, “MARTIN ENSERINK : Were you impressed by the intensity of the student protests last fall? VB. If you'we a minister for higher education 1nd you want to change things, then ‘you have to be prepared for demonstrations, strikes, and violent uproar. So [knew it was ‘coming. OF course, there was real opposition, but many of the stud mply had unfounded fears about the new law. I gave them reassurances, but also [iol th the law of the Republic, I's being mented, cannot repel it” (Q: How much will this reform really change the university Landscape? VB. It may not look like a big deal through aan Anglo-Saxon prism, but for France, is Our universities ic. They have huge elected! councils. Presidents are elected by 140 people. It takes 12 to 18 months to recruit one researcher. The law gives univ sities the ability vo handle their own budgets, their own human resourees. They ean to We maces ° Bena 2 Paya sae ‘own research and education nd they will bear responsibility ses of their labs and students, They can star foundations 10 private moncy. Thats revolutionary, 00. I think all of this will also lea change in culture. In France, there almost zo spirit of belonging to a university. Stu- denis come in, they study. and they leave, Even professors don’t feel very attached to the institute. T think people will star taking more pride in their universities, develop thei : The universities did not get the right to select their own students—they have to accept anybody who has passed the state- run baccalauréat exam—or set tuition fees. Why not? V.P.: The baccalauréat is our selection procedure. That costs millions of euros, and it takes full month, So why would wwe introduce another form of selection at the entrance of the university? As to tuition fees. my priority is for universities to Faise new money through partnerships with the private Sector and by offering “lifelong learning” programs, to be paid for by employers. L want them to try that first. I'm not sure that the French people could accep! a decision to let universities deiermine theit titi fees Q: Some scientists have expressed concern that your plans will undermine the role of big government institutes like the National Centre for Scientific Research (CNRS) and the National Institute for Health and Medical Research (INSERM). Some fear they might even be turned into funding agencies. Pz: They won't become funding agencies ‘but thoir organization will need to change About 80% of our research is done in so-called mixed units, made up of researchers from universities and CNRS INSERM. At the moment, they often have four or five jon, four oF That's toocomplex: there’ 100 much red tape, Ihave ereated 4 commission presided over by my predecessor, Frangois Aubert to look a this, Apart from that, I do want to inerease the empha- sis on project-funded sci- ence, which is something ‘completely new as well. Our National Research Agency (ANR) is only 2 years old, and its budge will increase by 25% until 2012 0: Yet_ many French researchers appear wary of project-based funding. They say it's an Anglo-Saxon model V.P.: They must never have visited Germany. Q: .». that creates a rat race and stifles researchers’ freedom and creativity. V.P. Well, science is atthe service of society Its paid for with public money that must be invested very efficiently and on the basis of excellence. Project-hased funding is part that strategy. In addition, we can use it to address new research priorities that would otherwise be neglected. And i's not ruc that itstifles creativity. The ANR is alsoa way to help young, very creative researchers who would net find th. bbureaueratie system, F way in the current, 11 JANUARY 2008 VOL319. SCIENCE wwrsciencemag.orgMEETINGBRIEFS>> AMERICAN GEOPHYSICAL UNION Getting a Quick Read on the Biggest Tsunami Earthquakes Asa huge tsunami raced unnoted across the Bay of Bengal toward India in December 2004, seismolo- sists feverishly sized up the earth ‘quake thathad generated. In those Fest minutes. the sivas pou from seismometers 3 ested its mange ally large enough to threaten India with tsunami, Wrong. It turned quake capable of generating a farctraveling destructive tsunami (Science, 14 January 2015, p.201) The magnitude based on con- Iy-arvivin ‘waves then seismologists' only means of rapidly determining the tsunami threat vastly underestimated the poner of the great quake. At the mecting, two groups reported new techniques for accurately determining the ‘suman threat in 10 10 20 minutes rather than Nica ‘saiting hours for reliable data. Seismologists Hiroo Kanamori of the California Insitute oF se tsunami | 10-14 DECEMBER 2007 Technology in Pasilena and Luis Rivera of Louis Pasteur Unive: : France, proposed using so-called W phases low-frequency seismic waves with periods of 100 seconds to 1000 seconds. After a 1992 a quake produced 2 surprisingly anamori recognized that cearlysarriving W phases accurately reflect 8 SAN FRANCISCO, CALIFORNIA quakes sunami-generating power But W phases were too difficult t extract fiom the seismic record, Kanamori and Rivera have now modified an existing technique so that it quickly picks W phases out of records ‘and extracis the needed information. Applied toahalfdozen quakes, the technique provided the same magnitde estimates as waves artiv- ing hours ler atthe same stations, Kanamori believes W phases can be used to determine an accurate magnitude of great quakes within 15 ‘© 20 minutes oftheir start, maybe 10 minutes if there are enough seismometers nearby. Scismolagiss Andrew Newman and Jaime Convers, both of the Georgia Institute of Te! nology in Atlanta. ‘ook a more empirical approach, Noting that “tsunami earthquakes” like the 1992 Nicaraguan quake produce weak bat long-lasting shaking, they simply plotted 440 large earthquakes by the amount of high- frequency energy they released—theie shak= 1g--against their duration. The tsunami sgeneraiing quakes clearly Sood zpar without ‘any false alarms And they could be identified ‘within 10 minutesof the quake, Newman said Both of the new techniques “archot forus says seismolo Pacific Tsunami Warning Center in Ewa Beach, Havaii, and will be made operational asquickly aspossble RICHARD A. KERR ty in Strasbou CLIMATE TIPPING POINTS COME IN FROM THE COLD Ting polies, once considered to alarmist for proper scientific icles, have entered the climate change mainstream. At the meeting, a nearly packed half-day session considered the prospeds for a climate system thatis sill creping through change but might soon cossa threshold into an entirely new way of operating. The new clmate regime may have no ‘ea iceinArcticsunmess, a much smaller cesheet on West Antarctica and higher sea levels, or willy redirected storm tracks. Cur ning glaciers! surpisingly agile ice tongues, which help stow glaciers rush fo the sea, Ané meltwater on the surfaces of claciers is plunging down giant cacks to glacar beds, where i’ lubricating the glaciers sea wad slipslidng. fa very small warming makes such adiference.” Alley sid, “it raises the question of what happens when more warming occurs.” Sea ce specials Josefina Comiso of NASA's Goddard Space Flight Cen. terin Greenbelt, Maryland, sad at the meeting that inthe tee understanding of cists sows that such dase “The tipping point kr. thetppng pn for perennial sea ethos Ul transtons can happen, the speakers agred, Cath may jal sea ice akeady been ache." ke persisting fomearto year has even bein the midst of one non. See Oe eT ee cing mare Wea TH) cael ‘As evidence, clacoiogist Richard Alley of Pennsyiva- Mas likely already —— susymersea ice accelerated inthe mid-1950; since then nia State University in State College cited Earth's resporse to the warming that has ocurted over the past 3 decades. Compared withthe soaring alobal tempera tures thatthe strengthening greenhouse could drive through the rest ofthis centuty, that warming has been rather smal, Alley sid. et i shaving immediate anc often unexpected offects, he observe Since the 19605, mountain laciers aroune the werld have begun to Shin and are dnindling rapcly. Arctic summer sea ie took a severe hit last year after decades of siow loses, And the Greenland ice sheet is now clearly shrinking undersome unexpected attacks. Warming sea are neak vowwsclencomag.org been reached.” —10serIno comiso, ‘GODDARD SPACE FLIGHT CENTER SCIENCE VOL3I9 summer ice has bee disappearing more than three times, faster than before. nd the feedback between solar warm ing of nenly ice-free Actic waters andthe los ofl more ice has become more and more obvious. Only colder sum mers and colder winters can save summer sea ice from oblivion, he said an unlikely development at this point. ‘Other speakers presented posi tipping points that have gotten lss attention: an evertual sudden shift in jet streams that would bring rapid ‘imate change to North America and Europe and the abrupt collapse of the Amazon topical forest, among athets. Clealy, the possibilities are proliferating faster than researchers can confirm or deny them. RAK. 11 JANUARY 2008 153154 CANCER IMMUNOLOGY Cancer's Bulwark Against Immune Attack: MDS Cells First noticed in the 1970s, mycloid-derived suppressor cells appear to play a key role in sustaining tumors; new methods of overcoming them are being tested For decades, researchers have been engaged ina frustrating effort w harness the power of the immune system to fight cancer. The approach works well enough in test tubes rental animals, Many types of and expe cancer cells are studded with antigens that activated immune cells ean seek out these targets and kil the cells that earry them, Yet sitempts to desirey tumors by sparking similar responses in human patients, using so-called cancer vaceines and other inmunotherapies, have largely ended in failure, Now, researchers may have an answer to this puzzle N recently ide immune cells m these efforts. ‘Within the past few y researchers have found that cells known as production myeloid-derived suppressor cells (MDSCs) is markedly iner in cancer patiens. As theit mame suggests, MDSCs are potent suppressors of several facets of the immune system. By damping down antitumer responses, SCS might contrite both [MDSC pioneers. Vincenzo Bron to the original growth of the cancers and to the failure of ima MDSCs mi yanotherapies, i help explain another wel: the appar- ent link between tumor growth and chronic inflammation (Science, $ November 2004, 1.966). Re 1y molecules, or eytokines ither by th cells ther: help trigger MDSC accumulation And many of these eytokines also promote inflammanon, suggesting that MDSCs ma} be at least partly responsible for inflamma alin nking MUSCé to cance grat, 08 VOL 319 eft and iry Gabitvieh (righ were (ose contact. NSCs (ed) are A shonn here interacting with C8 Teele (magenta) tion's careinogenic effects Some clinical of these findin: b immunologists learn what makes MDSCs tick, they are using that information to desi nplications. Iready ning to emerge. As cancer egies to counteract them in the hope that this will make anticancer vaceines and other immuanotherapies more effec= tive, Indeed, researchers have already identified drugs that inhibit MDSCs and have begun ry clinical tials. If what the field has learned so far is correct, “using different drugs [to block MDSC action} could drastically improve responses to can- ‘cer vaccines," predicts Dinitry Gabrilovich ‘ofthe H, Lee Moffitt Cancer Center and the University of South Florida in Tampa prelimi Early sightings Although MDSC-like cells ha known since the 1970s, with cancer is regent says Vineeno Bronte the association ‘ofthe Isinuto Oneologico Veneto in Pada, Italy It can be traced partly to researchers efforts to find out why cancer vaceines vveren't working About 10 year then working with cancer in 10. forexample, Bronte, munologist at the U.S. National Can- cer Institute in Bethesds, Maryland, got a Steven Rosenber result when he immunized mice surprisi witha tumor a shot of the same antigen 6 days later. The ind then gave a booster enhanced as expected. It was suppressed. instead, Bronte and is colleagues traced the problem to an unusual group of immune cells—later ealled MDSCs. that were somehow taking out the CD8*T cells that would normally respond to the Analysis revealed that these mature cells suppressors wel from the myeloid line that pro- duces macrophages and the den- dritic cells that are needed 10 tigger immune responses, Their normal function, the researchers proposed, is to help put the brakes on immune responses so tht they don't run cut of contra SCIENCE wwwrsciencemag.orgIn cancer patients, though, their long-term persistence is a problem, “There's nothing they're normal Immature myeloid eels,” Gabrilovich says. But, headds they “are supposed to differen tite normally snd not get setivated and hang around inthis state” Asrescarchers soon learned cancer leads to increased myeloid suppressor cells even without vaccination. In the late 1990s, Gabrilovich, in collaboration with M. Rita ‘Young at Loyola University Chicago in nois, was also trying to find out why cancer vaccines are so ineffective. "We started looking at mice with tumors,” he recalls, and found that as much as40% of the cells in the animals’ spleens—an organ that produces and stores various immune eells until they're needed-—were myeloid-derived suppressor cells, Human cancer patients, too, had three to five times more of the cells than did healthy controls. Meanwhile, the numbers ‘of dendritic cells were decreased. These cellular changes get more pro- nounced as tumors grow. Asa result, patents with advanced tumors precisely the ones who have been inmost clinical vaccine tials — have large numbers of suppressor cells that ‘could interfere with their trestment. “There's no question about it: we're going to have to deal with these eells to do immunotherapy.” says Suzanne Ostrand-Rosenber of the Uni versity of Maryland, Baltimene County. Researchers are beginning to explore sev- zal ways of dealing with MDSCs. One approach exploits the fact that they are devel- ‘opmentally immaxure, To promoxe the differ- ‘entiation of the cells, Gabrilovich and his col- leagues have turned wo allsrans retinoic aid {ATRA), which is already used clinically to treat people with promyelocytic leukemia, Ina pilot stialy, the researchers gave the drug to 18 kidney cancer patients, all of whom had elevated MDSC levels. The short-term study was not desizned to look for clinical improvements such as tumor shrinkage. But the immune status of the drug recipients improved: they had fewer MDSCs, more dendritic cells, and beter Immune responses. The Moffitt team is now § beginning a more extensive trial that will § testa combination of ATRA with a cancer g vaccine. “Simply eliminating these cells. § wan't do.” Gabrilovich says, “You have 1 ‘combine that with active immunotherapy.” & Versatile actors ¥ MDSCs tum out to have many ways of 5 blocking immane responses. They ea hi both the so-called innate and adaptive # branches of immunity. On the adapve side, wwwymsciencemag.org, they suppress antibody-produeing B cells and CDA (helper) T cells in addition to CDS" hile) Tells, ‘One way they inhibit Peels sby blosking anessential activation ste: the binding of antigen tothe Teel resepior. About 4 years ‘go, Calikxich ardhiscolleagues fra that MDSCs telease highly reactive molecules, including certain forms of exygen and peroxynivite. Findings fom Bronte’ group Angiogenesis promoters. A mouse tumor (bottom) exposed to VEGF producing MDSCs has more blood vessels and gros larger than 2 control tumor op) not exposed to the cals alsopointed ton important role for peroxyni- trite in immune suppression mediated by MDSCs. Ina study published in the July 2007 issue of anure Medicine, the Gabrilovieh team further showed dat peroxyniite causes nitrate addition to Fell receptors, rendering them incapable of binding antigens they ‘would otherwise recognize. ‘Other researchers are focusing on a key regulator of T cells the amino acid arginine hs importance originally emerged in studies of patients who experienced serious trauma, SCIENCE VOL319 NEWSFOCUS L including surgery. These individuals have low Teeell counts, making them very susceprible to infections, which can be fital, particularly if'they lead 10 a condition called sepsis, Researchers, ineluding a team led by brothers Juan Ochoa, « surgeon at the Uni- versity of Pittsburgh Medical Center in Pennsylvania, and Augusto Ochoa. an imme nologist at Louisiana State University (LSU) Health Sciences Center in New Orleans, have linked this immunosuppres: sion to low levels of arginine in the patients. They found. for ‘example, that in lab cultures, the amino acid is needed both for normal Tell replication and for production of the zeta chain of the T-cell receptor. “The next question,” Juan Ochoa says, “is ‘what was destroying arginine.” Further work showed that it was none other than MDSCs, ‘These cells are loaded with the ‘enzyme arginase, which degrades the aminoacid, About? yearsago, Juan Ochoa and his colleagues showed that mice subjected to sut= ekal sess pregice large numbers ofthe cells, which proved to be potent inhibitors of Feel activa- tion. The researchers have also ‘ound bigh anginase proxkaction in cells fom human traumo patients bur haven't yet pinned down the exact nature of those cells. Meanwhile, studies of both animal modetsand haman patents have pointed to asimilar mmuno- suppressive role of MDSC- produced arginase in cancer, Tn one study about 3 years ago, the Ochoas, with LSU’s Paulo Rodniguez and colleagues, shensed thot arginase produced by MDSCs associated with lung cancers growing in mice impairs T-cell unetion in the animals by decrease ing expression ofthe receptor zeta hain, MDSCs “interfere with the ‘Teall antigen receptor so that there is no si nal” to activate te cells, Augusto Ochoa says. ‘The researchers also showed that treat ‘ment with anarginase inhibitor significantly slowed the growth of lung tumors in mice, Since then, the Ochoas and others have found that MDSCs from human cancer patients produce large amounts of arginase and nitrie oxide synthase (NOS), another enzyme that degrales arginine “Those findings suggest that treatments that rise arginine kvels in T cells can alleviate the 11 JANUARY 2008 155a NEWSFOCUS 156 mmunosuppression occurring in trauma and ‘cancer patients, Indeed, dietary arginine sup- piments bane already proved uscfal in cou hating infections in trauma patient, and pre clinical work indicates that interfere ‘sith the synthesis or function oFarginase and NOS might counteract the immunosuppres- sive effects of MDSCs. Ivan Borrello and Paolo Serafini at Johns Hopkins University School of Medicine in Bakimore, Maryland. working with Padua’s Bronte have Ieoked at three such drugs—sildenafil (Viagra). tadalafil (Cialis), and vardenafil (Levitra) that are much better known for theit role in treating erectile dysfunction As Borrello and his colleagues reported. a Title move than a year ago in The Journal of Experimental Medicine, sildenafil in particular can decrease production of arginase and NOS by MDSCs. thereby boosting T-cell responses. In mice with colon of mammary tumors, treatment with both the drug and the T cells primed to rec ‘ognize the appropriate cancer produced much greater inhibition of tumor growth than treatment with the T cells alone. Bronte and his colleagues have found si lar effects ina mouse-iumor model with an aspirin derivative called NO-aspitin. The inflammation connection Much evidence throughout the pest several years has supported the idea that inflammation promotes tumor growth. Exactly how it ‘does that isn't clea, but recent evidence implicates MDSCs, Researchers have found that ‘cancer cells proakicea varity of proteins that either are directly inlammory or can trigger the production of inflammacery kines in the tumor env ronment. Some foster MDSC accumulation, and, to make matters worse, MDSCs them= selves have pro-inflammatory elects, thereby creating a vicious eycle that may perpet= uate their own maintenance as well as tumor growth, One carly sign of an flammatory link came from Gabrilovich and colleagues in 1996. They found that a pro- tein called vascular endothe lial growth factor (VEGF). which is released by tumor cells, promotes the accumu tion of MDSCs by blocking dendritic cell matura 11 JANUARY 2008 VOL319. SCIENCE Potent immunosuprresiors. OSC produced under the influence of VEGF, intesleukin-1B, and other factors released in the tumor ‘environment, can inhibit immune responses tothe tumor in several ways. These include blecking the activities of several types of cells needed for immune responses and tering type L macrophages. Natural killer cell * ‘Macrophage ype 1 > ype 2 VEGF helps tumors grow by stimulating angiogenesis, the formation of the new blood vessels they need. Angiogenesis is, also a component of inflammation. And out 4 years ago, owe independent teams, one led by Mario Colombo and Cecilia Melani of the Istituto Nazionale per lo Stu dio ela Cura dei Tamoei in Milan, Italy, and the other by P, Charles Lin of Vanderbilt University School of Medicine in Nashville, Tennessee, showed that MDSCs also pro" duce VEGE, thereby further promating tumor growth and their own formato “More recent work s 8 possible to break this vicious eyele. Lin and others have found that VEGF seeretion by MDSCS requires the activity of an enzyme called mealloprotcinase-9. Andthe Colombo ‘twam now reports that a drug that inhibits this enzyme can reduce VEGF concentrations and the number of erculating MDSCs in mice that hhavermammary tumors. The drug also boosted Responses toa vaccine directed against the tumor (The results appeared inthe December 2007 issuccof Cancer Research.) As shown by Osttand-Rosenberg and her colleagues, the pro-inflammatory cytokine interfeukin (IL)-If8 also stimulates MDSC production, making it another target For deups aimed at overcoming immune suppression in cancer patients, Evidence to support this idea comes fiom experime ng the Tumor cell vece EGE, tL) : : i ic =| mpsc Dendritic cell NOS, Ho other factors Arginase, receptor through which IL-1B exerts i ceflects. As the Maryland team reported in the ‘October issue of Cancer Researcl, mamwnary tumors implanted in the animals show reduced prowth and metastases, “This ked to hypothesize that [MDSCs] are one of the ‘connections between chronic inflammation and cancer” Ostrand-Rosenbarg say. “Tumor cells also produce COX-2, a key cenzyime in the pathway that makes inflam matory molecules such as prostaglandin E (PGE2). Ostrand-Rosenberg’s team has found that MDSCs have receptors for the prostaglandin and that drugs that mimic its effects inerease their formation while PGE: imhibitors block it. In addition, the Ochoas nd their colleagues have found that PGE2 stimulates arginase production by the cell, And both teams have shown in mouse mod cls that COX-2 inhibitors can slow tumor growth, That may help explain why uals who take CON-2 inhibitors. been widely used for treating arthritis and ‘other inflammatory conditions, seem less prone to developing cancer than people who don’t take the drugs. ‘Not only are MDSCs induced by inflam matory molecules but ina situation similarto that seen with VEGE, they themselves can promote inflammation, Macrophags are part of the innate immune system, come in uve types: ML macrophages promote activity of killer T cells through their production of I-12 and are thus antitumor, whereas M2 macrophages promote inflammatery responses through jonof IL-10. Tn work reported yearin The Journal of lmmunol- - Ostrand- Rosenbergs team, found that MDSCs enhance the growth of mammary tumors in mice by interacting with M1 macrophages and convert= ing them to the sets up a strony sy, to further enhance MDSC activity. The resul also indi- cate that the drug gemcitabine, which is already used to treat some cancers, exerts some ofits elects by restonng IL-12 pro- duction by macrophages. last Be Ball a All in all, researchers a are finding that MDSCS are exitemely versatile immune suppressors and leary a force Teall whe reckoned with ifirnmuny therapy isto succeed “JEAN MARX 2mag.org 5 i i iLETTERS LETTERS o1htod by Jonniter Sis BOOKS POLICY FORUM | Fighting Algae in Kaneohe Bay "CALLTHE HOSE BRIGADE! toremove a massive nuisance algae bloom kill (RANDOM SAMNPLES, LOAUGUST 2007, P. 729) DESCRIBES AN EFFORT orals in Kaneohe Bay, Havvall, by suck ing it up with huge barge-mounted vacuum cleaners. Unfortunately, this will give only temporary results.an will fai in the long run unless the nutrient ex that Fuel the rapid ‘growth is removed, Kaneohe Bay isa classic exarnple of coral wef eutrophication: Benthic when the outfall was removed, suburbanization ofthe watershed, uncontolled nutrients th ‘courses, lawn fertilizers, and road runoff have again raised the nutrient concent rae (4-6), Aside from the te Kancohe Bay, there are very few examples of algae being successfully removes e land-based nutrients were diverted, nuisance algae that were n weeks, and only a few dying clumps of weedy alg. 1 are starved of nutrients, they die very quickly sin exceeded. But no amountof sucking them of? ase they are overfertilized, It isthe suckers above the thresholds for nuisance bay in Jamaica where all choking the reef began to die remained 2 months later (7) Ia not returm unless nutrient threshold a will work shen they grow right back be paying for this well underlying ca entioned, but ultimately fi ses of eutrophication ae removed, igal blooms caused by point discharges of sewage killed the reef in the 1970s, but died allowing the reef to gradually recover (/). With continued dischargetothe bay from gol ions (2.3) effort who will be hosed unless the ‘TWOMAS). GOREAU lal Coral ee liane, 37 Peasant Suet, Cambie, MA 02339, USA. Ema cereau@ eset References A Binet Po. 206 Co eS. 2685 978. Stam Sti z (27 ber Hoven 208, Response T.], GOREAU FEELS STRONGLY THAT THE PR i reefs in Kaneohe Bay is etrophiction, We think he may have missed thepoine Whilewe are that mtrientcarchmen an overfishe ig are both important nas and corabalgal phase shifts on refs around ancoeBayinthe 1970s(7) the story tay is mach mer com plicated (8-12) Fist. the species of algae ta maty cause of algal overgrowth of the ce seted for remonal by the Super Sucker are non-native or alicn species introduced to Kaneohe Bay for aquaculture research in the 1970s and have Ma alo. 205, 95190) “Gotevu, K Thacker, Pree: Car Water Westenater Asse. 3. 98 11940. Gee pape preserte the Ep Neerg en ese Mareen Sl beé Deep Ses, Kaa, been growing unchecked since 1 These spocies are native to the western cal Pucifie and are cultivated for the car- enan and azar industries in numerous areas covering thousands of hectares where ceitophication isnot aproblem (73). Second, exotie species are considered one of the largest threats to global biodiversity wwhere they alter ecosystem structure and nd cause sibsta funetion 1 economic losses (4). The methods to remove alien algae fiom reets in Kaneohe Bay were devel ‘opedasa means to prevent or rece negative effects of an invading species, while buying for the development of biological time SCIENCE VOL 319 EDUCATION FORUM PERSPECTIVES Gracilaria solicornia in Kaneohe Bay, Hawai This exotic ed alga, shewn here ovegrowing ret building corals, i ene af the species targeted for removal using the undemwater vacuum ‘mown asthe Super Sucker. ‘control methods with the native sea urchin Tripneustes grata (15). Preliminary data (8) fare encouraging, as areas that have been red by the Super Sucker remain alicn algae and have increased coral rovruit- ment after just Thitd, some introduced species are suc= ‘cessfl in new environments because they are ‘competitively superior and because they have no natural predators. While nutrient enrich ment can increase algal growth rates, more recently published nutrient eoncensations from across Kaneohe Bay (/6) have consis tently reported values below Lapoinie’s “threshold values” Other factors such reduced herbivory are also clearly importa bu our data show that these algae are not px ferred food sources for herbivorous fishes in Hiwvaii (9). Because these alien alyae areable to grow in low-nuttienterwitonments and are not readily consumed by herbivorous fishes, they may be able to spread to Hawaii's mest pristine reefs, Given this, we believe that iti ‘our responsibility as sciemtists and conser= vation biologists to take action and help to prevent the death of yet another coral ref. JENNIFER E, SMITH," ERI. CONKLIN,! ‘CEUAM. STH? CYNTHIA L HUNTER ‘National eater fe Koopa Anayes ad Syrthess, Unwesyof clea, Santa Baars, (A 93101, USA Haire Canservare. Henaul, A. 96817. USA JANUARY 2008 187a LETTERS 158 “penne f Botany. Univesity of Hamat wana, oral 96822, USA. “Bllgy Prog, Ulva Nawal area Hook W685, USK “pmo comespondence should be addressed, Eli: nihgreemich.cle References DA led ol etre 429, £27 2009. T.Aughes et re, care 44,1583 0999 eae, Scene 265, 1547 (994), BE pei, iol Oceano 42,1239 197) BLE Lopeit nel Oeconoge #4 586199), 1+ Sith tel Coa esa 332 000) 5th eal ac S38, 279 (98 E ) conn dseritine, Uresy of Rona 3.) Sith, ia sien 7, 1029 2009. C Lae CH ta, Bul ar Se. 57,501 989. Tre Sth tal Be S56 298200. [Sean a Crt ee, 344200. WL Zenkeit, Oho.) Bel Py 1,368 yes. 14 PM Woke! a, Sate 27, 6980990. 15, | Sons eft te mo 51,161 2007. 16 feonett, te Ee Peg. 32,1 12008 Taihu Lake Not to Blame for Wuxi's Woes THEALGAL BLOOM OBSERVED IN TAIHU LAKE It the summer of 2007 and sensationalized in a News Focus story ("Doing battle with the green monster of Taihu Lake,” 31 August 2007, p. 1166) is certainly a serious environ- ‘mental and eoological proflem. However, the issue that drew public attention to Tai Lake and the very visible bloom was actually a sep arate incident that affecred the aesthetic qual- ity of water in the city of Wuxi Environmental monitoring indicated that she first ave of algal Mloom occurred in Tai Lake in late April 2007, However, the offensive ‘ase and odor inthe drinking water of Wasi City oceurred from the end of May to early June, It has since become clear thatthe taste and ovlor were not caused directly by algal ‘bloom in Taihu Lake, but were instead the result ofan intrusion ince the main water intake of iy bya distinct black water"“agglomer- rnknown origin: the duration of this agglomerate can be tied to ammonium levels, ‘which increased suddenly ~ from an average value of about 0.23 10 0.97 mp/liter—on 28 eee en Cag May and began to decrease gradually afer peaking at 4.0 mg/liter on 31 May. The ‘unusually high concentrations of ammonium observed during this time are not normally socined with the processes in agglomerate. Analysis ofthe samples, which had strong septic and marshy odors (I, 2), detected dimeth risulfide (3, 4) at concent tions of 11,399 and 1768 ng_liter in the two samples. respoctively—high enoughtoaccount for the odors (5. 6), Dimethyl trisulfide and related alkyl sulfide compournis ate produced by many bacteria (ep, Pseufomonas sp.) that break down the amino acids methionine and cysteine into hydrogen slfde, methylmere: tan, and dimethylpolysulfides (7-11). The sample analysis also detasted wo typical algal nxtabolies—2-methyiso-bomeo! ara geosmnin (J2-14)—that give earthy oF musty odor to water, bat these concentrations were much Jower than the dimethyl trisulfide. It is ear from these findings tha dimethyl wisulide and related alkyl sulfide compounds, ot 2-meilyl- ‘so-bormeo! and geosmin, were the main odor- causing compounds in Waxi’s water supply Although itis not clear where the block-water iglomerate and the alkyl sulfide compounds came from, tis unlikely that the: ae the direct metabolites of slaae Alegradation of ey anobacter dduce sich compounds. Tris well known that some cya ria—such as Microcystis aeruginosa, the visible culprit in Taihu Lake-—do pro- dduce a range of toxins that can be harmfl © human bealth. Further systematic monitoring dda of rw water samples from the same ‘water intake in Wai were collected on 4 and 8 June 2007 for the analysis of dissolved microcystins. The analytical results show that ‘mierocystin-Leu-Arg (MC-LR) and miero- cystin-Arg-Arg (MC-RR), some of the most frequently recorded microcystins associated \with algal blooms worldwide (/3, 16), were undetectable for the sample of 4 June and ‘vere present only in small amounts (64and 72 ng ler. respectively) inthe sample of § June The level of microoystins detected did not exceed the WHO Drinking Water Guidelines imsimum of 1 elite “The algal oom in Taihu Lake ip 2007 Jn fact not much differen fem those in previ- fous years, Aecording tothe local monitoring data algal density near the water intake during the odor event period (end of May 2007) was, ‘much lower than the highest value recorded in August 2003, The trigger for public concern about the water supply wasin reality comples chemical event of biological erigin, which has not previously been associated with Klooms of Microeystis aeruginasa in Taibu Lake. NIN YANG,* JANWEIYU,*Z0NGLAT LL? 2HAOHAL ‘GUO. MICHAEL BURCH? TSAIR-FUM LIN? "sate Koy Laboratory ot Environmental Aquatic Chemistry Ressitch Cone fr EeoEnevonmetl Scie, Cee deadomy of Sconces, Pot Othe Boy 2871. Eating, 200085, china "esr Water Quay Centre, Pirate it Ba 3, SeberySAS108, hala, Deparment ff Enveermertal Engineering, Natnal cheng KAN ewer, Dory Rae Tan Cx, 7010, Tan. References and Notes 1. HA Bae et, AM, Waker Works As 78,50 G89. AM ih tc Woe Teco 40451999. Abita eer Se Teal 25,97 292), Ah eal LAD ter Was ASB 150 Gysn. |-e Won Het, Chemespiere 14, 8569. [nee Sue Keni are Tame of ses and Odes in kre (mee We Woks Resear Fendt, Dees, cosen. 7, Jato et Ci sob 32, 23 0940, 1 He Raet ida Ana Rev cet 26,127 Gare. 9. 5 Roel, Bochon Cota 78,1205 (1979). Sober et, Chansphr 35,1687 (197). Te won, et er Seo 31, 87 995. Guage eal Ast Eon mel 43,78 Gsea. [ERA Salle Moe Wok Ao. 8,166 996. eRe Sul ol Me 50 Peo 80, 1.099% En ape etl, Mb Mu Foods 3,7 (Gaon. 1 Had, Che. Pa, Bl 52, 889 (2008. Thm nas spate ie watenal atl Sen asda fia 50525824 and 30621609, Correcting the Record on the Data Quality Act AFTER DONALD KENNEDY INDICATED IN HIS Eultorial oa medical marijuana (“Turning the tables with Mary Jane.” 4 May 2007, p. 661) thatthe Data Quality Act (DQA) (/) could be useful for public interest groups as well industry, Schick er af. (“The tobacco industry and the Data Quality Act” Leters, 17 August, . 898) complained that the Editorial failed t0 mention the documented leadership role that Phillip Morris played in the genesis of the DQA. However. the Schick vr af. Letter ‘confused the Data Access Act with the DQA. ‘The DQA implemented provisions of the Paperwork Reduction Act (PRA) of 1995 (2) that required the Office of Management and. Budget 10 issue guidance on federal infor- mation dissemination; it has nothing to do with access 1 raw data Neither Phillip Morris (a multiproduct company) nor any other tobacco company (or nontobacco company for that mai played a leadership rote nthe genesis ofthe DQA. While working with the Center for 11JANUARY 2008 VOL319° SCIENCE www.sciencemag.orgwulatory Effectiveness DC, 1 was personally involved with the development of the DOA. and no industry ‘entity contributed to its formulation, More ‘over. as isevident from its plain working, the genesis of the DQA lay in the information Uissernination provisions of the 1995 PRA, ‘and hearings and debate on those provisions began at least as early 2s 198, The DOA provisions underwent public ‘consideration by Congress starting in 1998, and discussions proceeded almos. continu ‘ously uni its enactment in 2000 fe. (3-5). Entire commentary atticles have been based ‘on the false premise tht it was enacted covertly e2, (6)] Fill uscdexteasively by public intr ul other non-industry peti tioners challenging govermmentinformation on subjects other than medical marijuana 7) WILAM 6. KELLY)R. ere for Regular ete, Og 1DE3422, USA p Washington, be References and Notes 1 SUS. 4 3816 rte, Pub L 20655, See 100) Unite, Sc SII Dec 21. 2000. ea doesnt Nae Seth ean i ety eres te sete rfommation uly et. 2 USC a0 35DR ate HA. op No 105-592 6-50 (22 e186. 1 Hang aloe Storie on Ts, Pest Seo nd Geer Coram gpm 1 Howe Comite en Aprpratne, 28 Nach 2000, ar 3t477-9,508-97 558 5. Hop. 17S 05-55, 49 (38) 2000, 5. Css, Ja 25,207 2006 7 tect sen masin 3 We ite th ice a cbs OOK ptr cabrio thon ad he TECHNICAL COMMENT ABSTRACTS Comment on “The Southern Ocean Biological Response to Aeolian Iron Deposition” Philip W. Boyd and Douglas Mackie Cassar eto (Regerts, 24 Avgst 2007, ». 1067 910 ‘0st tha aerosa-ton put enhances Seater Ocean ‘root production Tha cons crcay ceerd on ‘scroslon mocaingsinultions nt validated with ‘on-sepesion data ana os ister aes see Hortern Hemsoner atreephene hemil consis {oe oH Tvs éeminstesthe relevance ef hel tdi and demonstrates that applying such models to this tegion is premature Fulltext at wuuscencerasomieiontenul’319/ se4ors9a LETTERS lt Response To Comment on “The Southern Ocean Biological Response to Aeolian Iron Deposition’ Nicolas Cassar, Michael L. Bender, Bruce A. Barnett, Songmiao Fan, Walter J. Moxim, Hiram Levy ll, Bronte Tilbrook et conmsity production inthe Southem Oceanis cere laid wthsmustdloc eu depen andere so wth ‘deed depestion of stl Yon Nadel simulations thelater twe oper areconsitert wih ebsenatiorsin btn heirs These rests rei tong evidence tha! arson poston isa isiarcer contol on net Cemnmunty pocuenen ane expr production oer ge reac the Seuthern Osi Flleatat wes dencenapargkottonerutdt3195860" 1580 CORRECTIONS AND CLARIFICATIONS. problems” by. Ensrink (16 November, p. 1059). The oy sated that the lie TB wacne ace Glnete Geérn CG) mos developed by een a he Psu Insite in Pak. Infact. Albert Calmete and Camile Guerin did mast tte work athe Paste ints ite, being #1897 and persevering vecerocrersly if circumstances curing Waris War {In 2929, mete aie’ the Pasteur site f Ps, hy which time the vaccine development nas ese compete [CG ua tst edn Pats in 1821 Make a Gift to AAAS Through philanthropic support, you can make strong statement about your commitment lo AAAS's mission, Contributions from our members and friends are used in their entirety to support the [AAAS Fund for Excellence which enables us to Promote science n all forms. ‘We are pleased to offer multiple, convenient ‘methods for contributing to our programs and activities. Ifyou would ike to learn more about [AAAS or ways of giving, please visit our Web site at wwn.aaas.org and select “Make a Gift” in the lef-hane tower. Thank you for your support. MVAAAS The AAAS Development Team is availabe to help you in any way. Phone: (202) 326-6636 01 email: evelopment@aaas.or9, SCIENCE VOL319_ 11 JANUARY 2008 159160 HISTORY OF SCIENCE Delicious Tales of Guinea Pigs, Etc. Vassiliki Botly Smocovitis torah het nthe db so rtm et, ns ing room for his equations en the blackboard ‘one dey. he made an ersatz eraser out ofa fae tious guinea pig he had brought to class. The story happens to be untrue (as William Provine’s careful research showed {J)} but it ‘ean spice upan otherwise bland historical sew for nonspecilists. Along with other fun ance oes, imeresinng asides, and stating connec- tions, it appcars in Jim Endersby’s channing A Guanes Pig’ History of Biology ‘Tae book isnt all [un and games, however. tis part ofa growing trend among hist biology wo concent ‘ously used as model, experiment Jus plain object of study. In one guise, the rmxvement merely secks to explore the varied ways in which biologists’ organisms have shaped the development of biology: In another, itogive "oil eney 0 nonhumans though en te sujeet of much debate) So, silly as it seems, the books tile isn just a ue way to entice readers interes tis also a kind of word play on a body of Iiterature that has male “historical actors” of things like microbes and sea seallops (2,2). Blessed, discussion of such challengesto tradiional understanding of science is briet and included mostly in the preface and acknowledgments. The remaining 12 chap tersare devoted tothe subject at hand, whichis, riot so much the history of biology as the history of rx evolution retold onal additions microbiology. physiology: and cell biology) through some ofthe many prominent organisms studied. Each chapter is actually an inde= pendent essay that can be read alone; each is framed by am organism that has playedt historical role and arranged A Guinoa Pig's To Peet celebrity” organisms (es. the fruit My Drosophila melanogaster snd maize, Zea mays), others axe more obscure and news The reviewer i at the Department of Zoloyy and the Departeatf Wistar, Unversity of Fler, Gunes, FUS24T2 USK Eeratt banaconu de Senall Wright and one of his guinea pigs. extinet (ez. quagge, Equus quagga) or largely forgotten (e.g, Gregor Mendel pale hhawkweed, Hienteium aurieule, and Hugo de Vries’s evening primrose, Qenoihera Jamarckiona), while sill others are actively used by researchers (e.t., the cress Arabidopsis shaliana and zebrafish, Danio rerio), One chapier is devoted to a genetically ‘engineered organism (the famously trade- marked OncoMouse. What emerges is lighthearted retelling story that will appeal to wide audience, As we learn about the breeding pattems in horses and zebras wealsoleamabous the leisurely interests fof Vietorian aristocrats, radical political move~ ments, and the chale lenges of gander aan increasingly indus: ‘wialcomext. Whik g ing an understands of Victorian attempts vo stuely inheritance in ‘humans, we learn about the growing concern ‘with London's sanitation, the famous Heath Exhibition, and the development and use of industrial ceramics as toilet bowls and sewer pines by Doulton and Company’ (now known as Royal Doulton, the maker of fine dinner- ware): As we learn much about the guinea pig as moe! organism for genet appreciation ofits cul enon we gain an Although enjoyable, this approach has some drawbacks, Throughout the book, nec essary historical desails or critical develop- ‘ments are missing or “ofl” while irrelevant ressions and asides include far_m dlozail than needed, Forexample, the chapter framed by the guinea pi Cavia porcellus, (really the chapter ‘on the “modern” synthesis of evolu: tion) provides a fascinating dix sion of historical and ethnographic uses of the experimental cavy {along with descriptions of recipes) but a misleading picture ofthe his vorical event itis supposed to cover. That synthesis wasn't all due to the use of guinea pigs and Drosophila, the insights of theoretical popula- tion geneticists like Wright, or the field work and experiments of Theodosius Dobehanshy. Is Ledyard Steboins J. (among many others) and their et tions didn’t exist. Given the book's many plant exmples, Stebbins ‘whose classic book (4) brought botany ince the synthesis would havebeen 2 much more appropriate end point for the chapter than his fiend Dobzhansky. One must also won. der what kind of historical secount af evo- lution ean be told without fossils, And although the book is tobe lzuded for inclu ing so much from the botanical sie, the actual histo appoint Iesgreatto feature Onova forthe sexton on the “eclipse of Darvin” (the interval of time around 1900), but io give ita cen place in understanding the phenomenon of polyploidy isn't fair. That part properly belongs to the Kew primrose, Primula ewensis, and the histories of polyploidy pomixis, and hybridization are vastly more complicated than portrayed here In shor, the book offers lay readers sn engaging and lively introduction tothe bis tory of biology. Gut I'm not sure that i actually enriches historical understanding ofthe field, lysis is di References 1, WB Fine, Svelligh and boluioneryBolny (Wer fags re Crag, 1960. 2. B lat Faseriaton of Fen anor Wir. Pres ambige 3780 3 Malan Powe Action od Bei A New Sacilay ented, a Rosle on Kegan Pat, (on, 1985), 9195-25 4. GL Store, vretanend Ertan ans (lumtisnk res, em 1930, 26ers 115222 11 JANUARY 2008 VOL319 SCIENCE wuwusciencomag.orgPHYSICAL CHEMISTRY Keeping Time Stephen Gray B: to understand an ecu than ‘what actully applies to the world at large. They typically con tain much discussion from the perspective of the time- ere ete en dent re has grown more center stage It reflects how the time-cey quantum mechanical pic ature over the past 30 years, This has been especially true in the discipline of physisl chemistry (orchem- ical physics), where a number of major advances in time-domain theory andl experie ment have arise, developed! by Eric Heller and his collaborators starting inthe mig-1970s ledto anew way of viewing molec- tlar spectroscopy and reaction independent Schrodinger ei [i dynamies. For example, a ion (TIS), VO) £4). |e molecular absorption spectrum This equation determines the iiaiaaaal is viewed as resulting trom allowed stationary siates of [aaa placing an appropriate initial asysiem (defined by ts Hani wavepacket, YOu! = 0), onan 1), which from apari- could beanyth Pree cle such as an electron to a IR complex molecule contanit many atoms, Depending on the problem details, the stationary st gies (E) take on only certain discrete values (as in the well-known hyd Jem) or take on a continuous range of values (asin om involving collisions) Associated with each allowed energy, £. is a Yor system's coordinates ‘wavefunetion where x denotes the The absolute square, hy)? is related tothe likelihood! of Findin the system in specific region of space Burt for the most par, he universe isnt sta tionary: the positions of things change with time (7). For matters concerir turns to another equation, th Schriin TDSE), This equation ime-depenaent ewermines the time-evolving wavepacket, West and is writen i Wosy = 1d where # =I and fi is Planck's constant divided by 2x. The TOSE may appear briefly inthe early parts of quanturn mechanics books io later on, when spectrascopie t tioa ates ave discuss. However, one mst be DSi lucky to find a full chaprer of 1 although because it describes the system's evolutio through tn tance to Newton’ equations in the world of What we have in David Tannor’s dna duction to Quantum Mechanies is an ad anced texibook in which the TDSE occupies {he rvonora the Chemical Sciences and Enprantag Den, Begone Ratena Lars 9700 Seth Cott Avenue, kigonne,IL6D439, USA Ema gay QU an 3 Fr ex surface and then seeing how it evolves according to the TSE, The Fourier transform oft cert rstion Infereed from ¥(x1) is proportionate to the Although t \der this description may sound a litle obtuse, 1o many researchers theoreticians and exper: mentalist alike—this is a tremendous conceptual insight compared to the banal time-independent picture of ‘certain matrix elements lv or integrals) i Also crucial were advances laser technology that have allowed expert menial researchon time-domain qu tum dynamics to bloom. For example Ahmed Zewail 1999 Nobel Prize in Chemistry eeeived the for his cexperimensal work that studied chemni- cal reactions in realtime with ferme second (10°! s) spectroscopy. In ad tion, the combination of substantial al advances duc to e Koslof¥ and others sacting in Ronn the 1980s and the steady ‘computing power now make the ‘oF actually solv than ithas ever been. “The book offers a thorough dite treatment of time-dependent {quantum mechanics with an emphasis fof atomie and mol Throw! understand the mathematical structure behind the pictures and concepts. The extensive reference lists and ocea will help them sional historical ne dose, SCIENCE Visual appeal. An inital sition state for ache (op) subseauenty (bet) biurcaes, leading to diferent rod arrangements (RB + Cand A +60. BOOKS ‘One recurring theme is the correspon: en quantum andl mechanies: how quantum motion is int mately connected with the behavior of a corresponding classical system. Part of the g back to dence bewe sical appeal of wavepackets. (go: ‘Schréidinger’ original exposition of coher tent state wavepaichets) is Uhat they provide & direct and intuitive quantum analog of classical motion, Tannor (a professor ai the Weizmann Institute of Science, Israel) lucidly brings out this correspondence through numerous examples and. at a more rigorous mathematical level, a chapter on path integrals and Tannor provides a rigorous, self-contained 4 ‘quantum mechanics and discusses numerous lopment of modern time-dependent applications in melecular spectroscopy and reaction dynamics, With its fresh and con ceptlly appealing perspes Quantum Mechanics could change how ve, Inirodution quantum mechanics perceived and taught wepacket“aunched” atthe tan faction involving atoms A,B, and 31911 JANUARY 2008162 AU) ENVIRONMENT Ocean Iron Fertilization—Moving Forward in a Sea of Uncertainty Lampit™ Antony E Mich Anudeew J. Wasson'* hie consequences of global climate I hange are profound, and the scien- nity has an obligation to tions of poliey options for e gas emissions and enhancing CO, sinks in reservoirs other than the atmosphere (2) ‘Ocean iron fertlzation (OIF). one of sev eral ocean methods proposed for mitigating rising amosphericCO,, involves stimulating rt phytoplankton growth by releasing iron to certain parts of the surface ocean, The international oceanographic community studied OIF, including 12 major field pro- grams with small-scale, purposeful releases of iron since 1993 (3, 4). Although these experiments greatly improved our under- standing of the role of iron in regulating ‘ocean ecosystems and carbon dynamics, they were net designed to characterize OLF as a carbon mitigation strategy. The elficacy by which OIF sequesters atmospheric CO, to the deep sea remains poorly constrained, and swe do not understand the intended and un- intended biogeochemical and ecological impacts, Environmental perturbations from OFF are nonlocal and are spread over a areaby eeean circulation, which makes long- term Verification and assessment very dif assess the rami "Department et Ware Chemisty an Geocbemisty, Wonks Hole Gcesnog USA. Shoo of Ocean ond Ea Scene ad Tol, f Han, Hens, MUSA Nara te Reseach, Cee fr Genial iat, Stanton, CA USA ives fae, Ora ME lbs Cony Eames ‘sthedotiire scence, SA Sos Landing Marne abort, as Lncng, CX, USA Royal Nearest lr Rese, eo ee The ethalands rte of Marne ad Coastal cee, uty ives, New Bruns Ny, USA Mri sy Aevaram Reseach Inte, Moss Landa, CA, USA National Ocanoxaphy Cente, Souhasotn, UK tient fr Envitnrerta Sule, riety of Seuthern Calfomi, tes Artes, CAUSA. "tena Insitute of Oceano, Ge, ica. Aled Wecener Inne for Pol and Marne Gernary. "Deparment of Aquatic Bice, Tey, Tolga Jenan "Schoo of Enrnmeral senes, Unies EstAnaia Non UK *futber tr cnrespndees Esai ues 2 David M. Karl? Philp W. Boyd*Ken Calde Paul G. Falkowski: Kenneth S. Johnson Richard S. 1S. W.A. Naqui." Victor Smetacek.” Shigenobu Takeda.” Fei Ch cult, Modeling studies have addressed sequestration more directly and have sug- gested that OIF in areas of persistent high nutrients (so-called bigh-nutrient, low- chlorophyll areas) would be unlikely 10 sequester more than several hundred million tons of carbon per year. Thus, OIF eould ‘make only a partial contribution to mi tion of global CO, increases. Despite these tincertainties in the science, private organizations are making plans to ‘conduct larger-scale iron releases wo generate cd tha, 2 yet, there is no scientific basis for issuing such ceurbon credits for OIF. Adequate scientific information to enable a decision regarding. whether credits should be issued could ‘emerge from reducing uncertainties: this will fonly come through targeted research peo- ‘grams with the following specific auributes carbon offsets, We ate con ‘* Field studies on larger spatial and longer time scales, because ecological impacts and ‘CO, mitigation are seale-dependent ‘© Consideration of OTF in high- and low- processes that are affected by in nitrogen fixation and elemental soichiometr. ‘© Detailed measurements in the subsurface ‘ocean 10 verify the fate of fixed carbon, including remineralization length seales of cearbon, ion, and associated elements *# Broad assessment of ecological impacts from bi 1eochemistry t fish, seabirds, and marine mammals ‘* Characterization of changes to oxygen distribucions, biophysical climate feed= backs, and cyeling of non-CO, greenhouse gases, such as methane, nitrols oxide, and dimethylsulfide ‘* Long-term monitoring and use of models Wo assess downstream effects beyond the study area and observation period. ‘¢ Improved modeling stuies of the results and consequences of OIF, including higher spatial resolution, better ecosystem parame terization, inclusion of other greenhouse _248¢3, and improved iron biogeochemistry. ‘© Analysis of the costs, benefits, a such as sions to understand a wider range of Itis premature to sel carbon offsets from ‘ocean iron tertilzation unless researeh provides the scientific foundation to evaluate risks and benefits, impacts of OIF relative to other climate and carbon mitigation schemes and to the impacts of global change if we take on of such experiments is as critical as the scientific design. The scope of the problem will require individ national -philanthropies, and com es. Academic Scientists need to be involved but must maintain ind. pendence. This can be accomplished by regulating experiments in a uniform man- nner under such international agreements as the London Convention, widely disiribut- c plans and results via open and peer-reviewed journals, and requiring clear and explicit statements of conflicts of interes This group feels it is premature to sell carbon offsets from the first generation of commercial-scale OIF experiments unless there is better demonstration that OLF eff tively removes CO,, retains that carbon in the ocean fora quantifiable amount of time, and has acceptable and predictable environ mental impuets. As withany lation of the environment, OIF ca potential risks, 2 well as potential bene OIF should only be done pli itly thar it will result in alteration of ocean ecosystems and that some of the conse quences may be unforeseen, We are cur- rently facing decisions on climate regula- tions, such as the post-kyoto framework discussed in Bali, carbon cap-ande-itade bills in the U.S. Congress, and consideration of OIF by the parties to the London Convention, and we feel that ocean bio- ‘geochemical research will help inform thes importamt policy decisions, moving forward Reterences Contig tf Aan Ru nan Seer 28,2 (Goos. 2. Sara Sco See 305, 9582008 3 HW de tae) Grpny Re 120, C0985 2009, 1 RM Roye eta See 35,612 (2007 ma r20eeee 15405, 11 JANUARY 2008 VOL319. SCIENCE wwwrsciencomag.orgA Few to Flip the Angiogenic Switch he pil ation of Boo vesels. a I osu aca ts Ue sanpipae Ich ie tequleed for pogrertion of dormant or micrometastatic tumors to rrosoronssallc inet tae New Wood eel wi cer ogre Ga peering Fetus onesor frm de ovo by ee o- ang endotelel progentior eels erred frm he Bone marron (7-3, Although these propiaters cin acerporsie eg) human tunes el unpaid thse, thy do toinarall quer ising cuba physiol conrbutlon fo heeangioenle process On page 5 ofthis se, Gr eta Cstany dubai showing hac noth Sending tei low nabs reruiment of thes endl roentr sls isp or tie progresion of arascuar nicoenatle hunts oichlnecroctaats one (. "Ny asthe bso muh conf? tna bs tht only eertin pet oftunors 7). producing dst poanpogenichencines CeatD, dead bore maror-detved {util propender elt nite (7 and Dombiyfuluta nace eels WH {ile primary and mctetatie lesions (2), Indeed tet of progenitor celinconpor- ions axial elon aos nd inoetlaangresive carcinomas (2. But probaly the phenoila sinuses beter Teestpoltc ele snd ie ante pro eater ot (howe with boe nae repo fxng pote) (2.3, and the ec ur ales tvoled in npg and leclling tha nie amen of finetonal Hood eels Ineome wou undies, fe majrty of ts Deas marrod-deiel 6 hance sk nda but of hematopoietic ineage and were positional pervasclly fer than Incerported into the vessel lumen (15. 16) eos lew per ov sear ater Gib ceeelal prises were pln ro rcplet bone er Tocireanvent ese probit, Gabe wack ental progenitor ey ike fp wits geet feorercet rea tnd by g Score te eipesinot ease he ators ae at HonardMoghes Metal ste Well Carnell WedialCatege, ew York, NY 10065, USA mt 200 gpd ern es aie ees vowwsclencomag.org progenitor ces Blood vessel stuctural endothelial cells Angiogenic Arelativey small number of endothelial progenitor celis havea profound effect on tumor growth and metstais switch Few but mighty. Bone marrow-derived endothelial progeitor cells cortribute instructvely to micro- metastasis and structurally othe emergence of macremetasiatctumer nodules including the ‘molecules VE-cadherin and CDS Aareceptor for vascular endothelial growth fac- ton), and Id, a transeription factor tha pro motes angiogenesis, sing mouse models of lung (metastatic mouse Lewis Lung earci- noma) and breast (spontaneous MMTV: PyMIT) cancer mle, the authors demon= strate that about 12% of the endothelial cells Within macrometasiases were derived from ‘bone marrow, Remarkably. when the expres- sion oF Fd was reduced in dhese small ruanber of progenitors, thcit mobilization from bone marrow decreased by 967, angiogenesis was blocked, tumor formation decreased and the animal's survival improved, The inhibition of [dl did not affect tumor cell dissemination or the inital colonization of ‘organs by malignant cells, but rather, shut aff the mobilization and retuitment of particular endothelial progenitor cells (those expressing Tel, VE-cadherin, and low amour of CD31). These specific progenitor cells infiltrated ‘micrometastatic Lesions and produced proan- siogenic erowth factors before the ination of -meerometasiases. Ultimately, subsets of these progenitor cells differentiated (10 express VE- cdherinand inereased amounts of CD31) and integrated into the lumen of tumor nenvessels ‘These data suggest that bone marrow-derived endothelial progenitors are unigue in provid- ing both insiuctve (paracrine) and structural (vessel incorporation} roles to promote tumor -macrometastasis (see the figure). They also SCIENCE VOL3I9 extend previous studies demonstrating that hematopoietic progenitor cells initiate mete static colonization (/0), whereas endothelial, progenitor cells promote progression of the metastaic lesion How ean bone martews- derived endothe: progenitor cells be distinguished from vumor endothelium or hema- topoietic cells (7)? phenotypic definition by specific molecules (including the pres ence of Id, VE-cadherin, VEGFR2, CD31. CD13. and the gnowih Factor receptor e-Kit, but absence of the cell adhesion molecule CDIIb and the phosphatase CD43) have been used previously to mark endoshs progenitor cells incorporated in the lumen of tumor vasculature (/2). However, some of these markers are expressed by subsets of hematopoietic lineages, and therefore pheno- typing must be carefully performed (2, 3. Another complicating factor is the potential contribution of recently discovered cells simn- ilar to endothelial progenitor cells resident within organs other than the bone marrow (8), Lack of functional standardized bioas- saysto quantify the scarce populations of true endothelial progenitor cells is a major hunle inassessing whether bone marrow transplan tations performed indifferent hboratories(2, 3.15, 16) results in engrafiment of sufficient numbers of pr their contebuti Therefore, establishing standanti functional assays to detect and_qu 11 JANUARY 2008 1637 PERSPECTIVES 164. ‘populating progenitors is urgently needed. ‘Majorissues still need w be resolved. eis unclear why endothelial progenitor cells are recruited only by certain tumors, Andthe role of proangiogenic factors elaborated by fie to) endothelial progenitor cells needs further investigation. Whether their ‘continuous recruitment contibutes to min= taining stabilized tumor vessels also has yet tw be determined. Retorences 1 tyne ot a7, 1198 2000, 2 Sato en, Benea KHOI Be. et. ee Cone 26.200. 5 Fen Sad, ean 5. rebel a Coe 6635 2008. CANCER 4 A Pte tte Med 1, 2612909. E tram ALA lone, €SRC£ May, Crelten 412, 2051 0009 Gan etal, Scence 319,195 2008 NB Resa ae, Cnc Cal 8277 D039 ¥, shah eta Caer Ca7, 201 265) 1 Stadt Seance 313, 1765 2008) RA Kale Noe 834, 820 205) est. RM, Rnd mo 28, 296 2007. 1}. Nano oCees Dee 24, 546.2007 0.6 Detaerl, Bead 107, 2974 2008) 1H Spe, She 6 er) Hammer. ans, roc Rat end $6, USA 202, 6111 2008 Dafa et al, Conceal, 21.2005, [Lester at ood 308,169 2000, N.C Yor eal, led 2081803 2000. [A hertel re Re 100, $61 207, PB ewan BEE BeRe azssdene 1183625 Quo Vadis, Specificity? Hors Schreiber and Dor 1d A Rowley Mutations in cancer cells can gi rise to tumor-specific antigens, but abnormal processing of nor ‘mal molecules in these colls can also elicit an immune response, Peeities d by tumor cells is one of the urea! hopes inthe fight against cancer, because ther- Apeutically targeting such molecules, of anti- gens, should eradicate cancer without harming ‘normal tissue, The extremely large repertoite Of T cells bearing distinc: reeeptorsallows the immune system to recognize antigens with great specificity and selectivity (On page 215 of this issue, Savage er al. (D report that T cells recognize a fragment of a Ubiquitous nuclear protein, histone H4, yet somehow bypass recognizing normal cells, infiltrating prostate eancer instead. The auhersaein he Depa ol Pata. Urvesiy ef chkage, Chicago, 60637, USA. Email hs) hdr onticogs eds Neral elt Fett (amor speci ene mutation Normal sel-aeigen vay Normal slt-atigen Tumor-spetic antigen be proceseddiferontly ‘Tolerance or sequestered in cell ‘May tigger an immune . + No immune response response Antigen: presenting cel 11 JANUARY 2008 Cancer is caused by somatic mutations and/or the introduction of genes from sncer-causing viruses, which leads wo the expression of cancer-specific proteins and Potential antigens (see the figure). This has Jed to the controversial idea ofthe evolution ‘of adaptive immunity to prevent the devel- ‘opment of cancers. All cancers in man (and mouse) that have been analyzed express ‘nora Fide imor-specific antigens that could be targeted by T cells. In some cases, the same tumor types share mutations and anti- sgens 2, 3), But each patients cancer seems to have a unique set of mutations (¢, 5) that ccan provoke a powerful immune response (6). When it was shown that canger in mice could be eradicated if the animals were immunized with their own, autochthonous scaneer cells, it meant thatthe immune sy tem could be primed for subsequent chal- lenge by the same tumor, bearing unique, immune-reactive antigens (7). However, unique antigens have remained tnexploited clinically. because highly personalized ther- apy would be required, The mice with p prostate cancers studied by Sevaye ot af. mounted an immune response 10 a nonmutaied peptide derived from histone H4, a nuclear pretein, Mt first, this may not seem so surprising, because immune responses of eancer patients often recognize molecules expressed by both ean- cer cells and some normal cells, so-called selFantigens, What is remarkable and unex- plained is that histone Ha is expressed not ‘nly by prosiate cancer cells but also by all normal somatic cells, yet was recognized fonly in cancerous issue by the immune sys- tem. Perhaps the histone HA anti processed and* presented” atthe cell surface nan unusual way by prostate cancer cells in response 10 the tumor microenvironment. If 0, is this related to the cause (2 viral onc gene in the mouse model used by Savage ef al, of the cancer? Ishistone Hs also recog nized as an antigen in spontencous human prostate cancers (and in other murine models ‘of prostate cancer)? No selfreactivity of hharmful effects by the immune system occurted in normal mice, even with the abundance of T cells (CDS? subtype) expressing receptors specific for histone Ha, T cells localized and proliferated in the ean serous tissue in response to the peptide, but failed w produce estotoxie effector mole~ cules or eytokines (such as interferen-) that could further boost the immune response, Not s0 normal. Now molecules synthesized in cancer cells may elicit tumor specific immune ‘esponce Cancer cell ean alsoenpres genes encod {ng sol-molecules that ae leased and presented 107 cll by artigen-presening cells inthe tumor. Sell-molocuies may 2lso be aberratly precessed ‘and recegnized by immune cell. Factors in the tumor microenvironment coud tigger these eflec. VOL 319. SCIENCE wwwrscioncemag.crgand there wasn increase in animal survival. ‘The reason for this immunity breakdown, is unclear. Antibodies to growth factors (such as vascular endothelial growth factor) growth factor receptors (such as HER-2), or self= antigens (Such 2s CD20, expressed by B. eclls) have become important in the therapy of other cancers. It is unclear, however, whether T cells that target selfeamtigens on tumors could be similarly effective, even if ‘normal cells expressing those antigens were dispensable, Self-reactiveT cellsare readily doleted and or functionally inactivated, and when not deleted havea reduced eapacity to oanize target antigens (S). When self- ctive T cells are made effective (9), autoimmune damaze may occur. Even though one ean generate T cells bearing recepiors with high (nanomokar) affinity for self-antigens that are highly expressed in cancers, it is difficult to predict whether autoimmune damage will occur if used therapeutically. Much depends on whether the selFamtigen is only expressed on dispen sable normal tissues, Whether ubiquitous, normal self pro ins ate sufficienly seleative _gets on prostate cancer wo allow tumor era ication without detrimental autoimmune responses by the therapeutic T cells will become apparent once any functional dofeets of the antigen-specific T cells have been identified and reversed. Similarly, for use in adoptive T cell therapy in which autologous human T cells are activated, expanded in vitro, transduced to express specific T call receptors, and rein- ised into the patient, it will be necessary to compare mutated and normal se gens for efficaey as targets. Although the Feasibility and safety of such engineered T cells have been demonstrated in studies tar- ‘geting the normal melanoeyte-differentia- tion antigen MART-1 (10), only 2 of 17 patients responded to treatment. The autol- ‘ogous T cells expanded in vitro and rein fused into these patients likely contained able numbers of T cells that recognized tumor-specific antivens. Procedures are therefore needed for expanding 2 patient's T cells in vitro so that they recognize the autochthonous tumor cells specifically, Such T cells may not only be therapeutic PERSPECTIVES I upon infusion but also may be used to eluci= date the genetic origins of mutated tumor- specific antigens As effective drugs are generated to tar ‘get specific mutated proteins, and 2s can- ‘cer treatments become “personal” (/1), it is ironic that individual specificity still has to conquer the field of cancer immunol- ‘ogy. After all, it was the discovery of indi vidually distinet tumor-specific amigens. that ended gloom in the field over 30 years ago (/2). References PA Soe a Sece 319, 215 (2008. Niece Aa Med. Bl 57, 992008. Sry eal Core As 61,5368 091. Dumber We, Seber Seni. rman 8, 25795 5. L bale a, Sace 38,108,200. 6 B.A. weet ot tre 43019520. 7. Go 10. Se, Kl K€ els, acer ‘20.1561 090. 8 Ziwet ai. cn es 106 331 208) 9. Busewg ea 19. e191, 79 (200. Fe Aer etd, cece 38 126 2000. FA Kb. See 312, 1157 (2008) MWA basa, Concer tes 30, 28581970, osnzbedenceaisa7 BIOCHEMISTRY Dicey Assemblies Jo! Janin reins a made of polypeptide chains Pisses ams cqusnoryscties (7) Meta a ears ae, cgi Monod tnd corners Uvcopedite toy ase hae Ti ett pees on beat ey replated. The query stature allows proistotanesynnmeris hap ace fom aloery 29, Can hs ymmnety be manipulate by shecered agen? Oa pgs 206 Green ger poe that can) Their experiments ont ste of tet aunts my Monae Monol fa ated, en yrancral exer (a prtei ade of era pp fide chai) with deel sequences, every stele or inert roped 4 Befwoon two subunits wl ae al syne tryesnel conacte. For exmple a the Blechinie et Bophysque Molecular eCeluare, 6a 430 LAR 619 CHES, Unverst Pau, 91408 Ory, Fence, mat jatjeingu-pustt wowacioncemag.org, ‘Monod's dice. The dimerization mutans of the urocanase and Rua pic- teins prepared by Grucringe et. display the symmetnies illustrated here by assemblies of 7 dice. (Left Dihedraltno-old (0, symmetry (n= 4), (amide) cinedal four-fold (0, syrmecry (n= 8), (ight cyclic threefold ). Each ei represent 3 polypeptide chain, (synmety @ cightdice assembly shown in the figure, the dice form owe layers, exch with a C,(eyelic four-fold) symmeiry. The layersare related by two-fold axes that give the assembly a Dy (Gilvcral four-fold) symmetry. The snes form the imerface between the layers. [fone dot in each six is removed, that interface will SCIENCE VOL3I9 Site-directed mutagenesis allows the symmetry of protein assemblies to be ciected ina systematic manner Jose a vora of eight dot- dot contacts, “Monod eral. remarked that “mutations which ab- ‘lsh he interactions should fesquently be found tore sult in stabilization of a ‘monomeric sate” 3) and cited examples of muta- ons ofthat type ident ficd by classical genetics. Yer when molecular genet- ics allowed the introd= tion of uch mutations in a rational way, converting an oligomer into a stable monomer proved tobe dif- ficult, Mesatempts yelled products that were highly unstable and insol- uuble, because nenpolzr (and hence water- repelling) protein surfaces become exposed to water when subunit interfaces are dis rupted. The few successful cases all involve multiple mutations that make the interface less warer-repelling (3), 11 JANUARY 2008 1657 PERSPECTIVES 166 However, Monod ct als reasoning applies noc only 0 the destruction of a symmetrical oligomer but also wits creation: Any change that ean generae a favorable subunit contact inan oligomer with cyclic n-fold symmetry (C,) will do so 2 times, leading to dimeriza sion. ifthe contact is competible with dihedral afold (D,) symmetry. Contacts not compatie ble with Such a symmetry can still promote subunit association but will generate an in nite helical fiber rathor than a closed structure A\ classical example is sickle-cell anemia, in ‘which a point mutation in the B chain of ‘hemoglobin causes the protein to polymerize In other systems, conformation changes ratherthan mutations may causethe formation fof. fiber, and this can also lead to dimeriza- sion. The prion proven implicated in neuroe~ generative diseases (such as bovine spo Form encephatopathy in cows and Creutzfeldi- Jakob disezse in humans) undergoes both ‘ypes of self-association under different condi- ons (6), Thus, fiber formation and dimeriza- tion ate related, frequently observed, and pos sibly cempeting natural processes GGrazninger er al. have now achieved both dimerization and fiber formation by site= directed mutagenesis, engineering new sub- unit contacts in five different bacterial pro= ‘eins, They used the known crystal sructure of «hese proteins to model assemblies with a Wo fokdsymmeny and to select aminoacid Subs tutions that introduce nonpolar side chains at ‘he modeledinterface. They then generstedthe ‘mutations, purified the corresponding mutant proteins, and checked their molecular vweight by size-exclusion chromaregraphy and dynamic light scattering, They also erysial- lized several mutants and elucidated their stracturesto valida their solution data, In the cases of 6-phospho--galactosi- dase and O-acetylserine sulthydrylase, sev- eral mutant proteins showed! various degrees of dimerization in solution but did not ery lize, Inthe eases of urocanase and -tham= nulose-L-phosphate akdolase (Rua) substi tion of one ora few residues resulted in com: e dimerization, and crystal structures med the presence of extensive new ces involving the designed contacts, Urocanase is a C, dimer: subst tion of three surface residues yields a tetramer with approximate D, symmetry. Rua is a C, tetramer; single substitutions paver it xo vo diferent octamers (one with the D, symmeuy of Monod’s cightdice assembly, the other with a lower symmetry), A\ different Rua variant with three substitu tions aggregates into fibers Inanothersystem described by Gnveninger ct al—the bacterial MspA porin—dime tion results rom a deletion. The porin (a mem- brane-bound C, octamer) becomes a soluble Dy l6-mer afer the membrane-immersed part isdeleted. Acrysal sructureconfirmsthat the coniaet between oetamers involves the large protein surface, mosly nonpolar, revealed by the deletion. Thus the set of proteins prepared by Grueninger ef af. shows a variety of re- sponses to point mutations. Nov all the engi= rcered assemblies have the expected symme- ‘ry: some are only marginally table, or they aggregate instead of dimerizing. But on the ‘whole, the data indicate thatit is relatively ea ‘o convert a protein with 1 identical subunits stocne with hviethat number, at east for L subunit ier! ‘The suecessfil dimerization of three bac terial proteins by Grueninger eof, has impli- cations for the evolution of protein quate nary structures, The new subunit contacts ‘ereated! by mutation or deletion must show some specificity, because the mutant pro~ veins do not ageregate in the crowded ba ial cytoplasm, where they fold and assemble correctly, How can specificity arise in the absence of natural select The answer may be negative selection (7). Ina eytoplasmie protein with i sub- units and C, symmetry, nonpolar side chains must be disallowed at any surf site where they could stabilize an assembly with 2n subunits and D, symmetry. Mutat fons not compatible with that symmetry still promote aggregation, but a helical fiber lacks the multiple contacts that create ‘cooperative effects in a D, assembly. Thus, a single mutation may not suffice to stabi- lize a fier, unless the protein is present at 4 very high concentration, such as hemo- globin in red blood cells References 1. raestom ng | Sebati Te Ems 0. oper eater ss New Yo. 2.1989, Vol pp 5-510 2 era |e Caeoe FED Hol a 6306 Gs63. 2. Jr, yma 1.8 ange) Ma 32.28 (ses 4 D-Gnaingre a. scence 8. 206 2000, STAC Boene Aan ei. een Pe et Ace Se USA 9, 1515 1990) 5 MEP aiont Me Saya Dene Stace 8, 1. 0.8. utay 6 Stkhnove,) esa Salih | Ho Bal 365, 1896 200. on26adere 1152099 GEOPHYSICS What Triggers Tremor? Eliza Richardson and Chris Marone anager in peopl A stereo sot conmnly ger eau if eases cpl presen eng some esl bre are of ok ta foes thaloen rigger us ar me by" mahing them ater the esto Hower nye show tht ast theca step mci mons (0 ‘The asters ae athe lute Nationale € Geotcca © Vulanobogia Rome, ial, and the Department ot Geoscences,Peesyvana State Univers, Univesty Pn PL16402, USA Ema elipgeoc psec Now, on page 186, Rubinstein ef af, report that a seismic activity called nonvoleanie tremor is indeed triggered by lunar-selar tides (3) and, in some cases, as reported on. pave 173 by Gomberg e¢ a, by distant ‘earthquakes (4). Discovering how dynamic stresses trigger Fault failure may provide important clues about the onset of earth- (quake rupture, Earth tremor episodes involve quasi ‘continuous emissions of low-frequency seis- mic enengy that last longer than ordinary ‘earthquakes. Tremor is well known in vel- ccanie settings, where it is associated with Tidal forces and distant earthquakes can increase the low-frequency rumbling that ‘occurs where tectonic plates collide. ‘magma movement and fluid-cavity reso- nance (5. 6), The recent discovery of tremor in nonvoleanie settings (7) has inspired multi ple groundbreaking studies (8-/4), An «emerging question is how nonvolcanie tremor rates to aseismic (that i, radiating no mea~ sirable seismic energy) Fault slip simultaneously and in predictabl episodes in at Teast wo locations where they have been studied extensively (8,15, 16),The jon of nonvoleanie tremor with Fault iggests the tantalizing possibility that tremor gould be used in earthquake forecast- sitisin predicting volcano eruption (5). 11 JANUARY 2008 VOL319. SCIENCE wwrsciencemag.orgRubinstein era. fourdta clear correlation berween the domi- rant tidal foreing (at periods of 124 and 24 hours) and the umplitude of tremor along the ‘ascadia subduction zone off- shore Vancouver Island, Canada Tremor and aseismic fault slip recur periodically every 14 rmonihs in this area (8, 13), and tidal stressing modulates tremior implitude only during times of active tremor (3). This is an Important point. The work of Rubinstein era shows that tides are not sufficient to trigger tnemoe at arbitrary times during the cyele of repeated failure. In this sense, their result is actually ‘quite similar to tidal triggering of volcanoes and ordinary earth: quakes, when tides. primarily trigger earthquakes during times of extreme activity, for example just before or afier hinge earth: ‘quakes (/,2.17). In concast, @ recent study LU#) shows that the Cascadia tremor was triggered early in the failure cycle by the passaze of surface waves fom the magnitude 7.8 Denali, Alaska, earthquake on 3 November 2002, The Denali carthquake triggered the Cascadia tremor roughly 3 months before the predicted tremor episode in February 2003. Surface waves from Denali caused a spike in shear tress on the subduction interfoce at Cascadia (14). ‘much higher than the stress from tides (3). This implies that tremor ean b arbitrary times during the seismic ey long as the perturbation amplitude is cient and its orientation is favorable vo shear failure, Laboratory observations of triggered fictional stick-fip corroborate the ie. longer-amplitude perturbations are needed to trigger failure earlier in the seismic cycle (U3). In addition, both Laboratory experi= ments and earthauake studies suggest that complex combination of amplitude and fe= quency of dynamie stressing dexermines the ‘viggering threshold 19). The mechanism of noavoleanie wemor is poorly understood. Belore the work of Gombery eal, all studies ex have observed tremor where te ue subalacting. Asa rest, exph focused on uid migration and thermal release of volatile elements in subduction zones. The discovery by Gomberg et af that surface waves from the Denali earthquake triggered remor in rutiple locations along wowacioncemag.org, (ited sie fr earthquake rupture ‘amr goneratng si tees Tides and tembiors trigger tremor. Volcanic eath tremor often ‘generated by movement of magma, Nonvocanictemor may repre ‘ent starms of smal sp patches (Fed shaded regions that ace ‘only low-irequency energy. Rubinstein etal. and Gombere etal. show that prioic stress caused by tides and remote seismic activ- ity can increase nomvelcaric teror. The patches may then coalesce (Gashed line) to produce large earthquakes. the North America-Pacific plate boundary in ‘California suggests that these may not be the only viable mechanisms. Theoretical studies based on laboratory data suggest thot tran- sient, aseismic slip can arise spontaneously ven the right fault rheology (20), This see- nario is consistent with recent studies in Japan (10-12) suggesting that nomolanic tremor arises from shear failure on quasi dynamic slip patches that radiate low-fre= ‘quency seismic enengy: Shelly ef af. (/2) show that tremor can be explsinad as a swarm, of slow, low-frequency earthquakes. Thus, ‘central remaining question is: What causes ‘low fault slip? Special conditions appear to be necessary to limit acceleration during shear instability (2/), yet seismic obser= vations ofslow and sileat earthquakes ind cate that this mode of deformation is wide- spread (22, 23) ‘Tremor may provide clues about the onset of earthquake rupture. All earthquakes are thought to nucleate as small patches of unstae ble slip, with some events becoming large ‘earthquakes given the right combination of censray release and spatial homogeneity of uh. Tremor may represent slip on series of subcritical fault patches that radi- ate low-frequency energy (see the reflecting slip acceleration belore rea critical size associated with fully unstable behavior and high-frequency seismic radi SCIENCE VOL3I9 PERSPECTIVE sion. This idea is consistent with results from studies of small earthquakes, which docu- ‘ment the acceleration of rupture velocity and the resulting initiation of high-frequency ‘energy radiation associated with quake rupture (24, 25). ‘The studies by Rubinstein er af and Gomberg et ai. can guide future efforts to characterize norwoleanic tremor, both in ‘erm of observations and through laboratory ‘experiments. For example, how widespread is the occurrence of tremor far from subduction zoncs? Is nonvoleanie tremor triggered by small earthquakes or vice-versa’? What isthe recipe for triggering tremor via stress tran= sients (i.e. what roles do amplitude, fi quency, time during the seismic eycle, oF orie entation of the remote perturbation play’)? How do tremor, earthquakes, low-frequency seismicity, and aseismic slip interact in and space? Earth tremor represents one o awide spectrum of behaviors ranging. from aseismic fault ereep to ordinary fast earth- quakes. Future geodetic and seismic net- ‘souks should help us learn much more about these phenomena, References 1 ALE Tog ever, Oat Ea, Geen 30, sos ceca, 2. ES.coee (008. 3. Rabat, Lt Re) Eile 6 Geng, AG Wen Sdence, 319, 16 210, 4 | Gmbrg tt, Sen 328,179 2008, 5. Rome Ane or le $33,464 008. 6, L Bre a, Gest 95,283 2007 7, Ke Oban, Scece 296, 1679 2900. 8 Rage, HDrge, Sine 30, 19222003 9, RM Maen, Onn, Sence 07,389 2009, 10, OLR Shel 6. CBee, Se Nakane, Naor 2, 106 G00, 1 Sid O.R Shay CC Beam, Cease 34, aaoznzoocidzies0 cen. 2 B % ible, 5 ata, cence 306,164 Dik sol. Cees 5. le, Nore 46,205 (2000. 1. Bc Aer Glgy, 35,907 Geer. 573 Goon. eben, 0 Sane LL Rabin a, tre NWT Mets Seen 295, 2423 0003 26, 1 Ot hie, Yama, Kaur, Geophys Ae, Let 31, 101039200461 620886 (2008 1, tah Sine 297,348 (202 18. H.Soae,C Mone, Geophys Po 12, 80230, so.a2hi0asa000330 200 29, Rak ring € €.raty Dal Sel Se Am 96,371 2000. BD. Jui}. Ga, Pre Aol Geopys: 12,17 0988, 21. Nef € aan). Geophys. es 203, 13919 0. 22. GC bay eta] Gey es 95,2885 (50, 2B, J Mev, Meat THe, Mowe 434, 487 G00. 24, Chardon Mon bull Sima Soc Am 92 ‘706 2002, 25, LE Roem Re, Gop J 162,406 ccs. so rssceree 3152877 11 JANUARY 2008 cll 1677 PERSPECTIVES 168 CHEMISTRY Not So Simple Sohn Brauman T nisms. These mechanisms can be characterizedin terms ofthe number of molecules involved. geometic and structural features (including stereo- chemisiy) the presence orainence of intermediates andthe timing of ind vidual Seps. Knowledge of mecha nism is titical for predicting how ‘molecules may reactand for inventing ordeveloping new reactions, On pase 183 of tis issue, Mikosch ef a. (1) reveal devils ofthe timing, siuctaral changes, and energy exchange in @ paradigmatic re. hrentretieon r= CH C11¢1 + 1°. The work elegantly combines experiment and theory The action sted by the aithors isa simple example of a nucleophile dlsplacement(S,2) reaction, whishhas an exceptional place inorganic chem- istry because ofits apparent simplicity and sts utility, In this exetion, the rucleophile X- reacts with RY, which canbe any of wide variety of organic chemical structures, ving the products RX ante leaving group The Sy2 reaction is sensitive to the cond ‘ions under which its earl ou (2), suc vshatherit sperormed in soliton on the gas phase (soe the figure). Because the gas-phase reaction occursat lor presse there isenouzh nergy to eros the eaction baie. The sol tion reason is much slower. beans the reac ‘ants ae stabilized by solvation moce than the transition tate iss only a smal fraction ofthe mis has enough energy to proceed to oducts tany given time(3). ‘Mikosche a now use molecu bears to provi deled analysis ofthis eatin nthe 438 phase In these experiments, the tempera ‘ureand collision velocity ofthe reacting mole cules ean be contlled separately. The dire ‘ional dstrbution and veleiy ofthe products seveats much about the times involbed inthe reaction and—from considerations of conser= vationof eney—thedistbaton of ery in he detils of molecular trans- formations are often referred ro aschemical reaction mecha reactions The authors tho Department of Chemisty Stanford Universi, Stafore, 84305, USA Ema: rama sted 2 as phase Soltion Reaction coordinate Images and insights he abil to nage the eynamice af on molecale the gas phase allows ce insights into the details oa casi ‘organiccreical reaction, a repored by Mkosch eta. in his sue the products as kinetic energy or internal (ibrational enemzy. Recent advances in d tion allow the data to be accumulated and displayed as images that reflect the relative amountsof product produced ateach energy in every direction (4). This technique has been used 10 suly reactions of neutral molecules 6). The authors now apply ito re ‘ons nith molecules, ‘The details of solution reactions are often snferred rather than direcly observed because collisions with sobent control the trajectories ofthe molecules, so that the behavior ofthe ini- tially formed preduets cannot be deter In the current ease, the solution reaction is essentially a simple, one-step process in which the nucleophile attacks the neutral subsirate tions of stereochemical nversion of configuration reka- tiveto the starting material. Molecular dynam- ses simulzrions shen, however thr interactions with solvent ean cause products t retuin to reactants and eross back and forth many times before finally completing the reaction (7) Mikosch et af. now provide considerable Adevail about the resetion in the gas phase. At ‘Armolecular-beam study ofa classic organic reaction shows that its mechanism is more ‘complex than previously assumed. low collision energy, the reaction prod ets are distibused isotropically that is, equally probable in all directions showing that intermediate X“+RY complexes persist long enough to undergo many rotations, ‘At higher collision enemies, a new mechanism appears: The I departs direcly long the axis from which the Cr emers, and most of the energy is retained as kinetic enengy in the I> product. In this “direct” reaction, the ‘complexes do not last long encugh to rotate before the reaction occurs, Depending.en the calison energy, the “original processand the new processes compete, with the direct reaction becoming increasingly important as the collision energy i inereased. Direct eynamies trajectory simukt- tionsalsoreported by Mikosch eral. are consistent with the experiments in terms of energetics. but also show important details thatthe experiments do. aot completely reveal. At even higher collision energy, the indiect reaction reappears, but with an unex pected twiss The incoming CF collides wwithand inducesa rotation of CH, followed by hackside stack and displacement, Thisprocess «an involvermultipk rotaionsofthe CH,l,anda sina faction ofthe tpjectories show transient trapping inthe posereaction complex. The study by Mikosch ot af. ilusrates the exceptiona insighs imo deals of reaction dynamics that ‘ean be obiained with molecular beams. As more reactions are sted with this technique it should become possible to generalize and rmke predictions prior to detailed experiments ‘or calculations, Relerencer 1 lest el, ence 39, 183 20D. 2 E vty 0. A Dauphery, den PylOgenic hey Wriesy Sec Bos, St CA 2010) ap. 32 3. ML Lubin 6. Cig CK. ego | aun, Seine 279 1802 (150 4. lest el, Phy Oem. hem Py 8, 2970 Geos. 5. inde: Phys. Chm, 52, 139 (2090 5 M.S lvl 0 Chaar, See 302 1540 1203. 7. eg, 8.) Gee KR. on 1 Hye Pete: hy 06, 356 0987. nace 1152887 11 JANUARY 2008 VOL319. SCIENCE wwrsciencemag.orgClimate Change, Deforestation, and the Fate of the Amazon Yadvinder Math }. Timmons Roberts, ‘Wenhong Li? Carlos A. Nobre® Richard A. Betts,? Timothy ). Killeen, The forest biome of Amazonia is one of Earth’s greatest biological treasures and 2 major Component ofthe Earth system, This cent fom it Teces the dual threats of deforestation and stress ate change. Here, ne summarize some ofthe lates findings and thinking on these threats, explore the consequences for the forest ecosystem and its human residents and outine ‘options for the future of Amazonia. We aso discuss the implications of new proposals to finance preservation of Amazonian forest. T: fore of Amazonia (/) covered shout $8 mien kn? in 2001, agyroxirnaty Mode nisin extent 2). with in Brvil They host petaps a uarer oF the words tenesaial species (3) ane account for ahout 13% of photal ere phnesahesis (0) Euapction ad coensation over Anaacia ae engines of the global amnosphetic i ulation, having downs elas on psp tation across South Armerica ad Father ald acrns the Nogom Hemisphere (5,4) Anawo- ni fonsss have ben an importa’ and eo tindous part of Each sysem fuetining since the Croucoous By 2001, about 837.000 kin? of Amazonian fens ha bes eleag (2, wilh 1990s ares rates of ~25000 ka? year (8). Cha concentra in the “ae of defiresttion” om the southern and easier margins, driven prineily by expansion of cathe and soybean predoxtcn, and along the Andcan piedmont. Amavonia ies inside nine nations, but 80% of dooresation has been in Brazil (2) and 70% of that is provoked by cate ranching. Fro 1988 v0 2006, dotorest ation cates in Brann Amazonia avcraged 18,100 ka year, recom reaching 2700 kn year! in 2004, Brazilian deforestation rates had mors tra halved by 2007 1911000 an year haere ‘of a combination of illng prices fo so, increas steryth of the Brian currency, and acive Brazilian govemment intervention (9). Revly ‘6% deforested land has resid in exopane 62% in pasures, and 32% in regrowing vei tion (0), The overall dnc forint of hurnan activity in Amaaonia is much greater than dor “envtormental change rst, One Urivesiy Cece forthe enstonet, South Forks Rea. Oxer OXI 30, Uk. colege of Wil and May, Wildomar VA 23197, USA. Met Oi Hae Cee, ter OX1 378, tke “Caseration ierntenny Waster GC 20036, USA Sth. of earh and Atmosere Silence, Gag Insiuge of Teal, Aarts, GA 30332-0540, USA “insta Mana de sabes paca, 50 Hse dos canes. Bra “To wham cospantence sould be adlessed. Ema saibinermatigowe oxack yn scioncemag.org «station alone and includes loging, huning, and leckage (soe supping online text) Global Drivers of Amazonian Climate Change In recent docks, the rae of warming in Ama onia (J7) has boon about 025°C decade Under midrange greenhouse-gas emission nario, tomperatures aww proxcied to nse 33°C range 1.8 0 5.1°C) this century, sighly more in de interior in the dy season (12), or by’ upto 8°C if subsantial forest dicback affeets regional Diophysial properios 3). AC the end of the las glacial period, Amazonia, wanned (14) at only -0 1°C comury Changes in precipitation, paticubaly in th Probably the most eric dete ‘minant of the climatic te of the Amazon. There thay been a dying rend in none Amazonia ince the mil-1970s and no consisent multi docile! in dhe south (5), but some gal climate models (GCMs) project significant Amazonian drying over the 218 century, Pacific sea sufice taperata (SST) saration, dominstat by the EI Niio- Souther Osillaion (ENSO), is particularly important for wetseason rainfall EI Nifo events (warm eastem Pacific) suppress convection in norinem and caer Amazonia However, éry-scason rainfall is stay inthae enced by the tepical Adantie nonh-south SST adie intensification of the gradient (warm: ng of nether SSTS relative tothe south) sills the Intrtropial Convergence Zone nomads ingeramnual time seaks) and sremphens the Hadley Call cicultion (longer time scales), er Ihancing the duration axl inissity of the dry seseon in much of southern sid casters Arnazonia (26), a8 osc in 2005 nex sabi in the Athi grades ntuenoad by remete for ing such as ENSO ana the North Adantic Os cilltion, as well as by varixions iy evperation induced by suenghhering weakening of the local tradewinds (77), On longer time sees tbe Atan- fie SST grads may be stxnzthned by changes in the mah Allan, sueh as changes oF Ue ther- imchalne civulation diven by subpolar melting SCIENCE VOL 319 (U8), 0° a warmer noah Atlantic associated with ‘warmer neither hienisphste continents Forest influences on Regional and Global Climate Amazonian fress have @ substantial iaflaenoe fon regional and global climates, Hence, their removal hy deforestation can self be a diver of cfimaze change and 2 positive feedhack on ex- ternally forced climate change. They store 120 30 Pe.C in biomass carbon (79). of whieh 0.5 Pg C year! (0310 1.1) were deforestation inthe 19905 0), mounts may be bald in soil carbon, but Use are less vulaeable 40 bn after deforestation (CO) Ia scion, forest plot studies sages hat intact forest are a carbon sink (-06 Pe C ye (2), parieubely in more fete Wester Ama- zonia, The exience of this snk i debated ( but is stongly sepported by a necent rovaan tion of global sources and sinks of atmospheric carbon dioxide (23). It may be dkiven by ene hanced productivity associated with COy fri ‘zation, changes in ight regime, o oer fiers not yotientitied (2). ‘The extaction of sil water by tee ro9ts wp to 10 mdoxp, and its return tote atmosphere a is pets the most ime portant regional coosystem service, Basin-wide, 25 to 50% of ranfll is recycled fom forests (C5), but this effets particularly important in egions wre mos precipitation i derived form local convection (see below). Moderate and foe calized deforesstion may locally enbance com rgescale fest hose tends 10 reduce minfill (26), the magnitude of reduction being dependent on how wepional t= sultion of tmespheie moisture afi, Some monk! sts sugyes that the lime system may have two sible sates: Re- mval of 1010 40% ofthe forest could push rach fof Amazonia ino a penmuancntly dcr lite = sime (27), Dry season rainfall, the mest eitcal foe determining vegetation putems, is more often driven by lowaly gered convestion and may ‘he moe strongly afecta by detoresation, Loss of forest also results in (i) decreased clouatness and increased insolation, i) increased Tara surface reflectance, approximately oft ns chou fee (2, (il) changes in the aso loading of theatmspiew fom hyperean “groom ‘ocean aamosphere 10 a smoky and dusty cone ntl atmosphere that can mod inl pat terns (29), an iv chmges insures roughness (Grd hence wind speeds} and the lawe-scale con. vergsnce of atmospheric moisture tha generates preepitation (13), Risks of Amazon Forest Loss Due to Global climate Change Risks af a drying climore. The climate models employed in tbe 2007 Interzoveramental Pane fon Climate Change (IPCC) Four Assesment Report (/2) show no consistent trad in annual, 11 JANUARY 2008, 169170 VIEW Amazon-Wide rinfll over the 215 century, but 4 tendency te less dey season rain in the east and more rain in the west and in the wet season (Fig. 1, Taki the ensemble of 23 IPCC mod elvava crude metic of potable, some inter sifeation of ey seasons is about 80% probable in the southeast Amazon and Guyanas, 70% in the eas, 60% in the cater, and 30% in the west 0% > 20% > 50% cow caw OW Fig capture key clements of Amvonian climate ‘ariabiliy is nocd Whon the eflets of rising (exapasisce on evapotnsyation are inched, almost all models indicate increasing seasonal ‘water deficit in casts Amazonia (30), This Grying i exacerbated by ccosysem Sedbacks such as font die-back and reduced transpiration forests 3), osRgsesase Beseeses <_< osRssessss 8 8 2 1. A metric ofthe probability of enhanced drought in Amazoniz: the proportion of 23 ctimate models that show a decline in rainfall between 1980 to 1999 and 2080 to 2099 under midrange (228) global greenhouse gas emissions scenarios. (A) Any decine (fainfall dectine > 0%); (B) substantial decline (rainfall decline > 20°41; (C) severe decline (rainfall dectine > 50%). Dry season rainfall is particularly impoctant. Left column: December-January-February (dry season in north; right column: June-July-August (dry season in central and seuthern Amazonia) (Fig. 1A), The probabilities of mare subse decline are slightly lower. 70% inthe sous 607% inthe Guyana, $0 inthe cas KP inte ‘enter, and 20% inthe west. The probabiis of severe decline in dey season rainfall ate 50° the southeast, 0% in the Gyarns ant eat, and iM inthe center anal west. This metic is net ‘dal, ss models may share systemeaic biases and vay in thir ability to represent curt Amaia ian climate, most understate curert Amazonian rainfall and most do not incomorate the cima feedbacks rom forest ks. Tae, 4 mere cartil evaluation of rae ability 10 11 JANUARY 2008 VOL 319 SCIENCE “The zone of highest drought risk (south cast and cast) is also the zone of most active deforestation (Fig. 2). Deforesiation-riven changes in precipitation may be strongest in the castera dey corridor, 700 km inland from the coast, where geographical positioning re- sulin oscan-generated squall lines passing tough the region at night and being enable to trigger mach rainfall (37), aving a greater fraction of precipitwion gensrted locally. This, ca includes important agricultural and ranch ing foenirs that ae experiencing high levels of Aefersstation. In contas, the nortvestem Annizon is least likely to experience major drought. The high prciptation inthis region is conte by m0 ture convergence force by the Andes although itinay be vulnerable wo reduced prexipitaton re cycling upwind ia eastom Amazonia, This ston hosts the hiahest biodiversity and has been least affected by historical climate varsity and band use “The Andcan flank ofthe Amazon has excep tional rates of biodiversity, adjoins the most bio. diene regions of lowland Amazonia, and alo hosts. a mumber of orographic wet spots i other: wise dy ans (32). As conditions warmed end of the la ice ae, the Ans acted as ein fix many “lowland (now exchisvely Andean) tree spocies that were illadapted to warming topes (33), Andean cooysiems have their own fon of Vaerability, however: The ou foress betwen 1500 and 3000 m clear tion are ssceptble wo drying as cloud eves se face of warning temperatures (24), and higher elevation restricted endemics would be posticularly vulnerable Resilience of Amazonian forest ecosystems, Undestanding of Amazonian forest processes has greatly achaanced rough the recent Lange Scale Biosphere-Atmosphere program in Am zonia (LBA) (25). Thete is mounting evidence ‘fom anificial drought experiments (30), ux toviers and satellite remote sensing of forest, _goenmness (37) that inact Amazonian fore are more resiliet (although not invulnerable) te climatic drying than is currently represented in vegotation-climate models. Fist, dry scason ‘supply i grealy enhanced by rae sys toms accesing deep soil water and redisribut ing it ino the surface sl dough the process of hydtaolic lif, enabling the whole forest coo ain high aspiration and phox (38), Second, plant acelimation igher un derimenal elfets below 45°C [when proteins begin 10 de- nature (39), altbouh scleetve achantage by noved species may case changes in comm nity composition, as ogcuted athe last glacial ierglacial vransiion (33), Fially, ising COs may improve plant water use ellcioncics and offset tbe negative transpiration eflets of rising termporatuns, Southern Amazonia was consid: ray drier as ecenly 36 the early-mid Hole ‘ane, yet the region seems to have remined lgely forested (3), ‘The Interaction Between Human Pressures and Forest Resilience ‘The speed and mynitue of current human pres sures on forests are affecting forest resin. Forexs close 10 eds are vulnerable to elevated dssication, wee morality (40). and fe inpacs. Rain foress may become seasonally Dammable in dry year, but without aethmpogenic ignition sources fre isa rare occurence. Hence, fi has nn scioncemag.org,that allow them to survive even Lowi fires (41, Fie we for land management is. neatly ubiquitous in rural Amuzonia. About 28% of the Brazifan Amazon faces icipiot fie prc sure, being within 10 hm of a fre souree (42), Loawing and forest fagmentation also increase the flammability of forests by proving substan- Fig. 2. The potential ovetap between deforestation and diate change, Potential loss in forest cover (bronn) by 2050 under (A) business as usual and (B) increased governance scenario [derived From (2), superimposed on the Probability of substantial drought, which is defined as a >200% reduction in dry-seascn rainfall by the late 21st ‘century, 25 show in igre 1B. The dr season is defined as from December to Febxuary Gouth ofthe equator and from June to August north of tne equatod Precipitation scenarios ae from mic-ange 1B) glabal greenhouse gas ‘emissions scenarios, from the 21 clmate models employed in IPCC Fourth Assessment Report [exacted and medified from (25). til combustion material, cpening up the canopy and drying the understory and iter layer and sally increasing the amount of dry fireprone forest eg. This synergism henwcen fgmensa- tion and fire is becoming increasingly important, with 21600 10 50,000 km? of new fest ee being created annually in Brian Amazonia alone (43) Once buna, a forest becomes mare ‘vulnerable wo further bums (4), loses may pie mary forest species. and decreases sharply in biomass (47). A tipping poi may’ be reached when grasses ean establish in the Forest under= story, providing a renewable source of fal for repeated bums. in scenarios of increased drying, it 6 pose sible 19 ee this logging, fragmetation, cesi- cation, and repented uring 3s likely fie for many of Aneionia's frets, The 2005 drought provides evidknceof tis in soutnvest Amati: Remote forests remained fey’ unafista, but thew was subsanial penetration of es teen aggicutura awas into surounding, temporanly ‘ananable frosts (45). Despite the very rent slowdown in defor. ‘tation rates, there is portal for extensive dorestaion in Amazonia, 2 more roads Weth ‘offical and unplanncd are bai dhrough its core and conpeet aeoss © Paciie por ands inter= national demand for tropical timber, soybeans, and frecrange beet contin to gro, panicu- lacy from rapidly expanding Asian exonomies yn scioncemag.org (2, 46, 47) Existing pressures might be exac= crtaed by accolorating worldwide demand for biofels Current plans for infastructure expan sion and integration could raduos fowst cover fiom $4 milion ku? (2001, 87% of oxizinal tea) 3.2 million ka? (53%) by 2050 (2) (Fa ). This excoeds the likely threshold for rain- fall mainenance and would emit 32 = 8 Pg of carbon. Deforestation will be more concentrated inh south and cast, with >40% forest ess, and along the Andean picdmon, isola ing lowes from potential biotic rege inthe «cooler mountains (46). In this seer the now swestern Amazon is prvectel by ts embiness and wetness, but longer tr, his region is alo vultable «hydrocarbon exploation and ilk pal plaristions that are suitable for wet clic ‘mates and acid soils and have akcady replaced many of Asia's tropical minsorests (46). Drying ‘of Amazonia, whether caused by loal or gia river, could greatly expand the area suitable sugarcane, aselerating forest Planning for Climate Change ‘The probability of sibwatially enhances drought 1B) under mid-range greenhouse gasemis- ns semnarios ranges from >60M% in the soutls east 1) <2 in the west The severity of this ott threw mis planing for devslopraen, ‘conservation, and adaptation in all regions. Even iF the drought does net come, a well-conccived and implemented plan will bave buik resilience imo the Amazen social ecological system. Its almost inevitable that subsantial furor conversion of forest imo agricultural and pasture lands will occur as part ofthe economic devel- ‘opment of Amazonian counties (2, 40). The danger is that degradation of ecesysi services SCIENCE VOL 319 REVIEW i ‘could push seme subregions into a permanent- ly drier climate egime and aratly weaken the resilience ofthe entne region to possible Lan scale drought driven by SST chang. the challenge is to manage the ezanomic devel ‘opment of Amazonia so that it occurs where ap preprate and sustainable, ina way that mangas the inherem clenic resilience that dhe forest provides. Simulancously, this ‘would preserve the region's carbon stone and sink and its exceptional biodiversity, conibuing both toward ‘iting global arming and asst ing that biodiversiy to adapt v0 cli- mate change. Key axpecis of such a plan for Amazonia could inclute deforestation safely below possible climatic threshold values (about 30 to 40% cleared) in a matrix that ine cludes large protected arwas with limited fragmentation and rxanaged landscapes: tht maintain sufficient finest cover and unksepe: comecti= ity to presave species migration cor. ray and fret tanspiaion seviees. (i) Controlling fire ase through beth education and regulation, prob ably for not esonom bene {ily Maintaining broad. species ‘migration coridos in eentonal arcs tat are most likely to show early sig- raf climate impos sich as se bebe forest and savanna, between stands and the Bravilan and Guyana shield uplands, between dhe Andean picdmont and. montane forest. ara between montane foes and highland Andean gress. (iv) Conserving river corrns to act 35 nu rotgia and migration corns foe teres tial ecosystems and as sex boaters snd rofiugia for aquatics y southern uibutwics of the Amazon river run from dry fringes to the wet core and could asst the migration of wer-adapicd sposies. (0) Keoping the ore nomwest Amazon largely intact as a biological wage that hosts the highest biodiversity and isthe lest vulner- able to climatic dying Is auch plan shh? With the expansion of protec ancas and effective legal enforcement of private bend uss the projections of los oF 47% ‘of original forest area by 2080 could be hed 0 28% los 2), avoiding “17 PyC emissions (Fi 2B). Recent devclpanas sugyest that sch good sgovemance is achieve, Desi of the roe that be played by pretected ares, indigenous po iss. srmlholirs agoindastris and goverment text are deus in the supporting on Financing 2 Climate Resilience Plan for Amazonia A plan fr Reoping Arnaz and climatic decline faces sever challenges 11 JANUARY 2008, (i) Kesping the toxal exint of 7Bh ccvew the dive of globalizing market fines insuliient Financial rsources, provision of open sccoss to infomation, limited tehuical and govensece ‘aposity, ad inefletive enforcement of rule of ly. In panticuls new financial incentives ae needed {9 act as a countervailing force 10 the ‘economi pressures for deferestaton, uch incentives are now asicus possibility through the international markets in carbon spawned by the Kyoro Protocol, such as the European Union's Emissions Trading System, The weently apred-upon “Bali Reap” for extension of the Kyoto Protocol beyond 2012 includes plans for rainforest nations to be paid for reducing emisioes tom deforestation aad {dcgradion (REDD), cil thugh intznatonal carbon markets or a voluntary fund (48-50) Tropical forest carbon cai have pticular ‘alte within a climate mitigation siraeyy because they bring addtional direct climatic services [cloud torraxion and precipi, Hoal cooing bby exapotianpration (25) 35 well as other ewo- system serviees sich 2s hioiversityeonsration, watershed protection, and pollination. “These plans have the potatial w shill the balance of underying economic market forces that curently favor deforestation (45) by raising billions of dollars for the evosystem services provided by sainfrest regions but will require ‘excepbonal planning, execution, and long-tem follow-through. Such resourees could) support the expansion of capacity in forest montoring est freely available satellite-based monitoring, as already achieved by Brazil) and improved ‘governance and ruleof-bw in foaticr regions, ‘nut in paricular would nocd! to ensue that they Dring benef and incentives (6, improved social services hike health an lucien) x9 the ive uals and groups making decisions about Amazon band ue oma ily Rass be they indigenous pee ps, rua subsistonce dvselers, snllholdee ni sans, cr Lue privat landers, “The intractce betwen global climate cage nal deforestation may make Amazonian forests vulnerable 10 large-scale degradation. Ironically, it is also this linkage between the skal (cubon sequestering) ecosystem sence, for whieh the werld may be more willing to pas. and reyional(anspztion) services that mein the regioa’s climate that provides an opportunity to sisiain the climatic rsiience of Amazon ‘while contibuting towand its conservation and development 72 11 JANUARY 2008 VOL 319 SCIENCE “The next few years present a unique op- portunity, perhaps the as, 10 manta the resi fence, biodiversity, and ecosystem serviees of Amazonia in the face of a medium threat of Sapificant drying and a bigh th Seeesation, The best cline, nomic, and sccial science wil be neaded 16 de- velop. implement, ann) monitor effective policy sesponses for securing the region's foture, The ‘other key repre spoil will at the cal, rational, and iverational levels Roterances and Notes 1 ere dete 35th lp Azan Beal nd Aan fad ar aya egon ones 9 Bal 2,85, Ser th tf, Hote 4, $20 28, 4 Dim, PM Ree, Ene ie 28, 137 COE, C8 a AL J ond) Rad 9 aw, Soance 23, 237 G85 5. Gene 7. Vals, Gry: Rte, 3053 (0D, 1 eth, Avr). Gop. Re, Ames 187, 8087 (con 7 Me Msn, 0. Pip, 5. Congo ee Googe 30,477 0085). 4 hdr at See 297, 899 2002) 9, Nig a, Cor Bil 20,6 C200. 1B. N Buna Gleb Change Bek 32, SL 20D, AL. HaP J Meg ibs. Tne. Soc. Lan. B Bo Sa. 388,311 0068. 12. Stir ea, a Chnate ange 2007: he Fayed Scuce Soe’ Centro of WosigGrogp 1 toe Fear Asesanet poo te abnor Pane on Cinate Cane. 5-0. sen a. 65. (Coroner es, abrge a Hew or 200, ep Bs RA bana, Pe Al li 78, 187 O08) 214 sh A Stu, DH. Ue Scene 303, 827 (ast 35. LA Maceps, Mer AlCl. 78,79 2008. 6 WHLULIE Fe ALE Detnon, J Geos Re. 1 oon, toao2s/easiocnetss 2a) ay. eta, Suan th ep fo Lt 26 18 5 Ob. F. iton,Gepys es. Lte 29,1728, (eo {9 ¥ Hae et. ed. Change Bo. 12.1107 L098, 20. KW Hoes et, oat Bogece. ys 20 ‘aatoe 200 559.385 0009 22.5.1 weeds el 20, 855.2005) 25.8 8 sepens ta Serce 35,1152 07). 2S Umea, Pie rane tend 8 Be Ss 359,421 0908, 25 EA EBDM RL 805.01 Meer Sc 120, 26S oy Av J. Gen: es, 107, 8087 O02 21. MD. Opema CA eb Geophys es tee. 38, 2199 con. 78GB FL, PN, eo So USA 208 6550 con. 29M. Astrea Stee 303,137 2008. 3B LE Sua, GA Mabe, MLD, pom, Gees es ee 34, 103700 Geo. BL ME Ghsang, HL Mase | Haber, § Ge, | Seay lr Meter ey 122, ¢€8 (798, BRT.) ie, he Doug T Congo, FM Jest, naps, 5 Bape 34, 1357 GC 3B FE Ma, D] Being 0, Gsieg, MB Buh Pion oe Sac Lod el 5.399, 499 (2000 234 ese, at Se R55, 7 (ODN). 35, Ud nel ste hp cone tbat Bb RA iber tl Goh. Change Bol. 13,2361 2007, BY. ALR Mute tl Geapys Res Le 33, LOADS (a0, 98 RS Chia, 1 Owen 5.5.0. ages, DC Rept, Decloga 385 354208. 39.10. Say Sra, a Pysicegy ond eller toy o Stes aero oH hae, herds, 208), pp 101-13. 40, WF Lance tly See 278, 1217 99, {Odom CAPs Poe Fe Sc land BBLS 3,307 Geos. {2B Bane etl Homan Presi or te Bein Ana Fes Mad Rese tet, Masheion, 1c 0 and nazn, Bay, Bra, 2600. 18, WK Cv, Wel bun} Top, Ft 38,31, (oa A MUR Coane ea, Sine 204,102 (1999. 5. L0.€ mgie ea, Gps Res Let 34,1701 (con. 46 Tle, Arcsin oped Bde Scene Na 7 (Gripe Botiniy Sine, Conran Inerstons Wishing, C200 7, RAC Aleer, Lh Sang, D.C. Nepsd, Fee Appl 14,5139 000 48M Sul etl, Ci ange 74,207 2008) {9 RE alse ot cer 346, 9852007. 5, Manne, 5 Starman Topical Brest and Cima Chege CPA, Bn, te, 2909), SL his apr aad Lge the cnc “hate ‘hngean the fate af fe Rnoson bald Ore Calg, Urivesty a Odor 201622 aed 207, and ‘ned he ames Main 24t Cenry Sethe Enionmtetal ange naa, arth Cre fr Uantan sites, Ur f Ono. Cran sean able tweens avn eso 2pesertatnsphp We ok 3 Paripnte athe crtiece, parti E 8a, oy as, | Uo) Mang, Nepst Pit, and 8 Serr forthe comments en ie Ianeonp ke soprted by ten ooren, I bythe umes Nar 2 Crtay Sota the Coleg of Witla 3x May a6 RAB, by ej Dane aD iterated Cetera. We tank Manne se. Zosrwd for seitane Inet pean We scknmabge th Coiled Motel eteanparan Projet te tens roteing up lar peg tha di fr aa. ‘Supperting Online materat woncienemog epiererttunes960C1 Sou ee eters ats edited ote 72 Uovenbe 2007; oniaasesee 166861 Fae nosing ing ms cs nn scioncemag.org,AVN Widespread Triggering of Nonvolcanic Tremor in California Joan Gomberg,®* Justin L. Rubinstein? Zhigang Peng,? Kenneth C. Creager,? John E, Vidale.? Paul Bodin? Ri nave ernst and a do phil in High fogua ‘ie, Tmo has almost ‘exclusively baxn found in subduction zones Cascada, soutnwesiem Jeg, Mexico, Costa Ra, and Asa there ‘Sanly ene tay doce mening tremor outile 4 saixheton-dominaed sn, 2 the stake lip San Anis Fad in Patti, Catia (2, Jn Jun and Casali, noaoleani tea ha esr shown w oeur ceoncurety with si page across the intriice henwoen subducting and ovealying_ plates, to months (3) Pace and a sip are mh thn fone ch quakes tht ptr com- bly size alt acs, and ths these slow ‘events rae ss sci ine energy. The phys ical lation bao fe slow slip and remor croton is se tluve, Revert staics "Toes erm me eileen ft of rtp vs o ration fram cathguakes, tran Si nas ane lager duction, have fewer er no abe We camino’ all ails wecedings of the Donal eaagake aves fa ssismie stations in wolksnic tremor a hgh foguansy about 3 t9 |S He) nen: inpulive seismic enayy ht pulses wil the pied tenet og Late (N) FRecoraing Stations} ‘stlapa Valley ‘Calaveras ‘San Juan Bautista Paria ‘sSeniValley aHomet = ca 1 gras Fig. 1. Nap of the lations of ter sores as (I, stb that recorded Signal fam each tema source ranges clo coded to te respecte sources see legend Sats the showed 0 werer (tk bu are) and mejor als (ac nes sets) Examples of re temor Signals assodted wih fur eens vee syle ema sources oe Went. The Del surice waves hae ben fred ctw hight he werwr lak seisnogans), and cred ates show the tannese component of the surface waves fom Dera atone nerd becadbnd ston in each ceion tng that he altos on the ra and vera carport do otf sgaicanty, Dependg on the wenor st, we baad temo: tagereg by both Love and Rayagh nies, The at age sts fn the Hemet end Na Vly sia re craic of rey carbone. ach sesmegra has bre sce © make the tere esl efi, es ce ‘erence tothe Deal earn og ne and eer sats re abled ubduetion zones have deified Sot burs of wemor withthe same meaunble chaneterisies 1 those asec with slow Sip, bur tigen by dhe ston. aking of dia cathquahes (9), Bocane romwoleane tener 's prefrentally olsened i subhasion ons, realy all canstive mecnisns propos appl to conditions expecta in them, We show tht the ‘onions uid fr is genetic tex i a Wider vary of extn environments by preset ng obarvations of nonvoleank: tremor at Seven sis aloes the trnséem pte boundary in Cali- fem tiggered by the 2002 78 moment meg nitude Denali Fault, Abska, crthoua wawiscioncemag.org of the psi surice wanes. Thi ony 6 net sociated wih ncaiby cathquales cr wih the Deal cathe ise: We defied weno fan seven scutes tht we Fost by using Remar elopes a input to a ginbscarch algerthon (3). “Tha lesions range fom the dost scabs of Los Angels 10 Nap ley in the aoa (Fig. 11 ‘Although the observa ome buss Span a lage rast of Califia ive sources locate chase 19 on dim strike ub the San Anes, the San Jacin, and th Calera fats. The Sint Valley and Napa Valley sures ae key on more mince ful. Some mmakls of temor asecist SCIENCE VOL 319 wh stow asc ap in ttn aon ok fiona beavis expt in myn tase eo whe He fat adalat: exuurand whoa ci slgyine fs heb (6) Sack teeta ako at exh sw dep te bokow the top fev fon of Fah scents Arun to crap continu ae erly ton Abc sane and te tha ap fe to a ofthe dh The dsratim of hse eka ho avon i brown for mos Bulls in Cal However we fimo clear concn Fe woe the fate ane orig, ck or tonal and wher emer ooo Many tics ve spol he ane ip avd stor ae mtd othe refa of talsfom detain of te mang ps 7). Given th taawocn ais and nenvok Hetero we ann the a fon ss. thse tothe Coo and Gesem soa feds ‘Ne Hid es of mony bul no temor was apa. Tas wih pvis work on gece carpet thse sts and tthe hy doh Wiley Calder ant Mes Mo tag of tigger tenor in thee gor ons imps th igh hid reste andor en lca hy may be nce ne sulci o reduce rene usps Br sl att 0 where eR rigged unr aswell as wre ‘se dH ot The pi of uated wen Ty dha rp an is bck of consi wh teal abisn sip tor gest a vay sho cic condins (eg, tenpeais, posure, fi fxnten and sional pops) cont! where tear and eagles ona The wid gop cet of te gered moe Hcy Hi tare consnon tan prev rami an ht the messy cio et fn wie range ‘skrae enemies fateronces, 1. oar Shen 26 1679 0 2 ne 0 ts 0,289 WES ontouctece atone 2. ge get Sc 90,3882 GoD pte tne oy 0 nr a8 4. [tinct of ane 8 379 07) * heat i ateg *Joanovacoatonae 1. Sagano Sct: 94,528 0 Sapperting Online Material srmencan rf L391 ¢2001 ial od ce 2 aga pd 2 20 foniziceec aimee “US. Geog Sey Bx 351510, Seale, Wh 98195, Use “Orpen of tar and Sac Sece Ue of ashrezen. Sor 35130, Sate WA 98185, USA scat anh and Amosberie SOs Geog Inte of ‘etadoy 311 fe Ove, ta Gk 50832-0340, USA “To when catespondence shoud be adesed. Emait -genbergquescov 11 JANUARY 2008, 173174 Stellar Feedback in Dwarf Galaxy Formation Sergey Mashchenko,* James Wadsley, H. M. P. Couchman Dart galanies pose substantial challenges for cosmological models. In particular, carrent modes Drecict a darismatter density that i vergent athe center, which is in sharp contrast with observations that indicate 2 core of roughly constant density. Energy feedback, from supernova explosions and tear winds, fas been proposed as @ majo: factor shaping the evolution of dwarf galas. We present detailed cosmological simulations with suffcert resolution both to model the relevant physical processes and to directly assess tve impact of stellar feetback on obserable properties of cart ‘galas. Vle show that feedback crves large-scale, bulk motions ofthe interselar gs, resuting in substan 3 gravitational potential fuctuations anda consequent reduction inthe central matter density, bringing the theoretical predictions in agreement with observations. wa gales athe nxt commen ga D my pe (the Nowra pcre of cassie Graton, dv a {ns fn fin. coin ing ck fer be pis, Thanks of prin in the ol nese (ar Sone ead ‘ihn 20 pe of he San snr thee pa Trishine bree sind ea. Accs wee ting of te mas dking, fo the tere Tcofaight vei or fared of sta, ho evel ates apse sever hae Teas fr the sana coamlogkal rl peas, erp hat he dibtn o mat (whichis he donna rss comport thee guess) i of seat content Ey ira cet gion tis conpantle i ze © the str fryof he any (0) a he aided tery Foran Ua Nine, th ras of is ng = 40 an ~ 00 pe, espe fly (0. Ths ce a oe wih exing tologcal mde, whi ely pre the Auk masro fave a deren dena (8 csp) fie ale ctr (7) Ste da spoil tuts ako exh dh padi in the train, wih ts on dei in ay cones nd rere psn oe ang {ire estan dbo and Beng in Department ef Physics and Atvonany, Mester Uni ery, Haeton ON eS A, Canada “Io wham corespantence sou be assed. Eat: symaplyesmenatiia Fig. 1. Zooarin images of the cee teal part of the simulated forming dat aly at redshift = 53. This time was chosen to ilusrate the very dumpy 2s dsbution after a star bust. Gas is shown in Ble and stars are shown in re, (A) Gobal view (B) View ofthe galaxy. (0 The cestiel part of the galay. Several star dusters are vstle in (©, and the oldest (mareed) has an age of 200 My. 11 JANUARY 2008 VOL 319 SCIENCE ically wanner than more metabrch stars (8, 9, Fuster, the presence of glebular cher in many dwarfs is puzzling, because these massive, com pact systems of many thousands of sas would have sillred gravitational drag as they moved tough the dark-maer backround of the galasy hal, This dhraenial fiction would have usc the ghbular clusion to spiral in the sgalay center om time scales mivch shorter than the age of the galaxy [the Fomaac duaaf spbe- tidal guy is noble in this regu (5) Icis well established that massive sas inject. lange moun of noes ito the sumounding medium via séllar winds and superona expho sions suing in argosca (heeds of psc in large sans) an bulk mations of he gis atch tine pce (= LOLs! fee to typical ans tempat of 10" K) (10-12. “heeft of such perturbations is hrper for ovat alu, hoses they have lower ws pres as 2 res ofthe koser Gh of thee gravitated potacal wll, This sla faedback hs boss in Yoked to exp at ast some of the puzzing opis dae gsi. specu, there hus boca consirable date a to wheter oF Bo such feedback ca tam the theoetially pret ental dares cusp int a core (3-10. Previous theoretical Work fats eluded beth roncesmogical and cosmological axe High-esolation, noncovmotogical numerical sods wih detailed deseptions of relevant Physical pce 10, 17, 1) sal om realisically symmevic inital conditions and a sMaic descrgvicn of the darkamuter potential as Well as From the lack of gas accretion fom the atabient cosmic medium, Previous aents at selfconsient hydiedyramic cosmological sim- ubaions have tended to fcus on the fomnation of tie very fist small galany progenitors (9, 20) fron dwarf galaxy models without sufficient resolution oF the relevant physies to property model star formation and feedback because of the subsantal eornpatational challenges involved inseltconsistet smodeling (27,22, Hw we preset the rests of cosmological simulations of da galaxy formation and evo lation that adequately resol and model the processes of sa formation and stellar feeack, Tr good agiccment wih our previous sen analytical resus (16), cur sel-consisent mode dlemonsiracs thal, in. small golaxcs, random ‘bulk gas motions driven by sell feeack play 8 critical ole in deter galicic center The key resi mation ofthe central density profile fom a cusp to a forge core, This is a conssqucnce of nant heating of dusk matter in the Moctuating ppotcal dhat sults fom the bulk. gas motions. ‘We also demonstrate tha the same mechanism can exphin oder pucring features of dart galaxies, such as the stellar population aradions, Tow decay rate for globular cusier obits, and the low canta solar density ‘The simulations were ran with the gosmolog- ‘cal parallel wwe code Gasoline (28) This code represents dark and stellar mater as a colletion fof carkematter and star pales and scx the mooted particle hydeoynamics ieralsn describe gas evoluion, \ dsailed desertion of the code, cluding the prescriptions for star for mation and supemova fede, can be found (24, 25). The very high resohtion achieved in four mexkls required the ation of 10 key Features to the standard cosmological cod. Fit, Jow-temperatare (=10° K) adie cooling fiom the de-oxctaton of fin srocture and metas lines of heavy clments was necessary 10 or recy modal gas cooling in small agi (25) Second, because our mas reskition (<200 Mg) ‘suficient to noe incividtal spon introduced an innovative, stochastic prescription fbr stellar feecack (25). the trans nn scioncemag.org,We creatal cosmological initial conditions With fnpat constrains designed 19 proxkce a dart galaxy with tial mass ~ 10? Mo at ree shill 2= 6 within abe of size 4 co-moving Mp. A conta, highresohdion spberc, with radias 0.4 co-naving Mps, was popukted with gas panicles. The particle mses inside the high- solar were 1900 Mg for dark mater 70 Mey for gas. The mass of particles gen as ~ 120 Mp. AL the ttl ures of dak 10, crate! 10 rspasent Sa ‘end of the simatic mater, gis, an star panicles were 11 4S = 108, and 4S 10" respectively: The gra vio secng length was hse constant a 12 pe Fig. 2. Eoin ofthe cen- — teal quantities in the model ‘duait galaxy. (Top) Solid lines conespond to changes in the dark-matir (black, ‘925 ue), and star Ge mazes encod within the ‘centel 100 pe a5 a funtion (of 2. The cashed bse le ‘shone the evlation of the ‘endosed ges mas vithin the ‘cerral 1.6 ke (ual the vir ‘adivd. (Bottom) Green and back lines show the evo lution of the cert dake mater phasespoce density, fr the ncrodymemic and datkcmatoronly seulations, respectively, We abi show the evolution of the velocty ankatiopy, 1, for the sme darkmater patics as were wed to calla F énagerta line; horizontal back tine marks radial and tangential velocity dlspesions. log F Fusthor model dois including the desertion ‘of numerical conversence tests and tee paramcer stax can be found in 25), Two primary simulations were run, The fist fone included all the key physical effets: gas dynamics, sar formiaion, and stellar feeb, [This simulaion was by far the mast computa- tionally expensive, consuming 6 = 10° cera processing unit hours The second one was ark-matieronly contol simulion, The simu ons stated at =~ 180 and end at: ~ 8. Ine simulations, the mater distibuion &e- velops the chisic weblike oF filamentary sinc ture on brge seals, wih dhe mast mawive galaxy 0). Here, n= (o7-077Mo,%+ of, where o, and oy are, respectively, the one-dimensional Fig. 3. Evolution of the en- loved darkmater masses in the model galay at diffe entra. Dashed lines core spend othe esicmatereniy simulator, and sold lines ‘erespond to the hydiody amie dmuaten.. Jog M (M,) yn scioncemag.org SCIENCE VOL 319 REPORTS I forming around =~ 10 at the intersection of the Iajor filaments near the center of the compu tional bex (Fig. 1), The eveluticn of any is eltvely smooth (4c, there a mergers) betworn = ~ 8 and $. The star foam tion Br the dwarf galagy % Very “bursty” with major star bursts repeating roughly ery ~ 80 million years (My), which is consistent withthe noncesmological moxels of (0) Stars. form Drecdominantly in clusters, but 7 ‘quickly dispense. Stating at =~ 6, sgabcicsellar mass caches ~ 107 Mo, elusters that sivive unil the end ofthe simulation saxt to fon, These long-ived clusters have broadly the same sizes (= 10 pe, eserally unsolved in ‘our simulans), mases (~ 10° Mg), and bawy- clsment shurnce (~ 3% of tha of the Sun) as bela chistes observa i the local unvese In the Local Grp, no old (expe) var with sella mass <10” Mo we lobular clsts, Wwonen all brighter dar (ith the exception ‘of M32, which i soveraly tdlly sipped by its host galayy. MBI) have globular chasers (1) This suggests that a galaxy hats to be large ‘enough (7107 Mg in baryons) to prxluce glab- ular clusters, which isin good agreement with ‘our simulations. Feedback from the bursty and clustered star eration resus in a dramatically peta ine tentellar gos distribaton on lar scales. (hu eds of parses} (Figs 1 and 2 and movie SI). This is consistent with the observed (inegular) lisribution of gas in dwar galaxies (). thigh redshift this Redack does no expel ga fom the saleay, in contast to the maximum stellar anism (74). Instead, supernova compress gas into lege sells and “ilamens, which ae confined to the central part ‘of the galaxy and move with spoeds ~ 10 19 20 kins (whieh are comparable w the speats of dask-matir pastels), We showed previously (Zo) hat gas movion with these characteristics results in efficient grviatonel heating of the cxntal dak mater and flatening of the cusp “The heating of cork mate in our mod art sgaly ishighlyeffocive Figs. 2 to 4), Wherwas hoth density, p, and velocity dispersion, ¢, of the patos ae stongly looted by the variable ‘ont of gas and stars the galactic centr, the phase-space density, F~ pio? is much ks semi- five to adtatic compression of dak’ mater by baryons (Fig. 2). inthe dark-matter-only simul tion, F says roughly constant whereas inthe rode simustion, F wxhally decrees wi time a the rsut of the sear feedback and, the end of the evoltin, scones 10 mes as kw a the value for the dask-matteronly simulation. The dark-matter deity is somaly affeted by the sella feedback ony in te central region fof the gnkaxy (Fig. 3). This is the region in ch the enclosed gas mass oceasionally domi nates tha of the dark mattor and is where the 235 is most stonaly affected by the feedback A the end of the hydrodynamic Simulations, the dark-matier density atthe smallest resolved i> 11 JANUARY 2008, 175PORTS lt bocorns seve tres as small asthe density ‘obianad in th dark ariter-ony simulations Whereas the dwarf yalany halo inthe datke matieronily simulation develops a central cusp wit logarithmic slope 0.95, which is con- sisiert with previous predictions ofthe anand meds! (7, inthe hydrodynamic. simulations, reson Hearing realting fom sili fdbuck turns the esp ito a Hat core with radius 40 pe (Fig, 4) a average dsiy 0.2 My pe". These ‘ore parameters are close 1 those inferred for Fornax: ~ 400 pe (6) and ~ 0.1 Mg pe? (1). respoctively. The same mechanism produces 2 ‘cow of somewhat smaller radius (~ 300 pe) in the distrbution of stass and, sola, pushos newly formed globular eusers away from the sgalactc center. The four oldest globular clusters, for example, were born with ralial divance dis- persion 37 pe (essrly atthe lactic cent), Dut after ~ 200 My of evokiton, this distance had grown fo a timesiveraged valus of 280 pe ‘ovhich & comparable o the lar cone radia) We suggest tha resonant gravitational heating ean al least partly explain why globular chusers in Fomax, and in same other divas are located at large distances ffom the galactic center (5). Two mechanisms contribute the ceflet () The fesdback latins the central cusp, which reduces the eliciency of dynamical Seton in the central regions (3), ad (i) sear ‘eatback woul have ceria 10 heat he gb lular chaser orbits until stars stopped forma, around 200 millon years ago in Fomax (2), “The disriution of vebctcs i sopic wih in the com and shows slight radia anisotropy ‘outside the core (Fig. wheres the cow remains ‘soumpie throughout the evolution (Fi. 2) This ‘behavior is inconsient with a mec (26) making use of massive gas elows, passively or biting (ie driven by fewdhock) near the sgalois cote, which Hatin the dak: mater cusp via eating resulking fiom dynamical retin, thas been shown (27) hat this would result in Fig. 4. Radiol profes forthe mod- the development of substunial tangent ait. tepy within the core, which is not observed in ‘our sinutices, On the other band the gravee tional resonance heating (6) naturally produces isoopic cores because the Foedbackiven bulk {838 motions have rardom directions. “These results abo provide a natural explana tion for the site population graiens seen in many carh-ype dwarfs (8, 9 In our simu tions, star formation is concentra toward the igahtic conte Over time, Feedback gralually Feats the population of stars, resting in older (ara! more metal-poor) stars bem kinematically svarwer and having & lager spatial exten than younger (and mors metal-reh) stellar popu tions. Hence. we can repreduce: qualitavels, the age, matali, and yeloetydisponion gra dons observed in dwar galaxies ‘Our simulations were slpped at 2 = S, be: cause continuing beyond this point would. w= quire a much larger computational box (0 comectly mode! the growth of larger sructurss) and an infssie increase in computation time. Furthcanore, the impact of extemal ionizing ra ition, which was ignoeed in our mex, can ‘become substantial aller: ~ 65. Nevertheless, ‘we can seasonably ink the subscquert evolu tion of our model gabny, IT it 10 become one fof the carlyype galaxies in the local universe (hich are gae-poor, some mechanism will have to remove most oF all of is interstcae ‘medium. Some combination of a powerfil sae burs, increased mewgalactc ionizing radiation, and fam.pressure sipping coald rest in the dwar losing most of is gas (28). Its also Tike that only a faction of its sar clusters wil ure Vive unt the present ime. As aresul, our model galaxy ould end up reermbng a huge dwar spheroidal gslany inthe local universe: low tele sdensiy: mea-poor, wih of! sella popabtons having pronounced radial popukion wadiens: lage stellar and dark-mater cones (hiel are comparable in size and density to those in dat el galay at redshit 2 = 5.2 At this time, the central gas dest i very lon, minimizing the adiabatic com- pression of dark matte resting from baryons (which makes it ap- propriate for comparison with pres ‘enly observed. gaspoor dats). Green and red tines shew the dk matter and stl density (p) profi, 1 os respecvey, in the fyctodynamic simulation. The black tine c sponds to the darkemator density profile forthe datemateonly sine ulation. The magerta tine shows the 1 proffer the dark mater Gin the hygrodynanc simulation. 18 176 11 JANUARY 2008 2 26 9 a6 Jog F (Pe) VOL319 SCIENCE spheroidal: and pettus 2 few globular ese tes. In many’ respects, the galasy Would resem. ble the Fornax eval ‘Our noncosmological modeling (16) sax sxsted hat scFar ealback can be dey resp sible for the absence of darkemater cusps only in soll galaxies, with total mases < 10! Ma: Jn Tanger galaies, the dark-maner panicle ve losis become substantially larger than the ‘velocity ofthe random bulk gas motions, which 10 kms", Our eure, cosmeogical sims lacions ane consistent wih thy real as mass of our galaxy reaches 2° 10” My by 2 = 8). ‘Namrial simulations (29) have sigyssted that 8 nivel halo density profile (eter cuspy or comb. once sis preserved though subsequent Ihirrchial evolution (which is consistent with the analytical resah that dhe collisionless dark- smunter phase-space dersity ean only. decrease ‘over time), implying that our raecanism may alo lead wo cark-mater cores in are gales. (Oue simulations incivate that the gravitational heating of mater rshing fran feehaek-powera bulk gas motions isa crtical determinant of the prcpenies of daar? galaxies Large darksmenter ‘cores are an unavoidable consequence of early ste formation jn dwar? galaxies. Our move indicats that, iy prbmondal da galas, ghbulsr chs fem are formal in the most nutural place near the contr, where the gis pressure & highest and are then pushed by feedback io much larger dlisanees, This mechanism abo ensures that pkib- tbr clus and unclisered stars have a com parable distibuten, as observed in eatlytype dwarfs (30), Adgtionaly, the low stellar dos and. sell population yradion’s observa

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