Science 13.08.2021

The dubious ethics of clinical trials Weighing black holes with The promise of therapeutics
that withhold standard care p. 729 photometry pp. 734 & 789 made in plants p. 740

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ICE AGE
WANDERER

A tusk records the history
of a mammoth’s life p. 806

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CONTENTS

13 AUGUST 2021 • VOLUME 373 • ISSUE 6556

ILLUSTRATIONS (TOP TO BOTTOM : ESA/HUBBLE, M. KORNMESSER/CC BY 4.0; STEPHAN SCHMITZ NEWS INSIGHTS 734 & 789

IN BRIEF PERSPECTIVES 737 The cell of origin for Barrett’s
esophagus
720 News at a glance 734 How massive is that black hole? Undifferentiated cells that closely resemble
The flux of radiation emissions from gastric cells could be a biomarker for
IN DEPTH accretion disks correlates with black hole surveillance By K. Geboes and A. Hoorens
mass By P. Lira and P. Arevalo
723 Time grows short to curb warming, RESEARCH ARTICLE p. 760
report warns REPORT p. 789
IPCC science analysis concludes human role 738 Taking the long view on metabolism
‘unequivocal’ and impact ‘unprecedented’ 736 When did terrestrial plants arise? Measured energy expenditure across the
Microfossils suggest that co-option human life span reveals distinct metabolic
By C. O’Grady of algal genes may affect land plant phases By T. W. Rhoads and R. M. Anderson
origination time By P. G. Gensel
724 Streams that flow only part of the REPORT p. 808
year are getting even drier REPORT p. 792
Analysis of intermittent U.S. waterways finds 740 Plant-made vaccines and
many are shriveling earlier and remaining dry 729 therapeutics
for much longer By E. Stokstad Advances in technology and manufacturing
could boost the uptake of molecular farming
725 Science lost and lessons learned:
A lab plots its comeback By H. Fausther-Bovendo and G. Kobinger
A microbiology team regroups, with a more
virtual lab and a bigger focus on mental 742 Searching for life on Mars
health By D. Grimm and its moons
Sample-return missions will look for
726 ‘Mini–Manhattan Projects’ for energy extraterrestrial life and biomarkers on Mars
innovation wind down and Phobos By R. Hyodo and T. Usui
But hub model for bridging basic and applied
research lives on By A. Cho 743 Making machine learning
trustworthy
727 Genetics papers from China face Safety, transparency, and fairness are
ethical scrutiny essential for high-stakes uses of machine
Questions about consent and potential for learning By B. Eshete
abuse trigger investigations By D. Normile
PODCAST
F E AT U R E S
745 Richard C. Lewontin (1929–2021)
729 Failure to protect? Groundbreaking evolutionary geneticist
A study of asthmatic children, most of them
Black, shows how a common clinical trial By A. Berry and D. A. Petrov
design can expose vulnerable participants to
serious risks By C. Piller POLICY FORUM

PODCAST 746 Integrate biodiversity targets
from local to global levels
SCIENCE sciencemag.org A shared Earth approach links
biodiversity and people
By D. O. Obura et al.

13 AUGUST 2021 • VOL 373 ISSUE 6556 715

REVEALING THE
NEXT BREAKTHROUGH
IN IMMUNOLOGY

APPLICATIONS DUE:
OCTOBER 1, 2021

APPLY TODAY:
www.sciencemag.org/michelson

CONTENTS

ILLUSTRATION: ROBERT NEUBECKER BOOKS ET AL. 760 Cancer genomics 818 Coronavirus
Molecular phenotyping reveals the identity Structural and functional ramifications of
749 The matter of mind control of Barrett’s esophagus and its malignant antigenic drift in recent SARS-CoV-2 variants
Brainwashing case studies illuminate the transition K. Nowicki-Osuch et al. M. Yuan et al.
history of coercive persuasion
PERSPECTIVE p. 737 RESEARCH ARTICLE p. 759
By S. Marks
768 CRISPR biology 826
750 The alternative to despair is Structural basis for target site selection in
to build an ark RNA-guided DNA transposition systems D E PA R T M E N T S
H. G. Wells’s “world encyclopedia” J.-U. Park et al.
has merit beyond its seeming 719 Editorial
similarities to Wikipedia 774 Plant science Clarion call from climate panel
Secreted pectin monooxygenases
By Y. Benkler drive plant infection by pathogenic By Steven Sherwood and Brian Hoskins
oomycetes F. Sabbadin et al.
LETTERS 826 Working Life
REPORTS Keep quiet about homophobia or open up?
751 China’s algal bloom suffocates
marine life 779 Ultracold molecules By Brian Mustanski
By X. Guo et al. Observation of microwave shielding of
ultracold molecules L. Anderegg et al. ON THE COVER
752 Eastern Europe’s fraught Reproduction of a life-size oil painting of an
waterway plans 783 Polymer chemistry adult male woolly mammoth navigating
Chemically recyclable thermoplastics from a mountain pass in Arctic Alaska. Little is
By I. Kitowski and G. Grzywaczewski reversible-deactivation polymerization of known about the movement patterns of
cyclic acetals B. A. Abel et al. these extinct giants. Isotopic records from
752 Australia threatens to weaken a 17,100-year-old mammoth tusk reveal that
forest laws 789 Black holes the animal covered an extensive geographic
A characteristic optical variability time scale range during its lifetime. However, as the
By D. Lindenmayer and C. Taylor in astrophysical accretion disks
C. J. Burke et al. ice age ended and the
RESEARCH Arctic environment
PERSPECTIVE p. 734 began to change,
IN BRIEF maintaining this level
792 Paleobotany of mobility would have
754 From Science and other journals A fossil record of land plant origins from been increasingly
charophyte algae P. K. Strother and C. Foster difficult. See page 806.
REVIEW Illustration: James Havens/
PERSPECTIVE p. 736 The Havens Studio, Alaska
757 Neuroscience
Nicotinic acetylcholine receptor redux: 797 Superconductivity Science Staff .............................................. 718
Discovery of accessories opens therapeutic Multicomponent superconducting order New Products.............................................824
vistas J. A. Matta et al. parameter in UTe2 I. M. Hayes et al. Science Careers .........................................825

REVIEW SUMMARY; FOR FULL TEXT: 801 2D materials
DOI.ORG/10.1126/SCIENCE.ABG6539 Boridene: Two-dimensional Mo4/3B2-x with
ordered metal vacancies obtained by
RESEARCH ARTICLES chemical exfoliation J. Zhou et al.

758 Microbiology 806 Paleontology
Spatial transcriptomics of planktonic Lifetime mobility of an Arctic woolly
and sessile bacterial populations mammoth M. J. Wooller et al.
at single-cell resolution
D. Dar et al. 808 Metabolism
Daily energy expenditure through the human
RESEARCH ARTICLE SUMMARY; FOR FULL TEXT: life course H. Pontzer et al.
DOI.ORG/10.1126/SCIENCE.ABI4882
PERSPECTIVE p. 738
759 Coronavirus
Ultrapotent antibodies against 813 Microbiota
diverse and highly transmissible High-fat diet–induced colonocyte
SARS-CoV-2 variants dysfunction escalates microbiota-derived
L. Wang et al. trimethylamine N-oxide
W. Yoo et al.
RESEARCH ARTICLE SUMMARY; FOR FULL TEXT:
DOI.ORG/10.1126/SCIENCE.ABH1766
REPORT p. 818

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718 13 AUGUST 2021 • VOL 373 ISSUE 6556 sciencemag.org SCIENCE

EDITORIAL

Clarion call from climate panel

U nprecedented flooding, searing temperatures, bustly observed regional trends in these events are up- Steven Sherwood
and raging fires across Europe, Asia, and North ward and are projected to continue. One sobering finding is a professor at the
America this summer have created a stark back- is that even if global warming is limited to 2°C, heat events Australia Research
drop for this week’s release of the sixth physi- that once occurred twice per century will happen every 3 Council Centre
cal science assessment report (AR6) of the In- to 4 years—and will tend to coincide with droughts, com- of Excellence for
tergovernmental Panel on Climate Change pounding the impacts. Much better regional information Climate Extremes
at the University
(IPCC). These reports, initiated in 1990, arrive is provided than in previous reports. However, the lack of of South Wales,
Sydney, Australia.
about every 7 years at the request of the countries of adequate data in many regions, including most of Africa, s.sherwood@unsw.
edu.au
the United Nations Framework Convention on Climate is apparent and should be addressed.
Brian Hoskins
Change. They form the basis for UN discussions and The report dives into important new territory by em- is chair of the
Grantham Institute
have become a crucial means to take stock of the latest phasizing “low-probability, high-impact events” that are at Imperial College
London, London,
scientific developments. The reports’ future projections hard to quantify but unwise to ignore. For example, al- UK, and a professor
in the Department
about climate change have remained fairly stable over though the expected range of future sea level is similar of Meteorology at
the University of
the years and have, sadly, proven quite accurate. So, to previous predictions, AR6 indicates that rises of 2 m Reading, Reading,
UK. b.hoskins@
what does the new report add? or more by the end of the century imperial.ac.uk

Above all, AR6 expresses cannot be ruled out. Nor can the

greater confidence in famil- “…this may be the possibility of abrupt responses
iar findings, owing to stronger and “tipping points” in the cli-

evidence. A notable example last report that can… mate system. These are stark
concerns “equilibrium climate warnings compared with previ-

sensitivity,” a measure of how keep the climate ous reports. As the authors note,
much global warming ultimately targets of the 2015 the probabilities of forest die-
occurs if the atmospheric car- Paris Agreement back, ocean-circulation changes,
bon dioxide (CO ) concentration and other disturbing scenarios
within reach.” increase with global temperature.
2
Although the IPCC reports
doubles. Based on improved un- provide an invaluable resource
derstanding of cloud processes and periodic wake-up call, they
and climate changes that have come at a price. This report was
already occurred, AR6 concludes
that this figure is “likely” (a two-

thirds chance or greater) to lie written by 234 authors over 3

between 2.5° and 4°C—halving years, with similar effort in-

the spread of 1.5° to 4.5°C in previous reports. Global vested in two more reports on adaptation and mitiga-

temperatures had stalled in the period before the 2013 tion due next year. The process is arduous: Over 75,000

assessment (AR5) but have since surged, reaching 1.1°C review comments were individually addressed. The

above that of preindustrial times. Atmospheric CO has world’s climate modeling centers invest heavily in simu-
2

reached concentrations not seen for at least 2 million lations following common protocols, which is growing

years, and the new report expresses high confidence that steadily more taxing for them.

oceans, plants, and soils will become less efficient at ab- If another assessment is commissioned on schedule,

sorbing future carbon emissions. it will arrive not much before 2030. By then, if emis-

As always, uncertainty remains. The latest climate sions persist at current rates—that is, even if emissions

models predict a wider range for climate sensitivity, with growth is halted—nearly all the remaining “global car-

projected values implausibly weak in some cases but im- bon budget,” which gives a 50-50 chance of keeping

plausibly strong in others. This disagreement is largely global warming below 1.5°C, will have been exhausted.

a result of increased complexity in model representa- So, this may be the last report that can meaningfully

tions of cloud feedbacks in the midlatitude storm-track influence policy to keep the climate targets of the 2015

regions. AR6 shrewdly deals with this inconsistency Paris Agreement within reach. AR6 is intended to in-

by focusing on what happens at a given level of global form discussions at the UN Climate Change Confer-

warming (say, 2°C), separating this from the question of ence of the Parties (COP26) meeting in November. Our

when that warming level would be reached. children and grandchildren are waiting to see what

The report also provides new clarity on aspects like comes out of it.

changes in extreme rainfall and drought. Almost all ro- –Steven Sherwood and Brian Hoskins

Published online 10 August 2021; 10.1126/science.abl8490

SCIENCE sciencemag.org 13 AUGUST 2021 • VOL 373 ISSUE 6556 719

NEWS A worker cleans the
bar for a weightlifting
competition during the
Tokyo Olympic Games.

IN BRIEF

Edited by Jeffrey Brainard

PUBLIC HEALTH

COVID-19 largely spares Olympic games, but not Tokyo

O rganizers of the Tokyo Olympic Games said they government banned members of the public from attend- PHOTOS: (TOP TO BOTTOM CHRIS GRAYTHEN/POOL/AFP/GETTY IMAGES; MICHAEL STEELE/GETTY IMAGES
successfully minimized the spread of COVID-19 ing the games, and organizers’ other precautions in-
during the 2-week event. A total of 484 people of cluded daily testing of athletes. More than 70% of foreign
an estimated 50,000 involved in the games tested athletes and staff members at the games had been vac-
positive for SARS-CoV-2 between 1 July, when cinated against COVID-19, The Washington Post reported.
quarantining of foreign visitors began, and this Only about 33% of the Japanese population has been fully
week when Science went to press. Most (257) were con- vaccinated, and a majority of survey respondents opposed
tractors supporting the games, followed by 168 Olympics holding the games. Tokyo residents had a record number
personnel and volunteers, 30 journalists, and 29 ath- of new cases during the Olympics, but Japanese Prime
letes, who were automatically barred from competition. Minister Yoshihide Suga insisted the surge was unrelated
Most who tested positive are Japanese residents. Japan’s because the games’ precautions were stringent.

Scientists share Olympic glory Hugues Fabrice Zango, a Ph.D. candidate Mathematician
in electrical engineering at the University Anna Kiesenhofer
ATHLETICS | Among throngs of elite of Lille, became the first Olympic won gold
athletes, several researchers pedaled, medalist from Burkina Faso, winning in road cycling.
jumped, or sprinted their way to med- the bronze in the men’s triple jump. He
als during the Tokyo Olympic Games. aspires to teach at a university in his sciencemag.org SCIENCE
Among them: Austrian mathematician home country. And epidemiologist Gabby
Anna Kiesenhofer won a gold medal in Thomas of the United States earned
women’s road cycling in a dramatic finish. two medals: a silver in the women’s
Kiesenhofer is a postdoctoral fellow at 4x100-meter relay and a bronze in the
the Swiss Federal Institute of Technology 200 meters. Thomas is interested in
Lausanne who focuses on nonlinear health disparities, particularly among
partial differential equations in math- Black people, and is pursuing a master’s
ematical physics. In track and field, degree at the University of Texas, Austin.

720 13 AUGUST 2021 • VOL 373 ISSUE 6556

Long Covid tracked in children Perseverance’s shadow
appears next to a hole
E P I D E M I O LO GY | About 4% of U.K. it drilled in what scientists
children sickened by SARS-CoV-2 had dubbed a “paver rock.”
symptoms that lasted at least 4 weeks and
were suggestive of Long Covid, a study has PLANETARY SCIENCE
found. In adults, the condition has been
marked by extreme fatigue, heart palpita- Mars rover’s first drilling comes up empty
tions, neurological problems, and more.
In one of the largest studies of children to P uzzled NASA engineers are studying why the Perseverance rover last week
date, 77 of 1734 children ages 5 to 17 with a apparently failed to collect rocks and dust after it drilled Mars’s surface for the
positive test and acute symptoms still had first time. Perseverance recovered the tube meant to contain samples from the
them after 4 weeks, and 25, or 1.8%, of 1379 drill hole in Jezero crater, but data indicated the tube was empty. NASA says it
still had symptoms after 8 weeks. Older has not identified any equipment malfunctions, and engineers think unexpected
children were more likely than younger characteristics of the rock might explain the failure. To diagnose what went wrong,
ones to have persistent symptoms, the NASA will attempt to photograph the drill hole up close. The rover carries a total of
research team reported on 3 August in 43 titanium sample tubes, which were to be filled with material from various sites; some
The Lancet Child & Adolescent Health. will be stored in a cache until another mission can return them to Earth, where they
would be studied for signs of ancient life. “While this is not the ‘hole-in-one’ we hoped for,
Protein vaccine hits setback there is always risk with breaking new ground,” said Thomas Zurbuchen, NASA’s associ-
ate administrator for science. “I’m confident we have the right team working this, and
COVID 19 | Novavax announced last week we will persevere toward a solution to ensure future success.” Previous drilling on Mars
that the U.S. government has ordered it to by other NASA probes has also encountered snags. As Science went to press, the next
stop making its promising protein-based drilling attempt by Perseverance had not been scheduled.
coronavirus vaccine in the United States.
PHOTO: NASA/JPL CALTECH The government also ceased funding new or treatments. The new case occurred threatens to peel away subscribers and
manufacturing there; it can resume only close to Guinea’s borders with Liberia damage the industry financially; under
when the small Maryland firm meets and Sierra Leone, in the same area where an existing UKRI policy, authors had to
the U.S. Food and Drug Administration’s West Africa’s massive Ebola epidemic of wait up to 12 months. The new rules,
(FDA’s) standards for ensuring the quality 2013–16 began. Contact tracing is ongoing, which take effect in April 2022, also allow
and potency of its vaccine, the company but given the country’s fragile health care authors to pay journals for “gold” open
revealed in a quarterly Securities and system and the burden of the COVID-19 access, which makes a paper free to read
Exchange Commission filing on 5 August. pandemic, the World Health Organization on the publisher’s website—but only if
It added that it will not file for an emer- says the risk for the country and the the journal is transitioning to exclusively
gency use authorization (EUA) from FDA region is high. open access for all research papers. And
until the fourth quarter, instead of the the papers must bear a license allow-
third quarter as planned. But Novavax, U.K. agency pushes open access ing for text mining and free and liberal
which has received $1.75 billion in U.S. distribution of the work. The move brings
funding for developing and making its PU B L I S H I N G | The United Kingdom’s UKRI’s policy into alignment with Plan
vaccine, will continue to manufacture leading science funder announced last S, an open-access effort led by European
it in other countries. It announced last week a new policy that will allow authors research funders, including UKRI. The
week that, with its partner the Serum to post articles it finances in free-to- United Kingdom currently has one of the
Institute of India, it has filed for EUAs in read repositories upon publication, highest rates of open-access publication
India, Indonesia, and the Philippines—its with no embargo period. The move by in the world, with about three-quarters
first such filings. Novavax and the Serum UK Research and Innovation (UKRI) is of recently published papers free to read
Institute have agreements to provide being resisted by publishers, who say it upon publication.
more than 1.6 billion doses of the vaccine
worldwide, 1.1 billion of them destined for
low- and middle-income countries.

Marburg strikes West Africa

I N F ECT I O U S D I S E AS E S | West Africa
is again facing the threat of a deadly
hemorrhagic fever. A man who died in
Guéckédou prefecture in Guinea on
2 August suffered from Marburg disease,
laboratory tests in the Guinean capital
Conakry and Dakar, Senegal, have shown.
The Marburg virus is closely related to
the Ebola virus, but its outbreaks are
rarer and typically smaller; the biggest
one, in Angola in 2004–05, ended after
252 cases. There are no approved vaccines

SCIENCE sciencemag.org 13 AUGUST 2021 • VOL 373 ISSUE 6556 721

NEWS | IN BRIEF

Facebook, researchers square off considered public information. But the decision and for a tally of researchers and
company says the research violates its terms journalists whose accounts have been sus-
P O L I T I CA L SC I E N C E | A simmering fight of service and the privacy of its custom- pended this year.
between Facebook and a team of researchers ers. (Facebook had previously asked the
monitoring its political ads boiled over last researchers to stop, but said it would not Yemeni academics dismissed
week when the social media giant suspended take any steps until after the election.) On
their accounts. The scientists running New 4 August, Facebook disabled the accounts of I N T E R N AT I O N A L R E L AT I O N S | Saudi Arabia
York University’s Ad Observatory project, graduate student Laura Edelson and engi- is purging Yemeni scientists and other
begun in the runup to the November 2020 neering professor Damon McCoy, prompting scholars from universities and hospitals in
U.S. elections, contend that the data being an outcry from scientists. On 6 August, three southern provinces near its war-torn neigh-
collected from Facebook’s website, includ- Democratic senators asked Facebook CEO bor. Saudi Arabia is aiding the Yemeni
ing the names of advertisers, should be Mark Zuckerberg to explain the company’s government’s fight against Houthi rebels,
but the vast majority of those dismissed
are non-Houthis. At Najran University,
all 106 Yemeni faculty members received
written notices on 8 August that their job
contracts are terminated as of 15 August.
Similarly precipitous pink slips were
handed out to hundreds more Yemeni aca-
demics and medical professionals at other
Saudi institutions, says an expat Yemeni
scientist who helped organize a change.org
petition drawing attention to their plight.
“It seems the Saudi government wants
to clear the entire region of Yemenis,” he
says. Saudi officials have not commented.
For a foreign worker in the kingdom, los-
ing a job also means losing the right to
reside there. The displaced scholars and
their families fear political persecution if
they were to return to Yemen, the petition
notes, and have few other options as “only
a handful of countries are granting visas to
Yemeni nationals.”

ARCHAEOLOGY Continent-size radio array planned PHOTO: MUSEUM OF THE BIBLE/GREEN COLLECTION/ALL RIGHTS RESERVED, © MUSEUM OF THE BIBLE, 2017

Artifacts returned to Iraq ASTRONOMY | The U.S. National Science
Foundation (NSF) this week said it awarded
T he United States has returned to Iraq more than 17,000 looted ancient the National Radio Astronomy Observatory
artifacts and plans to give back a rare, 3500-year-old clay tablet bearing part $23 million to design a powerful radio
of the Babylonian Epic of Gilgamesh, Iraqi officials told Reuters last week. telescope with 263 dish antennas spread
The items had been smuggled out of Iraq during the chaos of the 2003 U.S. across North America. The Next Generation
invasion and the takeover of parts of Iraq by the Islamic State group 10 years Very Large Array would have resolving
later. The Hobby Lobby craft store chain and Cornell University had acquired most power—the ability to see fine detail—more
of the artifacts returned in late July. Hobby Lobby’s owner had intended to give than 10 times greater than NSF’s current
the artifacts to the Museum of the Bible in Washington, D.C., where the Gilgamesh Very Large Array in New Mexico. It is
tablet (above)–containing part of the world’s first known literary work, written expected to address fundamental questions
in the Akkadian language—has been displayed. In 2017, Hobby Lobby agreed to in all major areas of astrophysics and to
pay the U.S. government a $3 million fine for possessing smuggled artifacts. The complement existing arrays and planned
repatriation is considered the largest in Iraqi history. ones such as the Square Kilometre Array.
The project faces hurdles ahead, though:
722 13 AUGUST 2021 • VOL 373 ISSUE 6556 It awaits a decision by the U.S. National
Academies of Sciences, Engineering, and
Medicine whether to include it in the
forthcoming Astronomy and Astrophysics
Decadal Survey, a key blueprint for U.S.
spending in those fields, and the array also
needs additional funding from Congress.
Construction could begin by 2026 and full
scientific operations by 2035.

SCIENCEMAG.ORG/NEWS
Read more news from Science online.

sciencemag.org SCIENCE

IN DEPTH

Firefighters battle a blaze in
Greece on 5 August. Climate change

is stoking such extreme events.

CLIMATE CHANGE

Time grows short to curb warming, report warns

IPCC science analysis concludes human role ‘unequivocal’ and impact ‘unprecedented’

PHOTO:MICHAEL VARAKLAS/AP IMAGES By Cathleen O’Grady warm, says the report, which was assem- projected to peak midcentury at 1.6°C above
bled by hundreds of scientists from around preindustrial levels. Even in this scenario,
E very time the U.N. Intergovernmental the world, and climate change’s impact on Arctic sea ice is likely to vanish completely
Panel on Climate Change (IPCC) is- the planet is “unprecedented.” That blunt in at least one summer by 2050. In the worst
sues a new report surveying the science language reflects, in part, the substantial case scenario, warming will very likely reach
of global warming, the alarm sounds scientific advances that have occurred since 2.4°C by midcentury and rise to 4.4°C—and
louder. Now, 8 years after its last report, IPCC issued its last major assessment in potentially 5.7°C—by 2100. At higher emis-
the message of IPCC’s latest assessment, 2013. Climate models are more detailed and sions levels, “low-likelihood, high-impact”
released this week, is urgent and unequivo- powerful, and observational records cover consequences—such as mass ice sheet loss
cal: The window for mitigating the worst more ground—including the rapidly warm- in the Antarctic or the stalling of ocean
projected impacts of global climate change ing Arctic—as well as eight additional years currents—become more likely. The prob-
is closing. Average global temperatures are of warming. They have enabled research- ability of these abrupt, irreversible changes
now 1.1°C above preindustrial records, and ers to better “see the climate change signal is not well-understood, the report says, but
under every scenario for future greenhouse developing,” says Nerilie Abram, a climate they cannot be ruled out. Current emissions
gas emissions that the panel examined, av- scientist at Australian National University. are on IPCC’s mid- to higher trajectories,
erage warming of 1.5°C—a target set by the Imperial College London climate scientist
2015 Paris climate accord—will very likely be Growing evidence from ancient cli- Joeri Rogelj said at a briefing, and coun-
reached within the next 20 years. mates has also helped researchers con- tries’ pledges still fall short of achieving the
strain estimates of what is called climate lowest emissions scenario. “Let’s be clear,”
“This is a critical decade for keeping sensitivity—the amount of warming ex- he said, “about the work that still needs to
the 1.5°C target within reach,” says Jane pected if concentrations of atmospheric be done.”
Lubchenco, deputy director for climate and carbon dioxide (CO ) rise twice as high as in
the environment at the White House Office For the first time, the report elaborates
of Science and Technology Policy. The pro- 2 on how each increment of warming could
jections mean countries should come to the play out in different regions, stoking ex-
U.N. Climate Change Conference, scheduled preindustrial times, to 560 parts per million treme events such as flooding, heat waves,
for November, with the most “aggressive, (ppm). (Current levels are about 415 ppm droughts, and fire. Past reports focused on
ambitious” targets for reducing emissions and climbing fast.) The panel now estimates averages, Abram notes, but “people don’t
possible, she says. that a CO doubling would boost tempera- live in the global average.” One forecast
is that climate change will give extra po-
It is “unequivocal” and “established fact” 2 tency to existing natural variability in tem-
that human activities are causing Earth to
tures by 2.5°C to 4°C, a narrower range than
the previously estimated 1.5°C to 4.5°C.

In the best case scenario, with the world
cutting net emissions to zero by 2050, CO

2

will fall short of doubling and warming is

SCIENCE sciencemag.org 13 AUGUST 2021 • VOL 373 ISSUE 6556 723

NEWS | IN DEPTH

peratures and precipitation. With 1.5°C RIVER SCIENCE
of warming, for example, high daytime
temperatures that would be rare without Streams that flow only part of
climate change could occur four times a the year are getting even drier
decade; at 4°C of warming, such heat ex-
tremes could come nearly every year. Such Analysis of intermittent U.S. waterways finds many
projections illustrate that “every little bit are shriveling earlier and remaining dry for much longer
of warming counts,” says Claudia Tebaldi,
a climate scientist at Pacific Northwest By Erik Stokstad availability of water, especially in deserts.
National Laboratory and an author of
the report. But she and others emphasize “Just because the channel is dry does not
that targets like 1.5°C should not be seen
as precipices beyond which there is no re- S mall streams that dry up for part of make it biologically dead,” says river scien-
demption or hope. the year are easy to overlook. But these tist Ellen Wohl of Colorado State University.
intermittent streams are everywhere, It also has implications for water quality, as
It is now “established fact” that warming making up more than half of Earth’s microbes in damp sediments can remove ni-
is fueling extreme events, the report says. waterways. They help purify surface trogen pollution even after the last puddles
And since IPCC’s last report, scientific ad-
vances have made it possible to link cli- water and provide crucial habitat for have disappeared.
mate change to specific events, such as the
recent heat wave in northwestern North creatures such as the Sonoran Desert toad, The drying trend is clearest in arid re-
America, says Francisco Doblas Reyes, a
climate scientist at the Barcelona Super- fairy shrimp, and Wilson’s warbler. Now, gions, such as the Southwest. But even in the
computing Center and a report author. It’s
clear that “climate change is here now,” a study has found that ephemeral streams Southeast, which is relatively wet, streams
he says. “No region is spared,” adds Sonia
Seneviratne, a climate scientist at ETH across the continental United States have are drying earlier and staying dry longer.
Zürich and a report author. New extremes
in heat, precipitation, or drought have become less reliable over the past 40 years, In contrast, in the northern United States
been observed in nearly every global re-
gion. “We are starting to see events which likely as a result of climate change. Some ephemeral rivers are now flowing longer.
would have had near zero probability of
happening without human-induced cli- are dry for 100 days longer per year than One possible reason: Winters are warmer
mate change,” Seneviratne says.
in the 1980s. “That’s re- and shorter, meaning
Some global changes are already locked
in, the report notes, regardless of how much ally shocking,” says Sarah frozen landscapes thaw
humanity reduces emissions in coming de-
cades. Melting of glaciers and ice sheets and Null, a watershed scientist earlier, allowing streams
thawing of permafrost is now “irreversible”
for decades or centuries to come, it says. at Utah State University. to flow.
The warming, acidification, and deoxygen-
ation that are already damaging the world’s The findings, reported In some cases, human
oceans will continue for centuries to millen-
nia. Continued sea level rise, now estimated last month in Environ- activities such as operat-
at 3.7 millimeters each year between 2006
and 2018, is also inevitable: Over the next mental Research Letters, ing dams, irrigation, and
2000 years, oceans will likely rise by 2 to
3 meters if the planet warms by 1.5°C, and come from a study of groundwater pumping
up to 22 meters with 5°C of warming.
data collected between could be contributing to
Because of the ongoing COVID-19 pan-
demic, the hundreds of scientists who 1980 and 2017 by flow dewatering. But a warm-
wrote the assessment had to meet online to
wrestle with how to convey the extent of the gauges on 540 intermit- ing climate appears to be
climate crisis and the urgent need to act. It
was uncanny to see “the echoes of one crisis tent streams around the “the overarching orga-
in another,” Tebaldi says. And for many re-
searchers, the work isn’t done. The science United States. Most of nizer” of the shifts, Zipper
assessment—the sixth produced by IPCC
since 1990—is just the first of three major the gauges were on small says. “I definitely didn’t
reports that IPCC’s 195 member states will
release over the coming year. The next re- waterways in river head- Climate change is altering expect the pattern to be so
ports will examine how climate policies can
reduce emissions, and what actions will be waters, but a few tracked intermittent streams, such as this one regionally clear.”
needed to adapt to extreme events such as
flooding, heat waves, and drought. j large rivers that are inter- in California’s Death Valley. Broader monitoring

mittent in places, such as of intermittent streams

the Rio Grande, which flows sporadically in would help researchers and policymakers bet-

New Mexico and Texas. The sample covered ter understand the sometimes subtle impacts

just a small fraction of intermittent streams, that climate change is having on water quan-

the authors note, and left out some states, tity and quality, scientists say. “We should

such as Nebraska and Maine, that don’t have have many more gauges in small streams,”

any long-term gauges on these streams. Still, says Albert Ruhi, a freshwater ecologist

the analysis revealed some eye-opening re- at the University of California, Berkeley.

gional shifts, says Sam Zipper, one of the au- Others say the results highlight the need

thors and an ecohydrologist with the Kansas for stronger legal protections for intermit-

Geological Survey. tent tributaries that form the headwaters

More than half of the gauges showed of many rivers. Many such streams were

changes in the streams’ flow patterns since excluded from federal environmental laws PHOTO: TIM FITZHARRIS/MINDEN

1980. Some now shrivel earlier in the year under former President Donald Trump’s ad-

and remain dry for longer, for example, or ministration. (President Joe Biden’s admin-

they dwindle more quickly than before. At istration is now reviewing those exclusions.)

some 7% of gauges, dry periods expanded by Such streams can seem inconsequential,

100 days or more. Wohl says, but, “If you start chopping off the

That is bad news for the many plants and first joint of each finger, you’re going to lose

animals that time their reproduction to the functionality in your hand pretty fast.” j

724 13 AUGUST 2021 • VOL 373 ISSUE 6556 sciencemag.org SCIENCE

THE NEW NORMAL She dedicated the first 20 minutes of every
(now virtual) lab meeting to how people
Science lost and lessons learned: were feeling. “Sunny tried to set everyone’s
A lab plots its comeback mind at ease,” says Tzvi Pollock, a fifth-year
graduate student at the time. “She said
A microbiology team regroups, with a more virtual lab everyone experiences setbacks, whether it
and a bigger focus on mental health be from a pandemic or Hurricane Sandy.
That really reassured me.”
ILLUSTRATION: KATTY HUERTAS By David Grimm, in Philadelphia genomes that had taken years to breed.
Shin was concerned for the future of her Pollock says he needed the reassurance.
T he main door of Sunny Shin’s lab is During the pandemic, the depression and
plastered with pictures of happier research on Legionnaires’ disease—and, more anxiety he had battled for years returned. He
times: Shin photoshopped onto the importantly, for the future of her people. “I couldn’t work or sleep. He had frequent panic
cover of a Wheaties box, grad students worry that the pandemic will affect the ca- attacks. “It absolutely wrecked me,” he says.
chomping on corn cobs, a group photo reer trajectories of junior scientists for years
on the lawn of a beach house. “We used to come,” she says. He and his lab mates tried to write papers
to do a yearly retreat to the Jersey Shore,” or plan experiments from home. But there
says Shin, a midcareer microbial immuno- Some of those fears have come true, as was only so much they could do without ac-
logist here at the University of Pennsylvania universities across the country assess the cess to mice and cell lines. Things didn’t get
(UPenn). “Hopefully we can go back in 2022.” damage of a lost year—research programs much easier when UPenn reopened at half
derailed, job opportunities vanished, and capacity last summer. Core resources such
When the COVID-19 pandemic hit, Shin promising researchers lost to alternate ca- as tissue culture rooms and animal facilities
oversaw 12 people: seven Ph.D. students, reers. At the same time, “It’s incumbent upon filled up fast. Young graduate students like
three postdocs, an undergrad, and a lab us to learn something valuable from this ex- Víctor Vázquez Marrero had trouble shad-
manager. She was thinking about each of perience, and to use it to improve the lives owing older ones because they weren’t al-
them when the memo came down from of our students,” says Daniel Kessler, chair of ways allowed in the same room. And Nawar
an administrator in mid-March 2020: All UPenn’s cell and molecular biology graduate Naseer, then a fourth-year grad student,
non–COVID-19 work must stop, and most group. Among the legacies of the pandemic, chose to cram in a week of labwork between
rodents must be culled because few people UPenn and other schools are finding new Friday and Sunday, when she had access
would be around to care for them. “It was ways to support trainees, with both their ca- to the facilities she needed. “Even though
heartbreaking,” Shin said at the time, as reers and their mental health. I was back in lab 50% of the time,” Pollock
her lab manager began the agonizing task says, “I was only about 30% productive.”
of euthanizing 200 mice, some with unique When UPenn closed its labs and Shin’s
team faced 3 months of near-isolation, her The challenges continued at home. Shin’s
immediate priority was their well-being. daughter was 6 years old when the pandemic
struck. For months, Shin and her husband
worked in shifts. About half of those who
responded to a U.S. National Institutes of
Health (NIH) survey in October 2020 said
caretaking responsibilities made it “substan-
tially more difficult to be productive,” with
women reporting more issues than men.

Meanwhile, nearly 70% of the postdocs
surveyed said the pandemic would nega-
tively impact their careers, with those caring
for young children expressing the most anx-
iety. One of Shin’s postdocs left academia,
taking a job in industry that didn’t involve
bench research. “The COVID-19 pandemic
is dismantling the pipeline of investigators
who are essential to the future of biomedical
science,” fretted a recent article in The New
England Journal of Medicine.

Worried about supporting her postdocs if
she couldn’t renew her grants, Shin took a
6-month sabbatical during which the uni-
versity, rather than grants, covered most of
her salary. But instead of taking that time
off from her duties, she kept working and
funneled the saved money to her postdocs.
“My top priority was to keep the lab funded
to buy them enough time to bounce back.”

Her efforts joined a broader response.
Universities like UPenn have allowed post-
docs to apply for extensions, and young
faculty to add a year to their tenure clocks.
Meanwhile, in February NIH announced it

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NEWS | IN DEPTH

would extend many of the grants given to Steven Chu, who was then U.S. secretary of energy, visits the Joint Center for Artificial Photosynthesis in 2012.
grad students, postdocs, and young faculty.
ENERGY RESEARCH
Still, Michael Lauer, NIH’s deputy direc-
tor for extramural research, acknowledges ‘Mini–Manhattan Projects’ for
the agency won’t be able to help everyone. energy innovation wind down
“We’re still in a hypercompetitive environ-
ment,” for grants, a situation that predates But hub model for bridging basic and applied research lives on
the pandemic, he says. “If we give money
to one person, that’s less money for some- By Adrian Cho Alex King, a materials scientist retired from PHOTO: U.S. DEPARTMENT OF ENERGY/FLICKR
one else.” DOE’s Ames Laboratory.
T he Department of Energy (DOE) will
In all, Shin estimates her lab was set back soon wipe away a legacy of Steven Chu, a former president of AAAS, which
as much as 9 months. But things are slowly Chu, the Nobel Prize–winning physi- publishes Science, borrowed the basic pa-
returning to normal. She brought in five cist who served as secretary of en- rameters for the hubs from three bioenergy
undergrads, for a total of 15 people—more ergy from 2009 to 2013 under former research centers started by DOE under
than before the pandemic. She was able to President Barack Obama. According former President George W. Bush. Each
rebreed or reorder most of her mice. And her to the department’s budget request for next hub would receive $25 million a year for
team is back to working full days in the lab. year, DOE intends to wind down most of its 5 years, with the possibility of a renewal.
Energy Innovation Hubs, multidisciplinary, Instead of focusing on a research topic,
Some pandemic retrofits will stick around. multi-institutional centers that Chu devised each would strive to develop a practical
Lab meetings are in person again, but Shin to solve crucial energy-related problems solution for a single big problem, Chu said,
still starts them by asking how everyone is and invigorate the sclerotic department. uniting “under one roof ” everybody from
doing. Lab members also now have the op- scientists doing basic research to engineers
tion of attending remotely, and about one- Chu compared the hubs to the Manhattan developing a prototype. By 2013, DOE had
third do. “Some people just focus better in a Project, the World War II scramble to make initiated five hubs focused on challenges
virtual setting,” Shin says. “Others feel more an atomic bomb, and like the bomb project, ranging from converting sunlight to fuel to
comfortable asking questions.” they were meant to be ad hoc, temporary modeling nuclear reactors to improve their
efforts. Some DOE bureaucrats disliked the performance.
The lab has also embraced the instant way the hubs crossed organizational bound-
messaging platform Slack as a way to keep aries, but observers say they succeeded in The whole point of the hubs was to
in touch and check in on each other when making DOE’s research more responsive breach a long-standing boundary within
they’re not together. That situation is more and relevant. “The vision for the hub was, DOE, says Cherry Murray, a physicist at the
typical now, as trainees have realized that and still is, a great one,” says Eric Isaacs, University of Arizona and director of DOE’s
they can analyze data and write papers from president of the Carnegie Institution for Sci- Office of Science from 2013 to 2015. DOE’s
home. “The peer pressure to put in face time ence and former director of DOE’s Argonne basic and applied research are disconnected
has abated,” Shin says. National Laboratory. In fact, DOE appears because they’re funded out of different con-
to have embraced the once-controversial gressional budget lines. The two rub elbows
For its part, the university has put more model and has started several new projects at DOE’s 17 national laboratories, but “the
emphasis on mental well-being. Pollock that hew to it. “They look like a hub, and interface isn’t perfect,” Murray says. “So the
says that during the pandemic, “Penn had they walk like a hub, but they don’t have hubs are just trying to bring that [connec-
posters everywhere for all of the places this unfortunate malodorous name,” says tion] into a funding mechanism” to drive
you could call,” but because of what he ar- the innovation of new technologies.
gues is still a large stigma around mental
health, “people weren’t availing themselves
of those resources.”

In response, the university has created a
peer support network that allows students
to reach out to friends and colleagues in-
stead of going straight to a therapist. UPenn
is also building a trainee advocacy alliance,
which will partner students with peers and
faculty trained in active listening and men-
toring, who can help students navigate the
university’s mental health resources. “We
want to normalize that if you need help, it’s
OK to ask,” Kessler says. “When a student
enters our school, they will now have access
to multiple support systems from Day One.”

Pollock is getting back to normal him-
self, feeling productive again and mentor-
ing two undergrads this summer. He plans
to stay in academic science, and when he
gets a lab of his own he knows, now more
than ever, whom he wants to emulate. “Over
the past year, it’s been so clear that Sunny
cares more about me as a person than as a
producer of data,” he says. “I want to be the
kind of mentor she was to me.” j

726 13 AUGUST 2021 • VOL 373 ISSUE 6556 sciencemag.org SCIENCE

Each hub was managed by either the Of- replacements for certain materials, mostly RESEARCH ETHICS

fice of Science or an applied office, and each rare earth elements, or new sources of Genetics
papers from
was encouraged to have industrial collabo- them. “Right out of the gate, we had a really China face
ethical scrutiny
rators who could make sure what scientists good run of successes in developing tech-
Questions about consent
were doing was relevant, says Bill Madia, nologies and transferring them to industry,” and potential for abuse
trigger investigations
vice president emeritus at Stanford Univer- says King, who directed CMI from 2013 to
By Dennis Normile
sity. “That was a little bit outrageous,” he 2018. For example, he says, CMI developed
W hen Yves Moreau, a bioinforma-
says. “You will never see the Office of Sci- a red phosphor for fluorescent lighting that tician at KU Leuven in Belgium,
noticed a 2017 paper in Human
ence put out a solicitation [for an ordinary does not require rare europium. Genetics that described the “male
genetic landscape of China” based
grant] saying, ‘You better bring in GE for a In 2015, however, Republicans took con- on a set of almost 38,000 Y-STR
sequences, he saw a red flag. Y-STR stands
cost-sharing arrangement.’” trol of the Senate, and discouraged DOE for Y-chromosomal short tandem repeat
polymorphism, bits of repetitive DNA of-
One hub quickly crashed and burned. from doing research they thought industry ten used in forensic investigations. Some of
the samples came from Uyghurs and other
The Energy Efficient Buildings Hub in Phil- should do for itself. Industrial partners also minorities in China, and Moreau was skep-
tical that they had given informed consent
adelphia shut down in 2013 when Congress became reluctant to work openly with CMI, for the use of their genetic data or under-
stood that China might use it to profile their
pulled the plug, citing management issues. King says, explaining they feared a public people. In June 2020, he asked the journal’s
editors to retract the “indefensible” paper.
Another nailed its goals. The Consortium relations problem. “If you’re working with
Springer Nature, its publisher, launched
for Advanced Simulation of Light Water Re- [CMI], it must mean you have a supply an investigation that is still ongoing. So last
month, Moreau stepped up the pressure: He
actors (CASL), based at Oak Ridge National chain problem,” he says, “and that’s going to wrote to the journal’s entire editorial board
to complain about the lack of progress. For
Laboratory, produced high-resolution, affect your stock.” As a result, CMI began to Moreau, the paper is just one of many stud-
ies, primarily in forensic genetics, that de-
physics-based software that industry has lose its focus and to resemble a more typical serve scrutiny because of consent problems
in China and the potential for abuse of the
used to simulate new and existing reactors. research center, King says. data. He says he has flagged about 28 papers
at six journals over the past couple of years.
The Joint Center for Energy Storage Re- Now, DOE is winding down Chu’s hubs.
And his campaign is gaining traction.
search (JCESR) at Argonne set out to in- CASL closed down last year, and JCAP Eight of 25 members of the editorial board
of Molecular Genetics & Genomic Medicine,
crease the energy density of and CMI are wrapping up. published by Wiley, recently resigned to
protest the lack of progress in investigating
batteries by a factor of five, “The vision JCESR with receive its last a number of papers flagged by Moreau, as
compared with the lithium- for the hub was, funding next year, according The Intercept reported last week. A former
ion battery that powered the to the DOE budget request. editor-in-chief of Human Genetics, geneti-
cist Robert Nussbaum, has added his voice
2012 Nissan Leaf, at one-fifth and still is, (Crabtree says his under- to Moreau’s, complaining to the editors that
the cost. “Spoiler alert, we got standing is that JCESR will be the investigation of the 2017 paper “seems
to have been going on a long time.” Springer
three times the energy den- a great one.” funded into 2023.) Nature’s executive editor for medicine and
sity at a fifth the cost” in four Yet DOE is hardly aban- life sciences, Andrea Pillmann, says it is
investigating about 50 other papers, 29 of
novel batteries, says George Eric Isaacs, Carnegie doning the hub concept. Last

Crabtree, a materials scien- Institution for Science year, the department kicked

tist at Argonne and director off the National Alliance for

of JCESR. The hub also spun out multiple Water Innovation, which aims to develop

startups, he says, including one that is “technology that enables 90% of [waste]

building an iron-based grid storage battery waters to be reused,” says Meagan Mauter,

for an electric utility in Minnesota. a chemical and environmental engineer at

The most ambitious of the hubs illus- Stanford and the alliance’s research direc-

trated the key challenge: to keep a hub tor. DOE has also started the hublike Liquid

from losing sight of its goal and morphing Sunlight Alliance at Caltech and the Center

into just another research center. The Joint for Hybrid Approaches in Solar Energy to

Center for Artificial Photosynthesis (JCAP), Liquid Fuels at the University of North Car-

based at both the California Institute of olina, Chapel Hill, to follow on JCAP’s work.

Technology (Caltech) and Lawrence Berke- DOE has even extended the hubs con-

ley National Laboratory, aimed to make a cept beyond energy research. Last year,

self-contained photocell that would har- the department initiated five quantum in-

ness sunlight to convert water and carbon formation science centers, each funded for

dioxide into fuels with an efficiency of 10%, $25 million a year for 5 years and aimed at

10 times that of natural photosynthesis. developing a particular quantum technol-

JCAP researchers surpassed that goal with ogy, such as a quantum internet. “We took

a prototype that converts water to hydro- [the hubs concept] and turbocharged it” by

gen gas, ultimately reaching an efficiency of encouraging even closer ties with indus-

19.3%, says Harry Atwater, an applied physi- try, says Paul Dabbar, who helped launch

cist at Caltech and JCAP director. But the the quantum centers when he was DOE’s

cell wasn’t durable enough to be practical, undersecretary for science from 2017 to 2021

Atwater says, and JCAP turned to the harder under former President Donald Trump.

problem of transforming carbon dioxide Whether the Biden administration will

into specific hydrocarbons such as ethylene, be as enthusiastic for hubs remains to be

which it has not yet solved. “JCAP was too seen, as the Senate has yet to confirm the

aspirational and too science-y,” Murray says. White House’s nominees for director of the

External pressures can also alter a hub’s Office of Science and undersecretary of en-

character. The Critical Materials Institute ergy. But, for now, even as the hubs’ name

(CMI) at Ames Laboratory aimed to find dies, the concept has found new life. j

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NEWS | IN DEPTH

which already have an editor’s note of con- to verify identities at the region’s ubiquitous tee,” according to the May retraction notice.
cern attached to them. The company has put checkpoints—and DNA data. Moreau says A review by the editors found that the sec-
checks in place “to help us to identify po- DNA profiling does not directly enable mass ond, an evaluation of genetic markers in four
tentially concerning submissions in future,” internments or forced labor. Rather the im- different Chinese populations published in
Pillmann says. Meanwhile, the Charité Uni- pact is psychological, reinforcing citizens’ April 2019, had ethics approval for the par-
versity Hospital in Berlin has come under feelings of constant surveillance. Byler adds ticipation of Chinese Han individuals, but
fire for hosting the genetic database used in that DNA profiling “could be used to enforce not for the Tibetan, Uyghur, and Hui partici-
several papers under investigation. a ‘zero illegal births’ policy by tracking ma- pants. It was retracted in November 2020.
ternity and paternity,” and to find matches
Human rights activists welcome Moreau’s for organ harvesting from prisoners, “of The Human Genetics paper is particu-
efforts. “It is important for journals con- which there is some limited evidence.” larly problematic because of the sheer
cerned with research ethics to take into volume of data and the participation of co-
account the state violence that is endemic As authorities have tightened their grip authors from Chinese law enforcement or-
throughout the Uyghur and Tibetan re- on Xinjiang, Chinese researchers have ganizations in the study, Moreau says. The
gions,” says Darren Byler, a sociocultural stepped up research into the region’s cul- paper, co-authored by Chinese and German
researchers, states that the study “complies
A Uyghur man sits in a teahouse in China’s Xinjiang province, where government surveillance is intense. with the ethical principles of the 2000 Hel-
sinki Declaration,” which covers research
anthropologist who studies Uyghur issues ture and genetics, says Huang Futao, a in humans. But corresponding author PHOTO: KEVIN FRAYER/GETTY IMAGES
at Simon Fraser University, Vancouver. higher education scholar at Hiroshima Uni- Michael Nothnagel of the Cologne Center
versity. Some of this research is supported for Genomics now concedes that some of
Moreau has long been concerned about by the State Administration for Science, the data may have been collected in ways
threats to privacy posed by the use of genetic Technology and Industry for National De- “that did not meet relevant ethical stan-
data. Forensic use of DNA databases has fense, Huang says, and focuses on topics dards.” Nothnagel says the authors are
evolved from a narrowly focused law enforce- related to maintaining social safety and sta- working with the editors and Springer Na-
ment tool to a threat to personal privacy, he bility. The results have often been published ture to resolve the issue; he did not respond
says. The potential for abuse is, at the mo- in international journals. to an email seeking additional details.
ment, most clearly seen in China’s Xinjiang
Uyghur Autonomous Region, he adds. Since Yet, “It can be very difficult to judge the The data used in the paper are drawn
late 2017, evidence has grown that China is validity of informed consent in China,” says from the Y chromosome haplotype refer-
systematically oppressing Uyghur and other bioethicist Jing-Bao Nie of the University ence database (YHRD), based at Charité,
Muslim minorities in Xinjiang. Some call the of Otago, Dunedin: “Explicit and especially which includes Y chromosome data from
tactics—including mass internment, forced implicit pressure [to give consent] often ex- more than 300,000 individuals uploaded by
labor, suppression of religion, and efforts to ists in various forms.” contributors from around the world and is
slash birth rates—crimes against humanity. used by researchers and law enforcement
China claims the country is simply “coun- Moreau’s efforts have already led to the agencies. Moreau says there is no way to
tering violent terrorism and separatism,” as retraction of two papers by Chinese authors verify compliance with informed consent
Foreign Minister Wang Yi told the United in Springer Nature’s International Journal of standards for the data, which are at least
Nations Human Rights Council in February. Legal Medicine. One, a study of STR haplo- partly anonymized.
types in Uyghur, Kazakh, and Hui men pub-
As part of surveillance efforts in Xinjiang, lished online in March 2019, was found to In a letter posted on its website on 6 Au-
authorities have collected biometric data, in- have been “undertaken without the approval gust, Gen-ethical Network, a Berlin-based or-
cluding facial scans and fingerprints—used of [the authors’] institutional ethics commit- ganization promoting ethical use of genetic
technologies, called for an investigation into
allegations of YHRD’s “unethical handling of
genetic data from minorities.” The letter, co-
signed by three other groups, cited not only
the issues raised by Moreau about Uyghurs,
but also similar problems with genetic re-
search on Roma people in Europe. YHRD
managers did not respond to an email from
Science seeking comment.

Moreau’s concerns go beyond informed
consent. Any research that enables genetic
profiling “is harmful in the hands of an au-
thoritarian regime,” he says. And he worries
such studies reflect badly on the field: “Pub-
lic trust in human genetics depends on our
community’s ability to transparently abide
by its moral duties.”

Nie sees little chance of change on the
ground in China, where rising nationalism
often eclipses ethical concerns. “I doubt that
the issue of informed consent and privacy
will be improved in the near future in China,”
Nie says. That puts a greater responsibility
on international journals, Moreau says. j

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NEWS

FEATURES

FAILURE TO PROTECT?

A study of asthmatic children, most of them Black, shows how a common
clinical trial design can expose vulnerable participants to serious risks

ILLUSTRATION: STEPHAN SCHMITZ J uan Celedón, a respected pulmo- By Charles Piller daily high-dose vitamin D supplement for
nary researcher at the University about 1 year. The other half would serve as
of Pittsburgh, wanted to address and colleagues launched a major trial to controls. The researchers also made a deci-
an urgent national problem. Se- test that premise. sion that cast a shadow over the trial—and
vere asthma attacks send hun- inflamed a controversy confronting many
dreds of thousands of U.S. children With $4.3 million in funding from the other trials of similar design. Instead of
to the hospital every year. For de- National Heart, Lung, and Blood Institute treating the randomly chosen control group
cades, researchers have suspected (NHLBI) and support from a vitamin com- with a more modest dose of vitamin D—as
extra vitamin D—essential for pany and a drug firm, they enrolled asth- many medical authorities advise for chil-
bone growth and healthy development, and matic kids who had low or deficient levels dren with a deficiency of the vitamin—the
also an immune modulator in children and of vitamin D—many from urban, minority researchers chose to give them a placebo.
adults—might help them. In 2016, Celedón communities; most were Black. Half of the
400 planned participants would receive a When Seattle physician Bruce Davidson,

SCIENCE sciencemag.org 13 AUGUST 2021 • VOL 373 ISSUE 6556 729

NEWS | FEATURES

a pulmonary specialist who has studied vi- documents and others reveal new aspects sent a list of questions. The trial, its proto-

tamin D and asthma, heard about the “Vit- of the trial that concern asthma researchers col, and consent forms “underwent rigor-

D-Kids” trial, he was stunned. The children, like Davidson, medical ethicists, and spe- ous review before and after it was funded,”

as asthmatics treated with corticosteroids, cialists in clinical trial design who reviewed Celedón wrote in a brief note emailed to

already faced possible bone health problems the materials at Science’s request. Science, adding: “All regulatory bodies, in-

and diminished growth, and any vitamin “The advantages to society of this trial, cluding a [DSMB] and [IRBs] at seven pedi-

D deficiency would place them at greater because of the poor design, were likely atric hospitals, stated that the trial was both

risk for fractures. Yet Davidson discovered none. And the risks did outweigh the ben- safe and ethical.” In NHLBI’s statement to

that informed consent forms posted online efits,” says Charles Natanson, a physician Science, Kiley wrote, “The highest priority

failed to inform parents of enrolled children and expert on trial design at the NIH Clini- was to keep every child in the study safe.”

about those dangers. cal Center. “This trial did not, in my opin- Vit-D-Kids could easily be dismissed as a

Davidson, who had worked on a compara- ion, meet the standards set forth in The controversial outlier, but Natanson and oth-

ble vitamin D trial that rejected a placebo arm Belmont Report,” which in 1979 established ers suggest it instead exemplifies the growing

as unethical, repeatedly voiced his concerns ethical guidelines, adopted by the U.S. number of studies in humans that inappro-

about Vit-D-Kids to the scientists running it, government, for protecting human sub- priately reject control groups receiving “usual

institutional review boards (IRBs) that ap- jects. Keeping children on a placebo after care”—current best practice treatments used

proved it, and NHLBI. But trial researchers the trial was stopped for futility stood out by doctors. In a hunt for compelling results,

called the risks minimal. The placebo was as an “unconscionable” error, adds Ruth many researchers favor using sharply diver-

justified because vitamin D testing is not rou- Macklin, a medical ethicist at Albert Ein- gent treatment arms in a trial. But such ex-

tine, they argued. If not for the trial, the kids’ stein College of Medicine. treme comparisons mean doctors can’t learn

vitamin deficiency probably wouldn’t have Davidson and others suggest the study’s fo- whether a new treatment is better or worse

been detected, so they were no than usual care, says Natanson,

worse off in the study. who has analyzed the issue in

Davidson’s objections drew Hazard zones trials involving critically ill pa-
some media attention during the tients. He has found that many
trial and led to small changes The Vit-D-Kids trial tested children’s vitamin D blood levels multiple times over such trials mislabel one or more
to its enrollment criteria and the course of about 1 year. This chart categorizes readings from all 683 tests, arms as “usual care,” sometimes
consent forms, but Vit-D-Kids estimated from text and results graphs in its published report. In more than one- endangering participants and
third of the tests, kids had levels that were potentially hazardous according to the

pressed ahead. It wasn’t a suc- National Institutes of Health and other authorities. misinforming physicians, which

cess. Trial enrollment grew to he calls “a big problem.”

nearly 200 children but was Deficient and Su cient Possible added High and MORE THAN A DECADE AGO, NIH
halted early for “futility” in 2019 350 hazardous benefit hazardous supported an ambitious trial
after a data safety monitoring
Number of tests in each range
board (DSMB) concluded dur- 300 that foreshadowed the usual-
CREDITS: (GRAPHIC N. DESAI/SCIENCE; (DATA E. FORNO ET AL., JAMA, 324(8 :752 (2020; 10.1001/JAMA.2020.12384
ing an interim review of results 250 care issue in Vit-D-Kids. The
that vitamin D supplementation study’s researchers meant to

had failed to prevent asthma at- 200 solve a life-and-death medical

tacks. Yet the researchers kept an 150 conundrum affecting premature
unspecified number of kids, even infants: They depend on supple-

if very deficient in the vitamin, 100 mental oxygen to stay alive, but
on a placebo for up to six more 50 too much can cause blindness.
months—to ensure “an orderly The trial aimed to identify an

closeout,” James Kiley, director 0 oxygen level that would save

of NHLBI’s Division of Lung Dis- <20 20–29 30–50 >50 lives with the fewest side effects.

eases, later told a U.S. politician Vitamin D level (nanograms per milliliter) It assigned more than 1300

who asked about the decision. preemies to be maintained at

“That approach was stunning and cal- cus on minority children—which Kiley called a relatively low blood oxygen range (85%

lous,” Davidson says. And possibly harmful. “appropriate” in a statement to Science— to 89%) or a higher range (91% to 95%).

At least nine kids, across both arms of the only elevates their concerns about using a Most consent forms said either range rep-

trial, broke bones during the trial—nearly placebo. Jill Fisher of the University of North resented “usual” or “standard” care and

double the number expected among asth- Carolina, Chapel Hill, who wrote a book on that babies in both groups had the same

matic children over a comparable period. racial inequality in clinical trials, says Vit-D- likelihood of dying. Prominent supporters,

The fractures were neither disclosed as pos- Kids ignored the ethical imperative to treat including NIH Director Francis Collins, ar-

sible adverse events when the study was children at known risk from vitamin D de- gued that both infant groups met the stan-

published in JAMA last year nor noted in ficiency because of inadequate diet, poverty, dard of care as practiced at trial sites.

another public summary of the trial results. and a lack of Sun exposure in inner cities. But in a 2016 analysis in PLOS ONE, whose

A Science investigation of Vit-D-Kids re- “We shouldn’t say, ‘It’s unfortunate that there authors included Natanson, researchers ex-

viewed thousands of pages of trial protocols are these health and nutritional dispari- amined other trials of oxygen management

and consent forms; previously undisclosed ties, but it serves the interests of science to in preemies and concluded the bottom of

DSMB deliberations; emails from the trial’s have placebo-controlled trials,’” she says. It the trial’s low-oxygen range was not consid-

principal investigator, NHLBI officials, and is “structural racism” to scientifically exploit ered usual care in multiple countries. The

JAMA editors; and letters between National such inequalities, Fisher adds. trial departed from usual care in another

Institutes of Health (NIH) officials and Kiley and Celedón declined to be inter- respect, not noted on the consent forms:

a concerned member of Congress. Those viewed but provided statements after being By design, the oxygen monitors displayed

730 13 AUGUST 2021 • VOL 373 ISSUE 6556 sciencemag.org SCIENCE

inaccurate readings to prevent caregivers Each trial had eminent backers who said ac- and other ailments, but clinical trials often
from knowing a baby’s study group. cepted practices can be ambiguous, fueling failed to show such benefits, particularly for
divisive debates. “Usual care in Seattle may the high-dose pills touted by the supplement
Scores of bioethicists and clinicians— differ from usual care in San Antonio. This industry. How much vitamin D a growing
and the federal Office for Human Research applies particularly to uses of technology child needs also is debated, but most au-
Protections (OHRP)—said the informed and high-cost interventions,” said Edward thorities say kids need levels in the blood
consent forms inadequately described the Campion, an editor at The New England of 20 to 29 nanograms per milliliter (ng/
risks. About 20% of babies in the low- Journal of Medicine when it published the ml) to minimize risks of bone fractures and
oxygen range died, compared with 16% in infant oxygen study, at a public hearing. impaired immune response, and to protect
the high-oxygen group. lifelong skeletal health. Guidelines from the
Those issues came to a head again in American Academy of Pediatrics and Pedi-
Several other U.S. trials (see table, below) Vit-D-Kids. Vitamin D supplementation atric Endocrine Society call anything below
also became magnets for criticism that they has long been contentious. It is said to be a that threshold “deficient” or “insufficient”
violated usual-care safeguards seen as cru- remedy for diabetes, cancer, heart disease, and recommend supplements. The Vit-
cial, even if sometimes complex to define. D-Kids protocol also cites an Institute of
Medicine report that agrees with those as-
‘Usual-care’ controversies sessments. And NIH labels 20 ng/ml “inad-
equate” and below 12 ng/ml “deficient.”
Trials that compare alternate treatments but lack a usual-care group reflecting stan-
dard medical practice have grown increasingly common—and drawn a backlash from With sites at big-city hospitals, Vit-D-Kids
ethicists and clinical research experts. They say the approach sometimes endangers originally recruited asthmatic kids, ages
trial participants and may not offer clear clinical guidance. The trials below are among 6 to 16, who had vitamin D levels between
those that drew scrutiny. 10 and 29 ng/ml. Many kids were below
20 ng/ml—levels the study itself, in its pro-
Trial: Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial, tocol, deemed “deficient” and inadequate for
2005–09 musculoskeletal health. Yet that protocol,
Sponsor: National Institute of Child Health and Human Development posted publicly online and included with
Goal: Determine the optimum oxygen level for premature infants. the JAMA publication, also described the
Controversy: Critics charged that the trial paired high levels of oxygen with levels risk of leaving those children untreated as
below usual care and set oxygen monitors to provide false results—misleading parents “no greater than encountered in daily life by
and clinicians about the risk of death. Supporters argued that evidence to define usual healthy community-dwelling children.” But
care was unclear and both groups fell within that standard. the kids participating in the study, afflicted
with asthma and receiving powerful steroid
Trial: Established Status Epilepticus Treatment Trial, 2016–19 drugs to treat it, were far from healthy.
Sponsor: National Institute of Neurological Disorders and Stroke
Goal: Determine which of three anticonvulsant drugs most effectively treats seizures In his statement to Science, Kiley defended
lasting more than 5 minutes. Vit-D-Kids by saying vitamin D–deficient
Controversy: Critics said the study endangered subjects by randomly assigning them children were excluded in favor of those with
to a drug, when under usual care each patient’s history would be a key consideration. “vitamin D levels in the low to low-normal
Because the researchers were initially blinded as to which drug was given, it was range, who normally would not be treated
difficult for them to adjust treatment if patients did not respond. Researchers argued with supplemental vitamin D.” He cited a
the trial was essential to determine objectively which drug worked best. 2016 global consensus report on rickets, a
condition linked to vitamin D deficiency that
Trial: Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis Trial, ongoing causes soft bones and bow legs. Yet even the
Sponsor: National Heart, Lung, and Blood Institute (NHLBI) rickets report defined vitamin D levels of
12 to 20 ng/ml as “insufficient.”
Goal: Determine optimal treatment—drugs that constrict blood vessels plus limited
fluids, or a larger volume of fluids alone—for people with life-threatening septic shock. Vit-D-Kids compared inadequate treat-
ment and overtreatment, according to
Controversy: Critics said both treatments deviated sharply from usual care for septic Natanson. Kids in the treatment arm were
patients, increasing participants’ risk of death. Trial sponsors said they fell within the given daily vitamin D supplements of 4000
accepted range of care. international units, or seven times their
recommended daily allowance, and some
Trial: Myocardial Ischemia and Transfusion, ongoing reached serum levels above 100 ng/ml. NIH
Sponsor: NHLBI guidelines say anything above 50 ng/ml is
Goal: Determine the optimal blood transfusion strategy for heart attack patients with potentially hazardous; studies have sug-
anemia, using red blood cell levels to decide when more blood is needed. gested such levels encourage some cancers
Controversy: Critics said informed consent forms misled participants and the trial and cardiovascular problems or increase risk
placed those in the more restricted transfusion group at greater risk. Supporters said of death overall.
the trial would help resolve uncertainty about the best approach.
The trial protocol noted the high-dose
supplement was tested against a placebo
to avoid a “false negative” outcome. “They
wanted to maximize their chances of find-
ing a difference,” says physician Michael
Carome, a former top regulator at OHRP
who directs health research for the con-
sumer advocacy group Public Citizen.

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NEWS | FEATURES

Risky choices, rejected warnings

About 18 months after the Vit-D-Kids trial began, its researchers were challenged about the study’s ethical approach and methodology,
which critics said left many vulnerable children deficient in vitamin D, an essential nutrient.

February July 2017 August 2017 September 2017 December 2017 March 2019 May 2019 August 2020 October 2020
2016 Similar study, Trial halted for Representative Lloyd Trial published JAMA rejects
Vit-D-Kids published in Physician Bruce Similar study NHLBI data board futility—high-dose Doggett (D–TX) first in JAMA; letter from
JAMA, rejects vitamin D did not requests trial data fractures not Davidson about
enrolls use of placebo Davidson contacts co-authored by requires changes in reduce asthma from NHLBI; listed as adverse the trial’s
group as attacks. Placebo the agency reveals events in any ethics and
first child. unethical. investigators, review Davidson, published Vit-D-Kids, including and treatment nine fractures, public source. racial makeup.
groups continue four in the placebo
boards that approved in Chest, rejects use an increase in for 6 months. group, but refuses
to provide details.
trial and its funder, of placebo group participants’

the National Heart, as unethical. minimum blood

Lung, and Blood level of vitamin D.

Institute (NHLBI),

with concerns.

2016 2017 2018 2019 2020 2021

Science also reviewed versions of the in- In an email Davidson gave to Science, Greer izations or emergency department visits, GRAPHIC: N. DESAI/SCIENCE
formed consent forms used by Vit-D-Kids, expressed alarm about giving a placebo and according to the paper. JAMA had in 2018
some of which Davidson acquired through concerns about possible adverse effects in rejected a commentary Davidson submitted
a Freedom of Information Act (FOIA) re- the high-dose group. (NHLBI recused Greer criticizing the trial’s use of a placebo arm;
quest. Experts in trial design say those forms from discussions of the matter after learning after the study’s publication, he sent a let-
stressed potential benefits over harms and of Davidson’s communication with him.) ter to the editor outlining that concern and
were overly complex and confusing. questions about the trial’s racial mix. JAMA
Davidson then complained to NHLBI of- rejected that as well.
For example, instead of discussing vita- ficials. “[Davidson] makes very valid points
min D deficiency, the forms used the more and … [the investigators] need to address this JAMA’s editors declined interviews, but
benign-sounding term “low vitamin D,” says in a very substantive way,” Kiley subsequently wrote in a statement they were “aware” of
Columbia University cardiologist Raymond wrote to colleagues in an email Davidson ob- Davidson’s concerns and that the study was
Givens, who studies institutional racism in tained via a FOIA request. “I am inclined to designed to “ensure the safety” of partici-
medicine and medical publishing. Ethicist put a clinical hold on this study if we cannot pants. They noted the paper reported that
Harriet Washington, whose book Medical get [a DSMB] review done next week.” trial investigators stopped giving placebos to
Apartheid discusses clinical experiments on several kids, and referred them to an endocri-
Black Americans, also notes parents often After months of deliberation, the DSMB nologist, after their vitamin D levels dropped
misunderstand essential research terms. in early 2018 approved changes to the trial, below the study’s minimum requirement.
excluding any future enrollees with vitamin
The informed consent forms for Vit-D- D levels below 14 ng/ml, compared with the But Celedón and colleagues did not report
Kids called rickets, not bone fractures, the prior cutoff of 10 ng/ml, and adding new in the JAMA paper, or in results posted to
primary risk for children who received pla- wording to the consent form. The revised ClinicalTrials.gov, that kids in the trial broke
cebos. But rickets affects infants and very version said, “The risk to bone health is un- bones. Kiley disclosed that at least nine frac-
young children—far younger than those clear if the vitamin D level is 14–19 ng/ml. tures had occurred only when Representative
enrolled in Vit-D-Kids. The consent form However, many doctors would treat with vi- Lloyd Doggett (D–TX), who chairs an NIH
should have clearly stated that any child in tamin D at this level.” The board acted “out oversight panel and had been contacted by
the placebo group with insufficient vitamin of an abundance of caution,” Kiley wrote in Davidson, asked about the trial.
D would face a higher risk of broken bones, his recent statement.
says Boston University medical ethicist Five fractures had occurred among kids
George Annas. But if such an explicit con- Carome calls the revisions a tacit ac- given vitamin D and four in the placebo
cern had been noted, he suspects few par- knowledgment that the consent form used group, which is nearly twice the rate expected
ents would have signed the consent form to recruit many of the kids “failed to dis- for asthma sufferers in that age group. But
because “it almost sounds like child abuse.” close important information that parents Kiley told Doggett that the trial’s oversight
would have needed to make a fully informed board found no safety issues. (In an interview,
In his statement, Kiley wrote to Science decision.” He says the new form continued DSMB chair Dennis Ownby of Augusta Uni-
that the fracture risk from too little vitamin to obfuscate risk by implying that treating versity said his panel was told that the rate
D didn’t apply to the trial’s kids because vitamin D deficiency was a gray area. More- of fractures was very low, but does not recall
they used only inhaled steroids, not injected over, parents were never told what their independently verifying that information.)
or oral forms, which in adults cause bone children’s specific vitamin D levels were, ei- Kiley refused to share details of those frac-
to demineralize. But up to 14 children on ther at enrollment or later in the trial. Care tures with Doggett for unspecified “reasons
the placebo took systemic steroids at least decisions, including whether to supplement of patient privacy and scientific integrity.”
twice during the trial—enough to increase a kid’s vitamin D on their own, were effec-
the fracture risk, according to an authorita- tively out of their hands. Davidson, Natanson, and other trial design
tive asthma study. experts Science contacted were troubled that
WHEN JAMA PUBLISHED the results of Vit-D- Vit-D-Kids failed to report the fractures and
AFTER LEARNING many details of Vit-D-Kids, Kids in August 2020, it looked like just an- their details publicly. Although the compa-
Davidson in August 2017 sought advice from other failed vitamin supplement trial. The rable number of fractures in each arm might
Frank Greer, an emeritus professor of pedi- placebo group and treatment groups expe- suggest the placebo group was not at greater
atrics at the University of Wisconsin, Madi- rienced about the same number of adverse risk, they note the breaks are impossible to
son, and member of the Vit-D-Kids DSMB. events—mainly asthma-triggered hospital- interpret without information on their sever-
ity and precipitating events, such as contact

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sports versus low-stress activities. deeply illogical. And it fits a racist pattern.” combinations of fluids and drugs in ways that

“Letting kids spend 48 weeks as low as Kiley and Celedón declined to comment on departed sharply from usual care tailored to

10 ng/ml—and doing this primarily to mi- that issue. Ownby says he also sees asthma as each patient’s condition. In a public state-

nority kids while warning them about ir- a disease “primarily of lower socioeconomic ment, Carome called patients in the ongoing

relevant rickets instead, then covering up status,” closely linked to disadvantages ex- trial “unwitting guinea pigs in a physiology

bone fractures—is awful,” Davidson says. perienced by Black people and other people experiment that will not advance medical

“Those kids with the lower vitamin D levels of color and to the social issues Washington care for sepsis and likely will harm many.”

need to be located, carefully assessed, and notes. But he adds that “to try to look at them Trial organizers challenged that verdict but

treated if necessary. They need explanations all at once just isn’t within the scope of most last year OHRP and NHLBI forced changes

and oversight for a while to minimize their NIH grant studies. There’s just not enough in the trial’s protocol to allow individualized

future risk.” money.” Studying genetic questions, partic- care—improvements Public Citizen com-

ularly for those most affected by asthma, is mended but called insufficient. (At the time,

THE MAKEUP of the 192 trial participants, also important and ethical, Ownby says. NIH barred Natanson and another NIH sci-

which included 100 Black kids, intensified To Carome, Vit-D-Kids offers new evidence entist from commenting on the sepsis trial.)

the debate. Kiley in his statement defends that, overall, “our IRB system is broken.” He Natanson recently analyzed CER trials of

the trial’s demographics, noting that Black doubts that any hospital panel that green- critically ill people published over 1 year in

children “are twice as likely as white chil- lit the study asked how its own physicians three “high-impact journals with a reputa-

dren to be affected by asthma.” Yet even would normally treat asthmatic children de- tion for a rigorous review process—the best

with higher asthma rates, Black children ficient in vitamin D. None would fail to give clinical trial journals in the country.” The

were vastly overrepresented in the trial, in baseline supplements, he says. It’s a sign that yet-unpublished study examined roughly

comparison with their numbers at study IRBs tend to uncritically accept NIH funding 50 trials, identifying those that improperly

sites like Pittsburgh and Boston. excluded a usual-care arm. He

That concerns Givens and estimates that “up to half of the

others. “[If ] most of [a trial’s] Treatments on trial [CER] trials done in critically
subjects will be nonwhite, and ill subjects have this problem.”
a large proportion low-income National Institutes of Health (NIH) funding for clinical trials comparing different A huge proportion of trials of
and perhaps lacking advanced treatments rose starting in 2009. Spending on such comparative effective nonemergency interventions,
education among parents, there research increased sharply with the creation of the Patient-Centered Outcomes like Vit-D-Kids, also excludes a
Research Institute (PCORI).

is a need for heightened atten- usual-care arm, including more

tion to the ethics and appro- NIH funding PCORI funding than 70% of PCORI’s CER trials.

priateness of the trial,” he says, 3000 Natanson says scientific results,

including intensive community patient safety, and the informed
CREDITS: (GRAPHIC N. DESAI/SCIENCE; (DATA PCORI/NIH REPORTER
outreach before recruitment in 2500 consent process all suffer when a
Million dollars (cumulative)
poor or minority populations. 2000 usual-care comparator is absent.
Macklin calls it “surprising— But he acknowledges that trial

if not appalling—that IRBs in 1500 funders and IRBs struggle when
these major U.S. medical centers no bright line differentiates ex-

are willing to approve studies in 1000 perimental interventions from
which disadvantaged children usual care. Making those distinc-

are randomly assigned to a pla- 500 tions can require laborious ob-
cebo group, justified by the ar- servational studies and surveys.

gument that they are not being 0 PCORI itself says usual-care

made worse off than they would 2010 2012 2014 2016 2018 2020 comparators are often important

be if not enrolled in the study.” or necessary. But given frequent

Annas compares Vit-D-Kids to “no-care as as a stamp of approval, Carome adds. challenges in defining standard practice,

usual care” trials in resource-poor nations, Critics of Vit-D-Kids say the study, though the group actively discourages usual-care

such as NIH-funded trials in African nations an extreme case, also points to troubling arms—“unless they represent legitimate and

in the 1990s. In pregnant women, the antiviral trends amid an explosion of comparative ef- coherent clinical options.” That’s an abdica-

zidovudine, also known as AZT, was tested fectiveness research (CER) trials, which ex- tion, Natanson says. “It’s much easier to say,

against a placebo to see whether it blocked amine the benefits and harms of treatments. ‘I have two ideas, two strategies.’ … It’s much

mother-to-child HIV transmission. The drug U.S. funding for CER clinical trials and re- more difficult to say, ‘What is usual care?

was already the standard of care during preg- lated trial support rocketed from an annual How is it practiced? How can I design the

nancy for HIV-infected women elsewhere. average of about $34 million between 2009 trial so that … at least one arm is receiving

Washington said she was dismayed to and 2011 to $284 million since then—largely usual care?’”

learn the trial protocol and consent forms because of the government-created nonprofit A real-world benchmark can be essential

prominently discussed analyzing kids’ genes Patient-Centered Outcomes Research Insti- to evidence-based medicine—whether a trial

for clues connecting low vitamin D to asthma tute (PCORI), which specializes in assessing examines oxygen levels for preemies or vi-

but glossed over obvious inner-city risk fac- treatments side by side. tamin D for asthmatic kids, Natanson adds.

tors such as air pollution, stress, and poverty, Meanwhile, criticisms of such studies have “It’s just common sense. Why study two

which could also lead to vitamin deficiency mounted. In 2018 Public Citizen challenged things inside of a trial that nobody does out-

and asthma. The hunt for genetic explana- what it called “reckless” flaws in an NIH- side of the trial?” j

tions above social linkages “reinforces the backed study of treatments for septic shock, a

belief that … biological dimorphism drives a life-threatening effect of infection. The group This story was supported by the Science Fund for

lot of illnesses,” she says. “It’s unethical. It’s said the trial randomly assigned subjects to Investigative Reporting.

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INSIGHTS

PERSPECTIVES

ASTRONOMY ILLUSTRATION: ESA/HUBBLE, M. KORNMESSER/CC BY 4.0

How massive is that black hole?

The flux of radiation emissions from accretion disks correlates with black hole mass

By Paulina Lira1 and Patricia Arevalo2 times that of the Sun (1). It’s not clear how describe a method to make this determina-
such an entity arises. It could be the result tion on the basis of radiation emissions from
A black hole is a point in space that is a of the merger of smaller black holes or the the accretion disks of SMBHs. The approach
cosmic sink—the gravitational attrac- collapse of either a stellar cluster or large also shows a connection between SMBHs
tion is so strong that not even light gas clouds. Every large galaxy is thought to and much less massive objects, such as white
can escape. A supermassive black hole contain a SMBH. To understand how they dwarf stars.
(SMBH) is enormous, with a mass arise, we need to know how massive they
on the order of millions to billions of are. On page 789 of this issue, Burke et al. (2) As matter is gravitationally attracted (ac-
creted) toward a massive object, such as a

734 13 AUGUST 2021 • VOL 373 ISSUE 6556 sciencemag.org SCIENCE

An artistic rendering of a as well as angular momentum. Viscosity will the masses of the SMBHs (that were deter-
thin accretion disc circling a allow matter to gradually spiral down and mined by other means) over an impressive
feed the central object. This system is called range from 10,000 to 10 billion solar masses.
supermassive black hole. an accretion disk, and it is the mechanism The damping time scale (of the order of sev-
that feeds growing protostars (3), stars with eral hundreds of days) can only be measured
star or black hole, it cannot fall toward the close binary companions (4, 5), and SMBHs accurately if the lengths of the observations
central body in a straight line unless it was in the center of galaxies (6, 7). Through this are about 10 times longer than the time scale
initially at rest and nothing perturbs its tra- mechanism, it is believed that SMBHs grew itself. This requires dedicated monitoring
jectory. Any deviation from a straight path from small “seeds” in the early Universe to campaigns that track the brightness changes
will force the falling material to start orbit- the colossi observed today. in these sources stretching for many years.
ing the massive object or swing past it and This apparently important restriction is at
leave it behind. Gas that settles into an orbit Accretion disks around SMBHs can be present being overcome by large monitoring
around a massive central object has notable extremely bright because of the high tem- surveys, which are an accumulating time se-
properties: Through viscous interactions of peratures that are reached as the gas slows ries of the luminosity of millions of objects in
its individual particles, it can slow down the down through viscosity. These disks, not the sky, making this method applicable on a
falling speed and dissipate this kinetic energy much larger than the Solar System, can out- massive scale.
shine the whole galaxy that hosts them, in
1Department of Astronomy, Faculty of Physical and the optical, ultraviolet, and x-ray regions of As with the general SMBH flux variability,
Mathematical Science, University of Chile, Santiago, Chile. the electromagnetic spectrum. It is there- researchers have been struggling to interpret
2Department of Physics and Astronomy, University of fore at these wavelengths that astronomers the meaning of this damping time scale. The
Valparaiso, Valparaiso, Chile. Email: [email protected]; can study the accretion processes and de- findings of Burke et al. indicate that correla-
[email protected] termine the properties of the disks and of tion of this time scale with physical proper-
their central SMBHs. ties such as the mass of the SMBH should
provide further insight on the nature of both
Methods to measure the mass of a SMBH phenomena. As Burke et al. propose, other
are often indirect, such as scaling relations properties will likely play a role in determin-
with large-scale properties of their host gal- ing the time scales of the fluctuations, such as
axies (8, 9). Also, methods used now often the rate at which mass has been transferred
can only be applied to the nearest objects to the SMBH by the accretion disk and the
(about tens of megaparsecs from Earth) (10), SMBH spin, which determines the innermost
require very special conditions (such as hav- radius of the disk (14).
ing very dense disks of molecular gas orbiting
the black hole and positioned exactly edge- One of the most interesting aspects of
on as seen from Earth) (11), or require large the study of Burke et al. is that it extends its
amounts of telescope time (12). It also can findings to much less massive objects, such
be difficult to apply these methods to fainter as white dwarf stars, which emit radiation
accretion disks. Thus, new methods to deter- through a similar accretion disk mechanism
mine SMBH masses are very much needed. and can be regarded as miniature accreting
SMBHs. The authors found that stellar black
Burke et al. present a new method to holes and SMBHs follow almost the same
determine the mass of SMBHs by examin- damping time scale–mass relation. That the
ing the temporal variations of the emission same relation extends through many orders
from their accretion disks. Because accre- of magnitude suggests that the physics of ac-
tion disks are small and extremely ener- cretion disks is, at least in some aspects, scal-
getic, they are prone to instabilities that able and proves that the variations that we
change the amount of radiation that they see are indeed produced intrinsically by the
produce in a stochastic manner, a trade- accretion process. j
mark that has been known since the discov-
ery of the so-called quasars (very energetic REFERENCES AND NOTES
and distant accreting SMBHs) (13). The sto-
chasticity of the variable emission makes it 1. Event Horizon Telescope Collaboration et al., Astrophys.
difficult to isolate characteristic time scales J. 875, L1 (2019).
of an accretion disk, such as a particular
time associated with the orbital periods or 2. C.J. Burke et al., Science 373, 789 (2021).
any other “beat” signal from the structure 3. R. Cesaroni, D. Galli, G. Lodato, C. M.Walmsley, Q.Zhang,
of the disk (such as density waves or an or-
biting hot spot in the disk that creates a pe- in Protostars and Planets,V. B. Reipurth et al., Eds. (Univ.
riodic luminosity change). The exact nature Arizona Press, 2007), p. 197–212.
of the observed variations is not well under- 4. K. Mukai, Publ.Astron. Soc. Pac. 129, 062001 (2017).
stood and is an area of very active research. 5. C. Done, M. Gierlinski,A. Kubota, Astron.Astrophys. Rev.
15, 1 (2007).
The method presented by Burke et al. uses 6. A. Koratkar, O. Blaes, Publ.Astron. Soc. Pac. 111, 1 (1999).
the flux variability in radiation emission of 7. M. Giustini, D. Proga, Astron.Astrophys. Rev. 630,A94
67 well-observed accreting SMBHs to deter- (2019).
mine the time scale—days, weeks, months, 8. K. Gebhardt et al. Astrophys.J. 539, L13 (2000).
or years—on which the fluctuations become 9. L. Ferrarese, D. Merritt, Astrophys.J. 539, L9 (2000).
noticeably smaller. They found that this 10. L. Ferrarese, H. Ford, Space Sci. Rev. 116, 523 (2005).
“damping” time scale correlates well with 11. M. Miyoshi et al., Nature 373, 127 (1995).
12. B. M. Peterson et al., Astrophys.J. 613, 682 (2004).
13. H.J. Smith, D. Hoffleit, Astron.J. 68, 292 (1963).
14. C.W. Misner, K. S.Thorne,J.A.Wheeler, Gravitation
(Princeton Univ. Press, 1973).

10.1126/science.abk3451

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PA L E O N T O L O GY

When did terrestrial plants arise?

Microfossils suggest that co-option of algal genes may affect land plant origination time

By Patricia G. Gensel to the Ordovician Period (485 to 443 Ma) embryophyte or charophyte algal walls, but

(3)—bolster the macrofossil record of time not that of chlorophyte algal spores. The

E mbryophytes—or land plants—are of embryophyte origin. Recognizing which discovery of cryptophytes (5), which are
fundamental to life on Earth and in- cryptospores represent embryophytes or millimeter-sized axial, sporangiate plants
fluence systems that include carbon aeroterrestrial streptophytic algae is of- producing cryptospore dyads and tetrads,
cycling, sedimentation rates, and rock ten difficult, but criteria are emerging (3). from late Silurian to earliest Devonian,
weathering (1, 2). Although much Cryptospore data from the Early Paleozoic indicates that at least some represent the

is known about their probable mid- (about 540 Ma) suggest the presence of em- spores of embryophytes.

Ordovician appearance [about 450 million bryophytes in the Mid-Ordovician. Other evidence supporting microfossil-

years ago (Ma)] (3) and later diversification Understanding phylogenetic relation- based estimates of origination includes

on the basis of fossils from late Silurian and ships of land plants and their close relatives a presumed remnant of a sporangium (a

Early Devonian periods (about 420 Ma) (4, is as important as the analysis of aeroterres- structure containing spores) from the Late

5), the time of their origination has Ordovician (12). Comparable cryp-

been unclear. This knowledge is tospore morphologies and ultra-

important when considering geo- Phylogenetic relationships within structure from some late Silurian
logical processes and evolution- the green plant clade and earliest Devonian plants and
ary interactions. There has been in a few extant bryophytes (non-
a discrepancy in the time of land Recent genomic studies find certain streptophytic algae (part of the vascular embryophytes) strength-
plant origination between molecu- “charophytes” grade) as close sisters to land plants (embryophytes). Some ens the argument that some dyads
lar clock estimations (based on streptophytic algae are land-dwelling (aeroterrestrial) or have and tetrads represent spores of the
genes and RNA) and fossil record characteristics that allowed adaptation to aerial or subaerial environments. earliest plants.

estimates (based on morphology). Viridiplantae (green plants) Bower (13) postulated a stepwise
On page 792 of this issue, Strother Streptophyta acquisition of characteristics or
and Foster (6) describe fossilized adaptations leading to land plants

spores whose characteristics raise Embryophyta (Kingdom Plantae sensu stricto) and argues for the development of

the possibility that land plants Zygnematophyceae the walled spore before evolving

arose by co-opting algal genes, Coleochaetophyceae a sporophyte plant body. This in-

along with acquiring de novo Charophyceae “Charophytes” volves the deposition of sporopol-
genes, and that the former would Klebsormidiophyceae lenin onto the meiotic products

account for the molecular clock Mesotigmatophyceae or spores of an “ancestral plant”
predating the fossil record. (possibly aeroterrestrial strepto-

Molecular clock estimates (7, phytic algae) (3). Sporopollenin,

8) suggest that embryophytes a polymer that coats spore walls

have existed since the Late Pre- Chlorophyta in terrestrial plants (and possibly

cambrian (about 600 to 550 Ma), cryptospore walls), is deemed im-

whereas the earliest macrofossil of portant for their survival in aerial

a vascular plant is from the mid- Prasinodermophyta or subaerial conditions. Other

late Silurian (420 Ma). Molecular changes leading to the rise of land

studies indicate that the closest Glaucophyta plants would include a delay in
sister lineage to embryophytes is meiosis and mitotic division of

certain streptophytic green algae nuclei or cells, resulting in either

(Charophytes) (see the figure). Rhodophyta multinucleated cells or multiple

Some charophytes are aeroterres- cells or cells within the fertilized

trial—they live on land and share egg (zygote). Loss of meiosis (ster-

some ultrastructural and biochemical fea- trial streptophytic algae characteristics. The ilization) of some of those nuclei or cells

tures with embryophytes. The Streptophyta various configurations of spores are consis- would ultimately lead to producing an em-

and Chlorophyta (chlorophytic green algae) tent with a highly variable cytoskeletal ar- bryo and multicellular sporophyte and spo-

form the clade called Viridiplantae (“green chitecture (11). Until the Mid-Ordovician, rangia, as are now found in land plants (3).

plants”) and are part of the Archaeplastida cryptospore tetrads and dyads or groups of Again, the cryptospore record of the Earlier

(Kingdom Plantae sensu lato) in the tree of them are morphologically similar to later- Paleozoic is consistent with this scenario. GRAPHIC: N. DESAI/SCIENCE

life (9, 10). occurring ones but form very irregularly Whereas a clear distinction exists be-

Assemblages of microfossils called crypto- arranged tetrads or dyads (3). From the tween the highly variable groupings of

spores—from the Cambrian (581 to 485 Ma) Mid-Ordovician, they were very regularly cryptospores from the Cambrian to Mid-

arranged, suggesting canalization of mei- Ordovician period (as algal) and those

Biology Department, University of North Carolina, Chapel otic processes (11). The ultrastructure of the after this period (as nonalgal), Strother
Hill, NC 27599, USA. Email: [email protected] cryptospore wall resembles that of either and Foster present data from the Early

736 13 AUGUST 2021 • VOL 373 ISSUE 6556 sciencemag.org SCIENCE

Ordovician showing co-occurrence of these CANCER
two groups of spores. At first glance, this
appears to support an earlier origination of The cell of origin
plants (14). It also closes the gap between for Barrett’s esophagus
molecular and fossil estimates of the origin
time. However, the authors raise another Undifferentiated cells that closely resemble
possibility on the basis of accepting the fos- gastric cells could be a biomarker for surveillance
sil record and using molecular studies to
build on the idea of stepwise adaptations to By Karen Geboes1 and Anne Hoorens2 epithelium above the GEJ, characterized
land by plants from a probable aeroterres- by a salmon color and coarse texture.
trial streptophytic algae ancestor. Genomic B arrett’s esophagus (BE) is a prema-
studies demonstrate sequences in charo- lignant condition with increased Diagnosis of BE also requires histologi-
phycean algae comparable to those in em- risk for the development of esoph- cal confirmation. Histologically, specialized
bryophytes (9, 10, 15). Strother and Foster ageal adenocarcinoma (EAC). intestinal metaplasia is defined as colum-
propose that portions of the algal genome Surveillance relies on regular en- nar epithelium with the presence of goblet
were co-opted into the plant developmen- doscopy with biopsies to detect cells, which are epithelial cells that secrete
tal genome, along with de novo genes. They dysplasia (disordered cellular growth) mucus and which are normally found in the
further submit that algal-derived genes or and diagnose cancer at an early, treatable intestinal epithelium (4) (see the image).
gene sequences in plants might provide a stage. BE is a metaplastic response at the However, several studies have found a simi-
molecular signal for phylogenetic analyses gastroesophageal boundary to chronic tis- lar risk of progression to dysplasia or EAC
sue injury by acid reflux. Metaplasia is the in patients with and without goblet cells in
“There has been a discrepancy… transformation of one differentiated cell columnar-lined esophagus (4, 5). Indeed,
between molecular clock type to another differentiated cell type: BE the absence of goblet cells may be a conse-
estimations…and fossil record is characterized by replacement of normal quence of sampling error, warranting a new
estimates...” squamous epithelium by columnar epithe- endoscopy. Conversely, goblet cells may de-
lium with gastric and intestinal features. velop both in the distal esophagus and prox-
that underlie molecular clock studies. This The origin of metaplastic columnar cells imal stomach and are histologically and
is as reasonable an explanation for the time is unclear, and different candidate pre- histochemically identical. So, BE, especially
discrepancy as other hypotheses (14). cursor cells have been suggested. Better short segments, may be difficult to diagnose
knowledge about the pathogenesis of BE and monitor. Additionally, although BE is a
Comparison of algal and plant genomes may lead to better diagnosis, stratification, premalignant condition, most patients with
is still in early stages, but considerable in- and treatment, and might help to develop BE will not progress to EAC, and patients
formation already exists (15). It is limited targeted chemopreventive strategies in the with EAC do not always have evidence of BE
by not having fully sequenced genomes or future. On page 760 of this issue, Nowicki- at the time of diagnosis.
transcriptomes from closely related strep- Osuch et al. (1) find good evidence to sup-
tophytes, basal plants such as liverworts or port gastric cells as the origin of BE. The difficulty in determining the cel-
other bryophytes, and basal vascular plants. lular origin of BE is in part due to the
Such data, particularly those relating to Endoscopic surveillance of people with inability to observe the process of meta-
meiosis and spore formation, multicellular- BE to detect dysplasia or EAC is currently plastic conversion in vivo and the lack of
ity, and other features of embryophytes, as recommended (2, 3). However, it can be reliable physiological animal models (6).
well as additional fossil information, are difficult to confidently recognize BE by en- Epigenetic or genetic changes that alter
needed to test these hypotheses further. j doscopy, sampling errors may occur even protein expression, function, and/or ac-
with optimal adherence to surveillance tivity in squamous esophageal cells or in
REFERENCES AND NOTES protocols, there is interobserver variabil- stem or progenitor cells, such that they
ity in evaluating dysplasia, and definitions are reprogrammed to differentiate into co-
1. M. R. Gibling, N. S. Davies, Nat. Geosci. 5, 99 (2012). have been evolving over time and between lumnar cells, are driven by the inflamma-
2. W.J. McMahon, N. S. Davies, Science 359, 1022 (2018). regions. The squamo-columnar junction tory environment created by chronic acid
3. P. K. Strother,W.A.Taylor, in Transformative Paleobotany, (SCJ) is the site of transition between squa- reflux. There have been several proposed
mous epithelium of the esophagus and co- mechanisms for the occurrence of meta-
M. Krings, C.J. Harper, N. R. Cuneo, G.W. Rothwell, Eds. lumnar epithelium of the stomach and co- plasia. Transdifferentiation is the conver-
(Elsevier, 2018), pp. 3–20. incides with the gastroesophageal junction sion of one mature differentiated cell type
4. P. G. Gensel, Fern Gaz. 20, 217 (2017). (GEJ) in a normal esophagus. The gastric to another, without undergoing an inter-
5. D. Edwards,J. L. Morris,J. B. Richardson, P. Kenrick, New cardia (GC) is the part of the stomach just mediate pluripotent state (7). It seems un-
Phytol. 202, 50 (2014). below the GEJ. BE should only be diag- likely that this is the origin of BE because
6. P. K. Strother, C. Foster, Science 373, 792 (2021). nosed when there is a clear endoscopically full phenotypic conversion of cultured ma-
7. J. L. Morris et al., Proc. Natl.Acad. Sci. U.S.A. 115, E2274 visible change from squamous to columnar ture squamous cells has not yet been dem-
(2018). onstrated. Furthermore, the evidence of
8. Y. Nie et al., Syst. Biol. 69, 1 (2020). 1Department of Gastroenterology, Universitair Ziekenhuis new squamous epithelium, which develops
9. L. Li et al., Nat. Ecol. Evol. 4, 1220 (2020). Gent, Gent, Belgium. 2Department of Pathology, after endoscopic removal of BE, weakens
10. S.Wang et al., Commun. Biol. 4, 412 (2021). Universitair Ziekenhuis Gent, Gent, Belgium. the theory of transdifferentiation.
11. R. C. Brown, B. E. Lemmon, New Phytol. 190, 875 (2011). Email: [email protected]
12. C. H.Wellman, P. L. Osterloff, U. Mohiuddin, Nature 425, Another theory suggests that the meta-
282 (2003). plastic epithelium arises from a change
13. F. O. Bower, The Origin of a Land Plant: ATheory Based on
the Facts of Alternation (Macmillan, 1908).
14. T. Servais et al., Palaeogeogr. Palaeoclimatol. Palaeoecol.
534, 109280 (2019).
15. S.Wang et al., Nat. Plants 6, 95 (2020).

10.1126/science.abl5297

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INSIGHTS | PERSPECTIVES

in the commitment of pluripotent stem was suggested (10) that surveillance defi- M E TA B O L I S M
cells that are responsible for the constant nitions may need to be altered, if SPEM is
refreshing of the esophageal epithelium the precursor lesion and in itself possesses Taking the
(8). Transcommitment starts with repro- malignant transformation potential. long view on
gramming immature progenitor cells that metabolism
subsequently differentiate into another Indeed, because identification of BE and
cell type. Whether the cells of origin are surveillance for EAC have their limitations, Measured energy
esophageal progenitor cells, progenitor a better understanding of the cell of origin expenditure across the
cells in the esophageal submucosal glands, and the processes involved in metaplas- human life span reveals
proximally shifting progenitor cells from tic progression will hopefully allow the distinct metabolic phases
the GC, residual embryonic cells at the SCJ, identification of biomarkers for EAC. It is
or circulating bone marrow–derived stem therefore important that Nowicki-Osuch et
cells, the cells at the origin of BE would al. found EAC to express markers of undif-
have to undergo molecular reprogram- ferentiated BE cells, even when no BE was
ming that leads to a change in the cells’ visible. Again, this may point to a specific
phenotypic commitment (8, 9). precursor lesion with malignant transfor-
mation potential: If it can be confirmed
Nowicki-Osuch et al. analyzed freshly that undifferentiated BE cells exist in EAC,

By Timothy W. Rhoads1 and
Rozalyn M. Anderson1,2

This hematoxylin and eosin stain of Barrett’s esophagus shows the metaplastic change from squamous M etabolism is not just about en-
epithelium to columnar epithelium with goblet cells, which are normally found in the intestinal epithelium. ergy—how the body handles nutri-
ent fuel and converts it to useable
isolated human cells from superficial independent of the presence of metapla- energetic currency. Metabolism PHOTO: LIZHE ZHUANG
and submucosal compartments from the also encompasses synthesis, modi-
esophagus, GEJ, and GC of both healthy sia, this could lead to a drastic switch in fication, and exchange of the build-
individuals and patients. They performed ing blocks for all aspects of cellular func-
comprehensive phenotyping and multi- screening programs, whereby greater at- tion and acts as a sensor and regulator of
omic profiling of different epithelial cell cellular activities, in which individual moi-
types in normal esophagus, gastric epithe- tention is paid to detection of reflux and eties within metabolic pathways influence
lium, BE, and EAC. An undifferentiated BE cellular responses. A substantial amount of
cell type was identified that showed expres- resulting molecular changes instead of de- the energy taken in each day is required to
sion of markers of intestinal and BE stem simply sustain life; the energetic demands
cells, and it was found that BE cells most tection of BE. j of physical activity are superimposed on
closely resembled GC cells. The similarities a vastly integrated machinery. Metabolic
between GC and BE cells do not prove cau- REFERENCES AND NOTES status has been linked to innumerable dis-
sality. However, the findings of Nowicki- eases and disorders, including those most
Osuch et al. add to the evidence of shared 1. K. Nowicki-Osuch et al., Science 373, 760 (2021). prevalent with age (1–3). On page 808 of
features between BE and metaplasia in 2. P. Sharma et al., Gastroenterology 131, 1392 (2006). this issue, Pontzer et al. (4) analyze en-
the stomach. It has been proposed before 3. J. R.Triggs, G.W. Falk, Gastrointest. Endosc. Clin. N.Am. ergy expenditure in more than 6400 males
that a spasmolytic polypeptide–expressing and females from 29 countries across the
metaplasia (SPEM) precursor may account 31, 59 (2021). globe, aged between 8 days and 95 years,
for the proposed “gastric origin” (goblet) 4. W. M.Weinstein,A. F. Ippoliti, Gastrointest. Endosc. 44, and show distinct metabolic phases during
cell that migrates up from the stomach development and aging.
into the esophagus (10). Consequently, it 91 (1996).
5. N.Vakil, S.V. van Zanten, P. Kahrilas,J. Dent, R.Jones, An understanding of energy expenditure
across the life span must grapple with the
Am.J. Gastroenterol. 101, 1900 (2006). diversity of humans, including sex, race,
6. B.V. Naini, R. F. Souza, R. D. Odze, Am.J. Surg. Pathol. 40, body composition, and their environment.
Estimates of energy expenditure can be
45 (2016). captured with indirect calorimetry that
7. D. H.Wang, Cell. Mol. Gastroenterol. Hepatol. 4, 157 measures gas exchange and heat produc-
tion of sequestered individuals, or by the
(2017). doubly labeled water (DLW) method in
8. D. H.Wang, R. F. Souza, Adv. Exp. Med. Biol. 908, 183 free living individuals. The DLW technique
is based on the relative bodily elimination
(2016). rates of isotopes of oxygen and hydrogen
9. J. Que, K. S. Garman, R. F. Souza, S.J. Spechler, (5). In the time since methods were devel-
oped for application in humans (6), the
Gastroenterology 157, 349 (2019).
10. R. U.Jin,J. C. Mills, Dig. Dis. Sci. 63, 2028 (2018). 1Department of Medicine, School of Medicine and Public
Health, University of Wisconsin-Madison; Madison, WI, USA.
10.1126/science.abj9797 2Geriatric Research, Education, and Clinical Center, William
S. Middleton Memorial Veterans Hospital; Madison, WI, USA.
Email: [email protected]

738 13 AUGUST 2021 • VOL 373 ISSUE 6556 sciencemag.org SCIENCE

use of DLW has been steadily growing. indicate that life stage needs to be care- fat-free mass, this study peels some of this

Associated costs of isotope dosing have fully considered when choosing disease variance away to reveal intrinsic shifts in

limited most studies to relatively small models. This is particularly important for metabolism that are matched to life phase.

cohorts, but there has been commitment research on the etiology of age-associated There is considerable heterogeneity in

among the research community to share diseases and disorders (10). Pathways and how and when aging manifests in terms of

data and to develop integrative methods factors that are readily targetable in young disease incidence (13). It would be inter-

so that large-cohort data analysis might be growing animals may not be as sensitive esting to explore how mid-life disposition

undertaken (7). or even responsive in older animals, and informs outcomes in advanced age and

In the study of Pontzer et al., energy ex- young models fail to capture the aged en- how well disease burden among individu-

penditure was adjusted to fat-free mass to vironment and may miss interactions that als links to age-associated changes in their

account for differences in body size, reveal- emerge as a result of intrinsic differences tissue-specific metabolism.

ing intrinsic shifts in metabolic status over in metabolic status. The causal factors in age-related vulner-

the course of development, maturation, The impact of body size on metabolic ability to disease no doubt reside in the

and aging. The authors identify inflection rate has been discussed and explored for documented changes in cellular biology,

points that are the boundaries for four dis- decades (11). Total energy expenditure tissue physiology, and systemic homeo-

tinct phases. It seems clear from their data is sex dimorphic, with lower levels in fe- stasis. Studies of laboratory animals have

that infants and adolescents form two dif- males than in males; however, accounting honed in on metabolism as a central theme

ferent metabolic categories. It in aging and in delayed aging

has been said before, but chil- “Pathways and factors that are readily targetable in through caloric restriction
dren are not just small adults (14). Differences in metabolism
are predicted to affect deriva-
(8). That young people repre- young growing animals may not be as sensitive or tion of energy from nutrient
sent separate metabolic status sources, foundational material
categories has important impli- even responsive in older animals,and young models

cations for recommendations fail to capture the aged environment...” for synthesis of cellular ma-
about diet and physical activ- chinery and communication

ity, not to mention pharmaceu- relays, and the ability to opti-

tical dose recommendations for younger for fat-free mass removes this distinction. mize cellular activities according to pre-

persons. The remaining two phases cover It is important that contributions from vailing conditions, whether external or in-

adulthood and advanced age. Adjusted en- physical activity and tissue-specific meta- ternal. It will come as no surprise then that

ergy expenditure is notably stable from 20 bolic rates, both of which change over the recent efforts to identify pharmacological

years of age up to about 60 years of age, at human life span, must be accounted for agents that positively affect health in aging

which point a gradual decline is observed if computational models are to fit the ob- converge on metabolism (15). The Pontzer

(see the figure). served data. Although not the focus of the et al. study provides important new in-

The decline from age 60 is thought to work, Pontzer et al. identified substantial sights into human metabolism; the un-

reflect a change in tissue-specific me- heterogeneity in body composition among precedented scale and scope of the study is

tabolism, the energy expended on main- individuals. Challenges arising from het- matched by the outstanding collaborative

tenance. It cannot be a coincidence that erogeneity among individuals are reflected spirit that made it possible. j

the increase in incidence of noncommu- in the growing enthusiasm for precision REFERENCES AND NOTES
nicable diseases and disorders begins in medicine (12). It is abundantly clear that
this same time frame (9). These findings one size does not fit all. By adjusting for 1. N. N. Pavlova, C. B.Thompson, Cell Metab. 23,
27 (2016).

2. S. Costantino, F. Paneni, F. Cosentino, J. Physiol. 594,

2061 (2016).

Life span of metabolism 3. S. Camandola, M. P. Mattson, EMBO J. 36, 1474 (2017).
4. H. Pontzer et al., Science 373, 808 (2021).
Measures of energy expenditure (adjusted for fat-free mass) identify three inflection points over the human 5. J. R. Speakman, Am.J. Clin. Nutr. 68, 932S (1998).
life span. Energy expenditure increases during infancy and childhood and then declines through adolescence, 6. D.A. Schoeller, J. Nutr. 118, 1278 (1988).

a plateau phase lasts throughout adulthood, and a second declining phase occurs from 60 years of age. The 7. J. R. Speakman et al., Cell Rep. Med. 2, 100203 (2021).
marked rise in incidence of chronic disease from late middle age aligns with the shift in energy expenditure and 8. P. F. Saint-Maurice,Y. Kim, G.J.Welk, G.A. Gaesser, Eur.J.
loss of adiposity, suggesting that metabolism may be a driver in aging biology.
Appl. Physiol. 116, 29 (2016).
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(2018).

10. B. K. Kennedy et al., Cell 159, 709 (2014).

11. M. Kleiber, Physiol. Rev. 27, 511 (1947).

12. M.A. Haendel, C. G. Chute, P. N. Robinson, N. Engl.J. Med.

379, 1452 (2018).

13. D.J. Lowsky, S.J. Olshansky,J. Bhattacharya, D. P.

Goldman, J. Gerontol.A Biol. Sci. Med. Sci. 69, 640

(2014).

14. P. Balasubramanian, P. R. Howell, R. M.Anderson,

EBioMedicine 21, 37 (2017).

15. L. Partridge, M. Fuentealba, B. K. Kennedy, Nat. Rev. Drug

GRAPHIC: A. MASTIN/SCIENCE Discov. 19, 513 (2020).

ACKNOWLEDGMENTS

T.W.R. and R.M.A. are supported by NIH/NIA grants
AG040178,AG057408, and AG067330; the Department for
Veterans Affairs BX003846; and the Simons Foundation.

Adjusted energy expenditure Adiposity Chronic disease incidence Inflection point 10.1126/science.abl4537

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INSIGHTS | PERSPECTIVES

MEDICINE

Plant-made vaccines and therapeutics

Advances in technology and manufacturing could boost the uptake of molecular farming

By Hugues Fausther-Bovendo1 antibodies. Transient transfection systems alleviated this concern. In these large phase
and Gary Kobinger1,2 have also increased the production speed, 3 clinical trials, involving more than 20,000
with harvest possible within days after adults aged 18 to 94 years, a mixture of four
T herapeutic proteins such as vaccines, transfection of adult plants as opposed to separate VLPs, each containing the hemag-
antibodies, hormones, and cytokines months when stable expression was sought. glutinin proteins from a selected seasonal
are generally produced in bacteria or The production speed of molecular farming influenza virus strain, produced in tobacco
eukaryotic systems, including chicken is a critical asset. Indeed, plant-produced plants, have shown efficacy similar to that
eggs and mammalian or insect cell vaccines can readily be made against new of existing influenza vaccines (2). Notably,
cultures, with high production yield pathogens or emerging strains, with the immunization with this quadrivalent VLP
according to well-defined regulatory guide- first batch of vaccine candidates typically formulation was not associated with more
lines (1). The use of plants for the produc- produced within 3 weeks (3). The speed of adverse events or an increase in hypersen-
tion of therapeutic proteins, called molecu- molecular farming is particularly suited for sitivity reactions compared with individuals
lar farming, was proposed as an alternative personalized medicine in which pharma- receiving a licensed influenza virus vaccine.
biomanufacturing method in 1986. The first ceuticals need to be tailored to individual
and only plant-derived therapeutic protein patients, such as for cancer treatment (4). The plant-made vaccines against influ-
for human use was approved in 2012 for enza virus and SARS-CoV-2 are expected to
the treatment of Gaucher disease. In 2019, Constructing facilities capable of pu- be the first therapeutic proteins produced
a plant-produced influenza virus vaccine rifying therapeutic proteins produced in in whole plants for human use. The glu-
completed phase 3 clinical trials, with en- plants under good manufacturing practice cocerebrosidase enzyme, produced as an
couraging results (2). More recently, phase (GMP)–compliant conditions has also sup- injectable protein drug called taliglucerase
3 trials for an adjuvanted plant-made vac- ported clinical evaluation of plant-made alfa for the treatment of Gaucher disease,
cine (CoVLP) against severe acute respira- vaccines and therapeutics (5, 6). Moreover, is produced in a carrot cell culture rather
tory syndrome coronavirus 2 (SARS-CoV-2) the simplicity and low costs associated with than in actual plants (8). Several plant-
(NCT04636697) began in March 2021. These plant growth are an advantage, whereas ex- produced veterinary vaccines have also
successes have revived interest in plant- pensive GMP facilities are required for the been developed, and one is approved by
produced pharmaceuticals for human use, extraction, purification, and fill processes of the US Department of Agriculture for im-
which could include edible drugs. molecular farming. By contrast, the lower munization of chickens against Newcastle
yield, limited regulatory guidelines avail- disease. However, there is competition to
Molecular farming was initially pro- able, and limited manufacturing capacity reduce the selling price of farm animals, so
posed because growing plants only requires worldwide have dampened enthusiasm to- the cost of plant-made veterinary vaccines
light, water, and soil (or artificial support). ward molecular farming (1). needs to be substantially reduced to ensure
Procurement of greenhouses is cheaper than their widespread adoption (5).
bioreactor suites, which are required for bac- For vaccine purposes, plant-produced
terial, mammalian, and insect cell culture proteins have several advantages over their Although the increased immunogenicity
systems, making molecular farming par- counterparts produced in bacterial, mam- of plant-made protein is beneficial for vac-
ticularly attractive for developing countries. malian, or insect systems. Unlike bacte- cines, it can be detrimental for therapeutic
Furthermore, production can be scaled up or ria, plants are capable of posttranslational proteins, potentially reducing their in vivo
down based on the number of plants grown. modifications. Plants express different gly- efficacy and contributing to adverse events.
Additionally, unlike in the traditional pro- cans, which renders plant-derived proteins Despite these limitations, monoclonal an-
duction systems, zoonotic pathogens are un- more immunogenic than their mammalian tibodies against HIV (NCT01403792) and
able to infect plants and therefore cannot be counterparts (7). In plant-made vaccines, Ebola virus (NCT02363322, NCT02363322)
a source of contaminant in molecular farm- virus-like particles (VLPs) are produced that have reached clinical stages of development.
ing–derived products. comprise the target pathogen’s protein(s) of In human trials, intravenous (Ebola virus) or
interest (the immunogen) and plant compo- intravaginal (HIV) administrations of these
Technological progress, such as codon op- nents within the particles. These plant com- antibodies were generally well tolerated.
timization, the inclusion of organelle-spe- ponents of VLPs, such as lectins, glycans, Mild adverse events, such as hypotension and
cific promoters, humanization of N-glycans, saponins, and heat shock proteins, have fever, were observed following intravenous
and transient transfection systems, has in- adjuvant properties (7) that can further po- delivery (9, 10). Life-threatening reactions,
creased the performance of molecular farm- tentiate the immune response against plant- such as anaphylactic shock, have only been
ing, with yields above 1 mg/g of fresh plant made vaccines and may reduce the need for reported in a single recipient of 238 treated
weight. In comparison, yields between 5 and adjuvants in vaccine formulation. with antibodies against HIV or Ebola virus
20 g/liter are commonly reached in mam- (10, 11). The administration of antihistamine
malian Chinese hamster ovary cell cultures This increased immune stimulation may and antipyretic (fever-reducing) agents be-
that are used to manufacture monoclonal lead to hypersensitivity (allergic reactions) fore intravenous infusion of plant-produced
toward plant components. However, several pharmaceuticals has mitigated the occur-
1Faculty of Medicine, Université Laval, Quebec, QC, Canada. clinical trials, including phase 1 trials for rence of severe adverse events (11).
2Galveston National Laboratory, Galveston, TX, USA. CoVLP (NCT04450004) and phase 3 trials
Email: [email protected] for plant-made vaccines against influenza The use of plants engineered to express hu-
virus (NCT03301051, NCT03739112), have man glycans also reduces the immunogenic-

740 13 AUGUST 2021 • VOL 373 ISSUE 6556 sciencemag.org SCIENCE

ity of plant-made proteins. It is worth noting ously facilitating their administration. ible plant-made vaccines could now generate
that independently of the production system, The use of edible plants such as cereal meaningful immune responses. The use of
the intravenous injection of grams of antibod- edible plant vaccines in prime-boost immu-
ies is associated with some adverse events, crops, tomatoes, corn, and rice is under de- nization regimens, with an injectable vaccine
which are observed even with antibodies velopment for oral delivery of plant-made as a prime and an edible vaccine as a booster,
produced in mammalian cells. Another hur- therapeutic proteins (12). Parenteral admin- has also been investigated to improve the
dle for plant-made monoclonal antibodies is istration of tumor necrosis factor (TNF) an- clinical relevance of plant-produced oral vac-
limited manufacturing capacity. Unlike vac- tagonists is used for treating autoimmune cines against poliovirus (12, 14, 15). However,
cines, monoclonal antibody regimens usually diseases such as rheumatoid arthritis. In a further optimization is required before clini-
require larger doses (50 to 150 mg/kg) and phase 1 clinical trial, oral administration cal acceptance of these vaccine candidates
sometimes with repeated administrations. To of lyophilized tobacco plant–derived cells (14). Ensuring that edible plant-made vac-
achieve the required scale of plant-made an- expressing a TNF antagonist was safe and cines do not lead to hypersensitivity against
tibodies, a substantial expansion of current increased the amount of immunosuppres- the plant used for production is crucial, espe-
manufacturing capacity, which is currently sive regulatory T cells (Tregs) in human vol- cially plants that are widely consumed such
limited to less than 15 GMP facilities world- unteers, demonstrating the feasibility of as rice, cereals, and corn (see the figure).
wide, is required. Funding opportunities, this approach (13). In addition to reducing
similar to that of the US Defense Advanced adverse events, the oral route can favor the The plant-made quadrivalent VLP influ-
Research Projects Agency (DARPA), which fi- induction of tolerance to suppress autoim- enza vaccine will likely be licensed for use,
nanced the development of three large GMP mune or allergic responses. To date, the in- given the favorable outcome of the phase 3
facilities for the production of plant-made duction of tolerance by using recombinant clinical trials. Ongoing clinical development
vaccines in the US, are needed (5). proteins within edible plants is restricted to will continue to inform regulatory guide-
animal models of hypersensitivity or autoim- lines for plant-made therapeutic proteins.
However, because doses for therapeutics are
Molecular farming much higher than for vaccines, investment
in manufacturing infrastructure must in-
Using transient expression systems, plant-made vaccine and therapeutic proteins can be produced crease and production costs need to further
within weeks. For oral administration, edible plants that express therapeutic proteins require minimal decrease to achieve large-scale manufactur-
processing after harvest. By combining the reduced cost and ease of administering edible vaccines or ing of plant therapeutic products. Until then,
therapeutic proteins with the speed of transient expression systems, molecular farming could have a the speed of molecular farming will be useful
considerable impact on both human and animal health. for preclinical and early clinical evaluation of
therapeutic candidates. Edible, plant-made
Pharmaceutical products therapeutics are still predominantly in the
(for humans or farm animals) preclinical stage of development but, if suc-
cessful, could create new classes of pharma-
Antibodies Hormones Stable expression Extraction of ceutical products. Manufacturing of pharma-
or cytokines Nuclear DNA product ceutical proteins may remain dominated by
editing Labor-intensive current production systems until economic
Chloroplast processing and attractiveness through easy manufacture and
DNA editing purification technological progress, such as potent edible
plant-made therapeutics, shifts the balance
Transient expression Edible plants toward molecular farming. j
Viral vector Minimal
Agrobacterium processing, REFERENCES AND NOTES
dehydration
1. S. Schillberg, N. Raven, H. Spiegel, S. Rasche, M. Buntru,
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GRAPHIC: C. BICKEL/SCIENCE Oral administration of drugs is a user- munity. However, this could provide low-cost 2. B.J.Ward et al., Lancet 396, 1491 (2020).
friendly alternative to the intravenous route. and simple solutions to better manage and 3. F. Sainsbury, Curr. Opin. Biotechnol. 61, 110 (2020).
Furthermore, oral administration can miti- prevent the growing incidence of allergies to 4. U. Sahin, Ö.Türeci, Science 359, 1355 (2018).
gate the adverse events associated with in- common substances (12, 14). 5. N.Takeyama, H. Kiyono,Y.Yuki, Ther.Adv.Vaccines 3, 139
travenous administration of pharmaceuti-
cals. Gut immune responses are crucial for Edible vaccines are also under devel- (2015).
tolerance to food and self-antigens and play opment. The safety and feasibility of this 6. B. Shanmugaraj, C.J. I. Bulaon,W. Phoolcharoen, Plants
an important role in ensuring a balanced approach were demonstrated in proof-of-
immune system (12). Moreover, most phar- concept phase 1 clinical trials, to monitor the 9, 1 (2020).
maceutical proteins currently under clinical safety and immunogenicity of edible vaccine 7. V.A. Sander, M. G. Corigliano, M. Clemente, Front.Vet.
evaluation are purified before parenteral in- candidates against Escherichia coli, hepati-
jections. Given orally, plant-made therapeu- tis B virus, rabies lyssavirus, and norovirus, Sci. 6, 20 (2019).
tics might only require minimal processing, which occurred between 1998 and 2004. In 8. A.Zimran et al., Am.J. Hematol. 91, 656 (2016).
thus possibly skipping expensive and time- these trials, the proportion of immunized 9. J. K. C. Ma et al., Plant Biotechnol.J. 13, 1106 (2015).
consuming steps in the manufacturing pro- individuals who generated an immune re- 10. S. Mulangu et al., N. Engl.J. Med. 381, 2293 (2019).
cess. Products for oral delivery can also be sponse against the desired target was disap- 11. PREVAIL II Writing Group, N. Engl.J. Med. 375, 1448
stored in lyophilized (dehydrated) form at pointingly lower than in clinical trials involv-
room temperature for an extended period, ing standard vaccines administered via the (2016).
hence sharply reducing both their cost of parenteral route. The yield of recombinant 12. M. Merlin, M. Pezzotti, L.Avesani, Br.J. Clin. Pharmacol.
production and storage while simultane- proteins produced in plants has since in-
creased substantially, suggesting that new ed- 83, 71 (2017).
13. E.Almon et al., J. Immunol. Methods 446, 21 (2017).
14. S. Rosales-Mendoza, R. Nieto-Gómez, Trends

Biotechnol. 36, 1054 (2018).
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ACKNOWLEDGMENTS

The authors are supported by the International Development
Research Centre (109075-001); the Canadian Department
of Foreign Affairs,Trade and Development (BIO-2019-005);
and the Canadian Institutes of Health Research.Thanks to
L.Zeitlin for useful discussions.

10.1126/science.abf5375

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INSIGHTS | PERSPECTIVES

PLANETARY SCIENCE Should a martian biosphere exist, any

Searching for life on Mars biosignatures or biomarkers observed in the
samples from Jezero crater could be wide-
spread elsewhere on Mars and possibly oc-

and its moons cur on the surface of Phobos. Because mar-
tian ejecta has been thoroughly delivered to
Phobos by impact-driven random sampling,

Sample-return missions will look for extraterrestrial the biosignatures and biomarkers that may
be contained in the Phobos regolith could re-

life and biomarkers on Mars and Phobos flect the diversity and evolution of a potential
martian biosphere.

Martian Moons eXploration (MMX), de-

By Ryuki Hyodo and Tomohiro Usui tian ejecta than Deimos. Numerical simula- veloped by the Japan Aerospace Exploration

tions show that >109 kg of martian material Agency, plans to collect a sample of >10 g

T he scientific exploration of Mars over could be uniformly mixed in the regolith of from the Phobos surface and return to Earth
the past several decades has resulted Phobos (the resultant martian fraction is in 2029 (8). Detection of a “fingerprint” of
in increasing evidence that the mar- >1000 parts per million) (5). martian life and SHIGAI should be achiev-
tian surface hosted habitable envi- able through comprehensive comparative
ronments early in its history, as well Even if martian life-forms existed and studies using martian material from the
could survive the transport to Phobos with-

as evidence of the building blocks of out suffering from impact-shock decompo- Phobos surface and samples from Jezero cra-

life in the form of organic molecules (1). sition (with a peak pressure of <5 GPa) (5, ter returned by MMX and MSR, respectively.

Habitats on Mars that could harbor extant 6), the Phobos environment is highly inhos- The MSR samples have the potential to

martian life have been hypothesized, such pitable (7). Phobos does not have air or wa- contain a variety of biomarker molecules

as subsurface environments, caves, and ter, and its surface is constantly bathed in (e.g., lipids, such as hopanoids, sterols, and

ice deposits (2). Mars is currently rec- archaeols, and their diagenetic products)

ognized as a “paleo-habitable” planet, (4). The sample could include modern

reflecting its ancient habitability. Fully living organisms from Jezero crater, if

understanding the evolution of hab- they are present. Of course, MSR could

itability and whether Mars has ever return samples without any evidence

hosted life will be essential to under- of life because of the focus on a single

standing and exploring other extrater- location. A distinct advantage for MMX

restrial habitable environments and po- is the ability to deliver martian materi-

tential life-forms (3). Flagship missions als derived from several regions. The

of multiple space agencies in the 2020s random nature of the crater-forming

will play essential and complementary impacts on Mars statistically delivers all

roles and could finally provide an an- possible martian materials, from sedi-

swer to these long-standing questions. mentary to igneous rocks that cover all

The planned Mars Sample-Return of its geological eras.

(MSR) mission of NASA and the Euro- Mutual international cooperation

pean Space Agency should reveal more on MSR and MMX could answer ques-

about the habitability of Mars by help- Jezero crater on Mars is believed to be the site of an ancient tions such as how martian life, if pres-

ing to determine the geologic evolution lake. The Mars 2020 Perseverance rover aims to collect samples ent, emerged and evolved in time and

of Jezero crater and its surrounding ar- from the crater to analyze for evidence of life. place. If Mars never had life at all,

eas, which are believed to be the site of these missions would then be abso-

an ancient lake (see the photo). The Mars solar and galactic cosmic radiation. This in- lutely vital in unraveling why Mars is life-

2020 Perseverance rover will attempt to col- dicates that martian materials on Phobos’ less and Earth has life. Therefore, the mis-

lect samples that will allow scientists to ex- surface almost certainly do not contain any sions may eventually provide the means to

plore the evolution of Jezero crater and its living microorganisms. decipher the divergent evolutionary paths

habitability over time, as well as samples Instead, there may be dead biosignatures of life on Mars and Earth. j

that may contain evidence of biosignatures. on Phobos, which we have called “SHIGAI” REFERENCES AND NOTES PHOTO: NASA/JPL-CALTECH/MSSS/JHU-APL
A high-priority science objective for MSR (Sterilized and Harshly Irradiated Genes,
returned-sample science is to understand the and Ancient Imprints)—the acronym in 1. J. L. Eigenbrode et al., Science 360, 1096 (2018).
habitability of Mars and look for potential Japanese means “dead remains.” SHIGAI 2. B. L. Carrier et al., Astrobiology 20, 785 (2020).
signs of both extinct and extant life (4). includes any potential microorganisms that 3. B. L. Ehlmann et al., J. Geophys. Res. Planets 121, 1927
could have been alive on Mars and were
Mars is not alone because it has two small recently sterilized during or after the de- (2016).
moons, Phobos and Deimos. Throughout livery to Phobos, and the microorganisms 4. D.W. Beaty et al., Meteorit. Planet. Sci. 54, S3 (2019).
the history of Mars, numerous asteroidal 5. R. Hyodo et al., Sci. Rep. 9, 19833 (2019).
6. L. E. Nyquist et al., Space Sci. Rev. 96, 105 (2001).
7. K. Kurosawa et al., Life Sci. Space Res. 23, 85 (2019).
8. M. Fujimoto, E.J.Tasker, Nat.Astron. 3, 284 (2019).

impacts on Mars have produced martian and biomarkers that had been processed on ACKNOWLEDGMENTS
impact ejecta, and a fraction of the ejected ancient Mars before the delivery to Phobos,
material has been delivered to its moons (5). including potential DNA fragments. The We thank D.W.Beaty,M.Grady,and B.Carrier for comments and
Phobos is closer to Mars, so it has more mar- Mars-moon system is an ideal natural discussions on NASA-ESA MSR science.We thank H.Sugahara,
laboratory for the study of interplanetary M.Fujimoto,K.Kurosawa,and H.Genda for many useful discus-
Japan Aerospace Exploration Agency, Yoshinodai, transport and sustainability of SHIGAI on sions onJapanAerospace ExplorationAgency MMXscience.
Kanagawa 252-5210, Japan. Email: [email protected] airless bodies in the Solar System. This Perspective was constructed through discussions with
them and submitted on their behalf.

10.1126/science.abj1512

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COMPUTER SCIENCE

Making machine learning trustworthy

Safety, transparency, and fairness are essential for high-stakes uses of machine learning

By Birhanu Eshete Attacks can also abuse the input-output One common strategy, called membership

interaction of a model’s prediction inter- inference, enables an adversary to exploit

M achine learning (ML) has advanced face to steal the ML model itself (5, 6). By the differences in a model’s response to
dramatically during the past decade supplying a batch of inputs (for example, members and nonmembers of a training
and continues to achieve impres- publicly available images of traffic signs) dataset (7).
sive human-level performance on and obtaining predictions for each, a model
nontrivial tasks in image, speech, serves as a labeling oracle that enables an In response to these threats to ML mod-
els, the quest for countermeasures is prom-

and text recognition. It is increas- adversary to train a surrogate model that is ising. Research has made progress on de-

ingly powering many high-stake application functionally equivalent to the model. Such tecting poisoning and adversarial inputs to

domains such as autonomous vehicles, self– attacks pose greater risks for ML models limiting what an adversary may learn by

mission-fulfilling drones, intrusion detec- that learn from high-stake data such as in- just interacting with a model to limit the

tion, medical image classifica-

tion, and financial predictions

(1). However, ML must make Adversarial threats to machine learning
several advances before it can
be deployed with confidence in Machine learning models are vulnerable to attacks that degrade model confidentiality and model integrity
domains where it directly affects or that reveal private information.

humans at training and opera- Training data and model under attack Model stealing

tion, in which cases security, pri- Machine learning models can be victims of malicious attacks during training and Model evasion
vacy, safety, and fairness are all deployment. As users submit queries and receive answers through a prediction
essential considerations (1, 2). application programming interface (API), various tactics can steal the model, fool it, Membership
or exploit it to infer sensitive information. inference
The development of a trust-

worthy ML model must build Data Input x
in protections against several poisoning Output y
types of adversarial attacks (see
the figure). An ML model re-

quires training datasets, which Training data Training Model Prediction API User
can be “poisoned” through Adversary

the insertion, modification, or

removal of training samples

with the purpose of influenc- Malicious inputs Classified as
ing the decision boundary of a Data sets can be “poisoned” or
STOP

model to serve the adversary’s models can be fooled. For Input image
intent (3). Poisoning happens example, an adversary can fool
when models learn from crowd- a model of a self-driving car by Misclassified as
sourced data or from inputs putting tiny stickers on a tra c
they receive while in operation, stop sign to cause it to be YIELD
both of which are susceptible interpreted as a yield sign.

to tampering. Adversarially

manipulated inputs can evade Input image Adversarial image

ML models through purposely

crafted inputs called adversarial examples tellectual property and military or national extent of model stealing or membership

(4). For example, in an autonomous vehi- security intelligence. inference attacks (1, 8). One promising ex-

cle, a control model may rely on road-sign When models are trained for predictive ample is the formally rigorous formulation

recognition for its navigation. By placing a analytics on privacy-sensitive data, such as of privacy. The notion of differential pri-

tiny sticker on a stop sign, an adversary can patient clinical data and bank customer vacy promises to an individual who partici-

evade the model to mistakenly recognize transactions, privacy is of paramount im- pates in a dataset that whether your record

the stop sign as a yield sign or a “speed limit portance. Privacy-motivated attacks can belongs to a training dataset of a model or

GRAPHIC: KELLIE HOLOSKI/SCIENCE 45” sign, whereas a human driver would reveal sensitive information contained in not, what an adversary learns about you by

simply ignore the visually nonconsequen- training data through mere interaction interacting with the model is basically the

tial sticker and apply the brakes at the stop with deployed models (7). The root cause same (9).

sign (see the figure). for such attacks is that ML models tend to Beyond technical remedies, the lessons

“memorize” ancillary parts of their training learned from the ML attack-defense arms

Department of Computer and Information Science, data and, at prediction time, inadvertently race provide opportunities to motivate
University of Michigan-Dearborn, Dearborn, MI, USA. divulge identifying details about individu- broader efforts to make ML truly trustwor-
Email: [email protected] als who contributed to the training data. thy in terms of societal needs. Issues include

SCIENCE sciencemag.org 13 AUGUST 2021 • VOL 373 ISSUE 6556 743

INSIGHTS | PERSPECTIVES

how a model “thinks” when it makes deci- room photo with multiple objects), speech inputs (such as augmenting model deci-
sions (transparency) and fairness of an ML processing (voice assistants), and natural sions with explanations). The hope is that
model when it is trained to solve high-stake language processing (machine translation). these regulatory frameworks will eventu-
inference tasks for which bias exists if those The threats and countermeasures proposed ally evolve into ML governance modalities
decisions were made by humans. Making in the context of vision, speech, and text backed by legislation to lead to accountable
meaningful progress toward trustworthy domain hardly translate to one another, of- ML systems in the future.
ML requires an understanding about the ten naturally adversarial domains, such as
connections, and at times tensions, between network intrusion detection and financial- Most critically, there is a dire need for in-
the traditional security and privacy require- fraud detection. sights from diverse scientific communities
ments and the broader issues of transpar- to consider societal norms of what makes
ency, fairness, and ethics when ML is used Another important consideration is the a user confident about using ML for high-
to address human needs. inherent tension between some trustworthi- stake decisions, such as a passenger in a
ness properties. For example, transparency self-driving car, a bank customer accepting
Several worrisome instances of biases in and privacy are often conflicting because if investment recommendations by a bot, and
consequential ML applications have been a model is trained on privacy-sensitive data, a patient trusting an online diagnostic in-
documented (10, 11), such as race and gen- aiming for the highest level of transparency terface. Policies need to be developed that
der misidentification, wrongfully scoring in production would inevitably lead to leak- govern safe and fair adoption of ML in such
darker-skin faces for higher likelihood of age of privacy-sensitive details of data sub- high-stake applications. Equally important,
being a criminal, disproportionately favor- jects (14). Thus, choices need to be made as the fundamental tensions between adver-
ing male applicants in resume screenings, to the extent that transparency is penalized sarial robustness and model accuracy, pri-
and disfavoring black patients in medical to gain privacy, and vice versa, and such vacy and transparency, and fairness and
trials. These harmful consequences require choices need to be made clear to system pur- privacy invite more rigorous and socially
that the developers of ML models look be- chasers and users. Generally, privacy con- grounded reasonings about trustworthy
yond technical solutions to win trust among cerns prevail because of the legal implica- ML. Fortunately, at this juncture in the
human subjects who are affected by these tions if they are not enforced (for example, adoption of ML, a consequential window of
harmful consequences. opportunity remains open to tackle its blind
“…the lessons learned from the spots before ML is pervasively deployed and
On the research front, especially for the ML attack-defense arms becomes unmanageable. j
security and privacy of ML, the aforemen-
tioned defensive countermeasures have race provide opportunities to REFERENCES AND NOTES
solidified the understanding around blind motivate broader efforts
spots of ML models in adversarial settings 1. I. Goodfellow, P. McDaniel, N. Papernot, Commun.ACM
(8, 9, 12, 13). On the fairness and ethics to make ML truly trustworthy…” 61, 56 (2018).
front, there is more than enough evidence
to demonstrate pitfalls of ML, especially on patient privacy with respect to the Health 2. S. G. Finlayson et al., Science 363, 1287 (2019).
underrepresented subjects of training da- Insurance Portability and Accountability 3. B. Biggio, B. Nelson, P. Laskov, Proceedings of the
tasets. Thus, there is still more to be done Act in the United States). Also, privacy and
by way of human-centered and inclusive fairness may not always develop synergy. 29th International Conference on Machine Learning,
formulations of what it means for ML to be For example, although privacy-preserving Edinburgh, Scotland, UK,J. Langford and J. Pineau, Eds.
fair and ethical. One misconception about ML (such as differential privacy) provides a (Omnipress, 2012), pp. 1807–1814.
the root cause of bias in ML is attributing bounded guarantee on indistinguishability 4. K. Eykholt et al., Proceedings of the IEEE Conference on
bias to data and data alone. Data collec- of individual training examples, in terms of Computer Vision and Pattern Recognition (IEEE, 2018),
tion, sampling, and annotation play a criti- utility, research shows that minority groups pp. 1625–1634.
cal role in causing historical bias, but there in the training data (for example, based on 5. F.Tramèr, F.Zhang,A.Juels, M. K. Reiter,T. Ristenpart,
are multiple junctures in the data process- race, gender, or sexuality) tend to be nega- Proceedings of the 25th USENIX Security Symposium,
ing pipeline where bias can manifest. From tively affected by the model outputs (15). Austin,TX (USENIXAssociation, 2016), pp. 601–618.
data sampling to feature extraction, from 6. A.Ali, B. Eshete, Proceedings of the 16th EAI International
aggregation during training to evaluation Broadly speaking, the scientific commu- Conference on Security and Privacy in Communication
methodologies and metrics during testing, nity needs to step back and align the robust- Networks,Washington, DC (EAI, 2020), pp. 318–338.
bias issues manifest across the ML data- ness, privacy, transparency, fairness, and 7. R. Shokri, M. Stronati, C. Song,V. Shmatikov,
processing pipeline. ethical norms in ML with human norms. To Proceedings of the 2017 IEEE Symposium on Security
do this, clearer norms for robustness and and Privacy, San Jose, CA (IEEE, 2017), pp. 3–18.
At present, there is a lack of broadly ac- fairness need to be developed and accepted. 8. N. Papernot, M.Abadi, U. Erlingsson, I. Goodfellow, K.
cepted definitions and formulations of ad- In research efforts, limited formulations of Talwar, arXiv:1610.05755 [stat.ML] (2017).
versarial robustness (13) and privacy-pre- adversarial robustness, fairness, and trans- 9. I.Jarin, B. Eshete, Proceedings of the 7th ACM
serving ML (except for differential privacy, parency must be replaced with broadly ap- International Workshop on Security and Privacy
which is formally appealing yet not widely plicable formulations like what differential Analytics (2021), pp. 25–35.
deployed). Lack of transferability of notions privacy offers. In policy formulation, there 10. J. Buolamwini,T. Gebru, Proceedings of Conference on
of attacks, defenses, and metrics from one needs to be concrete steps toward regula- Fairness,Accountability and Transparency, New York, NY
domain to another is also a pressing issue tory frameworks that spell out actionable (ACM, 2018), pp. 77–91.
that impedes progress toward trustworthy accountability measures on bias and ethi- 11. A. Birhane,V. U. Prabhu, Proceedings of the IEEE/CVF
ML. For example, most ML evasion and cal norms on datasets (including diversity Winter Conference on Applications of Computer Vision
membership inference attacks illustrated guidelines), training methodologies (such (IEEE, 2021), pp. 1537–1547.
earlier are predominantly on applications as bias-aware training), and decisions on 12. N. Carlini et al., arXiv:1902.06705 [cs.LG] (2019).
such as image classification (road-sign de- 13. N. Papernot, P. McDaniel,A. Sinha, M. P.Wellman,
tection by an autonomous vehicle), object Proceedings of 3rd IEEE European Symposium on
detection (identifying a flower from a living Security and Privacy (London, 2018), pp. 399–414.
14. R. Shokri, M. Strobel,Y.Zick, Proceedings of the 2021
AAAI/ACM Conference on AI, Ethics, and Society, New
York, NY (2021); https://www.comp.nus.edu.sg/~reza/
files/Shokri-AIES2021.pdf.
15. V. M. Suriyakumar, N. Papernot,A. Goldenberg,
M. Ghassemi, FAccT‘21: Proceedings of the 2021
ACM Conference on Fairness,Accountability, and
Transparency (ACM, 2021), pp. 723–734.

10.1126/science.abi5052

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RETROSPECTIVE mity across the human species. Subsequent
studies confirmed these results. Fifteen years
Richard C. Lewontin (1929–2021) later, geneticist Rebecca Cann provided con-
text: Our species is young and only recently
Groundbreaking evolutionary geneticist ventured out of Africa, meaning that all hu-
man populations are closely related.
PHOTO: THE ERNST MAYR LIBRARY AND ARCHIVES OF THE MUSEUM OF COMPARATIVE ZOOLOGY, HARVARD UNIVERSITY By Andrew Berry1 and Dmitri A. Petrov2 the first study of DNA sequence variation in
natural populations. Lewontin does not ap- A brilliant and unsparing critic, Lewontin
R ichard Charles “Dick” Lewontin died pear as an author on that paper; he refused to found much to object to in applications of
at age 92 on 4 July, 3 days after Mary list himself as such unless he had contributed biological determinism to humans. Famously,
Jane, his wife of 73 years. Arguably the substantially to the research. he and Stephen Jay Gould savaged their
most influential population geneticist Harvard colleague, biologist E. O. Wilson,
of the second half of the 20th century, Lewontin’s theoretical work comple- after Wilson incorporated humans into
Lewontin laid the theoretical and ex- mented his empirical work. He introduced Sociobiology, his 1975 survey of the adaptive
perimental foundations of modern evolution- game theory to population biology in 1961 basis of animal behavior. For Lewontin, the
ary genetics. He was also a prominent social and pioneered computer simulation in the assertions of Wilson and others were naïve
critic and philosopher of science. field. With Ken-ichi Kojima, Lewontin coined and dangerous oversimplifications.
the term “linkage disequilibrium” to describe
Born 29 March 1929 in New York City, the correlation among alleles at multiple loci, With Gould, Lewontin went on to write
Lewontin earned his bachelor’s degree in an idea central to both modern genetic map- an eloquent reminder of the pitfalls of one-
biology from Harvard University in 1951. ping studies and population genomics. With dimensional adaptationist interpretation.
He then joined Theodosius Dobzhansky’s Jesse Krakauer, Lewontin devised an early Their wildly influential essay on the span-
genetics and evolutionary biology lab at statistical test to distinguish between selec- drels of San Marco is an appeal for plural-
Columbia University, completing his MS in istic thinking. Lewontin wrote extensively
mathematical statistics in 1952 and his PhD tive and neutral evolution, noting that dem- (with crystal clarity) for the public both in
in zoology in 1954. In the years that fol- ographic factors such as bottlenecks affect his books and as a regular contributor to the
lowed, he held positions at North Carolina variation throughout the genome, whereas New York Review of Books.
State University in Raleigh, the University selection affects only targeted loci. The test
of Rochester in New York, the University of had problems, but it underpins modern ap- Lewontin, a Marxist who resigned from
Chicago, and, from 1973 until his retirement proaches to genome evolution. Perennially the National Academy of Sciences to pro-
in 1999, Harvard. Throughout his academic interested in the interaction between the or- test its involvement in military research, has
career, Lewontin pursued what he called the ganism and its environment, Lewontin also been accused of tainting his science with his
central “problematic” of population genetics: pioneered niche construction theory. politics. If anything, though, the “dialectical”
describing patterns of genetic variation in approaches that he championed allowed him
natural populations and understanding the Lewontin worked primarily on Drosophila to remain open-minded yet rigorous when
evolutionary forces that shape them. flies but also coauthored important papers thinking about complex biological patterns.
on mice and crickets. In 1972, he took on He was dogmatically nondogmatic.
Because of the dearth of genetic markers, humans, using relatively crude data derived
population genetics in the 1950s was strong from serology and allozymes to map genetic His Marxism was arguably a key compo-
on theory but weak on data. Then in 1966 variation. His finding was important and nent of his scientific success. At Harvard, he
came Lewontin and biochemist John Lee counterintuitive: 85% of all human genetic designed his own research space, assigning
“Jack” Hubby with protein gel electrophore- variation can be found within a single popu- the desirable corner office to the Drosophila
sis. This simple technique—detecting allelic lation, with only 7% segregating among conti- “kitchen,” where fly food was prepared.
differences in proteins that change their nental groupings (or “races”). In other words, The worst job, Lewontin insisted, should
electrophoretic mobility—permitted the col- genetic variation shows remarkable unifor- be done in the nicest part of the lab. The
lection of protein polymorphism data in lab’s centerpiece was an enormous table for
any species. On finding unexpectedly large meetings, rather than the wet lab. Science,
amounts of genetic variation in populations, Lewontin believed, was forged through dis-
Lewontin and Hubby suggested that much cussion. At that table, Lewontin—animated,
of it might be selectively neutral. In biolo- hands waving, spectacles awry—steered
gist Motoo Kimura’s hands, this idea evolved conversations that rampaged across disci-
into the neutral theory of molecular evolu- plines spanning science, philosophy, poli-
tion, which became the dominant paradigm tics, history, and sociology.
in population genetics for decades to come.
The unexpectedly similar levels of diversity Lewontin’s legacy extends far beyond that
across species revealed by these studies—the table. He directly trained generations of sci-
“Lewontin paradox”—remains a puzzle still. entists, including both of us, and inspired
countless more. Despite his disdain for scien-
In 1983, a graduate student in his lab, tific celebrity, he received many awards, in-
Martin Kreitman, completed Lewontin’s 30- cluding the 2015 Crafoord Prize (shared with
year quest to quantify genetic variation, with theoretical geneticist Tomoko Ohta). He also
contributed to unexpected fields, collaborat-
1Department of Organismic and Evolutionary Biology, ing in the 1950s, for example, with architect
Harvard University, Cambridge, MA, USA. 2Department of Buckminster Fuller to design geodesic domes.
Biology, Stanford University, Stanford, CA, USA. However, Lewontin was much more than just
Email: [email protected] the sum of his intellectual contributions; he
was a loyal mentor and a beloved friend. j

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INSIGHTS

POLICY FORUM Momentum supporting increased tar-
gets for area under protection to 30 and
BIODIVERSITY 50% of global land and sea is growing, both
through scientific publications supported
Integrate biodiversity targets by new technologies and data streams
from local to global levels (1) and by campaigns (e.g., Campaign
for Nature, High Ambition Coalition for
A shared Earth approach links biodiversity and people Nature and People) based on and sup-
porting this science. This has amplified
By David O. Obura1,2,3, Yemi Katerere4, Indigenous communities and small-scale concern about the equity issues raised
Mariam Mayet5, Dickson Kaelo6, Simangele food producers exist; and there is a higher above (5), as well as the potential impacts
Msweli7, Khalid Mather8, Jean Harris8,9, dependence on nature for food, livelihoods, of higher protection on meeting peoples’
Maxi Louis10,11, Rachel Kramer8, Taye Teferi12, and culture. Only very recently has it been needs (2–5). An important factor in this de-
Melita Samoilys1,3, 13, Linzi Lewis5, Andrew acknowledged that over half of the high- bate is the lack of diversity in mainstream
Bennie5,14, Frederick Kumah7, Moenieba value land for conservation is traditionally scientific and conservation voices (5, 7, 11),
Isaacs15, Pauline Nantongo16 owned, used, or occupied by Indigenous resulting from a combination of barriers
peoples and local communities (IPLCs), to publishing and communicating from
D ecisions to be made at the 15th Con- acting as the de facto managers (8). The in- varied cultural and societal contexts. For
ference of the Parties (COP 15) to the creased conservation ambition in the past example, local and Indigenous knowledge
Convention on Biological Diversity decade, and now being projected into the is held within communities, not in the
(CBD) will shape biodiversity con- future, has focused on protecting very large scientific literature, and many conserva-
servation approaches for the next 30 and intact wilderness areas on land and at tion practitioners and even scientists from
years, a critical time for the future of sea, many of which overlap with these IPLC non-Western cultures may rarely publish
nature and people. Reflecting from our Afri- spaces. A consequence of this overlap is in- in accessible and mainstream literature.
can perspective, we applaud the necessary in- creasing concern with control of territory, This unequal representation of conserva-
crease in ambition to conserve nature (1), but undermining tenure of IPLC, and weaken- tion perspectives and approaches in main-
we share alarm about the limited equity and ing their links with nature. stream conservation science, and concern
justice in establishment of protected areas over perverse interpretations of area-based
and impacts on people (2–6). Further, raising The 2011–2020 strategy of the CBD estab- analyses (2), are particularly important
the burden of protection in the Global South lished the 20 Aichi Targets, and although where the scientific literature has a strong
while failing to address global economic driv- conservation actions have been essential role in developing and supporting policy,
ers of biodiversity decline will only repeat to prevent some species extinctions and as in multilateral processes such as the
and amplify historical cycles, and effort in- ecosystem declines, effort and resourcing GBF. This article seeks to at least partially
vested in conservation will be wasted. We see have been inadequate and none of the Aichi redress this imbalance in the literature.
hope in new and diversified approaches to Targets were achieved (9). Now the next set
conserved areas (7) and the development of of 10- and 30-year goals and targets for bio- Africa has a large share of remaining
other, less formal conservation mechanisms. diversity are under negotiation in the post- intact biodiversity; a small share of global
Here we offer a framework that can help to 2020 global biodiversity framework (GBF). funds for protection; a youthful demo-
integrate these with improved conventional Its current draft specifies four goals and 21 graphic presenting both challenges and op-
conservation approaches. targets (10), and its final form will be deter- portunities for conservation; a growing but
mined by countries at COP 15. One of the nonetheless limited technical, scientific,
Historically, conservation has empha- 21 targets is to raise the area under protec- and implementation capacity; and a sup-
sized protected areas in the most high- tion to 30% of land and sea. This builds on pressed voice in global negotiations. Africa
biodiversity and intact regions, supported two of the prior Aichi subtargets, on area faces particularly strong trade-offs between
by systematic conservation planning tools protection (17% of land and 10% of ocean; biodiversity protection and poverty alle-
set to select low-use areas for their low cost see the figure), that were nominally success- viation, with many of the voices express-
and high biodiversity benefit, and isolating ful. However, their success was not matched ing concern with how protected areas have
those places from people in strict no-use by achievement of linked effective manage- been implemented across this continent.
protected areas. A disproportionate burden ment and biodiversity representation sub- This experience is shared across the Global
of such protection has fallen on the Global targets (as many protected areas are too South, and to succeed, the GBF must resolve
South, where biodiversity condition is high degraded, a large proportion of protected these challenges in these places in socially
yet resources and public support are lim- areas are suboptimally located, and invest- relevant ways.
ited (6); effective protection is hampered by ment in management was insufficient, to
trade-offs with meeting peoples’ needs; his- protect biodiversity), nor by equity or sus- SHARED EARTH, SHARED OCEAN
tories of inequitable treatment of local and tainable use targets (9). Our framework grounds the GBF through
the concept of “shared” land and seascapes
(3, 8, 12), connecting people and nature
rather than separating them. The condition
of nature varies across all land and ocean

1CORDIO East Africa, Mombasa, Kenya. 2University of Queensland, Brisbane, Australia. 3Pwani University, Kilifi, Kenya. 4Independent: Environmental and Policy Expert, Harare, Zimbabwe. 5Africa
Centre for Biodiversity, Johannesberg, South Africa. 6Kenya Wildlife Conservancies Association, Nairobi, Kenya. 7African Wildlife Foundation, Nairobi, Kenya. 8Wildlands Conservation Trust,
Pietermaritzburg, South Africa. 9Institute for Coastal and Marine Research (CMR), Nelson Mandela University, Port Elizabeth, South Africa. 10Community Leadership Network (CLN) of Southern
Africa, Windhoek, Namibia. 11Namibian Association of Community Based Natural Resources Associations (NACSO), Windhoek, Namibia. 12Independent: Conservation Scientist, Nairobi, Kenya.
13University of Oxford, Oxford, UK. 14Department of Sociology, University of the Witwatersrand, Johannesburg, South Africa. 15Institute for Poverty, Land and Agrarian Studies (PLAAS), University
of the Western Cape, Cape Town, South Africa. 16EcoTrust, Kampala, Uganda. Email: [email protected]

746 13 AUGUST 2021 • VOL 373 ISSUE 6556 sciencemag.org SCIENCE

Shared Earth, shared ocean framework

(Left) The approximate proportion of land or ocean area in 2020 in which nature is intact, variably affected in shared spaces, or fully altered in anthromes [from (2)].
(Middle) Schematic allocation of effective conservation actions on land across the gradient of condition (as in left panel) in a country or territory. Protection of 17% of
total land under Aichi Target 12 is depicted in the 0 to 20% of land where nature is most intact. Protecting 20% of area under intact native habitat is shown in shared
spaces, from 21 to 80% of territory. Protecting 5% of area under intact habitat in anthromes is shown from 81 to 100% of territory. The sum of these meets the draft
global biodiversity framework target of 30% protected. Relative to the 30x30 campaign for protecting nature in areas most important for biodiversity, the shared Earth
approach spreads effort and benefits of additional conservation across space. (Right) The contribution of restored versus intact habitat will increase in more altered
shared spaces and in anthromes. The contribution of different governance regimes, such as by Indigenous people and local communities (IPLCs), conventional protected
areas (PAs), and “other” mechanisms, may vary across spaces. Axes labels are as in the middle panel.

Global condition of nature Shared earth and ocean framework Implementation options

Land Proportion meeting biodiversity criteria (%) Aichi 12 Shared earth 30x30 Restoration

Intact Shared Anthrome 100 100 Intact Restored
25% ~55% 21% 90
80

80 60
40
70

10 20 30 40 50 60 70 80 90 100 60 20
Proportion of land area (%) 50
40 0
30 10 20 30 40 50 60 70 80 90 100
20
Ocean Shared Anthrome Governance
>95% 1%
Intact 100
3% IPLC PA Other

10 80

0 60

10 20 30 40 50 60 70 80 90 100 10 20 30 40 50 60 70 80 90 100 40
Proportion of ocean area (%) Proportion of national territory (%)
20

0
10 20 30 40 50 60 70 80 90 100

GRAPHIC: K. FRANKLIN/SCIENCE (see the figure), from near-intact and “natu- are met, prioritizing local institutions and landscapes [e.g., tea-farming landscapes in
ral” in remote areas with low or no human rights holders, assisted by governments, central Kenya, or cocoa and mixed agro-
population (e.g., areas within the Amazon organizations, scientists, and others. Third, forestry landscapes in southern Cameroon
forest, Sahara desert, or high seas), through all relevant knowledge is integrated at this (14)], the proportion of intact nature may
increasingly modified in lightly to densely level. The local focus means that local and be well below 20% of the landscape. But
populated and used shared spaces that traditional knowledge, accumulated expe- with effective restoration and appropriate
still present functions and characteristics rience, and social and cultural concerns time horizons to allow for rebuilding of eco-
of a natural biome (e.g., extensive pasture- can be in the forefront. Relevant scientific logical integrity and function (15), restored
lands, or sparsely to moderately populated knowledge needs to be translated to this habitats could count toward conservation
rural areas or fished seas), to fully altered scale, using platforms that can help en- goals (see the figure), as well as increase
in high-intensity agricultural and urban sure consistency of local decisions across their contribution of benefits to people.
spaces, aquaculture, and intensively modi- locations and across scales, and to address
fied coastlines (classed as anthropogeni- larger-scale phenomena such as connectiv- In anthromes, a lower “intact habitat”
cally altered biomes or “anthromes”). Strict ity. Fourth, all relevant targets of the GBF threshold might be all that is possible, and
boundaries between categories of such should be addressed concurrently. decision-makers may focus on selected ben-
“spaces” are challenging to define, empha- efits, such as shading and temperature con-
sizing the continuum of nature–human in- Recent advances in the conservation lit- trol, or on nonmaterial benefits provided
teractions across them (8, 12). Across all of erature connecting nature and people sup- by urban green spaces. We illustrate an
these spaces, even where nature is in a de- port this approach (2–4, 6–8, 12–14), in par- arbitrary area target of 5% (see the figure),
graded state, it provides essential benefits ticular, to maintain 20% of local area under but existing guidance of 9 to 50 m2 of green
to people (13), particularly to those living intact native habitat (13), notably in “shared space per person may require variable lo-
in poverty or with few material or financial spaces” (12) (see the figure). Doing this can cally set targets.
assets. Whereas the dominant paradigm for adequately meet peoples’ needs and main-
nature conservation to date has focused on tain biodiversity functions, especially when Nature is most intact and human popu-
the most intact spaces for protection, we applied down to a square kilometer scale lation density lowest in intact spaces and
focus on the middle ground, where human so that benefits are within reach of those lightly altered shared spaces, where the pro-
interactions with nature cannot be resolved that need them. From this basis, multiple portion of land or sea meeting biodiversity
by separation. biodiversity targets relating to species, eco- criteria may approach 100% (see the figure).
systems, genes, and benefits to people (15) This area can enable the summed area of
Our approach is built on four pillars. may be addressed together, potentially from high protection to approach a global target,
First, it focuses at the local scale, from both the 20% of intact habitat and 80% of such as 30%. Where high levels of protec-
which decisions and measures are ag- “working” or “managed” area in the local tion are already established, our approach
gregated “from the ground up” to achieve land- or seascape (12) (see the figure). can help refine management to address lo-
targets. Second, it applies equity principles cal needs within the broader context and
to ensure that needs and rights of people In moderately and highly altered “shared potentially redress equity and rights issues
spaces,” such as extensive populated rural that may be unresolved from the past (5).

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INSIGHTS | POLICY FORUM

Local government (e.g., districts, coun- tial reach of the benefits they provide (e.g., loss (1), if it is pursued without equal at-
ties, states, municipalities) may provide through trade), as well as for their role in tention to equity, local custodianship, and
the relevant framework for applying this sustaining higher-level targets and global provisioning of benefits to people (3, 4, 15),
approach, enabling consistent replication, benefits (e.g., species conservation or car- errors of the past will likely be repeated (5,
locally differentiated targets, technical sup- bon sequestration in community forests). 6), as well as the level of achievement of the
port, and resourcing within national sys- Attention to local perceptions of justice Aichi Targets (9). Critics will question if our
tems. Within these, a wide variety of gover- and value, and innovative measures such approach will succeed better, but a renewed
nance models could be applied to protected as basic income grants for protected and approach is needed, and both societal (e.g.,
and conserved areas (see the figure), such conserved area-adjacent communities, Leaders Pledge for Nature) and scientific
as Indigenous and local community; pri- can help balance the benefits and costs of (5, 6, 8) voices are calling for a paradigm
vate, local, or central government; or mixed, conservation. shift toward sustainability, meeting peoples’
depending on national and local rights and needs, and equity that our approach helps
tenure regimes. “Protected areas” are gen- Looking into the future, conservation to implement. We call on countries, donors,
erally designated under national legislation and restoration may need to focus on and organizations to shift to this focus
and classified using International Union ecological functions and contributions on shared spaces and equity from local to
for Conservation of Nature categories. Less to people rather than the prior intact as- global scales as the best way to reconcile the
formal conservation mechanisms (e.g., semblage, particularly where climatic and challenges to delivering on the GBF and a
Indigenous and community lands, private other changes make a historical native “nature positive” outcome by 2050.
sanctuaries, etc.) are becoming classified state impossible to reinstate. In this con-
under emerging standards for other effec- text, regenerative development and agro- A particular challenge will be the design
tive conservation measures (OECMs) (7), ecological approaches linked to culture and and establishment of the multilevel and
though full inclusion and leadership by Indigenous practices at land- and seascape polycentric governance systems that will be
IPLCs in this process will be necessary for scales may best integrate biodiversity, pro- needed for success, underpinned by spatial
legitimacy. Our framework will facilitate visioning, and equity targets. By situating planning frameworks and incorporating di-
integration of protected areas, OECMs, and and aggregating local conservation within verse conservation and sustainable produc-
other measures across intact, shared, and larger spatial frames, this approach can tion actions that address the impacts and
anthrome spaces. also facilitate biodiversity and human ad- interests of multiple actors, sectors, and
aptation to climate change in landscape jurisdictions across spatial scales. However,
This framework integrates the three pil- mosaics that facilitate climate migration. without addressing the drivers of biodiver-
lars of the CBD and helps operationalize the sity decline arising from high-consumption
goals and many of the targets of the GBF AN APPROACH FIT FOR THE GLOBAL practices that underpin global inequalities,
simultaneously: the equity intent of CBD BIODIVERSITY FRAMEWORK no conservation-focused actions will be suf-
objective 3 and GBF goal C (which relate This “shared Earth and ocean” approach ficient to halt or reverse biodiversity decline
to equitable access to and benefit sharing meets a need identified within the GBF, or attain sustainable use at a global scale. j
of genetic resources), extending this to all for its global ambitions and elements to be
aspects of nature and its contributions to translated down to the local scale, founded REFERENCES AND NOTES
people; CBD objective 2 and GBF goal B on inclusion and equity, where the best sci-
on ensuring access to and provisioning of ence and praxis can be integrated in locally 1. J. E. M.Watson et al., Nature 578, 360 (2020).
a range of benefits from nature; and CBD relevant ways to meet multiple targets si- 2. M. Barnes, L. Glew, C.Wyborn, I. D. Craigie, PeerJ
objective 1 and GBF goal A on conserving multaneously. The interests of local com-
ecosystems, species, and genetic diversity, munities and rights holders require locally Preprints 10.7287/peerj.preprints.26486v1 (2018).
and restoring them where needed. contextualized solutions for conservation, 3. Z. Mehrabi, E. C. Ellis, N. Ramankutty, Nat. Sustain. 1, 409
across intact, shared, and fully altered
The framework can also help direct spaces, which can be aggregated and re- (2018).
conservation finance to local institutions ported to larger scales. It also offers a le- 4. J. Schleicher et al., Nat. Sustain. 2, 1094 (2019).
and actors, addressing goal D of the GBF. gitimate and people-focused way to spread 5. A.Agrawal, et al.,“An open letter to the lead authors
Objectives, expected results, and resourc- effort for conservation across the whole
ing for conservation and protection vary gradient of condition of nature (12) rather of‘Protecting 30% of the Planet for Nature: Costs,
along the continuum of condition of na- than isolating it away from people in only Benefits and Implications’”(2021); https://openletter-
ture. Large, intact critical ecosystems— the most intact regions. Like many innova- towaldronetal.wordpress.com/.
such as in wilderness areas and the high tive approaches, many of its elements are 6. RRI,“Rights-based conservation: The path to preserving
seas—play essential roles in global regula- known and established, but with a paradig- Earth’s biological and cultural diversity?”(Technical
tory functions (e.g., carbon sequestration), matic shift in focus—from the ground up, Report, Rights and Resources Initiative, 2020), p. 43.
as well as locally. Small habitat fragments and with equity and provisioning of bene- 7. H. D.Jonas et al, PARKS 27, 71 (2021).
in shared spaces and anthromes will be fits to people as priorities—the potential for 8. IPBES, The Global Assessment Report on Biodiversity
critical for daily contributions to peoples’ success is transformed. and Ecosystem Services - Summary for Policymakers
quality of life and well-being (e.g., food se- (2019); https://ipbes.net/sites/default/files/2020-02/
curity, pollination, water treatment) and The ambition and complexity of efforts ipbes_global_assessment_report_summary_for_poli-
in ensuring connectivity across land- or required to achieve the GBF will be consid- cymakers_en.pdf.
seascape mosaics, and with protected ar- erably greater than for the Aichi Targets. We 9. GBO5,“Global Biodiversity Outlook 5”(Convention on
eas. The responsibilities and mechanisms see merit in the full set of Targets proposed Biological Diversity, Montreal, Quebec, Canada, 2020),
for management and finance may vary for the GBF, mirroring the indivisibility of p. 212.
across these scales. For example, small the Sustainable Development Goals, not in 10. CBD,“First draft of the post-2020 global biodiversity
areas might be managed and supported any one target in isolation. For example, framework,”CBD/WG2020/3/3 (Convention on
based on functions such as maintaining although protecting 30% of nature is likely Biological Diversity, 2021), p. 12.
integrity and connectivity, and on the spa- necessary to adequately reduce biodiversity 11. D.Veríssimo et al., Conserv. Soc. 18, 220 (2020).
12. H. Locke et al., Natl. Sci. Rev. 6, 1080 (2019).
13. L.A. Garibaldi et al., Conserv. Lett. 14, e12773 (2021).
14. P.A. Minang et al., Eds., Climate-Smart Landscapes:
Multifunctionality in Practice (World Agroforestry
Centre, Nairobi, 2015).
15. S. Díaz et al., Science 370, 411 (2020).

ACKNOWLEDGMENTS

We acknowledge comments from E.Coppenger,S.Anderson,E.
Tambara,E.Omondi,C.Gordon,S.Mangubhai,and H.Dublin.

10.1126/science.abh2234

748 13 AUGUST 2021 • VOL 373 ISSUE 6556 sciencemag.org SCIENCE

Heiress Patty Hearst is escorted to court
by two federal marshals in 1976.

BOOKS et al. traced back much further to techniques used
in religious conversion and inquisition, but
PSYCHOLOGY the fear unleashed by the provocative term
precipitated the Central Intelligence Agen-
The matter of mind control cy’s infamous MKUltra experiments, which
made use of the hallucinogen LSD, sensory
Brainwashing case studies illuminate the history deprivation, and electroconvulsive therapy
of coercive persuasion during interrogations to coerce confessions
and reached their bleak crescendo with a
By Sarah Marks The jury was unconvinced and sentenced series of highly abusive experiments carried
out on psychiatric patients by McGill Uni-
Hearst to 35 years in prison. However, Pres- versity psychiatrist Donald Ewen Cameron
between 1957 and 1964.
I n 1976, Patty Hearst, the granddaughter ident Jimmy Carter found the arguments
of American publishing magnate William persuasive and commuted her sentence The book avoids making sweeping claims
Randolph Hearst, was found guilty of after 22 months, and President Bill Clinton about the nature of brainwashing, but af-
bank robbery, a crime she committed af- pardoned Hearst in 2001. This trial, and the ter a chronological assessment of each case
ter enduring a sustained period of time as debates surrounding it, is one of 10 key mo- study, Dimsdale presents a comparative
table of the key features at play, including
a captive of the domestic terrorist orga- ments in the history of the idea of brain- techniques such as sleep manipulation,
coercion and manipulation, intentional
nization known as the Symbionese washing examined by psychiatrist surreptitiousness, and participation in ac-
tivities not in the subject’s best interests.
Liberation Army. The trial, with its Joel E. Dimsdale in his new book, That some combination of these are pres-
ent in varying degrees in all of the cases
glittering cast of expert witnesses, Dark Persuasion. cited suggests that Dimsdale sees them as
necessary and sufficient criteria for describ-
became a test case for psychological A tragedy close to home inspired ing brainwashing with some degree of cer-
tainty. Some of the 21st-century examples
theories of brainwashing. Dimsdale to dive deeply into this he discusses briefly in the book’s last sec-
tion, including controversies surrounding
In addition to commenting on topic. In 1997, as the comet Hale- deep brain stimulation and the rise of social
media platforms and conspiracy theories,
Hearst’s intelligence and differenti- Bopp approached, his neighbors do not quite fit these criteria, however.

ating her behavior from those typi- committed suicide at the instruc- While there is novelty in the synthesis of
these case studies, Dark Persuasion does
cally displayed by malingerers, the Dark Persuasion tions of the leaders of the Heaven’s not offer much new material, and Dims-
experts invoked the experiences of Joel E. Dimsdale Gate cult, who were convinced that dale has not unearthed any substantial un-
US prisoners of war (POWs) in Ko- Yale University death was necessary to free mem- expected archival finds or generated new
rea and the concept of “debility, de- Press, 2021. 304 pp. bers of their “bodily vehicles” and oral histories. However, his account of the
Hearst trial is carefully researched and
pendency, and dread” to explain how allow them to ascend to heaven. supplemented with a wealth of scientific
papers from the time. And while the causal
PHOTO: BETTMANN/GETTY IMAGES Hearst, in their view, was not acting of her The word “brainwashing” was coined link he suggests between Pavlov’s experi-
ments with traumatized dogs and the in-
own free will when she committed the rob- in the early years of the Cold War by jour- terrogation and torture processes that led
to false confessions in Stalin’s show trials
bery. Instead, they argued, she was in thrall nalist Edward Hunter to describe reeduca- is based on slender evidence, Dimsdale’s
observations about the proximity of these
to the coercive persuasion of her captors. tion techniques used for indoctrination in events are nevertheless astute.

Communist China and was subsequently But historical rigor is not necessarily the
point of this highly readable and compelling
The reviewer is at the Department of History, Classics and invoked to make sense of the defection of book. Dimsdale’s goal is to prompt reflec-
Archaeology, Birkbeck, University of London, Bloomsbury, 21 American POWs to China after the Ko- tion on what he sees as the overlooked real-
London WC1E 7HX, UK. Email: [email protected] rean War. Elements of brainwashing can be ity of coercive persuasion at a broader level
and the ever-present threat that it poses to
individuals and to society at large—a threat,
he warns, that is becoming ever-amplified
by new technologies and mass media. In
this aim, he succeeds admirably. j

10.1126/science.abj8872

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INSIGHTS | BOOKS

CLASSICS REVISITED

The alternative to despair is to build an ark

H. G. Wells’s “world encyclopedia” has merit beyond its seeming similarities to Wikipedia

By Yochai Benkler university, the superficial finishing-school World Brain

B etween 1936 and 1938, H. G. Wells exercises of sportive young people mostly of H. G. Wells
delivered a series of lectures first the wealthier classes.” “The universities,” he Foreword by Bruce
published under the title World lamented, “go out to meet the tremendous Sterling and introduction
Brain in 1938. The standard reading challenges of our social and political life, like by Joseph Reagle
of that text over the past few decades men who go out in armour with bows and MIT Press, 2021. 176 pp.
arrows to meet a bombing aeroplane. They

has framed Wells as the utopian fu- are pushed aside by men like Hitler, Mus-

turist projecting from microfilm, radio, and solini creates academies in their despite, cial and ethnonationalist hate. Hundreds

telephone a world encyclopedia freely avail- Stalin sends party commissars to regulate of millions of people reject evolution and

able to all. Predicting, various authors have their researches.” science; reject vaccines in the teeth of a

written, the World Wide Web or Wikipedia, What, then, is Wells’s ark? “What I am devastating pandemic; and refuse to be-

World Brain naïvely imagined that such a saying,” he writes, “is…that without a World lieve in climate science, droughts, fires,

facility would provide the global community Encyclopaedia to hold men’s minds together floods, and famines notwithstanding.

with the knowledge base we would need to in something like a common interpretation Wells urges us to build the ark that we can

create world peace. After 5 years of research of reality, there is no hope whatever of any- rather than despair or waste time on design-

on propaganda and misinformation, I read thing but an accidental and transitory alle- ing arks that we cannot build. There is no

World Brain very differently. viation of any of our world troubles.” world in which the few, the expert, declare

In one of the early talks collected what is true and enforce it on the

in the book, Wells told his audience many. Wells himself wrote, “A pro-

“I do not agree with that inevita- fessor-ridden world might prove as

bility of another great war.” But by unsatisfactory under the stress of

1938, he conceded: “The Flood is modern life and fluctuating condi-

coming anyhow, and the alterna- tions as a theologian-ridden world.”

tive to despair is to build an ark. My What universities and research

other name is Noah, but I am like institutes can do is to produce the

someone who plans an ark while most conscientious “world encyclo-

the rain is actually beginning.” pedia” possible—a statement, con-

Fascism and communism loomed tinuously updated, of what we know

large in the world of propaganda to be true, what we know to be un-

that Wells decried. But his point was true, and what we believe to be in

both deeper and more banal than reasonable doubt—and to translate

these twin threats. “Big business in that constantly updated consen-

America,” he wrote, “appears to be sus into teaching materials for di-

completely bankrupt of political verse levels of education and other

and social philosophy. Probably it Authoritative reports from bodies like the IPCC align well with Wells’s vision. broadly intelligible and freely acces-

never had any. It had simply a set of sible formats. Such an effort would

excuses for practices that were for a time ex- Wells’s “world encyclopedia” is primar- need to be publicly funded and operate inter-

tremely profitable and agreeable.” The reader ily organizational, not technological. He nationally, so as to be resistant to corporate

cannot but think of the “merchants of doubt,” envisioned thousands of experts continu- manipulation and the influence of any single

as Naomi Oreskes dubbed them, selling cli- ously engaged in a global series of work- nation’s interests.

mate denial or the harmlessness of tobacco, shops and conferences refining a body of In some fields, such as the physical and

sugar, or opiates (1). authoritative knowledge. His world brain, biological sciences, this task will be hard. In

Yet Wells spent fewer pages decrying po- read so, is less like Wikipedia and more like others, such as history, sociology, or econom-

litical or business propaganda, or exalting a general-purpose Intergovernmental Panel ics, it may be impossible to offer definitive

the benefits of microfilms, than he did criti- on Climate Change (IPCC)—a collaborative answers to some questions. But clever tricks PHOTO: FABRICE COFFRINI/AFP/GETTY IMAGES

cizing our stagnant education and research global network of expert researchers from to fix social media will not address a prob-

systems. Overworked, underpaid elementary universities and public bodies working to lem with roots deeper and broader than the

school teachers and university professors in produce an authoritative statement on a tweet-length blink of our technological mo-

silly gowns are weighted down by bureau- matter of core global concern designed to ment. And we must do what we can. The wa-

cratic burdens and follow centuries-old guide action. ters are rising. j

teaching practices, he wrote, particularly We face an epistemic crisis. The world REFERENCES AND NOTES
on “the collegiate side of a contemporary is awash in falsehoods rooted in similar 1. N. Oreskes, E. M. Conway, Merchants of Doubt
dynamics to those Wells described in his (Bloomsbury, 2010).
The reviewer is at Harvard Law School, Cambridge, MA own time: religious fundamentalism, cor-
02138, USA. Email: [email protected] porate opportunism, and the politics of ra- 10.1126/science.abk0210

750 13 AUGUST 2021 • VOL 373 ISSUE 6556 sciencemag.org SCIENCE

LETTERS

Algae covers the beach in Qingdao, Shandong Province, China.

PHOTO: RUISHAN CHEN Edited by Jennifer Sills increases in extreme weather events, such as Jiangsu province, should com-
such as storms, destroy the infrastructure
China’s algal bloom that algal matter attaches to, facilitating pensate downstream provinces that bear
its spread to the sea. Meanwhile, coastal
suffocates marine life eutrophication increases nitrate and phos- the ecological and economic costs, such
phate levels, intensifying algal blooms (8).
Every summer since 2007, algal blooms Other human uses of the land, including as Shandong province. Alternatively,
have grown in China’s Yellow Sea (1). This large-scale fisheries, land reclamation,
year, covering about 1746 km2, the bloom and resource extraction, compete for land downstream provinces should compen-
is 2.3 times larger than the country’s in this coastal area, further exacerbating
previous record-holding bloom in 2013 algal production. As increasing eutro- sate upstream provinces for reducing
(2). Such massive quantities of algae block phication combines with climate change
sunlight from entering the ocean and and human use (9, 10), algae blooms will algal flows to below a certain threshold.
deplete oxygen levels, suffocating marine continue to threaten Yellow Sea marine
life (3). The algae also pose challenges for life in the years to come. Controlling China’s algal blooms requires
tourism and marine transport. The city
of Qingdao has deployed 12,686 boats to Integrated actions are needed to address regional collaborative governance to better
clean the water, collecting 457,700 tons future algal blooms. Water quality along
of algae by 12 July (2). The algae are the coast should be monitored and pollu- manage the development of the seaweed
expected to persist until mid-August (4), tion controlled to reduce eutrophication.
at enormous economic and biological An early warning system for algal blooms industry and its environmental impacts.
cost. Mitigating the damage will require should be established, including public
regional collaboration. engagement throughout the algal control Xiaona Guo1, Annah Zhu2, Ruishan Chen1*
process. Moreover, regional coastal and 1Shanghai Jiaotong University, Shanghai 200040,
The massive algae bloom is the result ocean industrial development should be China. 2Wageningen University, Wageningen
of a complex interaction between exces- better coordinated under China’s marine 6706KN, Netherlands.
sive coastal use for aquaculture, climate functional zoning and ecological red- *Corresponding author.
change, and coastal eutrophication. line policies, which divide marine areas Email: [email protected]
Booming seaweed aquaculture businesses into different types of basic functional
in neighboring Jiangsu province are areas and legislate to protect them. This REFERENCES AND NOTES
alleged to be the primary culprit for algal supervision helps guide the development
increases (5), which are then transported of the marine industry and control the 1. Y.Xiao et al., Mar. Pollut. Bull. 140, 330 (2019).
to coastal areas such as Qingdao by ocean expansion of aquaculture, but coastal and 2. F.Yang,Y. Hu,“Qingdao algal bloom reached the highest
currents and wind (6). Seaweed aquacul- ocean industrial development covers dif-
ture in Jiangsu has increased by more ferent marine functional areas, requiring value in history, experts say it may exist offshore for a
than an order of magnitude since 2000, increased coordination between provinces long time,” China News (2021); www.chinanews.com//
resulting in commensurate increases (11). Finally, an ecological compensation sh/shipin/cns/2021/07-19/news895145.shtml
in algae production (7). Compounding mechanism should be established at the [in Chinese].
the trend, warming ocean temperatures regional level (4). Upstream provinces 3. S. Dineva, Environ. Sci. Pollut. Res. 10.1007/s11356-021-
favor the growth and expansion of algae; that are the source of the algal blooms, 13475-8 (2021).
4. X. Chen, C.Wang,“The algal bloom in Qingdao will last
until mid-August, and political consultative committee
members call for an‘international chess game’to
manage it,”Newspaper of the Chinese People’s Political
Consultative Conference (2021); www.rmzxb.com.
cn/c/2021-07-07/2898577.shtml?n2m=1 [in Chinese].
5. E. Rees,“Algal blooms fed by climate change, farm pol-
lution and aquaculture,” China Dialogue (2014); https://
chinadialogue.net/en/climate/7271-algal-blooms-fed-
by-climate-change-farm-pollution-and-aquaculture/.
6. M.-J.Zhou et al., Estuar. Coast. Shelf Sci. 163, 3 (2015).
7. Q.Xing et al., Remote Sens. Environ. 231, 111279 (2019).
8. E. Marris, Nature 10.1038/news.2008.998 (2008).
9. G. M. Hallegraeff et al., Commun. Earth Environ. 2, 117
(2021).
10. Y.Wang et al., Harmful Algae 10.1016/j.hal.2021.102058
(2021).
11. W. Lu et al., Mar. Pol. 62, 94 (2015).

10.1126/science.abl5774

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INSIGHTS | LETTERS

Eastern Europe’s and Poland, there is a strong political will is illegal within water catchments where
to implement the project (1, 6), but areas of
fraught waterway plans global and regional environmental impor- terrain exceeds 30 degrees in slope (6, 7)
tance should not be put under pressure
In December 2020, the Ukrainian parlia- for political reasons. Scientists must work to limit erosion, conserve aquatic ecosys-
ment passed the Inland Water Transport to prevent the coming habitat destruction
Act, paving the way for the construction of by appealing to the governments of these tems, and ensure water quality for human
the E40 international waterway, Europe’s countries to postpone construction
longest water route (1). The proposed 2000- until the environmental consequences are consumption. Under the revised laws, these
km waterway would connect the Baltic Sea better understood.
port in Gdansk, Poland, with the Black Sea slope restrictions will be relaxed.
port of Kherson, Ukraine, likely within a Ignacy Kitowski1 and Grzegorz Grzywaczewski2*
decade. The waterway would include parts 1State School of Higher Education in Chelm, The current policy to protect forest on
of the Vistula, Wieprz, Bug, Pina, Pripyat, PL-22-100 Chelm, Poland. 2University of Life
and Dnieper rivers (2, 3), posing a threat to Sciences in Lublin, PL-20-950 Lublin, Poland. steep slopes, although scientifically sound,
the wetlands of Polesia, an ecosystem that *Corresponding author. Email: grzegorz.
has been referred to as Europe’s Amazon (4). [email protected] has been poorly enforced. Recent terrain
The Ukrainian government supports this
project as a symbol of geopolitical connec- REFERENCES AND NOTES analysis indicates that 75% of 204 logged
tion to Europe during the country’s conflict
with Russia (3) and will likely fund the first 1. O. Shevchenko,“Ukraina przyjęła ustawę istotną dla sites (called cutblocks) in one Victorian
part of the construction in its 2022 or 2023 odbudowy drogi wodnej E40”(2021); www.ecpp.org.pl/
budget, but thorough ecological assessments ukraina-przyjela-ustawe-istotna-dla-odbudowy-drogi- water catchment were on areas steeper
should take place before the project moves -wodnej-e40 [in Polish].
forward (2, 3). than 30 degrees; logging of these areas
2. G. Grzywaczewski, I. Kitowski, Oryx 53, 4 (2019).
The proposed E40 would require con- 3. I. Kitowski, M. Oskierko, Przeglad Geopolit. 30 (2019) therefore breached current laws (8). A
struction in protected areas such as Polesie
State Radioecological Reserve in Belarus [in Polish]. ministerial review (9) and legal cases have
and Mizhrichynsky Landscape Park and 4. P.Weston,“The race to save Polesia, Europe’s secret
Chernobyl General Zoological Reserve (part found that logging frequently breached
of the Chernobyl Radioecological Reserve) Amazon,”The Guardian (2020).
in Ukraine. In April, the Ukrainian govern- 5. Save Polesia,“E40 waterway removed from Ukrainian codes of practice (10).
ment removed the E40 from the updated
draft 2030 Chernobyl Exclusion Zone Exclusion Zone Strategy”(2021); https://savepolesia. Australia has been pilloried for its record
Development Strategy (5), allowing con- org/e40-waterway-removed-from-ukrainian-exclusion-
struction work on nearby river bottoms that zone-strategy. on climate inaction (11), biodiversity loss,
otherwise would have been forbidden. The 6. P. Nowak,“Droga wodna E40 ma połączyć Bałtyk
planned waterway would pass within 2 km z Morzem Czarnym. Eksperci ostrzegają: To grozi and under-spending on species conserva-
of the former Chernobyl nuclear plant (5, 6). katastrofą”(2020); https://kurierlubelski.pl/
Now that an exception has been made for droga-wodna-e40-ma-polaczyc-baltyk-z-morzem- tion (12). Weakened forest laws will further
its construction, the project will likely bring -czarnym-eksperci-ostrzegaja-to-grozi-katastrofa/ar/
radionuclides that were emitted during the c8-14940338 [in Polish]. accelerate biodiversity decline. Victoria’s
Chernobyl disaster from river bottoms to 7. Polish Society for the Protection of Birds,“Kosztowna
the surface (5, 6). droga wodna E40—ekspertyza ekonomiczna”(2020); government must resist industry pressure
https://otop.org.pl/2020/11/kosztowna-droga-wodna-
Poland also strongly supports the -e40-ekspertyza-ekonomiczna [in Polish]. to degrade environmental laws and weaken
planned construction (6, 7), despite the 8. G. Grzywaczewski, I. Kitowski, Science 365, 134 (2019).
risks the project poses to the country’s codes of forest practice and instead focus on
protected areas, including 12 Natura 10.1126/science.abk2377
2000 areas, 1 national park, 4 landscape strengthening enforcement of current laws.
parks, and 24 nature reserves (2). In Australia threatens
addition, the E40 would deprive the David Lindenmayer and Chris Taylor
772-km Bug river—the last and the longest to weaken forest laws Fenner School of Environment and Society,
unregulated river in Europe (2, 3, 6, 7)—of The Australian National University, Canberra,
its ability to perform ecosystem services, Victoria is one of Australia’s most for- ACT 2601, Australia.
threatening the drinking water supply ested jurisdictions. The state supports 7.2 *Corresponding author. Email: david.
for Warsaw’s 1.8 million inhabitants by million ha of forest, of which 1.8 million [email protected]
compromising the river’s role in treating ha are broadly allocated for logging (1).
contaminated water flowing to Poland The native forests of Victoria are critical REFERENCES AND NOTES
from Ukraine (3, 6, 7). for water production, carbon storage, and
biodiversity conservation (2). Victoria has 1. Commissioner for Environmental Sustainability
The E40 waterway is a serious threat taken steps to protect its natural forests by Victoria,“State of the Forests 2018”(Government of
to vulnerable species, such as the aquatic committing to phasing out all native forest Victoria, Melbourne,Australia, 2018); www.ces.vic.gov.
warbler (Acrocephalus paludicola) (8), and logging across the state by 2030 and to au/reports/state-forests-2018.
ecosystems that survived the communist substantially reducing current levels of cut-
period in Eastern Europe (2). In Ukraine ting starting in 2024 (3). However, Victoria 2. H. Keith et al., Nat. Ecol. Evol. 1, 1683 (2017).
is now updating its forest code (4). Instead 3. Government of Victoria,“Timber harvesting regulation”
of strengthening much-needed protections,
the state is considering changes that would (2021); www.vic.gov.au/timber-harvesting.
weaken current regulations and put its 4. Victoria Department of Environment, Land,Water
forests in renewed jeopardy.
and Planning,“2021 proposed variation of the Code of
Motivated by rapidly dwindling timber Practice for Timber Production”(2021); https://engage.
supplies (5), policy-makers in Victoria vic.gov.au/code-practice-timber-production.
have planned changes that will permit 5. Jaclyn Symes,“Review to protect Victoria’s forests, jobs
environmentally harmful practices that are and timber industry”(2020); www.jaclynsymes.com.
currently prohibited. For example, logging au/media-releases/review-to-protect-victorias-forests-
jobs-and-timber-industry/.
6. Victoria Department of Environment and Primary
Industries“Code of Practice for Timber Production
2014”(2014); www.forestsandreserves.vic.gov.
au/__data/assets/pdf_file/0016/29311/Code-of-
Practice-for-Timber-Production-2014.pdf.
7. Office of the Conservation Regulator,“Regulating
timber harvesting on steep slopes”(Office of the
Conservation Regulator, Melbourne,Australia, 2021).
8. C.Taylor, D. B. Lindenmayer, Environ. Sci. Pol. 120, 204
(2021).
9. J. Brockington, N. Finnegen, P. Rozen,“Independent
review of timber harvesting regulation: Panel report to
the Secretary of the Department of Environment, Land,
Water and Planning” (Victorian Government Library
Service, Melbourne,Australia, 2018).
10. M.Jagot,J. E. Griffiths, R. M. Derrington, FCAFC 92 Cost
Order (Federal Court of Australia, Melbourne,Australia,
2021).
11. M. Mazengarb,“Australia ranked dead last in world
for climate action in latest UN report,”Renew
Economy (2021); https://reneweconomy.com.au/
australia-ranked-dead-last-in-world-for-climate-action-
in-latest-un-report/.
12. A.Waldron et al., Nature 551, 364 (2017).

10.1126/science.abk3018

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RESEARCH

IN SCIENCE JOURNALS
Edited by Stella Hurtley

PLANT SCIENCE

Potato pectin falls to
Phytophthora

P hytophthora infestans is a plant
oomycete pathogen that drove the
potato famines of the 1800s and
continues to afflict potato fields
today. The polysaccharide pectin
makes up about a third of the cell wall
in potatoes. Sabbadin et al. identified a
family of lytic polysaccharide monooxy-
genases (LMPOs) that cleave pectin and
are up-regulated in P. infestans during
infection. Silencing the relevant LMPO
gene successfully inhibited P. infestans
infections. These findings open doors
for disease intervention targets and for
biotech applications. —PJH
Science, abj1342, this issue p. 774

Antique engraved illustration of Phytophthora
infestans, which causes potato blight

CORONAVIRUS impact of emerging mutations its specific heat, Hayes et are deepening our viewpoint. PHOTO: MIKROMAN6/GETTY IMAGES
in the receptor-binding domain al. reveal that this two-step Wooller et al. examined isotopes
Defenses against of the spike protein on binding superconductivity occurs in collected from the tusk of a
SARS-CoV-2 variants to the host receptor ACE2 and the compound uranium ditel- 17,000-year-old mammoth to
to a range of antibodies. These luride. Complementary optical elucidate its movements from
Our key defense against the studies may be helpful for measurements indicated the birth to death. This included its
COVID-19 pandemic is neu- developing more broadly effec- breaking of time reversal time—likely with a herd—as an
tralizing antibodies against tive vaccines and therapeutic symmetry, constraining the infant and juvenile, then as a
the severe acute respiratory antibodies. —VV possible symmetries of the prime-age adult, and then as a
syndrome coronavirus 2 order parameter in this mate- declining senior over its approxi-
(SARS-CoV-2) virus elicited by Science, abh1766, this issue p. 759, rial. —JS mately 28-year life span. —SNV
natural infection or vaccina- abh1139, this issue p. 818
tion. Recent emerging viral Science, abb0272, this issue p. 797 Science, abg1134, this issue p. 806
variants have raised concern SUPERCONDUCTIVITY
because of their potential to PA L E O N T O L O GY M E TA B O L I S M
escape antibody neutraliza- Constraining symmetry
tion. Wang et al. identified four A mammoth’s life A lifetime of change
antibodies from early-outbreak Most superconductors have
convalescent donors that are only one transition point and, Fossils have long given us Measurements of total and
potent against 23 variants, below a certain temperature, glimpses of the life that came basal energy in a large cohort
including variants of concern, their electrical resistance drops before us, but these glimpses of subjects at ages spanning
and characterized their binding to zero. In very rare cases, are generally static. They tell from before birth to old age
to the spike protein of SARS- another superconducting us a bit about species that document distinct changes that
CoV-2. Yuan et al. examined the transition appears at a lower lived, but not much about how occur during a human lifetime.
temperature. By measuring they lived. Evolving techniques Pontzer et al. report that energy

754 13 AUGUST 2021 • VOL 373 ISSUE 6556 sciencemag.org SCIENCE

expenditure (adjusted for enzyme that inhibits VEGF-C IN OTHER JOURNAL S Edited by Caroline Ash
weight) in neonates was like signaling (see the Focus by and Jesse Smith
that of adults but increased Künnapuu and Jeltsch). These
substantially in the first year mice had an expanded, non- AGING
of life (see the Perspective leaky lymphatic vessel network
by Rhoads and Anderson). It and improved resolution of Castration delays aging
then gradually declined until inflammation compared with
young individuals reached adult VEGF-C–injected mice. —WW A s we age, our genetic material changes, not only through
characteristics, which were DNA mutation but also by epigenetic modification.
maintained from age 20 to 60 Sci. Signal. 14, eabc0836, eabj5058 Indeed, chronological age can be estimated based on
years. Older individuals showed (2021). analysis of DNA methylation. Male and female mammals
reduced energy expenditure. display different average life spans, and a role for sex
Tissue metabolism thus ULTRACOLD MOLECULES hormones is expected in this effect. Sugrue et al. established
appears not to be constant but an epigenetic clock in sheep by examining methylated DNA
rather to undergo transitions at Shielding ultracold in samples from blood and ears. They show that castration
critical junctures. —LBR molecules extends an animal’s life span and feminizes the epigenome at
specific androgen-regulated loci during aging. —BAP
Science, abe5017, this issue p. 808; Ultracold molecules hold eLife 10, e64932 (2021).
see also abl4537, p. 738 promise for a wide range of
exciting applications. However, Castration prolongs the life of sheep by feminizing the epigenome to
BACTERIAL INFECTIONS such applications are cur- reduce androgen-regulated aging.
rently hampered by the limited
PHOTO: ZOONAR GMBH/ALAMY STOCK PHOTO Vaccines and antibiotic number of ultracold molecu- CANCER instruct tumor cells to divide
resistance lar ensembles that can be and have been approved to
created and by their short Brakes off cyclin drives treat a subset of breast cancers.
How can we predict or explain lifetimes. Anderegg et al. used memory Heckler et al. and Lelliott et
changes in antibiotic resis- a microwave dressing field to al. found that CDK4/6i can
tance after the introduction tune the collisional proper- Cyclin-dependent kinases 4 also promote the formation of
of new vaccines? Davies et ties of calcium monofluoride and 6 (CDK4/6) are enzymes immune memory to help fight
al. show that the association molecules trapped in opti- that stimulate cell proliferation. tumors. Short-term treatment
between penicillin consump- cal tweezers. This approach CDK4/6 inhibitor (CDK4/6i) of cancer cells with CDK4/6i
tion and penicillin resistance allowed a sixfold suppression drugs block the signals that
in Streptococcus pneumoniae of inelastic trap-loss collisions.
across 27 European countries This scheme paves the way
can be explained by four dif- for the creation of a variety of
ferent mathematical models of long-lived ultracold molecular
antibiotic resistance evolution. ensembles. —YS
Each model encapsulates an
alternative hypothesis for why Science, abg9502, this issue p. 779
antibiotic-sensitive and antibi-
otic-resistant bacterial strains BLACK HOLES
coexist in the same population.
Depending upon the model, Variability time scales
vaccination can either inhibit or in active galaxies
promote the spread of antibi-
otic resistance. —OMS Active galactic nuclei contain
Sci. Transl. Med. 13, eaaz8690 (2021). a supermassive black hole
(SMBH) surrounded by an
PHYSIOLOGY accretion disk. As disk mate-
rial falls toward the SMBH,
Denser lymphatics it heats up enough to emit
without leakage optical light. Burke et al.
investigated how such optical
The lymphatic system drains emission varies over time in a
excess fluid from tissues and sample of 67 active galaxies
enables immune cell migration. (see the Perspective by Lira
Exogenous administration of and Arevalo). They observed a
the lymphangiogenic growth characteristic variability in tim-
factor VEGF-C increases the ing that scaled with the SMBH
density, but also the leakiness, mass. The results elucidate
of lymphatics and results in the physical processes within
off-target inflammation. Kataru accretion disks and provide
et al. generated mice with a a method to estimate SMBH
lymphatic endothelial cell–spe- mass from optical variability
cific deficiency of PTEN, an observations. —KTS

Science, abg9933, this issue p. 789;
see also abk3451, p. 734

SCIENCE sciencemag.org 13 AUGUST 2021 • VOL 373 ISSUE 6556 755

RESEARCH | IN OTHER JOURNALS

Growing large amounts BIOENERGY CROPS has been proceeding for many
of bioenergy crops such as decades. Nitrogen deposition
shrub willows (Salix caprea, Where can we find in particular leads to higher
or pussy willow, shown) the fertilizer? ecosystem productivity at the
will require extensive fertilization. expense of biodiversity. In a
O ne strategy for meeting global experiment spanning 45
pushed activated CD8+ T our future energy needs sites, Tognetti et al. investigated
lymphocytes along a memory without fossil carbon how the addition of nitrogen
cell trajectory, which promoted is the use of planta- affected the leguminous plants
long-term tumor immunity in tions of bioenergy crops in grassland. Legumes under
mice. These findings may guide such as fast-growing trees natural conditions compete
the design of human clinical tri- or grasses. However, such successfully in low-nutrient
als using CDK4/6i as a cancer intensive growth operations conditions because of their abil-
pretreatment to kick-start the are not inherently sustainable ity to fix atmospheric nitrogen
immune response before the and will require fertilization using their rhizobial symbionts.
addition of immunotherapeutic to maintain productivity. Li However, excess nitrogen
agents. —PNK et al. estimated that in some deposition places them at a
scenarios, the amounts of competitive disadvantage, lead-
Cancer Discov. nitrogen, potassium, and phos- ing to declines in their biomass
10.1158/2159-8290.CD-20-1540, phorous fertilizer that would and abundance. In turn, these
10.1158/2159-8290.CD-20-1554 be required to balance their declines may have adverse
removal by biomass is nearly consequences for grassland
(2021). half of their current use for all biodiversity and food webs more
agricultural purposes. Fertilizer generally as nitrogen deposition
PHYSICS supplies are already under continues. —AMS
pressure. New strategies will
Tackling the be required if bioenergy crops Proc. Natl. Acad. Sci. U.S.A. 118,
Hubbard model are to be sustainable. —MAF e2023718118 (2021).

The Hubbard model describes Environ. Sci. Technol. NITROGEN FIXATION
the physics of interacting par-
ticles on a lattice and is thought 10.1021/acs.est.1c02238 (2021). Some light on diazotrophs
to contain elements essential
to the superconductivity of the model remains extremely the properties of ceramics About half of the planet’s PHOTO: ARTERRA PICTURE LIBRARY/ALAMY STOCK PHOTO
cuprates. Despite its apparent challenging, especially at finite and other materials. However, nitrogen fixation occurs out
simplicity, solving the Hubbard concentrations of hole dopants tracking the migration of grain at sea by prokaryote diazo-
and intermediate temperatures. boundaries is difficult. Wei trophs, yet we still have a
Wietek et al. used the minimally et al. used atomic-resolution poor understanding of which
entangled typical thermal states scanning transmission electron ones do what. Karlusich et al.
(METTS) method to calculate microscopy to trigger and probe applied a combination of image
the structural factors and grain boundary migration in capture and nitrogenase gene
thermodynamic properties for alumina. The authors found that (nifH) sequencing on globally
the two-dimensional Hubbard cooperative shuffling of atoms gathered data to map diazo-
model with strong correlations at the grain boundary ledge is trophs sampled at different
at a finite doping and for a range how migration proceeds, which depths. Unexpected hotspots
of temperatures. The research- leads to structural transitions. of diazotroph abundance were
ers found that a stripe order This new method for determin- discovered in the Mozambique
formed at low temperatures, ing the fine details of these Channel and the south Pacific
whereas at higher tempera- sorts of processes will help us Ocean. However, in the Arctic
tures, a phase resembling the better understand how micro- Ocean, nitrogen fixers were
experimentally observed pseu- structures develop in a range of found among ultrasmall bac-
dogap state took over. —JS materials. —BG terioplankton, whereas in the
tropics, larger cyanobacterial
Phys. Rev. X. 11, 0031007 (2021). Nat. Mater. 20, 951 (2021). symbionts and colony-dwelling
species such as Trichodesmium
CERAMICS ECOLOGY and Richelia dominated.
Although single-cell, free-living,
Watching grain Nitrogen discourages noncyanobacterial diazotrophs
boundaries legumes were the most abundant overall,
Trichodesmium dominated by
Grain boundaries play an Anthropogenic nutrient enrich- sheer size; however, several
important role in determining ment of the global environment species tended to co-occur in
assemblies. Whether or how such
assemblages interact will have
to await further study. —CA

Nat. Commun. 12, 4160 (2021).

756 13 AUGUST 2021 • VOL 373 ISSUE 6556 sciencemag.org SCIENCE

RESEARCH

ALSO IN SCIENCE JOURNALS
Edited by Stella Hurtley

NEUROSCIENCE revealed a heterogeneous at a precise distance from the land plant spores and earlier
phenotypic landscape, with programmed target sequence. forms of uncertain relationship.
Accessory proteins and oxygen availability shaping the Park et al. show that orientation This finding may help to resolve
nicotinic receptors metabolism at a spatial scale of information is communicated to discrepancies between molecu-
microns within a single contigu- the transposase TnsB using the lar and fossil data for the timing
Acetylcholine was the first ous biofilm segment. This tool unidirectional growth of a helical of land plant origins. —AMS
neurotransmitter identified, and should be applicable to complex filament made up of an AAA+
nicotinic acetylcholine receptors microbial communities in the protein, TnsC. ATP hydrolysis Science, abj2927, this issue p. 792;
(nAChRs) were the first neu- environment and the human trims the filament to a minimal see also abl5297, p. 736
rotransmitter receptors isolated. microbiome. —MAF unit that is marked by TniQ and
Recent studies have identified defined by the Cas12k protein M I C R O B I O TA
a multitude of molecules and Science, abi4882, this issue p. 758 to provide spacing information.
mechanisms that regulate This finding may help future Gut bugs and systemic
nAChRs in different tissues. In CANCER GENOMICS engineering of these systems for disease risk
a Review, Matta et al. discuss therapeutic applications. —DJ
these discoveries and their Identifying the origin What people eat has an imme-
implications for the cell biology of cancer Science, abi8976, this issue p. 768 diate selective effect on the
and medicinal pharmacology microbial populations resident
of nACHRs. Many accessory Many cancers are classified on POLYMER CHEMISTRY in the gut. A high-fat diet is
factors promote the assembly the basis of the organ or tissue associated with the occurrence
and function of diverse nAChRs. from which they originated. Tough recyclable of microbes that catabolize
Some factors are small mol- However, identifying the specific polyacetals choline and the accumulation of
ecules, some are proteins, some cells and conditions that pre- trimethylamine N-oxide (TMAO)
control receptor biogenesis, and cede tumorigenesis can help us Cyclic acetals such as dioxolane in the bloodstream, a contribut-
some regulate channel gating. understand and better treat the are appealing building blocks ing factor for heart disease. Yoo
These protein chaperones and resulting disease. Nowicki-Osuch for recyclable plastics but have et al. explored the microbial
auxiliary subunits elucidate the et al. used a single-cell approach proven to be difficult to polymer- organisms and pathways that
pharmacological and physi- to investigate the cell of origin ize controllably. Abel et al. show convert choline into TMAO in
ological processes regulated by for Barrett’s esophagus (BE) that optimal pairing of a bromo- mice. Although gene clusters for
acetylcholine. —PRS and the mechanisms leading to methyl ether and indium or zinc choline metabolism are found
the development of esophageal Lewis acid produces polydioxo- widely among the microbiota, it
Science, abg6539, this issue p. 757 adenocarcinoma (EAC) (see lane with high tensile strength is only the facultative anaerobes
the Perspective by Geboes and that may be advantageous for that become abundant in hosts
MICROBIOLOGY Hoorens). Analyses of healthy packaging applications. Heating on a high-fat diet. A high-fat diet
human esophageal tissues, this plastic in strong acid easily impairs mitochondrial uptake
Spying on microbial mutational lineage tracing, and breaks it back down to its acetal of oxygen into host enterocytes
communities, cell by cell organoid models revealed that monomer, which can then be and elevates nitrate in the
BE originates from the gastric recovered by distillation from mucus, which in turn weakens
Within any community of cardia and that EAC arises from mixed plastic waste streams in healthy anaerobic gut function.
organisms, gene expression undifferentiated BE cells. This high yield. —JSY Facultative anaerobes such as
is heterogeneous, which can analysis provides a map of the the pathobiont Escherichia coli
manifest in genetically identical transcriptional landscape of the Science, abh0626, this issue p. 783 become dominant, which leads
individuals having a different healthy esophagus that can be to an overall increase in the
phenotype. One has to look compared with mouse models of PA L E O B O TA N Y amount of choline catabolized
at individuals in context and disease. —LMZ into the precursor for TMAO.
analyze patterns in both space The timing of land Whether this pathway plays a
and time to see the full picture. Science, abd1449, this issue p. 760; plant origins role in heart disease remains
Aiming to fill a gap in current see also abj9797, p. 737 unclear. —CA
methods, Dar et al. developed a Until now, the first fossil evi-
transcriptome-imaging method CRISPR BIOLOGY dence of land plants was from Science, aba3683, this issue p. 813
named parallel sequential the Devonian era 420 million
fluorescence in situ hybridiza- Target site selection years ago. However, molecular 2D MATERIALS
tion (par-seqFISH). They applied in CAST systems phylogenetic evidence has sug-
this technique to the opportu- gested an earlier origin in the Boridene: a 2D boride
nistic pathogen Pseudomonas Exciting genomic engineering Cambrian. Strother and Foster
aeruginosa, focusing on biofilms possibilities exist for natural describe an assemblage of fossil A range of two-dimensional (2D)
where growth conditions can integration systems called spores from Ordivician deposits materials, including graphene
change at microscopic scale. transposons, which have co- in Australia dating to approxi- and hexagonal boron nitride,
Development of these com- opted CRISPR/Cas systems. mately 480 million years ago have been synthesized and
munities, as revealed by mRNA An unexplained feature of these (see the Perspective by Gensel). studied because of the unusual
composition, were followed in systems involves how they direct These spores are of intermediate properties that occur when one
space and time. The results insertions in a single orientation morphology between confirmed dimension becomes very small.
MXenes are a family of materials

SCIENCE sciencemag.org 13 AUGUST 2021 • VOL 373 ISSUE 6556 756-B

RESEARCH

made of layers of inorganic of plasmonic vortices, where
transition metal carbides and nanoscale twisted light oscil-
nitrides that are a few atoms lates together with the free
thick and are manufactured by electrons in metal. Spektor et al.
selective etching. Attempts to introduced the reflection from
make similar boridene materials structural boundaries as a new
have been challenging because degree of freedom to generate
of the reactive nature of boride and control this surface-con-
phases and because the parent fined angular momentum. They
materials tend to dissolve rather designed vortex cavities with
than selectively etch. Zhou et al. chiral boundaries, in which sub-
synthesized boridene in the form sequent reflections increased
of single-layer 2D molybdenum the vortex OAM by multiples
boride sheets by selective etch- of the chiral cavity order. They
ing in aqueous hydrofluoric acid then tracked the spatiotemporal
to produce sheets with ordered dynamics of the plasmon pulse
metal vacancies, opening up an trains within the vortex cavities
additional family of materials for using time-resolved photoemis-
study. —MSL sion electron microscopy with
sub-femtosecond resolution.
Science, abf6239, this issue p. 801 These results may have applica-
tions in quantum initialization
T CELLS schemes and potentially achieve
vortex lattice cavities with
A virtual memory dynamically evolving topology.
T cell spectrum —LNL

Virtual memory T (TVM) cells Sci.Adv. 10.1126/sciadv.abg5571
acquire a memory phenotype in
the absence of foreign antigen (2021).
and are believed to develop
in response to self-antigen
exposure. However, their role
in protective immunity against
foreign pathogens is not well
understood. Using specific
pathogen–free mice infected
with influenza A virus, Hou et
al. demonstrate that TVM cells
rapidly infiltrate the lungs in
a CXCR3-dependent manner,
where they expand and promote
early viral control. Compared
with naïve T cells, TVM cells
more efficiently gave rise to
resident memory cells, with
the CCR2+ and CCR2− subsets
poised for effector and memory
responses, respectively. Thus,
TVM cells undergo functional
specialization, and self-reactive T
cells can productively contribute
to antigen-specific responses
against invading pathogens.
—CO

Sci. Immunol. 6, eabg9433 (2021).

NANOOPTICS sciencemag.org SCIENCE

Plasmonic vortex
cavities multiply OAM

Orbital angular momentum
(OAM) of light can be confined
to metal surfaces in the form

756-C 13 AUGUST 2021 • VOL 373 ISSUE 6556

RESEARCH

◥ nicotine—a process that likely contributes
to tobacco addiction. Recent applications of
REVIEW SUMMARY proteomics, genetics, and expression cloning
have identified a bevy of partner proteins and
NEUROSCIENCE metabolites essential for nAChR function.
These accessories act at multiple steps in nAChR
Nicotinic acetylcholine receptor redux: biogenesis. Within the endoplasmic reticulum,
Discovery of accessories opens therapeutic vistas chaperones mediate nAChR subunit folding
and assembly. Other factors then promote
Jose A. Matta†, Shenyan Gu†, Weston B. Davini, David S. Bredt* nAChR trafficking to the plasma membrane.
Finally, auxiliary subunits associated with
BACKGROUND: One hundred years ago, experi- for lung cancer. Therapeutically, nAChRs provide surface nAChRs modulate channel activation.
ments on beating frog hearts identified acetyl- pharmacological targets of approved medicines These chaperones and auxiliary subunits in-
choline (ACh) as the seminal neurotransmitter. for cardiovascular and neurological disorders. clude both nAChR-specific regulators and
Sixty years later, fractionation of the eel electro- more pleiotropic factors. On the one hand,
plax isolated nicotinic ACh receptors (nAChRs) Nicotinic AChRs comprise multiple subunits NACHO (a neuronal endoplasmic reticulum–
as the first purified ion channel. We now ap- whose molecular folding and surface traffick- resident protein) serves as a client-specific
preciate that a family of nAChRs are differen- ing involve complex and tightly regulated pro- chaperone for neuronal nAChRs. By contrast,
tially expressed in numerous tissues, including cesses. As nAChRs often require tissue-specific transmembrane inner ear protein contributes
the brain, skeletal muscle, white blood cells, factors for functional expression, many sub- to both hair cell nAChRs and mechanosensitive
and cochlear hair cells. Paralleling this wide types fail to create receptor channels in recombi- channels, which modulate cochlear amplifica-
distribution, nAChRs mediate diverse physio- nant systems. Our limited understanding of tion and transduce sound waves, respectively.
logical functions, including cognition, muscle nAChR assembly has impeded basic research Interplay between nAChR accessory compo-
contraction, immunomodulation, and sound and drug development. nents can further regulate receptor distribution
discrimination. Neuronal nAChRs also account and function.
for the psychoactive and addictive properties of ADVANCES: Studies in the 1970s found that
tobacco and are the primary genetic risk factors smokers have increased nAChR density in OUTLOOK: Discovery of these molecules and
the brain owing to receptor stabilization by mechanisms is transforming basic and trans-
lational science concerning nAChRs. Inclusion
Plasma membrane Activation of appropriate chaperones during protein pro-
duction is enabling structural studies of nAChR
Trafficking subtypes. Accessory components are also per-
Assembly mitting biophysical studies of nAChR channel
properties. Furthermore, understanding mech-
Folding anisms that control trafficking and subunit
composition is defining roles for nAChRs in
Mood Endoplasmic reticulum biological processes and disease.

Cognition This research also provides therapeutic op-
portunities. The dearth of pharmacological
Sound discrimination agents for certain nAChRs results from chal-
lenges in recombinant expression of many re-
Muscle contraction ceptor types. The ability to express complex
nAChR subunit combinations in cell lines
Nociception “unlocks” them for the chemical screening
that initiates drug discovery. Auxiliary sub-
Immune modulation units can themselves provide pharmacological
targets. Furthermore, drugging chaperone path-
nAChRs ways may benefit myasthenia gravis and other
diseases associated with aberrant nAChR levels.
Schizophrenia,
dementia, addiction Despite being the archetypal neurotransmit-
Hearing disorders ter receptor, much remains unknown about
nAChRs. The identification of molecular part-
Myasthenia gravis ners and elucidation of regulatory mechanisms
provide a cell biological renaissance and can
Pain
▪suggest avenues for treating diseases associated
Inflammation
with nAChR dysfunction.
Accessory proteins assist nAChRs and drug discovery. Throughout the body, nAChRs are differentially expressed
in neurons, myocytes, leukocytes, and cochlear and vestibular hair cells. An array of nAChR chaperones and The list of author affiliations is available in the full article online.
auxiliary subunits (inset) mediate endoplasmic reticulum folding and assembly, intracellular trafficking, and plasma *Corresponding author. Email: [email protected]
membrane activation. The recent identification of receptor accessories enables drug discovery for these nAChRs, These authors contributed equally to this work.
which provide compelling targets for neurological, psychiatric, immunological, and auditory disorders. Cite this article as J. A. Matta et al., Science 373, eabg6539
(2021). DOI: 10.1126/science.abg6539

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https://doi.org/10.1126/science.abg6539

SCIENCE sciencemag.org 13 AUGUST 2021 • VOL 373 ISSUE 6556 757

RESEARCH

◥ ACh. The embryonic muscle AChR contains
a2bgd subunits, and this composition switches
REVIEW by birth to the adult form containing a2bed
(3, 4). The assembled receptor concentrates at
NEUROSCIENCE crests of junctional folds in association with a
cytoskeletal anchoring protein rapsyn. Motor
Nicotinic acetylcholine receptor redux: neuron–derived agrin induces nAChR cluster-
Discovery of accessories opens therapeutic vistas ing during synaptogenesis by binding LRP4
and signaling via MuSK (20). All nine of these
Jose A. Matta†, Shenyan Gu†, Weston B. Davini, David S. Bredt‡* genes have human mutations that cause in-
herited myasthenic syndromes, which are char-
The neurotransmitter acetylcholine (ACh) acts in part through a family of nicotinic ACh receptors acterized by fatigable muscle weakness owing
(nAChRs), which mediate diverse physiological processes including muscle contraction, to aberrant neuromuscular nAChR transmis-
neurotransmission, and sensory transduction. Pharmacologically, nAChRs are responsible for tobacco sion (11). Furthermore, in myasthenia gravis,
addiction and are targeted by medicines for hypertension and dementia. Nicotinic AChRs were the first autoantibodies that react with proteins at the
ion channels to be isolated. Recent studies have identified molecules that control nAChR biogenesis, neuromuscular junction mediate inflammation
trafficking, and function. These nAChR accessories include protein and chemical chaperones as well as and depletion of nAChRs (21).
auxiliary subunits. Whereas some factors act on many nAChRs, others are receptor specific. Discovery
of these regulatory mechanisms is transforming nAChR research in cells and tissues ranging from Symptomatic treatment for myasthenias
central neurons to spinal ganglia to cochlear hair cells. Nicotinic AChRÐspecific accessories also enable associated with reduced nAChR levels involves
drug discovery on high-confidence targets for psychiatric, neurological, and auditory disorders. blocking acetylcholinesterase to increase syn-
aptic levels of ACh (21). Cholinesterase inhibitors
M ore than 100 years ago, Loewi and Dale by affinity chromatography using the potent provide modest benefit, but better therapies
identified acetylcholine (ACh) as the antagonist a-bungarotoxin (5). In common are needed. Replacing the mutated gene in
first known neurotransmitter (1). We with all nAChRs, this receptor comprises a congenital myasthenias may be possible but
now appreciate that ACh mediates pentamer of subunits that each contain an requires complex gene therapies tailored for
diverse physiological functions by act- N-terminal extracellular domain for ligand specific patients (22). Interrupting the auto-
ing on a large family of receptors. Whereas binding followed by four transmembrane (TM) immune process in myasthenia gravis can
Loewi’s experiments on frog hearts involved a regions. A large cytosolic region between TM3 also provide a cure, but this requires lifelong
heterotrimeric GTP-binding protein (G protein)– and TM4 includes two structured helices MX immunosuppression (21).
coupled muscarinic ACh receptor (2), nicotinic and MA (15) and mediates interactions with
ACh receptors (nAChRs) are ligand-gated ion cytoskeletal anchoring proteins. Neuronal nAChR Enhancing nAChR assembly and surface ex-
channels (3, 4). These nAChRs are enriched in derives from nine a (a2 to a10) and three b (b2 pression provides another conceptual strategy
skeletal muscle, where they transduce nerve- to b4) subunits. The most abundant nAChRs for treating certain myasthenias. The sequen-
muscle communication, and in the brain, where in the brain are a7 homopentamers and a4b2 tial steps in subunit oligomerization and con-
they mediate synaptic transmission (5). Nico- heteropentamers, although other subunits can formational maturation that form muscle
tinic AChRs also occur in more-specialized loca- be included in these pentamers. Dozens of re- nAChR pentamers have been characterized
tions, such as beige adipocytes (6), lymphocytes ceptor combinations have been pharmacolog- (16). Forward genetic screening identified
(7), and cochlear hair cells (8). ically characterized. CRELD1, a protein disulfide isomerase, as an
evolutionarily conserved maturational enhancer
This widespread distribution of nAChRs Cellular assembly of nAChRs from their of muscle nAChRs (23). Whereas CRELD1 is
creates physiological roles for these receptors subunits involves complex, highly regulated widely expressed, muscle-specific targets would
in neuronal, sensory, metabolic, and immune processes (16). Essential factors for nAChR be more attractive. Drugs that enhance MuSK
tissues. Additionally, nAChRs can mediate assembly were initially found by forward ge- signaling to augment synaptic nAChR clusters
pathophysiological processes. The addictive netic screens of invertebrates. This is exemplified are being explored for the treatment of neuro-
properties of nicotine involve nAChRs in brain by ric-3, which is required for nAChR function muscular disorders (24).
circuits that mediate craving and reward (9). in Caenorhabditis elegans (17). Accessories
Mutations in nAChR subunits cause several for mammalian nAChRs were found through NACHO as a client-specific chaperone
genetic diseases, including epileptic (10) and analyses of developmentally regulated genes for neuronal nAChRs
neuromuscular (11) disorders. Polymorphisms that encode a-bungarotoxin–like neuropeptides,
in nAChRs are linked to lung cancer owing to such as lynx1, that modulate certain neuronal Whereas muscle nAChRs form active channels
increased preference for tobacco (12). Further- nAChRs (18). More recently, genome-wide cDNA when transfected into heterologous cell lines,
more, numerous approved and experimental screening (Fig. 1) has identified a trove of many neuronal nAChRs do not (25). The dis-
medicines for cardiovascular, psychiatric, and molecules and mechanisms that enable the covery of NACHO by genome-wide expression
cognitive disorders target nAChRs (13, 14). assembly and function of diverse nAChRs cloning (Fig. 1A) resolved why the a7 nAChR fails
(19). Here, we review the remarkable diver- to form functional receptors in non-neuronal
Just as ACh was the seminal neuronal mes- sity of processes and pathways that regulate the cells (26). NACHO is a neuronal endoplasmic
senger, the nAChR was the first biochem- assembly of nAChRs and focus on their rele- reticulum (ER)–resident protein that mediates
ically isolated neurotransmitter receptor. The vance in the development of therapies for neuro- a7 assembly (26). NACHO coexpression during
receptor was purified from fish electric organs logical, psychiatric, and sensory disorders. protein production recently facilitated the de-
termination of the elusive a7 nAChR structure
Neuroscience Discovery, Janssen Pharmaceutical Companies Skeletal muscle nAChR (27). NACHO also promotes the biogenesis
of Johnson & Johnson, San Diego, CA 92121, USA. and function of the broadly expressed a4b2
*Corresponding author. Email: [email protected] Excitation and contraction of skeletal muscle receptors and the more localized a6b2b3 re-
†These authors contributed equally to this work. are initiated by the motor neuron release of ceptors (28). NACHO knockout (KO) mice
‡Present address: MPM Capital, Brisbane, CA 94005, USA. show hyperlocomotive activity and impaired
cognitive function (28), consistent with altered

Matta et al., Science 373, eabg6539 (2021) 13 August 2021 1 of 8

RESEARCH | REVIEW

Fig. 1. cDNA screening plat- A Co-transfection
form for discovery of receptor
accessories. Plasmid-encoding Agonist Fluorescent Units
receptor of interest (blue) is Stimulation
cotransfected with individual
clones from a genome-wide Target cDNA [Ca2+] i
expression library. (A) Functional
assay can identify proteins
that enable receptor activity.
(B) High-content imaging can
identify proteins that promote
receptor trafficking.

Time (sec)

cDNA collection

B Co-transfection

Fluorescent
Labeling

Target cDNA Imaging

cDNA collection

nAChR expression. By contrast, NACHO KO channel function (33). These actions of RIC-3 found that nicotine enhances nAChR function
and Bcl-2 proteins on a7 synergize with NACHO in animals and that nicotine posttranslation-
mice show normal activity for all other recep- and involve distinct mechanisms (Fig. 2). Effects ally promotes nAChR levels (40). This is the
tors analyzed, including g-aminobutyric acid of NACHO require the extracellular and first opposite of what is typical for G protein–coupled
type A (GABAA), 5-HT3A, AMPA, and TRPV1 two TM domains of a7 (29), RIC-3 engages the receptors, such as opiate receptors, which are
(28). Therefore, NACHO appears to act as a amphipathic MA helix in the a7 cytosolic loop down-regulated by chronic agonist exposure.
“client-specific” chaperone for nAChRs. (34), and Bcl-2 necessitates a BH3-like motif in
this same MA helix (33). Mechanistically, nicotine interaction with the
NACHO enables receptor assembly through
actions on the second TM domain of a7 (29). Regulation of nAChR assembly by drugs ligand-binding site promotes nAChR penta-
Unexpectedly, NACHO does not directly inter- and metabolites mer formation and receptor surface expres-
act with a7 (26, 27). Instead, NACHO binds to
components of the N-glycan oligosaccharyl- Small molecules also regulate nAChR assem- sion. These effects are independent of receptor
transferase complex and to calnexin (29). This bly. These compounds can be separated into activation and are also observed with ortho-
fits with studies showing that a7 receptor three groups on the basis of their mechanisms steric antagonists (38).
function requires glycosylation at three aspar- of action. The first group comprises nAChR
orthosteric ligands that engage the ACh bind- In the brain, nicotine primarily enhances
agine residues in its N-terminal ectodomain ing pocket at subunit interfaces and stabilize b2-containing receptors (41). As the reinforc-
(30) and that NACHO effects on a7 also re- mature nAChRs (35). The second group in- ing properties of nicotine are mediated by
quire these asparagines (29). Furthermore, the cludes menthol (36) and polyamines (37)— mesolimbic b2-containing receptors, nAChR
ER chaperone calnexin is required for assem- compounds that directly bind to nAChR at up-regulation likely participates in nicotine
bly of numerous nAChR subtypes (31). These nonorthosteric sites and thereby modulate addiction (9). Menthol also up-regulates brain
results yield a model whereby NACHO links receptor assembly. The third group contains nAChRs (42). Menthol allosterically inhibits
molecules that work indirectly on AChRs as a4b2 nAChRs (43) by binding both to an extra-
the oligosaccharyltransferase and calnexin more-general mediators of protein folding, cellular channel pore site and to a membrane-
including 4-phenylbutyrate, valproate, and embedded site in the desensitized receptor (44).
(Fig. 2). In turn, calnexin mediates assembly butyrate, which are also histone deacetylase In transgenic mice, menthol increases assembly
inhibitors (38). of a4- and a6-containing nAChR in dopaminer-
by interacting reversibly with N-linked gly- gic neurons (36). This up-regulation of nAChRs
cans on a7 and by recruiting downstream Human studies in the 1980s first noted that in reward circuits may explain why smokers of
chaperones (29). nAChR levels in the brain are elevated in cig- menthol cigarettes have more difficulty quitting
arette smokers (39). Follow-up experiments smoking than nonmenthol smokers (45).
After NACHO-mediated assembly of a7, the
mammalian homolog of RIC-3 (32) promotes Beyond these pharmacological effects, ligand-
receptor surface trafficking (26). Certain anti-
apoptotic Bcl-2 proteins can also act after mediated assembly may also play an endogenous
NACHO to enhance a7 surface expression and

Matta et al., Science 373, eabg6539 (2021) 13 August 2021 2 of 8

RESEARCH | REVIEW Prototoxin α4β2 Prototoxin
Plasma membrane
Fig. 2. Regulation of a7 and α7
a4b2 assembly, trafficking, Cytosol
and activation by protein
chaperones, small molecules, Golgi
and accessory components.
Within the ER, NACHO conspires Polyamine
with calnexin and the oligosac-
charyltransferase (OST) proteins OSTNACHOCalnexin RIC-3/Bcl-2
RPN1/2 to promote the folding of
a7 and a4b2. In synergy with RPN1/2
NACHO, RIC-3 and Bcl-2 proteins Nicotine
enhance a7 assembly and
trafficking to the plasma mem-
brane. By engaging the a4b2
ligand-binding site, nicotine
enhances assembly of a4b2
receptors. Prototoxins associate
with a7 and a4b2 pentamers
and modulate channel trafficking
and activation.

nAChR subunit

Endoplasmic reticulum

role in the maturation of certain nAChRs. nAChR regulation by accessory proteins and -regulatory protein (BARP), lysosomal asso-
Genome-wide screening for factors that en- Protein chaperones assist receptor assembly
able the function of a9a10 nAChRs identified and trafficking; by contrast, auxiliary subunits ciated membrane protein 5 (LAMP5), and
choline acetyltransferase (ChAT), the biosyn- associate stably with receptors and control sulfotransferase SULT2B1 (55). These proteins
thetic enzyme for ACh (46). ChAT-mediated channel function. An auxiliary subunit for a exert differential effects on a6b2b3 (55). Where-
assembly of a9a10 reflects chemical chaper- nAChR was reported in C. elegans (50). Forward as NACHO promotes a6b2b3 assembly, LAMP5
oning by ACh. Mutating the ligand-binding genetic screening identified MOLO-1, a single- and SULT2B1 increase cell surface receptor
site on a9 abolishes receptor maturation and pass TM protein that positively modulates
surface trafficking (46). The fact that ACh worm nAChRs. Notably, MOLO-1 physically trafficking, and BARP enhances channel acti-
does not efficiently penetrate cell membranes interacts with levamisole-sensitive nAChRs and
suggests that its actions to enhance a9a10 enhances channel activation (50). Functional vation (Fig. 3A).
receptor levels can occur through extracel- activity of the EAT-2 nAChR in C. elegans re- BARP binds to the b subunit of voltage-
lular interactions that promote the assembly quires the single-pass TM protein EAT-1, which
of incomplete oligomers or stabilize transient serves as an essential auxiliary subunit (51). gated calcium channels and reduces channel
surface pentamers. Indeed, even extracellular function (56). By contrast, BARP enhances
application of a-bungarotoxin, which is also Several mammalian nAChRs also have aux- a6b2b3 activity by slowing channel desen-
not cell permeant, augments a9a10 levels (46). iliary subunits. Nicotinic AChRs containing an sitization and deactivation (55). BARP actions
This extracellular ACh-mediated assembly mech- a6 subunit are abundant in the striatum and
anism may help position functional a9a10 mediate acetylcholine-induced dopamine re- on nAChR show marked selectivity. It enhances
receptors at sites of ACh release (46). lease, but they do not express functionally in the activation of a3b2 receptors but does not
any recombinant system (52). a6 was origi- affect a4b2 or a3b4 receptors (55). Consistent
Expression cloning (Fig. 1B) for cDNAs that nally dubbed an orphan subunit until the co- with BARP’s regulation of a6b2b3-containing
enhance a4b2 surface trafficking (37) identified expression of chicken a6 and human b4 subunits nicotinic receptors, striatal synaptosomes from
spermidine/spermine acyltransferase (SAT1). produced ACh-gated currents in Xenopus oocytes
SAT1 is the rate-limiting enzyme for polyamine (53). In the striatum, a6 assembles with b2 and BARP KO mice show reduced nicotine-evoked
catabolism, which suggests that these ubiqui- b3 subunits to form a conotoxin MII–sensitive dopamine release and reduced [125I]conotoxin
tous linear polycations inhibit a4b2 expression. presynaptic receptor (52, 54). Insights re- MII–binding sites (55). The nAChR- and calcium
Indeed, blocking polyamine synthesis with di- garding a6b2b3-containing nAChR assembly channel–binding domains in BARP do not
fluoromethylornithine (DFMO) increases levels came from studies of NACHO KO mice, overlap, which suggests that BARP may phys-
of functional a4b2 and a7 receptors (37). Poly- which show reduced striatal binding sites
amines typically act by occluding the ion channel for [125I]conotoxin MII (28). Furthermore, in iologically link these ion channel complexes.
pore (47). By contrast, polyamine regulation of human embryonic kidney (HEK) cells, NACHO
nAChR assembly relies on interaction with the cotransfection promotes oligomeric assembly Indeed, nicotine-evoked dopamine release in-
large cytosolic region (37). Polymorphisms in but not functional expression of a6b2b3 re-
SAT1 have consistently been associated with ceptors (28). volves voltage-gated calcium channel activity
suicidal behavior (48). These findings provide downstream of nAChR activation (57).
additional validation to assess nicotinic agents Genome-wide screening to search for pro-
as a treatment for suicidal ideation (49). teins that conspire with NACHO to reconstitute Another pharmacologically important a6-
a6b2b3 channel function identified b-anchoring containing receptor is a diheteromer contain-
ing the b4 subunit that occurs in the sensory
neurons of dorsal root ganglia (58). BARP and
IRE1a are needed to reconstitute a6b4 re-
ceptors, which are curiously not affected by
NACHO (59). IRE1a is a sensor of the unfolded
protein response, which promotes protein
folding in the ER during cellular stress (60).
Effects on a6b4 involve the canonical IRE1a

Matta et al., Science 373, eabg6539 (2021) 13 August 2021 3 of 8