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CONTENTS
EDITORIAL
1538 1561

Volume 323

Issue 5921

CORRECTIONS AND CLARIFICATIONS

The Enlightenment Returns
Kurt Gottfried and Haro

ld Varmus

BOOKS ET AL.
1562

Sustaining Life
E. Chivian and A. Bernstein, Eds., reviewed by D. P. Mindell

NEWS OF THE WEEK
1546

Projections of Climate Change Go From Bad to Worse, Scientists Report Senate Majority Leader Hands NSF a Gift to Serve the Exceptionally Gifted Stronger Research Just One Item on Drug Agency’s Wish List Recipe for Rice Domestication Required Millennia
>> Report p. 1607

1563

Surviving 1,000 Centuries
R.-M. Bonnet and L. Woltjer, reviewed by G. F. Bignami

1548

1549

POLICY FORUM
1564

1550

Monitoring and Regulating Offshore Stem Cell Clinics
S. Kiatpongsan and D. Sipp

1551

An Unseen Link May Solve the Mystery of the Sun’s Superhot Corona
>> Report p. 1582

PERSPECTIVES
1566

page 1554 & 1578

Flexible Electronics
B. D. Gates >> Report p. 1590

1551 1552

From Science’s Online Daily News Site For Congress and NIH, Headaches Ahead on Stem Cells Stem Cell Center Looks to Recast Itself in Supporting Role From the Science Policy Blog
1570 1567

Two-in-One Designer Antibodies
P. W. H. I. Parren and D. R. Burton >> Report p. 1610

1552

1568

Dynamic DNA Methylation
J. A. Law and S. E. Jacobsen >> Report p. 1600

1553

NEWS FOCUS
1554

Fullerides in a Squeeze
E. Tosatti >> Report p. 1585

Rewiring Faulty Circuits in the Brain
>> Research Article p. 1578; Science Express Report by V. Gradinaru et al .; Science Podcast
1571

Stiffer Than Steel
J. D. W. Madden >> Research Article p. 1575

1557 1558

A Lifetime of Work Gone to Waste? Exxon Valdez Turns 20
1572

Copper Puts Arenes in a Hard Position
R. E. Maleczka Jr. >> Report p. 1593

LETTERS
1560

Pandemic Influenza: An Inconvenient Mutation
S. P. Layne et al.

BREVIA
1574

Flagellum Mediates Symbiosis
T. Shimoyama et al. A bacterium uses its flagellum to grip its archaeal symbiotic partner and to stimulate hydrogen consumption.
page 1562

Romanian Expatriates Face Career Obstacles
Z. Simon

Reversible Exploration Not Worth the Cost
S. C. Schon

CONTENTS continued >>

COVER Movement trajectories, each recorded during a 1-hour time period, for rats with brain lesions that reduce dopamine signaling. These animals serve as a model of Parkinson's disease and display severe difficulty in initiating movements, as illustrated by the white trajectories (on black background) showing limited locomotion. Black trajectories (on white background) illustrate the recovery of locomotive activity induced by electrical stimulation of the dorsal columns of the spinal cord. See page 1578.
Photo illustration: Yael Kats/Science; images: Per Petersson

DEPARTMENTS
1535 1539 1540 1543 1545 1620 1621

This Week in Science Editors’ Choice Science Staff Random Samples Newsmakers New Products Science Careers

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CONTENTS

RESEARCH ARTICLES
1575

1597

Giant-Stroke, Superelastic Carbon Nanotube Aerogel Muscles
A. E. Aliev et al. Applying a high voltage to very low density sheets of carbon nanotubes causes rapid expansion in one direction. >> Perspective p. 1571

The Burgess Shale Anomalocaridid Hurdia and Its Significance for Early Euarthropod Evolution
A. C. Daley et al. Hurdia, a Cambrian fossil, clarifies the morphology and evolution of early arthropod limbs and head.

1600

1578

Spinal Cord Stimulation Restores Locomotion in Animal Models of Parkinson’s Disease
R. Fuentes et al. Epidural stimulation of spinal neural pathways produces specific shifts in activity in neural circuits affecting movement. >> News story p. 1554; Science Express Report by V. Gradinaru et al .

A Role for RNAi in the Selective Correction of DNA Methylation Defects
F. K. Teixeira et al. An RNA interference–dependent DNA methylation rescue system helps to preserve a subset of DNA methylation marks in Arabidopsis. >> Perspective p. 1568

1605

Genetic Incompatibility Drives Sex Allocation and Maternal Investment in a Polymorphic Finch
S. R. Pryke and S. C. Griffith Female Gouldian finches bias the sex of their offspring on the basis of their partner’s color phenotype.

REPORTS
page 1570 & 1585 1582

Alfvén Waves in the Lower Solar Atmosphere
D. B. Jess et al. A special type of plasma wave has been observed that can heat the solar atmosphere to millions of degrees Celsius. >> News story p. 1551; Science Podcast
1607

The Domestication Process and Domestication Rate in Rice: Spikelet Bases from the Lower Yangtze
D. Q. Fuller et al. Remains of domestic and wild rice trace the process of rice domestication in China to between 6900 and 6600 years ago. >> News story p. 1550

1585

The Disorder-Free Non-BCS Superconductor Cs3C60 Emerges from an Antiferromagnetic Insulator Parent State
Y. Takabayashi et al. A well-ordered body-centered cubic phase of Cs3C60 reveals a pressure-driven transition from an insulator to a superconductor. >> Perspective p. 1570
1610

Variants of the Antibody Herceptin That Interact with HER2 and VEGF at the Antigen Binding Site
J. Bostrom et al. The antigen binding site of a therapeutic antibody for cancer simultaneously binds two proteins required for tumor growth. >> Perspective p. 1567

1590

Omnidirectional Printing of Flexible, Stretchable, and Spanning Silver Microelectrodes
B. Y. Ahn et al. Colloidal silver particles can be formed into flexible electrodes of arbitrary shape in three dimensions. >> Perspective p. 1566

pages 1551 & 1582

1614

Ankyrin-G Promotes Cyclic Nucleotide–Gated Channel Transport to Rod Photoreceptor Sensory Cilia
K. Kizhatil et al. The assembly and function of key photoreceptor proteins in neonatal mouse retinas is mediated by the protein ankyrin-G.

1593

A Meta-Selective Copper-Catalyzed C–H Bond Arylation
R. J. Phipps and M. J. Gaunt A copper catalyst functionalizes benzene derivatives at ring positions complementary to those accessed by standard methods. >> Perspective p. 1572
1617

The Surprising Power of Neighborly Advice
D. T. Gilbert et al. A stranger’s reaction to a social situation is a more accurate guide to our own reaction than is a written description of the situation. >> Science Podcast

pages 1550 & 1607

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CONTENTS

SCIENCEONLINE
SCIENCEXPRESS
www.sciencexpress.org

SCIENCESIGNALING
www.sciencesignaling.org The Signal Transduction Knowledge Environment

The Disappearance of the Progenitors of Supernovae 1993J and 2003gd
J. R. Maund and S. J. Smartt The presumed progenitor stars of supernovae are indeed absent in later images from these sites. 10.1126/science.1170198

RESEARCH ARTICLE: Obesity Increases Vascular Senescence and Susceptibility to Ischemic Injury Through Chronic Activation of Akt and mTOR
C.-Y. Wang et al. Chronic activation of Akt and mammalian target of rapamycin (mTOR) link diet-induced obesity with cardiovascular disease.

Optical Deconstruction of Parkinsonian Neural Circuitry
V. Gradinaru et al.
CREDITS: (SCIENCE NOW) RANDY MONTOYA/SANDIA NATIONAL LABORATORIES; (SCIENCE SIGNALING) JAY LIN/CHANG GUNG MEMORIAL HOSPITAL/TAIWAN; (SCIENCE CAREERS) EFLON/CREATIVE COMMONS

The therapeutic effects of high-frequency stimulation of the subthalamic nucleus result from direct effects on afferent axons. 10.1126/science.1167093 >> News story p. 1554; Research Article p. 1578

PERSPECTIVE: Bacterial FIC Proteins AMP Up Infection
C. R. Roy and S. Mukherjee A bacterial protein posttranslationally modifies and inactivates Rho family GTPases in host cells.

SCIENCENOW Dimmer future?

Circadian Clock Feedback Cycle Through NAMPT-Mediated NAD+ Biosynthesis
K. M. Ramsey et al. A transcriptional-enzymatic feedback loop controls interactions between metabolism and circadian rhythms in mouse cells. 10.1126/science.1171641

TEACHING RESOURCE: Measurement of Phosphorylated Extracellular Signal–Regulated Kinase 1 and 2 in an Undergraduate Teaching Laboratory with ALPHAscreen Technology
D. L. Hay Students use a high-throughput assay to monitor cellular responses to receptor activation.

γ-Secretase Heterogeneity in the Aph1 Subunit: Relevance for Alzheimer’s Disease
L. Serneels et al. Targeted knockout of only part of the γ-secretase complex lessens toxicity and still improves disease phenotypes. 10.1126/science.1171176

SCIENCECAREERS
www.sciencecareers.org/career_magazine Free Career Resources for Scientists

SCIENCESIGNALING Obese mice have heart conditions.

Bringing Community Into Translational Research
S. Webb Translational social scientists carry the lessons they learn in the community back to the lab.

Benzothiazinones Kill Mycobacterium tuberculosis by Blocking Arabinan Synthesis
V. Makarov et al. An enzyme required for cell-wall synthesis is a target for a possible alternative drug for tuberculosis treatment. 10.1126/science.1171583

Looking Up Your Career at the Library
L. Laursen The work of a science librarian offers a mix of research, teaching, and interacting with people.

Tooling Up: The Informational Interview
D. Jensen Landing an informational interview takes networking; making it pay off takes preparation.

SCIENCENOW
www.sciencenow.org Highlights From Our Daily News Coverage

SCIENCEPODCAST
www.sciencemag.org/multimedia/podcast Free Weekly Show Download the 20 March Science Podcast to hear about how the Sun’s corona gets so hot, the power of neighborly advice, deep brain stimulation, and more.

SCIENCECAREERS Careers for science librarians.

Southpaw Solar System
Meteorites might have seeded early Earth with ‘left-handed’ amino acids.

Oxygenated Oceans Go Way, Way Back
Seabed mineral suggests a much earlier start for photosynthesis.

A Hitch in Plans for ‘Sunshade Earth’
Dusting the skies could help with global warming but harm solar power.

ORIGINSBLOG
blogs.sciencemag.org/origins A History of Beginnings

SCIENCE (ISSN 0036-8075) is published weekly on Friday, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue, NW, Washington, DC 20005. Periodicals Mail postage (publication No. 484460) paid at Washington, DC, and additional mailing offices. Copyright ? 2009 by the American Association for the Advancement of Science. The title SCIENCE is a registered trademark of the AAAS. Domestic individual membership and subscription (51 issues): $146 ($74 allocated to subscription). Domestic institutional subscription (51 issues): $835; Foreign postage extra: Mexico, Caribbean (surface mail) $55; other countries (air assist delivery) $85. First class, airmail, student, and emeritus rates on request. Canadian rates with GST available upon request, GST #1254 88122. Publications Mail Agreement Number 1069624. Printed in the U.S.A. Change of address: Allow 4 weeks, giving old and new addresses and 8-digit account number. Postmaster: Send change of address to AAAS, P.O. Box 96178, Washington, DC 20090–6178. Single-copy sales: $10.00 current issue, $15.00 back issue prepaid includes surface postage; bulk rates on request. Authorization to photocopy material for internal or personal use under circumstances not falling within the fair use provisions of the Copyright Act is granted by AAAS to libraries and other users registered with the Copyright Clearance Center (CCC) Transactional Reporting Service, provided that $20.00 per article is paid directly to CCC, 222 Rosewood Drive, Danvers, MA 01923. The identification code for Science is 0036-8075. Science is indexed in the Reader’s Guide to Periodical Literature and in several specialized indexes.

SCIENCEINSIDER
blogs.sciencemag.org/scienceinsider
Science Policy News and Analysis

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EDITED BY CAROLINE ASH

Hello to Hurdia >>
Anomalocaridids are among the most famous of all Cambrian organisms, and have been dubbed the ‘’T. rex of the Cambrian’’ because of their large size and inferred predatory habits. Hurdia, described by Daley et al. (p. 1597), is the most common anomalocaridid in the Burgess Shale fossil beds in Canada. Hurdia has recently attracted interest because of its significance in arthropod evolution, yet it has remained effectively unknown because its fossil remains were misattributed among several other genera. Hurdia, with its unique and remarkable frontal carapace, provides critical new data on the gill structure of stem-group arthropods with a direct bearing on the recent debate about arthropod limb evolution.

Making Muscles Out of Materials
New materials are being investigated that can convert electrical, chemical, thermal, or photonic energy into mechanical energy. Aliev et al. p. 1575; see the Perspective by Madden) described the mechanical properties and electrostatic actuation of very low density multiwalled carbon nanotube sheets formed into aerogels. By electrostatically charging the sheets, a large expansion occurred in the direction perpendicular to the nanotube orientation, and a smaller contraction occurred parallel to the stretch direction. This work points the way to developing novel materials with highly directional mechanical properties.

VEGF-mediated cell proliferation in vitro, as well as tumor growth in mice, thus indicating the feasibility of a single therapeutic for cancer treatment.

Ordered into Superconducting
In unconventional superconductors, such as the cuprates, electrons form Cooper pairs by mechanisms other than electron-phonon coupling. These systems have a high density of defects and are chemically doped, so it can be difficult to observe smooth transitions between the superconductor and the parent electronic state from which they form. Takabayashi et al. (p. 1585; see the Perspective by Tosatti) showed that a particular phase of the alkali fulleride superconductor Cs3C60, which is well-ordered and exhibits a body-centered cubic symmetry, transformed from a spin-1/2 antiferromagnetic insulator to a superconductor as pressure was applied. The transition was purely electronic, in that no structural changes or disordering occurred. The dependence of the transition temperature on pressure was not accounted for by the standard model for superconductivity.

news story by Miller) tested electrical stimulation of the spinal cord dorsal column as an alternative strategy in animal models of Parkinson’s disease. They found that corticostriatal activity patterns preceded voluntary motor actions, which may offer some explanation for the mechanisms underlying volitional movements. Dorsal column stimulation markedly improved motor functions, and enhanced pharmacological treatment in the animals, and looks as if it holds considerable promise for the treatment of Parkinson’s disease patients.

Heating the Solar Atmosphere
The temperature of the Sun increases markedly as one moves from its surface to the outer layers of its atmosphere. Types of plasma waves called Alfvén waves, that are hypothesized to be incompressible and driven by magnetic tension, are considered to be the best explanation for how energy is transported through the solar atmosphere, but their unambiguous detection is still in doubt. Jess et al. (p. 1582; see the news story by Kerr) obtained high-resolution images of the Sun and found oscillations that bear the signatures of torsional Alfvén waves and that carry sufficient energy to heat the solar atmosphere.

Two-in-One Antibody
Textbook definitions of antibodies emphasize the exquisite specificity with which these proteins bind their target antigens. New research suggests that this “one antibody–one antigen” paradigm can be tweaked in the laboratory. Working with an engineered library of variants of Herceptin, a therapeutic monoclonal antibody targeting the breast cancer growth factor HER2, Bostrom et al. (p. 1610; see Perspective by Parren and Burton) successfully selected variants which had antibody-combining sites that simultaneously bound with high affinity to a second cancer-relevant antigen, vascular endothelial growth factor (VEGF). In preliminary assays of efficacy, the two-in-one antibodies inhibited HER2- and

CREDITS (TOP TO BOTTOM): ALLISON C. DALEY; BOSTROM ET AL.

Improving Parkinson’s Treatment
Deep brain stimulation has become a popular procedure for the treatment of motor symptoms in Parkinson’s disease. However, it is an invasive surgical technique and people have been trying to find alternative methods that carry less risk. Fuentes et al. (p. 1578; see the cover; see the SCIENCE VOL 323

Meta Addition
Friedel-Crafts reactions are among the oldest adopted in modern organic chemistry and have been used for over a century to attach various atoms around benzene rings and create components of dyes, drugs, and a wide range of functional
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This Week in Science

materials. These reactions install incoming groups on the ring carbons adjacent to or diametrically opposite electron-donating substituents such as amines. Modifying the intermediate (or meta) sites, two carbons away from existing substituents, has been challenging. Phipps and Gaunt (p. 1593; see the Perspective by Maleczka) discovered a copper catalyst that selectively adds incoming phenyl groups to the meta positions of amide-substituted benzenes. This kind of catalysis opens the way to the development of novel agrochemicals and pharmaceuticals.

Methylation Rescue
Methylation of genomic DNA occurs with high frequency at transposons and repetitive DNA sequences to repress transcription of these potentially damaging genome features. Methylation patterns are normally inherited during cell division as the methylated parental DNA strand provides a template for the methylation of the daughter strand. But sometimes methylation marks are ablated and lost in all subsequent generations. Teixeira et al. (p. 1600, published online 29 January; see the Perspective by Law and Jacobsen) found that Arabidopsis recovered methylation marks in a process requiring meiosis and the RNA interference–dependent DNA methylation machinery. After one to three generations, original methylation levels were recovered. This mechanism not only helps to maintain genome stability, but might also permit adaptive responses in epigenetic inheritance.

Conducting 3D Printing
One challenge to the development of more robust, flexible, or stretchable electronics is the printing of electrodes within devices and between devices. Ahn et al. (p. 1590, published online 12 February; see the Perspective by Gates) have formulated concentrated silver nanoparticle inks that can be printed in three dimensions. The electrodes are selfsupporting and can be patterned in complex ways as planar or 3D forms on a wide variety of substrates. Once sintered at moderate temperatures, the colloidal particles fuse together to make wires with electrical resistivities that approach the value for bulk silver.

Sorting Light Receptors
In the retina, cyclic nucleotide gated (CNG) channels initiate the electrical response to light in the sensory cilia of the rods. The channels are exclusively localized to outer segments of the cilia, but how they are positioned has been largely unknown. Working on Xenopus, Kizhatil et al. (p. 1614) showed that the CNG-β subunit bound to ankyrin-G, a membrane scaffolding protein, is not only required for the postGolgi transport of CNG channels, but is also required for rod outer segment development. A human mutation in the CNG-β subunit disrupts this targeting mechanism and is associated with retinitis pigmentosa. Similar ankyrin-G–based mechanisms may occur in olfactory cilia, in the sperm flagella, and other sites.

Take My Word for It
On issues of fact, such as whether the bus has just passed, we usually feel comfortable to accept information from a stranger; in situations where emotions are involved we are more likely to rely on our own feelings than what others report. Gilbert et al. (p. 1617) demonstrated that this confidence may be misplaced. In a speed-dating scenario, women were asked for their subjective evaluations before and after a 5-minute encounter with a single man. The women who had only been supplied with a man’s profile and photograph fared significantly worse in predicting their after-the-fact reaction to their date than women who were supplied with an evaluation of a man from their predecessor.

Mother Knows Best
Gouldian finches have two color morphs that tend to mate true. Pryke and Griffith (p. 1605) showed that females forced to mate with males of the opposite morph have more sons and invest less effort in rearing them than if allowed to mate with their own type. But if the males are painted to resemble the females’ preferred mates, the duped females will readjust their behavior and the sex ratio of the eggs. The results imply that female birds may be altering resource allocation to their female offspring in multiple ways. www.sciencemag.org SCIENCE VOL 323 20 MARCH 2009
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CREDIT: AHN ET AL.

EDITORIAL

The Enlightenment Returns
The authors of the Declaration of Independence and the Constitution of the United States were children of the Enlightenment. They understood the power that flows from combining human reason with empirical knowledge, and they assumed that the political system they were creating would thrive only in a culture that upheld the values of the Enlightenment. And thrive it did, in large part because our people and government upheld those values throughout most of U.S. history. Recently, however, the precepts of the Enlightenment were ignored and even disdained with respect to the manner in which science was used in the nation’s governance. Dogma took precedence over evidence, and opinion over facts. Happily, as was made clear by two policy announcements by President Barack Obama on 9 March 2009, the break in the traditionally harmonious relationship between science and government is now ending. The first announcement, which dealt decisively with a single important and politically volatile issue, the funding of stem cell research, received the most attention. But the second, on scientific integrity, has greater breadth and at least equal significance. For as the president put it, “promoting science isn’t just about providing resources—it is also about protecting free and open inquiry . . . free from manipulation or coercion, and listening to what [scientists] tell us, even when it’s inconvenient—especially when it’s inconvenient.” In using the words “manipulation” and “coercion,” the president was not speaking purely in the abstract; he was alluding to recent breaches of a code to which government must adhere if science is to play its proper role in advising the government on such complex issues as public health, climate change, or environmental protection. When the government systematically disregards this code, it undermines the historic role of science as a bulwark of an enlightened democracy. In the president’s Memorandum on Scientific Integrity last week, addressed to the heads of all executive departments and agencies, he directed those officials to neither suppress nor alter scientific and technological findings solicited in the process of policy formulation. He also asked that scientific information developed or used by the government be made readily available to the public. To put these directives in place, the president requested the director of the Office of Science and Technology Policy to develop, within 120 days, recommendations “designed to guarantee scientific integrity throughout the executive branch” and to ensure “that scientific data is never distorted or concealed to serve a political agenda.” The recommendations called for to sustain these bold ambitions would place scientific competence and integrity among the core principles of the government’s science-based endeavors. For example, they should ensure that the selection of scientists for government positions is based on scientific qualifications and experience, establish means for addressing instances in which scientific integrity may be compromised, and provide protections for those who draw attention to possible assaults on the integrity of scientific advice. The need for these measures derives, in part, from the many well-documented cases in which scientific integrity was recently breached, as when political appointees shut government scientists out of critical decisions that hinged on scientific information, prevented the transmission of scientific reports to Congress, appointed unqualified individuals to scientific panels because of their ideological or political persuasion, or censored government reports dealing with climate change and species extinction. The U.S. scientific community now has an opportunity to strengthen the president’s initiative by informing students, colleagues, and fellow citizens about the issues at stake; by willingly offering professional advice to government either informally or when invited to serve on agency panels; by supporting and encouraging scientists who are considering careers in government; or by taking a turn in government service. The president has taken a large and inspiring step to restore the historically beneficial balance between science and government; we should all now offer to help with the enlightened effort just launched.
– Kurt Gottfried and Harold Varmus
10.1126/science.1173563

Kurt Gottfried is a cofounder of the Union of Concerned Scientists and chair of its board of directors. He is professor of physics emeritus at Cornell University.

Harold Varmus is president of the Memorial SloanKettering Cancer Center, a cochair of the President’s Council of Advisors on Science and Technology, and a former director of the National Institutes of Health.

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CREDITS: (TOP RIGHT ) CORNELL UNIVERSITY; (MIDDLE RIGHT) JON FRIEDMAN; (LEFT) ISTOCKPHOTO.COM

EDITORS’CHOICE
EDITED BY STELLA HURTLEY AND JAKE YESTON
a fluid microchannel, so that the film bulged to allow more fluid storage as the overall pressure increased. Diodes, which permit flow in only one direction, were fabricated by bonding a deformable film on top of a weir, thus allowing flow only when the pressure was above a critical value. Through a combination of these circuit elements, fluid flow could be predicted and controlled by modulating a pressure source with time through a selection of resistive channels and capacitors. More complex flows were achieved by creating branched streams that merged at the output channel. The flow from each branch was regulated by the frequency of the pressure oscillations, effectively rendering the device a bandpass filter. Diodes, with their nonlinear response to pressure, were used to convert oscillatory flow to steady flow, similar to the conversion of electrical current from ac to dc. — MSL
Nat. Phys. 5, 231 (2009).

ECOLOGY

All Washed Up
Toxic algal blooms, or red tides, caused by dinoflagellates pose a danger for humans and many other vertebrates. In November 2007, a late red tide of Akashiwo sanguinea in Monterey Bay caused a mass stranding and high mortality of winter visiting seabirds. Jessup et al. report that the birds’ plumage had become coated in a sticky green froth exuded from the algae that contained surfactant mycosporinelike amino acids, which acted like a detergent to strip the feathers of their natural waterproofing oils. Consequently, the soaking birds, already weakened from migration, became hypothermic, and many died. If the surviving birds were cleaned as if they had been caught in an oil spill, then most made a full recovery. The algae seemed to have no other toxic activity, although inhaling aerosolized green scum apparently caused lung pathology. With the major shifts currently affecting the marine environment that are favoring other types of red tides, this kind of algal hazard is likely to become a more widespread occurrence. — CA
PLoS ONE 4, e4550 (2009).

MICROBIOLOGY

Do We Have a Quorum?
Bacteria can communicate with one another and act cooperatively as a group—a process known as quorum sensing (QS). However, such communication and cooperation can be exploited by “cheaters,” who benefit from the shared metabolic or otherwise beneficial activities without contributing to them. In the case of the pathogenic bacterium Pseudomonas aeruginosa, the signal molecules that facilitate population-wide QS regulate important disease-related processes, such as biofilm formation, swarming motility, and the production of secreted virulence factors. Rumbaugh et al. demonstrate that this potentially deadly cocktail of activities can be undermined by mutant bacteria that cheat. In a burn injury model in mice, infection with QS P. aeruginosa leads to rapid death of the host; infection with QS mutant bacteria resulted in significantly less mortality. The mortality caused by QS bacteria was substantially diminished in the presence of the mutant bacteria, which, through their exploitation of the QS bacteria, were able to flourish at their benefactors’ expense, reducing the overall virulence of the infection. Furthermore, the mutant bacteria, which cannot normally mount an effective systemic infection, were able to spread to the liver in the presence of the QS bacteria, presumably by piggy-backing on the social activities of the QS bacteria. QS mutants are known to arise in clinical settings and may thus affect the virulence and course of infections. — GR
Curr. Biol. 19, 341 (2009).

CREDITS (TOP TO BOTTOM): SANFORD BERRY/VISUALS UNLIMITED, INC.; JESSUP ET AL., PLOS ONE 4, E4550 (2009); LESLIE ET AL., NAT. PHYS. 5, 231 (2009)

CHEMISTRY

Clicking onto Nanofibers
Vertically aligned carbon nanofibers—stacked “cups” of grapheme—are of interest for electrochemistry because they expose a high fraction of edge sites with much faster electron transfer rates than the basal plane sites that predominate on carbon nanotubes. For applications such as sensing, it would be useful to attach redox-active groups to the surface of these materials. Landis and Hamers report that copper click chemistry can be used to attach groups such as ferrocene. The carbon nanofiber surfaces were functionalized with azide groups, and ethynyl-substituted ferrocenes were then covalently attached through the Cu(I)-catalyzed cyclization reaction. The attachment was quite stable—the redox couple could be cycled at least 1500 times. The rates through this pi-bonded bridge were similar to those for ferrocene groups attached through sat-

urated alkyl linkages, suggesting that electron transfer occurs through the aqueous solvent rather than the hydrocarbon bridges. — PDS
Chem. Mater. 21, 724 (2009).
APPLIED PHYSICS

Circuit Training for Fluids
A nagging problem in microfluidic reactor design is the need for bulky external apparatus to control the pumping and directing of the fluid flows. To circumvent this issue, Leslie et al. tried to mimic passive electrical circuits—resistors, capacitors, and diodes. Capacitors store electrical charge, a function mimicked by bonding a deformable elastomeric film to
Microfluidic circuit.

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RANDOMSAMPLES
E D I T E D B Y C O N S TA N C E H O L D E N

Graphic Science
What’s hotter than Harry Potter? In South Korea, at least, the answer is science— in comic-book form. The 50 titles in the English-titled Why? series have sold more than 20 million copies since 2001, outselling translations of J. K. Rowling’s blockbuster series 3 to 2, according to publisher YeaRimDang. Each 160-page, $6.50 book covers a different topic, including space, the sea, and puberty. These panels from Why? Electricity and Electronics explain how fuel cells combine hydrogen and oxygen to generate electricity, producing H2O as a byproduct. The dog admon-

ishes the fuel cell for “peeing all over the place.” “It’s just clean water,” says the fuel cell. French, Russian, Chinese, and Thai translations have already appeared. Japanese and North American versions may soon follow.

Czar’s Missing Children ID’d
On 17 July 1918, Czar Nicholas II of Russia, his wife, and five children were killed by the Soviets. A grave containing the remains of five family members was found in the 1970s, and in 1991, DNA testing established that the remains were those of the czar, his wife, and three of their children. Now, researchers say they have definitively identified the missing children—the couple’s hemophilic son, Alexei, and a girl—from bone fragments and teeth discovered near the original gravesite in 2007. Because the youngest daughters were only 2 years apart in age, the scientists couldn’t be sure who the girl was. A team led by Michael Coble of the DNA lab at the Armed Forces Institute of Pathology in Rockville, Maryland, made the matches by comparing mitochondrial and nuclear DNA from the remains with DNA from the earlier work and with Y chromosome markers from a living Romanov cousin, they reported 11 March in PLoS ONE. At the same time, says Coble, researchers in Yekaterinburg, Russia, analyzed bloodstains from a shirt—stashed for decades in the Hermitage Museum in St. Petersburg—that

CREDITS (TOP TO BOTTOM): YEARIMDANG PUBLISHERS; POPPERFOTO/GETTY IMAGES; ALASTAIR ROBINSON

Nicholas had been wearing when he was attacked while traveling in Japan in 1881. DNA from the blood showed “complete concordance” with DNA from one of Nicholas’s teeth. The newly discovered remains are now in a forensic lab in Yekaterinburg. Once the Russian Orthodox Church agrees that they are authentic, they can be buried with the rest of the family in a cathedral in St. Petersburg.

trapped in the pool and drown. The new giant pitchers, whose ilk turned to carnivory because of the nutrient-deficient soils they live in, enjoy a varied diet: One contained several large green beetles, black beetles, bees, and wasps. Dubbed N. attenboroughii, the plant is described in the February Botanical Journal of the Linnean Society.

Giant Bug-Eater Descried
Plant explorers have discovered a giant new species of carnivorous pitcher plant on a mountaintop in the Philippines. At 30 cm long and 15 cm wide, the plant’s pitchers may set a record for genus Nepenthes—the group that includes all 120-odd species of Old World pitcher plants. The team spied the plant after scrambling up a 6-m waterfall to reach the summit of Mount Victoria on the island of Palawan, says Alastair Robinson, an independent field botanist formerly at the University of Cambridge, U.K. Dangling from long tendrils attached to a central stem, the trumpet-shaped pitchers are “akin to an open stomach” filled with milky digestive fluids and water, Robinson says. Insects attracted to the pitcher’s nectar and color get SCIENCE VOL 323 20 MARCH 2009

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Awards
TURING AWARD. Barbara Liskov marvels at the technological gains in computer science in the 40 years since she earned her Ph.D. But progress on achieving gender equity has been much slower, says the first woman to earn a U.S. doctoral degree in the field. This month, Liskov, 69, a professor at the Massachusetts Institute of Technology, received the 2008 A. M. Turing Award from the Association for Computing Machinery. The award, which comes with a $250,000 prize, recognizes her development of CLU and Argus, computer languages based on object-oriented programming. Her work laid the foundation for today’s widely used programs Java and C++, which power most Internet software. “I think we’ve made progress [in closing the gender gap], but I don’t think we’re where we want to be,” says Liskov, who was one of only 10 women on the MIT faculty when she was hired in 1972. She’s also associate provost for faculty equity, overseeing efforts to increase the number of women and minorities on the faculty.

NONPROFIT WORLD
NEW KAVLI HEAD. An engineer who has managed a venture-capital firm will be the next president of the Kavli Foundation. Robert Conn, a former dean of engineering at the University of California, San Diego, says his first task will be to preserve the foundation’s endowment so it can continue to support its 15 university-based research centers. The foundation, started in 2000 by Norwegianborn businessman Fred Kavli, also awards biannual $1 million prizes in astrophysics, nanoscience, and neuroscience. Conn takes over next month from David Auston. CHANGE AT MACARTHUR. Robert Gallucci, a military and foreign policy expert who served as the chief U.S. negotiator during the 1994 North Korean nuclear crisis, will be the next president of the John D. and Catherine T. MacArthur Foundation. Gallucci has held several jobs in the U.S. government and helped create the International Science and Technology Center in Moscow, which

engages former Russian weapons scientists in nonweapons research. He’s currently dean of the School of Foreign Service at Georgetown University in Washington, D.C.

Honors >>
TO SERVE. For physicist Mildred Dresselhaus, mentoring other women in science is simply emulating what Nobelist Rosalyn Yalow, then a young faculty member at Hunter College in New York City, did for her as an undergraduate there. It’s also part of her credo: “Whenever I was asked to do something that would benefit others, I did it.” Last week, the National Science Board, the oversight body for the National Science Foundation, honored her service and her accomplishments in carbon science with its Vannevar Bush Award. A professor at the Massachusetts Institute of Technology since 1968, Dresselhaus has served as president of the American Physical Society and other societies including AAAS, which publishes Science. She also headed the U.S. Department of Energy’s Office of Science from 2000–01. At 78, Dresselhaus still begins work at 6 a.m. And she’s lost none of her enthusiasm for research and mentoring. “You can do a lot by getting people excited about science. We don’t do this for money, or awards, we do it for love.”

MOVERS
FAVORITE SON. Eric Isaacs, the new director of Argonne National Laboratory, plans to make energy the Illinois lab’s focus by expanding basic research already under way on storage, catalysis, alternative fuels, and combustion. For the condensed-matter physicist, energy conservation begins at home: An Argonne scientist since 2003 and deputy director since last May, Isaacs won’t even need a moving van when he takes over in May for the outgoing director, Robert Rosner. Simon Mochrie, a physicist at Yale University, predicts that Isaacs will be a good fit for the Department of Energy lab, which hosts the Advanced Photon Source synchrotron x-ray source. “Eric is a longtime user of x-ray facilities, and I think that will be a strength for Argonne,” says Mochrie.

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R I S I N G S TA R S
INTEL WINNERS. Eric Larson (left), a high school senior from Eugene, Oregon, has claimed the top prize—a $100,000 college scholarship—in the 2009 Intel Science Talent Search for his classification of new fusion categories, a type of algebraic structure with applications in string theory and quantum computation. Second- and third-place winners were William Sun, 17, of Chesterfield, Missouri, and Philip Streich, 18, of Platteville, Wisconsin. Sun (middle) receives a $75,000 scholarship for researching the newly discovered molecule Golgicide A as a potential drug to treat bacterial infections and prevent Alzheimer’s disease. Streich (right), a home-schooled student, earns a $50,000 scholarship for work demonstrating the solubility of carbon nanotubes; he and his mentor, chemist James Hamilton of the University of Wisconsin, Platteville, have filed for five patents.
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THIS WEEK

Science at FDA

The slow domestication of rice

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Friendly climate. Danish Prime Minister Anders Rasmussen (far right) quizzed four climate scientists at the Copenhagen meeting.

GLOBAL WARMING

Projections of Climate Change Go From Bad to Worse, Scientists Report
COPENHAGEN—Meeting 2 years after the most

energy. And inside, the organizers definitely recent report of the authoritative Intergovern- felt the wind at their backs. Unlike IPCC, mental Panel on Climate Change (IPCC), which is affiliated with the United Nations some 2000 scientists delivered a consistent if and its member governments, last week’s not unequivocal message here last week on the congress answered to no political bosses and, state of Earth’s warming climate. “The worst- therefore, participants were free to make precase IPCC projections, or even worse, are scriptive statements at its conclusion. “Inacbeing realized,” said the event’s co-chair, Uni- tion is inexcusable” and “weaker [emissions] versity of Copenhagen biological oceanogra- targets for 2020 increase the risk of crossing pher Katherine Richardson. Emissions are tipping points” were two of the six “messoaring, projections of sea level rise are higher sages” that organizers disseminated in a press than expected, and climate impacts release. Some scientists, however, around the world are appearing with felt that those messages suggested a increasing frequency, she told dele- COPENHAGEN false consensus among participants. CLIMATE gates in the opening session of the The meeting’s 58 sessions were CONGRESS 3-day meeting. grouped into three general themes: The 11 universities that conphysical climate science, prospects vened the Copenhagen Climate for mitigation, and impacts and Congress hoped to provide a comadaptation. On the prognosis for the prehensive picture of the status of world cli- climate system, Richardson warned that mate science before another set of delegates there’s “no good news.” Some scientists critimeets here in December to hammer out a fol- cized how the 2007 IPCC report addressed the low-up to the 1997 Kyoto Accords, which loss of the world’s ice sheets, because it expire in 2012. “This is our opportunity to get explicitly omitted calculations of the movescience back on the agenda,” said climate ment of glaciers, which at the time was poorly modeler Vicky Pope of the U.K. Met Office. understood (Science, 9 February 2007, British Member of Parliament Colin Challen, p. 754). Two years later, the picture is clearer. who attended several sessions, said the update Konrad Steffen of the Cooperative Institute was crucial as nations are making plans “on for Research in Environmental Sciences in data that’s out of date.” Boulder, Colorado, said that the loss of Outside the conference center, a 75-m Greenland ice was accelerating, with the wind turbine reminded delegates of the speedup of the glaciers contributing up to promise, yet unfulf illed, of sustainable two-thirds of the loss.

Another question left unanswered by the last IPCC report was whether the Antarctic ice sheets were losing mass. University of California (UC), Irvine, glaciologist Eric Rignot said that more recent data from satellites and field studies “very clearly” show that the ice sheets are shrinking. Rignot said the accelerating movement of glaciers in Greenland and Antarctica would, on the current trajectory, lead to sea level rise of 1 m or more by 2100— flooding coastal residents around the world. New modeling work presented by Jonathan Bamber of the University of Bristol, U.K., showed that a complete disintegration of the Greenland sheet would require a 6°C rise in global temperatures, double the conventional wisdom. But before the audience could digest what sounded like a rare piece of good news, Bamber added that a 15% loss to the sheet would translate into a 1-m rise in sea level. “[That] is a horrendous prospect whichever way you cut it,” Bamber told Science. Elsewhere, the science was just as gloomy. Ecologist Chris Field of the Carnegie Institution for Science, who is overseeing the next IPCC report’s section on impacts, gave an update on his analysis of the behavior of carbon stocks in the soil, permafrost, and plants. It’s a problem IPCC “underemphasized” 2 years ago, he said. The latest estimate of the amount of carbon in permafrost is 1.7 trillion tons, more than twice the 2007 estimate. Scientists know that warming temperatures could unlock this carbon, making the yearly effort to cut the atmospheric concentration of carbon dioxide “that much tougher” in the coming decades, Field says. Modeling of carbon frozen in soils remains primitive, he said. But new findings from f ield studies suggest that a type of soil known as Yedoma sediments could be especially problematic because it decomposes easily and 30% of its emissions are methane, a potent greenhouse gas. Plus, he said, scientists have been unable to find evidence for the hypothesis that some natural carbon sinks like forests may be increasing their ability to take in CO2 as the planet warms. A number of sessions examined the frightening possibility that warming temperatures could trigger catastrophic tipping points,

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Clues to how deep brain stimulation works

20 years after the Exxon Valdez

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such as the loss of the Amazon rainforest through drought, which would create a vicious feedback. For example, modelers from the U.K.’s Met Office presented new data showing that even a global cessation of greenhouse gas emissions by 2050 could lead to a loss of up to 40% of the Amazon rainforest. “We thought we didn’t need to worry till we got to 3°C of warming,” says Pope (see graphic). Tim Lenton, an Earth systems scientist from the University of East Anglia, U.K., describes the change in looking at deforestation as going from “high-impact, low-probability events [to] high-impact, larger probability events.” Atmospheric scientist Allan Gadian of the University of Leeds, U.K., says that the model “lacks credibility” because it fails to reproduce the current climate. But Chris Jones of the Met Office says the model closely replicates 20th century Amazon rain patterns. Energy in Denmark said that “surprisingly” turbulent wind conditions at sea have made the turbines less efficient but that scientists are having trouble studying the problem because the companies are concerned about giving their competitors an advantage by disclosing their data. Scientists also examined how carbonfriendly mitigation techniques might cause other problems. Dozens of companies are developing new strains of algae to make biodiesel fuel, said Anthony Marchese of Colorado State University in Fort Collins, but his studies show that the resulting fuel can emit

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plies. A better alternative would be to plant mixtures of species, he says, but that requirement is not included in the system. The conference included dozens of sessions on how scientists are helping countries begin to adapt to climate impacts. “Adaptation is rapidly evolving as a new area of science,” said Roger Street of the University of Oxford in the U.K. and an expert on impacts and adaptation. There’s a lot to learn, however. Oxford plant ecologist Pam Berry showed how adaptation can hinder efforts to mitigate emissions and protect biodiversity. “We need triple wins,” she said. A project to reroute streams to reduce the risk of flooding, for example, offered relatively cheap flood protection and increased aquatic biodiversity, she said. But the new ecosystem might feature additional sources of methane. Beachrestoration efforts to battle rising tides often involve the addition of sands, which have a chemical composition that can harm local AMAZON DEFORESTATION The challenge of change species. Scientists are learning that Although transforming the world climate change creates challenges 2050 2150 energy economy poses what Ian more complicated than the “single Chubb, vice-chancellor of Ausstressor, single species” models tralian National University in Canthat were used in the past, she said. berra, calls “a diabolical policy Attendees said that they problem,” sessions on mitigating appreciated the breadth of clicarbon emissions offered a mixed mate-related research presented bag. UC Berkeley energy scientist at the meeting, which was much Daniel Kammen explained how a more political than the average Berkeley city employee had come scientific conference but far more up with a novel financing techscientif ic than a gathering of Tree Density nique to fund residential energydiplomats. Still, Field echoed the efficiency upgrades and solar pancomments of several researchers Low High els. It’s too early to assess the sucin worrying about the stated mescess of the 6-month-old program, Emptying out. New models forecast that Amazonian forests could be decimated sage of the effort. Field said the which offers homeowners loans by 2150 even if greenhouse gas emissions fall to zero by 2050. scientists on stage in the final plethrough a city bond. But a handful nary session were overstating the of U.S. cities have adopted it, he says, and offi- higher organic carbon or NOx pollution levels level of support among climate scientists for cials in Lisbon and New York City are monitor- than fossil fuels do when burned. “We have to the scientific validity of the 2°C target. Also ing it. “Green growth is the answer to our consider issues like the emissions and health troubling, he said, was that the organizers of climate problems and our economic prob- effects, not just how much oil bio algae fuel the congress “were very unclear on the differlems,” Danish Prime Minister Anders Fogh provides,” he said. ence between [the messages] at the end of the Rasmussen told the delegates during an Along similar lines, Australian geographer meeting and the incredibly thorough, careful appearance in which he quizzed a panel of and ecologist Neville Crossman of the Aus- IPCC review and evaluation process.” scientists on what emissions cuts are required. tralian Commonwealth Scientific and IndusConference organizers plan to release a Nations like Denmark have shown the trial Research Organisation said that a car- 30-page, peer-reviewed summary report of reliability of wind power. But one challenge bon-trading system in Australia provided the conference findings in June. They hope has been getting businesses to work together. farmers with an incentive to plant certain the document will serve as a guide for this Danish engineering professor Erik Petersen native eucalyptus trees in dry areas. But the fall’s negotiators of the evolving science. of Risoe National Laboratory for Sustainable trees increase the demand on scarce water sup–ELI KINTISCH
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NEWS OF THE WEEK
MATHEMATICAL SCIENCES

Senate Majority Leader Hands NSF a Gift to Serve the Exceptionally Gifted
The budget of the National Science Foundation (NSF) has traditionally been free of congressional earmarks. But buried in the $410 billion federal spending measure enacted last week is a provision that gives NSF $3 million this year “to establish a mathematical institute devoted to the identification and development of mathematical talent.” The directive, which is backed by Senate Majority Leader Harry Reid (D–NV), is aimed at serving supersmart children whose needs aren’t being met in school. As it happens, a proposal to create a national program along those lines has just been submitted to NSF as part of a competition to choose a new batch of universitybased mathematical research institutes (www.mathinstitutes.org). A consortium that includes a group in Nevada is bidding to join a network, created in 2000, that is the biggest single activity within NSF’s $212 million Division of Mathematical Sciences. The seven current centers, with funding for up to 10 years, serve as user facilities for the mathematical community, providing jobs for graduate students and postdocs, temporary positions for senior professors, and a continuous stream of workshops, summer institutes, and public-outreach activities. Although each center also works with some precollege students and teachers, the focus is on exploring the frontiers of the mathematical sciences. Last spring, NSF announced a new competition for up to six centers, with grants of $3 million to $5 million a year. (NSF provides a large majority of the operating budget for each center, and their directors say that life without NSF funding would be nearly impossible.) The deadline for applications was 27 February, and incumbents— including four whose funding ends next year—were eligible to apply. Although NSF won’t disclose the number of applications it received, nor their identities, the four incumbents—at the Berkeley and Los Angeles campuses of the University of California, the University of Minnesota, and Ohio State University—have submitted proposals. So did a team led by educational psychologist Susan Assouline of the University of Iowa’s Belin-Blank International Center for Gifted Education and Talent Development. Linda Brody of Johns Hopkins University in Baltimore, Maryland, and Jill Adrian of the Davidson Institute for Talent Development in Reno, Nevada, are co-investigators on a proposal that Adrian describes as “a little bit out of the box.” The three researchers have spent decades working with the tiny population labeled “profoundly gifted.” Assouline and Brody were postdocs together in the late 1980s on the renowned longitudinal exceptional talent study at Hopkins, which Brody now directs. The nonprofit Davidson Institute was created 10 years ago by education software developers Bob and Jan Davidson, who also support the Davidson Academy, a one-of-a-kind public school for exceptionally gifted students on the campus of the University of Nevada, Reno.

Top talent. A student at the Davidson Academy in Reno, Nevada.

–JEFFREY MERVIS

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Assouline declined to describe the group’s proposal in detail, citing the confidentiality of NSF’s merit-review process. But a onepage project summary makes clear that the proposed National Institute for Mathematical Research would focus on prospective mathematicians—the youngest student at Davidson Academy is 9 years old—rather than the academic mathematicians—faculty members, postdocs, and graduate students—who populate the existing centers. It would likely expand the Davidson Institute’s young scholars program, which provides counseling for students around the country and their parents, as well as offering some students a chance to work with professors on genuine research projects. Hopkins and Iowa would provide additional sites in what would otherwise be a largely virtual institute. Although several states and local districts operate schools for high-end students, those with truly exceptional academic skills are usually left to fend for themselves, including home-schooling. “These kids need so much more than students in the average gifted and talented program, and not just with regard to academics,” says Adrian. The goal, says Assouline, is to create “an integrated, national system.” Assouline estimates that 10% of students at the new institute “will progress toward an active research agenda.” Assouline has a powerful friend in her corner in Reid. The $3 million in NSF’s 2009 budget is not the narrowest type of earmark that requires an agency to give money to a particular entity in a legislator’s district. But Peter March, head of NSF’s math division, says the language constitutes “directed spending” of the sort that limits the agency’s options. Although March declined to discuss the matter further, Science has learned that he met several times with aides to Reid to talk about how NSF could do more for profoundly gifted students. Reid staffers were also in touch with the Davidson Institute as the proposal was being prepared. Aides to the senator declined repeated requests to explain the language in the spending bill and would say only that Reid “supported … the additional funding” for the NSF program. Timing could be a touchy issue for NSF. The new centers aren’t expected to be chosen until fall and will be funded out of NSF’s 2010 budget. But the $3 million earmark is for the 2009 fiscal year, which ends on 30 September. Even if NSF doesn’t fund Assouline’s proposal as part of its current competition, it’s a good bet that the needs of this special student population have moved up on the list of NSF priorities.

NEWS OF THE WEEK
PUBLIC HEALTH

Stronger Research Just One Item on Drug Agency’s Wish List
The two public health veterans President Barack Obama has tapped to take charge of the U.S. Food and Drug Administration (FDA) face a daunting challenge. Margaret Hamburg, 53, and Joshua Sharfstein, 39, nominated to be FDA commissioner and deputy, respectively, will inherit an agency with fragmented authority and funding that has been stumbling from one crisis to the next. Their challenges stretch from f ixing antiquated information technology systems to managing overseas inspections of food and Safe? FDA is scrudrugs, but some of the tinizing a residue biggest are scientif ic. In in plastic. recent years, the agency has seen a flood of applications for novel medical therapies, such as those utilizing stem cells; at the same time it’s been encouraging companies to develop personalized gene-based drugs. For monitoring and enforcement, FDA desperately needs new ways to quickly detect food-borne illnesses like salmonella. Although FDA runs some in-house science efforts, including a sizable center for toxicological research in Arkansas, there’s been political pushback to supporting extensive research in-house. The agency is “not funded or empowered to do basic drug research,” says William Hubbard, a former FDA associate commissioner who spent nearly 30 years at the agency and recently retired. But while research is not its first priority, that doesn’t mean FDA can let expertise pass it by: “You can ill afford to have reviewers that are not very well experienced in the most advanced technologies when in fact those technologies are being brought to the agency” for decisions, says Gail Cassell, vice president for scientific affairs at Eli Lilly in Indianapolis, who chaired a panel that issued a scathing report on FDA’s science capabilities late in 2007 (Science, 7 December 2007, p. 1537). Hamburg and Sharfstein may be wellplaced to address some pressing issues. Both have headed big-city health departments: Hamburg in New York City during the 1990s, and Sharfstein as the current health commissioner of Baltimore. Both also have a long-standing interest in disease surveillance: for example, Hamburg served as an assistant secretary at the Department of Health and Human Services during the Clinton Administration, where she special- Turley says: “As you’re reading an [investiized in bioterrorism and planning a response gational new drug application] and you’re to a potential flu epidemic. trying to understand the readouts and the Funding has been a big part of FDA’s prob- tests, you have people on hand” who underlem: Its $2.66 billion budget for the 2009 fiscal stand the technology. year, while a boost from the previous year, still While Cassell praises the fellowship falls short of what many say the agency needs. program—her report urged FDA to bring in (Last year, FDA spent 6% of its budget on many more visiting scientists—several FDA basic research.) In addition, scientist turnover watchers say more radical change is needed. at FDA is twice that of other federal agencies, FitzGerald wants to see FDA fund academics Cassell’s report noted. Philip Bushnell, a to conduct research it needs done—for examtoxicologist at the Environmental Protection ple, in rapid detection or drug toxicology. He Agency who sat on an FDA subnotes that even when committee last fall that assessed the clear concerns arise, risks of bisphenol-A, a plastic found staff may lack the means in baby bottles, says FDA officials to explore them. With at that review “were not up to speed” Vioxx, an anti-inflamon the most current approaches to matory drug pulled risk assessment. from the market in 2004 It’s clear that FDA needs more after being linked to money, better morale, and imnumerous heart attacks, proved leadership, says Gar ret “there were people in FitzGerald, a pharmacologist at the the FDA who knew that University of Pennsylvania School there was a problem of Medicine who sits on the agency’s very early on, but they Science Board, a group of outside had no way of going to a advisers. But “let’s imagine all neutral testing ground” those things are fixed,” he continnot connected to the ues. That’s still not enough, he drug company. FitzGerald believes, to provide FDA with the envisions FDA farming scientific expertise it needs. this work out to academTo get that help, FitzGerald and ics and allowing them to others say, FDA needs to pursue pursue research with more scientific collaborations. The unapproved drugs. The agency has taken some steps in this idea would ruffle longdirection—in 2006, it helped initistanding conventions ate a consortium with the Founda- New blood. Margaret Hamburg about protecting comtion for the National Institutes of has been nominated to be pany secrets. Health, industry, and others to iden- FDA commissioner; Joshua But right now, FDA tify biomarkers for drug effective- Sharfstein, to be her deputy. lacks the funds—and ness and safety. A year ago, FDA possibly the initiative— appointed its f irst chief scientist, Frank to regularly nurture collaborations like these. Torti, a cancer biologist from Wake Forest And the agency is accustomed to taking the University School of Medicine. Torti has back seat, Torti suggested in an interview with been acting commissioner since January Science last month. He described seeing a when FDA head Andrew von Eschenbach poster on salmonella by FDA researchers and stepped down. He also launched an effort to assumed the work was paid for by FDA. The bring 50 scientists to FDA for 2-year fellow- response, he recalled: “ ‘Oh, we would never ship stints; the first class is there now. have the money to fund that—it was the Danielle Turley, who came to FDA as a Department of Homeland Security that felt fellow after a postdoc at Northwestern Uni- sorry for us and gave us the money.’ ” versity, is trying to identify biomarkers in Whether Hamburg and Sharfstein can shift stem cells drawn from bone marrow to help FDA’s culture will depend partly on the whims predict how safe and potent they’ll be. She and generosity of Congress and the Obama is one of more than 1000 who applied for Administration—and partly on how people in the first fellowships. Explaining why it’s the agency respond. important for FDA to support this research, –JENNIFER COUZIN
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NEWS OF THE WEEK
ARCHAEOLOGY

Recipe for Rice Domestication Required Millennia
Rice is delicious, nutritious, and the primary staple for about half of the world’s population. Most researchers agree that humanity’s close relationship with the grain (Oryza sativa) began thousands of years ago in China’s Yangtze River valley, but they have sharply debated when prehistoric farmers began domesticating wild rice and how long they took to do it. On page 1607 of this issue, archaeologists argue that rice remains from a 7000-yearold site in the Yangtze delta point to a later and slower domestication than has often been claimed. If correct, the findings suggest that the course of rice domestication paralleled that of cereal crops such as wheat and barley in the Near East, which apparently evolved only gradually into the domesticated plants we eat today (Science, 29 June 2007, p. 1830). “This is a very valuable and timely contribution to the sometimes heated debate about the dating and pace of rice domestication in China,” says James Innes, a paleoecologist at Durham University in the United Kingdom. But archaeologists who have argued that rice farming began as early as 10,000 years ago in China are not convinced. “The interpretation of this paper is simplistic,” says Yan Pan, an archaeobotanist at Fudan University in Shanghai, who says the debate cannot “be resolved by analyzing one single site.” The new data come from the site of Tianluoshan, just inland from Hangzhou Bay, south of Shanghai. Excavations between 2004 and 2007 revealed the wooden posts of buildings from a prehistoric village, along with boat paddles, stone axes, and thousands of plant remains. A team led by archaeologist Dorian Fuller of University College London and dig director Guo-Ping Sun of the Zhejiang Provincial Institute of Cultural Relics and Archaeology in the city of Hangzhou analyzed some 24,000 plant remains from the site, including about 2600 rice spikelets, which are attached to the stalk and carry the edible grain. In wild rice, the spikelets ripen and then fall to the ground naturally, allowing the plant to reproduce. But domesticated varieties require human action, such as threshing, to tear the spikelets from the stalk. Archaeologists can often tell the difference: The bases of wild spikelets have a smooth scar where they were attached to the plant, whereas domesticated spikelets have uneven scars from being torn off. cated spikelets has also been found at the nearby 8000-year-old Yangtze Delta site of Kuahuqiao, suggesting that the full transition from wild to domesticated rice cultivation took at least 2000 to 3000 years. Such a slow and late domestication clashes with the idea that rice domestication began 10,000 years ago in China. The most recent of such claims was made in a 2006 paper in Antiquity on the 10,000-yearold site of Shangshan, about 150 kilometers southwest of Tianluoshan. Archaeologists Leping Jiang of the Zhejiang Provincial Institute of Cultural Relics and Archaeology in China and Li Liu of La Trobe University in Melbourne, Australia, argued that some charred rice husks at the site were shorter and wider than those of wild rice. They said that rice at the site “probably was already in an early stage Early harvest. Prehistoric villagers at Tianluoshan cultivated of domestication.” But Fuller wild rice, distinguished by its spikelets (inset), eventually says detailed analysis, rather leading to domestication of the grain. than simple eyeballing, is required for such a claim. The The team focused on three archaeological paper sparked a heated debate among Fuller, levels spanning 6900 to 6600 years ago, based Jiang, Liu, Pan, and others in the pages of on radiocarbon dating of rice and other plant Antiquity and the journal Holocene, filling remains. (All dates are in calibrated calendar dozens of pages in 2007 and 2008. years.) Over that 300-year period, domestiLiu, Pan, and others say that Tianluoshan cated spikelets increased from 27.4% of the is not necessarily representative of the whole total to 38.8%; over the same time, rice Yangtze River valley region or, certainly, the increased from 8% to 24% of the total plant rest of China. Tianluoshan’s late rice domestiremains, which came from more than 50 cation does not invalidate the much earlier species including wild acorns and water chest- dates from Shangshan and several other sites, nuts. Fuller and his colleagues conclude that they say. Yongqiang Zong, a geoarchaeologist domestication was a slow process still under at the University of Hong Kong, agrees: way 6600 years ago, and that the villagers of “What Fuller et al. have reported is only repTianluoshan relied heavily on wild plants— resentative of the area on the southern side of such as wild rice and acorns—at that late date. the Hangzhou Bay.” The rise in domesticated spikelets over Even Fuller’s opponents in the debate time shows that the villagers also cultivated acknowledge the importance of Tianluwild rice: As they preferentially harvested oshan’s new evidence, however. “The quality and later replanted the grains that clung to the of the data is unprecedented,” says Liu, who stalk longer, they inadvertently selected for adds that the new study “is the most systemmutants that separated less easily from the atic and detailed” to date on rice domesticastalk. Evidence from other sites in the region tion. The paper is unlikely to resolve the suggests that early farmers often harvested debate, Innes says, but “it is exactly the kind wild rice when it was still immature to avoid of focused research that is needed to improve losing the grains, and the team also found our understanding of the complex ricemany immature spikelets at Tianluoshan. The domestication process.” team notes that a mix of wild and domesti–MICHAEL BALTER
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NEWS OF THE WEEK
SOLAR PHYSICS

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From Science’s Online Daily News Site
Split-personality superconductor. Researchers have long divided superconductors into two broad groups, depending on how they react to a magnetic field. Now, experiments by a group led by Victor Moshchalkov at the Catholic University of Leuven in Belgium show that one well-studied superconductor, magnesium diboride, actually belongs to both groups at the same time. That surprising finding suggests that superconductivity, which has already netted four Nobel Prizes, may be an even richer phenomenon that previously thought. The results will be published in Physical Review Letters. Self-medicating caterpillars. Woolly bear caterpillars (Grammia incorrupta) like to dine on plants loaded with toxic pyrrolizidine alkaloids. Evolutionary ecologist Michael Singer of Wesleyan University in Middletown, Connecticut, and his colleagues surmised that the toxin may help the caterpillars overcome an infestation with the larvae of parasitic tachinid flies, a common scourge of these caterpillars. In the lab, the researchers provided infested and uninfested woolly bear caterpillars with either pyrrolizidine alkaloids or sugar. Infested caterpillars ate twice as much toxin as their uninfested brethren did, and the alkaloids increased their survival by 20%. This suggests that when the caterpillars feed on toxic plants, they are self-medicating, says Singer. It is believed to be the first time scientists have shown that an invertebrate can self-medicate when sick. The findings were published online in PLoS ONE. Ancient lefties. Right-handed people may predominate here on Earth, but all of us are built from amino acids that are chemically “left-handed.” Two NASA scientists studying meteorites older than our planet report in the Proceedings of the National Academy of Sciences that they have found a majority of left-handed amino acids, suggesting that our solar system has always had a preference for southpaws. Read the full postings, comments, and more on sciencenow.sciencemag.org.

Unseen Link May Solve the Mystery Of the Sun’s Superhot Corona
Why would the sun’s faint, thin crown of ionized gas—so prominent during an eclipse—be at 1,000,000°C when the underlying surface is only 6000°C? Good question, solar physicists say. The energy ultimately comes from below, but how does it get to the corona? Researchers watching the sun from the g round in unprecedented detail think they have an answer: The energy is piped upward in the form of curious, twisty magnetic waves detected on the sun for the first time. The new observations are “very exciting,” says solar physicist Markus Aschwanden of Lockheed Martin’s Solar and Astrophysics Laboratory in Palo Alto, California. “The measurements are getting better and better.” Still, he adds, there are other explanations for what scientists are seeing, and most solar physicists remain unconvinced that it’s anything fundamentally new. On page 1582, solar physicist David Jess of Queen’s University Belfast and colleagues explain how they peered into an apparently empty layer just above the sun’s visible surface, or photosphere, looking for an energy connection to the corona. Both above and below the photosphere, the sun is nothing but ionized gas—plasma—permeated by powerful magnetic fields. Energy is flowing every which way in the form of waves and oscillations in the plasma and along the magnetic fields. The problem for solar physicists has been that none of the detectable energy flows looked big enough to heat the corona to a million degrees. Jess and his colleagues took a closer look at one patch of the sun using the Swedish 1-m Solar Telescope on La Palma in the Canary Islands. Using adaptive optics to remove blurring due to Earth’s turbulent atmosphere, they could resolve features as small as 110 kilometers and detect spectral shifts around the wavelength of the hydrogen-alpha absorption. Looking above a tight bunch of particularly bright spots on the photosphere, called a bright point group, they found distinctive oscillations in the motions of plasma revealed as Doppler shifts. The group interprets the oscillations as Alfvén waves driven upward from the churning photosphere in the form of a flaring tube to the bottom of the corona 5000 kilometers above. Long hypothesized but never directly detected on the sun, Alfvén waves are twisting oscillations along magnetic field lines formed as if you could grab the ends of the field lines and twist them one way and then the other, sending your energy out in the twists propagating along the f ield lines. The group calculates that there are enough bright point groups on the sun for their Alfvén waves to heat the corona to its observed million degrees. “We have conclusive evidence that Alfvén waves do exist [on the sun], and they have the potential to transport all the needed energy,” Jess says. “There’s definitely something there,” Aschwanden says. “The question is whether Alfvén waves are the only way to interpret it. Theirs is one interpretation. Their measurements must stand the test of time.” Most other solar physicists agree. Even if powerful Alfvén waves exist, they add, no one has explained how the waves break into the corona and dissipate their energy there. Many favor a different heating source, tiny but abundant solar nanoflares. AschwanTiny but potent? Magnetic waves from bright specks on the den’s conclusion: “We need better sun (here in false color) may be heating the solar corona. measurements.” –RICHARD A. KERR
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OBAMA EXECUTIVE ORDER

For Congress and NIH, Headaches Ahead on Stem Cells
With his long-awaited 9 March executive order lifting restrictions on federal funding for stem cell research, President Barack Obama has opened the door to some political fighting as nasty as any that has been seen so far on the subject of research with human embryonic stem (hES) cells. As scientists hoped, Obama left all the details of the policy, which erased limits imposed 8 years ago by President George W. Bush, to be determined by the National Institutes of Health (NIH). The Bush policy restricted federal funding to work on hES cell lines created before 9 August 2001 from surplus embryos slated for discard by fertility clinics. NIH has until 7 July to put out a draft set of regulations, digest the tsunami of public comment expected, and establish a final set of guidelines on just what it will fund. Scientists are thrilled that Obama is following their advice, but the new executive order leaves a void that, albeit temporary, is causing considerable anxiety in some quarters. At issue is the biological source of the hES cell lines now eligible for federal support. The question is whether work will still be limited to lines derived from surplus fertility clinic embryos or whether the government will approve the use of lines from embryos that have been created solely for research. Many scientists would like to work with lines created through research cloning, or somatic cell nuclear transfer (SCNT). This procedure—which has yet to be tried successfully—would enable a scientist to use a skin cell from a patient with Parkinson’s disease, for instance, to reprogram an egg to generate an embryo so a particular disease could be studied in a test tube. Ultimately, some believe cell lines from such embryos could be used in genetically tailored cell therapies. The Dickey-Wicker Amendment prohibits federally funded scientists from harming embryos, which means they would not be allowed to derive the cell lines they work with regardless of the source. But there is no federal law governing cloning—either for research or for reproduction—so scientists could obtain cell lines from privately sponsored sources. The stem cell community was expecting that as soon as Obama acted, Congress would codify the executive order by repassing a measure—twice vetoed by Bush—authorizing the government to support research, regardless of the date of derivation, on stem cell lines derived from excess embryos created for fertility treatments.

Now, however, with the source of eligible lines unspecified in the executive order, the bill’s sponsors are heading back to the drawing board. A Senate staffer won’t say whether they are thinking of eliminating the excess embryo restriction: “I think at this moment we are waiting to see what the NIH guidelines are going to be.” On the House side, an aide to Representative Diana DeGette (D–CO) e-mailed Science that “in light of the president’s Executive Order and in consultation with the experts, [sponsors of the bill] are reviewing past legislative efforts to assess what needs to be done going forward.” Apparently, the sponsors were caught flat-footed. “The White House wouldn’t tell us what was in the executive order before it was signed,” says a staffer. While Congress wants to wait to see what NIH says, people at NIH would like to find out more about what Congress wants as they struggle to get draft guidelines ready before the end of April. The traditional opponents of hES cell research are expecting the worst. Even with the derivation of new cell lines still banned, some fear the new policy will turn the federal government into an indirect supporter of cloning. The executive order “turned out to be far more extreme than [the] biggest proponents had hoped,” said the Family Research Council. “With no clear policy from the White House, you and I could be footing the bill for research that clones embryos just to scavenge their parts.” Psychiatrist and columnist Charles Krauthammer, a former member of the president’s bioethics commission, said in an



AUSTRALIA

Stem Cell Center Looks to Recast Itself in Supporting Role
MELBOURNE, AUSTRALIA—The Australian

sustain the center after 2011, when public the focus, he felt, should be on excellent Stem Cell Centre (ASCC), a controversial funding runs out. A second camp led by research, and commercial spinoffs would folexperiment in speeding the commercialization founder Alan Trounson, now leader of Cali- low. Trounson lost the battle and left in 2003. of stem cell research, is slated for a radical fornia’s stem cell program (see p. 1564), His departure did not ease tensions, which overhaul. For the next 2 years, the center plans argued that the time frame was unrealistic; came to a head last August after a governto turn away from its much-criticized ment review criticized ASCC’s busicommercial focus and recharge its ness plan. Livesey was sacked and the research effort. Then in 2011, ASCC is board purged (Science, 24 October likely to be transformed into an outfit 2008, p. 524). that provides technical and licensing With the clock ticking, ASCC scisupport for stem cell research. entists are reviewing research plans The government-funded consorand scoping out alternative funding tium of top stem cell researchers, which sources. The Australian government is has received $75 million since it was expected to decide by June whether to founded in 2002, has long suffered endorse a new business plan and from a clash of visions. One camp led release the final 2 years of ASCC’s by its former CEO, biotech entreprepublic funding—or close it down early. neur Stephen Livesey, championed a New map. Andrew Elefanty (left) and David Haylock are leading Andrew Elefanty, an embryonic model in which ASCC products would an effort to rethink stem cell research plans. stem cell researcher at Monash Univer-

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So far, there’s no available evidence that researchers anywhere are using lines other than from excess IVF embryos, says Willy Lensch, who works in Daley’s lab at Harvard. In a survey of the literature, he has found references to at least 783 lines. “I’ve never encountered a report that IVF was used specifically to make a line of hES cells,” he says. University of Pennsylvania bioethicist Jonathan Moreno, a member of the NAS embryonic stem cell committee, says, “I Supply lines. Obama has left it up to NIH and Congress to would be surprised if NIH went decide whether to restrict funding to cells derived from fertility beyond IVF discards” and opened the door to other embryo sources. clinic discards. But Daley says that even then, “the op-ed column that he does not oppose hES cell definition of ‘excess embryos from IVF’ is research but accused the president of “moral critical.” Would lines derived only from frozen abdication” in leaving it up to scientists blastocysts be allowed, as was proposed in the whether to create embryos solely for research. last days of the Clinton Administration, or On the contrary, says Harvard University’s lines from fresh discarded embryos, like those George Daley: “We need legislation that made in Daley’s lab, be included? allows [such] decisions … to be left to scienOut in the field, the executive order is lendtists.” Daley points out that guidelines ham- ing new energy to efforts in some states to mered out in 2005 by a committee of the clamp down on hES cell research. The GeorNational Academy of Sciences (NAS) and reg- gia Senate on 12 March passed a bill introularly updated, as well as recommendations by duced just that week with the support of Govthe International Society for Stem Cell ernor Sonny Perdue. It prohibits the creation Research, do not specify what biological of embryos for research—and covers not only sources should be used but focus on informed SCNT but also parthenogenesis, in which consent procedures for obtaining eggs, sperm, nonviable embryos are generated from unor embryos, and proper scientific procedures. fertilized eggs. –CONSTANCE HOLDEN

From the Science Policy Blog
The FBI is investigating the 7 March firebombing of a UCLA neuroscientist’s car by animal-rights extremists. It’s the latest in a string of terror attacks on University of California scientists that goes back to 2006. The university and local authorities are offering a reward of $445,000 for information related to the incident. The targeted scientist was not identified by authorities. ScienceInsider revealed that the Defense Advanced Research Projects Agency is looking into funding research on geoengineering, the deliberate tinkering with Earth’s climate to combat global warming. The secretive and risk-taking agency sponsored a nonclassified meeting this week in Palo Alto, California, to explore the topic. But at least one climate scientist invited to the meeting feels that the military shouldn’t be helping to develop such techniques. A Washington, D.C., meeting was convened to brainstorm ways to help the Iraqi academic and research enterprise get back on its feet. Despite billions of dollars in aid to the war-torn nation since the U.S. invasion in 2003, presenters at the conference reported little progress in rebuilding the scientific infrastructure. Among the ideas floated were fellowships to encourage young Iraqi scientists to visit the United States, but participants fear that could result in a brain drain. And in more sobering news from the Copenhagen Climate Congress (p. 1546), ScienceInsider blogged on alarming new results regarding polar ice shrinkage and the unappreciated threat of soil carbon. Researchers at the meeting also released a new scheme aimed at more fairly distributing emissions allocation certificates under a future greenhouse emissions cap, starting with the principle that every human should operate under the same emissions limit. And is Denmark really the green role model it advertises itself as? For the full postings and more, go to blogs.sciencemag.org/scienceinsider.

sity in Clayton, and hematologist David Haylock, whose lab studies adult stem cells at ASCC’s administrative center in Monash, were appointed last October to head a committee to chart a new course. The duo has upended the former management’s top-down approach—particularly its power to design projects and decide who should work with whom. “That’s not the way collaborations work best,” says Elefanty. “Right from the beginning, we were bleating: ‘You can’t force researchers to get into bed together.’ ” Now ASCC researchers are masters of their destinies. “Previously, everything had to be aligned with commercial due-diligence decisions, which tended to hamper scientists getting together and doing what they do,” says ASCC member Lars Nielsen, a biomedical engineer at the University of Queensland in St. Lucia. “Instead of a product pull, we now have a science push.” Last month, all ASCC researchers were required to submit proposals to the center for projects over the next 2 years.

CREDIT: JEFF MILLER/UNIVERSITY OF WISCONSIN, MADISON

That will better prepare them to compete for non-ASCC funding, says acting ASCC board chair Graham Macdonald. Under a revised business plan that ASCC expects to deliver to the government by the end of April, ASCC would focus on licensing key technologies developed by the center, such as Haylock and Susie Nilsson’s artificial niches for multiplying adult stem cells. ASCC would abandon attempts to commercialize a blood-cell product—the Holy Grail from its inception but a strategy that reviewers say was unattainable by 2011. Beyond July 2011, ASCC would cease conducting its own research. Instead, it would provide services such as stem cell cultivation and commercialization expertise, with an eye toward joining the ranks of 12 other national infrastructure facilities. Its 130 scientists, meanwhile, would stay with their home institutions and seek research funding from traditional sources. –ELIZABETH FINKEL
Elizabeth Finkel is a writer in Melbourne, Australia.

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Operation better mood. Doctors in Germany prepare to implant DBS electrodes in a man with severe depression.

cord—a far less invasive procedure—may have comparable benefits. Even less is known about how DBS might help people with psychiatric conditions, yet its use in this area is mushrooming: Last month, the U.S. Food and Drug Administration (FDA) approved DBS for treating severe, intractable cases of obsessive-compulsive disorder (OCD), and in the past year, two clinical trials for major depression were launched. All told, DBS is being used or investigated as a treatment for at least a dozen disorders. “The bionic age is here,” says Michael Okun, a neurologist and DBS researcher at the University of Florida in Gainesville. “Over the next 10 years, there’s going to be several hundred thousand people worldwide with these devices for all sorts of different disorders.” All this progress makes even some proponents of DBS slightly uneasy. Haunted by the frontal lobotomies and other horrors of early 20th century psychosurgery, they insist that rules be developed to ensure that the errors of the past are not repeated. Fortunately, knowledge of the brain, not to mention ethical standards, have improved considerably since then. Even so, many researchers and clinicians agree that DBS should be an option only when it’s backed by a strong scientific rationale and the fully informed consent of patients—not necessarily a trivial matter in those with severe mental disorders.

Rewiring Faulty Circuits in the Brain
A wide range of neuropsychiatric disorders seems to respond to deep brain stimulation—but how does it work, and where will it lead?
For some patients with severe movement disorders like Parkinson’s disease, years of struggle and frustration end with a flip of a switch that sends pulses of electric current through electrodes implanted deep inside the brain. Although it’s considered only as a last resort for patients who’ve failed to respond to less invasive treatments, deep brain stimulation (DBS) has helped more than 55,000 people suffering from Parkinson’s disease, essential tremor, or dystonia regain control of their bodies and their lives. But despite the many success stories, remarkably little is known about how DBS works. Two studies in rodent models of Parkinson’s disease published this week by Science provide some intriguing clues— and underscore how much remains to be figured out. One uses a sophisticated combination of genetic engineering and optics to investigate the mechanisms of DBS. The other suggests that stimulating the spinal
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Moving forward Parkinson’s disease affects the basal ganglia, a neural circuit deep in the brain that plays a crucial role in regulating movement. When dopamine-releasing neurons in one part of the basal ganglia die off, the circuit malfunctions, resulting in the disease’s hallmark tremor, rigidity, sluggish movement, and impaired balance. Drugs that restore dopamine help many patients but often stop working with time. The rationale for DBS grew out of studies with animal models of Parkinson’s disease that found that destroying certain nodes in the basal ganglia circuit reduced symptoms. Pulsing electrical current through thin wire electrodes placed in these brain regions had a similar effect, presumably by disrupting abnormal patterns of neural activity caused by the loss of dopamine. In people, DBS can reduce Parkinson’s symptoms for years. But the exact mechanism is unclear, and researchers don’t even agree on whether

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the benefits result from exciting or inhibitThe study demonstrates the power of optoing neurons near the electrode’s tip. genetics for dissecting the circuits involved in The answer may be neither, according to brain disorders, says Helen Mayberg, a neuwork reported online this week in Science rologist and DBS researcher at Emory Univer(www.sciencemag.org/cgi/content/abstract/ sity in Atlanta, Georgia. When Deisseroth pre1167093) by researchers at Stanford Univer- sented the work at psychiatry grand rounds at sity. Led by Viviana Gradinaru and Murtaza Emory a few weeks ago, Mayberg says, “peoMogri in the lab of Karl Deisseroth, the team ple sat there with their mouths open in total used exciting new “optogenetics” methods awe of the possibilities.” Mayberg and others (Science, 15 December 2006, p. 1674) to think it might eventually be possible to dissect the neural circuitry in a component develop optogenetics therapies for people. In of the basal ganglia that’s a principle, such treatments could common target for DBS therapy, maximize efficacy and minimize the subthalamic nucleus (STN). side effects, such as some of the The researchers injected viruses sciencemag.org mood and cognitive disturbances Podcast interview into the STN of rats and mice to in some Parkinson’s patients with with author introduce genes encoding light- Greg Miller. DBS—but only if the method, sensitive ion pumps and chanparticularly the genetic manipulanels originally found in archaebacteria and tion, proves safe to use in people. algae. When neurons produce these proteins In the meantime, a paper on page 1578 and stick them on their outer surface, their hints at the possibility of a simpler alternaactivity can be stimulated or inhibited— tive to DBS. Romulo Fuentes, Per Petersson, depending on the type used—by pulses of and Miguel Nicolelis of Duke University laser light delivered by an optical f iber and their colleagues report that stimulating inserted into the brain. By linking the pump electrodes placed on the surface of the spinal or channel genes to stretches of regulatory cord dramatically improved locomotion in DNA expressed only in certain cell types, mouse and rat models of Parkinson’s disthe researchers could target them to just ease. Nicolelis’s team also monitored neural those cells. This approach is, in effect, a activity in the basal ganglia and motor corsmarter form of DBS: Whereas the metal tex during spinal stimulation. These recordelectrodes used in DBS create an electrical ings suggested that spinal stimulation helps field that indiscriminately affects all nearby restore normal communication between cells, the laser affects only the targeted cells. these two brain regions by disrupting abnorIn one experiment, the researchers mal oscillations in neural firing caused by inserted light-activated chloride pumps into dopamine depletion. Nicolelis notes that the the primary type of excitatory neuron in the spinal electrodes stimulate fibers that conSTN. Pulses of laser light activated the vey tactile information to the brain, includpumps and squelched neural firing, enabling ing the motor cortex, and he speculates that the researchers to test the popular hypothesis this indirect stimulation of cortex somehow that turning off these neurons—and thereby breaks up the aberrant oscillations. dampening the overall level of neural activity in the STN—is the key to the therapeutic effect of DBS for Parkinson’s disease. That doesn’t appear to be the case. Turning off the excitatory STN neurons had no effect on movement abnormalities in Parkinsonian rats. Additional experiments failed to turn up evidence for a competing hypothesis: that DBS works by evoking rapid firing in the STN neurons, or for yet another proposal, that it works by activating nearby glial cells. Instead, Deisseroth and colleagues suspect that the key may be manipulating axons that carry signals into the STN from other areas, including the primary motor cortex, a movement-control region on the surface of the brain. When they optically stimulated cortical neurons whose axons extend down into the STN in Parkinsonian mice, symptoms diminished as much as they did with standard DBS. “If this were to be scalable to humans with Parkinson’s disease, it would be a major achievement,” says Andres Lozano, a neurosurgeon at Toronto Western Hospital in Canada. It’s a much simpler and potentially safer procedure than implanting DBS electrodes in the basal ganglia, he says. Both Science papers point to the cortex as an important player in the therapeutic effect of DBS for Parkinson’s disease, says Cameron McIntyre, a biomedical engineer at the Cleveland Clinic in Ohio. That idea has gotten relatively little attention because researchers interested in the mechanisms have focused on neurophysiological effects within the basal ganglia, McIntyre says. “We need to start understanding more about what’s happening at the cortical level,” he says. Mental stimulation For all the questions remaining about DBS and movement disorders, even less is known about why electrodes implanted in the brain help many patients with severe psychiatric illness. The first such condition to be treated experimentally by DBS was OCD. In a 1999 pilot study in The Lancet, Belgian and Swedish researchers reported encouraging results in three of four OCD patients achieved by implanting electrodes in the anterior limbs of the internal capsule, an axon bundle deep in the brain. Destroying this part of the brain had been shown to help people debilitated by severe cases of OCD, and the Belgian team reasoned that electrodes that disrupt neural activity might provide similar benefits without the finality of destroying brain tissue. Brain surgery may seem like an extreme intervention for OCD, but the worst cases are incredibly debilitating, says Wayne Goodman,
Enlightening. Researchers have used new optogenetics methods to shed light on the mechanisms of DBS for Parkinson’s disease.

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CREDIT: ALEX ARAVANIS AND KARL DEISSEROTH/STANFORD

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director of adult translational research at the studies, some patients reported elevated And in 2007, Lozano and colleagues National Institute of Mental Health (NIMH) mood, and a pilot study funded by described the curious case of a 50-year-old in Bethesda, Maryland, who helped develop Medtronic and published in February in Bio- man who’d received experimental electrode the clinical scale that’s used to assess the logical Psychiatry found that eight of 15 implants in his hypothalamus to try to treat severity of OCD symptoms. Among other patients with treatment-resistant depression morbid obesity. He didn’t lose weight, but in things, it considers the amount of time spent improved with DBS and four met the criteria the process of calibrating the electrodes, the on obsessive thoughts. “For the patients who for remission. The clinical trial will ulti- researchers discovered that certain stimulaare candidates for DBS, we’re talking more mately enroll 200 patients and, like the tion parameters evoked vivid memories from than 8 hours a day, and sometimes every St. Jude trial, will have a double-blind, the man’s youth and improved his performwaking minute being bombarded by placebo-controlled design in which some ance on memory tests. Lozano suspects that thoughts and being driven to perform rituals patients will not have the electrodes turned the memory-enhancing effect resulted from over and over,” Goodman says. “Their life is on immediately after implantation. the electrodes’proximity to the fornix, a bunconsumed by their illness.” More research is needed to see which dle of axons conveying signals to and from Approximately 50 such patients have DBS target is most effective for depression, the hippocampus, a crucial memory center. now received experimental DBS implants. or whether different targets might work better The serendipitous f inding prompted the Last year, researchers reviewed 26 cases in for different patients, says Thomas team to try a similar procedure in people with Molecular Psychiatry (Goodman and Okun Schlaepfer, a psychiatrist at the University of early stages of Alzheimer’s disease. They were among the 20 co-authors). All had tried Bonn in Germany. He and colleagues have have implanted electrodes in six people in multiple courses of medication and behav- been investigating a third target, the nucleus hopes of staving off additional memory ioral therapy without success. With DBS, accumbens, an integral part of the brain’s declines. “So far, we can tell you that it’s safe more than one-third of the patients went into reward circuitry. Until the advent of DBS, and it’s looking promising,” says Lozano, remission, and about two-thirds were living Schlaepfer says, psychiatrists had little to who plans to submit the findings for publicamore independently and functioning better offer patients with the most resistant forms of tion later this year, after all six patients have at school or work. Based largely on these depression and OCD beyond ever-changing had the implants for a full year. findings, in February 2009, the FDA granted combinations of drugs and ever-higher doses. In response to the growing interest in DBS device manufacturer Medtronic Inc. of “DBS is a new hope.” DBS, some researchers have called for Minneapolis, Minnesota, a humanitarian And not just for depression. Studies are guidelines to ensure that studies adhere to device exemption for chronic, severe OCD. under way to investigate its use for Tourette stringent ethical standards and employ This type of limited approval placebo controls, long-term folapplies to treatments for relalow up, and other experimental tively rare conditions, and it designs that maximize their scimarks the first approval of DBS entific value. In the checkered for a psychiatric condition in the history of early 20th century surUnited States. gical interventions for psychiA far larger patient population atric illness, informed consent that might benefit from DBS is and scientific rigor were often people suffering from major lacking, Goodman and NIMH depression. In a landmark 2005 Director Thomas Insel note in a Neuron paper, Mayberg, Lozano, February editorial in Biological and colleagues reported that elecPsychiatry. “The clinical and scitrodes implanted in the subcalentific community must assure losal cingulate gyrus and adjacent the public that the kind of miswhite matter caused remission in takes made before are not four of six patients who hadn’t repeated,” they wrote. responded to drugs, psychotherapy, Even if DBS is developed or electroconvulsive therapy. safely and ethically into a mainNeuroimaging studies indicate stream treatment, its very success that this region is hyperactive in might raise new quandaries. people with depression, and its Would people with implants for anatomical connections suggest it Shocking behavior. An x-ray image shows DBS electrodes implanted in a obesity or addiction have the is a hub in a network of brain patient with severe OCD. right to turn the stimulator off— regions involved in regulating and if so, would there be any emotion, Mayberg says. In 2008, she and her syndrome, epilepsy, and cluster headache, point to the treatment? Could violent crimicolleagues reported in Biological Psychiatry among other disorders. A smattering of case nals be given implants to inhibit aggression positive effects in 12 of 20 patients, and the studies published in recent years hint at addi- in exchange for reduced sentences? Should device manufacturer St. Jude Medical began tional possibilities. In 2006, for example, healthy people be allowed to receive a multicenter trial to test the treatment. researchers reported that electrodes implanted implants to boost their memory or other cogIn February, Medtronic announced it is in the thalamus partially restored some cogni- nitive faculties? If the bionic age is indeed starting its own trial to test DBS for depres- tive function in a minimally conscious man upon us, such questions may beg for answers sion, targeting the same region that proved with traumatic brain injury (sciencenow. sooner than we think. useful for treating OCD. In the initial OCD sciencemag.org/cgi/content/full/2006/1016/1). –GREG MILLER

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A mountain of data. John Stuckless (below) and the Yucca Mountain repository site.

more areas of geology than I would ever have attempted to learn had I not been on this program. We did everything, including climatology, seismology, and volcanology. It was a very broadening experience. Q: Was it worthwhile as a purely scientific exercise? J.S.: Yes. Maybe not at the cost that we ended up with. But certainly we advanced the knowledge of geology of the unsaturated zone—the region above the water table—by orders of magnitude. We learned a lot about paleoseismology. We learned a tremendous amount about paleoclimate in the region. It really kicked off a lot of interest in that area. We brought together paleontologists, chemists, geomorphologists. And I think we ended up with a much more complete picture than if these individuals had just been working on their own. Q: Can you think of another project like this? J.S.: No, I really can’t. There’s never been any reason to study any other point on the Earth to this degree. Q: One of your colleagues called Obama’s decision “a slap in the face to the energy and integrity of the scientists who have worked out there.” How do you feel? J.S.: I think it’s very irresponsible. What it basically says is, they have no faith in the people who did the work, and they have no faith in the Nuclear Regulatory Commission to make a good decision. I mean, if there is something wrong with the work, the NRC will find it. Decisions like that should be based on information, not on a gut feeling. The information we have is that there’s basically nothing wrong with that site, and you’re never going to find a better site. Q: Does it leave you with a sense of wasted effort? J.S.: No, because I’m moderately convinced that this is just a short-term hiccup in the road and that reason will prevail. But I don’t know how long it will take.

John Stuckless, a geochemist with the U.S. Geological Survey, spent 23 years probing the ancient history of Yucca Mountain, Nevada, and trying to predict its future. Working out of the survey’s Denver, Colorado, office, he helped lead a large-scale scientific effort, costing hundreds of millions of dollars, to determine whether the site could safely store highly radioactive waste from nuclear power plants for thousands of years. Last April, Stuckless, age 64, retired from the survey. Three months later, the Bush Administration formally applied for a license from the Nuclear Regulatory Commission to build a nuclear-waste repository at Yucca Mountain. Mission accomplished? Hardly. The long and expensive search for a suitable disposal site appears far from over. Nevada politicians have fought the repository ever since Congress chose Yucca Mountain in 1987 over alternatives in Texas and the state of Washington. Their hand was strengthened 2 years ago when the state’s senior senator, Democrat Har ry Reid, became majority leader. They also have the support of President Barack Obama. Declaring that storing nuclear waste at Yucca Mountain “is not an option,” the Administration’s budget request for 2010 cuts funding for the repository. Instead, officials are promising “a new strategy toward nuclear-waste disposal.” The last word on Yucca Mountain probably hasn’t been spoken. Many members of Congress still support the repository, and the Obama Administration has not withdrawn the government’s application for a license. Even so, Science wanted to know what it feels like to have the rug pulled out from under a quarter-century of scientific work. Here’s one man’s answer. –DAN CHARLES

Q: What brought you into the project? J.S.: It was the death of my wife. I had been working a lot internationally, and I had two small children. I wanted an assignment that didn’t require travel. Q: Was this considered a plum assignment, or was it something that people didn’t particularly want to work on? J.S.: That varied, depending with whom you spoke. A lot of the geologists did not like the idea of being directed in their research and [felt that the Department of Energy] really only wanted to know the favorable things. At least that was the perception. I don’t think it was actually true. Some of the people in the Geology Division weren’t very happy about working for DOE, so they moved the whole thing into Water Resources. The Water Resources people tended to take a lot of assignments working for others—whom they called “cooperators.” Q: Is that because hydrology was the key? J.S.: That’s not what drove it, but hydrology was really the main question that needed to be solved. Because if radioactive waste does move, it’ll be through water. But there also were scenarios involving major geologic things— volcanic eruptions and seismic activity. A lot of the research was driven by somebody’s belief that there was a problem. DOE would then direct us, or one of the national labs, to evaluate it. Q: Was it interesting work? J.S.: Yeah! I basically had to learn
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Twenty years after the Exxon Valdez oil spill, little remains in Prince William Sound to remind the eye of 1989’s striking images of oiled birds and sea otters, or of armies of workers in protective gear toiling to clean blackened beaches. Today, the waters of the sound are turquoise and the shorelines bristle with life, almost none of it human. But researchers are still studying the spill’s persistent aftereffects: Even as many species have recovered, others continue to struggle. Some may still come in contact with the oil that lingers, tucked away below the rocky surfaces of the beaches. Scientists—some of whom have studied the spill for the entire 2 decades and are now looking to retire—are taking stock of their results and working to determine how (and whether) they might encourage further recovery of the ecosystem. This month, the Exxon Valdez Oil Spill Trustee Council, which oversees research and restoration, released its summary report. “It’s not just research for the sake of research,” says Catherine Boerner, a restoration specialist with the Trustee Council. The science now looks squarely at how to manage the injured species, she says, such as by opening a fishery or culling predators. Before the incident, researchers had limited understanding of the long-term effects of a big spill. The Valdez studies are the largest, longest, and most expensive ever done. They suggest, for example, that oil

may persist much longer than expected, affecting intertidal organisms, and that chronic exposure to low levels of oil can inflict subtle damage on wildlife. Many of the hundreds of scientif ic reports are “incredibly influential papers” that “will be cited for a long time,” says marine chemist Christopher Reddy of Woods Hole Oceanographic Institution in Massachusetts, who did not work on the spill. Despite the mountain of studies, government-funded and Exxon-funded scientists still clash over the spill’s long-term effects and whether Exxon should pay the government an additional $92 million for yet more research. Government scientists say Exxon researchers don’t accept good evidence, while Exxon scientists charge bias, too. Government-funded studies tend to be “bleak and negative,” says Alan Maki, an environmental scientist who oversaw Exxon’s research until he retired in late 2007. “This spill has not behaved much differently than what you would expect from studies of other spills,” he says. Some questions provoke less rancor but still may never be answered, such as why the Pacific herring populations crashed. In part, because of the complexity of the ecosystem, “we’ll never know,” says Stanley Rice, who manages research on the oil spill at the National Oceanic and Atmospheric Administration’s (NOAA’s) Auke Bay Laboratories in Juneau.
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Aftermath of a disaster The spill occurred just after midnight on 24 March 1989, when the supertanker Exxon Valdez ran aground on Bligh Reef in Prince William Sound. Forty million liters of crude oil ended up in the sea and on the beaches, making it the largest spill in U.S. waters. The immediate impact was dramatic: About 250,000 sea birds died, along with 22 killer whales, 2800 sea otters, 300 harbor seals, and untold numbers of fish eggs. Scientists rushed to study the ongoing effects. Their efforts received a huge boost in 1991, when Exxon agreed to pay $900 million in a civil settlement with the U.S. and Alaskan governments to restore Prince William Sound. The Trustee Council has dedicated some $180 million to research, with the rest used to preserve land and reimburse cleanup expenses. The research efforts will continue indefinitely thanks to an endowment fund, currently about $100 million. The company now known as ExxonMobil has sponsored its own research, and the scientists it funds have published or presented more than 400 peer-reviewed papers and talks. Over the years, their conclusions have often clashed with those of the governmentfunded researchers. For example, one of the largest efforts has been to track the fate of the oil remaining in the sound years after the spill. In 2001, a team led by Jeffrey Short, a chemist then

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tons—and the fishery opened. But then in 1993, the population crashed: Only 20,000 tons of herring appeared. with NOAA, randomly sampled 91 beaches Was this due to the spill? Many scientists in the oiled parts of the sound, digging think not. A poor bloom of plankton in 1992 9000 pits. Short estimated that 55,000 liters left the fish hungry and vulnerable to disof oil remained, spread across and underneath ease, says fish pathologist Gary Marty of 11 hectares of beaches. the British Columbia Ministry of AgriculDavid Page, an Exxon-funded chemist at ture and Lands in Canada, who has been Bowdoin College in Brunswick, Maine, studying the herring since the spill. He and insisted, after conducting his own sampling, Terrance Quinn of the University of Alaska, that the government estimate was too high. Fairbanks, developed a model that he says Even though he later came to accept Short’s can “describe every blip in the population results, he and others still questioned for the past 15 years.” whether the lingering oil is affecting But Richard Thorne, an acoustics wildlife. They argue that other sources of researcher at the Prince William Sound hydrocarbon pollution outweigh what little Science Center, says hydroacoustic monitoroil remains from the 1989 spill. The remaining results suggest that the spill—and the ing oil, says Page, is sequestered. “If it were subsequent 3 years of f ishing—caused available to be harming wildlife, it would the population to crumble. In 1993, he have been long gone.” started conducting annual hydroacoustic Government researchers challenge those surveys, which use sonar to count fish. He claims. In 2005, Short’s team resampled 10 and Gary Thomas, a fisheries scientist at the of the beaches where oil University of Miami, noted that remained in 2001. They reported the acoustic results correlate in 2007 in Environmental Science well with aerial surveys of & Technology that the oil was herring spawn, which have been decaying at just 0% to 4% per done every year for more than year. “It will persist for decades 30 years, and suggest the decline up to a century,” says Short, who began in 1989. retired from NOAA a few months Unfortunately, most herring ago and now works for Oceana, a studies stopped after 1990, so marine conservation group. In neither side in this debate has another study reported last year in data about the critical precollapse Marine Environmental Research, years. As a result, researchers Short’s team found that biologimay never know for sure, says cally active contaminants in the George Rose, a fisheries conserregion were predominantly from vation expert at Memorial Unithe oil spill; he also thinks that versity in St. John’s, Canada. “In biomarkers such as a particular Swimming against the odds. One killer whale pod is slowly recovering from the a way, it doesn’t matter,” says liver enzyme reveal that organ- oil spill, but another is headed for extinction. NOAA’s Rice. “We need to know isms have been exposed to oil. why they don’t come back.” These conflicting claims have fiscal con- remain low in some heavily oiled areas That’s where $2 million of this year’s sequences: The 1991 settlement contained a where oil lingers in the intertidal zones. research has focused. With a better underso-called reopener clause allowing the gov- U.S. Geological Survey biologist James standing of factors such as disease, predators, ernment to claim up to $100 million more if Bodkin f itted 16 otters with time-depth and climate change, researchers hope to help by 2006 unanticipated damages from the recorders and reported in February at a the fish rebound. Ideas include establishing a spill appeared. That year, the government meeting of the Alaska Forum on the Envi- herring hatchery or targeted fishing for some asked Exxon for $92 million to f ind and ronment that shallow intertidal digging of the herring’s predators, like pollock. The remove the remaining oil, arguing that it was represented about 18% of female sea best thing for the fish may simply be to propersisting longer than expected. Both sides otters’ dives. “They’re going to get expo- tect them from fishing and other causes of have agreed to postpone negotiating the sure to oil,” says Rice. mortality, Rose says: “In rebuilding natural reopener until the government finishes more Most scientists do agree about the fate systems, the main ingredient is patience and oil studies, perhaps 2 years from now, says of at least one injured species: Pacific her- the other one is protection.” Patience indeed Craig O’Connor, a lawyer with NOAA. ring, whose populations are only 15% of is called for, many researchers agree. Two their prespill numbers. In the late 1980s decades may span most of a scientific career, A pod dwindles before the spill, the herring f ishery in but they hardly register in the transformation Scientists on both sides agree that many Prince William Sound was worth $12 mil- of an ecosystem. species have recovered in Prince William lion and the population was at a record –LILA GUTERMAN Sound, including bald eagles, cormorants, high. The year after the spill, the population Lila Guterman is a science writer in Washington, D.C. salmon, and river otters. But the oil, govern- seemed high again—estimated at 120,000 With reporting by Jacopo Pasotti.
Digging for oil. Oil rises from below the surface on a Prince William Sound beach.

ment scientists think, has had severe impacts on at least two photogenic animals: killer whales and sea otters. The two pods of whales photographed and identified in the oil slick in 1989 each lost about 40% of their members around the time of the spill, says Rice. “That is just totally unprecedented,” he says. One pod is recovering slowly, but the other, originally comprised of 22 whales, has lost all of its females of reproductive age and is down to seven or eight members. Eventually, Rice says, “they’re going to become extinct.” Because the two unrelated pods declined so suddenly and at the same time, researchers argued last year in Marine Ecology Progress Series, the deaths were almost certainly caused by the spill when the whales breathed oil fumes or ate contaminated prey. But Exxon scientists say the deaths can’t be conclusively linked to oil. Meanwhile, sea otters have rebounded in most of the sound, but populations

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COMMENTARY
Benefits from biodiversity Stem cell tourism

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LETTERS
edited by Jennifer Sills

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conceivable consequence, however unlikely, is accidental creation of a drug-resistant pandemic strain, a manmade analog of the feared naturally arising reassortant alluded to above. Most national stockpiles have appropriately favored neuraminidase inhibitors (mainly orally administered oseltamivir) over ionchannel blockers (oral adamantanes) for pandemic preparedness, given the wellrecognized rapid emergence of resistance to the latter when used in treatment (4). Now, as noted, transmissible oseltamivir resistance in human A/H1N1 strains makes this strategy problematic on many levels, including concern about efficacy in a pandemic, as well as emergence of a pandemic reassortant containing resistance genes (1). A complicating factor is increasing appreciation that secondary bacterial pneumonias have caused most deaths in past pandemics (5). Circulation of clinically aggressive community-acquired methicillin-resistant Staphylococcus aureus is an additional factor to be considered in planning for pandemic response. Taken together, these several developments suggest a need to continually examine and periodically reconfirm or update pandemic response strategies. Whatever strategies are adopted, it is clear that additional anti-influenza therapeutics are urgently needed. So far, vaccines and antivirals have targeted three influenza envelope proteins: hemagglutinin, neuraminidase, and the matrix 2 ion channel protein. We need new classes of antivirals that interfere with other necessary viral processes (e.g., polymerase complex activity, interferon antagonist activity, and viral assembly). The desired outcomes of existing and future therapies (reduced severity, mortality,

LETTERS I BOOKS I POLICY FORUM I EDUCATION FORUM I PERSPECTIVES

Pandemic Influenza: An Inconvenient Mutation
SEASONAL INFLUENZA AFFECTS 10% OF THE POPULATION ANNUALLY, KILLING UP TO ONE million persons worldwide. Pandemic viruses have even greater potential for mortality. We have several defenses, including personal and public health protective measures, vaccines immunologically matched to circulating strains, and two classes of antiviral drugs (neuraminidase inhibitors and adamantane ion-channel blockers). Our preventive options are limited by viral genetic diversity and a rapid viral mutation rate. Currently, two human influenza A subtypes (H1N1 and H3N2) and two influenza type B lineages cocirculate. About 425 million doses of trivalent influenza vaccine are produced annually, enough to protect less than 7% of the world’s population. In the event of a pandemic, well-matched protective vaccines against a novel agent would not be available for at least several months, highlighting the importance of therapeutic options. By 2009, however, 98% of circulating influenza A/H1N1 strains in North America have become resistant to the frequently prescribed and widely stockpiled neuraminidase inhibitor oseltamivir (Tamiflu), and 98% of A/H3N2 strains are resistant to the adamantanes. The alternative neuraminidase inhibitor zanamivir and the two approved adamantanes—amantadine and rimantadine—are all in short supply, and the adamantanes have substantial side effects. Influenza therapeutic options are clearly unraveling at a time when public health officials are appropriately concerned about pandemic emergence. The spread of high-level oseltamivir resistance in A/H1N1 strains is puzzling, as it appears to have occurred without antiviral selective pressure (1). Whether such levels of resistance will continue or diminish is unknown. Is high-level resistance an unfortunate byproduct of (still unknown) polygenic factors that confer viral fitness, such as balancing hemagglutinin and neuraminidase activity? Does resistance in influenza A/H1N1 imply a chance that resistance will develop in highly pathogenic avian A/H5N1 viruses, which bear the same neuraminidase subtype? Two past pandemic viruses (1957 and 1968) emerged after circulating human viruses reassorted with avian influenza viruses; emergence of a future pandemic strain by the same mechanism, but incorporating either an antiviralresistant H1N1 neuraminidase or A/H3N2 matrix gene, is a possibility that cannot be ignored. Pandemic planning envisions that if a virus with pandemic potential emerges, initial human-tohuman transmission can be spotted quickly and contained by nonpharmaceutical interventions and by rapid community administration of antiviral Preparing for a virus storm. agents and vaccines (2, 3). If this strategy fails, a

Letters to the Editor
Letters (~300 words) discuss material published in Science in the previous 3 months or issues of general interest. They can be submitted through the Web (www.submit2science.org) or by regular mail (1200 New York Ave., NW, Washington, DC 20005, USA). Letters are not acknowledged upon receipt, nor are authors generally consulted before publication. Whether published in full or in part, letters are subject to editing for clarity and space.

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Building in flexibility

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viral shedding, and transmission) should be considered with respect to both seasonal and pandemic influenza. The unpredictable nature of influenza presents a challenge for both research and pandemic preparedness planning. Our ability to anticipate pandemic events is poor, and our anti-pandemic armamentarium is weak. In an ever-shifting landscape of influenza evolution, we need to be farsighted and forceful in optimizing pandemic response capacity.
SCOTT P. LAYNE,1* ARNOLD S. MONTO,2 JEFFERY K. TAUBENBERGER3
1Department

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hold abroad is equivalent to the Romanian position immediately subordinate to the open position. The legal process to determine equivalency is cumbersome, and there is no definite authority who can certify equivalence. These ambiguous requirements often serve as an obstruction to expatriate scientists.
ZENO SIMON
Institute of Chemistry, Romanian Academy, Bd. Mihai Viteazul, 24, Timisoara 300223, Romania. E-mail: zsimon@ acad-icht.tm.edu.ro

of Epidemiology and Center for Rapid Influenza Surveillance and Research, University of California Los Angeles School of Public Health, Los Angeles, CA 90095, USA. 2Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA. 3Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. *To whom correspondence should be addressed. E-mail: scott.layne@ucla.edu

Reversible Exploration Not Worth the Cost
C. P. MCKAY (“BIOLOGICALLY REVERSIBLE exploration,” Policy Forum, 6 February, p. 718) makes an impassioned case for socalled biologically reversible exploration of Mars. However, such a strategy will impose additional costs on an already strained program (1), and it is neither feasible in the context of a robust Mars exploration program nor necessary to ensure the fidelity of future in situ scientific endeavors. The concept of biologically reversible exploration is focused on potential effects of forward contamination— the transport of terrestrial microorganisms to other planetary bodies. Using real options theory (2), we can evaluate the ability to preserve future decision paths (such as the ability to

“reverse” biological incursions) with present investments [such as spacecraft sterilization and constraints put in place on “special regions” (3)]. An accounting of present and future scientific costs and benefits must be made to critically assess this idea. In the near term, additional costs will result from spacecraft preparation regimes, compliance, and possibly reduced mission capability due to constraints on instrumentation and landing site restrictions. The suggestion that even human exploration should achieve “biological reversibility” will impose an enormous burden on such missions in terms of both direct costs and curtailed science from restrictions on access to the subsurface. In contrast, the supposed benefits are only potential benefits, mostly in the event of terraforming, and extremely long-term in nature. The exchange of meteorite material between Earth and Mars (4), the flotilla of existing landed missions, and the fleet of orbiters that will eventually crash into the surface already determine both the past and near-future two-way exchange of biological material between Earth and Mars. Special regions of scientific interest on Mars do call for prudent measures to reduce contamination, but the extreme measures advocated by McKay will not yield sufficient benefits to justify their high costs.
SAMUEL C. SCHON
Department of Geological Sciences, Brown University, Providence, RI 02912, USA. E-mail: samuel_schon@ brown.edu

References and Notes
1. N. J. Dharan et al., JAMA, 10.1001/jama.2009.294, published online 2 March 2009. 2. M. E. Halloran et al., Proc. Natl. Acad. Sci. U.S.A. 105, 4639 (2008). 3. A. S. Monto, Clin. Infect. Dis. 48, 397 (2009). 4. The United States has stockpiled 81 million doses of oseltamivir—one dose each for 25% of the population. 5. D. M. Morens, J. K. Taubenberger, A. S. Fauci, J. Infect. Dis. 198, 962 (2008). 6. This research was supported in part by the Intramural Research Program of the NIAID and the NIH.

References
1. A. Lawler, Science 322, 1618 (2008). 2. A. K. Dixit, R. S. Pindyck, Investment Under Uncertainty (Princeton Univ. Press, Princeton, NJ, 1994). 3. COSPAR, “Report on the 34th COSPAR Assembly,” COSPAR Inform. Bull. No. 156, 24 (April 2003). 4. B. J. Gladman, J. A. Burns, M. Duncan, P. Lee, H. F. Levison, Science 271, 1387 (1996).

Romanian Expatriates Face Career Obstacles
IN HIS NEWS FOCUS STORY “REACHING FOR the stars in Romania” (21 November 2008, p. 1183), M. Enserink gives a realistic description of some important problems of Romanian science. I would like to add another important issue: Successful expatriated Romanian scientists should be encouraged to return to Romania to hold important positions, and they should be appropriately compensated for doing so. In theory, expatriated scientists are encouraged to return and take leadership roles. In practice, these scientists have trouble securing their place in the applicant pool. To qualify for consideration, the expatriated scientists must demonstrate that the position they

CORRECTIONS AND CLARIFICATIONS
News of the Week: “NSF restores data on minority Ph.D.s” by J. Mervis (27 February, p. 1161). The National Science Foundation estimates that its new policy on reporting small numbers of minorities will suppress data on 3.7% of the new Ph.D.s in the Survey of Earned Doctorates. The original story incorrectly reported that 4% of the 280 subfields would be affected. News Focus: “Tales of a prehistoric human genome” by E. Pennisi (13 February, p. 866). The story mischaracterized James P. Noonan’s mouse experiment that used an enhancer showing human-specific activity. In that study (published in the 5 September 2008 issue of Science, p. 1346), the enhancer drove the expression of a reporter gene in the mice, but the researchers did not examine its effect on thumb development. News Focus: “On the origin of art and symbolism” by M. Balter (6 February, p. 709). Ochre expert Ian Watts was cited as saying that there was little sign that ochre found at Twin Rivers, Zambia, was ground into powder, as needed for decoration. This incorrectly states Watts’s view. Although only a small percentage of the approximately 300 pieces of ochre found at Twin Rivers show signs of grinding or other use, nearly all those that do are a dark, sparkly red. This leads Watts to conclude that they might have been preferentially chosen for symbolic purposes, although that is not certain. Reviews: “Darwin’s originality” by P. J. Bowler (9 January, p. 223). On page 226, reference 8 should read as follows: J. Browne, Charles Darwin: The Power of Place (Jonathan Cape, London, 2002). In reference 22, Transmutation Notebook D should have been Notebook B. Also in reference 22, two page numbers were missing: Natural Selection, p. 36, and Charles Darwin’s Notebooks, p. 180. Reports: “Observation of pulsed γ-rays above 25 GeV from the Crab pulsar with MAGIC” by The MAGIC Collaboration (21 November 2008, p. 1221). The e-mail address for N. Otte was incorrect. The correct address is nepomuk@scipp.ucsc.edu.

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species and how their activities contribute to ecosystems processes that influence water, air, and soil quality; erosion; climate change; and relative abundances of environmental toxins and human pathogens. David P. Mindell For example, studies following the 2004 Southeast Asian Sustaining Life he intimate connection between nature than 10% of the species on the tsunami illustrate the lifeHow Human Health and human survival is indistinct for planet have been described, saving value of healthy manDepends on Biodiversity many people, especially the most afflu- and our knowledge of the grove forests, plant-covered Eric Chivian and ent and intensive users of natural resources. The ecosystem functions for the sand dunes, and substantial Aaron Bernstein, Eds. good news is that the notion of “living sustain- fraction of species that we do coral reefs in reducing the ably” seems to be gaining cachet and even a few recognize is inadequate. These force of storm waves and their Oxford University Press, New York, 2008. 566 pp. adherents. The big challenge lies in moving nontrivial functions include devastation in densely popu$34.95, ?18.99. beyond the blandishments of greenwashing to decomposition of waste, cycllated coastal areas. Habitat ISBN 9780195175097. develop well-informed social, economic, and ing of vital nutrients, and mainchanges associated with deforenvironmental policies—the three pillars of tenance of healthy water, air, estation, agricultural developsustainability practice—to manage natural and soils. ment, climate change, and urbanization can resource use and economic development. At the same time, the number of known increase diseases transmitted to people by Facts linking fossil fuel consumption with species considered to be threatened with displaced or redirected animal vectors. climate change are now well established, and extinction is increasing across nearly all tax- Archaea in the tongue-twisting families onomic groups that have been eval- Methylococcaceae, Methylocystaceae, and uated, including roughly 12% of all Verrucomicrobiae break down the potent bird species, 20% of all mammals, greenhouse gas methane, thus influencing and a third of our fellow primates local and regional climates. Some also detox(1). Only two plant phyla have been ify chlorinated hydrocarbons, whether natuassessed in this regard, conifers rally occurring or from the pesticides widely (25% threatened) and cycads used in agriculture and malaria control. Our (52%). The diversity of micro- digestive tracts are home to thousands of difscopic life forms (including viruses, ferent kinds of archaea, bacteria, viruses, archaea, bacteria, and small euka- fungi, and microeukaryotes. Although we are rya) are only recently coming to mostly ignorant of their functions and taxlight, and their varieties, abilities, onomies, the services of a few are known— distributions, ecosystem functions, e.g., Bacteroides thetaiotaomicron helps us and conservation status are even digest starch and cellulose from plants, promore poorly known. These micro- duces antimicrobial compounds (hydrogen scopic forms are important in all peroxide, bacteriocins) that reduce bodily the nontrivial ways mentioned infections, and stimulates blood vessel above, as well as in a broad range of growth necessary for nutrient absorption. symbiotic relationships critical to Going beyond the usual observation that human health and disease. the majority of prescribed medicines in the In a comprehensive and com- United States and as much as 80% of all For the want of bees. The extinction of bees in Maoxian County, pelling fashion, Sustaining Life, medicines used in developing nations are China, has forced people to pollinate apple trees by hand. edited by Eric Chivian and Aaron derived from organismal species, the authors development of alternative energy sources is Bernstein (physicians at Harvard University’s offer valuable discussions of particular at least under way. But the links between loss Center for Health and the Global Environ- groups of medicines, existing or in developof species diversity in nature and the health of ment), makes the case that the maintenance of ment, and their original sources. These human populations are less well understood. biological diversity and human well-being are include: painkillers from poppies (Papaver), Unlike fluctuating oil prices, declining deeply entwined. Contributors synthesize cone snails (Conus), and frogs (Dendrobates species populations or outright extinctions do efforts to circumscribe biological diversity and and Epipedobates); anticancer medicines not have immediate, tangible impact on the current threats to it and to reveal biodiversity’s from sea squirts (Didemnidae), bryozoans cost of travel, food, or heat. Of course there many functional roles in supporting healthy (Bugula), sponges (Discodermia and Luffarare, and will be, substantial impacts from environments, in drug development and iella), and diverse plants (e.g., Artemisia and species loss, although our understanding of biomedical research, and in understanding Tabebuia); and antiviral drugs from red algae them is rudimentary. Handicapping our infectious diseases and best practices for agri- (Gigartina and Kappaphycus) and sea efforts, we still don’t have a detailed inventory culture. Well researched and with stunning cucumbers (Holothuroidea). People sufferof Earth’s organismal diversity. Probably less graphics, the volume could serve admirably as ing from obesity could benefit from appetite a college text or recommended reading for suppressants modeled after aminosterols in politicians, health and resource managers, and dogfish sharks. After more than a decade of The reviewer is at the California Academy of Sciences, 55 citizens at large. The authors place a primary intense focus on combinatorial chemistry for Music Concourse Drive, Golden Gate Park, San Francisco, focus on particular species or groups of drug development, it is clear that organisms, CA 94118, USA. E-mail: dmindell@calacademy.org
ENVIRONMENT AND HEALTH

Humans Need Biodiversity

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CREDIT: FAROOQ AHMAD AND UMA PARTAP/INTERNATIONAL CENTRE FOR INTEGRATED MOUNTAIN DEVELOPMENT, NEPAL

BOOKS ETAL.
having passed the tests of evolutionary time, still provide the best leads for compounds with medicinal value. Our continuing dependence on organismal diversity within healthy ecosystems is clear. However, much more research and funding are needed to characterize all the species involved and to discover their complex interactions, impacts on humans, and responses to change. Further, raising public awareness and the political will to sustain biological diversity over time will require more than just science. We also need advocacy (which Sustaining Life ably serves) and greater legal and ethical commitments to conservation practices. Perhaps shining a bright light on the tight connections between sustainability practices and human survival could make conservation not only a practical concern but an ethical and moral one as well. do this century. Although it may seem obvious, we are rightly reminded that we should leave enough space for wild fauna and flora and put an end to uncontrolled hunting, logging, and resource extraction. A species gone is lost forever, and from mammoths to dodos we have a very, very bad track record. The same concerns for conservation apply to our atmosphere. Let us make our response to the ozone hole a benchmark for future policy: recognize the danger, adopt world measures, and avoid disaster. Easier said than done, of course. And if we succeed in checking anthropogenic CO2 production fairly soon, another ice age would be expected in about 50,000 years. Alternatively, should the climate become inhospitable, would we leave Earth? And, if we decide to go, where to? Mars and Venus are close, but, as Bonnet and Woltjer (who should know) explain, to terraform them is not a realistic solution. To venture further aboard some autonomous but frighteningly lonesome Noah’s Ark moving close to the speed of light remains, at least for the moment, a figment of science fiction. So far, humans have only gone one light-second away and have yet to invent something substantially better than the Semyorka rocket that put Sputnik in orbit. While we don’t have the technology to emigrate, near-Earth, integrated space activities will have to be fully implemented if we are to manage our planet’s future through monitoring and husbanding energy and inorganic resources as well as water and organic resources. To find food for 11 billion people (the value at which the world population will stabilize) should be possible, we are told, even if we’ll all be 3 meters tall and live to 130 years. Energy too shouldn’t be an insurmountable problem, because we will have harnessed nuclear fusion. Inevitably, we will have installed a global governance, “an awful term but a vital concept,” according to Javier Solana, Secretary General of the Council of the European Union. One must be brave to predict the future. The physicist Charles Galton Darwin (grandson of Charles) offered a qualitative and sociological forecast of our world a million years on (1)—holding that forecasts for short timescales were difficult because of potential fluctuations introduced by individual events. Hats off to Bonnet and Woltjer, who manage to stay an order of magnitude closer to the present while being quantitative and learned yet amusing and daring.
References
1. C. G. Darwin, The Next Million Years (Hart-Davis, London, 1952). 10.1126/science.1172131

Must avoid falling rocks. The near-Earth asteroid Itokawa as observed in 2005 by the Japanese Hayabusa spacecraft.

approximately, of life here. So the authors remind us at the beginning, in an illuminating crash course on the early history of Earth. References They discuss why it ended up the way it did: 1. www.iucnredlist.org/documents/2008RL_stats_table_ 1_v1223294385.pdf. very different from Mars and Venus, siblings born from the same protoplanetary disc 10.1126/science.1170526 around the same star but now either too hot or too cold, with too much atmosphere or not enough. Without a knowledge of Earth’s hisFUTUROLOGY tory, we would be ignorant about its future. That history has largely been shaped by Earth’s oceans. They were a gift from heaven, rained down on the young planet in the form of watery cosmic debris (interstellar ice that might have carried who knows what else). Giovanni F. Bignami Teeming with life, the oceans rid Earth of all ouldn’t it be interesting to know that CO2 in its ur-atmosphere, in the process what our ancestors 100 millennia making the Great Barrier Reef, the Dolomites, ago thought would be happening and Carrara marble (which sat patiently waitabout now? We can’t, but Surviving 1,000 ing for Michelangelo). Centuries may be the next best Of course, humanity’s thing. Roger-Maurice Bonnet future could all end Surviving 1,000 Centuries (International Space Science Inabruptly, as did that of the Can We Do It? stitute, Bern) and Lodewijk Woltjer dinosaurs. We are fragile by Roger-Maurice Bonnet (Observatoire de Haute Provence), and can easily be wiped and Lodewijk Woltjer two of the top astronomers in out by various cosmic Europe, have the courage, intellicatastrophes, from local Springer, Berlin, in association with Praxis, Chichester, gence, and culture to describe supernovae to impacting UK, 2008. 442 pp. $39.95, ?20. what the circumstances will be asteroids to toxic volcaISBN 9780387746333. like on Earth circa 102,000 CE. noes. (Personally, I vote One can look at this fascinating for a nearby gamma-ray book as a mid-term report for the course burst: think how more elegant it would be to “Civilization 101.” Read it, and you will have go in a puff of gamma rays than to be done in a much better idea as to whether we will pass by a rock falling from the sky.) Chances of that the final exam and survive. happening in 105 years may add up, but in our A thousand centuries sounds like a lot of lifetime they are tiny—about the same as time, but it’s only about one-fifty-thousandth being eaten by a shark, averaged over the of the age of our beloved planet and also, world population. In any event, life itself is very tough. Come what may, some bug is likely to hang on and be ready to start it all The reviewer is at the Istituto Universitario di Studi over again as soon as the skies clear. Superiori, Viale Lungo Ticino Sforza 56, 27100 Pavia, Italy, As to what our planet and its biosphere will and the Accademia dei Lincei, Rome, Italy. E-mail: come to look like, a lot will depend on what we giovanni.bignami@gmail.com

A Crystal Ball for Our Blue Planet

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CREDIT: JAPAN AEROSPACE EXPLORATION AGENCY

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MEDICINE

Monitoring and Regulating Offshore Stem Cell Clinics
Sorapop Kiatpongsan1,2,3 and Douglas Sipp4,5*

Unverified medical treatments based on stem cells are proliferating and need oversight.

1Department

of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand 10330. 2Vincent Center for Reproductive Biology, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02114, USA. 3Science, Technology and Globalization Project/Science, Technology and Public Policy Program, Belfer Center for Science and International Affairs, John F. Kennedy School of Government, Harvard University, Cambridge, MA 02138, USA. 4RIKEN Center for Developmental Biology, Kobe, 6500047, Japan. 5Center for iPS Research and Application, Institute for Integrated Cell-Materials Sciences, Kyoto University, Kyoto, 606-8501, Japan. *Author for correspondence. E-mail: sipp@cdb.riken.jp

meant to countries not known as leaders in biomedical research (e.g., despite more than 30 years of legal actions in the United States against purveyors of laetrile, a discredited cancer remedy, it remains readily available in places such as Mexico and the Bahamas). The debate over human embryonic stem cell research in the United States under the George W. Bush administration not only opened the door to increased investment into stem cell research and its applications by Asian countries (5–7), but may have also distracted regulatory attention from the growing problem of unsubstantiated therapeutic claims involving adult stem cells. Nonetheless, several stem cell clinics have been closed by law enforcement or regulatory agencies in the United States (8), the
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raveling to another country in the hope of finding a stem cell–based treatment for a disease—“stem cell tourism”—has been the object of intense scrutiny in recent years, following reports of charlatanry, baseless claims, and adverse medical events (1). Providers of stem cell–based interventions vary widely in their assertions about the conditions that can be treated, the degree of improvement, and the cell types and protocols used (2), but there are many advertisements for medical procedures that have never been proven efficacious in appropriately designed clinical trials. To date, proven therapeutic applications for stem cells have been mainly for blood and immunological disorders. The scientific community and advocacy groups have begun to respond by formulating guidelines for physicians and scientists engaged in the clinical translation of stem cell research (3) and lists of questions for prospective patients to ask when considering an experimental stem cell treatment (3, 4). Inaction and occasional complicity on the part of the government and medical establishment in some countries, however, have made enforcement, selfpolicing, and the maintenance of patient trust problematic. Controversies involving unverified medical treatments are not a new thing, but the adoption of protective laws and their vigorous enforcement has enabled many countries, including the United States, to rein in claims

T

that can legally be made by providers or to relegate them to operating outside of their borders. The possibility of operating extraterritorially has meant that unapproved treatments could be had by those willing to travel abroad, but in the great majority of instances, this has

Netherlands (9), and Ireland (10); others have been forced out of business (11) or prevented from opening by negative publicity (12, 13). Successful clinics that remain in business are sometimes supported by local medical associations, governments, and regulatory agencies. Although the company Web sites suggest an awareness of the need for clinical trials, treatments costing $20,000 or more are being offered in the absence of prior publication of peer-reviewed studies demonstrating efficacy. For example, TheraVitae has an impressive list of Thai physicians, including the current presidents of the Thai Heart Association and the Thai Atherosclerosis Society (14), and recognition from the Davos-based World Economic Forum as a 2006 Technology Pioneer (15). However, the peerreviewed article listed by the company as “accreditation” for its therapeutic regime of adult stem cell therapy for heart disease was considered by the authors to be a safety study and did not use randomization or double-blind controls (16, 17). Perhaps as important as the government and medical establishment links are the marketing and patient recruitment strategies used by these companies. A number of companies, such as NuTech Mediworld, a human embryonic stem cell clinic, and Medra, Inc. (www.medra.com/), which uses human fetal cells, have enjoyed publicity in the form of published interviews, blogs, or YouTube videos describing subjective patient experiences following treatment (18, 19). TheraVitae, and its associated companies VesCell (www.vescell.com/) and Regenocyte (www.regenocyte.com/), use online patient testimonials (14), blogging activity (20), and patient recruitment seminars held within the United States (21). Beike Biotechnology and other China-based treatment centers have a vocal proponent in the China Stem Cells News’ Web site (www.stemcellschina.com/), which serves as an online portal highlighting

POLICYFORUM
news and treatment experiences from local and foreign patients. The site lists dozens of subjective accounts of “successful” (typically defined as “some improvement”) outcomes in people suffering conditions including autism, epilepsy, and stroke and includes a contact form for those with treatment inquiries. Major research nations have also seen the appearance of stem cell clinics and therapeutics companies. Companies in Japan advertise stem cell–based treatments for conditions such as diabetes, Alzheimer’s disease, and spinal cord injury (22–25). The X-cell Center (www.xcellcenter.com/) in Cologne, Germany, offers to treat ailments ranging from erectile dysfunction to amyotrophic lateral sclerosis (ALS). Adult stem cells as a treatment modality have been championed with particular fervor by numerous groups in the United States, which commonly cite lists of many conditions that have been treated with adult cells (26, 27). Such catalogs may introduce doubts and misunderstandings about the current state of the science. Companies such as Medra, Stemedica (www.stemedica.com/), Stem Cell Biotherapy (www.stemcellbiotherapy.com/cn/index.php/ lang/en), and Regenocyte have taken advantage of the resulting confusion and have occupied the current international regulatory vacuum. For example, Stem Cell Biotherapy and Regenocyte advertise procedures unavailable in the United States and arrange for patients to be sent to affiliated hospitals in other parts of the world. Of these, Medra became particularly notorious for the extraordinary claims made by its founder, psychiatrist William Rader, who has refused to share information on cell lines and techniques he claims can be used for treatment of conditions including spinal cord injury and Down syndrome (28). There are several effective measures to prevent companies from going too far in their business practices. In the United States, the Food and Drug Administration provides clear rules governing the purity, potency, and quality of medical products (including stem cells) (29); the Federal Trade Commission oversees truth in advertising (30). Similar laws and authorities are in place in the European Union, and Thailand is now making moves to regulate stem cell therapies more tightly. A committee convened by the Thai Medical Council, which governs practice by licensed physicians, has drafted recommendations that call for stricter oversight of procedures involving stem cells in conditions other than blood disorders (31). These only came following a period of confusion as stem cells were seen as neither drug nor typical medical treatment, which put them for a time outside the purview of both the medical and drugregulatory authorities. Such researcher-led efforts are to be encouraged and promulgated to regulatory agencies in other Asian countries as effective means of protecting patients as well as the national reputation. Media reports can also play an important role. An L.A. Times feature on Biomark International (32) raised public doubts about the company. A series of BBC documentaries revealed a trade in which human fetuses from the Ukraine were sold to stem cell tourism clinics in the Caribbean, which resulted in the closing of at least one major clinic, the Institute for Regenerative Medicine in Barbados, owing to loss of its clients (11). To ensure the truly global dissemination of guidelines and patient information regarding stem cell–based clinical applications, the international research community, represented by organizations such as the International Society for Stem Cell Research, could provide local language translations or summaries of relevant documents and could use their members to distribute them to the press and government authorities. The World Health Organization could also contribute by releasing a consensus position on the clinical application of stem cell research. Patient advocacy groups have begun to compile useful resources of physicians and hospitals offering stem cell procedures for conditions such as ALS (33). Although these serve only as anecdotal evidence, they tend to offer more balanced accounts, citing both positive and negative experiences, and may help to flag especially flagrant violators of patient trust. Stem cell and regenerative medicine research organizations might likewise consider steps toward identifying and dealing with members who have commercialized unproven treatments prematurely. Educational alliances between basic research, clinical, and patients groups, such as the Coalition for the Advancement of Medical Research, might prove to be an effective measure against the more egregious claims. To ensure that the potential of stem cell research has the chance to develop unhampered by tragedy or fraud, members of the research community must work together to lobby their own local authorities to put proper regulations in place and must accept as their duty following the hard road to the truth, not the most expedient or profitable one. Given the current limits of international law and scientific diplomacy, a global ban on unapproved treatments seems unlikely to succeed, so for now, each government must take great care when granting funds and recognition to programs that fall short of ethical or professional standards. And ultimately, those who look to stem cells with hope for cures must also share
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in the obligation to protect this nascent field by becoming not only patient advocates, but also advocates of patience.
References and Notes
1. N. Amariglio et al., PLoS Med. 6, e29 (2009). 2. D. Lau et al., Cell Stem Cell 3, 591 (2008). 3. International Society for Stem Cell Research, Guidelines for the Clinical Translation of Stem Cells (ISSCR, Deerfield, IL, 4 December 2008); www.isscr.org/ clinical%5Ftrans/. 4. Juvenile Diabetes Research Foundation International, Participating in a Clinical Trial; www.jdrf.org/index. cfm?fuseaction=home.viewPage&page_id= 91EC2BF7-1321-C844-134D2E25FB931863. 5. B. Einhorn, J. Veale, M. Kripalani, Business Week, 10 January 2005, p. 34; www.businessweek.com/magazine/ content/05_02/b3915052.htm. 6. J. Du et al., Stem Cell Mission to China, Singapore and South Korea (for the U.K. Department of Trade and Industry, Pera Innovation, London, 2005); www.oti. globalwatchonline.com/online_pdfs/36206MR.pdf. 7. D. Sipp, Stem Cell Report 2, 62 (2007). 8. M. Enserink, Science 313, 160 (2006). 9. The Netherlands Health Care Inspectorate, Utrecht, 3 October 2006; www.igz.nl/uk/files/379598. 10. S. Boseley, Guardian, 1 May 2006; www.guardian.co.uk/ society/2006/may/01/health.medicineandhealth. 11. S. Price, Nation News (Barbados), 26 November 2007; http://web.archive.org/web/20080128173958/http://www. nationnews.com/story/315095110731643.php. 12. “Stem cell firm drops Bermuda from website,” Royal Gazette, 18 August 2008; www.theroyalgazette.com/ siftology.royalgazette/Article/article.jsp?sectionId=60&ar ticleId=7d8893730030003. 13. M. Ebbin, Bermuda Sun, 14 September 2007; www. bermudasun.bm/main.asp?SectionID=24&SubSectionID= 270&ArticleID=34993. 14. TheraVitae, www.vescell.com/stem-cells-treatingphysicians.php. 15. World Economic Forum, www.weforum.org/en/ Communities/Technology%20Pioneers/SelectedTechPion eers/2006TechPioneers/index.htm. 16. Y. Porat et al., Br. J. Haematol. 135, 703 (2006). 17. K. V. Arom, P. Ruengsakulrach, V. Jotisakulratana, Asian Cardiovasc. Thorac. Ann. 16, 143 (2008). 18. A. Boxtel, http://amandaboxtel.wordpress.com/. 19. R. Kilgore, http://jp.youtube.com/ watch?v=kbozmOL1kSY. 20. J. Steele, VesCell Adult Stem Cell Therapy Blog, 19 December 2007; http://stem-cell-therapy.blogspot.com/ 2007/12/new-adult-stem-cell-blog.html. 21. Regenocyte, http://stem-cell-therapy.blogspot.com. 22. Elixcell, www.elixcell.com/. 23. Rejuvacell, http://rejuvacell-inc.com/Our%20Group.htm. 24. Stem Cell Sciences, www.stemcellsciences.com/. 25. Nichi-In Center for Regenerative Medicine, www.nichiin.org/. 26. D. Prentice, in Monitoring Stem Cell Research: A Report of the President’s Council on Bioethics (President’s Council on Bioethics, Washington, DC, 2004), Appendix K. 27. Repair Stem Cell Institute, www.repairstemcells.org/ DiseaseTreated.php. 28. D. Ono, KABC-TV news, Los Angeles, 2007; http://abclocal. go.com/kabc/story?section=news/local&id=5283114. 29. D. G. Halme, D. A. Kessler, N. Engl. J. Med. 355, 1730 (2006). 30. U.S. Federal Trade Commission, Frequently Asked Advertising Questions: A Guide for Small Businesses; www.ftc.gov/bcp/edu/pubs/business/adv/bus35.shtm. 31. Editorial, Bangkok Post, 22 June 2008; www.bangkokpost. com/220608_Perspective/22Jun2008_pers007.php. 32. A. Zarembo, Los Angeles Times, 20 February 2005; www.latimes.com/features/health/medicine/lasci-stemcells20feb20,1,3062179,full.story. 33. S. Byer, B. Byer, ALS Worldwide, Madison, WI; www.alsworldwide.net. 10.1126/science.1168451

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MATERIALS SCIENCE

Flexible Electronics
Byron D. Gates

Inkjet printing of metal wires yields bendable electrical connections for use in flexible electronic devices.

rganic polymers are the main com- and the drying time of the solvents. They then increases the density of features in the ponents of most flexible electronic extruded the ink through a nozzle that directed device. Although inkjet printing is a serial devices. These devices rely on the the selective deposition of silver particles onto process, Ahn et al. have demonstrated a compliant physical properties of organic poly- the flexible substrate. After annealing at wide range of benefits for this technology. mers to maintain electrical continuity when 250°C for ≤30 min, the printed wires exhibFlexible electronic devices compete with deformed. Electrical connections within these ited an electrical resistivity nearing that of paper-based media as well as existing elecdevices are a point of weakness and have lim- bulk silver. Annealing can also be done using tronic media. It is desirable to find a technolited the types of materials and processes that light or microwaves (9, 10). The resistivity of ogy platform that can be rolled or bent (as with can be used. Although inorganic semiconduc- the printed silver wires is about two orders of paper), yet robust enough to be unfurled and tors and metals have high conductivity, these magnitude lower than that of commonly used reused. The end use of the device will depend materials will not commonly sustain repeated conductive organic polymers (1). This im- on the functions incorporated into its architecbending or stretching. On page 1590 of this provement translates into lower power con- ture. Ahn et al. demonstrate a few features that issue, Ahn et al. (1) show how metal can be sumption and a lower heat load on the sur- might be desirable in a flexible device, includadded to components within flexible elec- rounding environment for devices incorporat- ing optical and optoelectronic components tronic devices, enabling conductivity to be ing these printed wires. such as light-emitting diodes (LEDs) and solar maintained even after repeated deformation. Controlling the deposition of the colloidal cells. Tuning the optical properties of a flexible Connections between electronic structures silver ink is essential for fabricating free- device is widely recognized as necessary, with have traditionally been designed with a planar standing wires that have both 2D and 3D com- research efforts directed toward both emissive architecture that is patterned through multiple ponents. The electrical connections demon- and reflective properties (2, 3, 11). Other applifabrication steps (2, 3). Much of the fabrication strated by Ahn et al. include springs and struc- cations of flexible device technology include technology used in flexible tures with built-in slack to accommodate the radio frequency identification (RFID) tags and electronics was initially stretching and bending of a flexible antennas that can be incorporated into perborrowed from existing device. The ability to form arched sonal identification, as well as packaging and Silver colloidal ink device fabrication platfeatures is also essential for other forms of transferable media. forms, such as those used avoiding direct contact when Traditional forms of print media, such as Inkjet printer nozzle to manufacture siliconone electrical connection newspapers and books, have been prevalent in based thin-film transistors. crosses over another. human lives for centuries. We have greatly Direct write process These techniques largely The authors further de- benefited from the ease with which informadepend on the selective liftoff monstrate the control pro- tion can be efficiently distributed in print or etching of materials, using vided by their technique media. Entire industries have been created Ag wire process conditions that are not always compatible with organic LED or solar cell polymers. Process techniques developed for the fabrication of flexible electronic devices must avoid large changes in temperature and pressure. These techniques must also minimize exposure to reagents that may degrade the conductivity, purity, or form of the organic polymer components in the device. Flexible material Compression of flexible material Inkjet printing has been used to pattern organic semiconductors (4), metal contacts on Flexible electrical metal connections. Wires connecting components within a flexible device can be fabriorganic semiconductors (5–7), and metallic cated by a direct-write process using inkjet printing of silver nanoparticles. As shown by Ahn et al., the techstructures (8) that require minimal further nique can be used to fabricate three-dimensional connections that span between components of a flexible processing. Ahn et al. have now used inkjet device and that flex when the device is deformed. printing to create three-dimensional (3D) metallic connections between functional com- by reporting silver wires with width-to- around the printing, distribution, and storage ponents of flexible devices (see the figure). length ratios up to 1:1000. These wires can of paper articles. Overcoming our dependence The authors first fine-tuned a colloidal ink of span gaps up to 1 cm wide. The narrow on paper will require its replacement with a techsilver nanoparticles by adjusting the unifor- dimensions of the printed wires (from ~2 to nology that is comparable to paper in its mity of the particles, the viscosity of the ink, ~10 ?m) are an additional benefit of this weight, flexibility, and ease of use. Key technolfabrication process. These small dimensions ogies are necessary to enable the manufacture minimize the footprint of the electrical con- of such an alternative form of media. The Department of Chemistry, Simon Fraser University, tact lines, which decreases the impact of the work of Ahn et al. is a transition from typical Burnaby, British Columbia V5A 1S6, Canada. E-mail: bgates@sfu.ca wires on the optical quality of the device and models of fabrication, providing possibilities

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for incorporating multiple functions into a single flexible device. Flexible electronic devices are becoming commonplace in our lives. Screens that can flex or otherwise distort have been incorporated into laptops, televisions, and mobile phones. Lightweight electronic display devices that can be rolled up for storage are being developed. The achievement of completely converting to a paperless society will be revolutionary in itself, but so are the technological advances necessary to make this new form of media commonplace in our daily lives.
References
1. B. Y. Ahn et al., Science 323, 1590 (2009); published online 12 February 2009 (10.1126/science.1168375). 2. S. R. Forrest, Nature 428, 911 (2004). 3. E. Menard et al., Chem. Rev. 107, 1117 (2007). 4. H. Sirringhaus et al., Science 290, 2123 (2000). 5. Y. Nogucki, T. Sekitani, T. Yokota, T. Someya, Appl. Phys. Lett. 93, 043303 (2008). 6. D. Kim, S. Jeong, H. Shin, Y. Xia, J. Moon, Adv. Mater. 20, 3084 (2008). 7. S. Gamerith et al., Adv. Funct. Mater. 17, 3111 (2007). 8. J. E. Smay, J. Cesarano III, J. A. Lewis, Langmuir 18, 5429 (2002). 9. J. Yun et al., Jpn. J. Appl. Phys. 47, 5070 (2008). 10. J. Perelaer, B.-J. de Gans, U. S. Schubert, Adv. Mater. 18, 2101 (2006). 11. B. Comiskey, J. D. Albert, H. Yoshizawa, J. Jacobson, Nature 394, 253 (1998).

10.1126/science.1171230

IMMUNOLOGY

Two-in-One Designer Antibodies
Paul W. H. I. Parren1 and Dennis R. Burton2

An antibody is engineered to recognize two different proteins with high affinity, opening the door to improved combination therapies for cancers and infections.

CREDIT: JOOST BAKKER/GENMAB BV

ancer and certain infectious diseases such as HIV-1/AIDS that are characterized by genetic heterogeneity are often difficult to treat with a single therapeutic agent. Combination therapies that target multiple disease-associated molecules are therefore widely deployed. For example, mixtures of antibodies are being tested for clinical use, despite high development, manufacturing, and treatment costs. The requirement for multiple antibodies is based on the prevailing one antibody-one antigen dogma. On page 1610 in this issue, Bostrom et al. (1) overthrow this dogma and describe a new “two-in-one” designer antibody concept in which the same binding site on an antibody is engineered to recognize two different antigens, both with high affinity. The two antigens studied by Bostrom et al. are vascular endothelial growth factor (VEGF) and human epidermal growth factor receptor 2 (HER2), representing well-known tumor targets. VEGF promotes blood-vessel formation for the growing tumor and is targeted by the antibody bevacizumab (Avastin), commonly used to treat colorectal cancer. HER2 is highly expressed by some breast tumors and is targeted by the antibody trastuzumab (Herceptin). The authors show that an engineered antibody binds tightly to both antigens and inhibits the growth of both VEGF- and HER2dependent tumors in animal models. The potential applications of the approach will need very careful exploration but will surely have far-reaching impact.

C

1Genmab,

Yalelaan 60, 3584 CM Utrecht, Netherlands. of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. E-mail: p.parren@ genmab.com, burton@scripps.edu
2Department

High-resolution crystal structures of one of these antibodies in complex with either VEGF (dissociation constant Kd = 300 nM) or HER2 (Kd = 26 nM) were solved to elucidate the mechanism of “two-in-one” binding at the molecular level. The binding surface on the antibody for each antigen overlapped, but within the buried surface of each binding site, distinct amino acids contributed to the binding strength for each antigen: VEGF binding was primarily mediated by light-chain residues and HER2 binding by heavychain residues. The overlapping binding areas indicate that each antibody binding site cannot bind both antigens simultaneously (see the figure). The antibody binding sites in the two-in-one antibody are therefore selectively promiscuous; each can interact with two different partners, but will only bind to one at a time. For subsequent studies, an affinity improved two-in-one antibody (VEGF Kd = 3nM, HER2 Kd = 0.2 nM) was generated. Approaches to generate antibody molecules with multiple binding moieties have been tried before, with varying success. Such molecules were engineered by “fusing” two or more antibody binding sites into a single molecule to increase binding avidity or bind multiple antigens Two for the price of one. An antibody consists of four (2, 3). Antibodies binding two antigens polypeptides, two heavy and two light chains, that form can also be generated by Fab arm extwo “Fab arms.” Each arm harbors an antigen binding site, change, which occurs naturally in vivo for formed by loops from the heavy and light chains. The bind- immunoglobulin G4 molecules (4), or can ing site in the two-in-one antibody shown can interact with be created in vitro by cell fusion or antiHER2 (red) and VEGF (green) through mostly unique, but body engineering (5). Antibodies in which also some shared (blue), elements. When affinity-matured, two binding sites recognizing distinct the antibody inhibits both HER2 and VEGF activity in vitro and in vivo. The source of the structure shown is antibody antigens are connected to a single Fab arm IgG1 b12 (16), RCSB PDB accession code 1HZH. The mol- represent another permutation (6). An ecule was rendered using VMD software and further mod- example that is perhaps the closest compaeled with 3D software (Bryce 6.1). Refining and colors rable break with the one antibody–one were done with Adobe Photoshop CS3. antigen dogma comes from chemically
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Bostrom et al. generated the two-in-one antibody by expressing the HER2-specific antibody trastuzumab on the surface of filamentous bacteriophage. Random nucleotide sequence was incorporated into the gene segments encoding the antigen-binding loops of the light chain to generate a large phage library. The library was selected for binding to HER2 and VEGF to generate a panel of twoin-one antibodies of varying affinity.

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programmed antibodies in which antigen recognition is modified by the insertion of different ligands into the antibody binding site via a common reactive group (7). The beauty of the two-in-one molecule created by Bostrom et al. is its simplicity. For the first time, dual specificity has been engineered into a naturally occurring and stable antibody isotype that should pose no obstacles for manufacturing and that has been well validated for clinical use. Two-in-one antibodies may replace combination therapies such as treatment of cancer with both bevacizumab and trastuzumab, which is currently in clinical trials. A practical limitation to this approach may be an inflexibility of dosing where optimal doses are discordant for the individual antigens targeted. A strong caveat comes from two recent studies that investigated the use of bevacizumab and chemotherapy in combination with either cetuximab (Erbitux) or panitumumab (Vectibix) [antibodies that inhibit epidermal growth factor receptor (EGFR)] for treating metastatic colorectal cancer (8, 9). The studies showed that adding either of these antibodies to bevacizumab (plus chemotherapy) worsened clinical outcomes. These effects were unexpected because the antibody combinations had shown promise in the preclinical setting. Two-in-one antibodies could also be used to target two nonoverlapping epitopes on the same antigen. Such antibodies would have a greater potential for aggregating targets than classical antibodies. For combinations of either EGFR or HER2 monoclonal antibodies (10, 11), for example, such aggregation increases anti-tumor effects. The presence of two or more binding sites against distinct epitopes on a soluble antigen furthermore has the potential to increase binding avidity and in vivo potency (12). The ability of antibodies to bind multiple antigens is, in itself, not a novel finding and has been described, for example, for the lowaffinity binding of dissimilar peptides to distinct regions in a single antibody binding site (13). Indeed, by harboring multiple, spatially separated, binding sites in a single structure, antibodies may exploit a mechanism that has been recognized as a major source for multispecificity of proteins (14, 15). The uniqueness of the work of Bostrom et al. is to show that promiscuous binding of antibodies is compatible with the high-affinity, pharmacologically relevant, binding of very different antigens. Promiscuous binding may even extend to natural immunity where it would represent a mechanism to maximally cover binding space by a given repertoire of antibodies. Cross-reactive antibodies, when isolated, are generally considered a nuisance and two-in-one antibodies may therefore have been overlooked. The increased availability of technologies for rapid and large-scale screening of antibody-antigen interactions should help identify promiscuous antibodies. The potential for high-affinity antibody binding of more than one antigen is intriguing and poses opportunities for future basic research and perhaps clinical development of antibody combination therapy.
References and Notes
1. J. Bostrom et al., Science 323, 1610 (2009). 2. P. J. Hudson, C. Souriau, Nat. Med. 9, 129 (2003). 3. D. Neri, M. Momo, T. Prospero, G. Winter, J. Mol. Biol. 246, 367 (1995). 4. M. van der Neut Kolfschoten et al., Science 317, 1554 (2007). 5. P. Carter, Nat. Rev. Cancer 1, 118 (2001). 6. C. Wu et al., Nat. Biotechnol. 25,1290 (2007). 7. F. Guo et al., Proc. Natl. Acad. Sci. U.S.A. 103, 11009 (2006). 8. J. R. Hecht et al., J. Clin. Oncol. 27, 672 (2009). 9. J. Tol et al., N. Engl. J. Med. 360, 563 (2009). 10. M. Dechant et al., Cancer Res. 68, 4998 (2008). 11. T. Ben-Kasus, B. Schechter, S. Lavi, Y. Yarden, M. Sela, Proc. Natl. Acad. Sci. U.S.A. 106, 3294 (2009). 12. A. Nowakowski et al., Proc. Natl. Acad. Sci. U.S.A. 99, 11346 (2002). 13. D. K. Sethi, A. Agarwal, V. Manivel, K. V. Rao, D. M. Salunke, Immunity 24, 429 (2006). 14. R. A. Mariuzza, Immunity 24, 359 (2006). 15. I. Nobeli, A. D. Favia, J. M. Thornton, Nat. Biotechnol. 27, 157 (2009). 16. E. O. Saphire et al., Science 293, 1155 (2001). 17. P. Parren is part of the management team of Genmab, a public company that develops human therapeutic antibodies including those against Her2 and VEGF. He is a named inventor on patents issued by Genmab. Amgen, Inc. is among Genmab’s partners. 10.1126/science.1172253

MOLECULAR BIOLOGY

Dynamic DNA Methylation
Julie A. Law1 and Steven E. Jacobsen1,2

The methylation of DNA during plant development is a much more dynamic process than previously assumed.

he silencing of gene expression through the methylation of cytosine nucleotide bases in DNA is observed in a wide variety of eukaryotic organisms. It occurs mainly at repetitive elements of genomes, and plays a critical role in silencing transposable elements (transposons). Its heritability is a key aspect of DNA methylation as a stable epigenetic mark of gene repression. However, two studies, by Teixeira et al. on page 1600 in this issue (1) and Slotkin et al. (2), show that DNA methylation and gene silencing can be much more dynamic than previously thought. In the model plant Arabidopsis thaliana, three different methylation systems maintain

T

1Department

of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA. 2Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. E-mail: jacobsen@ucla.edu

cytosine methylation in three different sequence contexts: CG [cytosine (C); guanine (G)], CHG [H is adenine (A), thymine (T), or cytosine (C)], and CHH (3). CG methylation is controlled by DNA METHYLTRANSFERASE 1 (MET1) and VARIANT IN METHYLATION 1 (VIM1) (4). The mammalian homolog of VIMI (UHRF1) recognizes hemimethylated CG DNA and facilitates its restoration to the fully methylated state (5, 6). Another critical factor is the chromatin-remodeling protein DECREASED DNA METHYLATION 1 (DDM1), whose mutation causes massive losses of methylation (7), and reactivates transposons (8). CHG methylation is maintained by the plant-specific CHROMOMETHYLASE 3 (CMT3), and KRYPTONITE (SUVH4), a histone protein methyltransferase. CMT3 binds to methylated histones (chromatin-associated proteins)
VOL 323 SCIENCE

and KRYPTONITE binds to methylated CHG sites, thereby creating a feedforward loop for maintaining CHG methylation (9). CHH methylation is controlled by a third DNA methyltransferase, DOMAINS REARRANGED METHYLTRANSFERASE 2 (DRM2). DRM2 is guided to its DNA targets by 24nucleotide small interfering RNAs (siRNAs) in a pathway called RNA-directed DNA methylation (9, 10). In addition to maintaining CHH methylation, the RNA-directed DNA methylation pathway also controls the establishment of DNA methylation in all sequence contexts (11). Although the details of these methylation systems are being quickly fleshed out, much less is known about the extent to which they are acting throughout plant development. Teixeira et al. show that some regions of the Arabidopsis genome can be efficiently

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Arabidopsis Methylated Genomic DNA Several generations later Unmethylated Several generations later

Locus A

Locus B

24-nt siRNAs

No siRNAs made

Impaired methylation system

Locus A

Locus B

Restored methylation system

Locus A

Locus B

DNA methylation

Somatic cell

Global loss of methylation

Remethylation only at loci that produce siRNAs Gene silencing

Gene silencing

Gene expression

Silenced, again. DNA methylation that is lost in previous generations (for example, through mutation of a gene required for methylation) can be restored in subsequent generations when a gene encoding the wild-type version of the protein is

reintroduced. However, remethylation is restricted to loci that produce siRNAs, and depends on the RNA-directed DNA methylation pathway. SiRNAs can thus selectively correct methylation defects to enforce silencing. nt, nucleotide.

remethylated if methylation was lost in previous generations. Using ddm1 mutants, which display a global reduction in DNA methylation, the authors investigated whether DNA methylation can be restored after a wild-type DDM1 is reintroduced. Roughly half the sequences they examined regained methylation, thus reestablishing gene silencing. Complete remethylation was observed only after several generations, consistent with the multigenerational nature of transgene silencing known for plants. The loci that became remethylated were characterized by the presence of high amounts of siRNAs, whereas loci that remained unmethylated lacked siRNAs (see the figure). Furthermore, reestablishing methylation required RNA-DEPENDENT RNA POLYMERASE 2, a key component of the RNAdirected DNA methylation pathway. Most siRNAs correspond to transposons and other highly repetitive DNA, which if expressed could lead to genome instability. Thus, the ability to specifically remethylate these sequences is likely beneficial in a multigenerational manner to reinforce silencing and to correct defects in methylation patterning that might otherwise lead to transposon activation. In mammals, DNA methylation is dynamic during development, and examples include gene-specific imprinting as well as genome-wide changes in some cell types (12). Arabidopsis and other flowering plants imprint specific genes by selective demethylation of promoters in the endosperm (nutritive tissue in seeds of plants) (9), but whether methylation patterns are altered globally in

different plant tissues or cell types has been unclear. Slotkin et al. (2) report that the vegetative nucleus of Arabidopsis pollen cells shows a global loss of gene silencing, coupled with reactivation of transposon expression. Pollen contain three nuclei: the vegetative nucleus, which powers the cell; a sperm nucleus, which fertilizes the egg to form the zygote; and a second sperm nucleus, which fertilizes the central cell in the ovule to form the endosperm. By comparing data from pollen with that of isolated sperm nuclei, Slotkin et al. (2) deduced that the vegetative nucleus was the location of transposon activation. Further, although new transposition events were detected in pollen, they were not inherited, again suggesting that transposon reactivation occurs in the vegetative nucleus, which does not contribute DNA to the zygote. Transposon reactivation was coupled with decreased expression of DDM1, and several genes that control RNA-directed DNA methylation, as well as reduced numbers of 24-nucleotide siRNAs. Interestingly however, a different class of transposon-related siRNAs (21 nucleotides in length) accumulates in pollen. The authors propose that these 21-nucleotide siRNAs, originating in the vegetative nucleus, may travel to the adjacent sperm cells to reinforce silencing, perhaps in a manner akin to that shown by Teixeira et al. for the remethylation of hypomethylated DNA in somatic tissue. Thus, only those transposons with the potential to be expressed (because they were expressed in the vegetative nucleus) would be targeted by siRNAs in sperm nuclei.
SCIENCE VOL 323

The results of Slotkin et al. raise the question of whether similar processes occur in the Arabidopsis female gametophyte—for instance, if loss of silencing in the central cell might cause reinforcement of silencing in the egg cell. There are also interesting parallels with the siRNA-mediated communication between nuclei seen in Tetrahymena thermophila, where small RNAs generated from the micronucleus target chromatin modifications (and eventually DNA deletion) to homologous genomic DNA sequences in the developing new macronucleus (13). In the future, it will be important to assess the extent to which the dynamic processes uncovered by these recent findings are utilized in other aspects of eukaryotic development.
References
1. F. K. Teixeira et al., Science 323, 1600 (2009); published online 29 January 2009 (10.1126/science.1165313). 2. R. K. Slotkin et al., Cell 136, 461 (2009). 3. S. W. Chan, I. R. Henderson, S. E. Jacobsen, Nat. Rev. Genet. 6, 351 (2005). 4. H. R. Woo, O. Pontes, C. S. Pikaard, E. J. Richards, Genes Dev. 21, 267 (2007). 5. M. Bostick et al., Science 317, 1760 (2007). 6. J. Sharif et al., Nature 450, 908 (2007). 7. A. Vongs, T. Kakutani, R. A. Martienssen, E. J. Richards, Science 260, 1926 (1993). 8. H. Hirochika, H. Okamoto, T. Kakutani, Plant Cell 12, 357 (2000). 9. I. R. Henderson, S. E. Jacobsen, Nature 447, 418 (2007). 10. B. Huettel et al., Biochim. Biophys. Acta 1769, 358 (2007). 11. S. W. Chan et al., Science 303, 1336 (2004). 12. W. Reik, Nature 447, 425 (2007). 13. K. Mochizuki, M. A. Gorovsky, Curr. Opin. Genet. Dev. 14, 181 (2004). 10.1126/science.1172782

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PHYSICS

Fullerides in a Squeeze
Erio Tosatti

The superconducting behavior of very different materials—fullerides and cuprates—could have more in common than previously believed.

International School for Advanced Studies and CNR-INFM Democritos National Simulation Center; and International Centre for Theoretical Physics, Trieste, Italy. E-mail: tosatti@ sissa.it

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CREDIT: (A) ADAPTED FROM (14); (B) ADAPTED FROM (15); (C) AND (D) FROM (1)

efore the discovery of cuprate superconductors, superconducting metals and Mott insulators—would-be metals turned insulating by repulsion between electrons—seemed to have nothing to do with one another. Yet in cuprates, superconductivity popped up by simply doping Mott insulators with some impurities (see the figure, panels A and B), opening up perhaps the most controversial physics field of the past 25 years. As Takabayashi et al. show on page 1585 of this issue (1), pressure works very much the same feat in a completely different material: the hyperexpanded body-centeredcubic A15-structured fulleride Cs3C60, an insulator that is turned into a superconductor by giving it a light squeeze. What else, if anything, do cuprates and fullerides have in common? And if they do, could one of them teach us something about the other? In fullerides, electron-donating alkali atoms are regularly interspersed in a lattice of C60 molecules (see the figure, panel C). The donated electrons are mobile between one C60 molecule and the next, turning the whole system into a metal. Upon cooling, these metallized fullerene crystals turn superconducting, and they do so at respectably high critical temperatures Tc of 20 to 30 K (2–4). At first sight, this is no big deal, because superconductivity in fullerides appears similar in many ways to that of conventional superconductors and unlike that in cuprates. For example, the symmetry of electron pairs— whose condensation gives rise to superconductivity—is conventional (s-wave) in fullerides but unconventional (d-wave) in cuprates. In addition, the mechanism that glues the two electrons together to form the superconducting pair is conventional (phonon exchange) in fullerides (3, 4), whereas an electronic and magnetic mechanism is more probable in cuprates, because electron correlations are strong in these systems (5). However, according to proponents of the “strongly correlated superconductivity” theory, the difference between fullerides and cuprates may be more superficial than substantial (6, 7). This theory identifies two basic elements that

B

A

B 400

300

Strange metal

Temperature (K)

200

Mott-insulating antiferromagnet

Pseudogap Fermi liquid

100

Superconductor 0.1 0.2 0.3

0 0

C

D

Hole doping
55 50 Antiferromagnetic insulator-superconductor coexistence

Temperature (K)

40 35 30 25 20 0

Antiferromagnetic insulator

45

Superconductor 5 10 15 20 25 30

Pressure (kbar)

Different yet similar. Cuprates such as Bi2Sr2CaCu2O8+d (13) (A) show a bell-shaped dependence of superconducting transition temperature Tc on doping density (14) (B). Takabayashi et al. now report that in the fulleride A15 Cs3C60 (C), a similar behavior can be induced through applying pressure (D).

are common to fullerides and cuprates: First, the contiguity between a Mott insulating and a metallic phase; and second, some spin selective electron-electron interaction—be it phononic or electronic in origin—favoring singlet spin pairing in the insulating state. It has been known for about a decade that fullerides can indeed be changed from metallic to Mott insulating by expanding the lattice. This was achieved in the past by inserting additional neutral molecules such as ammonia between the buckyballs; these molecules acted as spacers, exerting a kind of negative pressure and prying the lattice open. In these expanded compounds—exemplified by (NH3)K3C60 (8)—theory has long shown how the role of electronic repulsion is enhanced by expansion, tilting the fine balance between

metallic and Mott insulating state (3, 4, 7). The Mott insulating state is antiferromagnetic (nearest spins point opposite to one another), but the spin of each C60 site is only 1/2 instead of 3/2 as one might have expected for three electrons per molecule. The low spin state is due to coupling to phonon vibrations, known in molecular physics as the Jahn Teller effect. Under pressure, such a “Mott Jahn Teller” insulator (9, 10) should, according to theory, turn into a strongly correlated superconductor; and indeed it does (11). However, the lattice expansion caused by inserted molecules also changes the lattice symmetry and introduces disorder relative to the parent compound K3C60, introducing some ambiguity into the assessment of this insulator-superconductor transition.

PERSPECTIVES
The novel fulleride reported by Takabayashi et al. is born expanded, because the large Cs ions force the C60 lattice into a body-centeredcubic arrangement, which is more open than the face-centered-cubic structure of previous compounds (12). Takabayashi et al. show that the zero-pressure state of this fulleride is a true Mott Jahn Teller insulator; thus, it possesses both ingredients required by the strongly correlated theory. The insulating state is experimentally destroyed by a modest 2.5- to 4-kbar pressure—with no doping, no disorder, and no change of lattice symmetry. In the squeezed metal, magnetism disappears and is replaced by superconductivity below a Tc that rises from ~30 k at 2.5 kbar , peaks at ~38 k for 7 kbar, and then drops at higher pressure. This bell-shaped behavior (see the figure, panel D) is a general feature predicted by the stron

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