Science_-_18_01_2019

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CONTENTS Deadly pileups
of proteins
18 JANUARY 2019 • VOLUME 363 • ISSUE 6424

NEWS 217 FLOTILLA LAUNCHES LARGE SURVEY 218 Downloaded from http://science.sciencemag.org/ on January 21, 2019
OF ANTARCTIC KRILL
GRAPHIC: V. ALTOUNIAN/SCIENCE; PHOTO: CAVAN SOCIAL/ALAMY STOCK PHOTO IN BRIEF Health of stock is critical to fishery— 229 THE CEREBELLUM GETS SOCIAL
and to predators By E. Stockstad The cerebellum can regulate behavior
208 News at a glance by controlling dopamine release
FEATURES
IN DEPTH By E. D’Angelo
218 THE BONES OF BEARS EARS
211 SHAKE-UP THREATENS NOVEL U.S. Paleontologists struggle to protect sites ▶ RESEARCH ARTICLE P. 248
ECOLOGY FACILITY that could rewrite Earth’s history
NEON science head quits, advisers 230 ADAPTATIONS OF AN ANCIENT
fired after Battelle replaces two top By A. Reese MODULAR MACHINE
managers By J. Mervis Mechanism of energy conversion is
221 THE BRAIN’S TRAFFIC PROBLEMS conserved in the complex I superfamily
212 DID NEURONS ARISE FROM AN EARLY Disrupted flow into and out of the
SECRETORY CELL? nucleus may kill neurons By E. Dolgin By U. Brandt
Cell lineage studies of comb jellies and
other creatures may suggest a single INSIGHTS ▶ REPORT P. 257
ancient origin of the nervous system
PERSPECTIVES 231 GENE THERAPY FOR PATHOLOGIC
By E. Pennisi GENE EXPRESSION
224 WHEN EARTH GOT PUMMELED Haploinsufficiency in disease
213 IN CONGO, FIGHTING A VIRUS AND The frequency of impacts on Earth’s can be overcome by boosting gene
A GROUNDSWELL OF FAKE NEWS surface increased about 290 million expression with CRISPR
Armed conflict and political tensions years ago By C. Koeberl
stoke rumors and misinformation about By L. E. Montefiori and M. A. Nobrega
Ebola By L. Spinney ▶ REPORT P. 253
▶ RESEARCH ARTICLE P. 246
▶ PODCAST 225 IRON HITS THE MARK
Strongly electron-donating ligands 232 B CELLS, CMV, AND STEM CELL
214 DUELING SPACECRAFT LOOK DEEP enable nanosecond lifetimes of TRANSPLANT
INTO SATURN AND JUPITER iron(III) photoexcited states Host antibodies help prevent CMV
NASA probes reveal surprising contrasts dissemination after bone marrow
between two gas giants By P. Voosen By E. R. Young and A. Oldacre transplantation By M.-L. Alegre

▶ RESARCH ARTICLE BY L. IESS ET AL. ▶ REPORT P. 249 ▶ REPORT P. 288
10.1126/science.aat2965; PODCAST
227 MICROBIAL GUARDIANS OF POLICY FORUM
216 PAIN SPREADS FROM SHUTDOWN SKIN HEALTH
Historic spending impasse halts Skin microbes can promote skin 234 OVERSIGHT OF DIRECT-TO-CONSUMER
paychecks and projects By D. Malakoff immunity, repair, and antimicrobial NEUROTECHNOLOGIES
defense By A. Stacy and Y. Belkaid Efficacy of products is far from clear
SCIENCE sciencemag.org
Published by AAAS By A. Wexler and P. B. Reiner

BOOKS ET AL.

236 THE REVEALING HISTORY OF A
REVERED WATERWAY
Human and environmental stories
interweave in a meandering meditation
on the Ganges River By A. Rademacher

18 JANUARY 2019 • VOL 363 ISSUE 6424 203

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CONTENTS

237 NUCLEAR POWER AND PROMISE 239 282 BIODIVERSITY Downloaded from http://science.sciencemag.org/ on January 21, 2019
Deference to industry trumps Agriculturally dominated landscapes
PHOTO: EYEWELL PORTRAIT safety in the U.S., warns a 248 NEUROSCIENCE reduce bee phylogenetic diversity and
controversial former regulator Cerebellar modulation of the reward pollination services H. Grab et al.
circuitry and social behavior I. Carta et al.
By J. D. Hamblin 285 CILIA
RESEARCH ARTICLE SUMMARY; FOR FULL TEXT: Flagellar microtubule doublet
LETTERS dx.doi.org/10.1126/science.aav0581 assembly in vitro reveals a regulatory
▶ PERSPECTIVE P. 229 role of tubulin C-terminal tails
239 THE VALUE OF SMALL M. Schmidt-Cernohorska et al.
MANGROVE PATCHES REPORTS
288 IMMUNOTHERAPY
By D. J. Curnick et al. 249 INORGANIC CHEMISTRY Strain-specific antibody therapy
Luminescence and reactivity of a prevents cytomegalovirus reactivation
240 BRAZIL’S ENDANGERED charge-transfer excited iron complex after transplantation
POSTGRADUATE SYSTEM with nanosecond lifetime K. S. Kjær et al. J. P. Martins et al.

By H. Martelli Júnior et al. ▶ PERSPECTIVE P. 225 ▶ PERSPECTIVE P. 232

240 AIRBORNE IN THE ERA OF 253 IMPACT CRATERS 294 CELL DIFFERENTIATION
CLIMATE CHANGE Earth and Moon impact flux increased at H3K9me3-heterochromatin loss
the end of the Paleozoic S. Mazrouei et al. at protein-coding genes enables
By K. Jean and C. Wymant developmental lineage specification
▶ PERSPECTIVE P. 224 D. Nicetto et al.
RESEARCH
257 PHOTOSYNTHESIS DEPARTMENTS
IN BRIEF Structural adaptations of photosynthetic
complex I enable ferredoxin-dependent 207 EDITORIAL
241 From Science and other journals electron transfer J. M. Schuller et al. Why we need fetal tissue research

REVIEW ▶ PERSPECTIVE P. 230 By Sally Temple and
Lawrence S. B. Goldstein
244 ORGANIC CHEMISTRY 261 CHEMICAL PHYSICS
The importance of synthetic Observation of magnetically tunable 314 WORKING LIFE
chemistry in the pharmaceutical Feshbach resonances in ultracold Lessons from a postdoc gone wrong
industry K. R. Campos et al. 23Na40K + 40K collisions H. Yang et al.
By Victor S. C. Wong
REVIEW SUMMARY; FOR FULL TEXT: 265 SOLAR CELLS
dx.doi.org/10.1126/science.aat0805 A Eu3+-Eu2+ ion redox shuttle imparts ON THE COVER
operational durability to Pb-I perovskite
RESEARCH ARTICLES solar cells L. Wang et al. A three-dimensional
micrograph, color
245 IMAGING TECHNIQUES 270 ORGANIC CHEMISTRY coded by depth, of
Cortical column and whole-brain Concise total syntheses of neurons at the ellipsoid
imaging with molecular contrast and (–)-jorunnamycin A and (–)-jorumycin body in the brain of a
nanoscale resolution R. Gao et al. enabled by asymmetric catalysis fruit fly (Drosophila
E. R. Welin et al. melanogaster),
RESEARCH ARTICLE SUMMARY; FOR FULL TEXT: extracted from a
dx.doi.org/10.1126/science.aau8302 276 NEUROSCIENCE much larger dataset
An amygdalar neural ensemble that encompassing the entire brain. Combining
246 GENE THERAPY encodes the unpleasantness of pain expansion microscopy with lattice
CRISPR-mediated activation G. Corder et al. light-sheet microscopy enables rapid
of a promoter or enhancer rescues fluorescence imaging of neural circuits
obesity caused by haploinsufficiency and their molecular constituents over
N. Matharu et al. millimeter dimensions with nanoscale
resolution. See page 245. Image: Betzig Lab,
RESEARCH ARTICLE SUMMARY; FOR FULL TEXT: Janelia Research Campus/HHMI; Boyden
dx.doi.org/10.1126/science.aau0629 Lab, MIT Media Lab
▶ PERSPECTIVE P. 231
Science Staff ............................................. 206
247 ASYMMETRIC CATALYSIS New Products............................................ 298
Prediction of higher-selectivity catalysts AAAS Meeting Program ........................... 299
by computer-driven workflow and Science Careers ........................................ 309
machine learning A. F. Zahrt et al.

RESEARCH ARTICLE SUMMARY; FOR FULL TEXT:
dx.doi.org/10.1126/science.aau5631

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EDITORIAL

Why we need fetal tissue research

A vocal minority in the United States is intent on planting fetal tissue research, but that is incorrect.
stopping federal funding for research using hu- Organoids typically do not fully mirror the complex
man fetal tissue, citing stem cell–based or other cellular composition and architecture of fetal organs.
alternatives as adequate. This view is scientifical- Although organoids may prove valuable to model some
ly inaccurate. It ignores the current limitations of diseases, critically, access to fetal tissue is required for
stem cell research and disregards the value of fe- validation of these and any proposed alternatives. For

tal tissue research in finding therapies for incur- example, mice that model the human blood system are

able diseases. If there is to be continued rapid progress produced through transplants of human fetal liver and/ Sally Temple
is the scientific
in treating cancer, birth defects, heart disease, and infec- or thymus tissue to provide a near full complement of director of the
Neural Stem
tious diseases, then we need fetal tissue research. long-lived human blood cells. These animal models are Cell Institute,
Rensselaer,
Life-saving advances, including the development of vac- needed to develop therapies that involve the immune NY, USA. Downloaded from http://science.sciencemag.org/ on January 21, 2019
sallytemple@
cines against rubella, rabies, and hepatitis A viruses, and system, such as HIV vaccines and new chimeric anti- neuralsci.org

antiviral drugs that prevent gen receptor (CAR) T cell– Lawrence S. B.
Goldstein is a
HIV/AIDS, required fetal tis- based cancer treatments. professor in the
Department of
sue research. Today, fetal tis- Fetal brain tissue Alternative mouse models Cellular and
Molecular Medicine
sue is being used to develop using human neonatal thy- at the University
of California, San
new medicines including mus are being explored but Diego, CA, USA
and the scientific
vaccines for HIV/AIDS, pre- may lack the variety and director of the
Sanford Consortium
ventives for Zika virus, and sustained production of for Regenerative
Medicine.
immunotherapies to battle blood cells produced from [email protected]

untreatable cancers. fetal liver or autologous

Although research into bone marrow, and supply

alternatives is worthwhile, is limited to thymus taken

PHOTOS: (INSET) STEVE GSCHMEISSNER/SCIENCE SOURCE; (RIGHT TOP TO BOTTOM) SUZANNE KAWOLA, NSCI; DONNA COLEMAN PHOTOGRAPHY there are several aspects from infants undergoing

of fetal tissue research for congenital heart surgery,

which alternatives do not sometimes associated with

and will not exist. For ex- concomitant immune prob-

ample, to discover which lems that confound results.

fetal cells go awry and It would be a grave injus-

cause childhood cancers tice to the patients and

such as retinoblastoma, a families afflicted by dis-
cancer of the eye, or rhab- “…fetal tissue remains an essential eases that benefit from this

domyosarcoma, a muscle resource for many applications.” research to prematurely
cancer, we must understand halt production of fetal

which cells are the culprits. tissue models.

For that, we need access to relevant fetal tissues. Zika vi- Although alternatives may be established in some cases,

rus can cross the placenta and attack specific fetal brain fetal tissue remains an essential resource for many appli-

cells. To determine the mechanism of viral entry, which cations. It is important to remember that the fetal tissue

cell types are vulnerable, and how to prevent infection used in research would otherwise be discarded and thus

and damage, we need access to fetal brain tissue. Beyond unavailable in the fight against disease. U.S. researchers

diseases affecting children, some forms of hereditary Al- also follow rigorous, well-established medical and ethical

zheimer’s disease cause neural impairments in utero that standard practices for this research. Fetal tissue research

persist over decades and manifest later in life. Without has been supported for decades by both Republican and

access to fetal cells, we cannot understand and effectively Democratic administrations and congresses. Rigorous

combat diseases that begin in utero. U.S. government–sponsored review processes have also

Fetal tissue alternatives for some applications may concluded that this research is ethical and valuable.

be developed as science advances, but this will take If we are to achieve medical advances for currently

time. The transition to any new model of research incurable diseases, the path forward must include fetal

should be data-driven and based on scientific evidence. tissue research, for which continued public support is

Opponents of fetal tissue research state that human most critical at this time.

stem cell–derived organoids are adequate models, sup- –Sally Temple and Lawrence S. B. Goldstein

10.1126/science.aaw6299

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NEWS “We need a rigorous, scientific

postmortem on Russian misinformation to harden

”our democracy against future attacks.

Sinan Aral, of the Massachusetts Institute of Technology, in The Washington Post.

IN BRIEF India’s quantum computing push
Edited by Lila Guterman
FUNDING | The Indian government quietly
ENVIRONMENT unveiled a $12 million Quantum Enabled
Science & Technology program last week.
Fish kill reignites Australian water fight The funds, to be spent over 3 years, will
build infrastructure and hire researchers
Dead carp lie on the shores of Lake Hawthorn, part of the Murray-Darling Basin in Australia, in 2007. to help realize the country’s ambitious new Downloaded from http://science.sciencemag.org/ on January 17, 2019
goal: being at the forefront of the quantum
M ore than 1 million fish have died in the Murray-Darling river computing revolution within 10 years. PHOTO: AMY TOENSING/NATIONAL GEOGRAPHIC IMAGE COLLECTION
system in New South Wales and adjacent states in Australia Indian policymakers often lament that the
in recent weeks—despite a 2012 water-sharing agreement, country missed the computer hardware
touted as historic, that was supposed to avoid such catas- revolution of the 1970s, despite having
trophes. The die-off is due to the combined effects of a heat played a significant role in developing
wave, low water levels, and algae blooms, which starved software. Now, they don’t want to miss the
the fish of oxygen when they decayed. Farmers blame a monthslong quantum computing boat.
drought, but environmentalists say too much water has been drawn
for irrigation from the network of rivers, which stretches through Radio telescopes plan global pact
a 1-million-square-kilometer basin in the country’s southeast. The
2012 plan promised to balance the demand for drinking water and ASTRONOMY | Radio astronomers intend
irrigation with environmental needs (Science, 7 December 2012, to link two of their biggest planned projects,
p. 1273). But enforcement of water diversion limits has been lax, the Square Kilometre Array (SKA)—a
says John Quiggin, an environmental economist at the University of 12-nation effort to build thousands of radio
Queensland in Brisbane, Australia, and the federal government has antennas across swaths of South Africa and
refused to buy back water rights from farmers, as the plan stipulated. Australia—and the U.S. Next Generation
Climate change could exacerbate stresses on the ecosystem, he says, Very Large Array (ngVLA). Designs for the
and cause “irrecoverable damage.” ngVLA include 214 18-meter dishes across
New Mexico, Texas, Arizona, and northern
208 18 JANUARY 2019 • VOL 363 ISSUE 6424 Mexico, as well as 30 more far-flung dishes
in Hawaii, British Columbia in Canada,
the U.S. Virgin Islands, and elsewhere; the
dishes will pool their data to achieve un-
precedented resolution. Tony Beasley, direc-
tor of the U.S. National Radio Astronomy
Observatory in Charlottesville, Virginia, told
the American Astronomical Society meeting
in Seattle, Washington, last week that ngVLA
planners are in discussions with their SKA
counterparts on a reciprocal agreement to
allow researchers access to both observa-
tories. Neither array, however, has yet been
approved for construction.

Space ‘Cow’ mystery endures

ASTRONOMY | Astronomers admitted last
week they are flummoxed by an unusually
bright glow in the sky that appeared sud-
denly one day in June 2018. After months of
study, they still aren’t sure what the object—
officially called AT2018cow, but universally
referred to as the “Cow”—is or what caused
it. At the American Astronomical Society
meeting last week in Seattle, Washington,
researchers described using dozens of

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A mite-y record of the Incan Empire

T he history of the Andes might well be told through llama population boomed during the Incan Empire and plummeted
poop. During the Incan Empire, which lasted from 1438 to after the Spanish arrived, tracking the deaths of huge numbers
1533, thousands of llamas carrying trade goods such as of the Indigenous people and their animals. A more commonly
salt and coca leaves marched through the Marcacocha used environmental proxy, spores of the dung-dwelling fungus
Basin, once the site of a small lake in highland Peru. Their Sporormiella, didn’t track those historical events, the team
dung washed into the lake, where it was eaten by oribatid mites, reports in the Journal of Archaeological Science. Rather, the
a half-millimeter-long relative of spiders. The more llamas that number of spores boomed during dry periods that shrank the
passed through Marcacocha, the more excrement they left, lake. The researchers suggest that mites are better than the
and the larger the mite populations could grow. Researchers fungus for tracking llama populations in small, shallow lakes
counted the mites in a sediment core and found that their like Marcacocha.

PHOTOS: (TOP TO BOTTOM) ISTOCK.COM/OGPHOTO; R. MARGUTTI/W. M. KECK OBSERVATORY telescopes to study the Cow, located in a James Watson stripped of titles World Conference on Research Integrity, to
small galaxy about 200 million light-years be held in Hong Kong, China, in June, were
away. It didn’t behave like a distant super- PEOPLE | Cold Spring Harbor Laboratory surprised to receive an abstract that was,
nova, and its position ruled out a black hole (CSHL) in New York has severed its ties instead, full of apparent plagiarism. After
ripping apart a star. Its steady brightness to James Watson after the Nobel laureate combing through all 430 submissions, they
over several weeks suggests it was powered reiterated the belief that black people are discovered 11 additional cases of suspected
by some kind of “central engine.” Whatever intrinsically less intelligent than white plagiarism. When they reached out to the
the Cow is, says astronomer Liliana Rivera people. Watson retired as CSHL chancel- authors of the abstracts—two of which,
Sandoval of Texas Tech University in lor in 2007 and apologized after his earlier ironically, were about plagiarism—six
Lubbock, “It’s super weird.” comments appeared in London’s The didn’t respond, one withdrew their submis-
Times. But this month, Watson said in a sion, one blamed staff, and two said they
AT2018cow is the farther right of two bright spots PBS documentary that his views about had permission to use each other’s work.
in the lower right of this galaxy. genetics and intelligence have not changed. Only two gave “acceptable” explanations,
In a statement, CSHL said it “unequivocally the organizers reported last week on the
rejects [Watson’s] unsubstantiated and Retraction Watch blog.
reckless personal opinions” and has
revoked Watson’s titles of chancellor emeri- Harassment bill introduced
tus, Oliver R. Grace professor emeritus,
and honorary trustee. U.S. CO N G R ESS | Representative Eddie
Bernice Johnson (D–TX), who became chair
Plagiarism at integrity meeting of the science committee in the U.S. House
of Representatives this month, has already
ETHICS | Researchers studying integrity introduced three bills that signal her
might be expected to be full of that rare interest in topics that previous Republican
quality. That’s why organizers of the sixth leadership has shunned—and her interest

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NEWS | IN BRIEF

in bipartisanship. She teamed up with BioRxiv gains fans down on 1 February, 3 years before the end
Representative Frank Lucas (OK), the of his term. Kim, a physician and anthropo-
panel’s top Republican, on a bill that would 125,000 logist, was nominated by then-President
make agencies adopt common policies Barack Obama in 2012 and in 2016 was
for handling allegations of sexual harass- 100,000 New authors appointed to a new term that runs through
ment and encourage the National Science 75,000 2021. His departure has raised questions
Foundation (NSF) to do research on the 50,000 New and about whether the bank’s board will fol-
topic. The panel’s top lawmakers are also repeat authors low a long-standing tradition and accept
jointly sponsoring legislation to strengthen whomever the U.S. president nominates.
clean water programs at the Department 25,000 In a statement, the World Bank said Kim
of Energy. A third bill—likely much more plans to join a firm that will “focus on
controversial and lacking bipartisan 0 increasing infrastructure investments in
support—would authorize NSF and three 2013 2014 2015 2016 2017 2018 developing countries” and rejoin the board
other agencies to fund research on the of Partners in Health, a Boston-based
causes and consequences of gun violence. launched in 2013. Nearly two-thirds of nonprofit organization that provides health Downloaded from http://science.sciencemag.org/ on January 17, 2019
preprints posted in 2017 or earlier were care in developing countries.
Biologists flock to preprints later published in journals, report Richard
Abdill and Ran Blekhman of the University Germany inks open-access deal
PUBLISHING | Last year saw rapid growth of Minnesota in Minneapolis this week in
in the number of biologists posting papers a bioRxiv preprint. The researchers also PUBLISHING | This week, a consortium of
to the preprint server bioRxiv and in the unveiled Rxivist.org, a website that allows German libraries, universities, and research
total number of papers. The server still users to sort bioRxiv preprints by number institutes signed a first-of-its-kind open-
hosts only a small fraction of all new bio- of downloads or Twitter mentions. access deal with the publisher Wiley. In
logy papers, but it has provided an out- exchange for an annual lump sum, Wiley
let to authors looking to quickly share World Bank head resigns early will make papers from authors at more CREDITS: (GRAPHIC) J. BRAINARD/SCIENCE; (DATA) R. J. ABDILL AND R. BLEKHMAN, BIORXIV, 10.1101/515643 (2019); (PHOTO) TORSTEN BLACKWOOD/POOL/GETTY IMAGES
research findings. More preprints were than 700 institutions freely available online.
posted in the first 11 months of 2018— PEOPLE | Jim Yong Kim, president of Researchers at the German institutions will
18,825—than in the years since the server the World Bank in Washington, D.C., also gain access to all Wiley journal papers
announced last week that he would step published since 1997. At Wiley’s request,
the details of the payment plan won’t be
disclosed for 30 days. Negotiators for the
consortium, called Project DEAL, hope the
step will push Elsevier and Springer toward
similar deals. Hundreds of institutes in
Germany, including the Max Planck Society,
lost access to Elsevier journals after con-
tracts ran out.

C L I M AT E Europe plans newest collider

East Antarctica’s ice is melting rapidly PA RT I C L E P H YS I CS | This week, European
scientists released a conceptual design for
T he vast majority of Antarctica’s ice melt, which is responsible for at least a successor to the world’s biggest atom
13.8 millimeters of sea level rise over the past 40 years, was long thought to come smasher, the 27-kilometer-long Large
from the unstable West Antarctic Ice Sheet. Now, a study using 40 years of satel- Hadron Collider (LHC) at CERN, the
lite imagery finds that the East Antarctic Ice Sheet is losing a substantial quantity European particle physics laboratory near
of ice as well. Over the past 4 decades, that loss accounted for more than 30% Geneva, Switzerland. The plan envisions a
of the sea level rise attributed to the continent, researchers report this week in the ring 100 kilometers in circumference that
Proceedings of the National Academy of Sciences. East Antarctica, which has 10 times would collide electrons and positrons and
as much ice as the continent’s western half, was long thought to be insulated from cli- study in detail the Higgs boson, the weird
mate change because it rests on land, largely protected from warming ocean waters. A new particle the LHC discovered in 2012.
2018 Nature paper estimated the region was actually gaining ice. If confirmed, the new The €9 billion accelerator would begin to
results could dramatically reshape projections of sea level rise for the next century. operate around 2040, after the LHC shuts
down. After the electron-positron collider
210 18 JANUARY 2019 • VOL 363 ISSUE 6424 has done its work, its tunnel might house
an even more ambitious €15 billion collider
that, like the LHC, would bash protons
together, but would reach far higher ener-
gies than any previous machine. CERN has
competition from physicists in China with
similar plans.

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ENVIRONMENTAL RESEARCH

Shake-up threatens novel U.S. ecology facility

NEON science head quits, advisers fired after Battelle replaces two top managers

By Jeffrey Mervis Science, Technology & Education Advisory Ecologists take Board, NSF’s presi-
Committee (STEAC). “This has put the proj-
T he National Ecological Observatory ect at massive risk.” He and other former vegetation measure- dentially appointed
Network (NEON), a half-billion-dollar STEAC members want the advisory panel
facility funded by the National Sci- reinstated and its role strengthened. Dis- ments in 2018 at oversight body, wel-
ence Foundation (NSF), hopes to banding it “leaves NEON open to missteps
revolutionize ecology by collecting an and … is breeding mistrust in the user com- NEON’s Toolik Lake site comed the progress.
unprecedented amount of data about munity,” they wrote in a 14 January letter to
long-term environmental changes across Battelle executives and NSF leadership. in northern Alaska. “I feel we are in a
North America. But as NEON prepares to
begin full operations, an abrupt leadership The upheaval is NEON’s latest self- very happy place,”
shake-up threatens to alienate the scientists inflicted wound. First proposed by then–
who will be using those data and, thus, are NSF Director Rita Colwell in 2000, the said Inez Fung, an atmospheric scientist at
essential to its success. project has chewed up half a dozen scien-
tific directors—Collinge lasted less than a the University of California, Berkeley, who
On 8 January, Sharon Collinge, NEON’s year—ensnared two contractors, prompted
chief scientist and principal investigator, re- a congressional inquiry over spending and had led an ad hoc panel created to keep close
signed 4 days after Battelle Memorial Insti- management practices, and generated a
tute, which manages the network, fired two seemingly endless stream of critical reviews tabs on NEON. (Fung has since rotated off
senior managers without her knowledge or by outside experts. Many ecologists also
consent. Within hours of Collinge’s resigna- worry that NEON’s $65-million-a-year oper- the board.) “I am looking forward to very
tion, Battelle dissolved NEON’s 20-member ating budget will reduce the NSF funding
technical advisory committee, heading off a available for ecological research that doesn’t great discoveries,” she added.
possible mass resignation of panel members rely on data from the 81-site facility, which
opposed to Battelle’s actions. The rapid-fire is headquartered in Boulder, Colorado. But this month’s events have clouded
developments came after years of cost over-
runs, construction delays, and debate over Battelle took over NEON in 2016, after NSF NEON’s future. On 4 January, Battelle ex-
the project’s scientific merits and left many fired the project’s original contractor, and the
researchers bewildered and concerned. Columbus-based nonprofit is widely credited ecutives removed Richard Leonard, who
with putting the project on the right track.
Battelle “just burned some of the most By the end of 2018 it had completed work on had overseen the project’s turnaround, and
prominent ecologists in the country,” says all but one of NEON’s data-collecting sites,
Ankur Desai, an atmospheric scientist at for $10 million less than the latest projected ecologist Wendy Gram, a senior manager
the University of Wisconsin in Madison cost of $469 million. At a meeting in Novem-
who served on NEON’s now disbanded ber 2018, members of the National Science and head of engagement who had worked at

NEON since 2008. Within minutes, both had

been escorted out of NEON’s headquarters.

Collinge, who took a 2-year leave from

the University of Colorado in Boulder when

she joined NEON in February 2018, says

Battelle gave her no notice of the firings.

She sees them as the final straw in a series

PHOTO: THOMAS COLBY WRIGHT of developments that had undermined her

ability to lead the observatory.

“I have not been granted the authority

to be successful,” she wrote to Battelle of-

ficials as she announced her decision to re-

turn a year early to her tenured position as

a professor of environmental studies. Bat-

telle had promised that she would have the

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power to “allocate resources, both human EVOLUTION
and financial,” Collinge says, and the firings
were a breach of that agreement. Did neurons arise from
an early secretory cell?
Battelle, however, has said Collinge could
not have hiring and firing authority be- Cell lineage studies of comb jellies and other creatures may
cause she is not an employee of the non- suggest a single ancient origin of the nervous system
profit. And Patrick Jarvis, Battelle’s senior
vice president of marketing and commu- By Elizabeth Pennisi, in Tampa, Florida important,” says David Plachetzki, an evo- Downloaded from http://science.sciencemag.org/ on January 18, 2019
nications, says a management change was lutionary biologist at the University of New
needed as NEON shifts from construction S wimming through the oceans, vo- Hampshire in Durham. Among other mys-
to operation. raciously consuming plankton and teries, it could resolve a long debate about
other small creatures—and occasion- whether the nervous system evolved twice
“Since we are shifting our focus, we de- ally startling a swimmer—the beau- early in animal life.
cided to streamline our management struc- tiful gelatinous masses known as
ture to use our funds most efficiently,” Jarvis comb jellies won’t be joining Mensa Today, nerve cells are among the most
told Science. He says soil scientist Eugene anytime soon. But these fragile creatures specialized cell types in the body, able to
Kelly, who spent a year as NEON’s top sci- have nerve cells—and they offer insights transmit electrical signals, for example.
entist during the transition to Battelle, has about the evolutionary origins of all ner- Some versions talk to each other, others
agreed to return in an acting capacity until vous systems, including our own. Inspired relay information from the environment to
a permanent observatory director is hired. by studies of a glue-secreting cell unique to the brain, and still more send directives to
The new head will have “a free hand” in these plankton predators, researchers have muscles and other parts of the body. They
deciding how to reconstitute any advisory now proposed that neurons emerged in the are an almost universal feature of animals;
structure, Jarvis adds. last common ancestor of today’s animals— only sponges and placozoans, an obscure
and that their progenitors were secretory group of tiny creatures with the simplest
Restoring the committee is crucial, some cells, whose primary function was to release of animal structures, lack them.
former members of NEON’s advisory panel chemicals into the environment.
say. STEAC was “the primary means of com- When and how the animal nervous sys-
munication and guidance between the sci- Joseph Ryan, a computational evolution- tem arose has remained murky, however.
entific community and NEON,” they note ary biologist the University of Florida Whit- Ryan and Whitney lab postdoctoral fellow
in their letter. “These [advisory] structures ney Laboratory for Marine Bioscience in Leslie Babonis were drawn into the debate
must be able to tell an organization what St. Augustine, suggested that scenario last by their recent analysis of the developmen-
it may not want to hear, without fear of re- year after tracing the development of nerve tal origin of the colloblast, a specialized
taliation,” they write. That independence cells in embryos of comb jellies, among the cell unique to most comb jellies. Studding
was lacking, say former STEAC members, most ancient animals. Earlier this month at the tentacles of comb jellies, the cells se-
because the panel reported to Battelle, the annual meeting of the Society for In- crete glue that grabs passing prey.
not to NSF—a relationship that appears tegrative and Comparative Biology (SICB)
to be unique among the many large fa- here, he marshaled evidence from develop- By tracing the development of individ-
cilities that NSF has funded and operates mental studies of other animals, all point- ual cells in comb jelly embryos and moni-
through contractors. ing to common origins for some neuron toring each cell’s gene activity, Babonis
and secretory cells. discovered that colloblasts arise from the
How NSF responds to the latest crisis will same progenitor cells as the animal’s nerve
be key to NEON’s future. But its reaction “What Ryan is proposing is novel and cells. “That was not expected at all,” recalls
has been muted by the current partial gov- Ryan, whose team published those results
ernment shutdown, which has furloughed
the NSF staffers who oversee the project. The rudimentary nervous system of the warty comb jelly may help resolve how nerve cells arose. PHOTO: ANDREY NEKRASOV/ALAMY STOCK PHOTO

One question is whether Battelle’s con-
tract to manage NEON will be renewed
when the current agreement ends in Sep-
tember 2020. NSF selected the firm “be-
cause they know how to build things and
because we were facing a crisis,” says Fung,
adding that board members expect “a ro-
bust competition” for the next contract.

Some scientists wonder whether it’s time
for a change. “Battelle rescued NEON and
did an excellent job of building it out,” says
plant biologist Scott Collins of the Uni-
versity of New Mexico in Albuquerque, a
STEAC member who worked at NSF when
NEON was hatched. “But they don’t know
how to run an ecological observatory.”

Despite the current turmoil, ecologists
are still rooting for NEON to succeed. But a
tweet Desai posted shortly after getting the
news about this month’s shake-up reflects
what many worry might happen instead:
“Great data, no users, no trust = failure.” j

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on 30 August 2018 in Molecular Biology A member of UNICEF’s Ebola outreach team addresses the public in Beni, in the Democratic Republic of the Congo. Downloaded from http://science.sciencemag.org/ on January 17, 2019
and Evolution.
INFECTIOUS DISEASES
Since then, however, he’s learned of ad-
ditional studies pointing to common ori- In Congo, fighting a virus and
gins for neurons and other secretory cells a groundswell of fake news
in embryonic development—and perhaps
in evolution. In his talk at the SICB meet- Armed conflict and political tensions stoke rumors
ing, he noted that one team showed more and misinformation about Ebola
than 25 years ago that the stinging cells
PHOTO: © UNICEF/UN0228985/NAFTALIN of jellyfish, another specialized secretory By Laura Spinney International Children’s Emergency Fund
cell type, arise from the same embryonic (UNICEF) in New York City. “It is all about
precursors as the animal’s nerve cells. He T he Ebola epidemic in the Democratic information.” For the first time in an Ebola
cited similar evidence for hydra and fruit Republic of the Congo (DRC) is pro- outbreak, UNICEF and other agencies have
flies. “It’s a really generalizable thing,” viding a natural experiment in fight- joined forces as a single response team,
he says. ing fake news. Occurring in a conflict which answers to the DRC’s Ministry of
zone, amid a controversial presiden- Health in Kinshasa and includes dozens of
The finding could settle a long-standing tial election, the epidemic has proved social scientists. They use the airwaves, so-
debate. In 2013, a research team analyzing to be fertile ground for conspiracy theories cial media, and meetings with community
the newly sequenced genome of a comb and political manipulation, which can ham- and religious leaders to fight misinforma-
jelly known as the sea gooseberry (Pleuro- per efforts to treat patients and fight the tion. Responders also foster trust by mak-
brachia bachei) discovered it was missing virus’s spread. Public health workers have ing their work more transparent—in some
multiple genes active in the nervous sys- mounted an unprecedented effort to coun- cases literally. A new biosecure tent, called
tems of most animals: certain Hox genes, ter misinformation, saying the success or the Biosecure Emergency Care Unit for Out-
which control development, and the gene failure of the Ebola response may pivot on breaks (CUBE), allows relatives to visit and
for the neurotransmitter serotonin. That who controls the narrative. see Ebola patients during treatment.
discovery led the team to propose that
comb jellies evolved a nervous system Tensions are expected to rise in the wake With 600 confirmed cases and 343 deaths
independently from almost all other ani- of the 10 January declaration by the DRC’s recorded since August 2018, the outbreak
mals (Science, 25 January 2013, p. 391). But election commission that opposition leader is the second largest ever after the massive
many wondered how something so com- Felix Tshisekedi won the election, held on epidemic that struck West Africa 5 years ago
plex could have evolved twice. 30 December. Foreign observers and the Ro- and killed more than 11,000. Conflict has
man Catholic Church’s monitors say Martin smoldered for years in North Kivu, an anti-
Finding a common developmental source Fayulu, another opposition figure, garnered government stronghold, and some at-risk
for neurons in comb jellies, jellyfish, and more votes, and his supporters are alleging areas are inaccessible because they are con-
many other animals suggests it didn’t, Ryan fraud. Health workers know rumors thrive trolled by armed rebels or can’t be reached
and others now say. The work shows “the amid uncertainty. by road or rail. The outbreak has already
platform upon which the nervous system reached several urban centers, including
was built was there” in the last common “I usually tell my teams that we fight Butembo, a city of almost 700,000. An ex-
ancestor of animals, says Timothy Jegla, two outbreaks, Ebola and fear,” says Carlos perimental vaccine developed by Merck and
a neurobiologist at Pennsylvania State Navarro Colorado of the United Nations
University in University Park. “Relatively
simple reprogramming [of ] stem cells dur-
ing development can lead to whole new
cell types and tissues, and the nervous
system is probably just another example
of that.” Other researchers, however, say
it’s still possible that nerve cells had mul-
tiple origins after the last common ances-
tor, each time arising from the same stem
cell lineage.

Next, Ryan, Babonis, and Whitney lab
neurophysiologist Yuriy Bobkov hope to
learn how progenitor cells develop into
neurons by studying a simple sensory
organ—the “warts” of the warty comb jelly,
or sea walnut (Mnemiopsis leidyi). Recent
work shows that each wart contains about
500 nerve and muscle cells that react to
light, the smell of fish, and mechanical
stimuli. Warts regenerate if cut off, and
by tracing gene activity of their cells as
they regrow and specialize, Ryan hopes
his team can pin down the genes direct-
ing nerve cell formation—and perhaps, he
says, “peel back some of the complexity of
the evolution of neurons.” j

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NEWS | IN DEPTH

given to nearly 60,000 people so far has likely epidemic, says IFRC’s Ombretta Baggio. PLANETARY SCIENCE

slowed the virus but hasn’t stopped it. The CUBE, used for the first time in this Dueling
spacecraft
In West Africa, fear kept people away outbreak, is also a big help, says Tajudeen look deep
into Saturn
from clinics, causing Ebola cases, as well as Oyewale, UNICEF’s deputy representative and Jupiter

diseases such as measles and malaria to go in the DRC. In the past, visitors were kept NASA probes reveal
surprising contrasts
untreated. Mistrust of governments and aid at a safe distance from patients at ETCs or between two gas giants

workers ran high and rumors were rife. not permitted at all. Designed by a Senegal- By Paul Voosen

That’s even more true in the DRC now. In based organization called ALIMA, the CUBE, A clever use of radio signals from plan-
etary spacecraft is allowing research-
September 2018, an opposition politician, with its transparent walls and external arm ers to pierce the swirling clouds that
hide the interiors of Jupiter and Sat-
Crispin Mbindule Mitono, claimed on local entries—like those in a laboratory glove box— urn, where crushing pressure trans-
forms matter into states unknown
radio that a government lab had manufac- allows patients and their relatives to see and on Earth. The effort, led by Luciano Iess
of Sapienza University in Rome, turned
tured the Ebola virus “to exterminate the speak to each other up close. The €15,000, signals from two NASA probes, Cassini at
Saturn and Juno at Jupiter, into probes of
population of Beni,” a city that was one of the reusable units also improve care, because gravitational variations that originate deep
inside these gas giants.
earliest foci of the outbreak. Another rumor health workers don’t need to wear cumber-
What the researchers have found is fu-
has it that the Merck vaccine renders its re- some protective gear that limits their move- eling a high-stakes game of compare and
contrast. The results, published last year
cipients sterile. On 26 December, the national ments and can only be worn for a short time. in Nature for Jupiter and this week in
Science for Saturn, show that “the two plan-
election commission decided to exclude Beni Organized tours of the ETCs for mem- ets are more complex than we thought,”
says Ravit Helled, a planetary scientist at
and Butembo from the polls because of the bers of the local community have helped, the University of Zurich in Switzerland.
“Giant planets are not simple balls of hy-
epidemic; the following day, an Ebola evalua- too, as have creches for the children of drogen and helium.”

tion center was attacked during protests. sick mothers, located close to the centers. In the 1980s, Iess helped pioneer a radio Downloaded from http://science.sciencemag.org/ on January 17, 2019
instrument for Cassini that delivered an ex-
Although opposition organizations con- Ambulances in North Kivu no longer use ceptionally clear signal because it worked
in the Ka band, which is relatively free of
demned the commission’s decision, they sirens when transporting suspected Ebola noise from interplanetary plasma. By mon-
itoring fluctuations in the signal, the team
called for the Ebola response to be patients, as the sound was judged stigma- planned to search for gravitational waves
from the cosmos and test general relativ-
protected—which health workers saw as a tizing in West Africa. ity during the spacecraft’s journey to Sat-
urn, which began in 1997. Iess’s group put
small but significant victory. Burial practices keep evolv- a similar device on Juno, which launched
in 2011, but this time the aim was to study
“We’ve managed to get com- “I usually tell ing as well. In early Ebola Jupiter’s interior.
epidemics, victims were of-
munities to separate in their ten buried unceremoniously, Juno skims close to Jupiter’s surface
every 53 days, and with each pass hidden
minds Ebola control from the my teams that influences inside the planet exert a min-
ute pull on the spacecraft, resulting in tiny
broader political agenda,” says we fight two sealed in opaque body bags, Doppler shifts in its radio signals. Initially,
with no opportunity for rela-
Michael Ryan of the World tives and friends to say fare-

Health Organization in Geneva, outbreaks,

Switzerland. “That’s been re- Ebola and fear.” well. That bred resentment
ally helpful.” Ryan hands much and stoked rumors about

of the credit to social scientists Carlos Navarro corpses being stolen to sell

working for the various agen- Colorado, UNICEF their organs. In “safe and

cies involved in the response. dignified” burials, introduced

Along with community engagement workers, in the West Africa epidemic, families are

they make up one-third of the workforce. given more opportunities to spend time

Part of their role is to chart the social net- with the body. For the current epidemic,

works through which the virus spreads, but responders procured transparent body

they also gather information about commu- bags, allowing families to see their loved

nities’ perceptions, which is entered within one until the coffin is closed.

days into an online “dashboard” created by “One of the starkest lessons we learned in

the International Federation of Red Cross West Africa is that we don’t need to change

and Red Crescent Societies (IFRC) in Geneva. everything about a traditional burial,” says

The government has also recruited young anthropologist Juliet Bedford, director of

people to report misinformation circulating a consultancy called Anthrologica in Ox-

on WhatsApp, a major information channel ford, U.K. “We just need to make sure it is

in the DRC, says Jessica Ilunga, a spokes- medically safe.” Even touching the body is

person for the health ministry. sometimes allowed, provided relatives wear

As rumors surface, communications ex- protective clothing.

perts rebut them with accurate information Contingency plans are in place in case

via WhatsApp or local radio. They take care of further unrest, and the partner agencies

not to repeat the misinformation; research have bolstered preparedness in neighboring PHOTOS: NASA/JPL/SPACE SCIENCE INSTITUTE

has shown this is the best way to help the areas not yet touched by the epidemic. Ryan

public “forget” false news and reinforce the says the political problems may have an

truth. The vocal support of Ebola survivors upside: “Communities that resist are ener-

has helped as well. Grateful for their care, getic,” he says. “If you can turn that negative

some have become volunteers at Ebola treat- energy into positive energy, then it becomes

ment centers (ETCs). a force for good. You just have to know how

So far, the responders believe they are to pick that lock.” j

winning the information war. People who

might be ill are now far more willing to ac- Laura Spinney is a journalist based

cept a referral to an ETC than early in the in Paris.

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Iess and his team thought measuring those flow,” and the planet becomes rigid, says Material thousands of kilometers below the clouds of Downloaded from http://science.sciencemag.org/ on January 21, 2019
shifts wouldn’t be feasible at Saturn be- Yohai Kaspi, a planetary scientist at the Jupiter and Saturn tugs subtly on orbiting spacecraft,
cause of the gravitational influence of its Weizmann Institute of Science in Rehovot, revealing hidden structure and motions.
rings. But that obstacle disappeared earlier Israel, who worked with Iess. Jupiter has
this decade, after the Cassini team decided three times Saturn’s mass, which causes piter. “It is a major result. I don’t think we
to end the mission by sending the craft a far more rapid increase in atmospheric understand it yet.”
on a series of orbits, dubbed the Grand pressure—about three times faster. “It’s ba-
Finale, that dipped below the rings and sically the same result,” says Kaspi, but the Because Cassini’s mission ended with
eliminated their effects. As a result, Iess rigidity sets in at a shallower depth. the Grand Finale, which culminated with
and colleagues could use radio fluctuations the probe’s destruction in Saturn’s atmo-
to map the shape of gravity fields at both The Juno and Cassini data yield only sphere, “There’s not going to be a better
planets, allowing them to infer the density faint clues about greater depths. Scientists measurement anytime soon,” says Chris
and movements of material deep inside. once believed the gas giants formed much Mankovich, a planetary scientist at the
like Earth, building up a rocky core before University of California, Santa Cruz. But
One goal was to probe the roots of the vacuuming gas from the protoplanetary although the rings complicated the gravity
powerful winds that whip clouds on the disc. Such a stately process would have measurements, they also offer an opportu-
gas giants into distinct horizontal bands. likely led to distinct layers, including a nity. For some unknown reason—perhaps
Scientists assumed the winds would either discrete core enriched in heavier elements. its winds, perhaps the pull of its many
be shallow, like winds on Earth, or very But Juno’s measurements, interpreted moons—Saturn vibrates. The gravitational
deep, penetrating tens of thousands of kilo- through models, suggested Jupiter’s core influence of those oscillations minutely
meters into the planets, where extreme has only a fuzzy boundary, its heavy ele- warps the shape of its rings into a pattern
pressure is expected to rip the electrons ments tapering off for up to half its radius. like the spiraling arms of a galaxy. The re-
from hydrogen, turning it into a metal- This suggests that rather than forming a sult is a visible record of the vibrations,
like conductor. The results for Jupiter rocky core and then adding gas, Jupiter like the trace on a seismograph, which sci-
were a puzzle: The 500-kilometer-per-hour might have taken shape from vaporized entists can decipher to plumb the planet.
winds aren’t shallow, but they reach just rock and gas right from the start, says Mankovich says it’s clear that some of these
3000 kilometers into the planet, some 4% Nadine Nettelmann, a planetary scientist vibrations reach the deep interior, and he
of its radius. Saturn then delivered a differ- at the University of Rostock in Germany. has already used “ring seismology” to esti-
ent mystery: Despite its smaller volume, its mate how fast Saturn’s interior rotates.
surface winds, which top out at 1800 kilo- The picture is still murkier for Saturn.
meters per hour, go three times deeper, to Cassini data hint that its core could have a Cassini’s last gift may be to show how
at least 9000 kilometers. “Everybody was mass of some 15 to 18 times that of Earth, fortunate scientists are to have the rings
caught by surprise,” Iess says. with a higher concentration of heavy ele- as probes. Data from the spacecraft’s fi-
ments than Jupiter’s, which could suggest nal orbits enabled Iess’s team to show the
Scientists think the explanation for both a clearer boundary. But that interpreta- rings are low in mass, which means they
findings lies in the planets’ deep magnetic tion is tentative, says David Stevenson, a must be young, as little as 10 million years
fields. At pressures of about 100,000 times planetary scientist at the California Insti- old—otherwise, encroaching interplanetary
that of Earth’s atmosphere—well short tute of Technology in Pasadena and a co- soot would have darkened them (Science,
of those that create metallic hydrogen— investigator on Juno. What’s more, Cas- 22 December 2017, p. 1513). They continue
hydrogen partially ionizes, turning it into sini was tugged by something deep within to rain material onto Saturn, the Cassini
a semiconductor. That allows the mag- Saturn that could not be explained by the team has found, which could one day lead
netic field to control the movement of the winds, Iess says. “We call it the dark side of to their demise. But for now they stand
material, preventing it from crossing the Saturn’s gravity.” Whatever is causing this brilliant against the gas giant, with more
field lines. “The magnetic field freezes the tug, Stevenson adds, it’s not found on Ju- stories to tell. j

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Furloughed from his work on rocket tests, NASA
contractor Jack Lyons spends time in his workshop
making props for marching bands.

U.S. RESEARCH FUNDING NSF typically announces GRF winners by Downloaded from http://science.sciencemag.org/ on January 18, 2019
the beginning of April because U.S. gradu-
Pain spreads from shutdown ate schools require accepted students to
make a firm decision by 15 April. So far, the
Historic spending impasse halts paychecks and projects agency has no contingency plan in case its
review process is delayed. “Nobody knows
By David Malakoff from the pain because they are operated by what will happen because there’s been no PHOTO: AP PHOTO/DAVID GOLDMAN
contractors who get paid in advance, often guidance,” says a former GRF program
N o paychecks. No experiments. No re- on a quarterly basis. “But now that quar- manager who requested anonymity.
views of grant applications. And no terly check may or may not be coming,” says
stink bugs by mail. The financial, Benjamin Corb, public affairs director at At FDA, reviews of submitted drugs and
empirical, and entomological con- the American Society for Biochemistry and devices already paid for by industry fees
sequences of the partial shutdown Molecular Biology in Rockville, Maryland. can continue. But some researchers who
of the U.S. government for science “The uncertainty is creating a real mess.” want to continue other work—developing
multiplied this week, as it became the lon- new tools or methods for evaluating drugs,
gest such closure in history. More than a At the National Center for Atmospheric for example—must show that it is essential
half-dozen agencies that fund or conduct Research in Boulder, Colorado, which is for health, safety, or protecting a federal
research, including NASA, the National funded by NSF but operated by a consor- investment (such as continuing an animal
Science Foundation (NSF), the U.S. Depart- tium of universities, managers are be- experiment that has already begun). The
ment of Agriculture (USDA), and the Food ginning to consider ways to scale back justification process is “a heavily scruti-
and Drug Administration (FDA), have been activities. Staff could be given the option of nized rigmarole,” says one FDA employee
partly paralyzed since 22 December 2018 being furloughed without pay or continuing who asked to remain anonymous.
(Science, 11 January, p. 109). As Science went to work at reduced pay (with back pay once
to press, the fight between Congress and the shutdown ends). That could disrupt ef- Agricultural research is taking a partic-
President Donald Trump over spending forts to improve climate models and man- ularly heavy hit because it often involves
$5.7 billion on a border wall, which has shut- age massive data sets, officials say. collaborations between federal and private
tered about one-quarter of the federal gov- or academic laboratories. At the Virginia
ernment, showed no signs of being resolved. NSF’s closure is also creating anxiety for Polytechnic Institute and State University
would-be graduate students hoping to win in Blacksburg, veterinary pathologist Kevin
The impasse has already meant a lost pay- a prestigious Graduate Research Fellowship Lahmers has had to halt studies aimed
check for some 800,000 federal employees, (GRF) from NSF. Last year, the agency re- at evaluating the livestock disease threat
as well as missed payments for thousands ceived more than 12,000 GRF applications posed by the Asian longhorned tick, first
more contractors and academic researchers. and gave out 2000 awards, which provide discovered in the United States in 2017, be-
Agencies have canceled dozens of meetings graduate students with a $34,000 annual cause he is collaborating with a shuttered
to review thousands of funding proposals, stipend for 3 years. Managing that mas- USDA laboratory in Pullman, Washington.
at one of the busiest times for federal grant- sive operation requires sticking to a tight
making. Researchers inside and outside of schedule. Some 2000 reviewers had already Entomologist Don Weber, who works on
government have postponed, restructured, agreed to serve on about four dozen virtual biocontrol agents at USDA’s Beltsville Agri-
or just given up entirely on planned studies. panels set for later this month. But if NSF cultural Research Center in Maryland, isn’t
remains closed, those panels will not be completely immobilized. He is allowed to
The shutdown could soon paralyze feder- able to meet. (The agency had already can- enter his lab a few times a week to maintain
ally funded scientific facilities and research celed 33 other proposal review meetings as insect and plant populations. But he can’t
centers that have been largely insulated of 14 January, according to Corb.) do studies. Nor can he mail invasive stink
bugs from his colonies to other researchers
who want them, hobbling efforts to find a
defense against the farm pest. And Weber
hasn’t been able to order a synthesized
chemical that is key to an upcoming project
because his contract office is closed. “I’m
going to lose a field season,” he predicts.

Weber hasn’t let past closures derail his
research. During a 16-day funding impasse
in 2013, he went ahead and collected the fi-
nal data in a long-term field study “in defi-
ance of the shutdown,” he acknowledged in
a 2014 paper. “The way I saw it,” Weber says
now, “collecting that data was essential to
protecting a federal investment. Otherwise,
the money that had been spent would have
gone to waste.” j

With reporting by Jefrey Mervis and
Kelly Servick.

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NEWS | IN DEPTH

OCEANS graphic variables as well, such as tempera-

Flotilla launches large survey ture, currents, and plankton, to see whether
they can be used to predict krill abundance.

IMR will also test remote devices that

of Antarctic krill could gather krill data continuously and
more cheaply. The Haakon will deploy
moored sensors, as well as wave gliders and

Health of stock is critical to fishery—and to predators a sail-propelled buoy, in order to compare
their readings with the net and echosounder

data. “This is one of the most beneficial parts

By Erik Stokstad Antarctic Survey in Cambridge, who is not of the survey,” says Bettina Meyer, a krill eco-

involved in the project. physiologist at the Alfred Wegener Institute

K rill, crustaceans smaller than a ciga- CCAMLR organized the previous large in Bremerhaven, Germany.
rette, play an outsize role in the eco- krill survey, in 2000. The central finding— At the same time, land-based teams from
logy of the ocean around Antarctica: about 60 million tons of krill in the Scotia
Penguins, whales, and other preda- Sea—reassured managers that they had been IMR and the Norwegian Polar Institute will
tors feast on vast swarms of the adequately conservative. But much smaller track seals, whales, and penguins foraging
for krill in the Bransfield Strait, an im-

shrimplike animals. Now, research- surveys, conducted annually in a few places, portant feeding ground near the Antarctic

ers have launched a broad international have shown that regional krill populations Peninsula. Matching their feeding behavior

survey of krill’s main go through boom and with survey results “has big potential to get Downloaded from http://science.sciencemag.org/ on January 17, 2019

habitat in and around bust cycles, making it a better idea of the interactions between

the Scotia Sea—the first harder to gauge the the krill fisheries and the predators,” says

in nearly 20 years—to health of the overall So Kawaguchi, a marine ecologist with the

learn whether a growing stock from a single sur- Australian Antarctic Division in Kingston.

fishing industry is leav- vey. “We have pieces, The survey itself won’t be able to reveal

ing enough for krill’s but we are missing the how the overall krill population in the

natural predators. big picture,” says ma- Scotia Sea might have changed since the

The effort, led by rine biologist Rodolfo 2000 survey, given the variability of krill

the Institute of Marine Werner, an adviser to populations over space and time. Finding

Research (IMR) in Ber- the Pew Charitable out what drives population changes will

gen, Norway, began in Krill feed on phytoplankton and are a critical Trusts and the Ant- require more research on the seasonal

earnest last week when part of the food web. arctic and Southern movement of krill, for example, and the

CREDITS: (PHOTO) AUSCAPE INTERNATIONAL PTY LTD/ALAMY STOCK PHOTO; (MAP) A. CUADRA/SCIENCE; (DATA) INSTITUTE OF MARINE RESEARCH Norway’s new polar re- Ocean Coalition, who impact of climate change. Loss of sea ice,

search vessel Kronprins Haakon sailed is based in Bariloche, Argentina. which protects young krill from predators,

from Punta Arenas, Chile, for the Scotia Sea. During the survey, vessels will retrace the is expected to reduce their abundance, and

It and five other vessels will spend nearly previous transects, measuring krill swarms rising water temperatures and acidifica-

2 months mapping krill abundance across with echosounders, a kind of sonar, and tion could also pose serious threats—ones

an area about the size of Mexico. Beside confirming the identification with sampling that even the best management plan might

gauging population, the project will test trawls. Some ships will measure oceano- not avert. j

tools for cheaper, more frequent surveys

that could improve oversight of the fishery.

“With a more dynamic management sys- Area in Casting a wide net
tem, we can be more certain that the fishery detail
is not negatively affecting the krill popula- To estimate abundance of krill, a keystone species, six ships will use echosounders
tions or the predators,” says Bjørn Krafft, a and focus sampling around fishing hot spots.
marine biologist at IMR who is directing
the $5 million Norwegian cruise. South South Georgia
Atlantic Island
Soviet vessels were the first to ply Ocean
the Southern Ocean for krill, which was Falkland
ground into fish meal. By the 1980s, sci- Islands

entists began to worry about the effect on

krill-feeding predators. The Convention for

the Conservation of Antarctic Marine Liv- Sampling stations Scotia Sea
ing Resources (CCAMLR), a treaty organi- Ship echosounder transects

zation established in 1982, set tight limits

on fishing, now at 620,000 tons per year.

Most fishing stopped after the 1991 col-

lapse of the Soviet Union, but it has been

slowly growing again. Norway takes about South Sandwich
half the current catch, extracting omega-3 Islands
fatty acids for nutritional supplements.

“We absolutely need to know whether 0 400

the catch limit is still precautionary,” says Km
Simeon Hill, an ecologist with the British

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THE BONES OF Downloaded from http://science.sciencemag.org/ on January 17, 2019

BEARS EARS

Paleontologists struggle to protect sites that could rewrite Earth’s history

By April Reese, at Bears Ears National Monument in Utah

O n a rise with a sweeping view of the Looters stole—but later returned—this Now, those fossils, and the influx of spe- PHOTOS: (TOP TO BOTTOM) CAVAN SOCIAL/ALAMY STOCK PHOTO;
Indian Creek valley in southern snout from a fossilized phytosaur, a crocodilelike cial research funding that came with the JENNIFER DICKSON/THE WILDERNESS SOCIETY
Utah, skirts of red earth unfurling designation, are under threat. In Decem-
for kilometers in all directions, creature that once roamed Bears Ears. ber 2017, urged on by Utah officials, Presi-
Adam Huttenlocker crouches to dent Donald Trump slashed the size of the
examine a knee-high nub of Cedar history. The region’s rich paleontological 547,000-hectare monument by 85%, leaving
Mesa sandstone. Embedded in the and archaeological record—and the lobby- just 82,000 hectares split into two separate
rock is an ivory oval with a smoky ing of southwestern tribes whose ancestors units. Since Trump’s order took effect in Feb-
center. The paleontologist, from lived here—persuaded former President ruary 2018, the excised lands, which hold
the University of Southern California in Los Barack Obama to designate the area a na- thousands of Native American artifacts and
Angeles, leans in for a closer look. Other re- tional monument just over 2 years ago, in sites—and possibly the world’s densest cache
searchers gather round, and soon they iden- the waning days of his administration. of fossils from the Triassic period, roughly
tify the mysterious eyelike fragment: It is a 250 million to 200 million years ago—are
cross section of limb bone, probably from a open again to mining, expanded grazing, and
synapsid—the group of reptiles that gave cross-country trekking by off-road vehicles.
rise to mammals—that lived here more than
300 million years ago. That prospect spurred the typically apo-
litical Society of Vertebrate Paleontology
Thousands of such rare fossils pepper (SVP), based in Bethesda, Maryland, to sue
Bears Ears, a sweep of buttes and badlands the Trump administration in federal court,
whose candy-striped sedimentary rocks cat- joining archaeologists, environmentalists,
alog hundreds of millions of years of Earth’s outdoor companies, and five Native Ameri-

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The Valley of the Gods the first paleontologists to push for monu- sibly the world. Excavation has just begun, Downloaded from http://science.sciencemag.org/ on January 17, 2019
and its fossil riches are no ment designation. Without protection, he but already Gay and his team have found
says, “our knowledge of our planet [will be] rare fossil fragments of four phytosaurs—
longer protected within diminished forever.” 6-meter-long crocodilelike creatures that
the national monument. roamed these lands 212 million years ago.
FOR A LESSON in how monument status can Many other sites remain uninvestigated.
can tribes. Their argument: The 1906 An- pay off for paleontology, Gay motions to-
tiquities Act used to create Bears Ears only ward Grand Staircase-Escalante National Early on, says paleontologist Allison
allows presidents to establish monuments— Monument, 228 kilometers away across Stegner of the University of Wisconsin in
not to drastically reduce them. The cutbacks the mesas and canyons of southern Utah. A Madison, some locals skeptical of the monu-
represent an “extreme overreach of author- similarly rich fossil trove, from the era when ment came to share scientists’ enthusiasm
ity,” SVP said in announcing the lawsuit just dinosaurs ruled, helped make the case for for the resources it aimed to protect. When
days after Trump’s move. If SVP wins, the that monument, which was established by the Bears Ears designation was first pro-
ruling could set a precedent that would help then-President Bill Clinton in 1996 and cut posed, “people were excited to learn about
safeguard the boundaries of the 158 national in half by Trump in another December 2017 what was in their area. [They] were totally
monuments created under presidential au- proclamation. An influx of federal funding unaware that southeastern Utah is a world-
thority; if it loses, future presidents could followed, which Polly credits with allowing class destination for paleontology,” says
gain new powers to downsize them. researchers to uncover some of the world’s Stegner, who did local outreach for the Bu-
best records of the Late Cretaceous. reau of Land Management (BLM) while the
At Bears Ears, the potential loss to monument was under consideration. But
science—and society—is sizable, says former Within 10 years, researchers had discov- there was little money and staff to nurture
SVP President David Polly, a paleontologist ered fossils from 25 taxa new to science and the emerging goodwill, and the momentum
at Indiana University in Bloomington. Fos- documented the rise of flowering plants, was lost, she says. “Instead, what’s happened
sils here chronicle major events that remade insects, and the ancestors of mammals be- is a lot of animosity toward the monument.”
the world—from the evolution of early life tween 145 million and 66 million years ago.
on land 340 million years ago to the shift in “It was essentially the origin of modern eco- Many local and state officials were op-
climate at the end of the last ice age that ush- systems happening in the Cretaceous before posed to the monument from the start,
ered in the era of human civilization. the extinction of the dinosaurs,” Polly says. viewing its land use restrictions as too strin-
“And I think it is safe to say that we wouldn’t gent and its designation as an overreach of
“It’s a landscape of stories,” says Rob Gay, have that concept if it hadn’t been for the federal authority. Earlier this month, Trump
a paleontologist and education director with research at Grand Staircase.” He estimates acknowledged that Utah lawmakers influ-
the Colorado Canyons Association in Grand that 40% to 50% of SVP members have used enced his decision to carve out large pieces
Junction, who has studied the Bears Ears data from Grand Staircase-Escalante stud- of the monument, saying he did it for Sena-
area for more than a decade and was among ies, and another 10% have conducted re- tor Mike Lee (R) and a “very special person,”
search there themselves. now-retired Senator Orrin Hatch (R).

“Bears Ears is sort of like what Grand Mining companies, eyeing the area’s rich
Staircase was at one time—there were a few uranium deposits, also sought the rollback.
sites known [when the monument was cre- The low price of uranium is likely to keep
ated] and clearly a lot of potential,” he adds. companies from starting new digs anytime
soon, says David Talbot, a uranium and bat-
Bears Ears’s record begins earlier, more tery metals analyst with Eight Capital in To-
than 340 million years ago, when the super- ronto, Canada. But if the price does spike—it
continent Pangaea spanned much of the has been on the rise for 2 years—that could
planet. A tropical sea that covered the change. (Under a September 2018 court rul-
area began to fill with sediment shed by ing, however, BLM must notify the plaintiffs
the uplifting Rocky Mountains, leaving before approving any new development on
thousands of prehistoric sea creatures, the former monument lands.)
mammallike reptiles, and dinosaurs en-
tombed in hardened mudflats. Some of Now that the boundaries have been re-
those fossils help tell the story of the “great drawn, the Valley of the Gods and much of
dying” 252 million years ago, which killed the area where Gay’s Triassic cache lies are
96% of marine species and 70% of terrestrial outside the monument, as is the Indian
ones, clearing the way for dinosaurs. Others Creek bone bed where Huttenlocker spot-
chronicle the End Triassic extinction some ted the watchful eye. “As far as we can tell,
50 million years later, which wiped out 76% [the administration] gave no consideration
of terrestrial and marine life. to the vertebrate fossil sites when redraw-
ing the new boundaries,” Huttenlocker says.
Amid the red-rock spires of the Val- The two units that remain include important
ley of the Gods, for example, Huttenlocker paleontological and cultural sites, such as a
and his team are uncovering a trove of bed of more than 250 dinosaur tracks and an-
300-million-year-old fossils, including what cient Puebloan rock art in Shay Canyon. But
may be the most complete skeleton of a most of Bears Ears’s richest paleontological
sail-backed synapsid predator known as Di- treasures are now on the outside, Gay says.
metrodon. Meanwhile, with the help of high
school students, Gay has discovered what The loss of monument status means
could be the largest concentration of Trias- those treasures could be exposed to many
sic fossils in the United States—and pos- dangers. Off-road vehicles are now al-
lowed to crisscross the monument’s former

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Monumental reversal plan for the newly shrunken monument is
still under development, but in an August
In December 2017, President Donald Trump issued proclamations shrinking Bears Ears National Monument 2017 statement, BLM’s Utah director, Ed
by 85% and nearby Grand Staircase-Escalante National Monument by nearly half, leaving out fossil-rich areas Roberson, called Bears Ears a remarkable
such as the Valley of the Gods and the northern portion of Indian Creek. landscape and said the agency’s preferred
blueprint provides “maximum management
0 100 Moab flexibility while protecting Monument ob-
Km jects and resource values.” But unlike the
other three draft plans, one of which would
Salt Lake City “prioritize the protection of Monument ob-
jects and values over other resources,” BLM’s
UTAH Bears Ears preferred plan emphasizes “multiple uses.”
National (Because of the ongoing federal government
Grand Staircase- Monument shutdown, a BLM spokesperson could not
Escalante National respond to specific questions from Science.)
Monument Indian
Creek Research on the excised lands is now in
limbo, and Gay, Huttenlocker, and other
Bears Ears Monticello paleontologists are racing to do as much as Downloaded from http://science.sciencemag.org/ on January 17, 2019
National they can before their monument-tied funding
Monument Blanding dries up. Only one round of Bears Ears fund-
ing was doled out before Trump’s proclama-
Bears Ears White Mesa Mill tion. BLM has agreed to let researchers finish
buttes Bluf their work under those grants, but when that
money runs out, projects outside the new
Red Canyon 0 20 monument boundaries may be left without
Km crucial federal support, Polly says. And al-
Obama monument boundaries Cedar though paleontologists can still get permits
Trump monument boundaries Mesa to investigate and dig for fossils on the for-
mer Bears Ears lands, the process won’t be as
Valley of easy as before, when science was a priority,
the Gods Polly says. Now, paleontology is just one of
many uses, competing with mining, off-road-
Mexican Hat ing, and grazing.

UTAH In comments submitted to BLM, SVP
ARIZONA urged the agency to treat now-unprotected
areas as though they still had monument
grounds, which are once again open to min- tion from BLM officials, he fears the excised protection, giving priority to science and CREDITS: (GRAPHIC) A. CUADRA/SCIENCE; (DATA) SOUTHERN UTAH WILDERNESS ALLIANCE
ing (although new projects must go through areas are more vulnerable to pillaging. conservation. SVP also recommended that
BLM’s usual review process). The land will the agency hire four paleontologists for the
also lose out on resources aimed at beef- Scientists will also have to compete with greater Bears Ears area and continue to
ing up research, such as personnel—Grand law-abiding private fossil collectors. The support research there.
Staircase got its own paleontologist, for 2009 Paleontological Resources Preservation
example—and special funding to develop Act makes removing vertebrate fossils from As BLM proceeds with its plans for the
scientific and cultural resources. federal lands a crime for nonscientists. But shrunken monument, SVP and the other
the rules are different for plant and inverte- plaintiffs are hoping for a swift victory.
That money—part of federal funding for brate fossils, which are crucial to understand- They’ve already notched one win—having
BLM lands protected for their scientific ing ancient ecosystems and evolution. Within the case heard in Washington, D.C., instead
resources—not only funds ongoing projects a monument, those fossils, too, can be col- of Utah, which the administration consid-
and spurs new discoveries; it also helps lected only by researchers, but outside monu- ered more welcoming. They now await Dis-
ensure that scientists find those resources ment boundaries, anyone can gather and sell trict Judge Tanya Chutkan’s decision on a
before looters do. Looting has long been them. “Without special protection, [the sites] Department of Justice request to dismiss
a problem in San Juan County, where the are more vulnerable to vandalism, which the lawsuit.
monument is located. When Gay and his they have suffered in the past, and [fossils]
students found the phytosaur cache in can be more easily sold away to private buy- As the case wends its way through the
2016, for example, a snout from one of the ers or repurposed for other uses,” Gay says. courts, paleontologists are scrambling to
creatures was missing. It was eventually re- unlock Bears Ears’s secrets. In Los Angeles,
turned, but looters rarely repent, Gay says. BLM has long insisted that it does what’s Huttenlocker and his colleagues labor to
Without the protection and increased atten- needed to protect scientific and cultural piece together the story of their newly found
resources on public land. Its management Dimetrodon. In western Colorado, Gay is
eager to return to his phytosaur site before
looters do. Meanwhile, scientists hope the
sacred twin buttes that gave Bears Ears its
name will continue to guard its treasures. j

April Reese is a freelance journalist based
in Santa Fe.

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The normal compound fly eye (top) THE BRAIN’S Downloaded from http://science.sciencemag.org/ on January 20, 2019
is marred by cell death in a strain
PHOTOS: KIRSTIN MAULDING (bottom) with a mutation causing TRAFFIC
amyotrophic lateral sclerosis. PROBLEMS

SCIENCE sciencemag.org Disrupted flow into
and out of the nucleus
may kill neurons

By Elie Dolgin

T he compound eyes of the common
fruit fly are normally brick red. But
in neurologist Tom Lloyd’s lab at
Johns Hopkins University School of
Medicine in Baltimore, Maryland,
many of the fly eyes are pocked
with white and black specks, a
sign that neurons in each of their
800-odd eye units are shriveling
away and dying.

Those flies have the genetic equivalent of
amyotrophic lateral sclerosis (ALS), the de-
bilitating neurodegenerative disorder also
known as Lou Gehrig’s disease, and their
eyes offer a window into the soul of the
disease process. By measuring the extent
of damage to each insect’s eyes, researchers
can quickly gauge whether a drug, genetic
modification, or some other therapeutic in-
tervention helps stop neuronal loss.

Those eyes have also offered an answer to
the central mystery of ALS: just what kills
neurons—and, ultimately, the patient.

The flies carry a mutation found in about
40% of ALS patients who have a family his-
tory of the disease, and in about 10% of spo-
radic cases. The mutation, in a gene called
C9orf72, consists of hundreds or thousands
of extra copies of a short DNA sequence, just
six bases long. They lead to unusually large
strands of RNA that glom onto hundreds of
proteins in the cell nucleus, putting them
out of action. Some of those RNA-ensnared
proteins, Lloyd and his Hopkins colleague
Jeffrey Rothstein hypothesized, might hold
the key to ALS.

Over many months, the researchers sys-
tematically studied the role of each protein
by developing fly strains carrying both the
ALS mutation and an incapacitated or hyper-
active version of each protein’s gene. One set
of flies, bred to have elevated levels of a pro-

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NEWS | FEATURES

tein called RanGAP, stood out. Fifteen days other way, into the cytoplasm to protein- duced by the mutant C9orf72 gene seemed
after the flies emerged from their pupal cas- assembly platforms. The cell must regulate to stick to RanGAP near the nuclear pore
ings, their eyes remained a pure burnt sienna. that traffic through entry points known as and put the protein out of commission.
RanGAP “was by far the most potent suppres- nuclear pores. Choke off those portals and The loss of functioning RanGAP spurred a
sor of neurodegeneration,” Lloyd says. What it stands to reason cells will suffer. backup of the nuclear import system, result-
was known about its function was tantaliz- ing in the cytoplasmic buildup of proteins
ing: It serves as a courier, helping shuttle The first hints that disrupted nuclear such as TDP-43—cluttering a cell like bags
other proteins across the membrane that transport might underpin ALS came in of rotting trash during a garbage strike.
divides the cell nucleus from the cytoplasm. 2010, when researchers at King’s College
London, working with human nerve cancer Just as galvanizing was the team’s finding
The team’s result would upend neuro- cells, experimentally blocked the expression that a potential drug could preserve neuro-
scientists’ understanding of ALS and brain of proteins involved in the import business. nal health, at least in the flies. “All of a sud-
disease in general, and others were on the The result was something also seen in cells den it threw a potential treatment approach
same trail. In 2015, two more research teams from ALS patients: clumps of a protein into the ring,” says Dorothee Dormann, a
reported that defects in the cell’s nuclear called TDP-43 building up in the cytoplasm. biochemist from Ludwig Maximilian Uni-
transport system were hallmark features not versity in Munich, Germany.
only of ALS, but also of frontotemporal de- Few ALS researchers paid much atten-
mentia (FTD), another progressive brain dis- tion to that early report. What might be The team had no drug that could boost lev-
ease caused by C9orf72 mutations. Scientists gumming up the gears of the transport els of RanGAP in the cytoplasm and restore
would soon link dysfunctional trafficking
across the nuclear divide to other neurode- Fixing traffic jams RanGAP Importin Cytoplasm Downloaded from http://science.sciencemag.org/ on January 20, 2019
generative diseases—Alzheimer’s, Hunting- Ran
ton, spinocerebellar ataxia—and even to The flow of molecules through pores
normal aging. In all those ailments, the re- in the nucleus is key to the health TDP-43
sulting abnormal pileups of proteins some- of cells, particularly neurons. Traffic
how become rogue neuronal killers. problems may contribute to Nuclear
amyotrophic lateral sclerosis (ALS) pore
“I often get queasy when someone makes a and other brain diseases.
discovery and tries to explain the rest of the Exportin
world with it,” says Rothstein, a neurologist Normal
who directs the Johns Hopkins Brain Sci- Importin proteins bring TDP-43 C9orf72 RNA Stress granule
ence Institute. But here, he says, it seems and other cargo from the cytoplasm
to be true. through the nuclear pore, whereas
exportins take molecules out.
The findings are not merely academic.
They are inspiring therapeutic efforts to ALS
address the cause of general age-related In some ALS cases, abnormal RNA
neurodegeneration—a goal that has largely made by a mutant C9orf72 gene
eluded drug developers. If the gradual loss prevents RanGAP from mediating
of nucleocytoplasmic transport is a con- nuclear import, leading to protein
served feature of the aging brain, says Sami buildup in stress granules.
Barmada, a neurologist at the University of
Michigan in Ann Arbor, preventing it “might ALS + drug KPT-350
be a really broad and effective therapy.” A possible drug, KPT-350, impairs
the specific exportin XPO1 and may
Several biotech companies have jumped normalize nuclear traffic of proteins
on that idea, exploring it in animal models or bust up stress granules.
and planning the first human trials this year.
Chief among them: Biogen in Cambridge, machinery in ALS patients wasn’t clear, enough inflow to rescue the eye neurons. GRAPHIC: V. ALTOUNIAN/SCIENCE
Massachusetts, which in 2018 bought the and the researchers couldn’t say whether But Lloyd reasoned that blocking outflow of
rights to develop a drug compound called the buildup of TDP-43—a protein that nor- TDP-43 and other nuclear proteins may have
KPT-350 that directly targets the nuclear mally binds both DNA and RNA inside the the same beneficial effect. An experimental
transport pathway. The research under- nucleus to regulate multiple steps in gene compound called KPT-276 was known to
pinning that drug’s action is brand new. But, expression—was actually killing neurons or selectively inhibit a key nuclear export pro-
“The biology is there,” says Chris Henderson, was just a consequence of a different toxic tein called exportin 1 (XPO1). The approach
head of neuromuscular and movement disor- process. It would take another 5 years—and was a hack of sorts, marrying two wrongs—
ders research at Biogen. “Here’s a drug with Lloyd’s and Rothstein’s study of the flies defective inflow and outflow—to make a right,
a body of rationale,” he adds, “and we’re opti- with telltale eyes—for ALS scientists to take but it worked. When Lloyd gave KPT-276
mistic about getting this into trials.” nuclear transport more seriously. to his ALS flies, their eyes remained pristine.

THE LIPID MEMBRANE that divides the DNA- The Hopkins team’s result electrified col- KPT IS THE experimental compound code
packed nucleus from the rest of the cell is leagues in part because it had identified a used by Karyopharm Therapeutics, a small
like an international border busy with two- transport protein, RanGAP, as key to neuro- drug company in Newton, Massachusetts.
way industrial traffic. DNA-binding pro- degeneration. The team showed in both the Karyopharm formed in 2008 to develop
teins and other molecules are constantly fly model of ALS and in cells from human XPO1 inhibitors for treating cancer, the idea
flowing into the nucleus to help turn genes patients that the lengthy RNA readouts pro-
on and off, for example. The messenger
RNAs produced by those genes stream the

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being to trigger a buildup of tumor suppres- of KPT-350 could begin in ALS patients later In August 2018, findings from a study led

sor proteins in the nucleus, where they carry this year. If the drug shows promise against by neurobiologist Ludo Van Den Bosch of

out their anticancer watchdog function. A that disease, Biogen may expand its clinical VIB–Catholic University of Leuven in Bel-

decade on, the company’s first clinical candi- testing to other conditions, Henderson says. gium suggested that the transport protein

date, a drug for multiple myeloma, is widely XPO1 itself may play a role in stress granules.

expected to win marketing approval in the ALTHOUGH THE DRUG seems to work in the That means a drug such as KPT-350 may

coming months. laboratory, why or how is not at all clear. serve primarily as a stress granule buster, and

Chemists at Karyopharm developed a suite “The story started to get murkier as more any impact on transport may be secondary.

of XPO1 inhibitors, including KPT-276 and a data has come in,” notes Haines, now at “Things are more complicated than initially

relative called KPT-350, that had an impor- Regeneron Pharmaceuticals in Tarrytown, presented,” says Van Den Bosch, who has col-

tant attribute: They crossed the blood-brain New York. Initially, most scientists assumed laborated with Karyopharm.

barrier more readily than other candidates. that because it blocks XPO1, the drug pre- The open questions about KPT-350 have

KPT-350 proved more potent and less toxic in vents proteins such as TDP-43 from piling not discouraged other groups from pursu-

preclinical testing, so the firm looked for ways up in the cytoplasm by trapping them in ing additional strategies to sort out nu-

to use it to treat brain disease and injury. the nucleus. But last year, Dormann’s team clear traffic problems. In 2017, for example,

Lloyd’s and Rothstein’s results piqued the and another led by Philip Thomas, a bio- Guillaume Hautbergue and his colleagues

company’s interest. When Sharon Tamir, its chemist at the University of Texas South- at the University of Sheffield in the United

head of neurodegenerative and infectious western Medical Center in Dallas, indepen- Kingdom implicated another export fac-

diseases at the time, learned that the Hop- dently reported that TDP-43 and another tor in the neuronal loss experienced by

kins researchers were working with KPT- protein called FUS seem to exit the nucleus ALS flies with the C9orf72 mutation. Downloaded from http://science.sciencemag.org/ on January 20, 2019

276 and not KPT-350, she called them up to by passive diffusion, not through XPO1- Hautbergue is working on ways to target

propose a collaboration using the “better” mediated transport. (FUS also clumps in that protein to prevent the export of mu-

compound. Meanwhile, she began to dis- the cytoplasm of motor neurons in some tant RNAs produced by the gene.

tribute KPT-350 to other groups in Japan, patients with ALS or FTD.) Other researchers are focusing on break-

Belgium, and across the United States. Col- So if KPT-350 is not acting directly on the ing up stress granules. That approach should

lectively, those scientists showed the drug’s transport system, what is it doing? “It looks free up transport factors and pore proteins

neuroprotective effects across a range like the drug is targeting some more general held hostage in those granules, allowing

of human cell, fly, and rodent models of neurotoxic pathway,” Dormann says, “but it them to return to their usual posts in the

ALS, Huntington, and other brain diseases. remains to be clarified what the mechanism cell, explains James Shorter, a protein bio-

For example, treatment with chemist at the University of

KPT-350 preserved the health “Here’s a drug with a body of rationale, and Pennsylvania. He is developing
of axons, the long, signal- a way to equip cells with a gene

transmitting extensions of we’re optimistic about getting this into trials.” for making a “disaggregase”
nerve cells, and improved the protein and has begun to test
motor functions of mice with Chris Henderson, Biogen the therapeutic strategy in a

a multiple sclerosis–like con- mouse model of ALS.

dition, a team led by neuroscientist Jeffery really is and which nuclear transport de- A few drug companies, including De-

Haines at the Icahn School of Medicine at fects we’re correcting with this drug.” nali Therapeutics of South San Francisco,

Mount Sinai in New York City showed. And One possibility, recent research suggests, California, and Aquinnah Pharmaceuticals

in the Hopkins group’s hands, the drug kept is that the drug actually targets tiny, dense of Cambridge, are looking for small mol-

alive mouse neurons harboring the muta- packets of protein and RNA that form dur- ecules that can do basically the same thing.

tion associated with Huntington. ing times of cellular stress. In healthy cells, Those therapies may not directly target the

“There’s still a lot that needs to be explored those membraneless “stress granules” gener- nuclear transport pathway, but they would

about why the nuclear pore complex is so ally break down and their components dis- get the job done, says Aquinnah co-founder

susceptible to problems in different types perse after a viral infection, thermal shock, or and Chief Scientific Officer Ben Wolozin,

of neurons in different brain regions caus- some other environmental insult has passed. a neuropharmacologist at Boston Univer-

ing multiple different diseases,” says Gavin Not so in the diseased neurons of people with sity’s School of Medicine, because disman-

Daigle, a former postdoc in Rothstein’s lab ALS or FTD. In those cells, the stress gran- tling stress granules helps restore healthy

who worked on the Huntington project ules persist and turn sticky, recruiting pro- nuclear transport. “This is all part of an in-

and helped link disrupted pore function to teins such as TDP-43 and FUS and eventually tegrated biological response,” Wolozin says.

Alzheimer’s disease before joining AbbVie transforming into solid, toxic aggregates. Aquinnah hopes to begin to evaluate its

in Cambridge. But he stresses that all the Over the past year, several research teams lead compound in ALS patients this year,

research is showing one thing: “This is a have shown that components of the nuclear about the same time that Biogen is aiming to

pathway that can be targeted.” transport machinery—including import- get KPT-350 into the clinic. For now, Biogen

The results proved enough to convince Bio- ers, exporters, and parts of the nuclear pore scientists are still trying to pin down what the

gen, which bought the rights to test the drug itself—also can get tangled up in those ag- drug is doing in various genetic models of the

in humans. “The package of preclinical data gregates. The transportation system falters, disease, including the flies with marred eyes.

that Karyopharm was able to amass really and as more TDP-43 and other proteins are But to some extent, Henderson says, knowing

justifies the excitement,” says Laura Fanning, added to the stress granules, a feedback loop the exact mechanism of action doesn’t really

R&D project leader for KPT-350 at Biogen takes hold that grinds the molecular traffic to matter. “The relevant experiment,” he con-

(which has renamed the molecule BIIB100). a halt. “TDP-43 is not just a victim of nucleo- cludes, “is in the human patient.” j

“It’s not just a blip of efficacy in one strain cytoplasmic transport defects,” says Wilfried

of mice. It’s a broad base of evidence,” she Rossoll, a neuroscientist at the Mayo Clinic in Elie Dolgin is a science journalist based in

says. A first-in-human dose-escalation study Jacksonville, Florida. “It’s also a perpetrator.” Somerville, Massachusetts.

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When Earth PHOTO: ERNEST WRIGHT, NASA/GSFC SCIENTIFIC VISUALIZATION STUDIO
got pummeled
224
The frequency of impacts
on Earth’s surface increased
about 290 million years ago

By Christian Koeberl1,2

C ollisions and impact processes have
been important throughout the his-
tory of the solar system, including that
of Earth. Small bodies in the early so-
lar system, the planetesimals, grew
through collisions, ultimately forming
the planets. Recognizing the remnants of
impact events on Earth is difficult because
terrestrial processes either cover or erase the
surface expression of impact structures in
geologically short timespans. Because Earth
and the Moon are subjected to the same flux
of impactors, the latter’s crater record serves
as a proxy for that of Earth. On page 253 of
this issue, Mazrouei et al. (1) report that infra-
red images of the Moon taken by the Lunar
Reconnaissance Orbiter Diviner instrument
can be used to estimate the ages of young
lunar craters. They find the impact rate in-
creased within the last ~500 million years.

Impact cratering is a high-energy event
that occurs at more-or-less irregular inter-
vals, although over long periods of time, an
average cratering rate can be established
(2). The terrestrial rock record, in the form
of crustal rocks, extends back to only about
89% of Earth’s history, to ~4.0 billion years
ago, with the oldest rocks showing very lim-
ited exposures in Greenland and Canada.
The importance of the process of impact
cratering on a planetary scale has only
recently been recognized in the geologi-
cal sciences. During the past few decades,
planetary scientists and astronomers have
demonstrated, with the aid of many space
missions, that the surfaces of Earth’s moon,
Mercury, Venus, Mars, the asteroids, and
the moons of the outer gas planets are all
covered (some surfaces to saturation) with
meteorite impact craters.

Impact craters on the lunar surface persist
over billions of years and help to constrain Earth's
impact record. Orientale (shaded topographic
map shown) is a large and relatively young impact
basin on the Moon.

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Part of the problem regarding recognition face but suggested that more than 90 craters INORGANIC CHEMISTRY

of the remnants of impact events on Earth is with diameters ranging from 1 to 6 km have Iron hits
the mark
that terrestrial processes, such as sedimenta- yet to be discovered, as well as more than 250
Strongly electron-donating
tion, erosion, and plate tectonics, either cover craters between 0.25 and 1 km in diameter. ligands enable nanosecond
lifetimes of iron(III)
or erase the surface expression of impact In the larger-size range (larger than a 6-km photoexcited states

structures. Many impact structures are cov- diameter), Mazrouei et al. now demonstrate By Elizabeth R. Young and Amanda Oldacre

ered by younger (post-impact) sediments and that instead of an erosional bias for craters S olar energy can enable our society to
thrive as we endeavor to reduce our de-
are not visible on the surface. Others were in the age range of about 650 to 290 million pendence on fossil fuels. However, the
Sun is an intermittent form of energy.
mostly destroyed by erosion. To determine years ago, there is a lower-impact flux to be Solar-cell technology is well suited for
daytime electricity generation and us-
if specific rocks have been subjected to im- blamed, where the Snowball Earth ice ages age, but our society uses energy around the
clock. Thus, it is not only important to gen-
pact or not, it is necessary to identify criteria (when Earth was entirely or nearly entirely erate electricity for daytime use but also to
store solar energy for nighttime use. Chem-
that allow such processes to be distinguished frozen) might be responsible for erosion that ists see huge potential in molecules and ma-
terials that absorb light (that is, solar energy)
from those resulting from normal terrestrial destroyed any earlier craters. By contrast, a and use that energy to generate electrons
that then carry out chemical reactions to turn
geological processes. Most of the geological previous study suggested an increase in im- low-energy feedstocks into high-energy fuels.
To date, the transition metal complex (TMC)
features of meteorite impact structures are pact rate during the Phanerozoic period, 541 photosensitzers that have sufficiently long ex-
cited-state lifetimes to enable this chemistry
not unique. Such features can be the product million years ago to the present (5). (1) contain expensive and scarce metals, such
as complexes of ruthenium (Ru), osmium,
of conventional processes such as tectonic This still leaves a large part of Earth’s and iridium. On page 249 of this issue, Kjær
et al. (2) report an iron (Fe)–based photosen-
deformation, salt-dome formation, volcanic history lacking for impact structures. The sitizer with a quantum efficiency surpassing
that of [Ru(bpy) ]2+ (where bpy is 2,29-bipyri-
eruption, or internal igneous activity. Only early record of impact on Earth is rather
3
the presence of diagnostic shock metamor- limited and mostly circumstantial. Likely Downloaded from http://science.sciencemag.org/ on January 17, 2019
dine), the historical standard bearer. Further-
phic effects and, in some cases, the discovery impact debris layers (ejecta layers) have more, the new iron-based photosensitizer
has an excited-state lifetime of 2 ns, which is
of meteorites, or traces thereof, provide un- been documented in 3.2- to 3.47-billion- sufficiently long to transfer electrons to other
compounds (see the figure).
ambiguous evidence for an impact origin (3). year-old Archean successions in the Bar-
Ruthenium-based TMCs have received
As of 2018, about 190 impact structures have berton Greenstone Belt (South Africa) and much attention as photosensitizers because
of their long-lived metal-to-ligand charge-
been identified on Earth on the basis of these Pilbara Craton (Australia). The exact num- transfer (MLCT) excited state and general
photo- and chemical stability (3). Despite
criteria. With one exception, all of these are ber of ejecta layers is not known, but several their superior performance, ruthenium-based
TMCs are limited in their usefulness to soci-
younger than 2 billion years. different events between 3.4 ety because ruthenium is rare and expensive.
Not only is there not enough ruthenium to go
On some other planets and “The early record and 2.5 billion years ago, and around, even if there were, it is harmful to the
moons, the problem of geo- at 2.1 to 1.8 billion years ago, environment. A search for alternative earth-
logical processes destroying or of impact have been identified (6). abundant and less expensive metals has been
pursued for the past several decades. Iron,
obscuring the impact record on Earth is The oldest impact structure being in the same group of the periodic table
on Earth dates to 2.02 billion as ruthenium, shares certain similarities that
is much less severe than on years ago (Vredefort in South
Department of Chemistry, Lehigh University, Bethlehem, PA
Earth. It has long been known rather limited 18015, USA. Email: [email protected]

that Earth’s companion, the and mostly Africa), and for the “next” bil-
Moon, has been geologically circumstantial.” lions of years the impact re-
mostly inactive on its surface cord on Earth is quite sparse

for the past 3 billion years or in terms of both craters and

so. This makes it an ideal canvas on which ejecta layers. Thus, Earth's impact record

asteroids can leave their impact traces. Maz- is quite limited: nothing for the first billion

rouei et al. used Lunar Reconnaissance Or- years, then some ejecta layers until about 2.5

biter data to derive the impact flux on the billion years ago, and then less than a hand-

Moon for craters larger than about 10 km ful of impact craters prior to about 750 mil-

in diameter—and by proxy, also on Earth— lion years ago. Nevertheless, the discovery of

during the past billion years. This was done these ejecta layers aids in the discussion of

by determining the ages of all lunar craters the importance of impact events in Earth's

larger than 10 km using an inverse relation- early history. So, despite having a good ex-

ship between the absolute ages of craters planation for why a single time window in

and the “rockiness” of their ejecta, derived Earth’s history might have seen as many

from the Lunar Reconnaissance Orbiter Di- impacts as originally anticipated, the earlier

viner instrument. In previous studies, it was (pre–600 million years ago) impact record

usually assumed that the paucity of craters on Earth, which spans most of the age of the

on Earth is a direct result of the erosional planet, is still a wide open field of research. j

and other geological forces that destroy or REFERENCES
obscure such craters on Earth. Recently, an
estimate of the number of impact craters 1. S. Mazrouei et al., Science 363, 253 (2019).
that should be present at Earth’s surface was 2. E. M. Shoemaker et al. in Global Catastrophes in Earth
reported (4). The study noted no evidence
for any systematic incompleteness in the History,V. L. Sharpton, P. D.Ward, Eds. (Geological Society
available inventory of the craters larger than of America, Special Paper 247, 1990), pp. 155–170.
about 6 km in diameter exposed at the sur- 3. B. M. French, C. Koeberl, Earth Sci. Rev. 98, 123 (2010).
4. S. Hergarten,T. Kenkmann, Earth Planet. Sci. Lett. 425, 187
1Natural History Museum, Burgring 78, 1010 Vienna, (2015).
Austria. 2Department oif Lithospheric Research, 5. E. M. Shoemaker, in Meteorites: Flux with Time and Impact
University of Vienna, Althanstrasse 14, 1090 Vienna, Austria. Effects, M. M. Grady, R. Hutchison, G.J. H. McCall, D.A.
Email: [email protected] Rothery, Eds. (Geological Society of London, Special
Publication 140, 1998), pp. 7–10.
6. T. Schulz et al., Geochim. Cosmochim.Acta 211, 322
(2017).

10.1126/science.aav8480

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make it a potentially attractive target metal long-lived CT excited states has been tackled lecular orbital. The switch in orbital ordering
for use in TMCs. Iron-based TMCs would by inorganic chemists who have purposefully leads to a low-lying CT excited state that can
have several advantages, such as earth-abun- designed ligands to overcome this issue. Dur- be used to drive chemical reactions.
dancy, low toxicity, and strongly absorbing ing the past several years, Wärnmark and
charge-transfer (CT) excited states (4). colleagues have developed iron TMCs con- Second, the newly reported iron-based
taining strong s-donor ligands based on N- TMC contains iron(III) rather than iron(II).
However, the photophysics of iron TMCs heterocyclic carbenes (NHCs). These ligands The iron(III)-TMC contains an unpaired
have made their solar-driven applications destabilize the low-lying e MC state so that electron in the t ground state, so both the
relatively rare (5). Molecular orbital order-
ing dictates the ability of TMC excited states g 2g
to separate charge within the complex and
maintain this separation long enough to the MLCT excited state becomes the lowest- ground and ligand-to-metal charge transfer
carry out productive chemical reactions. energy transition. (LMCT) excited states are doublets. The ad-
Ruthenium(II)-based TMCs experience rel- vantages of the 2LMCT excited state are two-
atively large octahedral splitting that drives Further research by the Gros and Wärn- fold: There is no excited-state energy loss as
the e and t metal-centered (MC) states mark groups provided critical insight into a result of singlet-to-triplet conversion that
molecular design for iron(II)-based TMCs. is ubiquitous in many TMCs with singlet
g 2g In parallel, they reported on iron(II) NHC character, and the lower-lying MC scaven-
complexes with the longest triplet 3MLCT ger states (4MC and 6MC) are less accessible
than the scavenger states (3MC and 5MC) of
Iron complexes that stay excited the 3MLCT formed in iron(II)-based TMCs, Downloaded from http://science.sciencemag.org/ on January 17, 2019
which reduces nonradiative losses.
Most iron(II) complexes have short-lived, metal-centered (MC) photoexcited states that are unable to perform
chemical reactions. A new iron(III) complex reported by Kjær et al. overcomes these limitations. For years, the goal of designing ligands for
iron-based TMCs has been to separate charge
Typical ruthenium(II) complexes Most iron(II) complexes An iron(III) complex in the excited state (forming LMCT or MLCT
The ligand-centered (LC) orbital lies The LC orbital lies above Strong s-donor ligands drive the eg states) and to reduce the nonradiative decay
below the eg orbitals and receives the eg orbitals, and excited t2g orbital above the LC orbital. The sta- through the MC scavenger states. This new
photoexcited t2g electrons. electrons transfer quickly bilized iron(III) center yields a partially ligand design hits both marks. Kjær et al.
to the eg orbitals. Llled t2g orbital to receive excited report that [Fe(phtmeimb) ]+ (where (pht-
MC eg electrons from a lower lying LC state.
LC LC 2
eg eg
meimb)− is {phenyl[tris(3-methylimidazol-
LC 1ylidene)]borate}−) has a record quantum
yield of 2% {0.3% greater than the standard,
MC t2gEnergy t2g t2g [Ru(bpy) ]2+} and a lifetime of 2 ns. The tri-

GRAPHIC: A. KITTERMAN/SCIENCE 3
LC LC LC
dentate, facial phtmeimb ligand provides the
Achieving photoinduced electron transfer key design element, namely, large s-donor
Photoexcited electrons must transfer between LC and MC orbitals to generate charge-transfer (CT) excited states ability, which is more pronounced because of
and survive long enough to drive subsequent chemical reactions. the negative charge of the borate ligand.

LMCT The combination of time-correlated single-
photon counting and transient absorption
Photon NNN NB High-energy fuels spectroscopy indicates that emission occurs
NN Long-lived CT states from the 2LMCT state. Furthermore, the
NN Fe [Fe(phtmeimb) ]+ complex is a strong pho-
BN NN Low-energy feedstocks
N 2

Transfer from ligand to metal e– tooxidant [a standard reduction potential
E°(III*/II) = 1.0 V versus Fc+/0, where Fc is fer-
In [Fe(phtmeimb)2]+, the photoexcited electrons transfer from a Llled LC orbital to a MC t2g orbital and have been rocenium] and photoreductant [E°(IV/III*)
shown to react with electron donors and acceptors in photoinitiated reactions. = −1.9 V versus Fc+/0] and has been shown
to act as a facile photoredox agent in two
of ruthenium(II)-based TMCs far enough lifetimes to that point, 16.5 and 18 ps, re- model reactions. With this demonstration,
apart that a ligand-centered (LC) state falls spectively (8, 9). In 2017, Wärnmark and co- iron complexes can now feasibly be used as
between them (6). This molecular orbital workers reported an all-NHC coordination photosensitizers in energy-relevant small-
ordering generates a low-lying MLCT ex- iron(III) complex, [Fe(btz) ]3+, where btz is molecule activations, such as water oxidation
cited state that rapidly becomes populated to produce hydrogen and reduction of carbon
upon photoexcitation of a ruthenium(II)- 3 dioxide into chemical feedstocks. j
based TMC (7). By moving charge either
away from or onto the ligands, the result- 3,39-dimethyl-1,19-bis(p-tolyl)-4,49-bis(1,2,3- REFERENCES
ing excited state maintains the potential to triazol-5-ylidene), that extended the CT life-
drive a desired chemical reaction. time to 100 ps (10). 1. Y.-J.Yuan,Z.-T.Yu, D.-Q. Chen,Z.-G.Zou, Chem. Soc. Rev.
46, 603 (2017).
Iron(II)-based TMCs experience weak Kjær et al. build off these previous suc-
ligand-field splitting, such that the e state cesses using a two-pronged approach. First, 2. K. S. Kjær et al., Science 363, 249 (2019).
they used an exceptionally strongly s-donat- 3. D.W.Thompson,A. Ito,T.J. Meyer, Pure Appl. Chem. 85,
g ing ligand that is also negatively charged and
enforces a near perfect octahedral coordina- 1257 (2013).
falls below the LC state. The excited state is tion sphere in order to substantially destabi- 4. B. Bozic-Weber, E. C. Constable, C. E. Housecroft, Coord.
a low-energy MC state that cannot be used lize the otherwise low-lying e MC state in the
to carry out productive chemistry. The de- Chem. Rev. 257, 3089 (2013).
velopment of iron(II)-based TMCs that have g 5. Y. Liu, P. Persson,V. Sundström, K.Wärnmark, Acc. Chem.

iron-containing complex (7), causing the LC Res. 49, 1477 (2016).
state to become the lowest unoccupied mo- 6. P.A. Scattergood,A. Sinopoli, P. I. P. Elliott, Coord. Chem.

Rev. 350, 136 (2017).
7. A. M. Brown, C. E. McCusker,J. K. McCusker, Dalton Trans.

43, 17635 (2014).
8. T. Duchanois et al., Eur.J. Inorg. Chem. 2015, 2469 (2015).
9. T. C. B. Harlang et al., Nat. Chem. 7, 883 (2015).
10. P. Chábera et al., Nature 543, 695 (2017).

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MICROBIOLOGY

Microbial guardians of skin health

Skin microbes can promote skin immunity, repair, and antimicrobial defense

By Apollo Stacy1,2,3 and Yasmine Belkaid1,2 they peacefully coexist with the skin micro- cells are noted for acquiring target specific- Downloaded from http://science.sciencemag.org/ on January 21, 2019
biota. Because unchecked immune tolerance ity and orchestrating highly dynamic im-
S kin, our largest and outermost organ, to the skin microbiota could lead to micro- mune responses, ranging from effector (for
faces numerous challenges, includ- bial overgrowth, keratinocytes have likely example, aimed at eliminating a pathogen)
ing wounds, infections, inflammatory co-opted products of microbial metabolism to regulatory (suppressive). S. epidermidis
disorders, and cancer. Fortunately, it as cues to curb its proliferation. Short-chain can finely tune both types of responses. In
does not meet these challenges alone. fatty acids (SCFAs) are released by S. epider- early life, cells with regulatory function [for
Our skin is home to complex microbial midis and other skin microbes as metabolic example, regulatory T cells (T )] migrate
communities, the skin microbiota, that play waste. As such, SCFAs serve as effective prox-
a fundamental role in the protection and ies for the quantity of microbiota, and hence regs
control of this barrier surface. Here, we focus its potential threat to skin integrity. For in-
on Staphylococcus epidermidis as a “poster stance, the SCFAs propionate and valerate to skin after the skin microbiota colonizes
child” of the skin microbiota to illustrate the inhibit the activity of histone deacetylases hair follicles. As these T are microbiota-
remarkable diversity of functions a microbe (HDACs) in keratinocytes. This promotes
can exert on skin physiology and health. gene expression and thereby enables higher regs
keratinocyte production of proinflammatory
Some of the most abundant constituents cytokines (5). Thus, the metabolic activity of specific, they are instrumental to establish-
of the skin microbiota are the coagulase-neg- the skin microbiota may calibrate the acti- ing tolerance to skin microbes including S.
ative staphylococci, a group of bacteria that vation status of keratinocytes toward either epidermidis (4).
includes S. epidermidis. Although in the past tolerance or inflammation.
these microbes were merely considered fast- The two major subsets of effector T cells
growing “weeds” and potential pathogens, re- In the context of tissue damage, the dialog are helper (T ) and cytotoxic (T ) cells. Al-
cent studies highlight that, analogous to the between the skin microbiota and keratino-
oft-studied gut microbiota, this group also cytes is shaped by microbial products. Cer- HC
assumes prominent roles in promoting tissue tain cell wall products are sensed by the host
immunity, repair, and antimicrobial defense. through dedicated receptors, such as Toll-like though many skin microbes can promote
receptors (TLRs). In most host cells, micro- the accumulation of T cells, S. epidermidis
Of note, S. epidermidis is more than “one bial cell wall products trigger inflammation,
microbe.” Individual strains vary dramati- but in keratinocytes, S. epidermidis TLR2 H
cally in their genome content, functional signaling can, in some contexts, dampen in-
potential, and relationship to the host im- flammation processes (2, 6). This response is rare in its ability to recruit and license the
mune system. Furthermore, the context in benefits not only S. epidermidis, by ensuring function of T cells (1). Remarkably, T cells
which S. epidermidis is sensed—for exam- its stable colonization on skin, but also the
ple, by intact or inflamed skin—can have a host in contexts where excess inflammation CC
profound impact on interaction outcomes, is deleterious. For instance, S. epidermidis
explaining in part the diverse effects that it TLR2 signaling can limit inflammation after acquire specificity to S. epidermidis through
exerts on the host and on other microbes skin injury—an effect that promotes wound an evolutionarily ancient arm of immunity.
(1, 2). These functions can be mediated by healing (2)—as well as during infection with This pathway involves the presentation of S.
defined microbial features (see the figure), the acne-associated microbe Cutibacterium epidermidis peptides on nonclassical antigen-
some of which are specific to S. epidermidis acnes (6). This anti-inflammatory communi- presenting molecules by dendritic cells to T
[for example, unique cell wall products (2)], cation occurs through discrete mechanisms.
whereas others are shared among many In the context of wounds, TLR2 activation C
members of the skin microbiota [for ex- by S. epidermidis inhibits proinflamma-
ample, the ability to produce antimicrobials tory TLR3 signaling in response to double- cells (7). S. epidermidis–specific T cells can
(3) or the ability to colonize particular skin stranded RNA from damaged host cells (2), C
niches such as hair follicles (4)]. whereas in the context of C. acnes infection,
S. epidermidis TLR2 signaling induces a provide multiple benefits to the host through
As a skin inhabitant, S. epidermidis lives microRNA that limits TLR2 expression, coun- their ability to alter the behavior of keratino-
in tight association with keratinocytes, the teracting TLR2-driven inflammation (6). cytes. These benefits include protecting the
cells that constitute the top layer of this or- Given the structural and metabolic complex- skin against foreign pathogens (8) and accel-
gan. Keratinocytes represent a first line of de- ity of microbial cells, numerous microbiota- erating the healing of skin wounds (7).
fense, yet it remains poorly understood how derived ligands may yet be discovered that
are recognized by other host receptors. Antimicrobial peptides (AMPs) are se-
1Metaorganism Immunity Section, Laboratory of Immune System creted by keratinocytes to fortify the skin
Biology, National Institute of Allergy and Infectious Diseases, Members of the skin microbiota such as against pathogens. Notably, their production
Bethesda, MD 20892, USA. 2NIAID Microbiome Program, National S. epidermidis can also fully engage com- can be augmented by cues from S. epider-
Institute of Allergy and Infectious Diseases, Bethesda, MD ponents of the adaptive immune system, midis. These cues can be sensed directly via
20892, USA. 3Postdoctoral Research Associate Training Program, including different subsets of T cells. These TLR2 (2) or transduced by S. epidermidis–
National Institute of General Medical Sciences, Bethesda, MD specific T cells that instruct keratinocytes
20892, USA. Email: [email protected]
C

to express AMPs (1). Both pathways promote
keratinocyte AMP expression and killing of
diverse microbial pathogens, including bac-
teria and fungi (1, 2). Because S. epidermidis
has built-in defenses, such as modifying its
cell wall with positively charged residues that
repel AMPs (9), these responses may benefit
not only the host but also S. epidermidis by
eliminating its potential competitors.

S. epidermidis also interacts with other
microbes directly, independently of the host.
Often, these interactions are antagonistic,
revolving around competition for space and
nutrients. Antagonism is especially promi-
nent in the nasal cavity, a primary reservoir
of the pathogen S. aureus. In this niche, S.
epidermidis can displace S. aureus by secret-
ing the protease Esp that degrades S. aureus
adherence proteins (3). Microbes can further

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INSIGHTS | PERSPECTIVES

compete by producing antimicrobials, usu- vide an important strategy for the control of cular catheterization—promotes S. aureus
ally peptides, that directly kill specific spe- antibiotic-resistant pathogens. survival in the liver and reduces its infectious
cies or strains (bacteriocins) (3) or interfere dose (15).
with their coordination of microbial group However, S. epidermidis does not always
behaviors (quorum-sensing inhibitors) (10). act in the host’s interest. Although S. aureus Although many of the products made
In a systematic analysis of nasal isolates, S. predominantly colonizes strong AD flares, by S. epidermidis likely evolved for its sur-
epidermidis was identified as an especially mixed populations of S. epidermidis strains vival on skin, these products can also have
frequent producer of antimicrobials (11). As prevail in less severe flares (13). These strains unexpected, off-target effects. Remarkably,
such, S. epidermidis may play a dominant are genetically related to strains acquired in one such product, 6-N-hydroxyaminopu-
role in shaping the microbiota in defined hospitals, where S. epidermidis is one of the rine (6-HAP), an antimicrobial that nor-
settings. This is illustrated by the microbiota most frequent causes of sepsis in newborns mally targets skin pathogens, has recently
associated with atopic dermatitis (AD), a (9). A hallmark of these strains is the pres- been shown to inhibit tumor cell growth.
type of eczema that is characterized by re- ence of staphylococcal chromosome cassette 6-HAP, an analog of the DNA nucleotide
curring flares of dry, itchy skin. These flares (SCC) mec genetic elements that can encode base adenine, interferes with the essential
are thought to be driven by colonization with not only methicillin antibiotic resistance but process of DNA replication. Keratinocytes,
also a potent peptide toxin, the phenol-sol- however, are resistant to 6-HAP because,
unlike tumor cells, they highly express en-
The multifaceted roles of S. epidermidis in skin physiology zymes that can detoxify 6-HAP. In mice, Downloaded from http://science.sciencemag.org/ on January 21, 2019
topical application of 6-HAP–producing
S. epidermidis guards skin against inflammation, infections, and cancer through interactions with strains of S. epidermidis protects against
keratinocytes, T cells, and other members of the skin microbiota. These interactions are strain- and context- ultraviolet-induced skin tumors (16). In-
dependent, with some leading to negative outcomes for the host, including inflammation and infection. triguingly, such strains are commonly
found on the skin of healthy human indi-
Control of infammation viduals, which suggests that the composi-
tion of the skin microbiota could affect the
Innate receptor Treg development of skin tumors.
(e.g., TLR2)
S. epidermidis has emerged as an influen-
Promotion of Pathogens Dendritic Wound repair tial, keystone member of the skin microbiota.
infection (e.g., S. aureus) cell Although particular strains are contextually
Keratinocyte pathogenic, their multifarious roles in skin
Cell wall Antigens AMPs immunity and antimicrobial defense sug-
structures (e.g., gest that most S. epidermidis strains bolster
(e.g., lipoprotein) formylated Control of our skin health overall. Much remains to be
peptides) infection learned about the beneficial role of the nu-
Infammation merous other microbes that constitute the
skin microbiota. Precise editing of the micro-
T cell biota, such as by providing nutrients targeted
at promoting the growth of defined members
Toxin S. epidermidis of the skin microbiota such as S. epidermi-
dis, or the direct application of purified mi-
(e.g., PSM) crobiota-derived products may one day hold
strong therapeutic value in the fight against
Antimicrobials skin inflammatory disorders, infections,
wounds, and cancer. j
Metabolic
by-products REFERENCES AND NOTES
(e.g., SCFAs) 1. S.Naik et al.,Nature 520,104 (2015).
2. R.L.Gallo,T.Nakatsuji,J.Invest.Dermatol. 131,1974 (2011).
Keratinocyte 3. B.Krismer et al.,Nat.Rev.Microbiol. 15,675 (2017).
4. T.C.Scharschmidt et al.,Cell Host Microbe 22,1 (2017).
Infammation 6-HAP Pathogens 5. J.A.Sanford et al.,Sci.Immunol. 1,eaah4609 (2016).
(e.g., S. aureus, 6. X.Xia et al.,J.Invest.Dermatol. 136,621 (2016).
S. pyogenes) 7. J.L.Linehan et al.,Cell 172,784 (2018).
8. S.Naik et al.,Science 337,1115 (2012).
Control of cancer Control of atopic 9. M.Otto,Nat.Rev.Microbiol. 7,555 (2009).
dermatitis
10. A.E.Paharik et al.,Cell Host Microbe 22,746 (2017).
S. aureus and are associated with a loss of S. uble modulin PSM-mec. During sepsis, this 11. D.Janek et al.,PLOS Pathog. 12,e1005812 (2016). GRAPHIC: N. DESAI/SCIENCE
epidermidis strains that produce S. aureus– toxin mediates the killing of neutrophils (cru- 12. T.Nakatsuji et al.,Sci.Transl.Med. 9,eaah4680 (2017).
targeting bacteriocins. Reintroduction of a cial inflammatory immune cells), the survival 13. A.L.Byrd et al.,Sci.Transl.Med. 9,eaal4651 (2017).
cocktail of bacteriocin-producing microbes of S. epidermidis in blood, and ultimately 14. L.Qin et al.,PLOS Pathog. 13,e1006153 (2017).
decolonizes AD-affected sites of S. aureus host death (14). 15. E.Boldock et al.,Nat.Microbiol. 3,881 (2018).
(12), which suggests that this condition may 16. T.Nakatsuji et al.,Sci.Adv. 4,eaao4502 (2018).
represent a target for ecology-based ther- Furthermore, the ability of S. epidermidis
apy. This type of therapy, rather than elimi- to limit inflammation can be exploited to the ACKNOWLEDGMENTS
nating pathogens by brute force, leverages advantage of pathogens such as S. aureus. In
understanding of the preferred niche of a the liver, macrophage uptake of the cell wall Supported by the Intramural Research Program of the National
pathogen in order to make it less habitable. polymer peptidoglycan from S. epidermidis Institute of Allergy and Infectious Diseases (project number
The appeal of this approach is that, com- or other defined skin microbes strongly sup- 1ZIAAI001115-09) (A.S. and Y.B.) and by a Postdoctoral
pared to antibiotic therapy, it is much less presses production of antimicrobial reactive Research Associate Training fellowship from the National
likely to harm the indigenous microbiota in oxygen species. Because of this, bloodstream Institute of General Medical Sciences (project number
a patient. Such an approach could also pro- infection by S. aureus and S. epidermidis— 1FI2GM128736-01) (A.S.).
for example, as a consequence of intravas-
10.1126/science.aat4326

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The cerebellum is involved in the main cerebellum is activated in relation to motor
circuits that regulate social behavior in mice. commands, whereas the posterior cerebel-
lum and the hemispheres become activated
NEUROSCIENCE when, for example, we see actions performed Downloaded from http://science.sciencemag.org/ on January 17, 2019
by others, we evaluate sensory perceptions,
The cerebellum gets social and we feel emotions (12). Moreover, the cer-
ebellum shows coherent activation together
The cerebellum can regulate behavior by controlling with several areas of the cerebral cortex and
dopamine release hippocampus in the so-called fMRI resting-
state networks. These include the default-
PHOTO: BILDAGENTUR ZOONAR GMBH/SHUTTERSTOCK By Egidio D’Angelo and the hippocampus to allow spatial naviga- mode network, the salience network, and
tion (3). Although these stereotypes may help the attention networks, which regulate the
T he cerebellum contains the second to conceptualize how the behavioral response switch from an internal reference state to
main cortex of the brain and ~50% of is generated, they are oversimplifications (4) external target-oriented behaviors (13). The
the neurons that constitute the brain. because brain circuits are interconnected study of Carta et al. implies that the specific
Although the cerebellum has long at multiple levels and influence each other modules of the cerebellum, as part of these
been thought to subserve motor learn- through neuromodulatory systems, as dem- brain networks, contribute to action selec-
ing and coordination, more recently it onstrated by Carta et al. tion and behavioral switching.
has been recognized to take part in cognitive
and emotional processing. Additionally, evi- The cerebral cortex is bidirectionally con- Surprisingly, Carta et al. find that the
dence for cerebellar involvement in autism nected with the cerebellum through multiple cerebellum regulates the motivation and re-
spectrum disorder (ASD), schizophrenia, neural circuits (5–8). In humans, these cir- ward process that is typically attributed to
and addiction is growing. On page 248 of cuits involve the motor cortical areas but also the basal ganglia. The authors demonstrate
this issue, Carta et al. (1) extend this theme areas that regulate cognition, emotion, atten- that in mice, monosynaptic connections
and show that the cerebellum can activate tion, and social behavior. These nonmotor from the fastigial nucleus of the cerebellum
the ventral tegmental area (VTA). The VTA areas receive more than 80% of all the nerve regulate the activity of the VTA directly. In
is a mesencephalic nucleus giving rise to the fiber tracts that travel between the cerebel- this way, the cerebellum can regulate func-
mesocortical and mesolimbic fiber bundles lum and cerebral cortex through the deep tions related to decision-making, emotional
that release dopamine to the prefrontal cor- cerebellar nuclei and thalamus (9). control, and attentional switching. The
tex and ventral striatum. Dopamine, in turn, same group showed that the cerebellum
plays a fundamental role in cognitive and The prototypical mode of action of the communicates directly with the basal gan-
emotional functioning by regulating motiva- cerebellum has been characterized for mo- glia (14). The findings of Carta et al. reveal
tion and reward. This places the cerebellum tor coordination (5). The cerebral cortex a more complex scenario in which the two
into the main circuits regulating brain states elaborates the motor plan as a predictive main subcortical circuits coordinate dopa-
and social behavior. sensory state (6, 7), which is conveyed to the mine functions in the brain.
cerebellum through descending pathways.
Behavior can be defined as a coordinated In the cerebellum this plan is compared to Carta et al. suggest that dysfunction of the
series of motor acts and neurovegetative the actual sensory state, which is conveyed cerebellum-VTA connection could contribute
changes centered on a certain target (2). through the afferent sensory pathways. to the pathogenesis of diseases in which the
There are several elements that contribute According to the motor learning theory, dopaminergic system is dysregulated, includ-
to the behavioral response, and historically through this comparison the cerebellar cir- ing ASD and schizophrenia (15), and to condi-
these have been separated and attributed to cuit learns to minimize motor errors (10). It tions such as drug addiction. These proposals
different parts of the brain. The cerebral cor- has been argued that this process could be need critical validation in humans. This study
tex is classically thought to play a planning generalized to the cognitive and emotional opens a new avenue for interpreting the
and decisional role; the basal ganglia to con- domains (11). The results of Carta et al. imply function of the cerebellum and also for un-
trol action selection, motivation, and reward; that a similar mechanism could be used to derstanding social behavior and related pa-
the cerebellum to coordinate motor actions; regulate the motivation and reward cycle. thologies, with the potential to discover novel
therapies to treat these diseases. j
Department of Brain and Behavioral Sciences, University of In functional magnetic resonance imaging
Pavia, Pavia, Italy. Email: [email protected] (fMRI) studies, different areas of the cerebel- REFERENCES AND NOTES
lum are activated depending on the nature of
tasks performed by the subjects. The anterior 1. I. Carta et al., Science 363, eaav0581 (2019).
2. A. S. Pillai et al., Neuron 94,1010 (2017).
3. S.Arber et al., Science 360, 1403 (2018).
4. S. Grillner, Curr. Biol. 28, R162 (2018).
5. E. D’Angelo, Handb. Clin. Neurol. 154, 85 (2018).
6. S.J. Blakemore et al., Nat. Neurosci. 1, 635 (1998).
7. D. M.Wolpert et al., Trends Cogn. Sci. 2, 338 (1998).
8. J. Ghajar et al., Neuroscientist 15, 232 (2009).
9. F. Palesi et al., Sci. Rep. 7, 12841 (2017).
10. R. R. Llinas et al., Philos.Trans. R. Soc. London Ser. B 364,

1301 (2009).
11. E. D’Angelo et al., Front. Cell. Neurosci. 6, 116 (2013).
12. L. Casiraghi et al., Cereb. Cortex 10.1093/cercor/bhy322

(2019).
13. G. Castellazzi et al., Front. Cell. Neurosci. 12, 331 (2018).
14. C. H. Chen et al., Nat. Neurosci. 17, 1767 (2014).
15. J. D. Schmahmann,J. C. Sherman, Brain 121, 561 (1998).

ACKNOWLEDGMENTS

Supported by Human Brain Project SGA720270/SGA785907
and Centro Fermi MNL.

10.1126/science.aaw2571

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STRUCTURAL BIOLOGY

Adaptations of an ancient modular machine

Mechanism of energy conversion is conserved in the complex I superfamily

By Ulrich Brandt biological electron transfer, respiration, and (P ) from the multiple resistance and pH
I

photosynthesis were closely intertwined and (Mrp)–type sodium-proton antiporter, yield-

A ll expressions of life ultimately de- accompanied by the modular unfolding of ing the energy-converting hydrogenase (Ech)
pend on energy derived from redox the complex I superfamily of redox enzymes. that energetically connects electron transfer
chemistry and photosynthesis. On between ferredoxin and hydrogen to proton
page 257 of this issue, Schuller et al. The module common to all members of translocation across a membrane. The Mrp
(1) report the structure of photosyn- the complex I superfamily is provided by transporters also trace back to the last uni-
soluble [NiFe] hydrogenases (8). These hy-

thetic complex I at atomic resolu- drogenases have a [NiFe] active site and versal common ancestor, in which they are

tion. The authors have analyzed how the catalyze the reversible conversion of hydro- proposed to play a role in establishing the so-

distinct NADH [reduced form of oxidized gen to protons and electrons. They also fea- dium gradient across the plasma membrane

nicotinamide adenine dinucleotide (NAD+)] ture a chain of three iron-sulfur clusters and to drive primordial adenosine triphosphate

dehydrogenase subunit S (NdhS) facilitates harbor a substrate binding site for hydrogen (ATP)–synthase (7). The structure of the hy- Downloaded from http://science.sciencemag.org/ on January 17, 2019

electron transfer from ferredoxin, thereby (H-module) or plasto-, mena-, or ubiquinone drogen gas–evolving membrane-bound hy-

establishing efficient cyclic electron flow (Q-module). Although the active site evolved drogenase (Mbh) revealed that it retained

around photosystem I. The findings add an to bind chemically different substrates while the sodium translocating module (S) of Mrp

important piece to the puzzle of deciphering concomitantly losing the [NiFe] center— and expanded the P -module by adding three
I

the enigmatic mechanisms at work in the from soluble hydrogenase to mitochondrial additional subunits. This resulted in a com-

remarkable molecular machines of the com- complex I—both the sequence and struc- position very similar to that of the proximal

plex I superfamily encompassing photosyn- ture of nearby domains are conserved (3, 4, proton pumping (P ) module of complex I (6).
P

thetic and respiratory complex I, as well as 9, 10). Hydrogenases acquired a membrane Instead of the S-module, photosynthetic and

proton pumping hydrogenases. In combina- anchor and a proton-translocating module respiratory complex I retained the second

tion with high resolution struc- proton-translocating module of

tures of respiratory complex I Modular design of the Modules Mrp (P ), duplicating it to form
from bacteria (2), mitochondria complex I superfamily H Hydrogen binding II
(3–5), and membrane bound hy- Q Quinone binding
drogenase (6), it is now possible The complex I superfamily evolved S Sodium translocating the distal proton pumping (P )
to trace the modular evolution from different soluble hydrogenases F Ferredoxin binding D
and functional adaptations of and Mrp sodium–proton antiporters PD Distal proton translocating
the complex I superfamily at the by combining ancient modules dating PP Proximal proton translocating module. Strikingly, however,
atomic level. back to the last universal common
ancestor. Its members have adapted PI-II Proton translocating I and II as compared with Mbh, the P -
Evolutionary studies suggest to use diverse substrates, yet several P
that the metabolism of the last functional domains are conserved. N
universal common ancestor re- module is rotated 180° in the
lied on the reduction of carbon
dioxide and nitrogen by hydro- membrane plane in complex I,

probably retaining the relative

topology of the modules in Mrp.

This is particularly remarkable

because irrespective of the orien-

tation of the P -module, proton
P

pumping is driven by the redox

chemistry taking place in the ho-

gen and hydrogen sulfide, as- H PII PI S H mologous Q- or H-module.
sisted by transition metals such The membrane-bound hy-
as iron, nickel, and molybdenum Soluble Mrp sodium–proton NAD+-reducing
(7). This basal redox chemistry hydrogenase antiporters hydrogenase drogenases of the complex I su-
perfamily mostly use ferredoxin

provided the building blocks Complex I superfamily as the electron donor or accep-
for organic molecules, nucleic tor for the H-module. Ferredoxin

acids, and proteins. The integra- also reduces the Q-module of

tion of photosynthesis into this H photosynthetic complex I, pass-

primordial power supply tapped PD ing on electrons from photo-
sunlight as an unlimited energy system I. However, as shown

source. With the advent of water Energy-converting by Schuller et al., an additional
splitting photosynthesis and ter- hydrogenase NdhS subunit (see the figure,

minal oxidases, oxygen became module F) greatly facilitates

the major player in the overall recognition and binding of the GRAPHIC: V. ALTOUNIAN/SCIENCE

cycle of biological energy. Thus, F N redox protein, thereby optimiz-
going back to the origin of life, ing cyclic electron transfer. Re-

H Q Q spiratory complex I turned into

Radboud Institute for Molecular Life Sciences, S PP PD PP PD PP a NADH-dehydrogenase by cap-
Department of Pediatrics, Radboud University turing its electron input module
Medical Center, Geert Grooteplein-Zuid 10, Membrane bound Photosynthetic Respiratory from the NAD+-reducing hy-
Route 772, 6525 GA Nijmegen, Netherlands. hydrogenase complex I complex I drogenase. The H-module of this
Email: [email protected]

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group of [NiFe] hydrogenases is only dis- THERAPEUTICS
tantly related to the H/Q-module of the com-
plex I superfamily. Thus, respiratory complex Gene therapy for pathologic
I has evolved by combining ancient modules gene expression
from two different groups of hydrogenases
and Mrp sodium–proton antiporters. This Haploinsufficiency in disease can be overcome by boosting
core structure was then retained all the way gene expression with CRISPR
from bacterial to mammalian complex I.
By Lindsey E. Montefiori and tablished that SIM1 and MC4R control eat- Downloaded from http://science.sciencemag.org/ on January 17, 2019
Several conclusions can be drawn from Marcelo A. Nobrega ing behavior through their expression in the
the adaptive development of the super- hypothalamus (6–8); therefore, a relevant
family originating from simple soluble hy- H aploinsufficiency arises when one therapeutic intervention would target gene
drogenases and leading to the large and copy of a gene is functionally lost, of- expression specifically in the hypothalamus.
complicated molecular machine of mam- ten through nonsense or frameshift
malian complex I. Proton pumping by the mutations or small chromosomal Because Sim1 and Mc4r are expressed in
P /P -module is driven by redox chemistry deletions. The resulting monoallelic multiple tissues, an important first step was
expression is not sufficiently com- to address whether it is feasible to modu-
IP pensated for by the intact allele, ultimately late expression in a tissue-specific manner.
leading to decreased expression of the gene The authors tested two approaches, focus-
catalyzed by the H/Q module, irrespective of product and resulting in pathologic pheno- ing initially on Sim1: (i) Target CRISPRa to
its orientation in the membrane domain. Dif- types (1). What are the therapeutic options the promoter of the remaining functional
ferent additional ion-translocating modules for diseases rooted in insufficient gene ex- Sim1 gene to enhance expression wher-
from Mrp are docked onto this central unit. pression? One possible viable option is to ever Sim1 was already active, and (ii) tar-
In the P -module, even two closely related restore normal gene expression levels by get CRISPRa to a 270-kb distal enhancer
enhancing their transcription in a targeted that controls Sim1 expression specifically
D fashion. On page 246 in this issue, Matharu et in the hypothalamus (see the figure). Both
al. (2) report a CRISPR-based gene-activation approaches were employed in transgenic
modules are stacked onto the P -module. It approach that can increase the expression of animals expressing the CRISPRa reagents
P normal endogenous genes in a tissue-specific (dCas9 fused to the transcriptional activa-
manner, setting the stage for the develop- tor VP64), as well as recombinant adeno-
seems that this works because the central ment of new gene-regulating therapies for associated virus (rAAV)–mediated delivery
axes of protonable residues common to all gene dosage–associated diseases. of CRISPRa directly into the hypothalamus.
modules of the Mrp transporter can connect In all cases, hypothalamic Sim1 expression
flexibly with each other. This is in line with Among the emerging applications of was restored to wild-type levels and the
the proposed mechanism of electrostatic en- CRISPR-based gene editing are techniques mice did not become obese, demonstrat-
ergy transmission into the central axis from that use a catalytically inactive Cas9 en- ing robust prevention of a haploinsufficient
the H/Q-module and from one pump site to zyme (dCas9) fused to a protein domain to phenotype by enhancing endogenous gene
the next, both of which feature broken trans- modulate transcription (3). These fusion expression. Interestingly, the authors found
membrane helices found in many ion trans- proteins can be recruited by way of guide that they could manipulate Sim1 expression
porters. During the conversion from the H RNAs (gRNAs) to specific genomic locations, exclusively in the hypothalamus by target-
into the Q-module, the hydrogen reactive including promoters and cis-regulatory ele- ing the hypothalamic enhancer instead of
[NiFe] center was transformed into binding ments such as enhancers, which regulate the Sim1 promoter, indicating that to obtain
pockets for different kinds of hydrophobic gene expression. If the recruitment site is tissue-specific transcriptional modification,
quinones. Remarkably, the fold surrounding transcriptionally competent, the result is CRISPRa will likely need to be deployed to
this active site and even a substantial num- activation (CRISPRa) or repression/interfer- tissue-specific regulatory elements. Injec-
ber of critical residues are highly conserved ence (CRISPRi) of transcription. Although tion of rAAV-based CRISPRa into the hy-
(9). This holds in particular for a cluster of this strategy has been applied in human cell pothalamus of Mc4r haploinsufficient mice
three critical loops that connect the active culture and animal models (4, 5), the ulti- similarly prevented obesity, further demon-
site with the common membrane anchor, mate task of employing CRISPRa to thera- strating the strength of this approach.
which has been implicated in generating the peutically rescue pathologic gene expression
electrostatic pulse transmitted toward the has not been fully realized. Matharu et al. This strategy illustrates what could
pump modules in the membrane domain of use CRISPRa to restore the expression of emerge as an important new approach to
complex I (4, 11) and is already present in two haploinsufficient genes, single-minded 1 treating gene expression disorders and
membrane-bound hydrogenase (6). (Sim1) and melanocortin 4 receptor (Mc4r), raises the possibility of expanding the scope
to physiological amounts in mouse models of CRISPRa and CRISPRi technology to
Studying the conserved structural ele- of severe early-onset obesity. Haploinsuffi- treat diseases that involve pathogenic over-
ments and understanding the functional ciency of either gene causes severe obesity expression of a gene, particularly in cancer.
adaptions of complex I superfamily mem- in humans, and previous work in mice es- For example, somatic mutations in a subset
bers will greatly help to understand the still of pediatric T cell acute lymphoblastic leu-
poorly understood molecular mechanism of Department of Human Genetics, University of Chicago, kemia (T-ALL) result in the formation of a
these distinct redox-driven ion pumps. j Chicago, IL, USA. Email: [email protected] highly active enhancer that drives onco-
genic TAL1 gene overexpression (9). More-
REFERENCES

1. J. M. Schuller et al., Science 363, 257 (2019).
2. R. Baradaran et al., Nature 494, 443 (2013).
3. J.Zhu, K. R.Vinothkumar,J. Hirst, Nature 536, 354 (2016).
4. V.Zickermann et al., Science 347, 44 (2015).
5. K. Fiedorczuk et al., Nature 538, 406 (2016).
6. H.Yu et al., Cell 173, 1636 (2018).
7. M. C.Weiss et al., Nat. Microbiol. 1, 16116 (2016).
8. J.W. Peters et al., Biochim. Biophys.Acta 1853, 1350

(2015).
9. N. Kashani-Poor et al., J. Biol. Chem. 276, 24082 (2001).
10. A.Volbeda et al., Nature 373, 580 (1995).
11. A. Cabrera-Orefice et al., Nat. Commun. 9, 4500 (2018).

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INSIGHTS | PERSPECTIVES

over, MYC gene expression in human B cell phenotype later in life. Many haploinsuffi- IMMUNOLOGY
acute myeloid leukemia (AML) was recently cient disorders in humans are likely to be
shown to be dependent on a 1.7-megabase therapeutically actionable only after the B cells, CMV,
distal enhancer element (10). Both stud- disease phenotypes are partially or fully es- and stem cell
ies demonstrated that disrupting these en- tablished. Future experiments should test transplant
hancer elements negatively affected cancer the therapeutic benefit of targeting gene
cell survival, providing a precedent for de- expression with the goal of reversing a hap- Host antibodies help prevent
veloping CRISPRi as a therapeutic approach loinsufficient phenotype. Additionally, it is CMV dissemination after
to inactivate cancer-promoting enhanc- important to recognize that many enhanc- bone marrow transplantation
ers. Although transcription factors such as ers are dynamic, meaning that they may act
TAL1 and MYC are among the most potent at specific developmental stages and change By Maria-Luisa Alegre
oncoproteins, targeting them with small- their tissue specificity with time (11). Fortu-
molecule inhibitors has proven challenging. nately, the authors were able to capitalize
The results presented by Matharu et al. sug- on a developmentally stable tissue-specific
gest that it should be possible to circumvent enhancer, although it is unclear how often
protein-targeted therapies by quelling onco- this will be the case for targeting enhancers
gene expression at its source—transcription. of other haploinsufficient genes.

Enhancing endogenous gene expression with CRISPRa H ematopoietic stem cell transplanta- Downloaded from http://science.sciencemag.org/ on January 17, 2019
tion (HSCT) is a potentially curative
Most genes are biallelically expressed; however, heterozygous mutations can cause haploinsufficiency, therapy for various malignant and
resulting in 50% less functional protein. Recruitment of CRISPRa to the endogenous promoter or enhancer of nonmalignant conditions but can
the gene in mouse models causes up-regulation of the wild-type copy, leading to normal expression levels. be complicated by infections such
as reactivation of cytomegalovirus
Haploinsufcient gene mRNA CRISPRa enhances expression (CMV). CMV is a ubiquitous DNA herpes
virus comprising various distinct strains
Coding VP64 (1). Around 60 to 90% of healthy adults are
exons dCas9 seropositive, indicating past exposure to the
virus, although infections in healthy people
Allele 1 Tissue-speci1c enhancer Allele 1 are often mild or asymptomatic. After ini-
tial acute infection, CMV enters a latent
Nonsense mutation phase, similar to other herpes viruses. It
has been suggested that CMV infection may
Allele 2 Allele 2 confer an immunological benefit, perhaps
explaining its prevalence, because com-
A key advancement in the study by Naturally occurring and pathogenic gene parison of seropositive and seronegative GRAPHIC: KELLIE HOLOSKI/SCIENCE
Matharu et al. is their use of rAAV to deliver regulatory DNA elements provide a tailored individuals has shown that CMV infection
CRISPRa reagents in vivo. For a CRISPR- therapeutic route to targeting gene expres- results in greater responses to the flu vac-
based therapeutic to be relevant for use in sion. The results presented by Matharu et cine (2). The immune system is essential to
humans, it will likely need to be packaged al. underscore the importance of identifying control the initial infection and to prevent
within a virus and administered intrave- and carefully characterizing the enhancers later CMV reactivation, as demonstrated by
nously, because most targeted cell types will that control gene expression. Large-scale ef- the high incidence of CMV reactivation in
not be available for ex vivo manipulation and forts have identified thousands of putative immunosuppressed patients such as HSCT
implantation. rAAV is nonpathogenic and enhancers in hundreds of human cell types. recipients. Whereas the incidence and se-
displays a high delivery potential, making However, cell types representing diverse verity of CMV transcriptional reactivation
it a viable option for effectively introducing disease states, particularly from human pa- and cell-to-cell dissemination after HSCT
CRISPR reagents to human cells. CRISPRa tients, remain understudied. Knowing the has substantially diminished since the
and CRISPRi approaches have the added full repertoire of gene regulatory elements adoption of prophylactic or preemptive an-
benefit of modulating gene expression with- and their target genes (12) in these cell types tiviral therapies (3), CMV remains the most
out modifying the genome, thereby avoiding is likely to provide critical insight that can be important viral infection after HSCT, espe-
potential off-target mutations. Thus, pairing exploited for CRISPR-based therapeutic ap- cially in high-risk patients (such as seropos-
CRISPRa with rAAV to treat a gene expres- proaches to modify gene expression. j itive recipients of seronegative donors), and
sion disorder in vivo is an important step can lead to life-threatening CMV disease in
forward in the development of expression- REFERENCES AND NOTES ~10% of HSCT recipients (4). On page 288
based therapeutics. 1. N. Huang et al., PLOS Genet. 6, e1001154 (2010). of this issue, Martins et al. (5) make the
2. N. Matharu et al., Science 363, eaau0629 (2019). unexpected observation, in mice undergo-
Although Matharu et al. demonstrate 3. C.-H. Lau,Y. Suh, Transgenic Res. 27, 489 (2018). ing bone marrow transplantation (BMT) as
that CRISPR-based up-regulation of a hap- 4. M. L. Maeder et al., Nat. Methods 10, 977 (2013). a model of HSCT, that strain-specific CMV
loinsufficient gene can prevent obesity, this 5. H.Zhou et al., Nat. Neurosci. 21, 440 (2018). antibodies made by host B cells play a cru-
study also raises the important question 6. J. L. Michaud et al., Hum. Mol. Genet. 10, 1465 (2001). cial role in preventing CMV dissemination
of whether a disease phenotype can be re- 7. M.J. Krashes et al., Nat. Neurosci. 19, 206 (2016).
versed. Because the authors administered 8. C.Vaisse et al., J. Clin. Invest. 106, 253 (2000). Section of Rheumatology, Department of Medicine,
CRISPRa reagents to mice at 4 weeks of 9. M. R. Mansour et al., Science 346, 1373 (2014). University of Chicago, Chicago, IL 60637, USA.
age—before the onset of obesity—they did Email: [email protected]
not address the potential to rescue the 10. C. Bahr et al., Nature 553, 515 (2018).
11. A. S. Nord et al., Cell 155, 1521 (2013).
12. L. E. Montefiori et al., eLife 7, e35788 (2018).

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after BMT. They propose that passive trans- thus develop a reduction in CMV-specific tion of CMV that is inside infected cells. The
fer of antibodies that are matched to the la- antibody titers after HSCT. Prospective fol- authors show that neutralizing antibodies
tent CMV strain in HSCT recipients might lowing of CMV-specific antibody titers may that prevent cell infection are not as pro-
constitute a powerful and easy therapeutic be of interest in the clinic to see whether this tective when injected in vivo as those that
approach to prevent CMV disease. is indeed the case. prevent cell-to-cell dissemination in vitro,
which may provide insights for vaccine de-
It is thought that ab T cells, gd T cells, Prevention or treatment of CMV with im- sign. Much effort has been devoted to de-
natural killer (NK) cells, and B cells all con- munoglobulins has usually been ineffective veloping vaccines against human CMV (13).
tribute to curbing CMV infection (6) and in HSCT recipients (11). The authors argue The study of Martins et al. support giving
that anti-CMV CD8+ T cells are especially that this may be because these reagents, further consideration to the role of humoral
important in CMV immune surveillance and which come from sera pooled from many immunity in the prevention of reactivation
prevention of reactivation and dissemina- donors, may not contain sufficient concen- and dissemination of CMV after clinical
tion. Analysis of cadaveric organ donor tis- trations of antibodies specific to the CMV HSCT, the therapeutic potential of strain-
sue has revealed potential sites of active T strain infecting a given recipient. That hu- specific serum transfer, and the rational
cell–mediated CMV clearance in the blood, mans can experience successive infections vaccine design either for CMV-seronegative
bone marrow, and spleen and reservoirs of with different CMV strains (12) supports recipients or to boost or broaden responses
viral persistence in the lung coexisting with the possibility that the protective effect of of seropositive recipients before HSCT. j
active antiviral T cells (7). Indeed, transfer of CMV antibodies is strain specific or at least
anti-CMV CD8+ T cells from donors is one
of the approaches investigated to treat CMV B cells help prevent CMV reactivation Downloaded from http://science.sciencemag.org/ on January 17, 2019
reactivation in immunosuppressed patients
(8). Martins et al. found that in mice, T cell T cells, NK cells, and B cell–derived antibodies contribute to the prevention of mouse CMV dissemination
immunosuppression or depletion alone is after BMT. Killing of host B cells and plasma cells by alloreactive donor T cells (GVHD) in combination with
insufficient to enable CMV reactivation after therapeutic deletion of T cells and NK cells resulted in CMV infection of latently infected hosts.
BMT, and only when host B cells and plasma
cells are eliminated [by graft-versus-host Prevention of CMV dissemination Host infected
disease (GVHD), a process by which donor fbroblast
T cells can attack host cells, or by genetic Host anti-CMV
deficiency] in addition to T cell and NK cell CD8+ T cell
depletion does infection emerge (see the fig-
ure). Moreover, they demonstrate that pro- Prevention of CMV dissemination CMV
tection from CMV reactivation conferred Prevention of CMV dissemination dissemination
by antibodies is much more efficient if it is
strain specific. Additionally, protection by Host NK cell CMV antibodies
antibodies that prevent cell-to-cell dissemi-
nation is more effective than by antibod- Host anti-CMV Prevention of
ies that prevent cell entry. Whether these B cell CMV disease
discoveries in mice—by using a different
conditioning regimen from that used in the Prevention of CMV dissemination
clinic and, by necessity, mouse rather than
human CMV (which are quite different)— Host anti-CMV plasma cell
are relevant to the clinical situation merits
careful examination. GVHD

Recipients of allogeneic HSCT can be Decreased CMV Host anti-CMV plasma cell
treated with a variety of regimens to pre- antibodies
vent the host immune system from rejecting
the allogeneic stem cells, with a heavy focus Donor alloreactive Host anti-CMV B cell CMV
on T cell immunosuppression. These con- CD8+ T cell dissemination CMV disease
ditioning regimens may include total-body
GRAPHIC: N. DESAI/SCIENCE irradiation at high or low doses, cytoreduc- that antibodies generated after a given CMV REFERENCES
ing chemotherapy drugs, and antithymocyte infection are not broadly cross-protective
globulin (ATG) or anti-CD52 (alemtuzumab) against other strains. This is consistent with 1. H. Kaminski,J.A. Fishman, Am.J.Transplant. 16, 2254
to eliminate host T cells. Given the findings the observation of Martins et al. that in their (2016).
of Martins et al., it is compelling to con- mouse model, protection against CMV reac-
sider how these clinical treatments may af- tivation is only conferred by strain-specific 2. D. Furman et al., Sci.Transl. Med. 7, eaaa2293 (2015).
fect antibody-producing B cells and plasma serum and not when this serum is diluted 3. D. Lilleri, G. Gerna, Immunotherapy 8, 1135 (2016).
cells because CMV reactivation in the clinic, with sera containing antibodies reactive 4. E. Maffini et al., Expert Rev. Hematol. 9, 585 (2016).
unlike in mice, can occur in the absence of to other strains. If confirmed in the clinic, 5. J. P. Martins et al., Science 363, 288 (2019).
GVHD. Plasma cells are thought to be some- generation of a collection of sera specific for 6. A. Huygens et al., Front. Immunol. 5, 552 (2014).
what radioresistant, but ATG is a mixture each CMV genotype may be useful for pas- 7. C. L. Gordon et al., J. Exp. Med. 214, 651 (2017).
of polyclonal antibodies, some of which can sive antibody therapy in the future. 8. M. Cobbold et al., J. Exp. Med. 202, 379 (2005).
target B cells and plasma cells (9), and CD52 9. M. S.Zand et al., Transplantation 79, 1507 (2005).
is expressed on both T and B cells. HSCT An additional point to consider is how 10. E. Corre et al., Haematologica 95, 1025 (2010).
recipients have been reported to experience antibodies may work to prevent reactiva- 11. P. Raanani et al., J. Clin. Oncol. 27, 770 (2009).
prolonged B cell depletion (10) and might 12. C. Smith et al., J.Virol. 90, 7497 (2016).
13. P. R. Krause et al., Vaccine 32, 4 (2013).

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INSIGHTS

POLICY FORUM Direct-to-consumer marketing
of neurotechnologies is on the rise.
SCIENCE AND REGULATION Downloaded from http://science.sciencemag.org/ on January 17, 2019
gains from brain-training games are gener-
Oversight of direct-to- alizable (3), and whether the behavioral ef-
consumer neurotechnologies fects of EEG neurofeedback (4) and mental
health apps (5) are due to placebo.
Efficacy of products is far from clear
tDCS devices present the possibility of
By Anna Wexler1 and Peter B. Reiner2 UNCLEAR EFFICACY, POTENTIAL HARMS overt harms such as skin burns, which are PHOTO: FRANTIC00/SHUTTERSTOCK
These products are neurotechnologies inso- reported by a small portion of users (6).
M arketed for the purpose of modu- far as they appeal to the fruits of the brain Also worth mentioning are the potential
lating cognition or a variety of and cognitive sciences; indeed, the impri- psychological harms from DTC neurotech-
affective and mental states, a grow- matur of science is often an integral part nologies. For example, many consumer
ing ecosystem of neurotechnology of their marketing. One overarching issue EEG devices purport to “read” one’s emo-
products is being sold direct to is whether DTC neurotechnologies work as tional state (e.g., as stressed, meditative, or
consumers (DTC) without necessi- advertised. The problem is threefold. First, focused). Yet these devices have not been
tating the physician as intermediary. Offer- many companies have conducted little to independently validated and may provide
ing individuals the prospect of monitoring no original research on the effectiveness false information. If a consumer EEG device
and manipulating a range of brain func- of their products. Second, many DTC neu- erroneously shows that an individual is in
tions from memory to mental health, the rotechnology companies sell products that a stressed state, this may cause him or her
major product categories are neuromoni- are loosely based on scientific research, to become stressed or to enact this stressed
toring devices, cognitive training applica- yet it is unclear whether data gathered in state, resulting in unwarranted psychologi-
tions, neurostimulation devices, and mental the laboratory are applicable to consumer- cal harm (7). Individuals may learn from a
health apps. The market for these products grade products. For example, consumer smartphone app that they have symptoms
is predicted to top $3 billion by 2020 (1). Yet electroencephalography (EEG) devices are of depression—yet the diagnosis is provided
there are good reasons to conclude that reg- designed differently from research-grade without support structures that exist within
ulatory oversight of DTC neurotechnologies EEG devices (e.g., they employ fewer elec- the medical realm, such as a psychologist or
is insufficient. We suggest ways to provide trodes) and are used in different ways (e.g., mental health counselor.
systematic support for regulatory agencies, they require the individual himself or her-
funding bodies, and a public that is thirsty self, not a trained technician, to position PUBLIC UNDERSTANDING AND ETHICS
for knowledge about the efficacy of DTC the EEG headset). Third, in many domains It is difficult for the public to assess the
neurotechnology products. of DTC neurotechnology, there is a lack of validity of claims made by DTC neurotech-
scientific consensus with regard to efficacy: nology companies. Even those who are
1Department of Medical Ethics and Health Policy, Perelman Questions have been raised about whether interested in developments in neurotech-
School of Medicine, University of Pennsylvania, Philadelphia, devices that deliver transcranial direct cur- nology see navigating product claims as a
PA, USA. 2Department of Psychiatry and the Neuroethics rent stimulation (tDCS) can improve cog- key concern in the brain fitness field (8). Re-
Collective, University of British Columbia, Vancouver, BC, nitive performance (2), whether cognitive search has found that the public is unsure
Canada. Email: [email protected] of which activities actually benefit their
cognition. More than a quarter of adults age
40 and older believe that the best way to
maintain or improve brain health is to play
so-called “brain games” like Lumosity, even
though there is little scientific evidence to
support this notion (9).

No single DTC neurotechnology has yet
demonstrated the kind of overwhelming
efficacy that would result in widespread
public adoption. However, if a new tech-
nology were to display the sort of efficacy
that the field aspires to, a host of ethical
concerns would arise. One common issue
brought forward by neuroethicists is dis-
tributive justice: To the extent that cog-
nitive ability influences socioeconomic
status, premium pricing of cognitive en-
hancers could serve to exacerbate exist-
ing inequality gaps. Moreover, cognitive
enhancement technologies hold particular
appeal for populations such as the elderly,
for whom cognitive decline is among the
most frightening of prospects. The popu-
larity of brain fitness software in the face
of unproven efficacy is a testament to the
appeal of this class of product.

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REGULATORY INSUFFICIENCIES WHAT SHOULD WE DO? public. Dissemination strategies would in- Downloaded from http://science.sciencemag.org/ on January 17, 2019
One might imagine that DTC neurotech- Looking to the realm of supplements for volve identifying and partnering with orga-
nologies would be classified as medical guidance can be instructive, even if it nizations such as the American Association
devices. But in much the same way that does not provide a clear pathway forward. of Retired Persons that are well positioned
dietary supplements can avoid being clas- DSHEA mandated the creation of the Na- to communicate with key consumer groups,
sified as drugs by refraining from making tional Institutes of Health (NIH) Office of as well as sharing information with media
claims about treating or diagnosing dis- Dietary Supplements, which conducts sci- outlets. The working group would serve
ease, so, too, do most DTC neurotechnolo- entific research on dietary supplements as a clearinghouse for regulatory agencies
gies avoid classification as medical devices and translates knowledge for the public and such as the FDA and FTC, third-party orga-
by limiting their claims to wellness (e.g., policy-makers. In addition, independent or- nizations that monitor advertising claims,
“optimizing focus”). Indeed, a recent guid- ganizations provide evaluations and seals of industry, social and medical scientists,
ance from the U.S. Food and Drug Admin- approval for supplements (14). funding agencies, and the public at large.
istration (FDA) clarified that the agency
would not be enforcing medical device reg- In the realm of DTC neurotechnology, the We envision the working group, which
ulations for “low-isk” products marketed analogous needs are twofold: for additional would be housed independently or within a
for wellness purposes (10). This guidance research into the safety and effectiveness of reputable third-party organization, as draw-
suggested that tDCS products would fall products, as well as how they are used by ing on the expertise of scientists, health
within the agency’s jurisdiction, but the consumers; and for evaluations that can be professionals, consumer groups, industry
FDA has not taken public enforcement ac- made available to the public. representatives, ethicists, regulators, and
tion against consumer tDCS products. funders. The working group would survey
With regard to research, given that the the current landscape, incorporating new do-
Venture capitalists interested in financing DTC neurotechnology market is smaller mains of DTC neurotechnology and revising
neurotechnologies have publicly stated that it than that of supplements and the con- its appraisals. The group’s mandate would in-
would be difficult for them to invest in de- comitant public health risks are lower, we clude anticipating future developments, with
vices that require a premarket approval path do not suggest the creation of a dedicated an eye toward possible ethical concerns.
through the FDA (11). Although some com- NIH body at the present time. However,
panies, such as app developer Pear Thera- inasmuch as DTC neurotechnology can be Given that government agencies and
peutics, have pursued FDA approval, there is viewed as a downstream product of NIH- private enterprises are actively funding
incentive for companies to market products supported neuroscience research, we rec- research into new methods of modulating
for wellness to avoid FDA regulation. The ommend that the NIH consider specifically brain function, the present generation of
regulatory burden for DTC neurotechnolo- funding research on DTC neurotechnolo- DTC neurotechnologies may be only the
gies has largely fallen to the Federal Trade gies, potentially under the umbrella of neu- tip of the iceberg—making it all the more
Commission (FTC), which has authority to roethics research. imperative to create an independent body
take action in cases of deceptive advertis- to monitor developments in this domain. j
ing. Although the FTC has filed complaints As for evaluation, two approaches exist
against companies marketing brain-train- for mental health apps but none for the REFERENCES AND NOTES
ing software, there are thousands of mental remaining DTC neurotechnologies. At one
health apps on the market (12), as well as end of the spectrum, the nonprofit orga- 1. SharpBrains, Market Report on Pervasive
dozens of devices for cognitive enhance- nization Psyberguide provides consumer- Neurotechnology, (2018); https://sharpbrains.com/
ment, relaxation by entraining brain waves, oriented numerical ratings of individual pervasive-neurotechnology/.
improving motor function, and more. mental health apps based on factors that
include credibility, user experience, and 2. J. C. Horvath,J. D. Forte, O. Carter, Brain Stimul. 8, 535
The challenges of regulating DTC neuro- transparency; at the other end of the spec- (2015).
technologies are in many ways similar to trum, the American Psychiatric Association
those facing dietary supplements. In both developed a framework that gives psychia- 3. D.J. Simons et al., Psychol. Sci. Public Interest 17, 103
cases, the safety and efficacy of products trists (but not consumers) tools to evaluate (2016).
have not been well established, there are no the safety, efficacy, and veracity of mental
industry-wide standards, and the market health apps. 4. R.T.Thibault,A. Raz, Am. Psychol. 72, 679 (2017).
is flooded with companies advertising and 5. J.Torous,J. Firth, Lancet Psychiatry 3, 100 (2016).
selling products directly to consumers with We propose an approach that strikes a 6. A.Wexler, J. Cogn. Enhance 2, 114 (2018).
dubious health claims. In the United States, balance between the two: an independent 7. A.Wexler, R.Thibault, J. Cogn. Enhance. (2018); https://
supplements are regulated by the FDA via working group that would survey the main
the Dietary Supplement Health and Educa- domains of DTC neurotechnology and pro- doi.org/10.1007/s41465-018-0091-2.
tion Act (DSHEA) in a largely postmarket vide succinct appraisals of potential harms 8. SharpBrains,“The Digital Brain Health Market 2012–
approach (13). Just as federal regulatory and probable efficacy. Rather than evalu-
oversight from the FDA and FTC has been ating each and every product, which is 2020”(2016); https://sharpbrains.com/market-report/.
critiqued as being ill-suited to monitor the resource-intensive, or providing overarch- 9. L. Mehegan, C. Rainville, L. Skufca,“2017 AARP Cognitive
dietary supplement market (14), we suggest ing framing questions, the working group’s
that similar concerns exist for DTC neuro- appraisals would outline the evidence base Activity and Brain Health Survey”(AARP Research,
technologies: Given the sheer number of and potential risks and identify gaps in Washington, DC, 2017); https://doi.org/10.26419/
products, the dynamic nature of software current knowledge. Recent articles on the res.00044.001.
applications that can change with each home use of brain stimulation (15) and con- 10. Food and Drug Administration,“General Wellness: Policy
update, the flexibility required to oversee sumer EEG devices (7) provide guidance for Low Risk Devices”(2016), pp. 1–13.
them, and the potential ethical issues in- and critiques without evaluating individ- 11. J. Cavuoto, Regulatory Efficacy. Neurotech Business
volved, current regulatory oversight leaves ual devices or claims and could serve as a Report (2012); www.neurotechreports.com/pages/pub-
much to be desired. model for the working group’s appraisals. lishersletterOct12.html.
12. J. B.Torous et al., Psychiatr. Serv. 69, 498 (2018).
The working group would be tasked with 13. J. Dwyer, P. Coates, M. Smith, Nutrients 10, 41 (2018).
broadly circulating its appraisals to the 14. R. L. Bailey, Crit. Rev. Food Sci. Nutr. 39, 1 (2018).
15. R.Wurzman, R. H. Hamilton,A. Pascual-Leone, M. D. Fox,
Ann. Neurol. 80, 1 (2016).

ACKNOWLEDGMENTS

This paper is informed by a 2018 meeting at the Banbury
Center at Cold Spring Harbor that brought together regula-
tors, scholars, and representatives from various professional
organizations.A.W. acknowledges support from the Office of
the Director, NIH, under Award Number DP5OD026420. P.B.R.’s
funding derives from SSHRC grant 435-2018-0561.The content
is solely the responsibility of the authors and does not represent
the official views of funders.

10.1126/science.aav0223

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Offerings are prepared on the banks of the Ganges
River in Varanasi, Uttar Pradesh, India.

BOOKS et al. tal change melded together as ongoing pro-
cesses. The approach, like the Ganges’s very
ENVIRONMENTAL STUDIES name, favors dynamism over stasis; Sen Downloaded from http://science.sciencemag.org/ on January 18, 2019
notes that the Sanskrit root of Ganges, gam
The revealing history of a (“to go”), invites us to study the river through
revered waterway prisms of motion, flow, direction, and force.

Human and environmental stories interweave in From pilgrimage and myth, the book moves
a meandering meditation on the Ganges River through the heavily contested archaeological
quest to find and discern the river’s material
By Anne Rademacher we gain a clearer perspective on the river’s past. That quest guides the reader along the
vast tendrils of settled agriculture, reaching
present and potential futures. back nearly 15,000 years. We are led to reen-
vision the many lakes, marshes, forests, and
I nvoking the Ganges prompts two very Sen begins this history with the ancient grasslands that preceded the Ganges’s pres-
different visions. One imagines a sa- and enduring human practice of pilgrim- ent agrarian mosaic, in part through descrip-
cred destination for countless devout age. Recounting his own journey from Gan- tions from the Matsya Purana, a collection of
pilgrims and the site of rituals repeated gotri, where the Ganges begins its descent, texts that date between the 8th and 13th cen-
for thousands of years. Another sees to the river’s source at Gaumukh glacier, he turies. These accounts bring lush past land-
scapes, which today are all but lost, back to
a heavily polluted repository for the asks how it is that this single river came to conceptual life so that habitat transformation
made less discernable in spans of centuries
sewage and industrial wastes be imbued with sacred impor- now leaves a more vivid trace.

of dozens of Indian cities and tance—nothing short, he writes, Sen narrates the dramatic reworking of
the plant and animal world in part by trac-
yet water source for half a bil- of a “metaphysical threshold.” ing equally dramatic social transformation.
With settled agriculture came land owner-
lion people. In this dual vision, He begins to explore this ques- ship and taxation patterns, crop distribution
mosaics, and consequent trade patterns that
the Ganges seems to embody tion through the long and dy- remade the riverscape and its social compo-
sition. The Ganges and the kingdoms and
the disjuncture of our time: It is namic history of myths, which cities that rose around it organized spiritual
and political identity, legitimizing successive
both a dying piece of the planet narrate the river’s powerful cen- imperial projects whose armies, merchants,
artisans, and new religious practices carved
and an enduring natural symbol trality in both spiritual cosmol- and recarved territorial claims.

of life and absolution. Ganges ogy and the political imagination. Late in the book, Sen arrives at the pe-
Sudipta Sen’s Ganges: The Sudipta Sen Although the details of the many riod of European empire building, the time
Yale University Press, myths Sen recounts changed over at which more conventional histories of the
Many Pasts of an Indian River 2019. 459 pp. centuries, their core associations present-day Ganges begin. With the benefit
invites its reader across the with a feminine form of divinity of a fuller historical arc, we understand more
space and time of this iconic riv- clearly how and why the Ganges was central
to the Victorian imperial imagination and
erscape. Through a sweeping yet carefully reproduced the river as both a sacred center why the lower Ganges plains and the Ben- PHOTO: ISTOCK.COM/USER3A14F790_939
gal delta formed the heart of the East India
textured history, the layers of the Ganges’s and a symbolic locus of political legitimacy. Company’s imperial territories in India. It
also underscores why countless postcolonial
past assume a life that is both consequen- Ganges is neither social nor environmental leaders have repeatedly invoked its place, as
Sen recounts using Nehru’s words, as “a sym-
tial and contemporary. We come to un- history; it is inseparably both. Sen challenges bol and a memory of the past of India.”

derstand the Ganges as an expansive and us to notice the myriad ways that social and Ganges is a study of a river as many si-
multaneous places, temporalities, and expe-
dynamic social and natural system, and environmental transformation on this river- riences. It offers a way of thinking about a
river not only as it flows over a landscape
scape produced one another, often without a but as it assembles and connects aesthetics,
territories, habitats, and human beings. In
The reviewer is in the Department of Environmental Studies clearly linear story of cause and effect. Rather this sense, the book is an invitation to think
and the Department of Anthropology, New York University, than composing an explanatory history, then, about all environmental history not only as
New York, NY 10003, USA. Email: [email protected] he emphasizes how social and environmen- a story of a changing natural world but also
as a story about ourselves. j

10.1126/science.aav8514

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INSIGHTS

NUCLEAR POLICY

Nuclear power and promise

Deference to industry trumps safety in the U.S., warns a controversial former regulator

By Jacob Darwin Hamblin Reid fighting the project to store the nation’s tions. Recounting an episode in which he
tried to abolish enforcement discretion in
high-level radioactive waste at Yucca Moun- fire safety, Jaczko writes: “What happened
over the next several weeks was more brutal
L ess than a year after the Fukushima tain. He had a notoriously abrasive personal- than Roman imperial succession.”
nuclear accident in Japan, physicist ity, and that did not change while at the NRC.
Gregory B. Jaczko tried to break the The political infighting was particularly
“first commandment” of nuclear regu- Yucca Mountain set the tone for Jaczko’s intense after the 2011 Fukushima disaster.
lation: Thou shalt not deny a license to tenure, and his autocratic leadership style Jaczko visited Japan and grew impatient
alienated Republicans and Democrats alike. with the “litany of guarantees” from industry
about American nuclear facilities. He tried to
operate a reactor. As chairman of the When he terminated a licensing review for insist on new requirements to mitigate acci-
dents triggered by natural disasters such as
U.S. Nuclear Regulatory Commission (NRC), the storage project, the other commissioners floods, earthquakes, and tsunamis. One in-
ternal NRC report drafted after Fukushima
he knew that the tradition was to encourage interpreted it as an illegal abuse of authority. criticized the practice of relying on voluntary
industry initiative to address safety concerns.
doomed applications to be withdrawn. But The ensuing political fracas convinced Jacz- Jaczko’s descriptions of other commission-
ers’ attempts to quash or edit the report pro-
when one company refused, Jacz- ko that the nuclear industry used vide a disturbing glimpse of the dynamic of Downloaded from http://science.sciencemag.org/ on January 17, 2019
trust and betrayal within the agency.
ko dug in his heels and opposed the NRC as a tool for promoting
Confessions comes across as a story of one
the license. It turned out to be a rather than regulating nuclear man and his loyal staff against a whole indus-
try and its political toadies. Jaczko portrays
futile gesture that the other com- power. He believes that a national himself as a naïve scientist, pushing hard for
progressive reforms amid a corrupt bureau-
missioners opposed. But it was repository for radioactive waste cracy. His critics might not be persuaded.

one of many examples, he con- puts too much responsibility on Toward the end of his tenure, Jaczko’s
fellow commissioners lodged a formal com-
tends, of the weaknesses in the na- the taxpayer. “No other industry plaint against him, including accusations of
mistreatment of women in the workplace.
tion’s top nuclear regulatory body is able to complain so loudly that He survived the coup (his term) but ulti-
mately resigned in 2012 at the request of his
and an exemplar of its obeisance Confessions of someone else has failed to take old mentor Harry Reid, who wanted to use
to the nuclear power industry. a Rogue Nuclear care of its waste,” he laments. his position as a political bargaining chip.

Confessions of a Rogue Nuclear Regulator The answer is to stop produc- Although Jaczko’s account will become
Regulator is one part engrossing Gregory B. Jaczko ing nuclear waste, argues Jaczko, standard reading as an antinuclear book, his
memoir and another part seeth- Simon and Schuster, and indeed stop producing nu- reasons have more to do with regulation than
ing diatribe, depicting a govern- clear power at all. He wishes that nuclear energy per se. Jaczko sees two paths
ment agency that routinely caves 2019. 207 pp. as chairman, he’d “had the cour- ahead. One has a sustainable future with
nuclear reactors that includes widespread
to industry pressure. The book cannot help age to say this, but my courage had its limits.” recognition that accidents will happen and a
greater commitment to safety. The other path
but also feel like a rationalization of Jacz- Most of Jaczko’s short book hammers on is the one he witnessed as NRC chairman,
featuring waning public trust in a secretive,
ko’s own actions during his conflict-ridden the theme that industry lobbyists hold sway uncooperative industry that regards safety
regulations as unfair and cumbersome.
tenure as chairman, a position offered to over the would-be regulators. He highlights
The problem that plagued the old Atomic
him in 2009 by President Barack Obama. the longstanding concept of “enforcement Energy Commission—that the promoters and
regulators were too cozy with each other—is
Jaczko first came to the commission in discretion” and skewers it as one of nuclear clearly alive and well. Jaczko describes the re-
lationship as a “corrupt, toxic environment.”
2005, after working for Nevada senator Harry regulation’s “greatest oxymorons.” It may be a hard warning to hear, but it comes
from one who had a fuller view of the nuclear
Rather than demand safety compliance, regulatory landscape than most. j

The reviewer is at the School of History, Philosophy, the NRC historically has allowed nuclear
and Religion, Oregon State University, Corvallis, OR 97331, plants to develop alternative approaches
USA. Email: [email protected] and has granted exceptions and exemp-

PHOTO: ALEX WONG/GETTY IMAGES Gregory Jaczko prepares to testify at a Senate hearing on nuclear reactor safety on 15 December 2011. 10.1126/science.aav8854

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INSIGHTS

LETTERS Since 2016, when this photo was taken, Downloaded from http://science.sciencemag.org/ on January 17, 2019
much of Kulhudhuffushi island’s small
mangrove patch has been destroyed.

PHOTO: EYEWELL PORTRAIT Edited by Jennifer Sills The loss of relatively small patches for Environment and Development (LESTARI),
of mangrove may seem less concerning Universiti Kebangsaan Malaysia, 43600 Bangi,
The value of small than large-scale deforestation. However, Selangor, Malaysia. 4University of Glasgow, School
mangrove patches these patches are especially important of Geographical and Earth Sciences, Glasgow G12
to low-lying island nations vulnerable to 8QQ, UK. 5Department of Economics and School of
Mangroves provide crucial services to climate change and sea-level rise (1). Their Global Environmental Sustainability, Colorado State
humanity, including food, coastal pro- interconnectedness with adjacent habitats, University, Fort Collins, CO 80523, USA. 6Silvestrum
tection, fisheries support, and carbon such as coral reefs, allows them to provide Climate Associates, San Francisco, CA 94103, USA.
sequestration (1). However, up to 35% of substantial ecosystem services relative to 7Systems Ecology and Resource Management,
mangrove area has been lost since the their size (9). The continued loss of man- Université Libre de Bruxelles, B-1050 Brussels,
1980s, primarily due to coastal develop- grove patches further fragments mangrove Belgium. 8Department of Ecology and Biodiversity,
ment (2). Mangroves are protected under habitat, which creates barriers to species Vrije Universiteit Brussel, B-1050 Brussels, Belgium.
a plethora of international agreements, movement and dispersal (10). The loss also 9Conservation Programmes, Zoological Society
and they are key to meeting commitments drastically erodes local coastal resilience of London, Regents Park, London NW1 4RY, UK.
of the Paris Climate Agreement and miti- and pushes key mangrove ecosystems 10Department of Geography, National University of
gating the impacts of a changing climate toward collapse. Singapore, Singapore 117570, Singapore. 11Mangrove
on coastal communities (3). Despite Action Project, Seattle, WA 98104, USA. 12Leibniz
warnings about the ramifications of losing Given the recent Intergovernmental Centre for Tropical Marine Research, ZMT-GmbH,
mangroves (4), conversion and degrada- Panel on Climate Change’s projections (11), Bremen, Germany. 13School of Life Sciences and
tion still occur (5), especially for smaller we simply cannot afford to lose more man- Earth System Science Programme, The Chinese
mangrove patches. grove forests, irrespective of their size. We University of Hong Kong, Shatin, New Territories,
call on governments to move away from Hong Kong SAR, China.
The global disdain for small mangrove policy decisions that prioritize large areas *Corresponding author. Email: [email protected]
patches is exemplified by the 2017 decision and short-term local political gains and
by the Maldivian government to construct instead adopt a more holistic long-term REFERENCES
a new local airport on the regionally vision (12), whereby the value of smaller
significant mangrove patch (12 ha) on mangrove patches is better appreciated 1. S.Y. Lee et al., Glob. Ecol. Biogeogr. 23, 726 (2014).
Kulhudhuffushi island (6). This decision and safeguarded. 2. B.A. Polidoro et al., PLOS ONE 5, 10.1371/journal.
was made despite the socioeconomic
importance of the mangrove to the local David J. Curnick1,2, Nathalie Pettorelli1,2, pone.0010095 (2010).
community, the viable alternative solutions A. Aldrie Amir1,3, Thorsten Balke1,4, 3. P.Taillardat, D.A. Friess, M. Lupascu, Biol. Lett. 14,
that were identified (6), the island’s high Edward B. Barbier1,5, Stephen Crooks1,6,
risk for cyclones and tsunamis (6), and the Farid Dahdouh-Guebas1,7,8, 20180251 (2018).
substantial funding the Maldives received Clare Duncan1,2, Charlie Endsor1,9, 4. N. C. Duke et al., Science 317, 41 (2007).
for climate change mitigation and adapta- Daniel A. Friess1,10, Alfredo Quarto1,11, 5. S. E. Hamilton, D. Casey, Glob. Ecol. Biogeogr. 25,
tion [e.g., (7)]. Despite assurances that only Martin Zimmer1,12, Shing Yip Lee1,13
30% of the mangrove would be directly 729 (2016).
affected by this project, nearly 70% may 1Mangrove Specialist Group, International 6. Z. Hameed,“Environmental Impact Assessment
have already been destroyed (8). Union for the Conservation of Nature (IUCN),
Conservation Programmes, Zoological Society for the airport development project at Haa Dhaal
of London, Regents Park, London NW1 4RY, UK. Kulhudhuffushi” (2017).
2Zoological Society of London, Institute of Zoology, 7. Green Climate Fund (2018); www.mv.undp.org/content/
Regents Park, London NW1 4RY, UK. 3Institute maldives/en/home/operations/projects/environment_
and_energy/GreenClimateFund.html.
SCIENCE sciencemag.org 8. Transparency Maldives (2018);
http://transparency.mv/2018/09/
joint-press-statement-we-call-on-the-authorities-to-
ensure-the-protection-of-the-kulhudhuffushi-mangrove/.
9. E. B. Barbier, in Seascape Ecology, S.J. Pitmann, Ed.
(Wiley-Blackwell, NY, 2017), pp. 465–481.
10. L.Triest, Aquat. Bot. 89, 138 (2008).
11. O. Hoegh-Guldberg et al., in“Global warming of 1.5°C,” V.
Masson-Delmotte et al., Eds. (2018); www.ipcc.ch/sr15/.
12. A.A.Amir, Science 359, 1342 (2018).

10.1126/science.aaw0809

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INSIGHTS | LETTERS

Brazil’s endangered 7. E.A. Oliveira et al., Scientometrics 90, 429 (2011). they regularly raise, should model respon- Downloaded from http://science.sciencemag.org/ on January 17, 2019
8. Coordenação de Aperfeiçoamento de Pessoal de Nível sible behavior to the planet. To encourage
postgraduate system low-impact mobility, scientific institutions PHOTO: ISTOCK.COM/GUVENDEMIR
Superior (CAPES), Ministério da Educação,“Avaliação should adopt an avoid-mitigate-compensate
Over the past decade, Brazilian scientists quadrienal em números”(2017); www.ucs.br/site/ approach similar to that developed in eco-
have faced a dramatic reduction in finan- midia/arquivos/Avalia%C3%A7%C3%A3o_Quadrienal_ system conservation (6).
cial support (1–3). In 2017, the Ministry em_n%C3%BAmeros.pdf [in Portuguese].
of Science and Technology had a budget 9. Coordenação de Aperfeiçoamento de Pessoal de Nível To avoid unnecessary journeys, institu-
of only 2.8 billion reais, the equivalent of Superior (CAPES), Plano nacional de pós-graduação tions, department heads, and principal
US$700 million (4), the lowest in the past (PNPG) 2011-2020 (2010); www.capes.gov.br/plano- investigators should encourage scientists
14 years (5). Dwindling funding affects nacional-de-pos-graduacao [in Portuguese]. to consider or provide alternatives, such
a crucial population in Brazil’s scientific 10. Coordination for the Improvement of Higher Education as teleconferencing and virtual scientific
system: students working toward master’s Personnel (CAPES),“Budget—Evolution in Reais”(2018); conferences. To mitigate emissions result-
and Ph.D. degrees. www.capes.gov.br/orcamento-evolucao-em-reais ing from travel, scientists who must travel
[in Portuguese]. should replace flights with cleaner modes
Brazil’s postgraduate system plays a piv- 11. A. C. Moreno,“Quase 200 mil bolsistas da Capes of travel as much as possible. Participants
otal role in scientific output. A major portion podem ficar sem bolsa se orçamento de 2019 should prioritize local meetings, and orga-
of scientific research takes place in publicly sofrer corte,diz conselho,”globo.com (2018); https:// nizers should reduce distances traveled by
funded universities, and most scientific g1.globo.com/educacao/noticia/2018/08/02/ choosing central locations. To compensate
publications are driven by postgraduate pro- quase-200-mil-podem-ficar-sem-bolsa-se-orcamento- for travel, scientists should financially
grams (6, 7). Brazil’s 6303 master’s and Ph.D. de-2019-sofrer-corte-diz-conselho-da-capes.ghtml contribute to credible and traceable
programs (8) are primarily funded by the [in Portuguese]. projects for reducing and removing carbon
Coordination for the Improvement of Higher emissions. This should be the last resort,
Education Personnel (CAPES), a governmen- 10.1126/science.aav9015 given the questionable effectiveness of
tal agency within the Ministry of Education carbon offsetting (7).
(9). The CAPES budget has plunged from the Airborne in the era of
equivalent of US$1.9 billion in 2015 to the climate change There is increasing discussion about
equivalent of US$1 billion in 2018 (10). The the best way to evaluate scientists, teams,
budget for 2019 projects an additional cut of The Intergovernmental Panel on Climate and research projects (8), and including a
nearly 40% (11). The funding cuts will likely Change (IPCC) recently released its special carbon sobriety criterion could be a good
translate into a substantial drop in federal report on limiting global warming to way to reduce scientists’ carbon footprint.
grants, postdoctoral fellowships, support for 1.5°C (1). The IPCC’s 2050 target of carbon Individual involvement is crucial, but sup-
international collaborations, and student neutrality is strongly challenged by sec- portive institutional environments [e.g.,
scholarships. As student support falls, scien- tors with unavoidable emissions, such as (9)] are also required to incentivize carbon-
tific output will likely decrease as well. aviation. Forecasts of the sector’s growth neutral behavior at the scale and speed
predict that by 2050 it could have con- required. Institutions invariably have policies
Brazil’s scientific enterprise cannot func- sumed up to one-quarter of the total global for preventing and reducing harm, which
tion without qualified human resources, carbon budget for 1.5°C (2). The absence address problems such as physical safety and
who will in turn strengthen social and of substantial technical gains in aircraft data security. Surely the protection of plan-
economic development. Despite the polar- emissions implies that reduction of avia- etary health, through the dramatic carbon
ized political atmosphere, Brazil must tion impact will be unfeasible without a cuts that are now urgently required, has a
implement a strategic plan to improve the decrease in demand (3). Air travel contrib- place in institutional policy, too.
quality of science and innovation by invest- utes substantially to the carbon footprint
ing in the postgraduate system. of academic communities (4), despite calls Kévin Jean1,2* and Chris Wymant3
to travel less (5). In the current academic
Hercílio Martelli Júnior1,2, Daniella R. system, avoiding flying means accepting 1Laboratoire MESuRS, Conservatoire National des
trade-offs, such as greater challenges to Arts et Métiers, Paris, France. 2Unité PACRI, Institut
Martelli1, Ana Cristina Simões e Silva2,3, collaboration and networking. However, Pasteur, Conservatoire National des Arts et Métiers,
the cost of inaction and business as usual Paris, France. 3Big Data Institute, Li Ka Shing Centre
Maria Christina L. Oliveira3,4, is the growing global threat of climate for Health Information and Discovery, Nuffield
change, and scientists, given the alarms Department of Medicine, University of Oxford,
Eduardo A. Oliveira3,4* Oxford, UK.
Air travel accounts for much of the science *Corresponding author. Email: [email protected]
1Health Science/Primary Care Postgraduate community’s carbon footprint.
Program, State University of Montes Claros REFERENCES
(Unimontes), Montes Claros, MG 39401-089, Brazil.
2Interdisciplinary Programs, CAPES, Brasília, DF 1. “Global warming of 1.5°C,” V. Masson-Delmotte et al., Eds.
70.040-031, Brazil. 3Health Sciences Postgraduate (2018); www.ipcc.ch/sr15/.
Program, School of Medicine, Federal University of
Minas Gerais (UFMG), Belo Horizonte, MG 30130- 2. “Analysis:Aviation could consume a quarter of 1.5C carbon
100, Brazil. 4University of California, San Diego, La budget by 2050,”Carbon Brief (2016); www.carbonbrief.
Jolla, CA 92093–0630, USA. org/aviation-consume-quarter-carbon-budget.
*Corresponding author.
Email: [email protected] 3. A. Macintosh, L.Wallace, Energ. Pol. 37, 264 (2009).
4. A. Stohl, Atmos. Chem. Phys. 8, 6499 (2008).
REFERENCES 5. X.Anglaret, Lancet Planet Health 2, e382 (2018).
6. “An integrated framework and guidelines for avoiding, miti-
1. E. Gibney, Nature 526, 16 (2015).
2. C.Angelo, Nature 533, 19 (2016). gating, and compensating for wetland losses: Resolution
3. F. Marquez,“Funding in crisis,”Revista Pesquisa FAPESP XI.9”(Ramsar Convention, 2012); www.ramsar.org/sites/
default/files/documents/library/cop11-
256, 1 (2017). res09-e.pdf.
4. C.Angelo, Nature 10.1038/nature.2017.21766 (2017). 7. K. Hyams,T. Fawcett, Wiley Interdisc. Rev.: Clim. Change 4,
5. Ministério da Ciência,Tecnologia, Inovações e 91 (2013).
8. D. Moher et al., PLOS Biol. 16, e2004089 (2018).
Comunicações, Recursos Aplicados—Governo Federal 9. Tyndall Centre,“Tyndall Travel Strategy—Towards a culture
(2018); www.mctic.gov.br/mctic/opencms/indicadores/ of low carbon research for the 21st Century”(2014);
detalhe/recursos_aplicados/governo_federal/2_2_4. https://tyndall.ac.uk/travel-strategy.
html [in Portuguese].
6. A. F. Helene, P. L. Ribeiro, Scientometrics 89, 677 (2011). 10.1126/science.aaw1145

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RESEARCH Presenting a nanosecond-
excited iron complex

Kjær et al., p. 249

IN SCIENCE JOURNALS
Edited by Stella Hurtley

BIODIVERSITY

Ancestral history matters

B iodiversity is sometimes quantified
purely by the number of species within
a system that allow it to function to
produce ecosystem services. Grab et
al. show that simple species counting
is too simplistic. They combined remotely
sensed land-cover analyses and crop pro-
duction records with an extensive 10-year
pollinator community survey and a com-
plete species-level phylogeny generated
using genome-wide phylogenomic methods.
They found that the equivalent of millions
of years of pollinator evolution were lost in
highly altered agricultural environments,
which decreased pollination services above
and beyond what would be expected from
a simple numerical species count. —SNV

Science, this issue p. 282

Mining bee (Andrena nasonii)
on an apple (Malus pumila) flower

(PHOTO) KENT LOEFFLER; GRAPHIC) KJAER ET AL. IMPACT CRATERS over this period, implying that Schuller et al. solved a cryo– al. show that for the lead-iodine
terrestrial erosion affects all electron microscopy structure system, the introduction of the
Impact rates on Earth craters equally, regardless of of photosynthetic complex I rare earth europium ion pair
and the Moon their size. —KTS (see the Perspective by Brandt) Eu3+-Eu2+ can shuttle electrons
and went on to reconstitute and recover lead and iodine ions
The rate at which impacts Science, this issue p. 253; electron transfer using the elec- (Pb2+ and I−). Devices incorporat-
produce craters on the Moon is see also p. 224 tron carrier protein ferredoxin. ing this redox shuttle maintained
used to calibrate ages in plan- —MAF more than 90% of their initial
etary science. Earth should also PHOTOSYNTHESIS power conversion efficiencies
have received similar numbers Science, this issue p. 257; under various aging conditions.
of impacts, but many craters Plugging into the pump see also p. 230 —PDS
have been hidden by erosion,
ice sheets, and so on. Mazrouei Photosynthetic organisms use SOLAR CELLS Science, this issue p. 265
et al. used infrared images of light to fix carbon dioxide in
the Moon to estimate the ages a process that requires both A redox road to recovery NEUROSCIENCE
of young lunar craters (see chemical reducing equivalents
the Perspective by Koeberl). and adenosine triphosphate Device longevity is a key issue The emotional
They found that the impact (ATP). Balancing the ratio of for organic-inorganic perovskite dimension of pain
rate increased within the past these inputs is accomplished solar cells. Encapsulation can
~500 million years, a conclusion by a short circuit in electron limit degradation arising from The unpleasantness of pain is an
strengthened by an analysis of flow through photosynthetic reactions with oxygen and water, emotional phenomenon distinct
known impact craters on Earth. complex I, a proton pump that but light, electric-field, and from pain’s sensory qualities. To
Crater size distributions are the contributes to ATP produc- thermal stresses can lead to study how the brain processes
same on Earth and the Moon tion but does not increase net metastable elemental lead and pain-related emotions, Corder
reducing equivalents in the cell. halide atom defects. Wang et

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et al. used in vivo neural calcium Such a therapeutic strategy IN OTHER JOURNAL S Edited by Caroline Ash
imaging in freely behaving mice. would avoid some limitations and Jesse Smith
They identified brain circuits of cellular therapies for BMT
that respond to pain and directly patients. —STS M E TA L L O P R O T E I N S PREGNANCY PHOTO: CLAUDIO GIOVANNI COLOMBO/ALAMY STOCK PHOTO
tested their causal role in moti-
vational behaviors associated Science, this issue p. 288; A lanthanide secret Understanding
with acute and chronic pain. see also p. 232 handshake preeclampsia
—PRS
FIBROSIS Most metal ions in biology Preeclampsia is character-
Science, this issue p. 276 have distinct properties ized by the development of
When cell adhesion determined by atomic hypertension and kidney
CILIA promotes fibrosis number and oxidation state. dysfunction during late stages
However, some metals of pregnancy, and it is an
Assembly of the ciliary Inflammatory macrophages in the lower rows of the important cause of maternal
microtubule doublet produce the cytokine trans- periodic table are notorious and fetal mortality. Quitterer
forming growth factor–b for mimicking their lighter et al. found that increased
The cilium is a conserved (TGF-b), which induces the cousins: Trivalent yttrium complex formation between
organelle that is crucial for activation of fibroblasts into and lanthanides, for example, the G protein–coupled recep-
motility as well as for sensing myofibroblasts that secrete can replace divalent calcium tors angiotensin II AT1 and
the extracellular environment. extracellular matrix and ions in some proteins. Cook bradykinin B2 in vascular
Its core structure is charac- promote fibrosis. Lodyga et et al. determined the solu- smooth muscle cells triggered
terized by nine microtubule al. found that the adhesion tion structure of a protein preeclampsia in pregnant mice.
doublets (MTDs). The mecha- protein cadherin-11 (CDH11) that has evolved exquisite Evidence for the hyperactivity
nisms of MTD assembly are was enriched at contact points selectivity for these heavier of this heterodimer was also
unclear. Schmidt-Cernohorska between macrophages and ions over the lighter calcium. found in vascular structures in
et al. developed an assay to myofibroblasts in fibrotic lung Despite superficial similar- samples of placenta from preg-
reconstitute MTD assembly in tissues from mice and human ity to the calcium-binding nancies that had preeclampsia.
vitro. Tubulin carboxyl-terminal patients. CDH11-mediated protein calmodulin, there Using a small-molecule
tails played a critical inhibi- adhesion between macro- are large differences in the inhibitor to target AT1-B2
tory role in MTD formation. phages and lung fibroblasts overall protein structure, receptor signaling prevented
Molecular dynamics revealed triggered the activation of fibro- and an additional carboxylic preeclampsia in mice. Initial
that carboxyl-terminal tails of blasts into myofibroblasts and acid ligand is likely crucial data in patients with symptoms
the A11 microtubule protofila- targeted macrophage-produced for recognition of the heavier of preeclampsia indicate that
ment regulated MTD initiation. TGF-b to myofibroblasts, creat- ions. —MAF this is an avenue for treatment
Furthermore, live-cell imaging ing a self-sustaining profibrotic options. —GKA
showed an unexpected bidirec- niche. —AV Biochemistry 10.1021/acs.
tional isotropic elongation of the Cell 176, 318 (2019).
MTD. —SMH Sci. Signal. 12, eaao3469 (2019). biochem.8b01019 (2018).

Science, this issue p. 285 TUMOR IMMUNOLOGY

IMMUNOTHERAPY Neoantigen reactivity

Serotherapy treats a Increased frequencies of intra-
transplant hurdle tumoral CD4+ regulatory T cells
(Tregs) have typically been asso-
Cytomegalovirus (CMV) ciated with more-rapid tumor
infection and reactivation are progression, but the antigen
common and potentially fatal specificity of these Tregs within
complications after bone mar- tumors is not well understood.
row or hematopoietic stem cell Ahmadzadeh et al. character-
transplantation (BMT). Martins ized the T cell receptor (TCR)
et al. developed faithful pre- repertoire of intratumoral Tregs
clinical murine models of CMV from patients with metastatic
reactivation following BMT and melanoma, gastrointestinal,
found that humoral immunity and ovarian cancers. These
can prevent this process (see Tregs had a unique TCR rep-
the Perspective by Alegre). After ertoire different from other
BMT, antiviral antibodies that intratumoral CD4+ T cells, and
would have kept CMV at bay dominant TCRs were specific
dwindle because host plasma to tumors and neoantigens.
cells are ablated and the donor Similar cells were also found in
B cell pool reconstitutes poorly. the periphery, indicating that
CMV reactivation was prevented these Tregs may be expanding
by transferring antibody- from both compartments.
containing immune serum. —CNF

Sci. Immunol. 4, eaao4310 (2019).

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BIOGEOGRAPHY

Pathogens at the limits

T he factors controlling the geographical distribution of organisms are receiving
increasing attention in the context of climate change. Bruns et al. analyze the effects
of a different, little-studied factor—the role of disease in limiting the range of species.
In alpine plants in northwest Italy, they found that a pollinator-transmitted fungus that
causes sterilizing anther-smut infections in meadow flowers occurred throughout
the plant’s range. Reduced population densities of these plants at their range limits does not
affect the distribution of the insect-borne pathogen. Indeed, disease incidence was often
higher at the range limit, perhaps curtailing the plant’s distribution. These findings suggest
that the role of pathogens should receive more attention in biogeographical analysis. —AMS

J. Ecol. 107, 1 (2019). Sexually transmitted disease limits the distribution of
European alpine meadow flower populations.

GRAPHIC: H. ABACI ET AL., NAT. COMMUN. 2018) PHYSICS BIOTECHNOLOGY (C–H) bonds. The weakest among The generation and function of
them are easy to transform selec- hair follicles also requires spatial
Dynamics of repulsive Precision CRISPR editing tively, but the stronger ones tend arrangement of skin cells and
Fermi gases to be hard to discriminate. Zhao extracellular matrix, which has
The most popular gene-editing et al. report a manganese catalyst been difficult to reproduce in vitro.
Pump-probe techniques, tool, CRISPR-Cas9, generates that can selectively oxidize To address this challenge, Abaci
in which a short light pulse breaks in the genome that are CH2 centers in the presence of et al. used three-dimensional (3D)
knocks the system out of subsequently repaired by a mix of aromatic C–H bonds. The catalyst printing technology to generate
equilibrium and another pulse cellular pathways. Yet, the repair activates hydrogen peroxide with hair follicle–like microwells in a
is then used to monitor the outcomes are not random. Using the help of chloroacetic acid, three-dimensionally reconstructed
dynamics, are commonplace machine-learning algorithms to and despite targeting strong dermis. This allowed them to
in solid-state physics. Amico analyze large amounts of Cas9- C–H bonds, it tolerates halogen, arrange human cells critical for
et al. used such a technique mediated, genome-wide editing oxygen, and nitrogen functional- hair growth into a physiologically
in a fermionic atomic gas to events in a range of cells, Shen et ity. The protocol is demonstrated relevant configuration. Grafting of
study what happens when the al., Allen et al., and Chakrabarti et across a variety of pharmaceuti- vascularized versions of these skin
gas is plunged into a regime al. uncovered sequence deter- cally relevant compounds. —JSY constructs onto mice resulted in
where the atoms strongly minants of repair outcomes and the growth of human hair. —PAK
repel one another. The nature devised rules to predict editing Nat. Chem. 10.1038/s41557-018-
of this regime in an even products. These findings provide 0175-8 (2018). Nat. Commun. 9, 5301 (2018).
mixture of two spin states has insights into the repair process
been debated—a ferromag- and instruct the design of guide BIOMEDICINE 3D-printed template used to create
netic state was expected, RNAs to achieve more precise hair follicles in reconstructed dermis
but instead the atoms had a editing. —SYM Addressing
tendency to form pairs. Here, a hairy problem
the researchers disentangled Nature 563, 646 (2018).
the two pathways and found Nat. Biotechnol. 37, 64 (2019). Bioengineered skin grafts have
that correlations consistent Mol.Cell 10.1016/j.molcel.2018. helped many patients who have
with ferromagnetism initially suffered considerable skin loss
increased faster than the 11.031 (2018). caused by disease or injury.
pairs formed, but neither However, these grafts often lack
clearly dominated over the ORGANIC CHEMISTRY hair follicles, which are critical
other. —JS for thermoregulation, barrier
Targeting CH2 sites function, and wound healing.
Phys. Rev. Lett. 121, 253602 (2018).
Most organic compounds contain
SCIENCE sciencemag.org numerous carbon-hydrogen

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ALSO IN SCIENCE JOURNALS
Edited by Stella Hurtley

ORGANIC CHEMISTRY GENE THERAPY NEUROSCIENCE ORGANIC CHEMISTRY

Synthetic innovation in CRISPRa corrects The cerebellum and Journey to jorumycin
drug development haploinsufficient obesity reward-driven behavior
Jorumycin is a structurally
Chemical synthesis plays a key Loss-of-function mutation in one Damage to the cerebellum mani- complex, pentacyclic organic
role in pharmaceutical research gene copy, termed haploinsuf- fests itself in various forms of compound produced by a
and development. Campos et al. ficiency, can lead to insufficient cognitive impairment and abnor- marine mollusk. The success of
review some of the advantages protein levels and result in mal social behavior. However, the a similar compound, trabect-
that have come from recent human disease. Matharu et al. exact role the cerebellum plays edin, in treating certain types of
innovations in synthetic meth- tested whether a CRISPR-based in these conditions is far from cancer has focused attention on
ods. In particular, they highlight activation system (CRISPRa) clear. Working in mice, Carta et exploring jorumycin’s pharma-
small-molecule catalysts stimu- could rescue a haploinsufficient al. found direct projections from ceutical properties. Welin et al.
lated by visible light, enzymes phenotype by increasing the the deep cerebellar nuclei to the developed a succinct route to
engineered for versatility beyond gene expression levels of the brain’s reward center, a region synthesizing jorumycin and the
their intrinsic function, and existing normal copy (see the called the ventral tegmental area closely related jorunnamycin A
bio-orthogonal reactions to Perspective by Montefiori and (see the Perspective by D’Angelo). that deliberately diverges from
selectively modify proteins for Nobrega). By delivering this These direct projections allowed the putative biosynthetic path-
conjugation. High-throughput system into the mouse hypothal- the cerebellum to play a role way underlying prior chemical
techniques are also poised to amus using adeno-associated in showing a social preference. syntheses. This route, which
accelerate methods optimiza- virus, they rescued the obesity Intriguingly, this pathway was not hinges on a carefully optimized
tion from small-scale discovery phenotype caused by haploin- prosocial on its own. Cerebellar asymmetric catalytic hydrogena-
to large-scale production, and sufficiency of either of two genes inputs into the ventral tegmental tion, can be easily modified to
complementary machine-learn- known to promote obesity when area were more active during introduce unnatural structural
ing approaches are just coming mutated in mice and humans. social exploration. Depolarization diversity for functional optimiza-
into focus. —JSY These results highlight the trans- of ventral tegmental area neurons tion in further drug discovery
lational potential of the CRISPR thus represents a similar reward research. —JSY
Science, this issue p. 244 activation system to treat haplo- stimulus as social interaction for
insufficient disease. —BAP mice. —PRS Science, this issue p. 270
IMAGING TECHNIQUES
Science, this issue p. 246; Science, this issue p. 248; CHEMICAL PHYSICS
Combining expansion and see also p. 231 see also p. 229
the lattice light sheet Brief get-togethers
ASYMMETRIC CATALYSIS INORGANIC CHEMISTRY between NaK and K
Optical and electron micros-
copy have made tremendous Predicting catalyst Orange-glowing iron at Cooling molecules to nanokel-
inroads into understanding the selectivity room temperature vin temperatures places them
complexity of the brain. Gao under the tightest quantum
et al. introduce an approach Asymmetric catalysis is widely Many photoactive coordination mechanical constraints. Studies
for high-resolution tracing of used in chemical research and compounds contain precious in this intriguing regime have
neurons, their subassemblies, manufacturing to access just one metals. Replacing ruthenium been limited to diatomics:
and their molecular constituents of two possible mirror-image with more–earth-abundant iron Two cold atoms can be lured
over large volumes. They applied products. Nonetheless, the has been a long-sought goal, but together into weakly associated
their method, which combines process of tuning catalyst iron compounds generally relax Feshbach resonances, which
expansion microscopy and structure to optimize selectivity too rapidly after light absorption lasers can then shift into a more
lattice light-sheet microscopy, is still largely empirical. Zahrt et to channel the energy produc- stable molecular state. Yang
to the mouse cortical column al. present a framework for more tively. Kjær et al. prepared an et al. now report the observa-
and the entire Drosophila brain. efficient, predictive optimiza- iron compound with an excited tion of triatomic Feshbach
The approach can be performed tion. As a proof of principle, they state stable enough to emit light resonances in ultracold colli-
at speeds that should enable focused on a known coupling for nanoseconds, or that could sions between potassium (K)
high-throughput comparative reaction of imines and thiols cata- engage in bimolecular electron atoms and sodium potassium
studies of neural development, lyzed by chiral phosphoric acid transfer (see the Perspective by (NaK) diatomics. The findings
circuit stereotypy, and structural compounds. By modeling mul- Young and Oldacre). Targeting potentially set the stage for the
correlations to neural activity or tiple conformations of more than a ligand-to-metal rather than preparation and study of ultra-
behavior. —SMH 800 prospective catalysts, and metal-to-ligand charge-transfer cold triatomic molecules. —JSY
then training machine-learning state was key to the achievement,
Science, this issue p. 245 algorithms on a subset of experi- as was the octahedral coordina- Science, this issue p. 261
mental results, they achieved tion environment rigidly enforced
highly accurate predictions of by two tridentate carbene
enantioselectivities. —JSY ligands. —JSY

Science, this issue p. 247 Science, this issue p. 249;
see also p. 225

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CELL DIFFERENTIATION M E TA B O L I S M

Reversing chromatin An anti-ammonia
dynamics for development probiotic

Compacted chromatin regions, Hyperammonemia, or excess
marked by trimethylation of blood ammonia, is a serious
histone H3 at position lysine 9 condition that can result in
(H3K9me3), occur at highly brain damage and death. Kurtz
repeated DNA sequences, help- et al. modified the metabolism
ing to suppress recombination of a probiotic Escherichia coli
and gene expression. Because strain to overproduce arginine,
pluripotent cells contain low thereby sequestering some of
levels of H3K9me3 heterochro- the ammonia produced by gut
matin relative to differentiated bacteria into the amino acid mol-
cells, it has been thought that ecules. The engineered strain,
an increase in such hetero- called SYNB1020, lowered blood
chromatin helps to define cell ammonia and increased survival
differentiation. Nicetto et al. used in mouse hyperammonemia
two independent methods to models and showed repeat-
examine compacted heterochro- dose tolerability in nonhuman
matic domains and found that primates. A phase 1 dose-esca-
H3K9me3 compaction increased lation study in healthy human
at protein-coding genes during volunteers resulted in no serious
early mouse organogenesis. adverse events and indicated
During differentiation, these that the bacterium was meta-
domains open up to allow bolically active in vivo. —CAC
cell-specific expression. Loss
of heterochromatin by genetic Sci. Transl. Med. 11, eaau7975 (2019).
inactivation of the H3K9me3
methyltransferases caused ECOLOGY
ectopic expression of cell-
inappropriate genes and tissue Standardizing science for
pathology. —BAP conservation

Science, this issue p. 294 Assessments of biodiversity and
human impacts on the envi-
MICROBIOLOGY ronment often rely on species
distribution models that make
Dual roles of skin data-supported predictions
microbiota of species survival in chang-
ing environments. However, no
Like the gut, the skin is colo- agreed-upon standards for eval-
nized by microbes that can uating these models exist, and
be protective to help maintain their application to conservation
homeostasis or be pathogenic. policy is inconsistent. Araújo et
In a Perspective, Stacy and al. analyzed 400 model-based
Belkaid discuss the dual roles of studies over the past 20 years
Staphylococcus epidermidis on to assess the adequacy of the
skin. This microbe exemplifies models and their impacts on
how skin microbiota can pro- scientific interpretation and pro-
mote immune and antimicrobial jection. They make the case for
responses against pathogens the development of best-prac-
but, in certain contexts, aggra- tice standards and guidelines
vate pathologies such as eczema for the evaluation of data and
and possibly skin cancer. Skin is models used. Such standard-
often termed the largest human ized practices should ensure
organ, so it is important to more transparent and consistent
understand how skin microbiota translation of scientific results
contribute to health. —GKA into policy. —PJB

Science, this issue p. 227 Sci. Adv. 10.1126/sciadv.aat4858

(2019).

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RESEARCH

◥ previously unachievable. Furthermore, recent

REVIEW SUMMARY breakthroughs in molecular biology, bioinfor-

matics, and protein engineering are driving

ORGANIC CHEMISTRY rapid identification of biocatalysts that possess

The importance of synthetic chemistry desirable stability, unique activity, and exquis-
in the pharmaceutical industry
ite selectivity needed to accelerate drug dis-
Kevin R. Campos*, Paul J. Coleman*, Juan C. Alvarez, Spencer D. Dreher,
Robert M. Garbaccio, Nicholas K. Terrett, Richard D. Tillyer, covery. Recent developments in the merging
Matthew D. Truppo, Emma R. Parmee
fields of synthetic and biosynthetic chemis-

try have sought to harness these molecules

in three distinct ways: as biocatalysts for

novel and selective trans-

◥

ON OUR WEBSITE formations, as conjugates

Read the full article through innovative bio-
orthogonal chemistry, and
at http://dx.doi.

BACKGROUND: Over the past century, inno- that we believe are poised to transform the org/10.1126/ in the development of im-
vations in synthetic chemistry have greatly practice of drug discovery and development in science.aat0805 proved therapeutic mod-
enabled the discovery and development of im- the coming years. alities. The development
portant life-changing medicines, improving ..................................................
the health of patients worldwide. In recent ADVANCES: Over the past century, innova-
years, many pharmaceutical companies have tions in synthetic methods have changed the of high-throughput experimentation and
chosen to reduce their R&D investment in way scientists think about designing and
chemistry, viewing synthetic chemistry more building molecules, enabling access to more analytical tools for chemistry has made it
as a mature technology and less as a driver of expansive chemical space and to molecules
innovation in drug discovery. Contrary to this possessing the essential biological activity possible to execute more than 1500 simul- Downloaded from http://science.sciencemag.org/ on January 19, 2019
opinion, we believe that excellence and inno- needed in future investigational drugs. In or-
vation in synthetic chemistry continue to be der for the pharmaceutical industry to con- taneous experiments at microgram scale in
critical to success in all phases of drug discov- tinue to produce breakthrough therapies that
ery and development. Moreover, recent devel- address global health needs, there remains a 1 day, enabling the rapid identification of suit-
opments in new synthetic methods, biocatalysis, critical need for invention of synthetic trans-
chemoinformatics, and reaction miniaturiza- formations that can continue to drive new able reaction conditions to explore chemical
tion have the power to accelerate the pace and drug discovery. Toward this end, investment
improve the quality of products in pharma- in research directed toward synthetic methods space and accelerate drug discovery. Finally,
ceutical research. Indeed, the application of innovation, furthering the nexus of synthetic
new synthetic methods is rapidly expanding chemistry and biomolecules, and developing advances in computational chemistry and
the realm of accessible chemical matter for new technologies to accelerate methods dis-
modulating a broader array of biological tar- covery is essential. One powerful example of machine learning in the past decade are de-
gets, and there is a growing recognition that an emerging, transformative synthetic method
innovations in synthetic chemistry are chang- is the recent discovery of photoredox catal- livering real impact in areas such as new cat-
ing the practice of drug discovery. We identify ysis, which allows one to harness the energy of
some of the most enabling recent advances visible light to accomplish synthetic trans- alyst design, reaction prediction, and even new
in synthetic chemistry as well as opportunities formations on drug-like molecules that were
reaction discovery.

Evolution of synthesis as a driver of innovation in drug discovery. Past, present, and OUTLOOK: These advances position synthetic
future advances in synthetic chemistry are poised to transform the practice of drug discovery chemistry to continue to have an impact on
and development. the discovery and development of the next
generation of medicines. Key unsolved prob-
lems in synthetic chemistry with potential
implications for drug discovery include se-
lective saturation and functionalization of
heteroaromatics; concise synthesis of highly
functionalized, constrained bicyclic amines;
and C-H functionalization for the synthesis
of a,a,a-trisubstituted amines. Other areas,
such as site-selective modification of bio-
molecules and synthesis of noncanonical nu-
cleosides, are emerging as opportunities of
high potential impact. The concept of mo-
lecular editing, whereby one could selectively
insert, delete, or exchange atoms in highly
elaborated molecules, is an area of emerging
interest. Continued investment in synthetic
chemistry and chemical technologies through
partnerships between the pharmaceutical in-
dustry and leading academic groups holds
great promise to advance the field closer to a
state where exploration of chemical space is
unconstrained by synthetic complexity and
only limited by the imagination of the chem-
ist, enabling the discovery of the optimal chem-

▪ical matter to treat disease faster than ever

before.

The list of author affiliations is available in the full article online.
*Corresponding author. Email: [email protected]
(K.R.C.); [email protected] (P.J.C.)
Cite this article as K. R. Campos et al., Science 363, eaat0805
(2019). DOI: 10.1126/science.aat0805

Campos et al., Science 363, 244 (2019) 18 January 2019 1 of 1

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RESEARCH

◥ of drug discovery. Innovation in synthetic chem-
istry provides opportunity to gain more rapid
REVIEW access to biologically active, complex molecular
structures in a cost-effective manner that can
ORGANIC CHEMISTRY change the practice of medicine. An outstanding
example of the transformative power of synthetic
The importance of synthetic chemistry chemistry in drug discovery is the application of
in the pharmaceutical industry carbenoid N-H insertion chemistry to the syn-
thesis of b-lactam antibiotics (8). In the 1950s,
Kevin R. Campos1*, Paul J. Coleman1*, Juan C. Alvarez1, Spencer D. Dreher1, the synthesis of antibiotics such as penicillin Downloaded from http://science.sciencemag.org/ on January 19, 2019
Robert M. Garbaccio1, Nicholas K. Terrett1, Richard D. Tillyer2, represented a formidable challenge to medicinal
Matthew D. Truppo2, Emma R. Parmee1 chemists, and broad exploration of structure-
activity relationships (SAR) within this class of
Innovations in synthetic chemistry have enabled the discovery of many breakthrough compounds was hindered by a lack of good meth-
therapies that have improved human health over the past century. In the face of increasing ods of synthesis for these chemically sensitive
challenges in the pharmaceutical sector, continued innovation in chemistry is required to structures. Indeed, the first chemical synthesis of
drive the discovery of the next wave of medicines. Novel synthetic methods not only unlock penicillin took nearly a decade of dedicated ef-
access to previously unattainable chemical matter, but also inspire new concepts as to how fort to achieve (9) despite an intensive effort across
we design and build chemical matter. We identify some of the most important recent multiple laboratories. This lack of synthetic ac-
advances in synthetic chemistry as well as opportunities at the interface with partner cessibility prevented thorough evaluation of struc-
disciplines that are poised to transform the practice of drug discovery and development. turally related antibiotics that might have a
broader spectrum of activity and an improved
O ver the past century, innovations in syn- and find safe and effective therapeutic molecules resistance profile. The application of intramo-
thetic chemistry have greatly enabled the that appropriately modulate those targets. The lecular N-H carbenoid insertion chemistry (Fig. 1)
discovery and development of important current toolbox of synthetic methods and com- to these structures provided a disruptive solution
life-changing medicines, improving the mon chemical starting materials provides ac- to the preparation of these fused b-lactams. This
health of patients worldwide. In recent cess to chemical space (6) that can be efficiently synthetic method was applied to the preparation
years, many pharmaceutical companies have explored and mined to identify a suitable ligand of numerous natural and synthetic anti-infectives,
chosen to reduce their R&D investment in chem- and subsequently pursue studies of that prelim- including thienamycin (10), which subsequent-
istry, viewing synthetic chemistry more as a ma- inary lead compound toward its potential devel- ly led to the discovery and industrial manufac-
ture technology and less as a driver of innovation opment as a successful drug. Brown and Boström ture of the antibiotic imipenem. In this example,
in drug discovery (1–3). Contrary to this opinion, have noted that a historical overreliance on just synthesis enabled design, opening access to pre-
we believe that excellence and innovation in syn- a few robust synthetic transformations (amide viously unattainable molecules of high therapeu-
thetic chemistry continues to be critical to success bond formation, sp2-sp2 C-C cross-coupling, and tic value.
in all phases of drug discovery and development. SNAr reactions) has biased the output of many
Moreover, recent developments in new synthetic drug discovery efforts, leading to narrow sampling The development of targeted medicines for
methods, biocatalysis, chemoinformatics, and re- of chemical space (7). In other cases, the lack of the treatment of chronic hepatitis C infection, a
action miniaturization have the power to accel- any reasonable method of synthesis has, at mini- global health challenge (11), illustrates another
erate the pace and improve the quality of products mum, hampered thorough evaluation of chem- key advance that innovative synthetic chemistry
in pharmaceutical research. The application of ical space or, at worst, prevented it completely. has contributed to drug discovery in recent years.
new synthetic methods is rapidly expanding the The design and synthesis of hepatitis C virus
realm of accessible chemical matter for modulat- Conversely, the discovery of breakthrough syn- (HCV) NS3/4a protease inhibitors represents a
ing a broader array of biological targets, and there thetic methods can truly transform the process formidable challenge for medicinal chemists be-
is a growing recognition that innovations in syn- cause the active site of this protease has a shallow,
thetic chemistry are changing the practice of drug open binding site, and the enzyme possesses both
discovery (4, 5). Here, we identify some of the genotypic and mutational diversity. Early studies
most enabling recent advances in synthetic chem-
istry as well as opportunities that we believe are
poised to transform the practice of drug discov-
ery and development in the coming years.

The pharmaceutical sector is currently facing
multiple challenges: an increasing focus on com-
plex diseases with unknown causal biology, a
rapidly changing and highly competitive land-
scape, and substantial pricing pressures from
patients and payers. In this challenging envi-
ronment, drug discovery scientists must select
biological targets of relevance to human disease

1Global Chemistry, Merck & Co. Inc., Kenilworth, NJ 07033, Fig. 1. Synthetic method innovations enable discovery of important anti-infectives, imipenem
USA. 2Janssen Research & Development LLC, Spring House, and vaniprevir.
PA 19477, USA.
*Corresponding author. Email: [email protected] (K.R.C.);

[email protected] (P.J.C.)

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of peptide-based inhibitors and subsequent industry (20). The methodology addressed an bolic properties (26). Visible-light photoredox Downloaded from http://science.sciencemag.org/ on January 19, 2019
molecular modeling suggested that construc- unsolved problem to quickly and predictably ac- catalysis has been also been applied to the
tion of large, macrocyclic enzyme inhibitors cess aromatic and heteroaromatic amines from practical, direct trifluoromethylation of het-
could provide favorable ligand-protein binding simple precursors, and as a result it was rapidly eroarenes (27).
and potent inhibition of this essential viral pro- adopted by medicinal chemists. Further devel-
tease (12). The relatively flat and featureless opment of these methodologies by process chem- Adoption of photoredox catalysis in the phar-
protein surface requires a large ligand to gain istry groups for scale-up has resulted in optimized maceutical industry has been rapid, owing to
sufficient binding affinity, while constrained ligands and precatalysts, as well as generally the practicality of the process, the tolerance to
macrocyclic ligands minimize the entropic cost reliable protocols that have further advanced the functional groups in drug-like candidates, and
of inhibitor binding. The application of ring- application of this methodology in discovery the activation of nonconventional bonds in drug-
closing metathesis chemistry (13) has been trans- programs. Consequently, aromatic C-N bonds are like molecules (28). Application of photoredox
formative in the synthesis of many HCV NS3/4a common features in pharmaceutical compounds catalysis to the Minisci reaction was reported,
protease inhibitors of varying ring sizes and com- (21), highlighting the tremendous impact that enabling the facile and selective introduction of
plexity, including six approved drugs: simeprevir controlled construction of C-N bonds in aromatic small alkyl groups into a variety of biologically
(14), paritaprevir (15), vaniprevir (16), grazoprevir compounds has had on medicinal chemistry pro- active heterocycles such as camptothecin (29).
(17), voxilaprevir (18), and glecaprevir (19). Ring- grams. The next frontier is development of reliable Photoredox catalysis has also been used for the
closing metathesis chemistry enabled the dis- methods to accomplish Csp3-N couplings (22). direct and selective fluorination of leucine methyl
covery of these and related macrocycles, allowing ester to afford g-fluoroleucine methyl ester with a
rapid assembly of complex bioactive molecules As the development of transition metal–catalyzed decatungstate photocatalyst and NFSI (Fig. 2).
and broad exploration of SAR to address a range processes has advanced, application of cutting- Numerous processes have been reported to access
of properties. edge methods to the predictable activation of g-fluoroleucine methyl ester, a critical fragment of
C-H bonds for functionalization of complex lead the late-stage drug candidate odanacatib; how-
In the two examples described above, the dis- structures can enable novel vector elaborations, ever, this method enables the most direct and
covery of new synthetic pathways changed the changing the way analogs are prepared (23). In efficient method to access this key building block
way scientists thought about designing and build- particular, late-stage selective fluorination and in the fewest operations from a commodity feed-
ing molecules, which broadened the accessible trifluoromethylation of C-H bonds in an efficient, stock (30). More recently, photoredox catalysis was
chemical space and thereby furnished molecules high-yielding, and predictable fashion permits used to generate diazomethyl radicals, equivalents
possessing the biological activity required in fu- the modification of lead compounds to give ana- of carbyne species, which induced site-selective
ture drug candidates. The ability of the pharma- logs that potentially possess greater target affi- aromatic functionalization in a diverse array of
ceutical industry to discover molecules to treat nity and metabolic stability without resorting to drug-like molecules (31). This represents the
unmet medical needs and deliver them to pa- de novo synthesis. Methodological advances have latest of a series of very diverse, practical, and
tients efficiently in the face of an increasingly enabled preparation of fluorinated analogs of lead potentially impactful uses of photoredox tech-
challenging regulatory landscape is dependent structures under either nucleophilic or electro- niques to assemble libraries of drug-like scaf-
on continued invention of transformative, syn- philic conditions (24). One promising recent exam- folds for screening.
thetic methodologies. Toward this end, investment ple shows that electrophilic aromatic fluorination
in research directed toward synthetic methods can occur under mild conditions with a palladium Although the preceding examples highlight
innovation, furthering the nexus of synthetic catalyst and an electrophilic fluorine source such the power of photoredox catalysis to accomplish
chemistry and biomolecules, and developing new as N-fluorobenzenesulfonimide (NFSI) (25). In previously unimaginable reactivity under very
technologies to accelerate methods discovery is addition, trifluoromethylation of a structurally mild conditions (32, 33), even more remarkable
absolutely essential. Pertinent examples in these diverse array of drug discovery candidates using transformations are being reported via synergis-
three areas are reviewed below. zinc sulfinates, in the presence of iron(III) acetyl- tic catalysis, where both the photocatalyst and a
acetonate, generated analogs with improved meta- co-catalyst are responsible for distinct steps in
Synthetic methods innovation a mechanistic pathway that is only accessible

Over the past 20 years, several scientists have been Fig. 2. Synthetic methods with potential to enable drug discovery.
recognized with the Nobel Prize for the invention
of synthetic methodologies that have changed
the way chemists design and build molecules.
Each of these privileged methods—asymmetric
hydrogenation, asymmetric epoxidation, olefin
metathesis, and Pd-catalyzed cross-couplings—
have broadly influenced the entire field of syn-
thetic chemistry, but they have also enabled new
directions in medicinal chemistry research. Of
particular interest are new synthetic methods
that enable medicinal chemists to control reac-
tivity in complex, drug-like molecules, access non-
obvious vectors for SAR development, and rapidly
access new chemical space or unique bond for-
mations. Recently, there have been several re-
ported methods in these categories that have
been rapidly adopted by medicinal chemists as
a result of their practicality and broad utility.

Owing to the diverse biological activity of
nitrogen-containing compounds, the discovery
of Pd-catalyzed and Cu-catalyzed cross-coupling
reactions of amines and aryl halides to form C-N
bonds resulted in the rapid implementation of
these synthetic methods in the pharmaceutical

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with both catalysts present. For example, the and the long lead time required to optimize a ysis to efficiently build complex chemical matter Downloaded from http://science.sciencemag.org/ on January 19, 2019
combination of single-electron transfer–based biocatalyst through protein engineering (38). from simple starting materials (44).
decarboxylation with nickel-activated electro- The invention of a recombinant engineered
philes has provided a general method for the Merck/Codexis transaminase biocatalyst for the Bio-orthogonal chemistry
cross-coupling of sp2-sp3 and sp3-sp3 bonds. commercial manufacture of sitagliptin (Januvia)
This method establishes a new way of thinking has inspired the broader application of bio- Achieving selective reactions with biopolymers
about the carboxylic acid functional group as a transformations in the pharmaceutical indus- such as proteins presents a host of unique chal-
masked cross-coupling precursor, expanding the try (39). Tremendous advances have been made lenges to the synthetic chemistry community;
synthetic opportunities for a functional group in molecular biology, bioinformatics, and pro- proteins have multiple reactive centers, charged
that is ubiquitous in chemical feedstocks (34). tein engineering, enabling the development of residues, higher-order structure, and are usually
Furthermore, leveraging synergistic catalysis biocatalysts with desired stability, activity, and handled in an aqueous environment. Nonethe-
with photoredox has resulted in the discovery of exquisite selectivity. The impact of this area of less, the opportunity to create improved conju-
milder conditions for C-O (35) and C-N cross- research is exemplified by the 2018 Nobel Prize gates as therapies and imaging agents, or to
couplings, allowing application of these methods in Chemistry, recognizing Frances Arnold “for induce covalent interactions to identify protein
to more pharmaceutically relevant substrates the directed evolution of enzymes.” As a result, targets, represents important value to therapeu-
(36). The concise synthesis of the antiplatelet biocatalysis has become more prevalent as a tic drug discovery.
drug tirofiban (37) is an excellent example of how tool in drug discovery, as a valuable method for
the pharmaceutical industry can readily use this drug metabolite synthesis, and as a tool to enable Methods for selective conjugation to biomole-
methodology to facilitate drug discovery and rapid analog synthesis for SAR (40). For example, cules have undergone major synthetic evolution
development. As research continues to surge in in 2013, the important discovery that cyclic gua- over the past 20 years. The discovery and devel-
this field, additional breakthroughs are antici- nosine monophosphate–adenosine monophos- opment of a suite of click reactions has served
pated, and these will likely change how mole- phate (2′,3′-cGAMP) is the endogenous agonist as a powerful and broadly applied tool in protein
cules are designed and built. of STING, a protein involved in the activation bioconjugation (45). This highly bio-orthogonal
of innate immune cells, triggered an intense and biocompatible reaction offers a powerful al-
Intersection of synthetic chemistry interest in the synthesis of cyclic dinucleotide ternative to heterogeneous conjugation to sur-
with biomolecules (CDN) analogs (41). Typically, the total synthesis face lysines or engineered cysteines, and spurred
of CDNs by purely chemical transformations the development of complementary expression
Biopolymers including proteins, nucleic acids, requires long linear sequences and results in a technologies that could incorporate unnatural
and glycans have evolved to achieve exquisite time-consuming and low-yielding process. The elements or recognition tags into biopolymers.
selectivity and function in a highly complex en- optimization of STING agonists was greatly This evolution in conjugation chemistry is best
vironment. These properties are of great interest facilitated by the realization that the endoge- evidenced in the field of antibody-drug conju-
to the pharmaceutical industry not only from a nous enzyme cGAS, responsible for the in vivo gates (ADCs): The first generation of ADCs were
target perspective, but also from a therapeutic production of 2′,3′-cGAMP, could be engineered heterogeneous conjugates, whereas those of the
perspective. The success of monoclonal antibodies, and harnessed for the biocatalytic production second generation are now almost entirely ho-
peptides, and RNA-based therapies attests to the of non-natural CDNs (Fig. 3). The cyclization of mogeneous, with growing evidence that the site
power that nature’s platforms offer to our indus- various nucleotide triphosphate derivatives in of conjugation is an important determinant of
try and patients. Recent advances in merging the a single biosynthetic step considerably reduced overall ADC performance (46).
fields of synthetic and biosynthetic chemistry have the cycle time and increased the yield of CDN
sought to harness these molecules and to expand synthesis, inspiring the design of novel agonists The development of additional bio-orthogonal
useful manipulation of biomolecules in three dis- and the generation of SAR in this class (42). chemistries that can lead to selective reaction
tinct ways: as catalysts for novel and selective The continued investment in biocatalysis will with biomolecules, particularly without the re-
transformations, as conjugates through innovative lead to innovative solutions for unsolved prob- quirement for engineering a recognition ele-
bio-orthogonal chemistry, and in the development lems in synthetic chemistry in both the dis- ment into the biomolecule, is an important new
of novel and improved therapeutic modalities. covery and development arenas. This will be frontier for synthetic impact. Two recent exam-
driven by increased speed of protein engineer- ples of synthetic innovation suggest this toolset
Biocatalysis ing, access to enzymes with a variety of natural is expanding for proteins. In many cases, having
and even unnatural (43) catalytic activities, and the ability to conjugate at either the N or C ter-
Historically, the broad adoption of biocatalysis the implementation of biocatalytic cascade catal- minus of a wild-type protein should avoid un-
was held back by a limited availability of robust intended disruption of its function or secondary
enzymes, a relatively small scope of reactions, structure. The development of selective N-terminal
conjugation chemistry (47) and complementary

Fig. 3. Biocatalytic synthesis of novel cyclic dinucleotides. 3 of 8
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application of decarboxylative alkylation chem- space between synthetic small molecules and based therapies was the introduction of phos-
istry to the C terminus of a protein substrate (48) expressed large monoclonal antibodies. Peptides, phorothioates into the oligo backbone, which
offer new insights into achieving bio-orthogonal oligonucleotides, and bioconjugates have been ad- afforded improved stability to biological matrices
and highly site-selective conjugation with com- vanced particularly for biological targets deemed as well as improved membrane permeability
plex biomolecules (Fig. 4). These reactions take “undruggable” by small-molecule and antibody to aid with cytosolic delivery. Although these
advantage of local differences in basicity and platforms. Advances in these chemistries inspire and other improvements in stability and de-
ionization potential respectively and, in doing so, new platforms and improve the breadth of bio- livery have advanced the field and enabled
leverage the complexity that biopolymers offer. logical targets that we can address. Two exam- novel therapeutics to enter the clinic, many
ples of innovation in therapeutic modalities oligo-based therapies require high doses to
Synthetic innovation and through synthetic and biosynthetic chemistry are overcome barriers to delivery, and their use is
therapeutic modalities described below, although many others are being limited by their toxicity. Further improvements
invented in academic and industrial settings. in stability and potency of the oligonucleotide
As these advances in synthetic, biorthogonal, and should contribute to a widening of the ther-
biosynthetic chemistry merge, so too do our capa- In the first case, it has long been appreciated that apeutic index and dose lowering. Interesting-
bilities to improve therapeutic modalities in the a critical element of the success of oligonucleotide- ly, the chemistry used to introduce stabilizing
phosphorothioates leaves each center as a mix-
Fig. 4. Bio-orthogonal reactivity with proteins at N and C termini. ture of two P-stereoisomers. Therefore, most Downloaded from http://science.sciencemag.org/ on January 19, 2019
clinical phosphorothioate-containing oligos that
have 20 base pairs are, in reality, a large mixture
of stereoisomers (219), each with different po-
tency and stability characteristics. The ability to
control phosphorothioate chemistry through an
oxazaphospholidine approach by Wada and col-
leagues (49) led to a practical and scalable plat-
form (50) for stereopure antisense oligonucleotides
that demonstrate preclinical superiority to the
corresponding stereomixtures.

Within the peptide arena, there has been a
growing recognition that cyclic peptides offer
improved starting points for drug discovery pro-
grams relative to their linear counterparts, largely
due to improvements in entropic cost for binding
and proteolytic stability. Early display platforms
developed to discover cyclic peptides relied on
disulfide formation, and more recently on post-
translational introduction of bis-electrophiles

Fig. 5. High-throughput experimentation to accelerating reaction discovery. 4 of 8
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that can cyclize peptides with two cysteine resi- has been the foundation of hit discovery for erate enantioselectivity and low conversion using Downloaded from http://science.sciencemag.org/ on January 19, 2019
dues (51). Through combined application of a decades, and in recent years, the pharmaceu- chiral phosphoric acids. Rapid evaluation of a
ribozyme biocatalyst to enable unnatural amino tical industry has strategically invested in the large number of diverse scaffolds with H-bonding
acid incorporation into peptides, and then bio- creation of high-throughput experimentation capability in this transformation resulted in the
orthogonal chemistry for cysteine cyclization (HTE) tools for chemistry that enable scientists discovery of an efficient and highly selective bis-
through that unnatural amino acid, the Suga lab to test experimental hypotheses with hundreds of sulfonamide catalyst. Further HTE work enabled
has developed an improved mRNA display plat- arrayed experiments (53). In the same time frame the mechanistic understanding of the transfor-
form (52) that has demonstrated tremendous po- required for traditional single-reaction evalua- mation, leading to optimization of both the cat-
tential to identify peptide ligands for challenging tion, the different parameters that determine alyst structure and definition of optimal processing
targets. The merging of chemical synthesis and reaction outcome, discrete variables (catalysts, conditions. In this study and in many others (56, 57),
biosynthesis within a common platform inspires reagents, solvents, additives), and continuous novel bond-forming reactions were conceived by
further exploration of cyclic peptide modality; the variables (temperatures, concentrations, stoi- scientists, discovered through HTE, and then rap-
introduction of selection pressures and forced chiometries) can be holistically explored in par- idly industrialized for the commercial manufac-
evolution into this platform begins to resemble allel (54). As a result, the synthetic chemist now ture of late-stage drug candidates.
aspects of natural product generation that has has access to exponentially larger amounts of
historically inspired both organic synthesis and experimental data than ever before. One recent HTE tools have also begun to have an impact
drug discovery. example of the use of end-to-end HTE in process in drug discovery (58). As new catalytic methods
development was the discovery and develop- emerge that redefine which bonds can be forged,
Technologies to accelerate innovation ment of an organo-catalyzed, enantioselective, the breadth of the resulting substrate scope is
High-throughput experimentation aza-Michael reaction for the commercial man- poorly understood, as most test substrates com-
ufacture of the antiviral letermovir (Fig. 5) (55). monly demonstrated in the literature are simple
Given the need to invent and rapidly deliver In this work, a series of efficient synthetic path- and not representative of the complex func-
medicines to patients, the pharmaceutical indus- ways were envisioned by chemists and key tionality common in drug candidates. Pre-dosed,
try must invest in capabilities with the potential transformations were evaluated in parallel using reaction-specific HTE screening kits, contain-
to radically accelerate the discovery and indus- HTE. The emergence of an H-bonding catalysis ing a lab’s most successful and general catalyst
trialization of transformative synthetic method- mechanism was initially discovered with mod- systems, are used in discovery chemistry labs
ologies. High-throughput screening in biology to enable the rapid identification of reaction

Fig. 6. Application of computational modeling to new catalyst design. 5 of 8
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conditions that work for these complex substrates. cleoside at the 5′ hydroxyl over the 3′ hydroxyl with ance of a single reaction, a Buchwald-Hartwig Downloaded from http://science.sciencemag.org/ on January 19, 2019
Additionally, HTE has recently been leveraged stereocontrol at the phosphorus center is highly amination, against multiple variables: reactants,
to benchmark emerging methods against dif- challenging. A combination of mechanistic studies catalysts, bases, and additives (76). Application of
ferent catalytic procedures through the cre- using a variety of chiral catalysts and DFT calcula- machine learning holds considerable promise for
ation of arrays of complex, drug-like substrates tions of a proposed transition state further informed synthetic optimization of targets far exceeding
known as informer libraries (59) or through by experimental observations led to the rational those described herein, toward predicting routes,
addition of diverse molecular fragments that design of a dimeric phosphoramidation catalyst main products, side products, and optimal con-
can disrupt catalysis (60, 61). The use of these with an improved rate and excellent stereoselectivity. ditions, among others. The continued advance-
diagnostic methods allows exploration of the ment of these methods leverages the wealth of
relationship between reaction types and diverse Despite these successes, the process for ratio- public information in the scientific and patent
complex substrate structures, thus enabling nal computational design of a catalyst is arduous, literature as well as within pharmaceutical insti-
synthetic practitioners to make better decisions requiring the modeling of multiple mechanistic tutions. The quality, breadth, depth, and density
about which synthetic methods to prioritize in pathways and refinement of numerous molecules of the data within the domain of the predictions is
their problem-solving. Additionally, miniatur- and transition states. A program for automating critical for driving toward high-accuracy models.
ization of HTE to nanomole scale—for example, much of this process has been reported (71), and Inclusion of examples of both successful and un-
by automated nanomole-scale batch (62) and the advancement of such methods as well as the successful transformations is also highly important.
flow (63) approaches—now enables the execution continual increase in processing power will drive HTE is a highly attractive, complementary tech-
of more than 1500 simultaneous experiments further use of these tools in the future. nology for augmenting existing datasets by
at microgram scale in 1 day for rapid identifi- generating model-suitable data, maximizing in-
cation of suitable reaction conditions to explore The application of machine learning to syn- formation content through careful design of exper-
chemical space and accelerate drug discovery. thetic problems has also generated considera- iments and capacity to deliver large volumes of
This capability is augmented by advances in ble interest and excitement. One area of active data in a rapid and cost-effective manner.
rapid high-throughput analytics, such as MISER research is the use of algorithms for synthetic
(multiple injections in a single experimental run) route planning to a target molecule (72, 73). Future directions
and MALDI (matrix-assisted laser desorption/ Segler et al. combined Monte Carlo tree search
ionization) mass spectrometry techniques (64), and three neural networks to identify potential As we have discussed, breakthroughs in syn-
which have enabled the analysis of as many as synthetic routes (74). The success of the approach thetic chemistry have proven to be the inspi-
1536 reactions in very short time frames. Finally, was qualitatively evaluated through a double- ration for the discovery and development of new
nanomole HTE can also expedite the preparation blind A/B test, where 45 chemistry students medicines of important therapeutic value. Despite
of diverse, complex arrays of molecules and, when showed no preference between machine-suggested the many advances described above, the pace and
coupled directly with biological testing, can rad- synthetic routes versus literature routes for repre- breadth of molecule design is still constrained
ically alter how drug discovery is performed (65). sentative target molecules. Machine learning has because of unsolved problems in synthetic chem-
additionally been applied to forward reaction istry. Many opportunities still remain to advance
Computational methods prediction (75). Neural networks were used to the field, such that synthetic chemistry will never
predict the major product of a reaction using an constrain compound design or program pace,
The use of computer-assisted methods to guide algorithm that assigns a probability and rank to and should actually inspire access to uncharted
synthetic chemistry is emerging as an important potential products. Additionally, machine learn- chemical space in the pharmaceutical industry.
component in the practice of drug discovery. ing was used to successfully predict the perform-
Advances in computational chemistry and ma-
chine learning in the past decade are delivering Fig. 7. Molecular editing to enable drug discovery.
real impact in areas such as new catalyst design
(66) or showing considerable promise in others
such as reaction prediction (67). The application
of deep learning methods has the potential to
uncover new chemical reactions, expanding the
access to new pharmaceutical chemical matter.
Granda et al. (68) have reported promising results
toward this end. By combining automated syn-
thesis with machine learning, they reported the
discovery of four chemical transformations with
differentiated novelty.

Recently, computer-guided design has been
successfully applied to the preparation of cat-
alysts that provide asymmetric control of a cy-
cloisomerization reaction (69). Computational
methods were used to evaluate the catalytic path-
way of a previously unknown reaction, leading
to the hypothesis that the electronics of the cat-
alyst ligand influence both the rate and stereo-
selectivity of the transformation. Application of
quantum methods such as density functional
theory (DFT) provided optimal ligand designs
with markedly enhanced rate and selectivity over
the original ligand. A second example where the
use of computational methods aided in the de-
sign of a superior catalyst is reported in the syn-
thesis of a pronucleotide (ProTide, Fig. 6) (70).
Achieving selective phosphoramidation of a nu-

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Recently, we conducted a summit with key els that can predict successful reaction condi- 19. Y. S. Or et al., Preparation of macrocycles, especially Downloaded from http://science.sciencemag.org/ on January 19, 2019
opinion leaders to assess the state of field and proline-containing cyclic peptides, as hepatitis C virus
to identify areas of research in synthetic methods tions or even discover new reactions. The field of (HCV) NS3-NS4A protease inhibitors, WO2012/040167
that would have critical impact in the pharma- (2012).
ceutical industry. Key unsolved problems in syn- predictive chemical synthesis remains nascent,
thetic chemistry included selective saturation 20. P. Ruiz-Castillo, S. L. Buchwald, Applications of Palladium-
and functionalization of heteroaromatics, concise but opportunities to build prognostic algorithms Catalyzed C-N Cross-Coupling Reactions. Chem. Rev. 116,
synthesis of highly functionalized, constrained 12564–12649 (2016). doi: 10.1021/acs.chemrev.6b00512;
bicyclic amines, and C-H functionalization for the via machine-learning processes are likely to ex- pmid: 27689804
synthesis of a,a,a-trisubstituted amines. Other
areas, such as selective functionalization of bio- pand in the coming years. Continued investment 21. E. Vitaku, D. T. Smith, J. T. Njardarson, Analysis of the
molecules and synthesis of noncanonical nucleo- structural diversity, substitution patterns, and frequency of
sides, were identified as emerging areas of high in synthetic chemistry and chemical technologies nitrogen heterocycles among U.S. FDA approved
potential impact. We envision that partnerships pharmaceuticals. J. Med. Chem. 57, 10257–10274 (2014).
between the pharmaceutical industry and lead- has the promise to advance the field closer to a doi: 10.1021/jm501100b; pmid: 25255204
ing academic groups in the field hold great
promise to spur the invention of disruptive syn- state where exploration of chemical space is 22. R. Gianatassio et al., Strain-release amination. Science 351,
thetic chemistry to address these areas. 241–246 (2016). doi: 10.1126/science.aad6252;
unconstrained by synthetic complexity and is pmid: 26816372
The most intriguing idea to emerge from the
discussion was the concept of molecular editing, only limited by the imagination of the chemist. 23. T. Cernak, K. D. Dykstra, S. Tyagarajan, P. Vachal, S. W. Krska,
which would entail insertion, deletion, or ex- The medicinal chemist’s toolbox for late stage functionalization
change of atoms in highly functionalized com- Advancements in synthetic chemistry are certain of drug-like molecules. Chem. Soc. Rev. 45, 546–576 (2016).
pounds at will and in a highly specific fashion. doi: 10.1039/C5CS00628G; pmid: 26507237
Many innovations discussed above possess ele- to remain highly relevant to the mission of in-
ments of this aspirational goal; however, a truly 24. M. G. Campbell, T. Ritter, Late-Stage Fluorination: From
general method of this type would substantially venting new medicines to improve the lives of Fundamentals to Application. Org. Process Res. Dev. 18,
change the pace of drug discovery and reduce 474–480 (2014). doi: 10.1021/op400349g; pmid: 25838756
constraints on compound design. Figure 7 pro- patients worldwide.
spectively illustrates how analogs of a complex 25. K. Yamamoto et al., Palladium-catalysed electrophilic aromatic
lead scaffold might be accessed via site selective REFERENCES AND NOTES C-H fluorination. Nature 554, 511–514 (2018). doi: 10.1038/
C-H functionalization, heteroaromatic reduction, nature25749; pmid: 29469096
ring expansion, or ring contraction. The power to 1. P. Ball, Chemistry: Why synthesize? Nature 528, 327–329
modify this scaffold directly and specifically not (2015). doi: 10.1038/528327a; pmid: 26672538 26. C. A. Kuttruff, M. Haile, J. Kraml, C. S. Tautermann, Late-Stage
only avoids a potentially lengthy synthesis of Functionalization of Drug-Like Molecules Using Diversinates.
analogs, but also removes any limitation of 2. G. M. Whitesides, Reinventing chemistry. Angew. Chem. Int. Ed. ChemMedChem 13, 983–987 (2018). doi: 10.1002/
molecular design imposed by synthetic hurdles. 54, 3196–3209 (2015). doi: 10.1002/anie.201410884; cmdc.201800151; pmid: 29534329
We anticipate that breakthroughs in the area of pmid: 25682927
molecular editing will improve the pace and quality 27. J. W. Beatty et al., Photochemical Perfluoroalkylation with
of molecule invention, enabling the introduction 3. T. Laird, Is there a Future for Organic Chemists in the Pyridine N-Oxides: Mechanistic Insights and Performance on a
of new and important medicines at a faster rate. Pharmaceutical Industry outside China and India? Org. Process Kilogram Scale. Chem 1, 456–472 (2016). doi: 10.1016/
Res. Dev. 14, 749 (2010). doi: 10.1021/op1001676 j.chempr.2016.08.002; pmid: 28462396
Outlook
4. D. C. Blakemore et al., Organic synthesis provides opportunities 28. M. A. Miranda, M. L. Marin, Photocatalytic Functionalization
Synthetic chemistry has historically been a power- to transform drug discovery. Nat. Chem. 10, 383–394 (2018). for the Synthesis of Drugs and Analogs. Curr. Opin. Green Sustain.
ful force in the discovery of new medicines and is doi: 10.1038/s41557-018-0021-z; pmid: 29568051 Chem. 6, 139–149 (2017). doi: 10.1016/j.cogsc.2017.05.001
now poised to have an even greater impact to
accelerate the pace of drug discovery and expand 5. C. J. Gerry, S. L. Schreiber, Chemical probes and drug leads 29. D. A. Dirocco et al., Late-stage functionalization of biologically
the reach of synthetic chemistry beyond the tra- from advances in synthetic planning and methodology. active heterocycles through photoredox catalysis. Angew.
ditional boundaries of small-molecule synthesis. Nat. Rev. Drug Discov. 17, 333–352 (2018). doi: doi: 10.1038/ Chem. 126, 4902–4906 (2014). doi: 10.1002/ange.201402023;
New methods of synthesis can greatly expand nrd.2018.53; pmid: 29651105 pmid: 24677697
the rate of molecule generation while also provid-
ing opportunities to routinely synthesize complex 6. J. L. Reymond, L. Ruddigkeit, L. Blum, R. van Deursen, The 30. S. D. Halperin et al., Development of a Direct Photocatalytic
molecules in the course of drug discovery. Manip- Enumeration of Chemical Space. Wiley Interdiscip. Rev. C-H Fluorination for the Preparative Synthesis of Odanacatib.
ulation of biomolecules either as catalytic reagents Comput. Mol. Sci. 2, 717–733 (2012). doi: 10.1002/wcms.1104 Org. Lett. 17, 5200–5203 (2015). doi: 10.1021/acs.
(i.e., engineered enzymes) or as substrates for site- orglett.5b02532; pmid: 26484983
specific modulation is becoming more accessible 7. D. G. Brown, J. Boström, Analysis of Past and Present
and creating new opportunities for producing novel Synthetic Methodologies on Medicinal Chemistry: Where 31. Z. Wang, A. G. Herraiz, A. M. Del Hoyo, M. G. Suero, Generating
therapeutic entities. Academic research continues Have All the New Reactions Gone? J. Med. Chem. 59, carbyne equivalents with photoredox catalysis. Nature 554,
to be an important venue for producing novel 4443–4458 (2016). doi: 10.1021/acs.jmedchem.5b01409; 86–91 (2018). doi: 10.1038/nature25185; pmid: 29388953
reactivity, and rapid application of new methods pmid: 26571338
has the potential to further drive molecule inven- 32. J. Twilton et al., The merger of transition metal and
tion in drug discovery. New technologies such as 8. L. D. Cama, B. G. Christensen, Total synthesis of b-lactam photocatalysis. Nat. Rev. Chem. 1, 0052 (2017). doi: 10.1038/
HTE, automation, and new analytical methods antibiotics IX (±)-1-oxabisnorpenicillin G. Tetrahedron Lett. 19, nature25185; pmid: 29388953
are accelerating the discovery of new reaction 4233–4236 (1978). doi: 10.1016/S0040-4039(01)95189-5
methods. Further, integration of computational 33. C. R. J. Stephenson, T. P. Yoon, D. W. C. Macmillan,
reaction modeling with the vast quantities of 9. J. C. Sheehan, K. R. Henery-Logan, The Total Synthesis Visible Light Photocatalysis in Organic Chemistry
experimental data generated by nanoscale HTE of Penicillin V. J. Am. Chem. Soc. 79, 1262–1263 (1957). (Wiley-VCH, 2018).
has the potential to build more informative mod- doi: 10.1021/ja01562a063
34. A. Noble, S. J. McCarver, D. W. C. MacMillan, Merging photoredox
10. T. N. Salzmann, R. W. Ratcliffe, B. G. Christensen, and nickel catalysis: Decarboxylative cross-coupling of
F. A. Bouffard, A Stereocontrolled Synthesis of carboxylic acids with vinyl halides. J. Am. Chem. Soc. 137,
(+)-Theinamycin. J. Am. Chem. Soc. 102, 6161–6163 (1980). 624–627 (2015). doi: 10.1021/ja511913h; pmid: 25521443
doi: 10.1021/ja00539a040
35. J. A. Terrett, J. D. Cuthbertson, V. W. Shurtleff,
11. J. L. Horsley-Silva, H. E. Vargas, New Therapies for Hepatitis C D. W. C. MacMillan, Switching on elusive organometallic
Virus Infection. Gastroenterol. Hepatol. 13, 22–31 (2017). mechanisms with photoredox catalysis. Nature 524, 330–334
pmid: 28420944 (2015). doi: 10.1038/nature14875; pmid: 26266976

12. J. L. Kim et al., Crystal structure of the hepatitis C virus 36. E. B. Corcoran et al., Aryl amination using ligand-free Ni(II)
NS3 protease domain complexed with a synthetic NS4A salts and photoredox catalysis. Science 353, 279–283 (2016).
cofactor peptide. Cell 87, 343–355 (1996). doi: 10.1016/ doi: 10.1126/science.aag0209; pmid: 27338703
S0092-8674(00)81351-3; pmid: 8861917
37. C. P. Johnston, R. T. Smith, S. Allmendinger, D. W. C. MacMillan,
13. A. H. Hoveyda, A. R. Zhugralin, The remarkable metal- Metallaphotoredox-catalysed sp3-sp3 cross-coupling of
catalysed olefin metathesis reaction. Nature 450, 243–251 carboxylic acids with alkyl halides. Nature 536, 322–325 (2016).
(2007). doi: 10.1038/nature06351; pmid: 17994091 doi: 10.1038/nature19056; pmid: 27535536

14. Å. Rosenquist et al., Discovery and development of simeprevir 38. Y. Li, P. C. Cirino, Recent advances in engineering proteins for
(TMC435), a HCV NS3/4A protease inhibitor. J. Med. Chem. biocatalysis. Biotechnol. Bioeng. 111, 1273–1287 (2014).
57, 1673–1693 (2014). doi: 10.1021/jm401507s; doi: 10.1002/bit.25240; pmid: 24802032
pmid: 24446688
39. C. K. Savile et al., Biocatalytic asymmetric synthesis of chiral
15. D. Niu, D. Liu, J. D. Moore, G. Xu, Y. Sun, Y. Gai, D. Tang, amines from ketones applied to sitagliptin manufacture.
Y. S. Or, Z. Wang, US20090005387A1 (2009). Science 329, 305–309 (2010). doi: 10.1126/science.1188934;
pmid: 20558668
16. J. A. McCauley et al., Discovery of vaniprevir (MK-7009),
a macrocyclic hepatitis C virus NS3/4a protease inhibitor. 40. M. D. Truppo, Biocatalysis in the Pharmaceutical Industry:
J. Med. Chem. 53, 2443–2463 (2010). doi: 10.1021/jm9015526; The Need for Speed. ACS Med. Chem. Lett. 8, 476–480
pmid: 20163176 (2017). doi: 10.1021/acsmedchemlett.7b00114;
pmid: 28523096
17. S. Harper et al., Discovery of MK-5172, a Macrocyclic
Hepatitis C Virus NS3/4a Protease Inhibitor. ACS Med. 41. K. W. Knouse et al., Unlocking P(V): Reagents for chiral
Chem. Lett. 3, 332–336 (2012). doi: 10.1021/ml300017p; phosphorothioate synthesis. Science 361, 1234–1238 (2018).
pmid: 24900473 doi: 10.1126/science.aau3369

18. K. Bjornson et al., Preparation of N-(3-alkyl- and 3-
carbocyclyl)prolyl-1-aminocyclopropanecarboxylic acid
peptides as inhibitors of hepatitis C virus. WO2014/008285
(2014).

Campos et al., Science 363, eaat0805 (2019) 18 January 2019 7 of 8