The Science

CONTENTS 1116

7 DECEMBER 2018 • VOLUME 362 • ISSUE 6419 Adapting tissue
regeneration

CREDITS: (TOP TO BOTTOM) JOSHUA BIRD/SCIENCE; STEPHAN SCHMITZ/FOLIO ART; IMAGEBROKER/ALAMY STOCK PHOTO 1100 1095 DEMOTION DISMAYS RESEARCHERS 1113 CLIMATE CHANGE AND MARINE Downloaded from http://science.sciencemag.org/ on December 10, 2018
AT STORIED DANISH MUSEUM MASS EXTINCTION
NEWS Merger with biology department could The end of the Permian Period was
undermine research By G. Vogel catastrophic for life in high-latitude
IN BRIEF regions By L. Kump
FEATURES
1088 News at a glance ▶ RESEARCH ARTICLE P. 1130
1096 TAKING AIM
IN DEPTH After her own violent childhood, 1114 BIOENERGETICS THROUGH
emergency physician Rebecca THICK AND THIN
1090 WHAT NOW FOR HUMAN Cunningham is jump-starting research to Membrane fluidity influences
GENOME EDITING? prevent gun deaths in kids By M. Wadman the efficiency of oxidative energy
Claimed creation of CRISPR-edited metabolism By E. A. Schon
babies triggers calls for international ▶ PODCAST
oversight By J. Cohen ▶ REPORT P. 1186
1100 AT ARM’S LENGTH
1091 For China, a CRISPR first goes too far Major private research funders make 1116 ENDOTHELIAL CELL ADAPTATION
By D. Normile secretive offshore investments, raising IN REGENERATION
1092 UNCERTAINTY BOOSTS BREXIT ethical concerns By C. Piller Tissue-specific endothelial cells
JITTERS FOR U.K. SCIENTISTS maintain organ homeostasis and
Political turmoil in Parliament threatens ▶ PODCAST instruct regeneration
a disastrous crash out of the European
Union By E. Stokstad INSIGHTS By J. M. Gomez-Salinero and S. Rafii
1094 UNIVERSAL FLU VACCINE IS
‘AN ALCHEMIST’S DREAM’ BOOKS ET AL. 1118 MASTERING BOARD GAMES
The rapidly changing virus and a A single algorithm can learn to play
complex immune response stymie 1104 BOOKS FOR BUDDING SCIENTISTS three hard board games By M. Campbell
vaccine developers By J. Cohen
PERSPECTIVES ▶ EDITORIAL P. 1087; REPORT P. 1140
1122
1111 BARRIER(LESS) ISLANDS POLICY FORUM
SCIENCE sciencemag.org No stopping 1D crystals
1119 FLAWED ANALYSES OF U.S. AUTO FUEL
By B. Kahr and M. D. Ward ECONOMY STANDARDS
A 2018 analysis discarded at least $112
▶ REPORT P. 1135 billion in benefits By A. M. Bento et al.

1112 TOWARD A CHEMICAL VACCINE LETTERS
FOR MALARIA
A high-throughput screen puts us on 1122 MODEL VS. EXPERIMENT TO PREDICT
the road to protecting populations CROP LOSSES
against malaria
By C. Parmesan et al.
By M. A. Phillips and D. E. Goldberg 1122 Response By C. A. Deutsch et al.

▶ RESEARCH ARTICLE P. 1129 1123 NO CONFLICT OF INTEREST IN
DATA MONITORING
Published by AAAS
By J. L. Halperin

7 DECEMBER 2018 • VOL 362 ISSUE 6419 1083

CONTENTS 1113 & 1130

7 DECEMBER 2018 • VOLUME 362 • ISSUE 6419 Warming and hypoxia drove
Permian extinction

RESEARCH 1140 COMPUTER SCIENCE 1206 Downloaded from http://science.sciencemag.org/ on December 10, 2018
A general reinforcement learning
CREDITS: (TOP TO BOTTOM) E. HAECKEL; ROBERT NEUBECKER IN BRIEF algorithm that masters chess, shogi, 1186 BIOPHYSICS
and Go through self-play D. Silver et al. Viscous control of cellular respiration
1124 From Science and other journals by membrane lipid composition
▶ EDITORIAL P. 1087; PERSPECTIVE P. 1118 I. Budin et al.
REVIEW
1144 BATTERIES ▶ PERSPECTIVE P. 1114
1127 CARBON CYCLE Room-temperature cycling of metal
Animals and the zoogeochemistry of fluoride electrodes: Liquid electrolytes DEPARTMENTS
the carbon cycle O. J. Schmitz et al. for high-energy fluoride ion cells
V. K. Davis et al. 1087 EDITORIAL
REVIEW SUMMARY; FOR FULL TEXT: Chess, a Drosophila of reasoning
dx.doi.org/10.1126/science.aar3213 1149 VALLEYTRONICS
A valley valve and electron beam By Garry Kasparov
RESEARCH ARTICLES splitter J. Li et al.
▶ PERSPECTIVE P. 1118; REPORT P. 1140
1128 HUMAN GENOMICS 1153 QUANTUM MATERIALS
Early human dispersals within the Photonic crystals for nano-light in 1206 WORKING LIFE
Americas J. V. Moreno-Mayar et al. moiré graphene superlattices A short guide to working remotely
S. S. Sunku et al.
RESEARCH ARTICLE SUMMARY; FOR FULL TEXT: By Paul N. Frater and Lauren L. Sullivan
dx.doi.org/10.1126/science.aav2621 1156 MICROBIOLOGY
Salmonella persisters undermine host ON THE COVER
1129 ANTIMALARIALS immune defenses during antibiotic Starting from random
Open-source discovery of chemical leads treatment D. A. C. Stapels et al. play and given no
for next-generation chemoprotective domain knowledge
antimalarials Y. Antonova-Koch et al. 1161 HUMAN GENETICS except the game rules,
Quantifying the contribution the AlphaZero program
RESEARCH ARTICLE SUMMARY; FOR FULL TEXT: of recessive coding variation to taught itself to play
dx.doi.org/10.1126/science.aat9446 developmental disorders chess, shogi, and Go,
▶ PERSPECTIVE P. 1112 H. C. Martin et al. defeating a world cham-
pion program in each
1130 CLIMATE IMPACTS 1165 CANCER
Temperature-dependent hypoxia A mechanistic classification of clinical game. Blue translucent pieces represent
explains biogeography and severity of phenotypes in neuroblastoma AlphaZero’s possible moves; percentages
end-Permian marine mass extinction S. Ackermann et al. indicate the predicted outcome. A single
J. L. Penn et al. algorithm that can master several complex
SIGNAL TRANSDUCTION problems is an important step toward
RESEARCH ARTICLE SUMMARY; FOR FULL TEXT: 1171 LZTR1 is a regulator of RAS creating a general-purpose machine learn-
dx.doi.org/10.1126/science.aat1327 ing system to tackle real-world problems.
▶ PERSPECTIVE P. 1113 ubiquitination and signaling See pages 1087, 1118, and 1140.
J. W. Bigenzahn et al. Image: DeepMind Technologies Limited
REPORTS
1177 Mutations in LZTR1 drive human Science Staff ............................................1086
1131 POLYMERS disease by dysregulating RAS New Products............................................1193
Semiconducting polymer blends that ubiquitination M. Steklov et al. Science Careers ....................................... 1194
exhibit stable charge transport at high
temperatures A. Gumyusenge et al. 1182 MOLECULAR BIOLOGY
A DNA methylation reader complex that
1135 NANOMATERIALS enhances gene transcription
Building two-dimensional materials one C. J. Harris et al.
row at a time: Avoiding the nucleation
barrier J. Chen et al.

▶ PERSPECTIVE P. 1111

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1086 7 DECEMBER 2018 • VOL 362 ISSUE 6419 sciencemag.org SCIENCE

Published by AAAS

EDITORIAL

Chess, a Drosophila of reasoning

T he recent world chess championship saw Mag- braries of opening and endgame moves, AlphaZero starts
nus Carlsen defend his title against Fabiano out knowing only the rules of chess, with no embedded
Caruana. But it was not a contest between the human strategies. In just a few hours, it plays more
two strongest chess players on the planet, only games against itself than have been recorded in human
the strongest humans. Soon after I lost my re- chess history. It teaches itself the best way to play, reeval-
match against IBM’s Deep Blue in 1997, the short uating such fundamental concepts as the relative values

window of human-machine chess competition of the pieces. It quickly becomes strong enough to defeat

slammed shut forever. Unlike humans, machines keep the best chess-playing entities in the world, winning 28, Garry Kasparov
is the former world
getting faster, and today a smartphone chess app can drawing 72, and losing none in a victory over Stockfish. chess champion
and the author of
be stronger than Deep Blue. But as we see with the I admit that I was pleased to see that AlphaZero had Deep Thinking:
Where Machine
AlphaZero system (see pages 1118 and 1140), machine a dynamic, open style like my own. The conventional Intelligence Ends Downloaded from http://science.sciencemag.org/ on December 10, 2018
and Human
dominance has not ended wisdom was that machines Creativity Begins.
He is chairman of
the historical role of chess as would approach perfection the Human Rights
Foundation, New
a laboratory of cognition. with endless dry maneuver- York, NY, USA.
[email protected]
Much as the Drosophila ing, usually leading to drawn

melanogaster fruit fly be- games. But in my observa-

came a model organism for tion, AlphaZero prioritizes

geneticists, chess became a piece activity over material,

Drosophila of reasoning. In preferring positions that to

the late 19th century, Alfred my eye looked risky and ag-

Binet hoped that understand- gressive. Programs usually re-

ing why certain people ex- flect priorities and prejudices

celled at chess would unlock of programmers, but because

secrets of human thought. AlphaZero programs itself,

Sixty years later, Alan Turing I would say that its style re-

wondered if a chess-playing flects the truth. This superior

machine might illuminate, in understanding allowed it to

the words of Norbert Wiener, outclass the world’s top tradi-

“whether this sort of ability tional program despite calcu-

represents an essential dif- lating far fewer positions per

ference between the poten- second. It’s the embodiment
tialities of the machine and “…machine dominance has not of the cliché, “work smarter,

the mind.” ended the historical role of chess not harder.”
Much as airplanes don’t AlphaZero shows us that
flap their wings like birds, as a laboratory of cognition.” machines can be the experts,

machines don’t generate chess not merely expert tools. Ex-

moves like humans do. Early programs that attempted it plainability is still an issue—it’s not going to put chess

CREDITS: (INSET) DEEPMIND TECHNOLOGIES LIMITED; (RIGHT) IGOR KHODZINSKIY were weak. Success came with the “minimax” algorithm coaches out of business just yet. But the knowledge it

and Moore’s law, not with the ineffable human combina- generates is information we can all learn from. Alpha-

tion of pattern recognition and visualization. This prosaic Zero is surpassing us in a profound and useful way,

formula dismayed the artificial intelligence (AI) crowd, a model that may be duplicated on any other task or

who realized that profound computational insights were field where virtual knowledge can be generated.

not required to produce a machine capable of defeating Machine learning systems aren’t perfect, even at a

the world champion. closed system like chess. There will be cases where an

But now the chess fruit fly is back under the micro- AI will fail to detect exceptions to their rules. There-

scope. Based on a generic game-playing algorithm, fore, we must work together, to combine our strengths.

AlphaZero incorporates deep learning and other AI tech- I know better than most people what it’s like to com-

niques like Monte Carlo tree search to play against itself pete against a machine. Instead of raging against

to generate its own chess knowledge. Unlike top tradi- them, it’s better if we’re all on the same side.

tional programs like Stockfish and Fritz, which employ

many preset evaluation functions as well as massive li- –Garry Kasparov

10.1126/science.aaw2221

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Published by AAAS

NEWS 31% Increase in reported measles cases worldwide in 2017, according to the
World Health Organization. It blamed the 1-year rise partly on antivaccine
messages in Europe and the collapse of Venezuela’s health system.
Measles killed an estimated 110,000 people in 2017, most of them children.

IN BRIEF Brazil drops climate summit
Edited by Jeffrey Brainard
SC I E N C E P O L I CY | Brazil last week
SPACE SCIENCE withdrew its offer to host the 2019 United
Nations Climate Change Conference,
Sample return probe arrives at asteroid signaling a shift in the country’s stance
on global warming. President Michel
Temer’s administration cited budgetary Downloaded from http://science.sciencemag.org/ on December 6, 2018
constraints to explain the withdrawal,
A fter a 2-year journey, OSIRIS-REx, NASA’s $800 million aster- but President-elect Jair Bolsonaro, a far- PHOTO: NASA’S GODDARD SPACE FLIGHT CENTER/UNIVERSITY OF ARIZONA
oid sample return mission, arrived at its target, an ancient, right politician who will take office on
half-kilometer-wide space rock called Bennu, in search of clues 1 January 2019, later said he took part in
to the formation of the solar system. On 3 December, the space- the decision. Bolsonaro argues that the U.N.
craft pulled to within 20 kilometers of the diamond-shaped as- climate treaty, known as the Paris agree-
teroid. In January 2019, Bennu will become the smallest object ment, threatens the country’s sovereignty
circled by a spacecraft when OSIRIS-REx enters an orbit 1.25 kilo- over the Amazon; his pick as minister of for-
meters from the surface, enabling it to study the asteroid in detail. eign affairs, Ernesto Araújo, recently wrote
The probe will spend more than a year scouting for sampling sites that climate change is a “dogma” used
and in mid-2020 will swoop close enough to gather up to 2 kilograms in a globalist plot to hurt capitalism for
of dust and gravel using a 3-meter robotic arm. A capsule containing the benefit of China. Scientists and envi-
that haul will return to Earth in 2023—the first materials NASA will ronmentalists denounced the conference
have returned from space since the Apollo moon rocks. decision as ceding Brazil’s leadership role in
combatting global climate change.
1088 7 DECEMBER 2018 • VOL 362 ISSUE 6419
Gene drive moratorium blocked

B I OT EC H N O LO GY | For the second time in
2 years, a United Nations body last week
voted down a controversial proposal to
ban “gene drives,” technology that can
rapidly spread one or more genes through
animals in the wild and might be used to
control disease-causing mosquitoes and
other harmful organisms. Instead, the
Convention on Biological Diversity, meet-
ing in Sharm El Sheikh, Egypt, called on
governments to conduct risk assessments
before releasing gene drive organisms
in the wild and to get informed consent of
local communities or indigenous peoples.
Scientists had argued against a morato-
rium, citing the research’s potential in the
fight against malaria, for example, whereas
advocacy groups warned that gene drive
organisms could have unintended conse-
quences beyond the target populations.
In a separate decision, the convention
rejected a hotly debated proposal requir-
ing researchers to get permission from a
country before studying publicly available
genetic data on organisms originating
there. Scientists had warned that the plan
would stifle research (Science, 6 July, p. 14).
Conference delegates agreed only to com-
mission further study of the issue.

sciencemag.org SCIENCE

Published by AAAS

ENERGY Downloaded from http://science.sciencemag.org/ on December 6, 2018

Offshore mapping blasts off

I n a reversal, the U.S. National Oceanic and
Atmospheric Administration has agreed to allow
five oil and gas firms to conduct seismic
surveys—which use blasts of sound to map seafloor
geology—off the Atlantic coast from New Jersey to
Florida. The decision is certain to draw legal chal-
lenges from environmental groups, who say the agency
has underestimated the number of whales, turtles, and
other sea creatures likely to be harmed or bothered by
the intense noise from submerged air guns. The move
is part of a larger effort by President Donald Trump’s
administration to relax restrictions on offshore drilling
imposed by former President Barack Obama. Most
Atlantic coastal states oppose such development, worry-
ing it could harm tourism and fishing industries.

Underwater air gun bursts used for oil exploration off the U.S. Atlantic coast will create noise shown elsewhere to injure and disrupt migrations of whales and dolphins.

PHOTO: CHRISTIAN ÅSLUND Feynman’s unwelcomed prize sold Facebook that she had “chosen to open the the third. Fox Broadcasting and National
door to other deserving personalities.” The Geographic, which have aired Cosmos, say
PHYSICS | Richard Feynman, the Five Star Movement came to power in April, they are investigating the allegations, as did
iconoclastic physicist who helped lay the promising to scrap a law from the previous the American Museum of Natural History
theoretical foundation for modern particle government that had made 10 childhood in New York City, where Tyson directs the
physics, detested prizes and honors—so vaccinations mandatory. In 2017, Italy Hayden Planetarium.
much so that he considered refusing his reported 5098 cases of measles, a third of all
share of the 1965 Nobel Prize in Physics. reported cases in the European Union. DeepMind aces protein folding
Last week, Feynman’s heirs parted with
the irksome award, as Sotheby’s in New Celebrity astrophysicist accused CO M PU T E R SC I E N C E | Mastering chess
York City auctioned it for $975,000. Fifty- and Go was just for starters. Fresh off its
three years ago, Feynman’s third of the #METOO | Astrophysicist and science board-game triumphs, the Google-owned
prize money totaled $18,333—$129,000 in communicator Neil deGrasse Tyson came artificial intelligence firm DeepMind took top
today’s dollars. He said he was going to under investigation last week because of honors on 2 December in the 13th Critical
use the cash to pay his taxes. In a separate sexual misconduct allegations from three Assessment of Structure Prediction, a bi-
auction this week, Christie’s fetched nearly women. Ashley Watson, former assistant annual competition aimed at predicting the
$2.9 million for another relic of science on the documentary series Cosmos, which 3D structure of proteins. Competing teams
history, a 1954 letter in which Albert Tyson has periodically hosted, told Patheos, were given the linear sequence of amino
Einstein writes, “The word God is for me an interfaith dialogue website, that she acids for 90 proteins, for which the 3D shape
nothing but the expression of and product quit because of his inappropriate sexual was known but not yet published. Teams
of human weaknesses.” advances and comments. Physicist Katelyn then computed how those sequences would
Allers of Bucknell University in Lewisburg, fold up. Though DeepMind had not previ-
Italy dismisses health experts Pennsylvania, says Tyson groped her at an ously joined this competition, the predictions
afterparty of an American Astronomical of its AlphaFold software were more accurate
PU B L I C H E A LT H | Italian Minister of Society event in 2009. Patheos also reported than those of its 97 competitors. DeepMind
Health Giulia Grillo on 3 December fired 30 a year ago that musician Tchiya Amet said built on previous algorithm strategies; one
experts serving on the 56-member National Tyson drugged and raped her when they of them predicts the distance in 3D space
Health Council, sparking fears that she were graduate school classmates in 1984. between every pair of amino acids in a
could replace them with vaccine skeptics. In a Facebook post, Tyson claimed the first sequence, based on analyses of thousands
Grillo, who belongs to the vaccine-skeptic two incidents were misinterpreted gestures of known amino acid sequences and their
populist party Five Star Movement, wrote on for which he apologized, and he denied observed, folded protein structures.

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IN DEPTH Downloaded from http://science.sciencemag.org/ on December 6, 2018

BIOLOGY

What now for
human genome
editing?

Claimed creation of
CRISPR-edited babies
triggers calls for
international oversight

By Jon Cohen

F ew seemed more surprised by the tide this,” Doudna says. “By the end of the dinner It seems unlikely history will view He
of outrage unleashed by the claim that he was pretty upset and left quite abruptly.” in the same light as Edwards, who won a
the first gene-edited babies had been Nobel Prize, but the Chinese researcher cer-
created with the revolutionary lab tool Bioethicist Alta Charo of the University tainly is a disrupter. His claim has triggered
called CRISPR than He Jiankui, the of Wisconsin Law School in Madison says widespread calls for mechanisms to prevent
He seemed “quite sincere” in his aim to

scientist responsible. On the eve of the engineer babies who would not suffer the others from germline editing humans until

International Summit on Human Genome illness and stigma that had plagued their there’s an international consensus that the

Editing in Hong Kong, China, last week, He, HIV-infected father. He appeared to believe CRISPR technology has matured and there’s

a researcher at nearby Southern University of he had complied with ethical guidelines a convincing medical need. And it has

Science and Technology in Shenzhen, China, for what’s known as germline editing— sparked concern that his actions could set

had dinner at the city’s Le Méridien Cyber- creating heritable alterations in early em- back less problematic applications of gene

port with a few of the meeting’s organizers. bryos, sperm, or eggs. “That kind of rocked editing: treating diseases by editing non-

The news of He’s claim had just broken, and me back,” Charo says. “He talked about germ cells, which do not pass their DNA to PHOTOS: (TOP TO BOTTOM) ANTHONY KWAN/BLOOMBERG/GETTY IMAGES; ISAAC LAWRENCE/AFP/GETTY IMAGES

shock waves were starting to reverberate. But Robert Edwards, the ‘father’ of IVF [in vitro future generations. “I do hope that this very

the reports were still so fresh that the diners fertilization]. I got the strong impression visible misadventure does not cause a cloud

sat in the restaurant without being disturbed. that he saw Robert Edwards as a kind of over the entire area of gene editing for ther-

“He arrived almost defiant,” says Jennifer hero, a paradigm breaker, a disrupter, and apeutic benefit,” says Francis Collins, direc-

Doudna, who did landmark CRISPR work at that he wanted to model himself after that.” tor of the U.S. National Institutes of Health

the University of California (UC), (NIH) in Bethesda, Maryland, who

Berkeley. She and the other con- issued an unusually blunt con-

ference organizers politely asked demnation of He’s work. “I think

He questions about the scientific that would be utterly irrational.”

details and rationale of his work, First, though, scientists, ethi-

the permissions he had secured to cists, and government officials are

conduct it, and how he recruited trying to understand how and why

hopeful parents to participate and He staged this experiment, whether

informed them about risks. He it accomplished the limited success

asked them whether his planned he claims, and whether the babies

talk 2 days later should include are healthy. In a hastily arranged,

data about the twin girls, who had hourlong session at the summit, He

a gene altered to make them resis- reported that in one of the twins,

tant to HIV infection. “We were all his team had successfully mutated

like, ‘Uh, yes,’” Doudna says. both copies of the gene for CCR5, a

After more than an hour of ques- protein on immune cells that HIV

tioning, He had had enough. “He exploits to establish an infection.

just seemed surprised that people Several of his slides were too dense

were reacting negatively about At the summit, Nobel laureate David Baltimore condemned He Jiankui’s work. with information for the audience

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NEWS

For his talk at last week’s summit, He Jiankui was For China, a CRISPR first goes too far Downloaded from http://science.sciencemag.org/ on December 6, 2018
accompanied by security guards because of threats.
By Dennis Normile, in Shanghai, China
to immediately digest. But closer analysis led
many researchers to assert later that both Does a Chinese scientist’s claim that he used CRISPR to create two baby girls resistant
girls had evidence of at least one normal to HIV show that research ethics here are more permissive than elsewhere? Many Chi-
CCR5 gene, which would mean they were nese researchers dispute the notion, as do experts elsewhere. “I still believe there is no
completely susceptible to the AIDS virus. ethical divide between China and the West,” says Reidar Lie, a bioethicist at the Univer-
What’s more, He has not yet tested whether sity of Bergen in Norway who has written extensively about China’s bioethical issues.
HIV can infect cells taken from the girls. “This is clear,” he says, from the reactions of ministries, institutions, and scientists who
have forcefully condemned the study, by He Jiankui of the Southern University of Sci-
At the summit’s end, organizers called for ence and Technology (SUST) in Shenzhen, China. Lie adds that He “shares the same
an independent assessment of He’s work. characteristic as many other scientists at the frontiers of knowledge: overestimating
Some take comfort in the doubts. “I would the benefits of their own research, and underestimating the risks.”
actually hope … there’s not genome-edited
humans brought into this world yet,” says Yet in the wake of the scandal, some are calling for tighter regulations and better
pediatrician Matthew Porteus of Stanford oversight. “There is an urgent need for a national ethics review committee,” former
University in Palo Alto, California, one of the Vice Minister of Health Huang Jiefu told Global Times, a daily tabloid and website
organizers. “It just puts a pit in my stomach.” controlled by the Chinese Communist Party. Currently, every hospital and institute has
its own ethics committee, but many lack the medical, ethical, and legal expertise to
He said his team has a plan for long-term review cutting-edge procedures, Huang said. Lie agrees that there are gaps in China’s
follow-up of the twins’ health, although he regulatory efforts, but says the existing framework just needs strengthened enforce-
did not explain who would fund it. To the re- ment powers and upgraded expertise.
lief of many at the meeting, He did present
extensive, if preliminary, data indicating that Many questions remain about He’s work, including where he did it, how it was fi-
CRISPR had not made unwanted “off-target” nanced, and whether his scientific claims are valid (see main story, p. 1090). An official
cuts in the genomes of the babies, a key safety investigation by a joint team from Guangdong province and the city of Shenzhen is
concern in genome editing. During the ques- ongoing, and SUST has announced its own inquiry. He himself has not publicly spoken
tions, He revealed that a second woman is since he presented his work at a gene-editing meeting on 28 November and did not
pregnant with a gene-edited baby. A paper respond to requests for comment. But some details about his work have emerged.
on the twins is being considered by a peer-
reviewed journal, He said, adding he had In an online report that was later removed, for instance, Sanlian Life Week magazine
been dissuaded from posting it as a preprint. described how He turned to the HIV/AIDS support network Baihualin China League to
(He did not return requests for comment.) help recruit couples in which the man was infected with HIV. One told the magazine he
and his wife dropped out of the study because he was “unwilling to be a guinea pig,”
Taking the podium after He’s talk, David according to a copy of the article shared on Twitter. The network’s head said he regret-
Baltimore, a Nobel laureate from the Cali- ted his collaboration with He: “I am very worried about these families and children,” he
fornia Institute of Technology in Pasadena wrote in a statement.
who also helped organize the meeting, de-
cried the “failure of self-regulation” by He Until now, China’s share in the CRISPR revolution was a source of national pride. Chi-
and the scientific community. The central nese scientists were the first to create gene-edited monkeys, in 2014, and produced the
problem, Baltimore tells Science, is that “we first ever gene-edited human embryos a year later. In 2016, they became the first to start
had no authority to stop him,” which he says clinical trials using CRISPR to alter genes in somatic cells, which are not passed on to the
“is the dilemma in trying to police the inter- next generation; today, 10 CRISPR-related trials to treat diseases such as cancer and HIV/
national scientific world.” AIDS are recruiting patients in China, more than in the rest of the world combined. But the
scientific community “was nearly unanimous” that He’s work crossed a red line, says Wei
At the summit’s end, the organizing Wensheng, a molecular biologist at Peking University in Beijing. In a statement typical of
panel, which had representatives from eight many issued over the past week, the Chinese Academy of Medical Sciences in Beijing said
countries, concluded that He’s experiment gene editing is “still at a basic stage,” and that changing the germ line should be off limits.
was irresponsible, violated international
norms, failed to meet ethical standards, did He appears to have violated the Ethical Guiding Principles on Human Embryonic
not have a sufficient medical justification, Stem Cell Research, a brief document promulgated jointly by the health and science
and lacked transparency. Their statement ministries in December 2003 that prohibits implanting human embryos created for
mirrored reactions in China (see sidebar). research purposes into the womb. But the guidelines do not specify any penalties for
noncompliance. “In some countries, such activity would lead to imprisonment, but
The organizer’s statement noted the China still lacks a relevant legal and policy framework,” bioethicist Zhai Xiaomei of the
promise of heritable germline editing but Chinese Academy of Medical Sciences and Peking Union Medical College told China
said it still remained too risky. The state- Science Daily. She called for politicians to strengthen legislation as soon as possible.
ment disappointed some by not demanding
a strict moratorium, instead calling for “a Meanwhile, the news fascinated the Chinese public, according to the website What’s on
rigorous, responsible translational pathway Weibo, which tracks China’s most popular social media platform. “In 100 years time,
toward such trials.” The meeting organiz- this might be considered pioneering work,” said one comment. “This is unfortunate
ers pointedly noted that germline editing for the children, it is unfortunate for China, and it is unfortunate for mankind,” another
would require “strict independent over- Weibo user countered, reflecting the majority view.
sight” but offered no specific recommenda-
tions for how that might be done. “What He did will almost inevitably have a backlash from the public and possibly from
regulators,” says Wei, who worries that the actions of a single research group gone rogue
Several commenters recalled the biology will trigger new rules that could have punishing implications for legitimate research.
community’s response to the advent of ge-
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SCIENCE sciencemag.org

Published by AAAS

NEWS | IN DEPTH

time raised the specter of DNA-engineered about to launch a trial to do that, “I spent POLICY

microbes escaping from labs and wreaking the next 45 minutes telling him this was a Uncertainty
boosts Brexit
havoc. Baltimore, who played a prominent terrible thing to do and he needed to stop jitters for
U.K. scientists
role in the famed 1975 Asilomar conference immediately and talk to more people, par-
Political turmoil in
on that topic, says the field figured out a way ticularly people in China. My regret is I Parliament threatens a
disastrous crash out
to control the use of recombinant DNA tech- didn’t go public.” of the European Union

nology. “We never had any international au- To others, He was more coy about his By Erik Stokstad

thority, but we got international agreement, actions. “If I had any sense that he was U .K. scientists dreading the coun-
try’s impending departure from the
and, as far as I know everybody lived up to it.” actually trying to do this I would have or- European Union, known as Brexit,
now face possible outcomes rang-
In the United States, NIH established a Re- ganized a meeting with him and others,” ing from undesirable to potentially
disastrous—with an outside chance
combinant DNA Advisory Committee (RAC) says William Hurlbut, a physician and ethi- of a last-minute reprieve. Two and a half
years after a divisive popular vote to leave
to oversee related work that received federal cist at Stanford who met with He a handful the European Union, against the wishes of
most scientists, politicians must soon decide
government support. It no longer reviews of times and corresponded regularly with whether the divorce will be orderly or cha-
otic. “Everyone’s just holding their breath,”
many proposals, but, Collins says, “It’s likely him. “I was intentionally trying to slow him says economist Philip McCann of the Uni-
versity of Sheffield in the United Kingdom,
that a reinvented version” could serve as a down and influence his thinking.” part of a team studying the implications of
Brexit. “If it’s a disorderly exit, the conse-
public forum for “intense, scientific debate Collins, Doudna, and many others say quences could be very, very severe.”

about an area of some scientific potential they have difficulty coming up with any ge- On 11 December, Parliament will vote on
a withdrawal agreement that Prime Minis-
but where there are many unknowns—and netic disorders that should even be consid- ter Theresa May reached with the European
Union in November. It lays out the terms
this would certainly be one of them.” ered for germline editing now. Couples who of a costly but smooth departure from the
European Union, starting in March 2019.
James Wilson, who heads the gene therapy have concerns about passing on a disease If the agreement is rejected, the United Downloaded from http://science.sciencemag.org/ on December 6, 2018
Kingdom could crash out instead, trigger-
program at the University of Pennsylvania, mutation can use preimplantation genetic ing chaos at the border, food shortages, and
economic hardship. But a growing number
suggests the U.S. Food and diagnosis (PGD), notes Collins, of politicians, including former science
minister Sam Gyimah, who resigned last
Drug Administration (FDA) a procedure in which research- week to protest the withdrawal agreement,
are now agitating for a second referendum
could serve as an excellent over- ers can screen IVF embryos that might reverse the first one.
and implant only those with-
“I do hope thissight venue of the controversial Ever since that referendum in June 2016,
many U.K. scientists have lamented the loss of
research. But, he notes, the very visible out the mutation. Although EU membership perks that Brexit will mean.
agency would have to forgo its there are instances where par- It will end the free movement of researchers
many confidentiality restric- misadventure ents both have two copies of a across the English Channel and Irish Sea. It
could prevent U.K. researchers from apply-
tions and allow more public does not cause disease gene and are certain to ing to EU grant programs. And the country
discussion of proposals. pass it on to all embryos, those will leave the Euratom treaty, which governs
For now, FDA is not even a cloud over are exceedingly rare, he adds. the operations of the Joint European Torus,
a fusion facility near Oxford, U.K., and give
allowed to review germline the entire area Daley, part of a growing
editing experiments in hu- of gene editing camp that strongly disagrees,
mans. “It’s effectively prohib- counters that PGD doesn’t

ited in the United States,” says for therapeutic work 100% of the time. And,
Harvard Medical School Dean benefits.” he says, “Rarity alone doesn’t
George Daley, a stem cell re- detract from the imperative of

searcher in Boston who was a Francis Collins, trying to give medical support.”
summit organizer. National Institutes Researchers discussing He’s
of Health
The summit triggered a feat frequently refer to the case
discussion about whether the of Martin Cline, a hematologist

United Nations could serve as the home at UC Los Angeles who in 1980 conducted

for an international oversight group, and pioneering gene therapy research in other

its World Health Organization announced countries rather than wait for his own insti-

this week it would establish a team of ex- tution to approve his proposed studies. In the

perts to set guidelines and standards for aftermath of intense media scrutiny, Cline

human genome editing. resigned as chief of his school’s hematology-

An immediate response is needed, oncology division and lost several NIH

Doudna stresses. “I’d love to see the na- grants. “I regret to say this, but I think the

tional science academies from several consequences of my experiment set the field

countries within a month come up with back several years because of all the regula-

a set of draft guidelines that would be tions and oversights,” says Cline, who is re-

somehow affiliated with a RAC-like body,” tired and living in Stinson Beach, California.

she says. Daley agrees. “We have to aspire Cline says he paid a high price for what he

to some kind of a universal agreement now sees as having moved too fast. “I lost

amongst scientists and clinicians about a significant part of a career I loved,” says

what’s permissible,” he says. “Those who Cline, who switched to oncology.

violate those international norms are held Another human genome editing summit is

out in stark relief.” planned for 2021. It will be hard to surpass

Whether He would have consulted with Hong Kong’s drama. “One of our concerns

any oversight body is unclear. Several re- was this was going to be a really boring

searchers say He discussed with them the summit,” Charo says. “Everything you look

idea of implanting edited human embryos. at here, the closer you get, the stranger this

Porteus says when He informed him he was whole story becomes.” j

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Prime Minister Theresa May hopes to persuade
Parliament to accept a plan for an orderly Brexit.

up a role in ITER, a much larger fusion re- United Kingdom would leave the European Regardless of how the United Kingdom Downloaded from http://science.sciencemag.org/ on December 6, 2018
search reactor being built near Cadarache Union’s aviation regulations. New customs departs, it will have to negotiate new sci-
PHOTO: THIERRY ROGE/AVALON.RED/NEWSCOM in France. checks could strangle trade with Europe. ence agreements with the European Union.
An oversight committee in Parliament last The European Union’s Horizon Europe
Only a few U.K. scientists see more upside week called a lack of preparation at ports program will fund $113 billion in research
than down. Simon Willcock, a tropical ecolo- for consequences such as massive backlogs from 2021 to 2027, and the U.K. govern-
gist at Bangor University in the United King- of trucks “extremely worrying.” ment wants to participate as an associated
dom who supports Brexit, believes liberation member, a status Norway and a few other
from EU regulations will allow the United All that would hurt research. Many re- non-EU countries already have. But as-
Kingdom to set its own science-based pub- agents and other supplies, such as anti- sociate membership will likely cost more
lic policies, including reforms to agricultural bodies and cell-growth media, are imported. than it brings home in grants, and some
subsidies. “I can see the U.K. being more of U.K.-based pharmaceutical companies are fear the government might trim the do-
a risk taker, more of an innovator,” he says. stockpiling drugs used in some clinical trials mestic research budget to compensate. As
as well as routine medicines. Some research- an associate, the United Kingdom might
If both the United Kingdom and the Euro- ers are considering whether they also need to also lose influence over the program’s
pean Union accept the 585-page draft agree- stock up. “You don’t want to feel alarmist, but goals. “There’s no deal we could get that
ment, the landing could be soft. The deal you have to think about the sustainability of would be as good as the one we have at the
doesn’t specifically address research, but it your experiments,” says Jennifer Rohn, a cell moment,” says Anne Glover, head of The
would minimize disruption through a 2-year biologist at University College London who Royal Society of Edinburgh.
extension of the status quo while future par- needs expensive and perishable cell-growth
ticipation in EU programs is negotiated. U.K. media made in Europe. But Oscar Marín, a Nevertheless, both the United Kingdom
researchers could apply for EU grants during developmental neurobiologist at King’s Col- and the European Union would benefit
that period, for example. lege London, says a supply shortage is the from maintaining close scientific ties, so
least of his worries. “To be honest, the disrup- the chances are good for agreements on
The European Union is expected to green- tion will be of such an order that not having funding programs, research regulations
light the withdrawal agreement, which in- the right antibody will be meaningless.” on clinical trials, and Euratom, says Venki
cludes a $50 billion divorce bill and would Ramakrishnan, who heads The Royal So-
require the United Kingdom to follow EU A no-deal exit would also immediately ciety in London. Speed will be crucial, he
laws during the transition without any say void many research agreements. The U.K. says. “The longer the uncertainty, the less of
in them. Those conditions mean the agree- government has said that if the European a player we’ll be in European science.”
ment faces tough prospects in the U.K. Par- Union terminates grants to U.K. teams, the
liament. Hardline Brexit proponents within treasury will take over the payments. But To many, the largest risk that Brexit poses
May’s Conservative Party say it doesn’t offer U.K. researchers couldn’t apply for new EU for science is the same one that threatens the
enough independence. Other opponents in- grants. It’s also not clear whether they could whole United Kingdom: a recession, which
clude “Remainers” in the Labour and Con- continue to lead existing collaborations would jeopardize recent large increases in
servative parties, who argue that even a soft with European partners. The legal status of domestic research funding and could cause
Brexit would be too damaging. joint clinical trials—about 40% of U.K. tri- a brain drain. The end of free movement
als include sites in the European Union—is with the European Union also has “huge
A deadlocked Parliament could default murky, and how data might be transferred implications for science,” says Naomi Weir,
to a no-deal Brexit, which would send the is uncertain. deputy director of the Campaign for Sci-
value of the pound plummeting 25% and ence and Engineering in London, which
shrink the U.K. economy by 8% in the fol- “We are very concerned about a no-deal advocates for a smooth and affordable re-
lowing months, according to a report re- outcome,” says Beth Thompson, head of search immigration system. A long-awaited
leased last week by the Bank of England. U.K. and EU policy at the Wellcome Trust, a government white paper on immigration is
Airlines flying between the United Kingdom biomedical philanthropy in London. expected to be published this month. Min-
and Europe could be grounded, because the isters have said they will welcome foreign
talent, but Weir worries about an increased
burden on employers and an advisory com-
mittee proposal for a £30,000 minimum
salary for all immigrants, which could com-
plicate hiring of technical staff.

Some scientists want a do-over. “Brexit
is simply bad for science,” says Paul Nurse,
head of The Francis Crick Institute in Lon-
don. “The best thing would be to go back
and say we made a mistake.” But the politics
of a second referendum are tortuous, and
time is short. As the maelstrom intensi-
fies, many researchers are focusing on their
work. Nurse, however, urges more to speak
out. “The scientific community really has
to indicate why it’s so worried,” he says. “I
don’t think we’ve done enough.” j

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NEWS | IN DEPTH

BIOMEDICINE

Universal flu vaccine is ‘an alchemist’s dream’

The rapidly changing virus and a complex immune response stymie vaccine developers

By Jon Cohen, in Nashville shaped protein because it has many epitopes adults, who are ordinarily the least likely to

that differ little between viral subtypes. So far, die from influenza. Studies found this was

W hat if instead of lining up for a vaccines that feature this portion have under- because exposure to H1N1 triggered strong
flu shot of unknown effectiveness whelmed researchers. “Stem antibodies as a antibody responses to a virus of a different
each fall, people could receive one class are not very potent,” says James Crowe, subtype—likely H3N8—which they had seen
vaccine that protects against all an immunologist at Vanderbilt University as children a few decades before. “Tickle [the
strains and lasts for many years, if here who helped organize the meeting. memory B cells] a little bit and they explode,”

not for life? It could spare incalcu- A handful of other universal flu vac- says Scott Hensley, a molecular biologist at

lable amounts of suffering, and even elimi- cines are now in early human trials. Each the University of Pennsylvania’s Perelman

nate terrifying pandemics. Scientists have one exploits conserved regions of the virus School of Medicine. “And they dominate sub-

spent decades trying to concoct such a “uni- to maximize breadth, and some attempt to sequent immune responses,” causing the re-

versal” flu vaccine and, at times, they seem increase potency with immune stimulants sponse to a new virus to miss its mark. Downloaded from http://science.sciencemag.org/ on December 6, 2018

to have made solid headway. But it remains called adjuvants or other strategies. To learn more about “original antigenic

an “alchemist’s dream,” as one virologist de- David Morens, a pediatrician at NIAID, sin,” NIAID is evaluating proposals for a

clared last month at a gathering on the topic noted that many studies have found that study that would follow infants for up to

organized by the Human Vaccines Project, a antibody levels to the virus’s second surface 7 years to track how their initial influenza

nonprofit based in New York City. exposure impacts later immune re-

New funding has boosted the re- sponses. In the meantime, Hensley

search: $160 million next year from the suggests the first flu vaccine children

National Institute of Allergy and Infec- receive be packed with many versions

tious Diseases (NIAID) in Bethesda, of common human subtypes, a pos-

Maryland, up from $60 million 2 years sible step toward a universal vaccine

ago. But the quest is an exercise in hu- because it should offer broader pro-

mility, leading flu researchers said at tection than seasonal ones.

the meeting. “Every year we learn that Meeting presenters also described

we know less and less about this vi- how computer programs can help

rus,” says Martin Friede, a biochemist guide vaccine design. Ted Ross of the

who coordinates the Initiative for Vac- University of Georgia in Athens ex-

cine Research at the World Health Or- plained that his group scans the DNA

ganization in Geneva, Switzerland. encoding hemagglutinin’s head for

Each year, vaccinemakers concoct a conserved sequences that they can

new preparation that contains harmless then combine into a universal vac-

versions of flu strains in circulation the Universal flu vaccines must outwit ever-changing influenza surface cine. Crowe’s lab starts with antibodies

previous year. These seasonal vaccines proteins, hemagglutinin (orange) and neuraminidase (green). instead. They use a supercomputing

have a mediocre efficacy of 20% to 60%, technique to analyze the shape of bil-

in part because the vaccine is often a poor protein, neuraminidase, better correlate with lions of antibodies and select ones calculated

match for the virus people actually contract protection from disease. Improving seasonal to have the broadest reach; ultimately, they

(Science, 22 September 2017, p. 1222). Other, vaccines by selecting those that best trigger hope to reverse engineer proteins that, used

less obvious factors highlighted at the meet- neuraminidase antibody production is “po- in a vaccine, would trigger these antibodies.

ing also influence the response to the sea- tentially low-hanging fruit,” Morens says. The Lisa Wagar, an immunologist at Stanford

sonal vaccine, including the immune system’s same strategy could also improve the effec- University in Palo Alto, California, has cre-

memory of past exposure to viral variants. tiveness of potential universal vaccines. ated a new testbed for vaccine researchers.

In theory, a universal flu vaccine would Designers of a universal flu vaccine face Instead of monitoring the immune response

work if it contained parts of the virus that another quandary, speakers at the meet- in blood, she simulates the first immune de-

remained the same from year to year and ing noted: an immune phenomenon called fenses an invading virus meets in the respi-

do not vary between strains—so-called con- imprinting. The first influenza virus or flu ratory tract. She has used tonsils, which are

served epitopes. But no one has yet found vaccine children experience has a profound rich in mucosal tissue, taken from children IMAGE: KATERYNA KON/SCIENCE SOURCE

the viral pieces capable of stimulating an impact on the breadth and potency of their to grow tonsil-like “organoids” that can help

immune response that stops most flu vi- immune responses to later infections with evaluate experimental influenza vaccines.

ruses afflicting humans. different flu strains. For example, the infa- At the gathering’s closing, Wayne Koff,

Seasonal vaccines aim to trigger the im- mous 1918 influenza pandemic, which likely who heads the Human Vaccines Project,

mune system’s B cells to produce antibodies killed more than 100 million people, was said it was “sobering” that if a universal

against the top part of hemagglutinin, one of caused by a virus subtype known as H1N1. flu vaccine meeting had been held in the

two main proteins on the surface of influenza (“H” is for hemagglutinin and “N” is for 1960s it would have discussed the same ob-

viruses. Several candidate universal vaccines neuraminidase.) Oddly, the death rate was stacles. “We are really at the beginning of

focus instead on the “stem” of the mushroom- much higher than normal among young the dance,” Koff said. j

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A meteorite in a museum’s courtyard helped inspire
the discovery of a giant impact crater in Greenland.

NATURAL HISTORY tanical Museum and Library, Geological Downloaded from http://science.sciencemag.org/ on December 7, 2018
Museum, and Zoological Museum. The vi-
Demotion dismays researchers sion, says Eske Willerslev, who studies an-
at storied Danish museum cient DNA and heads the museum’s Centre
for GeoGenetics, was to “create a promi-
Merger with biology department could undermine research nent place where citizens could [find] the
best researchers and look over their shoul-
PHOTO: ISTOCK.COM/CARSTENBRANDT By Gretchen Vogel focus on curation and outreach. The other ders.” Research collaborations have since
half will become full faculty within the led to major discoveries about human mi-
O ver the past decade, the 40 research- biology department—including the geo- grations and the effects of climate change
ers at the Natural History Museum logists and astrophysicists. These scientists on biodiversity. Just last month, a team led
of Denmark in Copenhagen have will lose their museum affiliation, and ex- by a museum glaciologist announced in
published more than 100 papers change their curatorial roles for increased Science Advances the discovery of a giant
in Nature and Science, putting it teaching duties. impact crater under Greenland’s ice sheet
among the world’s top research mu- (Science, 16 November, p. 738).
seums. But budget pressures are forcing Divorcing the scientists’ dual roles will
a reorganization that will split museum curtail the fruitful cross-pollination of cu- But the museum is under financial pres-
research from curation and outreach. The ration and research, says Carsten Rahbek, sure. Although it will begin construction
museum’s scientists are dismayed, and who heads the museum’s Center for Macro- next year on a 950 million Danish kroner
several prominent group leaders say they ecology, Evolution and Climate and who is ($144 million) building to house state-of-
may leave. slated to become a biology professor. (The the-art exhibits, the museum has run bud-
center will move with him.) “The curation get deficits in recent years. Last week, it laid
Previously, the museum was its own is driven by the research,” he says. “It’s not off 17 people, including some research staff.
department within the University of Co- like a library where you go borrow a book Moving some of the researchers out of the
penhagen. But last month, the university and then go do cutting-edge research. If you museum and into the biology department—
announced that, as of 1 January 2019, the don’t have a say in how [the collection] de- and boosting their teaching loads—will help
museum will be demoted to a unit within velops, in 2 or 3 years you won’t be able to shore up finances, says Museum Director
the biology department. Roughly half of the use it anymore.” Peter Kjærgaard.
40 researchers will remain part of that unit;
they will give up some of their research to The museum grew out of a 2001 merger Kjærgaard says focusing the museum’s
of the university’s Botanical Garden, Bo- resources on curation and outreach will
make its collections more widely available
for researchers, the public, companies and
nonprofits. John Renner Hansen, dean of
the university’s Faculty of Science, says re-
searchers who want to maintain their mu-
seum affiliation will have to do significant
curation and outreach work. But he argues
that current collaborations can continue.
Labs and offices won’t move at all. “There
are no physical changes, just a change of or-
ganization,” he says.

But the formal separation of the re-
searchers from the museum is damag-
ing, even if it is not physical, says Minik
Rosing, a museum geochemist who is also
slated to join the biology department fac-
ulty. “It’s a redefinition of what a museum
is, and what it means,” he says. Rosing,
Rahbek, and Willerslev all say they may
leave the university if the plans go forward.
“We would prefer to stay and support the
museum, but if its mission changes so
completely, we will have to go elsewhere,”
Rosing says.

The separation is not only bad for the
researchers; public outreach will also suf-
fer, predicts Évelyne Heyer, who heads the
department of eco-anthropology at the Na-
tional Museum of Natural History in Paris.
“It’s not enough to present the collections,”
she says. “You have to teach the people what
the collection can do.” j

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NEWS

FEATURES

Downloaded from http://science.sciencemag.org/ on December 6, 2018

TAKING AIM PHOTO: MELANIE MAXWELL

After her own violent childhood, emergency physician Rebecca Cunningham
is jump-starting research to prevent gun deaths in kids

By Meredith Wadman, in Ann Arbor, Michigan

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ebecca Cunningham has only one est amounts from other agencies or private ing the young scientists who they hope will
kind of memory from her early funders (see table, p. 1098) to tackle a mas- come after them.
childhood: violence. Her father sive problem.
shattered mirrors, tore up the Cunningham’s grant “is unique” in U.S.-
house, and beat and threatened Now, there may be early signs of a thaw. funded gun violence research, and not just
to kill her mother. Cunningham, In March, in the wake of the mass shoot- for its size, says Garen Wintemute, a gun vio-
then less than 5 years old, remem- ing at a Parkland, Florida, high school, Con- lence researcher at the University of Califor-
gress wrote that CDC is free to probe the nia, Davis, who co-authored one paper with
R bers her older sister trying to pro- causes of gun violence, despite the Dickey Cunningham but is not part of this grant. “In
tect her. amendment. (The agency has not done so, the last 20 years this is the first time that an
“When my father would start in with citing a lack of money.) And annual firearm- award has been made not just to do a project,
my mother, my sister would cover my eyes related funding from NIH, according to a but to set up an infrastructure that would al-
and try to hide with me behind the couch,” search of its RePORTER database, roughly low a lot of projects to be done.”
recalls Cunningham, now a 48-year-old tripled after a 2013 presidential directive
emergency physician and researcher at the that was issued in the wake of the mass Although gun rights groups continue to
University of Michigan (UM) here. “The po- shooting at Sandy Hook Elementary School insist that public health scientists steer clear
lice were in and out of the house a lot. If in Newtown, Connecticut. Just as impor- of gun violence, some researchers are feel-
there had been a gun in my home in those tantly, the agency began to flag firearm vio- ing empowered to push back. Last week,
years, my mother certainly would have lence in some of its calls for research. surgeons writing in JAMA Surgery called
been killed.” on CDC to restart its own gun violence re-

One day Cunningham’s father, a lawyer, A heavy toll Downloaded from http://science.sciencemag.org/ on December 6, 2018
called her mother threatening to kill her. Her
mother changed the locks on their New Jer- Firearms are the second-leading cause of death in children in the United States, after motor vehicle crashes.
sey house. She sent Cunningham’s two older In the decade ending in 2016, more children died from gun injuries than from cancer.
siblings to live with a safely distant foster
family. And she bought a handgun. Fatalities of 1–18-year-olds (2006–2016)

Did that pistol make Cunningham and Motor vehicle crashes Cancer SuHocation
her mother safer? Public health experts can’t
answer that question: A 2003 study that ex- 41,216 19,125 12,091
amined whether abused women living apart
from their abusers are safer with a gun was Firearm-related deaths Congenital
inconclusive. No study since has delved into abnormalities
the issue. 22,724
10,809
It’s one of myriad questions about fire-
arms and violence that remain unanswered, Drowning
largely because of a dearth of funding to
explore them. Guns are the second-leading 10,020
cause of death of children and teens in the
United States, after motor vehicle crashes 330
(see graphic, right). In 2016, the most re- Undetermined
cent year for which data are available, they
killed nearly 3150 people aged 1 to 19, ac- 62.6% 30.8% 5.1%
cording to data from the Centers for Disease
Control and Prevention (CDC) in Atlanta. 14,231 7003 1160
Cancer killed about 1850. But this year, Homicide Suicide Accidents
the National Institutes of Health (NIH) in
CREDITS: (GRAPHIC) A. CUADRA/SCIENCE; (DATA) CDC Bethesda, Maryland, spent $486 million re- That’s why Cunningham is now in charge search. And last month, the National Rifle
searching pediatric cancer and $4.4 million of the largest firearm research grant that Association (NRA) in Fairax, Virginia, pro-
studying children and guns, according to its NIH has awarded in at least 30 years. With voked a firestorm when it tweeted that “self-
RePORTER database. $4.9 million from NIH’s Eunice Kennedy important anti-gun doctors” should “stay
Shriver National Institute of Child Health in their lane.” Hundreds of emergency de-
That’s because gun violence research has and Human Development (NICHD), she is partment doctors tweeted back, many in-
been operating under a chill for more than co-directing a 5-year project to build capac- cluding photographs of their scrubs, hands,
2 decades. In 1996, Congress crafted an ity for researching firearm injuries in chil- and shoes bloodied from treating gunshot
amendment, named for its author, then– dren. Cunningham and UM public health victims. More than 40,000 health care pro-
Arkansas Representative Jay Dickey (R), pre- expert Marc Zimmerman are leading 27 sci- fessionals, including Cunningham, signed
venting CDC—the government’s lead injury entists at a dozen institutions in work they an open letter to NRA complaining that the
prevention agency—from spending money hope will carry the field forward for years group has hobbled gun violence research, de-
“to advocate or promote gun control.” after this funding ends in 2022. claring, “This is our lane!”

That law was widely interpreted as ban- The grant is not designed to answer All the same, there’s still little public
ning any CDC studies that probe firearm one particular question. Rather, the goal money for gun research. And given the po-
violence or how to prevent it. The agency’s is to lay out what questions need answer- larizing politics, Cunningham’s team must
gun injury research funding was quickly ing first. The researchers are building a walk a fine line: probing gun violence
zeroed out, and other health agencies grew user-friendly archive of existing data and without being seen as advocating gun con-
wary. The few dozen firearm researchers launching pilot studies. And they are train- trol. But she’s betting that this is the begin-
who persisted were forced to rely on mod-

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NEWS | FEATURES

ning of the end of the funding chill. Her She contacted NICHD to make sure she Cunningham says her early experience
forward-looking NIH award “is more than had not misread its intent. She was told she helps her “understand that people some-
another grant,” she says. “[It’s] the end of had not. She and Zimmerman’s first proposal times buy guns when they think the law
the silencing of a generation of scientists.” was sent back for revisions. But on a second cannot protect them.”
try, it received a perfect score from an NIH
WEARING A WHITE COAT and with the requi- review panel. In late October, Cunningham convened
site stethoscope draped around her neck, the first in-person meeting of the FACTS
Cunningham recently showed visitors One week later, Donald Trump was elected team in a daylong event in a UM conference
around a trauma bay stuffed with monitors, president. Given that NRA had funneled room. The roughly two dozen researchers
tubing, and tanks at UM’s University Hos- $30 million to Trump’s campaign, NIH and handful of trainees present included
pital, which serves Ann Arbor and its rural officials privately fretted about gun re- many of the public health scientists actively
surroundings. She works in the emergency search. “The election makes everything doing firearm research today: grizzled
department here several times a month. (She more complicated,” one administrator epidemiologists who are still standing af-
is also associate vice president for health emailed to another (Science, 20 October ter the 22-year funding drought; surgeons-
sciences research at UM, and the fourth- 2017, p. 286). But in September 2017, the in-training; data mavens; and clinical
leading NIH grantee among U.S. emergency grant money arrived, and Cunningham’s psychologists such as Rinad Beidas, an as-
room doctors.) team went to work, calling itself the Fire- sociate professor at the University of Penn-
arm Safety Among Children and Teens sylvania who has been studying whether
The young trauma patients Cunningham (FACTS) Consortium. and how counseling parents on gun safety
sees here underscore the need for research could be incorporated into routine pediat-
on guns and children. “The teen suicide sur- A generation of scarcity ric visits. Downloaded from http://science.sciencemag.org/ on December 6, 2018
vivors that I remember most clearly are kids
or young adults who have blown off the front During the past 22 years, public funding for “The overarching purpose here is how
of their face,” Cunningham says. “Those are gun violence research has been modest. Private to rebuild the field,” Cunningham told
some of the worst trauma patients I have funders have tried to compensate. the meeting as it opened. “We want more
seen because they are awake and utterly mis- firearm researchers at the end of this who
erable. And they are going to have just dev- FUNDING SOURCE TOTAL FUNDING know what they are doing.”
astating injuries.” (1996–2018)
Their animating principle is that gun
After working her way through college U.S. National Institutes of Health $58 million violence, like any other public health bane,
and medical school, Cunningham did her can be tackled scientifically, divorced from
medical residency at UM in the late 1990s. U.S. Department of Justice $39 million any political agenda. “There is a science to
She spent months staffing an emergency injury prevention,” Cunningham says. She
department 80 kilometers north in Flint, State of California $6 million and others note that decades of studies on
Michigan, an impoverished city where she motor vehicle safety led to evidence-based
saw a different kind of gun violence. After Joyce Foundation $24 million policies such as car seat and seat belt laws,
street shootings, she saw victims “shot in which have dramatically reduced childhood
the leg, shot in the arm, shot in the belly, California Wellness Foundation $10 million motor vehicle fatalities even though many
shot in the chest … often multiple gunshot more cars are on the road.
wound victims in one night. More than Laura and John $20 million
once, the teen was the second in the fam- Arnold Foundation pledged (2018) In the case of firearms, Cunningham
ily to be killed. I cared for young children says, “the person, the gun, the home
caught in crossfire walking to school.” Four months later, a 19-year-old former environment—all are modifiable in some
student gunned down 17 students and way or another. We have not even started to
She was often pregnant with one of her staff at Marjorie Stoneman Douglas High try to address the ways that make the com-
three daughters when she had to sit down School in Parkland. “My inbox was flooded bination safer.”
with a mother to tell her that her child had with researchers wanting to join FACTS—
been shot and killed. It was, she says, “com- even to volunteer,” Cunningham says. The scientists discussed 10 candidate pi-
pletely senseless.” “The idea that the topic is too political to lot projects over 5 hours; Cunningham and
study is passing with the urgency created Zimmerman will soon decide which will
After her residency, Cunningham began after Parkland.” move forward.
2 decades of research studying the impacts
of violence on youth, but for many years she CUNNINGHAM’S OWN sense of urgency pre- One project proposes to enlist focus DATA: FOIA/NIH; NIH REPORTER DATABASE
saw no way to study gun violence in par- dates any news event. “My interest in gun groups of gun owners to craft effective
ticular. “No mentor of mine would touch it.” violence prevention has … roots [in] lived safe storage messages, aiming to curb teen
experience,” she says. After his wife kicked suicide in Michigan’s Upper Peninsula. In
In 2010, Cunningham finally published him out in the mid-1970s, Cunningham’s fa- such rural areas, the rate of suicide by gun
a paper with guns in the title—a survey of ther continued to stalk her and 5-year-old is almost twice that in urban areas of the
handgun access in teens visiting the emer- Cunningham, banging on the front door United States. Another proposed study,
gency department in Flint. Four years later, and breaking windows. To escape him, her a survey, would separately ask teens and
she came across a bigger opportunity. mother began a series of moves to low-rent their gun-owning parents how accessible
apartments in other towns. They relied on the household’s guns are, to reality check
In August 2014, NIH’s child health insti- food stamps while Cunningham attended parents’ views.
tute sent out a broad call for team propos- four schools in 3 years.
als to build research capacity for preventing A third proposal makes the chilling as-
any prominent cause of childhood injury. As “We were terrified,” Cunningham says. “I sumption that it won’t be long until the
Cunningham read the announcement, one was scared my mother would be killed. She next mass school shooting. In its aftermath,
sentence leapt off the page: “Increasingly, was scared she would be killed. My father Megan Ranney, an emergency physician
attention is being paid to firearm-related in- told her not infrequently that he had a gun at Brown University, would study young
jury as a serious public health concern.” and would find her.” The fear only lifted people’s use of social media to characterize
years later, after her father died. post-traumatic stress and anxiety, as well

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Family and friends commemorate DrayQuan Jones, 16, who was shot and killed this spring in Flint, Michigan. Guns disproportionately kill African-American children. Downloaded from http://science.sciencemag.org/ on December 6, 2018

PHOTO: JAKE MAY/THE FLINT JOURNAL-MLIVE.COM/AP PHOTOS as resilience. Fewer than 1% of gun deaths he says, “so it doesn’t happen in the future.” skirts of Ann Arbor, on a forested lot with
in children and teens occur in schools. But He adds of Cunningham: “She made me feel a chicken coop overseen by her daughters.
Ranney believes school shootings may have like my opinion mattered.” Her 77-year-old mother, who is also happily
much broader mental health impacts. remarried, lives nearby. She still has the
But hard-line gun rights groups have re- gun, stored away, unloaded.
Cunningham, who radiates both affabil- fused to work with the team. Only “the most
ity and the decisiveness of a seasoned emer- tame” groups have signed on, David Hemen- Like many U.S. parents, Cunningham
gency physician, ran the meeting as part way, a veteran injury prevention researcher finds her own children affected by gun
pep talk, part crash assignment. She shut at Harvard University’s T.H. Chan School of violence. “My kids come home after those
down digressions and poured on doses of Public Health in Boston, said at the meeting. shootings and they are terrified in school.”
budget reality when suggestions got too am-
bitious. “This is not a democracy, as I tell “It’s year one,” Cunningham replied. But despite powerful public reaction to
my children,” she reminded the group. “There’s more time for more voices.” But school shootings, some experts are not as
she acknowledged that local and na- sanguine about the future of gun research
Given the constraints imposed by the tional NRA chapters had failed to return as Cunningham. “I don’t see this as a turn-
congressional amendment, Cunningham her team’s repeated phone messages and ing point,” says David Studdert, a health
and her team are at pains to emphasize emails. (NRA also did not respond to policy expert at Stanford Law School in Palo
that they are not coming after anybody’s Science’s repeated requests for comment for Alto, California, who’s not part of the FACTS
guns. The official NIH project description this article.) The National Shooting Sports project. And pediatrician Fred Rivara, a
promises to respect “gun ownership as an Foundation in Newtown, the gun industry’s FACTS team member and veteran firearm
important part of the cultural fabric of trade association, declined to sign on be- researcher at the University of Washington
U.S. society.” cause of “concern about the ‘public health’ in Seattle, worries about future funding for
focus,” Bill Brassard, the group’s senior his young trainees.
Cunningham is blunt: “Our goals are not communications director, wrote in refusing
political. We are not aiming to decrease Cunningham’s request. However, Wintemute, who has studied gun
total gun numbers. We respect Second violence for 30 years, thinks this may be a
Amendment rights.” In a statement provided to Science last watershed moment. He notes Cunningham’s
month, Brassard added, “Though we do grant and other new money—his group re-
The team has signed up gun-owning not oppose research per se, too often ‘re- cently received a $5 million award from the
stakeholders to advise them. These include search’ from some in the public health field state of California—plus the groundswell of
groups like Gun Owners for Responsible is biased and designed to advance a pre- physician activity on Twitter. “It’s entirely
Ownership, based in Lake Grove, Oregon, determined antigun policy outcome. … Gun- possible that this is the beginning of a new
and individuals like James Berlin, police related violence is largely a criminal justice mobilization,” he says.
chief and former SWAT team leader in the matter and not a public health issue.”
Detroit suburb of Roseville, Michigan. Cunningham is confident that the prob-
FOR A WOMAN WHO began life at more risk lem of gun violence can be solved with
Berlin, in a phone interview, said he has than most for gun violence, Cunningham science—and with participation from all
turned down other research groups over has landed well. She divorced—because sides. So, she keeps searching for common
the years because “it seemed like they were “marriages are miracles”—then remarried ground. “We are not having any conversa-
trying to find facts that fit their foregone and now co-commands a blended fam- tions here that are an ‘us and them’ narra-
conclusions.” Cunningham’s team struck ily of five teenagers. She lives on the out- tive,” she told scientists at the meeting. “We
him differently. “They are actually trying to are about reducing kids dying.” j
get the answers” on pediatric gun deaths,

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NEWS few years ago, scientists funded Downloaded from http://science.sciencemag.org/ on December 10, 2018
by the Wellcome Trust, one of the
AT ARM’S LENGTH world’s wealthiest private philan- ILLUSTRATION: STEPHAN SCHMITZ/FOLIO ART
thropies, published sobering find-
Major private research funders make secretive ings about the deadly effects of
offshore investments, raising ethical concerns air pollution. In a long-term study
of elderly residents of Hong Kong,
By Charles Piller
A China, those exposed to higher
Published by AAAS levels of smog—especially tiny
particles of soot produced by burning fossil
fuels—were more likely to die of cancer than
people who breathed cleaner air.

The study, published in Cancer Epidemio-
logy, Biomarkers & Prevention in 2016 by
researchers from the University of Hong
Kong and the University of Birmingham in
the United Kingdom, is one of many to high-
light the health threats posed by soot. And
it is just one product of the extensive invest-
ments that Wellcome, with $29.3 billion in
assets, has made in environmental science.
“We aim to stimulate research excellence
and develop global collaborations to drive
change,” the London-based philanthropy
explains on a web page that highlights its
commitment to making “cities healthy and
environmentally sustainable.”

The trust does not highlight, however,
that some of the more than $1.2 billion it has
handed out annually in recent years comes
from investments in companies that contrib-
ute to the same problems the philanthropy
wants to solve. Not long before the Hong
Kong study was published, for example, the
trust became an investor in Varo Energy, a
company based in Cham, Switzerland, that
sells fuel to shipping firms. One of Varo’s
main products is bunker fuel for marine en-
gines: a cheap, sulfurous residue of oil refin-
ing that is a major source of soot pollution.
Particulates billowing from ship stacks con-
tribute to the premature deaths of 250,000
people annually, researchers estimate.

Wellcome didn’t invest directly in Varo.
But according to a trove of confidential
documents known as the Paradise Papers,
many of them leaked from a law firm that
helped manage such deals, Wellcome com-
mitted $50 million to an offshore invest-
ment fund, Carlyle International Energy
Partners, based in the Cayman Islands.
That fund, in turn, owns a stake in the en-
ergy firm. (Wellcome declined to give de-
tails on its offshore holdings.)

Large investors commonly use offshore
funds to maximize returns, in part by re-
ducing the taxes investors would other-
wise pay to their home nations. Though
offshore investments can be legal, they are
controversial—partly because the funds’
activities are nearly always tightly held se-
crets. And Wellcome’s investment in bunker
fuel illustrates a common contradiction
facing some major scientific grantmakers

sciencemag.org SCIENCE

NEWS | FEATURES

involved in offshore investing. Specifically, • The Howard Hughes Medical Institute by parking it in the anonymous numbered

offshore investments can have impacts that in Chevy Chase, Maryland, which accounts made famous by Swiss banks. In

diminish or negate the high-minded social has $20.4 billion in assets, holds at least recent decades, however, the popularity and

experiments, education, and research backed $891 million in offshore funds, from complexity of offshore investing has grown

by science funders, according to a Science in- which it earned $123 million in the year dramatically. Some small nations and

vestigation. And their routine use of offshore ending 31 August 2017, according to territories—including the Cayman Islands,

funds raises questions about transparency, public documents. It declined to discuss Bermuda, and Malta—have aggressively

accountability, and social responsibility. its investments. moved to become offshore havens by prom-

Critics of offshore investing also say that • The Robert Wood Johnson Foundation ising secrecy, light regulation, and low or no

foundations, by lending their sterling repu- in Princeton, New Jersey, which has taxes on profits.

tations to offshore strategies, are helping $10.8 billion in assets, has placed at least As of 2014, at least 8% of the world’s

legitimize tactics that others widely use to $3 billion in offshore havens. Founda- financial wealth—some $7.6 trillion—was

bend or break the law—including inves- tion officials discussed their investing invested in funds based in offshore havens,

tors eager to conceal lawful but extreme tax practices with Science. estimates Zucman, who wrote a seminal

avoidance as well as criminals seeking to • The Bill & Melinda Gates Foundation in 2015 book on the topic. Offshore funds

hide illicit profits and launder money. Such Seattle, Washington, has no apparent in- enabled companies to legally avoid paying

practices deprive governments around the volvement in offshore funds, according to $130 billion in U.S. taxes each year, he es-

world of revenue, the critics note, worsen- the Paradise Papers and public documents. timates. And illegal tax evasion involving

ing economic inequality and undermining • Three other private research funders— offshore funds subtracted an additional

efforts to repair crumbling infrastructure. the David and Lucile Packard Foundation, $35 billion annually. Downloaded from http://science.sciencemag.org/ on December 10, 2018

The secrecy surrounding offshore funds the Gordon and Betty Moore Foundation, In the past, many philanthropies—which

complicates efforts to document exactly and the William and Flora Hewlett national governments ordinarily exempt

how much money major research charities Foundation, all based in Silicon Valley in from most taxes because they are seen as

have moved into such vehicles—or where California—have made offshore invest- providing a public service—would have

the cash ends up. Science gained some in- ments of up to $168 million each, accord- viewed tax avoidance as shameful, says

sight by reviewing publicly available tax ing to the Paradise Papers and public Brooke Harrington, an economist at Copen-

returns and financial statements and by documents. In written statements, the hagen Business School. But no more. In the

searching the roughly 13.4 million leaked foundations said they comply with tax United States, for example, many founda-

documents in the Paradise Papers, more laws but declined to comment otherwise. tion officers regard minimizing taxes “al-

than half of which came from Ap- most as a necessity,” she says. “If

pleby, a global law firm founded in you don’t do that, you’re not fulfill-

Hamilton, Bermuda, and one of the “Shouldn’t we be more than a private ing your responsibility to donors.
world’s leading offshore dealmak- Kind of the way corporate directors

ers. (The papers were shared with investment company that uses its excess will say: ‘It’s our duty to maximize
Science by the International Con- shareholder value, and that in-
sortium of Investigative Journalists cash flow for good?” cludes reducing our tax payments

in Washington, D.C., which ac- Dana Bezerra, Heron Foundation to as close to zero as possible.’”
quired them from the Süddeutsche But some foundation officials

Zeitung newspaper in Munich, Germany.) Foundation officials and philanthropy ex- tell Science that, because their tax burdens

Science examined seven of the largest perts say offshore investment can play an are already low, other factors are more im-

private research funders and found that, ac- important role in enabling those charities portant to their decisions to invest offshore.

cording to conservative estimates, they have to meet their fiduciary responsibility to nur- For example, fund managers increase prof-

in recent years placed and committed more ture their endowments. But the practice also its for themselves and their clients by avoid-

than $5 billion to funds in offshore tax and opens the foundations to intense criticism. ing costly regulatory red tape, says Edmond

secrecy havens. Missing data and a lack of “Foundations that invest in tax havens need Ghisu, chief investment counsel at Robert

precision in many documents, however, to know that … they are alongside criminals, Wood Johnson. Offshore havens often have

suggest the philanthropies’ investments are tax evaders, and kleptocrats,” says Gabriel minimal requirements on “how many re-

larger (see table, p. 1102). Among the investi- Zucman, a University of California, Berkeley, cords [funds] need to have” and “how open

gation’s findings: economist who has studied offshore invest- their books and records need to be to in-

• Wellcome committed more than ing. Such foundations are helping “normalize vestors,” he says. The Cayman Islands, for

$926 million of its holdings to at least these practices and blow up the volume, so example, “has risen to the top” in popular-

57 tax haven funds, documents from the infrastructure exists also for the illegal ity among money managers because it has

the Paradise Papers indicate. Other uses,” says Annette Alstadsæter, an economist scant reporting requirements, Ghisu says.

offshore investments were shown in the at the Norwegian University of Life Sciences Offshore funds can also open doors to a

foundation’s tax returns. (Totals could in Oslo. “They are robbing the taxpayers,” wider array of investment options and top

not be determined but in 2007, Well- says economist and Nobel laureate Joseph advisers, who often run the funds from of-

come’s offshore holdings were so exten- Stiglitz of Columbia University, and “are fices in financial centers such as New York

sive that Appleby ranked the foundation giving life to an institutional arrangement City or London. Ghisu, for instance, says his

as its 14th largest client.) In a statement which is basically nefarious and bad for our foundation looks first for “the best manag-

to Science, Wellcome officials declined global society.” ers, to maximize our returns so that we have

to discuss the size or placement of its as- resources that we can deploy in support of

sets in offshore accounts, saying they FOR AT LEAST A CENTURY, wealthy individu- our mission.” Wellcome takes a similar po-

“do not collect or keep” data relating als and institutions have moved money sition. “Many of the best-performing funds

to tax domicile. outside their home nations—for example, have offshore domiciles,” it wrote in a state-

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ment. “Our successful long-term investment tax funds for public services while shifting can wield influence through moral suasion

strategy,” it added, “is based on exposure to the tax burden from companies and wealthy or proxy votes, critics of offshore investing

a globally diversified range of asset classes.” individuals to the middle class. And, as note that such engagement is rarely possible

Normally, fund managers, not the foun- studies funded by Robert Wood Johnson it- for investors in offshore energy funds, which

dations, choose investments. But some self have suggested, inequality can damage are often structured to insulate owners from

foundations bar certain investments that public health. For example, the foundation company actions.

they believe would pose conflicts of interest. underwrote a landmark 2015 study showing Wellcome also notes that its invest-

Robert Wood Johnson, for instance, says it extreme income inequality—rather than pov- ment profits—directly from Shell or indi-

has no involvement in firearms, alcohol, or erty alone—is a key contributor to ill health rectly through Cayman Islands funds that

tobacco. “For us to invest in, say, a tobacco and shorter life expectancy. The foundation invest in energy firms—fuel the trust’s

company, would be so antithetical to what has also funded grassroots campaigns to good works, including projects that fight

we want to do that it would be a travesty,” address such problems, including a public- the impacts of global warming. But Dana

says Brian O’Neil, the foundation’s chief in- private partnership in Richmond, where Bezerra, a prominent advocate for ethi-

vestment officer. residents suffer from some of the nation’s cal investing by charities and head of the

Yet Robert Wood Johnson’s offshore in- worst income inequality. But O’Neil rejects Heron Foundation in New York City, ques-

vestments and managers have still gener- the suggestion that the foundation’s own in- tions that reasoning. “It’s a justice question,”

ated controversy. Tax returns show that vestment practices contribute to inequality. she says. “I have yet to meet a community

since at least 2014, the foundation has in- “I don’t think you can take the harm that is willing to trade off our ability to generate

vested heavily in Cayman Islands funds caused by that and impute it to us.” returns with their clean water and healthy

managed by GSO Capital Partners, a unit At Wellcome, where researching the ef- soil, on the promise that we’ll be back to Downloaded from http://science.sciencemag.org/ on December 10, 2018

of the investment titan Blackstone Group, fects of climate change has become one fix it with charitable dollars in the future.”

headquartered in New York City. The foun- focus of giving, officials consider environ- (Heron, she says, screens its entire $307 mil-

dation’s most recent filing showed lion investment portfolio to ensure

about $50 million in those funds. that it supports—or at least does not

GSO has drawn harsh criticism When money flows offshore counter—the foundation’s philan-
for how it handles credit default thropic goal to fight poverty.)
swaps—a once-exotic type of risk- The Paradise Papers and publicly available financial statements reveal
hedging security that became noto- some, but not all, offshore investments and commitments by TO SOME CRITICS of offshore invest-
rious for contributing to the Great seven private foundations that are major funders of scientific research. ing, its biggest downside is secrecy.

Recession. U.S. lawmakers and FOUNDATION ENDOWMENT KNOWN OFFSHORE The lack of transparency can make
regulators have reined in the swaps, ASSETS* INVESTMENTS it difficult for donors, grant recipi-
which are legal, but they remain less Bill & Melinda Gates Foundation ents, and the public to reach their
$51.8 billion None

regulated elsewhere. “The hedge Wellcome Trust $29.3 billion $926 million own conclusions about whether an

fund industry can’t do what it wants Howard Hughes Medical Institute $20.4 billion $891 million offshore investment poses a poten-
to do under the onshore regulations Robert Wood Johnson Foundation $10.8 billion $3+ billion tial conflict.
of the U.S. because it’s too risky,”
Most offshore funds, for ex-

Harrington says. “But the Caymans William and Flora Hewlett Foundation $9.9 billion $168 million ample, carry vague names that of-

will let them do it.” David and Lucille Packard Foundation $7.9 billion $140 million fer few hints about their purpose.
In particular, GSO has drawn Gordon and Betty Moore Foundation $6.9 billion $40 million For example, Howard Hughes
holds $187 million in “Coastland
scrutiny for swaps that involve dis-

tressed companies and a strategy in *Restricted and unrestricted net assets, as of most recent audited financial statements Relative Value Fund Ltd.” and “Cer- DATA: PARADISE PAPERS; FOUNDATIONS’S MOST RECENT TAX RETURNS AND AUDITED FINANCIAL STATEMENTS

which GSO offers a troubled firm an berus HH Partners LP” (managed

incentive to intentionally default on a loan, mental issues when making investment by a company named after the mytho-

triggering a process that enables GSO to re- choices, the trust said in a statement to logical three-headed hound that prevents

alize hefty profits. For years, such deals have Science. But Wellcome declined to dis- the damned from escaping through the

attracted substantial media attention and cuss how those concerns have shaped its gates of hell). Robert Wood Johnson has

lawsuits. A recent investigative story in the offshore investments. And public records $143 million in another canine-inspired

Financial Times said such practices made indicate environmental issues have not pre- fund, “Hound Partners OS.” All three are

GSO the industry’s “biggest predator.” GSO vented the foundation from taking hefty, based in the Caymans.

told the paper it has acted legally and in a ongoing, direct equity stakes in fossil fuel The funds rarely reveal to the public

manner “consistent with the expectations of companies—including Royal Dutch Shell of where they place investments—and normally

its sophisticated market participants.” The Hague, Netherlands, and Schlumberger also bar their investors from sharing that in-

In April, the U.S. Commodity Futures of Houston, Texas—whose operations have formation. Both Wellcome and Robert Wood

Trading Commission took notice, decrying drawn criticism from climate change, envi- Johnson, for example, say confidentiality

the kinds of actions taken by GSO as “ma- ronmental, and human rights advocates. agreements with fund managers prohibit

nipulation” that “may severely damage the Wellcome has resisted calls to divest from them from making such disclosures. Fund

integrity” of the market. GSO then stepped the firms, saying the investments serve as le- managers often want to avoid leaks of sensi-

away from a pending deal. At about the verage to influence corporate practices. “En- tive information that could move markets or

same time, Robert Wood Johnson officials gaging with these companies will strengthen aid competitors.

raised their own concerns with GSO. O’Neil their commitments toward reducing carbon Sometimes, even investors don’t know

says the firm has “really backed off” from emissions more effectively than divestment,” how offshore funds use their money. O’Neil

the controversial swaps. it argued. The foundation declined to de- says in his experience, there are “only a few

Critics contend that offshore machina- scribe how it engages with the companies or funds that really don’t tell us anything.” But

tions increase income inequality by reducing to what effect. But even if direct shareholders contracts revealed in the Paradise Papers

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A cargo ship steams through the Bosphorus past Istanbul, Turkey. The Wellcome Trust invests through an offshore fund in a firm selling ship fuel, which is a major source of Downloaded from http://science.sciencemag.org/ on December 10, 2018
particulate air pollution. It also funds studies that highlight the dangers that particulate pollution poses to human health.

PHOTO: BULENT KILIC/AFP/GETTY IMAGES specify that investors often have no “liabil- Landis Zimmerman of Howard Hughes “There is a tension,” Smith says, “between
ity, obligation, or responsibility whatsoever” made $3 million. Each was by far the high- the philanthropic mission that the trust has
for how a fund operates or any obligation est paid employee of his foundation. as a charity and the way in which it invests
to verify that the fund has actually used its to maximize the income … which [charity of-
money for planned investments. At Wellcome, the incentives are based ficials] say they have a duty to do.” But the
on performance of the portfolio as a whole. tensions surrounding offshore investments
Such opacity is not appropriate for chari- Robert Wood Johnson ties compensation never came up at any board meeting he at-
table institutions, established for social for O’Neil and others to both investment tended, he says. Smith didn’t pass judgment
benefit, Bezerra says. “Not only should performance and “alignment of investment when asked whether the trust’s holdings in a
you [provide investment details], but you objectives with foundation’s mission and bunker fuel merchant contradict the charity’s
are compelled to because you are manag- strategic objectives,” such as maximizing goals. But, “If there were things that were
ing money in the public trust,” she says. returns and ensuring that no funds are in- ethically dubious, then I would have expected
“Shouldn’t we be more than a private in- vested in tobacco, alcohol, or firearms. it to be discussed at the board level,” he says.
vestment company that uses its excess cash
flow for good?” Requiring managers to place social, en- James Gavin, a physician and diabetes
vironmental, and philanthropic goals—not expert at Healing Our Village, a health care
TO REDUCE ETHICAL CONFLICTS, Stiglitz says just investment returns—at the heart of company in Atlanta, who served as a trustee
policymakers should change charity gover- their investment choices need not mean of Robert Wood Johnson a decade ago, says
nance rules to make it “a violation of fidu- they will miss financial targets, Bezerra that if offshore investing undermines the
ciary responsibility to engage in something says. Last year, Heron’s holdings gained foundation’s philanthropic goals, “that would
that might have reputation risk,” such as nearly 16%, according to the foundation. In be of extreme concern.” But he, too, doesn’t
investing in an offshore tax haven with a comparison, at Robert Wood Johnson—the recall board discussions of the practice.
“sleazy” repute. major science philanthropy most heavily
concentrated in offshore funds—the portfo- The increased scrutiny surrounding off-
Persuading policymakers to make such lio rose by about 13%. shore investing, driven partly by the release
changes, however, is likely to be difficult, of the Paradise Papers, is making it more
in part because foundations typically Such policy changes would probably re- likely that charities—including research
operate under a patchwork of national quire approval from a foundation’s board funders—will have to grapple with the is-
and local laws. Instead, some observ- of directors. In general, however, board sue, observers say. That’s a good thing, says
ers believe action will have to come from members often prefer to focus on grant- Dana Lanza, who heads the Oakland, Cali-
foundation board members and officials. making and rarely become deeply involved fornia, nonprofit Confluence Philanthropy,
One needed reform, Bezerra says, is to in investment decisions, philanthropy which encourages foundations to align in-
end—or at least curb—the “perverse in- experts say. At Wellcome, for instance, vestment choices with their philanthropic
centive” that foundations create for their former board member Peter Smith says mission. Foundations that invest heavily in
investment officers, who make many of the investment issues arose just a few times offshore havens, she says, need to ask them-
day-to-day decisions about how to grow during his 10-year tenure, from 2005 to selves a basic question: “Do you owe it to
or protect a charity’s endowment. Their 2014. In one case from 2013, he recalls, the world to be an ethical investor?” j
compensation is often tightly tied to how board members learned from media re-
well their investment portfolio performs. ports that Wellcome had invested in a pay- The methodology for this story is online at
And good performance is handsomely re- day lender accused of preying on the poor. https://scim.ag/OffshoreMethodology.
warded. In 2016, Wellcome’s Danny Truell The 13-member board ultimately directed Jia You contributed reporting. The story
(who retired last year) made $5.8 million trust staff to divest from the company, says was supported by the Science Fund for
and O’Neil made $1.8 million; last year, Smith, an epidemiologist at the London Investigative Reporting.
School of Hygiene & Tropical Medicine.

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BOOKS et al. Downloaded from http://science.sciencemag.org/ on December 10, 2018

AAAS/SUBARU SB&F PRIZES FOR EXCELLENCE IN SCIENCE BOOKS study. All in all, this is a great story for more
sophisticated junior biologists.
Books for budding scientists
Champion: The Comeback Tale of the American
From audacious space missions and quantum physics to clean cookstoves and Chestnut Tree, Sally M. Walker, Henry Holt and
coral nurseries, this year’s finalists for the AAAS/Subaru SB&F Prizes for Excel- Co., 2018, 144 pp.
lence in Science Books dare to go where few children’s titles have gone before.
Sponsored by Subaru of America and facilitated by the American Association for My First Book of
the Advancement of Science (AAAS, the publisher of Science), the competition Quantum Physics
celebrates high-quality children’s science books. Read on for reviews written by
the staf of the Science family of journals and a few friends. —Valerie Thompson Reviewed by Jelena Stajic2

MIDDLE GRADES SCIENCE BOOK trees with resistant varieties. The second ap- Quantum physics has an image problem. ILLUSTRATION: KAILEY WHITMAN
proach was to inoculate vulnerable trees with Spooky, wacky, strange—the adjectives often
Champion weakened blight fungus to stimulate their used to describe its inner workings—paint
immunity. Last, genetically modified saplings a picture of an esoteric discipline. Yet, it is
Reviewed by Caroline Ash1 bearing a gene for an enzyme that reduces the rules of quantum physics that dictate
levels of toxic oxalic acid produced by the the structure of matter, that help interpret
The American chestnut once grew straight, blight were developed. the signals from distant stars, and that make
tall, and true in the forests of the United your smartphone run. This message is nicely
States. Then at the start of the 20th century, Descriptions of the technical details en- conveyed in My First Book of Quantum Phys-
a fatal fungus blight disease nearly made this tailed at each step are very clearly explained ics, an illustrated guide for children 8 and
prized tree extinct. But thanks to the persis- throughout the text, without shying away older (and their parents).
tence of American chestnut lovers and sci- from complexity. The story of how the re-
entists in China, Europe, and America, this search unfolded is told through the voices The book follows the development of
iconic tree is on the way to restoration. In of the dedicated scientists involved. Clearly, quantum physics largely chronologically, ex-
Champion, Sally Walker tells the story of how the establishment of the breeding programs plaining why classical physics was not suffi-
disaster was averted, revealing the technical were long labors of love, spanning decades; cient to describe the subatomic world. It then
details of the three-pronged rescue program. a little more of this passion could have been moves on to concepts such as particle-wave
transmitted in the text. Still, there is a lot of duality, the uncertainty principle, and radio-
The first step was to cross-breed American inspiring biology to be learned from this case activity. A number of physicists make appear-
ances, from Isaac Newton to Marie Curie,

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but it is the familiar cartoon form of Albert gitimate reasons to be concerned and there Itch! Downloaded from http://science.sciencemag.org/ on December 10, 2018
Einstein that serves as a guide throughout is an ongoing need to track celestial objects
the book (Einstein’s ambivalent attitude that could cause major damage. In starting Reviewed by Seth Scanlon4
toward quantum mechanics notwithstand- Impact! with the story of a meteor that ex-
ing). The illustrations are clear, eye-catching, ploded over the Russian city of Chelyabinsk In this delightful—if slightly disquieting—
and consistent; the authors occasionally an- in 2013, Elizabeth Rusch captures the terror work, Anita Sanchez artfully describes the
thropomorphize inanimate objects to make and damage larger space debris can cause. ways in which a variety of organisms make
concepts more accessible (for example, an Even though the impact site was more than us itch. Much attention is directed toward
electron “feels comfortable” in its orbit) but 80 km outside the city, the shock wave it cre- familiar insects and arachnids that cause
largely avoid sounding condescending. ated shattered glass, rattled buildings, and humans discomfort. In addition, Sanchez
caused roofs to collapse. elucidates the various ways that fungi (such
Most commendably, the narrative does not as those that cause athlete’s foot) and plants
stop in the 1930s. Particle accelerators, the Spotting and tracking asteroids is almost (such as nettle, poison ivy, cacti, and prickly
Standard Model of particle physics, and the as hard as finding needles in haystacks, while pears) can induce the urge to scratch.
Higgs boson all get well-deserved mentions, identifying and deciphering previous impacts
but so do everyday “quantum gadgets,” such requires careful detective work. This is es- These pruritogenic pests also allow the
as laser pointers and light-emitting diode pecially true when trying to analyze a large author to pivot onto various historical top-
(LED) lights. The book leaves young readers impact crater that might be kilometers in di- ics in a fun and appealing manner. Lice,
with a sense of quantum physics as a vibrant, ameter, where the impact both compressed for example, serve as a jumping-off point
active pursuit that has and will continue to the ground and turned the layers of earth to describe the unhygienic conditions ex-
influence their lives in very real ways. and rock upside down. Rusch introduces us perienced by soldiers during World War I,
to individuals who either track celestial ob- whereas fleas are introduced in the context
My First Book of Quantum Physics, Kaid-Sala jects or investigate past impacts and to the of the hugely popular flea circuses of the
Ferrón Sheddad, Illustrated by Eduard Altar- tools of the trade required to study them. 19th century.
riba, Button Books, 2018, 48 pp. She even reveals how amateur scientists can
get involved. And if your interests veer from Along the way, Sanchez offers a whole
Impact! science to science fiction, she closes with a host of useful tips for preventing or reliev-
range of ways one might alter the trajectory ing itchiness. After reading this book, you
Reviewed by Marc S. Lavine3 of an asteroid, should the need ever arise. should be able to remove embedded cater-
pillar bristles, soothe a nettle’s sting, avoid
Although movies have magnified the poten- Impact!, Asteroids and the Science of Saving mosquito bites, and deodorize a pet that
tial damage that Earth might suffer from the the World, Elizabeth Rusch, Photography has encountered a skunk. This wealth of in-
arrival of an asteroid or comet, there are le- by Karin Anderson, HMH Books for Young formation is reinforced with approachable,
Readers, 2017, 80 pp. humorous, and eye-catching illustrations
by Gilbert Ford.

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The book concludes with a thought-
provoking discussion of the neurological
and immunological origins of itch. In ad-
dition, Sanchez discusses how scratching
can (at least temporarily) allay irritation as
well as other benefits it can provide. This
author/illustrator team is to be commended
for conveying a cornucopia of data in an en-
joyable and engaging way.

Itch!: Everything You Didn’t Want to Know About
What Makes You Scratch, Anita Sanchez, Illus-
trated by Gilbert Ford, HMH Books for Young
Readers, 2018, 80 pp.

Trash Revolution Downloaded from http://science.sciencemag.org/ on December 10, 2018

Reviewed by Hadassah Nusinovich
Ucko, Solomon Nusinovich Ucko, and
Yevgeniya Nusinovich5

Trash Revolution explains how common Pedestrians walk along the rewilded High Line park in New York City.
materials are produced and recycled and
suggests solutions to various real-world Rewilding CHILDREN’S SCIENCE PICTURE BOOK PHOTO: YUEN MAN CHEUNG/ALAMY STOCK PHOTO
problems related to resource consumption,
waste management, and climate change. Reviewed by Sacha N. Vignieri6 Living Things and
In addition to widely known recommen- Nonliving Things
dations such as “reduce, reuse, recycle,” As the human population grows, we are re-
the authors present many solutions made lentlessly encroaching on the natural habi- Reviewed by Tage Rai7
possible by cutting-edge research, such as tats that surround us. This book defines
making biodegradable plastics from stale and describes the science and process of an If we wanted to define “games,” we might
food and using bacteria to grow composta- increasingly important mechanism for con- say they involve competing, keeping score,
ble fabrics. servation known as “rewilding.” following rules, and having fun. However,
in some games, players cooperate and don’t
The technical information is interspersed Rewilders, we learn, want to restore habi- keep score. And while all games have rules, so
with humor and kid-friendly touches— tats to their prehuman states, creating en- do many other activities that may or may not
“#gratitude,” for example, is associated vironments that can support native species be fun. In this book, Kevin Kurtz extends this
with the invention of toilet paper. In ad- and give them room to thrive. The authors line of argument to the nature of life.
dition to general information, the authors first describe the basics of this process, in-
provide handy reference charts comparing cluding why it is important, and then dis- Are living things the only ones that move,
the benefits and drawbacks of different cuss several examples of where, why, and or grow, or reproduce? Kurtz elegantly re-
materials, as well as specific recommenda- how rewilding is happening. These include veals that some nonliving things can do these
tions for handling them. However, some of everything from the Pleistocene rewilding things, whereas some living things can’t.
these suggestions seemed unattainable to plan, which advocates reintroducing mod-
us. For example, the authors recommend ern stand-ins for megafauna that went ex- Astute readers may find themselves wish-
making your home “a junk-mail-free zone,” tinct at the end of the last ice age, to the ing for a deeper discussion of viruses. Viruses
but offer no suggestions for how that could rewilding of New York City’s “High Line,” an lack cells of their own, but they confiscate
be achieved. abandoned, elevated train track where lace- their host’s cellular machinery to replicate
wing insects have been released to prevent themselves, thus complicating any cellular
We noted a few minor problems, such infestations of harmful bugs. definition of life. The conceptual ambiguity
as a mistaken characterization of deute- of viruses underscores a deeper, albeit under-
rium as an extra molecule inside water The book is well targeted toward mid- standable, omission from the book: the exis-
molecules, a gratuitous negative comment dle-grade readers because it accurately tential quandary of death.
about genetically modified organisms, and describes rewilding while remaining ac-
a surprisingly positive discussion of waste cessible and interesting. The authors’ posi- Ultimately, Kurtz ends with the unset-
incinerators that neglected to mention any tive tone is both refreshing and important. tling realization that there is no categorical
concerns about their fumes and effects on They present rewilding stories in a way that distinction between living and nonliving.
human health. Overall, however, it is very clearly lays out why the process is ecologi- Instead, he proposes a family resemblance
informative, with thoughtful explanations cally important and why it is important for model in which something that has many
of what we can all do to make environmen- human society as well. of the characteristics shared by living things
tally friendly choices. probably belongs to the category.
Rewilding: Giving Nature a Second Chance, Jane
Trash Revolution: Breaking the Waste Cycle, Drake and Ann Love, Annick Press, 2017, 88 pp. The book is beautifully illustrated with
Erica Fyvie, Illustrated by Bill Slavin, Kids high-quality photographs of nature, animals,
Can Press, 2018, 64 pp.

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and inventions. Despite its simple text, Liv- poop. Wombats, for example, excrete upward ing a floating nest made of bubbles to pro- Downloaded from http://science.sciencemag.org/ on December 10, 2018
ing Things and Nonliving Things is decep- of 100 cube-shaped droppings every evening tect its babies.”
ILLUSTRATION: ALLISON BLACK AND SIMON & SCHUSTER tively deep and provides a valuable lesson in to mark their territory, whereas sloths de-
scientific uncertainty. scend from their treetop habitat to poop on Illustrator Robbin Gourley’s playful yet
the ground just once a week. beautiful renderings reinforce the book’s
Living Things and Nonliving Things: A Compare message. “Look up—a house in the sky!”
and Contrast Book, Kevin Kurtz, Arbordale How do zoos deal with animal waste? reads another page. The common swift, ren-
Publishing, 2017, 32 pp. Some is just sent off to landfills, but some is dered in muted browns against a pale blue
also used to monitor the health of the ani- sky, spends months on the wing, we learn,
Many mals. Some is processed into compost for lo- eating, drinking, and sleeping in the air.
cal gardens, and some is recycled to make
Reviewed by Jennifer Sills8 useful products such as paper and fuel. Young children are naturally curious about
animals. Jenkins’s sweet exploration of how
In Many, a rosy-cheeked, red-haired explorer Although there’s no main character, every and where they live provides an opportunity
tries to answer the question so many scien- animal is easily related to. The drawings are to connect with older readers and to dig a
tists have pondered: “How many different vivid and, by and large, accurate. (Wombats, little deeper together.
kinds of living things are there on the planet?” however, do not build a scat-fence, as one il-
She discovers elephants and oak trees, mush- lustration seems to suggest.) A House in the Sky: And Other Uncommon
rooms and beetles, and mites and microbes. Animal Houses, Steve Jenkins, Illustrated by
All of these species, she realizes, are interde- Most of the animals highlighted in this Robbin Gourley, Charlesbridge, 2018, 32 pp.
pendent, forming complex ecosystems. book are mammals, but it would have been
fun to read about the excretions of other spe- The Brilliant Deep
Here, the story takes a dark turn: Humans cies. Perhaps this will be the topic of a follow-
have been poisoning and destroying these up title (book “number 2,” if you will). Reviewed by Julia Fahrenkamp-Uppenbrink10
ecosystems, and many living things have dis-
appeared forever. We have a responsibility, What Do They Do with All That Poo?, Jane Kurtz, With sparing words and mesmerizing, soft-
our forlorn narrator warns: We don’t want Illustrated by Allison Black, Beach Lane Books, colored paintings, The Brilliant Deep tells
to reach a point at which we have to “count 2018, 40 pp. the story of Ken Nedimyer, an American fish
down instead of up.” collector and “live rock farmer” who found
A House in the Sky a way to restore the world’s coral reefs by
The story’s whimsical tone, which belies growing coral colonies in underwater nurser-
its sobering message, will engage readers, but Reviewed by Sacha N. Vignieri6 ies and then planting them onto dying reefs.
the highlights of the book are the detailed
watercolor illustrations that infuse each The sight of a common squirrel can inspire Nedimyer has long loved the ocean. One
landscape and statistic with warmth and ap- squeals of delight from young children. of the book’s most memorable images shows
peal. Vibrant colors throughout the pages of They might ask, “Is it going home?” as the him as a boy, looking out over the sea, all its
discovery contrast with the abrupt shift to squirrel disappears up a tree. A House in secrets hidden beneath the surface. On the
muted browns on the pages of destruction. the Sky, Steve Jenkins’s lovely story on ani- next page, he is snorkeling through an un-
The emotional punch the images deliver will mal homes, provides answers that will sat- derwater world teeming with life. We follow
be more effective in motivating readers to act isfy such questions while providing more along as he learns to scuba dive and begins
than trivia about mushrooms ever could be. detail for a similarly curious adult or older to collect fish to study in aquariums at home.
child. “Some houses are made of bubbles,”
Many: The Diversity of Life on Earth, Nicola reads one passage, for example. Below, the As an adult, Nedimyer uses his expertise
Davies, Illustrated by Emily Sutton, Candle- author elaborates: “A Siamese fighting fish with growing “living rocks”—rocks covered
wick, 2017, 40 pp. takes a gulp of air and then blows it back with sponges and other invertebrates that are
out. It does this over and over again, creat- used in aquariums—to cultivate coral. The
What Do They Do book ends on a note of hope as Nedimyer and
with All That Poo? his organization, the Coral Restoration Foun-
dation, begin to help other countries save
Reviewed by Steve Mao9 their reefs as well.

On any given day, an individual zoo can The simple scientific explanations given
produce more than 5000 pounds of animal throughout the book are easy to understand
waste. So, “what do they do with all that and are woven into the story in a way that
poo?” does not distract. However, the main text
does not mention climate change or other
The first part of this book makes it clear human threats. A two-page spread at the end
that poop comes in different sizes, shapes, and merely cites complicated reasons, including
colors and that these properties are related changing ocean temperatures and overfish-
to the distinct diets, anatomies, and physi- ing, for the decline of coral reefs. This is a
ologies of different animals. How animals use missed opportunity. Nevertheless, I can only
their waste can also affect the characteristics recommend this beautiful and inspiring
of their poop, as well as how and when they book, which shows what love for nature com-
bined with human ingenuity can achieve.

The Brilliant Deep: Rebuilding the World’s Coral
Reefs, Kate Messner, Illustrated by Matthew
Forsythe, Chronicle Books, 2018, 48 pp.

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Published by AAAS

Awakened by his mother’s coughing—the result of cooking indoors over an open flame—Iqbal contemplates how to win his school’s sustainability-themed science fair.

Iqbal and His HANDS-ON SCIENCE BOOK me, that show the richness of his life, such Downloaded from http://science.sciencemag.org/ on December 10, 2018
Ingenious Idea as Bell’s role in connecting Helen Keller
Alexander Graham with her teacher, Anne Sullivan, and Bell’s ILLUSTRATION: REBECCA GREEN/KIDS CAN PRESS LTD.
Reviewed by Jennifer Sills8 Bell for Kids role in supporting Science magazine dur-
ing its early years.
Amid monsoons and the daily prayers of Ra- Reviewed by Marc S. Lavine3
madan, Iqbal dreams of winning his school’s Alexander Graham Bell for Kids: His Life &
sustainability-themed science contest. His Alexander Graham Bell is best known Inventions with 21 Activities, Mary Kay Carson,
mother and baby sister Rupa have developed for his invention of the telephone, but Chicago Review Press, 2018, 144 pp.
a cough from sitting inside cooking food over this wasn’t the work that he found most
an open fire. With the help of his other sister, rewarding. Teaching deaf students to fin- Light Waves
Sadia, Iqbal finds a way to help them by turn- ger spell and to speak, using the visible
ing an umbrella into a solar cooker. alphabet developed by his father, was his Reviewed by Marc S. Lavine3
lifelong passion. Bell’s grandfather voice
Iqbal’s story is steeped in the customs and trained students with speech problems From the dim flicker of a candle flame to
language of Bangladesh while celebrating such as stuttering, and his mother had se- the daily illumination provided by the Sun,
universal human qualities such as curiosity vere loss of hearing. His interest in speech visible light enables us to see our world.
and ingenuity. Sadia’s role is realistic; she and sound was critical to many of his fu- Despite its presence all around us, the
joins her brother in school and helps him ture inventions. properties of light can be confusing and
build his stove, but unlike Iqbal, she is ex- counterintuitive. Why, for example, does
pected to help with childcare and cooking. In Alexander Graham Bell for Kids, Mary light, which travels in a straight line, ap-
Kay Carson weaves together key events pear to bend, when looking at a straw in a
Author Elizabeth Suneby seamlessly and influences that shaped Bell’s life, and glass of water? Or why does our reflection
weaves Bengali words into the text, describ- in turn how he shaped the world around invert when we look at the front of a metal
ing, for example, how Iqbal offers the first him. Although he was a poor student in spoon? Using a mix of illustrations and
serving of “semai”—a dessert made with ver- school, Bell spent his life learning from simple experiments aimed at a younger
micelli noodles served at “Eid al-Fitr” (the the written works of others, from ongoing reader, David Adler explains the basic com-
holiday that marks the end of Ramadan)—to tinkering and innovation, and from the position, behavior, and properties of light.
Sadia to thank her for her help. Illustrator many colleagues and connections he made
Rebecca Green’s colored pencil illustrations throughout his life. Through the casting of shadows by using
depict Iqbal’s family and their village in vivid a flashlight and a tower of wooden blocks,
detail. The book’s appendices provide an ex- Bell’s invention of the telephone has Adler teaches readers about objects that
planation of the benefits of clean cookstoves largely overshadowed his many other are transparent, translucent, or opaque. We
and a glossary of Bengali words. contributions, such as his work on early are shown how to divide white light into a
versions of the phonograph and metal spectrum of colors when it passes through
Readers can also follow instructions to detectors and his work on airplanes and a prism, and from this, we are taught why
create their own solar cooker. The project hydrofoil boats. These inventions often objects have different colors depending on
will require a pizza box, aluminum foil, brought him into conflict with other inven- which part of the visible spectrum they re-
plastic wrap, and a lot of patience—the tors of the day, including Thomas Edison flect rather than absorb.
stove will take 30 or 40 minutes to heat up and Elisha Gray.
in the sun. At times, the writing seems aimed at older
The book includes many sidebars to ex- readers; however, a glossary at the end help-
Iqbal and His Ingenious Idea: How a Science plain the scientific principles behind each fully pulls together all the optics terminology.
Project Helps One Family and the Planet, invention, as well as 21 hands-on activities,
Elizabeth Suneby, Illustrated by Rebecca that enhance the narrative. But perhaps Light Waves, David A. Adler, Illustrated by
Green, Kids Can Press, 2018, 32 pp. the true value of the books comes from all Anna Raf, Holiday House, 2018, 32 pp.
the little stories, previously unknown to

1108 7 DECEMBER 2018 • VOL 362 ISSUE 6419 sciencemag.org SCIENCE

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INSIGHTS | BOOKS

Dog Science What the book does not provide are Alongside the garden projects are recipes Downloaded from http://science.sciencemag.org/ on December 10, 2018
Unleashed broad insights into dog behavior or social- that can be the source of the seeds or sprout-
ization. But focusing on more universal ing material. The pairing might encourage
Reviewed by Brent Grocholski11 and less variable traits is probably for the picky eaters to give celery or herbs a chance,
best in a home experiment–driven book. although I would not expect to harvest much
Dogs make for the perfect assistants for from your sprouts and seedlings unless you
the activities in Dog Science Unleashed. Dog Science Unleashed: Fun Activities to Do with have a working garden already.
This vivid volume lays out two dozen or so Your Canine Companion, Jodi Wheeler-Toppen,
exercises that double as experiments, the Photography by Matthew Rakola, National Nevertheless, intrepid young gardeners
goal of which is to better understand ca- Geographic Kids, 2018, 80 pp. should find these projects inspiring and will
nine senses and physiology. hopefully want to learn more about how
Dig In! their food is grown as a result.
The experiments are well described,
with step-by-step instructions and photos. Reviewed by Michael Funk12 Dig In!: 12 Easy Gardening Projects Using
Most are easy to set up and only require Kitchen Scraps, Kari Cornell, Photography by
household items. Exceptional photogra- Modern agriculture has given us seedless Jennifer S. Larson, Millbrook Press, 2018, 64 pp.
phy accompanies the instructions and watermelons, tomatoes in February, and
helps readers to understand the activities. apple varieties with trademarked names Bug Lab for Kids
The wild card, as you might guess, is your and intensive marketing. However, there
pooch’s willingness to help unleash the remains something magical about planting Reviewed by Lauren Kmec13
dog science. But that shouldn’t be a prob- a seed, watching it sprout, and after a long
lem for most dogs; many of the activities season, tasting the fruit (or vegetables) of How do you measure a beetle’s strength or
involve treats and toys. one’s work and dedication. Dig In! encour- the speed of a centipede? Bug Lab for Kids,
ages kids to get in the kitchen and rescue ne- by entomologist John Guyton, reveals the
In an activity called “A Puzzle for Your glected stems and seeds for experimentation answers to these questions, among others.
Pooch,” the authors provide instructions in the garden.
for setting up an experiment to see whether The book is divided into nine well-
your dog can learn to extract treats from a The book features 12 simple projects, organized units, each containing several
muffin tin. In another, readers learn how some of which may be better controlled lab exercises. An introductory section pro-
to craft a homemade stethoscope out of a versions of events already happening in vides helpful advice regarding appropriate
funnel and an empty paper towel tube and your crisper drawer. In particular, growing attire for fieldwork, first aid treatment for
to use it to listen to their dog’s heartbeat. lettuce, onions, and potatoes from sprouts bites and stings, and the importance of
is nearly foolproof. Others, such as garlic keeping a field notebook. Another unit of-
Some of the activities are more targeted and ginger, might require some prepara- fers a straightforward primer on the scien-
to helping understand the particular dog tion. Growing plants from seeds requires tific method.
you are working with. In “Half Bath,” for the most patience, but the wonder of seeing
example, readers are encouraged to deter- sprouts emerge from soil is sure to delight Would-be entomologists start by learn-
mine whether shampoo is right for their kids of all ages. ing how to make and use a collection net,
pup by washing only one side and monitor- as well as how to care for live critters. More
ing odor, dirt, and oil levels over a month. The projects in Dig In! are simple and can sophisticated collection techniques, such as
However, the book sticks to a scientific ap- be started in an old cup or newspaper pots. the use of an aspirator to capture very tiny
proach, even for these activities. insects, are also covered. Readers can then
embark on a variety of activities to observe
PHOTO: MATTHEW RAKOLA FOR NATIONAL GEOGRAPHIC KIDS insects in their natural habitat. 

Other labs include a spiderweb search, a
papier-mâché wasp’s nest construction proj-
ect, a multiweek butterfly-rearing opera-
tion, and a taste test of edible insect “treats”
(not for the faint of heart!). Although special
equipment such as a blacklight is required
for some experiments, many of the neces-
sary tools can be constructed from house-
hold materials or purchased inexpensively.

Interspersed throughout the book are fun
and surprising snippets of bug trivia: Moths
navigate by the moon, bees “dance” to com-
municate with other bees, and horned
dung beetles can pull 1000 times their own
weight. These tidbits bolster Guyton’s mes-
sage that although bugs may not be cute or
cuddly, they are indeed fascinating.

A human-pooch foot race teaches young readers how to create a repeatable experiment. Bug Lab for Kids: Family-Friendly Activities for
Exploring the Amazing World of Beetles, But-
terfies, Spiders, and Other Arthropods, John W.
Guyton, Quarry Books, 2018, 144 pp.

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INSIGHTS | BOOKS

YOUNG ADULT SCIENCE BOOK David Grinspoon. This provides great insider real.” But whiz-bang technical feats alone Downloaded from http://science.sciencemag.org/ on December 10, 2018
access, although it’s clearly a subjective view. cannot solve problems such as our water cri-
Rocket Men ses, for example. This points to perhaps the
A brief introduction explains how Pluto biggest shortcoming of the book: a missing
Reviewed by Laura M. Zahn14 was discovered in 1930 and why, in the 1980s, discussion of how public policy interfaces
planetary scientists began to lobby for a mis- with large engineering projects and the pro-
The year was 1968. Protests against the Viet- sion to visit it. Teenagers may struggle with cesses by which such projects are planned,
nam war filled the streets of America, and the the subsequent chapters, however, which funded, administered, and maintained.
United States and the Soviet Union were rac- describe how the mission was designed and
ing to the moon. In 1969, men would walk on funded. These sections are a labyrinth of In all, Built is a welcome addition to the
its surface. However, before we could accom- NASA committees, working groups, design library of accessible reads on engineering.
plish this feat, we needed to be sure that they proposals, and advisory reports. The second
could get there and return safely. half of the book is far more engaging, cover- Editor’s Note: For a full-length review of Built,
ing the spacecraft’s launch in 2006, its flyby see “Behind the scenes of the built environ-
Focusing on the Apollo 8 mission—the of Jupiter in 2007, and the Pluto encounter ment,” Science 359, 1108 (2018).
first manned mission to orbit the moon—in itself. Those chapters come alive with the au-
Rocket Men, Robert Kurson vividly transports thors’ passion for exploration and the excite- Built: The Hidden Stories Behind Our Structures,
the reader into the minds of the people in- ment of finally reaching the destination. Roma Agrawal, Bloomsbury USA, 2018, 320 pp.
volved, especially the astronauts and their
wives, as they prepared for and underwent Throughout Chasing New Horizons, there Spying on Whales
this perilous mission. The possibility of death is a strong sense of the team’s drive to make
is a recurring theme. Kurson repeatedly re- the most of the brief Pluto flyby and the me- Reviewed by Sacha N. Vignieri6
minds the reader of the fatal fire that claimed ticulous planning that required. The authors
the lives of the Apollo 1 astronauts and the emphasize the important roles played by en- Whales are massive, their habitat is enor-
experimental nature of space travel. Yet, fear gineers, project managers, and mission con- mous, their life spans can be much longer
was not at the forefront for Frank Borman, trollers, reminding readers that it takes more than our own, and their intellect is both com-
Bill Anders, and Jim Lovell. Instead, the book than a good idea and talented scientists to fly pelling and mysterious. We are captivated by
emphasizes how these brave men were will- a successful mission. whales, yet they remain difficult to know.
ing to sacrifice everything for their country.
Chasing New Horizons: Inside the Epic First Mis- Nick Pyenson enters into this long affair
This story, about a little-recalled but major sion to Pluto, Alan Stern and David Grinspoon, from a paleontological perspective, being
move forward into space, will captivate read- Picador, 2018, 320 pp. most interested in how these remarkable
ers of all ages, but as a full-length chapter creatures evolved from four-legged terrestrial
book with few illustrations or pictures, older Built ancestors to marine leviathans and in the
readers will have an easier time with this many forms they took in between. As he de-
book. Kurson’s evocative writing places the Reviewed by Donna Riley16 scribes his pursuit of this knowledge, we see
Apollo 8 mission into historical perspective how challenging it really is to study these ani-
and allows us to vicariously experience the Roma Agrawal’s Built is a full-throated cele- mals, both those that existed in the past and
launch of the Saturn V rocket and the awe bration of structural engineering. The book those with whom we share the world now.
felt by the first men to leave low Earth orbit. nicely balances innovative new builds such
as The Shard in London with tried-and-true Throughout the book, Pyenson brings his
Rocket Men: The Daring Odyssey of Apollo 8 and designs such as the Middle Eastern water readers where he goes, whether it be on an
the Astronauts Who Made Man’s First Journey to transport system known as the qanat. Clas- adventure in the Atacama desert to solve a
the Moon, Robert Kurson, Random House, 2018, sic narratives of the Brooklyn Bridge and mystery involving dozens of intact fossil
384 pp. the Hancock Tower are interspersed with whale skeletons, or to an internal destina-
more obscure examples, including a lovely tion—his heart—as he contemplates the fact
Chasing New Horizons description of spider silk as bridge material. that in a single right whale’s lifetime, the
world has gone from being rich with whales
Reviewed by Keith T. Smith15 Agrawal makes passing reference to work- to being nearly without them. In the end, the
place gender discrimination. Stark in their reader takes away an improved knowledge of
On 14 July 2015, the New Horizons spacecraft normalcy and minimized as anomalies, her whales, especially their history, but perhaps
flew past Pluto, capturing headlines around vignettes nonetheless may elicit a #metoo even more importantly, a deeper understand-
the world. Chasing New Horizons tells the from many readers as they serve to remind ing of the intertwining of our fates.
story of that mission: how it was designed, us how far we have yet to go in building in-
funded, built, launched, and operated. The clusive work environments in engineering. Spying on Whales: The Past, Present, and Future
narrative is as recalled by Alan Stern, the of Earth’s Most Awesome Creatures, Nick Pyen-
mission’s principal investigator, written up by Agrawal, like many engineers, is almost ab- son, Viking, 2018, 336 pp.
the astrobiologist and science communicator solute in her optimism: “The possibilities are
limited only by our imaginations—for what- 10.1126/science.aav9720
ever we can dream up, engineers can make

1The reviewer is a senior editor at Science. Email: [email protected] 2The reviewer is a senior editor at Science. Email: [email protected] 3The reviewer is a senior editor at Science. Email: mlavine@
aaas.org 4The reviewer is an associate editor at Science. Email: [email protected] 5The reviewer is a senior editor at Science Translational Medicine. Email: [email protected] 6The reviewer is a
deputy editor at Science. Email: [email protected] 7The reviewer is an associate editor at Science. Email: [email protected] 8The reviewer is the letters editor at Science. Email: [email protected] 9The reviewer
is a senior editor at Science. Email: [email protected] 10The reviewer is a deputy editor at Science. Email: [email protected] 11The reviewer is an associate editor at Science. Email: bgrochol@
aaas.org 12The reviewer is an associate editor at Science. Email: [email protected] 13The reviewer is a lead content production editor at Science. Email: [email protected] 14The reviewer is a senior editor
at Science. Email: [email protected] 15The reviewer is an associate editor at Science. Email: [email protected] 16The reviewer is the Kamyar Haghighi head of the School of Engineering Education,
Purdue University, West Lafayette, IN 47907, USA. Email: [email protected]

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PERSPECTIVES

N A N O M AT E R I A L S

Barrier(less)
islands

No stopping 1D crystals

By Bart Kahr and Michael D. Ward

C rystal nuclei—the minute collections Peptides assemble from solution onto a surface of MoS2 as highly ordered 2D arrays through the Downloaded from http://science.sciencemag.org/ on December 6, 2018
of molecules needed to spark crys- assembly of 1D rows (yellow). Nucleation of the 1D rows has no energetic barrier, which is characteristic
tal growth—are small, short-lived, of 2D crystalline films and 3D crystals.
and generally unobserved. Classical
ILLUSTRATION: MICHAEL PERKINS/PACIFIC NORTHWEST NATIONAL LABORATORY nucleation theory, a model for the have diad symmetry at best, the rows of di- nematic mesophases made of 1D chains by
earliest stages of crystallization, is an mers adopt three equivalent orientations on isodesmic noncovalent association—that
accounting of the free-energy debits for cre- the surface. Dimers measuring 1.1 nm by 4.7 is, when molecular chains line up in an en-
ating an interface between crystals and the nm are canted by 60° with respect to the lon- tropically driven process of liberating sol-
medium from which they grow, and the free gitudinal row direction, tantamount to 1D vating water molecules (9). In the system
energy credits for enlarging the interior of crystals with a pseudo-rectangular unit cell of Chen et al., row-by-row growth likewise
the crystal (1, 2). On page 1135 of this issue, 0.55 nm (longitudinal) by 4.1 nm (lateral). may be entropically driven as more surface
Chen et al. (3) report the growth of one-di- Only the former dimension is commensurate water can be expelled from MoS if the rows
mensional (1D) peptide crystals in rows on with the MoS lattice, however.
crystalline substrates, which subsequently 2
assemble laterally row by row into films 2
(and ultimately 2D arrays) (see the figure). associate in parallel to form a dense film.
Growth rates along and perpendicular to A 2D circular crystal, according to clas- Coupled with strong interactions between
the rows, measured by scanning probe sical nucleation theory, grows through a the rows, this effect may compensate for
microscopy, support the absence of an ac- competition between the unfavorable line incommensurism with the substrate in the
tivation barrier that typically must be sur- tension of the perimeter and the favorable lateral direction.
mounted to overcome the surface energy. area free energy. The former grows as the
This unexpected challenge to the classical first power of the radius, and the latter Chen et al. have shown that the earli-
nucleation theory arises from high-res- grows with the square of the radius. Com- est stages of crystal growth point to the
olution imaging that captures kinetic petition between oppositely signed terms limitations of classical nucleation theory, a
measurements for very small molecular ag- of different dimensional dependencies also theory that has never anticipated a crystal
gregates (4). No matter the sophistication gives rise to a critical radius and nucleation for which size and perimeter both scale in
of our models, looking ever more closely activation barrier. Likewise, in 3D crys- the same way with a geometric measure.
at growing crystals often reveals unantici- tals, there exists a competition between These observations may guide further the
pated mechanisms (5). quadratic (surface) and cubic (volume) de- design and fabrication of crystalline mo-
pendencies. But what happens when the lecular films using epitaxial growth (10).
A crystallization process without an ac- nucleus is quasi–one dimensional, as in the They could inform on the fabrication of
tivation barrier for nucleation suggests in- self-assembling rows of peptides on MoS ? thin films with unique and highly ordered
difference. But epitaxy (6, 7)—the oriented structures otherwise not attainable, with
overgrowth of a crystal on a crystalline 2 potential impact on electronic devices,
substrate—strongly guides peptide assem- from solar cells to light-emitting diodes to
bly. Chen et al. used the latter process and As Chen et al. note, for a 1D nucleus just field effect transistors. j
observed that peptides (each consisting of one dimer wide, both the line tension and
seven amino acids) associated pairwise at the free energy of the row scale with the REFERENCES
their carboxyl termini through hydrogen first power of the length. Thus, longitudi-
bonds, resulting in palindromic dimers. Ag- nal growth rates decreased linearly with de- 1. P.J. M. Smeets et al., Proc. Natl.Acad. Sci. U.S.A. 114,
gregates of just eight dimers long assembled creasing peptide concentration, reaching a E7882 (2017).
at 30° from one of the three principal lattice value of zero near the equilibrium peptide
vectors, which were defined by the closest concentration. This signals the absence of 2. P. G.Vekilov, in Kinetics and Thermodynamics of Multistep
distance between sulfur atoms in the molyb- an activation barrier for nucleation and a Nucleation and Self-Assembly in Nanoscale Materials, S.A.
denum disulfide (MoS ) crystalline substrate. critical size of zero, a concept that is coun- Rice et al., Eds. (Wiley, 2012), pp. 79–109.
terintuitive to everyday crystal growers.
2 3. J. Chen et al., Science 362, 1135 (2018).
Two-dimensional “island” growth of 4. Y. Ono,J. Kumaki, Macromolecules 51, 7629 (2018).
Because MoS is trigonal and the peptides crystals was observed to occur row by row, 5. A. G. Shtukenberg et al., Proc. Natl.Acad. Sci. U.S.A. 110,
2 and the lateral growth rate appears to de-
part from the exponential dependence on 17195 (2013).
Department of Chemistry, Molecular Design Institute, New peptide concentration expected from clas- 6. M. Meissner et al., ACS Nano 10, 6474 (2016).
York University, New York, NY 10003, USA. Email: bart.kahr@ sical nucleation theory (8). This behavior 7. M. D.Ward, ACS Nano 10, 6424 (2016).
nyu.edu; [email protected] is reminiscent of small-molecule, lyotropic 8. D. Gebauer et al., Chem. Soc. Rev. 43, 2348 (2014).
9. P.J. Collings et al., Liq. Cryst. Rev. 3, 1 (2015).
10. M. Gobbi et al., Adv. Mater. 30, 1706103 (2018).

10.1126/science.aav7009

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INSIGHTS | PERSPECTIVES

INFECTIOUS DISEASE

Toward a chemical vaccine for malaria

A high-throughput screen puts us on the road to protecting populations against malaria

By Margaret A. Phillips1 and pacity to feed compounds through the drug pound does not have activity on both stages

Daniel E. Goldberg2 development pipeline for chemoprotection. and therefore does not put selective pressure

As efforts to eliminate malaria increase, on a large blood-stage parasite load.

D espite considerable progress in com- the need for chemoprotective agents to pro- Plasmodium falciparum is responsible
bating malaria, it remains one of tect vulnerable populations will also increase for most malaria cases, and it is the most
the world’s most important infec- (3). The idea is to find a long-lasting agent deadly, whereas Plasmodium vivax has the
tious diseases, with 50% of the world to treat infections before they become symp- greatest global distribution. Antonova-Koch
population at risk of developing the tomatic and to develop these into a chemical et al. made a strategic choice to use the

disease and a mortality rate of ~0.5 vaccine (that is, a drug that protects against rodent malaria parasite Plasmodium ber-

million annually (1). The lack of an effective disease). The best malaria stage of infection ghei for their screen. This conferred many

vaccine and the relentless ability of the Plas- to target for this approach is the one in the advantages over using a human parasite:

modium parasite responsible for malaria to liver. The malaria life cycle begins when an ease of production, minimal biohazard risk, Downloaded from http://science.sciencemag.org/ on December 10, 2018

develop drug resistance has contributed infected mosquito injects sporozoites into a more rapid life cycle, and ability to infect

to the continuing disease bur- hepatoma cell lines that are

den (2–4). Artemisinin-com- more facile to use and do not

bination therapies (ACTs) are Life cycle of the P. falciparum malaria parasite detoxify the compounds be-
the mainstay of current treat- ing screened. From an initial
ment regimens, but decreased An infected mosquito injects sporozoites, which replicate in the liver using hit rate of ~4%, a subset (~104)
effectiveness, particularly in enormous metabolic activity. From each hepatocyte, ~105 merozoites enter the were prioritized for evaluation
Southeast Asia, threatens our bloodstream, invade red blood cells (RBCs), and set up an amplifying cycle. A in confirmation assays, lead-
chemical vaccine that targets the early liver stage could minimize resistance.

ability to control this disease. Parasite loads ing to the validation of ~103
A global effort to develop new compounds with good drug-

drugs for the treatment and 101 105 1012 like properties that have potent
prevention of malaria is un- Liver invasion Liver egress Infected RBCs liver-stage activity and minimal
der way but not guaranteed to cytotoxicity on host liver cells.

succeed (3, 5, 6). These efforts Of these, 631 were profiled on

include a systematic attempt additional Plasmodium species

to target all life-cycle stages of and life-cycle stages. Interest-

the parasite to allow combina- Sporozoites ingly, two-thirds of these hits are
tion therapies to be developed, specific for liver-stage parasites,

which are also likely to reduce highlighting the previously un-

the development of resist- known biology of this stage and

ance. High-throughput screens Liver stages Chemoprotection RBC stages promising new cellular insights
(HTSs) designed to identify Massive DNA replication and (chemical vaccine) Symptomatic stage with if compound targets can be de-
small drug-like molecules that high demand for pyrimidines a high parasite burden termined. This is a goal that will
prevent growth of blood-stage from mitochondria • Liver stage only and high therapeutic require innovative approaches.
parasites (7, 8) and target-based resistance potential The subset of compounds that
approaches have identified new • Low parasite burden were also active against blood-
compounds that are currently stage P. falciparum parasites
in preclinical development • Low resistance contained a high proportion
potential

• High bar for safety
and stability

and/or various stages of hu- of mitochondrial inhibitors

man clinical trials for treatment of malaria person, some of which find their way to the (43%) across diverse scaffolds. The mito-

(3). Missing from these efforts has been a liver to establish infection (10) (see the fig- chondrion in malaria parasites is critical

high-throughput technology to find liver ure). After replication in hepatocytes, malaria for pyrimidine biosynthesis, a pathway that

stage–specific chemotypes. On page 1129 of parasites burst out and infect erythrocytes, is essential for cell replication to generate

this issue, Antonova-Koch et al. (9) report setting up an amplifying intraerythrocytic the mature schizont in both blood and liver

an HTS effort that has filled this gap. They cycle. From 101 sporozoites that reach the infections (see the figure). Demand for py-

identify a substantial number of new chem- liver, up to 105 merozoites will emerge into rimidine nucleotide bases is even greater in

ical starting points with potent liver-stage the blood, and up to 1012 will then build up the liver stage, in which one sporozoite is GRAPHIC: A. KITTERMAN/SCIENCE

antimalarial activity, promising a new ca- in the bloodstream during a severe infection. replicated to generate 20,000 merozoites

A drug that blocks parasite replication in the (10). Drugs that target enzymes required for

1Department of Biochemistry, University of Texas liver works on a much lower parasite burden pyrimidine nucleotide biosynthesis are ef-
Southwestern Medical Center, Dallas, TX 75390, USA. and thus has a lower chance of encountering fective for both malaria treatment and che-
2Division of Infectious Diseases, Department of Medicine and and selecting for a rare parasite with a resis- moprevention, including the cytochrome
Department of Molecular Microbiology, Washington University tance mutation than do blood stage–active bc1 inhibitor atovaquone, which is an ap-
School of Medicine, Saint Louis, MO 63110, USA. Email: compounds. This is particularly so if a com- proved antimalarial agent used mainly for
[email protected]; [email protected]

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Published by AAAS

chemoprevention, and DSM265, an inhibi- PA L E O N T O L O GY
tor of dihydroorotate dehydrogenase, cur-
rently in clinical development (3, 5, 6). The Climate change and marine
surprisingly high percentage of dual-acting mass extinction
compounds that hit these targets suggests
that this pathway is one of the most vulner- The end of the Permian Period was catastrophic for
able pathways shared between the blood life in high-latitude regions
and liver stages.
By Lee Kump rocks (8) and by numerical modeling of the
Not all hits from the P. berghei HTS
worked on liver-stage P. vivax infections; Permian ocean-atmosphere system (9).
the crossover was only ~25%. This may be
partially explained by assay differences and V oluminous emissions of carbon dioxide Once considered nonselective, mass extinc-
by compound metabolism in the primary to the atmosphere, rapid global warm- tions are increasingly revealing patterns of
human hepatocytes used for the P. vivax ing, and a decline in biodiversity—the differential impact across species, lifestyles,
assay. This latter issue could be engineered storyline is modern, but the setting is and geographic locations through their fos-
out of any compound series during lead op- ancient: The end of the Permian Pe- sil records (10). A geographic pattern to
timization. It remains to be seen how many
of the identified chemotypes will ultimately riod, some 252 million years ago. For Permian extinction, however, has remained Downloaded from http://science.sciencemag.org/ on December 10, 2018
have liver-stage activity against both P.
vivax and the deadly P. falciparum. Extrap- the end-Permian, the result was catastrophic: elusive. Benefiting from the paleontological
olating from experience with compounds
on blood stages of the rodent and human the greatest loss of plant and animal life in community’s creation of the expansive Paleo-
parasites, a large majority are likely to be
effective against all Plasmodium species. Earth history (1). Understanding the details biology Database (11), Penn et al. discovered

Now comes the hard work of prioritizing of how this mass extinction played out is a meridional gradient to extinction intensity:
these hit compounds and optimizing them
to have the properties of a chemical vac- thus crucial to its use as an analog for our Groups of organisms that were restricted to
cine for clinical development. Recent work
to develop chemical vaccines for HIV (11) future. On page 1130 of this issue, Penn et al. higher latitudes prior to the extinction suf-
and to formulate atovaquone as an inject-
able for chemoprevention in malaria (12) (2) add an intriguing clue: The extinction was fered higher proportions of extinction than
provide the beginnings of proof of concept
for this strategy. The potential advantages most severe at high latitudes. Using a state- those established at low latitudes. What was
of liver stage–specific chemoprotection in
terms of simpler field implementation and of-the-art climate model that was interpreted it about living at high latitudes that predis-
low resistance propensity must be balanced
with a need for high safety when used to in terms of physiological stress, the authors posed marine organisms to extinction?
protect a whole asymptomatic commu-
nity (more so than a short-term treatment further identify the killer as Penn et al. took an innova-
given to a discrete population of patients).
Additionally, compounds must be stable, hypoxia, which was brought tive approach to answering
have a long half-life, and be amenable to
slow delivery formulation, such as a long- on by warm temperatures “If warming and this question by coupling
acting injectable that will also have the ben- and ocean deoxygenation. state-of-the-art computer
efit of improving compliance. Because of
these complexities, there is a need to have A number of kill mecha- oxygen loss... simulations of end-Permian
a substantial list of candidate compounds.
Thanks to the work of Antonova-Koch et al., nisms for end-Permian happened quickly, environmental change to a
we have such a list. j extinction have been pro- quantitative estimate of habi-

REFERENCES posed, most triggered by the massive die-off tat loss for presumed Perm-
tremendous volcanic activ- ian ecotypes. To establish the
1. World Health Organization (WHO), World Malaria Report ity associated with the em- was destined to environmental (temperature
(WHO, 2017); www.who.int/malaria/publications/
world-malaria-report-2017/en. placement of the vast lava occur.” and oxygen) tolerance of
Permian ecotypes, Penn et
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Med. 7, a025486 (2017). explaining the 10° to 15°C tropical warming each ecotype, reflecting the critical balance
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10.1126/science.aav7479 marine fossils (5). On land, unbearably hot temperature and oxygen distributions before

temperatures and hypoxia likely were the and during the end-Permian event were then

main cause of mass extinction of plants used to map regions of the ocean where the

and animals (6), although ultraviolet radia- metabolic index fell below the critical value

tion exposure from a collapsed ozone shield (hypoxic threshold) at which oxygen supply

contributed as well (7). Rapid warming also (fundamentally related to the oxygen concen-

likely led to the loss of oxygen from the tration of the water in which the organism

ocean’s interior, extending up onto the con- lived, itself a function of ocean circulation,

tinental shelves—a conclusion supported temperature, and rates of aerobic decompo-

both by the widespread distribution of in- sition) could not support the physiological

dicators for marine anoxia in sedimentary demands of daily life (feeding, reproduction,

and defense). The authors found that eco-

Department of Geosciences, College of Earth and Mineral types that favored high latitudes before the
Sciences, The Pennsylvania State University, University Park, event preferentially suffered extinction be-
PA 16802, USA. Email: [email protected] cause of their relatively high hypoxic thresh-

SCIENCE sciencemag.org 7 DECEMBER 2018 • VOL 362 ISSUE 6419 1113

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INSIGHTS | PERSPECTIVES

old. In other words, as the waters in which nomic biases, including a bias in the data on M E TA B O L I S M
they had lived warmed and lost oxygen, they living organisms toward more active life-
had nowhere to go to avoid hypoxic stress. styles relative to that which predominated in Bioenergetics
Tropical ecotypes were preadapted to low the Permian, have no substantial impact on through
oxygen and higher temperatures, and thus their general conclusions. Other limitations thick and thin
were better able to survive global warming of their study include both potential biases
(see the figure). in the fossil record and required assumptions Membrane fluidity
concerning the nutrient inventory of the influences the efficiency
Paleoenvironmental reconstruction is Permian ocean and the oxygen concentration of oxidative
challenging enough, but paleophysiological of the atmosphere at that time. Nutrients and energy metabolism
studies like that of Penn et al. are particularly atmospheric oxygen are important determi-
vexing because the organisms whose traits nants of the oceanic pattern and severity of By Eric A. Schon
one would like to understand and incorpo- anoxia at a given climate state of the past,
rate into a model are gone. Instead, studies yet there are limited data on these factors. T he cells in all biological systems are
of living organisms must be used. Penn et al. Another factor not considered in this study composed of a limited number of mo-
are aware of this limitation of their study and is the rate of climate change during the end- lecular constituents, mainly proteins,
they go to great lengths to show that taxo- Permian event. If warming and oxygen loss nucleic acids, carbohydrates, and lip-
were imposed slowly, perhaps high-latitude ids. Of these, lipids tend to receive the
Marine mass extinction organisms could have adapted to warming shortest shrift, as they are typically Downloaded from http://science.sciencemag.org/ on December 6, 2018
and oxygen loss, whereas if these changes considered to be merely the building blocks of
Modeled patterns of ocean warming (top) and happened quickly, massive die-off was des- membranes that provide a scaffold in which
oxygen depletion (middle) suggest that hypoxia may tined to occur. Existing geochronological con- the “important” molecules, such as enzymes
explain why extinction of marine organisms straints on the fossil record (3) suggest that or signaling proteins, reside. In recent years,
(bottom) was more intense at high latitudes than the rates of these changes were rapid. and with the advent of advanced lipidomics
in the tropics during the latest Permian Period. techniques, we have learned that “a lipid is
As our understanding of the drivers and a lipid is a lipid” is simply not true, and that
∆ Temperature (°C) consequences of end-Permian climate change the lipid composition of membranes can have
and mass extinction improves, the lessons profound effects on the behavior and activity
0 9 10 15 18 for the future become clear. Our modern-day of its resident macromolecules. For example,
500 “Siberian Trap” is fossil fuel burning, which some lipids, such as members of the phospha-
1000 is driving up atmospheric carbon dioxide to tidylinositol family, are important signaling
concentrations that Earth has not witnessed molecules. However, what is less appreci-
Depth (m) 2000 for millions of years. The planet is warming ated is that the physical composition of lipid
and the oceanic response of deoxygenation is membranes can have profound effects on cel-
3000 already being detected in coastal zones and lular behavior as well. On page 1186 of this
the open ocean (12). The Permian world may issue, Budin et al. (1) use the Gram-negative
4000 −50 0 50 have been more susceptible to rapid climate bacterium Escherichia coli and the budding
Latitude change and its attendant environmental yeast Saccharomyces cerevisiae as model sys-
and biotic effects; carbon cycle–stabilizing tems to show that the fluidity of a membrane,
∆ Oxygen (mmol/m3) calcareous plankton hadn’t yet evolved (13), as determined by its lipid composition, can
and the supercontinent of Pangaea’s arid in- have huge effects on the efficiency of aerobic
–200 –100 0 50 teriors and sluggish tectonics lowered the energy production (respiration) by the highly
0 threshold for abrupt climate change (14). hydrophobic, membrane-embedded, oxida-
Depth (m) 500 But even if it represents an extreme case, the tive phosphorylation (OxPhos) system.
1000 lesson is clear: Continued or accelerated fos-
sil fuel burning presents a risk that must be The OxPhos system in aerobic organisms,
2000 reversed or mitigated so that we can avoid a located in the plasma membrane of prokary-
fate anything like that of the end-Permian. j otes and in the mitochondria of eukaryotes,
3000 comprises two elements: a multicomponent
REFERENCES respiratory chain that pumps H+ ions (pro-
4000 −50 0 50 tons) derived from the reduced forms of nico-
Latitude 1. D. Erwin, Extinction: How Life on Earth Nearly Ended 250 tinamide adenine dinucleotide (NADH) and
100 Million Years Ago (Princeton Univ. Press, 2015). flavin adenine dinucleotide (FADH ) across
80 Fossil record
60 2. J. Penn et al., Science 362, eaat1327 (2018). 2
Extinction (%) 40 5 to 95% 3. S. D. Burgess, S.A. Bowring, S.-Z. Shen, Proc. Natl.Acad. GRAPHIC: J. YOU/SCIENCE
20 con0dence level a topologically closed membrane, generating
Sci. U.S.A. 111, 3316 (2014). a proton gradient, and an adenosine triphos-
0 −50 0 50 4. H. Svensen et al., Nature 429, 542 (2004).
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6. R. B. Huey, P. D.Ward, Science 308, 398 (2005). Development, Columbia University Medical Center, New York,
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(2004).
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McCauley, Science 353, 1284 (2016).
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12. A. Oschlies, P. Brandt, L. Stramma, S. Schmidtko, Nat.

Geosci. 11, 467 (2018).
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859 (2003).
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10.1126/science.aav736

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The OxPhos system Complex I Complex II Complex III Complex IV
NADH NAD+ + H+ Succinate Fumarate + H+
The human respiratory chain ATP
showing complexes I–IV, ATP H+
synthase, CoQ10, and the CoQ10 H+ H+ 2e– ADP + Pi
binding site within complex I. 2H+
Proton (H+) and electron (e–)
flow are shown for illustrative H2O ½ O2 H+
purposes. Complexes I, III (a
dimer), and IV can assemble into Matrix 2H+ CoQH2 2CoQH2 CoQH2 H+
a supercomplex (bottom). CoQ 2CoQ CoQ
CoQ H+
Supercomplex e– Complex V
CoQH2 H+ (ATP synthase)
Intermembrane
space Cytochrome c

H+

O

H3C–O CH3 CoQ10

H3C–O
O

phate (ATP) synthase that uses this gradient mediated reactions, Budin et al. concluded “free” complex I in the mitochondrial inner Downloaded from http://science.sciencemag.org/ on December 6, 2018
to drive ATP synthesis. The requisite electro- that CoQ diffusivity indeed influences respi-
GRAPHIC: V. ALTOUNIAN/SCIENCE BASED ON LETTS ET AL. (15) neutrality is maintained by transferring an ratory flux—a result that had been predicted membrane, as well as “free” complex II, which
equivalent number of electrons through the on kinetic grounds decades earlier by a num-
respiratory electron transport chain to mo- ber of groups (2–5). is not a component of the supercomplex.
lecular oxygen. The primary source of the
electrons is complex I (an NADH dehydroge- The experimental elegance of this work The identification of CoQ as a rate-limiting
nase) and complex II (a succinate dehydro- was made possible, in part, by the use of bac-
genase). The electrons are transferred first teria and yeast, which have relatively simple molecule in electron flow along the respi-
to a highly hydrophobic and mobile mem- OxPhos systems and well-defined genetics.
brane-localized electron carrier called coen- The downside of this approach, however, is its ratory chain not only has relevance for our
zyme Q (CoQ; also called ubiquinone), then unclear relevance to mammalian bioenerget-
to complex III (a CoQ reductase), then to a ics. Specifically, complex I in E. coli comprises understanding of the basic biology and bio-
cytochrome, and finally to complex IV (a cy- only 14 subunits (versus 45 in humans) and
tochrome oxidase), where oxygen is reduced binds not only CoQ but also menaquinone, physics of aerobic energy metabolism, but
to produce water (see the figure). or vitamin K , a CoQ lacking methoxy groups
has medical implications as well. There are
Do collisional interactions among the 2
various respiratory components affect ATP a number of human diseases associated with
production? Budin et al. hypothesized that that is not synthesized in humans. Also, al-
by altering membrane fluidity they might though some fungi contain a complex I en- CoQ deficiency (human CoQ has a hydro-
be able to answer this question and perhaps zyme that is similar to that in mammals (6), 10
determine which component of the OxPhos S. cerevisiae does not; instead, it contains two
system is diffusion-limited. By titrating the unrelated NADH dehydrogenases (7). It might phobic side chain composed of 10 isopren-
viscosity of the OxPhos-containing plasma be useful to explore mitochondrial membrane
membrane in E. coli, they showed that the fluidity in one of these other fungi. oid subunits), both primary (for example,
growth rate and aerobic respiration of the
cells was increased at low viscosity—which Another aspect of the CoQ-diffusivity mutations in CoQ biosynthesis genes) and
allows for greater lateral movement of connection that is still unclear is its role in
membrane-embedded molecules—and was electron transfer as a component of “super- secondary (for example, CoQ deficiency as
decreased at high viscosity. This implies that complexes” (also called “respirasomes”). In 10
increased membrane fluidity accelerated in- higher organisms, including humans, com-
teractions among the OxPhos components. plexes I, III, and IV can co-assemble into su- a downstream consequence of other causes)
The result was also replicated in a eukaryote percomplexes (8), but neither E. coli nor S.
(S. cerevisiae) in which mitochondrial mem- cerevisiae contain supercomplexes that incor- (11), with attempts to ameliorate them by
brane fluidity was manipulated. porate a relevant complex I analogous to that
in humans (7, 9). This is important because treating with CoQ or with CoQ analogs,
These data support a role for diffusion of complex I contains a channel that allows 10
the OxPhos components within the mem- for the entry of CoQ and the exit of reduced
brane, but did not single out any component CoQH for transfer of electrons to complex such as MitoQ and EPI-743 (12). Thus, the
that could diffuse more rapidly and thereby
be controlling. There is an obvious candidate 2 role of membrane fluidity in controlling the
for this role: CoQ, a dwarf among the giant
respiratory complexes. Using a combination III. In the supercomplex, there is essentially efficiency of OxPhos in mammals, both in
of energy-transfer experiments and math- no lipid barrier to this transfer, and the prox-
ematical modeling based on assumptions imity of complexes I and III in the supercom- normal (13) and diseased (14) states, is an
of random molecular motion and collision- plex could mean that if CoQ redox turnover is
increased, it occurs via a non–lipid-mediated important but relatively unexplored aspect
mechanism, although currently there is no
evidence to support this (10). However, even of aerobic energy metabolism that deserves
in this situation there still may be an appre-
ciable degree of viscosity-mediated control of further investigation. j
electron transfer to complex III, as there is
REFERENCES AND NOTES

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ACKNOWLEDGMENTS

Supported by NIH, the U.S. Department of Defense, and the
J.Willard and Alice S. Marriott Foundation.

10.1126/science.aav7629

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INSIGHTS | PERSPECTIVES

R E G E N E R AT I O N

Endothelial cell adaptation in regeneration

Tissue-specific endothelial cells maintain organ homeostasis and instruct regeneration

By Jesus M. Gomez-Salinero and reprogramming of adult human and mouse of other organs, including pancreas, myo- Downloaded from http://science.sciencemag.org/ on December 10, 2018
Shahin Rafii ECs by transducing them with FGRS TFs into cardium, central nervous system, and even
engraftable hematopoietic stem cells for the reproductive organs, including testes and
E ndothelial cells (ECs) cover the in- treatment of blood disorders (4). Identifying ovaries (1). Notably, at steady state and dur-
ner wall of blood and lymph vascula- other pioneer TFs that direct conversion of ing organ regeneration, microenvironmental
ture in normal and malignant tissues. ECs to nonvascular cell types will advance cues program ECs to establish a nurturing
It is widely appreciated that ECs are the field of direct reprogramming for thera- vascular niche to choreograph self-renewal
endowed with unique phenotypic, peutic organ regeneration. and differentiation of tissue-specific stem
structural, functional, and angiocrine cells, including hematopoietic, spermato-
secretory attributes, generating specialized Functional plasticity refers to the capacity gonial, and neural repopulating cells (1, 7).
vascular subpopulations with organotypic of ECs to tailor and adapt cellular processes Similarly, excessive release of tumor vascular
and diseased-tissue signatures (1, 2). To to completely different tissue-specific chores, niche–derived angiocrine factors supports the
achieve this high level of organ and tumor such as sustaining the blood-brain barrier or emergence of tumor-initiating cells (which
heterogeneity, ECs have acquired malleable adjusting the dynamic filtration function of have stem cell–like properties) that promote
cellular features that allow them to adapt to liver sinusoids and kidney glomeruli. The tis- chemoresistance (8).
normal physiological stressors and to pro- sue-specific specialization of ECs orchestrates
mote tissue homeostasis and regeneration. organogenesis during development, stem cell During organ repair, aberrant signals
This is exemplified during liver regeneration homeostasis, and regeneration throughout might corrupt the regenerative functions of
in which defined angiocrine (meaning EC- adulthood. The precise mechanism by which ECs, leading to fibrosis and tumorigenesis.
derived) signals from liver sinusoidal ECs ini- ECs acquire this level of heterogeneity is Persistent stress-induced stimulation of ECs
tiate and resolve liver regeneration through unknown and could be mediated by as yet could alter the organ-specific function of
paracrine signaling to hepatocytes. By con- unrecognized intrinsic genetic and epigen- ECs, favoring scarring through a maladapta-
trast, stressed and irritated ECs maladapt etic regulators governed by signals relayed tion process, including endothelial-to-mesen-
to a pathological microenvironment, such from the extrinsic microenvironment. These chymal transition (3), whereby ECs acquire
as inflamed or chronically injured tissues, signals emanate from the immediate sur- fibroblastic features. An association between
favoring fibrosis and tumorigenesis. Thus, rounding microenvironment, including non- several chronic diseases and deregulated en-
EC adaptive functions have beneficial or det- vascular cells, extracellular matrix, metabolic dothelium has recently been established, for
rimental effects in organ physiology. Under- signals, and biomechanical forces. Chronic instance, in dementia or cardiovascular dis-
standing the molecular determinants of EC stressors, such as inflammatory and injury eases (9, 10). Mechanistically, differential sig-
adaptability could reveal therapeutic targets signals, elicit an aberrant vascular response, naling pathway activation in ECs can favor
to facilitate wound healing without fibrosis, setting the stage for fibrosis, organ dysfunc- fibrosis over regeneration. For example, in
combat tumorigenesis, or develop efficacious tion, and tumorigenesis (3). the liver, differential activation of the C-X-C
strategies for organ regeneration, long-term chemokine ligand 12 (CXCL12) cognate recep-
engraftment of bioartificial organs, and tis- On the contrary, during regeneration, tors, with CXCR7 predominantly expressed
sue transplantation. angiocrine cues supplied from activated over CXCR4, on ECs induces expression of
ECs in response to injury of surround- angiocrine factors that promote healing
Endothelial cells manifest at least two ing tissue orchestrate scar-free regenera- without fibrosis (7). By contrast, chronic in-
modes of plasticity: cellular and functional. tion. For example, release of angiogenic flammation caused by the ligation of biliary
Cellular plasticity encompasses their capac- factors by neighboring parenchymal cells ducts results in dominant CXCR4 activation
ity to generate different EC types (in arteries, induces liver ECs to deploy angiocrine over CXCR7, which promotes healing with
veins, or capillaries) and even nonvascular factors, such as angiopoietin-2 (ANG2), profibrotic changes. These dichotomous re-
cell types, including hematopoietic cells and R-spondin-3 (RSPO3), and WNT9B, that sus- sponses of liver ECs indicate that differential
parenchymal cells (3). During development tain hepatic homeostasis; or angiocrine secre- expression and activation of specific inflam-
and in adulthood, this plasticity is regulated tion of hepatocyte growth factor (HGF) and matory receptors on ECs could relay external
in part by the induction of organotypic tran- WNT2 from liver ECs that mediate mouse cues in favor of regeneration instead of fibro-
scription factors (TFs) that instruct ECs to liver regeneration after partial hepatectomy sis and vice versa.
transition into defined cellular states. Discov- (1, 5). In response to injury, lung epithelial
ery of the molecular pathways that master- cells produce vascular endothelial growth fac- Stress-induced responses of ECs also play
mind the cellular plasticity of ECs has paved tor A (VEGF-A) and fibroblast growth factors important roles in promoting cancer at the
the way for designing strategies to generate (FGFs) that activate lung ECs to supply matrix expense of regeneration. The malleability of
adult hematopoietic stem cells in vitro. For metalloprotease–14 (MMP14) and bone mor- ECs forces them to participate in two-way
example, identification of four TFs, collec- phogenetic protein 4 (BMP4) and increase cross-talk with their disrupted microenviron-
tively termed FGRS TFs, has enabled in vitro the bioavailability of epidermal growth factor ment, inducing the release of abnormal an-
(EGF) ligands and thrombospondins, thereby giocrine factors and thereby setting the stage
Division of Regenerative Medicine, Ansary Stem Cell Institute, igniting lung epithelial regeneration (1, 6) (see for tumorigenesis and tumor growth. For ex-
Department of Medicine, Weill Cornell Medicine, New York, NY, the figure). Similarly, tissue-specific ECs sup- ample, the excessive and dysregulated release
USA. Email: [email protected] ply defined angiocrine factors that contribute of FGF4 by tumor cells triggers the expression
to organogenesis and metabolic homeostasis of the E26 transformation-specific TF ETS2

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Published by AAAS

and the cell surface receptor Jagged-1 in the set the stage for the treatment of aging-asso- placement of current decellularized scaffolds
tumor endothelium. This maladaptive EC re- ciated maladies. in patients often results in poor functional
sponse activates the angiocrine release from recovery due to poor vascularization. Popu-
ECs of protumorigenic insulin-like growth Uncovering the molecular determinants lating the decellularized matrix with durable
factor 1 (IGF1) and decreases expression of of EC adaptability could enable deconvolu- and adaptable ECs will enhance the life span
antitumorigenic IGF binding protein IGFBP7, tion of the intricate pathways that drive adult and improve the survival of these potentially
reinforcing aggressive and chemoresistant tu- organ repair that has defied developmental lifesaving implants (15).
mor growth (8). Moreover, ECs in distant, non- biologists for decades. For example, although
cancerous organs can respond to the signals development of in vitro techniques, such as Translation of these concepts to the clini-
supplied by tumor cells, thereby facilitating tissue-specific organoids and organ-on-a- cal setting poses a herculean task and is com-
metastasis through the activation of Notch chip models, have enhanced our understand- pounded by two major obstacles: social and
and the expression of vascular cell adhesion ing of tissue morphogenesis, these models scientific. From a social standpoint, one of
molecule 1 (VCAM1) on the distal endothe- do not fully explain the mechanism for the the main obstacles to overcome is the ram-
lium (11). These tumor-associated changes resistance of certain tissues such as lung, pant proliferation of pseudoscientific clinics
in the endothelium favor the persistence of heart, intestines, and kidneys to self-repair. and stem cell tourism that promise false hope
invasiveness and treatment-refractory cancer The development of vascularized organoids to desperate patients (16). Their unsuper-
stem cells. Therefore, tumor EC–derived an- will not only allow deciphering of the path- vised approach without regulatory oversight
giocrine factors or their triggers are potential ways that choreograph tissue repair, but also could adversely affect the health of patients
druggable anticancer targets. enable manufacturing of mini-organs for because nonvalidated treatments may delay
regenerative medicine and facilitate their the approval of evidence-based treatments.
From a scientific perspective, capitalizing on
Endothelial cells in organ regeneration the regenerative and rejuvenating functions Downloaded from http://science.sciencemag.org/ on December 10, 2018
of ECs by employing tissue-specific TFs, the
Endothelial cells (ECs) are key mediators in the regulation of organ physiology and malignant cell conversion of autologous adult ECs into or-
pathophysiology. They form vascular conduits and also supply angiocrine factors (such as WNTs, HGF, and ganotypic ECs, and vascularizing organ mod-
MMPs) that regulate organ homeostasis. Under stress conditions, ECs can maladapt, supplying factors els in vitro so that they reach human size will
that promote the development of fibrosis, cancer, and other maladies. The use of tissue-specific ECs will be lead to innovative therapeutic strategies. For
essential to choreograph functional organ regeneration and repair. example, these approaches could open the
door to the development of artificial organs
Homeostasis and regeneration Maladaptation Regenerative medicine for transplantation, as well as the manufac-
ture of human organs in donor animals. Im-
Induction of Lungs EC-derived factors promote Revascularization portantly, one of the main limitations yet to
MMP14 and BMP4 cancer progression of decellularized be circumvented is the development of non-
in ECs ignites lung and metastasis organs and matrix immunogenic organs.
regeneration.
Notwithstanding these caveats, translation
Alveoli EC Cancer to the regeneration field could be augmented
cells by formulating standard procedures to in-
Release of WNT2, WNT9B, ANG2, and Delivery of ECs corporate vascular networks within implants
CXCR4 CXCR7 for the treatment that can sustain their long-term engraftment
HGF orchestrate liver regeneration. EC of age-associated disorders and provide the proper tissue-specific angio-
Liver crine signals to drive organ repair without
CXCL12 scarring and tumorigenesis. Achievement of
these goals will bring us closer to fulfilling
Injured Vascularization the promise of regenerative medicine to treat
hepatocyte of organoids millions of disabled patients worldwide who
need organ replacement. j
Hepatocyte Activation of CXCR4 over CXCR7
on ECs promotes liver fbrosis. REFERENCES AND NOTES
1. S. Rafii et al., Nature 529, 316 (2016).
GRAPHIC: JOSHUA BIRD/SCIENCE The intrinsic malleability of ECs makes long-term in vivo engraftment. Additionally, 2. D.J. Nolan et al., Dev. Cell 26, 204 (2013).
them ideal for regenerative medicine, as vascularized tumoroids (tumor organoids) 3. E. Dejana et al., Nat. Commun. 8, 14361 (2017).
does their localization in vessel walls, allow- could be developed to evaluate the influence 4. R. Lis et al., Nature 545, 439 (2017).
ing easy access to infused drugs, and their of different drugs in the emergence of can- 5. H. G.Augustin et al., Science 357, eaal2379 (2017).
expression of organ-specific markers allows cer during organ regeneration processes, as 6. J.-H. Lee et al., Cell 156, 440 (2014).
the development of strategies to modulate ECs have a primary role in tumor develop- 7. B.-S. Ding et al., Nature 505, 97 (2014).
the function of specific EC types. Further- ment and expansion (8). Clearly, innovating 8. Z. Cao et al., Cancer Cell 31, 110 (2017).
more, EC regeneration has potential for the techniques to generate adaptable autologous 9. C. Iadecola, Neuron 80, 844 (2013).
treatment of aged organs. For example, oxi- ECs that can arborize organoids may lead to
dative stress leads to attrition of ECs, which transformative therapeutic paths in the near 10. M.J. Gimbrone Jr. et al., Circ. Res. 118, 620 (2016).
increasingly occurs with age, altering hema- future. However, engineering of long-lived, 11. E.Wieland et al., Cancer Cell 31, 355 (2017).
topoietic stem cell activity and perturbing responsive, and malleable organotypic ECs 12. A. P. Kusumbe et al., Nature 532, 380 (2016).
lineage differentiation. Notably, intravenous from, preferably, patient ECs is necessary and 13. M. G. Poulos et al., J. Clin. Invest. 127, 4163 (2017).
transplantation of ECs from young mice can a main challenge to overcome. 14. S. Fraineau et al., Stem Cell Rep. 9, 1573 (2017).
revert this phenotype in aged mice (12, 13). 15. A. F. Pellegata et al., Front. Bioeng. Biotechnol. 6, 56
Moreover, epigenetic manipulation of human Decellularized human organ scaffolds are
blood-circulating EC progenitors transiently another area of active regenerative medi- (2018).
augments vasculogenesis after ischemia (14). cine investigation to enable organ replace- 16. D. Sipp et al., Nature 561, 455 (2018).
Rejuvenation of the senescent EC state, by ments. This approach has been hampered by
the infusion of specific as yet unrecognized the lack of proper seeding of adaptable ECs ACKNOWLEDGMENTS
cytokines or the infusion of young ECs, could within the narrow confines of decellularized
capillaries. This is a major problem because S.R. is the founder of, and an unpaid consultant to,Angiocrine
Bioscience, San Diego, California.

10.1126/science.aar4800

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INSIGHTS | PERSPECTIVES

COMPUTER SCIENCE community, with much analysis and com-
mentary on the amazing style of play that Al-
Mastering board games phaZero exhibited (see the figure). Note that
neither the chess or shogi programs could
A single algorithm can learn to play three hard board games take advantage of the TPU hardware that
AlphaZero has been designed to use, making
By Murray Campbell value in chess or shogi programs. The stron- head-to-head comparisons more difficult. Downloaded from http://science.sciencemag.org/ on December 10, 2018
gest programs in both games have relied on
F rom the earliest days of the computer variations of the alpha-beta algorithm, used Chess, shogi, and Go are highly complex
era, games have been considered impor- in game-playing programs since the 1950s. but have a number of characteristics that
tant vehicles for research in artificial in- make them easier for AI systems. The game
telligence (AI) (1). Game environments Silver et al. demonstrated the power of state is fully observable; all the information
simplify many aspects of real-world combining deep reinforcement learning needed to make a move decision is visible to
problems yet retain sufficient complex- with an MCTS algorithm to learn a variety the players. Games with partial observability,
ity to challenge humans and machines alike. of games from scratch. The training method- such as poker, can be much more challenging,
Most programs for playing classic board ology used in AlphaZero is a slightly modi- although there have been notable successes
games have been largely human-engineered fied version of that used in the predecessor in games like heads-up no-limit poker (11, 12).
(2, 3). Sophisticated search methods, complex system AlphaGo Zero (5). Starting from ran- Board games are also easy in other important
evaluation functions, and a variety of game- domly initialized parameters, the neural net- dimensions. For example, they are two-player,
specific tricks have allowed programs to sur- work continually updates the parameters on zero-sum, deterministic, static, and discrete,
pass the best human players. More recently, all of which makes it easier to perfectly simu-
a learning approach achieved superhuman Contemplating the next move late the evolution of the game state through
performance in the hardest of the classic arbitrary sequences of moves. This ability to
games, Go (4), but was specific for this game In the game between AlphaZero (white) and easily simulate future states makes MCTS,
and took advantage of human-derived game– Stockfish (black), there were several moves that were as used in AlphaZero, practical. Multiplayer
specific knowledge. Subsequent work (5) re- reasonable for AlphaZero to consider. After 1000 video games such as StarCraft II (13) and Dota
moved the need for human knowledge, and move-sequence simulations, the red moves were 2 (14) have been proposed as the next game-
additional algorithmic enhancements deliv- rejected, and after 100,000 simulations, AlphaZero playing challenges as they are partially ob-
ered further performance improvements. On chose the blue move over orange. servable and have very large state spaces and
page 1140 of this issue, Silver et al. (6) show action sets, creating problems for AlphaZero-
that a generalization of this approach is effec- 8 bcdef gh like reinforcement learning approaches.
tive across a variety of games. Their Alpha- 7
Zero system learned to play three challenging 6 Games have been popular research do-
games (chess, shogi, and Go) at the highest 5 mains in AI in part because it is easy to
levels of play seen. 4 identify games in which humans are better
3 than computers. Chess, shogi, and Go are
AlphaZero is based on reinforcement learn- 2 immensely complex, and numerous human
ing (7), a very general paradigm for learning 1 players have devoted much of their lives to
to act in an environment that rewards useful understanding and playing these games at
actions. In the case of board games, the learn- a the professional level. The AlphaZero ap-
ing agent plays moves in the game and is proach still has limitations that could be
typically trained by playing large numbers of the basis of the outcome of self-play games. addressed (for example, large computa- GRAPHIC: N. CARY/SCIENCE
games against itself. The first major success AlphaZero learned to play each of the three tional requirements, brittleness, and lack
for reinforcement learning and games was board games very quickly by applying a large of interpretability), but this work has, in ef-
the TD-Gammon program (8), which learned amount of processing power, 5000 tensor fect, closed a multidecade chapter in AI re-
to play world-class backgammon in the early processing units (TPUs), equivalent to a very search. AI researchers need to look to a new
1990s by using neural networks. More re- large supercomputer. generation of games to provide the next set
cently, deep (many-layer) neural networks of challenges. j
were combined with reinforcement learning Once trained, evaluating the systems is not
in an approach dubbed “deep reinforcement entirely trivial, and there are many pitfalls REFERENCES AND NOTES
learning,” which received widespread interest that can affect the measurements. Silver et
after it was successfully applied to learn Atari al. used a large variety of testing conditions 1. C. Shannon, Philos. Mag. 41, 256 (1950).
video games directly from screen input (9). which, taken together, provide convincing 2. J. Schaeffer et al., AI Mag. 17, 21 (1996).
evidence of the superiority of the trained sys- 3. M. Campbell et al., Artif. Intell. 134, 57 (2002).
The approach described by Silver et al. tems over the previous state-of-the-art pro- 4. D. Silver et al., Nature 529, 484 (2016).
augments deep reinforcement learning with grams. Some of the early test games played 5. D. Silver et al., Nature 550, 354 (2017).
a general-purpose searching method, Monte between AlphaZero and the chess program 6. D. Silver et al., Science 362, 1140 (2018).
Carlo tree search (MCTS) (10). Although Stockfish were released to the public and cre- 7. R. Sutton,A. Barto, Reinforcement Learning: An
MCTS has been the standard searching ated something of a sensation in the chess
method used in Go programs for some time, Introduction (MIT Press, 1998).
until now, there had been little evidence of its 8. G.Tesauro, Commun.ACM 38, 58 (1995).
9. V. Mnih et al., Nature 518, 529 (2015).
IBM Research, T.J. Watson Research Center, Yorktown Heights, 10. R. Coulom, Int. Conf. Comput. Games 2006, 72 (2006).
NY 10598, USA. Email: [email protected] 11. M. Moravčík et al., Science 356, 508 (2017).
12. N. Brown,T. Sandholm, Science 359, 418 (2018).
13. O.Vinyals et al.,arXiv:1708.04782 [cs.LG] (16August 2017).
14. OpenAI, OpenAI Five, 25 June 2018; https://blog.openai.

com/openai-five/.

ACKNOWLEDGMENTS

Thanks to T. Klinger and G.Tesauro for their comments.

10.1126/science.aav1175

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POLICY FORUM

ENVIRONMENTAL ECONOMICS

Flawed analyses of U.S. auto
fuel economy standards

A 2018 analysis discarded at least $112 billion in benefits

By Antonio M. Bento1,2, Kenneth Gillingham3,2, Mark R. Jacobsen4,2, Christopher R. In addition to greenhouse gas emissions and fuel
Knittel5,2, Benjamin Leard6, Joshua Linn7, Virginia McConnell6, David Rapson8, James M. economy, analyses must also consider effects on
Sallee9,2, Arthur A. van Benthem10,2, Kate S. Whitefoot11 pollution, safety, and traffic congestion.

C orporate Average Fuel Economy that determine the relevant baseline against Valuation parameters are critical for Downloaded from http://science.sciencemag.org/ on December 10, 2018
(CAFE) and greenhouse gas (GHG) which the standards are compared. converting impacts into costs and ben-
PHOTO: ISTOCK.COM/PLHERRERA emissions standards for passenger efits. The value of a statistical life is used
vehicles and light trucks have long Modeling consumer behavior should in- to value fatalities, whereas the social cost
been a centerpiece of the U.S. strategy clude the purchase of general goods and of carbon is used for valuing the benefits
to reduce energy use and GHG emis- new or used vehicles. Consumers trade off of reduced gasoline use (11, 12). Other
sions and increase energy security. Under vehicle prices for various vehicle attributes valuation parameters reflect the value
the authority of the Energy Independence (for example, performance, safety features, of energy security and the health costs
and Security Act, the Environmental Protec- seating capacity, and so on). They also de- of tailpipe emissions. A comprehensive
tion Agency (EPA), and the National High- cide how much to drive and whether to protocol should also account for other fac-
way Traffic Safety Administration (NHTSA) keep or scrap their older vehicles. tors, including changes in gasoline prices
jointly set GHG and CAFE standards to over time.
reach 55 miles per gallon by 2025. A 2016 A comprehensive analysis would allow
draft technical assessment report (TAR) automakers to comply with standards by TWO FLAWED ANALYSES
affirmed by the EPA in January 2017 con- adjusting vehicle prices, improving fuel econ- Both the 2016 and 2018 analyses deviate
cluded that the 2022–2025 standards were omy, and altering performance and other ve- from the comprehensive protocol outlined
technologically feasible and that benefits hicle attributes (2–5). It would also recognize above because they do not explicitly model
far exceeded costs. But under the current that technology is determined by automaker consumer choices and tend to miss impor-
administration, those agencies are now chal- investments, while accounting for learning- tant trade-offs between general consump-
lenging that conclusion in a 2018 Notice of by-doing and knowledge spillovers that, over tion, vehicle choice, and VMT. On the supply
Proposed Rulemaking (NPRM), which pro- time, may lower the compliance costs. side, the modeling of the new and used car
poses freezing standards at model year (MY) markets does not fully consider important
2020 levels through 2025. Its analysis finds Modeling of the interaction between new interactions between these markets. As a
that the costs of the previous standards now and used vehicle markets is critical to deter- consequence, multimarket adjustments,
exceed benefits. With the agencies currently mine the resulting size of the total fleet and and resulting outcomes such as the size of
in the process of determining whether the its composition, as well as the prices of ve- the fleet, fleet composition, and prices of
rule should be finalized, we describe how the hicles (relative to the price of other goods). vehicles, are captured imperfectly. Incom-
2018 analysis has fundamental flaws and in- Prices, fuel economy, and other attributes plete accounting for such adjustments also
consistences, is at odds with basic economic determine the total cost of ownership, which affects the magnitudes of the external costs
theory and empirical studies, is misleading, affects total vehicle miles traveled (VMT), as and benefits.
and does not improve estimates of costs and well as willingness to pay for vehicles (1, 6).
benefits of fuel economy standards beyond The 2018 analysis did attempt to incor-
those in the 2016 analysis. A comprehensive protocol should also porate several channels of adjustment that
consider costs and benefits that arise from were missing from the 2016 TAR (see table
A COMPREHENSIVE PROTOCOL “external effects,” including GHG emissions, S1, fourth column). However, the most im-
A benefit-cost analysis (see table S1) for fuel energy security, local air pollution, safety, pactful channels were added in an ad hoc
economy standards grounded on basic eco- and traffic congestion (7), which are af- way that runs afoul of the proposed proto-
nomic principles must consider the behavior fected by fleet size and its composition and col outlined above, existing research, and
of consumers and automakers as well as keep the total number of miles driven. basic economic principles. As a result, the
account of several externalities (1). It must changes in the 2018 NPRM are misleading.
consider a range of parameter values and In the case of safety, four additional Although we do not endorse the 2016 TAR,
assumptions to account for inherent uncer- outcomes are relevant: changes in vehicle the 2018 analysis failed to advance our un-
tainty as well as the impact of related policies weights and sizes, distribution of weights derstanding of the true costs and benefits of
and sizes in the entire fleet, distribution of fuel economy standards.
vehicle vintage, and sorting of individuals
into vehicles on the basis of their risk pref-
erences, risk profiles, and preferences for
other vehicle attributes (8–10).

1University of Southern California, Los Angeles, CA, USA.2National Bureau of Economic Research, Cambridge, MA, USA.3Yale University, New Haven, CT, USA.4University of California, San Diego, CA, USA.
5Massachusetts Institute of Technology, Cambridge, MA, USA. 6Resources for the Future, Washington, DC, USA.7University of Maryland, College Park, MD, USA.8University of California, Davis, CA, USA.
9University of California, Berkeley, CA, USA.10University of Pennsylvania, Philadelphia, PA, USA.11Carnegie Mellon University, Pittsburgh, PA, USA. Email: [email protected]

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INSIGHTS | POLICY FORUM

There are stark differences between the 2016 and 2018 benefit-cost a result of the standard (see the SM for addi-
costs and benefits assigned to the 2022– analyses of CAFE standards tional discussion). As a result, this new model
2025 standards in the 2016 and 2018 analy- violates simple economic principles; leads to
ses, reflecting differences in assumptions. Stark differences between the 2016 and 2018 misleading conclusions related to the overall
The figure shows the costs and benefits estimates reflect fundamental flaws size of the fleet, fleet composition, and the
from the affirmed 2022–2025 CAFE stan- and inconsistencies in the 2018 analysis. amount of scrappage; and undermines EPA
dards, relative to the proposed rollback See supplementary materials. and NHTSA modeling efforts to improve the
levels as calculated by the agencies [see understanding of the costs and benefits of
supplementary materials (SM) section G for 2016 2018 fuel economy standards.
the GHG emissions standards]. To interpret 400 326
impacts of a rollback of the standard in the These 6 million “missing” vehicles have
context of the figure, one should change 200 190 important implications. A larger fleet leads
the signs of all costs and benefits. For the to higher miles driven, gasoline use, and ex-
CAFE standard, the 2016 review finds a net Billions of dollars, 2016 0 Benefts ternal costs. Total driving, excluding the re-
benefit of $87.6 billion, whereas the 2018 –200 Costs bound effect, should increase (as opposed to
analysis finds a net loss of $176.6 billion. decrease) with the rollback relative to keeping
Or, in other words, the proposed rollback –102 the previous standards. Driving scales with
of the standard (relative to existing levels) fleet size, and newer cars are driven more.
would generate a net benefit based on the –400 As VMT increases, gasoline consumption Downloaded from http://science.sciencemag.org/ on December 10, 2018
assumptions made in the 2018 analysis and and the external effects of GHG emissions,
a net loss based on the 2016 analysis; for the Benefts local air pollution, traffic fatalities, conges-
GHG emissions standard, the 2016 review tion, and energy security of the rollback will
finds a net benefit of $97.2 billion, whereas Pretax fuel savings –502 be larger than reported in the 2018 analysis,
the 2018 analysis finds a net loss of $200.6 potentially by considerable amounts.
billion (see the SM for details). Energy security Costs
Crash fatalities and injuries can increase
The 2018 analysis reports benefits that CO2 damages avoided Vehicle technology costs (as opposed to decrease) with the rollback.
are roughly twice as high as those in the Non-GHG damages Rebound crash costs The 2018 analysis concludes that the roll-
2016 analysis, primarily from benefits ow- back will result in a $90.7 billion gain from
ing to lower driving costs that increase miles avoided Nonrebound crash costs reduced fatalities and property damages, a
traveled that consumers value (that is, the result driven almost exclusively by a 2.4% re-
rebound effect). The 2018 analysis doubles Refueling benefts Noise and congestion duction in fleet-wide VMT (changes in fleet
the magnitude of the rebound effect despite composition play a minor role in the 2018
recent literature estimating smaller rebound Rebound benefts Maintenance analysis). If we hold fleet size fixed (adding
effects (see the SM for details). Whereas in back the missing 6 million used cars), this
the NPRM analysis, the higher rebound effect sive used vehicles, on average, because they $90.7 billion gain is likely to fall to near zero. GRAPHIC: N. CARY/SCIENCE
hardly affects net benefits—as additional ben- are substitutes for new vehicles (6). As a This is a conservative calculation and should
efits from avoided car crashes under the roll- consequence, as standards increase vehicle be interpreted as a lower bound, because we
back are offset by lost benefits from reduced prices, total fleet size should decrease over anticipate that rollback would cause the fleet
VMT—it doubles the number of avoided fa- time. Conversely, a rollback should lead to to grow, possibly driving this term below zero
talities generated by this effect, contributing increased demand for vehicles, resulting in (see the SM for further details).
to a total of 12,700 lives. The assumption re- a larger fleet that will be newer, on average.
garding the higher rebound effect may lead COMPLIANCE COST INCONSISTENCIES
to unfounded concerns about unintended By contrast, the 2018 proposal argues The EPA and NHTSA estimate costs of hun-
safety consequences of the current standards. that the rollback in standards will shrink dreds of different fuel-saving technologies
the overall fleet by 6 million vehicles in and model how manufacturers will add these
Accounting only for domestic benefits the year 2029, compared with the current technologies and combinations of technolo-
from reducing carbon emissions (ignoring standards. This is inconsistent with basic gies using least-cost algorithms. For the 2016
international benefits) scaled down the social economic principles. If prices of vehicles TAR analysis, the estimates of costs by the
cost of carbon from $48 per metric ton to $7 decrease (relative to other general-purpose EPA for GHG standards are less than half of
per metric ton, reducing GHG benefits from goods), we expect more individuals to pur- the costs for the same rule estimated by the
$27.8 billion in 2016 to $4.3 billion in 2018. chase vehicles and drive them rather than NHTSA for CAFE standards. This is in part
A more minor difference is that the analyses use other modes of travel. The 2018 NPRM because the EPA assumes that California and
make slightly different assumptions about analysis reaches the opposite conclusion other states’ Zero Emission Vehicle (ZEV)
the extent to which consumers value future based on ad hoc integration of a newly de- mandate will be in place in future years. With
fuel savings from driving a more fuel-efficient veloped vehicle scrappage model with the many electric vehicles already in the fleet,
car (see SM section C for further discussion NHTSA’s Volpe model (the CAFE Compli- the incremental cost of meeting the higher
of the impact on net benefits). ance and Effects Modeling System). fuel economy standards of the federal rule is
considerably lower. The NHTSA implicitly as-
SIX MILLION MISSING USED CARS We have identified two major shortcom- sumes that there is no ZEV mandate, which
A central difference between the 2016 and ings of this approach. First, this newly de- leads to higher calculated costs. The 2018
2018 reports is the projection of the total veloped model departs substantially from NPRM does the same.
fleet size of cars and light-duty trucks. Eco- state-of-the-art vehicle scrappage models (6,
nomic theory predicts that tighter standards 13) (see the SM for further details). Second, For a clearer comparison of technology
make new vehicles more expensive, on aver- in relation to the comprehensive framework, costs, we focus on differences in the NHTSA’s
age. This also translates into more expen- the 2018 NPRM does not account for changes estimates of costs in the 2016 and 2018 analy-
in used vehicle prices that result from inter- ses (see the figure). According to the NHTSA,
actions between new and used car markets as

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the 2018 costs are more than two times higher is necessary to meet the standards: 24% of borrowing credits and by using pessimistic Downloaded from http://science.sciencemag.org/ on December 10, 2018
than the earlier TAR costs. Some of the cost vehicles in the 2018 analysis are projected to assumptions regarding technology costs.
differences are a result of plausible changes be strong hybrids by MY 2025, whereas only
in economic conditions, such as an increase 2.6% are in the 2016 analysis. Given the substantial departure from a
in future new vehicle sales owing to higher comprehensive protocol for benefit-cost anal-
income growth and lower gasoline prices. Third, the analysis assumes that longer ysis, we cannot conclude that the rollback
Another important difference, however, is time periods are required to redesign many will produce welfare gains, and we instead
due to the fact that the agencies changed the vehicles to meet the standards in a given predict that it will result in unintended con-
model years affected by the standards in the year, requiring manufacturers to add fuel- sequences. For example, in anticipation of
2018 analysis. In the 2016 analysis, the costs saving technologies earlier, thereby incur- higher standards, automakers accumulated
of the MY 2022–2025 standards are assessed ring higher costs for more years. CAFE credits, which they intended to use in
relative to a baseline fixed at MY 2021 levels. the future as a strategy for lowering compli-
By contrast, the 2018 NPRM argues that the Fourth, the specified costs for electri- ance costs. A rollback of the standard would
standards should be frozen a year earlier and fied vehicles are considerably higher (20 lead to a de facto devaluation of these credits,
compares the costs of meeting the existing to 50%) than in the 2016 analysis owing to penalizing automakers who have been lead-
standards for MY 2021–2025 relative to stan- different battery assumptions (for example, ers in technological innovation.
dards fixed at the MY 2020 level. The agen- electrode thickness limited to 100 microns)
cies claim that the previous standards are no and including additional vehicle electrifica- Furthermore, economic theory predicts
longer feasible and appropriate, but they do tion components (for example, liquid cool- that, for the same level of standard, costs of
not even examine the technology costs for ing systems) recommended by the National compliance decline as a result of learning-by-
this change in the standards in the 2018 as- Academies (14). In summary, although some doing and spillover benefits from technology
sessment of alternatives. We can show, how- of the changes in technology assumptions development across automakers. Therefore,
ever, that this change accounts for roughly in the 2018 analysis are plausible, overall we see no economic justification to keep the
12% of the difference in costs for the 2016 it uses pessimistic assumptions of future standard flat from 2020 to 2025, even ignor-
and 2018 standards (see the figure; for more technology availability and performance ing the external societal benefits of the stan-
discussion of this point, see the SM]. compared with the 2016 analysis. dard. Instead, standards should increase over
time in stable and predictable ways.
Notwithstanding these differences, we SAFETY VALVE INSTEAD OF ROLLBACK
still find that reported per-vehicle costs We conclude that the 2018 analysis has sev- We certainly recognize the inherent un-
with the GHG emissions standards are eral fundamental flaws and inconsistencies. certainty in estimating costs of compliance
about 80 to 150% higher for MY 2022–2025 In addition to the points we have raised, through technologies, but we recommend the
vehicles in the 2018 proposal than in the others have articulated why a global, rather introduction of a safety valve to address this
2016 NHTSA analysis (see fig. S3 for de- than a domestic, social cost of carbon is the concern, rather than a rollback. Safety valves,
tails). In addition to the difference in model appropriate parameter to value GHG emis- common in cap-and-trade programs, allow
years being regulated, four other main fac- sions reductions (11, 12), and we agree. Us- firms to purchase compliance credits at a pre-
tors account for these cost differences. ing a global estimate of the social cost of determined price, effectively capping compli-
carbon and the correct impact of changes ance costs and allowing for less technology
First, automakers can comply with the to total fleet size reduces the net benefits improvement if it turns out to be highly ex-
regulations by transferring fuel economy of the rollback for the CAFE standard (from pensive (15). A rollback is an unnecessarily
“credits” between their passenger car fleet $176 billion to $64 billion). Or, in other blunt way to achieve the same goal and intro-
and their light-truck fleet, so that if one fleet words, at least $112 billion was discarded duces regulatory uncertainty into an industry
overcomplies with the regulations, the other in the 2018 analysis. Furthermore, of this, that needs to make long-run technological in-
can undercomply within some limit. Credit at least $88.3 billion comes from account- vestments for the future. j
transferring is also possible across years, so ing for the missing 6 million cars. For the
that if an automaker exceeds fuel economy rollback to have negative net benefits, one REFERENCES
performance in one year, it can meet a less only needs to reduce the 2018 technology
stringent standard in another year. But costs by 26%, which still doubles the costs 1. A.M.Bento et al.,Am.Econ.Rev. 99,667 (2009).
these flexibilities were not included in the from the 2016 analysis; using the technol- 2. M.Jacobsen,Am.Econ.J.Econ.Policy 5,148 (2013).
2018 analysis for MY 2021–2025 (although ogy costs from the 2016 analysis implies 3. K.Whitefoot et al.,Environ.Sci.Technol. 51,10307 (2017).
credit transferring was possible from years that the standard will have large positive 4. T.Klier,J.Linn,RandJ.Econ. 1756 (2012).
before 2021), raising the estimated costs. net benefits. In general, these conclusions 5. C.Knittel,Am.Econ.Rev. 101,3368 (2011).
The NHTSA is prohibited by statute from also apply to the GHG emissions standard 6. M.Jacobsen,A.van Benthem,Am.Econ.Rev. 105,1312
considering all of these flexibilities in the (see the SM for further details).
setting of standards, whereas the EPA is not (2015).
subject to this restriction. In the 2016 TAR, Under any scenario, the case for a roll- 7. I.Parry et al.,J.Econ.Lit. 45,373 (2007).
compliance flexibilities were included in back could be made if compliance costs are 8. M.R.Jacobsen,Am.Econ.J.Appl.Econ. 5,1 (2013).
the NHTSA analysis but did not influence sufficiently high, but both the 2016 TAR and 9. M.L.Anderson,M.Auffhammer,Rev.Econ.Stud. 81,535
the setting of the standards. 2018 NPRM have likely overestimated com-
pliance costs. Neither analysis considers (2013).
Second, the 2018 analysis removed some the full extent of options that manufactur- 10. A.M.Bento et al.,“The effect of fuel economy standards on
projected future technology options that ers have available to respond to these poli-
were considered in the 2016 analysis (for ex- cies, including changes in vehicle prices, vehicle weight dispersion and accident fatalities”(Working
ample, Atkinson engines with cylinder deac- performance, and other attributes. Relative paper w23340,National Bureau of Economic Research,
tivation and exhaust recirculation). Omitting to the 2016 TAR, the 2018 NPRM seems to 2017).
these projected lower-cost options, the 2018 compound this mistake, leading to greater 11. W.Pizer et al.,Science 346,1189 (2014).
analysis predicts that a substantially higher overestimates of compliance cost by not ac- 12. NationalAcademies of Sciences,Engineering,and Medicine,
deployment of more-expensive technologies counting for the full extent of banking and Valuing Climate Damages: Updating Estimation of the Social
Cost of Carbon Dioxide (The NationalAcademies Press,
Washington, DC, 2017).
13. A.M.Bento et al.,EnergyJ. 39,1 (2018).
14. National Research Council,Cost,Effectiveness,and
Deployment of Fuel EconomyTechnologies for Light-Duty
Vehicles (NationalAcademies Press,Washington,DC, 2015).
15. B.Leard,V.McConnell,Rev.Environ.Econ.Policy 11,207
(2017).

SUPPLEMENTARY MATERIALS

www.sciencemag.org/content/362/6419/1119/suppl/DC1

10.1126/science.aav1458

SCIENCE sciencemag.org 7 DECEMBER 2018 • VOL 362 ISSUE 6419 1121

Published by AAAS

INSIGHTS

5. R.Tito, H. L.Vasconcelos, K.J. Feeley, Glob. Change Biol.
24, E592 (2018).

6. C. Lesk, E. Coffel,A.W. D’Amato, K. Dodds, R. Horton, Nat.
Clim. Change 7, 713 (2017).

10.1126/science.aav4827

LETTERS Insects affected Response Downloaded from http://science.sciencemag.org/ on December 6, 2018
by warming
Edited by Jennifer Sills Our Report draws attention to a complex PHOTO: IMAGEBROKER/ALAMY STOCK PHOTO
temperatures but understudied issue: How will cli-
Model vs. experiment have reduced mate warming alter losses of major food
to predict crop losses commercial maize crops to insect pests? Because empirical
yield in Peru. evidence on plant-insect-climate inter-
In their Report “Increase in crop losses actions is scarce and geographically
to insect pests in a warming climate” In an experiment estimating effects of localized, we developed a physiologically
(31 August, p. 916), C. A. Deutsch et al. moderate warming on maize in Peru, based model that incorporates strong and
use expected effects of higher tempera- commercial yield was reduced by more well-established effects of temperature on
tures on insect metabolic rates to predict than 90% (far more than Deutsch et al.’s metabolic rates and on population growth
increasing rates of consumption by pests prediction), a reduction that was, indeed, rates. We acknowledged that other factors
and increasing pest population densi- ascribed mainly to increased herbivory (5). are involved, but the ones we analyzed are
ties. These predictions fail to recognize The question tackled by Deutsch et al. is general, robust, and global (1–3).
the complexity and idiosyncratic nature extremely important, but the answers will
of plant-insect relationships. They do not vary among regions and be specific to each Parmesan and colleagues argue that
take into account changes in plant defense, crop-pest interaction. We need experiments our model is overly simplistic and that
which can respond to both warming that compare yields of target crops in repli- any general model is premature. They
temperatures and enhanced CO2 (eCO2) cated experimental treatments that simulate are concerned that our model does not
in ways that harm some insects and help future conditions of both climate and eCO2 incorporate admittedly idiosyncratic and
others (1, 2). Furthermore, Deutsch et al. in the presence and absence of pests. These geographically localized aspects of plant-
assume that insects will develop predict- experiments seem not yet to exist (6). When insect interactions. Some local effects,
ably faster in response to winter warming. they do, we should be able to generate bet- such as evidence that warmer winters will
However, warmer winters actually retard ter-informed predictions, both of changes in harm some insects but not others, were in
development in species whose springtime crop yield and of the roles that insect pests fact evaluated in our sensitivity analyses
awakening requires accumulated winter will play in those changes. and shown to be minor (see the Report’s
chilling (vernalization) (3). Finally, Deutsch Supplementary Materials). Other phenom-
et al. assume that pest population dynamics Camille Parmesan1,2,3*, Michael E. Hanley2, ena, such as plant defenses that benefit
are simple functions of developmental rates. Michael C. Singer1,2 some insects and threaten others, are
We doubt this is realistic in the presence of relevant but are neither global nor direc-
temperature-sensitive predators and dis- 1Theoretical and Experimental Ecology, CNRS/ tional. Furthermore, because Parmesan et
eases and in the context of pest control (4). Université Paul Sabatier, 09200 Moulis, France. al. present no evidence that such idio-
2Biological and Marine Sciences, Plymouth syncratic and localized interactions will
Deutsch et al. may have oversimplified University, Drake Circus, Plymouth PL48AA, UK. outweigh the cardinal and universally
the problem, but their concern is justified. 3Geological Sciences, University of Texas, Austin, strong impacts of temperature on popula-
Austin, TX 78712, USA. tions and on metabolic rates (1–3), their
*Corresponding author. conclusion is subjective.
Email: [email protected]
We agree with Parmesan and colleagues
REFERENCES that the question of future crop losses is
1. P. Stiling,T. Cornelissen, Glob. Change Biol. 13, 1 (2007). important and needs further study, that
2. C. Robinet,A. Roques, Integrat.Zool. 5, 132 (2010). targeted experimental data are needed
3. S. Stålhandske, K. Gotthard, O. Leimar, J.Anim. Ecol. 86, (as we wrote in our Report), and that our
718 (2017). estimates are likely to be conservative (as
4. V. Seufert, N. Ramankutty,J.A. Foley, Nature 485, we concluded, but for reasons different
229 (2012). from theirs). However, we strongly dis-
agree with their recommendation to give
research priority to gathering localized
experimental data. That strategy will only
induce a substantial time lag before future
crop losses can be addressed.

We draw a lesson from models project-
ing future climates. Those models lack the
“complexity and idiosyncratic nature” of
many climate processes, but by building
from a few robust principles, they suc-
cessfully capture the essence of climate
patterns and trends (4). Similarly, we hold
that the most expeditious and effective

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Published by AAAS

way to anticipate crop losses is to develop 4. T. F. Stocker et al., in Climate Change 2013: The Physical the database and has agreed to correct Downloaded from http://science.sciencemag.org/ on December 6, 2018
well-evidenced ecological models and use Science Basis. Contribution of Working Group I to the Fifth these errors.
them to help guide targeted experimental Assessment Report of the Intergovernmental Panel on
approaches, which can subsequently guide Climate Change,T. F. Stocker et al., Eds. (Cambridge Univ. Serving on a DMC does not involve
revised ecological models. Experiments Press, 2013), pp. 33–115. conducting research, and I did not conduct
and models should be complementary, 10.1126/science.aav7405 research on any drug for AstraZeneca after
not sequential. serving on the FDA panel. The DMCs on
No conflict of interest which I served oversaw the safety of par-
Curtis A. Deutsch1,2*, Joshua J. in data monitoring ticipants enrolled in two postapproval trials
funded through research contracts with
Tewksbury3,4,5, Scott C. Merrill6, Raymond The News Feature “Hidden conflicts?” academic institutions, not contracts with
(C. Piller, 6 July, p. 16) alleges that after AstraZeneca. Members of DMCs are required
B. Huey2, David S. Battisti7, serving as a member of a Food and Drug to act independently of trial sponsors; they
Administration (FDA) advisory panel are not investigators. Their responsibility
Rosamond L. Naylor8 for a nominal per diem payment, I later is to ensure the safety of trial participants
received inappropriate payments from the and scientific integrity of studies to advance
1School of Oceanography, University of Washington, manufacturer (AstraZeneca) for serving on research. In this case, the outcomes of both
Seattle, WA 98195, USA. 2Department of Biology, and chairing data monitoring committees trials were unfavorable to AstraZeneca.
University of Washington, Seattle, WA 98195, USA. (DMCs) overseeing AstraZeneca-sponsored Regardless of the outcome, however, I had
3Future Earth, University of Colorado, Boulder, CO research. Those assertions are inaccurate. no financial relationship with the company;
80303, USA. 4Department of Environmental Studies, The universities conducting clinical tri- the fees, which were nominal, came to me
University of Colorado, Boulder, CO 80303, USA. als, not AstraZeneca, compensated DMC through the university. Serving on a DMC is
5School of Global Environmental Studies, Colorado members for their time. More important, not a conflict of interest but a public service.
State University, Fort Collins, CO 80523, USA. the OpenPayments database still reports My role was to protect the interests of
6Department of Plant and Soil Science, University of inaccurate payments far in excess of the patients, science, and the public.
Vermont, Burlington, VT 05405, USA. 7Department amount I received from the university.
of Atmospheric Sciences, University of Washington, AstraZeneca has acknowledged that it mis- Jonathan L. Halperin
Seattle, WA 98195, USA. 8Department of Earth takenly reported my name and attributed
System Science and the Center on Food Security inaccurate amounts to me in its filing to Icahn School of Medicine at Mount Sinai,
and the Environment, Stanford University, Stanford, New York, NY 10029-6574, USA.
CA 94305, USA. Email: [email protected]
*Corresponding author. Email: [email protected]
10.1126/science.aau9738
REFERENCES

1. R. B. Huey, D. Berrigan, Am. Nat. 158, 204 (2001).
2. V. M. Savage et al., Am. Nat. 163, 429 (2004).
3. U. M. Irlich,J. S.Terblanche,T. M. Blackburn, S. L. Chown,

Am. Nat. 174, 819 (2009).

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Published by AAAS

RESEARCH Progress toward practical
valleytronic devices

Li et al., p. 1149

IN SCIENCE JOURNALS
Edited by Stella Hurtley

Fluorescence imaging CANCER
of highly motile
neuroblastoma cells A systematic look at a
in a mouse model childhood tumor

N euroblastomas—the most common
tumor type in infants—develop from
fetal nerve cells, and their clinical course
is highly variable. Some neuroblastomas
are fatal despite treatment, whereas
others respond well to treatment and some
undergo spontaneous regression without
treatment. Ackermann et al. sequenced more
than 400 pretreatment neuroblastomas and
identified molecular features that charac-
terize the three distinct clinical outcomes.
Low-risk tumors lack telomere maintenance
mechanisms, intermediate-risk tumors har-
bor telomere maintenance mechanisms, and
high-risk tumors harbor telomere mainte-
nance mechanisms in combination with RAS
and/or p53 pathway mutations. —PAK

Science, this issue p. 1165

MICROBIOLOGY Salmonella could reemerge and among South Asians with high transcribed but had no effect IMAGES (TOP TO BOTTOM): LI ET AL.; VSHYUKOVA/SCIENCE SOURCE
cause disease. —CA parental relatedness, rather than on transcriptionally silent genes
Actively persistent most of the disorders arising such as transposable elements.
Salmonella Science, this issue p. 1156 from inherited variants, fewer The complex thereby counter-
than half had a recessive coding acts the repression effect
A proportion of Salmonella cells HUMAN GENETICS diagnosis. —LMZ caused by transposon insertion
can enter a reversible state of in neighboring genes while leav-
growth arrest, which allows Genetic architecture of Science, this issue p. 1161 ing transposons silent. Thus,
them to tolerate environmen- developmental disorders by balancing both repressive
tal stress such as antibiotics. MOLECULAR BIOLOGY and activating transcriptional
Stapels et al. found that these The genetics of developmental effects, DNA methylation can
cells are not dormant but disorders (DDs) is complex. DNA methylation act to fine-tune gene expres-
are actively modulating their Martin et al. wanted to deter- promotes transcription sion. —SYM
environment. Salmonella within mine the degree of recessive
their host macrophage niche inheritance of DDs in protein- DNA methylation generally Science, this issue p. 1182
deployed a specialized type 3 coding genes. They examined represses transcription, but
secretory system called SPI-2 to the exomes of more than 6000 in some instances, it has also MATERIALS SCIENCE
deliver virulence factors, includ- families in populations with high been implicated in transcrip-
ing SteE, into host cells. SteE and low proportions of consan- tion activation. Harris et al. Tunable materials
changed the cytokine profile guineous marriages. They found identified a protein complex in respond to magnetic field
of the infected macrophages that 3.6% of DDs in individuals Arabidopsis that is recruited
to reprogram them into a of European ancestry involved to chromatin by DNA methyla- Although certain four-dimen-
noninflammatory and infection- recessive coding disorders, less tion. This complex specifically sional (4D) printed materials
permissive state. Thus, when than a tenth of the levels previ- activated the transcription of can respond to external stimuli,
antibiotics were removed, the ously estimated. Furthermore, genes that are already mildly these are hard to control or

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Published by AAAS

feature long response times. programs specializing in these IN OTHER JOURNAL S Edited by Caroline Ash
Jackson et al. created tunable three games. The ability of and Jesse Smith
materials that can respond AlphaZero to adapt to various
to an applied magnetic field game rules is a notable step Fire feedback
by incorporating liquids that toward achieving a general explains the Miocene
contain ferromagnetic mic- game-playing system. —JS
roparticles into 3D-printed expansion of the
polymer tubes. In tests, these Science, this issue p. 1140; grassland biome.
structures responded to a see also pp. 1087 and 1118
magnetic field in under a sec- PA L E O E C O L O GY
ond. The approach could see B AT T E R I E S
broad applications in fields that Fire and grassland evolution
include soft robotics, trans- Working toward
portation systems, and smart fluoride batteries G lobal grassland underwent a massive expansion in the
wearable technology. —PJB late Miocene epoch, 5 million to 8 million years ago.
Owing to the low atomic weight Karp et al. examined the role of fire in this expansion,
Sci. Adv. 10.1126/sciadv.aau6419 of fluorine, rechargeable through measurements of fire-derived hydrocarbons
(2018). fluoride-based batteries could and grass-diagnostic carbon isotopes in sediments in
offer very high energy density. Pakistan. They found evidence of a simultaneous increase
IMMUNOLOGY However, current batteries in seasonality of precipitation and the occurrence of regular
need to operate at high temper- fire along with the opening of the landscape and the expan-
Optimal affinity atures that are required for the sion of grasslands. Their results indicate that a grassland-fire
molten salt electrolytes. Davis feedback system was a key driver in the expansion of grass-
Germinal center (GC) B cells are et al. push toward batteries that lands, a relationship that has remained an integral feature of
essential to generating protec- can operate at room tempera- this ecosystem ever since. —AMS
tive antibody responses and ture, through two advances.
are selected through a process One is the development of Proc. Natl. Acad. Sci. U.S.A. 115, 12130 (2018).
of affinity maturation. Kwak et a room-temperature liquid
PHOTO: RICHARD DU TOIT/MINDEN PICTURES/GETTY IMAGES al. now define intrinsic proper- electrolyte based on a stable NEUROSCIENCE substructure for the acquisi-
ties of human GC B cells that tetraalkylammonium salt–fluo- tion of memories is less clear.
are critical to antigen affinity rinated ether combination. The Inhibition in the fear- Tipps et al. used neuron-specific
discrimination. They identified B second is a copper–lanthanum learning circuitry chemogenetics to system-
cell antigen receptor–containing trifluoride core-shell cathode atically probe the circuitry and
actin-rich pod-like structures material that demonstrates Many mental health disorders signaling mechanisms involved
that facilitated formation of reversible partial fluorination can be traced to abnormal asso- in auditory fear learning in mice.
highly stable immunological and defluorination reactions. ciative learning. The basolateral Stimulating inhibitory inter-
synapses and antigen internal- —MSL amygdala of the brain plays neurons or inhibiting pyramidal
ization when GC B cells engaged a central role in associative cells was enough to induce an
high-affinity antigens. These Science, this issue p. 1144 learning and the formation of association between a behavior
structures were important in emotional memories and moti- and an auditory cue. This under-
setting thresholds for affinity QUANTUM MATERIALS vated behaviors. The relevance standing is key to developing
selection and driving GC B cell of the amygdala’s anatomical
responses. —CNF Twisting a route for
surface plasmons
Sci. Immunol. 3, eaau6598 (2018).
Graphene is an atomically thin
COMPUTER SCIENCE material that supports highly
confined plasmon polaritons, or
One program nano-light, with very low loss.
to rule them all The properties of graphene can
be made richer by introduc-
Computers can beat humans ing and then rotating a second
at increasingly complex layer so that there is a slight
games, including chess and angle between the atomic reg-
Go. However, these programs istry. Sunku et al. show that the
are typically constructed for a moiré patterns that result from
particular game, exploiting its such twisted bilayer graphene
properties, such as the sym- also provide confined conduct-
metries of the board on which it ing channels that can be used
is played. Silver et al. developed for the directed propagation of
a program called AlphaZero, surface plasmons. Controlling
which taught itself to play Go, the structure thereby provides
chess, and shogi (a Japanese a pathway to control and route
version of chess) (see the surface plasmons for a nano-
Editorial, and the Perspective by photonic platform. —ISO
Campbell). AlphaZero man-
aged to beat state-of-the-art Science, this issue p. 1153

SCIENCE sciencemag.org 7 DECEMBER 2018 • VOL 362 ISSUE 6419 1125

Published by AAAS

RESEARCH | IN OTHER JOURNALS localization has been studied in
one-dimensional systems. In two
WATER RESOURCES dimensions, experiments indicate
that the localization persists, but
Managing an unwelcome effect because it is difficult to tell the
difference between no thermal-
O ne of the biggest challenges presented by climate change is water resource management. In ization and slow thermalization,
the western United States, the storage and release of water by the mountain snowpack is a more theoretical work is needed.
critical component controlling the summertime flow of headwaters of California’s major res- Relying on an approximate
ervoirs. Rhoades et al. describe how mountain snowpacks will be affected by climate change numerical method, Wahl et al.
in that region and how that can be expected to influence peak water volume, peak timing, undertook large-scale simulations
accumulation rate, and melt rate of water discharge. Among other effects, they project that by the of a two-dimensional lattice of
end of the century, peak snowpack timing will occur 4 weeks earlier and peak water volume will bosonic atoms in the presence of
be 80% lower under a high–greenhouse gas–emissions scenario. —HJS interactions and disorder. At inter-
mediate disorder strengths, the
Geophys. Res. Lett. 10.1029/2018GL080308 (2018). on-site entanglement entropies
exhibited a bimodal distribu-
Climate change will have a large impact on tion, indicating a coexistence
the timing and size of the Sierra Nevada snowpack. of localized and thermalized
states; as disorder was increased,
localized states took over. The
authors were able to extract a
critical disorder strength and set
a benchmark for future experi-
ments. —JS

Nat. Phys. 10.1038/

s41567-018-0339-x (2018).

therapies for diseases in which to show this property. Reticular et al. show that they can control MICROBIOME PHOTO: ISTOCK.COM/SIERRARAT
associative learning has been adhesions lack several com- the trajectory of electrons within
disrupted. —PRS ponents of classical adhesion the two-dimensional plane of Global aeroplankton
complexes, including talin and graphene using a double pulse dispersal
eNeuro 5, ENEURO.0272- actin. A key constituent of retic- from a laser. Tuning the relative
18.2018 (2018). ular adhesions is integrin b5, polarization between the two Airborne particulates include
and a lack of it interfered with pulses by carefully varying the large numbers of living organ-
CELL BIOLOGY the retention of spatial localiza- time delay between them allows isms, as well as dust, pollutants,
tion through normal mitotic cell the direction electron flow to be and other chemicals. Cáliz
Keeping a toehold divisions. —SMH manipulated on femtosecond et al. collected aeroplankton
on the matrix time scales. Such an optical tech- fortnightly for 7 years in the
Nat. Cell Biol. 20, 1290 (2018). nique offers a relatively simple Spanish Pyrenees. High-
Within our bodies, most tissues route to study the electronic and throughput sequencing of 16S
are organized in association OPTOELECTRONICS topological properties of other and 18S amplicons identified
with an extracellular matrix. The two-dimensional materials on microbes, including potential
matrix keeps cells where they Steering electrons ultrafast time scales. —ISO pathogens, that had made land-
are supposed to be, and cells in graphene fall in rain and snow. Distinct
adhere to the matrix via integ- Phys. Rev. Lett. 121, 207401 (2018). seasonal and climate signals
rin-containing cell adhesions. Guiding and controlling the move- in the data associated with the
During mitosis, cells round up ment of electrons in solid-state PHYSICS origin of the air masses. For
and release their tight associa- systems is crucial for applications example, winter microbial fall-
tion with the matrix. Lock et al. such as ultrafast electronics and Identifying localization out originated from as far away
show that despite this, mitotic the generation of high-harmonic in two dimensions as the North American taiga,
cells ensure that they retain light. Although such electronic and summer-occurring organ-
their correct location by using control is readily achieved in Disordered interacting quan- isms contained desert-adapted
a so-called reticular form of cell semiconductors, metals and tum many-body systems can bacteria from North Africa. Over
adhesion. A range of adherent small-bandgap materials can become hopelessly localized. the collection period, air-mass
cultured human cells was found pose more of a challenge. Heide This so-called many-body origins shifted, possibly as a
result of climate change. Most
atmospheric microbes are
cosmopolitan, and it seems the
upper atmosphere acts as a
global highway for many taxa.
—CA

Proc. Natl. Acad. Sci. U.S.A. 115,

12229 (2018).

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RESEARCH

ALSO IN SCIENCE JOURNALS
Edited by Stella Hurtley

CARBON CYCLE Antonova-Koch et al. investi- which occurred at the end of “valleys” in their band structure.
gated the possibilities of drugs the Permian Period. Referred to Researchers in the emerging
Animals count against liver-stage parasites as the “Great Dying,” this event field of valleytronics hope that
(see the Perspective by Phillips saw the loss of up to 96% of these valley degrees of freedom
Flux across the carbon cycle is and Goldberg). To do so, they all marine species and 70% of can be exploited as information
generally characterized by con- devised a luciferase-reporter terrestrial species. Penn et al. carriers, but making valleytronic
tributions from plants, microbes, drug screen for the rodent para- explored the extinction dynam- devices is tricky. Li et al. created
and abiotic systems. Animals, site Plasmodium berghei. Three ics of the time using Earth chiral valley Hall states on the
however, move vast amounts of rounds of increasingly stringent system models in conjunction boundary between oppositely
carbon, both through ecosystem screening were used. From this with physiological data across gated regions of bilayer gra-
webs and across the landscape. regime, several chemotypes that animal taxa (see the Perspective phene. They then guided these
Schmitz et al. review the differ- inhibit Plasmodium mitochon- by Kump). They conclude that so-called kink states through
ent contributions that animal drial electron transport were increased marine temperatures their sample using spatially
populations make to carbon identified. Excitingly, several new and reduced oxygen availability modulated gating, demonstrat-
cycling and discuss approaches scaffolds, with as-yet-unknown were responsible for a major- ing right and left turns, as well as
that allow for better monitoring modes of action but solely ity of the recorded extinctions. a valley valve function. —JS
of these contributions. —SNV targeting the parasites’ liver Because similar environmen-
stages, emerged as promising tal alterations are predicted Science, this issue p. 1149
Science, this issue p. 1127 drug leads for further develop- outcomes of current climate
ment. —CA change, we would be wise to take BIOPHYSICS
HUMAN GENOMICS note. —SNV
Science, this issue p. 1129; How membrane viscosity
Complex processes in the see also p. 1112 Science, this issue p. 1130; affects respiration
settling of the Americas see also p. 1113
N A N O M AT E R I A L S In bacteria, energy production
The expansion into the Americas P O LY M E R S by the electron transport chain
by the ancestors of present day No barriers to occurs at cell membranes and
Native Americans has been diffi- growing a row Beating the heat by can be influenced by the lipid
cult to tease apart from analyses blending composition of the membrane.
of present day populations. Classical nucleation theory Budin et al. used genetic
To understand how humans predicts that two-dimensional Charge carriers move through engineering to influence the
diverged and spread across islands on a surface must semiconductor polymers by concentration of unsaturated
North and South America, reach a critical size before they hopping transport. In principle, branched-chain fatty acids and
Moreno-Mayar et al. sequenced continue to grow; below that these polymers should be more thus control membrane viscosity
15 ancient human genomes from size, they dissolve. Chen et al. conductive at higher tempera- (see the Perspective by Schon).
Alaska to Patagonia. Analysis of used phage display to select for tures. In practice, conductivity Experimental measurements
the oldest genomes suggests short peptides that would bind drops at high temperatures and mathematical modeling
that there was an early split to molybdenum disulfide (MoS2) because interchain contacts are indicated that rates of respira-
within Beringian populations, (see the Perspective by Kahr disrupted, which limits potential tory metabolism and rates
giving rise to the Northern and and Ward). Hexagonal arrays of applications. Gumyusenge et of cell growth were depen-
Southern lineages. Because these peptides grew epitaxially al. now show that appropriate dent on membrane viscosity
population history cannot be as dimers but without a size bar- blending of a semicrystalline and its effects on diffusion.
explained by simple models rier—the critical nuclei size was conjugated polymer with an Experiments on yeast mitochon-
or patterns of dispersal, it zero. Although two-dimensional insulating polymer that has a dria also showed similar effects.
seems that people moved out arrays formed, growth occurred high glass-transition tempera- Maintaining efficient respiration
of Beringia and across the one row at time. Classical nucle- ture creates a morphology that may thus place evolutionary
continents in a complex manner. ation theory indeed predicts the stabilizes a network of semicon- constraints on cellular lipid com-
—LMZ absence of a barrier for such ductor channels. High charge position. —LBR
one-dimensional growth. —PDS conductivity was maintained
Science, this issue p. 1128 in these materials up to 220°C. Science, this issue p. 1186;
Science, this issue p. 1135; —PDS see also p. 1114
ANTIMALARIALS see also p. 1111
Science, this issue p. 1131 R E G E N E R AT I O N
A path to tackle liver- CLIMATE IMPACTS
stage parasites VALLEYTRONICS Do endothelial cells hold
Drivers of the the key to success?
Malaria parasites are evolu- “Great Dying” Making a practical
tionarily prepared to resist valleytronics device Endothelial cells line the
drug attack. Resistance is Though our current extinction inner vascular wall, and their
emerging to even the latest crisis is substantial, it pales Two-dimensional materials phenotype and behavior can
frontline combination therapies, in comparison to the largest with a hexagonal lattice, such vary according to the organ in
which target the blood stages extinction in Earth’s history, as graphene, have two distinct which they are situated and
of the Plasmodium parasite.
As an alternative strategy,

1126-B 7 DECEMBER 2018 • VOL 362 ISSUE 6419 sciencemag.org SCIENCE

Published by AAAS

the environment. Not only do protein-coding exons. Laumont
endothelial cells form the barrier et al. took a different approach
of vessel walls, they also can and found numerous TSAs that
participate in signaling with the derived from aberrant expres-
surrounding tissue to promote sion of noncoding sequences in
regeneration and growth. In a murine cell lines and in B-lineage
Perspective, Gomez-Salinero acute lymphoblastic leuke-
and Rafii discuss how endothelial mia and lung cancer patient
cells contribute to wound heal- samples. They validated the
ing, regeneration, and disease immunogenicity and efficacy
states, such as cancer, and how of TSA vaccination for select
our growing understanding of antigens in mouse models of
endothelial cell plasticity might cancer. Noncoding regions are a
advance regenerative medicine potentially rich source of TSAs
and the development of artificial that could greatly expand the
organs for transplant. —GKA number of targetable antigens
across different cancers, includ-
Science, this issue p. 1116 ing those with low mutational
burdens. —CAC
SIGNAL TRANSDUCTION
Sci. Transl. Med. 10, eaau5516 (2018).
Regulation of RAS by
ubiquitination CELL BIOLOGY

The protein LZTR1 is mutated Cleaving a different
in human cancers and devel- function for p62
opmental diseases. Work from
two groups now converge to The scaffold protein p62 has a
implicate the protein in regu- critical role in autophagy, the
lating signaling by the small regulated intracellular degrada-
guanosine triphosphatase RAS. tion of proteins and organelles.
Steklov et al. showed that mice Sanchez-Garrido et al. identified
haploinsufficient for LZTR1 reca- a proteolytic fragment of human
pitulated aspects of the human p62, called p62TRM, that had a
disease Noonan syndrome. Their distinct function from full-length
biochemical studies showed p62 (see the Focus by Martens).
that LZTR1 associated with RAS. Instead of promoting autophagy,
LZTR1 appears to function as an p62TRM regulated responses to
adaptor that promotes ubiquiti- nutrient availability. This function
nation of RAS, thus inhibiting its was lost in p62 variants with
signaling functions. Bigenzahn disease-associated mutations
et al. found LZTR1 in a screen for in the cleavage site, suggesting
proteins whose absence led to that defective nutrient sensing
resistance to the tyrosine kinase may account for some of the
inhibitors used to treat cancers symptoms of patients with p62
caused by the BCR-ABL onco- mutations. —WW
gene product. Their biochemical
studies and genetic studies in Sci. Signal. 11, eaat6903,
fruitflies also showed that loss of eaav3530 (2018).
LZTR1 led to increased activity
of RAS and signaling through the
mitogen-activated protein kinase
pathway. —LBR

Science, this issue p. 1177, p. 1171

CANCER 7 DECEMBER 2018 • VOL 362 ISSUE 6419 1126-C

Expanding the landscape
of immunotherapy targets

Most searches for drug-
gable tumor-specific antigens
(TSAs) start with an examina-
tion of peptides derived from

SCIENCE sciencemag.org

Published by AAAS

RESEARCH

◥ dances or diversity vary naturally. Our review

REVIEW SUMMARY of these studies, which cover a wide diversity of

CARBON CYCLE taxa (vertebrates and invertebrates and large-

Animals and the zoogeochemistry and small-bodied organisms) and ecosystems,
of the carbon cycle
reveals that animals can increase or decrease
Oswald J. Schmitz*, Christopher C. Wilmers, Shawn J. Leroux, Christopher E. Doughty,
Trisha B. Atwood, Mauro Galetti, Andrew B. Davies, Scott J. Goetz rates of biogeochemical processes, with a median

change of 40% but ranging from 15 to 250% or

more. Moreover, models that embody zoogeo-

chemical effects reveal the

◥

ON OUR WEBSITE potential for considerable

Read the full article under- or overestimates

at http://dx.doi. in ecosystem carbon bud-

org/10.1126/ gets if animal effects are
science.aar3213 not considered. The key
challenge, in light of these
..................................................

BACKGROUND: Modern advances in remote- late spatial patterning of vegetation biomass findings, is comprehensively accounting for
sensing technology are providing unprecedented and carbon uptake and soil carbon retention.
opportunities to accurately measure the global But such zoogeochemical effects are not mea- spatially dynamic animal effects across land-
distribution of carbon held in biomass within sured by current remote-sensing approaches
ecosystems. Such highly spatially resolved mea- nor are they factored into carbon cycle models. scapes. We review new developments in spa-
sures of biomass carbon are intended to provide Studies are now providing new quantitative
an accurate inventory of global carbon storage insights into how the abundance, diversity, tial ecosystem ecology that offer the kind of
within ecosystems. They are also needed to test and movement of animal species across land-
the accuracy of carbon cycle models that predict scapes influence the nature and magnitude of analytical guidance needed to link animal Downloaded from http://science.sciencemag.org/ on December 6, 2018
how global changes that alter biogeochemical zoogeochemical affects. These insights inform
functions—such as carbon assimilation via pho- how to account for animals in remote-sensing movement ecology to geospatial patterning
tosynthesis, carbon losses via plant and microbial applications and in carbon cycle models to
respiration, and organic matter deposition in more accurately predict carbon exchange be- in ecosystem carbon uptake and storage. Con-
soils and sediments—will affect net ecosystem tween ecosystems and the atmosphere in the
carbon uptake and storage. Emerging ecolog- face of global environmental change. siderations of animal movement will require
ical theory predicts that wild animals stand
to play an important role in mediating these ADVANCES: Zoogeochemical effects have been highly resolved spatially explicit understand-
biogeochemical processes. Furthermore, many measured using manipulative experiments that
animal species roam widely across landscapes, exclude or add focal wild animal species or ing of landscape features, including topogra-
creating a spatial dynamism that could regu- along landscape gradients where animal abun-
phy, climate, and the spatial arrangement of

habitat patches and habitat connectivity with-

in and among ecosystems across landscapes.

We elaborate on advances in remote-sensing

capabilities that can deliver these critical data.

We further review new geospatial statistical

methods that, when combined with remote-

sensing data and spatial ecosystem modeling,

offer the means to comprehensively under-

stand and predict how zoogeochemical-driven

landscape processes regulate spatial patterns

in carbon distribution.

CO2 in OUTLOOK: There is growing interest to slow
atmosphere climate change by enlisting ecological pro-
NPP cesses to recapture atmospheric carbon and
store it within ecosystems. Wild animal species
NPP are rarely considered as part of the solution.
Instead, it is often held that managing habitat
Trampling No space to conserve wild animals will conflict
Trampling with carbon storage. Our integrative review
offers a pathway forward for deciding when
NPP and how conserving or managing a diversity of
animal species could in fact enhance ecosystem
Soil carbon carbon uptake and storage. Such understand-
ing informs international climate and bio-
NPP Microbial diversity initiatives such as those described by
Decomposition the United Nations Convention on Biological
Diversity and national biodiversity strategies
Trampling and Animal and climate action plans. All of these initiatives
soil compaction Decomposition require better resolution of how biodiversity
effects on ecosystem structure and biogeo-
CREDIT: NICOLE FULLER/SAYO-ART Soil carbon
▪chemical functioning will become altered by
The myriad animal zoogeochemical effects on carbon cycling. Animals can mediate net
carbon sequestration by plants (net primary productivity, NPP) by altering CO2 uptake into (black global change.
arrows) and from (red arrows) ecosystems. Herbivore grazing and tree browsing can alter the
spatial distribution of plant biomass. Predators can modify herbivore impacts via predation and The list of author affiliations is available in the full article online.
predator-avoidance behavior. Animal trampling compacts soils and alters soil temperatures by *Corresponding author. Email: [email protected]
changing the amount of solar radiation reaching soil surfaces (yellow arrows). Animals also change Cite this article as O. J. Schmitz et al., Science 362, eaar3213
the chemical quality of organic matter that enters the soil pool (orange arrows). (2018). DOI: 10.1126/science.aar3213

Schmitz et al., Science 362, 1127 (2018) 7 December 2018 1 of 1

RESEARCH

◥ removed by herbivores and attendant changes
in plant species composition, inferring how such
REVIEW changes influence the fate of carbon in ecosystems
(13). However, herbivorous and nonherbivorous
CARBON CYCLE animals are hypothesized to influence carbon
cycling via many other mechanisms that affect
Animals and the zoogeochemistry ecosystem biogeochemical processes and prop-
of the carbon cycle erties directly (9, 12). These influences, which
we call zoogeochemical effects, include media-
Oswald J. Schmitz1*, Christopher C. Wilmers2, Shawn J. Leroux3, tion of carbon uptake via photosynthesis, auto- Downloaded from http://science.sciencemag.org/ on December 6, 2018
Christopher E. Doughty4, Trisha B. Atwood5, Mauro Galetti6, trophic and heterotrophic respiration, and soil
Andrew B. Davies7, Scott J. Goetz4 organic matter deposition and alteration of the
physical and chemical properties of organic mat-
Predicting and managing the global carbon cycle requires scientific understanding of ter and soils and sediments.
ecosystem processes that control carbon uptake and storage. It is generally assumed that
carbon cycling is sufficiently characterized in terms of uptake and exchange between We review here studies that have explicitly mea-
ecosystem plant and soil pools and the atmosphere. We show that animals also play an sured the zoogeochemical effects by a diversity of
important role by mediating carbon exchange between ecosystems and the atmosphere, at animal taxa (vertebrates and invertebrates and large-
times turning ecosystem carbon sources into sinks, or vice versa. Animals also move and small-bodied organisms) in several ecosystems
across landscapes, creating a dynamism that shapes landscape-scale variation in carbon globally. Additionally, animals can control the
exchange and storage. Predicting and measuring carbon cycling under such dynamism magnitude of carbon exchange with soil reser-
is an important scientific challenge. We explain how to link analyses of spatial ecosystem voirs, influencing both short- and long-term car-
functioning, animal movement, and remote sensing of animal habitats with carbon bon turnover rates (Fig. 1). Such zoogeochemical
dynamics across landscapes. effects are not measured by current remote sensing,
nor are they included in carbon cycle models (2),
U nderstanding the biogeochemical processes entering soils by characterizing fundamental and therefore contribute to critical uncertainties
and feedbacks regulating carbon uptake biogeochemical processes driving ecosystem about the fate of carbon in key global reservoirs.
and storage within ecosystems is key to carbon exchange and storage. These processes This currently limits our ability to accurately cal-
predicting and managing atmospheric include carbon assimilation via photosynthesis, culate carbon budgets and predict future climate
CO2 concentrations and the rate and ex- losses via autotrophic (plant) and heterotrophic change. We show how to overcome this limita-
tent of climatic change (1–3). Concerted efforts, (microbial) respiration, and organic matter tion by reviewing recent efforts to estimate the
abetted by modern advances in remote-sensing deposition in soils and sediments. implications of changes in animal species abun-
technology, are providing unprecedented oppor- dance on regional carbon budgets.
tunities to accurately measure the global distri- Carbon cycle models typically do not, however,
bution of carbon held in biomass within ecosystems account for the biomass or effects of animals A further consideration is that many animal
(3–5). Such highly resolved measures of spatial (herbivores and carnivores) in higher trophic species roam widely across landscapes (14). Ani-
variation in biomass carbon are needed to pro- levels of ecosystems. Granted, herbivores and mal movements create a spatial dynamism that
vide an accurate inventory of global carbon carnivores in many ecosystems tend to be pro- connects geographic locations across landscapes
storage within ecosystems (5, 6) and reliably test gressively less abundant (by orders of magnitude) via active transport of nutrients and seeds and
and refine carbon cycle models used to make pre- than plants, owing to low transfer efficiencies of temporal variation in the location and abundance
dictions about the relationships between eco- nutrients and carbon from plants to these higher of herbivores and carnivores. Disrupting animal
system structure, biogeochemical functioning, trophic levels (5, 9, 10). The existence of such a movements can alter the spatial patterning of
and carbon storage (2). pyramidal trophic structure has led to the reason- plant and animal biomass across landscapes
ing that animals are entirely dependent upon the and trophic controls over ecosystem functioning
Contemporary carbon cycle models have large- availability of plant biomass. Furthermore, their (14–17). These spatial effects are not embodied in
ly evolved [e.g., (3, 7, 8)] under the assumption comparative rarity makes it unlikely that they conventional carbon cycle models (3, 7, 8) or car-
that carbon uptake and allocation to biomass is will exert strong feedback control on ecosystem bon inventories (5). If lessons from historical
controlled by nutrient and water limitation, processes (9, 10). Hence, it may seem reasonable losses of large migratory animals are any indi-
microbial mineralization of organic matter to assume that animals are unlikely to have cation, these spatial effects need to be included
and weathering of geological parent material, and substantial effects on biogeochemical processes because they can be large (18). It is estimated that
climate and hydrological regimes. The models and carbon storage, and consequentially con- population reductions and extinctions of large
account for carbon that is distributed in live struct the carbon budget without considering migratory mammals during ancient and more
plant biomass, plant detritus, and organic matter their contributions (6). But animals can cause modern times in Earth’s history have resulted in
important positive and negative feedback effects alterations of global methane emissions to the
1School of Forestry and Environmental Studies, Yale that alter the trophic structure of ecosystems (11) atmosphere by 0.8 to 34.8% (18). Attendant changes
University, New Haven, CT, USA. 2Department of and, furthermore, may influence carbon cycling in land surface cover affecting both global atmo-
Environmental Studies, University of California, Santa Cruz, (9, 12) despite their comparatively low biomass spheric CO2 concentrations and biophysical prop-
Santa Cruz, CA, USA. 3Department of Biology, Memorial representation within ecosystems. Failure to ac- erties such as albedo or evapotranspiration have
University of Newfoundland, St. John’s, NF, Canada. 4School count for these feedbacks could result in under- or been noted as well (19, 20). Modern global envi-
of Informatics, Computing and Cyber Systems, Northern overestimates in the capacity of ecosystems to ronmental changes such as habitat fragmenta-
Arizona University, Flagstaff, AZ, USA. 5Department of take up and store carbon (Fig. 1). tion and land-use conversion continue to alter
Watershed Sciences and the Ecology Center, Utah State the composition and abundance of animal species
University, Logan, UT, USA. 6Instituto de Biociências, Until very recently, most studies measuring in many ecosystems (21) and change the extent
Departamento de Ecologia, Universidade Estadual Paulista, animal feedback effects have focused on herbi- and geospatial locations of their movements across
Rio Claro, Brazil. 7Department of Global Ecology, Carnegie vores. Numerous studies have experimentally landscapes (22). Evidence shows that such loss and
Institution for Science, Stanford, CA, USA. measured the amount of plant biomass that is disruption of movement introduces the risk that
*Corresponding author. Email: [email protected] ecosystems could even flip from being carbon
sinks to sources (Fig. 1). To address this uncertainty,
we review recent modeling efforts that can be used

Schmitz et al., Science 362, eaar3213 (2018) 7 December 2018 1 of 10

RESEARCH | REVIEW

to integrate zoogeochemical effects with carbon and remote sensing—the kind of integration that rect interactions among carnivores, herbivores,
models and budget estimates. We further discuss is needed to improve the ability to accurately pre- and plants within food chains in ecosystems
model developments that include animal move- dict and manage the carbon cycle across landscapes. (9, 12, 13). Herbivorous animals directly remove
ment ecology, using case examples to show how plant biomass, assimilate some of the embodied
such integration can deepen understanding of Mechanisms and magnitudes of animal nutrients and carbon to build animal biomass
carbon cycling in the face of global environmental effects on ecosystem carbon balance through growth and development, and release
changes. Ultimately, we offer insights about how to additional carbon to the soil via egestion and to
link animal spatial ecology, ecosystem modeling, Fundamentally, zoogeochemical effects become the atmosphere via respiration (9, 12). Herbivory
manifested as a consequence of direct and indi-

Fig. 1. Remote sensing does not measure A R +R Remote-sensing data
important animal controls on landscape AH

carbon. (A) Modern remote-sensing methods Carnivores

measure biogeochemical processes, including

plant carbon uptake via photosynthesis and Herbivores
autotrophic (RA) and heterotrophic (RH) respi-
ration, and inventory standing biomass carbon

across landscapes. These measures can be used Plant Biomass Photosynthesis
to estimate landscape-scale carbon cycle

processes, including GPP, NPP, and NEE, which

is information used to test carbon cycle models Soil C D Downloaded from http://science.sciencemag.org/ on December 6, 2018
and construct carbon budgets. These methods
focus on the plant trophic level (green) and do GPP = photosynthesis
not include the biogeochemical contributions of NPP = GPP - R
herbivore and carnivore trophic levels (blue and
purple, respectively) that tend to be less A

NEE = GPP - (R + R )
AH

B

abundant in ecosystems. Remote sensing also

cannot measure carbon storage in the soil

reservoir (gray). (B to D) Animals directly (solid

arrows) and indirectly (dashed arrows) control

carbon dynamics in ecosystems though trophic

interactions that reduce plant and animal

biomass (red arrows), which ramify to have

positive indirect effects on carbon uptake and

storage in plants and in soil reservoirs. Failing to

account for animal effects can lead to biases in

carbon accounting. Consideration of animal

effects will become increasingly important as

global environmental changes such as land

conversion, habitat loss, and exploitation stand

to alter animal abundances and impacts across

landscapes. Loss of predators such as wolves

from boreal forest ecosystems (B) can lead to a

rise in moose herbivore abundances, leading to

declines in forest tree biomass and soil carbon

storage (gray box). Loss of migrating grazing

wildebeest herbivores in savanna ecosystems

(C) can lower grazing pressure and lower

soil carbon (gray box), owing to a concomitant 250 Tree NPP (mg C . km2 . year-1) 500 25000 5

rise in the frequency and extents of wildfires Tree Biomass C (mg . km2) 200 400 1500 150 Tree Biomass C (mg . km2) 20000 Soil C Concentration (%) 4
that consume combustible standing grass and 150 300 Tree Biomass C (mg . km2) 15000 3
woodland biomass. Loss of large mammal frugi- 100 200 Soil C uptake (mg . km2 . year-1) 10000 2
vores and attendant reduction in dispersal of large
5000

seeds in tropical forests (D) can lead to changes in 50 100 1200 100 0 1

tree community composition via reduction in 0 0 900 50 Low High 0
abundance and biomass production of carbon Moose Moose Moose Moose Mammal Diversity Low High
dense trees (trees with black shading). Data from Absent Present Absent Present 600 0 Mammal Diversity
experimental and observational analyses (as 75
shown in the graphs) reveal that variation in Litterfall (mg C . km2 . year-1) 150 RH (cumulative 26 week mg C . g soil-1) 20 300 -50 Tree Diversity (number of species)
animal abundances can lead to large variation in 60
120 16 0 -100
Low High Low High 45
90 12
Wildebeest Abundance Wildebeest Abundance

carbon exchange and storage, sometimes even 60 8 30

causing ecosystems (e.g., savanna) to switch from 30 4 15
being carbon sources when animals are not
abundant to becoming carbon sinks when they are 0 0 0
highly abundant. C, carbon. Data were obtained Moose Moose Moose Moose Low High
Absent Present Absent Present Mammal Diversity

from the following references: (B) boreal forest (28), (C) savanna (15), and (D) tropical forest (36). [Photos (from left to right): Serg Zastavkin/Shutterstock;

mdd/Shutterstock; Costa Rodrigues/Shutterstock. Images: Vertyr/Depositphotos (African tree); Sonechko/Depositphotos (trees and grasses); airin.dizain/

Depositphotos (wildebeest); YurikswO/Depositphotos (moose); Cundrawan703/Depositphotos (wolf)]

Schmitz et al., Science 362, eaar3213 (2018) 7 December 2018 2 of 10

RESEARCH | REVIEW

leaves less plant biomass available for photo- and chemical processes (e.g., redox potential as a level system. The strength of this effect varied, Downloaded from http://science.sciencemag.org/ on December 6, 2018
synthesis, and plant stress from herbivore damage measure of organic matter decomposition and however, with the level of nutrient supply. Nutrient
may further decrease plant photosynthetic rates microbial carbon mineralization) via compaction enrichment, which enhanced algal production,
and increase rates of autotrophic respiration (RA) from trampling (24). But in other cases—such as magnified the difference in CO2 exchange be-
and heterotrophic respiration (RH), all of which caribou, muskox, and geese in the arctic; marmots, tween the two kinds of systems. The effect of
could decrease net primary productivity (NPP) mice, and invertebrates in alpine meadows; and nutrient enrichment of algal production along
and alter net ecosystem carbon exchange (NEE). moose in boreal forests—grazing and browsing with predator control of algal-feeding zooplankton
Herbivores may also selectively feed on different herbivores cause a 15 to 70% decrease in CO2 meant that the three-level system became a net
plant species, thereby potentially altering the plant uptake (Fig. 2) by altering plant community com- CO2 sink. The four-level system became net carbon
diversity and carbon density of standing biomass, position, photosynthetic rates, and ecosystem neutral. Consequently, there was 90% less CO2
given that plant species vary in their capacity to fix respiration (26–29). Some cases, such as muskox retained in the lake in the presence of bass than
carbon and allocate it toward structural tissue and in arctic mire and barnacle geese in arctic wet in their absence (Fig. 2).
antiherbivore defense (9, 12). Predators, through meadows (Fig. 2), reveal that animals can have
direct interactions with herbivore prey, could conflicting positive and negative effects on dif- Manipulative experiments have been completed
reverse the effects of herbivores. By reducing ferent biogeochemical processes and properties. within small spatial extents—most on the order of
herbivore abundances and by causing changes in For example, muskox-caused CH4 release could tens to hundreds of square meters but sometimes
herbivore behavior and physiology, predators can offset any gains in carbon storage owing to their reaching up to several hectares—because of logis-
have indirect effects on plant biomass, photo- enhancement of CO2 uptake, and barnacle geese tical constraints imposed by the need to physi-
synthesis, and respiration, ultimately affecting enhance soil carbon retention despite reducing cally control for animal presence or absence and
NPP and NEE and fluxes of CO2 and CH4 be- CO2 uptake by plants (25, 30). extraneous environmental variables, and to make
tween ecosystems and the atmosphere (12, 13). precise measures of carbon storage and exchange.
Frugivorous animals disperse consumed seeds Manipulating the trophic structure of ecosys- This inevitably begs the question of whether the
during the course of their movement, thereby tems shows that predators can reverse the effects insights are scalable to the large spatial extents
determining the spatial distribution and diver- of herbivores (Fig. 2). In grasslands, grasshoppers needed for management to make a difference in
sity and abundance of plant species that take cause a 17% reduction in CO2 uptake, relative to the carbon budget but also scalable to the extent
up and store carbon within ecosystems. Large experimental controls that contain only plants. that variation in the magnitude of biophysical
animals can further influence ecosystem pro- As with vertebrate herbivores, the grasshoppers environmental factors could swamp out any animal
cesses by trampling and compacting or perturbing modify the plant community composition, which effect. Observational studies that have measured
soil surfaces and sediments, which can alter sur- cascades to alter NEE through changes in rates animal effects across larger spatial extents of entire
face temperatures and chemical reactions that of photosynthesis and whole-ecosystem respira- ecosystems reveal that the insights about mecha-
enhance soil or sediment carbon retention or tion (31). The addition of spider predators, which nisms and magnitude of effects are indeed scalable.
exacerbate carbon release. Finally, animals can control grasshopper foraging, more than reverses
influence soil or sediment microbial activity by the grasshopper effect by increasing CO2 uptake Grazing halos, patches largely devoid of sea-
altering the amount and chemical content of by 46% (Fig. 2). The net effect of predators is that grasses and macroalgae, surround many coral reef
organic matter that becomes available to mi- the fully intact food chain causes 22% more CO2 patches globally. They are large and ubiquitous
crobes for decomposition (12, 13). uptake than experimental plant-only control con- enough to be detected by high-resolution remote
ditions in which there are no animals. In humic sensing (35). Analyses in a ~10-km2 area near
Resolving the magnitude of zoogeochemical lakes, zooplankton feed on methanotrophic Heron Island in Australia’s Great Barrier Reef
effects requires the use of manipulative experi- bacteria—bacteria that consume and metabolize revealed that predators can cause the appearance
ments that systematically exclude or add focal methane as their carbon source for energy—with of these halos by altering foraging behavior of
animal species or of observational studies that the consequence that lakes emit CH4 to the herbivorous fishes (35). Sharks persistently cruise
take advantage of variation in natural animal atmosphere (32). The reduction of zooplankton hunt near the reef patches. The perceived threat
abundance across landscape locations. We searched abundance after experimental introduction of of predation causes herbivorous fish to feed heav-
(23) the published literature for studies that fit zooplanktivorous perch caused a 50% reduction ily near the coral patches, staying in close prox-
the dual criteria of (i) having measured wild- in CH4 emission (Fig. 2) by releasing the bacteria imity to the escape cover afforded by the coral. As
animal effects explicitly on biogeochemical pro- from heavy consumption by zooplankton. In a consequence, the highly grazed halos have lower
cesses using (ii) experimental animal removals or other experimental systems (freshwater ponds vegetation canopy height and cover and, hence,
additions, or systematic analyses across gradients and streams), predatory stickleback fish and 24% less carbon stored in their sediments than do
of animal abundances or diversity. Studies that stonefly insects enhance carbon capture and areas beyond the halos that have little or no
met these criteria reveal that animal effects are retention by 88 to 90% (Fig. 2). Here, predation grazing impact (35).
consistent with the various hypothesized mech- on zooplankton and macroinvertebrates increases
anisms (Fig. 2). algal CO2 uptake for production, thereby reducing Wildebeest in the 25,000-km2 Serengeti savanna-
the concentrations of dissolved inorganic carbon woodland were decimated by disease and poaching
Herbivore exclusion experiments show that in the water column that could otherwise be before the 1960s, reducing their numbers from
animals can affect carbon dynamics by changing released to the atmosphere (33). Food chain inter- about 1.2 million to 300,000 animals (15). In turn,
the species composition of the plant community actions in lakes can also modulate CO2 exchange the accumulated, ungrazed aboveground vegeta-
—including tundra herbs and shrubs, saltmarsh in ways that depend on the number of predatory tion fueled wildfires that consumed 80% of the
grasses, and boreal and tropical forest trees—by trophic levels present (Fig. 2). In three-trophic- ecosystem annually, leading to a net release of CO2
selectively foraging. Individual cases show her- level lakes containing minnow predators, zoo- to the atmosphere. Disease management and anti-
bivore effects ramify by triggering changes in any plankton prey, and algae, minnows controlled poaching enforcement over the ensuing decades
or all of the following: above- and belowground the abundance of zooplankton, releasing algae has led to wildebeest population recovery, reducing
plant biomass allocation, photosynthesis (gross from zooplankton grazing (34). The addition of the extent and intensity of wildfires (15). Wilde-
primary production, or GPP) and NPP, and eco- bass predators to create a four-trophic-level sys- beest grazing is now causing a large fraction of
system respiration rates (RA + RH). In some cases, tem in which bass prey on minnows reversed carbon from combustible aboveground plant
such as muskox in arctic mire and geese and hares this effect, resulting in more zooplankton and biomass to be released as dung that becomes
in tidal saltmarshes (Fig. 2), herbivore presence less algal biomass (34). Although lakes tend to be incorporated by insects into soil reservoirs that
enhances CO2 uptake and carbon storage by 20 to a net source of CO2 to the atmosphere, the three- are not prone to burning. The recovered grazing
25% (24, 25). Large grazers furthermore can pro- level system emitted 27% less CO2 than the four- regime restored the Serengeti as a net CO2 sink—
tect carbon in sediments by changing physical estimated to be large enough today to offset all of
east Africa’s annual fossil fuel CO2 emissions (9)—by

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