Science
Science
Science
467 A Curiosity Moment for Tropical Biology? 480 Fishing for Answers off Fukushima
C. H. Cannon K. O. Buesseler
page 470
The Real Costs of Research 482 Decoding the Neuronal Tower of Babel
H. R. Rawlings III et al. C. J. McBain
>> Report p. 536
Duty of Care:
Protecting Researchers Abroad 483 Can Intellectual Property Save
B. Pafford and R. Macpherson Drug Development?
G. A. FitzGerald
469 CORRECTIONS AND CLARIFICATIONS
469 TECHNICAL COMMENT ABSTRACTS SCIENCE PRIZE ESSAYS
485 Student-Directed Discovery of the Plant
Microbiome and Its Products
C. A. Bascom-Slack et al.
487 A Mutant Search—Caenorhabditis elegans
and Gene Discovery
C. C. LaRue and P. A. Padilla
COVER DEPARTMENTS
Skull and shoulders of “Selam”—a 3.3-million-year-old female 439 This Week in Science
child Australopithecus afarensis from Dikika, Ethiopia. The upside- 444 Editors’ Choice
down view reveals her palate, vertebral column, and both shoulder 446 Science Staff
blades (in this orientation, the scapula on the right measures 60 489 AAAS News & Notes
millimeters across). The scapulae were recently freed from their 549 New Products
sandstone matrix and are described in the Report on page 514. 550 Science Careers
The scapulae display several apelike characteristics, implying that
A. afarensis was still a capable climber.
Image: Zeresenay Alemseged/Dikika Research Project
ONLINEHIGHLIGHTS
SCIENCEXPRESS SCIENCESIGNALING
www.sciencexpress.org www.sciencesignaling.org
Publication Ahead of Print The Signal Transduction Knowledge Environment
A Global Pattern of Thermal Adaptation in Marine 23 October issue: http://scim.ag/ss102312
Phytoplankton RESEARCH ARTICLE: Akt Phosphorylates the
M. K. Thomas et al. Transcriptional Repressor Bmi1 to Block Its Effects
10.1126/science.1224836 on the Tumor Suppressing Ink4a-Arf Locus
Akt-Mediated Regulation of Autophagy and Y. Liu et al.
Tumorigenesis Through Beclin 1 Phosphorylation PODCAST SCIENCESIGNALING
R. C. Wang et al. S. D. Nimer and A. M. VanHook Silencing a transcriptional silencer.
10.1126/science.1225967 Akt counteracts growth-promoting signals by
stimulating the transcription of tumor suppressor
The Legionella Effector RavZ Inhibits Host
genes.
Autophagy Through Irreversible Atg8 SCIENCECAREERS
Deconjugation PERSPECTIVE: PKR-Dependent Inflammatory www.sciencecareers.org/career_magazine
A. Choy et al. Signals Free Career Resources for Scientists
10.1126/science.1227026 R. Kang and D. Tang http://scim.ag/SciCareers26October2012
The RNA-dependent protein kinase activates the
A Bipolar Spindle of Antiparallel ParM Filaments inflammasome to promote inflammation. Experimental Error: A Cure for Listlessness
Drives Bacterial Plasmid Segregation A. Ruben
P. Gayathri et al. PRESENTATION: The Effect of Acute and Chronic Our columnist lists the top N of everything in science
10.1126/science.1229091 Stress on Growth careers, where N = fun.
L. Sävendahl
Binary Millisecond Pulsar Discovery via The glucocorticoids and inflammatory cytokines
Teaching Postdocs to Be Professors
Gamma-Ray Pulsations M. Price
induced by stress can impair bone growth.
H. J. Pletsch et al. An NIH program readies teaching-focused postdocs—
10.1126/science.1229054 PRESENTATION: The Effects of Acute and Chronic especially minorities—for lab-and-classroom jobs.
Stress on Diabetes Control Life at the Bottleneck
M. L. Marcovecchio and F. Chiarelli
TECHNICALCOMMENTS R. Müller
Stress-induced hormonal changes alter glucose
A social scientist discusses how career pressures
Comment and Response on “Conspecific Negative homeostasis in both diabetic and healthy patients.
affect how postdocs work and relate in the lab.
Density Dependence and Forest Diversity“ PRESENTATION: P450 Oxidoreductase
Comment: I. A. Dickie et al. SCIENCEPODCAST
Deficiency—A Disorder of Steroidogenesis with
http://dx.doi.org/10.1126/science.1225520
Multiple Clinical Manifestations www.sciencemag.org/multimedia/podcast
Response: D. J. Johnson et al.
http://dx.doi.org/10.1126/science.1225996 W. L. Miller et al. Free Weekly Show for 26 October 2012
Mutations in a steroid biosynthetic enzyme cause a Listen to stories on the Twitter vote, our climbing
range of clinical symptoms. ancestors, science and the next U.S. president,
SCIENCENOW
and more.
www.sciencenow.org SCIENCETRANSLATIONAL MEDICINE
Highlights From Our Daily News Coverage www.sciencetranslationalmedicine.org
Raw Food Not Enough to Feed Big Brains Integrating Medicine and Science
A new study supports the idea that cooking helped 24 October issue: http://scim.ag/ss102412
human ancestors expand their minds.
RESEARCH ARTICLE: NADPH Oxidase Inhibits the
http://scim.ag/Big_Brains
Pathogenesis of Systemic Lupus Erythematosus
Caesar, the Orchid Chief A. M. Campbell et al.
A temple erected by a Roman emperor is among the Neutrophil NETs are not required for SLE development
earliest evidence of orchids in Western art. in a mouse model.
http://scim.ag/Evidence_Orchids SCIENCE (ISSN 0036-8075) is published weekly on Friday, except the last
RESEARCH ARTICLE: Targeting Cancer with a Lupus week in December, by the American Association for the Advancement of
Science, 1200 New York Avenue, NW, Washington, DC 20005. Periodicals Mail
Antibiotic-Resistant Bugs Go Wild Autoantibody postage (publication No. 484460) paid at Washington, DC, and additional mailing
Researchers find deadly hospital bacterium in rabbits J. E. Hansen et al. offices. Copyright © 2012 by the American Association for the Advancement of
Science. The title SCIENCE is a registered trademark of the AAAS. Domestic individual
and a migratory shorebird. membership and subscription (51 issues): $149 ($74 allocated to subscription).
http://scim.ag/Hospital-Bacterium FOCUS: Lupus Antibody Tops Cancer Cells Domestic institutional subscription (51 issues): $990; Foreign postage extra: Mexico,
J. M. Ford Caribbean (surface mail) $55; other countries (air assist delivery) $85. First class,
airmail, student, and emeritus rates on request. Canadian rates with GST available
A cell-penetrating lupus anti-DNA antibody inhibits upon request, GST #1254 88122. Publications Mail Agreement Number 1069624.
DNA repair and is toxic to cancer cells. Printed in the U.S.A.
Change of address: Allow 4 weeks, giving old and new addresses and 8-digit account
RESEARCH ARTICLE: Quantitative Image Analysis 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
of Cellular Heterogeneity in Breast Tumors includes surface postage; bulk rates on request. Authorization to photocopy
Complements Genomic Profiling 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
Y. Yuan et al. registered with the Copyright Clearance Center (CCC) Transactional Reporting Service,
Quantitative image analysis of breast tumors provided that $30.00 per article is paid directly to CCC, 222 Rosewood Drive, Danvers,
CREDIT: Y. HAMMOND/AAAS
MA 01923. The identification code for Science is 0036-8075. Science is indexed in the
contributes to a predictor of survival. Reader’s Guide to Periodical Literature and in several specialized indexes.
Badrinarayanan et al. (p. 528) used noninvasive millisecond single-molecule imaging to understand
SMC complex molecular biochemistry in living bacterial cells with super-resolution spatial precision.
Escherichia coli SMC complexes, which are important for chromosome segregation, formed dimers that
bound to DNA in an adenosine triphosphate (ATP)–dependent manner and that could be released upon
ATP-hydrolysis. By functioning in pairs, the complexes are likely to be able to undergo multiple cycles of
105
ATP-hydrolysis without being released from DNA.
sheep to pair bonding in voles (see the Perspective by Emmons). Now, Garrison et al. (p. 540) and
Beets et al. (p. 543) extend the evolutionary reach of these social neuropeptides to the invertebrate
nematode worm, Caenorhabditis elegans. A similar neuropeptide was found to function in mating
and also to modulate salt-taste preference, based on prior experience, suggesting an ancient role in
associative learning.
membercentral.aaas.org
www.sciencemag.org SCIENCE VOL 338 26 OCTOBER 2012
Published by AAAS
EDITORIAL
that allow only the most capable people to advance to the many positions of responsibility and
authority in a nation’s institutions. Rules that support automatic tenure and promotion, so as
to “protect individual rights,” may seem well-meaning, but such rules have calamitous results.
Each nation will thrive only to the extent that its institutions promote and maintain individuals
in positions of responsibility based on their demonstrated performance, irrespective of senior-
ity, family connections, or national origins. Can Americans agree that it is crucial to constantly
enhance policies that build and encourage such a merit-based society?
Finally, institutions thrive when they are rooted in scientific principles—in rational thought,
scientific knowledge, and the innovations derived from scientific understanding to benefit
humanity. No matter how contentious the topic, whether climate change, the immunization
of children, or the benefits of genetically modified crops, scientists and politicians must work
together much more effectively to ensure that the scientific research needed for wise decision-
making by vital institutions is both supported and never ignored. I am certain that millions of
U.S. scientists are ready to contribute. Can all Americans agree? – Bruce Alberts
10.1126/science.1231652
*J. J. Hamre, Science 338, 304 (2012). †D. Acemoglu, J. Robinson, Why Nations Fail: The Origins of Power, Prosperity,
and Poverty (Crown Publishers, New York, 2012).
Launched in 1977, the two Voyager spacecraft have traveled deep into space, but they
The Core from Above
are still transmitting data back to Earth. Having crossed the termination shock, the point Earth’s core is split into a solid inner core and
where the solar wind is abruptly slowed down by the interstellar medium surrounding the a fluid outer core. The convection and rotation
solar system, both spacecraft are currently in the outermost layer of the heliosphere—the of the outer core produce Earth’s magnetic field
heliosheath. Richardson and Wang report recent data from the plasma instrument on Voy- and redistribute mass within the planet. Mea-
ager 2, which crossed the termination shock in 2007 as solar activity was approaching its sured from orbiting satellites, variations in the
minimum. Previous data had shown a decrease in the solar wind density at the position of magnetic field over time indicate changing outer
Voyager 2 6 months after it crossed the termination shock; now data from 2011 and 2012 core dynamics. Mass redistribution from fluid
reveal an increase in the plasma density back to the levels observed just after termination motion in the outer core should be detectable by
shock crossing, before the decrease was observed. These results may signal the end of solar gravity-sensing satellites, but surface processes
minimum conditions in the heliosheath. — MJC such as the movement of water in the oceans and
Astrophys. J. 759, L19 (2012). within river basins tend to dominate local gravity
measurements. Mandea et al. reexamined global
magnetic data to determine how the outer core
E D U C AT I O N tested peers in the school system. A teacher’s changed over 8 years and correlated them with
performance is measured as the sum of her/ variations in gravitational data over the same
Pay for Percentile his students’ individual percentile ranks among time frame. Both sets of data show a distinct
What gets measured gets done. So claim their respective peer comparison groups. The spatial feature centered under Africa, suggesting
advocates of high-stakes academic testing, authors show how “contests” among teachers that core contributions to the gravity field are in-
arguing that paying teachers on the basis of based on this summed ranking can elicit ef- deed measurable. A physical explanation for this
student performance can improve education. ficient teacher effort in every classroom. — BW feature may be related to density heterogeneity
Opponents of “pay for performance” argue that Am. Econ. Rev. 102, 1805 (2012). or interactions between the core and overly-
such a system pressures those being measured ing mantle; however, more data collected from
to game the system, which distorts the process NEUROSCIENCE ongoing and future high-resolution satellites
being monitored. High-stakes assessments Countering Impaired Cognition are needed to better understand the short-term
commonly use similar test topics, items, and dynamics of the outer core. — NW
formats to maintain consistency of the rating Cognitive impairment is a cardinal feature of Proc. Natl. Acad. Sci. U.S.A. 109, 10.1073/
scale over time. This provides opportunity and many psychiatric disorders, including schizophre- pnas.1207346109 (2012).
incentive to “teach to the test,” rather than nia. Blockade of 5-HT6 receptors is a potential
improving student understanding and achieve- strategy for correcting the cognitive deficits of BIOCHEMISTRY
ment. Barlevy and Neal detail an approach to schizophrenia and other central nervous system
disorders. However, the molecular mechanisms
A Viral Turn-Off
motivate teachers on the basis of student test
performance, while limiting the opportunity underlying the deleterious impact of 5-HT6 Chronic hepatitis C virus (HCV) infection is a
to teach to the test by using completely new receptors on cognitive function are still unknown. major cause of liver failure. The NS3 protein of
CREDIT: NASA
tests each time. With each new test, a student’s Using an unbiased proteomic approach to find HCV has been aggressively pursued as a drug
achievement is reported as an ordinal ranking protein partners and signaling mechanisms target because it is involved in viral polyprotein
among a cohort of similarly achieving, similarly engaged by 5-HT6 receptors, Meffre et al. identi- processing, through a serine protease domain,
M AT E R I A L S S C I E N C E
took the gas-enshrouded ice giant’s first and only close-up As planetary astronomer Lawrence Sromovsky of the Uni-
in 1986 (left), but even tweaking the contrast (middle pole, versity of Wisconsin, Madison, and colleagues reported at
in false color) could not reveal much character to the sun’s last week’s meeting of the Division for Planetary Sciences
seventh most distant planet. in Reno, Nevada, Uranus has cloud bands reminiscent of
Now, new technology and exceptionally good observ- Saturn and Jupiter and, surprisingly, “popcorn” clouds in
ing conditions one night last July have yielded the sharpest its north polar region (right side). Although such convective
views yet of Uranus. Astronomers used the 10-meter Keck II clouds typify summer thunderstorms on Earth, the team will
telescope on Hawaii’s Mauna Kea—equipped with a near- be watching to see whether this oddball convection shuts
infrared camera to up the clouds’ contrast and adaptive down as uranian summer comes on.
who lost his wife and daughter in the quake. Bernardinis from those of the rest of the com-
“It wasn’t a trial against science; it was a wrong could mean a conviction mission, telling the court that, according to
trial against those who didn’t know how to Picuti, “De Bernardinis suddenly becomes
evaluate the risk, who didn’t know to miti- for manslaughter?” a prophet” insofar as he made his infamous
gate the risk.” —SANDY STEACY, comments before and not after the meet-
But scientists, thousands of whom signed UNIVERSITY OF ULSTER ing. Barberi’s lawyer, Francesco Petrelli,
remarks” avoided. He also warns that scien- in the stem cell transplants thrown into largely to Moriguchi himself. He was attend-
tists will “need to become much more liti- question, although on only one patient as ing the annual translational research confer-
gation aware.” –EDWIN CARTLIDGE opposed to the six originally claimed. ence of The New York Stem Cell Foundation
Edwin Cartlidge is a science writer in Rome. Moriguchi perpetuated his alleged fraud in New York City, where a poster of his was
Hot seat. Investigations are under way into Hisashi hospital was not supporting any iPS research. periodic contact, and Chung was a co-author
Moriguchi’s iPS cell treatment claims. It turned out that Moriguchi’s undergraduate on nine of Moriguchi’s papers, seven of which
training was in nursing and his master’s degree carried the Harvard/MGH affiliation. Chung
on display. It contained a bombshell: results in health promotion. The university confirms declined to speak to Science, but McGreevey
from the first-ever human transplants of that under a system common in Japan, he later writes in an e-mail that Chung did not read
cells derived from induced pluripotent stem earned a Ph.D. from the University of Tokyo the final manuscripts of those articles. Six of
(iPS) cells, which are mature cells repro- for a dissertation related to hepatitis C without the papers were correspondence published
grammed to behave like those from an early going through a formal doctoral course. in the journal Hepatology. Chung primar-
embryo. Based on an abstract obtained by By Friday evening, Moriguchi’s master’s ily provided “editorial assistance,” for exam-
Science, Moriguchi and co-author Chifumi adviser and frequent co-author, Sato, who ple, making sure the English was correct,
Sato claimed to have generated iPS cells and specializes in liver disease and health promo- McGreevey says.
then derived cardiac muscle cells that were tion at Tokyo Medical and Dental University Chung “was not sent any of the proofs for
transplanted into six cardiac patients. Japa- (TMDU), appeared at a hastily called press review,” McGreevey writes to Science. “Dr.
nese reporters were well-represented at the conference and apologized for his role in the Moriguchi was the corresponding author,
conference because Kazutoshi Takahashi commotion. Ikuo Morita, a TMDU trustee in and Dr. Chung had no notification of changes
of Kyoto University was being awarded the charge of research, promised an investigation Dr. Moriguchi may have made to the origi-
foundation’s Robertson Prize. On the first into the validity of all of Moriguchi papers nal manuscripts or proofs.” In a follow-up
both the Japanese and English sites of the at the Harvard School of Public Health and called discovery of his and that they were not
Yomiuri. (Yomiuri apologized to its readers for Chung agreed to let Moriguchi work in his interested in patenting it,” and over the course
the erroneous stories the following day.) The MGH lab for a month late that year, accord- of “many, many e-mails” sought help from
University of Tokyo Hospital confirms that ing to Susan McGreevey, a spokesperson for Chung. On 7 July 2011, Chung and Mori-
Moriguchi had a post there but states that the MGH. In the 13 years since, the two were in guchi filed a U.S. patent application, titled
“Methods and Compositions for Repro- agy, a process of cellular degradation. In that he has informed Scientific Reports he would
gramming Cells.” McGreevey says this was same e-mail to Science, Zhang writes that he like to retract the papers.
based on the papers on which Chung was a checked out Moriguchi’s credentials and saw Zhang says he performed “data analy-
co-author. The owner, or assignee, of the pat- numerous publications in respected journals, sis, assessment, and interpretation of manu-
ent was The General Hospital Corporation, a previous news article in Yomiuri Shimbun scripts.” He says he has requested that the
the legal entity that runs MGH. The inventors that included his Harvard/MGH title, and Scientific Reports papers be withdrawn, if
listed were Moriguchi and Chung. “We have business cards listing him as a visiting lec- appropriate. “It turns out my mistake [was] to
asked the patent office to abandon the appli- turer at Harvard Medical School and MGH. put trust in him,” Zhang wrote to Science.
cation,” McGreevey says. “He looks like a serious scientist, collabora- The publications in Scientific Reports were
Both Sato and the University of Tokyo tive, good-willing,” Zhang writes. peer-reviewed. Still, journals vary widely in
Hospital write in e-mails to Science that the Less than 5 months after meeting what they expect of authors. Like most, Nature
fact that MGH had submitted a patent appli- Moriguchi, in October 2011, Zhang journals do not verify author affiliations. They
cation bolstered Moriguchi’s claims to be con- abruptly left the lab. In an e-mail, he tells also don’t require that all the authors see a
ducting iPS research in the United States. Science that he ran into visa problems and final version of the manuscript. “Submission
Asked whether Chung had violated any moved to Canada with his wife and young to a Nature journal is taken by the journal to
Harvard or MGH policies or would be sanc- sons. Calderwood says he learned about mean that all the listed authors have agreed to
tioned in any way, McGreevey says not as far his departure the day he left. Zhang corre- all the contents,” writes Ruth Francis, head
with Glover and Kirschen, who is now at Others argue that the chance, however recommendations through a notice in the NIH
the Children’s Hospital of Philadelphia, slim, of saving lives like Hilgenberg’s is worth Guide for Grants and Contracts. The consoli-
publishing numerous papers and conven- delving into that gray area and is practically dated document is “a huge step forward” in
ing working groups to develop clearer pro- feasible for researchers. Since the Stanford providing clearer guidance to funding agen-
tocols for researchers dealing with IFs. On Radiological Sciences Laboratory opened cies, researchers, and IRBs, Illes says. The
18 October, she gathered 28 prominent neu- in 1990, they’ve kept a radiologist on call, fact that the group was able to reach consen-
roscientists, clinicians, ethicists, and law- Glover says. Although not every scan is read sus, she adds, shows “how far we’ve come in
yers in Washington, D.C., to hash out new by a radiologist, students and researchers are solidifying partnerships between neuroscien-
guidance as part of a working group spon- trained to report anything odd. Hilgenberg, tists and ethicists.”
sored by the National Institutes of Health now an instructor of pediatrics at Lucile Pack- –EMILY UNDERWOOD
PROMISES DOMINATE POLITICAL CAMPAIGNS. But once the election is over, either Mitt
Romney or Barack Obama will have to govern.
This package examines the science-related issues facing the next occupant of the Oval
Office and, for the few that have been featured in the campaign, the positions the candidates
have taken on them. At the top of the president’s “to-do” list will be trying to resolve the cur-
rent budget deadlock; legislators will have another chance to address that next month during
a lame-duck session of Congress. And while science needs funding to thrive, there are a host
of other areas, including energy, education, the environment, space, and
Online
sciencemag.org
biomedicine, in which direction may be just as important as dollars.
Of course, not all wisdom resides in the White House. Next
month’s election will also determine the makeup of Congress for the
Podcast inter-
view with David next 2 years. So we bring you one House of Representatives race in
Malakoff (http://scim.ag/ which federal science policy is receiving an unusual amount of atten-
pod_6106). tion (p. 463). Another story explores new research on negative adver-
tising, a reviled but increasingly popular mode of trying to influence
voters (p. 465). And we also look at a passel of state initiatives appearing on the ballot that
affect the scientific community, including a hotly contested proposal in California to label
genetically modified foods (p. 464).
–JEFFREY MERVIS AND DAVID MALAKOFF
BARACK OBAMA AND MITT ROMNEY have promised, as president, to the $31 billion National Institutes of Health, for example, that trans-
maintain U.S. scientific excellence while paring down a $1.4-trillion- lates into a $2.5 billion reduction. The $7 billion National Science
a-year budget deficit. And it’s the second half of the sentence that Foundation would lose $580 million, and the Department of Energy’s
really worries the U.S. academic community. Although each man has $4.9 billion Office of Science programs would drop by $423 million.
said he believes basic research is essential for economic develop- Those cuts, called sequestration, were intended to be a last resort
ment, it’s not at all clear how much is enough, and which areas should under a two-step agreement struck in August 2011 between the White
be emphasized. House and Congress to begin reducing what is now a $1.4 trillion
President Obama has been proud to run on his record of support annual deficit. The two sides shook hands on more than $900 billion
for science. He has repeatedly honored a pledge, first sounded by in projected cuts through 2021, starting with $21 billion in the 2012
President George W. Bush, to boost the nation’s investment in the fiscal year that ended on 30 September. The law created a commit-
physical sciences and engineering through a 10-year doubling of tee to find an additional $1.2 trillion in some combination of spend-
the budgets of the National Science Foundation, the Department of ing cuts and increased revenues, but last December, Congress failed
Energy’s Office of Science, and the National Institute of Standards to adopt the committee’s recommendations. That inaction started the
and Technology, although Congress has typically trimmed his annual clock running on sequestration.
requests for those agencies. The president has also set a goal of boost- So far this year, Congress has made no headway on resolving the
ing the nation’s overall spending on research to 3% of the country’s deadlock. In fact, it’s gone in the opposite direction, extending cur-
WILL THE 2% SOLUTION SURVIVE? The next of engineering, mathematics, and computer science.
president will need to decide whether to Military planners say research is essential for a modern fight-
honor a long-standing commitment to grow ing force. And former defense secretary Robert Gates—who served
the Department of Defense’s (DOD’s) rela- under both Obama and his Republican predecessor, George W.
tively small basic research budget by 2% Bush—promised to prevent basic science spending from stagnating.
annually over the next 4 years despite overall Gates is gone, however, and his successors confront the tumultuous
cuts in military spending. task of figuring out how to “rightsize” the Pentagon.
Although basic science accounts for less The Obama administration has said cuts must be made but it will
than 0.5% of the Pentagon’s annual budget, the $2.1 billion is a life- try to limit the damage to DOD’s basic research programs. Romney
line for many academic researchers. Roughly half goes to universi- has promised to increase overall defense spending but hasn’t said
ties, and DOD is the single largest government funder in many fields whether basic science would also grow. –DAVID MALAKOFF
WHAT TO KEEP AND WHAT to trim from the Department of all fusion budget, close several U.S.-based fusion laboratories, or
Energy’s (DOE’s) sprawling $11 billion research portfolio is the big reevaluate its support for ITER.
question facing the winner of next month’s election. Neither candi- Fusion researchers may also be squeezed out of working on
date has said much during the campaign about how tightening bud- the National Ignition Facility (NIF) at the Lawrence Livermore
gets (see p. 457) would affect the department’s research prior- National Laboratory in California, a $3.5 billion laser
ities, but they have offered divergent views on the govern- facility built for both fusion research and nuclear
ment’s role in commercializing technologies. weapons studies. Last month, NIF scientists missed
Scientists involved in physics and fusion stud- a DOE deadline for igniting a fusion reaction inside
ies that require big, expensive machines are par- a tiny capsule filled with hydrogen fuel (Science,
ticularly anxious about where fundamental studies 21 September, p. 1444). As a result, NIF’s focus is
that offer little promise of immediate practical pay- now shifting to weapons research.
offs will rank among the priorities in an Obama or It is unlikely that either Obama or Romney has
Romney administration. Particle physicists, for instance, strong views on these in-the-trenches science deci-
are wondering if the White House will back a nearly sions, so the person serving as energy secretary
$800 million plan to build a scaled-down version of the Long- could play an influential role. Nobel laureate Steven Chu
Baseline Neutrino Experiment (LBNE). In addition to document- hasn’t said whether he expects to serve in a second Obama admin-
IT IS HARD TO FIND TWO issues that more as far or as fast on environmental issues as they claim they’d like to.
starkly highlight the differences between Just as Obama has been stymied on a number of fronts by Congress,
Barack Obama and Mitt Romney than the courts, and political opposition from both the left and the right,
climate change and environmental regu- Romney would face a host of obstacles to undoing present policies.
lation. At the same time, whoever wins Still, there are several areas where the winner can act unilaterally.
the election will have to cope with sharp For instance, Romney could rescind with a stroke of a pen several
constraints on his ability to implement Obama-era executive orders that require government agencies to
those policies. reduce greenhouse gas emissions and make “green” purchases. He
Obama agrees that humans are causing cli- could also slow the implementation of recent rules aimed at cutting
mate change and says the federal government should take action carbon emissions from existing coal-fired power plants and essen-
to curb the emission of greenhouse gases that are contributing to tially block efforts to extend those rules to new plants.
global warming; Romney says the causes need more study, and that It’s less clear, however, that he could undo court rulings that have
it’s not clear that the government should do anything about green- upheld the Environmental Protection Agency’s finding that those
house gases. Obama has adopted or set in motion a panoply of new emissions “endanger” public health under the Clean Air Act and,
CREDIT (TOP TO BOTTOM):
rules aimed at reducing pollution and protecting habitat from devel- therefore, require regulatory action. And Romney could also face
opment; Romney has vowed to roll back most if not all of them, legal tangles if he attempts to roll back other regulations targeting
arguing they harm the economy. mercury pollution and ground-level ozone. In contrast, reelection
Neither candidate, however, has acknowledged the dirty little would give Obama a chance to consolidate and entrench these regu-
secret of environmental politics: Few presidents are able to move latory approaches, but he could also face new legal challenges.
FOR BETTER OR WORSE, TEACHERS have captured the lion’s share of a more technology-savvy workforce. Obama has also run on his
the meager attention given to education during this year’s presiden- record of fostering state-based educational innovations through a
tial election. Their political activism infuriates Mitt Romney, who $4 billion Race to the Top competition for schools, as well as a
would like to ban teachers’ unions from making campaign contribu- public-private partnership, called Educate to Innovate, created to
tions. In addition, his support for vouchers—channeling fed- attract more students, in particular women and minorities,
eral funding for low-income and disabled students to par- into STEM fields.
ents rather than to local and state agencies—is designed Romney hasn’t ignored the subject, although he
in part to blunt the influence of teachers’ unions in mak- has much less to say about science and math educa-
ing policy. In contrast, President Barack Obama has tion. He believes that Washington has no business
relied on these unions to help get out the vote, and he financing implementation of the so-called Common
frequently mentions that funds from his massive 2009 Core, a voluntary effort by 45 states and the Dis-
federal stimulus package have kept hundreds of thou- trict of Columbia to adopt a similar curriculum in
sands of classroom teachers on the payroll. math and language arts, and a companion common
But what do the two candidates think about the job assessment of student performance. That stance
that those teachers are paid to do? Both men have said that teachers presumably would also apply to the pending next-generation sci-
are the essential ingredient in a good school. And although it may ence standards that have yet to be embraced by the states. At the
The two candidates also differ on how to protect habitat on fed- shown little appetite for the subject recently, however, and Congress
eral land. Obama has taken a two-pronged approach: Honor exist- fiercely opposes any deal that it believes puts the United States at
ing moratoria on oil and gas drilling in federal waters off the coasts an economic disadvantage. The Romney campaign, meanwhile, has
of California and Florida and oppose drilling in Alaska’s Arctic said that it is skeptical of any global discussions, especially given the
National Wildlife Refuge (ANWR), but move cautiously to allow uncertainty surrounding the causes and impacts of climate change.
exploratory wells in Arctic seas off Alaska. He also has stiffened Although few are betting on any global agreement any time
regulatory requirements for companies wanting to drill, mine, or soon to curb emissions, the issue isn’t going away. In Septem-
log on public lands. ber 2013, the U.N. Intergovernmental Panel on Climate Change
Romney, in contrast, has said he would push to open for drilling will start releasing its next big report on the science, impacts, and
ANWR and other coastal areas, as well as offering greater incentives potential mitigation of climate change. The new data are expected
to quickly develop areas that are already open to leasing. He has criti- to rekindle debate on the topic.
cized Obama for crippling efforts to exploit public holdings and said Striking the right balance between protecting the environment
he would give states a greater say in how to use federal lands within and fostering economic development lies at the heart of another
their boundaries. issue facing the next president, namely, how best to rewrite the Toxic
The next administration will also need to decide how much politi- Substances Control Act. It’s the nation’s flagship law regulating the
cal capital to invest on reaching an international deal to address cli- use of new and existing chemicals. One especially thorny issue is
mate change. Obama has said the U.S. will stay involved in desul- how to regulate the minuscule products of nanotechnology without
tory efforts to persuade other major greenhouse gas emitters—most hobbling commercialization of that nascent field.
notably China—to act in concert to curb their emissions. China has –DAVID MALAKOFF
THE BUDGETS FOR SPACE SCIENCE and space exploration at NASA may be comparable BIODEFENSE HAS BEEN WELL below the
in size, but that’s where their similarity ends. Human flight and the hardware needed to radar in the election campaign, but the
make it happen get most of the attention from Congress and the public, thanks in part next administration will have to make an
to the clout of the aerospace industry and the popular appeal of astronauts. But scien- early decision on how much further to
tific missions, such as Hubble and the Mars Curiosity rover, have racked up the biggest go in regulating basic research involving
achievements in recent years. potentially risky pathogens. In March,
The next president will be challenged to find a way to keep both sectors healthy, the Obama administration expanded reg-
and it promises to be a tall order for either man. Critics of President Barack Obama say ulatory requirements for federally funded
he lacks a comprehensive vision for human exploration and that NASA’s pipeline of scientists working with 15 particularly
robotic missions is running dry. Meanwhile, Mitt Romney has settled for criticizing his dangerous agents after a global contro-
opponent’s record without offering any substantial plan of his own. versy over whether
There is no shortage of scientific decisions facing the next administration. The scientists should
agency’s plans for exploring Mars in the next decade are only beginning to take shape, p u b l i s h t wo
following the Obama administration’s recent decision to cancel NASA’s participation studies show-
in the European-led ExoMars mission. NASA is under pressure to deliver the $8.8 bil- ing how they
lion James Webb Space Telescope by 2018, its new launch date, and the next president made the H5N1
ON THE CAMPAIGN TRAIL, PRESIDENT Barack Obama defeated a Republican-backed bill that included a
and Mitt Romney differ sharply on what to do about “stapling-lite” provision because many Democrats
illegal immigration, including the 12 million undocu- objected to how it would be implemented. Conven-
mented persons living in the United States. tional wisdom says that such changes will have to be
But the candidates are not far apart on the issue of part of comprehensive immigration reform, which so
legal immigration, which gets much less attention. And far has eluded Congress.
they hold nearly identical positions on how to make it But next year could be different. “I can deliver, Gov-
easier to retain the most talented foreign students after ernor, a whole bunch of Democrats to get comprehen-
they graduate with advanced science and engineering sive immigration reform done,” Obama promised during
degrees from U.S. universities. Their solution, often shortened to last week’s debate at Hofstra University in Hempstead, New York.
the sound bite “Staple a green card to their diplomas,” is also a key Not to be outdone, Romney replied: “I’ll get it done, first year.” If
objective for the U.S. high-tech community. the next president keeps his word, foreign-born scientists could find
But the politics of immigration make achieving that goal dif- themselves with a much easier path toward permanent residency.
ficult. Last month, for instance, the House of Representatives –JEFFREY MERVIS
In Race for a Seat in Congress the 2007 America COMPETES Act, which
authorized increases aimed at doubling the
budgets for the National Science Founda-
A physicist takes on a longtime friend of science in a tight Illinois race in which tion, the National Institute of Standards and
research matters Technology, and DOE’s Office of Science
over 10 years.
Candidates for Congress rarely fight over mittee, where he could directly influence sci- Biggert says she strongly favors basic
how fervently they support science. But it’s ence funding. research over applied efforts. For example,
happening in Illinois’s newly redrawn 11th But during the debate, Foster counter- COMPETES also established the Advanced
district, a contorted swath of Chicago’s south- attacked on science. “You voted for the Ryan Research Projects Agency–Energy (ARPA-
western suburbs. The election for a seat in the budget,” he began, referring to the cost- E), a program to quickly develop promis-
House of Representatives pits Democrat Bill cutting federal budget proposed by Repub- ing ideas from energy-related research.
Foster, a physicist who served in Congress lican vice-presidential nominee Paul Ryan, But Biggert worried that ARPA-E, which
from 2008 through the start of 2011, against who chairs the House of Representatives stresses more applied science, would take
Republican Judy Biggert, the seven-term Budget Committee. “You claim to be a sup- money away from DOE’s fundamental
incumbent who has served on the House sci- porter of science, and yet the Ryan budget research programs. So she lobbied success-
ence committee for her entire career. has been analyzed and it provides for a 30% fully for language in COMPETES that said
Science features in the race because the cut to federal research budgets.” (An analy- ARPA-E would receive money only after
district includes part of Argonne National sis by AAAS, the publisher of Science, esti- DOE’s basic research efforts were fully
Laboratory, a multipurpose lab owned by the mates that nondefense research spending funded. ARPA-E launched in 2009 with a
Department of Energy (DOE). It also runs could drop by 27% under the Ryan budget.) one-time allocation of $400 million from
just south of DOE’s Fermi National Accel- Scientists clearly prefer Foster. Records the massive stimulus package. Its budget
erator Laboratory (Fermilab), the sole U.S. from the Federal Election Commission show this year is $275 million, compared with
laboratory specializing in particle physics. that hundreds of researchers from all over $4.9 billion for the Office of Science.
Polls show Biggert, 75, and Foster, 57, in a the country have donated nearly $400,000 to Foster argues that his scientific expertise
dead heat, and the votes of scientists proba- his campaign. Only two donors who identify will make him a more effective advocate for
bly won’t decide the contest. But the at-times- themselves as scientists show up on Biggert’s the labs. He worked at Fermilab for 22 years
nasty campaign raises the question of whether tally. “If you think about the problems fac- before leaving in 2006. As a teenager, Foster
it’s better for researchers to have a longtime ing the country, most of the solutions involve and his younger brother started a theater light-
ally or one of their own on Capitol Hill. science at some level,” says Michael Turner, ing company that has made them wealthy. So
CREDIT: JOHN J. KIM/MCT/LANDOV
The candidates are trading potshots over a Foster donor and a cosmologist at the Uni- Foster describes himself as “a scientist and a
science. In a recent debate, Biggert, whose versity of Chicago, which manages Argonne businessman.”
old district encompassed Argonne, all but for the DOE. In March 2008, Foster won a special
accused Foster of abandoning his colleagues: But Washington insiders say scientists midterm election to represent a district that
“My opponent couldn’t get on the science often overestimate the influence that one of was home to Fermilab and gained a full term
committee even though he’s a scientist.” After their own might exert in Congress, which is 8 months later. But in November 2010 he
the debate, Foster told Science that if elected, home to only a handful of scientists and engi- lost his seat to Republican Randy Hultgren.
he’d prefer a seat on the appropriations com- neers. “Personally, I would not vote for or Foster takes an explicitly quantitative
would require labels on any food containing sumers from buying them. If that happens, In South Dakota, Referred Law 14 would
more than one part in 200 of GM material. scientists say, reduced demand could pre- tap a portion of the taxes collected from con-
That’s an even lower threshold than the levels vent advances in plant genetics from being tractors to provide grants for in-state proj-
in existing labeling laws in Europe and Japan. commercialized. ects costing more than $5 million, including
Those in favor of Prop 37, one of “We have some very serious problems in research on alternative energy technologies
11 issues being put to California voters on agriculture, and we need to use all of the sci- and improving agricultural practices. New
6 November, say it’s needed to educate ence that we can to solve these problems,” Jersey’s Question 1 would authorize the state
consumers. But they also worry about the says Robert Goldberg, a plant biologist at to issue $750 million in bonds to upgrade
effects of GM food on health and the envi- the University of California, Los Angeles. facilities at all manner of public colleges and
ronment. In fact, many supporters hope that Goldberg calls the arguments for Proposition universities. It includes $52.5 million for
mandatory labeling will be the first step 37 “antiscience” and “ideological.” private institutions with small endowments.
toward an outright ban of GM food prod- Although surveys earlier in the year found –MEGHNA SACHDEV
100
follow-up papers. 90
off adverti
5
50
eakdow
20
John Geer, a political scientist at Vander-
%b
10
bilt University in Nashville, assembled a 0
CREDIT: (DATA SOURCE) WESLEYAN MEDIA PROJECT-KANTAR MEDIA/CAMPAIGN MEDIA ANALYSIS GROUP
472 474
LETTERS I BOOKS I POLICY FORUM I EDUCATION FORUM I PERSPECTIVES
LETTERS
edited by Jennifer Sills
The Real Costs of Research and building of facilities. there has not been a commensurate increase
Current data suggest that the National in the reimbursement of indirect costs (5),
IN THEIR 27 JULY EDITORIAL (“ICEBERG ALERT Institutes of Health (NIH) and other federal resulting in billions of dollars of additional
for NIH,” p. 390), H. R. Bourne and M. research agencies do provide critical sup- funding from universities to cover the full
O. Lively assert that “faculty, administra- port for salaries, but the majority of salary is costs of research.
tors, research institutions, and NIH must still paid by the institutions. A recent survey Finally, universities invest substantially
work together” to address the challenges of its members by the Association of Amer- to “nourish their own faculty” beyond pro-
of research funding during a time when the ican Medical Colleges showed that the per- viding facilities and administrative support.
nation is struggling to regain its fiscal health. centage of full-time faculty salaries derived A 7-year study of new faculty hires at the
However, they mischaracterize the way insti- from sponsored-program funds was, on aver- University of Rochester School of Medicine
tutions handle faculty salaries, indirect costs, age, only 15.4% (1). When full-time faculty and Dentistry showed that the school had to
add about 40 cents on every grant dollar to *To whom correspondence should be addressed. E-mail: tions faced by junior lab researchers. However,
hunter.rawlings@aau.edu
cover all the costs of research, and recovered there may be a greater danger facing interna-
only 81% of its facilities and administration References tional researchers: preventable accidents or
costs and none of its start-up costs during 1. M. Goodwin, A. Bonham, A. Mazzaschi, H. Alexander, J. illnesses when traveling outside their home
Krakower, “Sponsored program salary support to medical
this time (6). school faculty in 2009” (Association of American Medical country, especially to developing regions (for
Research stakeholders—universities, Colleges, Analysis in Brief, 2011), vol. 11; www.aamc. example, sustaining injuries while traveling
scientists, trainees, and agencies—have org/download/170836/data/aibvol11_no1.pdf. on rugged roads or contracting malaria while
2. NIH Office of Extramural Research, “Ways of managing
much to gain by thinking creatively and col- NIF research” (2011); http://report.nih.gov/UploadDocs/
conducting field work in Africa). This will
lectively about improving regulations, re- Ways%20to%20Manage%20Final.pdf. likely be the next area where academic institu-
engineering the training and workforce pipe- 3. Association of Chairs of Departments of Physiology, ACDP tions and senior researchers find themselves
line, and communicating the positive bene- Space and Budget Surveys (www.acdponline.org/Surveys. held liable for injuries or death.
htm).
fits of research. But when considering how 4. National Science Board, “Science and engineering indi- Historically, persevering over adversity
best to allocate limited resources, it is time cators 2010” (National Science Foundation, NSB 10-01, was seen as a “rite of passage” for young
to stop portraying institutions and investiga- Arlington, VA, 2010). researchers, and although most safety risks
5. T. Smith, J. Trapani, A. DeCrappeo, D. Kennedy, “Reform-
tors as being in competition with each other ing regulation of research universities” Issues in Science
can now be easily mitigated or avoided,
for research dollars and begin to talk about and Technology (Summer 2011); www.issues.org/27.4/ junior researchers rightly sense that voic-
the full and real costs of research, as well as smith.html. ing concerns about safety could harm their
Ian King
Director of Marketing and Membership, AAAS
bility in the event of injury or illness. Data CORRECTIONS AND CLARIFICATIONS for rare tree species. We show that their results are due
on adverse events during research are rare, to a statistical bias in their analysis caused by the exclu-
News Focus: “Mountains of data” by R. Service sion of joint absences.
and determining the true scale of the problem (17 August, p. 793). Microsoft Research is located in Full text at http://dx.doi.org/10.1126/science.1225520
would be an important initial step in improv- Redmond, Washington, not Richmond, Washington.
ing safety. It is imperative that academic News & Analysis: “Are world oil’s prospects not declining Response to Comment on
leadership at every level address the problem, all that fast?” by R. A. Kerr (10 August, p. 633). The credit “Conspecific Negative Density
providing adequate pre-deployment training, line should have been “Credits: (graph) Adapted from S.
proper safety equipment, and a safe work- Sorrell et al., Energy 37 (2012), with permission from Dependence and Forest Diversity”
Elsevier; (data source) M. Höök et al., Natural Resources Daniel J. Johnson, Wesley T. Beaulieu, James
ing environment abroad. A project’s primary Research 18 (2009); (photo) Shutterstock.” The credit
measure of success should not be publication D. Bever, Keith Clay
has been corrected in the HTML and PDF versions online.
or grant renewal, but that everyone returned Dickie, Hurst, and Bellingham question some of the
Reports: “Divergent nematic susceptibility in an iron methods of our recent study on conspecific density
safely. We must not wait for another bright, arsenide superconductor” by J.-H. Chu et al. (10 August, dependence in forests. Here, we reanalyze our data set
ambitious student to lose his or her life due to p. 710). References 12 and 13 should have been with the inclusion of joint absence plots of each species.
inattention to safety and security before mak- switched. Ref. 13 should be S. Kasahara et al., Nature We find that our results are robust to further analyses
ing the necessary changes. 486, 382 (2012), and Ref. 12 should have been “Mate- and that patterns of abundance and richness correlate
rials and methods are available as supplementary mate- with our measure of density dependence, supporting
BENNETT PAFFORD1* AND ROBERT MACPHERSON2
rials on Science Online.” The references have been cor- our original conclusions.
Comment on “Conspecific
We applied the same procedures to 1144
20-m by 20-m forest plots on a systematic 8-km
by 8-km grid spanning from 34°53'S to 47°13'S
Negative Density Dependence and across all natural forests in New Zealand (2).
We found overall positive conspecific density de-
1200
A B
800
800
1000
1000
600
600
Frequency
Frequency
400
400
Tree abundance
800
800
200
200
600
600
0
−4 −2 0 2 4 −2 −1 0 1 2
400
400
200
200
0
−6 −4 −2 0 2 −6 −4 −2 0 2
“S
ome people look forward to the African Americans),which pleiotropy.” Nonetheless, he
prospect of germ line genetic failed because “[f]ew peo- The Promise and Peril of has a grasp on what pleiotropy
engineering as an opportu- ple understood what it meant Genetic Engineering implies about the complex
nity to reengineer the human species. They for a genetic disorder to be by Maxwell J. Mehlman nature of gene action: “Evo-
call themselves ‘transhumanists,’ a term recessive.” With its history of Johns Hopkins University lutionary biologists worry …
coined by Julian Huxley.” Bioethicist Max- errors, one wonders whether Press, Baltimore, 2012. 286 pp. that even a small number of
well Mehlman thinks that we will inevitably the public health system has $29.95. ISBN 9781421406695. changes in pleiotropic genes
reengineer the human species, and he writes the sophistication to respond could have dramatic effects on
about that and the mistakes we might make to long-term (on an evolution- the human species.”
in the process. ary scale) rather than short-term problems. One of the strengths of Mehlman’s
rifts between the genetic haves and the have- Were there precedents? Was “The sponge philosopher.”
nots reminiscent of the Eloi and the Mor- it “in the air”? How much Robert Edmond Grant.
locks as our divergent descendants in H. of it was his and his alone?
G. Wells’s The Time Machine (2). Yet while What, if anything, did he Beagle voyage? I’ve always
Mehlman is certainly cautious—recogniz- owe to predecessors? supposed it was for more
ing the importance of unanticipated genetic It is on this worry, or less superficial reasons:
consequences, the risk of genetic engineer- one that plagued Dar- getting out of England and
ing—not once do I get the feeling that I’m win through continuously away from his father, travel
reading the words of a Luddite. revised editions of the is what other young men
Mehlman has published extensively on the Origin, that Rebecca Stott of means were doing at the
challenges and excitement of genomics and masterfully hangs Dar- time, the romance of voy-
genetic enhancement. Accessible while hav- win’s Ghosts—a beautiful aging, and other such sim-
ing enough scientific substance to be taken tapestry of the scientific ple youthful motives. And
seriously, Transhumanist Dreams provides a and philosophical search then, being a careful book-
thought-provoking read for genetics profes- for the answer to how life came to be the keeper, the evidence just kind of piled up
sionals, ethicists, interested scientists, and way it is on this planet. The book begins until, lo and behold, the idea of evolution by
concerned citizens. However, this dystopian with Darwin constructing a list of possible natural selection came to him. That is a story
A
rguments over attribution are among sion. One after another, great thinkers grap- ing to locals, fishermen or their wives selling
the most contentious in science. From ple with the notion that species cannot possi- the creatures in the market, and extracting
authorship on papers, to correct cita- bly be immutable, as the dominating biblical remarkable bits of intuitive knowledge from
tions of the preceding literature, to the choice story says, but can’t quite see through to the them. That investigative strategy appears in
of only three winners of a Nobel Prize, there crucial idea of natural selection working its the Origin as his discussions with pigeon
is always disagreement about undirected way through mul- fanciers and domestic breeders of all sorts.
priority, contribution, and sig- Darwin’s Ghosts titudes of mutations. So many It may have been Grant, through his amaz-
nificance. Of course, attribu- The Secret History of were so close for so long, ingly detailed experiments and observations
tion encompasses more than Evolution / In Search of you find yourself wanting to of sponges in search of an understanding of
often seemingly petty argu- the First Evolutionists scream to Lamarck or Diderot species mutability, who introduced Darwin to
ments over order in the author or a host of others, “No, no, the method of using a detailed problem to ask
CREDIT: LITHOGRAPH BY T. BRIDGFORD/WELLCOME LIBRARY, LONDON
by Rebecca Stott
list; it speaks to deeper issues just look a little bit over here and answer a big question (think barnacles,
in the history and philosophy Spiegel and Grau, and all will be crystal clear.” worms, and carnivorous plants)—to this day,
New York, 2012. 415 pp.
of science—where do “new” But of course hindsight is the way much of biology progresses. Grant
$27. ISBN 9781400069378.
ideas come from, and what Bloomsbury, London. £25.
always easy, and the impor- and Darwin fell out after a couple of years,
constitutes a “new” idea. ISBN 9781408809082. tance of appreciating the state and Grant died in obscurity. Stott brings
Darwin’s new idea (also of knowledge (or rather of deserved attention to this remarkable charac-
Wallace’s, of course) was ignorance) that prevailed prior ter and his influence on a young Darwin.
arguably the most seminal, world-altering, to the moment of discovery is too often for- Grant’s engaging story is one of many
paradigm-shifting conceptual leap in mod- gotten. All great leaps one day become com- recounted in Darwin’s Ghosts. Every chapter
ern science, certainly in the life sciences. But mon knowledge. seems a travelogue in scientific history and
did it spring de novo from Darwin’s mind? I was especially taken with a short digres- culture, full of interesting material you didn’t
sion on the young Darwin in the years he know or only thought you knew. Stott gives us
spent in Edinburgh, apparently failing at his a fascinating view of the evolution of one of
The reviewer is at the Department of Biological Sciences,
Columbia University, New York, NY 10027, USA. E-mail: medical studies. Have you ever wondered the biggest ideas ever—evolution.
sjf24@columbia.edu what motivated Darwin to go off on the 10.1126/science.1228701
I
n the United States, social media results. The hyperlinks are considered algorithm to defuse Google bombs on con-
sites—such as Facebook, Twit- US “votes of support,” and the weights gressional candidates by restricting the selec-
ter, and YouTube—are cur- are a computed measurement of tion of the top search results when querying
rently being used by two out of ELECTION importance assigned to Web pages their names (8). During the 2008 and 2010
three people (1), and search engines (the nodes in the graph). It is also the elections, it proved impossible to launch any
are used daily (2). Monitoring what target of propaganda attacks, known successful Google bombs on politicians, and
users share or search for in social media as “Web spam” (6). A Web spammer is it is hoped that the trend will continue.
and on the Web has led to greater insights into trying to alter the weighted Web network by During the 2010 Massachusetts Special
what people care about or pay attention to at adding connections and values that support Election (MASEN) to fill the seat vacated by
any moment in time. Furthermore, it is also his or her cause, aimed at affecting the search the death of Senator Ted Kennedy, we saw
A more sophisticated effort to create a larity in clicks they achieve. Insulting-while- aware of how that works and be prepared to
fake grassroots movement [often referred funny pictures typically attract the curiosity search for the truth behind the messages.
to as “astroturf ” (10)] was the creation of of the users and can go viral, allowing propa-
a “prefab tweet factory” (11). Designed to gandists to pass their message, while avoid- References and Notes
evade Twitter’s spam detection, a spammer ing any automatic filtering by the search 1. Pew Foundation, 65% of online adults use social net-
working sites (2011); http://bit.ly/OWHYwA.
created daily sets of tweets targeting journal- engines (16). Although this was observed 2. Pew Foundation, Search engine use 2012 (2012); http://
ists and urging other similarly minded users during the 2010 elections (16), there is some bit.ly/T9t814.
to tweet. The effect of this spam was to give evidence that search engines are working to 3. M. C. Petermann, The Twitter underground economy: A
the impression to the targeted journalists that clean their organic results, by asking users to blooming business (2012); http://bit.ly/W84BhK.
4. P. T. Metaxas, in Lecture Notes in Business Information
their reporting was monitored and was not report images they find offensive. Processing (Springer-Verlag, New York, 2010), vol. 45,
appreciated by “the public” and, thus, applied Owing to their popularity and ease of pp. 170–182; http://bit.ly/ffYsuC.
pressure to the reporters to modulate their access, social media data have been used 5. A. Broder et al., Comput. Netw. 33, 309 (2000).
views (11). We do expect to see such low- to attempt to predict future events, such as 6. C. Castillo, B. D. Davison, Found. Trends Inform. Retriev.
4, 377 (2010).
budget prefabricated tweets in the next elec- movie box-office revenues (17, 18), product 7. Google bomb, Wikipedia (2012); http://bit.ly/TjOeKa.
tions and whenever opportunity for putting sales (19), stock market fluctuations (20), and 8. P. T. Metaxas, paper presented at Workshop on Infor-
mation and Decision in Social Nets, MIT Media Lab,
Cambridge, MA, 31 May to 1 June, 2011; http://bit.ly/
The Risks of Overfishing individual species but also the overall integrity
of marine ecosystems.
Ellen K. Pikitch
O
n page 517 of this issue, Cascading effects of overfishing.
Costello et al. (1) paint Predators that feed on commercially
a dismal picture of the exploited fishes have seen substantial
state of the world’s fisheries. The declines. Costello et al. now report on
authors report that globally, the the state of global fisheries. They show
vast majority of exploited fish that poorly understood fisheries are in
much worse shape than relatively well-
populations have been depleted
studied fisheries, and that the vast
to abundance levels well below majority of fisheries are deteriorating.
those recommended by conven- These trends potentially have far-reach-
tional management guidance. Of
buffer to guard against the ecological, eco- account the profound impacts that fishing can proof would require demonstration of no
nomic and social risks of overfishing that have on habitat, nontarget species caught as serious impact before fishing could proceed.
can result from uncertainty (3, 4). bycatch, genetic diversity and integrity, com- It is justified not least because the risks of
Tiered management approaches, in petition and predation, and other aspects of continuing fishing when it results in serious
which larger buffers are set in situations the structure and function of marine ecosys- negative consequences are generally much
with less certain information, are increas- tems. In this approach, it may be necessary to greater than the risks of curtailing fishing
ingly recommended and applied (3, 5). For curtail fishing of a target species substantially when it does not have a deleterious impact.
example, Restrepo et al. have recommended below that indicated by an MSY approach to As Costello et al. show, the probability of
avoid unacceptable impacts to other species making a mistake that leads to overfishing and
and the overall ecosystem (6). depleted fish populations is higher in the infor-
Institute for Ocean Conservation Science, School of Marine
and Atmospheric Sciences, Stony Brook University, Stony Empirical and modeling evidence pro- mation-poor circumstances that dominate
Brook, NY 11794, USA. E-mail: ellen.pikitch@stonybrook.edu vides support for the view that fishery deple- contemporary global fisheries. At the same
time, emerging research is highlighting the References 4. A. E. Punt et al., ICES J. Mar. Sci. 69, 624 (2012).
danger of irreversible effects of current fish- 1. C. Costello et al., Science 338, 517 (2012); 5. E. K. Pikitch et al., Little Fish, Big Impact: Managing a
10.1126/science.1223389.
eries on overall ecosystems. These insights 2. B. Worm et al., Science 325, 578 (2009).
Crucial Link in Ocean Food Webs (Lenfest Ocean
Program, Washington, DC, 2012).
provide forceful arguments for a more precau- 3. V. R. Restrepo, G. G. Thompson, P. M. Mace, W. L. Gabriel, 6. E. K. Pikitch et al., Science 305, 346 (2004).
tionary approach to fisheries management, in L. L. Low, A. D. MacCall, R. D. Methot, J. E. Powers, B. L. 7. J. A. Estes et al., Science 333, 301 (2011).
which fishing is restricted to those places and Taylor, P. R. Wade, J. F. Witzig, Technical Guidance on 8. P. M. Cury et al., Science 334, 1703 (2011).
the Use of Precautionary Approaches to Implementing 9. A. D. M. Smith et al., Science 333, 1147 (2011).
amounts where it can be conducted safely and National Standard 1 of the Magnuson-Stevens Fishery 10. P. K. Dayton, Science 279, 821 (1998).
with minimal risk of jeopardizing the integrity Conservation and Management Act (NOAA Technical
of marine ecosystems. Memorandum NMFS-F/SPO 31, 1998). 10.1126/science.1229965
NEUROSCIENCE
The behavioral effects of two hormones on
the human brain are similar to those of a
The Mood of a Worm neuropeptide on sensory neurons in the worm.
T
he human nervous the neuroendocrine system
system is a vastly of the human brain (see the
complex network of figure). C. elegans uses this
functionally interconnected peptide to regulate behaviors
cells whose detailed struc- similar to those modulated
ture is at present beyond by oxytocin and vasopres-
reach. All our actions, cal- sin. Neuropeptides and other
culations, feelings, memo- types of hormones are one of
ries, dreams—conscious- the three ways in which cells
ness itself—emerge from its of the nervous system com-
workings. To understand this municate with one another
colossal, enigmatic structure, and with other tissues, the
experimentally amenable others being chemical syn-
model animals with tractable apses and gap junctions
nervous systems many orders (electrical synapses). Oxy-
of magnitude smaller are tocin and vasopressin, sim-
studied. A popular choice has ilar short peptides of nine
been the worm Caenorhab- amino acids, are secreted by
ditis elegans, a nematode 1 Sex and salt. (A) Neurons in the hypothalamus of the human brain secrete the hor- neurons in the hypothalamus
mm long with a nervous sys- mones oxytocin to regulate sexual and reproductive behaviors, and vasopressin to control and released into the blood
tem containing fewer than water balance. (B) Secretion of nematocin from neurons in the head and tail of the worm stream and central nervous
400 neurons. On pages 540 C. elegans regulates related behaviors—sexual behavior and salt chemotaxis. Names of system. Although both have
and 543 in this issue, Garri- neurons and muscles in the worm are indicated. widespread effects, oxytocin
son et al. (1) and Beets et al. regulates primarily sexual
(2), respectively, add to a growing body of evi- don’t “fire” (discharge a short-lived electrical and reproductive behavior, whereas vaso-
dence that even at the highest levels of coor- impulse, or action potential), but are analog pressin is involved in homeostatic regulation
dinating fundamental and complex behaviors, devices with graded electrical responses. But of water balance, with effects on the kidneys,
the same neural mechanisms are at work in the relevance of C. elegans was supported by vascular system, feelings of thirst, and drink-
worms and humans. genome sequencing. The C. elegans genome ing behavior.
C. elegans neurons do not conform to a contains nearly the same suite of genes— Garrison et al. demonstrate that similar
long-held principle of neuroscience that neu- encoding neurotransmitters, neurotransmit- to oxytocin, the C. elegans peptide, named
rons are polar, with a clear input side consist- ter receptors, ion channels, components of the nematocin, is required for normal sexual
ing of the cell body with branching extensions synapse, transcription factors, and so forth— behaviors by the male. Mutant males lack-
called dendrites and a dedicated output pro- that underlie nervous systems of other ani- ing nematocin explored their environment
cess called an axon. Many C. elegans neurons mals, including humans (3). In addition, in in search of mates less frequently than wild-
are unbranched. Sites of input and output are some parts of the male nervous system, C. ele- type males. When mutant males encountered
often intermingled along processes, prevent- gans neurons are highly branched and form a a mating partner, they initiated copulation
CREDIT: C. BICKEL/SCIENCE
ing a clear distinction between dendrite and neural network with connectivity patterns also more slowly and executed poorly. This dif-
axon. Moreover, some C. elegans neurons found in the human brain (4). fuse set of defects led the authors to specu-
Garrison et al. and Beets et al. show that late that nematocin primes a variety of neu-
C. elegans, like other animals, expresses a ral circuits to stimulate an overall appetitive
Department of Genetics, Albert Einstein College of Medi-
cine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. neuropeptide related to oxytocin and vaso- behavioral drive. Beets et al. show that nema-
E-mail: scott.emmons@einstein.yu.edu pressin, key peptide hormones released by tocin allows worms to modify their behav-
ior in light of recent experience. Normally, of neurons such that functional circuitry is been done for C. elegans and is the goal of
worms are attracted to salt. But if they experi- changed within fixed structural circuitry (7). the field of connectomics (4, 8–10). Interac-
ence salt in the absence of food, they quickly The reason for multiple modes of communi- tions due to widely diffusing neuropeptides
learn to avoid it. The authors observed that cation within the nervous system may have to and other hormones can only be discovered
nematocin-deficient worms cannot do this. do with the time scales over which they oper- by experimentation, which necessitates the
Function in salt attraction is reminiscent of ate. Gap junction– and chemical synapse– use of tractable model systems. Just as today’s
vasopressin’s role in water balance. A role for mediated communication occur over millisec- major roads and highways may once have
nematocin in memory of experience in the onds to seconds, allowing for quick reactions. been ancient trails, biological systems can
worm is similar to the roles of both oxytocin Neuropeptides and other types of hormones, retain essential features derived from their
and vasopressin in establishing memory in by contrast, allow new points of communica- origins. Although it is a mistake to consider
parental, pair-bonding, and social settings in tion between cells not in physical contact, and small invertebrates as primitive, their sys-
mammals (5, 6). their effects can also persist over much longer tems may be closer to the ancestral condition
An advantage of C. elegans is that every periods. Thus, they establish behavioral states, than those of their larger cousins. Insights into
cell is known and the same in every animal. enabling the nervous system to adjust its out- what that ancestral condition was can help us
Garrison et al. and Beets et al. identify the put to correspond to more slowly changing understand function today.
relevant cells that secrete nematocin and the environmental and physiological circum- References
cells that bear nematocin receptors. In both stances, or intrinsic conditions such as sex or
ASTRONOMY
How do you go about accurately measuring the
Measuring Solar Magnetism magnetic field in the solar atmosphere?
Alfred G. de Wijn
T
he importance of magnetic fields Magnetic field diagnostics are most 300 years show the cyclical magnetic activity
in astrophysical processes has long mature for the solar photosphere, the deepest of the Sun (6).
been recognized. A thriving field of layer that can be directly observed with opti- Most quantitative measurements to
research is centered on the life cycle (the cal telescopes. During the past decade, mea- date have relied on the Zeeman effect (7),
creation, evolution, and destruction) of mag- surements of the photospheric magnetic field whereby a magnetic field separates the sin-
netic fields in astrophysical plasmas, and have become routine with the development gle spectroscopic line of the degenerate
prominently in solar physics. The discovery of the SpectroPolarimeter instrument of the atomic energy levels into three (or more)
by Hale in 1908 that sunspots are associ- Hinode Solar Optical Telescope (2, 3) and the components. The separation of the compo-
ated with strong magnetic fields (1) spurred Helioseismic and Magnetic Imager (4) on the nents depends on the effective Landé factor
advances in spectroscopy, polarimetry, Solar Dynamics Observatory (5). Diagnos- of the line and the field strength. The for-
instrument development, and research into tics of the magnetic field in the chromosphere mer can be calculated from atomic mod-
solar magnetism. Magnetism is now known and corona above the photosphere are in their els or measured by atomic spectroscopy, so
to be the key to most unsolved problems in infancy but are becoming more common. that if the extent of the line separation can
solar physics, including the 11-year activ- There are, broadly speaking, two classes be measured, then the field strength can be
ity cycle, chromospheric and coronal heat- of magnetic field diagnostics: qualitative and determined. For regions of strong magnetic
ing, flares, coronal mass ejections, and space quantitative. Of the former, the best known field in the photosphere, such as sunspots,
weather. Even though more than a century is proxy magnetometry, which involves the the separation can be larger than the line
has passed since the discovery of magnetism identification of locations of magnetic field width (see the figure, panel B). For weaker
in the solar atmosphere, these measurements through features associated with the field, fields, the splitting is small and effectively
remain difficult. such as sunspots (see the figure, panel A). only broadens the line. In this case, it is dif-
Despite its limited diagnostic power, proxy ficult or impossible to determine the separa-
magnetometry has contributed substantially tion from the intensity measurement alone.
High Altitude Observatory, National Center for Atmospheric
Research, Boulder, CO 80307–3000, USA. E-mail: dwijn@ to our understanding of solar magnetism; Fortunately, the two shifted components are
ucar.edu records of sunspot observations going back circularly and oppositely polarized (see the
–50
ognition techniques have been successfully
–60
applied to spectropolarimetric observations
of chromospheric structures such as promi-
–70 nences (12) and filaments (13).
The difficulty of reconstructing the plasma
–80 parameters from the observation of line pro-
files is exacerbated by ambiguities in the
–90
data. For instance, the azimuth of the mag-
netic field can only be determined with an
–10 0 10 20 30 630.15 630.25 630.15 630.25 630.15 630.25 630.15 630.25 ambiguity of 180°. This problem is inherent
Heliocentric X (arc sec) λ (nm) λ (nm) λ (nm) λ (nm) to the nature of polarization and can only be
–30 F G H resolved by making additional assumptions.
Other ambiguities are more readily dealt
ANTHROPOLOGY
The shoulder bones of a juvenile australopith
Did Australopiths Climb Trees? resemble those of extant apes, suggesting that
tree climbing continued to be important for
these bipedal early human ancestors.
Susan Larson
W
hat was the lifestyle of early mem-
bers of the human lineage, such as
Australopithecus afarensis? All
fossil australopith skeletons display a mix of Supraspinatus
fossa Glenoid
humanlike and apelike characteristics, but fossa
their lower limb features leave little doubt that
these early members of our lineage walked on A.L. 288-1
two legs. However, this mixture is more dif- Adult
ficult to interpret for the upper limb. Some
investigators see the apelike upper-limb char- Scapular
CREDIT: A.L. 288-1/SUSAN LARSON; DIK-1-1, FROM (8); APES AND HUMANS/ESKELETONS.ORG/LICENSED BY CREATIVE COMMONS
facing socket for the shoulder joint (glenoid
fossa); in humans, the glenoid faces out to (DIK-1-1), offered the first real glimpse at started out life with a very different glenoid
the side. Further, australopith scapulae have an intact australopith scapula (11). The ini- orientation than seen in DIK-1-1. Similarly,
an apelike obliquely oriented scapular spine tial analysis of the right scapula, still partially Green and Alemseged show that an oblique
(the ridge of bone running across the shoulder embedded in a sandstone matrix, revealed scapular spine (see the figure) was a charac-
blade); this ridge is more nearly horizontal in an overall similarity to juvenile gorillas, teristic of australopiths throughout their life
humans (see the figure). although the conclusions were equivocal span, as it is in apes. The human pattern of
For those investigators inclined to inter- regarding the implications of this result (11). development is again different, with spine
pret anatomy in terms of function, these ape- Green and Alemseged have now analyzed angle decreasing during growth.
like features are evidence for the continued the left and right scapulae of this juvenile par- The shoulder forms the foundation for
importance of tree climbing in A. afarensis tial skeleton, freed from matrix. They show the upper limb’s range of motion. Contrast-
(1, 2). However, those who believe that the that the upward glenoid orientation character- ing patterns of scapula growth suggest dif-
ability to climb trees no longer played a major istic of adult australopiths is also apparent in fering functional demands on the shoulder
role in australopith life argue that these char- the DIK-1-1 scapulae. This feature suggests as individuals matured. Overhead use of the
acteristics are primitive retentions that offered that australopiths, like apes, maintained a upper limb while moving in trees begins early
no obvious disadvantage. In addition, it has consistent upward glenoid orientation as they in the life of apes and continues to have sur-
been suggested that variation in these features grew up. Humans, in contrast, start out with vival value even among large-bodied adults.
is influenced by body size, implying that their a somewhat downward-facing glenoid that A similar growth pattern in australopiths,
appearance in A. afarensis—for example, an gradually changes to face more directly out- therefore, supports the view that some ability
upward facing glenoid of the partial scapula ward as individuals mature (see the figure). to climb trees continued to contribute to sur-
from the famous “Lucy” skeleton (A.L. 288- The fact that australopiths began life with vival in our bipedal early ancestors. Humans
1)—simply reflects small body size (9, 10). a very different glenoid orientation than a do various things with their upper limbs, but
The discovery of a partial skeleton of a modern human makes it clear that the upward without a major focus on overhead postures
juvenile A. afarensis from Dikiki, Ethiopia facing glenoid in Lucy is not merely a reflec- their scapulae follow a very different growth
tion of small body size as has been argued trajectory.
(9, 10). Occasionally, the scapula of a small The DIK-1-1 scapulae resemble those
Anatomical Sciences, School of Medicine, Stony Brook
University, Stony Brook, NY 11794, USA. E-mail: susan. human can have a glenoid angle comparable of juvenile apes, particularly juvenile Afri-
larson@stonybrook.edu to that of Lucy, but that human would have can apes, in other characteristics as well. For
example, they have a relatively broad supra- oblique scapular spine indicate that over- Refereces
spinous fossa and a relatively narrow infra- head use of their upper limbs to climb and 1. J. T. Stern Jr., R. L. Susman, Am. J. Phys. Anthropol. 60,
279 (1983).
spinous fossa (see the figure). Unfortunately, balance in trees remained part of their over- 2. R. L. Susman et al., Folia Primatol. (Basel) 43, 113 (1984).
little is known about these characteristics in all survival strategy. 3. R. L. Susman, J. T. Stern Jr., in Origine(s) de la bipédie
adult australopiths because most fossil scapu- The scapula of the early Homo erectus (H. chez les hominidés, Y. Coppens, B. Senut, Eds. (CNRS,
Paris, 1991), pp. 121–131.
lae are incomplete. ergaster) Turkana Boy (KNM-WT 15000) 4. J. T. Stern, Evol. Anthropol. 9, 113 (2000).
Comparison of the DIK-1-1 scapulae to indicates that by about 1.8 million years ago, 5. C. O. Lovejoy, Sci. Am. 259, 118 (1988).
those of adult australopiths confirms ape- the shoulder of human ancestors had under- 6. B. Latimer, in Origine(s) de la Bipédie Chez les Homini-
dés, Y. Coppens, B. Senut, Eds. (CNRS, Paris, 1991), pp.
like shoulder characteristics in these early gone a dramatic transformation. As in modern 169–176.
human ancestors. Their shoulder blades humans, the glenoid no longer faced upward, 7. C. V. Ward, Yearb. Phys. Anthropol. S35, 185 (2002).
do not closely resemble those of any spe- the scapular spine was transversely oriented, 8. D. J. Green, Z. Alemseged, Science 338, 514 (2012).
9. R. P. Mensforth, B. Latimer, S. Senturia, Am. J. Phys.
cific living ape, reflecting the fact that they and the infraspinous fossa was broad (8). This Anthropol. 81, 267 (1990).
were habitual bipeds on the ground. Nev- reconfiguration was likely part of the emer- 10. S. E. Inouye, B. T. Shea, Int. J. Primatol. 18, 629 (1997).
ertheless, the developmental stability in A. gence of our own genus Homo and a growing 11. Z. Alemseged et al., Nature 443, 296 (2006).
afarensis of an upward facing glenoid and dependence on tools and culture for survival. 10.1126/science.1230128
C
hirality (handedness) represents an logs stemmed from their inertness to both to other classes of ligands (e.g., phosphines),
intrinsic property of many objects nucleophilic or electrophilic reagents, their the application of chiral Cp derivatives in
(such as hands and some molecules). strong binding to metal centers, and the easy asymmetric catalysis has met with far less
The increasing demand for just one isomer of modification of their steric and electronic success, (7) likely because of the inher-
a compound, especially for pharmaceuticals, properties by varying the substituents on the ent difficulties of designing chiral versions
has been met largely by purifying racemic Cp ring (6). Nevertheless, in sharp contrast of the Cp ligand. Despite this challenge, in
mixtures of chiral compounds. A powerful
alternative to separation is to use chiral cata- A O O
lysts (1) to generate only the desired enan- O R +
tiomer; chiral metal complexes bearing spe- N R’ Chiral catalyst NH
H
O * R’
cialized ligands based on heteroatoms such
as phosphines and N-heterocyclic carbenes B Me C
have been commonly used. In contrast, on H
O N
pages 504 and 500 of this issue (2, 3), the O Biotin
authors achieved highly asymmetric C–H Me Rh
Rh (Dimer)
functionalizations (4) (see the figure, panel
Cl Cl
A) by introducing chiral features to one of HN
the most common ligands used in organo- Biotin
metallic chemistry, cyclopentadienyl (Cp). H O
Ye and Cramer (2) report a chemical route Rh O
HN N
to create a chiral Cp derivative, and Hyster H OPiv
Biotin
et al. (3) describe a biochemical approach H O
Rh H
that uses a modified Cp in a chiral protein Rh H
Ph
environment. N H Mutant streptavidin
N H
The discovery of ferrocene (FeCp2) and O PivO
O MeO
the identification of its sandwich struc- O O
O OtBu
ture by Woodward, Wilkinson, and Fischer
Preferred approach Preferred approach
in the 1950s triggered important develop-
ments in modern organometallic chemistry
Hand(ednes)s on an old ligand. Two research groups report on different ways of modifying the Cp ligand
(5). The wide-scale use of Cp and its ana-
so that Rh(III)-catalyzed C−H functionalization (A) would create preferred enantiomeric products (R and R′ are
organic substituents; the star marks the product’s chiral carbon). (B) Ye and Cramer chemically synthesized a chi-
ral Cp ligand that determined the arrangement of substrate and reactant, resulting in high enantioselectivity (Me,
Organisch-Chemisches Institut, Westfälische Wilhelms-
Universität Münster, Corrensstrasse 40, 48149 Münster, methyl; Ph, phenyl; and tBu, tert-butyl). (C) Hyster et al. biochemically modified Cp to create an artificial metal-
Germany. E-mail: glorius@uni-muenster.de; honggen. loenzyme. An appropriately positioned glutamate side chain within the host protein accelerated the C−H activa-
wang@uni-muenster.de. tion step, and the asymmetric environment around the metal led to stereoselective coupling (Piv, pivaloyloxy).
many cases, the Cp moiety is an attractive ence of a basic residue in appropriate prox- or late transition metal complexes are argu-
candidate for chiral induction because it is imity to the metal center should help facili- ably more synthetically useful, and Cp is
often the only ligand that remains bound to tate C−H activation (12), Hyster et al. cre- frequently responsible for their stability and
the metal throughout the catalytic cycle. ated an artificial metallodyad by introducing reactivity, the successful design of chiral Cp
Ye and Cramer synthesized an elegant a basic carboxylate residue within the pro- derivatives will offer tremendous opportu-
chiral C2-symmetric Cp ligand and then tein through computational modeling and nities for late transition metal asymmetric
applied it in asymmetric catalysis with a rho- genetic engineering. An extensive survey of catalysis.
dium catalyst system of the type [(η5-C5H5) mutated streptavidin showed that a double
RhL1L2L3)] (see the figure, panel B), where mutant (Ser112 to Tyr and Lys121 to Glu) gave References
1. E. N. Jacobsen, A. Pfaltz, H. Yamamoto, Eds., Com-
the Cp ligand should selectively determine the desired product in excellent yield, with prehensive Asymmetric Catalysis, Vol. I-III, suppl. I-II
the spatial arrangement of the other three good regioselectivity and, most important, (Springer, New York, 1999).
ligands—L1, L2, and L3—around the metal. up to an enantiomeric ratio of 93:7. Only a 2. B. Ye, N. Cramer, Science 338, 504 (2012).
To achieve the required selectivity, three few examples were demonstrated, indicat- 3. T. K. Hyster, L. Knörr, T. R. Ward, T. Rovis, Science 338,
500 (2012).
ligand features were critical. First, a C2-sym- ing a limited substrate scope, but consid- 4. M. Wasa, K. M. Engle, D. W. Lin, E. J. Yoo, J. Q. Yu, J. Am.
metric ligand (one that is chiral and has only ering the high specificity of natural bioca- Chem. Soc. 133, 19598 (2011).
one 180° rotational symmetry axis) avoided talysis, this result is exciting and encourag- 5. H. Werner, Angew. Chem. Int. Ed. 51, 6052 (2012).
the formation of two isomeric complexes ing. It represents a rare case of an artificial 6. J. Hartwig, Organometallic Transition Metal Chemistry:
T
active catalyst. The reaction scope is quite he triple disaster of the 11 March nese are among the world’s highest per capita
general with high yields and er’s, suggesting 2011 earthquake, tsunami, and sub- consumers of seafood. On 1 April 2012, reg-
that the catalyst system is robust. sequent radiation releases at Fuku- ulators tightened restrictions for cesium-134
The biological approach taken by Hys- shima Dai-ichi were, and continue to be, and cesium-137 in seafood from 500 to 100
ter et al. functionalized Cp with biotin so unprecedented events for the ocean and for becquerels per kilogram wet weight (Bq/kg
that biotin-protein interactions would drive society. More than 80% of the radioactivity wet) in an effort to bolster confidence in the
the incorporation of the Cp-metal com- from Fukushima was either blown offshore domestic supply. In fact, this measure may
plex (which continues to act as a catalyst) or directly discharged into the ocean from have had the opposite effect, as the public
within a protein scaffold to form an artifi- waters used to cool the nuclear power plants now sees more products considered unfit for
cial metalloenzyme (which creates a chiral (1). Although offshore waters are safe with human consumption.
environment) (11) (see the figure, panel C). respect to international standards for radio- The Japanese Ministry of Agriculture,
The introduction of an appropriately posi- nuclides in the ocean (2), the nuclear power Forestry and Fisheries (MAFF) has been
tioned functional group within the protein plants continue to leak radioactive contam- monitoring radionuclides in fish and other
should further facilitate the reaction. They inants into the ocean (3); many near-shore seafood products since 23 March 2011. They
also used the Cp*Rh(III)-catalyzed synthe- fisheries remain closed. What are the pros- have been releasing these data on a regular
sis of dihydroisoquinolones as a test reac- pects for recovery? basis, most notably in a single annual com-
tion (8, 9). A biotinylated Rh(III) complex Public anxieties in Japan about seafood pilation of more than 8500 samples of fish,
[RhCp*biotinCl2]2 was designed and incorpo- safety remain high, in part because the Japa- shellfish, and seaweeds collected at major
rated within wild-type streptavidin. landing ports and inland freshwater sites,
Initially, the substrate conversion was Woods Hole Oceanographic Institution, Woods Hole, MA particularly in the most affected coastal
disappointingly low. Noting that the pres- 02543, USA. E-mail: kbuesseler@whoi.edu areas near Fukushima (4).
Apr 1
May 1
Jun 1
Jul 1
Aug 1
Sep 1
Oct 1
Nov 1
Dec 1
Jan 1
Feb 1
Mar 1
Apr 1
May 1
release March 2011 to March 2012); www.jfa.maff. 11. Ministry of Education, Culture, Sports, Science and
cesium and other radionuclides is needed to
go.jp/e/inspection/index.html. Technology, Japan (2012), “Readings of marine soil
predict long-term trends in fish and other sea- 5. Japan Ministry of Agriculture, “Results of the inspection monitoring in sea area,” http://radioactivity.mext.go.jp/
food. Such knowledge would support smarter on radioactivity materials in fisheries products” (28 en/list/260/list-1.html.
and better targeted decision-making, reduce September 2012); www.jfa.maff.go.jp/e/inspection/index. 12. D. J. Madigan, Z. Baumann, N. S. Fisher, Proc. Natl.
html. Acad. Sci. U.S.A. 109, 9483 (2012).
public concern about seafood, and potentially 6. Tokyo Electric Power Company, “Nuclide analysis results
help to revive local fisheries safely, with con- of fish and shellfish” (August 2012); www.tepco.co.jp/en/ Acknowledgments: Supported by the Gordon and Betty
fidence, and in a timely manner. nu/fukushima-np/images/handouts_120821_01-e.pdf. Moore Foundation. I thank S. Clifford for compilation of MAFF
7. International Atomic Energy Agency, Sediment Distribu- data and K. Kostel for assistance in writing.
References and Notes tion Coefficients and Concentration Factors for Biota in
1. N. Yoshida, J. Kanda, Science 336, 1115 (2012). the Marine Environment, Technical Report Series No. 422
2. K. O. Buesseler et al., Proc. Natl. Acad. Sci. U.S.A. 109, (IAEA, Vienna, 2004). Supplementary Materials
5984 (2012). 8. H. Doi, T. Takahara, K. Tanaka, PLoS ONE 7, e29295 www.sciencemag.org/cgi/content/full/338/6106/480/DC1
3. K. O. Buesseler, M. Aoyama, M. Fukasawa, Environ. Sci. (2012). Fig. S1
Technol. 45, 9931 (2011). 9. D. J. Rowan, J. B. Rasmussen, Can. J. Fish. Aquat. Sci. 51, Reference
4. Japan Ministry of Agriculture, “Results of the inspection 2388 (1994).
on radioactivity materials in fisheries products” (press 10. D. J. Rowan, J. B. Rasmussen, J. Appl. Ecol. 32, 739 (1995). 10.1126/science.1228250
Chris J. McBain
I
ndividual neurons in the mammalian
central nervous system communicate
CA1 axon
with their downstream targets by means
of subcellular specializations in their axon.
Arranged like pearls on a necklace, these pre- Low Pr High Pr
synaptic terminals enable the rapid release
Neurotransmitters
of neurotransmitter in response to an elec-
trical action-potential wave front that travels Elfn1 ?
from the cell body to the far reaches of the
axon. A single axon may contact hundreds
of downstream targets, including numerous O-LM cell Basket cell
distinct cell types. Though separated by only
a few micrometers, each of these presynap-
tic release sites is often tuned to the partic-
Tailoring one neuron to two synapses. In the hippocampus, somatostatin-containing O-LM and parvalbumin-
ular cell type it innervates such that trans- containing basket cells receive common afferent input from CA1 pyramidal neurons. The postsynaptic expres-
mission may be robust onto one particular sion of the leucine-rich repeat protein Elfn1 in O-LM cells acts to set the presynaptic initial transmitter release
cell type yet weak at another, despite all ter- probability (Pr) low, ensuring short-term facilitation of synaptic transmission. In contrast, the absence of
minals sensing the same action-potential Elfn1, of the presence of an as yet undiscovered trans-synaptic protein, endows CA1 pyramidal neuron syn-
waveform (1). This arrangement allows dif- apses onto basket cells with a high initial release probability, depressing synaptic transmission.
ferent terminals in the axon to behave inde-
pendently and “translate” presynaptic action containing 1 (Elfn1) plays an important role are triggered early in the train, which then
potentials into their own unique chemical in establishing such target-specific differen- rapidly wane as the train progresses (i.e.,
language to effect both short- and long-term tial transmission. short-term depression). In contrast, synaptic
synaptic transmission and plasticity (2, 3). CA1 pyramidal neurons of the hippocam- events onto O-LM cells start small and grow
Whether elements in the presynaptic termi- pus form synapses with many downstream as the train of action potentials progresses
nal, postsynaptic membrane, or transynap- inhibitory interneuron targets, including the (a process termed short-term facilitation,
tic proteins dictate this differential synaptic parvalbumin-containing fast-spiking basket and indicative of synapses with a low initial
processing has been unclear. On page 536 in cell and the somatostatin-positive oriens- transmitter release probability). Sylwestrak
this issue, Sylwestrak and Ghosh (4) show lacunosum moleculare (O-LM) neuron. and Ghosh demonstrate that Elfn1 is selec-
that postsynaptic expression of the extra- Under normal conditions, a train of presyn- tively expressed in O-LM inhibitory inter-
cellular leucine-rich repeat fibronectin- aptic action potentials in the CA1 pyrami- neurons and that its punctate expression on
dal neurons triggers robust synaptic trans- dendrites reveals a strong enrichment at syn-
Eunice Kennedy Shriver National Institute of Child Health mission onto basket cells (such synapses are apses where the neurotransmitter glutamate
and Human Development, Porter Neuroscience Center,
Room 3C903, Lincoln Drive, Bethesda, MD 20892, USA. referred to as having a high initial release but not the neurotransmitter γ-aminobutyric
E-mail: mcbainc@mail.nih.gov probability), such that larger synaptic events acid is released. Targeted elimination of
Elfn1 from O-LM neurons with a lentivi- sion into facilitation. The available data sug- the underlying mechanism is unclear. The
rus construct containing short hairpin RNA gest that the default setting for excitatory available data suggest that Elfn1 must have
increased the evoked excitatory postsynaptic synapses onto interneurons may occupy the downstream diffusible or trans-synaptic
current amplitude and strongly reduced the middle ground of release probability, such partners that can act to regulate the avail-
degree of short-term facilitation observed that Elfn1 acts to lower release probability ability of synaptic glutamate for presynap-
across a range of frequencies. Elimination at O-LM synapses and an as yet unidentified tic kainate receptors.
of Elfn1 in early postnatal neurons had the element acts to elevate the release probabil- The two Elfn genes have highly comple-
greatest impact on transmission, suggest- ity of basket cell synapses. mentary expression patterns in mammalian
ing an instructive role in the development Although structural roles for proteins central neurons. Elfn2 is largely confined to
and maturation of synaptic function. Elfn1 containing leucine-rich repeat (LRR) cortical and hippocampal principal gluta-
loss of function was not accompanied by motifs in axon guidance, synapse target matergic neurons (6). Although Sylwestrak
changes in postsynaptic properties, con- selection, maturation, and myelination are and Ghosh show high enrichment of Elfn1 in
sistent with a role for Elfn1 in establishing well established (5), functional roles for somatostatin-containing O-LM cells, a wider
low–presynaptic release probability syn- LRR proteins in regulating synaptic trans- pattern of expression among other unidenti-
apses onto O-LM cells (see the figure). Sur- mission are also not without precedent. For fied inhibitory interneuron subtypes is sug-
prisingly, despite this apparent Elfn1 con- example, neurotrophins and their LRR- gested (6, 7). Whether such expression coin-
trol over release probability, the absence of containing Trk receptors have both struc- cides with other excitatory inputs with low
MEDICINE
Garret A. FitzGerald
T
he imbalance between the roughly partnerships between academia and indus- that the current approach to drug develop-
constant rate of new drug approvals try (1). However, radical reform of the iron ment is vulnerable to abrupt changes in mar-
and the exploding cost estimates of rules of intellectual property (IP) worldwide ket forces, as has occurred in other markets
drug development—mostly the cost of fail- will be necessary if we are to harvest and including news media, movies, music, and
ure—has raised concern about the declining integrate the efforts of scientists and clini- transportation.
productivity of the pharmaceutical indus- cians scattered across companies, universi- What might be a less costly and more
try. Efforts to address the situation have ties, and countries, best qualified to generate efficient path to develop drugs? An ideal
included an investment in human capital— new therapies. approach would be to engage talent, from
particularly those individuals who can proj- Traditionally, large pharmaceutical com- discovery through to approval, from the
ect science across the translational divide panies embraced the entire process of drug experts most relevant to a particular chal-
(bench to clinic)—and investment in infra- discovery, development, approval, and mar- lenge, irrespective of their geographic loca-
structure, as exemplified by Clinical and keting, but such large, “vertically” integrated tion or professional setting. Such a modular
Translational Science Awards in the United companies are disintegrating. A recent mar- means has worked well in the nonprofit sec-
States and Biomedical Research Centers ket capital analysis of the 19 largest phar- tor (such as the Medicines for Malaria Ven-
in the United Kingdom, and an increase in maceutical companies indicated that invest- ture and One World Health), where altru-
ment was $1 billion for sales that amounted ism, the provision of capital by governments,
The Institute for Translational Medicine and Therapeutics,
Perelman School of Medicine Translational Research Center,
to only $75 million from 2005 to 2010—a charities, companies, the opportunity to
10th Floor, 3400 Civic Center Boulevard, Philadelphia, PA decline of more than 70% in yield compared trade shares of IP, and so-called credit default
19104–5158, USA. E-mail garret@upenn.edu to the previous 8 years (2). This suggests swaps (a type of insurance policy where the
issuer—in this case, the drug so that the cost and design of
developer—pays out when a phase 3 clinical trial can be
Academia Industry
it defaults)—have prompted refined. Here, more of the
Enhanced flow
the collapse of IP barriers, Shift to modular and use of data,
reward would be assigned to
adherence to timelines, and collaboration reagents, and clinical researchers. In both
hand-off of results to the next knowledge cases, the coalition of part-
Nonprofit
partner in the chain of pro- ners would move together
duction. This procedure has through all stages of the
enabled the rapid introduc- development process and
tion of new drugs against the model for distribution of
malaria, tuberculosis, and reward could be iteratively
Chagas disease into clinical Shift in intellectual refined in a Bayesian fashion
trials. If a variation of this property management (with prospective agreement
model could be exported to Composition of matter Final approved drug of all the partners) and final-
for-profit drug development, (unknown value) (value realized) ized upon drug approval.
it could enable the assembly a If further studies of a new
range of stakeholders drawn drug after its approval for
grated companies, a focus on the composi- dation of the basic biology. In this case, more Times, 7 October 2012; www.nytimes.com/2012/10/08/
tion of matter was logical; in the unlikely of the reward would be assigned prospec- technology/patent-wars-among-tech-giants-can-stifle-
event that a molecule became a drug, all tively to those who solve these problems. In competition.html.
5. “Does the law support inventors or investors?” New York
employees who had shares in the company the case of the lipid-lowering drug, a barrier Times, 10 October 2012; www.nytimes.com/
(not just the chemists) stood to profit. Mov- might be predicted to arise later in the devel- roomfordebate/2012/10/10/does-the-law-support-
ing to a collaborative model, how should opment process, such as defining populations inventors-or-investors.
partners from different sectors and countries in which the new drug worked well and safely 10.1126/science.1231170
M
acroscopic organisms, even when
healthy, harbor diverse micro-
organisms that influence their
development, physiology, and fitness. This
microbial diversity is accompanied by
chemical diversity, which provides a plat- Collection theme Fieldwork Microbe isolation Bioactivity assays Purification Chemical analysis
form for integrative research training span-
demonstrated, but underexplored, potential (CURE) (8) indicates that alumni of the Yale
to make novel chemical products important program consistently self-report a readiness Acknowledgments: We thank K. Kucera, L. Boulanger,
for human sustainability (7). Students select for more demanding research, greater self- and the teaching fellows and students who have contributed to
each program. S.A.S., C.A.B.-S., and colleagues are supported
and culture a subset of their endophytes on confidence, and a better understanding of the by a Professorship to S.A.S. from Howard Hughes Medical Insti-
a larger scale for use in standard bioassays, research process. The vast majority (>80%) tute and NSF grant 0853408. A.E.A. is supported by NSF (DEB-
testing culture filtrates and extracts for enzy- continue their research in subsequent semes- 0702825, 1045766) and awards with colleagues B. Klein, M.
Shimabukuro, and M. Wilch.
matic activities relevant to industry, agricul- ters. Upon graduation, they matriculate into
ture, and medicine (e.g., cellulase, ligni- Ph.D. programs at a rate about three times
Supplementary Materials
nase, and protease activity or activity against that of other Yale graduates with a science www.sciencemag.org/cgi/content/full/338/6106/485/DC1
human and plant pathogens). Each student degree. Diné College students highlight this
also identifies an assay in conjunction with experience in their applications to 4-year 10.1126/science.1215227
W
ith ~36,000 students enrolled, the
University of North Texas is the
fourth largest state university in
Texas. To provide each of the >1800 under-
graduate Biology majors the opportunity to
participate in a discovery-based project, we
developed “Worm Mutants,” a worm mutant
screen module for the required genetics lab-
movement look for a worm mutant that does logical function. In addition to these concep- base, WormBase; relevant scientific papers;
not move normally. tual challenges, student teams do not know and C. elegans nomenclature. In a prior lab
if they will identify the mutant of interest lesson, students are familiarized with wild-
Department of Biological Sciences, University of North and, therefore, there are no “right” answers type and common mutant phenotypes (table
Texas, Denton TX 76203, USA. to the lesson (see the first figure). Instead, the S1) (2, 3).
worm mutant screen challenges students to Students discuss the range of biological
*IBI, Science Prize for Inquiry-Based Instruction;
www.sciencemag.org/site/feature/data/prizes/inquiry/. think about observable mutant phenotypes processes that intrigue them and which pro-
Author for correspondence. E-mail: pamela.padilla@unt.edu and biological processes. cesses can be studied using C. elegans as a
PHOTO CREDITS: (TOP LEFT) ALYSSA PADILLA (P.P.); (BOTTOM RIGHT) CANDACE LARUE (C.L.)
lated many mutants with various phenotypes communication, teamwork, and the devel-
C (see the second figure). opment of scientific ideas.
Aside from the isolation of C. elegans
mutants, student-learning experiences References and Notes
D include teamwork, time management, 1. S. Brenner, Genetics 77, 71 (1974).
2. L. R. Girard et al., Nucleic Acids Res. 35 (Database issue),
recording of results, problem-solving, data D472 (2007).
collection, and scientific communication. 3. K. Yook et al., Nucleic Acids Res. 40 (Database issue),
Furthermore, students have shown innova- D735 (2012).
4. E. M. Jorgensen, S. E. Mango, Nat. Rev. Genet. 3, 356
tion and creativity by using smart phones
E and video to capture images of lab tools,
(2002).
techniques, and experimental animals; have Acknowledgments: This work has been supported in
gained a sense of independence and own- part by an NSF CAREER grant to P.A.P. We thank L. Finn for
graphic art assistance for fig. S2. We thank the Department of
ership of discovery (“my mutant” is often
C. elegans mutants with observable phenotypes. heard); and have achieved experimental Biological Sciences, Genetics teaching assistants, and the Lab
Coordinator for support of this project and A. Colon-Carmona
These were isolated by undergraduate students. (A)
accomplishments not often observed with for comments.
Wild-type; (B) small mutant (adults are small); (C)
Dumpy mutant (adult animals are short and thick);
“cookbook” laboratory lessons. To demon-
(D) egg laying–defective mutant (adult animals strate their communication skills, students’ Supplementary Materials
rarely lay eggs, so embryos mature and hatch inside research proposals describe background, www.sciencemag.org/cgi/content/full/338/6106/487/DC1
the hermaphrodite); (E) protruding vulva mutant. hypotheses, methods, preliminary data col-
Scale bar, 50 µm. lection (their mutant identified), data inter- 10.1126/science.1215229
SCIENCE DIPLOMACY
Fifty Years after Cuba Crisis, said. Nations or organizations that might
have crude arsenals or ìthat donít subscribe
to the established rules and normsî present
New Roles for S&T in Arms Control different challenges to arms control veriˇca-
tion, monitoring, and diplomacy.
ATLANTA, GEORGIA—Pierce Corden re- Technological advances and science diplo- In all, 183 nations have signed the Com-
members well a mild night in late Octo- macy will be crucial to a new generation of prehensive Nuclear-Test-Ban Treaty, which
ber 1962: President John F. Kennedy was nuclear security, said experts gathered at seeks to prohibit all nuclear explosions,
addressing the nation, describing the place- the Georgia Institute of Technology. and 157 have ratiˇed it. Ambassador Tibor
ment of Soviet nuclear weapons in Cuba, ìIn terms of U.S. diplomacy, some of TÛth, executive secretary of the Prepara-
just 90 miles from Florida, and warning of the greatest assets we have are not only in tory Commission for the Comprehensive
the potential for war. In the following days, our government agencies, but in our foun- Nuclear-Test-Ban Treaty Organization,
tists and engineers into the fields of arms and then to a series of arms control agree- ìThe distance that almost caused nuclear
control and science diplomacy. ments in ensuing years. catastrophe is also a distance where we
While the Cold War has receded, arms Today, however, the nature of nuclear share so many resources and interests,î
control remains a global priority, driven threats is far different than 50 years ago, said Turekian said. ìThatís where this whole
by fears of terrorism, nuclear programs in Adam N. Stulberg, codirector of the center at issue of science and diplomacy, and how
Iran and North Korea, and creeping ten- Georgia Tech. There are more nuclear play- it can help lead to peace and prosperity, is
sions between the United States and Russia. ers with ìdifferent idiosyncracies,î Stulberg really important.î
its open hearing at 2:30 p.m. on 16 February 2013 in the Republic Ballroom of the Sheraton
Boston Hotel. A copy of the full council agenda will be available for inspection in the AAAS
headquarters office in the Hynes Convention Center in Boston.
100 Transplanted
75 Saline treated tiation speaks to the efforts that may be anti-
Untreated cipated in developing NSCs and GPCs as vehicles
50
for intracerebral enzyme replacement in the meta-
25
bolic leukodystrophies.
0
0 50 100 150 200 250 300 350 400 The intracerebral delivery of GPCs would
Age in days seem an especially promising approach for treat-
hN
ing those enzyme-deficiencies associated with
E early demyelination, which may require both en-
zyme replacement and structural remyelination.
Metachromatic leukodystrophy (MLD), for ex-
ample, is characterized by deficient expression of
arylsulfatase A, which results in sulfatide misac-
hN MBP hGFAP cumulation and oligodendrocyte loss. Experimen-
tal models of MLD have responded well to GPC
F grafts, with broad dispersal and integration, as
well as enzymatic rescue and sulfatide clearance
(41). Krabbe’s disease, characterized by galacto-
cerebrosidase deficiency and early demyelination,
is another storage disorder that may prove ame-
hN hGFAP nable to concurrent GPC-based enzymatic re-
pletion and myelin restoration. When children
G H with Krabbe’s disease were transplanted with um-
bilical cord stem cells, they manifested slower
disease progression, but the benefits of trans-
plantation to children engrafted after symptom
onset seemed minimal (42). Yet the intracerebral
infiltration of umbilical cord stromal derivatives
MBP NF Kv1.2 CASPR is modest, suggesting that treatment of these chil-
dren with GPCs, which are able to achieve broad
parenchymal dispersal as well as structural re-
Fig. 2. Glial progenitor cell graft-mediated myelination of a dysmyelinated host. (A) A 13-month-old myelination, might involve a more promising
shiverer (shi/shi) × rag2−/− mouse, neonatally xenografted with A2B5+/PSA-NCAM– hGPCs. MBP, myelin basic treatment strategy.
protein (shown in green). Shiverer mice do not express MBP; all immunolabeled myelin is of donor origin. (B) The experimental assessment of GPCs as
Sagittal view through the cerebellum. All cells were stained with 4′,6-diamidino-2-phenylindole (blue); donor vectors for remyelination has proceeded most
cells were identified by human nuclear antigen (hN, red) and MBP (green). (C) Kaplan-Meier plot comparing aggressively in animal models of congenital
survival of neonatally engrafted shiverer × rag2−/− mice to untreated and saline-injected controls. (D) CD140a-
hypomyelination. In an early study of cell-based
selected GPCs transplanted into neonatal shiverer × rag2−/− mice expanded and migrated extensively,
myelin repair, mouse neural stem cells were
rendering the brains chimeric. Red dots indicate individual human cells (hN); sacrificed at 3 months. (E and
F) Coronal sections of a neonatally engrafted shiverer brain at 3 months, revealing donor-derived transplanted into newborn shiverer mice, a hypo-
myelination (MBP, red) and astrocytic infiltration [human glial fibrillary acidic protein (GFAP), green] of myelinated mutant deficient in myelin basic
the corpus callosum. (G) Myelin (MBP, red) produced by CD140a-selected hGPCs ensheathes mouse protein, and yielded context-dependent myeli-
neurofilament-positive axons (NF, green), at 3 months. (H) Reconstituted nodes of Ranvier in the cervical nation (43). On that basis, we transplanted sorted
spinal cord of a transplanted and rescued 1-year-old shiverer × rag2–/– mouse, showing paranodal Caspr human GPCs into neonatal shiverers, so as to as-
protein and juxtaparanodal voltage-gated potassium channel protein Kv1.2, symmetrically flanking each sess the relative myelinogenic potential of GPCs
axonal node. Untransplanted shiverer brains do not have organized nodes of Ranvier and, hence, cannot (13). When delivered as highly enriched isolates,
support saltatory conduction by central axons (Caspr, red; Kv1.2, green). Scale bars: (A) and (B), 1 mm; (E), fetal human GPCs spread widely throughout
50 mm; (F) and (G), 10 mm; (H), 5 mm. (A) and (B), from (54); (C) and (H), from (5); (D) to (G), from (10). the brain (Fig. 2, A, B, and D), developing as
ρ[Y (t)|MX]−ρ[X(t)|MY]
0.8 0.4
0.3
1.25 0.9
0.2
0.6
0.8
β y,x
0.2 0 1
ρ
0.4 0.7
−0.2
ρ[Y (t)|MX]
0.1 0.75
ρ[Y (t)|MX]
0.2 X(t)|MY −0.4 0.6
0.2 Fig. 3. Detecting causation with CCM. With convergence, the skill of cross-map esti-
0.2
ρ
0.75 SST as well as between anchovies and SST (Fig.
5, E and F), meaning that temperature information
100
0.7 Para. xmap Didi. is encoded in both fishery time series. The recov-
Didi. xmap Para. erable temperature signature reveals a weak coupling
0 0.65
0 5 10 15 20 25 30 10 20 30 40 50 60 of temperature to sardines and anchovies. Thus, al-
Time (days) L though sardines and anchovies are not actually
REPORTS
alytic scaffold remains a major challenge (2–5).
Biotinylated Rh(III) Complexes in One class of strategies has relied on the incor-
poration of non-natural metal cofactors within
Engineered Streptavidin for Accelerated a protein scaffold to afford artificial metalloen-
zymes (6–9). The main focus in the area has been
improving the selectivity of the hybrid catalysts,
Asymmetric C–H Activation rather than reaction rates, which are, by and large,
dictated by the first coordination sphere interac-
Todd K. Hyster,1,2 Livia Knörr,2 Thomas R. Ward,2* Tomislav Rovis1* tions around the metal (10–12). Among the var-
ious cofactor localization strategies (13, 14), the
Enzymes provide an exquisitely tailored chiral environment to foster high catalytic activities and biotin-(strept)avidin technology has proven ver-
selectivities, but their native structures are optimized for very specific biochemical transformations. satile: The geometry of the biotin-binding pocket
Designing a protein to accommodate a non-native transition metal complex can broaden the scope of is ideally suited to accommodate organometallic
enzymatic transformations while raising the activity and selectivity of small-molecule catalysis. Here, we moieties, leaving enough room for substrate bind-
report the creation of a bifunctional artificial metalloenzyme in which a glutamic acid or aspartic acid ing and activation (15–19).
residue engineered into streptavidin acts in concert with a docked biotinylated rhodium(III) complex to
enable catalytic asymmetric carbon-hydrogen (C–H) activation. The coupling of benzamides and alkenes
to access dihydroisoquinolones proceeds with up to nearly a 100-fold rate acceleration compared with the 1
Department of Chemistry, Colorado State University, Fort
activity of the isolated rhodium complex and enantiomeric ratios as high as 93:7. Collins, CO 80523, USA. 2Department of Chemistry, Uni-
versity of Basel, Basel CH-4056, Switzerland.
hanks to the advent of genetic engineer- displacing established organometal-catalyzed
A D
Active Site
Tailoring
Base
Asn 118A
Metal Metal
B O O
OPiv [RhCp*biotinCl2]2
N NH
H + Streptavidin
R with engineered R
carboxylate
H Me
S N
H Me Me
HN O Me
H Rh
NH
O [RhCp*biotinCl2]2 Cl Cl Ser 112B
2
Lys 121B
C BiotinNH
1-2
Sav
Cp*
H O
Rh O
N OPv Asn 118B
O
Fig. 1. (A) Synergistic action of a basic residue introduced by site-directed Postulated transition state for the C–H activation step. (D) Auto-Dock model
mutagenesis and a biotinylated RhCp*biotinCl2 moiety acting as catalyst for of biotinylated RhCpbiotin(OAc)2 complex anchored in the proposed active site
an abiotic reaction. (B) Benzannulation reaction catalyzed by the artificial me- of the streptavidin tetramer with key residues highlighted (adjacent complex
talloenzyme for the synthesis of enantioenriched dihydroisoquinolones. (C) in Sav monomer B omitted for clarity).
the desired product in 95% yield, 19:1 regioiso- 18 S112V Acetate Buffer 4 5:1 81:19
meric ratio (rr), and 91:9 er (Table 1, entry 23). 19 S112Y Acetate Buffer 30 12:1 88:12
This transformation proved applicable to a 20 S112W Acetate Buffer 32 12:1 86:14
variety of substrates (Fig. 2). Ethyl vinyl ketone
21 S112Y-K121D H2O 30 20:1 90:10
was highly reactive under the reaction conditions,
22 S112Y-K121E H2O 80 20:1 90:10
resulting in benzannulated product in good yield,
high regioselectivity, but poor enantioselectivity. 23 S112Y-K121E MOPS Buffer 95 19:1 91:9
When methyl acrylate was replaced with benzyl *Yield determined by gas chromatography integration.
acrylate, yield and enantioselectivity were di- †Reaction conducted for 36 hours.
minished. Substitution on the benzamide was better ‡Sav preloaded with excess biotin for 10 min and then treated with [RhCp*biotinCl2]2.
tolerated under the reaction conditions. Bromo-
substituted and naphthyl benzamides delivered
product in good yield, with a modest erosion of
er in comparison to the parent system. The enan- [RhCp*biotinCl2]2 (1 mol %)
tioselectivity increased with para-substituted nitro- O O
R S112Y-K121E (0.66 mol %)
benzamides, albeit at the expense of lower yield. OPiv yield (%)
N NH r.r.
The remaining mass balance is represented by H MOPS Buffer/MeOH (4:1) e.r.
unreacted starting material. R' 23 °C, 72h R' R
1a-d 2a-c 3b-f
The data presented above argue for the syn-
ergistic action of both the carboxylate side O O
O
chain and the chiral cavity inside the metallo-
enzyme for optimal reactivity and selectivity. NH NH NH
We sought further support for the role of the Et OBn OMe
critical basic amino acid residue by conduct- Br
ing mechanistic studies. Using the monodeu- 95% yield O 61% yield O 64% yield O
terated benzamide d1-1a, we observed a kinetic 10:1 15:1 3c 14:1 3d
3b
56:44 73:27 88:12
isotope effect (kH/kD) (KIE) value of 3.8 for the
O
reaction with [RhCp*biotinCl2]2 under buffered O
conditions [1:4 MeOH:acetate buffer (pH = 5.9, NH NH
0.69 M) for the internal competition KIE study] OMe
O2N OMe
(figs. S1 to S3). In the presence of WT Sav un-
der identical conditions, a KIE value of 2.8 was 30% yield O 80% yield O
obtained. With the most active mutant, N118K- 32:1 22:1
93:7 3e 89:11 3f
K121E, a KIE value of 4.8 was found under
acetate-free conditions (4:1 H2O:MeOH). These Fig. 2. Substrate scope.
90 90 90
80 80 80
70 70 70
60 60 60
bound - 3x more reactive bound - 92x more reactive bound - 34x more reactive
50 50 50
0 2 4 6 8 10 12 0 2 4 6 8 10 12 0 2 4 6 8 10 12
equivalents of metal monomer
Fig. 3. Determination of the relative catalytic rates of free and Sav-bound catalysts using (A) WT Sav, (B) N118K-K121E, and (C) S112Y-K121E. Blue crosses,
results suggest a primary kinetic isotope effect eight equivalents, mbound = mfree = 4); %(R)bound 16. C.-C. Lin, C.-W. Lin, A. S. C. Chan, Tetrahedron
in all cases. Subtle differences in the geometry of and %(R)free are the %(R) for the Sav-bound and Asymmetry 10, 1887 (1999).
17. M. T. Reetz, J. J. P. Peyralans, A. Maichele, Y. Fu,
the CMD mechanism (Fig. 1C) is a likely source the free catalyst (i.e., %(R)free = 0.515, Table 1, M. Maywald, Chem. Commun. 41, 4318 (2006).
of the slightly different KIE values. entry 1). Using Eq. 1 and performing a least-square 18. M. Skander et al., J. Am. Chem. Soc. 126, 14411
To provide further support for the critical minimization on the calculated and experimen- (2004).
role of the carboxylate residue within the en- tally determined %(R) (green line and blue crosses 19. T. R. Ward, Acc. Chem. Res. 44, 47 (2011).
zyme’s active site, we conducted competition respectively, in Fig. 3) (also see table S1), we 20. T. Satoh, M. Miura, Chem. Eur. J. 16, 11212 (2010).
21. N. Guimond, S. I. Gorelsky, K. Fagnou, J. Am. Chem. Soc.
experiments between protein-bound and free can determine the relative rates krel = (kbound)/ 133, 6449 (2011).
[RhCp*biotinCl2]2 catalyst precursors. The very (kfree). For WT Sav, we compute a 3-fold rate 22. S. Rakshit, C. Grohmann, T. Besset, F. Glorius, J. Am.
limited solubility of the starting material precludes acceleration compared with the protein-free cat- Chem. Soc. 133, 2350 (2011).
the use of classical Michaelis-Menten kinetic ex- alyst. This phenomenon of protein acceleration 23. T. K. Hyster, T. Rovis, J. Am. Chem. Soc. 132, 10565
periments. Because the free biotinylated catalyst is enhanced in the presence of carboxylate-bearing (2010).
24. D. Lapointe, K. Fagnou, Chem. Lett. 39, 1118
leads to nearly racemic product (51.5:48.5 er) Sav isoforms: In pure water and for N118K-K121E (2010).
(Table 1, entry 1), whereas the Sav-bound cat- and S112Y-K121E, we compute rate accelerations 25. L. Xu, Q. Zhu, G. Huang, B. Cheng, Y. Xia, J. Org. Chem.
alyst leads to enantioenriched product, a com- of 92 and 34, respectively. The substantially in- 77, 3017 (2012).
parison of the er as a function of the number of creased rate is diagnostic of the key role of the 26. T. Reiner, D. Jantke, A. Raba, A. N. Marziale, J. Eppinger,
equivalents of RhCp*biotinCl2(H2O) versus tetra- active-site carboxylate in the turnover-limiting step, J. Organomet. Chem. 694, 1934 (2009).
27. N. M. Green, Methods Enzymol. 18A, 418 (1970).
meric Sav provides an estimate of the relative which we suggest is the C–H activation event.
28. After optimization, the ideal conditions with WT Sav were
rates of the protein-bound (kbound) and the free This confirms the hypothesis that the engineered found to be aqueous solvent [1:4 MeOH:acetate buffer
biotinylated catalyst (kfree) (31). These experi- carboxylate residue within the active site is key (0.67M, pH=5.9)] with a 1.3:1 ratio of Sav binding sites
ments were performed with WT Sav, N118K- to generating a highly active and selective arti- to biotinylated rhodium monomer, delivering product
K121E, and S112Y-K121E as host protein (Fig. ficial benzannulase. in 23% yield with 9:1 regioselectivity after 36 hours.
Identical product distribution was obtained upon using
3, A, B, and C, respectively). Because the er [Cp*biotinRh(H2O)3]2+.
with up to four equivalents RhCp*biotinCl2(H2O) References and Notes 29. G. M. Morris et al., J. Comput. Chem. 30, 2785
remains essentially constant, we conclude that 1. C. K. Savile et al., Science 329, 305 (2010). (2009).
the four Sav-bound catalysts operate indepen- 2. B. Seelig, J. W. Szostak, Nature 448, 828 (2007). 30. M. T. Reetz, Angew. Chem. Int. Ed. 50, 138 (2011).
dently (i.e., no cooperative effect) and induce the 3. H. S. Park et al., Science 311, 535 (2006). 31. J. Collot, N. Humbert, M. Skander, G. Klein, T. R. Ward,
4. S. D. Khare et al., Nat. Chem. Biol. 8, 294 (2012). J. Organomet. Chem. 689, 4868 (2004).
same level of enantioselectivity. Past four equiv- 5. D. Röthlisberger et al., Nature 453, 190 (2008).
alents and if the relative rates kbound and kfree 6. Y. Lu, N. Yeung, N. Sieracki, N. M. Marshall, Nature Acknowledgments: We thank the National Institute of General
are identical, the er is expected to sharply and 460, 855 (2009). Medical Sciences (GM80442), the Swiss National Science
asymptotically decrease (orange lines in Fig. 3). 7. T. Heinisch, T. R. Ward, Curr. Opin. Chem. Biol. 14, Foundation (grant 200020-126366), the National Center of
184 (2010). Competence in Research Nanoscale Sciences, the Marie Curie
The rate acceleration provided by the protein-
8. G. Roelfes, Chem. Cat. Chem. 3, 647 (2011). Training Network (FP7-ITN-238434), Amgen, and Roche for
environment can be estimated by Eq. 1 9. P. F. Mugford, U. G. Wagner, Y. Jiang, K. Faber, support. We thank Johnson Matthey for a loan of rhodium
R. J. Kazlauskas, Angew. Chem. Int. Ed. 47, 8782 salts and C. R. Cantor for the Sav gene. We thank M. J. Zimbron
%ðRÞcalculated ¼ (2008). for providing an initial sample of [RhCp*biotinCl2]2 and for
kbound •mbound •%ðRÞbound þ kfree •mfree •%ðRÞfree 10. N. Yeung et al., Nature 462, 1079 (2009). stimulating discussions.
11. Y.-W. Lin et al., Proc. Natl. Acad. Sci. U.S.A. 107,
kbound •mbound þ kfree •mfree 8581 (2010). Supplementary Materials
www.sciencemag.org/cgi/content/full/338/6106/500/DC1
ð1Þ 12. Y.-W. Lin et al., J. Am. Chem. Soc. 132, 9970 (2010).
Materials and Methods
13. P. J. Deuss, R. den Heeten, W. Laan, P. C. J. Kamer,
Figs. S1 to S3
where kbound and kfree are the rate constants for Chem. Eur. J. 17, 4680 (2011).
Table S1
14. A. J. Boersma, R. P. Megens, B. L. Feringa, G. Roelfes,
the Sav-bound and the free catalyst, respective- Chem. Soc. Rev. 39, 2083 (2010). References (32–36)
ly. The parameters mbound and mfree are the 15. M. E. Wilson, G. M. Whitesides, J. Am. Chem. Soc. 100, 15 June 2012; accepted 21 September 2012
number of Sav-bound and free catalysts (i.e., at 306 (1978). 10.1126/science.1226132
S cyclopentadienyl (Cp)–coordinated metal arising from a face-selective approach of the third Cp ligand would favor the two orientations of the
the reaction media, ligand exchange/protonation 10. A. Gutnov, H.-J. Drexler, A. Spannenberg, G. Oehme,
Acknowledgments: This work is supported by the European
regenerates 5 and expels product 4 and t-butyl hy- B. Heller, Organometallic 23, 1002 (2004).
Research Council (ERC) under the European Community’s
11. G. P. McGlacken, C. T. O’Brien, A. C. Whitwood,
drogen carbonate, which collapses to CO2 and Seventh Framework Program (FP7 2007–2013)/ERC
I. J. S. Fairlamb, Organometallics 26, 3722 (2007).
tBuOH without changing the overall acidity of the 12. A. Gutnov et al., Angew. Chem. Int. Ed. 43, 3795 (2004).
Grant agreement 257891. We thank R. Scopelliti for x-ray
crystallographic analysis of 1c. CCDC 898196 contains the
medium during the course of the reaction. The 13. B. Heller et al., Chemistry 13, 1117 (2007).
crystallographic data for 1c. These data can be obtained
absolute configuration of product 4a was determined 14. M. Hapke et al., J. Org. Chem. 75, 3993 (2010).
free of charge from the Cambridge Crystallographic Data
15. Sandwich complexes containing two Cp moieties such as
to be (R)-4a (36). The underlying selectivity of the ansa-ebthi metallocenes of Ti, Zr, or Hf are versatile catalysts
Centre, www.ccdc.cam.ac.uk/data_request/cif.
reaction was visualized by a graphical model rep- for several asymmetric reactions. For an overview, see (16).
resenting the complex 1c (Fig. 3) (37). The back 16. A. H. Hoveyda, J. P. Morken, Angew. Chem. Int. Ed. Engl. Supplementary Materials
35, 1262 (1996). www.sciencemag.org/cgi/content/full/338/6106/504/DC1
wall forces styrene to approach from the open face Materials and Methods
17. C. P. Lenges, M. Brookhart, J. Am. Chem. Soc. 119, 3165
with the phenyl group oriented away from the Cp (1997). Figs. S1 to S3
ring. Conformer C1 having its hydroxamate moiety 18. H. Chen, S. Schlecht, T. C. Semple, J. F. Hartwig, Science References (38–43)
turned away from the steering side wall is the 287, 1995 (2000). 4 July 2012; accepted 10 September 2012
faster-reacting isomer, leading to (R)-4a. 19. J. F. Hartwig et al., J. Am. Chem. Soc. 127, 2538 (2005). 10.1126/science.1226938
In conclusion, we have described a class of chiral
Cpx* analogs with low molecular weight that de-
symmetrize a rhodium(III)-catalyzed directed C–H
bond functionalization. The reaction proceeds under Fluorescence Enhancement
mild conditions and is high yielding and enantiose-
lective. This development should become a stepping-
stone to unlock the potential of chiral Cp analogs as
at Docking Sites of DNA-Directed
steering ligands in enantioselective late-transition
metal catalysis with half-sandwich complexes.
Self-Assembled Nanoantennas
G. P. Acuna,* F. M. Möller, P. Holzmeister, S. Beater, B. Lalkens, P. Tinnefeld*
References and Notes
1. R. H. Crabtree, The Organometallic Chemistry of the We introduce self-assembled nanoantennas to enhance the fluorescence intensity in a plasmonic
Transition Metals (Wiley, New York, ed. 3, 2001). hotspot of zeptoliter volume. The nanoantennas are prepared by attaching one or two gold nanoparticles
2. E. N. Jacobsen, A. Pfaltz, H. Yamamoto, Eds., (NPs) to DNA origami structures, which also incorporated docking sites for a single fluorescent dye
Comprehensive Asymmetric Catalysis: Vol. I-III, Suppl. I-II,
(Springer, New York, 1999).
next to one NP or in the gap between two NPs. We measured the dependence of the fluorescence
3. A. H. Hoveyda, J. P. Morken, Angew. Chem. Int. Ed. Engl. enhancement on NP size and number and compare it to numerical simulations. A maximum of
35, 1262 (1996). 117-fold fluorescence enhancement was obtained for a dye molecule positioned in the 23-nanometer
4. U. Siemeling, Chem. Rev. 100, 1495 (2000). gap between 100-nanometer gold NPs. Direct visualization of the binding and unbinding of short DNA
5. R. L. Halterman, K. P. C. Vollhardt, Organometallics 7,
883 (1988).
strands, as well as the conformational dynamics of a DNA Holliday junction in the hotspot of the
6. R. L. Halterman, Chem. Rev. 92, 965 (1992). nanoantenna, show the compatibility with single-molecule assays.
7. H. Schumann et al., Eur. J. Inorg. Chem. 2002, 211 (2002).
ingle-molecule fluorescence measure- intermediates, structure, stoichiometry of subpop-
8. R. L. Halterman, L. D. Crow, Tetrahedron Lett. 44, 2907 (2003).
9. A. Gutnov, B. Heller, H.-J. Drexler, A. Spannenberg,
G. Oehme, Organometallics 22, 1550 (2003). S ments report on kinetic processes without
the need for synchronization, lifetimes of
ulations, and the choreography of biomolecu-
lar processes (1, 2). Yet, only a small number
A II B C 10
4 D
I: no NP 10
3 II: monomer 104
2000 2000 2000
counts / 10 ms
2
10
10
0
101
50 0 4 8 0 4 8 0 4 8
III time (ns) 100 time (ns) time (ns)
1000 1000 1000
0
I 0
2 4 2 4 III: dimer
5 µm 0 0
0
2 4 2 4 2 4
time (s) time (s) time (s)
Fig. 2. (A) Confocal fluorescence image of NADS with binding sites for two NPs. Three spots with different intensities are highlighted: I (no NP), II (one NP),
and III (two NPs). (B to D) Corresponding intensity transients together with their fluorescence decays (insets).
40 to the hotspot of a dimer NADS (Fig. 4E and fig. NADS created fluorescence enhancement
20 S1). The HJ was directly incorporated to the DNA in ultrasmall hotspots in the zeptoliter range that
origami structure as in (28) and was labeled with could be used for single-molecule detection at
0
Cy3 and Cy5 dyes (18). The anticorrelated inten- elevated dye concentrations. Additional time-
fluorescence enhancement
70 Dimer sity changes of the green (donor excitation/donor gated detection making use of the difference
Monomer
60 emission) and red (donor excitation/acceptor of the fluorescence lifetimes inside and out-
50
emission) detection channels shown in Fig. 4F side of the hotspot could almost fully recover
80
Simulation radial
70 Simulation tangential
60 Monomer
50
40
30 B F 60
20 photon count (kHz) 50 3
10
10 100 40
1
rel. intensity (a.u.)
0 10 0 4 8
20 40 60 80 100 80 30 time (ns)
nanoparticle diameter (nm)
20
C 90 60
10
fluorescence enhancement
80 Measurement
Simulation radial 40
70 0
Simulation tangential 0 2 4 6
20 time (s)
60 Dimer G
50 1000
0
0 10 20 30 40 50 60
photon count (kHz)
30 C D
80 80 600 1
20 10 0 4 8
60 60 time (ns)
10 400
40 40
0 green-green
20 40 60 80 100 20 20 200 FRET
nanoparticle diameter (nm) red-red
0 0
24.0 24.8 25.0 25.1 0
Fig. 3. (A) Scatter plot of fluorescence intensity time (s) time (s) 0.0 0.2 0.4 0.6 0.8 1.0 1.2
time (s)
versus lifetime with a corresponding lifetime his-
togram of the ATTO647N-labeled DNA origami Fig. 4. (A) Sketch of the modified DNA pillar for the DNA binding assay. ssDNA sequences mod-
pillar with binding sites for one (monomer) and ified with ATTO655 (red) at 100 nM transiently hybridize with complimentary sequences (green) at
two (dimer) particles. Au NPs with 80-nm diameters the hotspot between the NPs. (B) Fluorescence intensity transient showing several binding and un-
were used. Based on the lifetime, three populations binding events on a DNA origami pillar with two NPs. Background was subtracted, and the intensity was
are identified. The mean fluorescence enhancement normalized to the fluorescence without NPs. (C and D) Enlarged views reveal the magnitude of en-
(normalized) for different NP sizes, together with hancement, as well as the effect of rotating linear excitation polarization. (E) Sketch of the DNA origami
numerical simulations assuming a radial or tan- dimer with an incorporated HJ labeled with green and red dyes. Fluorescent intensity and FRET tran-
gential orientation of the dye’s dipole, is shown sients show oscillations of the HJ for a pillar with no NPs (F) and a NP dimer (G). The green, red, and
for a monomer (B) and a NP dimer (C). Error bars brown transients represent donor excitation/donor emission, donor excitation/acceptor emission (FRET), and
indicate the SD for the measurements and consider acceptor excitation/acceptor emission, respectively. Fluorescence decays of acceptor excitation/acceptor
the size distribution of NPs for the simulations. emission are shown in the insets.
C D
il
fe
mc
E F
Fig. 2. Canonical variates analysis (CVA) plots. (A) The first CVA considered complete Woranso-Mille specimen, KSD-VP-1/1 (table S7). Although this CVA
three angular and 10 size-corrected, linear measures (table S5). Homo, KNM-WT did not distinguish the extant taxa as effectively as the previous analysis, Homo
15000, and Pongo separated from Pan, Gorilla, and DIK-1-1 positively along separated from the African apes along the first root and Pongo fell inter-
the first root. Homo could be further distinguished from Pongo along the second mediately between the two groups. The two DIK-1-1 scapulae did not sig-
root, as could Pan from Gorilla. The DIK-1-1 scapulae were most similar to those nificantly differ from one another and fell among the Pongo and Gorilla data.
of Gorilla juveniles, whereas KNM-WT 15000 fell among the juvenile Homo KNM-WT 15000 was most similar to Homo juveniles, whereas KSD-VP-1/1 fell
data. (B) A second CVA considered five angular measures and also the less near the intersection of adult Homo and Pongo. See also tables S6 and S8.
reveals that although 63% have a biomass (B) Fig. 2. Time trend of median
below what would produce maximum sustain- B/Bmsy for unassessed fisheries
able yields (MSY), nearly half of these (45%) (red) and assessed fisheries (black)
have lowered exploitation rates sufficient for re- with small landings (i.e., lifetime
covery (3). A complementary analysis by the landings for a fishery is less than
U.N. Food and Agriculture Organization (FAO) the median lifetime landings for
found that 32% of 441 studied stocks are either all fisheries; solid line) and large
overexploited (28%), depleted (3%), or recover- landings (dashed line).
ing (1%) (4). However, it is unclear whether these
results extend to the remainder of global fisheries;
although 20% of global catch comes from assessed
species (5, 6), <1% of species have assessments,
largely owing to intensive data requirements and
cost. Here, we explore the status of thousands
of previously unassessed fisheries and use the
estimates to inform the challenges and benefits
surrounding global fisheries recovery.
The scientific literature includes widespread
speculation on global fisheries status because of
considerable ecological, social, and food security
implications. One approach relies on indirect mea-
sures of fishery status (e.g., fraction of fisheries and fishery development (6) and species’ life- timating the status of collections (including the
with declined catch, mean trophic level of catch, history traits (15). Building on fishery science, global status) of previously unassessed stocks.
percentage of primary production appropriated our method assumes that the status of a popula- Regression models estimating log(B/Bmsy) pre-
by fishery catches) (2, 7–12), but these approaches tion is a function of its life-history traits and harvest dict stock status for assessed fisheries; we use six
have many potentially confounding explanations. history, and the manner in which these variables models of varying complexity (14) that are con-
For example, declining catch is a necessary but collectively affect fishery status is consistent across sistent with the scientific literature [e.g., (16–18)].
not sufficient indicator of collapsed fisheries, re- species with similar characteristics. Specifically, B/Bmsy is higher when catch shows
sulting in unreliable estimates of stock status (13). Our approach uses the same kinds of varia- an upward trajectory and lower when current
A different approach uses status estimates from a bles (life history, fishery catch, etc.) as do stock catches are consistently lower than historic lev-
smaller collection of “data-rich” fisheries (with assessments. Yet the approach departs fundamen- els. Small, quickly maturing species that can re-
formal assessments) as indicators for all fisheries tally from traditional stock assessment because at cover rapidly from mismanagement have higher
(13), which also leads to unreliable predictions if no time do we specify a structural model linking B/Bmsy than slow-growing species that take longer
data-rich fisheries differ fundamentally from un- these variables to stock status and we have no to reach sexual maturity and have lower sustain-
assessed fisheries (3). indices of abundance trends. By building a panel able exploitation rates.
Building on this literature, we developed a (i.e., longitudinal data set), our approach captures To predict the status of unassessed fisheries,
multivariate regression approach to identify pre- both time-series effects (e.g., how long the fish- we compiled a companion database of 7721 ma-
dictors of stock status (B/Bmsy) from assessed ery has operated) and cross-sectional effects (e.g., rine fisheries from the FAO landings database (6).
fisheries and use these models to estimate the anchovies and sharks may respond differently to There are strong caveats around aspects of these
status of unassessed fisheries (14). We couple the the same series of catch). This approach does not data (19), but they remain the best source of
compilation of existing stock assessments (5) to produce precise estimates for individual fisheries global fisheries catch records. This database de-
an extensive database of characteristics of each and therefore is not a substitute for formal assess- termines the finest resolution for analysis—species
unassessed fishery, such as time series of catch ment. However, it does provide a method for es- caught by a country within an FAO region (fig. S2).
A + CIP C
Fertilized egg MO: Ctrl XErp1
CSF
Time (h)
0.5 1 2 3 4 5 6 7 8 9 11 13 15 mRNA: H 2O H2O XErp1(WT) XErp1(Fbox- ) XErp1(ZBR- )
Mr (K) at 20°C
80 XErp1
20h
50 (st.11.5)
CycE1
60
CycA1
22h
50 CycA2 (st.12)
100 Cdc27
XErp1(Fbox- )
XErp1(ZBR- )
120 28h
successful blastopore closure
XErp1(WT)
100
H2O
80 Mr (K) Fig. 1. XErp1 is essential for early embryonic divisions. (A) Immunoblot
100 - myc-XErp1
60 analyses of calf intestinal phosphatase (CIP)–treated samples harvested at
80 -*XErp1 the indicated time points. (B and C) One-cell embryos were injected with
40 anti-XErp1 WB XErp1-MO or control MO and H2O or mRNA encoding WT, Fbox– mutant,
100 - myc-XErp1 or ZBR– mutant XErp1; 24-hpf phenotypes were quantified (B) or images
20 were taken at the indicated times (C). (D) Embryos used in (B) were lysed
80 *
anti-myc WB at 6 hpf and immunoblotted. Asterisk marks nonspecific band. Cyc, cyclin.
0
MO: Ctrl XErp1 XErp1 XErp1 XErp1
mRNA: H2O H2 O WT Fbox- ZBR- 50 tubulin
(n=86) (n=84) (n=94) (n=98) (n=119) anti-tubulin WB
XErp1
Input
00
15
30
45
00
15
00
15
30
45
00
15
Mr (K) at 20°C
Ctrl
6:
6:
6:
6:
7:
7:
6:
6:
6:
6:
7:
7:
∆XErp1
∆XErp1
90 Mr (K)
XErp1
Input
80 120
Cdc27
Mr (K)
50 CycB2 120 *
XErp1 100
tubulin 90
50 XErp1
80
B ∆XErp1 Ctrl
F - CIP treatment
Mr (K) 0 10 20 40 60 90 0 10 20 40 60 90 Time (min)
Mr (K) 135 140 145 150 155 160 165 170 175 180 Time (min)
35
S-Securin
120 * 20°C
120 * 100 XErp1
100 90
XErp1
160
80
Gwl
120 120
Cdc27
100
50 CycB2
C ∆XErp1+buffer ∆XErp1+myc-XErp1WT
0 10 20 40 60 90 0 10 20 40 60 90 Time (min) tubulin
50
Mr (K)
35S-Securin
4 cells 8 cells
120 *
Fig. 2. XErp1 is required for timely destruction of APC/C substrates. (A)
XErp1
90 One-cell embryos were injected with control MO (Ctrl) or XErp1-MO, lysed at
the indicated time points, and immunoblotted. (B) Embryo extract depleted
of XErp1 or control immunoglobulin G extract was supplemented with 35S-
labeled securin and at the indicated time points, samples were analyzed by immunoblot and autoradiography analysis. (C) XErp1-depleted extract was
supplemented with buffer or IVT myc-XErp1WT and samples were analyzed as in (B). (D) Extract from (C) was treated with CIP and immunoblotted for XErp1.
Asterisk marks nonspecific band. (E) At 4 hpf, embryos were lysed, and XErp1 and control immunoprecipitates were immunoblotted for XErp1 and Cdc27.
(F) Non–CIP-treated embryo lysates were immunoblotted. Gwl, greatwall kinase.
Cdc27
Cdc27
percent of embryos (6h 20°C)
100
buffer
buffer
50nM
25nM
50nM
25nM
Ctrl
Ctrl
Input
Mr (K) CycB∆90 - + - - + + OA
80 Mr (K)
100 90
XErp1 XErp1
MO: XErp1
90 80
60
120 Cdc27 120 Cdc27
40 100 100
+MG-262 +CIP +MG-262 +CIP
20
E DMSO OA G
DMSO
buffer
0
∆90
Mr (K) 0 10 20 0 10 20 Time (min)
OA
XErp1(6A) XErp1(6A, ZBR- ) XErp1 MO H2O WT 6A 6A, ZBR - Mr (K)
+ mRNA: (n=111) (n=122) (n=131) (n=72) 35S-Sec
Cdc27 IP
100 Cdc27
50
C buffer 50nM CycB∆90 25nM CycB∆90 CycB2
- CIP
80 XErp1
Mr (K) 0 10 20 40 0 10 20 40 0 10 20 40 Time (min) 120 *
35S-Securin 90 XErp1 100 Cdc27
Input
50 90 80
XErp1
CycB2 XErp1
+ CIP
60 tubulin
120 *
50 tubulin
100 + CIP
XErp1
80
H α flag IP I GST-PD (2h at 20°C)
120 Cdc27 B’56α B’56β B’56ε flag-PP2A-B
B’56 ε
B55 δ
H2O
100 flag-PP2A-B
Mr (K) Mr (K) WT 4A WT 4A WT 4A GST-XErp1301-400
Fig. 3. XErp1 is regulated by phosphorylation. (A and B) One-cell embryos 100 60
XErp1 flag
were injected with XErp1-MO and H2O or mRNA encoding WT, Cdk1 (PP2A-B)
phosphomutant ST5 → 6A (6A), or Cdk1 phosphomutant XErp1 defective in 80 60
50
flag 40 CBB
APC/C-inhibition (6A,ZBR–). At 6 hpf, images were taken (A) and phenotypes
(PP2A-B) (XErp1)
quantified (B). (C) Embryo extract was supplemented with nondegradable cyclin 50
B (CycBD90) and analyzed by immunoblot. Time course started with CycBD90 CycBD90 or incubated in 2 mM OA for 30 min. Cdc27 immunoprecipitates were CIP-
addition. (D) Cdc27 was immunoprecipitated from extracts treated as in (C) and treated and analyzed by immunoblot. (H) mRNA encoding FLAG-tagged PP2A B
supplemented with MG-262. Samples were CIP-treated before immunoblotting for subunits or H2O (control) was incubated in embryo extract and immunoprecipitated
Cdc27 and XErp1. (E) Embryo extract was supplemented with 1 mM OA or dimethyl using antibodies to FLAG. Precipitates were analyzed for XErp1 and FLAG epitope.
sulfoxide (DMSO) as solvent control, and samples were CIP-treated as indicated (I) Extracts were incubated with B′56 mRNAs and GST-tagged XErp1301-400 WT
and analyzed as in (C). (F) From extracts treated as in (E) and supplemented with or PKA phosphomutant (4A) XErp1. After reisolation of GST-tagged proteins,
MG-262, Cdc27 was immunoprecipitated. Samples were CIP-treated and immuno- interacting B′56 subunits were analyzed by immunoblot. Inputs [(H) and (I)]
blotted for XErp1 and Cdc27. (G) One-cell embryos were injected with 50 nM are shown in fig. S3, F and G. CBB, Coomassie Brilliant Blue.
0 10 20 0 10 20 Time (min)
∆Ctrl
Mr (K) 60 60
32 P
160 32P Mr (K) MBP
50 50
40 PKA 60 40
160 CBB
CBB 60 tubulin PP2A-C
50
anaphase
buffer
120 120
H89
PKI
percent of embryos (24h 20°C)
100 100
Mr (K) Mr (K)
220 220 Cdk1 Cdk1
phospho
80 80
RXXS/T
Cdk1 activity
120 120
- CIP
60 APC/C
60 90
90
70 XErp1 XErp1
40 40 70
0 0
70 70 B’56 B’56
MO: Ctrl XErp1 XErp1 XErp1 buffer PKI DMSO H89
mRNA: H2O H2O WT 4A 500nM 200µM tubulin
50 50 net result: APC/C “off” APC/C “on”
(n=78) (n=79) (n=70) (n=77) (n=81) (n=92) (n=61) (n=79)
Fig. 4. PKA phosphorylates XErp1 at sites critical for PP2A B′56-recruitment. immunoblot. (E) One-cell embryos were injected with XErp1-MO or control MO
(A) In vitro PKA phosphorylation assay using [g-32P]ATP and MBP-tagged full- and H2O or mRNA encoding WT or PKA phosphomutant (4A) XErp1; at 24 hpf, the
length WT or PKA phosphomutant (4A) XErp1. g-32P incorporation was indicated phenotypes were quantified. Images and immunoblots are shown in fig.
analyzed by autoradiography. (B) Embryo lysate depleted of PKA (DPKA) or S4, B and C. (F) One-cell embryos were incubated with H89 or injected with PKI to
treated with control antibodies (DCtrl) were immunoblotted for PKA and inhibit PKA; at 24 hpf, the indicated phenotypes were quantified. Images are shown
tubulin. (C) Embryo lysates from (B) were supplemented with [g-32P]ATP and in fig. S4H. (G) Embryos were treated as in (F); samples were taken at 6 hpf,
phosphorylation of MBP-XErp1BD was analyzed by autoradiography. Recom- CIP-treated as indicated, and immunoblotted for XErp1 and the phosphoryl-
binant PKA was added to DPKA lysate. (D) MBP-XErp1BD was phosphorylated ated PKA consensus motif (RXXpS/pT, where X stands for any amino acid and
by PKA in vitro and incubated for 20 min in embryo extract. After repurification of pS/pT for phosphorylated serine or threonine) to monitor PKA activity. (H)
MBP-XErp1BD, the associated PP2A catalytic subunit (PP2A-C) was analyzed by Model of APC/C regulation in early mitotic divisions.
Maturation-Dependent HIV-1 Surface by the stiffness of the immature Gag lattice un-
derneath the viral membrane restricting mem-
brane fusion (12) or by alterations in Env lateral
Protein Redistribution Revealed mobility that may prevent clustering of sparsely
distributed Env trimers. Superresolution fluores-
by Fluorescence Nanoscopy cence microscopy provides an opportunity to
analyze subviral structures on a statistically signif-
icant number of particles. Here, we used stimu-
Jakub Chojnacki,1 Thorsten Staudt,2 Bärbel Glass,1 Pit Bingen,2 Johann Engelhardt,2 lated emission depletion (STED) microscopy (13)
Maria Anders,1 Jale Schneider,2 Barbara Müller,1 Stefan W. Hell,2,3 Hans-Georg Kräusslich1* to investigate the distribution of Env molecules
on the surface of individual HIV-1 particles.
Human immunodeficiency virus type 1 (HIV-1) buds from the cell as an immature particle requiring Env was immunolabeled with the human
subsequent proteolysis of the main structural polyprotein Gag for morphological maturation monoclonal antibodies 2G12 (14) or b12 (15),
and infectivity. Visualization of the viral envelope (Env) glycoprotein distribution on the surface which recognize the gp120 domain. Antibody-
of individual HIV-1 particles with stimulated emission depletion (STED) superresolution fluorescence induced clustering was avoided by using purified
microscopy revealed maturation-induced clustering of Env proteins that depended on the Fab fragments (fig. S1). To identify the position
Gag-interacting Env tail. Correlation of Env surface clustering with the viral entry efficiency of individual HIV-1 particles in the image, we
revealed coupling between the viral interior and exterior: Rearrangements of the inner protein used the viral accessory protein Vpr tagged with
lattice facilitated the alteration of the virus surface in preparation for productive entry. We enhanced green fluorescent protein (eGFP) (16)
propose that Gag proteolysis-dependent clustering of the sparse Env trimers on the viral surface as a “counterstain” reference. Visualization of HIV-1
may be an essential aspect of HIV-1 maturation. in the confocal mode of our STED microscopy
setup showed blurred spots in the eGFP (green)
he lipid envelope of human immunode- Biochemical and cryo-electron microscopy (cryo- channel (Fig. 1A). An overlay with a confocal
Fig. 2. Quantitation of Env trimers on mature and immature HIV-1. (A) Flu- Mean T SD values are shown with Wilcoxon rank-sum test for significance.
orescence intensity distribution of reference samples acquired by STED micros- (D) Amounts of gp120 and CA or Gag in purified virus preparations from
copy. Fab fragments were labeled with Atto 565. Black bars: anti-human cells transfected with pCHIV or pNL4-3, respectively, were determined by
Fab; light gray bars: recombinant monomeric Env stained with primary and quantitative immunoblotting. The number of Env trimers per particle was
secondary Fab; dark gray bars: recombinant trimeric Env stained with calculated by assuming an average of 2400 CA or Gag molecules per particle
primary and secondary Fab. (B) The number of Env trimers on individual ma- (26). Mean T SD values are shown with Wilcoxon rank-sum test for sig-
ture and immature HIV-1 particles was estimated from the average fluores- nificance (n = 4 experiments). (E) A representative immunoblot showing
cence intensity of the recombinant trimeric Env reference sample analyzed in Fab binding to mature and immature HIV-1, respectively. Purified particles
parallel. Mean T SD values are shown with Wilcoxon rank-sum test for sig- were incubated with 2G12 or control Fab fragments and analyzed for Fab
nificance. (C) Env trimer incorporation classified according to Env distribu- binding by quantitative immunoblotting. The ratio of gp120 to Fab in ma-
tion class and shown for the combined data of mature and immature HIV-1. ture particles was set to 1.
Fig. 1. MukBEF imaging. (A) Representative frame-average and slimfield mean two-dimensional spatial distributions for slimfield images with a
MukB-YPet cell images (yellow), brightfield and cell outline overlaid (white). 3-ms integration time; N = 197 to 237 spots. Estimates for full width at half
(B) Photobleaching of MukBEF-YPet spots, high (upper row) and low stoi- maximum s and sx /sy for Gaussian fits parallel to x and y axes (SD error).
chiometry data (expanded sections, lower row), raw (blue) and filtered (red). (E) Live-cell PALM, diffusing (gray brightfield, tracks colored) and immobile
(C) Stoichiometry distributions; N = 51 to 84 cells. Four-molecule interval MukB-PAmCherry (different clusters colored), expanded indicating tracks
grid lines, power spectra (arbitrary units) inset. (D) False-color plots for (black) and clusters (red).
that turnover of MukBEF complexes from the same distinctive architecture (24, 25). Al- 22. C. D’Ambrosio, G. Kelly, K. Shirahige, F. Uhlmann,
chromosomes is slower than predicted from in though they capture DNA topologically in appa- Curr. Biol. 18, 1084 (2008).
23. M. T. Ocampo-Hafalla, F. Uhlmann, J. Cell Sci. 124, 685
vitro adenosine triphosphatase (ATPase) lev- rent heterodimeric complexes (26), higher-order (2011).
els (8, 19) (fig. S1F) supports a model where complexes might form and exploit the type of 24. D. Gerlich, T. Hirota, B. Koch, J. M. Peters, J. Ellenberg,
ATP hydrolysis within each ATPase head pair rock-climbing mechanism described here. Curr. Biol. 16, 333 (2006).
is independent, with all four ATP molecules 25. R. A. Oliveira, S. Heidmann, C. E. Sunkel, Chromosoma
in the two closed dimer of dimer heads need- 116, 259 (2007).
References and Notes 26. C. H. Haering, A. M. Farcas, P. Arumugam, J. Metson,
ing to be hydrolyzed almost simultaneously K. Nasmyth, Nature 454, 297 (2008).
1. S. Gruber, Mol. Microbiol. 81, 855 (2011).
to completely release a single DNA-bound com-
2. K. Nasmyth, C. H. Haering, Annu. Rev. Biochem. 74, 595
plex. A multimeric form of MukBEF would (2005). Acknowledgments: R.R.-L. held the Todd-Bird Junior Research
therefore allow release of one DNA segment 3. A. J. Wood, A. F. Severson, B. J. Meyer, Nat. Rev. Genet. Fellowship of New College (Oxford University). S.U. was
and capture of a new segment without releas- 11, 391 (2010). supported by a Mathworks scholarship. M.C.L. was supported
ing the complex from the chromosome, a pro- 4. H. Niki et al., EMBO J. 11, 5101 (1992). by a Royal Society University Research Fellowship. We
cess akin to a rock climber making trial grabs 5. K. Yamanaka, T. Ogura, H. Niki, S. Hiraga, Mol. Gen. Genet. thank R. Oliveira for assistance with FRAP experiments and
250, 241 (1996). A. Kapanidis for discussions and provision of the PALM
to reach a hand hold, and one which could 6. O. Danilova, R. Reyes-Lamothe, M. Pinskaya, D. Sherratt, equipment. The experimental work was funded by an
lead to ordered MukBEF movement within a C. Possoz, Mol. Microbiol. 65, 1485 (2007). Engineering and Physical Sciences Research Council grant
chromosome, perhaps leading to DNA remod- 7. S. Hiraga et al., Res. Microbiol. 142, 189 (1991). to M.C.L. (EP/G061009) and by a Wellcome Trust program
8. J. S. Woo et al., Cell 136, 85 (2009). grant to D.J.S. (WT083469MA). All data are presented in
eling (fig. S1F). This is analogous to the pro- the supplementary materials, and bacterial strains are
cessive “walking” of the molecular motors 9. R. Reyes-Lamothe, D. J. Sherratt, M. C. Leake, Science
328, 498 (2010). available on request. The authors declare that they have
kinesin and dynein along microtubules (20). 10. M. C. Leake et al., Nature 443, 355 (2006).
no competing financial interests. The project was conceived
The functional advantage of dimeric SMC com- by all authors, each of whom contributed to writing
11. B. Huang, M. Bates, X. Zhuang, Annu. Rev. Biochem. 78,
the manuscript. A.B., R.R.-L., and S.U. performed the
plex oligomerization may be exploited by other 993 (2009).
experiments, M.C.L. developed the millisecond microscopy
SMC complexes, irrespective of the mecha- 12. Z. M. Petrushenko, C. H. Lai, V. V. Rybenkov, J. Biol. Chem.
and biophysical/analytical methods, and S.U. implemented
nism of multimerization. Like MukBEF, bacte- 281, 34208 (2006).
live-cell PALM. M.C.L., A.B., and S.U. did the analysis.
13. R. Fennell-Fezzie, S. D. Gradia, D. Akey, J. M. Berger, D.J.S. and M.C.L. contributed equally.
rial SMC-ScpAB forms relatively immobile EMBO J. 24, 1921 (2005).
complexes that accumulate at a few chromo- 14. M. Gloyd, R. Ghirlando, A. Guarné, J. Mol. Biol. 412, 578
some positions. Bacillus subtilis SMC-ScpAB (2011). Supplementary Materials
can form multimeric complexes in vitro, with 15. M. Hirano, T. Hirano, EMBO J. 23, 2664 (2004). www.sciencemag.org/cgi/content/full/338/6106/528/DC1
SMC and ScpB forming homodimers and ScpA 16. B. Hu et al., Curr. Biol. 21, 12 (2011). Materials and Methods
17. P. Arumugam et al., Curr. Biol. 13, 1941 (2003).
forming monomers or dimers (15, 21). Eukaryote Figs. S1 to S11
18. S. Weitzer, C. Lehane, F. Uhlmann, Curr. Biol. 13, 1930 Tables S1 to S6
SMC complexes also share similar character- (2003). References (27–46)
istics to MukBEF in maintaining chromosomes, 19. N. Chen et al., J. Bacteriol. 190, 3731 (2008).
accumulating at discrete chromosome loci (22, 23), 20. C. Kural et al., Science 308, 1469 (2005). 9 July 2012; accepted 4 September 2012
and turning over in seconds, as well as having 21. J. Mascarenhas et al., BMC Cell Biol. 6, 28 (2005). 10.1126/science.1227126
CA3 SC
CA1 s.o. apses from pyramidal cell axon collaterals as they
Pyr exit CA1 in the alveus, where they can be selec-
Alveus
s.p. tively stimulated (7) (Fig. 2B). Control GFP-
OLM infected neurons showed a strong facilitation to
Elfn1
PV
s.o. alvear stimulation (Fig. 2C). In marked con-
C trast, short-term facilitation was substantially re-
Sst::tdTomato PV::tdTomato
duced in neurons expressing the Elfn1 shRNA
ISH: Elfn1 Elfn1 (Fig. 2C). The deficit in short-term facilitation
IHC: tdTomato (Sst) tdTomato (PV) D
Sst::tdTomato tdTomato was seen across several different interstimulus
Elfn1 intervals, suggesting that Elfn1 regulates short-
tdTomato+Elfn1 term facilitation across a range of physiologi-
100 cally relevant input frequencies (Fig. 2D). When
% of Horiz. Cells
PV
Ss
at pyramidal-O-LM synapses.
E Facilitating synapses have low release prob-
α -Elfn α -PSD95 Merge abilities. Their release depends on accumulation of
calcium through several action potentials (14–16).
α -Elfn α -Gephyrin Merge
If the reduced facilitation mediated by Elfn1
shRNA is due to increased release probability,
Fig. 1. Elfn1 is expressed in hippocampal O-LM interneurons. (A) CA1 axons contact PV cells and O-LM
cells, which provide feedback inhibition. DG, dentate gyrus; Pyr, pyramidal cell. (B) ISH for Elfn1 and Table 1. Elfn1 expression by cell type.
somatostatin at P14, both showing expression in the stratum oriens and hilus of the hippocampus. s.p.,
stratum pyramidale; s.o., stratum oriens. Scale bars indicate 25 (left) or 10 (right) mm. (C) ISH (blue) for Cell type % of Elfn+ cells % of each
Elfn1 and immunostaining (brown) for tdTomato in transgenic mouse lines in which tdTomato is ex- with marker cell type with Elfn
pressed in Sst or PV interneurons. Elfn1 expression is highest near the alveus in somata (arrows) and GAD 97 18
proximal dendrites (arrowheads) of Sst-tdTomato neurons. Elfn1-expressing cells show little colocal- CamKII 0 0
ization in tdTomato-PV mice (asterisks). Scale bars indicate 25 or 2.5 mm. (D) Quantification of the
Sst 96 69
percent of horizontal cells in each mouse line that contain Elfn1, tdTomato, or both. Sst:tdTomato, n =
PV 4 3
145 cells, PV::tdTomato, n = 157 cells. (E) Dendrites of neurons from dissociated hippocampal cultures
mGluR1a 97 88
stained for Elfn1 and PSD95 or gephyrin. Scale bar, 5 mm.
Spike Probability
0.8
0.6
shElfn1 0.4
Uninfected
0.2
shElfn1
0
50 pA 0 2 4 6 8 10
50 ms Stimulus number
Uninfected 8 8
1.5 7 ** 7
broadly regulate circuit dynamics in the central
*
6 Control ** 6 Control nervous system and consequently exert consid-
50 pA 5 NS102 ** 5 NS102
50 ms 1 erable influence on cortical output and cognitive
4 4 * *
PV-tdTomato + 3 3 ** function.
Elfn1-GFP 0.5 2 2
1 1
0 0 0 References and Notes
1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1. H. L. Atwood, S. Karunanithi, Nat. Rev. Neurosci. 3, 497
Stimulus number Stimulus number Stimulus number (2002).
C 2. H. J. Koester, D. Johnston, Science 308, 863 (2005);
CA1 Axon CA1 Axon
TA SC 10.1126/science.1100815.
Low Pr High Pr 3. A. Reyes et al., Nat. Neurosci. 1, 279 (1998).
Pyr 4. A. B. Ali, J. Deuchars, H. Pawelzik, A. M. Thomson,
Elfn1 J. Physiol. 507, 201 (1998).
OLM Cell OLM PV Cell 5. A. B. Ali, A. M. Thomson, J. Physiol. 507, 185
PV (1998).
6. J.-C. Lacaille, A. L. Mueller, D. D. Kunkel, P. A. Schwartzkroin,
Fig. 4. Elfn1 is sufficient to modulate CA1 outputs. (A) Lentivirus overexpressing Elfn1-GFP is injected J. Neurosci. 7, 1979 (1987).
into P5 PV::tdTomato mouse pups. Stratum pyramidale or stratum oriens PV neurons in the infected area 7. F. Pouille, M. Scanziani, Nature 429, 717 (2004).
are targeted for recording. (Left) Response of control and shElfn1-expressing PV neurons to five stimuli 8. E. S. Lein et al., Nature 445, 168 (2007).
delivered to the alveus at 20 Hz. (Right) Quantification of short-term plasticity in Elfn1 overexpressing PV 9. J. Dolan et al., BMC Genomics 8, 320 (2007).
cells. *P < 0.05 by Mann-Whitney U test. (B) (Right) Example recording and quantification of evoked EPSC 10. J. de Wit, W. Hong, L. Luo, A. Ghosh, Annu. Rev. Cell
in GFP-infected Sst neurons before and after application of the GluR6-selective kainate receptor Dev. Biol. 27, 697 (2011).
antagonist, NS102 (20 mM). (Left) Average postsynaptic response of GFP-infected Sst interneurons before 11. S. Hippenmeyer et al., PLoS Biol. 3, e159 (2005).
12. L. Madisen et al., Nat. Neurosci. 13, 133 (2010).
and after NS102, n = 8. (Right) Average postsynaptic response of shElfn1-infected Sst interneurons before
13. H. Taniguchi et al., Neuron 71, 995 (2011).
and after NS102, n = 14. *P < 0.05; **P < 0.01 by ANOVA with Tukey’s post-hoc test. (C) Model of Elfn1 14. A. A. Biró, N. B. Holderith, Z. Nusser, J. Neurosci. 25,
function at the synapse. In CA1, Elfn1 is selectively localized to excitatory synapses onto O-LM 223 (2005).
interneurons. Elfn1 signals transsynaptically to contacting CA1 axons to reduce probability of release 15. H. Kamiya, R. S. Zucker, Nature 371, 603 (1994).
and create a facilitating synapse. 16. B. Katz, R. Miledi, J. Physiol. 195, 481 (1968).
Fig. 3. Nematocin-deficient
males exhibit mating defects.
(A) Steps in male mating be-
havior. The black arrow notes
the direction of male move-
ment. (B) Reproductive effi-
ciencies of wild-type (WT, gray
bars) and mutant males (black
bars) in long-term single-pair
mating crosses (no. of cross-
progeny/no. of total progeny).
(C) Percentage of males that
successfully transferred sperm within 5 min of first tail contact with a hermaph- behavioral transitions in ethograms of male mating behavior (figs. S8 and S9);
rodite. (D) Mean number of hermaphrodites that a male’s tail contacted before the arrow width indicates the probability of behavioral transitions. (G) Male
he initiated mating. (E) Mean total number of turns a male executed around mate search behavior, measured as the rate at which a single male leaves food
the hermaphrodite’s body before locating the vulva. (F) Summary of the in the absence of hermaphrodites (15). *P < 0.01, **P < 0.001, ***P < 0.0001.
E F
pe
pe
0)
0)
)
85
65
85
65
68
ty
ty
ty
23
23
27
27
Pgcy-7::ntr-1 Pflp-1::ntc-1
(k
k2
ild
ild
ild
tm
tm
(tm
(tm
(o
w
w
1(
1(
m
r-1
r-1
r-1
os
c-
c-
nt
nt
nt
Advertising and agencies to address important agricultural/environmental issues in California. Interest in international
agriculture is desirable. Teaching is assigned by the department chair and will include responsibilities in
the Sustainable Agriculture and Food Systems undergraduate major and include courses in sustainable
For full advertising details, go to agriculture systems, agroecosystem management and crop ecology. Graduate teaching will involve teach-
ScienceCareers.org and click ing activity in the Horticulture and Agronomy and/or Ecology Graduate Groups. Creative approaches to
For Employers, or call one of teaching will be encouraged, including experiential and problem-based learning. Advising and mentoring of
our representatives. undergraduate and graduate students is expected. The position is an academic year (9 month) tenure-track
position. This Assistant Professor position will include and appointment in the Agricultural Experiment
Station. Faculty members who hold an Agricultural Experiment Station appointment have a responsibility
Tracy Holmes
to conduct research and outreach relevant to the mission of the California Agricultural Experiment Station.
Worldwide Associate Director
Science Careers
The successful candidate will be expected to participate in departmental, college, and campus committees
Phone: +44 (0) 1223 326525 and with state, regional and national organizations as appropriate.
QUALIFICATIONS: Candidates must have a strong and well-documented background in agroecology,
crop ecology agroecosystem management, agronomy or related fields and a Ph.D. or equivalent degree in
THE AMERICAS
an appropriate discipline.
E-mail: advertise@sciencecareers.org SALARY: Commensurate with qualifications and experience.
Fax: 202-289-6742 TO APPLY: Candidates should begin the application process by registering online at http://recruitments.
Tina Burks plantsciences.ucdavis.edu/
East Coast/West Coast/South America For technical or administrative questions regarding the application process please email Melanie Greenleaf
Phone: 202-326-6577 at mjgreenleaf@ucdavis.edu. Review of the applications for all positions will begin January 1, 2013. The
Allyson Rosen position will remain open until filled.
Midwest/Canada/Corporate UC Davis is an Affirmative Action/Equal Employment Opportunity Employer and is dedicated to
Phone: 202-326-6578 recruiting a diverse faculty community. We welcome all qualified applicants to apply, including women,
Marci Gallun minorities, veterans, and individuals with disabilities.
Sales Administrator
Phone: 202-326-6582
Online Job Posting Questions
Phone: 202-312-6375
CHINA & TAIWAN Required Qualifications: Ph.D. and postdoctoral experience in a discipline related to Bioinformatics
Ruolei Wu is expected by the start date of the appointment; potential for excellence in research in Bioinformatics;
Phone: +86-1367-1015-294 commitment to teaching life sciences courses; and strong record of research accomplishments in at
E-mail: rwu@aaas.org least one of the following areas: modeling of macromolecular structure and interactions, modeling
of protein networks, genomics, and systems biology.
For the full position announcement and to apply online, go to: http://employment.ku.edu and search
All ads submitted for publication must comply
with applicable U.S. and non-U.S. laws. Science by key words “Bioinformatics/Computational Biology”. Submit a CV, letter of application, state-
reserves the right to refuse any advertisement ment of past and future research, statement of teaching interests and philosophy, and a list of at least
at its sole discretion for any reason, including three references who may be contacted via telephone or e-mail. Initial review of applications begins
without limitation for offensive language or November 19, 2012 and will continue as long as needed to identify a qualified pool. Direct inquiries
inappropriate content, and all advertising is
subject to publisher approval. Science encour-
to Dr. Ilya Vakser (vakser@ku.edu).
ages our readers to alert us to any ads that
they feel may be discriminatory or offensive. The University of Kansas is especially interested in hiring faculty members who can contribute
to four key campus-wide strategic initiatives: (1) Sustaining the Planet, Powering the World; (2)
Promoting Well-Being, Finding Cures; (3) Harnessing Information, Multiplying Knowledge; and
(4) Building Communities, Expanding Opportunities. See www.provost.ku.edu/planning/themes/
for more information.
Imagine working at the cutting edge of quantitative biomedicine to tackle the challenges
of drug discovery… surrounded by reminders of the earliest days of American history.
Janssen Research & Development is based in Spring House, Pennsylvania, a quiet
escape from urban life that had its beginnings in the 1700s. Within our Spring House
campus, you will be interacting with a multidisciplinary team of researchers focused on
bringing therapies to patients. Looking for more excitement? Philadelphia, New Hope,
Princeton, Lancaster, New York City and the New Jersey beaches are an easy, scenic
drive away. Can you picture yourself here? Come work with us.
We are looking for experts from around the globe with a driven, passionate, and
pioneering spirit to join our team. This is an outstanding opportunity to make a
difference in the lives of people living with chronic diseases, and to work in a beautiful
setting that is far from ordinary.
Help us make history.
We are currently recruiting outstanding scientific leaders with experience If you need assistance
and expertise for the following roles: locating these positions on
• Head, Computational & Systems Biology our website, please email
Requisition# 3489120829 JRegan14@ITS.JNJ.com.
• Head, High Performance Computing
Requisition# 2671120821
• Senior Scientist, Computational & Systems Biology
Requisition# 3468120829
• Senior Scientist, High Performance Computing
Requisition# 2568120816
Relocation packages are available.
© Johnson & Johnson Services, Inc. 2012. Janssen Research & Development, LLC, is a member of the Janssen Pharmaceutical
Companies of Johnson & Johnson. Johnson & Johnson companies are equal opportunity employers.
online @sciencecareers.org
Jiangsu Academy of
Agricultural Sciences
Open position as Deputy Director and Full Professor in the
Institute of Agricultural Facility and Equipment
www.westernu.edu
Founded in 1911, The University of Hong Kong is committed to the highest international Faculty Positions in Microbiology/Virology and
standards of excellence in teaching and research, and has been at the international
forefront of academic scholarship for many years. The University has a comprehensive other disciplines available for 2013
range of study programmes and research disciplines spread across 10 faculties and The College of Osteopathic Medicine of the Pacific – Northwest (COMP-Northwest)
about 100 sub-divisions of studies and learning. There are over 23,400 undergraduate
and postgraduate students coming from 50 countries, and more than 1,800 members of inaugurated its first class of physicians-in-training in Lebanon, Oregon in Fall, 2011. As the
academic and academic-related staff, many of whom are internationally renowned. newest expansion of Western University of Health Sciences in Pomona, California, we have
Tenure-Track Professor established a thriving center for medical education and human health care in Oregon.
in the Department of Physics A major responsibility of the Department of Basic Medical Sciences is to provide preclinical
(Ref.: 201200995) education for the first and second-year students in COMP. Our current initiative is to add
Applications are invited for a tenure-track appointment as Professor in the Department instructional and research strength within the discipline of Microbiology/Virology. This is
of Physics, from as soon as possible. The post will initially be made on a three-year a 12-month, tenure-track appointment at the Assistant/Associate/ or full Professor rank
term basis, with the possibility of renewal subject to mutual agreement. Tenure may
be offered to qualified candidates. depending upon qualifications. Successful candidates will join a large intercampus
The position will be in any field of Physics. Existing research activities in the Department faculty in the department of Basic Medical Sciences and be located either at the COMP-
include astrophysics, condensed matter physics, high energy physics, and materials Pomona campus, California, or at the new campus in Lebanon. Applicants must have a
science. Candidates with excellent qualifications and commitment to high-quality Ph.D. in Microbiology or related fields and at least two years of postdoctoral experience.
research and excellence in teaching are encouraged to apply. The appointee is
expected to provide academic leadership in research and teaching. Similar positions in biochemistry and pharmacology are also available at both campuses.
A globally competitive remuneration package commensurate with the appointee’s Preference is given to effective educators with a record of excellence in teaching, significant
qualifications and experience will be offered. The appointment will attract a contract- scholarly activity and strong potential for independent grant-supported research. Submit a
end gratuity and University contribution to a retirement benefits scheme, totalling up current curriculum vitae and a cover letter describing your teaching experience, research
to 15% of basic salary, as well as housing benefits, leave, and medical benefits. At activity and goals. Please include contact information for at least three references. These
current rates, salaries tax does not exceed 15% of gross income.
positions will remain open until filled.
Forenquiriesabouttheexistingresearchactivitiesandthespecificjobrequirements,please
write to Professor F.C. Zhang, Head, Department of Physics (e-mail: physhead@hku.hk). Nissar A. Darmani, PhD
Interested applicants should submit a completed application form, together with Associate Dean for Basic Sciences and Research
a full C.V., a detailed publication list, a research plan, and a statement on teaching
philosophy to scphy@hku.hk. Please indicate clearly “Ref.: 201200995 (Tenure-Track Department of Basic Medical Sciences
Professor in Department of Physics)” in the subject of the email. College of Osteopathic Medicine of the Pacific
Applicationforms(341/1111)canbeobtainedathttp://www.hku.hk/apptunit/form-ext.doc. Western University of Health Sciences
Further particulars can be obtained at http://jobs.hku.hk/. Closes December 8, 2012. 309 E. Second Street, Pomona, CA 91766-1854
The University thanks applicants for their interest, but advises that only shortlisted Email Address: ndarmani@westernu.edu
applicants will be notified of the application result.
The University is an equal opportunity employer and is committed to a No-Smoking Policy Western University of Health Sciences is an equal opportunity employer.
online @sciencecareers.org
CH
IN
A
RE
TU
RN
EE
S
Life Technologies is the world’s most innovative biotechnology
company, formed from the merger of Applied Biosystems and
Invitrogen. Accelerate your career in the world’s fastest-growing
economy by joining a fast-growing company that’s committed to
shaping discovery and improving life.
Invitrogen™ Applied Biosystems® Gibco® Molecular Probes® Novex® TaqMan® Ambion® Ion Torrent™
online @sciencecareers.org
The Department of Biochemistry & Molecular Biology and the Hollings Cancer
Center at the Medical University of South Carolina (MUSC) are pleased to
announce openings for senior level faculty with research experience in cancer
lipid signaling and/or metabolism, including various aspects of cancer biology
and/or therapeutics, such as regulation of PI/PI3K signaling, RNA transcription/
translation, lipid-protein interaction, and/or anti-cancer drug function. State-of-
the-art laboratories, outstanding resources and research support are available.
Endowed chair positions are available for qualified candidates. We are seeking
outstanding basic and/or clinical scientists who would complement and expand
existing programs at MUSC. Faculty Positions at School of
Candidates should have a national reputation, outstanding track record, and solid Chemical and Biomedical Engineering (SCBE)
record of collaborative and peer-reviewed funded research. The Hollings Cancer Nanyang Technological University (NTU) in Singapore is ranked 47th in the
Center is a National Cancer Institute Designated Center, and with its state-of-the- 2012 QS World University Rankings and is the fastest-rising university in the
art research and shared resource facilities, including an outstanding Lipidomics worlds top 50.
Core, it has a strong culture of promoting basic and translational research. SCBE at NTU invites applications for Assistant, Associate or Full Professors.
Located on the Atlantic coast in South Carolina, Charleston boasts one of the For more information, visit www.scbe.ntu.edu.sg/About_Us/Pages/Open_
Positions.aspx
nation’s most historic downtown areas, beaches and year-round outdoor life,
as well as international cultural events such as the Spoleto Festival USA and Research Areas
outstanding cuisine. Chemical and Biomolecular Bioengineering Division
Interested researchers should submit a CV, summary of research interests, and Engineering Division · Cardiovascular biomechanics
contact information for three references online at website: www.jobs.musc.edu/ · Process systems engineering · Bioinstrumentation
applicants/Central?quickFind=189086. · Product and process design · Biosignal processing and imaging
Philip H. Howe, Ph.D. · Pharmaceutical engineering
Besim Ogretmen, Ph.D.
· Food engineering · Neuro bioengineering
Professor & Chair Professor
· Separation technology · Nature inspired bioengineering
Biochemistry & Molecular Biology Biochemistry & Molecular Biology
Associate Director of Basic Sciences Program Leader Application Details
Hollings Cancer Center Guidelines: www.ntu.edu.sg/ohr/Career/SubmitApplications/Pages/Faculty.aspx
Medical University of South Carolina Email: scbe_recruit@ntu.edu.sg
PO Box 25063
Charleston, SC 29425
campbetb@musc.edu
MUSC is an Equal Opportunity Employer, promoting workplace diversity.
online @sciencecareers.org
Director, Division of Biomedical Technology, Bioinformatics, and Computational Biology
National Institute of General Medical Sciences
National Institutes of Health
Department of Health and Human Services
The Person: The ideal candidate will have considerable research experience demonstrating a strong understanding of computational, technological, and biological
issues. In addition, candidates should possess recognized research management and leadership abilities. Candidates with substantial training and experience in
computation/informatics, biomedical technology, and biomedical research will be considered. A strong understanding of the role of computation, informatics,
and technology in uncovering biological principles and in advancing research on human health and disease is desired. This individual will report to the Director,
National Institute of General Medical Sciences (NIGMS), but will also have access to the Director, National Institutes of Health (NIH), in coordinating activities
across NIH and among federal agencies.
The Challenge: A significant challenge for the biomedical research community is the integration of the vast amount of accumulating scientific data in order to
develop predictive understanding of basic biological processes. The ability to meet this challenge will be critically dependent on advances in bioinformatics and
computational biology and on discovery and deployment of new technologies. The Division of Biomedical Technology, Bioinformatics, and Computational Biology
(BBCB) is responsible for stimulating and funding research in these areas of importance for NIGMS. The Division supports research on bioinformatics, databases,
and data mining; modeling of complex biological systems; algorithmic development and software engineering; mathematical biology, high-performance computing,
molecular imaging, structural biology, and proteomics, among other areas. In addition, the Division is responsible for managing the NIH Biomedical Information
Science and Technology Initiative (BISTI), an agency-wide effort to stimulate and coordinate use of computer science and technology to address problems in
biology and medicine. The Division also actively collaborates with other NIH components and federal agencies in developing policies in these areas. NIGMS is
seeking a leader in this field to direct the Division and the BISTI efforts, and to coordinate the work of both with other interested federal agencies and the broader
scientific community. Information about the Division and BISTI is available at: http://www.nigms.nih.gov/About/Overview/bbcb.htm and http://bisti.nih.gov.
Position Requirements: Candidates must have an M.D., Ph.D., or equivalent degree in a field relevant to the position. Please see the official vacancy announce-
ment for qualification requirements and what to submit. The position will be filled under a Title 42 excepted service appointment.
Salary/Benefits: Salary is competitive and will be commensurate with the experience of the candidate. A recruitment or relocation bonus may be available,
and relocation expenses may be paid. A full package of Federal Civil Service benefits is available, including: retirement, health and life insurance, long term
care insurance, leave, and a Thrift Savings Plan (401K equivalent). The successful candidate is subject to a background investigation and financial disclosure
requirements.
How to Apply: The official vacancy announcement is available at: http://www.nigms.nih.gov/About/Job_Vacancies/
Information about the NIGMS can be found at http://www.nigms.nih.gov/About/.
NIGMS will begin accepting applications on October 26, 2012, and plans to have the position open for at least 30 days, but will not to close the application
process until a candidate has been selected.
You may contact Krystal Kelly with questions about this vacancy at kellykry@od.nih.gov or 301-594-3827.
Research Associate
Karolinska Institutet announces funding for
30 Research Associates within:
• Medical Sciences
• Cancer
• Cell and Tumor Biology
• Clinical Microbiology
• Epidemiology/Biostatistics
• Immunogenetics
• Immunology
• Infection Biology Millennium: The Takeda Oncology Company is proud to have been recognized as
one of Fortune Magazine’s 100 Best Companies to Work For in 2011 and 2012.
• Neuroscience
• Focused on Oncology Drug Development
• Entrepreneurial Culture
• Outstanding Benefts
• Flexible Work Environment
Application deadline
To learn more and apply, visit:
November 15th 2012 Follow us on Linkedin
ki.se/job ©2012 Millennium Pharmaceuticals, Inc. All rights reserved. “From FORTUNE Magazine, February 6, 2012 © 2012 Time Inc. FORTUNE is a registered
trademark of Time Inc. and is used under license. FORTUNE and Time Inc. are not affiliated with, and do not endorse products or services of, Licensee.”
online @sciencecareers.org
TEMPLE UNIVERSITY
Department of Biology
Faculty Positions
Recruiting Faculty in
Biochemistry and Molecular Biology
(Associate/Full Professor)
The Department of Biochemistry and Molecular Biology at the Medical As part of an ongoing expansion, the Department of Biology
University of South Carolina (MUSC) invites applications for tenure track
at Temple University anticipates hiring multiple faculty over
positions in all areas of biochemistry and molecular biology. Exceptional
candidates with strong commitments to research and teaching excellence the next several years. This year, we invite applications
are encouraged to apply. Rank will be commensurate with experience and for positions at the Associate and Full Professor levels.
endowed chair positions are available for outstanding candidates. We are We are especially interested in candidates with funded,
seeking outstanding scientists who would complement and expand existing innovative research programs in areas that complement
research foci and programs at MUSC. and extend departmental strengths in Molecular/Cellular/
Located on the Atlantic coast in South Carolina, Charleston boasts one Developmental Biology, Integrative/Organismal Biology,
of the nation’s most historic downtown areas, beaches and year-round Ecology/Evolution, and Neurobiology. Substantial laboratory
outdoor life, as well as international cultural events such as the Spoleto space and additional resources provide opportunities for
Festival USA. research program expansion. Candidates also are expected
Applicants must provide a cover letter, curriculum vitae, and a detailed to contribute to undergraduate and graduate teaching.
research plan online at website: www.jobs.musc.edu/applicants/
Central?quickFind=190056 Applicants should submit a curriculum vitae, a research
Junior candidates must also provide contact information for three program summary, and a statement of teaching philosophy
references. to: http://bio.cst.temple.edu/search. Review of applications
Philip H. Howe, Ph.D. will begin immediately, with priority given to applications
Professor and Chair received by December 15, 2012. For additional information
Department of Biochemistry and Molecular Biology please see https://bio.cst.temple.edu/.
Medical University of South Carolina
173 Ashley Avenue, MSC 509 Temple University is an Equal Opportunity, Equal Access,
Charleston, SC 29425
simmonva@musc.edu Affirmative Action Employer committed to achieving a
diverse community (AA, EOE, M/F/D/V).
MUSC is an Equal Opportunity Employer,
promoting workplace diversity.
online @sciencecareers.org
Faculty of Arts & Science
University of Lethbridge
The Chair will reside at the Canadian Centre for Behavioural Neuroscience (CCBN), a
60,000 sq ft, world-class research facility equipped with exceptional infrastructure, including
3 NMRs, electron microscope, multiphoton and several confocal microscopes, high throughput
digital imaging, flow cytometer, deep sequencing platform, in vitro recording facilities, multiple
in vivo ensemble single unit recording suites, PCR, dense-array electroencephalography,
voltage-sensitive dye recording lab, dedicated parallel computing cluster, and numerous state-
of-the-art surgical and behavioural testing suites.
The Chair will be part of a research intensive group, all of whom focus on fundamental problems in
the neurobiology of cerebral functioning. The Chair will develop a research program focusing on
mechanisms underlying normal and disordered memory, including research that sheds light
on brain changes in normal aging or dementia.
For more information about the University please visit our website at uleth.ca, or the CCBN
website at ccbn.uleth.ca. For a detailed job description visit:
uleth.ca/hum/Services/career_fac/Neuroscience_August_2012.htm
FACULTY POSITIONS IN
BIOCHEMISTRY AND
EVOLUTIONARY
GENETICS
Tenure-track position in Microbiology: The successful candidate will be expected to develop an externally-funded research program and
to teach courses in general microbiology, microbial physiology and general biology at the undergraduate level as well as graduate courses
in his/her area of expertise. Individuals whose research focuses on a prokaryotic system with biomedical relevance will be preferred.
Email: microsearch@nmsu.edu
Tenure-track position in Animal Physiology: The successful candidate will be expected to develop an externally-funded research program and to
teach courses in human physiology, comparative physiology, and general biology at the undergraduate level as well as graduate courses in his/her area
of expertise. Email: physiolsearch@nmsu.edu
Applicants for the nine-month, tenure-track positions above must submit, to the designated email address, a single pdf consisting of a cover letter, CV, and
concise (2-pages each, maximum) statements of (a) research interests and accomplishments and (b) teaching philosophy and experience. Applicants must
also arrange to have 3 letters of reference sent by e-mail to the same address. Applicants for each position must have a Ph.D. in Biology or a related field,
a minimum of one year of post-doctoral experience, a strong track record of research productivity commensurate with experience, and a demonstrated
commitment to undergraduate and graduate education.
Non-tenure-track College Assistant Professor: This is a 9-month, renewable position at the College Assistant Professor level with opportunity for promotion.
Applicants must have a Ph.D. in Biology or a related field and prior teaching experience. Preference will be given to applicants with a demonstrated
commitment to teaching at all levels of the undergraduate curriculum and the development of innovative teaching methods and materials. The successful
candidate will be responsible for three courses per semester covering a variety of introductory biology offerings for majors and non-majors as well as
upper division courses in his/her area of expertise. Applicants must submit a single pdf consisting of a cover letter, CV, and concise statement of teaching
philosophy and experience to biolecturer@nmsu.edu and arrange to have three letters of reference sent by e-mail to the same address.
For all searches preference will be given to applications completed by the initial review date of November 30, 2012. Applications lacking any of the required
components will not be reviewed. Please direct inquiries to the designated email addresses. Full details of the position are available at http://hr.nmsu.edu/
employment-hr/jobs-at-nmsu/ (Requisition numbers: Microbiologist 2012002392, Physiologist 2012002393, College Track 2012002394)
NMSU is a public, land grant, minority-serving institution recognized by the Carnegie Foundation as RU/H (research university with high research activity).
The Department of Biology is a thriving community of 20 faculty members supporting undergraduate majors in Biology, Microbiology, Genetics and
Conservation Ecology. More than 70 graduate students are currently enrolled in MS and PhD programs within the department. The department supports
core facilities for microscopy, isotope chemistry, tissue culture, next-generation sequencing, and natural history collections. Opportunities exist to participate
in NIH-, NSF- and HHMI-sponsored training programs. For more information see: http://biology-web.nmsu.edu/.
Why not
change the world?
We welcome candidates who will bring diverse intellectual, geographical, gender and ethnic perspectives to Rensselaer’s work and campus communities.
Rensselaer Polytechnic Institute is an Affirmative Action/Equal Opportunity Employer.
AAAS is here – helping scientists achieve career success.
Every month, over 400,000 students and scientists visit ScienceCareers.org in search of the information, advice, and
opportunities they need to take the next step in their careers.
A complete career resource, free to the public, Science Careers offers a suite of tools and services developed specifically
for scientists. With hundreds of career development articles, webinars and downloadable booklets filled with practical
advice, a community forum providing answers to career questions, and thousands of job listings in academia, govern-
ment, and industry, Science Careers has helped countless individuals prepare themselves for successful careers.
As a AAAS member, your dues help AAAS make this service freely available to the scientific community. If you’re not
a member, join us. Together we can make a difference.
online @sciencecareers.org
The DEPARTMENT OF BIOMEDICAL ENGINEERING (BME) at WASHINGTON UNIVER-
SITY IN ST. LOUIS invites applications and nominations for the tenured position of Professor and
Department Chair. The department is ranked #15 for graduate programs and #13 in undergraduate
Science Scholarships and Fellowships
programs in Biomedical Engineering in US News and World Report. The department has 19.5 full-time
The UNCF•Merck Science Initiative is an faculty members and 57 additional graduate group faculty members from the Schools of Engineering,
innovative approach that creates Medicine and Arts & Sciences. The BME undergraduate enrollment is 448 students and the graduate
opportunities in the biological, chemical enrollment is 115 PhD students. The department has $12.9 million annually in research expenditures.
and engineering sciences for African The department’s strategic vision emphasizes a broad synergistic effort on multiscale bioengineering
American students throughout the country. with a holistic focus on cell/tissue regeneration and degeneration in development, aging, and medicine.
Current research areas include biomaterials and tissue engineering, cardiovascular engineering, imaging,
molecular cellular and systems engineering, and neural engineering.
The successful candidate will have an earned doctorate and be internationally recognized for research
excellence, leadership, and scholarship in an area of biomedical engineering. Additionally, s/he will have
a sound vision for the future of biomedical engineering, the ability to lead and advance a research-ori-
ented department, and mentor faculty and staff to be successful. The ideal applicant is expected to have
developed a thriving independent research program; led multi-investigator awards; participated in the
development of novel curricula; and have a record of academic and professional leadership. Excellent
organizational and communication skills are also required.
Serving as the executive officer of the department, the Department Chair reports directly to the Dean of
the School of Engineering & Applied Science. The Department Chair is expected to serve for a minimal
initial term of 5 years with the expectation for reappointment. The Department Chair is expected to provide
leadership in all matters of department policy, including appointments, promotions, instruction, research
and administration and will conduct research, publish in peer-reviewed journals and conferences, teach
relevant courses, advise students, and participate in University service.
Applicants should submit their curriculum vitae, a short summary of past research accomplishments and
future plans, a teaching statement, and the names of at least three references electronically as a single
PDF file to bmechairsearch@seas.wustl.edu. Review of applications will begin November 1, 2012
and will continue until the position is filled.
UNDERGRADUATE Washington University is an Equal Opportunity Affirmative Action Employer. Women and
Science Research Scholarships underrepresented minorities with established leadership credentials will receive strong consideration.
n Scholarships up to $25,000 Employment eligibility verification will be required upon employment.
n Internship opportunities
n Mentoring and networking opportunities
n Eligibility: College juniors, science or
engineering majors, 3.3 GPA A year of research in the
GRADUATE unparalleled collections of the
OPEN
Science Research Dissertation Fellowships Library of Congress focusing
n Fellowships up to $53,500
n Mentoring and networking opportunities
on the societal implications of
n Eligibility: Ph.D. or equivalent degree
candidates engaged in dissertation new windows astrobiology
t o t h e
research in the biological, chemical or
engineering fields
The Baruch S. Blumberg
POSTDOCTORAL
Science Research Fellowships UNIVERSE NASA/Library of Congress
n Fellowships up to $92,000
n Mentoring and networking opportunities Chair in Astrobiology
n Eligibility: Ph.D. or equivalent degree
recipients in the biological, chemical or CALL FOR APPLICATIONS AND NOMINATIONS
engineering fields
Deadline December 1
More information: loc.gov/kluge
APPLY ON-LINE
UNCF.org/umsi
Submit by December 3, 2012 The Library of Congress is America’s oldest federal cultural institution, the world’s largest library and
home of the John W. Kluge Center, bringing scholars from around the world to the U.S. capital for
T 202 810 0331 study, discourse and interaction with Washington’s leaders.
F 202 234 0225
E uncfmerck@uncf.org
Washington University is an Equal Opportunity Employer. The David Geffen School of Medicine at UCLA is an Affirmative Action/
AA/EOE M/F/D/V. Equal Opportunity Employer. Women and Minorities are
encouraged to apply.
ANNOUNCEMENTS
ESPCA/São Paulo School of Advanced Science
FACTS&FICTION
Careers in Industry and Academia
Trying to figure out the next step in your career? Join us for a roundtable
discussion that will look at facts and fiction surrounding academic and
industry career options for PhD-level scientists. Get some nuts and bolts
advice on how to research career options, what questions to ask, and
how to best prepare for various careers.
• Do industry and academic careers require different skill sets?
• Do industry jobs have better compensation? Less autonomy?
• Do academic scientists have less work/life balance?
Webinar
thetic Biology. Researchers in this area may be crat- and upper-level Human Anatomy and Physiology be-
ing designer molecules, novel metabolic and molecular ginning in August of 2013. Commitments to excellent
networks, developing artificial cells and organisms, and teaching, supervising undergraduate research, and the
carrying out quantitative modeling all leading to bio- educational mission of a liberal arts Lutheran college
technology or biomedical breakthroughs. Preference are expected. Online application process at website:
will be given to a scientist whose interests take advan- http://www.cord.edu/Offices/hr1.php. Appli-
Want to learn more about exciting cation review will begin December 3 and continue
tage of existing strengths at UH. The University of
and rewarding careers outside of Houston has outstanding facilities in DNA sequencing, until position is filled. Concordia College is an Equal Op-
academic/industrial research? proteomics, structural biology, single-molecule studies, portunity Employer seeking a diverse faculty.
View a roundtable discussion that and computational modeling. Applicants should have
looks at the various career options a Ph.D. in a related field, an outstanding record of
research, and a strong commitment to education. The
open to scientists and strategies
position can be filled at any rank. Please submit a cur-
you can use to pursue a riculum vitae and an outline of future research interest
nonresearch career. to e-mail: synbiosrch@nsm.uh.edu. Please also ar-
range for three letters of recommendation to be elec-
tronically sent to e-mail: synbiosrch@nsm.uh.edu.
Consideration of applications will begin immediately
Find
and will continue until the position is filled. The Uni-
versity of Houston is an Affirmative Action/Equal Opportunity
Employer. Minorities, women, veterans, and person with disabil-
ities are encouraged to apply.
your future
Now Available
here.
↓
On Demand TENURE-TRACK ASSISTANT PROFESSORS in
www.sciencecareers.org/ Ecology and Animal Physiology
webinar The Department of Biology, University of Wisconsin-
Stevens Point, offers two tenure-track, nine-month fac-
ulty positions (Assistant Professor), beginning August
2013.
Ecology—Teaching includes general ecology, plant
or community ecology, and introductory biology.
Animal Physiology—Teaching includes animal phys-
iology to biology and natural resource majors, a senior
seminar, and an upper level course in specialty.
Research involving undergraduates, service, and stu-
www.ScienceCareers.org
dent advising are expected. Broad training in biol-
ogy and Ph.D. with emphasis in specialty is required.
Teaching and research experience are required. We seek
applicants from underrepresented groups. Applications
should include a cover letter, curriculum vitae, state- MARKETPLACE
Produced by the
Science/AAAS Business Office. ments of teaching philosophy and research interests,
three letters of recommendation, undergraduate and Widely 8¢/u
graduate transcripts. Send application materials to:
Dr. Christopher Yahnke, Chair; Biology Department,
University of Wisconsin-Stevens Point, Stevens Point,
Recognized
Original &
Guaranteed
KlenTaq1 Truncated
Taq DNA
Polymerase
WI 54481. Review begins 3 December 2012. For more Withstand 99oC
information, telephone: 715-346-2455, fax: 715- US Pat #5,436,149 e-mail: abpeps@msn.com
Call: 1•800•383•3362
346-3624, e-mail: cyahnke@uwsp.edu. Fax: 314•968•8988 www.abpeps.com
Affirmative Action/Equal Opportunity Employer.
Coverage
Competing Array
80%
75%
70%
MAF >1% MAF >5%
Axiom Genotyping Solution adapts to the needs of your research—coverage and flexibility like never before. Contact
your Affymetrix representative today or come see us at booth #918/920 at ASHG 2012.
©Affymetrix, Inc. All rights reserved. “For Research Use Only. Not for use in diagnostic procedures.”
MILLIONS OF STUDENTS AND
RESEARCHERS USE ENDNOTE
TO MANAGE THEIR REFERENCES
AND CREATE BIBLIOGRAPHIES.
WHY NOT YOU?
IntRoDUCIng
ENDNOTE® X6
Collect. Collaborate. Create. From Anywhere.
simplify
this step on the way to your ultimate discovery. Basic microvolume
measurements
NanoDrop™ 2000
Full-spectrum microvolume
measurements
© 2011 Thermo Fisher Scientific Inc. All rights reserved.
NanoDrop 8000
Higher throughput, full-spectrum
microvolume measurements
NanoDrop 3300
Full-spectrum microvolume
fluorescence measurements
I seek the future.
I seek the future.
Achieve high-quality NGS data and get the most from precious samples with:
■ Highly efficient and specific removal of ribosomal RNA
■ Selective target enrichment of your genes of interest
■ Unbiased whole genome amplification from a single cell
■ High-precision, qPCR-based library quantification
■ Outstanding results on any sequencing platform
Visit www.qiagen.com/goto/NGS and keep up-to-date on our expanding portfolio of new and
NGS1012S1WW
Is true “single-cell”
RNA-seq feasible?
United States/Canada: +1.800.662.2566 • Asia Pacific: +1.650.919.7300 • Europe: +33.(0)1.3904.6880 • Japan: +81.(0)77.543.724
Clontech Laboratories, Inc.
ATakara Bio Company Illumina and HiSeq are registered trademarks or trademarks of Illumina, Inc. Clontech, the Clontech logo, and SMARTer
are trademarks of Clontech Laboratories, Inc. ©2012 Clontech Laboratories, Inc.
Continuously Monitor
n Our commitment to you: Confidently rely on our dedicated service
Cell Invasion and professionals, on-site reagent stocking, customized research solutions,
Migration and much more.
Study the Role of Let Roche help you reveal the cellular and molecular mechanisms of
Proteins in Cancer
cancer. Learn more by visiting www.cancer-research.roche.com
RNAscope ®
visualize
ECL Prime SuperSignal in situ hybridization.
West Dura
SignaLOCK
easy. powerful.
SignaLOCK ™
ChemiWestern Kits
Each kit contains a powerful chemiluminescent substrate,
a non-protein blocker, and a background-reducing wash buffer.
SCIENCELAB SOLUTIONS
CLEAN Excellent signal : noise
EASY Optimized protocol
Visit www.kpl.com/SignaLOCK_Science
to learn about our introductory
promotional pricing.
1-877-576-3636 | www.acdbio.com | order@acdbio.com
LIFE
LI FE S CI
CIEN
ENCE
CE T EC
ECHN
HNOL
OLOG
OGIE
IESS
Genomics
Lambda ™
TLED
Epigenomics: Transmitted
The New Technologies Light
of Chromatin Analysis
Source
In This Issue
Multicellular organisms are essentially clonal. Every cell possesses
the same DNA as every other. So what distinguishes a liver cell High-output white light LED!
from a neuron? Epigenetics, that constellation of noncoding
RNAs, protein-DNA interactions, and molecular modiÃcations that
FEATURES
>10,000 hour lifetime
govern which genes are expressed and which stay silent. Epigen-
NE
etic mechanisms inÄuence processes from stem cell differentia-
tion to cancer, and researchers are keen to understand how these TTL control (with polarity switch)
events differ at the genomic scalethe so-called epigenome. The
Very stable output
problem is daunting, but the research community is resourceful.
Compact stand-alone design
The epigenome has never seemed closer.
Easy installation
See full story on page 546.
Upcoming Features
Tissue Engineering: 3-D/ScaffoldingDecember 7
The ConnectomeJanuary 18, 2013 PHONE: 415.883.0128 | FAX: 415.883.0572
GenomicsFebruary 15, 2013
EMAIL: INFO@SUTTER.COM | WWW.SUTTER.COM
Eppendorf Xplorer Æ plus
With additional functions
www.eppendorf.com/xplorer
eppendorfÆ, Eppendorf PhysioCare ConceptÆ, PhysioCare ConceptÆ and Eppendorf XplorerÆ
are registered trademarks and Eppendorf Xplorer plus is a trademark of Eppendorf AG.
All rights reserved incl. graphics and photos. Copyright © 2012 by Eppendorf AG.
Cambridge Healthtech Institute’s 12th Annual
PIPELINE 1: FORMULATION
Optimizing Biologics Formulation Development
Lyophilization and Emerging Drying Technologies
The Protein Science Week Protein Aggregation and Emerging Analytical Tools
PIPELINE 3: BIOTHERAPEUTICS
Recombinant Protein Therapeutics
Antibodies for the 21st Century
Bispecific Antibody Therapeutics
PIPELINE 4: EXPRESSION
Engineering Genes, Vectors, Constructs and Clones
ADVANCE REGISTRATION RATES AVAILABLE Fine-Tuning Expression in CHO
Register Early and Save up to $400! Choosing, Designing, and Optimizing Hosts and Platforms
Genomics
Epigenomics:
The New Technologies of
Chromatin Analysis
Multicellular organisms are essentially clonal. Every cell possesses
the same DNA as every other. So what distinguishes a liver cell from
a neuron? Epigenetics, that constellation of noncoding RNAs, protein-
DNA interactions, and molecular modiÀcations that govern which genes
are expressed and which stay silent. Epigenetic mechanisms inÁuence
processes from stem cell differentiation to cancer, and researchers are
keen to understand how these events differ at the genomic scaleó
the so-called epigenome. The problem is daunting, but the research
community is resourceful. The epigenome has never seemed closer.
By Jeffrey M. Perkel
ìWeíve got the technology, weíve got the need, people are starting to do this, the lack of reference sets and
new technologies are holding the Àeld back. That was why [epigenomics] was identiÀed as a good investment.î
n early 2008, the U.S. National Institutes of Health (NIH) an- ping not just DNA methylation and histone modiÀcations, but also
546 www.sciencemag.org/products
Pr
Produ
oduced
ced by th
thee Sci
Scienc
ence
e/AA
/AAAS
AS Cus
Custom
tom Pu
Publi
blishi
shing
ng Off
Office
ice LIFE SCIENCE TECHNOLOGIES
G enomii cs
Genomics
The San Diego Epigenome Center builds its maps with the two
key technologies of epigenomics: chromatin immunoprecipitation
(ChIP)-Seq, which uses next generation DNA sequencing technolo-
gy to identify the location of speciÀc histone modiÀcations across the
genome, and MethylC-Seq, a genome-wide method for determining
the position of 5-methylcytosine modiÀcations. BisulÀte sequencing,
MethylC-Seq is basically an optimized version of bisulÀte sequenc-
ing for todayís blazing-fast next-gen DNA sequencers. The problem as it turns out, cannot
it solves is this: Standard DNA sequencing methods cannot distin-
guish cytosine from 5-methylcytosine (5-mC). But if the DNA is Àrst
distinguish between
treated with sodium bisulÀte they can, because bisulÀte converts un-
modiÀed cytosines to uracil, which appears in DNA sequencer reads
5-mC and 5-hmC.
as thymine (T). By comparing bisulÀte-treated samples against an
untreated control, researchers can determine which bases were
methylated and which were not.
Researchers have been using bisulÀte conversion to interrogate that 5-hmC plays a role in regulating transcriptional enhancers. ìThis
methylation at the nucleotide level for decades, and in 2008 Joseph type of element has a high abundance of hydroxymethylcytosine,î
Eckerís team at the Salk Institute in San Diego (Ecker is also an in- he says, ìand a correspondingly lower level of methylcytosine in the
vestigator in the San Diego Epigenome Center) updated the method same sequence.î
for the Illumina Genome Analyzer. Thatís MethylC-Seq. But in 2009 New England Biolabs is working on an alternative method to in-
a new wrinkle appeared. That year, teams led independently by Na- terrogate 5-hmC directly. The company recently described the en-
thaniel Heintz at the Rockefeller University in New York and Anjana zymatic properties of the PvuRts1I family of proteins, which binds
Rao at Harvard Medical School reported that mammalian DNA con- 5-hmC (or its glucosylated form, 5-(ћ-glucosyloxymethyl)cytosine)
tains a previously undiscovered methylated base, 5-hydroxymethyl- and cleaves 9 to 13 bases on either side, releasing a 24-base frag-
cytosine (5-hmC). ment with the modiÀed base in the center. These fragments can then
BisulÀte sequencing, as it turns out, cannot distinguish between be sequenced directly, an approach the company calls ìABASeq,î
5-mC and 5-hmC, meaning that at least some sites reported as con- (ìlike the musical group, but only one B,î Pradhan quips) in honor of
taining the former, may in fact contain the latter. AbaS1, the PvuRTS1I family member used in the assay.
ìWhat it means to the scientiÀc community is that whatever infor- ìYou donít need a bisulÀte conversion; you donít need any kind of
mation we had before is not true, because we donít know what per- Tet-based approach or oxidation-based approach,î Pradhan says.
centage of the apparent 5-methycytosines are actually 5-hydroxy- ìYour sequence output is just going to align with the genome se-
methylcytosine,î says Sriharsa Pradhan, head of the RNA Biology quence.î According to Pradhan, the team has already used this ap-
division at New England Biolabs, which sells restriction enzyme- proach to map 5-hmC residues in a mouse embryonic stem cell line,
based kits to distinguish between the two bases. though those data are not yet published.
This year, researchers Ànally developed strategies to circumvent
this problem. The Àrst, developed by a team in Cambridge, UK, and CATALOGING HISTONE MODIFICATIONS
called oxidative bisulÀte sequencing (oxBS-Seq), uses an oxidiz- Another recipient of NIH Epigenome Project funding is Brian
ing reagent (potassium perruthenate) to oxidize 5-hmC residues to Strahl, associate professor of biochemistry and biophysics at the
5-formylcytosine (5-fC), which reads as T after bisulÀte conversion. University of North Carolina (UNC) School of Medicine. With
The second method, developed in a collaboration between Renís UNC colleague Xian Chen, Strahl submitted an application focusing
lab, Chuan He at the University of Chicago, and Peng Jin at Emory on the discovery of novel epigenetic marks.
University, uses an enzyme to selectively protect 5-hmC residues. ìOne of the questions we wanted to address is whether there were
Called Tet-assisted bisulÀte sequencing (TAB-Seq, commercialized novel sites of histone modiÀcation that had gone undetected,î Strahl
by a Chicago-area Àrm named WiseGene), this method uses a ten- explains. ìThis is relevant because to really understand epigenom-
eleven translocation (Tet)-family oxidase enzyme to convert 5-mC ics, or even epigenetics, you need to know Àrst what are all the modi-
to 5-carboxylcytosine (5-caC), which also reads as T after bisulÀte Àcations on histones to begin with.î
treatment. (The Tet enzyme progressively oxidizes 5-mC to 5-hmC, Put another way, you cannot map modiÀcations you donít know
and then to 5-fC, and Ànally to 5-caC.) exist. Those can be of two types: known modiÀcations in novel loca-
First though, TAB-Seq uses ћ-glucosyltransferase to couple a glu- tions, and novel modiÀcation types.
cose moiety to 5-hmC, protecting it from Tet. Thus, the only residues To Ànd both types, many researchers turn to mass spectrometry.
that should appear as cytosines during sequencing should be 5-hmC. Strahl and Chen, for instance, have used top-down proteomics anal-
Comparison with standard bisulÀte-converted and sequenced DNA yses on a Bruker Daltonics 12-Tesla Fourier transform ion cyclotron
should reveal the balance of 5-mCs. (New England Biolabsí EpiMark resonance (FT-ICR) mass spectrometer to show that histone H2B ly-
5-hmC and 5-mC Analysis Kit is based on a similar principle; it uses sine 37 in Saccharomyces cerevisiae contains a previously unknown
ћ-glucosyltransferase to render a sequence resistant to a restriction modiÀcation.
enzyme.) ìOne of the peaks that came out Ö was, as far as we can tell, di-
Ren and Heís team used TAB-Seq to decipher the methylome of methylated on one particular lysine that had not been reported else-
human embryonic stem cells, identifying some 691,000 5-hmC sites. where,î Strahl says. ìUnfortunately, we couldnít link any particular
Based on the distribution of that epigenetic mark, Ren says, it appears biology to it; itís just too new.î continued>
www.sciencemag.org/products 547
LIFE SCIENCE TECHNOLOGIES Pr
Produ
oduced
ced by th
thee Sci
Scienc
ence
e/AA
/AAAS
AS Cus
Custom
tom Pu
Publi
blishi
shing
ng Off
Office
ice
Genomics
Thatís not to say the modiÀcation FEATURED PARTICIPANTS But he did reveal that ìit has
isnít important, he says. ìIf the a functional sort of twist to it,
cell cares that much to burn so Ben May Department The Rockefeller University some personality Ö that looks
many ATPs to get a particular for Cancer Research, www.rockefeller.edu very exciting and different from
modiÀcation on a residue, itís got University of Chicago what has been well-accepted
benmay.uchicago.edu San Diego Epigenome
to be there for a reason,î he says. for acetyl-lysine.î
Center
Researchers are also discover- Bruker Daltonics epigenome.ucsd.edu Or Gozani, associate profes-
ing entirely novel modiÀcations. www.bdal.com sor of biology at Stanford Uni-
One team that has made several Stanford University versity, another Epigenome
such discoveries is led by Ying- Cornell University www.stanford.edu Project grant winner, uses an al-
www.cornell.edu
ming Zhao, a professor in the Thermo Fisher ScientiÀc ternate strategy for reader iden-
Ben May Department for Cancer Illumina www.thermoscientiÀc.com tiÀcation, probing microarrays of
Research at the University of www.illumina.com modiÀed histone peptides with
University of North Carolina
Chicago and another Epigenome puriÀed candidate reader pro-
Ludwig Institute for Cancer at Chapel Hill School of
Project grant recipient. Research, UCSD Medicine teins. Currently, Gozaniís arrays
Using high-resolution mass www.ludwigsd.org www.med.unc.edu contain about 100 peptides, and
spectrometry, Zhao has discov- in one recent study his team, in
ered several new posttranslational New England Biolabs University of Pennsylvania collaboration with Dinshaw Pa-
www.neb.com Perelman School of
modiÀcations on histone proteins, tel at Memorial Sloan-Kettering
Medicine
including lysine propionylation NIH Common Fund OfÀce www.med.upenn.edu Cancer Center in New York,
and butyrylation in 2007, lysine of Strategic Coordination used them to determine that a
crotonylation in 2011, and earlier Epigenomics Program WiseGene protein associated with DNA
this year, lysine succinylation and commonfund.nih.gov/ www.wisegeneusa.com replication called ORC1 binds
malonylation. epigenomics speciÀcally to dimethylated ly-
Zhaoís discovery of lysine croto- sine-20 on histone H4.
nylation is actually a case study in why researchers should always ìThereís a lot of room left to discover new readers,î Gozani says.
verify what the computer tells them. In this case, that due diligence And there are a lot of new methods in the epigenomics application
yielded a high-proÀle paper in Cell. space to study them. But that doesnít mean the Àeld has achieved
At the time, Zhaoís lab had already discovered lysine butyrylation. technological maturity, says Kenneth Zaret, codirector of the epi-
Now, using a high-end Thermo ScientiÀc LTQ Orbitrap Velos sys- genetics program at the University of Pennsylvania School of
tem, they were trying to map sites of that modiÀcation. Normally in Medicine. ìBase technologiesî like ChIP-Seq work best with immor-
this type of study, researchers rely on computers to chew through the talized cell lines that can provide the hundreds of thousands or even
data and map observed ion masses against possible modiÀcations. millions of cells required to make that technique work; when sample
Itís simply too laborious to do it manually. But computers can make size is limited, during stem cell development or embryogenesis, for
mistakes, so Zhaoís team double-checks the computerís math. instance, these techniques are harder to pull off. What is needed,
When they checked the spectral assignments in this case, they Zaret says, is a way to apply epigenomics approaches to smaller
noticed that some didnít quite match upóthey were off by 2 daltons cell populations.
(Da). Looking more closely, they were able to narrow down the modi- Already, he and others are making headway. Cornell Uni-
Àcationís molecular formula to C4H5O, a crotonyl group. versity Professor Paul Soloway, with colleague Harold Craighead,
Using a homemade ìpan-crotonylî antibody, Zhaoís team used has developed a nanoÁuid approach called SCAN (single chromatin
ChIP-Seq to tackle the markís distribution throughout the genome, analysis at the nanoscale) to monitor groups of modiÀcations simul-
and found that it is associated with transcriptional start sites, enhanc- taneously on anywhere from one to 10 nucleosomesóasking, for in-
ers, and active genes, and also ìplays a role in the reprogramming of stance, whether a single nucleosome contains both H3K27-trimethyl
gene expression in postmeiotic male germ cells,î he says. and methylated DNA.
Zaret is using Áuorescence-activated cell sorting to isolate discrete
OF READERS AND DOWNSIZING cell populations, which he then analyzes using a modiÀed ChIP pro-
Of course, a histone modiÀcation is just that: a modiÀcation. Itís like tocol. Applying that approach to nine transcriptionally silent genes in
a genomic street sign, and signs donít exist in a vacuum. There must a few thousand mouse stem cell progenitors, Zaretís team discov-
also be proteins that add and remove those signs, and ìreaderî pro- ered distinct ìprepatternsî that appear to position different sets of
teins that interpret what they mean. genes in different ways. Now the team is scaling this approach up to
To Ànd those readers, researchers like C. David Allis, head of the the genomic level.
Laboratory of Chromatin Biology and Epigenetics at Rockefeller Look for these data and more from the NIH Roadmap Epig-
University, sift through protein extracts, looking for activities that can enome Project in the months and years ahead. In the meantime,
recognize, add, or remove a given modiÀcation. The key, says Allis: those hoping to mine the epigenome datasets can do so today at
ìFractionate, fractionate, fractionate.î Using that strategy, Allis says the Projectís ofÀcial data-coordination website, www.genboree.org/
his team has begun to home in on what they believe are a family of epigenomeatlas.
enzymes that can add a crotonyl group to histonesóthat is, histone
crotonylases. Jeffrey M. Perkel is a freelance science writer based in Pocatello, Idaho.
The results are not yet published, so Allis is fairly tight-lipped. DOI: 10.1126/science.opms.p1200069
548 www.sciencemag.org/products
Pr
Produ
oduced
ced by th
thee Sci
Scienc
ence
e/AA
/AAAS
AS Cus
Custom
tom Pu
Publi
blishi
shing
ng Off
Office
ice LIFE SCIENCE TECHNOLOGIES
New Products: Genomics
DNA METHYLATION KIT
The new EZ DNA Methylation-Lightning Kit is for complete bisulÀte conversion
of DNA prior to methylation analysis by polymerase chain reaction (PCR),
MSP, array, or next-gen sequencing. The ready-to-use liquid format Lightning
Conversion Reagent is added directly to a DNA sample (as low as 100 pg)
for conversion in about an hour. High yield, converted DNA can be eluted
into minimal volumes using Zymoís unique spin columns, 96-well spin plates
oróa Àrst of its kindómagnetic bead format. This new format enables bisulÀte
treatment of DNA to be used in conjunction with automated platforms (e.g.,
Tecan - Freedom EVO) for high throughput processing applications. The EZ
DNA Methylation-Lightning Kit is designed to simplify DNA methylation analysis
and epigenetic research.
Zymo Research Corporation
For info: 888-882-9682 www.zymoresearch.com
Electronically submit your new product description or product literature information! Go to www.sciencemag.org/products/newproducts.dtl for more information.
Newly offered instrumentation, apparatus, and laboratory materials of interest to researchers in all disciplines in academic, industrial, and governmental organizations are
featured in this space. Emphasis is given to purpose, chief characteristics, and availability of products and materials. Endorsement by Science or AAAS of any products or
materials mentioned is not implied. Additional information may be obtained from the manufacturer or supplier.
www.sciencemag.org/products 549
INTRODUCING MERCK’S
NEW POSTDOCTORAL
RESEARCH FELLOW
PROGRAM
Join the Merck Networks Bringing important medicines and vaccines to people around the world through innovative
for immediate news and science is what we do. At Merck, we strive to improve human life, achieve scientific
recruitment alerts: excellence, operate with the highest standards of integrity, expand access to our products
and employ a diverse workforce that values collaboration.
Merck Research Laboratories is proud to announce the launch of a new Postdoctoral Research
Fellow Program that will build on our legacy of scientific excellence and innovation.
merckcareers1 merck If you join us, you’ll be a part of a team of motivated scientists working to discover and
develop medicines and vaccines that help meet the world’s unmet medical needs.
You will work alongside outstanding researchers and collaborators as part of Merck’s
industry-leading research and development organization. Our postdocs will:
At Merck, our passion is improving health. This is what keeps us at the forefront of scientific
discovery and innovation. We invite you to apply.
T/A ligation
Blunt ligation
• Blunt/TA Ligase Master Mix, optimized for blunt-end
Transformation efficiency (%)
75
and single-base overhang substrates
• Instant Sticky-end Ligase Master Mix, uniquely formulated 50
for the rapid ligation of sticky-end substrates
• T7 DNA Ligase, specific for sticky ends 25
from NEB. Duplicate ligation reactions of blunt or T/A vector/insert pairs were set up according to the
master mix vendors’ suggestions. Equal amounts of ligated DNA were used to transform NEB
10-beta Competent E. coli (NEB #C3019) and triplicate plating was performed. Transformation
results were averaged and graphed as a percentage of the highest performing reaction, T/A
To request a FREE SAMPLE of our new DNA Ligase ligation using the Blunt/TA Ligase Master Mix.