| science
Trang 2Volume 318, Issue 5853
COVER DEPARTMENTS
Acollection of undersea robots 1031 Science Ontine and ocean-observing platforms 1033 ThisWeek in Science
monitor upwelling during the 1039 Editors’ Choice 2003 Autonomous Ocean Sampling 1042 Contact Science Network program in Monterey Bay, 1045 Random Samples
California See the special section 1047 Newsmakers ‘on robotics beginning on page 1083, ape Dal erseke 1159 New Products 1160 Science Careers EDITORIAL 1037 Robot Ethics by Robert Sawyer SPECIAL SECTION Robotics INTRODUCTION ARobotic Future 1083 NEWS
Making Machines That Make Others of Their Kind 1084 Robots’ Allure: Can It Remedy What Ails Computer Science? 1086 REVIEWS
Self-Organization, Embodiment, and Biologically Inspired 1088 Robotics
R Pfeifer, M Lungarella,F lida NEWS OF THE WEEK
Mobile Robots: Motor Challenges and Materials Solutions 1094 Did Merck's Failed HIV Vaccine Cause Harm? 1048
4.0 Madden Privacy Policies Take a Toll on Research, Survey Finds 1049
Robotics in Remote and Hostile Environments 1098 Panel Calls for Pilot Program for National Indicators 1051
1.6 Bellingham and K Rajan 20licEtcifE 16)
PERSPECTIVE New Analysis Questions Push for More Degrees 1052 Learning in and from Brain-Based Devices 4408 New Jersey Rejects Bonds for Stem Cell Institute 1053, G.M Edelman Scientists Say Continued Warming Warrants 1054 trop, 1037; Nos 1055, 1056, ond 1060; Report 1355; eee ae
Trang 3MOLECULAR BIOLOGY
Orchestration of the DNA-Damage Response by the RNF8 Ubiquitin Ligase WN K Kolas et al
‘Akey ubiquitin ligase builds polyubiquitn chains at radiation-caused DNA lesions, hich subsequently receuit other factors necessary fr repair
10.1126iscience.1150034 MATERIALS SCIENCE
High-Performance Carbon Nanotube Fiber K Koziol etal
‘Aeragels of carbon nanotubes can be twisted and compacted to produce fibers of exceptional strength and stifiness
LETTERS
The Origins of Human Bipedalism 1065 1H Schwartz Response S K S Thorpe et al
Technical D.R Begun etal and, H.C tal What's in a Name? R Baserga
The Carbon Benefits of Fuels and Forests G, Marland et al Response R Righelato and 0 V Spracklen
Eyeing a New Network / M MacDonald et al
CORRECTIONS AND CLARIFICATIONS 1066
BOOKS £7 AL
Dynamics of Cancer incidence, Inheritance, and 1070
Evolution Steven A Frank, reviewed by O C Krakauer
Burroughs Wellcome & Co Knowledge, Tust, Profit 1071 and the Transformation ofthe British Pharmaceutical
Industry, 1880-1940 R Church and E M Tansey, reviewed by A E Simmons
POLICY FORUM
Biobanks in Developing Countries: 1074 Needs and Feasibility
S K Sgaier etal
PERSPECTIVES
When Oxides Meet Face to Face 1076 E, Dagotto >> Research Article p, 1214
Widespread Monoallelic Expression 1077 R Ohlsson www.sciencemag.org, SCIENCE EXPRESS mg F8 lcexoress.or: 10.1126/;cence.1147635 CONTENTS CELL BIOLOGY
‘The Arabidopsis Circadian Clock Incorporates a cADPR-Based Feedback Loop ALN Dodd etal
InArabidopsis cyic ADP ribose, aytoplasmic signatng molecule, modulates the ican clock, driving periodic Ca* release and boosting robustness of te oscilator
10.1126 science.1146757
CELL BIOLOGY
Rev-erbcr, a Heme Sensor That Coordinates Metabolic and Circadian Pathways L Yin etal
‘Anuclear receptors a heme sensor that coordinates cicadian and metabolic uncions by Controlting the expression ofa major clack component and the gene for generating sugar 10.1126/science.1150179 CELL BIOLOGY
Daily Watch on Metabolism i y, J Sch
T Imaizumi, S.A Kay, J 1 Schroeder 3i64104468064150380 DNA Circuits Get Up to Speed 1078
R, Bar-Ziv >> Report p
The Gene Topography of Cancer 1079 J.M Trent and} W.Touchman >> Research Article p 120
Hidden Mars 1080
PH, Schultz >> Reportp 1225
TECHNICAL COMMENT ABSTRACTS
ANTHROPOLOGY
Comment on “Origin of Human Bipedalism Asan 1066 Adaptation for Locomotion on Flexible Branches”
D.R Begun, B G Richmond, D S Strait
Response to Comment on “Origin of Human Bipedalism {As an Adaptation for Locomotion on Flexible Branches” R.H Crompton and S K 5 Thorpe
BREVIA
ECOLOGY
Hurricane Katrina's Carbon Footprint on 1107 U.S Gulf Coast Forests
1.0 Chambers etal
Hurricane Katrina killed or damaged about 320 milion large trees, representing alos of about 105 teragrams of stored carbon RESEARCH ARTICLES MEDICINE The Genomic Landscapes of Human Breast and 1108 Colorectal Cancers L.D Wood et al
Tumor gronth seems tobe driven by many genes mutated at low frequencies, most of which act through well-known signaling pathways Pe 3 PHYSICS Orbital Reconstruction and Covalent Bonding atan 1114 Oxide Interface J Ghakhatian et al
Trang 4Science REPORTS ‘APPLIED PHYSIC: Generation and Photonic Guidance of Multi-Octave 1118 Optical-Frequency Combs F Couny etal
‘Anew theory of how photonic-crystal fibers guide light is used to design a hydrogen-filled fiber that emits light from 325 to 2300 nanometers at low input power
CHEMISTRY
Engineering Entropy-Driven Reactions and 1121 Networks Catalyzed by DNA
D.¥ Zhang, A }.Turberfield, 8 Yurke, E Winfree
Biochemical circuits based on nucleic acids can use output strands of oligonucleotides as catalysts for subsequent reactions to amply small signals for use in sensors, >> Perspective p, 107
PLANETARY SCIENCE
Radar Sounding of the Medusae Fossae Formation 1125, ‘Mars: Equatorial Ice or Dry, Low-Density Deposits?
TR Watters et al
Radar sounding of equatorial hill on Mars suggests that they contain a large subsurface feature with low density, either a large volume of water ice or light volcanic ash >> Perspective p 108
GEOPHYSICS
Three-Dimensional Splay Fault Geometry and 1128 Implications for Tsunami Generation
GF Moore et al
Detailed seismic imaging ofa thrust faut off Japan shows that slip along a near-vertical splay faut may explain why this prt ofthe faultsystem generated a devastating tsunami
PALEONTOLOGY
Rise and Fall of Species Occupancy in Cenozoic = 1131 Fossil Mollusks
M Foote et al
New Zealand molluscan species, while extant, expand into diverse habitats, yielding a brief peak, then contract toward eatinction, following a genera pattern seen for genera
EVOLUTION
Transgenerational Plasticity Is Adaptive in the Wild 1134 LF Galloway and j.R.Etterson
Ald herb nongenetcally adapts to local light conditions and asses the adaptation to offspring, ilustratng how sedentary organisms cope with variable envionments
GENETICS
Widespread Monoalletic Expression on 1136 Human Autosomes
A Gimelbrant, J N Hutchinson, B R Thompson, A Chess Rather than being expressed from both the maternal and paternal alleles, 5% of human genes surprisingly large fraction, are
CONTENTS ll
IMMUNOLOGY
Promotion of Tissue Inflammation by the Immune 1141 Receptor Tim-3 Expressed on Innate immune Cells,
A.C Anderson et al
‘cell surface immune receptor, which usually suppresses immune responses, unexpectedly promotes inflammation when activated ‘on immune cells of the brain,
NEUROSCIENCE
‘Melatonin Suppresses Nighttime Memory Formation 1144 in Zebrafish
0 Rawashdeh et al
Zebrafish learn poorly at night, an effect of higher melatonin Levels secreted from the pineal gland,
NEUROSCIENCE
Fast-Forward Playback of Recent Memory Sequences 1147 in Prefrontal Cortex During Sleep
D R Euston, M Tatsuno, B L McNaughton
‘Neural firing patterns that occur inthe prefrontal cortex during a complex task are replayed there during subsequent sleep at about seven times the awake rate
NEUROSCIENCE
Time-Dependent Central Compensatory Mechanisms 1150 of Finger Dexterity After Spinal Cord Injury
Y, Nishimura et al
Alter suffering damage to the spinal cord, monkeys recover finger function by sequential reorganization of distinct regions of the motor and premotor cortices
BEHAVIOR
Social Integration of Robots into Groups of 1155 Cockroaches to Control Self-Organized Choices
J Halloy etal
Small autonomous robots integrated into groups of cockroaches can influence collective decision making and coax the group toward an inappropriate shelter >> ews story p 105
expressed from only one allele >> Perspective p 107
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ADVANCING SCIENCE, SERVING SOCIETY AY#SS te cots ‘eatlegn ese 6254 S22 ates ———— asi ry! 85 fet as, sem tse and ee tes nage nan ates Wh ST tal ypemet ner OSL SLM pr en 0 pee os Printed on
Trang 5
Dental clues from an ancient ape SCIENCENOW
vwivnsciencenow.org 0 ‘Superbug Knocks Out Patient's Defense ‘Strains of MRSA found outside of hospitals destroy hte blood cell
New Ape Fossils Found in Africa
Discovery casts doubt on notion that apes went extinct in Africa and were replaced by others from Eurasia Glia Stoke Morphine’s Fires
Helper cells in the brain are linked to addictive effects of opioids,
Small hearts and tong lite
SCIENCE'S STKE
wwwestke.org SIGNAL TRANSDUCTION KNOWLEDGE ENVIR PERSPECTIVE: Adenylyl Cyclase 5—A New Clue in the Search for the “Fountain of Youth”?
J.-A Chester and V J Watts
‘deficiency in adenylyl cyclase type S leads to a long life span PERSPECTIVE: Entrainment of the Drosophila Circadian Clock—More Heat Than Light
J-Y Fan M J Muskus, J L Price
Astudy now provides the first insight into the molecular ‘mechanisms by which temperature cycles synchronize circadian cythms with the environment Finding qualities beneath the surface, SCIENCE CAREERS vr sciencecareers.org CAR US: In Person—Hiring for Hidden Value 8.Allen ‘Atechnical professional describes innovative ways of uncovering hidden tatent US: Opportunities—The Golden Chapter P Fiske
Create your own career options by considering the direction you want to head in and then seeking opportunities to get you there, UK: A Career “Framework”—Guiding Light or Empty Words E, Quill
Wil the U.K Council for Science and Technology's recommendation fora science careers flow chart work?
US: From the Archives—Supply Without Demand D Kennedy, C Taylor, K Urquhart, J Austin
Bad estimates have become routine in the part of science policy called “ientiic manpower”
ŠCIENCEPODCAST
Download the 16 November Science Podcast to hear
interviews relating to this week's special section on robotics Topics include robotics in extreme environments, robot ethics, the social behavior of robot cockroaches, and more
vt scencemag org/aboutpodcast tt
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Trang 6EDITED BY STELLA HURTLEY AND PHIL SZUROMI << Cockroach Coercion
Robotics offer new possibilities for studying and modulat- ing animal behavior Halloy et al (p 1155; see the news story by Pennisi) observed collective decision-making by mixed groups of cockroaches and autonomous mini- robots The robots, similar in size (though not in shape) to the cockroaches, were coated in a blend of cuticular hydrocarbons that mimic the natural cockroach cuti- cle, The robots and the insects made shared decisions regarding choice of shelter, and the robots could mod- ulate the collective decision-making process and pro- duce a behavior pattern—choice of an inappropriate shelter—not observed in groups of cockroaches alone Thus, a small number of robots can change the global pattern by altering feedbacks between
eee (oe
individuals in the system
Reconstructing output oligonucleotides that are released go Equatorial Water
3 on to act as catalysts for other reactions The
Interface Orbitals on Mars?
The rich phase diagram of the transition metal oxides and the recent demonstrations of pattern- ing and tuning the interface region, which can lead to unexpected phenomena such as the quantum Hall effect and superconductvity, have generated much interest in developing oxide electronics Chakhalian et al, (p 1114, pub: lished online 11 October; see the Perspective by Dagotto) now report on an x-ray spectroscopy study on the interface between high-tempera- ture superconducting (Y,Ca)Ba,Cu,0, and metal lic Lag gag :MnO, with surface-sensitive as well as bulk-sensitive configurations Charge trans- fers from the Min oxide layer to the
Cu oxide layer, but does not simply move into the d,2_,2 orbitals of Cu in a rigid manner Instead, orbital reconstruction occurs that involves population of the 3,2_,2 orbital Cal- culations show that the orbital reconstruction is consistent with a scenario in which the Cu atom forms a covalent bond with the Mn atom, Entropy-Driven
DNA Networks
Akey aspect of electronic circuits is amplifica- tion or gain, so that low signals can be distin- guished from any persistent background Zhang et al (p 1121; see the Perspective by Bar-Ziv) show how gain can be achieved in bio: chemical circuits They have designed complex Catalytic networks based on DNA in which the
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process is designed to be entropy driven so that the pathways for reactions are well controlled and can be modified at wil Possible applica: tions lie in the field of catalysis, sensor devel opment, the development of enzyme-free alter: native for the polymerase chain reaction, and the construction of nanomachines
Photonic Route to the High Notes
Excitation of microstructured optic fibers with intense femtosecond laser pulses can generate
broadband white light, and applications range from metrology to the generation of ultrafast pulses of a chosen wavelength The princ: ples behind white-light generation and optical ‘guidance have not been well understood, and the control ofthe loca~ tion and spectral range of the generated light has been limited Couny et a (p 1118) devel- oped theoretical insights into the guidance of light and generation of higher-order modes in the ‘microstructured fibers that has allowed the gener- ation ofa frequency comb spanning an extremely ‘wide spectral range with modest input power The authors discuss how this approach could enable a simplified route to femto- and attosecond pulse generation and arbitrary waveform synthesis
SCIENCE VOL318 16 NOVEMBER 2007
Water on Mars is primarily locked up in the polar ice deposits Watters ef al (p 1125,
published online 1 November; see the Perspec- tive by Schultz) show that comparable amounts ‘of water could be hidden at the equator in the
hills of the Medusae Fossae Formation, which are believed to be formed of volcanic ash and wind-blown sediments Radar sounding with the Mars Advanced Radar for Subsurface and Jonospheric Sounding instrument aboard the ‘Mars Express spacecraft saw reflections from the underlying terrain beneath the sediments that have a dielectric signature consistent with the presence of water ice If these hills are ice rich, they must contain more dust and sand than the polar layered deposits but could host a volume of water similar to that of the south polar layered deposits
Megasplay Faults and Tsunami Production
Tsunamis often result when there is rapid uplift of the sea bed, but their sizeis very sensitive to the local fault geometry Megasplay faults, which are long thrust faults that rise from the plate boundary megathrust and intersect the sea floor, are thought to be particularly effective in trans- ferring displacement to the surface By creating a three-dimensional seismic view of a megasplay fault zone in the Nankai Trough off Japan, ‘Moore et al (p 1128) show hiow such a fault operates and suggest that its stip may have
Continued on page 1035
Trang 72ek in Science
contributed to devastating historic tsunamis such as the 1944 Tonankai event Similarly, megasplay geometries may affect tsunami generation in subduction zones worldwide
THE HUDSONALPHA
Spreading the Silence "
The maternal and paternal copies of most genes are generally thought to be expressed at comparable (VU han)
levels, but there are several examples known where this isnot the case Imprinted genes have either BIOTECHNOLOGY
the maternal or the paternal allele shut down, and in X-inactivation, one of the two X chromosomes is
leukins—are known to have one or other copy inactivated Gimelbrant etal (p.1136; see the Per
spective by Ohlsson) looked across the entire human genome and found that in 5% of analyzed loci FIRST RESIDENT
either the paternal or the maternal allele is randomly and stably inactivated This fraction is much
higher than had been anticipated ASSOCIATES
LƠ 10 0c)
Cancer's Mutational
Landscape
The genomes of human tumors contain many sequence alterations, a subset of which help drive tumor growth, Wood et al (p 1108, published online 11 October; see Perspective by Trent and Touchman) have now under taken a systematic sequence analysis of >18,000 genes in human breast and colorec: tal tumors Depiction of the mutational data on a topographic map indicates that each of these tumor types contains only a few gene
“mountains” mutated at high frequency and a much larger number of gene “hills” mutated at low Open Biosystems, Ine frequency Importantly, while a large fraction of the mutations driving tumor growth reside in the
gene hills rather than the mountains—a finding that underscores the heterogeneity of human can
er—it appears that many of the mutated genes function through cellular signaling pathvrays that SourcefF, Inc are already well known [To U04 sant Healthcare Systems, Inc ` a Biotechnology Division Efpression Genetios, Inc ExtremoZyme, lne Microarrays Inc New Century Pharmaceuticals RUC) Theragnostix Reference Laboratorie‹
The Yin-Yang of Inflammatory Responses
Inflammatory responses in the nervous system are very tightly regulated In particular, T helper 1 type SHARING THE BELIEF
T cell responses must be kept in check, and a potent negative regulator of these cells is the surface
receptor TIM3, a member of the T cell immunoglobulin and mucin family, However, Anderson et al Use dell
(p 1141) report the unexpected finding that TIM3 also promotes inflammation through expression on AND INNOVATION WILL
cells of the innate immune system—namely, dendritic cells and microglia of the brain The opposing EXPEDITE THE SHIFT FROM
roles for the same immune protein when expressed on different populations of immune cells raises
intriguing questions about the balance between the promotion and inhibition of tissue inflammation KNOWLEGE AND IDEAS TO
CC 2Q PVC, 1Á)
Playback During Sleep FOR PATIENTS IN NEED
During sleep, hippocampal cells play back sequences of activity recorded beforehand during running of a maze task Euston et al (p 1147) report a similar, although more compressed, form of activity
playback, but in the medial prefrontal cortex (mPFC) rather than the hippocampus The mPFC has been implicated in memory storage and retrieval, and it receives direct inputs from hippocampus
HUDSONALPHA
Spinal Cord Injury and Cortical Compensation ginaatees
Neuro-rehabilitation is based on the concept that training recruits intact neuronal systems to com- Pea Mee)
pensae for brain injury However, the neuronal basis of the underlying mechanisms is still poorly eee eet)
understood Nishimura et al (p 1150) carried out a longitudinal study in macaques using a well:
defined lesion ofthe direct cortico-motoneuronal connection at mid-cervcal segments ofthe spinal otd, Functional recovery ater lesion ofthe corticospinal tract involved a variety of widely distributed
cortical networks The contribution of each different cortical region changed depending on the post: Soe a
Trang 8
Robert} Sawyer isa Hugo and Nebula ‘Award-winning science-
Robot Ethics
(-3PO AND R2-D2 MAY BE TWO OF THE WORLD'S MOST FAMOUS FICTIONAL ROBOTS, ‘but a quasi-robot named MQ-SBYC is perhaps more interesting just now: On 1 September 2007, ‘operators used this unmanned airborne drone to locate and drop a bomb on two individuals who appeared to be planting explosives near Qayyarah, Irag, As we make robots more intelligent and autonomous, and eventually endow them with the independent capabilit
need to consider how to govern their behavior and how much freedom to aecord them roboethies Science fiction dealt with this prospect decades ago: governments are ‘wrestling with it today Why now’? I'S not only because robots are killing people, IkSalso because they have become household consumer-electronies items and because some now look and act like humans (Honda's Asimo can even dance)
We have an instinctive reaction that a threshold has been crossed
The notion of killer robots is a mainstay of science fiction: but then agai so is the idea of robots with builtin safeguards against that In hs 1942 story “Runaround.” Istac Asimov offered his now-famous Three Laws of Robotics: A robot may not injure a human being or, through inaction, allow a human ‘being to come to harm: a robot must obey orders given to it by human beings except where such orders would conflict with the First Law: and a robot ust protect its own existence as long.as such protection does not conflict ‘with the First or Second Law Most of Asimov's stories deal with things ‘going awry because these laws don’t equip robots to tackle real-world ions In his 1947 story “With Folded Hands,” Jack Williamson had robots adhere to an even simpler directive: To serve and obey and ward men from harm That, oo, had an unwelcome result totalitarian society in which robots prohibit humans from participating in almostall activities, lest one of us be injured
Indeed all attempts to govern complex robotic behavior with coded strictures may be misguided Although the machines will execute
whatever logie we program them with, the real-world results may not always be what we want And yet, we seem unable to resist trying, and so governments are now drafiing their versions of Asimov's and Williamson's laws This year, South Korea's Ministry of Commerce, Industry, thics Charter, which sets ethical guidelines concerning robot functions The move anticipates a time when intelligent service robots are part of daily life EURON (the European Robotics Research Network) also announced plans to develop ‘guidelines for robots in five areas: safety, security, privacy, traceability, and identifiability Japan's Ministry of Economy, Trade, and Industry has joined in too With an aging population and robot caregivers being developed there (and elsewhere in the world), the Japanese foresee robots in many homes and have issued policies for how they should behave and be treated,
The United States has yet to jump on the roboethics bandwagon That many U.S robots are created for the military and designed to harm humans may be the reason Still itis likely that the ‘most interesting litigation defining robot responsibilities and rights will emerge in the United States Forstarters, a Michigan jury awarded the family of the first human ever killed by a robot (accidentally, in 1979) $10 million, which was, at that time, the largest personal-injury award in the state's history
Trang 9How Old Is the Canyon?
Much about the timing of formation of the Grand Canyon in Arizona remains uncertain The process is closely tied into the history of uplift of Western North ‘America during the Cenozoic, including even recently, as well as regional climate change One approach toward improved understanding isto date past positions of the Colorado River as it deepened the canyon To do this, Karlstrom et al have taken advantage of the many volcanic fields in the western part of the canyon; some of these poured lava into the canyon during the past several million years In fortunate cases, remnants of these flows are preserved perched on ledges or beaches in the canyon, marking past river levels #°Ar/Ar dating of these young flows shows that the western part of the canyon has continued to deepen by about 100 to 150 m since about 1.5 million years ago To the east, across a major fault, the canyon has been deepening at 2 to 3 times that rate Further dates show that this pattern of active differential uplift, facilitated by faulting, has operated over the past 5 to 6 million years and has continued to modify the canyon even geolog-
ically recently — BH
MICROBI0L06Y
More than Skin Deep
‘kin fungi cause conditions ranging from flaky scalps and eczema to weeping dermatitis and invasive disease Major culprits are the
‘Matassezia spp., which are closely related to plant pathogenic basidiomycetes, such as Ustilago ‘maydis ina proteomic-genomic study, Xu et al discovered that when Malassezia grows on the human scalp, it secretes over 50 proteins, which are generally more similar to those secreted by other skin-parasitizing fungi, such as Candida albicans, than to those of its plant parasite cousins The secreted proteins include allergens responsible for atopic eczema, but the ones criti «al for the Malassezia lifestyle are lipases; these enzymes are required in order to harvest host Lipids in compensation for an apparent fungal inability to synthesize fatty acids de novo The secteted enzymes include a distinctive arsenal of
extracellular hydrolases, another similarity to Candida Furthermore, sequencing of the haploid genome revealed mating type genes and a pheromone-responsive MAP kinase module, like
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Geol Soc Am Bull 129, 1283 (2007) those found in yeast It could be that sex pro- ‘motes skin colonization and the exchange of Virulence determinants — CA Proc Nat Acad Sci USA 104, 10.1073/pnas.0706756104 (2007) MATERIALS SCIENCE A Matter of Coexistence
Alloys such as Ge,Sb, Te, (GSD find use in non: volatile electronic memory and as recording ‘media in DVDs because they undergo a fast and reversible transition between amorphous and caystalline phases with distinct optical and elec tronic properties It was initially assumed that the amorphous form was simply a disordered
version of the metastable cubic (rock salt) form However, experiments on quenched thin films and simulations have given a different and often conflicting picture Caravati et a used ab initio ‘molecular dynamics simulations to probe the amorphous structure, They started with meta: stable cubic GST with Te occupying one sublattice and Ge, Sb, or vacancies randomly occupying the other For a quenched and annealed sample
SCIENCE VOL318
EDITED BY GILBERT CHIN AND JAKE YESTON
at 300 K, the calculated x-ray scattering factor was in good agreement with experimental results from the literature The Ge and Sb atoms were mostly four-coordinate and the Te atoms mostly three-coordinate in defective octahedral-like sites, resembling cubic crystalline GST However, about one-third of the Ge atoms occupied a tetrahedral environment, absent in the crys talline phase but supportive of the large number ‘of homopolar Ge-Ge, Ge-Sb and Sb-Sb bonds that formed The authors believe the coexistence of these two arrangements accounts for the rapid phase changes and strong optical contrast between the phases — MSL
‘Appl Phys Lett 91, 173906 (2007 VIROL06Y
Come In and Take Your Coat Off
The replication of animal viruses relies on their ability to cross a cellular membrane on their way into the host cell's cytoplasm Simian virus 40 (SV40) is a non-enveloped DNA virus that enters cells via caveolar endocytosis, followed by vesicular transport to the endoplasmic retic: tulum (ER)-the entry portal of the host cel’s secretory pathway-whence it crosses into the ‘cytosol en route to the nucleus Schelhaas et al wondered why the viruses follow this relatively ‘complex itinerary They
found that ER-tocal: ized enzymes that promote the isomerization of cysteines between their thiol and disulfide states were required for viral entry, and that two ER membrane proteins, Deslin-1 and Sel1L, which are known to mediate the retrotransloca: tion of misfolded host proteins from the ER back into the cytoplasm, were also important Specifically, the oxidoreductase ERp57 cat alyzed a rearrangement of disulfides within the ‘capsid, resulting in a loosening of the pen: tamer-hexamer joints in the virus coat, Once in the cytosol, the reduced levels of calcium may promote viral capsid disassembly, facilitating release of the genome — SMH elt 132, 495 (2007, Continued on page 1041
‘Aportion of the capsid showing the target cysteines (red)
Trang 108 š Ễ Ệ
Nitrogenase enzymes use an elaborate metal luster to catalyze the reduction of dinitrogen to ammonia under remarkably mild conditions Two ‘questions about this process continue to puzzle researchers: What are the elementary steps underlying the scission of the nitrogen triple bond, and how isthe cluster that guides these steps assembled? Curatti et a shed light on the latter question by reconstituting from purified ‘components a system for in vitro synthesis of the cluster—which contains 7 Fe, 95, Mo, homoci trate, and one as-yet unidentified light atom and is called the FeMto cofactor Of 11 nitrogen fixa tion (Nit) proteins previously shown to be involved in Fetto cofactor biosynthesis, they find that NifB, NIIEN, and NifH are key NifB assem: bles ferrous iron, sulfide, and S-adenosyimethio nine into the NifB cofactor (a precursor of the FeMo cofactor) under reducing conditions; NifEN
pushes the synthesis one step further by convert ing the NifB cofactor into the VK cluster, to which molybdate and homocitrate are then added in a NitH-dependent fashion The other Nif proteins are thought to supply the relevant forms of Fe, 5, ‘and Mo under in vivo conditions and also to pro: tect labile intermediates The catalytic compe- tency of the synthesized Fetto cofactor (whose structure is still unknown) was confirmed by its www.stke.org given in conjunction with ch CHOICE ability to combine with apo-NifDK into a holoen zyme that reduced nitrogen — GJC
Proc Natl Acad Sci U.S.A 104, 17626 (2007)
Many desirable materials properties tend to have tradeoffs For example, engineered cross-linked polymer networks can have high tensile strength, but though lighter than metals, they have much poorer extensibility —their rigidity causes them to fail after a small increase in length Some pro teins, such as the muscle protein titin, do com bine high strength and elasticity, in part because
they have a modular structure that unfolds upon deformation Kushner et al mimicked this property in their design for cross-links in a poly(n-butyl acrylate) network Side chains that could form four hydrogen bonds also carried long-chain terminal olefinic groups, which through ring-closing metathesis formed flexible covalent links between the hydrogen bonding pairs (much like the safety chain on a car trailer), providing two levels of chain cross-linking Com- pared to a control material with a poly(ethylene lycol) cross-link, the tensile strength increased by 700% for similar elongations at a cross-link density of 6% — PDS
J Am Chem Soc 229, 10.102 00742176 (2007,
<< A New Angiogenesis Weapon
Tumors need blood, and they secrete angiogenic molecules such as vascular endothelial growth factor (VEGF) to encourage new blood vessels to form Although an antibody directed against VEGF (aVEGF) can prolong life when motherapy to individuals with certain cancers, inhibiting VEGF signaling can elicit adverse side effects and switch on alternative angiogenic mechanisms in tum Noting that placental growth factor (PIGF, a VEGF family member) is not required for normal development of the vasculature but has been implicated in pathological angiogenesis, Fischer et al inves tigated the effect on tumors of an antibody directed against PIGF (GPIGP).In a mouse model, aPIGF by itself inhibited the growth or metastasis of melanoma and of colon and pancreatic carcinomas, calls Metastases of a pancreatic tumor in mesenteric lymph nodes and enhanced inhibition of tumor growth by the chemotherapeu:
tic agents gemcitabine and cyclophosphamide, as well as the anticancer effects of an antibody directed against the VEGF receptor (EGFR) The processes inhibited included tumor angiogen: esis and lymphangiogenesi
as well as the recruitment of proangiogenic macrophages On the
other hand, aPIGF did not turn on the expression of proangiogenic genes, nor did it mimic or enhance e:VEGFR-dependent side effects; indeed, preanant mice treated with cPIGF delivered tt ters of healthy pups Thus, the authors hope that cPIGF might representa useful addition to the
anticancer armamentarium, — EMA
Trang 11wwnw.sciencemag.org Science 11200 New York Avene, NW ‘Washington, DC 20005 i 2023256550, 20229-1562 Nw: 202-326-6581, FX 20233719227 ‘Bateman House, 82-88 Mill Road ‘Cambridge, UK C82 119 “+44 (0) 122532650, Fx +440) 1223326501 Sumer Sevets For change of aes, missing sues, new des ad renewals nd payer autos: 86643045 G27) or 202 326-6419, FX 202-642-1055 Mang aes AAS, PO, oc 96178, Woshingto, OC 20080 i78 r MAS Member Sevces, 1200 NewYork ree, HW, Washington, 20008 lusttanoma ste ttasts pease cll 202-526-6755 for any {orstons or rormaton
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Trang 12Training Your Gut
I you love chocolate, you can thank—or blame—the microorganisms in your gut People who are hot for chocolate, researchers say, harbor different bacteria from those who are indifferent to the treat
Biochemists from Nestlé chocolate company and Imperial College London spent 5 days studying 22 healthy volunteers, half of them avowed chocoholics, on a set diet They analyzed urine and blood samples for the metabolic
byproducts of different types of bacteria The results, published in the November Journal of Proteome Research, reveal that levels of dozens ‘of these compounds in the two groups differ
The differences are “not just a product of our genes,” says biochemist and proj @ that indians who move to the in gut bacteria Kochhar thinks they become attuned over time to a
S&S person's lifestyle and, in turn,
ences—sometimes in a positive direction Researchers found that chocoholics’ blood had lower levels of bad cho: lesterol and higher levels of albumin, a nutri- ologist at the University of Reading, U.K., says understanding how diet affects gut activity can lead to the development of personalized nutri tion plans that can nudge bacteria in the direc
United States show changes
—
can influence future prefer-
ent-carrying protein Glenn Gibson, a microbi:
tion of good health,
Phony Scoop on CO,
Global warming is actually caused by growing numbers of CO,-emitting bacteria on the sea floor, says a study published online on 3 November in the Journal of Geoclimatic Studies “Those who subscribe to the [human: «caused climate change] theory have overlooked the primary source” of CO, emissions, write Daniel Klein and colleagues at the University of Arizona in Tucson
The problem is that Klein and his team don’t exist Neither does their Department of Climatology; Okinawa University, where the journal is purportedly published; or its editor, OU climatotogist Hiroko Takebe
It's a hoax designed “to expose the credulity and scientific illiteracy of ‘climate skeptics,’ * according to “Mark Cox,” the self-described real author of the article, Cox says several anti~ global warming Web sites cited the paper but hastily erased their coverage when the hoax was revealed, Science got an e-mail from Cox after speaking with David Thorpe, a U.K.-based science
wwwsciencemag.org
Md
EDITED BY CONSTANCE HOLDEN
Boys in Delhi pore over a globe that atthe press of a button will show different peoples ofthe world speaking their native tongues It's part of a science exhibit on a train that will travel 15,000 kilo meters over the next 7 months, stopping in more than 55 cities throughout India The 14-car-long Science Express is chock full of multimedia exhibits covering topics such as black holes and CERN’s search for the Higgs boson, It also has a hands-on lab where children can do experiments such as mixing cement or separating chemicals with paper chromatography The $10 million indo German project is a mobile version of the Max Planck Society's long-running “Science Tunnel,” which has been on display in Hannover, Germany, and has traveled to several cities in Asia joumalist and Web site designer Thorpe says he
Created the site but denies writing the article The paper report that algal blooms have gradually killed off “brachiopod molluscs of the genus Tetrarhynchia” and other organisms that prey on CO, producing bacteria, allowing bac
teria populations to explode The paper has some clever ideas,” says geochemist Steven D'Hondt of the University of Rhode Island in Kingston, but “some fairly fundamental flaws,’ such as meaningless equations He also notes that brachiopods and
mollusks are two different phyla
A Probable
Killer?
Is Lucia de Berk, a Dutch nurse, a serial Ailler or the victim of
shoddy statistics? Dutch courts sentenced De
Berk to life in prison for ‘murdering seven patients and attempting to kill three others But
dozens of statisticians last week petitioned the Dutch justice department to reopen the case
Suspicions first arose in 2001 after a SCIENCE VOL 318
De Berk shown as witchlike in cartoons
‘6-month-old girl died under murky circum stances while De Berk was on duty Prosecutors found that nine other suspicious incidents had ‘occurred during her shifts at three hospital Although no direct evidence implicated De Berk, the courts decided that it was unlikely—only ‘one chance in 342 million, according to one wit nness—that so many deaths could have occurred accidentally while she was nearby
That conclusion is based on “every statisti ‘al mistake in the book,”
says Leiden University statistician and petition organizer Richard Gill For instance, he says, several deaths were deemed natural and only later declared sus picious by doctors who knew De Berk had been øn duty And fewer people died during De Berk’s 2-year stint at one hospital ward than during the prior 2 years “Nobody was murdered by anybody,” Gill concludes
Last month, a justice department panel rec ‘ommended that the case be reopened The decision now rests with the Supreme Court 16 NOVEMBER 2007
Trang 13
IBN AWN EDITED BY YUDHI]IT BHATTACHARJEE
ASECOND LOOK The gripping story of Mario Capecchi'’ childhood in wartime Italy made headlines throughout the world last month when he won the Nobel Prize in physiology or medicine (Science, 12 October, p 178) But the extra fame has triggered a new level of scrutiny that casts doubt on some details
The questions arose after the Associated Press (AP) reported th: story Capecchi has repeatedly described—surviving on the streets from
to 9 after his mother was arrested in 1941 by the Gestapo and taken to the Dachau concentration camp—ecan’t have happened that way The AP found no record of Capecchi’s mother being held at Dachau, and historians say that the Gestapo was not working in Italy then Other records suggest that Capecehi spent at least part of that time living with his father After AP showed him the new information, Capecchi released a statement saying that “what I have said and written is my most accurate recollection of my early childhood.” He has said that the stories were based on what his mother and uncle told him after the war,
A longtime collaborator, molecular biologist Kirk Thomas of the University MOVERS
TROPICAL TRAINING A fledgling medical school in Singapore has lured tropical disease specialist Duane Gubler away from the sun and sands of Hawaii to set up a research program in emerging infectious diseases The school, established by Duke University and the National University of Singapore, opened this summer with the goal of strengthening gradu- ate-level medical training in the city-state
Gubler, an expert on dengue, now directs the Asia-Pacific Institute of Tropical Medicine and Infectious Diseases at the University of Hawaii, Manoa He expects to assemble a team of 10 principal investigators to do basic, clini cal, and translational research, as well as to train grad students and postdocs He also hopes to knit new field labs into an emerging infec- tious diseases regional network “Singapore is in an ideal position to provide regional leader- ship,” Gubler says
ON FIRMER GROUND After 2 years of uncertainty, the leading journal of environ- mental health has a new editor in chief Hugh
Tilson, 61, a neurotoxicologist and adminis- trator at the Environmental Protection Agency, will head Environmental Health Perspectives (EHP), published by the National Institute of Environmental Health Sciences (NIEHS) in Research Triangle Park, North Carolina In 2005, then-NIEHS director David Schwartz proposed privatizing the open-access journal but later scuttled the plan after protests from scientists, environmentalists, and Congress
Tilson filsa slot that’s been empty for the past year He says NIEHS will restore cuts to EHP’s budget and bring back some features He hopes to expand the role of associate editors wwwsciencemag.org of Utah in streets of Capecchi’s optimism, all survival skills apacity to
and publish more research on risk assessment “We are confident that [Tilson] will provide sta- bility and scientific rigor to the journal,” says Jennifer Sass of the Natural Resources Defense Council in Washington, D.C
MONEY MATTERS
FOR GREATER GOOD David Heymann has spent a lifetime fighting the spread of infec- tious diseases, most recently teaming up with epidemiologists and health professionals around the world to stop SARS in its tracks Those efforts earned the 61-year-old World Health Organization expert a $250,000 prize from the Heinz Family Foundation last month, which he’s now donating to work on the global monitoring and prevention of infectious diseases
The money will go to the Emory University Global Health institute in Atlanta, Georgia, to support the training of young epidemiologists in developing countries The initiative, to be ‘manager wit! science prog Lubelt ofthe SCIENCE VOL 318
It Lake City, says the details of C:
“If you asked me what makes him a great scientist, I think torn Italy probably h:
Office of Science, filling the new posi
ecchi’s story are unimportant
owing up on the something to do with it,” he says 0 focus, and ability to make tough decisions “are
‘Thomas adds,
coordinated through the International
‘Association of National Public Health Institutes (IANPHI)-—a nonprofit funded by the Bill and Melinda Gates Foundation—is “totaly consi tent with David's own dedication and passion
How could I keep
in public health,”
i - \
Vee
a this award to myself
says IANPHI president and Heymann’ longtime friend Jeffrey Koplan, who describes Heymann as a “remarkably humble
when there are so many others working to protect the human condition,” Heymann says, citing individuals such as "Red Cross workers fighting Ebola or Marburg disease in the Congo” and “community volunteers trudging to remote villages to stop polio in Afghanistan.”
and self-effacing soul.”
< INSIDE GOVERNMENT
DOE SHAKEUP Patricia Dehmer has become the top research, hin the Department of Energy's (DOE's) $4 billion of deputy director of ams under Raymond Orbach Orbach, who isalso
tndersecretary for science, promoted Dehmer last month from head of basic eneray sciences to overseer of all six DOE research programs—which also encompasses high-energy physics, nuclear physics, fusion, biological and environmental sciences, and advanced computing—whose managers previ- ously reported directly to Orbach
“Pat is an extremely effective communicator,” says Michael ‘American Physical Society "She understands very, very well how to deal with members of Congress and with DOE.”
Trang 141048
AIDS RESEARCH
said “no” t0 tem collfund
Did Merckcs Failed HIV Vaccine Cause Harm?
SEATTLE, WASHINGTON—A common cold Virus has walloped the already aili
vaccine field
AIDS researchers, who are still stagger ing from the unexpected failure in September of the most promi candidate in clinical trials, met here last week to explore an even more alarming finding: The vaccine, made by Merck and Co., may actually have increased the risk of HIV infection
study participant, Working with the academic- based HIV Vaccine Trials Ne in some Cumulative HIV Infections (males)*
understand what they mean has required an enormous amount of work,” said Merck's Michael Robertson, a co-chair of the study
In the first full accounting of the trial results, Merck
researchers and their partners reported that, as of 17 October, HIV hhad infected 83 people in the placebo-controlled Scientists debate g60engineering
AdS antibody levels When data th ed that this concern had been overblown,
they doubled the trial size in July 2005 to include people with high AdS immunity Most participants were men who have sex with men, although 38% were women, many of whom were sex workers
The interim analysis in September that revealed the vaccine wasn't working looked only at the low-Ad5-antibody group
When the researchers subsequently ‘examined the high AdS-antibody group, they were startled to find 21 infeet- ions in vaccinees versus nine in the placebo group
work (HVTN) and the U.S cell alae eis
National Institutes of Health 2 50 49Vacdne Em, Typically, researchers deem a (NIH) in Bethesda, Maryland, Š Ỹ 21 acing difference as significant if it Merck researchers stopped the = 4 Ew has a 95% probability of not multicountry study afteran 23 i SN being duetochance—a P value
interim analysis revealed that Ễ £ of less than 0.05 By these st
the vaccine did not work Zw 9 Placebo dards, the finding, with a
(Science, 5 Oetober p.28) § Š P value of 0.029, was signifi- Now further analysis suggests s cant But Steven Self, HVTN'S that the vaccine may have i seiuecoosy bead statistician at the Univer=
helped HIV infect a subset of participants who at the trial’s start had high levels of anti- body to adenovirus 5 (AdS) which causes the common cold and is also a component of the vaccine “This is the worst pos- sible outcome in a vaccine
trial,” said AIDS researcher Erie Hunter of Emory University in Atlanta, Geon
the study sites
The finding is as befuddling a and its implications are The data presented here to some
at an HVTN meeting on 7 November found “tend”toward what’ called “enhance- leaving investigators wondering whether the elevated number of infections in vaceinees who had high AdS immunity was due to chance, behavior, ora vaccine-induced problem Despite int sive investigations, no gical mechanism has emerged to explain how preexisting immunity to AdS could make vaccinated people more susceptible to HIV “The data are very complex, and trying to 16 NOVEMBER 2007 VOL318 SCIENCE 0 230050 OT OH @ 102030 40% ‘Weeks Weeks
Double trouble The vaccine clearly failed (lft), but in men with high AdS antibodies (ight, it may have increased their risk of infection (Women were excluded from this analysis because only one became infected during the study.)
trial, Of these, 49 were vaccinated and 34 received saltwater injections This differ- cence clearly indicates that the vaccine does not
protect a tions in and likel
The discovery of possible enh the so-called Step Study also owes som to chance The vaccine contains three HIV _genes stitched intoa modified Ad vector that reating HIV proteins that teach the immune system how to attack the real
AIDS viru tors
worried that high levels of preexisting AdS antibodies might attack the vector and cripple the vaccine So when Step began in December 2004, they enrolled 1500 people at high risk of infects cells, From the outset, investi
sity of Washington (UW), Seat- tle, cautioned that this compar- ison merits a more stringent cutoft for sig 0.025 and 0.0025, bee study was not designed to 70 00 cause the assess potential harm, nor did investigators p aluate a subset ofthe study population Still, Self said
rend” deserves close examination Sev
efforts to make sense of the t
UW's Juliana McElrath,
who directs HVTN’s lab program, explored
what many consider the most likely explana
tion: that people in the high-AdS-antibody ‘group were more vulnerable to HIV because of “immune activation.” Specifically, HIV «establishes an infection by attaching to T cells that have surface receptors known as CD4 and CCRS Natural infection with AdS creates
memory banks of these very T cells, which
Trang 15
same Way, creating more targets for HIV But McElrath’s preliminary work found no evi- dence for this
ar
Behavioral changes don’t seem to provide an explanation: Study co-chair Susan
Buchbinder of the San Francisco Department of Public Health said risk behaviors had decreased across the board and more so in the high-AdS-antibody group Buchbinder said investigators still are sorting out many vari- ables related to HIV transmission, including circumeision, coinfection with oth
transmitted diseases, and genetic factors ‘One thing is clear: The monkey studies that suggested that the vaccine could thwart the AIDS virus, fueling much excitement, misled Merck researchers, times lie, and humans never li er sextally “Mice lie, monkey some- id EPIDEMIOLOGY
Johnston, head of NIH’s AIDS vaccine pro- gram, “Some monkeys have lied to us this me.” Other attendees stressed that Merck elied on a wimpy strain of the AIDS virus to challenge” vaccinated monkeys and that challenges with stronger strains predicted that the vaccine would fail
trial participants if they received the vac or the placebo A more recently
study of the same vaccine in South Arica was stopped and quickly “unblinded” after learn- ing the Step results, notifying everyone of their vaccine status (Science, 2 November, p 729) After much debate here Step’s scientific steering committee recommended unblinding, and an oversight committee con- Robots ta traffic ‘curred on 13 November
The specterof enhancement alsoafleets the AIDS vaccine field's next-best hope This NIH-made vaccine uses a similar AdŠ vector and was slated to entera $130 million trial this fall without sereening people immu- “Steps results demand that we reexamine and redesign our stud
gator and Step collaborator Scott Hammer of Columbia University
Merck's Mark Feinberg wamed colleagues that “the whole field will come apart at the seams” if it doesn’t properly investigate and respond to the Step results “I've never seen more complicated data to emerge from a study.” Feinberg said "And thisone focuses on as important a question as I've ever known,” “JON COHEN Privacy Policies Take a Toll on Research, Survey Finds
A federal rule aimed at protecting patient data is hindering epidemiology research, adding costsand delays without enhancing confiden- tiality, according to a study this week in the Journal of the American Medical Association (JAMA) The survey responses from 1500 epidemiologists reflect the first systematic analysis of privacy rules that researchers have complained about for 4 years
The problems stem from the Health Insurance Portability and Accountability Act (HIPAA), passed by Congress II y
to make it easier for people to transfer their health insurance A so-called Privacy Rule that took effect in April 2003 requiring health care providers to protect the privacy records also affects research, tors must it’s medical da
§ potential participants If that is not poss the researchers can try to get by with a d: set stripped of identifiers, such as name and address, or they can seek a waiver from an nstitutional ethics board
These requirements have had a major impact on population-based health research, headed by epidemi- igist Roberta Ness of the University of Pittsburgh in Pennsylvania Survey invita tions were e-mailed to more than 10,000
3 members of 13 epidemiology societies, and wwwsciencemag.org
1537 of them completed a Web survey About 68% said the Privacy Rule has made research a great deal more difficult: half reported major delays: and nearly 40% faced much higher costs (see table) Only one-
quarter said the rule has greatly improved confidentiality, Of those who modified a
Epidemiologists’ Views on the Privacy Rule ford Made research more đifcult Enhanced confidentiality 47 rene) Delayed time to study completion
Overprotected? Arule meant to ensure the privacy of medical data jis hampering research, according to survey of epidemiologists protocol to comply with HIPAA, two-thirds
said it was much harder to recruit subjects The results support anecdotal evidence that the Privacy Rule has slowed enrollment and threatened some studies, says Ness (Science, 9 July 2004, p 168: 17 March 2006, p 1547) For example, at the Univer- sity of Michigan, researchers were required to obtain consent fora survey of patients with SCIENCE VOL 318 Agreat deal
heart disease care by mail rather than by phone, resulting ina drop in the response rate from 96% to 34% and a bias toward older, ‘married participants Ness’s survey ests that US surveillance of inf
sure what they can report Three years ago, an advisory panel urged the Department of Health and Human $
(HHS), which administers the Pri- vacy Rule, to ease the burden on researchers by revamping the rule The agency never formally responded But HHS and other organizations commissioned the USS National Academies" Insti- tute of Medicine (TOM) to exam- ine the issue broadly: one of the results is the JAMA survey Researchers in other disciplines have told the panel of difficulties, too, For instance, clinical oncologist Richard Schilsky of the University of Chicago Med ical Center says HIPAA has been “a huge
problem” for studies involy
Trang 16ENVIRONMENT
Panel Calls for Pilot Program For National Indicators
US agencies that track the health of the envi- ronment should kick-start a pilot project to establish a national system of environmental indicators, a blue-ribbon review panel has rec- ‘ommended In the same Way that the gri national product tracks the state of the econ- ‘omy, environmental inl
of wetlands, would monitor prog
meeting environmental goals The panel urged theagencies to start now and develop a plan for the remainderof the Bush Administration; they recommended water quantity stored in lakes, aquifers and snowpacksasa test-bed indicator Observers last week voiced support fora pilot project but stressed that users and contributors Of data must be included in the design process ifit isto be politically viable
Many agencies monitor aspects of the envi- ronment, In 2004, the Govert ‘ount- ability Office recommended that the White House Council on Environmental Quality (CEQ) figure out how to coordinate federal efforts After a yearlong series of meetings
states and nongovernmental organizat- :Q in 2006 asked an interagency team ure out how to proceed The team’ white ized in September, laid out several options and recommended the creation of an interagency council to set policy, another inter- agency teamto manage the technical work, and anadvisory panel The Department of the Inte- rior (DON), one of five agencies involved, had asked the National Academy of Public Admin- istration to evaluate the wam’s ideas
Chaired by Hermann Habermann, former {statistician ofthe US Census Bureau, the
month sent DOL an adva
‘mary of its final report” due out in December The panel agreed with the overall approach but tressed the need for immediate action, ‘What's needed at this juncture is not a new organizational chart but concerted leadership said project manager Don Ryan ata workshop hheld last week by the nonprofit National Coun- «il for Science and the Environment
A national indicator of water quantity would be a good place to start, Ryan explained, because this measure is relatively straightforward—compared to water quality,
® for example—and people care about supplies
of water for drinking irigation, and wildl 3 Ultimately dozens of indicators might cover 8 ¢ i
“A Green Compass: Institutional Options for Developing a National System of Environmental Indicators
www sciencemag.org
Shrinking reservoir Water scarcity, suchas Atlanta is experiencing, could be a prototype national indicator of the state ofthe environment
everything from air quality to biodiversity to outdoor recreation, The panel felt that the agencies should request funds for the pilot project in the 2009 budget: although it didn’t come up with a figure, Ryan
hhuge sum to get rolling.”
Reaction was mixed Although the panel recommended that indicators be usefl tohigh- level policymakers, such a “crosscutting indi- ator of water availability for the whole coun- try doesn’t make much sense,” said CEQ Ted Heintz at the workshop “Water use is loca However, he and others emphasized that the ‘main point ofa pilot program would be to help federal agencies learn to work together better, and for that, water quantity might suffice
Robin O'Malley, who heads the Heinz Center's Environmental Reporting Program in Washington, D.C.,.and others say that building broad support for a national system of indie: tors will be especially crucial now, because the
political leadership at the agencies will change ‘with the new Administration in January 2008 “The action plan has got to be about making sure it rooted in the community when there is ‘no one at the transition to save this.” O’ Malley said "You take a big risk by keeping people out.” he says
Officials at DOL and CEQ are expected to decide in the next few weeks about whether and how to proceed ERIK STOKSTAD SCIENCE VOL318 iN ee
Texas Votes for Cancer Research
Texas researchers are looking ahead to 2009 for the first grants from a $3 billion bond measure that voters approved easily last week The project, which will fund as much as '$300 million a year for 10 years in cancer research, was championed by several promi nen Texans, including Governor Rick Perry and Lance Armstrong, the former cycling champion and cancer survivor (Science, 31 August, p 1154) John Mendelsohn of
the University of Texas M D Anderson Cancer Center in Houston says he expects that “out- standing scientists, hopefully from outside the state,” will help review research proposals for the institute, ~]OCELYN KAISER
Tests on Tests Urged
‘A.group of scientific advisers wants the U.S Department of Health and Human Services to tighten oversight of genetic tests, a growing enterprise regulated by a patchwork of federal rules Last week, the Secretary's Advisory Com mittee on Genetic, Health, and Society released a 192-page draft report on genetic testing that called for new research to evaluate the clinical Utility of genetic tests and for the expansion of public databases of gene mutations The group also urged better proficiency testing of tabs performing genetic tests
“There's been very litle movement for- ‘ward in more aggressively regulating these tests, says Gail Javtt of the Genetics and Pub- lic Policy Center in Washington, D.C., whose director helped write the report Public com- iments are due by 21 December (wwiv4.o4.nih govloba/SACGHS/public_comments.htm)
“JENNIFER COUZIN
Europe Maintains Orbit
BERLIN—The European Space Agency (ESA) should maintain a human presence in low Earth orbit even if, as some have suggested, NASA pulls out ofthe international space station in
the next decade, says ESA Director General Jean-Jacques Dordain “Iam convinced that uti- lization ofthe space station wil bring scientific progress and technological progress,” Dordain said at a press conference last week atthe nter- national Space Exploration Conference in Bertin ‘Although the space station without NASA “isa scenario that is very difficult to imagine,” he said, “itwill not be an end We will continue to offer capability in low Earth orbit.” ESA will unveil a formal proposal forthe project next summer, Dordain says Any decision about plans will come next November at a meeting of ministers from ESAmember states ~GRETCHEN VOGEL
Trang 17i NEWS OF THE WEEK
1052
SCIENTIFIC WORK FORCE
New Analysis Questions Push for More Degrees
Academics, business leaders, and politicians
have warned repeatedly that the United
States risks losing its economic edge unless
it produces more scientists and engineers
also say that the country’s system of nce and math education is not up to snuff, But a new study” questions two basic
tenets of t argument, concluding that
work force data do not support claims of a looming labor shortage and that test scores indicate U.S students are doing at least as
well in science and math as their inter-
national counterparts are
The supposedly sorry state of STEM (sei- ence, technology engineering, and mathe- matics) education was a driving force behind enactment this summer of the America COMPETES Act, which authorizes $44 bil- lion for a cornucopia of research and educa tion programs across several federal agencies (Science, 10 August, p 736) The bill drew heavily on a 2005 U.S National Academies’ report, the title of which, Rising Above the Gathering Storm, refers to the impending economic crisis facing the United States unless it bolsters STEM education (Seience, 21 October 2005
But sociologist Harold Salzman of the Urban Institute and demographer B, Lindsay Lowell of Georgetown University, both in Washington, D.C., say that the academies’ report paints a misleading picture and that its assumptions are leading to flawed STEM education policies They note that the annual US production of bachelor's, mas- ter’s, and doctoral degrees in STEM fields * www.urban.org/UploadedPDF/411562_ Salzman, Science.pdf
‘Against the grain Harold Salzman (center) told Congress last week thatthe United States produces enough technical workers for the economy
16 NOVEMBER 2007 VOL318 SCIENCE
has averaged three times the annual growth of science and engineering jobs between 1985 and 2000 They also point out that fewer than one-third of the 15.7 million workers with at least one STEM degree at ny level hold jobs that require such train ing Given those numbers, says Salzman,
expanding our production of scientists and engineers just defies market reality.” Last week, Salzman made his case twice on the same day, at a talk at the Urban Institute titled “Houston, Do We Really Have a Prob- lem Here?” and in a hearing before the House Committee on Science and Technol- ogy on how globalization affects the U.S science and engineering work force
The authors also say that US students are keaming more than critics give them credit for For example, they note
National Assessment of Educational Progress, (NAEP) for students in eighth grade rose 15 points from 1973 to 2004 And contrary to popular belief that they trail the pack, says Salzman, U.S, students rank in the middle tier of countries on an international assessment of
5-year-olds in math and science
Norman Augustine, former CEO of Lockheed Martin and chair of the panel that produced the Gathering Storm report, does not buy their arguments In an e-mail to other members of the panel, Augustine notes, that “what the [new analysis] does not observe is that an undergraduate degree in {science or] engineering isa prized creden- tial for those who wish to attend business school, law school, medical school or [20 to] a number of other fields{.] If the Gathering Storm repor is incorrect, we Will end up having devoted additional dollars to
improving our children’s education and to the discovery of new knowledge On the other hand, if Drs Lowell and Salzman are wrong, America may well face a serious growth in unemployment and a commensu- rate decline in its standard of living
Those who argue for strengthening US science education say that NAEP is not the right yardstick for measuring what today’s students need to know “In a global economy with a global labor pool it is insufficient to compare American students past performance to American students’ current performance.” says Bill Bates of the Council on Competitiveness, one of sev- eral groups that lobbied heavily for the COMPETES Act, Salzman and Lowell say that they are not arguing for the status quo but rather that any new policies should address the real problems in STEM educa- tion, ary and secondary schools, they call for more resources for the lowest performing students, many of whom are minorities And within higher education, they say that scholarships should be based on market demand for workers trained in individual disciplines rather than across- the-board support Salzman also recom- mends that universities put greater emphasis on teachi tions and teamwork skills.“ -ess has had more to do with its creative design rather than its
he say
istine says Salzman and Lowell have important issues but that he is worried their criticism could undermine efforts to boost the research and training budgets of federal research agencies slated for growth in the COMPETES Act However, David Goldston, the top staffer on the House Science Committee before he retired from the government last year, doesn’t think their paper will weaken the case for greater investments in science and ering “It’s worthwhile te what the nature of tments should be what part of the social scale they should be targeted toward, and what competitive- ness really comes from,” he says Ifthe new study sparks those discussions, Goldston
Trang 18a3
U.S STATE ELECTIONS
Bond slayer Steven Lonegan (ổn necktie) pumped up Vot
9 defeat tem celLinitia
New Jersey Rejects Bonds For Stem Cell Institute
A proposal to ratchet up stem cell research in New Jersey was defeated last week by an array of hard-working opponents and a sense of overconfidence by supporters Despite recent polls showing that the $450 million bond issue would be approved the state's vot-
ers last week rejected it by a margin of 53% to 47%, “[We] were a little bit too confident” and didn’t shift into high gear until too late, 's Martin Grumet, director of the W M Keck Center for Collaborative Neuroscience at Rutgers University in New Brunswick
The bond measure, which was on a ballot featuring contests for various local and state offices, would have supplied an additional $45 million a year for stem cell research over the next 10 years to researchers at both public and private entities in New Fersey Itwas backed by a succession of New Jersey governors: the incumbent, Jon Corzine, even donated
$150,000 of his own money to th
passed Last year, Corzine signed into law allocation of $270 million—New Jersey'sshare ‘ofa national tobacco settlement—for new stem cell research facilities OF this, $150 million is for the Stem Cell Institute of New Jersey in New Brunswick, for whi
broken last month
As recently as October, polls were predict le win But a combination of fort to get it ground was ing a comforta
religious and fiscal conservatives carried the § day Catholic churches showed a video dis-
= paraging embryonic stem cell research, and § Bishop John M Smith of Trenton sent out a
B letter on 7 October urging Catholies—who
§ make up 43% of New Jerseyites—to pray © against the referendum, Antiabortion groups 8 nicknamed the measure “Loan to Clone Ỹ
‘The measure also drew the ire of a
called America oup
for Prosperity that wants to
www sciencemag.org
củrh 'overnment spending Steven Lonegan, former mayor of Bogota, New Jersey, who heads the group's state chapter, says the issue caught fire in the past few months, “
1ed more people on the groun in the state ina long tim,
Citing the state Shigh tax rates and $30 billion debi, the group offered voters a simple mes- sige about three fiseal proposals before them: “Vote No on All Ballot Measures.”
Rutgers neuroscientist Wise Young,
co-founder of the stem cell institute, says
that the referendum was fatally hurt by the
record-low turnout of 26,6% of eligible vor-
ers Participation was lowest in counties
where support for stem cell research was highest, he added
Corzine says he will continue to press for
more money for stem cell research, both
from public funds and the private sector New Jersey, the first state to direct funds to stem cell research, has spent $15.2 million since 2005, according to the New Jerse
Commission on Science and Technolog with $10.7 million budgeted for the curren
at Young says he hopes pharmac cal companies, which have a heavy presen in the state, will piteh in, fiscal re pushing a
Supporters regard the defeat as an expres~ sion of taxpayer frustration rather than
rejection of the research itself Young says advocacy groups are already rallyin
around the idea of another referendum next November, to coincide with the presidenti and congressional races And they vow to be prepared this time “It’s going to be a huge fight all the way down the line.” says Young CONSTANCE HOLDEN SCIENCE VOL318 16 NOVEMBER 2007 iN ee
New Limits on Defense Grants
U.S lawmakers last week put the squeeze on Universities that receive basic-research grants from the military by tightening the amount of money that universities can be reimbursed for the cost of facilitating that research The new language limits overhead costs to 35% of the total amount of the grant That's the equivalent of a 54% indi rect cost rate, and many schools won't notice the difference because their rates do not exceed that amount
But Barry Toiv of the Association of Amer can Universities says at least 40 universities could be affected by the decision, and lobby ists fear that Congress might eventually apply the same formula to the government's entire
research portfolio “A cap on reimbursement is a first step down a potentially slippery slope,” says Toiv “Preventing universities from reim: bursing all the real and necessary costs of conducting research will discourage them from applying for defense grants.”
~YUDHIIT BHATTACHARJEE
Moonstruck
India and Russia have signed an agreement to jointly explore the moon As a first joint venture, India envisages using one of its rockets to launch a crewless mission in 2011 called Chandrayaan-I (a second moon mission for India) Together, Russia and India will develop a robotic rover that will be deployed from a lunar
orbiter to probe the moon's surface for geological data and took for helium-3, a potential fuel for fusion
reactors The collaboration is “an area of great prom: ise” for the two countries, said Indian Prime Minister Manmohan Singh at a meeting in Moscow this week with Russian Presi dent Vladimir Putin
The predecessor to this mission is India’s Chandrayaan-I, a resource-mapping project that India plans to launch on its PSLV rocket (above) in April 2008 It will carty two Ameri: can research payloads and involves no Russ ian participation However, India and Russia have collaborated on space projects for decades: India’s only astronaut, Rakesh Sharma, lifted off in @ Russian Soyuz rocket in 1984, and Russia supplied the cryogenic engines that have carried India’s heavy com munications satellites into space
~PALLAVA BAGLA
Trang 19i NEWS OF THE WEEK
1054
Chilling conclusion Rapid arctic metting ha stimulated interest in Perr?
CLIMATE CHANGE
Scientists Say Continued Warming
Warrants Closer Look at Drastic Fixes
CAMBRIDGE, MASSACHUSETTS—Should sci- entists study novel ways to alter Earth’s cli- mate to counteract global warming? Last week, a group of prominent research;
who gathered here gave a qualified “yes” after ag hat the road to understand- ing the science is fraught with booby traps and that deliberately tinkering with the cli- mate could make the problem worse Some even admitted to being surprised by their affirmative
“My objective going [into the meeting] \was to stop people from doing something stu- pid” says climate modeler David Battisti of the University of Washington, Seattle, But
rising temperatures and carbon emissions, combined with little meaningful action by politicians, convin
that it was time for mainstre: edhim and his colleagues
ence to look more closely at g
Even so, Battisti suspects that the partici- pants share the hope of many of those who took part in the Manhattan Project to build the atom bomb: that society would never they provided “It
have to use the knowle, would be incomprehensible th
this,” Battisti says, emphasizing the greater need to cut carbon emissions we deploy
Organized by the University of Calgary and Harvard University, the event allowed
50 elite climate, energy, and economics researcher
to explore and debate geoengi- the subject has been ges of science fic-
ch But
‘by Nobelist
mostly confined to the p; tion and unfunded by rẻ 4 2006 paper in Climatic Chang
16 NOVEMBER 2007 VOL318 SCIENCE
20 October 2006, wabler” to drive dis- Paul Crutzen (Science
p 401) served as an
cussion among scientists of the once-taboo topic says Harvard environmental chemist Scot Martin, Harvard geochemist Daniel Schrag and physicist David Keith of the Uni versity of Calgary in Canada then decided to ‘ambridge event ‘organize the
‘One reason most scientists have bee leery of probing the topic was the fear that such technical fixes were taken seriously, public support for cutting carbon emissions would be even more difficult to achieve “The very best would be if emissions of the greenhouse gasses could be reduced so much that the [geoengineering] experiment would ba 4/1{{1\{ Tdi
A sea change? Some scientists have proposed creating white clouds over the oceans to help cool the globe
mitt
not have to take place." Crutzen wrote kast year “Currently this looks like a pious wish,
Some scientists, however have been thinking about geoengineering for quite some time The field's roots lie in dueling Soviet and U.S weather-modification pro- grams of the 1960s Since then, advocates
have dreamed up schemes to f by blocking sunl ant spa or by creating sea clouds to
albedo of the ocean In 1997, physicist and Star Wars stalwart Lowell Wood and col- leagues affiliated with Livermore Berkeley National Laboratory suggested usi
aerosolsto mimic the cooling effect of volca noes, and a handful of modeling papers since have simulated that effect
One of Wood's central points is that the aerosol method is cheap In 1992, recalls Harvard physicist Robert Frosch, a National Academies’ panel on climate resisted his
restion to include the cost of
coengi-
neering options in a figure on possible solu- tions to global warming One relatively si ple option: Inject sulfur dioxide into the stratosphere to reduce the amount of solar 2 Earth’s surface "Nobody wanted to put the geoengineering line on the figure because it looked too [economically] reachin;
rosch told participants
That cost was a major factor behind the discussions here, with a number of prelimi- nary technical studies hinting that the SO,
option could be deployed for a few billion
dollars a year That amount could make geo- engineering attractive to politicians looking for radical fixes ina warming world “The decision on whether to do this will not be made by this group.” Schrag told his col- leagues sitting in the wood-paneled premises of the American Academy of Arts and Sci- ences But what scientists can do, he said, is offset the input of ‘oups driven by profit or ideol-
‘ogy with solid research on the pos sible side effects of various geo- engineeri
And to certl
echniques
et started, the group ested plenty of side effects Atmospheric dynami- acked the few modeling
studies that have simulated geo- engine forts for down-
playing details such as ocean cur- rents or complex feedbacks (Modelers defended their stud- ies, which use simplified models, as preliminary.) Ecolog pointed out that artificial coolin;
could lead to serious dryin the tropics and that any fix that »
Trang 20lowers Earth’s temperature wouldn't address
the problem of the steadily acidifying ocean, Modeler Raymond Pierrehumbert of the University of Chicago in Illinois warned that eoen 1g could become a global addic- tion, ‘ually work on geoengineer- don't
ing.” he told the group “But now that the e nie's out of the bottle, I feel Ihave to.” Inone unpublished experiment, Pierrehumbert simu- lated a future scenario, presumably in the next century, in which the amount of atmospheric CO, had quadrupled but Earth was kept cool bya yearly dose of geoengineering His model showed that a halt in the
effort—"by, sa
result in an 7°C temperature jump in the trop- iesin 30 years That rise, he says, would trigger
unimaginable ecological effects
Sallie Chisholm, an MIT biological oceanographer, urged caution, She told Science that her colleagues are downplaying the dif how “inher- ently unpredictable” biospheric feedbacks will react to “turning the temperature knob We the biosphere’ response to an intentional reduction in global temperature through geoengineering.”
Other scientists were more willing to entertain the idea of studying climate manip- ulation but warned about a likely public back- lash, Political scientist Thomas Homer-Dixon of the University of Toronto in Canada talked bout street protests "Some people may con- sider geoengineering to be an act of ultimate hubris.” he says “ItS going to provoke fear, anger, guilt, and despair.”
Others, however, viewed public alarm about geoengineering as a potentially positive effect “If they see us talking about this as a last-ditch effort, itmight inerease their alarm” and drive them to cut emissions, explained Harvard t Peter Huybers during one of the By the end of the 2-day event, participants were stunned that they had come so far “In this room, we've reached a remarkable consensus that there should be research on this.” announced climate ‘modeler Chris Bretherton of the University of Washington, Seattle, Nobody dissented
Mixed in with his new sense of “responsi bility?” Batt is dismay that the climate problem has grown so serious ato drive scien tists to contemplate steps that, in theory, might lead to more serious problems than continued warming Afr speaking on the phone with his \wife from his hotel room, B:
told her this meeting is terri
(For a discussion of the topic with some of the meeting participants, go to www sciencemag.org/hottopics/geoengineering.) ~ELl KINTISCH wwwsciencemag.org BEHAVIOR
NEWS OF THE WEEK L
Robot Cockroach Tests Insect Decision-Making Behavior
cience-fiction writers have long envi- sioned societies in which the boundaries between humans and lifelike droids blurand ‘man and machine freely intermingle José Halloy has taken the first steps toward creat- ing that world, at least for insects His tiny, autonomous robots lack legs wings, and antennae, but they nonetheless pass muster with cockroaches Indeed, these wheeled machines are so well accepted by the house~ hold pests that the robots become part of the insects’ collective decision-making process, Halloy, a theoretical biologist at the Fre University of Bru
colleagues report on pas The robots persuaded many of their insect “peers” to hide in theories of colle behavior among iors very easily ina model, but doing so in experiments is ~
often challenging.” explains
ethologist Jerome Buhl of the University of Sydney, Australia Others have used remote-controtled robots to study animal behavior but not autonomous ones that inter- ‘with animals on their own, “In many ways, {the work] isa big step in the study of collec- tive behavior in animals.” says animal behav- iorist Stephen Pratt of Arizona State Univer- sity in Tempe
Halloy and his Brussels colleague Grégory Sempo picked cockroaches for these robot experiments in part because they had earlier found that cockroaches typically sel-organize:
within a few hours, for example, they setle together in one place, preferring darker spots when available, For those experiments, and the later ones with the robots, Hallay Sempo, and their colleagues built a L-meter-diameter arena with two “shelters.” the roofs of which made of plastic dises covered by red By adding layers of filters, Halloy Sempo can make one shelter darker than the other
Based on observations of insects in this arena, Halley and his colleagues developed a ‘mathematical mode! that predicts which shel- tera cockroach should pick depending on the SCIENCE VOL 318
level of darkness of the shelter and the num- berand activity ofits fellow roaches Halloy’s group then used this model to program robots designed by him and Francesco Mondada and at the Ecole Polytechnique Fédérale de Lausanne, Switzerland,
The roaches usually ran away from the robots but not if the machines smelled like the insects, For the experiments, Halloy and Sempo covered the robots with a filter paper containing the pheromone equivalent of one cockroach
Halloy initially programmed the robots to have the same darkness preference as the cockroaches, and they joined the cockroaches at whatever shelter the majority chose to rest in, Next, Halloy programmed the robots to prefer the lighter shel- ter About 60% of the time, the robots tipped the group's preference Can't we be friends? Cockroaches seem to accept this robot as one of their own once it's coated with pheromone
in favor of the light shelter “This is a true example of automated leader- ship.” says David ‘Sumpter of Uppsala University in Sweden “Instead of the robots rounding up the cock- roaches like sheepdogs, they lead through social attraction
But Coby Schal, an urban entomologist at North Carolina State University in Raleigh, has reservations about the effectiveness of the pheromone guise in convincing the roaches that the robot is just like them, He ‘wonders if the physical presence of the robots made the lighter shelter more attractive sim- ply by increasing the structural complex this hiding place “In my view, the jury is still
out” on whether the robots became part of the decision-making, says Schal
Trang 211056
NEWSFOCUS
24/24
[UP 10071717377 1117)//17173))07c7-Í by thousands of: i[Bmeters of fiber~
optiểfấfffpoýe,cab[Ss điim fo retolutionize oceanography, But will
Set 2cieficð-0f0jectS also hamstring the future of ocean research?
ca
SEATTLE,WASHINGTON—Whhen John Delaney first started using ships and submersibles to explore the underwater voleanoes off the coast of Washington state back in the early 1980s, the experience, he says, was exhilaral- ing Delaney was part of the team that in 1984 discovered the Endeavour vent, a 70-kilometer Jong volcanic ridge where magma from Earth’s mantle wells up between a pair of
earch
tectonic plates As exciting as thos trips were, they were equally exasperati
nographer at the Uni- on (UW), Seattle, who looks every inch the bearded sea captain and is fond of reciting T S Eliot, Ralph Waldo Emerson, a says Delaney, an oc versity of Washin \d Robert Frost “They offered
snapshots” he says “We would get ship and
sub for a couple of weeks, come home, pub- lish our results, and then write another set of
nts We woul
2 id see something inter- esting But it was or3 years before we could come back and see what was going on That became very frustrating”
Delaney’s frustration convinced him that there had to be a better way
up a sustained research presence in the ocean, means to set
Ocean buoys outfitted with sensors of course have continuously monitored conditions suchas sea-surface temperatures for decades But that was harder to do 1000 meters or
16 NOVEMBER 2007 VOL318 SCIENCE
care Jaa
more below the ocean’s surface, and deep- water devices suffered from weak power sup- plies and either could transmit only small amounts of data back to shore or had to be retrieved after months of data collection
In 1987, Delaney hatched the idea of
using underwater telecommunications cables to wire the sea floor Such cables already crisscrossed the ocean carrying phone calls and computer data between continents If re archers could tap into those cables, per-
haps they could use them as both a power source and a conduit to link to a new
tion of sensors, robots, and autonomous vehi- cles The idea lay dormant for a few years but
slowly started 1 twas like a
snowball goi ” Delaney says “People sail “If ;oing to do that, then 1 can hook into it to look at fish stocks, tsunamis, pollution, and so on:
1998, Delaney successfully pitched the idea for a feasibility study to the National Oceanographic Partnership Program, which fosters collaborations among US federal
he says In
universities, and companies to pro
issues At about the same time, researchers at other major oce §eraphic institutions such as the Scripps Institution of Oceanography (SIO) in San Diego Califor- nia, and the Woods Hole Oceanographic
3 Te ee eb
Institution (WHOI) in Massachusetts also began pushing the same notion,
Now, after dozens of meetin;
and reviews, ocean scientists are
upa handful of deep-water cabled observatories and are gearing up for a new wave of ocean research Bi in 2010, researchers from UW, SIO, WHOI, and Oregon State
University (OSU) in Corvallis plan to string
cables to sites scattered around an entire the Juan de Fuca Plate off on and Washi continental plate- the coasts of Or ure, p 105 on state (see fi ) Cable was recently laid for
Canadian arm of the project as well as for a deep-water cabled-observatory test bed off the coast of Monterey, California Early next year, the European Union will link instruments to three separate cables cur- rently
trino observatories, g used to Wire up underwater neu-
nd its members are considering further dedicated cable systems down the road And Japan and Taiwan have recently installed cabled systems, largely for seismic research
Trang 22High definition, Cabled observatories will scrutinize ocean hot spots such as these black smokers
global reach about 100 years later, “What we're looking at now is a third phase.” Delaney says Iv’s one in which continuous power and data channels offer researchers the ability todevelop a new array of instruments that can is continuous
-am of microtremors at a mid- the DNA of under- \water organisms on the spot and shipping the data back to researchers continuously Until now, the ocean has been close to a black box: says Marcia McNutt, president and
CEO of the Monterey Bay Aquar- ium Research Institute (MBARD in Moss Landing, California “I will be very surprised if we do not make startling new discoveries, cause we will be there 24/7 and can study the ocean on our terms,” MeNut says
But although proponents of the system are quick to liken the Utility of the new cabled observa tories to the revolution sat lites provided to oceanography, detrac- {ors Say a more apt comparison is, the international space station: a money sink that provides se tific value to relatively few researchers The concern, they say, is that the cabled observato- ries will be so expensive to main- tain and operate that they will inevitably siphon money from other area
s of ocean sciences
“Ocean scientists are always of one mind when it comes to ships,” says Peter Niiler, a physical oceanographer who retired this summer from SIO “We are usu- ally of one mind when it comes to
satellites We are not of one mind on this”
Growing appetite While Delaney has sper
complete his vision of a cabled underwater himoutofthe
observatory, others have bea
gate, In 1992, researchers led by physical oceanographer Scott Glenn of Rutgers Uni- versity in New Brunswick, New Jersey, launched a near-coast cabled observatory called LEO-15, which was built off the coast just north of Atlantic City, New Jerse ‘water 15 meters deep and thus could be serv- iced and maintained by scuba divers “It really whetted the appetite of the science
Š community to do more.” McNutt says in wwwsciencemag.org Wired Oceanographers plan TY TỶ Researchers in Hawaii took the next step in 1998, when they we
doned undersea telephone cable that runs from the Hawaiian island of Oahu to Califor- nia They made it the backbone of the first deep-water cabled monitoring system, known as the Hawaii-2 Observatory Below 5000 meters of water, researchers inserted a jun tion box with eight ports for tapping into the cable's power supply and hooked up a variety of seismometers, pressure sensors, and a hydrophone The network operated for only 5 years but helped persuade oceanographers to push for purpose-built cabled observatories
iven use ofan aban- DI Coca Nodes: IAN DE FUCA eo PLRTE Such observatories, proponents, have two bi
these provide is unlimited power and the abil: ity to get data back to shore in real time That's
fabulous,” says MeNutt Oc:
instruments including buoys at the surface and seismometers and other sensors on the sea floor—have traditionally worked with very limited power, supplied either by bater-
ies or by small wave-powered generators and the like Therefore, they typically haven't been able to record or transmit larg
of data, That has tended to limit them to tak- ing periodic measurements that were either sent back to shore by a low-bandwidth satel- amounts SCIENCE VOL 318 at Dee Sei 16 NOVEMBER 2007 NEWSFOCUS L
lite connection or archived onboard for retrieval months later “If you think how con- trolled we have been by the whims of the ocean, this takes away those limitations and will allow us to say for the first time what
really happens during hurricanes, earth- quakes, and other events,” MeNutt says
MeNutt, Delaney, and other propon say that cables now being laid off the coasts of California and British Columbia will
researchers the first glimpse of oceanogra- phy’s future Of California s coast, th kilometer Monterey Accelerated Research System cable—about the width of
hose—will carry fiber
and 10,000 volts of electricity to “nodes underwater transformers that science essentially
reduce the voltage and sit alon
side eight ports Instruments will connect directly to the ports or be linked to them by underwater extension cords
The instruments vary widely
, called the Eye in the Sea,
On
will use a video camera that nplifies stray photons to in deep-water bioluminescent organisms Another, a robotic
microbiology lab, will analyze DNA and RNA samples to deter- n
ent and possibly even discover new life forms Yet another known as the benthic rover robot the size of a riding lawn mower that will creep across the n floor taking measurements effort to sort out the long- mystery of just how ine which organisms are pres- from above and reaches the deep ocean floor, Because the such experiments are power-hungry and typically operate continu
ously, they represent science that can’t be done with traditional instrumentation Another advani yys marine biologist Ken Smith of MBARI, who heads the team of
scientists working on the benthic rover, is that
if researchers spot something interesting in the data one day, the next day they can repro- gram their instruments on the fly to monitor it, “Td love to have cabled observatories all over the sea floor.” Smith says
Vigorous discussion
Despite their obvious upside, cabled obser- vatories have long proven a tough sell The issue, Niiler says, stems from the wide
Trang 23Bie
1058
WSFOCUS,
diversity of disciplines in the ocean sci- ences, including geologists and geophysi- cists interested in understanding plate t tonics, fisheries biolo;
ish stocks, and physical oceanographers inter- ested in tracking how earbon dioxide moves between the atmosphere and the oceans “Oceanography is not one sei says Niiler ne for scientists that t’sa catcha ïl need a common f that is unique which is ships.”
In the United States, however, those com- munities essentially compete for one pot of money as the lion's share of funding for basic
nces research comes from the ence Foundation (NSF) This year, Congress gave NSF $5 million to begin nstruction of the $331 million Ocean Observatories Initiative (OL); NSF hopes fora big funding spike in 2009-11 to finish the job The largest portion of funds estimated to be about $170 million—will go to build the deep-water cabled observatory offthe Oregon and Washington coasts When the idea for this expensive observatory first began to gain traction several years ago, the broader oceanography community balked until additional components—a few buoys
designed to operate at high latitudes a net- work of instruments off the Oregon coast, and a cyberinfrastructure component to handle the expected surge of data—were added “In order to get community buy-in to the OOL idea, there were some compromises made? MeNutt says
However, although Congress agreed to pay for the new infrastructure, it didn’t provide any exirt money to run or maintain OOT's cables and instruments That money—expected to total about $50 million a year—will have to come out of NSF's general budget of about $300 million a year for ocean sciences Niiler and other critics angue that because the cabled
‘observatories are fixed in place on the ocean floor, they will primarily benefit underwater
16NOVEMBER 2007 VOL318 SCIENCE Cerner Oot new đe robots TT orcs Ínstrument th
geologists and geophysicists Ye, because the operations and maintenance funding will come from the ocean-sciences community asa whole, the high price tag could force cuts in other areas, “I worry that small, individual principal investigator-driven science will be harmed in its breadth and depth by
much for these observatories
be named out of concern that ite chances of acquiring future NSF funding
“We agree that operations and mainte- nance funding is the ongoing strugele of sci-
ence right now.” say
physicist at OSU, who is currently serving as program director for ocean sciences at NSF However, he and others point out that geolo-
gists and geophysi- cists aren't the only
‘ocean scientists get- ting new equipment these days Other researchers have received, from NSF and other sources 3 $120 million ship for arctic research, $100 million for a new drilling ship, submersibles, and a global oc network “Now w
new capability that will not appeal to everyone As an
organization, we have to find a balance Schultz says Julie Morris, director of NSF'S
in sciences division, adds that if Con- ress and President George W Bush con- tinue their push to double spending on phys- ical sciences research and development, that could obviate much of the funding concems
For his part, Delaney is quick to deny that deep-water cabled observatories are of little an float alled Argo
Creeper This robotic rover will track how much T ‘organic carbon reaches the sea floor
ime
est to anyone but geologists.“ Matly dis- “he ‘There is a tremendous
agre ays
amount of oceanographic science to be done in the waters overlying the Juan de Fuca Plate.” Niiler acknowledges that a cabled
observatory offers advantages for studying ‘ocean vents and the chemistry and onganisms
the ocean and atmosphere affeets climate change, he says, the cabled observatory has far less rele hey just don’t go together, ‘To pretend they do is
just not
Critics also fear that once major new observatories are built, future research grants
\ill tilt in favor of scientists who propose to work on them “It will be hard for [funding s] 10 resist the temptation to feed this ” says the anonymous U.S.-based nographer “It’s exactly like the finter- national] space station,” adds Russ Davis,
another oceanographer recently retired from
Scripps “We will have to have guys use this, thing once we put this togethe
Delaney and others respond that all the scientific projects associated with the cabled observatories will be peer-reviewed, although Delaney readily acknowledges that the oceanography community is still coming to grips with the facilities “It’s a vigorous discussion, as it should be.” he says Christoph Waldmann, a member of the
European Sea Floor Observatory Net- work steer mittee loo a new European cabled-observatory system, says the dia- k der way in Europe and else- where is much the same But he and others repeat that proponents of cabled observatories are not out to do away with anyone else’s earch but rather seek to open dra- matie new possibili- ‘The science commu ng into eu
ties to ocean research
Trang 24PUBLIC HEALTH
In the HIV Era, an Old TB Vaccine
Causes New Problems
The only TB vaccine available can be deadly for HIV-infected children That puts public health officials in a difficult dilemma
It's well-known that HIV and tuberculosis (TB) form dual, deadly epidemies that fuel each other, More than 13 million people, most of them in sub-Saharan Africa, are infected with the pathogens that cause both diseases Recently, researchers have found that HIV- infected chikiren—who need protection from TB more than anyone else—are also much more susceptible to side effects of a widely used anti-TB vaccine The live vaccine, devel- ‘oped more th 1d known as Bacille Calmette-Guerin (BCG), can lead to a generalized infection that may be fatal in as many as 75% of cases Based on these data, experts,
baby with HIV should be vace TB But that’s easier said than doi
infected infants isn’t feasible in many countries with high HIV rates What’ more, researchers worry that discussing these side effects could give the vaccine a bad name and lead to a drop in overall vaccination rates, “It really aterrible dilemma,” says pediatrician Elizabeth Talbot of the Dartmouth-Hitehcock Medical Center in Lebanon, New Hampshire
As vaccines go, BCG was always a mixed blessing, Researchersat the Pasteur Institute in Paris developed it by weakening a strain of
Mycobacterium bovis, a cousin of M, tuber cculosis, the agent that causes human TB (The process was inspired by vaccinia, the smallpox vaccine most likely derived from cowpox.) BCG doesn’t appear to do much for adults, but it protects children from the most serious forms of TB during the first that no ated ag identity years of life parts of the worl
BCG isthe only TB vaccine that exist almost every country in the world uses it
Recently, many Western countries have started limiting their use to high-risk groups, such as immigrants from endemic counties, cause dropping TB rates have made the vac~ cine less cost-effective But in regions with high TB rates, it's still an important line of defense In Africa, most children are vac nated right after birth Some studies have even shown that BCG reduces mortality from ‘causes other than TB as well, perhaps because it boosts the immune system
Researchers have long known that BCG wwwsciencemag.org
could cause adverse events in immunocompro- mised people, ranging from local reactions to disseminated BCG disease a life-threatening infection “But until now, we didn’t have any solid data” on the magnitude of the problem, says T Mark Doherty of the Statens Serum Institute in Copenhagen, Denmark In areas WHERE ! TB AVI nERE Double-edged sword Experts stress that to prevent TB—which has infected this Nairobi gir— BCG use should continue in Hiv-negative children
with high HIV rates, babies are prone to so many other diseases—including TB, mal
\d gastrointestinal infections—that a vaccine- specific reaction is hard to notice And dia nosing BCG disease requires culturing the bacteria from infected children—a time~ consuming process—and then using a poly merase chain reaction test to determine that they are M ovis, not M tuberculosis:
Sowhen Anneke Hesseling of the Desmond ‘Tutu TB Centre of Stellenbosch University near e Town, South Africa, started looking care- fully ina hospital in the Western Cape province, 5 NEWSFOCUS L
lished in Vaccine in January, Hesseling con- cluded that disseminated BCG disease ‘may occur in one in every 240 HIV-infected ceinees at that hospital; that’s more than 500 times the risk for healthy children
A new, unpublished study based on better surveillance in more hospitals suggests that the risk for HIV-infected children may be two times higher still, she adds The concems about BCG are corroborated by an as-yet-unpublished study in Argentina, presented at 2005 meeting by Aurelia Fallo of Children’s Hospital Ricardo Gutiérrez in Buenos Aires
The solution sounds easy: Children bom to HIV-infected mothers should be tested and if HIV-positive, should not get BCG But in many African countries, mothers aren’t tested for HIV to begin with What’s more mother-to-child transmission of HIV occurs mostly around birth, so tests can't be reliably done until at least 6 weeks later That would mean postpor
vaccinate HI during that period
The Western Cape is consider- n1o do just that, says g the decision to posed children
in South Africa; in many other African countries, it likely not feasible A ge in standard vaccination schedules i
major undertaking, she says, and post- poning vaccination carries the risk that some ofthe children will never come back Even in counties with high HIV rates, a large major children are HIV-negative points out; if they missed the cine because ofa policy chang would be a disaster ion (WHO) for after reports from two expert panels, WHO began advising against vaccinat- ing HIV-positive babies But th
mendations are “not all that helpful Hesseling In an e-mail to Science
communications officer said that “there is concern that recommendations might become counter-productive if BCG use ceases or is discontinued in HIV-endemie population WHO continues to recommend using BCG if nothing is known about a child’s HIV status
The agency is in a difficult position, Doherty says as it will be blamed if overall tion rates drop “In situations like this, she wrote
where both HIV and TB are rampant, the out- always a tendency to err on the side of come came asa shock to many Ina paper pub thestatus quo.” he says - -MARTIN ENSERINK
SCIENCE VOL318 16NOVEMBER 2007
Trang 25Bie 1060 WSFOCUS ROBOTICS
Robotic Cars Tackle Crosstown Traffic—and Not One Another
In DARPA's Urban Challenge, cars that drive themselves face off in a strange, soulless rush hour Are human drivers about to go the way of the buggy whip?
VICTORVILLE, CALIFORNIA—The Land Rover
nical por- neer at the y
bristles with sensors like a me cupine, John Leonard, an
Massachusetts Institute of Technolo (MIT) in Cambridge, ticks off the robo features On the roof spins a conical laser range finder called a lidar that sees in three dimensions A dozen lidars that see in one direction, 15 radars and six di
look out every which way Computers fill the back of the truck, and a generator sup- plies the 3.5 kilowatts of power they need It's impressive But all this so the truck can turn left across traffic by itself?
The robot is one of nearly three dozen vying in the Urban Challenge a competition sponsored by the U.S Def
Advanced Research Projects Agency (DARPA) It’s the third ‘and most demanding in a series that aims to spur the developme: of autonomous vehicles, which the U.S military hopes to press into service by 2015 In 2004 and 2005, robots raced one at a time across open terrain This time,
they must navigate the streets of an abandoned air base here in the Mojave Desert without colliding, with one another or with humal
‘guided vehicles
The competition showcases some of the world’s best talent in robotics “We were drawn to the
Urban Challenge because it requires real-time decision-making in a dynamic environment and in the presence of uncertainty.” Leonard says Italso serves the higher purpose of try- to save lives, as worldwide, 1.2 million people die each year in traffic accidents that robotic cars might help avoid
‘And yet the Urban Challenge is at le slightly absurd It looks a bit like a real race
Engineers wear bright shirts emblazoned with the logos of sponsors—GM, Ford, Intel, Google Teams have hauled in tractor trailers full of equipment and plastered their robots with decals Besides the $2 million first prize, the appeal of the challenge is obvious I's hard, and by pitting idea against id technology against technology, t
mines what technical DNA moves to the next generation” in the evolution of autonomous vehicles says roboticist William “Red” Whittaker of Carnegie Mellon University in Pittsburgh, Pennsylvania
Still, the task the robots will attempt seems so ordinary They must obey the Ca fornia traffic laws (although if two collide, they won't have to exchange insurance infor- mation as human drivers are required to do) We're all here to wateh traffic But we won't see with our own eyes Instead, we'll have to watch iton television, Ir'snot even clear what DARPA gets out of this well-crafted media circus The competition is meant to stimulate the development of cars that drive them-
Comeback kid After a delayed start, Carnegie Mellon's Boss cruises brisly toa victory
selves—and it has—but DARPA does not require winners to reveal to the agency the details of their technologies
Go ahead, bend the rules At the decaying fighter ba:
road from the new federal prison here in Victorville, 11 teams have made the final competition Three years ago, not one robot traversed more than a dozen kilometers of the 230-kilometer off-road course A year later, four completed a similar course And this year’s robots are far more capable than last year’s crop, possessing better sensors, more powerful computers, and, most important, ‘more sophisticated programming “Driving is a software problem, not a hardware problem, \cross the
Stanford, we can’t build a better
‘can make a smarter ear.”
Computationally, this year’s challenge is much more difficult than the first two researchers say In the desert races, the robots had only to identify obstacles in a static land- scape and plot a safe path around them, This time, the vehicles will have to avoid other cars, including other robots, while at the same time obeying the relatively a
laws To do that, each robot’s computer must calculate the likely trajectories of all the objects around it and plan to miss them, Of course, a robot cannot know exactly where another car will go, so the machines generally employ layers of probabilistic algorithms to decide their next moves,
MIT has decked its robot, Talos, with the most sensors The radars see distant objects, the lidars see at an intermediate range and the ‘cameras spot things close by explains David Barrett, a team member from the Franklin W, Olin College of Engineering in Needham, Massachusetts Talos depends mainly on its sensors to nav Barrett says Tha because the team assumed, incorrectly itturns ‘out, that DARPA would not let robots use sig- nals from the satellite-based Global Position- ing System (GPS) all over the course
Researchers from Stanford, who won the 2005 competition, say that they focus on the algorithms programmed into their robot Merely encoding the traffic laws can leave the robot stymied, says Stanford computer scien- tist Sebastian Thrun For example, when two robots arrive at a four-way stop simultane- ‘ously, each may try to yield to the other end- lessly To avoid such deadlock, the team lets its robot skirt the laws, “Ourcar hasa hierarchy it follows,” Thrun says “At the top, it obeys strict rules, And ifit gets stuck, it ignores more and more rules.” Fair enough Why expect more from a robot than a human?
Team AnnieWAY, one of two German squads in the final, has taken a minimalist approach to guiding its Volkswage
The team relies almost entirely on the $75,000 three-dimensional (3D) lidar, which Bruce Hall and colleagues at Velodyne Acousties Ine in Morgan Hill, California, developed to compete in the 2005 DARPA challenge The sensor may be all you need, says Séren Kammel ofthe Karlsruhe Institute of Technology in Germany “I think some teams have a lot of sensors because they have alot of sponsors, and everybody wants their sensor on the ear” he says
Trang 26
of Central Florida in Ork “ve outfitted Knight Rider, a 1996 aru Outback that belonged to Harper's wife and has 99,257 miles (159,705 km) on it, with just enough gizmos to get around the course—they hope Instead of the spinning 3D lidar, they use two lidars that see in one direction and rock them back and forth “If just one wire falls off, something essential is not going to work.” Harper says Still, the team made the final having invested only $130,000 in the project
Robots, start your engines!
Race day usually brings the intoxicating smell of high-octane fuel and the electri- fying scream of engines But not here At 8:00 a.m., the robots leave the startin;
area, one by one, like rental cars leaving a lot There's a glitch Interference from a jumbo TV sereen knocks out the GPS
of first qualifier, Boss, Carne; Mellon's Chevy Tahoe The team replat the unit and has to wait 30 minutes to
Odin, a Ford hnic Institute ersity in Blacksbu Junior, Stanford's Volkswagen Passat: and the others head out, hesitating and swerv- ing as if driven by octogenarians After a half-hour, all 11 robots—plus their chase cars and 37 other cars—are on the road
There's only one curve from which to glimpse the robots, so DARPA has hired a the event on three huge sereens ina vast tent, Jamie Hyneman and 3 Grant Imahara of the geeky cable-television § reality show Mythbusters provide commen-
5 tary Its like watching hybrid ofa NASCAR helicopter and is televisit wwwsciencemag.org \ \ race and the infamous O J Simpson low- speed police chase
space in alot, traversing an off-road passage, or navigating between two places After each mission, the robots return to the start area to download the specifications for the next, and each machine must travel 60 miles (97 kilo- meters) in less than 6 hours
At first, the action comes fast and heavy, An hour into the race, TerraMax, the hulking, vehicle entered by military contractor Oshkosh Truck Corp in Wisconsin, turns toward a pillar and gets stuck staring at it Forty-five minutes later, Central Florida runs straight toward a house Caroline, the robot from Team CarOLO the other German squad, collides with MIT's Talos and loses sensors By 11:00 a.m five robots have either failed or been disqualified
Then things settle down, The remaining robots’ “personalities” emerge Carnegie Mellon’s Boss zooms confidently away from
stops, a hard charger like team leader Whi taker Stanford's Junior glides around smoothly, so much so you hardly notice it
MIT's Talos is ie—it also clips Cornell's Chevy Tahoe, Skynet—but skittish off-road, stopping and starting like a cat creeping downa steep slope
Around 1:30 p.m., three teams have nearly completed their missions, and spectators swarm back tothe grandstands, At 1:42, Stan- ford cruises across the finish line, followed a minute and a half later by Carnegie Mellon, Upstart Virginia Tech cruises home third even without the 3D lidar “We knew we were SCIENCE VOL 318
Junior and Virginia
“Tech's Odin negotiate
an intersection
good” says Virginia Tech's Alfred Wicks “We'd done our home- work.” The University of Pennsyl- vania’s Toyota Prius, Little Ben, straggles in an hour later Some- time past 3:30 p.m., MIT slips in just before Comell
The outcome seems obvious Carnegie Mellon spotted Stan-
ford and Virginia Tech a 20- minute head start and made up almost all of it It seems the v tory should be theirs DARPA officials will make the final call, however And, some participants grumble, DARPA never fully explains its judgments,
Make it out to
But the next morning brings no surprises Carnegie Mellon walks off with the win, Stanford takes second and $1,000,000, Virginia Tech takes third and $500,000 “There's tremen- dous satisfaction in what the whole field accomplished” Whittaker says “That was a day that stunned the world.” DARPA Dit tor Anthony Tether also gushes “Quite frankly, I watched these things and I forgot after a while that there wasn’t anybody in historie day—bot on Maybe there's something to the grandiose rhetoric, Now only a Luddite could doubt that soon cars will guide themselves, at least in a pinch to avoid collisions In fact, the technol- ogy already seems ripe for low-risk applica- tions, such as automating farm equipment, and the leading teams are pushing to com- mercialize their software, “I think it’s to come Reinholtz | and an engine
bits and pieces,
\der of the Virginia Tech team at Embry-Riddle Aeronauti- cal University in Daytona Beach, Florida
Ironically the success of the Urban Chal- lenge could reduce the chances that DARPA will stage another competition “DARPA never finishes anything.” Tether says “All we doisshow that itcan be done” in the hope that industry takes over and pushes further devel- opment Clearly, when it comes to making robotic cars, the Urban Challenge has shown that itis possible
Trang 271062 BEHAVIORAL G ETICS
Evidence Linking DISC1 Gene to
Mental Illness Builds
Animal studies add weight to the view that an important gene for brain development plays a role in diseases such as schizophrenia and depression
Every clan has its misfits, but an extended family in northern Scotland is extraordinary More than half have suffered from schizo- phren ther form of mental illness A group of Scottish researchers reported in 1990 that the affected people all carried the same genetic anomaly—a translocation, or swap, of two stretches of DNA on the lo arms of chromosomes | and 11 With mod- esty, the investigators wrote that this “may be 4 promising area to examine” for genes that predispose people to mental illness
The area turned out to be very promising indeed By the year 2000, it had led researchers to a gene called DISC/ which may be a key player in the chain of events Jeading to mental illness The circumstantial evidence for assigning a major role to DISCI (Disrupted-in-Schizophrenia 1) is strong Several studies have linked the gene to schizophrenia, major depression, bipolar disorder, and autism; recent findings on DISC1’s biological function appear to sup- port the hypothesis,
Animal studies have shown that the gene or some
is needed for normal brain development both in the embryo and later in life and that
blocki tbnor-
malities in brain structure resembling those sn in patients with schizophrenia The pro- tein encoded by the gene also turns out to be part of a nerve cell signaling pathway involved in learning, memory, and mood “I
its function produces subtle a
16NOVEMBER 2007 VOL318 SCIENCE
think this gene is really the first big break- through in schizophrenia and other men- tal diseases,” says Christopher Ross of Johns Hopkins University School of Medicine in Baltimore, Maryland
Afier decades of following false leads, researchers are cautiously optimistic that they are on the right track with /2/SC/, Bút the evi- dence isn’t airtight, Except
in the Scottish family
researchers haven't cons tently linked any particular DISC] variant to a mental
cautions psychia-
trist Daniel Weinberger of the National Institute of Mental Health in Bethesda, Maryland But ifthe connec tion of DISC/ to mental dis- orders holds up,
to better therapies for treat- g the conditions—espe cially schizophrenia, a dev- astating disease that is now poorly controlled at best
The hunt begins
Gene hunters have had a down the in mental
disorders mainly because the diseases are complex,
Held in place An RNAi that blocks DISC2 synthesis prevents migration of neurons (green) to the upper layer of the cortex in mice (ight micrographs); controls are on the let
meaning that sẽ as well as envi ronmental factors, contribute to their devel- ‘opment That's why the Scottish family proved to be such a boon The 1990 study, which was conducted by a team including David St Clair, Douglas Blackwood, and Walter Muir of the University of Edinburgh, ion disrupted by the translocation seen in affected members of the Scottish fi
nily held one or more genes involved in the disorders
eam led by David Porteous and Kirsty Millar, also at Edinburgh, identified twvo previously unknown genes on chromo- some I that were interrupted by the
anomaly, Attention has focused on the first DISCI which normally produces a large pro-
n the structure of which su: interacts with other proteins
Shortly after identifi
follow-up study by the Edinbur buttressed a causative role for the
mental disorders of the Scot
linkage analysis had a high degree of sta- tistical validity—a LOD se 3
as you could get.” Porteous ‘nvironmental influences may
considered good In this close to causalit
says Even so,
still be important, asa few members carry the translocation but remain unaffected
The Scoitish family is unusual because so many members develop bipolar disorder and depression, as well as schizophrenia, and no ‘one has detected a similar DISCI abnormality in other families In 2003, however, Leena Peltonen of the National Public Health Institute in Helsinki, Finland, and her colleagues reported a link- age between a particu of three singl lar set nucleotide variants (single-nucleotide polymorphisms) in D/SC1 and schizophrenia in a group of 438 Finnish fami- lies “Thisis the first genetic evidence that DISC/ has something to do with the more common garden variety of schizophre Peltonen says
Trang 28Research on DISC/’S normal function has strengthened the case that it is involved in mental disease For starters, the gene is
expressed in many tissues, but particularly in brain areas such as the hippocampusand cere- bral cortex that are affected in schizophrenia
That puts the gene’s protein product in the
of the mental disease
In addition, as predicted from DISCI’s structure, researchers have unmasked numer- ‘ous binding partners for the protein, The rent count stands at about 50, Porteous says, including “10 or 12 where the interaction influences function.” Several ofthese partners estarole for DISC in brain development and cognition
For example, about 5 years ago, three inde- pendent groups, those of Porteous, Akira Sawa of Johns Hopkins University School of
ine, and Christopher Austin at Merck Research Laboratory in West Point, Pennsylva- nia, found that DISCT binds toa protein called NUDEL (for NudE-lke) that is needed for the neuronal migrations that occur during brain development Several other partners of DISCI, including FEZ 1, LISI, dynein, and tubulin, are also involved in nerve-cell migrations
That suggests that brain development might go awry if DISC/’S function is altered or missing Evidence supporting that idea includes the demonstration about 3 years ago by the Sawa team that inhibiting DISCT syn- thesis in mouse embryos with small interfer- ing RNAs causes abnormal migration of neu- rons to the cerebral cortex
More evidence comes from animal models developed in the past year This fall, two Johns Hopkins groups, one led by Sawa and the ‘other by Mikhail Pletnikov, published reports ‘on two similar mouse models produced by introducing a truncated version of the DISCI gene into mice Both lines showed similar changes “The brain is superficially normal but isn’t wired correctly.” says Ross, a: mem- ber of the Pletnikov team
Outgrowth of neuronal projections called neurites, which help guide neuronal mig tions, was reduced In addition, interior brain spaces called ventricles were larger than nor- mal—an alteration also seen in people with schizophrenia, And although it’s not possible to diagnose mice as “schizophrenic.” the ani
mals showed certain behavioral changes seen in human patients, such as hyperactivity
and cognitive impairment (The team’ results were published online 3 At in the Proceedings of the National Academy of Sciences: those of the Pletnikov team appeared online in Molecular Psychiatry on 11 September.) wwwsciencemag.org
In these mi nt DISCI protein exerted its effects in the embryos Another Johns Hopkins group led by Hongjun Song
has traced the gene's effects in the brains of adult mice In these experiments, described in the 21 September issue of Cell, the archers showed that inhibiting 2/SC/ expression in newly formed adult brain ne rons produces effects opposite to those seen in the other mouse models Neurite outgrowth cd rather than decreased, and neurons migrated farther than normal “If you disrupt DISC/ function, everything goes faster.”
sa notes that there are precedents forthe same molecule having opposite effects depending on its context Indeed, he is now working with Song and Pletnikov to identi the molecular change that ean switch DISC
activity from inhibiting to stimulating neu- ronal migration, But whatever the outcome,
Cento tant
4 6 4
Brain disruption Putting a mutant human DJSC† gene in mice produces enlarged lateral ventricles similar to those of human schizophrenia patients researchers have long thought that schizo- phrenia is the result of aberrant brain develop- ‘ment, and the results with these models but- tress the case that irregularities in DISCT function contribute to that,
AcAMP connection
Although it may not be possible to help patients by correcting abnormalities in brain development, work by Porteous and Millar, in collaboration with Miles Houslay of the Uni versity of Glasgow, U.K., suggests another tack to take Two years ago, this group identi- fied an enzyme called phosphodiesterase 4B (PDE4B)as one of DISCI’s many binding partners This enzyme is a key regulator of cyclic adenosine monophosphate (cAMP), which transmits nerve signals into cellular responses, including those needed for mem- ory formation,
The PDE4B enzyme breaks down cAMP after it has done its job in the cell, and further work by the Edinburgh group indicates that SCIENCE VOL 318 NEWSFOCUS L
DISC1 inhibits this activity until rising cAMP concentrations cause it to drop off the PDE4B molecule Alterations in DISC/ structure that disrupt the normal DISC/-PDEAB interaction might therefore interfere with learning and memory, among other things “This is very important work,” Sawa says “Memory and cognition are both disturbed in schizophrenia and bipolar disease
Additional evidence that disrupting the DISCI-PDEAB interaction can affect mental states comes from work on mouse models developed by Steven Clapeote and John Roder of Mount Sinai Hospital in Toronto, Canada, and their colleagues in collaboration with the Porteous team, (The results appeared on 3 May in Neuron.) By screening, library of mutant mice at the RIKEN research institute in Japan, the researchers identified two lines oftmice, each witha different DISC/ mutation that reduces DISC binding to PDE4B,
Behavioral studies further showed that mice with one mutation display symptoms construed as schizophrenia-like including hyperactivity and impaired learning and ‘memory Those symptoms were reduced by treatment with the drug rolipram, a PDE4B inhibitor, and also by treatment with two drugs used to treat human schizophrenia, The other mouse strain, Porteous says had more depression-like symptoms For example, ‘when placed in water, the animals quickly gave up trying to escape and simply floated These animals responded to treatment with antidepressant drugs Developing drugs to an enzyme such ay PDEAB might lead to better ways of treating schizophrenia and other mental disorders
The fact that DISC/ associates with so many different proteins might help explain the diversity of conditions to which it has been linked “It seems that DISC/ acts as a scaffold around which other proteins cluster’ Porteous says Thus, the symptoms that develop in a given individual might depend on which interaction is altered by a genetic tion in DISC] And conversely varia- any of DISCI’s pariners could also tions
ead to abnormal brain development or func: tion, Geneticists have begun hunting for link- ages between these other proteins and various mental disorders
Trang 29LETTERS | BOOKS |
LETTERS
POLICY FORUM
edited by Jennifer Sills
The Origins of Human Bipedalism
THE REPORT BY S K S THORPE ET AL ON HAND-ASSISTED ARBOREAL bipedalism in orangutans certainly deserves attention (“Ot f human bipedalism asan adaptation for locomotion on flexible branches?
1 June, p 1328) But does the discovery of orangutans en; human-like straight-leg bipedalism actually mean that " bipedalism is h]uman less an innovation than an exploitation of a locomotor
behavior retained from the common great ape ai Altho embraced by P O'Higgins and S Elton in their accompanying Perspective (“Walking on trees.” | June, p 1292), this interpretation
embodies the Lamarckian ust disuse expectation that the poste features unique to humans and their fossil relatives would have emerged because a common human-ape ancestor had originally stood bipedally But no known ape—fossil or extant—possesses the posteranial features associated with human-like bipedalism, and to anticipate that any num-
ber of years of early ape
nding up in trees would have led to the developmental rec that underlies such profoundly human morphological novelty (/), while engagi ation, unduly stretches the bounds of biology JEFFREY H SCHWARTZ Departments of Anthropology and History and Philosophy of Science, Univesity of Pittsburgh, Pitsburgh, PA 15260, USA Reference 1 C0 Lovejoy, M.) Cohn, TD White, Proc Nal Acad Sci USA 96, 13247 (1999) Response
SCHWARTZ IS INCORRECT TO CLAIM THAT OUR
proposal is Lamarckian We refer to selection
and the main contribution of our
paper is to identify a selective pressure that could have favored the adoption of upright,
ed bipedality
some of the posteranial features such posture may be controlled bya limited number of developmental genes (2) is interesting, but unless Schwartz is pro- posing that natural selection cannot operate ‘on such genes, itis not relevant to an assess- ment of our paper
The most striking feature of modern human bipedalism compared with that of other vertebrates is that we walk with extended hips and knees (2) permitt substantial energy savings by exch: of potential and kinetic energies In th facultative bipedalism, untrained captive n an arboreal www sciencemag.org
orangutans and, as we show, wild oranj tutans (3) adopt trunk, hip, and knee postures much closer to those seen in human bipedal- ism than in untrained chimpanzees, bono- bos, or gorillas Even abnormally raised or trained chimpanzees that are habitually bipedal do not match the hip and knee extension seen in bipedalism of untrained orangutans (3) This strongly suggests tha the anatomical features that permit erect,
ight-legged bipedalism in orangutans, however controlled, have indeed been the subject of positive selection These charae- teristics of orangutan bipedalism have almost ertainly been selected for in an arboreal context, as part of a continuum of largely orthograde locomotor behaviors
Because the common ancestor of crown hominoids is likely to have had a similar niche to orangutans—that is, to have been a ripe- fruit eater exploiting the peripheral canopy of SCIENCE VOL318 | | PERSPECTIVES EDUCATION FORUM |
tropical forest trees (4) highly relevant tounderstandi
human bipedalism, Features of the trunk and pelvis favoring upright walking were already present in early, arboreal, crown hominoids such as Piermlapithecus and Hispanopithecus (Dryvopithecus) laietanus (5) {the latter also
showing orangutan-like features of the hand (6)], and there is strong evidence for highly and habitually extended hips in the much later, partially or wholly arboreal crown hominoid Orrorin (7) These adaptations would certainly facil- itate the adoption of habitual terrestrial bipedality by early hominins Terrestrial bipedalism would then be expected to select for features of the hominin post- cranium that enhance the effectiv of human (terrestrial) bipedalism (7) €.g., adaptations limiting abduction of the thigh on the trunk (such as a short ilium) and a talocrural joint that favors tal motion of the legs over the stance paras:
foot, also at the expense of abduction—as
first in Australopithecus anamensis (8)
Such selective forces eventually lead to the
modern form of the human foot and pelvis,
although thismay not have been in place even
in early Homo
S KS THORPE,*R L HOLDER?
R H CROMPTON? School of Biosciences, University of Birmingham, Edgbaston, Birmingham 815 277, UK ‘Department of Primary Care and General Practice, Unversity of iming- ham, Edgbaston, Bitmingham B15 217, UK *School of Biomedical Sciences, University of Liverpool, Sherrington Buildings, Ashton Sret, Liverpool L69 3GE, UK
References
1 €.0 Lovejoy M.} Cohn, T.O White, Proc Not Acad Sci USA.96, 13247 0999), 2 RMeN Alexander) Anat 204, 321 2009)
3 RLM Crompton 115 2003) et a, Cour Forsch, inst Senchenb, 243, 4, D Pilbeam, in The Primate a (Cambridge Univ ress, Cambridge, 2002), Fossil Record, W.C Hartwig,
pp 303-310
5 CV Ward, in Hondbook of Poleoanthopology ‘Primate Evolution and Harmon Origins, W Henle, L Wo 2: Tatesal, Es Springer, Heidelberg, Germany, 2007), pp 1011-1030,
6 Š.Aimedj, D M ba, S,Nojơ-Sd, Me, Proc Soc tondon Ser B 214, 2315 (200) 2 B Senut, in Human Origins ond Environmental ‘Backgrounds, M\hida, RH Tl, M Pickford,
Trang 30Ẵ LETTERS
1066
What's in a Name?
IF THE NAME LUPA FOR THE EUROPEAN DOG genome studly was chosen afierthe Roman she- wolf (“Europe going to the dogs.” E Pennisi, News Focus 21 September p 1670), the choice is not a f
legend was dismissed even by the Roman historian Titus Livius, who explained that the ‘mother of Romulus and Remus was a certain Acca Laurentia,a very prosperous sex worker (to use a Dutch expression) —so prosperous that she left a lot of money to the city founded by herons In popular Latin, lupa meant s
wolf, but it also meant whore Even today, in certain languages, we speak of brothelsas lupa- nari (in Ialian; the French havea similar word)
Obviously, no one wants to have a whore on their
legend came about Tam affaid that our Euro- pean colleagues made the same mistake as Mussolini, who called the preschool Italian children Figli della Lupa, hus sendingacollec- tive insult to Italian mothers Ifthe LUPA con- sortium were to change their name, I suggest JASPER, the name of my German shepherd, who is, of course, the best specimen of the best of all possible breeds, RENATO BASERGA Department of Cancer Biology, Thomas Jtferson Univesity, Philadelphia, PA 29107, USA,
The Carbon Benefits of
Fuels and Forests
THE POLICY FORUM “CARBON MITIGATION BY biofuels orby saving and restoring forests?” by R Righelato and D V Spracklen (17 August, 902) provides limited perspective a a result relatively short time horizon and a limited consideration of the options available Righelato and Spracklen conclude thatthe bon sequestered by saving or restoring forest greater than the emissionsavoidedby the use of the liquid biofuels Although they may be cor- rect given current technology, the case studies they analyzed, and a 30-year time horizon, their conclusion is dependent on site technology and time, and it does not apply to biomass used for direct combustion or gasification, Marland and Schlamadinger (/) showed that the carbon balance between restoring forests and proxue- Isis site-specific and depends on bio- mass productivity, the efficiency with which harvested material is used, the initial state of the surface vegetation, and the fossil fuel to be dis- placed, When forest products are used eff ciently to displace carbon-intensive fossil fuel, and when productivity is high, sustainable
16NOVEMBER 2007 VOL318 SCIENCE
ieitous one The she-wolf'
andards, and that show the she-wolf'
CORRECTIONS AND CLARIFICATIONS
[News of the Week: “CDC director's message on risk runs afoul of White House ets" by E Kitsch (2 November, p 726) The photo caption should not have said that White House science adviser John Marburger wanted to remove parts of pro- posed testimony by CDC Director Julie Geberding onthe public health effects of global warming Marburger raised ques tions about portions of her testimony but didnot suggest any cuts
TECHNICAL COMMENT ABSTRACTS:
Comment on “Origin of Human Bipedalism As an Adaptation for Locomotion on Flexible Branches”
David R Begun, Brian G Richmond, David S Strait
Thorpe et al (Reports, 1 June 2007, p 1328) concluded that human bipedalism evolved from a type of bipedal posture they observed in extant orangutans with seemingly human-like extended knees However, humans share knuckle- walking characters wit Arian apes that are absent in orangutans These are mast parsimonious explained by positing ‘a knuckle-walking recurso to human bipedalism,
Ful text at wunsciencemag,oro/cgicontentfull3 18/585 3/1066d
Response To COMMENT ON “Origin of Human Bipedalism As an Adaptation for
Locomotion on Flexible Branches”
Robin H Crompton and Susannah K S Thorpe
‘Begun eta purport to present technical concerns regarding our case fr an arboreal origin or terestialbipedalsm in early hominins, but merely reiterate their knuckle-walking hypothesis, which lacks support rom the fossil record and is highly unparsimonious The technical concerns ae refuted by published studies cited in our study and thus do not affect, ‘ur original conclusions,
Ful text at wunesciencemag,oro/cgicontentfull318/585 3/1066 harvest yields the greater carbon benefit, espe- cially over a longer time period Current- technology liquid biofuels represent low- efficiency conversion of harvest to energy, but direct combustion or gasification is more eff cient at displacing carbon from fossil fuels Righelato and Spracklen show that, over 30 years, even producing diesel fuel from woody biomass can begin to look “compatible” to reforesting temperate cropland As we wrote in 1997, “there is not a one-size-fts-all strategy for optimal management of all land available for forest management to mitigate CO, emis-
sions” (J) However, in many circumstance:
biomass can produce greater carbon bene! than saving or restoring forests
GREGG MARLAND, *? MICHAEL OBERSTEINER,* BERNHARD SCHLAMADINGER®
‘untenational institute for Applied Systems Analysis, ‘42361 Lovebug, Asta "Ervitonmertal Sciences Dison, (Oak Ridge National Laboratory, Oak Ridge, TN 37831-6335,
USA Joanneum Research, A-8010 Graz, Aust Reference
1 G.Marlan, 8, Sclamadinge, Biomass Bioenergy 13, 389 1997)
Response
IN OUR POLICY FORUM (17 AUGUST, P 902), ‘we explicitly considered only liquid biofuel hich substitute for petrol and diesel La scale replacement of fossil fuels in transporta- tion isa more intransigent problem than the substitution of fossil carbon for heat and power considered by Marland and Schlamadinger
(2), for which a range of carbon-free options exist, such as nuclear, wind, and solar power We took a window of 30 years for ourcompar- ison of biofuels and forest restoration beeause this isthe time scale that will likely be needed to develop and implement carbon-free transport-fite! technology On this
the current biofuels reduce carbon dioxide emissions less effectively than restoration of forests As Marland, Obersteiner and Schlamadinger indicate, there may be net carbon benefits from biofuels if longer time periods and new technology are considered However, these avoided emissions would be too small and too late to meet ta
more reduction in emissions by 2050
Trang 31Ẵ LETTERS
solution to our energy needs, but by appearing to be a “quick fix.” they may distract us from developing effective, long-term, carbon-free solutions inthe time window available to us
RENTON RIGHELATO® AND DOMINICK V SPRACKLEN? ‘World and Trust, Halesnorth, Sufok, IP19 8A8, UK 2chool of Earth and the Environment, University of Leeds, Leeds 52 97, UK Reference
1G Marland, 8 Schlamadingr, 389 (1997 Biomass Boeneray 13,
Eyeing a New Network
| S KOHANE AND HIS COLLEAGUES’ POLICY Forum (11 May, p 836) on *Reestablishing the researcher-patient compact” should evoke a response from clinical researchers, Health- care organizations are keen to use large data- bases of information that have accumulated through record-keeping for clinical care delivery Unfortunately, the consent process did not necessarily allow the freedom to con- tact patients as research subjects The authors
propose a prospective approach in developi formed cohorts, with linked medical and
genomic information, to enable clinical re- arch and the ability to recontact patients We provide one example of how clinicians, their atients, and researchers can fully participate inand benefit from research,
In 2003, the National E: vened a broadly representati siona National Genotypi ited eye diseases with two goal
resource for ophthalmic research in inherited ocular disorders, and to allow access to geno- typing for patients and their doctors A ne Work of certified laboratories (7) was orga- nized with a coordinating center to which a secure Web-based database was linked In September 2006, the eveGENE™ Network received its first sample (2) Phenotypic infor~ ‘mation was entered by the patients doctor with the understanding that the patient ¢ Institute con= roup to envi- letwork forinher o provide a
result and that the physician would provide enetic counseling for that result, The anon
data, was then pla repository to enable future research To date, the repository has 205 samples representing a diverse collection of
heritable ocular conditions The Network has not encountered any issues related to breaches in patient confidentiality or concerns about ‘employment or insurance discrimination This research project has been enthusiastically received by the ophthalmic and optometric ‘community and stands as an example of how ‘genomic research can be translated to patients, IAN M, MACDONALD, BRIAN P BROOKS, PAULA SIEVING National ye insttute, NIH, Bethesda, MD 20892-1860, USA
References and Notes
1 Laborateries Laberatery improvement Amendments (CL were certified according tothe Clink 2 The National Ophthalmic Disease Genotyping Network,
_eeGENE™ (nnn neiih govlesourceseyegene 25)
Letters to the Editor
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Trang 321070
MEDICINE
The Universal Darwinism of Disease
David C Krakauer
ost remember the title
Mei bassin sot jonary book, On the
Origin of Species by Means of Natural Selection, but then for- get the subtitle, Or, the Preser vation of Favoured Races in the Struggle for Life Whereas the former pertains to change and Variation, the latter relates to sta~ bility and uniformity The math matical theory of evolution has sought to explore the cons
quences of mutation and vari tion on change and those con- straints and evolved mechanisms
that confer robusiness on 0 robustness mi
to the prevention and elimination of disea Evolutionary theory is the right framework toadopt when we are seeking to
account forthe sources and con- straints of variation in mutable lineages within large popula-
tions This where
appropriate, the application of Darwinism toa stunning range of phenomena, from the the pro- gression of disease, and the processes of speciation to the licenses, eC dynamics of genom DỊ origin of language Incachcase, iW
we are dealing with random develop- ment, replication, drift, and
selection But the effectiveness of the theory as for all powerful scientific theories, turns on the subtleties of quantitative rigor
In The Dynamies of Cancer evolutionary biologist Steven Frank (Un
fornia, Irvine) explores a theoretical immunol- y perspective on cancer—seeki abundant data on coarse-pr Evolution processes of variatio cersity of Cali- toconnect ined phenotypic patterns to detailed microscopic, muta
selection dynamics The core macroscopic focus of the book is the age incidence curve
of cancer, and the microscopic explanation
ression
-e records the number of cancer cases per year for a particular
The reviewer is atthe Santa Fe Institute, 1399 Hyde Park Road, Santa Fe, NM 87501, USA, E-mail: krakauer@ santalsedu 16NOVEMBER 2007 VOL318 SCIENCE DỤ ere by Steven A Frank
Spectral karyotype Multicolored painting probes reveal chromo somal rearrangements in an oral cancer cel
group divided by the number of people in that ige group When representing age against inci- dence on a double logarithmic plot, one fre- quently observesa straight line that canbe fit by function of the form = ct, where / is the incidence, ¢ the
age, and n the number of stages
through which the cancer pro-
esses The constant ¢ varies
according to a number of differ cent det hic and disease factors Different cancers and different
females, for example) tend to show very different patterns of
oups (males versus
ae incidence Moreover, the slopes n depart from ind their gradients (accelera- tion) carry important information It is these patterns—incidence and acceleration—that Frank seeks to explain, as he sees them as the primary quantitative signatures of cancer
The key to understanding incidence acceleration is a multistage progre
describes a sequence of mutational events through which a tissue must transit on its path toward cancer, These mutations can be classi- fied according to their impact on the b
cell birth and cell death Mutations in involved in programmed cell death abro the ability of cells to kill themselves when detecting damage Mutations in tumor suppres- sors remove key constraints on cellular prolif eration, and mutations in oncogenes typi stimulate cell division Mutations in DNA repair pathways can lead to hypermutation and chromosomal instability, accelerating the rate
‘of mutation toward cancer, Lastly, mutations in
certa n-genes cause tumors to promote the ‘growth of blood vessels required for tumor sur- vival The mutational spectrum is vast, but the underlying logic is often fairly simple Important contributions of the bookare the two theory chapters in which Frank develops a
series of simple mutation-selection models Building on pioneering work of Knudson,
Armitage, Doll, and others, he aims to capture how variation in the sequential accumulation of
mutations can generate the panoply of age inc dence curves
Frank's forte in the book is his search for the simplicity that is often masked by the com- plexities of cancer With his mathematical
‘models in hand, he tumsto the details of cancer
gen
novel integrative insights For example his models identify potential causes for the slow carcinogens, and agi x and provides
eration of melanoma versus the rapid tion of pancreatic cancer Frank par- simony-based approach to theory leads hin to stress comparative analysis rather than curve- fitting The comparisons follow a hypothetico- deductive model, whereby differences in progression are used to hypothesize differ- ences in the a ¢ incidence curves of different why males tend to have more
cancers, €.2
ancers early in life than females Fitting typi- ally seeks to match a family of models to a single body of data in order to infer the unde lying dynamics With a comparative (bottom- up) approach, there are fewer parameters and very dramatic differences to explain: with fi ting (top-down) there isa high likelihood that the fitreveals litle beyond the flexibility of the
mode! assumptions
A pervasive theme in the book concerns the lamentable, growing distance between molec- and the kind of macroscopic the- ory Frank favors As our measurement tech- ular genet
nology has become more precise and efficien microscopic data enumeration has been
emphasized over synthesis This tendency is driven partly by expediency in the laboratory and partly by the absence of theory inthe train- ing of many molecular biologists One of sys- tems biol owed objectives is to unite coarse-grained mathematical and comp tional theory with microscopic labo data, Cancer has had a long history asa test bed for this kind of interdisciplinary approach
Trang 33PHARMACEUTICALS A Company with Great Impact ‘Anna E Simmons
he history of Burroughs Welleome and ] Company is synonymous with the development of a modern, research- based pharmaceutical industry in the United Kingdom The firm was the first in the coun- try to adopt many industry characteristics, stich as the establishment of research labora- toriesand the use of detail men, andit was also a leader in product innovation and ethical advertising In Burroughs Welleome historians Roy Chureh and Tilli Tansey pro- vide a detailed, profusely illustrated account of the company’s first 60 years
‘The reviewer sat the Department of the History of Scence, Technology, and Medicine, The Open Univesity, Walton Hall, Milton Keynes MK7 6AA, UK E-mail: a simmons@
‘openacuk
Burroughs Wellcome was established in London in 1880 by two American pharmacist Silas Mainville Burroughs and Henry Solomon Wellcome Both brought key skill to the part- nership: Burroughs contributed initial capital and innovation, foundations that Wellcome then built on The firm soon expanded its business ‘overseas and introduced detail m
products directly to medical practitioner | druggists In its first decade, the company underwent a tran-
sition from trading to man- facture, which culminated in the 1889 opening of its main factory in
Kent, and established itself as a leader in the British pharmaceutical industry
The themes of knowl edge, trust, and profit are central to understanding the firm’ development
Trust provides a particularly interesting per- spective highlighting both strengths and weak- nesses in the business operation Despite the many achievements, Burroughs and Welk distrusted one another to the extent tha BOOKS cri L various disagreements, Burroughs sought to terminate the partnership Wellcome tri- ‘umphed in the bitter legal battle that followed, but the dispute was still continuing in 1895 ‘when Burroughs suddenly died in Monte Carlo from pneumonia, Later on, an absence of trust between key staff members would cause diffi- culties during the interwar period
However these personnel problems did not affect customers’ trust in the firm, A reputation for high-quality products and ethical advertising was central to itsrelations with both physicians and pharmacists This trustwor- thy reputation was enhanced by Henry Welleome’s objective to advance medical knowledge through the creation of research laboratories, whose scientists could publish freely and pursue independent lines of research
uch an ethos undoubtedly
assisted Henry Wellcome’s eventual suc- cess in 1901 in registering the Wellcome Physiological Research Laboratories under the 1876 Cruelty to Animals Act That achieve- ‘ment—which the authors describe as “possibly CELL BIOLOGY most advanced stem cel yc Guide today all the leading tools for cel products A om/OneBook MILLIPORE
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Trang 34‘cReom
WeLcoMe
Lana
LONDON
the most important conitibu- tion Wellcome made to med- ical research in Britain”
allowed the firm to carry out the animal testing required for the production of anti- toxins and set a precedent for the registration of other Jaboratories associated with ‘commercial manufacturers,
While recognizing the worth of trust and knowl- edge in pharmaceutical manufacturing, Henry Well- ‘come also understood com- mercial demands, and he ‘emphasized the importance
‘of “quality for profit” In the years leading up to the First World War, net profits grew steadily to just over £80,000, This growth did not con-
ined sharply between the 1920s and 1930s, g the business in the context of wider
Church and Tansey provide a more nerpretation of the problems
Burroughs Wellcome en- countered than have pre- vious histories Holdin
ick from directly ap- pealing to consumers through the mass media and remaining loyal to individual retail chemists, (rather than discounting Prices for multiple-outlet wholesalers such as Boots), the company was le behind by cru ‘developments in pharma- ceutical retailing, De- spite ts history of research ellence it launched only oneimportant innovative product (Digoxin, a substitute for digitalis) during the 1930s, while it also failed to diversify and develop new lines of general goods Knowledge, trust, and profit, the authors argue, are also cen- tral to understanding the difficulties the
cy of Burroughs and Wellcome stretches well beyond the firm they created and
BOOKS cra L
trained in the Wellcome laboratories later car- ried out pharmaceutical and medical research in academia, government, and industry The caliber of the researchers is striking: the authors zht 17 Wellcome scientists who became fellows of the Royal Society and one Nobel laureate, Henry Dale Such individuals also shaped the growth of a research and devel- opment-based pharmaceutical industry in as Burroughs Wellcome inadvertently supplied many of its rivals with ready-trained ' By 1940, Boots, May & Baker, axo, and British Drug Houses all employed research directors who had previously worked for Burroughs Wellcome These influences have continued The Welleome Trust is the largest private funder of medical research in Britain and, with the recent opening of the
‘come Collection in London, brings F Wellcome’ legacy to a much wider audien (The Trust also provided “generous funding support” forthe book.) Much more than a com= pany history, this attractively presented and comprehensively researched book shows how one firm transformed the pharmaceutical industry in Britain 10.11264ience.1147950
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Trang 351074
PUBLIC HEALTH
Biobanks in Developing Countries:
Needs and Feasibi
S.K Sui
One in developing coun-
tries, yet only 10% of globa ver 90% of the global Biobanks lity '* Jha,'†.Mony2A Kurpad? V Lakshmi R Kumar,‘N K Ganguly®
Technological advances coupled with use of existing resources can be used to create biological repositories that may lead to better health in developing countries
wide due to HIV/AIDS, tuber- culosis.or malaria are in devel- oping countries Even inf have cofactors,
research addresses many of a of biohank Size Startup cost” Chronie Infectious which make their acquisition these diseases Between 1975 {age group) (cost per person) disease disease or conversion to clinical dis- and 1999, ~1% of new mar- EựS0WG12100 ease more likely, such as
keted drugs were for tropical | 98 (40-69 0) (-s240) * No smokingandtuberculosis (5)
diseases and tuberculosis (J) stnian Genome <A miont 525mMMeE — ye No Genetic or undiscovered Repositories of biological Piet (3250) copathogens may help ex- samples linked with medical Keane decode 25000 $22milon Yes, No plain the unprecedented in-
data from individuals (bio- B9B3Mđ ($850) creases in HIV-1 in eastern
banks) are infrastructures [or Kadooie study of Chronic 500.000 $22 milion Yes some and southern Africa, Natural sustained research on the bio- _ DSeass in China 5-74) (550) resistance to HIV appears to logical determinants of dis: thedesc Cty 160000 = 5 be evolving among select
ease and promise to acceler- Prospective Study (5+ y0 Morante X4 populations (6) that are con-
ate the discovery of vaccines, TheGambianNatlonal $0.6 million! esl stantly being challenged by
drugs, and diagnostics How- DNABank Soa (515) No “ the virus Understanding how
ever, the distribution and TheldanNalawal focusofeurrentbiobanks suz- | BESSA ~2-3mllớU 20-830 milion 8x) cống Yes Yes_—_the immune systems have so evolve fo Fight thoke Intec:
gests that their discoveries will not sufficiently benefit those living in developing - Innovative use of :chnological advan-
sting infrastructure platforms make biobanks cost-effective and feasible in devel- oping countries Biobanks as a Platform
The Human Genome Project, annotation of millions of single-nucleotide polymor- phisms (SNPs) within the genome, develop- ment of ultrahigh-throughput genotyp- ing, small-molecule detection methods, and powerful software to analyze the mass of data that is generated, now make possible the
discovery of the allelic and biological va ants that underlie complex d ses (such centre fr Global Health Reseach, t Michael's Hospital (USKUKRO), Univesity of Toronto, Toronto, ON, MSBICS, Canada, 25 John’s Research Institue, Bangalore 560034, India ?Nizam’s Institute of Medical Sciences, Hyderabad, 500082, india ‘School of Public Health, Post Graduate institute of Medical Education and Research, Chandigarh, 160022, India Sndian Council of Medical Research, New Delhi, 110029,1ndia
“Present address: Howard Hughes Medical institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA
‘Author for correspondence Email: Prabhatjha@ Wtort.ca
16NOVEMBER 2007 VOL318 SCIENCE
'#sinxie IS đolà, {sis 75% othe Estranpoptin fora pl poet of 10,00 paicpants ‘aml kage uses ae posite rhe wo Bans nd geet ‘etnks Bet Mor he ests years fond to doe contac nnksal T andr malas rd te ADS, wh has iow pelea The Gambia sPesenly at the cegn age
as cardiovascular diseases, cancer, diabetes,
tuberculosis, and AIDS) Common genetic variants likely involve moderate effects,
such asa relative risk of 1.2 Reliable assess-
ment of these variants in different popula-
tions (including documenting any interac
tions between genes and other risk factors) requires studies with thousand oreven tens, of thousands, of cases and controls,
A few biobanks have already been estab- lished in developing countries such as the Chinese Kadoorie study (2), the Mexican biobank (3) and the Gambian national DNA bank (4) (see table, above) The Chinese and Mexican biobanks were designed primarily to discover correlates of noncommunicable diseases in adults over age 35 years, and the Gambian study is relatively small These studies are not sufficiently representative of the major causes of death and disability in developing countries or of the age groups at which disease strikes In particular, HIV AIDS, tuberculosis, and malaria require larger studies in diverse popu! Disease Burdens in Developing Countries More than 75% of the 5 million deaths world-
ation esr posible fr a tions can enable new drugs and vaccines Focused biol ical research on the genetic and other biological corre lates of infectious dis is under way, most notably by the Grand Challenges in Global Health (7) These need to be complemented by more open-ended platforms for unpredictable discoveries, as is possible with larger biological repositories linked to medical data,
Developing countries, unlike most developed countries, suffer from the dual burdens of chronic (chiefly noncommuni- cable) diseases and infectious diseases (3) Already, four out of five chronic disease deaths occur in developing countries The genetic and environmental variations that contribute to complex chronic diseases are sarily the same in geographically segregated populations Indeed, common ‘onic diseases can have surprising cor- prospective study in China, for example, found higher risks of vascular deaths among people with exces-
ly low, as well as those with exces-
siv
sively high, body mass even after adjusting
for smoking and blood pressure (9) Two
small studies in India (/0) and in Iraq (//)
found that low body mass and diabetes were correlated with tuberculosis history
and a positive tuberculin test, respectively
Trang 36
.A Way Forward Typieal biobanks are expensive partially because the serum samples that they col- lect and keep must be keptcold continuously
Dried blood spots (DBS), in contrast, do not require reftis eration during col- lection or transport (2) DBS simplescan be easily collected and safely transported by regular mail The higher acceptability
by participants of - DBS versus whole-
blood collection, lower
costs, and ease of handling also enable much larger sample sizes to be achieved within a
Despite their small volume, DBS samples have been increasingly used for molecular, enzymatic | biochemical, and hematopoietic analyses SNPS within the \whole genome can now be reliably assessed from DBSs (/3) The continuous decline in the sample volume and the cost of SNPs and the development of high-throughput analyses, mean that biobanks based on DBSs are becoming economical, as well as scienti cally practicable The major roadblock is get- ting reliable epidemiological evidence about the relevance of variables measured to the development of d Appropriately large-scale epidemiological fieldwork in developing countries to acquire blood sam- ples systematically linked to relevant me: ures of disability and future mortality is eru- cial Biobanks in Westem countries use their national health systems, with physi collecting samples and medical data for their patients In developing countries, how- ever, fewer people have access to medical and linkage to routine health care is, not yet possible
Several developing countries have established disease and mortality surveil- lance systems, which could be cost-effe tive platforms for biobanks A good exam- ple is the antenatal clinic HIV surveillance system recommended by the World Health Organization to track changes in HIV prevalence among pregnant women in 132 countries This widely implemented sys- tem is not used adequately to understand the transmission and correlates of HIV infection, primarily because collected samples are usually discarded after HIV £ www.sciencemag.org ‘MDS health surveyor collecting a DBS sample the field
testing Modest enhancement of this sys- tem with additional demographic and med- ical information, as well as reliable archiv- 1g of samples, would provide a widely cticable resource to investigate the bio- I correlates of HIV Other examples lished surveillance systems include surveys of malaria parasites and the INDEPTH network of 37 demographic surveillance sites—26 of which are in Africa (14)
India: A Case Study
Over the past 30 years, the Indian govern- ment has built a population-monitoring framework called the Sample Registration System—a nationally representative sam- ple of 7.6 million people in 1.3 million households across the country The “Mil- lion Death Study” (MDS) (15) is under way within this system The Indian Council of Medical Research, Registrar General of India, and the University of Toronto are col- laborating to explore the logistics of build- ing a national Indian biobank to assess the underlying risk factors and correlates of disease in India The MDS is unique because it collects data that will allow both family-based genetic studies and case-con- trol association studies The design and seale should ensure that for each complex disease of interest, several thousand cases and controls (efficiently tested through “nested” case-control design) will be avai able for association studies with sufficient statistical power to detect modest but med-
ally relevant associations, We are exploring methodolo logistical issues of build biobank in Indi blood pres ‘al and a national Medical and family history, ure, body mass, smoking and SCIENCE VOL 318 16 NOVEMBER 2007 POLICYFORUM |
alcohol use, other variables, and DBSs were
collected in household surveys in 2006 from 2700 adults aged 18 years or older in six dis triets in three states (see figure left) Only 5% of the people interviewed refused to give DBSs, in contrast to refusal rates of nearly 40% in a similar study collecting a serum
costs of a DBS-based
Indian biobank would be at least 1/20th the cost per person of the ongoing serum-based
UK Biobank (see table, p 1074) Toward a Global Consortium of Biobanks
National or regional biobanks are a first step Others have called for a global con- sortium of biobanks to address common ethical issues, data ownership, and data sharing (17, 78) We see these consortia arising for two reasons First, joint analy- ses of important, but uncommon, gene variants will be needed to generate more definitive results than can be generated from individual (and likely underpow- ered) studies Second, reasonable expee- tations from funders and beneficiaries will push toward collaboration, as has pened with the Human Genome Project (19) and the Global HIV Vaccine Enter- prise (20) The promise is enormous: cessible and affordable studies in diverse populations to permit imaginative search for common and rare genetic and other biological correlates of global diseases,
References and Notes
2 Peller eta, Lancet 359, 2188 (202 2 2.Cheneta ft -Epdemiok 34, 1243 2005) 3 RlapiaConyere al, nt Epdemiol 35, 283 e006 4, G.Siugoet ol, Nat Geet 36,785 (2008
5 V Goji & Peto, 15, Kana, ha Lancet 362, 507 (2003) 6 Le Heney AG Dag, RA Wes, Since 323, 462 (2006) 7 H.Varmuset al, Science 302, 398 2003) 8 CO Mather, Loner, PS 3, e442 (2008) 9 2 Gheneta, it} Epidemil 35,181 2008) 0 H.Shety,M.Sherko, Ma, D'Sou, nt aber ‘ung D's 10, 802008) 11, W.ALKubasy AA Dutayme 0.5, Hashim, Eos Medier: Heath 9, 675 2003 22 K, Stenberg et ol, Epidemiology 13, 246 2089 1B, RLA Payer etal, Cancer Epidenial Biomarkers Pree 15,2533 (2006) 14, INDEPTH Network, wm indepth etn ogi roils, sitesi 1, Phvet ol, Pas ed 3, 182006, 16 Prospective Urban and Ral Eidenilogial Sty,
mccmemasttapureide
Trang 371076
PHYSICS
When Oxides Meet Face to Face
Elbio Dagotto
tilayer structures have
Ms ssearch topic now that
atomically precise methods for preparing them are available, In particular, researchers expect that ‘oxide multilayers may lead to interesting artificial mate with novel properties (see the fi
everal of the oxides used in er systems belong, of compounds with strongly correlated electrons The exotic properties of these oxides include high-transition tempera- ture (7) superconductivity, with critical temperatures far higher than in standard superconductors, and colossal magnetore
(CMR), where the app! magnetic fields of a few tests
report x-ray analysis and calculations of the interface between two such oxides
These authors prepared a heterostructure with layers of (¥.Ca)Ba,Cu,O, (YBCO) and La,,Ca,Mn0, (LCMO) and observed a transfer of charge from the Mn oxide to the Cu oxide This induces important modifications in ‘tronic orbitals of the atoms atthe inter- ‘or example, the orbitals designated dy (2) are considered irrelevant in bulk cuprates because they are fully occupied and cannot act as bridges for current flow At the interface, however, they become partially ‘occupied and can move electrons between the ‘wvo oxides The interfacial orbitals undergo “reconstruction” —that is, they are deformed shape so that the electronic structures of the two different oxides can blend, Most ofthe oxides under consideration forhet- cerostructures are very Sensitive to reconstru tion, something that must be considered in all future designs of artificial oxide multilayers,
High-7, superconductivity and CMR are examples of “emergent” phenomena—new properties that cannot be anticipated from the
The author isin the Department of Physic, University of Tennessee, Knosvile, TN 37996, USA, and the Materials Science and Technology Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA E-mall:edagotto@ utkedu
16NOVEMBER 2007 VOL318 SCIENCE
Oxide interfaces Models of heterostructures of lanthanum alumi- nate between strontium titanate layers The atoms are represented by colored spheres (oxygen, white; lanthanum, orange; aluminum, yellow, strontium, large blue; and titanium, small dark blue) ‘Although the materials alone are insulating, the electrical conductiv- ity ofthe bottom interface (purple spheres, brighter onthe Left ini Cating higher conductivity) can be tuned due to coupling withthe top interface (12)
local interact ions among the electron: between electrons and the lattice, Many recent and
investigations ha led the complex nature of these materials in bulk These hard ceramic materials seem to hide a “Soft” elec- tronic component that produces nonlinear responses to small perturbations, as well as emergent behavior (3, 4)
Antficial thin-film oxide structures could thus make the already complex individual properties of bulk strongly correlated oxides even more interesting The oxides used in these structures could have different bulk properties
but they all have similar lattice constants (i distances between atoms), allowing fora good ‘mateh at the interfaces The number of combi- nations of these oxides is enormous, and the potential for novel behavior is a strong motiva tion for these investigation
If interfaces of semiconductors—which are rather featureless materials with a non- ‘magnetic rigid lattice—can nonetheless lead to fascinating physies such as the quantum Hall effect, imagine what could be done with oxides A variety of exotic two-dimensional electronic systems could be stabilized at the oxide interfaces, exploiting spin, charge, and orbital interactions as well as lattice vibra- tions Recent investigations have already shown that both a metal (5) and a superco
New devices may be possible once we understand the interface between oxide ‘materials such as superconductors and ferromagnets
ductor (6) can be induced at the interface of tự Is, and the number of surprises will surely continue to grow
Charge transfer at oxide interfaces (1 7) produces novel two-dimensional phases, as well as charge doping without the typical disorder caused by chemical doping Thus interfaces provide an interesting venue for doping oxide perovskites (such as the high-T materials) with carriers (8) Technological applications are also possible For example, several groups are working on composition- ally graded interfaces made from mang: with the hope of achieving high-performance
etic tun junctions (9) ‘oxide electronics” i
fast (/0) although achieving the mobility levels and purity ‘miconductor heterostructu ains a challenge The issues is what makes oxide heterostructures so interesting: This area of research is located at the intersection between fundamental science investigations and technological applications
Previous studies of oxide heterostructures, were framed in terms of “lattice reconstruc: tion.” That is, because interfacial ions are sub-
{ject to forces different from those in bulk, th atoms can change position And the mere trans- fer of charge at interfaces can lead to “elee- tronic reconstruction” (7, 11) In this case, the different electronic density atthe interface rela- tive to the bulk is the origin of the exotic prop- erties Chakhalian er ai have now introduced orbital reconstruction as a third process Although the ds orbital is widely thought to be unimportant in bulk cuprates, itis known to becrucial nites As cluster calcu- lations suggest (/), the reported strong Cu-O- Mn bond that leads to the orbital reconstruction is precisely caused by the dy,
Despite recent activity the
interfaces remains virtually unexplored What might happen if we could mix materials with vasily different properties such as ferromag- antiferromagnets, superconductors, fer- roelectries, multiferroies, geometrically frus- trated spin systems, heavy fermions, and oth- ers? Considering this enormous number of combinations, theoretical guidance is needed But for theory to be usefil, the calculations must be reliable, at least qualitatively Powerful techniquesare needed to study inter-
Trang 38
faces of strongly correlated electronic sys- tems Reliable procedures to calculate and measure work functions of individual mat
re also needed to predict the direction of transfer at interfaces The collective
als
cha
responses and nonlinearities of models for oxide interfaces must be carefully analyzed By this multilevel effort, the potential new functionalities and exotic phases of the oxide ‘combinations under scrutiny will hopefully be revealed Lattice, electronic, and now orbital
reconstructions will all be essential in the effort to understand and use oxide interfaces
References and Notes
1 J Ghathaian eo, Science 318, 1114 2007); published online 11 October 2007 (10.1126écence 1140338) 2 Forth shape ofthe orbitals, see, for example, hitp:/orelate8.physuth edu/graup! (goto "dorbita” onthe te 3 E.Dagoto, Sience 309,257 (2009) -4 Y TBlưa, N Nagsos, S:lee 288, 462 (2000 5 A.Ohtoma, H.¥ Hwang, Nature 427,423 (2004) PERSPECTIVES L
6, NeReyren eo, Science 317, 1196 (2007); published ‘online 1 August 2007 (10.2126/science 1146008) $ Okamoto, A Mil, Nature 428,630 (200) 5 Yunok eta, Phys Re B76, 064532 2007) 9 Yamada el, Science 308, 66 (2008), and
references therein,
10 A.P.Ramicez, Science 325, 1377 (2007) 11, ML Huijpen eta, Mot Mater 5,556 (2006)
12 Supported by NSF grant ONRO7 06020 and bythe Division of Materials Sciences and Engineering, US Department of Energy, under contract with U-Batlle, LC 1041126/ience1151094 GENETICS Widespread Monoallelic Expression Rolf Ohlsson
‘ost eukaryotic cells have two copies ing) chromosomes Although both copies (alleles) of individual genesare usually expressed in each diploid cell, one of the alle- Jes is inactivated in a subset of genes (/) Itis Of profound interest that monoallelic expres~ sion in somatic cells does not simply represent a rheostat control for gene expression Rather, it often operates in some selective function, such as determining the repertoire of odorant receptors or T cell receptors that are expressed (2, 3) Moreover, the parental alleles of some mouse genes, such as those that encode cytokines, are expressed in random patterns, in which either, neither, or both alleles are inactivated, potentially influencing the selec tion and expansion of particular on T cells (4), Onpage 1136inthis issue, Gimelbrantetal, (5) report that the mammalian genome em- ploys random, monoallelic expression more tersively than thought This may be to gener- ate diversity in expression patterns on an un= precedented scale, which has important impli- cations for the ontogeny of human diseases
nelbrant et al determined the propor- tion of human be expressed ‘monoallelically in patterns that are epigenet cally stable (for example, chemical modifica tions of DNA, such as cytosine methylation, that do not alter the sequence but are heritable within cell populations) They identified expressed alleles in cloned cell populations of human B lymphocytes by taking advantage of polymorphie sequences, or single-nucleotide
‘The author isin the Department of Development and Genetics, Uppsala University, Norbyvigen 18A, 5-752 36 Uppsala, Sweden E-mail: rol ohlsson@ebc.wu.se www sciencemag.org polymorphisms (SNPs) By modifying a method for detecting SNPs in DNA “*A50M ms sequences, Gimelbrant et E al, were able to track ex- a=
pressed messenger RNA (mRNA) sequences Be- cause most of the SNPs for the 3939 genes that were assessed are located in non- coding introns that are not present in mature mRNA, the authors included pre- cursor forms of mRNAs (vhich contain introns) in the samples that were ana- lyzed, They identified 371 genes (nearly 10%) as ‘monoallelically expressed in epigenetically stable pat- tems in at least one popu tion of cells derived from a single B cell clone, Al- though most of these genes
‘were also found to be biallelically expressed in some other B cell populations, up to 20 could be consistently expressed from one of the parental alleles in some B cell clones Thus,
each cell population displays a vast hetero- geneity in patterns of mono- and biallelic gene expression, providing numerous combinator- ial patterns of gene expression (see the figure)
Although other patterns of monoallel expression have been described in human cells (6, 7), Gimelbrant et al go much further in two important respects Fist, they analyze large number of genes, thereby increasing the generality of their conclusions Indeed, based on their findings, the authors argue that more SCIENCE VOL318 Random inactivation of alleles indifferent cells yf x
Different possible combinations of expressed alleles ina cell population Diversity of possible outcomes (e.g, cell fate, disease)
The surprisingly high prevalence of random allele inactivation in human cells can generate diversity in gene expression that affects cell fate and physiology
Generating diversity Alleles are ran- domly inactivated on a pair of chromo- somes in a human somatic cell The various patterns of inactivation in progeny cells are then stabilized (epi- genetically) This can generate diverse cellular and physiological outcomes
than 1000 genes in the human genome can potentially be mono- allelically expressed at any given amazing degree of diversity in possible com- binations of expressed alleles
genes encoding cell surface receptors are overrepre- sented in this subset, suggesting the enormous potential for epi- genetic regulation of receptor mediated cell-cell communica tions and hene
cell diversity and cell fate (8) Second, Gimelbrant et al hint at the fascinating possibility that the same set of genes can be monoallelically expressed at certain stages of development in a subset of tissue cells and/or perhaps in only
some individ
Trang 39i PERSPECTIVES
1078
out concerns about stochastic monoallelic transcription events postulated to occur at low levels of transcription (/), Perhaps both alleles are in different transcriptional environments within the nucleus Indeed, alleles that display asynchronous replication, a hallmark of many monoallelically expre: es (2), can ‘occupy different positions within the nucleus (9).Ltmay also be that limitingamounts of pro- tein complexes that remodel chromatin (the DNA and protein constituents of
somes) could randomly inactivate alleles Finally, differentially modified (methylated) DNA regions that are adjacent, far apart, or even on different chromosomes might interact and modulate allele-specific epigenetic states and transcription (/0) Such possible explana- tions can now be tested
‘The data fiom Gimelbrant er al could fun-
damentally influence current views on the ‘mechanisms of some pathological conditions uch as haploinsufficiency (having only one functional allele, which produces insufficient amounts of product) or the loss of function of tumor suppressor genes In both cases, the loss of one allele might lead to a dramatie eff if the remaining allele already carries epig netic marks that render it inactive (I1), Consequently, anyone unfortunate enough to possess the “wrong” set of monoallelically expressed genes might be susceptible to the earlier onset of a complex disease such Alzheimer’s disease The interplay among genotype epigenotype, and gene inactivation will now become more important for under- standing developmental mechanisms, pene- trance of diseases, and responses to medi atments in an individual,
References and Notes
1 R Ohisson 8 Tek, C Sapienza, lends Genet 14, 435 (1998) 2 BLM, Shykind, Hum Mol Genet 14 pec no 1), R33 (205) 3 M Golémit,¥ Bergman, immuno Rev 200, 197 (2008), 4 BLL Kally, RM Locksley, Immunol 165, 2982 (2000) 5 A Gimelbant, JN Hutchinson, Chess, Science 318, 1136 (2007) 8 RThompson, A 6 PL Pant etal, Genome Res 16, 31 (2006) 1 1.Pastnen eto, Physiol Genomics 16, 184 (2004) 8 5 sum eto, Wot Genet 37, 171 (2008) 9 PK Yang Kuroda, Cell 128,777 (2007) 10 R Ohlsson, A Gondor, Cur Opin Cel Bil 39, 321 0007) 11, H.Raslow eta, J Clin Invest, 124, 77 (2004) 112 Supported by rants fram the European Union (HEROIC), Swedish Cancer Research Foundation, and Snedish Research Counc, 10.11365dence.1150705 MATERIALS SCIENCE DNA Circuits Get Up to Speed Roy Bar-Ziv shown that DNA can be programmed into higher-order structures and used to encode mathematical computation (/-3) Many attempts have been made to crea DNA-based devices and machines of mechanical and computational nature (3-5) Yet DNA nanotechnologists still face substan- tial challenges in passing fiom proof-of-prin- ciple demonstrations to functional devices that are reliable, quick, and extendable On page 1121 of this issue, Zhang et al (6) report an important step toward this goal,
In contrast to solid-state devices, DNA- based systems operate at the nanometer scale in an aqueous environment, where thermal motions render molecular interactions impr
se Hence, in seeking programmable bio- ical functions, scientists must invent ns that are hierarchical and resilient to spurious interactions and signal degradation,
Living organisms rely on genetie biochem- -al networks to regulate complex functions such as sensing, adaptation, timing, and ultimately— reproduetion These networks have evolved in noisy environments and are hence inherently robust, often endowed with high-fidelity capabilities They are composed Of genes and their respective RNA and protei
T the past three decades, scientists have
The author & in the Department of Materials and Interfaces, Weizmann Institute of Science, Rehovot 76100, Israel E-mail ry.bar-ziv@veizmann.acit
16NOVEMBER 2007 VOL318 SCIENCE catalyst at Fuel Intermediate 234 45 T135
The catalytic cycle of Zhang et al The catalysts 5 domain binds thes tochold ofthe substrate triggering a rapid branch migration process that leads tothe intermediate complex and the release ofthe signal strand Subsequently, the 3 domain of the fuel binds the intermedi-
ate’s 3, inducing two branch migrations and releasing the output
strand, a waste complex, and the catalyst for another turnover products and exhibit a variety of dynamie pat-
terns Key players in these biochemical [unc- tions are enzymes that can pick up even faint chemical signals, amplify th lì the oreanism, and relay them rapidly for sub- sequent processin;
Ati chemi try may one day play an analogous role in human-made systems, Imagine circuits that control DNA- based motors and sensors, similar to electrie circuits controlling electromechanical devices, For example, a recent report described DNA circuits (4) in which the input and output sig- nals, as well as the logic gates, were rep!
‘An amplification mechanism brings DNA circuits closer to practical applications
sented by distinct DNA Substrate strands—all in a test tube 2 Computations were per-
formed by hooking up and cascading gates and signals in a manner similar to ele tric circuits However, adding more components incurred long response time and signal loss, thereby forming a bottl neck for nontrivial computa- tion, Hence, a fast and modu- lar amplification mechanism is essential
Zhang et al now propose an elegant solution to this
nal amplification bottleneck In essence, they emulate the concept of the biochemical enzyme, but with DNA strands only The ism alters no covalent bonds and is driven by entropy (rather than
most biological catalysis) The desi on the separation of binding energy s making it easy to understand, robust, modular, and potentially usef\
The basic species are six short, singh stranded DNA domains that interac Watson-Crick base pairing Strands com- posed of these domains make up all the play- ers in the reaction: substrate, fuel, output nals, catalyst, and waste (see the figure) The
Trang 40and 4) are paired to the signal and output
strands, whose domains 1 and 6 are unpaired,
as is the substrate’s dangling end domain, 5
The goal is to release the signal and output strands Naively, in the absence of a catalyst, this can be done solely by the fuel—a strand composed of domains 2, 3, and 4—which replaces the two strands The signal and output strands are then released to solution along with a waste by-product composed of the sub- strate core and the fuel In this catalyst-free exchange reaction, the same domains are base-paired in the initial and final states so there is no net change of binding energy However, the overall configurational entropy ses in passing from two to three free s The reaction is thus thermody ly favorable Yet a lange kinetic barrier is incurred because the catalyst-free exchange reaction must proceed by unzipping the sub- strate one base afier another—a highly improbable sequence of events that would takea very long time
To push forward the reaction, Zhang et a troduce a catalyst composed of domains 4 and 5 The catalysts dom: now pair with the substrate’s domain § to trigger the rapid displacement of the signal by a proc called branch migration The catalyst thus reduces the kinetic barrier and stabilizs an
mediate complex (see the figure) The fuel matches the exposed domain 3 of the intermediate and, using the same branch migration trick, displaces the output while irreversibly sealing a waste duplex and eject- ing the catalyst back to solution for another turnover This catalytic eyele can aceelerate the initial reaction by four orders of magnitude
Zhang et al demonstrate two applications of amplification using their catalytic scheme First, a two-stage cascade was constructed by introducing an upstream catalyst system whose output acts as the catalyst to another system The circuit amplifies the initial eata- lyst by a factor of 900 Second, an autocat- lytic circuit was constructed by encoding the catalyst asa part of the output, such that reac- tion closes a loop on itself, displaying expo- nential growth kinetics
Why
Embedded in a biochemical logic circuit, it can be used to amplify weak signals and thus
must be avoided Zhang er al
design, because complements of the long, strongly binding “spe
4 and 6) never appear in single-stranded form, Molecules can interact only via the
PERSPECTIVES L
short, weakly binding “tochold” domains (3 and 5) This separation of energy scales renders the design extendable and tractable
Catalytic DNA citeuits of the kind de- seribed by Zhang ef al could be coupled to various biochemical reactions to analyze heterogeneous macromolecular mixtures, detect weak biochemical signals, and control nnoscale devices Combining such enzyme- free DNA circuits with biosynthetic reactions may get us closer to understanding nature’ design principles DNA circuits could also be integrated into materials platforms, such as gels, polymers, and surfaces, to generate
ive programmable systems (4, 7-10) References
NC Seeman, Theor Bol 99,237 (1982) LM Adleman, Science 266, 1023 (1994), LC Seeman, rends Bachem Sc, 30,119 (2005) - G Selig, Ð.%lovechit, D.Y.Zhang, € Wire, Science 314, 1585 (2008) 5 BLK Rothemund, Noture 440,297 (2006) 6 0.¥-Zhang, A.J Tuber, Burke, Winfree, Science 318, 1121 (2007) 7 Ve Moiteau,R BarZiy, A Libchabe, Proc Sci USA 100, 12672 (2003) Not Aco 8 M Ieln, C (emele,L Serano,Plo§ Bo 3, 488 (2008), 9 W.U Dittmer, 5 Kemptr, JO Raley, FC Simmel, Small, 709 (2005) 10 A Busboim etal, Small 3, $00 2007)
10.1126/xience:1150200
CANCER
The Gene Topography of Cancer
Jeffrey M Trent and Jeffrey W Touchman
here are three key questionsany cancer
Ts cn wie saftey hinge her diagnosis: What type of cancer do 1
have? What is my outlook? What can be done about it? Increasingly, the answers are coming from DNA-based sequence information Decades ago, sciemtists discovered that de- use eancer (1, 2), thereby hing a paradigm for tumor biology and providing an important motivation for embarking on the Human Genome Project Yet this remarkable sequencing achievement marked only the beginning of the quest to fully understand the biology of cancer With the complete sequence of nucleotide bases in normal human DNA available, scientists now classify the wide array of human genes ording to their involvement in tumorigene- sis On page 1108 of this issue, Wood et a (3) The authors are at the Translational Genomics Research Insitute, Phoenix, AZ 85004, USA E-mail jrent@tgen.org_ www sciencemag.org
advance this endeavor by describing
tional spectrum of nearly every well-anno- tated human gene [18,191 distinct genes from the Reference Sequence (RefSeq) resource] in
11 breast and 11 colorectal tumors through systematic sequencing of coding exons
The resulting sequence “landscape’ these tumor genomes is striking The authors
ering of five well-studied genes commonly mutated (which they call ‘mountains”), as well over 200 genes mutated a lower frequency (“hills”) in these two can- cers For the first time, there is evidence that most of the mutations that drive cancer may not occur in such gene mountains, but rather are spread across heterogeneous gene hills
These findings are generating some interesting opinions Viewpoints differ as to the value and timeliness of using current established technologies (e.g., polymerase chain reaction and Sanger sequencing) to define the mutational landscape of cancer, of SCIENCE VOL318
Despite debates over technologies and statistics, a new catalog of genes associated with colon and breast cancer is close at hand
versus waiting for the “certain” promise of next-generation, whole-genome sequencing approaches In the 1990s, the argument for waiting for technology improvement was ‘one of expense and throughput as well as the limited expectations of identifying med- ally useful information To some extent, that is the argument again today as new tech- nologies will likely be less expensive pro- ide haploid resolution (that is, differentiate the maternal from the paternal contribution to the genome), and hold the possibility of much more complete genome-wide sequence coverage Even granting that tech-